NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®)

Acute Lymphoblastic Leukemia

NCCN Evidence BlocksTM
Version 2.2024 — July 19, 2024
[Link]
NCCN recognizes the importance of clinical trials and encourages participation when applicable and available.
Trials should be designed to maximize inclusiveness and broad representative enrollment.

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Acute Lymphoblastic Leukemia Table of Contents
Discussion
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*Bijal Shah, MD/Chair † Nitin Jain, MD † ‡ Olalekan Oluwole, MD ‡
Moffitt Cancer Center The University of Texas Vanderbilt-Ingram Cancer Center
*Ryan J. Mattison, MD/Vice-Chair † ‡ Þ MD Anderson Cancer Center Jae Park, MD †
University of Wisconsin Carbone Cancer Center Brian Jonas, MD, PhD † ‡ Memorial Sloan Kettering Cancer Center
Ramzi Abboud, MD † ‡ ξ UC Davis Comprehensive Cancer Center Amanda Przespolewski, DO ‡
Siteman Cancer Center at Barnes- Suzanne Kirby, MD ‡ Roswell Park Comprehensive Cancer Center
Jewish Hospital and Washington Duke Cancer Institute Sravanti Rangaraju, MD † ‡
University School of Medicine Michaela Liedtke, MD ‡ O'Neal Comprehensive Cancer Center at UAB
Peter Abdelmessieh, DO, MSc ξ Stanford Cancer Institute Caner Saygin, MD ‡
Fox Chase Cancer Center Mark Litzow, MD ‡ The UChicago Medicine
Ibrahim Aldoss, MD ‡ Mayo Clinic Comprehensive Cancer Center Comprehensive Cancer Center
City of Hope National Medical Center Aaron Logan, MD, PhD ‡ ξ Marc Schwartz, MD † ‡
Patrick W. Burke, MD † ‡ UCSF Helen Diller Family University of Colorado Cancer Center
University of Michigan Rogel Cancer Center Comprehensive Cancer Center Paul Shami, MD ‡
Daniel J. DeAngelo, MD, PhD † ‡ Meixiao Long, MD, PhD ‡ Huntmsan Cancer Institute
Dana-Farber/Brigham and Women’s The Ohio State University at the University of Utah
Cancer Center | Mass General Cancer Center Comprehensive Cancer Center Benjamin Tomlinson, MD † ‡
Shira Dinner, MD † ‡ Selina Luger, MD † Case Comprehensive Cancer Center/University
Robert H. Lurie Comprehensive Cancer Abramson Cancer Center Hospitals Seidman Cancer Center and
Center of Northwestern University at the University of Pennsylvania Cleveland Clinic Taussig Cancer Institute
Amir T. Fathi, MD † ‡ Þ James K. Mangan, MD, PhD ‡ ξ Jonathan Webster, MD †
Mass General Cancer Center UC San Diego Moores Cancer Center The Sidney Kimmel Comprehensive
Jordan Gauthier, MD, MSc ‡ Stephanie Massaro, MD, MPH € ‡ Cancer Center at Johns Hopkins
Fred Hutchinson Cancer Center Yale Cancer Center/Smilow Cancer Hospital
Michael Haddadin, MD ‡ ξ William May, MD € NCCN
Fred & Pamela Buffett Cancer Center UCLA Jonsson Comprehensive Cancer Center Ajibola Awotiwon, MBBS, MSc
Katie Stehman, MMS, PA-C

ξ Bone marrow † Medical oncology

transplantation ≠ Pathology
‡ Hematology/Hematology € Pediatric oncology
NCCN Guidelines Panel Disclosures Continue oncology * Discussion Section
Þ Internal medicine Writing Committee

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Acute Lymphoblastic Leukemia Table of Contents
Discussion
NCCN Evidence BlocksTM
NCCN Acute Lymphoblastic Leukemia Panel Members
Find an NCCN Member Institution:
NCCN Evidence Blocks Definitions (EB-1) [Link]
institutions.
Diagnosis (ALL-1) NCCN Categories of Evidence and
Clinical Risk Stratification (ALL-2) Consensus: All recommendations
Cytogenetic and Molecular Prognostic Risk Stratification for B-ALL (ALL-3) are category 2A unless otherwise
Workup (ALL-4) indicated.
Ph+ B-ALL (AYA and Adult) Treatment Induction and Consolidation Therapy (ALL-5) See NCCN Categories of Evidence
Ph- B-ALL (AYA and Adult) Treatment Induction and Consolidation Therapy (ALL-6) and Consensus.
T-ALL (AYA and Adult) Treatment Induction and Consolidation Therapy (ALL-7) NCCN Categories of Preference:
Surveillance (ALL-8) All recommendations are considered
appropriate.
Relapsed/Refractory Disease, Treatment (ALL-9)
See NCCN Categories of Preference.
Familial Genetic Alterations in ALL (ALL-A)
Evaluation and Treatment of Extramedullary Involvement (ALL-B)
Supportive Care (ALL-C)
Principles of Systemic Therapy (ALL-D)
Response Assessment (ALL-E)
Minimal/Measurable Residual Disease Assessment (ALL-F) NCCN Guidelines for Patients®
available at [Link]/patients
Abbreviations (ABBR-1)

The NCCN Guidelines® are a statement of evidence and consensus of the authors regarding their views of currently accepted approaches to
treatment. Any clinician seeking to apply or consult the NCCN Guidelines is expected to use independent medical judgment in the context of individual
clinical circumstances to determine any patient’s care or treatment. The National Comprehensive Cancer Network® (NCCN®) makes no representations
or warranties of any kind regarding their content, use or application and disclaims any responsibility for their application or use in any way. The NCCN
Evidence BlocksTM and NCCN Guidelines are copyrighted by National Comprehensive Cancer Network®. All rights reserved. The NCCN Evidence
BlocksTM, NCCN Guidelines, and the illustrations herein may not be reproduced in any form without the express written permission of NCCN. ©2024.
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Acute Lymphoblastic Leukemia Table of Contents
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NCCN EVIDENCE BLOCKS CATEGORIES AND DEFINITIONS Example Evidence Block
5 E = Efficacy of Regimen/Agent 5 E=4
4 S = Safety of Regimen/Agent 4 S=4
3 Q = Quality of Evidence 3 Q=3
C = Consistency of Evidence C=4
2 2
A = Affordability of Regimen/Agent A=3
1 1
E S Q C A E S Q C A
Efficacy of Regimen/Agent Quality of Evidence
5 Highly effective: Cure likely and often provides long-term 5 High quality: Multiple well-designed randomized trials and/or
survival advantage meta-analyses
4 Very effective: Cure unlikely but sometimes provides long-term 4 Good quality: One or more well-designed randomized trials
survival advantage 3 Average quality: Low quality randomized trial(s) or well-designed
3 Moderately effective: Modest impact on survival, but often non-randomized trial(s)
provides control of disease 2 Low quality: Case reports or extensive clinical experience
2 Minimally effective: No, or unknown impact on survival, but 1 Poor quality: Little or no evidence
sometimes provides control of disease
1 Palliative: Provides symptomatic benefit only Consistency of Evidence
5 Highly consistent: Multiple trials with similar outcomes
Safety of Regimen/Agent
4 Mainly consistent: Multiple trials with some variability in outcome
5 Usually no meaningful toxicity: Uncommon or minimal
toxicities; no interference with activities of daily living (ADLs) 3 May be consistent: Few trials or only trials with few patients,
whether randomized or not, with some variability in outcome
4 Occasionally toxic: Rare significant toxicities or low-grade 2 Inconsistent: Meaningful differences in direction of outcome
toxicities only; little interference with ADLs between quality trials
3 Mildly toxic: Mild toxicity that interferes with ADLs 1 Anecdotal evidence only: Evidence in humans based upon
2 Moderately toxic: Significant toxicities often occur but life anecdotal experience
threatening/fatal toxicity is uncommon; interference with ADLs
is frequent Affordability of Regimen/Agent (includes drug cost, supportive
care, infusions, toxicity monitoring, management of toxicity)
1 Highly toxic: Significant toxicities or life threatening/fatal
toxicity occurs often; interference with ADLs is usual and severe 5 Very inexpensive
4 Inexpensive
Note: For significant chronic or long-term toxicities, score decreased by 1
3 Moderately expensive
2 Expensive
1 Very expensive

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EB-1
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Acute Lymphoblastic Leukemia Table of Contents
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DIAGNOSIS

Patients should undergo evaluation and treatment at specialized centers

The diagnosis of ALL generally requires demonstration of ≥20% bone marrow lymphoblastsd,e on
hematopathology review of bone marrow aspirate and biopsy materials, which includes:
• Morphologic assessment of Wright-Giemsa–stained bone marrow aspirate smears, and hematoxylin and
eosin (H&E)–stained core biopsy and clot sections
• Comprehensive flow cytometric immunophenotypingc,f
• Baseline flow cytometric and/or molecular characterization of leukemic clone to facilitate subsequent
minimal/measurable residual disease (MRD) analysis (ALL-F)
• Karyotyping of G-banded metaphase chromosomes

MOLECULAR CHARACTERIZATION
Acute • Cytogenetic and molecular prognostic risk stratification for B-cell ALL (B-ALL) (ALL-3)
Clinical Risk
lymphoblastic • Optimal risk stratification and treatment planning require testing marrow or peripheral blood lymphoblasts
Stratification
leukemia for specific recurrent genetic abnormalities using:
(ALL-2)
(ALL)a,b,c Interphase fluorescence in situ hybridization (FISH) testing, including probes capable of detecting the
major recurrent genetic abnormalities
Reverse transcriptase polymerase chain reaction (RT-PCR) testing BCR::ABL1 in B-ALL (quantitative or
qualitative) including determination of transcript size (ie, p190 vs. p210)
Comprehensive testing by next-generation sequencing (NGS) for gene fusions and pathogenic mutations
is recommended.
• Additional optional tests include:
Assessment with chromosomal microarray (CMA)/array comparative genomic hybridization (cGH) in
cases of aneuploidy or inadequate karyotype.

CLASSIFICATION
Together, these studies allow determination of the World Health Organization (WHO) and International
Consensus Criteria (ICC) ALL subtypes and cytogenetic and clinical risk groups.

Footnotes on ALL-1A

Note: For more information regarding the categories and definitions used for the NCCN Evidence Blocks™, see page EB-1.
All recommendations are category 2A unless otherwise indicated.
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ALL-1
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FOOTNOTES FOR DIAGNOSIS
a Criteria for classification of mixed phenotype acute leukemia (MPAL) should be based on the WHO 2016 criteria. Note that in ALL, myeloid-associated antigens such
as CD13 and CD33 may be expressed, and the presence of these myeloid markers does not exclude the diagnosis of ALL, nor is it associated with adverse prognosis.
b Burkitt leukemia/lymphoma, see the NCCN Guidelines for B-Cell Lymphomas.
c T-cell acute lymphoblastic leukemia/lymphoma (T-ALL/T-LBL) subtypes include T-ALL/T-LBL, not otherwise specified (NOS), cortical type, mature type, and early T-cell
precursor (ETP) lymphoblastic leukemia/lymphoma; ETP-ALL typically lacks expression of CD5, CD8, and CD1a and expression of one or more myeloid/stem cell
markers. The mature subtype often also lacks expression of CD1a and frequently is accompanied by T-ALL11 or T-ALL12 rearrangement.
d While these guidelines pertain primarily to patients with leukemia, patients with lymphoblastic lymphoma (LL) (B- or T-cell) also benefit from ALL-like regimens versus
traditional lymphoma therapy. Such patients should be treated in a center that has experience with LL. See Discussion.
e If there are sufficient numbers of circulating lymphoblasts (at least 1000 per microliter as a general guideline) and clinical situation precludes bone marrow aspirate and
biopsy, then peripheral blood can be substituted for bone marrow.
f The following immunophenotypic findings are particularly notable: CD10 negativity correlates with KMT2A rearrangement; CD20 positivity: definition not clear, most
studies have used >20% of blasts expressing CD20. See Discussion.

Note: For more information regarding the categories and definitions used for the NCCN Evidence Blocks™, see page EB-1.
All recommendations are category 2A unless otherwise indicated.
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ALL-1A
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CLINICAL RISK STRATIFICATION

HIGH-RISK FEATURESg

B-ALL T-ALL
Age >35 years >35 years
White blood cell (WBC) count >30 x 10 /L 9
>100 x 109/L
Phenotype N/A ETP-ALL
Cytogenetics/Molecular risk group See Cytogenetic and Molecular Prognostic RAS/PTEN mutation and/or NOTCH1/FBXW7 wild
Risk Stratification for B-ALL (ALL-3) type

Workup (ALL-4)

g ALL arising from prior chemotherapy or underlying hematologic malignancy may be associated with adverse outcomes. Saygin C, et al. Blood Adv 2019;3:4228-4237.

Note: For more information regarding the categories and definitions used for the NCCN Evidence Blocks™, see page EB-1.
All recommendations are category 2A unless otherwise indicated.
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ALL-2
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CYTOGENETIC AND MOLECULAR PROGNOSTIC RISK STRATIFICATION FOR B-ALLh

RISK GROUPS CYTOGENETIC AND MOLECULAR ALTERATIONS

• Hyperdiploidy (51–65 chromosomes)

Cases with trisomy of chromosomes 4, 10, and 17 appear to have the most favorable outcome
• t(12;21)(p13;q22): ETV6::RUNX1i
• t(1;19)(q23;p13.3): TCF3::PBX1
Standard risk
• DUX4 rearranged
• PAX5 P80R
• t(9;22)(q34;q11.2): BCR::ABL1j without IKZF1 plusk and without antecedent chronic myeloid leukemia
(CML)
• Hypodiploidyl,m (<44 chromosomes)
• TP53 mutation
• KMT2A rearranged (t[4;11] or others)
• IgH rearrangedn
• HLF rearranged
• ZNF384 rearranged
• MEF2D rearranged
• MYC rearranged
Poor risk • BCR::ABL1-like (Philadelphia chromosome [Ph]-like) ALL
JAK-STAT (CRLF2r,o EPORr, JAK1/2/3r, TYK2r, mutations of SH2B3, IL7R, JAK1/2/3)
ABL class (rearrangements of ABL1, ABL2, PDGFRA, PDGFRB, FGFR)
Other (NTRKr, FLT3r, LYNr, PTK2Br)
• PAX5alt
• t(9;22)(q34;q11.2): BCR::ABL1j with IKZF1 plusk and/or antecedent CML
• Intrachromosomal amplification of chromosome 21 (iAMP21)
• Alterations of IKZF1k,p,q
• Complex karyotype (5 or more chromosomal abnormalities)

Clinical Risk Stratification ALL-2

Workup ALL-4
Footnotes ALL-3A

Note: For more information regarding the categories and definitions used for the NCCN Evidence Blocks™, see page EB-1.
All recommendations are category 2A unless otherwise indicated.
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ALL-3
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FOOTNOTES FOR CYTOGENIC AND MOLECULAR PROGNOSTIC RISK STRATIFICATION FOR B-ALL
h FISH probes that may be useful include: centromeric probes for chromosomes 4, 10, and 17 to detect hyperdiploidy; dual-color probe set to detect cryptic t(12;21),
which will also allow detection of iAMP21 (when ≥5 copies of the RUNX1 gene are detected); probes to detect BCR::ABL1 and KMT2A rearrangements; probes to
detect ABL1, ABL2, and PDGFRB rearrangements; probes for CDKN2A at 9p21.3 to detect deletions; probes to detect cryptic t(X;14)(p22;q32)/t(Y;14)(p11;q32)
IGH::CRLF2 rearrangements; and probes to detect JAK2 rearrangements.
i The translocation t(12;21)(p13;q22) is typically cryptic by karyotyping and requires FISH or PCR to identify.
j Interphase FISH for the detection of BCR::ABL1 transcript on blood granulocytes is recommended to differentiate between de novo blast phase CML (BP-CML) and de
novo Ph-positive ALL. See NCCN Guidelines for Chronic Myeloid Leukemia for the management of BP-CML.
k IKZF1 deletions with co-occurring deletions in CDKN2A, CDKN2B, PAX5, or PAR1 in the absence of ERG deletion, which are called IKZF1 plus, as well as those with
concomitant 22q11.22 deletions, are especially associated with worse outcomes in pediatric patients with B-ALL.
l There are other results that are not < 44 chromosomes that may be equivalent to hypodiploidy and have the same implications. It is important to distinguish true
hypodiploidy from masked hypodiploidy, which results from the doubling of hypodiploid clones. Carroll AJ, et al. Cancer Genet 2019;238:62-68.
m Alternatively defined as DNA index less than protocol-defined threshold or other clear evidence of hypodiploid clone. Hypodiploid ALL is also often associated with
TP53 loss of function mutations and Li-Fraumeni syndrome.
n Includes IGH::IL3 rearrangement.
o Jain N, et al. Blood 2017;129:572-581; Roberts KG, et al. N Engl J Med 2014;371:1005-1015.
p Mullighan CG, et al. N Engl J Med 2009;360:470-480; Stanulla M, et al. J Clin Oncol 2018;36:1240-1249.
q Emerging evidence suggests DUX4r ALL is favorable. Additionally in cases of DUX4r, IKZF1 alterations do not confer poor prognosis.

Note: For more information regarding the categories and definitions used for the NCCN Evidence Blocks™, see page EB-1.
All recommendations are category 2A unless otherwise indicated.
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ALL-3A
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WORKUPr ALL SUBTYPEu
• History and physical examination (H&P)
• Complete blood count (CBC), differential, chemistry profile, liver function tests (LFTs)
• Disseminated intravascular coagulation (DIC) panel: d-dimer, fibrinogen, prothrombin time (PT), partial
thromboplastin time (PTT)
• Tumor lysis syndrome (TLS) panel: lactate dehydrogenase (LDH), uric acid, potassium, calcium,
phosphorus (See Tumor Lysis Syndrome in the NCCN Guidelines for B-Cell Lymphomas) Treatment
• Hepatitis B/C, human immunodeficiency virus (HIV) testing Ph+ B-ALL (ALL-5)
• Pregnancy testing, fertility counseling, and preservation
• CT/MRI of head with contrast, if neurologic symptomss
• Lumbar puncture (LP)s,t with intrathecal (IT) therapy
Evaluation and Treatment of Extramedullary Involvement (ALL-B)
• CT of neck/chest/abdomen/pelvis with IV contrast, as indicated for symptoms
Consider PET/CT if lymphomatous involvement is suspected and/or confirmed by CT imaging Treatment
Ph- B-ALL
• Testicular examination, including scrotal ultrasound as indicated (ALL-6)
• Infection evaluation:
Screen for opportunistic infections, as appropriate (NCCN Guidelines for Prevention and Treatment
of Cancer-Related Infections)
• Echocardiogram or cardiac nuclear medicine scan should be considered in all patients, since
anthracyclines are important components of ALL therapy, but especially in patients with prior cardiac Treatment
T-ALL (ALL- 7)
history and prior anthracycline exposure or clinical symptoms suggestive of cardiac dysfunction.
• Central venous access device of choice
• Strongly consider early transplant evaluation and donor search.
• For patients with possible cancer predisposition syndromes, principles of cancer risk assessment
and counseling should be taken into consideration (NCCN Guidelines for Genetic/Familial High-Risk
Assessment: Breast, Ovarian, and Pancreatic and ALL-A)

r The following list represents minimal recommendations; other testing may be warranted
according to clinical symptoms and discretion of the clinician.
s For patients with major neurologic signs or symptoms at diagnosis, appropriate imaging t The Panel recommends first LP be performed at time of initial
studies should be performed to detect meningeal disease, chloromas, or central nervous scheduled IT therapy unless directed by symptoms to perform earlier.
system (CNS) bleeding. See Evaluation and Treatment of Extramedullary Involvement (ALL-B). u Clinical Risk Stratification (ALL-2).

Note: For more information regarding the categories and definitions used for the NCCN Evidence Blocks™, see page EB-1.
All recommendations are category 2A unless otherwise indicated.
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RISK TREATMENT INDUCTIONbb,cc,dd CONSOLIDATION THERAPYbb,cc,dd
STRATIFICATIONu,v
Blinatumomab ±
TKIee,ff,kk,ll,mm
Persistent/ Consider
or allogeneic
Rising
MRDjj Multiagent hematopoietic cell
Clinical trial therapy + TKIee,hh,kk transplantation
(HCT)ll,pp,qq,rr
or or
Adolescents tyrosine kinase Inotuzumab
and young inhibitor (TKI) + ozogamicin ± Post-HCT
adults (AYAs)x,y multiagent therapyee MRD
TKIee,ff,mm,nn
assessment TKI when
and adults <65 or
or feasibleee,ss,tt,uu
yearsz without TKI + (ALL-F)
substantial corticosteroidee TKIee,kk,oo
comorbidities or Complete
TKI + remission Blinatumomab + Maintenance
blinatumomabee,ff,gg (CR)ii TKIee,ff,mm therapyee +
or TKIee,tt,uu
Surveillance
or
Multiagent (ALL-8)
Consider
Ph+ MRD- therapy + TKIee,hh allogeneic
B-ALLw
Response or HCTpp,qq,rr
assessment TKIee,oo
(ALL-E) or
Clinical trial
or Allogeneic HCT in Post-HCT
TKI + appropriate TKI when
Adults ≥65 corticosteroidee,hh candidatespp,qq,rr feasibleee,ss,tt,uu
yearsz,aa or or
with substantial TKI +
comorbidities multiagent therapyee,hh
or
TKI + Less than CR Relapsed/refractory disease (ALL-9)
blinatumomabee,ff,gg

Footnotes on ALL-5A

Note: For more information regarding the categories and definitions used for the NCCN Evidence Blocks™, see page EB-1.
All recommendations are category 2A unless otherwise indicated.
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FOOTNOTES FOR Ph+ B-ALL (AYA/ADULT) TREATMENT INDUCTION AND CONSOLIDATION THERAPY
u Clinical
 Risk Stratification (ALL-2). jj The prognostic significance of MRD positivity may be regimen-, ALL subtype-,
v Cytogenetic and Molecular Prognostic Risk Stratification for B-ALL (ALL-3). and/or ALL risk-dependent. MRD timepoints and levels prompting allogeneic
w It is reasonable to approach the initial treatment of BP-CML with similar strategies HCT should be guided by the specific treatment protocol being used. For patients
to Ph+ ALL, with a goal of proceeding to HCT. with negative MRD by flow cytometry but positive MRD by an FDA-approved
x The ALL Panel considers AYA to be within the age range of 15–39 years. However, NGS assay, consider repeat testing before consolidation is started to confirm
this age range is not a firm reference point because some of the recommended MRD status. In general, MRD positivity at the end of induction predicts high
regimens have not been comprehensively tested across all ages. relapse rates and should prompt evaluation for allogeneic HCT. Therapy aimed at
y For additional considerations in the care of AYA patients with ALL, see the NCCN eliminating MRD prior to allogeneic HCT is preferred when possible (Discussion).
Guidelines for Adolescent and Young Adult (AYA) Oncology. kk Consider using an alternative and more broadly acting TKI. Treatment options
z Chronological age is a poor surrogate for fitness for therapy. Patients should be are based on BCR::ABL1 mutation profile (ALL-D 1 of 28).
evaluated on an individual basis, including for the following factors: end-organ ll Although long-term remission after blinatumomab + TKI is possible, allogeneic
reserve, end-organ dysfunction, and performance status. HCT can be considered as consolidative therapy.
aa For additional considerations in the care of adult patients ≥65 years with ALL, see mm Blinatumomab + TKI is preferred in consolidation regardless of MRD status for
the NCCN Guidelines for Older Adult Oncology. those who have not previously received blinatumomab.
bb TKI options include (in alphabetical order): bosutinib, dasatinib, imatinib, nilotinib, nn Although there are limited data, the Panel recommends waiting at least 4 weeks
or ponatinib. Not all TKIs have been directly studied within the context of each from the completion of inotuzumab ozogamicin monotherapy and the start of
specific regimen and the Panel notes that there are limited data for bosutinib in conditioning therapy for allogeneic HCT to minimize risk of sinusoidal obstruction
Ph+ ALL. Use of a specific TKI should account for anticipated/prior TKI intolerance, syndrome (SOS). SOS occurred less frequently when fewer alkylators were used
dose used, BCR::ABL1 mutations, and disease-related features. Imatinib use as part of the conditioning regimen. Kantarjian H, et al. Cancer 2013;119:2728-
in first line should be restricted to patients who cannot tolerate broader acting 2736.
TKIs. Jabbour E, et al. J Clin Oncol 2023;41(Suppl):Abstract 398868. For oo TKI monotherapy is seldom effective as induction; however, it may be
contraindicated mutations, see ALL-D 1 of 28. considered as consolidation/maintenance in those unfit for additional therapies.
cc ALL treatment regimens include CNS prophylaxis. See Evaluation and Treatment pp Optimal timing of allogeneic HCT is not clear. For fit patients, additional therapy
of Extramedullary Involvement (ALL-B). is recommended to eliminate MRD prior to transplant. Proceeding to allogeneic
dd Principles of Supportive Care (ALL-C). HCT with MRD is not optimal.
ee Principles of Systemic Therapy (ALL-D). qq Data suggest that for patients aged ≤21 years, particularly for those who
ff Supportive Care: Toxicity Management (ALL-C 2 of 4). achieve MRD negativity, allogeneic HCT may not offer an advantage over
gg Prior to blinatumomab initiation, cytoreduce with TKI + corticosteroid to peripheral chemotherapy + TKI. Schultz KR, et al. J Clin Oncol 2009;27:5175-5181; Schultz
WBC count of <10 x 109/L. Foà R, et al. N Engl J Med 2020;383:1613-1623. KR, et al. Leukemia 2014;28:1467-1471.
hh Consider dose modifications appropriate for patient age and performance status. rr Many variables determine eligibility for allogeneic HCT including donor
See Principles of Systemic Therapy - Treatment of Adults ≥65 years or Adults availability, depth of remission, comorbidities, and social support.
with Substantial Comorbidities (ALL-D 2 of 28). ss See Discussion for use of different TKIs in this setting.
ii Adequate count recovery per protocol is recommended before transitioning to tt TKI should be continued for at least 2 years post-HCT. The recommended
post-remission therapy, even in the presence of MRD negativity. If count recovery duration of TKI during maintenance chemotherapy is at least until completion
is not achieved, additional follow-up for MRD may be warranted. Assess for of maintenance chemotherapy. The optimal duration of TKI is unknown in both
myelosuppression secondary to TKI and consider dose reduction. settings.
uu Consider sequential MRD monitoring for patients with complete molecular
remission (undetectable levels). Increased frequency may be indicated for
detectable levels or for those discontinuing TKI.

Note: For more information regarding the categories and definitions used for the NCCN Evidence Blocks™, see page EB-1.
All recommendations are category 2A unless otherwise indicated.
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ALL-5A
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RISK TREATMENT INDUCTIONcc,dd CONSOLIDATION THERAPYcc,dd
STRATIFICATIONu,v
Blinatumomabee,ff,yy,zz
Persistent/
or Allogeneic
Rising
Inotuzumab HCTpp,rr,bbb
MRDjj
Clinical trial ozogamicinee,ff,nn,zz
or
Pediatric-
AYAx,y inspired MRD
regimensee Continue multiagent
assessment therapy alternating with
or (ALL-F) Surveillance
blinatumomabee,ff,aaa Maintenance
Multiagent
therapyee (ALL-8)
therapyee or
MRD- or Blinatumomabee,ff,yy
CRww MRD or
unavailablexx
Adults Consider allogeneic
Clinical trial HCTpp,rr (especially if
<65 yearsz or Response
Ph- high-risk features)u,v
without assessment
B-ALL Multiagent
substantial (ALL-E)
comorbidities therapyee

Clinical trial
Less than CR Relapsed/Refractory Disease (ALL-9)
or
Adults ≥65 Multiagent
yearsz,aa therapyee,hh
or with or
substantial Inotuzumab
comorbidities ozogamicinee,ff,vv
or
Palliative
corticosteroid

Footnotes on ALL-6A

Note: For more information regarding the categories and definitions used for the NCCN Evidence Blocks™, see page EB-1.
All recommendations are category 2A unless otherwise indicated.
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FOOTNOTES FOR Ph- B-ALL (AYA/ADULT) TREATMENT INDUCTION AND CONSOLIDATION THERAPY
u Clinical Risk Stratification (ALL-2). vv Stelljes M, et al. J Clin Oncol 2023:JCO2300546; Wieduwilt MJ, et al. J Clin
v Cytogenetic and Molecular Prognostic Risk Stratification for B-ALL (ALL-3). Oncol 2023;41:7006-7006.
x The ALL Panel considers AYA to be within the age range of 15–39 years. However, ww Adequate count recovery per protocol is recommended before transitioning to
this age range is not a firm reference point because some of the recommended post-remission therapy, even in the presence of MRD negativity. If count recovery
regimens have not been comprehensively tested across all ages. is not achieved, additional follow-up for MRD may be warranted.
y For additional considerations in the care of AYA patients with ALL, see the NCCN xx If MRD is unavailable, consider retesting for MRD at first available opportunity.
yy Blinatumomab can be considered for consolidation in patients who are MRD
Guidelines for Adolescent and Young Adult (AYA) Oncology.

z Chronological age is a poor surrogate for fitness for therapy. Patients should be negative/unavailable after multiagent therapy, or in patients for whom multiagent
evaluated on an individual basis, including for the following factors: end-organ therapy is contraindicated, and for consolidation in persistent/rising MRD.
zz Blinatumomab is preferred for those with persistent or rising MRD who have not
reserve, end-organ dysfunction, and performance status.
aa For additional considerations in the care of adult patients ≥65 years with ALL, see previously received blinatumomab.
aaa Blinatumomab should be incorporated into frontline therapy as a post-remission
the NCCN Guidelines for Older Adult Oncology.
cc ALL treatment regimens include CNS prophylaxis. See Evaluation and Treatment approach based on data from ECOG1910.
bbb Although long-term remission after blinatumomab monotherapy is possible,
of Extramedullary Involvement (ALL-B).
dd Principles of Supportive Care (ALL-C). allogeneic HCT can be considered as consolidative therapy.
ee Principles of Systemic Therapy (ALL-D).
ff Supportive Care: Toxicity Management (ALL-C 2 of 4).

hh Consider dose modifications appropriate for patient age and performance status.
See Principles of Systemic Therapy - Treatment of Adults ≥65 years or Adults
with Substantial Comorbidities (ALL-D 2 of 28).
jj The prognostic significance of MRD positivity may be regimen-, ALL subtype-,
and/or ALL risk-dependent. MRD timepoints and levels prompting allogeneic
HCT should be guided by the specific treatment protocol being used. For patients
with negative MRD by flow cytometry but positive MRD by an FDA-approved
NGS assay, consider repeat testing before consolidation is started to confirm
MRD status. In general, MRD positivity at the end of induction predicts high
relapse rates and should prompt evaluation for allogeneic HCT. Therapy aimed at
eliminating MRD prior to allogeneic HCT is preferred when possible (Discussion).
nn Although there are limited data, the Panel recommends waiting at least 4 weeks
from the completion of inotuzumab ozogamicin monotherapy and the start of
conditioning therapy for allogeneic HCT to minimize risk of SOS. SOS occurred
less frequently when fewer alkylators were used as part of the conditioning
regimen. Kantarjian H, et al. Cancer 2013;119:2728-2736.
pp Optimal timing of allogeneic HCT is not clear. For fit patients, additional therapy is
recommended to eliminate MRD prior to transplant. Proceeding to allogeneic HCT
with MRD is not optimal.
rr Many variables determine eligibility for allogeneic HCT including donor availabilty,
depth of remission, comorbidities, and social support.

Note: For more information regarding the categories and definitions used for the NCCN Evidence Blocks™, see page EB-1.
All recommendations are category 2A unless otherwise indicated.
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RISK TREATMENT INDUCTIONcc,dd,ccc CONSOLIDATION THERAPYcc,dd
STRATIFICATIONu
Persistent/ Consider
Rising MRD allogeneic Surveillance (ALL-8)
Clinical trial and/or HCTpp,rr
or High-risk or
Pediatric- featuresddd
inspired Continue
AYA patientsx,y multiagent
regimenee
or CR/CR with therapyee
MRD
Multiagent incomplete Assessment
therapyee hematologic (ALL-F)
recovery (CRi) Maintenance therapyee
Adults
<65 yearsz Clinical trial
or Response
T-ALL without assessment (ALL-E) Continue
substantial Multiagent multiagent
comorbidities therapyee therapyee
Other patients or
Clinical trial Consider
Adults ≥65 or allogeneic Surveillance (ALL-8)
Multiagent Less than Relapsed/Refractory HCTpp,rr
yearsz,aa CR/CRi disease (ALL-9)
or with therapyee,hh
substantial or
comorbidities Palliative
cc ALL
treatment regimens include CNS prophylaxis. See Evaluation and Treatment of
corticosteroid
Extramedullary Involvement (ALL-B).
dd Principles of Supportive Care (ALL-C).
u Clinical Risk Stratification (ALL-2). ee Principles of Systemic Therapy (ALL-D).
x The ALL Panel considers AYA to be within the age range of 15–39 years. However, this hh Consider dose modifications appropriate for patient age and performance status. See
age range is not a firm reference point because some of the recommended regimens Principles of Systemic Therapy - Treatment of Adults ≥65 years or Adults with Substantial
have not been comprehensively tested across all ages. Comorbidities (ALL-D 2 of 28).
y For additional considerations in the care of AYA patients with ALL, see the NCCN pp Optimal timing of allogeneic HCT is not clear. For fit patients, additional therapy is
Guidelines for Adolescent and Young Adult (AYA) Oncology. recommended to eliminate MRD prior to transplant. Proceeding to allogeneic HCT with MRD is
z Chronological
 age is a poor surrogate for fitness for therapy. Patients should be not optimal.
evaluated on an individual basis, including for the following factors: end-organ reserve, rr Many variables determine eligibility for allogeneic HCT including donor availabilty, depth of
end-organ dysfunction, and performance status. remission, comorbidities, and social support.
aa For additional considerations in the care of adult patients ≥65 years with ALL, see the ccc The addition of nelarabine to selected induction regimens may be beneficial (ALL-D 20 of 28).
NCCN Guidelines for Older Adult Oncology. ddd High-risk features include ETP-phenotype or RAS/PTEN classifier (ALL-2).

Note: For more information regarding the categories and definitions used for the NCCN Evidence Blocks™, see page EB-1.
All recommendations are category 2A unless otherwise indicated.
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SURVEILLANCEeee

• Year 1 (every 1–2 months):

Physical examination
CBC with differential
LFTs until normal
• Year 2 (every 3–6 months):
Physical examination
CBC with differential
• Year 3+ (every 6–12 months or as indicated):
Physical examination
CBC with differential
Relapsed/Refractory Disease (ALL-9)
Other General Measures
• Bone marrow aspirate can be considered as clinically indicated at a frequency of
up to 3 to 6 months for at least 5 yearsfff
If bone marrow aspirate is done: Flow cytometry with additional studies that
may include comprehensive cytogenetics, FISH, molecular testing, and MRD
assessment [Minimal/Measurable Residual Disease Assessment (ALL-F)]
• Periodic BCR::ABL1 transcript-specific quantification (Ph+ ALL)
• Refer to Survivorship recommendations in the NCCN Guidelines for Survivorship
• Refer to the ALL Long-term Follow-up Guidelines from the Children’s Oncology
Group (COG): [Link]

eee Surveillance recommendations apply after completion of chemotherapy, including maintenance.

fff While
 there is insufficient evidence to guide MRD monitoring for patients with Ph-negative diseasefollowing completion of maintenance therapy, the approval of
blinatumomab, and potentially future therapies for the MRD-positive relapse, may warrant testing in this regard. Alternatively, for patients showing evidence of
symptomatic relapse, the diagnostic workup should be repeated as per ALL-1 and ALL-4 as applicable.

Note: For more information regarding the categories and definitions used for the NCCN Evidence Blocks™, see page EB-1.
All recommendations are category 2A unless otherwise indicated.
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RELAPSED/REFRACTORY DISEASE TREATMENTiii
Clinical trial
or
TKIjjj ± multiagent therapy or TKIjjj ± corticosteroid
or
Blinatumomabff ± TKIjjj
or
Ph+ B-ALL ABL1 kinase domain Inotuzumab ozogamicinff,nn ± TKIjjj
(AYAx & Adult) mutation testing or
Brexucabtagene autoleucel (following therapy that has
included TKIs)ff,kkk
or
Tisagenlecleucel (patients <26 y and with refractory
disease or ≥2 relapses and following therapy that has
included 2 TKIs)ff,kkk,lll

Consider
Clinical trial
HCTnnn,ooo
or
Blinatumomabff (category 1)
or
Molecular
Inotuzumab ozogamicinff,nn (category 1)
Relapsed/ characterization and
Ph- B-ALL or
refractoryggg,hhh MRD assessment, if
(AYAx & Adult) Brexucabtagene autoleucelff,kkk
not previously done
or
(ALL-1)
Tisagenlecleucel (patients <26 y and with
refractory disease or ≥2 relapses)ff,kkk,lll
or
Multiagent therapymmm

Clinical trial
T-ALL or
Relapsed/Refractory regimensmmm (ALL-D 28 of 28)

Footnotes on ALL-9A

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All recommendations are category 2A unless otherwise indicated.
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FOOTNOTES
x The ALL Panel considers AYA to be within the age range of 15–39 years. However, this age range is not a firm reference point because some of the recommended
regimens have not been comprehensively tested across all ages.
ff Supportive Care: Toxicity Management (ALL-C 2 of 4).
nn Although there are limited data, the Panel recommends waiting at least 4 weeks from the completion of inotuzumab ozogamicin monotherapy and the start of
conditioning therapy for allogeneic HCT to minimize risk of sinusoidal obstruction syndrome (SOS). SOS occurred less frequently when fewer alkylators were used as
part of the conditioning regimen. Kantarjian H, et al. Cancer 2013;119:2728-2736.
ggg Isolated extramedullary relapse (including CNS and testicular) requires systemic therapy to prevent relapse in marrow. Consider CNS prophylaxis for relapsed/
refractory disease. The role of CNS prophylaxis in the setting of cellular therapy is still being studied.
hhh NCCN Guidelines for Palliative Care.
iii See Principles of Systemic Therapy (ALL-D 26 of 28, ALL-D 27 of 28, and ALL-D 28 of 28).
jjj Treatment Options Based on BCR::ABL1 Mutation Profile (ALL-D 1 of 28).
kkk NCCN Guidelines for Management of Immunotherapy-Related Toxicities.
lll The role of allogeneic HCT following cellular therapy is unclear.
mmm For patients in late relapse (>3 years from initial diagnosis), consider treatment with the same induction regimen (for Ph-negative B-ALL, see ALL-D 10 of 28; for
T-ALL, see ALL-D 19 of 28).
nnn If second remission is achieved prior to HCT and patient has not had a prior HCT, consolidative HCT is recommended.
ooo For patients with relapsed disease after allogeneic HCT, a second allogeneic HCT and/or donor lymphocyte infusion (DLI) can be considered.

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All recommendations are category 2A unless otherwise indicated.
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FAMILIAL GENETIC ALTERATIONS IN ALL
• Hereditary predisposition to ALL is increasingly recognized.1,2 As many as 4% of children with ALL carry a germline cancer predisposition
gene mutation.3
• Referral for genetic counseling, germline tissue testing, and potential extension of these services to appropriate family members should
be considered in select patients (eg, those with a suggestive family history of leukemia, other hematologic cancers, or the associated
conditions listed in the table below). See the NCCN Guidelines for Breast, Ovarian, and Pancreatic Cancer.
• Hereditary forms of ALL may impact HCT donor and regimen selection.4 Therefore, an expeditious evaluation for germline ALL
predisposition mutations is of particular importance prior to allogeneic transplantation.
Name of Syndromea Causative Pattern of Characteristic Other Other Associated Conditions Recommended
Gene(s) Inheritance Malignancy Hematopoietic Diagnostic Test
Abnormalities
Familial platelet RUNX1 Autosomal • Myelodysplastic Thrombocytopenia Exon sequencing and
disorder with propensity dominant syndrome (MDS) Platelet gene rearrangement
to myeloid malignancies • Acute myeloid dysfunction testing for RUNX1
(OMIM 601399) leukemia (AML)
• T-ALL
Thrombocytopenia 5 ETV6 Autosomal • MDS Thrombocytopenia Exon sequencing and
(OMIM 616216) dominant • AML Platelet gene rearrangement
• Chronic dysfunction testing for ETV6
myelomonocytic
leukemia (CMML)
• B-ALL
• Multiple myeloma
PAX5-associated PAX5 Autosomal • B-ALL Exon sequencing and
leukemia predisposition dominant gene rearrangement
(OMIM 615545) testing for PAX5
IKZF1-associated IKZF1 Autosomal • B-ALL Immunodeficiency Exon sequencing for
leukemia predisposition dominant • T-ALL IKZF1
(OMIM 613067)
Li-Fraumeni syndrome TP53 Autosomal • MDS Adrenocortical carcinoma, osteosarcoma, Exon sequencing for
(OMIM 151623) dominant • AML brain cancer, breast cancer, choroid plexus TP53
• Low-hypodiploid carcinoma, colon cancer, lung carcinoma,
ALL sarcoma, other tumors; therapy-related
neoplasms may emerge after treatment for
solid tumors
1 Pui CH, Nichols KE, Yang JJ. Somatic and germline genomics in paediatric acute lymphoblastic leukaemia. Nat Rev Clin Oncol 2019;16:227-240.
2 Klco JM, Mullighan CG. Advances in germline predisposition to acute leukaemias and myeloid neoplasms. Nat Rev Cancer 2021;21:122-137.
3 Bloom M, Maciaszek JL, Clark ME, et al. Recent advances in genetic predisposition to pediatric acute lymphoblastic leukemia. Expert Rev
a Other syndromes have rarely been associated with ALL. Hematol 2020;13:55-70.
4 Furutani
For a full list, see references 1–4. E, Shimamura A. Germline genetic predisposition to hematologic malignancy. J Clin Oncol 2017;35:1018-1028.

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EVALUATION AND TREATMENT OF EXTRAMEDULLARY INVOLVEMENT
• The aim of CNS prophylaxis and/or treatment is to clear leukemic cells within sites that cannot be readily accessed by systemic
chemotherapy due to the blood-brain barrier, with the overall goal of preventing CNS disease or relapse.
• CNS involvement should be evaluated (by LP) at the appropriate timing:
Timing of LP should be consistent with the chosen treatment regimen.
Pediatric-inspired regimens typically include LP at the time of diagnostic workup.
The Panel recommends that IT therapy be administered with initial LP.
• Classification of CNS status:
CNS-1: No lymphoblasts in cerebrospinal fluid (CSF) regardless of WBC count.a
CNS-2: WBC <5/mcL in CSF with presence of lymphoblasts.
CNS-3: WBC ≥5/mcL in CSF with presence of lymphoblasts.
If the patient has leukemic cells in the peripheral blood, the LP is traumatic, and WBC ≥5/mcL in CSF with blasts, then compare the CSF
WBC/red blood cell (RBC) ratio to the blood WBC/RBC ratio. If the CSF ratio is at least two-fold greater than the blood ratio, then the
classification is CNS-3; if not, then it is CNS-2.
• All patients with ALL should receive CNS prophylaxis. Although the presence of CNS involvement at the time of diagnosis is uncommon
(about 3%–7%), a substantial proportion of patients (>50%) will eventually develop CNS leukemia in the absence of CNS-directed therapy.
• CNS-directed therapy may include cranial irradiation, IT therapy (eg, methotrexate, cytarabine, corticosteroid), and/or systemic
chemotherapy (eg, high-dose methotrexate, intermediate or high-dose cytarabine, pegaspargase [PEG]). Generally, IT therapy should start
during the induction phase.
• CNS leukemia (CNS-3 and/or cranial nerve involvement) at diagnosis, or persisting after induction, may warrant treatment with cranial
irradiation of 18 Gy in 1.8–2.0 Gy/fraction. The recommended dose of radiation, where given, is highly dependent on the intensity of systemic
chemotherapy; thus, it is critical to adhere to a given treatment protocol in its entirety. The entire brain and posterior half of the globe should
be included. The inferior border should include C2.
• Note that areas of the brain targeted by the radiation field in the management of ALL are different from areas targeted for brain metastases of
solid tumors.
• With the incorporation of adequate systemic chemotherapy (eg, high-dose methotrexate, intermediate or high-dose cytarabine) and IT
therapy regimens (eg, methotrexate alone or with cytarabine and a corticosteroid, which constitutes the triple IT regimen), it may be possible
to avoid the use of upfront prophylactic cranial irradiation except in cases of overt CNS leukemia at diagnosis, and to reserve the use of
irradiation for relapsed/refractory therapy settings.
• Adequate systemic therapy should be given in the management of isolated CNS relapse.
• Patients with clinical evidence of testicular disease at diagnosis that is not fully resolved by the end of the induction therapy should
be considered for radiation to the testes in the scrotal sac, which is typically done concurrently with the first cycle of maintenance
chemotherapy. Testicular total dose should be 24 Gy in 2.0 Gy/fraction.

a Flow cytometry may be considered. Patients who have CNS-1 disease with leukemia
detected only by flow cytometry may be at higher risk but data are still forthcoming.

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All recommendations are category 2A unless otherwise indicated.
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Acute Lymphoblastic Leukemia Table of Contents
Discussion
NCCN Evidence BlocksTM
SUPPORTIVE CARE
Best Supportive Care ◊ Steroid-induced psychosis and mood alteration
• Infection control (NCCN Guidelines for Prevention and Treatment of – Consider anti-psychotics. If no response, consider dose
Cancer-Related Infections) reduction.
For infection risk, monitoring, and prophylaxis recommendations – Use of a histamine-2 antagonist or proton pump inhibitor (PPI)
for immune-targeted therapies, see INF-A in the NCCN Guidelines should be considered during steroid therapy.
for Prevention and Treatment of Cancer-Related Infections – There may be important drug interactions between PPIs and
• Acute TLS (See Tumor Lysis Syndrome on NHODG-B in the NCCN methotrexate that need to be considered prior to initiation of
Guidelines for B-Cell Lymphomas) methotrexate-based therapy.
• Toxicity Management for Inotuzumab Ozogamicin, Blinatumomab, – There are significant interactions between PPIs and TKIs
Tisagenlecleucel, and Brexucabtagene Autoleucel (ALL-C 2 of 4) regarding the bioavailability of certain BCR::ABL1 TKIs with
• Asparaginase Toxicity Management (ALL-C 3 of 4 and ALL-C 4 of 4) gastric acid suppression that should be considered.
• Methotrexate and Glucarpidase Long-term side effects of corticosteroids
Trimethoprim/sulfamethoxazole may be held when high-dose ◊ Osteonecrosis/avascular necrosis (Discussion)
methotrexate is administered and restarted when methotrexate – Obtain vitamin D and calcium status and replete as needed.
clearance is achieved per protocol or institutional guidelines. – Consider radiographic evaluation with x-rays or MRI or bone
If a patient receiving high-dose methotrexate experiences delayed density study.
elimination due to renal impairment, glucarpidase is strongly – Consider withholding steroid in patients with severe avascular
recommended when: necrosis.
◊ plasma methotrexate concentrations are two standard deviations • Transfusions
above the mean expected plasma concentration as determined Products should be leukoreduced/irradiated.
by [Link] • Use of granulocyte colony-stimulating factor (G-CSF)
or Recommended for myelosuppressive blocks of therapy or as
◊ plasma methotrexate level is >30 μM at 36 hours, >10 μM at 42 directed by treatment protocol
hours, or >5 μM at 48 hours. • Hyperleukocytosis
Optimal administration of glucarpidase is within 48 to 60 hours Although uncommon in patients with ALL, symptomatic
from the start of methotrexate infusion. Leucovorin should be hyperleukocytosis may require emergent treatment (see NCCN
continued for at least 2 days following glucarpidase administration Guidelines for Acute Myeloid Leukemia).
and should be administered at least 2 hours before or 2 hours after • Antiemetics (NCCN Guidelines for Antiemesis)
glucarpidase. Given as needed prior to chemotherapy and post chemotherapy
• Steroid management Routine use of corticosteroids as antiemetics are avoided
Acute side effects • Gastroenterology
◊ Steroid-induced diabetes mellitus Consider starting a bowel regimen to avoid constipation if receiving
– Tight glucose control using insulin to decrease infection vincristine.
complications • Nutritional support
Consider enteral or parenteral support for greater than 10% weight
loss.
• Palliative treatment for pain (NCCN Guidelines for Adult Cancer Pain)
Continued
Note: For more information regarding the categories and definitions used for the NCCN Evidence Blocks™, see page EB-1.
All recommendations are category 2A unless otherwise indicated. ALL-C
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Acute Lymphoblastic Leukemia Table of Contents
Discussion
NCCN Evidence BlocksTM
SUPPORTIVE CARE
Toxicity Management for Inotuzumab Ozogamicin, Blinatumomab, Tisagenlecleucel, and Brexucabtagene Autoleucel
Inotuzumab Ozogamicin:
• Cytoreduction should be considered for those with absolute blast count ≥10,000 cells per microliter. On clinical trial, hydroxyurea or a
combination of steroids and vincristine was used.
• Myelosuppression is common, and prophylactic antimicrobial strategies in accordance with institutional practice should be used.
• Liver enzymes, and particularly bilirubin, should be closely monitored, as SOS (sinusoidal obstruction syndrome; or veno-occlusive disease
[VOD]) may occur, particularly among patients at higher risk (including those who are status-post allogeneic HCT, those whose treatment
extends beyond two cycles, and/or those who previously received or will receive double alkylator conditioning prior to allogeneic HCT).
For those patients receiving inotuzumab ozogamicin as a bridge to allogeneic HCT, double alkylator conditioning is strongly discouraged.
Ursodiol may be considered for SOS prophylaxis.
• Consider defibrotide for patients who develop SOS related to inotuzumab ozogamicin toxicity.1,2

Blinatumomab:
• Cytoreduction should be considered for those with absolute blast count ≥15,000 cells per microliter, as high tumor burden may increase the
risks of toxicity. On clinical trial, steroids were most commonly used.
• Patients should be monitored for cytokine release syndrome (CRS), a systemic inflammatory condition characterized by fever or
hypothermia, that may progress to hypotension, hypoxia, and/or end organ damage. Infusion should be held with consideration for steroids
and/or vasopressors for those with severe symptoms in accordance with manufacturer guidelines and prescriber information. Consider
tocilizumab for patients with severe CRS.
• Because concurrent severe infection may mimic CRS, an evaluation for underlying infection and consideration of empiric antimicrobial
therapy in accordance with institutional practice should be performed.
• Patients should be monitored for neurologic toxicity, which may include confusion, word-finding difficulty, somnolence, ataxia, tremor,
seizure, or syncope. Infusion should be held with consideration of steroids for those with severe symptoms in accordance with
manufacturer guidelines and prescribing information, and re-started (once symptoms have sufficiently improved) with dosing adjustments
as per manufacturer guidelines and prescribing information.

Tisagenlecleucel/Brexucabtagene Autoleucel:
• Severe CRS and/or neurologic toxicity may accompany therapy, and should be managed in accordance with the manufacturer Risk
Evaluation and Mitigation Strategies (REMS) program, to include tocilizumab (preferred for CRS) and steroids (preferred for tocilizumab-
refractory CRS and/or neurologic toxicity).
• Prophylaxis with anti-seizure medication may be considered during the first month after chimeric antigen receptor [CAR] T-cell infusion.
• Severe neutropenia, T-cell depletion, and B-cell aplasia can occur, for which growth factor, prophylactic antimicrobial therapy, and IV
immunoglobulin (Ig) administration should be considered, in accordance with institutional practice (NCCN Guidelines for Management of
Immunotherapy-Related Toxicities). 1 Kebriaei P, Cutler C, de Lima M, et al. Management of important adverse events associated with inotuzumab
ozogamicin: expert panel review. Bone Marrow Transplant 2018;53:449-456.
2 Giglio F, Xue E, Greco R, et al. Defibrotide Prophylaxis of Sinusoidal Obstruction Syndrome in Adults Treated With
Inotuzumab Ozogamicin Prior to Hematopoietic Stem Cell Transplantation. Front Oncol 2022;12:933317.
Continued
Note: For more information regarding the categories and definitions used for the NCCN Evidence Blocks™, see page EB-1.
All recommendations are category 2A unless otherwise indicated. ALL-C
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Acute Lymphoblastic Leukemia Table of Contents
Discussion
NCCN Evidence BlocksTM
SUPPORTIVE CARE
Asparaginase Toxicity Management3
• Asparaginase should only be used in specialized centers and patients • Anaphylaxis or other allergic reactions of Grade 3–4 severity (CTCAE v5.0)c
should be closely monitored in the period during and after infusion for merit permanent discontinuation of the type of asparaginase that caused the
allergic response. reaction.
• There are three formulations of asparaginase in clinical use: 1) PEG, 2) • For Grade 1 reactions and Grade 2 reactions (rash, flushing, urticaria, and
calaspargase pegol-mknl (Cal-PEGa) (in patients aged 1 to ≤21 years), and drug fever ≥38°C) without bronchospasm, hypotension, edema, or need
3) asparaginase Erwinia chrysanthemi (recombinant)-rywn (ERW-rywn).b for parenteral intervention, the asparaginase that caused the reaction may
PEG is a common component of therapy for children and AYAs with ALL. be continued, with consideration for anti-allergy premedication (such as
The preferred route for administration for both PEG and Cal-PEG is IV. hydrocortisone, famotidine or ranitidine, diphenhydramine or cetirizine, and
The toxicity profile of these asparaginase products presents significant acetaminophen).
challenges in clinical management. The following guidelines are intended • Measures that can be considered for preventing or limiting severity of
to help providers address these challenges. infusion reactions or hypersensitivity reactions include slowing the infusion
• The Panel recommends that the dose of PEG or Cal-PEG should be capped to ≥ 2 hours, infusing normal saline concurrently, and use of premedications
at one vial (3750 IU). provided above.
• All toxicity grades refer to CTCAE v5.0.c • If anti-allergy premedication is used prior to PEG or ERW-rywn
• For ERW-rywn, a phase 2/3 study supports a new IM dosing schedule of 25 administration, TDM using commercially available asparaginase activity
mg/m2 Monday/Wednesday, 50 mg/m2 Friday based on positive risk:benefit assays is highly recommended, since premedication may “mask” the
ratio.4 systemic allergic reactions that can indicate the development of neutralizing
• Consider anticoagulation prophylaxis if no contraindications.5 antibodies.6
TDM for asparaginase therapy using the serum asparaginase activity (SAA)
Hypersensitivity, Allergy, and Anaphylaxis is available as a CLIA-certified test with a turnaround time of less than 1
There is a significant incidence of hypersensitivity reactions with week, allowing real-time decision-making and therapeutic adjustments.
asparaginase products in some regimens. Of particular concern are Grade Generally accepted SAA assay targets include a minimum trough of
2 or higher systemic allergic reactions, urticaria, or anaphylaxis, because greater than or equal to 0.1 IU/mL. However, data indicate that when SAA
these episodes can be (but are not necessarily) associated with neutralizing levels fall below 0.4 IU/mL, asparagine is no longer completely depleted,
antibodies and lack of efficacy. Therapeutic drug monitoring (TDM) can and begins to rebound, suggesting an optimal trough of ≥ 0.4 IU/mL. The
be considered for patients with low-grade systemic reactions to confirm optimal timing for PEG trough is 14 days, for Cal-PEG trough is 21 days,
efficacy and allow continuation of asparaginase. Patients who experience a and for ERW-rywn trough is 48 hours.
grade 1 or 2 reaction but demonstrate adequate asparaginase activity can be
considered for rechallenge.
• ERW-rywn should be used as a second-line agent in patients who have
developed a systemic allergic reaction or anaphylaxis due to PEG
hypersensitivity.
3 For more detailed information, refer to Stock W, Douer D, DeAngelo DJ, et al. Prevention
and management of asparaginase/pegasparaginase-associated toxicities in adults and older
adolescents: recommendations of an expert panel. Leuk Lymphoma 2011:52:2237-2253.
4 Maese LD, Loh ML, Choi MR, et al. Recombinant erwinia asparaginase (JZP458) in acute

a In lymphoblastic leukemia: Results from the phase 2/3 AALL1931 study. Blood 2023;141:704-712.
the setting of AYA/Adult ALL, Cal-PEG is substituted for PEG in patients aged 15 to 5 Hu Z, Persaud Y, Ahuja S. A systematic review and meta-analysis of the effectiveness of
≤21 years for more sustained asparaginase activity. primary thromboprophylaxis in acute lymphoblastic leukemia during early-phase therapy
b ERW-rywn is for patients who had an allergic reaction to E. coli-derived asparaginase.
c National Institutes of Health; National Cancer Institute. Common Terminology Criteria including asparaginase or its prolonged form. Crit Rev Oncol Hematol 2024;197:104347.
6 Bleyer A, Asselin BL, Koontz SE, Hunger SP. Clinical application of asparaginase activity levels
for Adverse Events (CTCAE) version 5.0 2017. Available at: [Link] following treatment with pegaspargase. Pediatr Blood Cancer 2015;62:1102-1105.
protocoldevelopment/electronic_applications/[Link]
Continued
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All recommendations are category 2A unless otherwise indicated. ALL-C
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Acute Lymphoblastic Leukemia Table of Contents
Discussion
NCCN Evidence BlocksTM
SUPPORTIVE CARE
Asparaginase Toxicity Management (continued)
Pancreatitis
• Permanently discontinue asparaginase in the presence of Grade 3 or 4 pancreatitis. In the case of Grade 2 pancreatitis (enzyme elevation or
radiologic findings only), asparaginase should be held until these findings normalize and then resume.

Non-CNS Hemorrhage
• For Grade 2 or greater hemorrhage, hold asparaginase until Grade 1, then resume. Consider coagulation factor replacement. Do not hold for
asymptomatic abnormal laboratory findings.

Non-CNS Thromboembolism
• For Grade 2 or greater thromboembolic event, hold asparaginase and treat with appropriate antithrombotic therapy. Upon resolution of
symptoms and antithrombotic therapy stable, consider resuming asparaginase.
• Consider checking antithrombin (AT) III levels if administering heparin.

Intracranial Hemorrhage
• Discontinue asparaginase. Consider coagulation factor replacement. For Grade 3 or less, if symptoms/signs fully resolve, consider resuming
asparaginase at lower doses and/or longer intervals between doses. For Grade 4, permanently discontinue asparaginase.
• Perform magnetic resonance angiography (MRA)/magnetic resonance venography (MRV) to rule out bleeding associated with venous sinus
thrombosis.

Cerebral Thrombosis, Ischemia, or Stroke

• Discontinue asparaginase. Consider antithrombotic therapy. For Grade 3 or less, if symptoms/signs fully resolve, consider resuming
asparaginase at lower doses and/or longer intervals between doses. For Grade 4, permanently discontinue asparaginase.

Hyperglycemia
• Treat hyperglycemia with insulin as indicated. For Grade 3 or higher, hold asparaginase and steroids until blood glucose has been regulated
with insulin, then resume.

Hypertriglyceridemia
• Treat hypertriglyceridemia as indicated. For Grade 4, hold asparaginase until normalized, then resume.

Hepatotoxicity (elevation in bilirubin, aspartate aminotransferase [AST], alanine aminotransferase [ALT])

• For direct bilirubin ≤3.0 mg/dL, continue asparaginase. For direct bilirubin 3.1–5.0 mg/dL, hold asparaginase until <2.0 mg/dL, then resume.
For direct bilirubin >5.0, either discontinue asparaginase or hold asparaginase until <2.0 mg/dL, then resume with consideration for dose
reduction and close monitoring.
• For Grade 3 AST or ALT elevation, hold until Grade 1, then resume. For Grade 4 AST or ALT elevation, hold until Grade 1. If resolution to
Grade 1 takes 1 week or less, then resume. Otherwise, either discontinue or resume with very close monitoring.

Note: For more information regarding the categories and definitions used for the NCCN Evidence Blocks™, see page EB-1.
All recommendations are category 2A unless otherwise indicated. ALL-C
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Acute Lymphoblastic Leukemia Table of Contents
Discussion
NCCN Evidence BlocksTM
PRINCIPLES OF SYSTEMIC THERAPY
GENERAL CONSIDERATIONS
• The ALL Panel considers AYA to be within the age range of 15–39 years. However, this age range is not a firm reference point because some
of the recommended regimens have not been comprehensively tested across all ages.
• For infection risk, monitoring, and prophylaxis recommendations for immune and targeted therapies, see INF-A in the NCCN Guidelines for
Prevention and Treatment of Cancer-Related Infections.
• For toxicity management for blinatumomab, inotuzumab ozogamicin, brexucabtagene autoleucel, and tisagenlecleucel, see Supportive Care
ALL C 2 of 4.
• Although there are limited data, the Panel recommends waiting at least 4 weeks from the completion of inotuzumab ozogamicin
monotherapy and the start of conditioning therapy for allogeneic HCT to minimize risk of sinusoidal obstruction syndrome (SOS). SOS
occurred less frequently when fewer alkylators were used as part of the conditioning regimen. Kantarjian H, et al. Cancer 2013;119:2728-2736
• Leucovorin is always used in combination with high-dose methotrexate.
• Mesna is always used in combination with ifosfamide and used in combination with cyclophosphamide as clinically indicated.

Mutation Profile Principles

TREATMENT OPTIONS BASED ON BCR::ABL1 MUTATION PROFILE
Therapy Contraindicated Mutations
Bosutinib T315I, V299L, G250E, or F317L
Dasatinib T315I/A, F317L/V/I/C, or V299L
Nilotinib T315I, Y253H, E255K/V, or F359V/C/I or G250E
Ponatinib None

• Mutations contraindicated for imatinib are too numerous to include. There are compound mutations that can cause resistance to ponatinib,
but those are uncommon following treatment with bosutinib, dasatinib, or nilotinib.
• Nilotinib may be preferred over bosutinib in patients with F317L mutation.
• Ponatinib has activity against T315I mutations and is effective in treating patients with resistant or progressive disease (PD) on multiple
TKIs. However, it is associated with a high frequency of serious vascular events (eg, strokes, heart attacks, tissue ischemia). See package
insert for more details. The PhALLCON study suggests improved MRD responses with ponatinib compared to imatinib. Jabbour E, et al. J
Clin Oncol 2023;41(Suppl):Abstract 398868.
• For patients receiving mercaptopurine (6-MP), consider testing for TPMT gene polymorphisms, particularly in patients who develop severe
neutropenia after starting 6-MP. Testing for both TPMT and NUDT15 variant status should be considered, especially for patients of East Asian
descent. Relling MV, et al. Clin Pharmacol Ther 2019;105:1095-1105.

Continued

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All recommendations are category 2A unless otherwise indicated. ALL-D
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Acute Lymphoblastic Leukemia Table of Contents
Discussion
NCCN Evidence BlocksTM
PRINCIPLES OF SYSTEMIC THERAPY
GENERAL CONSIDERATIONS
Maintenance Principles
• Ph+ B-ALL
The optimal duration of TKI maintenance is unknown.
◊ The recommended duration of TKI during maintenance chemotherapy is at least until completion of maintenance chemotherapy.
◊ TKI should be continued for at least 2 years post-HCT.
• Dose modifications for antimetabolites in maintenance should be consistent with the chosen treatment regimen. It may be necessary to
reduce dose/eliminate antimetabolite in the setting of myelosuppression and/or hepatotoxicity.

CNS Prophylaxis Principles

• All regimens include CNS prophylaxis with systemic therapy (eg, methotrexate, cytarabine) and/or IT therapy (eg, IT methotrexate, IT
cytarabine; triple IT therapy with methotrexate, cytarabine, corticosteroid).
• Refer to specific references/protocols, and/or chemotherapy order templates (where available) for appropriate timing in phases of treatment.

Adults ≥65 Years or Adults with Substantial Comorbidities

• Adults who are ≥65 years benefit from therapy, despite higher treatment-related morbidity and mortality.
• Chronological age is a poor surrogate for fitness of therapy. Patients should be evaluated on an individual basis, including for the following
factors: end-organ reserve, end-organ dysfunction, and performance status.
• Careful assessment of comorbid conditions, performance status, and ability to attend to activities of daily living (ADLs) and instrumental
ADLs (IADLs) is important when deciding treatment intensity.
• For tools to aid optimal assessment and care of adults ≥65 years with cancer, see the NCCN Guidelines for Older Adult Oncology.
• Dose reduction of pegylated asparaginase (1000 IU/m2), anthracycline (50% dose), and/or other myelosuppressive agents may be warranted.
• The categorization of regimens as low, moderate, or high intensity is based on two factors: 1) the presence or absence of myelosuppressive
cytotoxic agents; and 2) the relative dose intensity of the included agents.
• All regimens should include CNS prophylaxis, antimicrobial prophylaxis, and growth factor support.
• For appropriate fit individuals achieving remission, consideration of allogeneic HCT may be appropriate.

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Acute Lymphoblastic Leukemia Table of Contents
Discussion
NCCN Evidence BlocksTM
PRINCIPLES OF SYSTEMIC THERAPY
Ph-POSITIVE B-ALL INDUCTION REGIMENSa,b

AYA Patients & Adults <65 years without Substantial Comorbidities: Adults ≥65 Years or Adults with Substantial Comorbidities:
Frontline Frontline & Relapsed/Refractory
Other Recommended Regimens Other Recommended Regimens
• TKIc in combination with: • Low intensity
Blinatumomabd,1-3 TKIc in combination with:
CALGB 107014,5 ◊ Corticosteroid7,8,22-24
Corticosteroide,6-8 ◊ Vincristine + dexamethasone15,25,26
Dose-adjusted HyperCVAD9-13
Vincristine + dexamethasone14,15 • Moderate intensity
Other multiagent therapy16-19 TKIc in combination with:
EsPhALL (only for AYA)18,20,21 ◊ CALGB 107014,5
◊ EWALL27

• High intensity
TKIc + Dose-adjusted HyperCVAD9,13

• Immunotherapy (Low intensity)

TKIc + Blinatumomabd,1-3

See Evidence Blocks on ALL-D (EB-1)

Regimen components on ALL-D 4 of 28

References on ALL-D 8 of 28

a There are data to support the benefit of rituximab in addition to chemotherapy (excluding immunotherapy) for AYA patients and adults aged <65 years without
substantial comorbidities with CD20-positive disease (especially in patients aged <60 years).
b An FDA-approved biosimilar is an appropriate substitute for rituximab.
c TKI options include (in alphabetical order): bosutinib, dasatinib, imatinib, nilotinib, or ponatinib. Not all TKIs have been directly studied within the context of each
specific regimen and the Panel notes that there are limited data for bosutinib in Ph+ ALL. Use of a specific TKI should account for anticipated/prior TKI intolerance,
dose used, BCR::ABL1 mutations, and disease-related features. Imatinib use in first line should be restricted to patients who cannot tolerate broader acting TKIs.
Jabbour E, et al. J Clin Oncol 2023;41:41(Suppl):Abstract 398868. For contraindicated mutations, see ALL-D 1 of 28.
d Prior to blinatumomab initiation, cytoreduce with TKI plus corticosteroid to a peripheral WBC count of <10 x 109/L. Foà R, et al. N Engl J Med 2020;383:1613-1623.
e TKI + corticosteroid as induction should be followed by TKI + multiagent therapy or TKI + blinatumomab consolidation.

Note: For more information regarding the categories and definitions used for the NCCN Evidence Blocks™, see page EB-1.
All recommendations are category 2A unless otherwise indicated. ALL-D
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NCCN Guidelines Version 2.2024 5

4
E = Efficacy of Regimen/Agent
S = Safety of Regimen/Agent NCCN Guidelines Index
Acute Lymphoblastic Leukemia 3
2
Q = Quality of Evidence
C = Consistency of Evidence Table of Contents
A = Affordability of Regimen/Agent
Discussion
NCCN Evidence BlocksTM
1
E S Q C A

EVIDENCE BLOCKS FOR Ph-POSITIVE B-ALL INDUCTION REGIMENS EVIDENCE BLOCKS FOR FRONTLINE AND RELAPSED/
Adults <65 Years REFRACTORY REGIMENS FOR ADULTS ≥65 YEARS OR ADULTS
AYA Patients WITH SUBSTANTIAL COMORBIDITIES
without
without Substantial
Substantial Regimens for Ph-Positive B-ALL According to Intensity
Comorbidities:
Comorbidities: Other Recommended Regimens
Frontline
Frontline
Low Intensity
Other Recommended Regimens
Corticosteroid + TKI†
Blinatumomab + TKI†
Vincristine/dexamethasone + TKI†
CALGB 10701 + TKI†
Moderate Intensity
Corticosteroid + TKI†
CALGB 10701 + TKI†
Dose-adjusted hyperCVAD + TKI†
EWALL + TKI†
Vincristine/dexamethasone + TKI† High Intensity
Other multiagent therapy + TKI† TKI† + dose-adjusted hyperCVAD

EsPhALL + TKI† — Immunotherapy

Blinatumumab + TKI†

†TKI options include (in alphabetical order): bosutinib, dasatinib, imatinib, nilotinib, or ponatinib. Not all TKIs have been directly studied within the context of each specific regimen and the panel notes that there
are limited data for bosutinib in Ph+ ALL. Use of a specific TKI should account for anticipated/prior TKI intolerance, dose used, BCR::ABL1 mutations and disease-related features. Imatinib use in first line
should be restricted to patients who cannot tolerate broader acting TKIs. Jabbour E, et al. J Clin Oncol 2023;41, no. 36_suppl. 398868. For contraindicated mutations, see ALL-D 1 of 28.

Note: For more information regarding the categories and definitions used for the NCCN Evidence Blocks™, see page EB-1.
ALL-D
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® ® ®
EB-1
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Acute Lymphoblastic Leukemia Table of Contents
Discussion
NCCN Evidence BlocksTM
PRINCIPLES OF SYSTEMIC THERAPY
Ph-POSITIVE B-ALL INDUCTION COMPONENTSa,b,f,g,h,i

AYA Patients without Substantial Comorbidities: Adults <65 years without Adults ≥65 Years or Adults with
Frontline Substantial Comorbidities: Substantial Comorbidities: Frontline
Frontline & Relapsed/Refractory
Other Recommended Regimens
• Blinatumomabd + TKIc,1-3
• CALGB 107014,5 + TKIc: Cyclophosphamide, daunorubicin, dexamethasone, vincristine
• Corticosteroide + TKIc,6-8 • Corticosteroid + TKIc,7,8,22-24
• EsPhALL19,20,21 + TKIc: Cyclophosphamide, cytarabine, • EWALL27 + TKIc: Cyclophosphamide,
dexamethasone, doxorubicin, mercaptopurine, dexamethasone, vincristine
pegaspargase, thioguanine, vincristine
• Dose-adjusted HyperCVAD9-13 + TKIc: Hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone, alternating with
high-dose methotrexate, dose-adjusted cytarabine
• Other multiagent therapy16-19 + TKIc: Cyclophosphamide, daunorubicin, prednisone, vincristine
• Vincristine + dexamethasone + TKIc,14,15,25,26

References on ALL-D 8 of 28
a There are data to support the benefit of rituximab in addition to chemotherapy e TKI + corticosteroid as induction should be followed by TKI + multiagent therapy
(excluding immunotherapy) for AYA patients and adults aged <65 years without or TKI + blinatumomab consolidation.
substantial comorbidities with CD20-positive disease (especially in patients aged f All regimens include CNS prophylaxis with systemic therapy (eg, methotrexate,
<60 years). cytarabine) and/or IT therapy (eg, IT methotrexate, IT cytarabine; triple IT
b An FDA-approved biosimilar is an appropriate substitute for rituximab. therapy with methotrexate, cytarabine, corticosteroid).
c TKI options include (in alphabetical order): bosutinib, dasatinib, imatinib, g For full details on all phases of therapy, including induction IA; induction IB; CNS
nilotinib, or ponatinib. Not all TKIs have been directly studied within the context phase; early intensification; delayed intensification; continuation; consolidation
of each specific regimen and the Panel notes that there are limited data for IA, IB, IC, and II; reinduction I and II; and interim maintenance I and II, see
bosutinib in Ph+ ALL. Use of a specific TKI should account for anticipated/prior attached references or chemotherapy order templates, where available.
TKI intolerance, dose used, BCR::ABL1 mutations, and disease-related features. h For patients who develop hypersensitivity to Escherichia coli-derived
Imatinib use in first line should be restricted to patients who cannot tolerate asparaginase, ERW-rywn should be substituted as a component of the multi-
broader acting TKIs. Jabbour E, et al. J Clin Oncol 2023;41(Suppl):Abstract agent therapeutic regimen to complete the full treatment course.
398868. For contraindicated mutations, see ALL-D 1 of 28. i PEG is substituted with Cal-PEG, an asparagine-specific enzyme, in AYA patients
d Prior to blinatumomab initiation, cytoreduce with TKI plus corticosteroid aged 15 to ≤21 years and adults aged 18 to ≤21 years for more sustained
to a peripheral WBC count of <10 x 109/L. Foà R, et al. N Engl J Med asparaginase activity. Silverman LB, et al. Blood 2016;128:175; Angiolillo AL, et
2020;383:1613-1623. al. J Clin Oncol 2014;32:3874-3882.

Note: For more information regarding the categories and definitions used for the NCCN Evidence Blocks™, see page EB-1.
All recommendations are category 2A unless otherwise indicated. ALL-D
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Acute Lymphoblastic Leukemia Table of Contents
Discussion
NCCN Evidence BlocksTM
PRINCIPLES OF SYSTEMIC THERAPY
Ph-POSITIVE B-ALL CONSOLIDATION REGIMENSa,b

Persistent/Rising MRD MRD Negative

• Blinatumomab ± TKIc,j,k,1-3 • Blinatumomab + TKIc,j,k,1-3
• Multiagent therapyl + TKIc,16-19 (see ALL-D 6 of 28) • Multiagent therapyl + TKIc,16-19 (see ALL-D 6 of 28)
• Inotuzumab ozogamicinm ± TKIc,j,28 • TKIc,n,6-8,22-24
• TKIc,n,6-8,22-24

Regimen components on ALL-D 6 of 28

See Evidence Blocks on ALL-D (EB-2)
References on ALL-D 8 of 28
a There are data to support the benefit of rituximab in addition to chemotherapy (excluding immunotherapy) for AYA patients and adults aged <65 years without
substantial comorbidities with CD20-positive disease (especially in patients aged <60 years).
b An FDA-approved biosimilar is an appropriate substitute for rituximab.
c TKI options include (in alphabetical order): bosutinib, dasatinib, imatinib, nilotinib, or ponatinib. Not all TKIs have been directly studied within the context of each
specific regimen and the Panel notes that there are limited data for bosutinib in Ph+ ALL. Use of a specific TKI should account for anticipated/prior TKI intolerance,
dose used, BCR::ABL1 mutations, and disease-related features. Imatinib use in first line should be restricted to patients who cannot tolerate broader acting TKIs.
Jabbour E, et al. J Clin Oncol 2023;41(Suppl):Abstract 398868. For contraindicated mutations, see ALL-D 1 of 28.
j Blinatumomab + TKI is preferred in consolidation regardless of MRD status for those who have not previously received blinatumomab.
k Blinatumomab should be incorporated into frontline therapy as a post-remission approach based on data from ECOG1910. Gokbuget N, et al. Leuk Lymphoma
2020;61:2665-2673. Topp MS, et al. J Clin Oncol 2011;29:2493-2498. Litzow MR, et al. Blood 2022;140(Suppl):Abstract LBA-1.
l Refer to induction regimen references, consolidation components on ALL-D 6 of 28, or chemotherapy order templates (where available), for components if not listed.
m Inotuzumab ozogamicin can be incorporated into frontline therapy as a post-remission approach. Jabbour E, et al. Blood 2024;143:417-421.
n TKI monotherapy is seldom effective as induction; however, it may be considered as consolidation/maintenance in those unfit for additional therapies.

Note: For more information regarding the categories and definitions used for the NCCN Evidence Blocks™, see page EB-1.
All recommendations are category 2A unless otherwise indicated. ALL-D
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NCCN Guidelines Version 2.2024 5

4
E = Efficacy of Regimen/Agent
S = Safety of Regimen/Agent NCCN Guidelines Index
Acute Lymphoblastic Leukemia 3
2
Q = Quality of Evidence
C = Consistency of Evidence Table of Contents
A = Affordability of Regimen/Agent
Discussion
NCCN Evidence BlocksTM
1
E S Q C A

EVIDENCE BLOCKS FOR Ph-POSITIVE B-ALL CONSOLIDATION REGIMENS

Persistent/ Rising MRD MRD Negative
Other Recommended Regimens
Blinatumomab —

Blinatumomab + TKI†

Inotuzumab ozogamicin —

Inotuzumab ozogamicin + TKI† —

TKI†

†TKI options include (in alphabetical order): bosutinib, dasatinib, imatinib, nilotinib, or ponatinib. Not all TKIs have been directly studied within the context of each specific regimen and the panel notes that there
are limited data for bosutinib in Ph+ ALL. Use of a specific TKI should account for anticipated/prior TKI intolerance, dose used, BCR::ABL1 mutations and disease-related features. Imatinib use in first line
should be restricted to patients who cannot tolerate broader acting TKIs. Jabbour E, et al. J Clin Oncol 2023;41, no. 36_suppl. 398868. For contraindicated mutations, see ALL-D 1 of 28.

Note: For more information regarding the categories and definitions used for the NCCN Evidence Blocks™, see page EB-1. ALL-D
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® ® ®
EB-2
The NCCN Evidence Blocks™ are subject to certain U.S. and foreign patents. Each approved use of the design of the NCCN Evidence Blocks™ requires the written approval of NCCN. Visit [Link]/patents for current list of applicable patents.
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Acute Lymphoblastic Leukemia Table of Contents
Discussion
NCCN Evidence BlocksTM
PRINCIPLES OF SYSTEMIC THERAPY
Ph-POSITIVE B-ALL CONSOLIDATION COMPONENTSa,b,f,g,h,i

AYA Patients without Substantial Adults <65 years without Substantial Adults ≥65 Years or Adults with
Comorbidities Comorbidities Substantial Comorbidities
4,5 c
CALGB 10701 + TKI : Cytarabine, etoposide
EsPhALL18,20,21 + TKIc: EWALL27 + TKIc: Cytarabine, high-
Cyclophosphamide, cytarabine, dose methotrexate, pegaspargase
daunorubicin, dexamethasone,
etoposide, ifosfamide, high-dose
methotrexate, pegaspargase,
vincristine
Dose-adjusted HyperCVAD9-13 + TKIc: Hyperfractionated cyclophosphamide, vincristine, doxorubicin,
dexamethasone, alternating with high-dose methotrexate, dose-adjusted cytarabine
Other multiagent therapy16-19 + TKIc: Cytarabine, high-dose methotrexate,
methylprednisolone
Vincristine + dexamethasone + TKI14: Cyclophosphamide, cytarabine,
dexamethasone, doxorubicin, high-dose methotrexate, vincristine

References on ALL-D 8 of 28

a There are data to support the benefit of rituximab in addition to chemotherapy (excluding immunotherapy) for AYA patients and adults aged <65 years without
substantial comorbidities with CD20-positive disease (especially in patients aged <60 years).
b An FDA-approved biosimilar is an appropriate substitute for rituximab.
c TKI options include (in alphabetical order): bosutinib, dasatinib, imatinib, nilotinib, or ponatinib. Not all TKIs have been directly studied within the context of each
specific regimen and the Panel notes that there are limited data for bosutinib in Ph+ ALL. Use of a specific TKI should account for anticipated/prior TKI intolerance,
dose used, BCR::ABL1 mutations, and disease-related features. Imatinib use in first line should be restricted to patients who cannot tolerate broader acting TKIs.
Jabbour E, et al. J Clin Oncol 2023;41(Suppl):Abstract 398868. For contraindicated mutations, see ALL-D 1 of 28.
f All regimens include CNS prophylaxis with systemic therapy (eg, methotrexate, cytarabine) and/or IT therapy (eg, IT methotrexate, IT cytarabine; triple IT therapy with
methotrexate, cytarabine, corticosteroid).
g For full details on all phases of therapy, including induction IA; induction IB; CNS phase; early intensification; delayed intensification; continuation; consolidation IA, IB,
IC, and II; reinduction I and II; and interim maintenance I and II, see attached references or chemotherapy order templates, where available.
h For patients who develop hypersensitivity to E. coli-derived asparaginase, ERW-rywn should be substituted as a component of the multi-agent therapeutic regimen to
complete the full treatment course.
i PEG is substituted with Cal-PEG, an asparagine-specific enzyme, in AYA patients aged 15 to ≤21 years and adults aged 18 to ≤21 years for more sustained
asparaginase activity. Silverman LB, et al. Blood 2016;128:175; Angiolillo AL, et al. J Clin Oncol 2014;32:3874-3882.

Note: For more information regarding the categories and definitions used for the NCCN Evidence Blocks™, see page EB-1.
All recommendations are category 2A unless otherwise indicated. ALL-D
Version 2.2024, 07/19/24 © 2024 National Comprehensive Cancer Network (NCCN ), All rights reserved. NCCN Evidence Blocks™, NCCN Guidelines , and this illustration may not be reproduced in any form without the express written permission of NCCN.
® ® ®
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The NCCN Evidence Blocks™ are subject to certain U.S. and foreign patents. Each approved use of the design of the NCCN Evidence Blocks™ requires the written approval of NCCN. Visit [Link]/patents for current list of applicable patents.
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Acute Lymphoblastic Leukemia Table of Contents
Discussion
NCCN Evidence BlocksTM
PRINCIPLES OF SYSTEMIC THERAPY
Ph-POSITIVE B-ALL MAINTENANCE THERAPYa,o

If MRD Negative
• POMP (mercaptopurine, vincristine, methotrexate, prednisone) + TKIc
• Vincristine + prednisone + TKIc
• TKIc,n monotherapy (for patients who previously received blinatumomab + TKI)

See Evidence Blocks on ALL-D (EB-3)

a There are data to support the benefit of rituximab in addition to chemotherapy (excluding immunotherapy) for AYA patients and adults aged <65 years without
substantial comorbidities with CD20-positive disease (especially in patients aged <60 years).
c TKI options include (in alphabetical order): bosutinib, dasatinib, imatinib, nilotinib, or ponatinib. Not all TKIs have been directly studied within the context of each
specific regimen and the Panel notes that there are limited data for bosutinib in Ph+ ALL. Use of a specific TKI should account for anticipated/prior TKI intolerance,
dose used, BCR::ABL1 mutations, and disease-related features. Imatinib use in first line should be restricted to patients who cannot tolerate broader acting TKIs.
Jabbour E, et al. J Clin Oncol 2023;41(Suppl):Abstract 398868. For contraindicated mutations, see ALL-D 1 of 28.
n TKI monotherapy is seldom effective as induction; however, it may be considered as consolidation/maintenance in those unfit for additional therapies.
o Refer to induction regimen references or chemotherapy order templates (where available), for components. Include IT chemotherapy per protocol, or as clinically
indicated.

Note: For more information regarding the categories and definitions used for the NCCN Evidence Blocks™, see page EB-1.
All recommendations are category 2A unless otherwise indicated. ALL-D
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NCCN Guidelines Version 2.2024 5

4
E = Efficacy of Regimen/Agent
S = Safety of Regimen/Agent NCCN Guidelines Index
Acute Lymphoblastic Leukemia 3
2
Q = Quality of Evidence
C = Consistency of Evidence Table of Contents
A = Affordability of Regimen/Agent
Discussion
NCCN Evidence BlocksTM
1
E S Q C A

EVIDENCE BLOCKS FOR Ph-POSITIVE B-ALL MAINTENANCE REGIMENS

If MRD Negative
POMP + TKI†

Vincristine/prednisone + TKI†
TKI† monotherapy (for patients who previously
received blinatumomab + TKI)

†TKI options include (in alphabetical order): bosutinib, dasatinib, imatinib, nilotinib, or ponatinib. Not all TKIs have been directly studied within the context of each specific regimen and the panel notes that there
are limited data for bosutinib in Ph+ ALL. Use of a specific TKI should account for anticipated/prior TKI intolerance, dose used, BCR::ABL1 mutations and disease-related features. Imatinib use in first line
should be restricted to patients who cannot tolerate broader acting TKIs. Jabbour E, et al. J Clin Oncol 2023;41, no. 36_suppl. 398868. For contraindicated mutations, see ALL-D 1 of 28.

Note: For more information regarding the categories and definitions used for the NCCN Evidence Blocks™, see page EB-1. ALL-D
Version 2.2024, 07/19/24 © 2024 National Comprehensive Cancer Network (NCCN ), All rights reserved. NCCN Evidence Blocks™, NCCN Guidelines , and this illustration may not be reproduced in any form without the express written permission of NCCN.
® ® ®
EB-3
The NCCN Evidence Blocks™ are subject to certain U.S. and foreign patents. Each approved use of the design of the NCCN Evidence Blocks™ requires the written approval of NCCN. Visit [Link]/patents for current list of applicable patents.
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Acute Lymphoblastic Leukemia Table of Contents
Discussion
NCCN Evidence BlocksTM
PRINCIPLES OF SYSTEMIC THERAPY
Ph-POSITIVE B-ALL REFERENCES
1 Foa
 R, Bassan R, Vitale A, et al. Dasatinib-blinatumomab for Ph-positive acute 11 Thomas
 DA, Kantarjian HM, Cortes J, et al. Outcome after frontline therapy
lymphoblastic leukemia in adults. N Engl J Med 2020;383:1613-1623. with the hyper-CVAD and imatinib mesylate regimen for adults with de novo or
2 Gökbuget
 N, Zugmaier G, Dombret H, et al. Curative outcomes following minimally treated Philadelphia chromosome (Ph) positive acute lymphoblastic
blinatumomab in adults with minimal residual disease B-cell precursor acute leukemia (ALL) [abstract]. Blood 2008;112(Suppl 11):Abstract 2931.
lymphoblastic leukemia. Leuk Lymphoma 2020;61:2665-2673. 12 Thomas DA, O'Brien SM, Faderl S, et al. Long-term outcome after hyper-CVAD
3 Jabbour
 E, Short NJ, Jain N, et al. Ponatinib and blinatumomab for Philadelphia and imatinib (IM) for de novo or minimally treated Philadelphia chromosome-
chromosome-positive acute lymphoblastic leukaemia: a US, single-centre, single- positive acute lymphoblastic leukemia (Ph-ALL) [abstract]. J Clin Oncol
arm, phase 2 trial. Lancet Haematol 2023;10:e24-e34. 2010;28:Abstract 6506.
4 Wieduwilt
 MJ, Yin J, Wetzler M, et al. A phase II study of dasatinib and 13 Jabbour EJ, Kantarjian H, Ravandi F, et al. Combination of hyper-CVAD with
dexamethasone as primary therapy followed by transplantation for adults with ponatinib as first-line therapy for patients with Philadelphia chromosome-positive
newly diagnosed Ph/BCR-ABL1-positive acute lymphoblastic leukemia (Ph+ ALL): acute lymphoblastic leukaemia: a single-centre, phase 2 study. Lancet Oncol
Final results of Alliance/CALGB Study 10701. Blood 2018;132:309. 2015;16:1547-1555.
5 Wieduwilt
 MJ, Yin J, Wetzler M, et al. Dasatinib and dexamethasone followed 14 Chalandon Y, Thomas X, Hayette S, et al. Randomized study of reduced-
by hematopoietic cell transplantation for adults with Ph-positive ALL. Blood Adv intensity chemotherapy combined with imatinib in adults with Ph-positive acute
2021;5:4691-4700. lymphoblastic leukemia. Blood 2015;125:3711-3719.
6 Chiaretti
 S, Ansuinelli M, Vitale A, et al. A multicenter total therapy strategy for 15 Rousselot P, Coude MM, Gokbuget N, et al. Dasatinib and low-intensity
de novo adult Philadelphia chromosome positive acute lymphoblastic leukemia chemotherapy in elderly patients with Philadelphia chromosome-positive ALL.
patients: final results of the GIMEMA LAL1509 protocol. Haematologica Blood 2016;128:774-782.
2021;106:1828-1838. 16 Towatari M, Yanada M, Usui N, et al. Combination of intensive chemotherapy
7 Foa
 R, Vitale A, Vignetti M, et al. Dasatinib as first-line treatment for adult patients and imatinib can rapidly induce high-quality complete remission for a majority of
with Philadelphia chromosome-positive acute lymphoblastic leukemia. Blood patients with newly diagnosed BCR-ABL-positive acute lymphoblastic leukemia.
2011;118:6521-6528. Blood 2004;104:3507-3512.
8 Vignetti
 M, Fazi P, Cimino G, et al. Imatinib plus steroids induces complete 17 Kim DY, Joo YD, Lim SN, et al. Nilotinib combined with multiagent chemotherapy
remissions and prolonged survival in elderly Philadelphia chromosome-positive for newly diagnosed Philadelphia-positive acute lymphoblastic leukemia. Blood
patients with acute lymphoblastic leukemia without additional chemotherapy: 2015;126:746-756.
results of the Gruppo Italiano Malattie Ematologiche dell'Adulto (GIMEMA) 18 Slayton W, Schultz KR, Kairalla JA, et al. Dasatinib plus intensive chemotherapy
LAL0201-B protocol. Blood 2007;109:3676-3678. in children, adolescents, and young adults with Philadelphia chromosome-
9 Ravandi
 F, O'Brien S, Thomas D, et al. First report of phase 2 study of dasatinib positive acute lymphoblastic leukemia: results of Children’s Oncology Group
with hyper-CVAD for the frontline treatment of patients with Philadelphia Trial AALL0622. J Clin Oncol 2018;36:2306-2314.
chromosome-positive (Ph+) acute lymphoblastic leukemia. Blood 2010;116:2070- 19 Yoon JH, Yhim HY, Kwak JY, et al. Minimal residual disease-based effect and
2077. long-term outcome of first-line dasatinib combined with chemotherapy for adult
10 Thomas DA, Faderl S, Cortes J, et al. Treatment of Philadelphia chromosome- Philadelphia chromosome-positive acute lymphoblastic leukemia. Ann Oncol
positive acute lymphocytic leukemia with hyper-CVAD and imatinib mesylate. 2016;27:1081-1088.
Blood 2004;103:4396-4407. 20 Schultz KR, Bowman WP, Aledo A, et al. Improved early event-free survival with
imatinib in Philadelphia chromosome-positive acute lymphoblastic leukemia: a
children's oncology group study. J Clin Oncol 2009;27:5175-5181.

Continued

Note: For more information regarding the categories and definitions used for the NCCN Evidence Blocks™, see page EB-1.
All recommendations are category 2A unless otherwise indicated. ALL-D
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Acute Lymphoblastic Leukemia Table of Contents
Discussion
NCCN Evidence BlocksTM
PRINCIPLES OF SYSTEMIC THERAPY
Ph-POSITIVE B-ALL REFERENCES
21 Biondi A, Schrappe M, De Lorenzo P, et al. Imatinib after induction for treatment
of children and adolescents with Philadelphia-chromosome-positive acute
lymphoblastic leukaemia (EsPhALL): a randomised, open-label, intergroup study.
Lancet Oncol 2012;13:936-945.
22 Ottmann OG, Wassmann B, Pfeiffer H, et al. Imatinib compared with
chemotherapy as front-line treatment of elderly patients with Ph-chromosome
positive acute lymphoblastic leukemia. Cancer 2007;109:2068-2076.
23 Papayannidis C, Fazi P, Piciocchi A, et al. Treating Ph+ acute lymphoblastic
leukemia (ALL) in the elderly: the sequence of two tyrosine kinase inhibitors
(TKI) (nilotinib and imatinib) does not prevent mutations and relapse. Blood
2012;120:Abstract 2601.
24 Martinelli G, Piciocchi A, Papayannidis C, et al. First report of the GIMEMA LAL
1811 prospective study of the combination of steroids with ponatinib as frontline
therapy of elderly or unfit patients with Philadelphia chromosome-positive acute
lymphoblastic leukemia. Blood 2017;139:99.
25 Rousselot P, Coude MM, Huguet F, et al. Dasatinib and low intensity
chemotherapy for first-line treatment in patients with de novo Philadelphia
Positive ALL aged 55 and over: final results of the EWALL-Ph-01 study [abstract].
Blood 2012;120:Abstract 666.
26 Rea D, Legros L, Raffoux E, et al. High-dose imatinib mesylate combined with
vincristine and dexamethasone (DIV regimen) as induction therapy in patients
with resistant Philadelphia-positive acute lymphoblastic leukemia and lymphoid
blast crisis of chronic myeloid leukemia. Leukemia 2006;20:400-403.
27 Ottmann OG, Pfeifer H, Cayuela JM, et al. Nilotinib (Tasigna®) and low intensity
chemotherapy for first-line treatment of elderly patients with BCR-ABL1-positive
acute lymphoblastic leukemia: Final results of a prospective multicenter trial
(EWALL-PH02). Blood 2018;132:Abstract 31.
28 Jabbour
 EJ, Haddad FG, Short NJ, et al. Phase 2 study of inotuzumab
ozogamicin for measurable residual disease in acute lymphoblastic leukemia in
remission. Blood 2024;143:417-421.

Note: For more information regarding the categories and definitions used for the NCCN Evidence Blocks™, see page EB-1.
All recommendations are category 2A unless otherwise indicated. ALL-D
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Acute Lymphoblastic Leukemia Table of Contents
Discussion
NCCN Evidence BlocksTM
PRINCIPLES OF SYSTEMIC THERAPY
Ph-NEGATIVE B-ALL INDUCTION REGIMENSa,b

Only for AYA Patients Only for Adults <65 years For both AYA Patients & Adults Adults ≥65 Years or Adults with Substantial
without Substantial without Substantial <65 years without Substantial Comorbidities: Frontline & Relapsed/
Comorbidities: Comorbidities: Frontline Comorbidities: Frontline Refractory
Frontline
Preferred Regimens Other Recommended Preferred Regimens Other Recommended Regimens
• CALGB 10403c,1 Regimens • ECOG 1910 (preferred for adults • Low Intensity
• DFCI ALL regimen • Dose-adjusted CALGB <65 years)10 Vincristine + prednisone18
based on DFCI 8811 Larson4,5 POMP19: mercaptopurine, vincristine,
Protocol 00-01c,2 • Inotuzumab ozogamicin Other Recommended Regimens methotrexate, prednisone
+ mini-hyperCVD6-8 • ECOG 1910 (for AYA patients)10
Other Recommended • MRC UKALLXII/ECOG • GRAALL-2005c,11 • Moderate Intensity
Regimens 29939 • Dose-adjusted HyperCVAD12-14 ALLOLD07 (PETHEMA-based regimen)20
• PETHEMA ALL-96 (if • USC/MSKCC ALL regimen EWALL21
aged <30 years)c,3 based on CCG-1882 regimen (if GMALL22 + rituximabb for CD20-positive
aged ≥18 to <60 years) c,15,16 disease
• Linker 4-drug regimen (if aged GRAALL23
<60 years)17 Modified DFCI 91-01 protocol24

• High Intensity
CALGB 911125
ECOG 191010
Dose-adjusted HyperCVAD12,26

• Immunotherapy (Moderate intensity)

ALL-INITIAL-127: Inotuzumab ozogamicin/
dexamethasone (category 2B)
ALLIANCE A04170328: Inotuzumab
ozogamicin (category 2B)
Inotuzumab ozogamicin +
mini-hyperCVD6-8
Regimen components on ALL-D 11 of 28
a Thereare data to support the benefit of rituximab in addition to chemotherapy (excluding References on ALL-D 17 of 28
immunotherapy) for AYA patients and adults aged <65 years without substantial b An FDA-approved biosimilar is an appropriate substitute for rituximab.
comorbidities with CD20-positive disease (especially in patients aged <60 years). c Pediatric-inspired regimen.

See Evidence Blocks

Note: For more information regarding the categories and definitions used for the NCCN Evidence Blocks™, see page EB-1.
All recommendations are category 2A unless otherwise indicated.
on ALL-D (EB-4) and ALL-D (EB-5) ALL-D
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® ® ®
10 OF 28
The NCCN Evidence Blocks™ are subject to certain U.S. and foreign patents. Each approved use of the design of the NCCN Evidence Blocks™ requires the written approval of NCCN. Visit [Link]/patents for current list of applicable patents.
Printed by FATIH AKYÜZ on 11/15/2024 1:41:40 PM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 2.2024 5

4
E = Efficacy of Regimen/Agent
S = Safety of Regimen/Agent NCCN Guidelines Index
Acute Lymphoblastic Leukemia 3
2
Q = Quality of Evidence
C = Consistency of Evidence Table of Contents
A = Affordability of Regimen/Agent
Discussion
NCCN Evidence BlocksTM
1
E S Q C A

EVIDENCE BLOCKS FOR Ph-NEGATIVE B-ALL INDUCTION REGIMENS

AYA Patients without Substantial Comorbidities Adult Patients <65 years without Substantial Comorbidities
Preferred Regimens Preferred Regimens
CALGB 10403 regimen ECOG1910

DFCI ALL regimen (based on DFCI Protocol 00-01) ECOG1910/rituximab (for CD20-positive disease)
Other Recommended Regimens Other Recommended Regimens
PETHEMA ALL-96 Dose-adjusted CALGB 8811 Larson

ECOG1910 Inotuzumab ozogamicin/mini-hyperCVD

ECOG1910/rituximab (for CD20-positive disease) MRC UKALLXII/ECOG2993

GRAALL-2005 GRAALL-2005

GRAALL-2005/rituximab (for CD20-positive disease) GRAALL-2005/rituximab (for CD20-positive disease)

Dose-adjusted hyperCVAD Dose-adjusted hyperCVAD

Dose-adjusted hyperCVAD/rituximab (for CD20- Dose-adjusted hyperCVAD/rituximab (for CD20-positive disease)

positive disease)
USC/MSKCC ALL regimen (based on CCG-1882 USC/MSKCC ALL regimen (based on CCG-1882 regimen)
regimen)
Linker 4-drug regimen
Linker 4-drug regimen
Linker 4-drug regimen/rituximab (for CD20-positive Linker 4-drug regimen/rituximab (for CD20-positive disease)
disease)

Note: For more information regarding the categories and definitions used for the NCCN Evidence Blocks™, see page EB-1. ALL-D
Version 2.2024, 07/19/24 © 2024 National Comprehensive Cancer Network (NCCN ), All rights reserved. NCCN Evidence Blocks™, NCCN Guidelines , and this illustration may not be reproduced in any form without the express written permission of NCCN.
® ® ®
EB-4
The NCCN Evidence Blocks™ are subject to certain U.S. and foreign patents. Each approved use of the design of the NCCN Evidence Blocks™ requires the written approval of NCCN. Visit [Link]/patents for current list of applicable patents.
Printed by FATIH AKYÜZ on 11/15/2024 1:41:40 PM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 2.2024 5

4
E = Efficacy of Regimen/Agent
S = Safety of Regimen/Agent NCCN Guidelines Index
Acute Lymphoblastic Leukemia 3
2
Q = Quality of Evidence
C = Consistency of Evidence Table of Contents
A = Affordability of Regimen/Agent
Discussion
NCCN Evidence BlocksTM
1
E S Q C A

EVIDENCE BLOCKS FOR FRONTLINE AND RELAPSED/REFRACTORY REGIMENS

FOR ADULTS ≥65 YEARS OR ADULTS WITH SUBSTANTIAL COMORBIDITIES

Regimens for Ph-Negative B-ALL According to Intensity

Other Recommended Regimens
Low Intensity
Vincristine/prednisone

POMP
Moderate Intensity
ALLOLD07 (PETHEMA-based regimen)

EWALL

GMALL

GMALL + rituximab (for CD20-positive disease)

GRAALL

Modified DFCI 91-01 protocol

High Intensity
CALGB 9111

ECOG 1910

Dose-adjusted hyperCVAD
Immunotherapy (Moderate Intensity)
ALL-INITIAL-1: Inotuzumab ozogamicin/dexamethasone

ALLIANCE A041703: Inotuzumab ozogamicin

Inotuzumab ozogamicin/mini-hyper-CVD

Note: For more information regarding the categories and definitions used for the NCCN Evidence Blocks™, see page EB-1. ALL-D
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® ® ®
EB-5
The NCCN Evidence Blocks™ are subject to certain U.S. and foreign patents. Each approved use of the design of the NCCN Evidence Blocks™ requires the written approval of NCCN. Visit [Link]/patents for current list of applicable patents.
Printed by FATIH AKYÜZ on 11/15/2024 1:41:40 PM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 2.2024 NCCN Guidelines Index

Acute Lymphoblastic Leukemia Table of Contents
Discussion
NCCN Evidence BlocksTM
PRINCIPLES OF SYSTEMIC THERAPY
Ph-NEGATIVE B-ALL INDUCTION COMPONENTSa,b,d,e,f,g

AYA Patients without Substantial Comorbidities: Frontline

Preferred Regimens
• CALGB 10403c,1: Daunorubicin, pegaspargase, prednisone, vincristine
• DFCI ALL regimen based on DFCI Protocol 00-01c,2: Doxorubicin, high-dose methotrexate, pegaspargase, prednisone, vincristine
Other Recommended Regimens
• PETHEMA ALL-96 (if aged <30 years)c,3: Cyclophosphamide, daunorubicin, pegaspargase, prednisone, vincristine
Only for Adults <65 years without Substantial Comorbidities: Frontline
Other Recommended Regimens
• Dose-adjusted CALGB 8811 Larson4,5: Cyclophosphamide, daunorubicin, pegaspargase, prednisone, vincristine
• Inotuzumab ozogamicin + mini-hyperCVD6-8: Hyperfractionated cyclophosphamide, vincristine, dexamethasone, inotuzumab ozogamicin alternating
with cytarabine, methotrexate, inotuzumab ozogamicin
• MRC UKALLXII/ECOG 29939: Cyclophosphamide, cytarabine, daunorubicin, mercaptopurine, pegaspargase, prednisone, vincristine
For both AYA Patients and Adults <65 years without Substantial Comorbidities: Frontline
Preferred Regimens
• ECOG 1910 (preferred for adults <65 years)10: Cyclophosphamide, cytarabine, daunorubicin, dexamethasone, mercaptopurine, pegaspargase,
vincristine, rituximab for CD20-positive disease
Other Recommended Regimens
• ECOG 1910 (for AYA patients)10: Cyclophosphamide, cytarabine, daunorubicin, dexamethasone, mercaptopurine, pegaspargase, vincristine, rituximab
for CD20-positive disease
• GRAALL-2005c,11: Cyclophosphamide, daunorubicin, pegaspargase, prednisone, vincristine, rituximab for CD20-positive disease
• Dose-adjusted HyperCVAD12-14: Hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone, alternating with high-dose
methotrexate, dose-adjusted cytarabine, rituximab for CD20-positive disease
• USC/MSKCC ALL regimen based on CCG-1882 regimen (if aged ≥18 to <60 years)c,15,16: Cyclophosphamide, cytarabine, daunorubicin,
mercaptopurine, pegaspargase, prednisone, vincristine
• Linker 4-drug regimen (if aged <60 years)17: Cyclophosphamide, daunorubicin, pegaspargase, prednisone, vincristine, rituximab for CD20-positive
disease

Footnotes on ALL-D 12A of 28 References on ALL-D 17 of 28

Continued

Note: For more information regarding the categories and definitions used for the NCCN Evidence Blocks™, see page EB-1.
All recommendations are category 2A unless otherwise indicated. ALL-D
Version 2.2024, 07/19/24 © 2024 National Comprehensive Cancer Network (NCCN ), All rights reserved. NCCN Evidence Blocks™, NCCN Guidelines , and this illustration may not be reproduced in any form without the express written permission of NCCN.
® ® ®
11 OF 28
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NCCN Guidelines Version 2.2024 NCCN Guidelines Index

Acute Lymphoblastic Leukemia Table of Contents
Discussion
NCCN Evidence BlocksTM
PRINCIPLES OF SYSTEMIC THERAPY
Ph-NEGATIVE B-ALL INDUCTION COMPONENTSb,d,e,f,g

Adults ≥65 Years or Adults with Substantial Comorbidities: Frontline and Relapsed/Refractory
Other Recommended Regimens
• Low Intensity
Vincristine + prednisone18
POMP19: Mercaptopurine, vincristine, methotrexate, prednisone

• Moderate Intensity
ALLOLD07 (PETHEMA-based regimen)20: Cyclophosphamide, cytarabine, dexamethasone, idarubicin, vincristine
EWALL21: Cyclophosphamide, dexamethasone, vincristine
GMALL22: Cyclophosphamide, cytarabine, dexamethasone, idarubicin, vincristine, rituximab for CD20-positive disease
GRAALL23: Cyclophosphamide, dexamethasone, doxorubicin, vincristine
Modified DFCI 91-01 protocol24: Dexamethasone, doxorubicin, methotrexate, pegaspargase, vincristine

• High Intensity
CALGB 911125: Cyclophosphamide, daunorubicin, prednisone, pegaspargase, vincristine
ECOG 191010: Cyclophosphamide, cytarabine, daunorubicin, dexamethasone, mercaptopurine, pegaspargase (age < 55 years),
vincristine, rituximab for CD20-positive disease
Dose-adjusted HyperCVAD12,26: Hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone, alternating with
high-dose methotrexate, dose-adjusted cytarabine, rituximab for CD20-positive disease

• Immunotherapy (Moderate intensity)

ALL-INITIAL-127: Inotuzumab ozogamicin/Dexamethasone (category 2B)
ALLIANCE A04170328: Inotuzumab ozogamicin (category 2B)
Inotuzumab ozogamicin + mini-hyper-CVD6-8: Hyperfractionated cyclophosphamide, vincristine, dexamethasone, inotuzumab
ozogamicin alternating with cytarabine, methotrexate, inotuzumab ozogamicin

Footnotes on ALL-D 12A of 28 References on ALL-D 17 of 28

Note: For more information regarding the categories and definitions used for the NCCN Evidence Blocks™, see page EB-1.
All recommendations are category 2A unless otherwise indicated. ALL-D
Version 2.2024, 07/19/24 © 2024 National Comprehensive Cancer Network (NCCN ), All rights reserved. NCCN Evidence Blocks™, NCCN Guidelines , and this illustration may not be reproduced in any form without the express written permission of NCCN.
® ® ®
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Acute Lymphoblastic Leukemia Table of Contents
Discussion
NCCN Evidence BlocksTM
PRINCIPLES OF SYSTEMIC THERAPY
Ph-NEGATIVE B-ALL INDUCTION COMPONENTS FOOTNOTES
a There are data to support the benefit of rituximab in addition to chemotherapy (excluding immunotherapy) for AYA patients and adults aged <65 years without
substantial comorbidities with CD20-positive disease (especially in patients aged <60 years).
b An FDA-approved biosimilar is an appropriate substitute for rituximab.
c Pediatric-inspired regimen.
d All regimens include CNS prophylaxis with systemic therapy (eg, methotrexate, cytarabine) and/or IT therapy (eg, IT methotrexate, IT cytarabine; triple IT therapy with
methotrexate, cytarabine, corticosteroid).
e For full details on all phases of therapy, including induction IA; induction IB; CNS phase; early intensification; delayed intensification; continuation; consolidation IA, IB,
IC, and II; reinduction I and II; and interim maintenance I and II, see attached references or chemotherapy order templates, where available.
f For patients who develop hypersensitivity to E. coli-derived asparaginase, ERW-rywn should be substituted as a component of the multi-agent therapeutic regimen to
complete the full treatment course.
g PEG is substituted with Cal-PEG, an asparagine-specific enzyme, in AYA patients aged 15 to ≤21 years and adults aged 18 to ≤21 years for more sustained
asparaginase activity. Silverman LB, et al. Blood 2016;128:175; Angiolillo AL, et al. J Clin Oncol 2014;32:3874-3882.

Note: For more information regarding the categories and definitions used for the NCCN Evidence Blocks™, see page EB-1.
All recommendations are category 2A unless otherwise indicated. ALL-D
Version 2.2024, 07/19/24 © 2024 National Comprehensive Cancer Network (NCCN ), All rights reserved. NCCN Evidence Blocks™, NCCN Guidelines , and this illustration may not be reproduced in any form without the express written permission of NCCN.
® ® ®
12A OF 28
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NCCN Guidelines Version 2.2024 NCCN Guidelines Index

Acute Lymphoblastic Leukemia Table of Contents
Discussion
NCCN Evidence BlocksTM
PRINCIPLES OF SYSTEMIC THERAPY
Ph-NEGATIVE B-ALL CONSOLIDATION REGIMENSa

Persistent/Rising MRD MRD Negative/Unavailable

• Blinatumomabh • Multiagent therapyk alternating with blinatumomabi
• Inotuzumab ozogamicinh,j,29 • Blinatumomabl

See Evidence Blocks on ALL-D (EB-6)

Regimen components on ALL-D 14 of 28

References on ALL-D 17 of 28

a There are data to support the benefit of rituximab in addition to chemotherapy (excluding immunotherapy) for AYA patients and adults aged <65 years without
substantial comorbidities with CD20-positive disease (especially in patients aged <60 years).
h Blinatumomab is preferred for those with persistent or rising MRD who have not previously received blinatumomab.
i Blinatumomab should be incorporated into frontline therapy as a post-remission approach based on data from ECOG1910. Gokbuget N, et al. Leuk Lymphoma
2020;61:2665-2673. Topp MS, et al. J Clin Oncol 2011;29:2493-2498; Litzow MR, et al. Blood 2022;140(Suppl):Abstract LBA-1.
j Inotuzumab ozogamicin can be incorporated into frontline therapy as a post-remission approach. Jabbour E, et al. Blood 2024;143:417-421.
k Refer to induction regimen references, consolidation components (ALL-D 14 of 28), or chemotherapy order templates, where available, for components if not listed.
l Blinatumomab can be considered in patients for whom multiagent therapy is contraindicated.

Note: For more information regarding the categories and definitions used for the NCCN Evidence Blocks™, see page EB-1.
All recommendations are category 2A unless otherwise indicated. ALL-D
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® ® ®
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NCCN Guidelines Version 2.2024 5

4
E = Efficacy of Regimen/Agent
S = Safety of Regimen/Agent NCCN Guidelines Index
Acute Lymphoblastic Leukemia 3
2
Q = Quality of Evidence
C = Consistency of Evidence Table of Contents
A = Affordability of Regimen/Agent
Discussion
NCCN Evidence BlocksTM
1
E S Q C A

EVIDENCE BLOCKS FOR Ph-NEGATIVE B-ALL CONSOLIDATION REGIMENS

Persistent/Rising MRD MRD Negative/Unavailable

Blinatumomab

Inotuzumab ozogamicin —

Multiagent therapy alternating with blinatumomab —

Note: For more information regarding the categories and definitions used for the NCCN Evidence Blocks™, see page EB-1. ALL-D
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® ® ®
EB-6
The NCCN Evidence Blocks™ are subject to certain U.S. and foreign patents. Each approved use of the design of the NCCN Evidence Blocks™ requires the written approval of NCCN. Visit [Link]/patents for current list of applicable patents.
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NCCN Guidelines Version 2.2024 NCCN Guidelines Index

Acute Lymphoblastic Leukemia Table of Contents
Discussion
NCCN Evidence BlocksTM
PRINCIPLES OF SYSTEMIC THERAPY
Ph-NEGATIVE B-ALL CONSOLIDATION COMPONENTS (MRD NEGATIVE/UNAVAILABLE)a,b,d,e,f,g,i
AYA Patients without Substantial Comorbidities
Preferred Regimens
• CALGB 104031: Cyclophosphamide, cytarabine, mercaptopurine, pegaspargase, vincristine
• DFCI ALL regimen based on DFCI Protocol 00-012: Dexamethasone, doxorubicin, mercaptopurine, methotrexate, pegaspargase, vincristine
Other Recommended Regimens
• PETHEMA ALL-96 (if aged <30 years)3: Cyclophosphamide, cytarabine, daunorubicin, dexamethasone, etoposide, mercaptopurine, high-dose
methotrexate, pegaspargase, vincristine
Only for Adults <65 years without Substantial Comorbidities
Other Recommended Regimens
• Dose-adjusted CALGB 8811 Larson4,5: Cyclophosphamide, cytarabine, dexamethasone, doxorubicin, mercaptopurine, pegaspargase, thioguanine,
vincristine
• Inotuzumab ozogamicin + mini-hyper-CVD6-8: Hyperfractionated cyclophosphamide, vincristine, dexamethasone, inotuzumab ozogamicin alternating
with cytarabine, methotrexate, inotuzumab ozogamicin, with or without sequential blinatumomab
• MRC UKALLXII/ECOG 29939: Cyclophosphamide, cytarabine, daunorubicin, dexamethasone, etoposide, thioguanine, vincristine
For both AYA Patients and Adults <65 years without Substantial Comorbidities
Preferred Regimens
• ECOG 1910 (preferred for adults <65 years)10: Cyclophosphamide, cytarabine, daunorubicin, dexamethasone, etoposide, mercaptopurine, high-dose
methotrexate, pegaspargase, vincristine, rituximab for CD20-positive disease, alternating with blinatumomab
Other Recommended Regimens
• ECOG 1910 (for AYA patients)10: Cyclophosphamide, cytarabine, daunorubicin, dexamethasone, etoposide, mercaptopurine, high-dose methotrexate,
pegaspargase, vincristine, rituximab for CD20-positive disease, alternating with blinatumomab
• GRAALL-200511: Cyclophosphamide, cytarabine, dexamethasone, etoposide, mercaptopurine, high-dose methotrexate, pegaspargase, vincristine,
rituximab for CD20-positive disease
• Dose-adjusted HyperCVAD12-14: Hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone, alternating with high-dose
methotrexate, dose-adjusted cytarabine, rituximab for CD20-positive disease, with or without sequential blinatumomab
• Linker 4-drug regimen (if aged <60 years)17: Cytarabine, etoposide, mercaptopurine, high-dose methotrexate, pegaspargase, rituximab for CD20-
positive disease
• USC/MSKCC ALL regimen based on CCG-1882 regimen (if aged ≥18 to <60 years)15,16: Cyclophosphamide, cytarabine, daunorubicin,
dexamethasone, high-dose methotrexate, pegaspargase, prednisone, thioguanine, vincristine
Continued

Footnotes on ALL-D 15A of 28 References on ALL-D 17 of 28

Note: For more information regarding the categories and definitions used for the NCCN Evidence Blocks™, see page EB-1.
All recommendations are category 2A unless otherwise indicated. ALL-D
Version 2.2024, 07/19/24 © 2024 National Comprehensive Cancer Network (NCCN ), All rights reserved. NCCN Evidence Blocks™, NCCN Guidelines , and this illustration may not be reproduced in any form without the express written permission of NCCN.
® ® ®
14 OF 28
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NCCN Guidelines Version 2.2024 NCCN Guidelines Index

Acute Lymphoblastic Leukemia Table of Contents
Discussion
NCCN Evidence BlocksTM
PRINCIPLES OF SYSTEMIC THERAPY
Ph-NEGATIVE B-ALL CONSOLIDATION COMPONENTS (MRD NEGATIVE/UNAVAILABLE)d,e,f,g,i

Adults ≥65 Years or Adults with Substantial Comorbidities: Frontline and Relapsed/Refractory
Other Recommended Regimens
• Low Intensity
Vincristine + prednisone18
POMP19: mercaptopurine, vincristine, methotrexate, prednisone

• Moderate Intensity
ALLOLD07 (PETHEMA-based regimen)20: Cytarabine, high-dose methotrexate, pegaspargase
EWALL21: Cytarabine, high-dose methotrexate, pegaspargase
GMALL22: Cytarabine, methotrexate, rituximab for CD20-positive disease
GRAALL23: Cyclophosphamide, cytarabine, dexamethasone, doxorubicin, mercaptopurine, vincristine
Modified DFCI 91-01 protocol24: Dexamethasone, doxorubicin, mercaptopurine, pegaspargase, vincristine

• High Intensity
CALGB 911125: Cyclophosphamide, cytarabine, dexamethasone, doxorubicin, mercaptopurine, pegaspargase,
thioguanine, vincristine
ECOG 191010: Cyclophosphamide, cytarabine, daunorubicin, dexamethasone, etoposide, mercaptopurine, high-dose
methotrexate, pegaspargase, vincristine, rituximab for CD20-positive disease, alternating with blinatumomab
Dose-adjusted HyperCVAD12,26: Hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone,
alternating with high-dose methotrexate, dose-adjusted cytarabine, rituximab for CD20-positive disease, with or without
sequential blinatumomab

• Immunotherapy
Low intensity
◊ ALLIANCE A04170328: Blinatumomab
Moderate intensity
◊ ALL-INITIAL-127: Cyclophosphamide, cytarabine, dexamethasone, idarubicin, high-dose methotrexate,
pegaspargase, vincristine, with rituximab for CD20-positive disease
◊ Inotuzumab ozogamicin + mini-hyperCVD6-8: Hyperfractionated cyclophosphamide, vincristine, dexamethasone,
inotuzumab ozogamicin alternating with cytarabine, methotrexate, inotuzumab ozogamicin, with or without sequential
blinatumomab

Footnotes on ALL-D 15A of 28 References on ALL-D 17 of 28

Note: For more information regarding the categories and definitions used for the NCCN Evidence Blocks™, see page EB-1.
All recommendations are category 2A unless otherwise indicated. ALL-D
Version 2.2024, 07/19/24 © 2024 National Comprehensive Cancer Network (NCCN ), All rights reserved. NCCN Evidence Blocks™, NCCN Guidelines , and this illustration may not be reproduced in any form without the express written permission of NCCN.
® ® ®
15 OF 28
The NCCN Evidence Blocks™ are subject to certain U.S. and foreign patents. Each approved use of the design of the NCCN Evidence Blocks™ requires the written approval of NCCN. Visit [Link]/patents for current list of applicable patents.
Printed by FATIH AKYÜZ on 11/15/2024 1:41:40 PM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 2.2024 NCCN Guidelines Index

Acute Lymphoblastic Leukemia Table of Contents
Discussion
NCCN Evidence BlocksTM
PRINCIPLES OF SYSTEMIC THERAPY
Ph-NEGATIVE B-ALL CONSOLIDATION COMPONENTS (MRD NEGATIVE/UNAVAILABLE) FOOTNOTES
a There are data to support the benefit of rituximab in addition to chemotherapy (excluding immunotherapy) for AYA patients and adults aged <65 years without
substantial comorbidities with CD20-positive disease (especially in patients aged <60 years).
b An FDA-approved biosimilar is an appropriate substitute for rituximab.
d All regimens include CNS prophylaxis with systemic therapy (eg, methotrexate, cytarabine) and/or IT therapy (eg, IT methotrexate, IT cytarabine; triple IT therapy with
methotrexate, cytarabine, corticosteroid).
e For full details on all phases of therapy, including induction IA; induction IB; CNS phase; early intensification; delayed intensification; continuation; consolidation IA, IB,
IC, and II; reinduction I and II; and interim maintenance I and II, see attached references or chemotherapy order templates, where available.
f For patients who develop hypersensitivity to E. coli-derived asparaginase, ERW-rywn should be substituted as a component of the multi-agent therapeutic regimen to
complete the full treatment course.
g PEG is substituted with Cal-PEG, an asparagine-specific enzyme, in AYA patients aged 15 to ≤21 years and adults aged 18 to ≤21 years for more sustained
asparaginase activity. Silverman LB, et al. Blood 2016;128:175; Angiolillo AL, et al. J Clin Oncol 2014;32:3874-3882.
i Blinatumomab should be incorporated into frontline therapy as a post-remission approach based on data from ECOG1910. Gokbuget N, et al. Leuk Lymphoma
2020;61:2665-2673. Topp MS, et al. J Clin Oncol 2011;29:2493-2498. Litzow MR, et al. Blood 2022;140(Suppl):Abstract LBA-1.

Note: For more information regarding the categories and definitions used for the NCCN Evidence Blocks™, see page EB-1.
All recommendations are category 2A unless otherwise indicated. ALL-D
Version 2.2024, 07/19/24 © 2024 National Comprehensive Cancer Network (NCCN ), All rights reserved. NCCN Evidence Blocks™, NCCN Guidelines , and this illustration may not be reproduced in any form without the express written permission of NCCN.
® ® ®
15A OF 28
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NCCN Guidelines Version 2.2024 NCCN Guidelines Index

Acute Lymphoblastic Leukemia Table of Contents
Discussion
NCCN Evidence BlocksTM
PRINCIPLES OF SYSTEMIC THERAPY
Ph-NEGATIVE B-ALL MAINTENANCE THERAPY (MRD NEGATIVE/UNAVAILABLE)a,b,m

• POMP (mercaptopurine, vincristine, methotrexate, prednisone)

• Blinatumomab alternating with POMPn

See Evidence Blocks on ALL-D (EB-7)

References on ALL-D 17 of 28
a There are data to support the benefit of rituximab in addition to chemotherapy (excluding immunotherapy) for AYA patients and adults aged <65 years without
substantial comorbidities with CD20-positive disease (especially in patients aged <60 years).
b An FDA-approved biosimilar is an appropriate substitute for rituximab.
m Refer to induction regimen references, or chemotherapy order templates (where available), for components. Include IT chemotherapy per protocol, or as clinically
indicated.
n For maintenance in patients induced with inotuzumab ozogamicin + mini-hyper-CVD + blinatumomab regimen or hyperCVAD + blinatumomab regimen.

Note: For more information regarding the categories and definitions used for the NCCN Evidence Blocks™, see page EB-1.
All recommendations are category 2A unless otherwise indicated. ALL-D
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NCCN Guidelines Version 2.2024 5

4
E = Efficacy of Regimen/Agent
S = Safety of Regimen/Agent NCCN Guidelines Index
Acute Lymphoblastic Leukemia 3
2
Q = Quality of Evidence
C = Consistency of Evidence Table of Contents
A = Affordability of Regimen/Agent
Discussion
NCCN Evidence BlocksTM
1
E S Q C A

EVIDENCE BLOCKS FOR Ph-NEGATIVE B-ALL CONSOLIDATION REGIMENS (MRD Negative/Unavailable)

Ph-Negative B-ALL Maintenance Therapy Regimens

POMP

Blinatumumab alternating with POMP

Note: For more information regarding the categories and definitions used for the NCCN Evidence Blocks™, see page EB-1. ALL-D
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® ® ®
EB-7
The NCCN Evidence Blocks™ are subject to certain U.S. and foreign patents. Each approved use of the design of the NCCN Evidence Blocks™ requires the written approval of NCCN. Visit [Link]/patents for current list of applicable patents.
Printed by FATIH AKYÜZ on 11/15/2024 1:41:40 PM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 2.2024 NCCN Guidelines Index

Acute Lymphoblastic Leukemia Table of Contents
Discussion
NCCN Evidence BlocksTM
PRINCIPLES OF SYSTEMIC THERAPY
Ph-NEGATIVE B-ALL REFERENCES
1 Stock
 W, Luger SM, Advani AS, et al. A pediatric regimen for older adolescents 11 Maury
 S, Chevret S, Thomas X, et al. Rituximab in B-lineage adult acute
and young adults with acute lymphoblastic leukemia: results of CALGB 10403. lymphoblastic leukemia. N Engl J Med 2016;375:1044-1053.
Blood 2019;133:1548-1559. 12 Jabbour
 E, Short NJ, Jain N, et al. Hyper-CVAD and sequential blinatumomab
2 DeAngelo
 DJ, Stevenson KE, Dahlberg SE, et al. Long-term outcome of a for newly diagnosed Philadelphia chromosome-negative B-cell acute
pediatric-inspired regimen used for adults aged 18-50 years with newly diagnosed lymphocytic leukaemia: a single-arm, single-centre, phase 2 trial. Lancet
acute lymphoblastic leukemia. Leukemia 2015;29:526-534. Haematol 2022;9:e878-e885.
3 Ribera
 JM, Oriol A, Sanz MA, et al. Comparison of the results of the treatment of 13 Thomas
 DA, O'Brien S, Faderl S, et al. Chemoimmunotherapy with a modified
adolescents and young adults with standard-risk acute lymphoblastic leukemia hyper-CVAD and rituximab regimen improves outcome in de novo Philadelphia
with the Programa Espanol de Tratamiento en Hematologia pediatric-based chromosome-negative precursor B-lineage acute lymphoblastic leukemia. J Clin
protocol ALL-96. J Clin Oncol 2008;26:1843-1849. Oncol 2010;28:3880-3889.
4 Larson
 RA, Dodge RK, Burns CP, et al. A five-drug remission induction regimen 14 Kantarjian
 H, Thomas D, O'Brien S, et al. Long-term follow-up results
with intensive consolidation for adults with acute lymphoblastic leukemia: cancer of hyperfractionated cyclophosphamide, vincristine, doxorubicin, and
and leukemia group B study 8811. Blood 1995;85:2025-2037. dexamethasone (Hyper-CVAD), a dose-intensive regimen, in adult acute
5 Stock
 W, Johnson JL, Stone RM, et al. Dose intensification of daunorubicin and lymphocytic leukemia. Cancer 2004;101:2788-2801.
cytarabine during treatment of adult acute lymphoblastic leukemia: results of 15 Douer
 D, Aldoss I, Lunning MA, et al. Pharmacokinetics-based integration of
Cancer and Leukemia Group B Study 19802. Cancer 2013;119:90-98. multiple doses of intravenous pegaspargase in a pediatric regimen for adults
6 Kantarjian
 H, Ravandi F, Short NJ, et al. Inotuzumab ozogamicin in combination with newly diagnosed acute lymphoblastic leukemia. J Clin Oncol 2014;32:905-
with low-intensity chemotherapy for older patients with Philadelphia chromosome- 911.
negative acute lymphoblastic leukaemia: a single-arm, phase 2 study. Lancet 16 Geyer
 MB, Ritchie EK, Rao AV, et al. Pediatric-inspired chemotherapy
Oncol 2018;19:240-248. incorporating pegaspargase is safe and results in high rates of minimal residual
7 Jabbour
 E, Sasaki K, Short NJ, et al. Long-term follow-up of salvage therapy disease negativity in adults up to age 60 with Philadelphia chromosome-
using a combination of inotuzumab ozogamicin and mini-hyper-CVD with or negative acute lymphoblastic leukemia. Haematologica 2021;106:2086-2094.
without blinatumomab in relapsed/refractory Philadelphia chromosome-negative 17 Wieduwilt
 MJ, Jonas BA, Schiller G, et al. A phase II study of pegylated
acute lymphoblastic leukemia. Cancer 2021;127:2025-2038. asparaginase, cyclophosphamide, rituximab, and dasatinib added to
8 Jabbour
 E, Short NJ, Senapati J, et al. Mini-hyper-CVD plus inotuzumab the UCSF 8707 (Linker 4-drug) regimen with liposomal cytarabine CNS
ozogamicin, with or without blinatumomab, in the subgroup of older patients with prophylaxis for adults with newly diagnosed acute lymphoblastic leukemia
newly diagnosed Philadelphia chromosome-negative B-cell acute lymphocytic (ALL) or lymphoblastic lymphoma (LBL): University of California Hematologic
leukaemia: long-term results of an open-label phase 2 trial. Lancet Haematol Malignancies Consortium Study (UCHMC) 1401. Blood 2018;132:4018.
2023;10:e433-e444. 18 Hardisty
 RM, McElwain TJ, Darby CW. Vincristine and prednisone for the
9 Rowe
 JM, Buck G, Burnett AK, et al. Induction therapy for adults with acute induction of remissions in acute childhood leukaemia. Br Med J 1969;2:662-
lymphoblastic leukemia: results of more than 1500 patients from the international 665.
ALL trial: MRC UKALL XII/ECOG E2993. Blood 2005;106:3760-3767. 19 Berry
 DH, Pullen J, George S, et al. Comparison of prednisolone, vincristine,
10 Litzow
 MR, Sun Z, Paietta E, et al. Consolidation therapy with blinatumomab methotrexate, and 6-mercaptopurine vs. vincristine and prednisone induction
improves overall survival in newly diagnosed adult patients with B-lineage therapy in childhood acute leukemia. Cancer 1975;36:98-102.
acute lymphoblastic leukemia in measurable residual disease negative
remission: Results from the ECOGACRIN E1910 randomized phase III National
Cooperative Clinical Trials Network trial. Blood 2022;140 (Suppl 2):LBA-1.
Continued

Note: For more information regarding the categories and definitions used for the NCCN Evidence Blocks™, see page EB-1.
All recommendations are category 2A unless otherwise indicated. ALL-D
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The NCCN Evidence Blocks™ are subject to certain U.S. and foreign patents. Each approved use of the design of the NCCN Evidence Blocks™ requires the written approval of NCCN. Visit [Link]/patents for current list of applicable patents.
Printed by FATIH AKYÜZ on 11/15/2024 1:41:40 PM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 2.2024 NCCN Guidelines Index

Acute Lymphoblastic Leukemia Table of Contents
Discussion
NCCN Evidence BlocksTM
PRINCIPLES OF SYSTEMIC THERAPY
Ph-NEGATIVE B-ALL REFERENCES
20 Ribera
 JM, Garcia O, Oriol A, et al. PETHEMA group: Feasibility and results
of subtype-oriented protocols in older adults and fit patients with acute
lymphoblastic leukemia: results of three prospective parallel trials from the
PETHEMA group. Leuk Res 2016;41:12-20.
21 Ottmann
 OG, Pfeifer H, Cayuela JM, et al. Nilotinib (Tasigna®) and low intensity
chemotherapy for first-line treatment of elderly patients with BCR-ABL1-positive
acute lymphoblastic leukemia: Final results of a prospective multicenter trial
(EWALL-PH02). Blood 2018;132:Abstract 31.
22 Goekbuget
 N, Beck J, Bruggemann M, et al. Moderate intensive chemotherapy
including CNS prophylaxis with liposomal cytarabine is feasible and effective
in older patients with Ph-negative acute lymphoblastic leukemia (ALL): results
of a prospective trial from the German multicenter study group for adult ALL
(GMALL). Blood 2012;120:1493.
23 Hunault-Berger
 M, Leguay T, Thomas X, et al. A randomized study of pegylated
liposomal doxorubicin versus continuous-infusion doxorubicin in elderly patients
with acute lymphoblastic leukemia: the GRAALL-SA1 study. Haematologica
2011;96:245-252.
24 Martell
 MP, Atenafu EG, Minden MD, et al. Treatment of elderly patients with
acute lymphoblastic leukaemia using a paediatric-based protocol. Br J Haematol
2013;163:458-464.
25 Larson
 RA, Dodge RK, Linker CA, et al. A randomized control trial of filgrastim
during remission induction and consolidation chemotherapy for adults with acute
lymphoblastic leukemia: CALGB 9111. Blood 1998;92:1556-1564.
26 O’Brien
 S, Thomas DA, Ravand F, et al. Results of the hyperfractionated
cyclophosphamide, vincristine, doxorubicin and dexamethasone in elderly
patients with acute lymphocytic leukemia. Cancer 2008;113:2097-2101.
27 Stelljes M, Raffel S, Alakel N, et al. Inotuzumab ozogamicin as induction
therapy for patients older than 55 years with Philadelphia chromosome-negative
B-precursor ALL. J Clin Oncol 2023:JCO2300546.
28 Wieduwilt MJ, Yin J, Kour O, et al. Chemotherapy-free treatment with
inotuzumab ozogamicin and blinatumomab for older adults with newly
diagnosed, Ph-negative, CD22-positive, B-cell acute lymphoblastic leukemia:
Alliance A041703. J Clin Oncol 2023;41:7006-7006.
29 Jabbour EJ, Haddad FG, Short NJ, et al. Phase 2 study of inotuzumab
ozogamicin for measurable residual disease in acute lymphoblastic leukemia in
remission. Blood 2023 2024;143:417-421.

Note: For more information regarding the categories and definitions used for the NCCN Evidence Blocks™, see page EB-1.
All recommendations are category 2A unless otherwise indicated. ALL-D
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NCCN Guidelines Version 2.2024 NCCN Guidelines Index

Acute Lymphoblastic Leukemia Table of Contents
Discussion
NCCN Evidence BlocksTM
PRINCIPLES OF SYSTEMIC THERAPY
T-ALL INDUCTION REGIMENSa

Only for AYA Patients For both AYA Patients Only for Adults <65 years without Adults ≥65 Years or Adults with Substantial
without Substantial & Adults <65 years Substantial Comorbidities: Comorbidities: Frontline & Relapsed/
Comorbidities: without Substantial Frontline Refractory
Frontline Comorbidities: Frontline
Preferred Regimens Other Recommended Other Recommended Regimens Other Recommended Regimens
• CALGB 10403b,1 Regimens • Dose-adjusted CALGB 8811 • Low Intensity
• COG AALL 0434b,2-4 • GRAALL-2005 (if aged Larson12 Vincristine + prednisone18
<60 years)b,9 • Dose-adjusted POMP: mercaptopurine, methotrexate,
Other Recommended • Dose-adjusted GRAALL-201413,14,15 prednisone, vincristine19
Regimens HyperCVAD10 • MRC UKALLXII/ECOG 299316,17
• DFCI ALL regimen • Linker 4-drug regimen • Moderate Intensity
based on DFCI (if aged <60 years)11 ALLOLD07 (PETHEMA-based regimen)20
Protocol 00-01b,5 GMALL21
• PETHEMA ALL-96 (if GRAALL22
aged <30 years)b,6 Modified DFCI 91-01 protocol23
• USC/MSKCC ALL
regimen based on • High Intensity
CCG-1882 regimen (if CALGB 911124
aged ≥18 years)b,7,8 Dose-adjusted HyperCVAD10

See Evidence Blocks on ALL-D (EB-8) and ALL-D (EB-9)

Regimen components on ALL-D 20 of 28

References on ALL-D 25 of 28

a All
regimens include CNS prophylaxis with systemic therapy (eg, methotrexate, cytarabine) and/or IT therapy (eg, IT methotrexate, IT cytarabine; triple IT therapy with
methotrexate, cytarabine, corticosteroid).
b Pediatric-inspired regimen.

Note: For more information regarding the categories and definitions used for the NCCN Evidence Blocks™, see page EB-1.
All recommendations are category 2A unless otherwise indicated. ALL-D
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The NCCN Evidence Blocks™ are subject to certain U.S. and foreign patents. Each approved use of the design of the NCCN Evidence Blocks™ requires the written approval of NCCN. Visit [Link]/patents for current list of applicable patents.
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NCCN Guidelines Version 2.2024 5

4
E = Efficacy of Regimen/Agent
S = Safety of Regimen/Agent NCCN Guidelines Index
Acute Lymphoblastic Leukemia 3
2
Q = Quality of Evidence
C = Consistency of Evidence Table of Contents
A = Affordability of Regimen/Agent
Discussion
NCCN Evidence BlocksTM
1
E S Q C A

EVIDENCE BLOCKS FOR FRONTLINE REGIMENS FOR T-ALL

AYA Patients without Substantial Comorbidities Adult Patients <65 y and without Substantial Comorbidities
Preferred Regimens Other Recommended Regimens

CALGB 10403 * Dose-adjusted CALGB 8811 Larson *

COG AALL0434 * GRAALL-2005 *

COG AALL0434/nelarabine * Dose-adjusted GRAALL-2014 *

Other Recommended Regimens
Dose-adjusted GRAALL-2014/nelarabine *
DFCI ALL regimen (based on DFCI Protocol 00-01) *
Dose-adjusted hyperCVAD *
GRAALL-2005 *
Dose-adjusted hyperCVAD/nelarabine *
Dose-adjusted hyperCVAD *
Linker 4-drug *
Dose-adjusted hyperCVAD/nelarabine *
MRC UKALLXII/ECOG2993 *
Linker 4-drug *

PETHEMA ALL-96 *

USC/MSKCC ALL (based on CCG-1882) *

*Evidence Block development in progress

Note: For more information regarding the categories and definitions used for the NCCN Evidence Blocks™, see page EB-1. ALL-D
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EB-8
The NCCN Evidence Blocks™ are subject to certain U.S. and foreign patents. Each approved use of the design of the NCCN Evidence Blocks™ requires the written approval of NCCN. Visit [Link]/patents for current list of applicable patents.
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NCCN Guidelines Version 2.2024 5

4
E = Efficacy of Regimen/Agent
S = Safety of Regimen/Agent NCCN Guidelines Index
Acute Lymphoblastic Leukemia 3
2
Q = Quality of Evidence
C = Consistency of Evidence Table of Contents
A = Affordability of Regimen/Agent
Discussion
NCCN Evidence BlocksTM
1
E S Q C A

EVIDENCE BLOCKS FOR FRONTLINE AND RELAPSED/REFRACTORY REGIMENS FOR ADULTS ≥65 YEARS
OR ADULTS WITH SUBSTANTIAL COMORBIDITIES

Regimens for T-ALL According to Intensity

Other Recommended Regimens
Low Intensity
Vincristine/prednisone *
POMP *
Moderate Intensity
ALLOLD07 (PETHEMA-based regimen) *
GMALL *
GRAALL *
Modified DFCI 91-01 *
High Intensity
CALGB 9111 *
Dose-adjusted hyperCVAD *
Dose-adjusted hyperCVAD/nelarabine *

*Evidence Block development in progress

Note: For more information regarding the categories and definitions used for the NCCN Evidence Blocks™, see page EB-1. ALL-D
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® ® ®
EB-9
The NCCN Evidence Blocks™ are subject to certain U.S. and foreign patents. Each approved use of the design of the NCCN Evidence Blocks™ requires the written approval of NCCN. Visit [Link]/patents for current list of applicable patents.
Printed by FATIH AKYÜZ on 11/15/2024 1:41:40 PM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 2.2024 NCCN Guidelines Index

Acute Lymphoblastic Leukemia Table of Contents
Discussion
NCCN Evidence BlocksTM
PRINCIPLES OF SYSTEMIC THERAPY
T-ALL INDUCTION COMPONENTSa,c,d

Only AYA Patients without Substantial Comorbidities: Frontline

Preferred Regimens
• CALGB 10403b,1: Daunorubicin, pegaspargase, prednisone, vincristine
• COG AALL 0434b,2-4: Daunorubicin, pegaspargase, prednisone, vincristine
Other Recommended Regimens
• DFCI ALL regimen based on DFCI Protocol 00-01b,5: Doxorubicin, methotrexate, pegaspargase, prednisone, vincristine
• PETHEMA ALL-96 (if aged <30 years)b,6: Cyclophosphamide, daunorubicin, pegaspargase, prednisone, vincristine
• USC/MSKCC ALL regimen based on CCG-1882 regimen (if aged ≥18 years)b,7,8: Cyclophosphamide, cytarabine, daunorubicin,
mercaptopurine, pegaspargase, prednisone, vincristine
For both AYA Patients & Adults <65 years without Substantial Comorbidities: Frontline
Other Recommended Regimens
• GRAALL-2005 (if aged <60 years)b,9: Cyclophosphamide, daunorubicin, pegaspargase, prednisone, vincristine
• Dose-adjusted HyperCVAD10: Hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone, alternating with high-
dose methotrexate, dose-adjusted cytarabine +/- nelarabine
• Linker 4-drug regimen (if aged <60 years)11: Daunorubicin, dexamethasone or prednisone, pegaspargase, vincristine
Only for Adults <65 years without Substantial Comorbidities: Frontline
Other Recommended Regimens
• Dose-adjusted CALGB 8811 Larson12: Cyclophosphamide, daunorubicin, pegaspargase, prednisone, vincristine
• Dose-adjusted GRAALL-201413,14,15: Cyclophosphamide, daunorubicin, pegaspargase, prednisone, vincristine
• MRC UKALLXII/ECOG 299316,17: Cyclophosphamide, cytarabine, daunorubicin, mercaptopurine, pegaspargase, prednisone, vincristine

Continued

References on ALL-D 25 of 28

a Allregimens include CNS prophylaxis with systemic therapy (eg, methotrexate, cytarabine) and/or IT therapy (eg, IT methotrexate, IT cytarabine; triple IT therapy with
methotrexate, cytarabine, corticosteroid).
b Pediatric-inspired regimen.
c For patients who develop hypersensitivity to E. coli-derived asparaginase, ERW-rywn should be substituted as a component of the multi-agent therapeutic regimen to
complete the full treatment course.
d PEG is substituted with Cal-PEG, an asparagine-specific enzyme, in AYA patients aged 15 to ≤21 years and adults aged 18 to ≤21 years for more sustained
asparaginase activity. Silverman LB, et al. Blood 2016;128:175; Angiolillo AL, et al. J Clin Oncol 2014;32:3874-3882.

Note: For more information regarding the categories and definitions used for the NCCN Evidence Blocks™, see page EB-1.
All recommendations are category 2A unless otherwise indicated. ALL-D
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The NCCN Evidence Blocks™ are subject to certain U.S. and foreign patents. Each approved use of the design of the NCCN Evidence Blocks™ requires the written approval of NCCN. Visit [Link]/patents for current list of applicable patents.
Printed by FATIH AKYÜZ on 11/15/2024 1:41:40 PM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 2.2024 NCCN Guidelines Index

Acute Lymphoblastic Leukemia Table of Contents
Discussion
NCCN Evidence BlocksTM
PRINCIPLES OF SYSTEMIC THERAPY
T-ALL INDUCTION COMPONENTSa,c,d

Adults ≥65 Years or Adults with Substantial Comorbidities: Frontline and Relapsed/Refractory
Other Recommended Regimens
• Low Intensity
Vincristine + prednisone18
POMP19: mercaptopurine, vincristine, methotrexate, prednisone

• Moderate Intensity
ALLOLD07 (PETHEMA-based regimen)20: Cyclophosphamide, cytarabine, dexamethasone, idarubicin, vincristine
GMALL21: Cyclophosphamide, cytarabine, dexamethasone, idarubicin, vincristine
GRAALL22: Cyclophsphamide, dexamethasone, doxorubicin, vincristine
Modified DFCI 91-01 protocol23: Dexamethasone, doxorubicin, methotrexate, pegaspargase, vincristine

• High Intensity
CALGB 911124: Cyclophosphamide, daunorubicin, pegaspargase, prednisone, vincristine
Dose-adjusted HyperCVAD10: Hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone,
alternating with high-dose methotrexate, dose-adjusted cytarabine +/- nelarabine

References on ALL-D 25 of 28

a Allregimens include CNS prophylaxis with systemic therapy (eg, methotrexate, cytarabine) and/or IT therapy (eg, IT methotrexate, IT cytarabine; triple IT therapy with
methotrexate, cytarabine, corticosteroid).
c For patients who develop hypersensitivity to E. coli-derived asparaginase, ERW-rywn should be substituted as a component of the multi-agent therapeutic regimen to
complete the full treatment course.
d PEG is substituted with Cal-PEG, an asparagine-specific enzyme, in AYA patients aged 15 to ≤21 years and adults aged 18 to ≤21 years for more sustained
asparaginase activity. Silverman LB, et al. Blood 2016;128:175; Angiolillo AL, et al. J Clin Oncol 2014;32:3874-3882.

Note: For more information regarding the categories and definitions used for the NCCN Evidence Blocks™, see page EB-1.
All recommendations are category 2A unless otherwise indicated. ALL-D
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® ® ®
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The NCCN Evidence Blocks™ are subject to certain U.S. and foreign patents. Each approved use of the design of the NCCN Evidence Blocks™ requires the written approval of NCCN. Visit [Link]/patents for current list of applicable patents.
Printed by FATIH AKYÜZ on 11/15/2024 1:41:40 PM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 2.2024 NCCN Guidelines Index

Acute Lymphoblastic Leukemia Table of Contents
Discussion
NCCN Evidence BlocksTM
PRINCIPLES OF SYSTEMIC THERAPY
T-ALL CONSOLIDATION COMPONENTSa,c,d

Only AYA Patients without Substantial Comorbidities: Frontline

Preferred Regimens
• CALGB 10403b,1: Cyclophosphamide, cytarabine, mercaptopurine, pegaspargase, vincristine
• COG AALL 0434b,2-4: Cyclophosphamide, cytarabine, mercaptopurine, pegaspargase, vincristine, +/- nelarabine
Other Recommended Regimens
• DFCI ALL regimen based on DFCI Protocol 00-01b,5: Dexamethasone, doxorubicin, mercaptopurine, methotrexate, pegaspargase, vincristine
• PETHEMA ALL-96 (if aged <30 years)b,6: Cyclophosphamide, cytarabine, daunorubicin, dexamethasone, etoposide, mercaptopurine, high-
dose methotrexate, pegaspargase, vincristine
• USC/MSKCC ALL regimen based on CCG-1882 regimen (if aged ≥18 years)b,7,8: Cyclophosphamide, cytarabine, daunorubicin,
dexamethasone, high-dose methotrexate, pegaspargase, prednisone, thioguanine, vincristine
For both AYA Patients & Adults <65 years without Substantial Comorbidities: Frontline
Other Recommended Regimens
• GRAALL-2005 (if aged <60 years)b,9: Cyclophosphamide, cytarabine, dexamethasone, etoposide, mercaptopurine, high-dose methotrexate,
pegaspargase, vincristine
• Dose-adjusted HyperCVAD10: Hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone, alternating with high-dose
methotrexate, dose-adjusted cytarabine, +/- nelarabine
• Linker 4-drug regimen (if aged <60 years)11: Cytarabine, daunorubicin, dexamethasone or prednisone, etoposide, mercaptopurine,
methotrexate, pegaspargase, vincristine
Only for Adults <65 years without Substantial Comorbidities: Frontline
Other Recommended Regimens
• Dose-adjusted CALGB 8811 Larson12: Cyclophosphamide, cytarabine, dexamethasone, doxorubicin, mercaptopurine, pegaspargase,
thioguanine, vincristine
• Dose-adjusted GRAALL-201413,14,15: Cyclophosphamide, cytarabine, dexamethasone, etoposide, mercaptopurine, high-dose methotrexate,
pegaspargase, vincristine +/- nelarabine
• MRC UKALLXII/ECOG 299316,17: Cyclophosphamide, cytarabine, daunorubicin, dexamethasone, etoposide, thioguanine, vincristine

Continued
a All regimens include CNS prophylaxis with systemic therapy (eg, methotrexate, cytarabine)
and/or IT therapy (eg, IT methotrexate, IT cytarabine; triple IT therapy with methotrexate, References on ALL-D 25 of 28
cytarabine, corticosteroid).
b Pediatric-inspired regimen. d PEG is substituted with Cal-PEG, an asparagine-specific enzyme, in AYA patients aged
c For patients who develop hypersensitivity to E. coli-derived asparaginase, ERW-rywn 15 to ≤21 years and adults aged 18 to ≤21 years for more sustained asparaginase activity.
should be substituted as a component of the multi-agent therapeutic regimen to complete Silverman LB, et al. Blood 2016;128:175; Angiolillo AL, et al. J Clin Oncol 2014;32:3874-
the full treatment course. 3882.

Note: For more information regarding the categories and definitions used for the NCCN Evidence Blocks™, see page EB-1.
All recommendations are category 2A unless otherwise indicated. ALL-D
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Acute Lymphoblastic Leukemia Table of Contents
Discussion
NCCN Evidence BlocksTM
PRINCIPLES OF SYSTEMIC THERAPY
T-ALL CONSOLIDATION COMPONENTSa,c,d

Adults ≥65 Years or Adults with Substantial Comorbidities: Frontline and Relapsed/Refractory
Other Recommended Regimens
• Low Intensity
Vincristine + prednisone18
POMP19: mercaptopurine, vincristine, methotrexate, prednisone

• Moderate Intensity
ALLOLD07 (PETHEMA-based regimen)20: Cytarabine, high-dose methotrexate, pegaspargase
GMALL21: Cytarabine, methotrexate
GRAALL22: Cyclophosphamide, cytarabine, dexamethasone, doxorubicin, mercaptopurine, vincristine
Modified DFCI 91-01 protocol23: Dexamethasone, doxorubicin, mercaptopurine, pegaspargase, vincristine

• High Intensity
CALGB 911124: Cyclophosphamide, cytarabine, dexamethasone, doxorubicin, mercaptopurine, methotrexate,
pegaspargase, thioguanine, vincristine
Dose-adjusted HyperCVAD10: Hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone,
alternating with high-dose methotrexate, dose-adjusted cytarabine, +/- nelarabine

References on ALL-D 25 of 28

a Allregimens include CNS prophylaxis with systemic therapy (eg, methotrexate, cytarabine) and/or IT therapy (eg, IT methotrexate, IT cytarabine; triple IT therapy with
methotrexate, cytarabine, corticosteroid).
c For patients who develop hypersensitivity to E. coli-derived asparaginase, ERW-rywn should be substituted as a component of the multi-agent therapeutic regimen to
complete the full treatment course.
d PEG is substituted with Cal-PEG, an asparagine-specific enzyme, in AYA patients aged 15 to ≤21 years and adults aged 18 to ≤21 years for more sustained
asparaginase activity. Silverman LB, et al. Blood 2016;128:175; Angiolillo AL, et al. J Clin Oncol 2014;32:3874-3882.

Note: For more information regarding the categories and definitions used for the NCCN Evidence Blocks™, see page EB-1.
All recommendations are category 2A unless otherwise indicated. ALL-D
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Discussion
NCCN Evidence BlocksTM
PRINCIPLES OF SYSTEMIC THERAPY
T-ALL MAINTENANCE COMPONENTSc,d,e

Maintenance Regimen (if not already included in a multi-part regimen)

• Weekly methotrexate + daily mercaptopurine + monthly vincristine/prednisone pulses (duration based on regimen)
Specific Maintenance Regimens
• COG AALL 0434b,2-4 (AYA without substantial comorbidities): Mercaptopurine, methotrexate,
prednisone, vincristine, +/- nelarabine
• PETHEMA ALL-96 (AYA without substantial comorbidities) (if aged <30 years)b,6: Mercaptopurine,
methotrexate, pegaspargase, prednisone, vincristine
• Dose-adjusted HyperCVAD10: Hyperfractionated cyclophosphamide, doxorubicin, dexamethasone,
mercaptopurine, methotrexate, pegaspargase, prednisone, vincristine, +/- nelarabine
• Dose-adjusted GRAALL-201413,14,15 (Adults <65 years without substantial comorbidities):
Mercaptopurine, methotrexate, prednisone, vincristine, +/- nelarabine

See Evidence Blocks on ALL-D (EB-10)

References on ALL-D 25 of 28

b Pediatric-inspired regimen.
c For patients who develop hypersensitivity to E. coli-derived asparaginase, ERW-rywn should be substituted as a component of the multi-agent therapeutic regimen to
complete the full treatment course.
d PEG is substituted with Cal-PEG, an asparagine-specific enzyme, in AYA patients aged 15 to ≤21 years and adults aged 18 to ≤21 years for more sustained
asparaginase activity. Silverman LB, et al. Blood 2016;128:175; Angiolillo AL, et al. J Clin Oncol 2014;32:3874-3882.
e Refer to induction regimen references or chemotherapy order tempates, where available, for components. Include IT chemotherapy per protocol, or as clinically
indicated.

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All recommendations are category 2A unless otherwise indicated. ALL-D
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NCCN Guidelines Version 2.2024 5

4
E = Efficacy of Regimen/Agent
S = Safety of Regimen/Agent NCCN Guidelines Index
Acute Lymphoblastic Leukemia 3
2
Q = Quality of Evidence
C = Consistency of Evidence Table of Contents
A = Affordability of Regimen/Agent
Discussion
NCCN Evidence BlocksTM
1
E S Q C A

EVIDENCE BLOCKS FOR FRONTLINE REGIMENS FOR T-ALL

Maintenance Regimen (if not already included in a multi-part regimen)

Weekly methotrexate/daily 6-MP/monthly vincristine/
prednisone pulses (duration based on regimen) *

*Evidence Block development in progress

Note: For more information regarding the categories and definitions used for the NCCN Evidence Blocks™, see page EB-1. ALL-D
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® ® ®
EB-10
The NCCN Evidence Blocks™ are subject to certain U.S. and foreign patents. Each approved use of the design of the NCCN Evidence Blocks™ requires the written approval of NCCN. Visit [Link]/patents for current list of applicable patents.
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Acute Lymphoblastic Leukemia Table of Contents
Discussion
NCCN Evidence BlocksTM
PRINCIPLES OF SYSTEMIC THERAPY
T-ALL REFERENCES
1 Stock
 14 Boissel N, Graux C, Huguet F, et al. Frontline consolidation with nelarabine for adults with
W, Luger SM, Advani AS, et al. A pediatric regimen for older adolescents and young
adults with acute lymphoblastic leukemia: results of CALGB 10403. Blood 2019;133:1548- high-risk T-Cell acute lymphoblastic leukemia. Results of the Graall-2014/T Atriall Phase 2
1559. Study. Blood 2023;142(Suppl):Abstract 962.
2 Winter SS, Dunsmore KP, Devidas M, et al. Improved survival for children and young adults 15 Trinquand A, Tanguy-Schmidt A, Ben Abdelali R, et al. Toward a NOTCH1/FBXW7/RAS/

with T-lineage acute lymphoblastic leukemia: Results from the Children's Oncology Group PTEN-based oncogenetic risk classification of adult T-cell acute lymphoblastic leukemia:
AALL0434 methotrexate randomization. J Clin Oncol 2018;36:2926-2934. a Group for Research in Adult Acute Lymphoblastic Leukemia study. J Clin Oncol
3 Dunsmore KP, Winter SS, Devidas M, et al. Children's Oncology Group AALL0434: A phase 2013;31:4333-4342.
16 Rowe JM, Buck G, Burnett AK, et al. Induction therapy for adults with acute lymphoblastic
III randomized clinical trial testing nelarabine in newly diagnosed T-cell acute lymphoblastic
leukemia. J Clin Oncol 2020:38;3283-3293. leukemia: results of more than 1500 patients from the international ALL trial: MRC UKALL
4 Hayashi RJ, Winter SS, Dunsmore KP, et al. Successful outcomes of newly diagnosed T XII/ECOG E 2993. Blood 2005;106:3760-3767.
17 Mansour MR, Sulis ML, Duke V, et al. Prognostic implications of NOTCH1 and FBXW7
lymphoblastic lymphoma: Results from Children's Oncology Group AALL0434. J Clin Oncol
2020;38:3062-3070. mutations in adults with T-cell acute lymphoblastic leukemia treated on the MRC UKALLXII/
5 DeAngelo DJ, Stevenson KE, Dahlberg SE, et al. Long-term outcome of a pediatric-inspired ECOG E2993 protocol. J Clin Oncol 2009;27:4352-4536.
18 Hardisty RM, McElwain TJ, Darby CW. Vincristine and prednisone for the induction of
regimen used for adults aged 18-50 years with newly diagnosed lymphoblastic leukemia.
Leukemia 2015;29:526-534. remissions in acute childhood leukaemia. Br Med J 1969;2:662-665.
6 Ribera JP, Oriol A, Sanz MA, et al. Comparison of the results of the treatment of 19 Berry DH, Pullen J, George S, et al. Comparison of prednisolone, vincristine,

adolescents and young adults with standard-risk acute lymphoblastic leukemia with the methotrexate, and 6-mercaptopurine vs. vincristine and prednisone induction therapy in
Programa Español de Tratamiento en Hematología pediatric-based protocol ALL-96 J Clin childhood acute leukemia. Cancer 1975;36:98-102.
20 Ribera JM, Garcia O, Oriol A, et al. PETHEMA group: Feasibility and results of subtype-
Oncol 2008;10:1843-1849.
7 Douer D, Aldoss I, Lunning MA, et al. Pharmocokinetics-based integration of multiple doses oriented protocols in older adults and fit patients with acute lymphoblastic leukemia: results
of intravenous pegaspargase in a pediatric regimen for adults with newly diagnosed acute of three prospective parallel trials from the PETHEMA group. Leuk Res 2016;41:12-20.
21 Goekbuget N, Beck J, Bruggemann M, et al. Moderate intensive chemotherapy including
lymphoblastic leukemia. J Clin Oncol 2014;32:905-911.
8 Geyer MB, Ritchie EK, Rao AV, et al. Pediatric-inspired chemotherapy incorporating CNS prophylaxis with liposomal cytarabine is feasible and effective in older patients with
pegaspargase is safe and results in high rates of minimal residual disease negativity in Ph-negative acute lymphoblastic leukemia (ALL): results of a prospective trial from the
adults up to age 60 with Philadelphia chromosome-negative acute lymphoblastic leukemia. German multicenter study group for adult ALL (GMALL). Blood 2012;120:1493.
22 Hunault-Berger M, Leguay T, Thomas X, et al. A randomized study of pegylated
Haematologica 2021;106:2086-2094.
9 Huguet F, Chevret S, Leguay T, et al. Intensified therapy of acute lymphoblastic leukemia liposomal doxorubicin versus continuous-infusion doxorubicin in elderly patients with acute
in adults: Report of the randomized GRAALL-2005 clinical trial. J Clin Oncol 2018;36:2514- lymphoblastic leukemia: the GRAALL-SA1 study. Haematologica 2011;96:245-252.
23 Martell MP, Atenafu EG, Minden MD, et al. Treatment of elderly patients with acute
2523.
10 Abaza Y, Kantarjian HM, Faderl S, et al. Hyper-CVAD plus nelarabine in newly diagnosed lymphoblastic leukaemia using a paediatric-based protocol. Br J Haematol 2013;163:458-
adult T-cell acute lymphoblastic leukemia and T-lymphoblastic lymphoma. Am J Hematol 464.
24 Larson RA, Dodge RK, Linker CA, et al. A randomized control trial of filgrastim during
2018;93:91-99.
11 Linker C, Damon L, Ries C, Navarro W. Intensified and shortened cyclical chemotherapy remission induction and consolidation chemotherapy for adults with acute lymphoblastic
for adult acute lymphoblast leukemia. J Clin Oncol 2002;20:2464-2471. leukemia: CALGB 9111. Blood 1998;92:1556-1564.
12 Larson RA, Dodge RK, Burns CP, et al. A five-drug remission induction regimen with
intensive consolidation for adults with acute lymphoblastic leukemia: cancer and leukemia B
study 8811. Blood 1995;85:2025-2037.
13 Boissel N, Huguet F, Leguay T, et al. In adults with Ph-negative acute lymphoblastic
leukemia (ALL), age-adapted chemotherapy intensity and MRD-driven transplant indication
significantly reduces treatment-related mortality (TRM) and improves overall survival -
results from the GRAALL-2014 trial. Blood 2022;140(Supplement 1):112-114.

Note: For more information regarding the categories and definitions used for the NCCN Evidence Blocks™, see page EB-1.
All recommendations are category 2A unless otherwise indicated. ALL-D
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25 OF 28
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Acute Lymphoblastic Leukemia Table of Contents
Discussion
NCCN Evidence BlocksTM
PRINCIPLES OF SYSTEMIC THERAPY
REGIMENS FOR RELAPSED OR REFRACTORY Ph-POSITIVE B-ALLa,b
Other Recommended Regimens
• TKIc (dasatinib,1,2 imatinib,3 ponatinib,4 nilotinib,5 or bosutinib6)
The TKIs noted above may also be used in combination with any of the regimens noted on ALL-D 3 of 28 that were not previously given.
• Blinatumomab ± TKI7,8
• Inotuzumab ozogamicin ± TKI9,10
• Tisagenlecleucel (patients aged <26 years and with refractory disease or ≥2 relapses and following therapy that has included 2 TKIs)11
• Brexucabtagene autoleucel (following therapy that has included TKIs)12
• The regimens listed on ALL-D 27 of 28 for Ph-negative B-ALL may be considered for Ph-positive B-ALL refractory to TKIs.

See Evidence Blocks on ALL-D (EB-11)

References on ALL-D 26A of 28

a Allregimens include CNS prophylaxis with systemic therapy (eg, methotrexate, cytarabine) and/or IT therapy (eg, IT methotrexate, IT cytarabine; triple IT therapy with
methotrexate, cytarabine, corticosteroid).
b The safety of relapsed/refractory regimens in adults ≥65 years or adults with substantial comorbidities has not been established. Please see ALL-D 2 of 28 for
additional information.
c TKI options include (in alphabetical order): bosutinib, dasatinib, imatinib, nilotinib, or ponatinib. Not all TKIs have been directly studied within the context of each
specific regimen and the Panel notes that there are limited data for bosutinib in Ph+ ALL. Use of a specific TKI should account for anticipated/prior TKI intolerance,
dose used, BCR::ABL1 mutations, and disease-related features. Imatinib use in first line should be restricted to patients who cannot tolerate broader acting TKIs.
Jabbour E, et al. J Clin Oncol 2023;41(Suppl):Abstract 398868. For contraindicated mutations, see ALL-D 1 of 28.

Note: For more information regarding the categories and definitions used for the NCCN Evidence Blocks™, see page EB-1.
All recommendations are category 2A unless otherwise indicated. ALL-D
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NCCN Guidelines Version 2.2024 5

4
E = Efficacy of Regimen/Agent
S = Safety of Regimen/Agent NCCN Guidelines Index
Acute Lymphoblastic Leukemia 3
2
Q = Quality of Evidence
C = Consistency of Evidence Table of Contents
A = Affordability of Regimen/Agent
Discussion
NCCN Evidence BlocksTM
1
E S Q C A

EVIDENCE BLOCKS FOR REGIMENS FOR RELAPSED OR REFRACTORY Ph-POSITIVE B-ALL

Other Recommended Regimens

Dasatinib

Imatinib

Ponatinib

Nilotinib

Bosutinib

Blinatumomab

Blinatumomab + TKI†

Inotuzumab ozogamicin

Inotuzumab ozogamicin + bosutinib

Inotuzumab ozogamicin + dasatinib, imatinib, nilotinib, or ponatinib

Tisagenlecleucel (patients <26 y & with refractory disease or ≥2 relapses and following therapy that has included 2 TKIs)

Brexucabtagene autoleucel (following therapy that has included TKIs)

†TKI options include (in alphabetical order): bosutinib, dasatinib, imatinib, nilotinib, or ponatinib. Not all TKIs have been directly studied within the context of each specific regimen and the panel notes that there
are limited data for bosutinib in Ph+ ALL. Use of a specific TKI should account for anticipated/prior TKI intolerance, dose used, BCR::ABL1 mutations and disease-related features. Imatinib use in first line
should be restricted to patients who cannot tolerate broader acting TKIs. Jabbour E, et al. J Clin Oncol 2023;41, no. 36_suppl. 398868. For contraindicated mutations, see ALL-D 1 of 28.

Note: For more information regarding the categories and definitions used for the NCCN Evidence Blocks™, see page EB-1. ALL-D
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® ® ®
EB-11
The NCCN Evidence Blocks™ are subject to certain U.S. and foreign patents. Each approved use of the design of the NCCN Evidence Blocks™ requires the written approval of NCCN. Visit [Link]/patents for current list of applicable patents.
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Acute Lymphoblastic Leukemia Table of Contents
Discussion
NCCN Evidence BlocksTM
PRINCIPLES OF SYSTEMIC THERAPY
REFERENCES FOR REGIMENS FOR RELAPSED OR REFRACTORY Ph-POSITIVE B-ALL
1 LillyMB, Ottmann OG, Shah NP, et al. Dasatinib 140 mg once daily versus 70 mg twice daily in patients with Ph-positive acute lymphoblastic leukemia who failed
imatinib: Results from a phase 3 study. Am J Hematol 2010;85:164-170.
2 Ottmann O, Dombret H, Martinelli G, et al. Dasatinib induces rapid hematologic and cytogenetic responses in adult patients with Philadelphia chromosome positive
acute lymphoblastic leukemia with resistance or intolerance to imatinib: interim results of a phase 2 study. Blood 2007;110:2309-2315.
3 Ottmann OG, Druker BJ, Sawyers CL, et al. A phase 2 study of imatinib in patients with relapsed or refractory Philadelphia chromosome-positive acute lymphoid
leukemias. Blood 2002;100:1965-1971.
4 Cortes JE, Kim DW, Pinilla-Ibarz J, et al. A phase 2 trial of ponatinib in Philadelphia chromosome-positive leukemias. N Engl J Med 2013;369:1783-1796.
5 Kantarjian H, Giles F, Wunderle L, et al. Nilotinib in imatinib-resistant CML and Philadelphia chromosome-positive ALL. N Engl J Med 2006;354:2542-2551.
6 Gambacorti-Passerini C, Kantarjian HM, Kim DW, et al. Long-term efficacy and safety of bosutinib in patients with advanced leukemia following resistance/intolerance
to imatinib and other tyrosine kinase inhibitors. Am J Hematol 2015;90:755-768:
7 Martinelli G, Boissel N, Chevallier P, et al. Complete hematologic and molecular response in adult patients with relapsed/refractory Philadelphia Chromosome-positive
B-Precursor acute lymphoblastic leukemia following treatment with blinatumomab: results from a phase II, single-arm, multicenter study. J Clin Oncol 2017;35:1795-
1802.
8 Kantarjian H, Stein A, Gökbuget N, et al. Blinatumomab versus chemotherapy for advanced acute lymphoblastic leukemia. N Engl J Med 2017;376:836-847.
9 Kantarjian HM, DeAngelo DJ, Stelljes M, et al. Inotuzumab ozogamicin versus standard therapy for acute lymphoblastic leukemia. N Engl J Med 2016;375:740-753.
10 Jain N et al. Inotuzumab ozogamicin with bosutinib for relapsed or refractory Philadelphia chromosome positive acute lymphoblastic leukemia or lymphoid blast phase
of chronic myeloid leukemia. Am J Hematol. 2021;96:1000-1007.
11 Maude SL, Laetsch TW, Buechner J, et al. Tisagenlecleucel in children and young adults with b-cell lymphoblastic leukemia. N Engl J Med 2018;378:439-448.
12 Shah BD, Ghobadi A, Oluwole OO, et al. KTE-X19 for relapsed/refractory adult B-cell acute lymphoblastic leukemia. Lancet 2021;398:491-502.

Note: For more information regarding the categories and definitions used for the NCCN Evidence Blocks™, see page EB-1.
All recommendations are category 2A unless otherwise indicated. ALL-D
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Acute Lymphoblastic Leukemia Table of Contents
Discussion
NCCN Evidence BlocksTM
PRINCIPLES OF SYSTEMIC THERAPY
REGIMENS FOR RELAPSED OR REFRACTORY Ph-NEGATIVE B-ALLa,b,d,e
Preferred Regimens
• Blinatumomab (CD19 antigen directed) (category 1)1
• Inotuzumab ozogamicin (CD22 antigen directed) (category 1)2
• Tisagenlecleucel (CD19 antigen directed) (patients aged <26 years and with refractory disease or ≥2 relapses)3
• Brexucabtagene autoleucel (CD19 antigen directed)4
Other Recommended Regimensc
• Inotuzumab ozogamicin + mini-hyperCVD with or without sequential blinatumomab (cyclophosphamide, dexamethasone, vincristine, alternating
with methotrexate, cytarabine)5,6
• Augmented HyperCVAD: hyperfractionated cyclophosphamide, intensified vincristine, doxorubicin, intensified dexamethasone, pegaspargase;
alternating with high-dose methotrexate, cytarabine7
• Clofarabine alone8-11 or in combination (eg, clofarabine, cyclophosphamide, etoposide)9,12,13
• MOpAD regimen: methotrexate, vincristine, pegaspargase, dexamethasone; with rituximabf for CD20-positive disease14
• Fludarabine-based regimens
FLAG-IDA: fludarabine, cytarabine, G-CSFg ± idarubicin15
FLAM: fludarabine, cytarabine, mitoxantrone16
• Cytarabine-containing regimens: eg, high-dose cytarabine, idarubicin, IT methotrexate17
• Alkylator combination regimens: eg, etoposide, ifosfamide, mitoxantrone18

See Evidence Blocks on ALL-D (EB-12)

a All regimens include CNS prophylaxis with systemic therapy (eg, methotrexate,
cytarabine) and/or IT therapy (eg, IT methotrexate, IT cytarabine; triple IT therapy
with methotrexate, cytarabine, corticosteroid).
b For patients in late relapse (>3 years from initial diagnosis), consider treatment References on ALL-D 27A of 28
with the same induction regimen (see ALL-D 10 of 28).
c The safety of relapsed/refractory regimens in adults ≥65 years or adults with
substantial comorbidities has not been established. Please see ALL-D 2 of 28 for e PEG is substituted with Cal-PEG, an asparagine-specific enzyme, in patients
additional information. aged 15 to ≤21 years for more sustained asparaginase activity. Silverman LB, et
d For patients who develop hypersensitivity to E. coli-derived asparaginase, ERW- al. Blood 2016;128:175; Angiolillo AL, et al. J Clin Oncol 2014;32:3874-3882.
rywn should be substituted as a component of the multi-agent therapeutic regimen f An FDA-approved biosimilar is an appropriate substitute for rituximab.
to complete the full treatment course. g An FDA-approved biosimilar is an appropriate substitute for filgrastim.

Note: For more information regarding the categories and definitions used for the NCCN Evidence Blocks™, see page EB-1.
All recommendations are category 2A unless otherwise indicated. ALL-D
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NCCN Guidelines Version 2.2024 5

4
E = Efficacy of Regimen/Agent
S = Safety of Regimen/Agent NCCN Guidelines Index
Acute Lymphoblastic Leukemia 3
2
Q = Quality of Evidence
C = Consistency of Evidence Table of Contents
A = Affordability of Regimen/Agent
Discussion
NCCN Evidence BlocksTM
1
E S Q C A

EVIDENCE BLOCKS FOR REGIMENS FOR RELAPSED OR REFRACTORY Ph-NEGATIVE B-ALL

Preferred Regimens
Blinatumomab (CD19 antigen directed)

Inotuzumab ozogamicin (CD22 antigen directed)

Tisagenlecleucel (CD19 antigen directed; patients <26 years and with refractory disease or ≥2 relapses)

Brexucabtagene autoleucel (CD19 antigen directed)

Other Recommended Regimens
Inotuzumab ozogamicin + mini-hyperCVD

Inotuzumab ozogamicin + mini-hyperCVD + sequential blinatumumab

Augmented hyper-CVAD

Clofarabine

Clofarabine, cyclophosphamide, etoposide

MOpAD

MOpAD regimen/rituximab (for CD20-positive disease)

FLAG

FLAG-IDA

FLAM

Cytarabine-containing regimens (eg, high-dose cytarabine, idarubicin, IT methotrexate)

Alkylator combination regimens (eg, etoposide, ifosfamide, mitoxantrone)

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Discussion
NCCN Evidence BlocksTM
PRINCIPLES OF SYSTEMIC THERAPY
REFERENCES FOR REGIMENS FOR RELAPSED OR REFRACTORY Ph-NEGATIVE B-ALL
1 Kantarjian H, Stein A, Gökbuget N, et al. Blinatumomab versus chemotherapy for advanced acute lymphoblastic leukemia. N Engl J Med 2017;376:836-847.
2 Kantarjian HM, DeAngelo DJ, Stelljes M, et al. Inotuzumab ozogamicin versus standard therapy for acute lymphoblastic leukemia. N Engl J Med 2016;375:740-753.
3 Maude SL, Laetsch TW, Buechner J, et al. Tisagenlecleucel in children and young adults with b-cell lymphoblastic leukemia. N Engl J Med 2018;378:439-448.
4 Shah BD, Ghobadi A, Oluwole OO, et al. KTE-X19 for relapsed/refractory adult B-cell acute lymphoblastic leukemia. Lancet 2021;398:491-502.
5 Jabbour E, Ravandi F, Kebriaei P, et al. Salvage chemoimmunotherapy with inotuzumab ozogamicin combined with mini-Hyper-CVD for patients with relapsed or
refractory Philadelphia chromosome-negative acute lymphoblastic leukemia: A phase 2 clinical trial. JAMA Oncol 2018;4:230-234.
6 Jabbour E, Sasaki K, Short NJ, et al. Long-term follow-up of salvage therapy using a combination of inotuzumab ozogamicin and mini-hyper-CVD with or without
blinatumomab in relapsed/refractory Philadelphia chromosome-negative acute lymphoblastic leukemia. Cancer. 2021;127:2025-2038.
7 Faderl S, Thomas DA, O'Brien S, et al. Augmented hyper-CVAD based on dose-intensified vincristine, dexamethasone, and asparaginase in adult acute lymphoblastic
leukemia salvage therapy. Clin Lymphoma Myeloma Leuk 2011;11:54-59.
8 Jeha S, Gaynon PS, Razzouk BI, et al. Phase II study of clofarabine in pediatric patients with refractory or relapsed acute lymphoblastic leukemia. J Clin Oncol
2006;24:1917-1923.
9 Alkhateeb HB, Damlaj M, Lin T, et al. Clofarabine based chemotherapy in adult relapsed/refractory acute leukemia/lymphoma: a single institution. Blood
2015;126:4910.
10 Kantarjian H, Gandhi V, Cortes J, et al. Phase 2 clinical and pharmacologic study of clofarabine in patients with refractory or relapsed acute leukemia. Blood
2003;102:2379-2386.
11 Kantarjian HM, Gandhi V, Kozuch P, et al. Phase I clinical and pharmacology study of clofarabine in patients with solid and hematologic cancers. J Clin Oncol
2003;21:1167-1173.
12 Miano M, Pistorio A, Putti MC, et al. Clofarabine, cyclophosphamide and etoposide for the treatment of relapsed or resistant acute leukemia in pediatric patients. Leuk
Lymphoma 2012;53:1693-1698.
13 Hijiya N, Thomson B, Isakoff MS, et al. Phase 2 trial of clofarabine in combination with etoposide and cyclophosphamide in pediatric patients with refractory or
relapsed acute lymphoblastic leukemia. Blood 2011;118:6043-6049.
14 Kadia TM, Kantarjian HM, Thomas DA, et al. Phase II study of methotrexate, vincristine, pegylated-asparaginase, and dexamethasone (MOpAD) in patients with
relapsed/refractory acute lymphoblastic leukemia. Am J Hematol 2015;90:120-124.
15 Specchia G, Pastore D, Carluccio P, et al. FLAG-IDA in the treatment of refractory/relapsed adult acute lymphoblastic leukemia. Ann Hematol 2005;84:792-795.
16 Giebel S, Krawczyk-Kulis M, Adamczyk-Cioch M, et al. Fludarabine, cytarabine, and mitoxantrone (FLAM) for the treatment of relapsed and refractory adult acute
lymphoblastic leukemia. A phase study by the Polish Adult Leukemia Group (PALG). Ann Hematol 2006;85:717-722.
17 Weiss MA, Aliff TB, Tallman MS, et al. A single, high dose of idarubicin combined with cytarabine as induction therapy for adult patients with recurrent or refractory
acute lymphoblastic leukemia. Cancer 2002;95:581-587.
18 Schiller G, Lee M, Territo M, Gajewski J, Nimer S. Phase II study of etoposide, ifosfamide, and mitoxantrone for the treatment of resistant adult acute lymphoblastic
leukemia. Am J Hematol 1993;43:195-199.

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All recommendations are category 2A unless otherwise indicated. ALL-D
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Acute Lymphoblastic Leukemia Table of Contents
Discussion
NCCN Evidence BlocksTM
PRINCIPLES OF SYSTEMIC THERAPY
REGIMENS FOR RELAPSED OR REFRACTORY T-ALLa,b,c,d,e
Preferred Regimens
• Nelarabine1-4 ± etoposide, cyclophosphamide5-7
Other Recommended Regimens
• Bortezomib-containing regimen8
• Daratumumab-containing regimen (category 2B)9-13
• High-dose cytarabine-containing regimen14,15
• Mitoxantrone, etoposide, cytarabine16
• Venetoclax-containing regimen (eg, decitabine, dose-adjusted HyperCVAD, nelarabine, mini-hyperCVD) (category 2B)17-19
The following regimens for relapsed/refractory Ph-negative B-ALL may be appropriate/considered for relapsed/refractory T-ALL:
• Augmented HyperCVAD: hyperfractionated cyclophosphamide, intensified vincristine, doxorubicin, intensified dexamethasone, pegaspargase;
alternating with high-dose methotrexate, cytarabine20
• Clofarabine alone21-24 or in combination (eg, clofarabine, cyclophosphamide, etoposide)22,25,26
• MOpAD regimen: methotrexate, vincristine, pegaspargase, dexamethasone
• Fludarabine-based regimens
FLAG-IDA: fludarabine, cytarabine, G-CSFf ± idarubicin27
FLAM: fludarabine, cytarabine, mitoxantrone28
• Cytarabine-containing regimens: eg, high-dose cytarabine, idarubicin, IT methotrexate29
• Alkylator combination regimens: eg, etoposide, ifosfamide, mitoxantrone30

See Evidence Blocks on ALL-D (EB-13)

a All regimens include CNS prophylaxis with systemic therapy (eg, methotrexate,
cytarabine) and/or IT therapy (eg, IT methotrexate, IT cytarabine; triple IT therapy
with methotrexate, cytarabine, corticosteroid).
b The safety of relapsed/refractory regimens in adults ≥65 years or adults with References on ALL-D 28A of 28
substantial comorbidities has not been established. Please see ALL-D 2 of 28 for
additional information.
c For patients in late relapse (>3 years from initial diagnosis), consider treatment
with the same induction regimen (see ALL-D 19 of 28). e PEG is substituted with Cal-PEG, an asparagine-specific enzyme, in patients
d For patients who develop hypersensitivity to E. coli-derived asparaginase, ERW- aged 15 to ≤21 years for more sustained asparaginase activity. Silverman LB, et
rywn should be substituted as a component of the multi-agent therapeutic regimen al. Blood 2016;128:175; Angiolillo AL, et al. J Clin Oncol 2014;32:3874-3882.
to complete the full treatment course. f An FDA-approved biosimilar is an appropriate substitute for filgrastim.

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All recommendations are category 2A unless otherwise indicated. ALL-D
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NCCN Guidelines Version 2.2024 5

4
E = Efficacy of Regimen/Agent
S = Safety of Regimen/Agent NCCN Guidelines Index
Acute Lymphoblastic Leukemia 3
2
Q = Quality of Evidence
C = Consistency of Evidence Table of Contents
A = Affordability of Regimen/Agent
Discussion
NCCN Evidence BlocksTM
1
E S Q C A

EVIDENCE BLOCKS FOR REGIMENS FOR RELAPSED OR REFRACTORY T-ALL

Preferred Regimens
Nelarabine

Nelarabine + etoposide and cyclophosphamide

Other Recommended Regimens
Bortezomib containing regimen

Daratumumab containing regimen

High-dose cytarabine containing regimen

Mitoxantrone, etoposide, cytarabine

Venetoclax containing regimen (eg, decitabine, hyper-CVAD, nelarabine, mini-hyper-CVD)

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EB-13
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Acute Lymphoblastic Leukemia Table of Contents
Discussion
NCCN Evidence BlocksTM
PRINCIPLES OF SYSTEMIC THERAPY
REFERENCES FOR REGIMENS FOR RELAPSED OR REFRACTORY T-ALL
1 DeAngelo DJ, Yu D, Johnson JL, et al. Nelarabine induces complete remissions in adults with relapsed or refractory T-lineage acute lymphoblastic leukemia or
lymphoblastic lymphoma: Cancer and Leukemia Group B study 19801. Blood 2007;109:5136-5142.
2 Zwaan CM, Kowalczyk J, Schmitt C, et al. Safety and efficacy of nelarabine in children and young adults with relapsed/refractory T-lineage acute lymphoblastic
leukaemia or T-lineage lymphoblastic lymphoma: results of phase 4 study. Br J Haematol 2017;179:284-293.
3 Gokbuget N, Basara N, Baumann H, et al. High single-drug activity of nelarabine in relapsed T-lymphoblastic leukemia/lymphoma offers curative option with
subsequent stem cell transplantation. Blood 2011;118:3504-3511.
4 Candoni A, Lazzarotto D, Ferrara F, et al. Nelarabine as salvage therapy and bridge to allogenic stem cell transplant in 118 adult patients with relapsed/refractory T-cell
acute lymphoblastic leukemia/lymphoma. A CAMPUS ALL study. Am J Hematol 2020;95:1466-1472.
5 Luskin MR, Ganetsky A, Landsburg DJ, et al. Nelarabine, cyclophosphamide and etoposide for adults with relapsed T-cell acute lymphoblastic leukaemia and
lymphoma. Br J Haematol 2016;174:332-334.
6 Commander LA, Seif AE, Insogna IG, Rheingold SR. Salvage therapy with nelarabine, etoposide, and cyclophosphamide in relapsed/refractory paediatric T-cell
lymphoblastic leukaemia and lymphoma. Br J Haematol 2010;150:345-351.
7 Whitlock J, dalla Pozza L, Goldberg JM, et al. Nelarabine in combination with etoposide and cyclophosphamide is active in first relapse of childhood T-acute
lymphocytic leukemia (T-ALL) and T-lymphoblastic lymphoma (T-LL). Blood 2014;124:795.
8 Horton TM, Whitlock JA, Lu X, et al. Bortezomib reinduction chemotherapy in high-risk ALL in first relapse: a report from the Children's Oncology Group. Br J Haematol
2019;186:274-285.
9 Ofran Y, Ringelstein-Harlev S, Slouzkey I, et al. Daratumumab for eradication of minimal residual disease in high-risk advanced relapse of T-cell/CD19/CD22-negative
acute lymphoblastic leukemia. Leukemia 2020;34:293-295.
10 Ruhayel SD, Valvi S. Daratumumab in T-cell acute lymphoblastic leukemia: A case report and review of the literature. Pediatr Blood Cancer 2020;68:e28829.
11 Cerrano M, Castella B, Lia G, et al. Immunomodulatory and clinical effects of daratumumab in T-cell acute lymphoblastic leukemia. Br J Haematol 2020;191:e28-e32.
12 Mirgh S, Ahmed R, Agrawal N, et al. Will daratumumab be the next game changer in early thymic precursor-acute lymphoblastic leukemia? Br J Haematol
2019;187:e33-e35.
13 Bonda A, Punatar S, Gokarn A, et al. Daratumumab at the frontiers of post-transplant refractory T-acute lymphoblastic leukemia-a worthwhile strategy? Bone Marrow
Transplant 2018;53:1487-1489.
14 Rudnick SA, Cadman EC, Capizzi RL, Skeel RT, Bertino JR, McIntosh S. High dose cytosine arabinoside (HDARAC) in refractory acute leukemia. Cancer.
1979;44:1189-1193.
15 Kantarjian HM, DeAngelo DJ, et al. Inotuzumab ozogamicin versus standard therapy for acute lymphoblastic leukemia. N Engl J Med 2016;375:740-753.
16 Liedtke M, Dunn T, Dinner S, et al. Salvage therapy with mitoxantrone, etoposide and cytarabine in relapsed or refractory acute lymphoblastic leukemia. Leuk Res
2014;38:1441-1445.
17 Richard-Carpentier G, Jabbour E, Short NJ, et al. Clinical experience with venetoclax combined with chemotherapy for relapsed or refractory T-Cell acute
lymphoblastic leukemia. Clin Lymphoma Myeloma Leuk 2020;20:212-218.
18 Parovichnikova E, Gavrilina O, Troitskaya V, et al. Veneotoclax plus decitabine in the treatment of MRD-persistent and relapsed/refractory T-cell acute lymphoblastic
leukemia. European Hematology Association Congress 2020;EP427.
19 Jain N, Stevenson KE, Winer ES, et al. A multicenter phase I study combining venetoclax with mini-hyper-CVD in older adults with untreated and relapsed/refractory
acute lymphoblastic leukemia. Blood 2019;134:3867.

Continued

Note: For more information regarding the categories and definitions used for the NCCN Evidence Blocks™, see page EB-1.
All recommendations are category 2A unless otherwise indicated. ALL-D
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Discussion
NCCN Evidence BlocksTM
PRINCIPLES OF SYSTEMIC THERAPY
REFERENCES FOR REGIMENS FOR RELAPSED OR REFRACTORY T-ALL
20 Faderl S, Thomas DA, O'Brien S, et al. Augmented hyper-CVAD based on dose-intensified vincristine, dexamethasone, and asparaginase in adult acute lymphoblastic
leukemia salvage therapy. Clin Lymphoma Myeloma Leuk 2011;11:54-59.
21 Jeha S, Gaynon PS, Razzouk BI, et al. Phase II study of clofarabine in pediatric patients with refractory or relapsed acute lymphoblastic leukemia. J Clin Oncol
2006;24:1917-1923.
22 Alkhateeb HB, Damlaj M, Lin T, et al. Clofarabine based chemotherapy in adult relapsed/refractory acute leukemia/lymphoma: a single institution. Blood
2015;126:4910.
23 Kantarjian H, Gandhi V, Cortes J, et al. Phase 2 clinical and pharmacologic study of clofarabine in patients with refractory or relapsed acute leukemia. Blood
2003;102:2379-2386.
24 Kantarjian HM, Gandhi V, Kozuch P, et al. Phase I clinical and pharmacology study of clofarabine in patients with solid and hematologic cancers. J Clin Oncol
2003;21:1167-1173.
25 Miano M, Pistorio A, Putti MC, et al. Clofarabine, cyclophosphamide and etoposide for the treatment of relapsed or resistant acute leukemia in pediatric patients. Leuk
Lymphoma 2012;53:1693-1698.
26 Hijiya N, Thomson B, Isakoff MS, et al. Phase 2 trial of clofarabine in combination with etoposide and cyclophosphamide in pediatric patients with refractory or
relapsed acute lymphoblastic leukemia. Blood 2011;118:6043-6049.
27 Specchia G, Pastore D, Carluccio P, et al. FLAG-IDA in the treatment of refractory/relapsed adult acute lymphoblastic leukemia. Ann Hematol 2005;84:792-795.
28 Giebel S, Krawczyk-Kulis M, Adamczyk-Cioch M, et al. Fludarabine, cytarabine, and mitoxantrone (FLAM) for the treatment of relapsed and refractory adult acute
lymphoblastic leukemia. A phase study by the Polish Adult Leukemia Group (PALG). Ann Hematol 2006;85:717-722.
29 Weiss MA, Aliff TB, Tallman MS, et al. A single, high dose of idarubicin combined with cytarabine as induction therapy for adult patients with recurrent or refractory
acute lymphoblastic leukemia. Cancer 2002;95:581-587.
30 Schiller G, Lee M, Territo M, et al. Phase II study of etoposide, ifosfamide, and mitoxantrone for the treatment of resistant adult acute lymphoblastic leukemia. Am J
Hematol 1993;43:195-199.

Note: For more information regarding the categories and definitions used for the NCCN Evidence Blocks™, see page EB-1.
All recommendations are category 2A unless otherwise indicated. ALL-D
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RESPONSE ASSESSMENT

Response Criteria for Blood and Bone Marrowa,1-3

Complete remission (CR) • No circulating lymphoblasts or extramedullary disease
No lymphadenopathy, splenomegaly, skin/gum infiltration, testicular mass, CNS involvement, or other
extramedullary involvement
• Trilineage hematopoiesis (TLH) and <5% leukemic blasts
• Absolute neutrophil count (ANC) ≥1000/microL
• Platelets ≥100,000/microL
CR with partial hematologic • Meets all criteria for CR except with partial recovery of peripheral blood counts (platelets ≥50,000/microL
recovery (CRh) and ANC ≥500/microL)
CR with incomplete • Meets all criteria for CR except without recovery of platelet count or without recovery of ANC (platelets
hematologic recovery (CRi) <100,000/microL and ANC ≥1000/microL or platelets ≥100,000/microL and ANC <1000/microL)

Response assessment for those not achieving CRa,1-3

Morphologic leukemia-free • Leukemic blasts <5% and no measurable extramedullary leukemia
state (MLFS) • ANC <500/microL and platelets <50/microL
• The marrow shows ≥10% cellularity, with at least 200 cells enumerated from an aspirate that contains
spicules
Aplastic marrowb • All criteria for MLFS are met, but with <10% cellularity and/or an aspicular aspirate with <200 cells that
can be enumerated
Refractory disease • CR not achieved at the end of induction
Progressive disease (PD) • Appearance of circulating leukemic blasts or an increase of at least 25% in the absolute number of
circulating or bone marrow blasts or development of extramedullary disease
Relapsed disease • Reappearance of blasts in the blood or bone marrow (>5%) or in any extramedullary site after a CR

Response Criteria for CNS Disease and Lymphomatous Extramedullary Disease (ALL-E 2 of 2)

1 Bloomfield CD, Estey E, Pleyer L, et al. Time to repeal and replace response criteria for acute myeloid
leukemia? Blood Rev 2018;32:416-425.
2 Buchmann S, Schrappe M, Baruchel A, et al. Remission, treatment failure, and relapse in pediatric ALL: An
a MRD assessment is not included in morphologic international consensus of the Ponte-di-Legno Consortium. Blood 2022;139:1785-1793.
assessment and should be obtained (ALL-F). 3 Shah BD, Ghobadi A, Oluwole OO, et al. KTE-X19 for relapsed or refractory adult B-cell acute lymphoblastic
b This entity may not be consistent with a response. leukaemia: phase 2 results of the single-arm, open-label, multicentre ZUMA-3 study. Lancet 2021;398:491-502.

Note: For more information regarding the categories and definitions used for the NCCN Evidence Blocks™, see page EB-1.
All recommendations are category 2A unless otherwise indicated. ALL-E
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RESPONSE ASSESSMENT

Response Criteria for CNS Disease

CNS remission • Achievement of CNS-1 status (ALL-B) in a patient with CNS-2 or CNS-3 status at diagnosis.
CNS relapse • New development of CNS-2 or CNS-3 status or clinical signs of CNS leukemia such as facial nerve palsy, brain/eye
involvement, or hypothalamic syndrome without another explanation.

Response Criteria for Lymphomatous Extramedullary Disease

• CT of neck/chest/abdomen/pelvis with IV contrast and PET/CT if lymphomatous involvement is suspected and/or confirmed by CT, imaging
should be performed to assess response for extramedullary disease.
CR • Complete resolution of lymphomatous enlargement by CT. For patients with a previous positive PET scan, a post-
treatment residual mass of any size is considered a CR as long as it is PET negative.
Partial remission • >50% decrease in the sum of the product of the greatest perpendicular diameters (SPD) of the lymphomatous
(PR) enlargement. For patients with a previous positive PET scan, post-treatment PET must be positive in at least one
previously involved site.
PD • >25% increase in the SPD of the lymphomatous enlargement. For patients with a previous positive PET scan, post-
treatment PET must be positive in at least one previously involved site.
No response (NR) • Does not meet criteria for either PR or PD.
Relapse • Recurrence of lymphomatous enlargement after achieving CR.

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All recommendations are category 2A unless otherwise indicated. ALL-E
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MINIMAL/MEASURABLE RESIDUAL DISEASE ASSESSMENT
• MRD refers to the presence of leukemic cells below the threshold of detection by conventional morphologic methods or standard
immunophenotyping.
• MRD quantification is an essential component of patient evaluation over the course of sequential ALL therapy.
• Studies in children and adults with ALL have demonstrated a strong correlation between the presence of MRD during remission and risk for
relapse, as well as the prognostic significance of MRD measurements after induction and consolidation therapy.1
• The preferred sample for MRD assessment is the first small volume (of up to 3 mL) pull of the bone marrow aspirate, if feasible.
• If validated MRD assessment technology with appropriate sensitivity (at least 10-4) is not available locally, there are commercially available
tests.
• The most frequently used methods for MRD quantification include an FDA-approved NGS-based assay to detect fusion genes or clonal
rearrangements in Ig and T-cell receptor (TCR) loci (does not require patient-specific primers) (preferred), flow cytometry assays2,3
specifically designed to detect abnormal MRD immunophenotypes at low frequency, real-time quantitative PCR (RQ-PCR) assays (eg,
clonally rearranged Ig, TCR genes), and RT-qPCR assays (eg, BCR::ABL1).
• High-sensitivity flow cytometry with validated analysis algorithms or PCR methods can quantify leukemic cells at a sensitivity threshold of
1 × 10-4 (0.01%) bone marrow mononuclear cells (MNCs).2,3 NGS and some PCR methods can detect leukemic cells at a sensitivity threshold
of 1 x 10-6 (0.0001%) MNCs.4,5
If MRD is negative by flow cytometry, an FDA-approved NGS assay should be considered to confirm negativity.
• For flow cytometric quantification of MRD, notify laboratory performing the assay if the patient has received immunotherapy (such as
monoclonal antibodies, bispecific antibodies, or CAR T cells) or HCT as these treatments can affect interpretation. Such testing should be
performed in a laboratory with experience performing MRD testing in this clinical setting.
• Timing of MRD assessment:
Upon completion of initial induction.
End of consolidation
Additional time points should be guided by the regimen used and risk features.
Serial monitoring frequency may be increased in patients with molecular relapse or persistent low-level disease burden.
For some techniques, a baseline sample (ie, prior to treatment) is needed to characterize the leukemic clone for subsequent MRD
assessment.

1 Berry DA, Zhou S, Higley H, et al. Association of minimal residual disease with clinical
outcome in pediatric and adult lymphoblastic leukemia. JAMA Oncol 2017;3:e170580.
2 Gaipa G, Cazzaniga G, Valsecchi MG, et al. Time point-dependent concordance
of flow cytometry and real-time quantitative polymerase chain reaction for minimal 4 Bruggemann M, Schrauder A, Raff T, et al. Standardized MRD quantification
residual disease detection in childhood acute lymphoblastic leukemia. Haematologica in European ALL trials: proceedings of the Second International Symposium
2012;97:1582-1593. on MRD assessment in Kiel, Germany, 18-20 September 2008. Leukemia
3 Denys B, van der Sluijs-Gelling AJ, Homburg C, et al. Improved flow cytometric 2010;24:521-535.
detection of minimal residual disease in childhood acute lymphoblastic leukemia. 5 Campana D. Minimal residual disease in acute lymphoblastic leukemia.
Leukemia 2013;27:635-641. Hematology Am Soc Hematol Educ Program 2010;2010:7-12.

Note: For more information regarding the categories and definitions used for the NCCN Evidence Blocks™, see page EB-1.
All recommendations are category 2A unless otherwise indicated.
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ALL-F
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NCCN Guidelines Version 2.2024 NCCN Guidelines Index

Acute Lymphoblastic Leukemia Table of Contents
Discussion
NCCN Evidence BlocksTM
ABBREVIATIONS

6-MP 6-mercaptopurine CRi complete remission with ICC International Consensus

incomplete hematologic recovery Classification
ADL activity of daily living CRS cytokine release syndrome Ig immunoglobulin
ALL acute lymphoblastic leukemia CSF cerebrospinal fluid IT intrathecal
ALT alanine aminotransferase CTCAE common terminology criteria for
adverse events LDH lactate dehydrogenase
AML acute myeloid leukemia
AST aspartate aminotransferase LFT liver function test
DIC disseminated intravascular LL lymphoblastic lymphoma
AT antithrombin coagulation
AYA adolescent and young adult LP lumbar puncture
DLI donor lymphocyte infusion

B-ALL B-cell acute lymphoblastic MDS myelodysplastic syndrome(s)

ETP early T-cell precursor
leukemia MLFS morphologic leukemia-free state
BP- blast phase chronic myeloid MNC mononuclear cell
CML leukemia FISH fluorescence in situ hybridization
MRD minimal/measurable residual
disease
CAR chimeric antigen receptor G-CSF granulocyte colony-stimulating
factor
CBC complete blood count N/A not applicable
cGH comparative genomic hybridization NGS next-generation sequencing
H&E hematoxylin and eosin
CMA chromosome microarray analysis NOS not otherwise specified
H&P history and physical
CML chronic myeloid leukemia NR no response
HCT hematopoietic cell transplant
CMML chronic myelomonocytic leukemia
HIV human immunodeficiency virus
CNS central nervous system PCR polymerase chain reaction
COG Children’s Oncology Group
IADL instrumental activities of daily PD progressive disease
CR complete remission living PEG pegaspargase
CRh complete remission with partial iAMP21 intrachromosomal amplification of
hematologic recovery Ph Philadelphia chromosome
chromosome 21
PR partial remission
Continued

ABBR-1
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NCCN Guidelines Version 2.2024 NCCN Guidelines Index

Acute Lymphoblastic Leukemia Table of Contents
Discussion
NCCN Evidence BlocksTM
ABBREVIATIONS

PT prothrombin time
PTT partial thromboplastin time

RBC red blood cell

RT- reverse transcription polymerase
PCR chain reaction

SOS sinusoidal obstruction syndrome

SPD sum of product of greatest
perpendicular diameters

T-ALL/ T-cell acute lymphoblastic

T-LBL leukemia/lymphoma
TCR T-cell receptor
TDM therapeutic drug monitoring
TKI tyrosine kinase inhibitor
TLS tumor lysis syndrome

VOD veno-occlusive disease

WBC white blood cell

ABBR-2
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NCCN Guidelines Version 2.2024 NCCN Guidelines Index

Acute Lymphoblastic Leukemia Table of Contents
Discussion
NCCN Evidence BlocksTM
NCCN Categories of Evidence and Consensus
Category 1 Based upon high-level evidence (≥1 randomized phase 3 trials or high-quality, robust meta-analyses), there is
uniform NCCN consensus (≥85% support of the Panel) that the intervention is appropriate.
Category 2A Based upon lower-level evidence, there is uniform NCCN consensus (≥85% support of the Panel) that the
intervention is appropriate.
Category 2B Based upon lower-level evidence, there is NCCN consensus (≥50%, but <85% support of the Panel) that the
intervention is appropriate.
Category 3 Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate.
All recommendations are category 2A unless otherwise indicated.

NCCN Categories of Preference

Interventions that are based on superior efficacy, safety, and evidence; and, when appropriate,
Preferred intervention affordability.
Other recommended Other interventions that may be somewhat less efficacious, more toxic, or based on less mature data;
intervention or significantly less affordable for similar outcomes.
Useful in certain
Other interventions that may be used for selected patient populations (defined with recommendation).
circumstances
All recommendations are considered appropriate.

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Acute Lymphoblastic Leukemia

Discussion This discussion corresponds to the NCCN Guidelines for Initial Treatment in AYA Patients with Ph-Positive B-ALL .................. 16
Acute Lymphoblastic Leukemia. Last updated: July 19, 2024 Initial Treatment in Adults with Ph-Positive B-ALL ............................. 20
Treatment of Relapsed Ph-Positive B-ALL ........................................ 23
Table of Contents NCCN Recommendations for Ph-Positive B-ALL .............................. 27
Management of Ph-Negative ALL ..................................................................................29
Overview ........................................................................................................................ 2

Guidelines Update Methodology ..................................................................................... 3 Initial Treatment in AYA Patients with Ph-Negative ALL .................... 29
Initial Treatment in Adults with Ph-Negative ALL ............................... 36
Literature Search Criteria................................................................................................ 3
Treatment of Relapsed Ph-Negative ALL .......................................... 42
Sensitive/Inclusive Language Usage .............................................................................. 3
NCCN Recommendations for Ph-Negative B-ALL ............................. 47
Diagnosis ....................................................................................................................... 3
NCCN Recommendations for T-ALL ................................................. 50
Clinical Presentation and Diagnosis ................................................... 3 Management of Lymphoblastic Lymphoma ...................................................................51

Immunophenotyping........................................................................... 5 Evaluation and Treatment of Extramedullary Disease ...................................................51

Cytogenetic and Molecular Subtypes.................................................. 6
CNS Involvement in ALL .................................................................. 51
Workup ........................................................................................................................... 8
NCCN Recommendations for Evaluation and Treatment of
Prognostic Factors and Risk Stratification ....................................................................... 9 Extramedullary Involvement ............................................................. 52
Response Assessment and Surveillance .......................................................................53
Prognostic Factors in AYA Patients with ALL ...................................... 9
Prognostic Factors in Adults with ALL .............................................. 10 Response Criteria ............................................................................ 53
NCCN Recommendations for Risk Assessment in ALL ..................... 12 Surveillance ..................................................................................... 54
Overview of Treatment Phases in ALL Management..................................................... 13 Role of MRD Evaluation ................................................................................................54

Induction .......................................................................................... 13 MRD Assessment in Childhood ALL ................................................. 55

CNS Prophylaxis and Treatment ...................................................... 14 MRD Assessment in Adult ALL ......................................................... 58
Consolidation ................................................................................... 14 NCCN Recommendations for MRD Assessment ............................... 60
Hematopoietic Stem Cell Transplantation ......................................... 14 Supportive Care for Patients with ALL ...........................................................................60

Maintenance .................................................................................... 14 NCCN Recommendations for Supportive Care ................................. 61

Targeted Agents .............................................................................. 15 References ...................................................................................................................66
Management of Ph-Positive B-ALL ............................................................................... 16
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Acute Lymphoblastic Leukemia

Overview overall survival (OS) rates of 89% and 61%, respectively. 18,19 However,
Acute lymphoblastic leukemia (ALL) is a heterogeneous hematologic survival rates for adult patients remain low at approximately 20% to
disease characterized by the proliferation of immature lymphoid cells in 40%.20-22 Survival rates are especially poor in adult patients who are
the bone marrow, peripheral blood, and other organs.1 The age-adjusted older, at approximately 20%. 21,23,24 Although the exact OS percentage
incidence rate of ALL in the United States is 1.8 per 100,000 individuals can vary based on how the age range is defined for pediatric, AYA, and
per year,2 with approximately 6550 new cases and 1330 deaths estimated adult patients, the trend is nonetheless clear that OS decreases
in 2024.3 The median age at diagnosis for ALL is 17 years, with 53.5% of substantially with increased age. 21 The exception is infants <1 year of
patients diagnosed at <20 years of age.2 In contrast, 29.6% of patients are age, which is an age group that has not seen any improvement in
diagnosed at ≥45 years of age and only approximately 13.7% of patients survival over the last 30 years. The 5-year OS in this population is
are diagnosed at ≥65 years of age.2 ALL represents 75% to 80% of acute 55.8%18 (see Cytogenetic and Molecular Subtypes). Cure rates for AYA
leukemias among children, making it the most common form of childhood patients with ALL remain suboptimal compared with those for children,
leukemia; by contrast, ALL represents approximately 20% of all leukemias although substantial improvements have been seen with the adoption of
among adults.1,4 pediatric treatment regimens. 25 AYA patients represent a unique
population, because they may receive treatment based on either a
Risk factors for developing ALL include age >70 years, exposure to pediatric or an adult protocol, depending on local referral patterns and
chemotherapy or radiation therapy, and genetic disorders, particularly institutional practices. Favorable cytogenetic subtypes, such as
Down syndrome.5,6 Although rare, other genetic conditions have been ETV6::RUNX1 ALL and hyperdiploidy, occur less frequently among AYA
categorized as a risk factor for ALL and include Li-Fraumeni syndrome,7 patients compared with children, whereas the incidence of ALL in
neurofibromatosis,8 Klinefelter syndrome,9-11 Fanconi anemia,12,13 high-risk subgroups such as BCR::ABL (Philadelphia chromosome
Shwachman-Diamond syndrome,14,15 Bloom syndrome,16 and ataxia [Ph]-positive ALL) or with Ph-like ALL26 is higher in AYA patients.
telangiectasia.17
The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®)
The cure rates and survival outcomes for patients with ALL have improved for Acute Lymphoblastic Leukemia were developed as a result of meetings
dramatically over the past several decades, primarily among children.18 convened by a multidisciplinary Panel of ALL experts, with the goal of
Improvements are largely owed to advances in the understanding of the providing recommendations on standard treatment approaches based on
molecular genetics and pathogenesis of the disease, the incorporation of current evidence. The NCCN Guidelines focus on the classification of ALL
minimal residual disease (MRD) testing, the refinement of risk-adapted subtypes based on immunophenotype and cytogenetic/molecular markers;
treatment algorithms, the advent of new targeted agents, and the use of risk assessment and stratification for risk-adapted therapy; treatment
allogeneic hematopoietic cell transplantation (HCT). strategies for Ph-positive and Ph-negative ALL for both AYA and adult
patients; and supportive care considerations. Given the complexity of ALL
Analyses from the SEER database have shown improvements in survival treatment regimens and the required supportive care measures, the
for pediatric and adolescent and young adult (AYA) patients with 5-year

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Acute Lymphoblastic Leukemia

NCCN ALL Panel recommends that patients be treated at a specialized inclusive of individuals of all sexual orientations and gender identities.
cancer center with expertise in the management of ALL. NCCN Guidelines incorporate non-gendered language, instead focusing
on organ-specific recommendations. This language is both more accurate
Guidelines Update Methodology and more inclusive and can help fully address the needs of individuals of
The complete details of the Development and Update of the NCCN all sexual orientations and gender identities. NCCN Guidelines will
Guidelines are available at [Link]. continue to use the terms men, women, female, and male when citing
statistics, recommendations, or data from organizations or sources that do
Literature Search Criteria not use inclusive terms. Most studies do not report how sex and gender
Prior to the update of the NCCN Guidelines® for Acute Lymphoblastic data are collected and use these terms interchangeably or inconsistently.
Leukemia, an electronic search of the PubMed database was performed to If sources do not differentiate gender from sex assigned at birth or organs
obtain key literature in acute lymphoblastic leukemia published since the present, the information is presumed to predominantly represent cisgender
previous Guidelines update, using the following search terms: acute individuals. NCCN encourages researchers to collect more specific data in
lymphoblastic leukemia, B-cell acute lymphoblastic leukemia, and T-cell future studies and organizations to use more inclusive and accurate
acute lymphoblastic anemia. The PubMed database was chosen as it language in their future analyses.
remains the most widely used resource for medical literature and indexes
peer-reviewed biomedical literature.27 Results were confined to the Diagnosis
following article types: Clinical Trial, Phase II; Clinical Trial, Phase III; Clinical Presentation and Diagnosis
Clinical Trial, Phase IV; Guideline; Practice Guideline; Meta-Analysis; The clinical presentation of ALL is typically nonspecific, and may include
Randomized Controlled Trial; Systematic Reviews; and Validation Studies. fatigue or lethargy, constitutional symptoms (eg, fevers, night sweats,
weight loss), dyspnea, dizziness, infections, and easy bruising or
The data from key PubMed articles as well as articles from additional
bleeding.1,28 Among children, pain in the extremities or joints may be the
sources deemed as relevant to these Guidelines and discussed by the
only presenting symptom.1 The presence of lymphadenopathy,
Panel during the Guidelines update have been included in this version of
splenomegaly, and/or hepatomegaly on physical examination may be
the Discussion section. Recommendations for which high-level evidence is
found in approximately 20% of patients. Abdominal masses from
lacking are based on the Panel’s review of lower-level evidence and
gastrointestinal (GI) involvement, or chin numbness resulting from cranial
expert opinion.
nerve involvement, are more suggestive of mature B-cell ALL (B-ALL).1,28
Sensitive/Inclusive Language Usage The diagnosis of ALL generally requires demonstration of ≥20% bone
NCCN Guidelines strive to use language that advances the goals of marrow lymphoblasts on hematopathology review of bone marrow aspirate
equity, inclusion, and representation. NCCN Guidelines endeavor to use and biopsy materials. Peripheral blood may be substituted for bone
language that is person-first; not stigmatizing; anti-racist, anti-classist, marrow provided there is a significant amount of circulating disease,29,30
anti-misogynist, anti-ageist, anti-ableist, and anti-weight-biased; and with the NCCN ALL Panel suggesting a general guide of ≥1000 circulating
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lymphoblasts per microliter. The WHO classification lists ALL and t(5;14)(q31;q32), IL3::IGH.31 During the 2016 WHO classification update,
lymphoblastic lymphoma as the same entity, distinguished only by the two new provisional entities were added to the B-ALL classification:
primary location of the disease.31 When the disease is restricted to a mass B-lymphoblastic leukemia/lymphoma with translocations involving tyrosine
lesion primarily involving nodal or extranodal sites with no or minimal kinases or cytokine receptors (BCR::ABL1–like ALL or Ph-like ALL)32-34
involvement in blood or bone marrow (generally defined as <20% and B-lymphoblastic leukemia/lymphoma with intrachromosomal
lymphoblasts in the marrow), the case would be consistent with a amplification of chromosome 21 (iAMP21).32,35 Two new provisional
diagnosis of lymphoblastic lymphoma.31 Lymphoblastic lymphoma was entities were also added to T-cell ALL (T-ALL): early T-cell precursor
previously categorized with non-Hodgkin lymphoma (NHL) and is (ETP) lymphoblastic leukemia and natural killer (NK) cell lymphoblastic
associated with exposure to radiation or pesticide and congenital or leukemia/lymphoma.32 The Ph-like ALL, B-ALL with iAMP21 and ETP
acquired immunosuppression. However, based on morphologic, genetic, T-ALL subtypes are no longer considered provisional entities.
and immunophenotypic features, lymphoblastic lymphoma is
indistinguishable from ALL. Patients with lymphoblastic lymphoma With the 2022 WHO classification update, two new entities were added to
generally benefit from treatment with ALL-like regimens versus traditional the B-ALL classification: B-ALL with TCF3::HLF fusion and B-ALL with
lymphoma therapy and should be treated in a center that has experience ETV6::RUNX1-like features.31 In addition, multiple subtypes were added to
with lymphoblastic lymphoma (see Management of Lymphoblastic the classification of B-ALL with other defined genetic abnormalities,
Lymphoma). including B-ALL with rearrangements in DUX4, MEF2D, or ZNF384, B-ALL
with IG::MYC fusion, and B-ALL with PAX5alt or PAX5 p.P80R.
Hematopathology evaluations should include morphologic examination of
malignant lymphocytes using Wright-Giemsa–stained slides and Presence of recurrent genetic abnormalities should be evaluated using
hematoxylin and eosin–stained core biopsy and clot sections; karyotyping of G-banded metaphase chromosomes (conventional
comprehensive immunophenotyping with flow cytometry (see cytogenetics), interphase fluorescence in situ hybridization (FISH) assays
Immunophenotyping); and baseline flow cytometric and/or molecular that include probes capable of detecting the genetic abnormalities, and/or
characterization of leukemic clone(s) to facilitate subsequent analysis of reverse transcriptase-polymerase chain reaction (RT-PCR) testing, using
MRD. qualitative or quantitative methods, to measure transcript sizes (ie, p190
vs. p210) of BCR::ABL1 in B-ALL. If samples are BCR::ABL1/Ph–negative
Identification of specific recurrent genetic abnormalities is critical for or Ph-like, comprehensive testing by next-generation sequencing (NGS)
disease evaluation, optimal risk stratification, and treatment planning (see for other gene fusions and pathogenic mutations associated with Ph-like
Cytogenetic and Molecular Subtypes). Subtypes of B-ALL with recurrent ALL is recommended. In cases of aneuploidy or inadequate karyotype,
genetic abnormalities include the following: hyperdiploidy (51–65 additional assessment may include chromosomal microarray (CMA)/array
chromosomes); hypodiploidy (<44 chromosomes); t(9;22)(q34;q11.2), comparative genomic hybridization (aCGH). The translocation
BCR::ABL1; t(4;11) and other KMT2A rearranged, t(v;11q23); t(12;21)(p13;q22) is typically cryptic by karyotyping and requires FISH or
t(12;21)(p13;q22), ETV6::RUNX1; t(1;19)(q23;p13.3), TCF3::PBX1; and PCR to be identified.

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Immunophenotyping (56%), medullary/mature (21%), and early (23%) T-ALL.36 The latter is
Immunophenotypic classification of ALL involves flow cytometry to further divided between ETP-ALL and early immature T-ALL. Early
determine the presence of cell surface antigens on lymphocytes. ALL can immature T-ALL includes both pro-T-ALL and pre-T-ALL
be broadly classified into three groups based on immunophenotype, which immunophenotypes.
include precursor B-ALL, mature B-ALL, and T-ALL.1,36 Among children,
B-cell lineage ALL constitutes approximately 88% of cases37; in adult ETP-ALL represents a distinct biologic subtype of T-cell lineage ALL that
patients, subtypes of B-cell lineage ALL represent approximately 75% of accounts for 12% of pediatric T-ALL (and about 2% of ALL), and is
cases (including mature B-ALL that constitutes 5% of adult ALL), whereas associated with poor clinical outcomes even with contemporary treatment
the remaining 25% comprise T-cell lineage ALL.37,38 Within the B-cell regimens. This subtype is characterized by the absence of CD1a/CD8,
lineage, the profile of cell surface markers differs according to the stage of weak expression of CD5 (<75% positive lymphoblasts), and the presence
B-cell maturation, which includes early precursor B-cell (early pre-B-cell), of 1 or more myeloid or stem cell markers (CD117, CD34, HLA-DR, CD13,
pre-B-cell, and mature B-ALL. Early pre-B-ALL is characterized by the CD33, CD11b, or CD65) on at least 25% of lymphoblasts.44 The mature
presence of terminal deoxynucleotidyl transferase (TdT), the expression of subtype, on the other hand, often lacks expression of CD1a and frequently
CD19/CD22/CD79a, and the absence of CD10 (formerly termed common is accompanied by T-ALL11 or T-ALL12 rearrangement.
ALL antigen) or surface immunoglobulins. CD10 negativity correlates with
KMT2A rearrangement and poor prognosis.39,40 Pre-B-ALL is A pivotal study from Zhang et al45 identified a high frequency of activating
characterized by the presence of cytoplasmic immunoglobulins and mutations in the cytokine receptor and RAS signaling pathways that
CD10/CD19/CD22/CD79a expression1,28,31,38,41 and was previously termed included NRAS, KRAS, FLT3, IL7R, JAK3, JAK1, SH2B3, and BRAF.
common B-ALL due to the expression of CD10 at diagnosis. Mature B-ALL Furthermore, inactivating mutations of genes that encode hematopoietic
shows positivity for surface immunoglobulins and clonal lambda or kappa developmental transcription factors, including GATA3, ETV6, RUNX1,
light chains, and is negative for TdT.1 The definition of CD20 positivity is IKZF1, and EP300, were observed. These mutations are more frequent in
unclear, though most studies use ≥20% of blasts expressing CD20.42 myeloid neoplasms than in other subtypes of ALL, suggesting that
myeloid-derived therapies and targeted therapy may be better treatment
CD20 may be expressed in approximately 50% of B-cell lineage ALL in
options for select ALL subtypes. The data indicate a need for alternative
adults, with a higher frequency (>80%) observed in cases of mature
treatments to standard intensive chemotherapy in this subpopulation. Due
B-ALL.42,43
to the nature of ETP-ALL, myeloablative therapy followed by HCT in first
remission may be an alternative. This regimen had previously
T-cell lineage ALL is typically associated with the presence of cytoplasmic
demonstrated superior results for patients with T-ALL and poor early
CD3 (T-cell lineage blasts) or cell surface CD3 (mature T cells) in addition
responses.46
to variable expression of CD1a/CD2/CD5/CD7 and expression of
TdT.1,28,31,41 CD52 may be expressed in 30% to 50% of T-cell lineage ALL Hematologic malignancies related to ALL include acute leukemias with
in adults.1 Combined data from the German Multicenter Study Group for ambiguous lineage (ALALs), such as the mixed phenotype acute
Adult ALL (GMALL) 06/99 study and the GMALL 07/03 study revealed a leukemias (MPALs). MPALs include bi-lineage leukemias, in which two
distribution of T-cell lineage ALL among three subgroups: cortical/thymic
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distinct populations of lymphoblasts are identified, with one meeting the Table 1: Common Chromosomal and Molecular
criteria for acute myeloid leukemia (AML). Bi-phenotypic MPAL is defined Abnormalities in ALL
as a single population of lymphoblasts that expresses markers consistent
with B-cell or T-ALL, in addition to expressing myeloid or monocytic Cytogenetics Gene Frequency Frequency
in Adults in
markers. Notably, myeloid-associated markers such as CD13 and CD33
Children
may be expressed in ALL, and the presence of these markers does not
Hyperdiploidy -- 7% 25%
exclude the diagnosis of ALL, nor is it associated with adverse
(>50 chromosomes)
prognosis.31 The initial immunophenotyping panel should be sufficiently Hypodiploidy -- 2% 1%
comprehensive to establish a leukemia-associated phenotype that may (<44 chromosomes)
include expression of non-lineage antigens; these are useful in t(9;22)(q34;q11): BCR::ABL1 25% 2%–4%
classification, particularly for MPAL. In the 2022 update of the WHO Philadelphia
classification of hematolymphoid tumors, ALALs/MPALs were separated chromosome (Ph)
into those with defining genetic abnormalities and those defined based on t(12;21)(p13;q22) ETV6::RUNX1 2% 22%
immunophenotyping alone.47 Lineage assignment criteria were refined to (TEL-AML1)
highlight principles of intensity and pattern. t(v;11q23) [eg, t(4;11) KMT2A 10% 8%
and others], t(11;19) rearranged
Cytogenetic and Molecular Subtypes t(1;19)(q23;p13) TCF3::PBX1 3% 6%
(E2A::PBX1)
Recurrent chromosomal and molecular abnormalities characterize ALL
t(5;14)(q31;q32) IL3::IGH <1% <1%
subtypes in both adults and children (Table 1), and often provide
t(8;14), t(2;8), t(8;22) c-MYC 4% 2%
prognostic information that may weigh into risk stratification and treatment
t(1;14)(p32;q11) TAL-1a 12% 7%
decisions. The frequency of certain subtypes differs between adult and t(10;14)(q24;q11) HOX11 8% 1%
childhood ALL, which partially explains the difference in clinical outcomes (TLX1)a
between patient populations. Among children with ALL, the most common t(5;14)(q35;q32) HOX11L2a 1% 3%
chromosomal abnormality is hyperdiploidy (>50 chromosomes; 25% of t(11;14)(q11) [eg, TCRα and 20%–25% 10%–20%
cases) seen in B-cell lineage ALL compared to 7% in the adult ALL patient (p13;q11), (p15;q11)] TCRδ
population.37,48 The ETV6::RUNX1 subtype (also within the B-cell lineage) BCR::ABL1–like/Ph–like variousb 10%–30% 15%
resulting from chromosomal translocation t(12;21) is among the most B-ALL with iAMP21 RUNX1 -- 2%
commonly occurring subtypes in childhood ALL (22%) compared to adults ETP variousb 2% 2%
(2%).37 Both hyperdiploidy and ETV6::RUNX1 subtypes are associated Ikaros IKZF1 25%–35% 12%–17%
aAbnormalities observed exclusively in T-cell lineage ALL; all others occur
exclusively or predominantly in B-cell lineage ALL. bSee text for more
details.

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with favorable outcomes in ALL.48-50 Emerging evidence suggests B-ALL with iAMP21 is characterized by amplification of a portion of
t(1;19)(q23;p13.3): TCF3::PBX1, DUX4r, and PAX5 P80R are also chromosome 21, detected by FISH with a probe for the RUNX1 gene.61,62
associated with favorable outcomes in ALL.51 Ph-positive ALL has been Occurring in approximately 2% of children with ALL, B-ALL with iAMP21 is
historically associated with poor prognosis; however, the NCCN Panel associated with adverse prognosis.61,62 Cases of iAMP21 typically occur in
now considers Ph-positive ALL without IKZF1 plus and without antecedent children who are older, with a median age of 9 years, and have low
chronic myeloid leukemia (CML) as standard risk. Ph-positive ALL is platelet counts and low white blood cell (WBC) counts.63
relatively uncommon among childhood ALL (3%), whereas this
abnormality is the most common subtype among adults (25%).37 The Other cytogenetic and molecular subtypes are associated with ALL and
frequency of Ph-positive ALL increases with age (10%, patients 15–39 prognosis. Although not as common, translocations in the KMT2A gene [in
years; 25%, patients 40–49 years; 20%–40%, patients >50 years).49,52-54 particular, cases with t(4;11) translocation] are known to have poor
Moreover, children aged 1–9 years with Ph-positive ALL have a better prognosis.25,43 Hypodiploidy, alternatively defined as DNA index less than
prognosis than adolescents with this subtype.55 protocol-defined threshold or other clear evidence of hypodiploid clone, is
associated with poor prognosis and is observed in 1% to 2% of cases.25,64
BCR::ABL1–like or Ph–like ALL is a subgroup of B-cell lineage ALL Low hypodiploidy (30–39 chromosomes)/near triploidy (60–68
associated with unfavorable prognosis.33,34 A study using gene expression chromosomes) and complex karyotype (≥5 chromosome abnormalities)
signatures to classify pediatric patients with ALL into subtypes estimated are also associated with poor prognosis, and occur more frequently with
the 5-year disease-free survival (DFS) in the BCR::ABL1–like ALL group increasing age (1%–3%, patients 15–29 years; 3%–6%, patients 30–59
to be 60%.33 In adult patients with BCR::ABL1–like ALL, the 5-year years; 5%–11%, patients >60 years).49 Of note, low hypodiploidy is
event-free survival (EFS) is significantly lower (22.5%; 95% CI, 14.9%– associated with a high frequency of TP53 alterations and Li-Fraumeni
29.3%) compared to patients with non-BCR::ABL1–like ALL (49.3%; 95% syndrome.65-67 In addition, masked hypodiploidy, which results from a
CI, 42.8%–56.2%).34 Although this subgroup is Ph-negative, there is an doubling of hypodiploid clones, needs to be distinguished from true
otherwise similar genetic profile to the Ph-positive ALL subgroup including hyperdiploidy to allow appropriate treatment selection.68
mutation of the IKZF1 gene.56 Genomically, this subtype is typically
associated with gene fusions and mutations that activate tyrosine kinase In B-ALL, mutations in the Ikaros gene (IKZF1) are associated with a poor
pathways as the common mechanism of transformation. These gene prognosis and a greater incidence of relapse.69 IKZF1 mutations are seen
fusions and mutations include ABL1, ABL2, CRLF2, CSF1R, EPOR, in approximately 15% to 20% cases of pediatric B-ALL70,71 and at a higher
JAK1, JAK2, JAK3, TYK2, PDGFRβ, PDGFRα, FGFR, EBF1, FLT3, IL7R, frequency of >75% in patients who also have BCR::ABL positive
NTRK3, PTL2B, and SH2B3 genes.33,56-59 A genomic profiling study found disease.56,71,72 Incidence in adults with B-ALL is about 25% to 35%73-76 and
kinase-activating alternations in 91% of Ph-like ALL cases,57 suggesting about 65% in patients with BCR::ABL positive disease.77,78 A study
potential for ABL-class tyrosine kinase inhibitors (TKIs) or other targeted evaluating the relationship between BCR::ABL1–like and IKZF1 in children
therapies to significantly improve patient outcomes in this subgroup.60 with B-cell precursor ALL showed that 40% of cases had co-occurrence of
these mutations.79 The presence of either mutation was indicative of poor

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prognosis and was independent of conventional risk factors.56 Both pregnancy testing and all patients with testes should be evaluated for
mutations are considered strong independent risk factors for B-ALL and testicular involvement of disease, including a scrotal ultrasound as
are applicable across a broad range of stratified ALL including the setting indicated; testicular involvement is especially common in cases of T-ALL.
of intermediate MRD. IKZF1 deletions with co-occurring deletions in Fertility counseling and preservation options should be presented to all
CDKN2A, CDKN2B, PAX5, or PAR1 in the absence of ERG deletion, patients. CT scans of the neck, chest, abdomen, and pelvis with IV
which are called IKZF1 plus, as well as those with concomitant 22q11.22 contrast are recommended as indicated by symptoms, and if any
deletions, are especially associated with worse outcomes in pediatric extramedullary involvement is suspected, a PET/CT may be considered
patients with B-ALL. However, DUX4 rearrangements with IKZF1 for diagnosis and follow-up.
alterations do not confer poor prognosis.56,72,80
All patients should be evaluated for opportunistic infections as appropriate
A genomic analysis of patients treated on the UKALLXII/ES992 trial (see NCCN Guidelines for Prevention and Treatment of Cancer-Related
revealed that patients with MYC rearranged ALL had significantly worse Infections). In addition, an echocardiogram or multigated acquisition
outcomes than patients with DUX4 rearranged (standard-risk) ALL.51 (MUGA) scan should be obtained for all patients due to the use of
Patients with PAX5alt, ZNF384 rearranged, and MEF2D rearranged ALL anthracyclines as the backbone of nearly all treatment regimens.
had inferior RFS compared to patients with DUX4 rearranged ALL, but Assessment of cardiac function is particularly important for patients with
with a lower level of significance. prior cardiac history, prior anthracycline exposure, or clinical symptoms
suggestive of cardiac dysfunction, and for patients who are older. An early
The hematopathology review and molecular characterization studies
transplant evaluation and donor search should be strongly considered.
described above allow determination of the WHO31 and ICC81 ALL
subtypes and cytogenetic and clinical risk groups.
Appropriate imaging studies (eg, CT/MRI scan of the head with contrast)
Workup should be performed to detect meningeal disease, chloromas, or central
nervous system (CNS) bleeding for patients with major neurologic signs or
The initial workup for patients with ALL should include a thorough medical
symptoms at diagnosis. CNS involvement should be evaluated through
history and physical examination, along with laboratory and imaging
lumbar puncture (LP) at timing that is consistent with the treatment
studies (where applicable). Laboratory studies include a complete blood
protocol. Pediatric-inspired regimens typically include LP at diagnostic
count (CBC) with differential, a blood chemistry profile, liver function tests,
workup; the NCCN ALL Panel recommends that the first LP be performed
a disseminated intravascular coagulation panel (including measurements
at the time of initial scheduled intrathecal (IT) therapy unless directed by
for D-dimer, fibrinogen, prothrombin time, and partial thromboplastin time),
symptoms to perform earlier (see NCCN Recommendations for Evaluation
and a tumor lysis syndrome (TLS) panel (including measurements for
and Treatment of Extramedullary Involvement).
serum lactate dehydrogenase [LDH], uric acid, potassium, phosphate, and
calcium). Other recommended tests include hepatitis B/C and HIV It should be noted that the recommendations included in the guidelines
evaluations. Individuals of childbearing potential should undergo represent a minimum set of workup considerations, and that other

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evaluations or testing may be needed based on clinical symptoms. response to induction chemotherapy also re-categorized patients into this
Procurement of cells should be considered for purposes of future research group.87-89 Conversely, criteria were refined for lower risk and included
(in accordance with institutional practices or policies). hyperploidy, the t(12;21) chromosomal translocation (ETV6::RUNX1
subtype),90 or simultaneous trisomies of chromosomes 4, 10, and 17.64,91
Prognostic Factors and Risk Stratification Presence of extramedullary disease and early response to treatment also
Various disease-related and patient-specific factors may have prognostic modified risk. Early marrow response to therapy was a strong positive
significance in patients with ALL. In particular, patient age, WBC count, prognostic factor while the presence of extramedullary disease at
immunophenotypic/cytogenetic and molecular subtype, presence of CNS diagnosis was correlated with a poorer prognosis. Using the refined risk
disease, and response to induction/consolidation therapy have been assessment, four risk categories for B-ALL, designated as low risk,
identified as important factors in defining risk and assessing prognosis for standard risk, high risk, and very high risk, were identified encompassing
both adult and childhood ALL. 27%, 32%, 27%, and 4% of cases, respectively.64

Prognostic Factors in AYA Patients with ALL Risk stratification of T-ALL has been more difficult than in B-ALL. Although
In 1993, a common set of risk criteria was established by the Pediatric T-cell lineage has previously been considered a high-risk feature in ALL,
Oncology Group (POG) and Children’s Cancer Group (CCG) at an modern treatment protocols have resulted in improved survival outcomes
international conference hosted by the National Cancer Institute (NCI).82 In for these patients. The identification of genetic mutations and the use of
this system, two risk groups were designated: those with standard risk and targeted therapies may change the way T-ALL is treated and ultimately
those with high-risk disease. Standard-risk disease was assigned to how these patients are assessed for risk.
patients 1 to <10 years of age and with a WBC count <50 × 109 cells/L,
Historically, the AYA population has been treated on either a pediatric or
whereas all other patients with ALL, including T-ALL (regardless of age or
an adult ALL regimen, depending on referral patterns and the institution.
WBC count), were considered to have high-risk disease.64 It should be
Over the last two decades, several retrospective studies from both the
noted that despite exclusion from this report, patients <1 year of age
United States and Europe have shown that AYA patients (15–21 years of
should also be considered to have very high-risk disease.83,84 The POG
age) treated on a pediatric protocol have substantially improved EFS
and CCG have since merged to form the Children’s Oncology Group
compared to same-aged patients treated on adult ALL regimens.25,50
(COG) and subsequent risk assessment has produced additional risk
Comparison of adult and pediatric protocols has shown that adults
factors, particularly in precursor B-ALL, to further refine therapy.
received lower doses of nonmyelosuppressive chemotherapy and less
Specifically, in B-ALL, a group identified as having very high-risk disease
intense IT chemotherapy regimens.92,93 Adult protocols are also more
was defined as having any of the following characteristics: t(9;22)
likely to include allogeneic HCT compared to pediatric protocols, but the
chromosomal translocation (ie, Ph-positive ALL) and/or presence of
benefits of HCT in the AYA population have not been sufficiently studied,
BCR::ABL1 fusion protein; hypodiploidy (<44 chromosomes)85;
and the available data include conflicting findings.94-98 There is clearly a
BCR::ABL1–like or Ph-like ALL86; iAMP2184; or inability to achieve
significant difference between the way adults and pediatric patients are
remission with induction therapy.25,64 KMT2A rearrangements and a poor
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treated and this may be a variable in the treatment of AYA patients. Thus, AYA patients,107 which may be due to greater parental supervision of the
the choice of initial treatment regimen can have a profound impact on treatment and better insurance.108
overall clinical outcomes in AYA patients.
Prognostic Factors in Adults with ALL
Despite improved outcomes for AYA patients treated on pediatric-inspired Both age and initial WBC count have historically been considered clinically
regimens versus adult ALL regimens, studies have shown poorer significant prognostic factors in adults with ALL.36,43 Early prospective
outcomes among patients in the AYA group compared with children <10 multicenter studies defined values for age >35 years and higher initial
years of age.99 This may be attributed to factors that are based on biology WBC count (>30 × 109/L for B-cell lineage; >100 x 109/L for T-cell lineage)
and social differences. Compared to the pediatric population, AYA patients that were predictive of significantly decreased remission duration.109,110
have a lower frequency of favorable chromosomal/cytogenetic Subsequent studies have confirmed the prognostic importance of these
abnormalities, such as hyperdiploidy or ETV6::RUNX1,100 and a greater clinical parameters, although the cutoff values differed between
incidence of poor-risk cytogenetics including Ph-positive ALL, Ph-like ALL, studies.36,43
hypodiploidy, and complex karyotype,101 and a higher incidence of
ETP-ALL.44,102 Furthermore, the positive prognostic values of the In one of the largest studies to date (n = 1521) conducted by the Medical
ETV6::RUNX1 mutation and hyperdiploidy are greater in patients <10 Research Council (MRC) UKALL/ Eastern Cooperative Oncology Group
years of age, suggesting that the benefits decline with age.101 The effects (ECOG), both age (>35 years) and WBC count (>30 × 109/L for B-cell
of treatment are also shown to be different in the AYA population lineage; >100 × 109/L for T-cell lineage) were found to be significant
compared to the pediatric population. In vitro studies showed that ALL independent prognostic factors for decreased DFS and OS among
cells from children >10 years of age are more resistant to chemotherapy patients with Ph-negative ALL; the independent prognostic value remained
compared to the cells from children <10 years of age.103 The COG significant when these factors were evaluated as continuous variables in
AALL0232 study reported an initial delay in response to induction therapy multivariate analysis.111 All patients, regardless of Ph status, had received
in AYA patients aged 16 to 30 years compared to patients aged 1 to 15 induction therapy followed by intensification (for patients who achieved a
years.104 There was a statistically significant reduction in the number of complete response [CR] postinduction) with contemporary chemotherapy
patients in the aged 16 to 30 year cohort who experienced negative combination regimens. Patients who achieved a CR after induction
end-induction MRD compared to the aged 1 to 15 year cohort (59% vs. received allogeneic HCT (for patients <50 years of age and with human
74%; P < .0001) with fewer patients achieving M1 marrow on day 15 of leukocyte antigen [HLA]-compatible siblings), autologous HCT, or
induction (67% vs. 80%, respectively; P = .0015). In addition to the consolidation/maintenance treatment. Because Ph-positive ALL is
biological differences, the social component of treating AYA patients is associated with a very poor prognosis, patients with this subtype were
important. Enrollment in clinical trials has been shown to improve patient assigned to undergo allogeneic HCT (including matched, unrelated donor
outcomes105; however, only 2% of AYA patients enroll in clinical trials [URD] HCT) when possible. The 5-year OS rate among patients with
compared to the 60% enrollment of pediatric patients.106 Pediatric patients Ph-positive and Ph-negative disease was 25% and 41%, respectively.111
have been shown to be more adherent to treatment protocols compared to Among patients with Ph-negative ALL, those >35 years or with elevated

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WBC count (>30 × 109/L for B-cell lineage; >100 × 109/L for T-cell lineage) ALL.113 Based on multivariate Cox regression analysis reported in the
at diagnosis were initially identified as having high-risk disease, whereas MRC UKALL XII/ECOG E2993 study, t(8;14), low hypodiploidy/near
all others were classified as having standard-risk disease. The 5-year OS triploidy, and complex karyotype remained significant independent
rates for the Ph-negative high-risk and standard-risk subgroups were 29% predictors for risk of relapse or death; the prognostic impact of these
and 54%, respectively.111 Further analysis of the Ph-negative population cytogenetic markers was independent of factors such as age, WBC count,
according to risk factors showed that patients could be categorized as or T-cell immunophenotype, and their significance was retained even after
having low-risk disease (no risk factors based on age or WBC count), excluding patients who had undergone postinduction HCT.112
intermediate-risk disease (either age >35 years or elevated WBC count),
or high-risk disease (both age >35 years and elevated WBC count). The The importance of cytogenetics as a prognostic factor for survival
5-year OS rates based on these risk categories were 55%, 34%, and 5%, outcomes was shown in other studies, including the Southwest Oncology
respectively, suggesting that patients with Ph-negative ALL in the high-risk Group (SWOG) study conducted with 200 adult patients with ALL.114 In
subgroup had even poorer survival outcomes than patients in the overall this study, the prognostic impact of the different cytogenetic categories
Ph-positive subgroup.111 outweighed that of the more traditional factors, such as age and WBC
count; in multivariate analysis for both relapse-free survival (RFS) and OS,
In a subsequent analysis from this MRC UKALL XII/ECOG E2993 study, cytogenetics remained a significant independent predictor of outcomes,
cytogenetic data were evaluated in approximately 1000 patients.112 The whereas factors such as age and WBC count lost prognostic
analysis confirmed the negative prognostic impact of Ph-positive status significance.114 Moreover, the subgroup (n = 19) of patients with disease
compared with Ph-negative disease, with a significantly decreased 5-year with very-high-risk cytogenetic features [identified based on outcomes
EFS rate (16% vs. 36%; P < .001, adjusted for age, gender, and WBC from the MRC/ECOG study mentioned earlier: presence of t(4;11) KMT2A
count) and OS rate (22% vs. 41%; P < .001, adjusted for age, gender, and (MLL) translocation; t(8;14); complex karyotype; or low hypodiploidy] had
WBC count). Among patients with Ph-negative disease, the following substantially decreased 5-year RFS and OS rates (22%, for both
cytogenetic subgroups had significantly decreased 5-year EFS (13%– endpoints). Analysis by ploidy status was not possible because there were
24%) and OS rates (13%–28%) based on univariate analysis: t(4;11) only two cases of low hypodiploidy/near triploidy. The 5-year RFS and OS
KMT2A translocation, t(8;14), complex karyotype (≥5 chromosomal rates among patients with Ph-positive ALL (n = 36) were 0% and 8%,
abnormalities), and low hypodiploidy (30–39 chromosomes)/near triploidy respectively.114
(60–78 chromosomes).112 In contrast, del(9p) or high hyperdiploidy (51–65
chromosomes) was associated with more favorable 5-year EFS (49%– As previously discussed in Immunophenotyping regarding patients with
50%) and OS rates (53%–58%).112 An earlier report of data from patients T-ALL, ETP-ALL is associated with poor clinical outcomes even with
treated on the French ALL study group (LALA) protocols suggested that contemporary treatment regimens. In a study of 239 patients with T-ALL,
near triploidy (60–78 chromosomes) may be derived from duplication of gene expression profiling, flow cytometry, and single nucleotide
hypodiploidy (30–39 chromosomes); both aneuploidies were associated polymorphism array analysis were used to identify patients with
with poor DFS and OS outcomes similar to that of patients with Ph-positive ETP-ALL.44 ETP-ALL was associated with a 10-year OS of 19% (95% CI,

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0%–92%) compared with 84% (95% CI, 72%–96%) in patients with non– management of ALL in AYA can be found in the NCCN Guidelines for
ETP-ALL. The 10-year EFS was similarly poor in patients with ETP-ALL Adolescent and Young Adult (AYA) Oncology. For Ph-negative B-ALL and
(22%; 95% CI, 5%–49%) compared with patients with non–ETP-ALL T-ALL, the AYA patient population is considered separately from the adult
(69%; 95% CI, 53%–84%). Inability to achieve remission and hematologic population (defined as age ≥40 years). Given the poor prognosis
relapse were significantly higher for patients with ETP-ALL (P < .0001).44 associated with Ph-positive B-ALL and the wide availability of agents that
specifically target the BCR::ABL kinase, initial risk stratification for all
A Group for Research in Adult Acute Lymphoblastic Leukemia (GRAALL) patients with B-ALL (AYA or adult) is based on the presence or absence of
study found that the presence of RAS/PTEN mutations and/or the t(9;22) chromosomal translocation and/or BCR::ABL fusion protein.
NOTCH1/FBXW7 wild type was associated with poor prognosis and that For adult patients with B-ALL (Ph-positive or Ph-negative) and T-ALL,
the favorable prognostic significance of mutations in NOTCH1/FBXW7 these guidelines further stratify patients by age, using 65 years as the
was only seen in the absence of RAS/PTEN mutations.115 Estimated cutoff, to guide treatment decisions. However, chronologic age alone is a
5-year cumulative incidence of relapse (CIR) was 15% in patients with poor surrogate for determining patient fitness for therapy. Patients should,
mutations in NOTCH1/FBXW7 compared to 50% in those with therefore, be evaluated on an individual basis. In the NCCN Guidelines for
NOTCH1/FBXW7 wildtype (P < .001). Conversely, in those with ALL, specific age references are not included for AYA and adult
RAS/PTEN mutations, estimated 5-year CIR was similar in patients with categories, considering that age is not a firm reference point and some of
mutations in NOTCH1/FBXW7 and in those with NOTCH1/FBXW7 the recommended regimens have not been comprehensively tested
wildtype (58% vs. 57%; P =.78). Estimated 5-year RFS and OS rates for across all ages.
patients with mutations in NOTCH1/FBXW7 were 85% and 82% compared
to 45% and 37% in those with NOTCH1/FBXW7 wildtype (P < .001 for AYA patients and adult patients <65 years of age (or for those with no
both RFS and OS). Conversely, in those with RAS/PTEN mutations, substantial comorbidities) with Ph-negative ALL can be further categorized
estimated 5-year RFS (36% vs. 43%; P =.78) and OS (49% vs. 32%; P = as having high-risk disease, which may be particularly helpful when
.43) were similarly poor in patients with mutations in NOTCH1/FBXW7 and consolidation with allogeneic HCT is being considered. Patients may be
in those with NOTCH1/FBXW7 wildtype. considered as having high-risk disease if their disease is MRD positive,
they have an elevated WBC count (>30 × 109/L for B-cell lineage; >100 ×
NCCN Recommendations for Risk Assessment in ALL 109/L for T-cell lineage), or poor-risk cytogenetics as previously defined.
Although some debate remains regarding the risk stratification approach to The absence of all poor-risk factors is considered standard risk. Evaluation
ALL, the Panel suggests the following approaches for defining risk in these of WBC count and age for determination of prognosis should ideally be
patients. made in the context of treatment protocol-based risk stratification. These
additional risk stratification parameters are generally not used for patients
The NCI defines the age range for AYA patients as 15 to 39 years. For ≥65 years of age (or for patients with substantial comorbid conditions) with
Ph-positive B-ALL, the AYA patient population is grouped with fit, adult Ph-negative ALL. Similar to AYA patients, elevated WBC count (≥30 ×
patients <65 years of age. However, additional considerations for the 109/L for B-cell lineage; ≥100 × 109/L for T-cell lineage) has been

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considered a high-risk factor based on some earlier studies. However, The BFM/COG regimens are mainly based on a 4-drug induction regimen
studies in adult patients have demonstrated that WBC counts may lose that includes a combination of vincristine, an anthracycline, a
independent prognostic significance when cytogenetic factors and MRD corticosteroid, and L-asparaginase.116-120 Some studies from the CALGB
assessments are considered. Data showing the effect of WBC counts on group have utilized a 5-drug regimen, which adds cyclophosphamide to
prognosis in adult patients with ALL are less firmly established than in the the above 4-drug combination.121 Randomized studies comparing the use
pediatric population and likely superseded by MRD quantification after of dexamethasone versus prednisone as part of induction therapy in
treatment. Therefore, adult patients with ALL may not necessarily be children with ALL showed that dexamethasone significantly decreased the
classified as high risk based on high WBC count alone. risk of isolated CNS relapse and improved EFS outcomes compared with
prednisone.122,123 The observed advantage in outcomes with
Overview of Treatment Phases in ALL Management dexamethasone may partly be attributed to improved penetration of
The treatment approach to ALL represents one of the most complex and dexamethasone into the CNS.124 In a meta-analysis comparing outcomes
intensive programs in cancer therapy. Although the specific treatment with dexamethasone versus prednisone in induction regimens for
regimens and selection of drugs, dose schedules, and treatment durations childhood ALL, dexamethasone was associated with a significantly
differ between AYA patients and adults, and among different subtypes of reduced event rate (ie, death from any cause, refractory or relapsed
ALL, the basic treatment principles are similar. The most common leukemia, or second malignancy; risk ratio [RR], 0.80; 95% CI, 0.68–0.94)
treatment regimens used in patients with ALL include modifications or and CNS relapse (RR, 0.53; 95% CI, 0.44–0.65).125 However, no
variations of multiagent therapy regimens originally developed by the advantage was seen with dexamethasone regarding risk for bone marrow
Berlin-Frankfurt-Münster (BFM) group for pediatric patients (eg, regimens relapse (RR, 0.90; 95% CI, 0.69–1.18) or overall mortality (RR, 0.91; 95%
used by COG for children and AYA patients, or the CALGB regimen for CI, 0.76–1.09), and dexamethasone was associated with a significantly
adult patients), and the hyper-CVAD regimen developed at MD Anderson higher risk of mortality during induction therapy (RR, 2.31; 95% CI, 1.46–
Cancer Center (MDACC). In general, the treatment phases can be largely 3.66), neuropsychiatric adverse events (RR, 4.55; 95% CI, 2.45–8.46),
grouped into induction, consolidation, and maintenance. All treatment and myopathy (RR, 7.05; 95% CI, 3.00–16.58) compared with
regimens for ALL include CNS prophylaxis and/or treatment. prednisone.125 Although dexamethasone was reported to reduce the risks
for CNS relapse and improved EFS, toxicities may be of concern, and an
Induction advantage for OS has yet to be conclusively shown.
The intent of initial induction therapy is to reduce tumor burden by clearing
as many leukemic cells as possible from the bone marrow. Induction The hyper-CVAD regimen may be considered a less complex treatment
regimens are typically based on a backbone that includes a combination of regimen compared with the CALGB regimen, and comprises eight
vincristine, anthracyclines (eg, daunorubicin, doxorubicin), and alternating treatment cycles with the “A” regimen (hyper-CVAD:
corticosteroids (eg, prednisone, dexamethasone) with or without hyperfractionated cyclophosphamide, vincristine, doxorubicin, and
L-asparaginase and/or cyclophosphamide.1,25,36,43,50 dexamethasone) and the “B” regimen (high-dose methotrexate and
cytarabine).20,126,127 CNS prophylaxis and/or CNS-directed treatment

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(which may include IT chemotherapy, cranial irradiation, and/or systemic Hematopoietic Stem Cell Transplantation
therapy for patients with CNS leukemia at diagnosis) and maintenance As part of postremission consolidative therapy, the decision to proceed
treatment are also used with the hyper-CVAD regimen (see CNS with allogeneic HCT or prolonged maintenance are mutually exclusive
Prophylaxis and Treatment and Maintenance). approaches in ALL therapy. Each case will need to be individualized
based on disease setting and features. Allogeneic HCT is more likely to be
CNS Prophylaxis and Treatment
a primary part of post-consolidative therapy in AYA and adult patients with
The goal of CNS prophylaxis and/or treatment is to prevent CNS disease disease with evidence of high-risk features (including Ph-like disease, or
or relapse by clearing leukemic cells within sites that cannot be readily persistent MRD). Notably, while younger patients may experience lower
accessed with systemic chemotherapy because of the blood-brain barrier. transplant-related mortality, older age is by itself not a contraindication.
CNS-directed therapy may include cranial irradiation, IT chemotherapy For this reason, HLA typing and bone marrow transplant referral should be
(eg, methotrexate, cytarabine, corticosteroids), and/or systemic considered for all patients with newly diagnosed disease and patients with
chemotherapy (eg, high-dose methotrexate, intermediate-/high-dose relapsed disease who have not yet undergone transplant to facilitate
cytarabine, L-asparaginase).1,50,124 CNS prophylaxis is typically given to all timely donor identification, and ultimately allogeneic transplant if
patients throughout the entire course of ALL therapy, from induction, to warranted.
consolidation, to the maintenance phases of treatment. CNS prophylaxis
should be considered for relapsed/refractory disease as well. The role of Maintenance
CNS prophylaxis in the setting of cellular therapy is still being studied. The goal of extended maintenance therapy is to prevent disease relapse
after postremission induction and consolidation therapy. Most
Consolidation
maintenance regimens are based on a backbone of daily 6-MP and
The intent of postinduction consolidation is to eliminate any leukemic cells weekly methotrexate (typically with the addition of periodic vincristine and
potentially remaining after induction therapy, further eradicating residual corticosteroids) for 2 to 3 years.25,36,43,50 Maintenance therapy is omitted for
disease. The postremission induction phase of treatment (but before patients with mature B-ALL (see the NCCN Guidelines for B-Cell
long-term maintenance therapy) may also be described as intensification Lymphomas: Burkitt Lymphoma), given that long-term remissions are seen
therapy. The combination of drugs and duration of therapy for early with short courses of intensive therapy in these patients, with
consolidation regimens vary largely among studies and patient populations relapses rarely occurring beyond 12 months.36,128
but can comprise combinations of drugs similar to those used during the
induction phase. Methotrexate, cytarabine, 6-mercaptopurine (6-MP), Factors that affect the bioavailability of 6-MP can significantly impact
cyclophosphamide, vincristine, corticosteroids, and asparaginase are patient care. Oral 6-MP can have highly variable drug and metabolite
frequently incorporated into consolidation/intensification concentrations among patients.129,130 Furthermore, age, gender, and
regimens.28,36,43,50,119,120 genetic polymorphisms can affect bioavailability.131-133 The concomitant
use of other chemotherapeutic agents such as methotrexate can alter
toxicity.134 The efficacy of maintenance therapy is determined by the
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NCCN Guidelines Version 2.2024

Acute Lymphoblastic Leukemia

metabolism of 6-MP to the antimetabolite chemotherapeutic agent who have higher neutrophil counts,107,151 emphasizing the need for optimal
6-thioguanine nucleotide (6-TGN); however, other pathways compete for dosing of 6-MP.
6-MP, thereby reducing the amount of active metabolite produced. The
three enzymes that metabolize 6-MP are xanthine oxidase (XO), Nonadherence also results in undertreatment, particularly in the AYA
hypoxanthine-guanine phosphoribosyltransferase (HPRT), and thiopurine population. Adherence issues should be addressed for patients without
methyltransferase (TPMT). Because 6-MP is administered orally, it can be cytopenia. If increasing doses of 6-MP are given during maintenance but
converted to an inactive metabolite in the intestinal mucosa and liver.135,136 no drop in the counts is observed, this may be indicative of
Diet has been shown to affect absorption of 6-MP.137,138 6-MP can undergo nonadherence.134 Quantification of 6-MP metabolites can be very useful in
thiol methylation by TPMT. The balance between metabolism by HPRT is determining whether the lack of myelosuppression is due to nonadherence
inversely related to the activity of TPMT as demonstrated by the ability of or hypermetabolism.
TPMT polymorphism to affect metabolite production.139 Compared to the
Targeted Agents
wild-type TPMT phenotype, patients who are homozygous TPMT-deficient
require a 10- to 15-fold reduction in 6-MP to alleviate hematopoietic The emergence of targeted therapies for hematologic malignancies,
toxicity.140,141 Heterozygosity at the TPMT gene locus occurs in 5% to 10% including the treatment of Ph-positive disorders with TKIs, including
of the population and has been shown to have intermediate enzyme imatinib, dasatinib, nilotinib, ponatinib, and bosutinib represents an
activity.139,142,143 Therefore, a 10% to 15% reduction in 6-MP dose is important advancement in ALL therapy.152-160 Incorporation of TKIs into
necessary in these patients to prevent toxicity.144,145 Determination of treatment regimens should include evaluation of clinical
patient TPMT genotype using genomic DNA is recommended to optimize pharmacokinetics.161 Clinicians should be aware of variation among the
6-MP dosing, especially in patients who experience myelosuppression at TKIs relating to absorption from the GI tract. Additionally, histamine-2
standard doses.146-148 antagonists or proton pump inhibitors can affect the bioavailability of some
TKIs.
Dose reductions may be necessary if patients have genetic
polymorphisms and/or experience hepatotoxicity, whereas dose escalation Other targeted agents include an anti-CD20 monoclonal antibody (eg,
may be necessary in patients who do not experience myelosuppression. rituximab) for CD20-expressing B-cell lineage ALL (especially for mature
This should be performed in accordance with the protocol being used. In B-ALL).162,163 In addition, the purine nucleoside analog nelarabine has
general, protocols (including the ECOG/CALGB study) recommend a dose been approved for the treatment of relapsed/refractory (R/R) T-cell lineage
increase by 25% if an ANC >1500 is observed for more than 6 weeks. In ALL or lymphoblastic lymphoma.164-166 These agents may be incorporated
2014, the U.S. Food and Drug Administration (FDA) approved an oral as part of frontline induction, consolidation, and/or maintenance regimens
suspension of 6-MP, which may be more amenable to dose adjustments during the course of initial ALL therapy, and in the relapsed or refractory
than the tablet form.149 This may be especially beneficial for dose disease settings.
adjustment in pediatric patients.150 Outcomes are better in patients who
achieve myelosuppression during maintenance compared with patients

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NCCN Guidelines Version 2.2024

Acute Lymphoblastic Leukemia

Management of Ph-Positive B-ALL of allogeneic HCT in the era of imatinib and whether imatinib-based
Initial Treatment in AYA Patients with Ph-Positive B-ALL therapies provided an additional benefit to HCT.

Ph-positive ALL is rare in children with ALL, occurring in only COG AALL-0031 Regimen
approximately 3% of pediatric cases compared with 25% of adult cases.37 In a multicenter COG study (AALL-0031) of children and adolescents with
The frequency of Ph-positive ALL among AYA patients ranges from 5% to high-risk ALL, the group of patients with Ph-positive ALL (n = 92; aged 1–
25% and increases with age,112,120 although this subtype is still uncommon 21 years) was treated with an intensive chemotherapy regimen combined
relative to the incidence in adults who are older. Historically, children and with imatinib (340 mg/m2/day; given during postremission induction
adolescents with Ph-positive disease had a poorer prognosis compared therapy and maintenance).168 Among the cohort (n = 44) who received
with patients with Ph-negative B-ALL. However, improvements in the continuous imatinib exposure (280 consecutive days before maintenance
treatment options are closing this gap. initiation), the 3-year EFS rate was 80.5% (95% CI, 64.5%–89.8%). This
outcome compared favorably with that of a historical population of patients
Hematopoietic Cell Transplant
with Ph-positive ALL (n = 120) treated on a POG protocol, which showed a
In a retrospective analysis of children with Ph-positive ALL treated
3-year EFS rate of only 35% (P < .0001).168 Moreover, the 3-year EFS
between 1986 and 1996 (n = 326) with intensive chemotherapy regimens
rates were similar among the groups of patients who received
with or without allogeneic HCT, the 7-year EFS and OS rates were 25%
chemotherapy combined with continuous imatinib (88%; n = 25) or
and 36%, respectively.55 This benefit with HCT versus chemotherapy
allogeneic HCT from a related donor (57%; n = 21) or URD (72%; n = 11).
alone was not observed with autologous HCT or with HCT from matched
No major toxicities were found to be associated with the addition of
URDs. This study showed that allogeneic HCT from a matched related
imatinib to the intensive chemotherapy regimen.168 Subsequent follow-up
donor offered improvements in outcomes over chemotherapy alone.
after 5 years confirmed these outcomes.169 In a phase II single-arm COG
In a subsequent analysis of outcomes in children with Ph-positive ALL trial (AALL-0622) of children and young adults with Ph-positive ALL (n =
treated between 1995 and 2005 but also without targeted TKIs, the 7-year 60; aged 1–30 years), imatinib was replaced with dasatinib on induction
EFS and OS rates were 32% and 45%, respectively.167 Outcomes with day 15 and combined with the same chemotherapy used in AALL-0031.170
allogeneic HCT from either matched related donors or URDs appeared The 5-year overall OS and EFS rates (± standard deviation [SD]) were
similar, and HCT improved disease control over intensive chemotherapy 86% ± 5% and 60% ± 7%, respectively, and outcomes were similar to
alone.167 Although this analysis showed an improved 7-year EFS rate, those observed in AALL-0031.170
outcomes remained suboptimal in patients with Ph-positive ALL.
EsPhALL

Allogeneic HCT has been considered the standard of care for AYA The European intergroup study of post-induction treatment of
patients with Ph-positive ALL; however, its role has become less clear with Ph-chromosome positive ALL (EsPhALL) reported results of the
the advent of BCR::ABL–targeted TKIs. Several studies evaluated the role randomized open-label trial designed to evaluate the safety and long-term
efficacy of discontinuous postinduction imatinib plus chemotherapy with

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Acute Lymphoblastic Leukemia

the BFM backbone intensive treatment versus chemotherapy alone.171 The 29% of patients achieved a molecular response, which increased to 60%
study enrolled 108 patients with “good-risk” disease and 70 patients with after 2 cycles of blinatumomab. ABL1 mutations occurred in six patients
poor-risk disease aged 1 to 18 years. Patients with good-risk disease were who experienced an increase in MRD, however were cleared upon
randomized 1:1 and patients with poor-risk disease were all assigned to treatment with blinatumomab. Few toxic effects of grade 3 or higher were
receive chemotherapy plus imatinib. There was a trend towards improved observed, with CMV reactivation or infection occurring in six patients. As a
4-year DFS for those with “good-risk” disease who received imatinib plus result of high molecular response, OS and DFS at a median follow-up of
chemotherapy versus those who received chemotherapy alone (72.9% vs. 18 months was achieved in 95% and 88% (95% CI, 90–100; 80–97) of
61.7%; P = .24). In the as-treated analysis, patients with good-risk disease patients, respectively.174 DFS was lower in the setting of IKZF1 deletions.
who received imatinib with chemotherapy had a 4-year EFS of 75.2%
versus 55.9% in patients who did not receive imatinib (P = .06). The The safety and efficacy of blinatumomab in combination with TKIs has
incidence of serious adverse events was not statically different between been evaluated in the treatment of Ph-positive ALL.175-177 In a small
the two groups (P = .64).171 Enrollment in this trial was stopped in 2009 retrospective study, adults with R/R Ph+ ALL (n = 9) and CML (n = 3) who
following results of the COG AALL0031 study that demonstrated a benefit had previously been treated with one line of chemotherapy and one class
of continuous imatinib. The EsPhALL study was amended into a of TKIs were treated with the combination blinatumomab and a TKI
single-arm study to add continuous imatinib on induction day 15, with 97% (ponatinib, dasatinib, or bosutinib). Of the 12 total patients, 75% (9/12)
of patients achieving first CR.172 However, the 5-year EFS and OS rates achieved complete molecular responses with no cardiovascular adverse
(57% and 71.8%, respectively) were similar in cohorts that received events.175
discontinuous postinduction imatinib and continuous imatinib plus
A single arm phase II study explored the chemotherapy free combination
chemotherapy with the BFM backbone intensive treatment.171,172
of blinatumomab plus ponatinib in 54 patients ≥18 years of age with newly
Additionally, a phase II trial evaluated the safety and efficacy of adding
diagnosed or R/R Ph-positive ALL.179 Among patients with evaluable data,
continuous dasatinib at day 15 to the intensive BFM regimen in pediatric
87% of patients in the newly diagnosed cohort and 92% of patients in the
patients with newly diagnosed Ph-positive ALL (n = 109 enrolled; age
R/R cohort achieved a complete molecular response. Three patients had
range, 1–17 years).173 The efficacy analysis included 104 patients, who all
to discontinue ponatinib secondary to adverse events (coronary artery
achieved CR; 15 of the patients received allogeneic HCT at first CR
stenosis, cerebrovascular ischemia, and portal vein thrombosis).
(CR1). An interim analysis showed a 3-year EFS of 66.0% (95% CI,
54.8%–75.0%) and a 3-year OS of 92.3% (95% CI, 85.2%–96.1%).173 TKIs Combined with Hyper-CVAD
A phase II study at MDACC evaluated imatinib combined with the
Blinatumomab
hyper-CVAD regimen in patients with previously untreated or minimally
Treatment of adults with newly diagnosed Ph-positive ALL was evaluated
treated ALL (n = 54; median age, 51 years; range, 17–84 years); 14
in a phase 2 single-group trial using dasatinib chemotherapy-free induction
patients underwent subsequent allogeneic HCT.159 The 3-year OS rate for
followed by first-line consolidation therapy with blinatumomab.174
this regimen was 54%. Among the patients ≤40 years of age (n = 16), a
Sixty-three patients, aged 24 to 84, were enrolled. At the end of induction,
strong trend was observed for OS benefit with allogeneic HCT (3-year OS
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rate, 90% vs. 33%; P = .05).159 Among patients ≤60 years of age, no 24), whereas those who achieved complete remission with good molecular
statistically significant difference was observed in the 3-year OS rate response but without a donor were eligible for autologous HCT (n = 10).
between patients who received HCT and those who did not (77% vs. Nine patients did not receive HCT and were treated with imatinib-based
57%). maintenance therapy. The 4-year OS rate did not differ significantly for
patients with a sibling donor compared to patients undergoing autologous
Studies have shown the promising activity of other TKIs, including HCT (76% vs. 80%). The 4-year OS for patients who received only
dasatinib and ponatinib when incorporated into frontline regimens for maintenance imatinib was 33%.183 These data suggest that improved
patients with ALL. In a phase II study from MDACC, dasatinib was survival with imatinib-based therapy can be further enhanced by the
combined with hyper-CVAD and subsequent maintenance therapy in addition of HCT.
patients with previously untreated Ph-positive ALL (n = 35; median age, 53
years; range, 21–79 years; 31% were >60 years); four of the patients In the subgroup of patients with Ph-positive ALL (n = 94; median age, 47
received allogeneic HCT in CR1.180 The 2-year OS and EFS rates were years; range, 19–66 years) from the Northern Italy Leukemia Group study
64% and 57%, respectively. The efficacy and safety of ponatinib combined (NILG-09/00), outcomes were compared among patients who received
with hyper-CVAD was examined in patients with Ph-positive ALL (n = 37; chemotherapy with imatinib (n = 59) or without imatinib (n = 35), with or
aged ≥18 years; median age, 51 years; 12 patients were ≥60 years) in a without subsequent HCT (allogeneic or autologous).184 The patients who
phase II prospective trial.153 Of the 32 patients with disease with received imatinib (63% of eligible patients underwent allogeneic HCT) had
Ph-positive metaphases at the start of therapy, all 32 patients (100%) significantly higher 5-year OS (38% vs. 23%; P = .009) and DFS rates
achieved an overall complete cytogenetic response. By multiparametric (39% vs. 25%; P = .044) compared with those who did not receive imatinib
flow cytometry, 35 of 37 patients (95%) achieved MRD negativity after a (39% of eligible patients underwent allogeneic HCT).184 The 5-year OS
median of 3 weeks of therapy.153 However, it is worth noting that only half rates by treatment type were 47% for allogeneic HCT (n = 45), 67% for
of the patients ≥60 years of age completed therapy with this regimen, and autologous HCT (n = 9), 30% for imatinib without HCT (n = 15), and 7%
were switched to alternate TKIs. The 2-year OS and EFS rates were 80% for no imatinib and no HCT (n = 13); the corresponding treatment-related
and 81%, respectively. A follow-up study (n = 76; age ≥18 years; median mortality rates were 17%, 0%, 36%, and 23%, respectively. The 5-year
age, 47 years) demonstrated long-term efficacy for ponatinib and relapse rates were 43%, 33%, 87%, and 100%, respectively.184
hyper-CVAD with a 3-year EFS rate of 70%.181
The Japan Adult Leukemia Study Group (ALL-202) treated patients with
TKIs Combined with Multiagent Therapy Ph-positive ALL (n = 100) with chemotherapy combined with imatinib
In the phase II study from the GRAALL (GRAAPH-2003), patients with administered during induction, consolidation, and maintenance
previously untreated Ph-positive ALL (n = 45; median age, 45 years; phases.185,186 An early analysis (n = 80; median age, 48 years; range, 15–
range, 16–59 years) received imatinib in combination with chemotherapy 63 years) reported a 1-year OS rate of 73% among patients who
during either induction or consolidation therapy.182,183 Patients who underwent allogeneic HCT, compared with 85% for those who did not.186 A
achieved complete remission with a donor received allogeneic HCT (n = subsequent analysis compared outcomes for the subgroup of patients who

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NCCN Guidelines Version 2.2024

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received allogeneic HCT at first CR in this study (n = 51; median age, 38 (median age 54 years) with newly diagnosed Ph-positive ALL.189
years; range, 15–64 years) versus those for a historical cohort of patients Treatment was continued for 20 cycles, through induction, consolidation,
who received allogeneic HCT without prior imatinib (n = 122).185 The and post-consolidation. Following 20 cycles, single agent ponatinib or
3-year OS (65% vs. 44%; P = .015) and DFS rates (58% vs. 37%; P = imatinib was continued until disease progression or unacceptable toxicity.
.039) were significantly higher among patients treated with imatinib Many patients discontinued study treatment, with the most common
compared with the historical cohort; the 3-year non-relapse mortality rate reasons being the decision to proceed with HCT, adverse events, and lack
was similar between cohorts (21% vs. 28%, respectively).185 of efficacy. Seventy-eight patients remained on protocol at the time of data
cutoff. Among these 78 patients, MRD negative CR rates were
A multicenter phase II study from the Adult Acute Lymphoblastic Leukemia significantly higher among the ponatinib cohort compared to the imatinib
Working Party of the Korean Society of Hematology investigated the cohort (34.4% vs. 16.7%; P = .002). Median follow up was 20 months vs
effects of multiagent therapy combined with nilotinib in patients with newly 18 months for ponatinib vs imatinib, respectively. There was also a trend
diagnosed Ph-positive ALL (n = 90; median age, 47 years; range, 17–71 towards improved EFS (hazard ratio [HR] = 0.652, 95% CI, 0.385–1.104)
years).187 Chemotherapy combined with nilotinib was administered during and time to treatment failure with ponatinib (HR = 0.455), though survival
induction, consolidation, and maintenance phases. Of 90 evaluable data was not mature. Rates of treatment-emergent adverse events of any
patients, 82 (91%) experienced complete hematologic remission with a grade were comparable between the two cohorts. Based on this data, the
median time of 27 days (range, 13–72 days). The 2-year hematologic RFS FDA approved ponatinib with chemotherapy for adult patients with newly
and OS rates were both 72%.187 diagnosed Ph+ ALL on March, 19, 2024.190
In a phase II multicenter trial (CALGB 10701), patients with newly Inotuzumab ozogamicin
diagnosed Ph-positive ALL (n = 64; median age, 60 years; range, 22–87 Inotuzumab ozogamicin (InO) is a calicheamicin-based antibody-drug
years) were treated with multiagent therapy combined with dasatinib, and conjugate targeting CD22 that is FDA approved for treatment of adults
the efficacy of different post-remission strategies were evaluated including with R/R B-ALL. A recent phase II study evaluated the use of InO in the
allogeneic HCT, autologous HCT, and chemotherapy alone, followed by induction setting for patients with ALL (n = 26; median age, 46 years;
maintenance with dasatinib.188 The CR rate was 97% with no induction range, 19–70 years) in 1st or 2nd CR with positive MRD (≥10-4).191 Sixty-two
deaths. With a median follow-up of 48 months for survivors, 3-year OS percent of patients had Ph+ ALL and received up to 6 cycles (median, 3
and DFS were 55% and 43%, respectively.188 For patients who underwent cycles) of InO with a concurrent BCR::ABL1 TKI (ponatinib or dasatinib).
consolidation with allogeneic HCT, autologous HCT, or chemotherapy, Among the entire cohort, 69% of patients achieved MRD negative status,
3-year OS was 75%, 71%, and 55%, respectively, with median OS not including 10 patients with Ph+ ALL, with 2-year RFS and OS rates of 54%
reached (NR) for all groups. The 3-year DFS was 55%, 43%, and 46%, and 60%, respectively. Two patients with Ph+ positive ALL developed
respectively.188 hepatic sinusoidal obstruction syndrome (SOS), formerly known as
veno-occlusive disease (VOD). Otherwise, most adverse events (AEs)
PhALLCON, is an ongoing phase III study comparing ponatinib versus
were low grade.
imatinib combined with reduced-intensity chemotherapy in 245 patients
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Initial Treatment in Adults with Ph-Positive B-ALL The Center for International Blood and Marrow Transplant Research
Historically, treatment outcomes for adult patients with Ph-positive ALL (CIBMTR) group conducted a multicenter retrospective analysis examining
have been extremely poor. Before the era of targeted TKIs, the 3-year OS the efficacy RIC and MAC allogeneic HCT in adult patients with
rates with chemotherapy regimens were generally <20%.192 Ph-positive ALL (n = 197).196 At a median follow-up of 4.5 years, the
1-year transplant-related mortality was significantly lower in the RIC
Hematopoietic Cell Transplant versus MAC group (13% vs. 36%; P = .001), and 3-year OS rates were
Allogeneic HCT, in the pre-imatinib era, resulted in some improvements similar (39% vs. 35%, respectively).196
over chemotherapy alone, with 2-year OS rates of 40% to 50%193,194 and
3-year OS rates of 36% to 44%.95,185 In the large, international, TKIs Combined with Hyper-CVAD
collaborative MRC UKALL XII/ECOG E2993 trial conducted in patients Studies evaluating TKIs plus hyper-CVAD have included both AYA and
with previously untreated ALL, the subgroup with Ph-positive disease (n = adult patients.153,159,180 For discussion of these studies, refer to the
267; median age, 40 years; range, 15–60 years) was eligible for allogeneic previous section (see Initial Treatment in AYA Patients with Ph-Positive
HCT if its patients were <50 (in the ECOG E2993 trial) or <55 (in the MRC ALL).
UKALL XII trial) years of age and had a matched sibling or matched
TKIs Combined with Multiagent Therapy
URD.195 Among the Ph-positive cohort, postremission treatment included
Studies evaluating TKIs plus multiagent therapy have been discussed in
matched sibling allogeneic HCT (n = 45), matched URD allogeneic HCT (n
the previous section182-185,187,188,199 (see Initial Treatment in AYA Patients
= 31), and chemotherapy alone (n = 86). The 5-year OS rate according to
with Ph-Positive ALL). Several studies evaluating the efficacy of TKIs
postremission therapy was 44%, 36%, and 19%, respectively, and the
combined with multiagent therapy in patients with previously untreated
5-year EFS rate was 41%, 36%, and 9%, respectively.195 Both the OS and
ALL have shown improved outcomes, particularly when treatment was
EFS outcomes for patients who underwent allogeneic HCT (related or
followed by allogeneic HCT.156,184-186,188 A multicenter trial from the
unrelated) were significantly improved compared with those who received
European Working Group for Adult ALL (EWALL; EWALL-PH02)
only chemotherapy. The incidence of transplant-related mortality was 27%
evaluated the efficacy and safety of nilotinib with multiagent therapy in
with matched sibling allogeneic HCT and 39% with matched URD HCT.
patients aged 55 to 85 years with Ph-positive ALL (n = 79 [72
An intent-to-treat analysis of patients with a matched sibling donor versus
evaluable]).156 The CR rate was 94.4% and the MRD response
those without a matched sibling donor showed no statistically significant
(BCR::ABL1/ABL1 ratio ≤0.1%) increased from 41% after induction to 86%
difference in 5-year OS rates (34% vs. 25%, respectively).195 The
after consolidation II. At 4 years, the EFS and OS rates were 42% and
incorporation of imatinib in the treatment regimen for Ph-positive ALL has
47%, respectively. By landmark analyses using median time to transplant
led to improvements in outcomes over chemotherapy alone.159,186,192
as a cutoff, the 4-year OS rate was 61% in patients who underwent
Some retrospective studies suggest similar outcomes between allogeneic HCT.
myeloablative conditioning (MAC) and reduced-intensity conditioning (RIC)
followed by allogeneic HCT in adult patients with Ph-positive ALL.196-198

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TKIs Combined with Corticosteroids years) were treated with chemotherapy induction followed by a
The treatment of patients who are older with Ph-positive ALL may pose a consolidation regimen with imatinib and methylprednisolone.202 The 1-year
challenge, because patients who are older or those with comorbidities may OS rate in this study was significantly higher compared with the historical
not tolerate aggressive regimens with multiagent therapy combined with control population who received the same induction therapy but did not
TKIs.200 Several studies have evaluated outcomes with imatinib induction, receive imatinib as part of consolidation (66% vs. 43%; P = .005), and the
with or without concurrent corticosteroids, in adults who are older with median OS in this study was longer than that of the control group (23 vs.
Ph-positive ALL. In a study that randomly assigned patients aged 54 to 79 11 months, respectively). In addition, the 1-year RFS rate was significantly
years with Ph-positive ALL (n = 55; median age, 68 years; 94.5% were increased with the addition of imatinib (58% vs. 11%; P < .001).202 A
≥60 years of age) to induction therapy with imatinib versus chemotherapy phase II study by GIMEMA (LAL0201-B study) also evaluated imatinib
alone, followed by imatinib-containing consolidation therapy, the estimated combined with corticosteroids in patients >60 years of age with Ph-positive
2-year OS rate was 42%; no significant difference was observed between ALL (n = 29 evaluable; median age, 69 years).203 Patients received
induction treatment arms.201 The median OS was numerically higher (but imatinib in combination with prednisone for induction. The estimated
not statistically significant) among patients who received imatinib induction 1-year DFS and OS rates were 48% and 74%, respectively; the median
compared with those randomized to receive chemotherapy induction (23.5 OS was 20 months.203 In a separate study from GIMEMA (LAL-1205),
vs. 12 months). However, the incidence of severe adverse events was patients with Ph-positive ALL (n = 53 evaluable; age range, 24–76.5
significantly lower with imatinib induction (39% vs. 90%; P = .005), which years) received induction therapy with dasatinib and prednisone.152
suggested that induction therapy with imatinib may be better tolerated than Postinduction therapy included no further therapy (n = 2), TKI only (n =
chemotherapy in patients in this age group with Ph-positive ALL.201 19), TKI combined with chemotherapy (n = 10) with or without autologous
HCT (n = 4), or allogeneic HCT (n = 18). All patients experienced a CR
In a study by GIMEMA (LAL-1205), patients with Ph-positive ALL (n = 53 after induction therapy. The median OS was 31 months and the median
evaluable; median age, 54 years; range, 24–76.5 years) received DFS (calculated from day +85) was 21.5 months. At 20 months, the OS
induction therapy with dasatinib and prednisone.152 Twelve patients were and DFS rates were 69% and 51%, respectively.152
>60 years of age. Postinduction therapy included no further therapy (n =
2), TKI only (n = 19), TKI combined with chemotherapy (n = 10) with or A phase II study from GIMEMA (LAL1811) also evaluated the efficacy and
without autologous HCT (n = 4), or allogeneic HCT (n = 18). All patients safety of ponatinib and prednisone in adult patients aged 27 to 85 years
experienced a CR after induction therapy. The median OS was 31 months with untreated Ph-positive ALL (n = 42 evaluable; median age, 68
and the median DFS (calculated from day +85) was 21.5 months. At 20 years).204 Dose reduction of ponatinib was allowed for adverse events. At
months, the OS and DFS rates were 69% and 51%, respectively.152 T315I week 24, the primary endpoint of the study, complete hematologic
mutation was detected in 12 of 17 cases of relapsed disease (71%). response, was prematurely reached in 75% of patients. During the study,
75 adverse events were reported; 36 were related to ponatinib.204
In a small phase II study from GRAALL (AFR-09 study), patients ≥55
years of age with Ph-positive ALL (n = 29 evaluable; median age, 63

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NCCN Guidelines Version 2.2024

Acute Lymphoblastic Leukemia

TKIs Combined with Vincristine and Dexamethasone In the EWALL-Ph-01 study, induction therapy with dasatinib combined with
The phase II GRAALL study (GRAAPH-2005) compared induction therapy low-intensity chemotherapy (vincristine and dexamethasone) was
with high-dose imatinib (800 mg daily, days 1–28) combined with evaluated in patients ≥55 years of age with Ph-positive ALL (n = 71;
vincristine and dexamethasone (arm A) versus imatinib (800 mg daily, median age, 69 years; range, 58–83 years). The CR rate after induction
days 1–14) combined with hyper-CVAD (arm B) in patients <60 years of was 96% and MRD response (BCR::ABL1/ABL1 ratio ≤0.1%) was
age with previously untreated Ph-positive ALL.205,206 Eligible patients observed in 65% of patients.208 At 3 years, the RFS, EFS, and OS were
proceeded to HCT (allogeneic or autologous) after induction/consolidation 33% (95% CI, 22%–44%), 31% (95% CI, 21%–42%), and 41% (95% CI,
phases. The primary endpoint was noninferiority of the less intensive arm 29%–52%), respectively.208 At 5 years, the cumulative incidence of relapse
A regimen in terms of MRD response (BCR::ABL/ABL ratio <0.1% by was 54% (95% CI, 42%–66%). These studies suggest that the use of TKIs
quantitative PCR) after induction/consolidation. In an early report from this in combination with less intensive therapies (eg, corticosteroids with or
study (n = 118; n = 83 evaluable; median age, 42 years), 52 patients without vincristine) may provide an alternative treatment option for patients
proceeded to HCT (allogeneic, n = 41; autologous, n = 11). The estimated who are older with Ph-positive ALL for whom intensive regimens are not
2-year OS rate was 62%, with no significant difference between patients appropriate.
who received imatinib with vincristine and dexamethasone and those who
received imatinib with hyper-CVAD (68% vs. 54%, respectively).205 The TKIs in Maintenance Therapy
2-year DFS rate was 43%, with no significant difference between induction Collectively, the incorporation of TKIs into the therapeutic regimen has
arms (54% vs. 32%, respectively). demonstrated improved outcomes for adult patients with Ph-positive ALL,
particularly when administered before allogeneic HCT. Given that patients
In an updated analysis from the GRAAPH-2005 study with a median can experience relapse following allogeneic HCT, strategies are needed to
follow-up of 4.8 years (n = 268; median age, 47 years), the CR rate was prevent disease recurrence. One strategy involves the incorporation of
higher in arm A compared to arm B (98% vs. 91%; P = .006), but MRD post-HCT maintenance therapy with TKIs, which has been investigated in
response rates after 2 cycles of therapy were similar between arm A and several studies. In a small prospective study in patients with Ph-positive
arm B (66.1% vs. 64.5%).207 The estimated 5-year EFS and OS rates were leukemias who underwent allogeneic HCT (n = 15 with ALL; median age,
37.1% and 45.6%, respectively, and no significant differences were 37 years; range, 4–49 years), imatinib was administered from the time of
observed between arm A and arm B.207 Among patients who proceeded to engraftment until 1 year after HCT.209 The median time after HCT until
allogeneic HCT or autologous HCT after MRD response, the outcomes initiation of imatinib was short, at 27 days (range, 21–39 days). Molecular
were similar in terms of the 5-year post-transplant RFS (48.3% vs. 46.1%) remission (by PCR) was observed in 46% of patients (6 of 13) prior to
and OS (56.7% vs. 55.1%) rates. This study suggests that outcomes with HCT and 80% (12 of 15) after HCT. Two patients died after hematologic
less intensive chemotherapy regimens (using high-dose imatinib) may relapse and one patient died due to acute respiratory distress syndrome
offer similar benefits to more intensive imatinib-containing chemotherapy approximately 1 year post-HCT. At a median follow-up of 1.3 years, 12
regimens.207 patients (80%) were alive without detectable disease.209 This was one of
the first prospective studies to show the feasibility of administering imatinib

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NCCN Guidelines Version 2.2024

Acute Lymphoblastic Leukemia

maintenance early in the post-HCT period (<90 days) when the leukemic HCT. Imatinib was discontinued prematurely in the majority of patients in
tumor burden tends to be low. both arms (67% in the prophylaxis arm; 71% in the MRD-triggered arm),
primarily because of toxicities.211 Ongoing CR was observed in 81% of
Maintenance therapy with imatinib was also evaluated in a prospective patients in the prophylaxis arm (median follow-up, 30 months) and in 78%
study in patients who underwent allogeneic HCT (n = 82; median age, of patients in the MRD-triggered arm (median follow-up, 32 months). No
28.5 years; range, 3–51 years).210 Imatinib was scheduled for a period of 3 significant differences were found between the prophylaxis and
to 12 months (until three consecutive tests were negative for BCR::ABL MRD-triggered arms in terms of relapse rate (8% vs. 17%), 5-year DFS
transcripts or sustained molecular CR for at least 3 months). Among the (84% vs. 60%), EFS (72% vs. 54%), or OS (80% vs. 74.5%).211 However,
patients who received imatinib (n = 62), the median time after HCT until MRD positivity was predictive of relapse regardless of treatment arm; the
initiation of imatinib was 70 days (range, 20–270 days). In this group of 5-year RFS rate was significantly lower among patients with detectable
patients, 84% were alive with a molecular CR at a median follow-up of 31 MRD compared with those who achieved MRD negativity (70% vs. 100%;
months.210 Imatinib was discontinued in 16% of patients receiving P = .017). Moreover, early MRD positivity (within 100 days after HCT) was
treatment due to toxicities. The remaining patients (n = 20) who did not associated with significantly decreased EFS compared with late MRD
receive maintenance with imatinib (due to cytopenias, infections, detection (median, 39 months vs. NR; 4-year EFS, 39% vs. 65%; P =
graft-versus-host disease [GVHD], or patient choice) constituted the .037).211 This trial suggested that imatinib given post-allogeneic HCT
non-imatinib group. The estimated 5-year relapse rate was significantly (either prophylactically or based on MRD detection) resulted in low relapse
lower with imatinib compared with no imatinib (10% vs. 33%; P = .0016) rates and durable remissions. However, imatinib may not provide benefit
and the estimated 5-year DFS (81.5% vs. 33.5%; P < .001) and OS rates for patients who experience early molecular relapse or persistent MRD
(87% vs. 34%; P < .001) were significantly longer with imatinib compared following HCT. Although no randomized controlled trials have yet been
with no imatinib.210 conducted to establish the efficacy of TKIs (compared with observation
only or other interventions) following allogeneic HCT, the collective results
The previous study was not designed as a randomized controlled trial, and
from these studies suggest that TKI maintenance may have a potential
the number of patients in the non-imatinib group was small. A multicenter
role in reducing the relapse risk in this setting.
randomized trial evaluated imatinib given prophylactically (n = 26)
compared with imatinib given at the time of MRD detection (ie, molecular Treatment of Relapsed Ph-Positive B-ALL
recurrence; n = 29) in patients who underwent allogeneic HCT with a
The treatment of patients who experience relapse after initial therapy for
planned duration of imatinib therapy for 1 year.211 MRD was defined by the
ALL remains a challenge, because these patients have a very poor
appearance of BCR::ABL transcripts, as assessed by quantitative RT-PCR
prognosis. Several large studies using conventional chemotherapy for
performed at a central laboratory. In the prophylactic arm, imatinib was
adults with relapsed disease have reported a median OS of 4.5 to 6
started in 24 patients (92%) at a median time of 48 days (range, 23–88
months, and a 5-year OS rate of 3% to 10%.212-215 One major factor
days) after HCT. In the MRD-triggered arm, imatinib was started in 14
associated with poorer survival outcomes after subsequent therapy for
patients (48%) at a median time of 70 days (range, 39–567 days) after
relapsed ALL is the duration of response to frontline treatment. In an
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NCCN Guidelines Version 2.2024

Acute Lymphoblastic Leukemia

analysis of data from the PETHEMA (Programa Español de Tratamientos limited data are available. Evidence from prospective studies is needed to
en Hematologia) trials, patients with disease that relapsed >2 years after establish the role of DLI, with or without TKIs, in the treatment of relapsed
frontline therapy had significantly higher 5-year OS rates than the groups disease.
with disease that relapsed within 1 to 2 years or within 1 year of frontline
Tyrosine Kinase Inhibitors
therapy (31% vs. 15% vs. 2%; P < .001).213 Similarly, in the MRC UKALL
XII/ECOG E2993 trial, patients with disease that relapsed >2 years after The emergence of resistance poses a challenge for patients who
initial diagnosis and frontline therapy had a significantly higher 5-year OS experience relapse after initial treatment with TKI-containing regimens.
rate than those whose disease relapsed within 2 years (11% vs. 5%; P < Point mutations within the ABL kinase domain and alternative signaling
.001).212 In the pre-imatinib era, patients with Ph-positive B-ALL who pathways mediated by the SRC family kinase have been implicated as
experienced relapse after frontline therapy had dismal outcomes; mechanisms of resistance.225-227 The former has been identified in a large
subgroup data from the large, prospective trials LALA-94 and MRC UK proportion of patients who experience disease recurrence after
XII/ECOG E2993 showed a median OS of 5 months and a 5-year OS rate imatinib-containing therapy.228,229 Moreover, ABL kinase domain mutations
of 3% to 6% among patients subsequently treated for relapsed Ph-positive may be present in a small group of patients not yet treated with imatinib
B-ALL.212,214 even before initiation of any TKI therapy.230,231

Hematopoietic Cell Transplant CNS relapse has been reported in both patients with disease responsive
Treatment options are extremely limited for patients with Ph-positive to imatinib therapy (isolated CNS relapse with CR in marrow) and patients
B-ALL who experience relapse after receiving consolidation with with disease resistant to imatinib therapy.232-235 The concentration of
allogeneic HCT. Some investigators have reported on the feasibility of imatinib in the cerebrospinal fluid (CSF) has been shown to be
inducing a second molecular CR with dasatinib in those who have approximately 2 logs lower than that achieved in the blood, suggesting
experienced an early relapse after first allogeneic HCT, which allowed for that this agent does not adequately penetrate the blood-brain barrier to
a second allogeneic HCT.216,217 Studies that include donor lymphocyte ensure CNS coverage.233,235 A study showed that among patients with ALL
infusion (DLI) to induce further graft-versus-leukemia effect in those who treated with imatinib and who did not receive routine prophylactic IT
experience relapse after allogeneic HCT have reported little to no benefit, therapy or cranial irradiation, 12% developed CNS leukemia.234 Patients
though it has been suggested that this is due to excessively high leukemic with imatinib-resistant disease who developed CNS disease rapidly died
burden.218,219 Indeed, published case reports have suggested that the use from progressive disease (PD); conversely, patients with imatinib-sensitive
of DLI for residual disease or molecular relapse (as noted by levels of disease who developed isolated CNS relapse could be successfully
BCR::ABL fusion mRNA measured with PCR) after allogeneic HCT may treated with IT therapy with or without cranial irradiation.232,234
eliminate residual leukemic clones and thereby prevent overt hematologic
Dasatinib and nilotinib are second-generation TKIs that have shown
relapse.220-222 Moreover, case reports have described using newer TKIs,
greater potency in inhibiting BCR::ABL compared with imatinib, and
such as dasatinib and nilotinib, along with DLI to manage relapse after
retention of antileukemic activity in cells with certain imatinib-resistant ABL
allogeneic HCT.223,224 Although these approaches are promising, only
mutations.157,236-238 In addition, dasatinib has better CNS penetration than
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NCCN Guidelines Version 2.2024

Acute Lymphoblastic Leukemia

imatinib, and therefore may have advantages in preventing CNS relapse. advanced leukemia [AP CML (n = 79), BP CML (n = 64), or ALL (n = 24)]
Both TKIs have been evaluated as single-agent therapy in patients with who were previously treated with at least one TKI.245,246 Of the 22
Ph-positive ALL that is resistant to imatinib treatment.239-241 A randomized evaluable patients with ALL, two patients (9%) attained or maintained a
phase III study examined the activity of dasatinib administered as confirmed overall hematologic response by 4 years.245 Common overall
once-daily (140 mg daily) versus twice-daily (70 mg twice daily) dosing in treatment-related adverse events reported in patients with advanced
patients with Ph-positive leukemia resistant to imatinib240; the once-daily leukemia included diarrhea (74%), nausea (48%), and vomiting
dosing resulted in a higher response rate (major cytogenetic response) (44%).245,246
than the twice-daily dosing (70% vs. 52%). Although the median OS was
shorter with the once-daily dosing (6.5 vs. 9 months), the median Ponatinib is a third-generation TKI that was initially approved by the FDA
progression-free survival (PFS) was longer (4 vs. 3 months).240 These in December 2012 for the treatment of adult patients with chronic, AP, or
differences in outcomes between the dosing arms were not statistically BP Ph-positive CML or Ph-positive ALL, with resistance to prior therapy,
significant. and was added as a treatment option for R/R Ph-positive ALL in 2013.
Though temporarily removed from the market in November 2013,
Dasatinib in combination with the hyper-CVAD regimen ponatinib distribution resumed in December 2013 following revision to both
(hyper-fractionated cyclophosphamide, vincristine, doxorubicin, and the prescribing information and risk evaluation and mitigation strategies
dexamethasone) was investigated in a phase II trial that included patients program to address the risk for serious cardiovascular adverse events.
with Ph-positive relapsed ALL (n = 19) and lymphoid blast phase (BP) This TKI has been shown to inhibit both native and mutant forms of
CML (n = 15).242 An overall response rate (ORR) of 91% was obtained, BCR::ABL (including those resulting from T315I mutation) in preclinical
with 26 patients (84%) achieving complete cytogenetic remission, 13 studies.247 In a multicenter, open-label, phase II study (PACE trial; n =
patients (42%) achieving a complete molecular response, and 11 patients 449), ponatinib showed substantial activity in patients with Ph-positive
(35%) achieving a major molecular response. There were nine patients leukemias resistant or intolerant to second-generation TKIs.248 Major
who went on to receive allogeneic HCT, including two patients with ALL. In hematologic response was observed in 41% of the subgroup with
the patients with relapsed ALL, 30% remained in complete remission at 3 Ph-positive ALL (n = 32). In the subset of patients with Ph-positive ALL
years with a 3-year OS of 26%. At the median follow-up of 52 months with ABL T315I mutation (n = 22), major hematologic response was
(range, 45–59 months), two patients (11%) with ALL were still alive. observed in 36%.248 Common overall treatment-related adverse events in
the PACE trial included thrombocytopenia (37%), rash (34%), and dry skin
Bosutinib, a second-generation TKI that acts as a dual inhibitor of (32%). Additionally, arterial thrombotic events were observed and 7.1% of
BCR::ABL and SRC family kinases,243,244 was approved in September patients experienced cardiovascular events,248 though dose reduction may
2012 by the FDA for the treatment of chronic, accelerated phase (AP), or impart a lower risk.
BP Ph-positive CML in adult patients with disease resistant to prior TKI
treatment based on an open-label, multicenter phase I/II trial.244 Efficacy Not all imatinib-resistant ABL mutations are susceptible to the newer TKIs.
and safety analyses of bosutinib monotherapy included patients with For instance, dasatinib is not as active against cells harboring the ABL

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NCCN Guidelines Version 2.2024

Acute Lymphoblastic Leukemia

mutations T315I, V299L, and F317L.227,237,249,250 Thus, for patients with standard therapy, InO produced a significantly higher CR/CR with
disease resistant to TKI therapy, it becomes important to identify potential incomplete hematologic recovery (CRi) rate (80.7% vs. 29.4%; P < .001)
ABL mutations that may underlie the observed resistance to treatment. A and higher MRD-negative rates (78.4% vs. 28.1%; P < .001).254 Notably,
panel of experts from the European LeukemiaNet published responses were consistent across most subgroups, including those with
recommendations for the analysis of ABL kinase domain mutations in high marrow burden, and those with Ph-positive leukemia. The overall
patients with CML, and treatment options according to the presence of incidence of severe adverse events was similar across treatment arms,
different ABL mutations.251 (See Principles of Systemic Therapy in the with a higher incidence of hepatic SOS, observed in the InO group,
algorithm for TKI treatment options for Treatment Options Based on related in part to dual alkylator-based transplant conditioning
BCR::ABL1 Mutation Profile). administered in remission. These data translated into a significant benefit
in the median duration of remission (4.6 vs. 3.1 months; P = .03), median
Blinatumomab
PFS (5 vs. 1.8 months; P < .001), and mean OS (13.9 vs. 9.9 months; P
In December 2014, the FDA approved blinatumomab for the treatment of = .005).254 In August 2017, InO received full approval from the FDA for
relapsed or refractory Ph-negative precursor B-ALL (see Treatment of the treatment of R/R precursor B-ALL.
Relapsed Ph-Negative ALL for a detailed discussion of blinatumomab). In
July 2017, blinatumomab received full approval from the FDA for the CAR T Cells
treatment of R/R precursor B-ALL (Ph-negative and Ph-positive). A Currently, HCT is the only cure for R/R ALL, but many patients are not
follow-up, open-label, single-arm, multicenter, phase II study evaluated the eligible for transplant based on age or progression of the disease. The
efficacy and safety of blinatumomab in patients with R/R Ph-positive ALL generation of chimeric antigen receptor (CAR) T cells to treat ALL
who experienced disease progression after imatinib and at least one represents a significant advance in the field and has shown significantly
second- or third-generation TKI (n = 45).252 During the first 2 cycles of greater OS than current regimens.255 Pre-treatment with CAR T cells has
blinatumomab, 36% achieved complete remission or complete remission served as a bridge for transplant, and patients who were formerly unable
with partial hematologic recovery, and 88% of these responders achieved to be transplanted due to poor remission status achieve a CR and
a complete MRD response.252 Notably, responses were independent of ultimately proceed to transplantation. CAR T-cell therapy relies on the
T315I mutation status (see Initial Treatment in AYA Patients with genetic manipulation of a patients’ T cells to engender a response against
Ph-Negative ALL for a discussion of studies related to blinatumomab and a leukemic cell-surface antigen, most commonly CD19256 (see Treatment
chemotherapy-resistant MRD). of Relapsed Ph-Negative ALL for a detailed discussion of CAR T cells).
CAR T-cell therapy with tisagenlecleucel was recommended for
Inotuzumab ozogamicin
accelerated approval by the FDA Oncologic Drug Advisory Committee in
Following the generation of encouraging single-agent phase II data,253 a July 2017 and fully approved by the FDA in August 2017 for the treatment
randomized study was conducted comparing InO with standard intensive of patients <26 years of age with R/R precursor B-ALL. In October 2021,
chemotherapy regimens in Ph-negative or Ph-positive ALL in first or the FDA approved the second CAR T-cell therapy for adults with relapsed
second relapse, defined as >5% marrow blasts (n = 326). Compared to

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NCCN Guidelines Version 2.2024

Acute Lymphoblastic Leukemia

or refractory B-ALL: brexucabtagene autoleucel. This treatment is the first patient to receive allogeneic HCT is unclear; however, proceeding to
CAR T-cell therapy for patients ≥26 years of age in this setting. allogenic HCT with MRD is not optimal and additional therapy is
recommended to eliminate MRD before transplant.
NCCN Recommendations for Ph-Positive B-ALL
AYA and Adult Patients with Ph-Positive B-ALL In cases of persistent or rising MRD, consolidation therapy options may
The panel recommends that Ph-positive B-ALL AYA and adult patients include blinatumomab with or without TKI,174,179 InO with or without TKI191,
<65 years of age and no substantial comorbidities be treated in a clinical or continuation of multiagent therapy or corticosteroid combined with a
trial, when possible. In the absence of an appropriate clinical trial, the TKI. Blinatumomab with TKI is preferred in consolidation regardless of
recommended induction therapy would comprise multiagent therapy, MRD status for those who have not previously received blinatumomab.
blinatumomab, or corticosteroids combined with a TKI. Prior to initiation of Although long-term remission after blinatumomab with TKI is possible,
blinatumomab, cytoreduction to a peripheral WBC count of <10 x 109/L is allogeneic HCT in appropriate candidates can also be considered
recommended, which can frequently be achieved with a TKI plus following MRD positivity at the end of induction. In AYA patients ≤21 years
corticosteroid.174 However, the panel notes that not all TKIs have been of age, emerging data suggest that allogeneic HCT may not confer an
studied within the context of each regimen, and there are limited data for advantage over chemotherapy combined with TKIs.168 Maintenance
bosutinib in Ph-positive B-ALL. Use of a specific TKI should account for therapy with a TKI, with or without monthly pulses of vincristine/prednisone
anticipated or prior TKI intolerance, dose used, BCR::ABL1 mutations, and (for 2–3 years), is recommended. Although the optimal duration of
disease-related features. The PhALLCON study suggests improved MRD post-transplant or maintenance TKI is unknown, TKI should be continued
responses with ponatinib compared to imatinib.189 Imatinib use in first-line for at least 2 years post-transplant. TKI should be started as soon as
treatment should be restricted to patients who cannot tolerate broader feasible post-transplant. Sequential MRD assessments should be
acting TKIs. Treatment regimens should include adequate CNS considered for patients who have achieved a complete molecular
prophylaxis for all patients. It is also important to adhere to the treatment remission (undetectable levels). The frequency may be increased if MRD
regimens for a given protocol in its entirety, from induction therapy to levels are detectable or for those discontinuing TKI. For patients with
consolidation/delayed intensification to maintenance therapy. CD20-positive disease, consider adding rituximab to chemotherapy
(excluding immunotherapy).
For AYA and adult (<65 years of age) patients experiencing a CR after
initial induction therapy, an MRD assessment should be performed prior to For patients who achieve MRD negativity, consolidation therapy after a CR
consideration of consolidation with allogeneic HCT in appropriate should comprise a continuation of blinatumomab, multiagent therapy, or
candidates. For patients with negative MRD by flow cytometry but positive corticosteroid combined with a TKI, with consideration of dose
MRD by an FDA approved NGS assay, repeat testing before consolidation modifications as appropriate for patient age and performance status.
is started should be considered to confirm MRD status. Many variables These patients should continue to receive post-consolidation maintenance
determine eligibility for allogeneic HCT, including donor availability, depth therapy with a regimen that includes a TKI. Weekly methotrexate and daily
of remission, comorbidities, and social support.257 The optimal time for a 6-MP may be added to the maintenance regimen, as tolerated; however,

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the doses of these antimetabolite agents may need to be reduced in the therapy based on factors such as age, performance status, end-organ
setting of hepatotoxicity or myelosuppression. Individuals who inherit a function, and end-organ reserve. Dose modifications for patients age and
nonfunctional variant allele of the TPMT gene are known to be at high risk performance status should also be considered.
of developing hematopoietic toxicity (in particular, severe neutropenia)
after treatment with 6-MP.145 Testing for the TPMT gene polymorphism For adult patients who are ≥65 years of age or who have substantial
should be considered in patients receiving 6-MP as part of maintenance comorbidities, consolidation therapy is recommended to follow the same
therapy, particularly those who experience severe bone marrow toxicities treatment preferences and considerations noted for AYA and adult
(see Role of MRD Evaluation). Allogeneic HCT may be useful in patients (see NCCN Recommendations for Ph-Positive B-ALL; AYA and
appropriate candidates who have achieved MRD negativity, and post-HCT Adult Patients with Ph-Positive B-ALL).
TKI should be started when feasible.
Patients with Relapsed/Refractory Ph-Positive B-ALL

Adequate count recovery per protocol is necessary before transitioning to Mutation testing for the ABL1 kinase domain is recommended in patients
post remission therapy, even in the presence of MRD negativity. If count with Ph+ B-ALL that have experienced relapse after or have disease
recovery is not achieved, additional follow up for MRD may be warranted. refractory to initial TKI-containing therapy. The panel has largely adopted
Myelosuppression secondary to TKI should also be assessed, and the recommendations for treatment options based on ABL mutation status
consideration should be made for dose reduction. for CML, as published by the European LeukemiaNet.251 If not
administered during initial induction, TKIs (imatinib, dasatinib, nilotinib,
The treatment approach for AYA or adult patients experiencing less than a bosutinib, or ponatinib) are recommended options for patients with R/R
CR after initial induction therapy (ie, having primary refractory disease) Ph+ B-ALL. The PhALLCON study suggests improved MRD responses
would be similar to that for patients with R/R ALL (see Patients with with ponatinib compared to imatinib.189
Relapsed/Refractory Ph-Positive B-ALL).
For second- and third-generation TKIs, relevant BCR::ABL1 mutations
Adult Patients ≥65 Years of Age with Ph-Positive B-ALL should be considered as outlined in the algorithm table titled, Treatment
For adult patients with Ph-positive B-ALL ≥65 years of age or with Options Based on BCR::ABL1 Mutation Profile.
substantial comorbidities, the panel recommends treatment in a clinical
trial, when possible. In the absence of an appropriate clinical trial, the For all patients with R/R Ph-positive B-ALL, participation in a clinical trial is
recommended induction therapy would initially depend on the patient’s preferred. In the absence of an appropriate trial, patients may be
age and/or presence of comorbid conditions. Treatment regimens should considered for second-line therapy with an alternative TKI (ie, different
include adequate CNS prophylaxis for all patients, and a given treatment from the TKI used as part of induction therapy) alone, TKI combined with
protocol should be followed in its entirety. Although the age cutoff multiagent therapy, or TKI combined with corticosteroids (especially for
indicated in the guidelines has been set at 65 years, it should be noted patients who are older who may not tolerate multiagent combination
that chronologic age alone is not a sufficient surrogate for defining fitness; therapy). Blinatumomab with or without TKI may also be considered. For
patients should be evaluated on an individual basis to determine fitness for patients with disease refractory to or with intolerance to TKIs, InO with or
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without TKI is recommended. Compared to standard care, InO is Management of Ph-Negative ALL
associated with increased hepatotoxicity, including fatal and Initial Treatment in AYA Patients with Ph-Negative ALL
life-threatening hepatic SOS, and increased risk of post-HCT non-relapse
The AYA population with ALL can pose a unique challenge given that
mortality.258 Although there are limited data, it is recommended to wait at
patients may be treated with either a pediatric or an adult protocol,
least 4 weeks from InO monotherapy and the start of conditioning for
depending on local referral patterns and institutional practices.
allogeneic HCT to minimize risk of SOS. SOS has been shown to occur
Retrospective analyses based on cooperative group studies from both the
less frequently when less alkylators are used as part of the conditioning
United States and Europe have consistently shown the superior outcomes
regimen.259 Brexucabtagene autoleucel is an option for AYA and adult
for AYA patients (age range, 15–21 years) treated on pediatric versus
patients with R/R Ph-positive B-ALL following therapy that has included
adult ALL regimens. In the AYA population, 5-year EFS rates ranged from
TKIs. Tisagenlecleucel is also an option for patients <26 years of age and
63% to 74% for patients treated on a pediatric study protocol versus 34%
with refractory disease or ≥2 relapses and following therapy that has
to 49% for those receiving the adult protocol.92,93,120,261,262 In a
included 2 TKIs.
retrospective comparative study that analyzed outcomes of AYA patients
If patients who have not yet undergone transplant experience a second (age range, 16–20 years) treated on a pediatric CCG study protocol (n =
CR prior to transplant, consolidative allogeneic HCT should be strongly 197; median age, 16 years) versus an adult CALGB study protocol (n =
considered. For patients with disease that relapses after an initial 124; median age, 19 years), patients treated on the pediatric regimen
allogeneic HCT, other options may include a second allogeneic HCT compared with those on the adult regimen had significantly improved
and/or DLI. However, the role of allogeneic HCT following treatment with 7-year EFS (63% vs. 34%, respectively; P < .001) and OS (67% vs. 46%,
tisagenlecleucel is unclear. Persistence of tisagenlecleucel in peripheral respectively; P < .001) rates.120 Moreover, AYA patients treated on the
blood and persistent B-cell aplasia has been associated with durable adult protocol experienced a significantly higher rate of isolated CNS
clinical responses without subsequent allogeneic HCT. In the global relapse at 7 years (11% vs. 1%; P = .006). The substantial improvements
registration trial, estimated 3-year RFS rates were 52% and 48% with and in outcomes observed with the pediatric regimen in this study, and in the
without censoring for subsequent therapy, with only 22% of patients earlier retrospective analyses from other cooperative groups, may be
proceeding to HCT.260 Further study will be required before conclusive largely attributed to the use of greater cumulative doses of drugs, such as
recommendations can be made. In the absence of an appropriate clinical corticosteroids (prednisone and/or dexamethasone), vincristine, and
trial, for patients with T-ALL that is refractory to TKIs, regimens for R/R L-asparaginase, and to earlier, more frequent, and/or more intensive
Ph-negative ALL can be considered. (See Treatment of Relapsed CNS-directed therapy compared with adult regimens.120 Given the success
Ph-Negative ALL). seen with multiagent intensive therapy regimens for pediatric patients with
ALL, several clinical trials have evaluated pediatric-inspired regimens for
the AYA patient population.

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Acute Lymphoblastic Leukemia

Hematopoietic Cell Transplant HCT did not result in significant benefit compared with chemotherapy
For AYA patients with Ph-negative ALL in first CR, allogeneic HCT may be alone.
considered for high-risk cases—particularly for patients with disease that
is MRD positive any time after induction; or patients with elevated WBC In the PETHEMA ALL-93 trial, adult patients with high-risk ALL [defined as
counts; or patients with B-ALL and poor-risk cytogenetics [eg, having at least one of the following criteria: 30–50 years of age; WBC
hypodiploidy, KTM2A (MLL) rearrangement] at diagnosis. A large count ≥25 × 109/L; presence of t(9;22), t(4;11), or other 11q
multicenter trial (LALA-94 study) evaluated the role of postinduction HCT rearrangements; and t(1;19)] received postremission induction therapy (n
as one of the study objectives in adolescent and adult patients with ALL = 222 eligible; median age, 27 years; range, 15–50 years) with allogeneic
receiving therapy for previously untreated ALL (n = 922; median age, 33 HCT (n = 84; if matched related donor available), autologous HCT (n =
years; range, 15–55 years).95 Patients were stratified into four risk groups: 50), or chemotherapy alone (n = 48).263 Based on intent-to-treat analysis
1) Ph-negative standard-risk disease [defined as achievement of CR after of data from patients with Ph-negative high-risk disease, no significant
1 course of chemotherapy; absence of CNS disease; absence of t(4;11), advantage was observed in a donor versus no-donor comparison of
t(1;19), or other 11q23 rearrangements; WBC count <30 × 109/L]; 2) median DFS (21 vs. 38 months), median OS (32 vs. 67 months), 5-year
Ph-negative high-risk ALL (defined as patients with non–standard-risk DFS rate (37% vs. 46%), or 5-year OS rate (40% vs. 49%). In addition,
disease and without CNS involvement); 3) Ph-positive ALL; and 4) when the analysis was conducted based on the actual postremission
evidence of CNS disease. After induction therapy, patients with treatment received, no significant differences were noted between
Ph-negative high-risk ALL were eligible to undergo allogeneic HCT if a treatment arms for 5-year DFS rates (50% for allogeneic HCT; 55% for
matched sibling donor was available; those without a sibling donor were autologous HCT; and 54% for chemotherapy alone).263
randomized to undergo autologous HCT or chemotherapy alone.95 Among
The role of allogeneic HCT in adults with ALL was also evaluated in the
the subgroup of patients with Ph-negative high-risk ALL (n = 211), the
large multicenter MRC UKALL XII/ECOG E2993 study (n = 1913; age
5-year DFS and OS rates were 30% (median, 16 months) and 38%
range, 15–59 years).96 In this study, high risk was defined as ≥35 years of
(median, 29 months), respectively. Based on intent-to-treat analysis,
age; time to CR >4 weeks from induction; elevated WBC counts (>30 ×
outcomes in patients with Ph-negative high-risk ALL were similar for
109/L for B-ALL; >100 × 109/L for T-ALL); or the presence of Ph
autologous HCT (n = 70) and chemotherapy alone (n = 59) in terms of
chromosome. All other patients were considered to have standard-risk
median DFS (15 vs. 11 months), median OS (28 vs. 26 months), and
disease. Patients experiencing a remission with induction therapy were
5-year OS rate (32% vs. 21%).95 Outcomes were improved in patients with
eligible to undergo allogeneic HCT if a matched sibling donor was
Ph-negative high-risk ALL and those with CNS involvement allocated to
available or, in the absence of a sibling donor, were randomized to
allogeneic HCT. The median DFS was 21 months for these patients, and
undergo autologous HCT or chemotherapy. The 5-year OS rate was
the median OS has not yet been reached; the 5-year OS rate was 51%.95
higher for patients randomized to chemotherapy alone compared with
Thus, it appears that in patients with Ph-negative high-risk disease,
autologous HCT (46% vs. 37%; P = .03). A donor versus no-donor
allogeneic HCT in first CR improved DFS outcomes, whereas autologous
comparison in all patients with Ph-negative ALL showed that the 5-year

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Acute Lymphoblastic Leukemia

OS rate was significantly higher in the donor group than in the no-donor In a retrospective analysis of 169 patients who underwent URD HCT
group (53% vs. 45%; P = .01). This advantage in OS outcomes for the during first CR, 60 patients (36%) had one poor prognostic factor and 97
donor group was observed for patients with standard-risk disease (62% (57%) had multiple risk factors. The 5-year survival rate was 39%, which is
vs. 52%; P = .02) but not for those with Ph-negative high-risk disease higher than survival rates reported in studies of patients with high-risk
(41% vs. 35%).96 This was partly because of the high rate of non-relapse disease receiving chemotherapy alone.265 The most significant percentage
mortality observed with the donor group compared with the no-donor of treatment-related mortality occurred in patients who were given
group in patients with high-risk disease (36% vs. 14% at 2 years). Among mismatched donors compared to partially or well-matched donors. There
patients with standard-risk disease, the non-relapse mortality rate at 2 was no significant difference in outcome between patients <35 years of
years was 19.5% for the donor group and 7% for the no-donor group. age and patients >35 years of age, suggesting that URD transplants may
Relapse rate was significantly lower in the donor group than in the be an option for patients who are older. In a follow-up retrospective study
no-donor group for both patients with standard-risk disease (24% vs. 49%; by the same group, RIC was evaluated to lower treatment-related
P < .001) and those with high-risk disease (37% vs. 63%; P < .001).96 mortality.266 RIC conditioning most commonly comprised busulfan (9
Nevertheless, the high non-relapse mortality rate in the donor group mg/kg or less), melphalan (150 mg/m2), low-dose total body irradiation
among patients with high-risk disease seemed to diminish the advantage (TBI) (<500 cGy single dose or less than 800 cGy fractionated), or
of reduced risk for relapse in this group. This study suggested that fludarabine plus TBI of 200 cGy. RIC is more prominent in the treatment of
allogeneic HCT in first CR was beneficial in patients with standard-risk patients who are older; therefore, the median age for patients receiving
ALL. full-intensity (FI) conditioning was 28 years (range, 16–62 years), and for
patients receiving RIC, the median age was 45 years (range, 17–66
The benefit of matched sibling allogeneic HCT in adults with standard-risk years). Despite the variation in age, results from the study have shown no
ALL was also reported by the HOVON cooperative group. In a donor difference in relapse (35% vs. 26%;, P = .08) or in treatment-related
versus no-donor analysis of patients with standard-risk ALL undergoing mortality (FI, 33%; 95% CI, 31%–36% vs. RIC, 32%; 95% CI, 23%–43%;
postremission therapy with matched sibling allogeneic HCT or autologous P = .86) at 3 years.266 The 3-year survival for HCT was similar following
HCT, the donor arm was associated with a significantly reduced 5-year first CR (FI, 51%; 95% CI, 48%–55% vs. RIC, 45%; 95% CI, 31%–59%)
relapse rate (24% vs. 55%; P < .001) and a higher 5-year DFS rate (60% and second CR (FI, 33%; 95% CI, 30%–37% vs. RIC, 28%; 95% CI, 14%–
vs. 42%; P = .01) compared with the no-donor arm.264 In the donor group, 44%). The DFS was similar in both groups following first CR (FI, 49%;
the non-relapse mortality rate at 5 years was 16% and the 5-year OS rate 95% CI, 45%–53% vs. RIC, 36%; 95% CI, 23%–51%) and in second CR
was 69%.264 (FI, 32%; 95% CI, 29%–36% vs. RIC, 27%; 95% CI, 14%–43%).266
As evidenced by the previously described studies, matched sibling HCT A systematic review and meta-analysis of published randomized trials on
has been established as a valuable treatment strategy for patients with post-remission induction therapy in adults with ALL reported a significant
both standard and high-risk Ph-negative ALL, but subsequent studies reduction in all-cause mortality with allogeneic HCT in first CR (RR, 0.88;
have examined the role of URD transplants in high-risk Ph-negative ALL. 95% CI, 0.80–0.97) compared with autologous HCT or chemotherapy.267 A

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NCCN Guidelines Version 2.2024

Acute Lymphoblastic Leukemia

subgroup analysis showed a significant survival advantage with allogeneic response (all of whom received the augmented-intensity regimen), the
HCT in standard-risk ALL, whereas a nonsignificant advantage was seen 5-year EFS rate was 71%.270
in high-risk ALL.267 Autologous HCT in first remission was not shown to be
COG AALL0232
beneficial relative to chemotherapy in several large studies and
meta-analyses.95,96,267,268 The AALL0232 trial enrolled 2154 patients between the ages of 1 and 30
years who were diagnosed with high-risk B-ALL.271 In this study patients
CCG-1961 were randomly assigned to receive dexamethasone versus prednisone
The CCG-1961 trial was a seminal study that allowed comparison of adult during induction and high-dose methotrexate versus Capizzi
versus pediatric regimens in AYA patients. In an analysis of outcomes in escalating-dose methotrexate plus pegaspargase (PEG) during interim
children and AYA patients treated in the Dana-Farber Cancer Institute maintenance. High-dose methotrexate showed improved 5-year EFS (80%
(DFCI) ALL Consortium Protocols (1991–2000), the 5-year EFS rate vs. 75%; P = .008) and OS (88.9% ± 1.2% vs. 86.1% ± 1.4%; P = .25)
among younger AYA patients (age range, 15–18 years; n = 51) was 78%, rates compared to Capizzi escalating-dose methotrexate. No statistically
which was not significantly different from the EFS rates observed for significant difference was reported in the occurrence of mucositis,
children aged 10 to 15 years (77%; n = 108) or those aged 1 to 10 years neurotoxicity, osteonecrosis, or other toxicities. The ALL0232 trial
(85%; n = 685).269 The CCG 1961 study was designed to evaluate the compared dexamethasone 10 mg/m2/day for 14 days to 60 mg/m2/day of
benefit of augmented versus standard postinduction intensification therapy prednisone for 28 days. Dexamethasone showed improved outcomes
in children aged 1 to 9 years with high WBC counts (≥50 × 109/L) or in during induction in patients <10 years of age; however, it was associated
children and adolescents aged 10 to 21 years.119 Patients were stratified with a higher risk of osteonecrosis in patients ≥10 years of age. These
by their initial response to induction therapy as either having slow early data suggest that age may be an important factor for the selection of a
response (>25% bone marrow blasts on day 7 of induction) or rapid early corticosteroid.271
response. Among those who experienced rapid early response to
PETHEMA ALL-96 Regimen
induction (n = 1299), the augmented postinduction intensity arm was
associated with significantly increased rates of 5-year EFS (81% vs. 72%; In the PETHEMA ALL-96 trial, adolescent (n = 35; aged 15–18 years) and
P < .0001) and OS (89% vs. 83%; P = .003) compared with the young adult (n = 46; aged 19–30 years) patients with standard-risk
standard-intensity arm.119 In the subgroup of AYA patients (aged 16–21 Ph-negative ALL [defined as WBC count <30 × 109/L; absence of t(9;22),
years; n = 262) from the CCG 1961 study treated with either augmented or t(1;19), t(4;11), or any other 11q23 rearrangements] received frontline
standard-intensity regimens, the 5-year EFS and OS rates were 71.5% therapy with a 5-drug induction regimen (vincristine, daunorubicin,
and 77.5%, respectively.270 Among the AYA patients who experienced prednisone, L-asparaginase, and cyclophosphamide),
rapid early response, the augmented-intensity (n = 88) and consolidation/reinduction, and maintenance, along with triple IT therapy
standard-intensity (n = 76) arms showed no statistically significant throughout the treatment period.272 The 6-year EFS and OS rates for the
differences in rates of 5-year EFS (82% vs. 67%, respectively) or OS (83% entire patient cohort were 61% and 69%, respectively. No difference in
vs. 76%, respectively). For the AYA patients who experienced slow early EFS rate was observed between adolescents (60%; 95% CI, 43%–77%)

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NCCN Guidelines Version 2.2024

Acute Lymphoblastic Leukemia

and young adults (63%; 95% CI, 48%–78%); similarly, no significant untreated ALL; however, further follow-up data are needed to evaluate
difference was observed in OS for adolescents (77%; 95% CI, 63%–91%) long-term survival outcomes.
versus young adults (63%; 95% CI, 46%–80%).272 Based on multivariate
GRAALL-2005 Regimen
regression analysis, slow response to induction therapy (defined as having
>10% blast cells in the bone marrow aspirate performed on day 14 of The prospective phase II GRAALL-2003 study evaluated a
treatment) was the only factor associated with a poor EFS (odds ratio pediatric-inspired regimen using intensified doses of vincristine,
[OR], 2.99; 95% CI, 1.25–7.17) and OS (OR, 3.26; 95% CI, 1.22–8.70).272 prednisone, and asparaginase for adolescents and adults with
Ph-negative ALL (n = 225; median age, 31 years; range, 15–60 years).276
DFCI ALL Regimen Based on DFCI Protocol 00-01 The induction regimen comprised vincristine, daunorubicin, prednisone,
A multicenter phase II trial evaluated the pediatric-inspired regimen based L-asparaginase, and cyclophosphamide. Patients with high-risk disease
on the DFCI Childhood ALL Consortium Protocol 00-01 in AYA and adult and donor availability were allowed to proceed to allogeneic HCT. The
patients (aged 18–50 years) with previously untreated ALL; 20% of the EFS and OS rates at 42 months were 55% and 60%, respectively. When
patients in this study had Ph-positive disease.273 The treatment regimen data from patients who underwent transplantation at first CR were
comprised induction (vincristine, doxorubicin, prednisone, L-asparaginase, censored, the DFS rates at 42 months were 52% for patients with high-risk
and high-dose methotrexate), triple IT therapy, intensification, and disease and 68% for patients with standard-risk disease (risk assignment
maintenance. Among the 75 patients with evaluable data, the estimated based on GRAALL protocol); these DFS outcomes by risk groups were
2-year EFS and OS rates were 72.5% and 77%, respectively.273 Adverse similar to outcomes using the MRC UKALL/ECOG definition for risk
events included 1 death from sepsis (during induction), pancreatitis in 9 classification.276 Age >45 years was predictive of poorer survival outcomes
patients (12%; including 1 death), osteonecrosis in 2 patients (3%), on this study; the OS rate at 42 months was 41% for patients >45 years of
thrombosis/embolism in 14 patients (19%), and neutropenic infection in 23 age compared with 66% for those <45 years of age. Moreover, compared
patients (31%).273 After a median follow-up of 4.5 years, the 4-year DFS to patients <45 years of age, patients >45 years of age had a higher
rate for patients with Ph-negative ALL (n = 64) and those who achieved cumulative incidence of therapy-related deaths (23% vs. 5%) and deaths
CR was 71% (95% CI, 58%–81%), and the 4-year OS rate for all patients in first CR (22% vs. 5%).276 Thus, it seems that the benefit of this
with Ph-negative ALL was 70% (95% CI, 58%–79%).274 A phase II pediatric-inspired regimen outweighed the risks for therapy-related deaths
successor trial was initiated to determine whether PEG could be only for those patients up to 45 years of age with Ph-negative ALL. The
substituted for L-asparaginase in this regimen.275 A high frequency of design of the GRAALL-2005 study was similar to the GRAALL-2003 trial,
asparaginase toxicities precipitated reverting to L-asparaginase during with the addition of randomized evaluation of hyperfractionated
induction and a dose-reduction of PEG during consolidation. After 4 cyclophosphamide during induction and late intensification, as well as
weeks, the CR rate was 89%, and with a median follow-up of 39 months, randomized evaluation of rituximab in patients with CD20-positive
the estimated 3-year DFS and OS rates were 73% and 75%, Ph-negative ALL (n = 209; median age, approximately 40 years; range,
respectively.275 These data suggest that intensive pediatric regimens are 18–59 years).277 The estimated 2-year EFS rate in the rituximab group
feasible, with potential modifications, in young adults with previously was 65% (95% CI, 56%–75%) compared to the control group at 52% (95%

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NCCN Guidelines Version 2.2024

Acute Lymphoblastic Leukemia

CI, 43%–63%). After a median follow-up of 30 months, EFS was longer in (for 2–3 years), and radiotherapy (for patients with testicular or CNS
the rituximab group than in the control group (HR, 0.66; 95% CI, 0.45– disease or those with T-ALL). Results from 295 patients with evaluable
0.98; P = .04).277 data (median age, 24 years; range 17–39 years) reported 2 post-remission
deaths and 3% overall treatment-related mortality.280 The median EFS was
USC/MSKCC ALL Regimen Based on CCG-1882 Regimen
78.1 months (95% CI, 41.8 months – NR) and the 3-year EFS rate was
The USC ALL trial based on the pediatric CCG-1882 regimen has studied 59% (95% CI, 54%–65%). The estimated 3-year OS rate was 73% (95%
the regimen of daunorubicin, vincristine, prednisone, and methotrexate CI, 68%–78%).280 It was also noted that post-induction MRD positivity,
with augmented PEG in patients between 18 and 60 years of age with Ph-like gene expression signatures, and obesity were associated with
newly diagnosed ALL (n = 51).278,279 The augmented arm included one worse treatment outcomes.280
long-lasting PEG dose in each cycle of the 6 total scheduled doses. Each
dose of PEG (2000 IU/m2 IV) was preceded with hydrocortisone for COG AALL0434 Regimen
hypersensitivity prophylaxis followed by 1 to 2 weeks of oral steroids. Nelarabine is a nucleoside metabolic inhibitor and a prodrug of ara-G,
Patients on this trial received a mean of 3.8 doses per patient with 45% of approved for the treatment of patients with T-ALL with disease that has not
patients receiving all 6 doses, while 20% of patients discontinued responded to or that has relapsed after at least 2 chemotherapy regimens.
treatment based on toxicity. The 7-year OS was 51% (58% of these The randomized phase III COG study (AALL0434) evaluated the safety of
patients had Ph-negative disease) and the 7-year DFS was 58%. The nelarabine as part of frontline therapy, using the augmented BFM
dose of PEG was lower than the FDA-approved dose of 2500 IU/m2 and chemotherapy regimen, with or without nelarabine, and showed that the
adjustments to the dosing interval were made to be ≥4 weeks. This toxicity profiles were similar between patients with high-risk T-ALL who
deviated from the pediatric protocol to account for the difference in drug received nelarabine (n = 47) and those who did not (n = 47).281 No
enzymatic activity in adults. Study data suggest that adaptation of the significant differences were observed in the occurrence of neurologic
pediatric regimen to the adult population may be feasible with adverse events between these groups, including peripheral motor
modifications to reduce toxicity. neuropathy, peripheral neuropathy, or CNS neurotoxicity. The incidence of
adverse events such as febrile neutropenia and elevation of liver enzymes
CALGB 10403 Regimen
was also similar between treatment groups. These initial safety data
A multicenter phase II Intergroup study (CALGB 10403) was conducted to suggest that nelarabine may be better tolerated in frontline regimens than
evaluate a pediatric-inspired regimen in the treatment of AYA patients with in the R/R setting.281
Ph-negative ALL. One of the study objectives was to compare the
outcomes of patients treated in this trial with those of a similar group of Results from the efficacy phase of this study evaluated data from 1895
patients (in regard to age and disease characteristics) treated by pediatric patients with newly diagnosed T-ALL and T-LL.282 Patients were
oncologists in the COG trial (AALL-0232). The treatment protocol included randomized to receive escalating dose methotrexate without leucovorin
a 4-drug induction regimen with IT cytarabine and IT methotrexate, rescue and PEG or high-dose methotrexate with leucovorin rescue.
consolidation, interim maintenance, delayed intensification, maintenance Patients with intermediate and high-risk T-ALL and T-LL all received

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Acute Lymphoblastic Leukemia

prophylactic or therapeutic cranial irradiation and were randomized into was more frequent among patients ≥60 years of age. The 5-year OS in
arms with or without nelarabine (650 mg/m2/day). The 4-year DFS rate for patients >60 years of age was 17%. 20 A subsequent retrospective review
patients with T-ALL in the nelarabine arm (n = 323) versus those who did from the same institution suggested that this may be related to higher
not receive nelarabine (n = 336) was 88.9% ± 2.2% and 83.3% ± 2.5%, rates of death in remission (34%) relative to patients <60 years of age
respectively (P = .0332).282 Compared to the high-dose methotrexate and (7%).286
nelarabine arm, use of escalating-dose methotrexate and nelarabine
appeared to enhance the 4-year DFS rates.282 Another report from the Based on retrospective analyses of data from adults with B-ALL treated in
COG AALL0434 study determined that compared to high-dose clinical trials, CD20 positivity (generally defined as CD20 expression on
methotrexate, escalating-dose methotrexate combined with augmented >20% of blasts) was found to be associated with adverse outcomes
BFM chemotherapy improves DFS and OS outcomes in patients with measured by a higher cumulative incidence of relapse, decreased CR
T-ALL.283 duration, or decreased survival.42,287 Given the prognostic significance of
CD20 expression in these patients, treatment regimens incorporating the
A single-arm phase II study from the MDACC evaluated the efficacy of CD20 monoclonal antibody rituximab have been evaluated. A phase II
hyper-CVAD plus nelarabine as frontline therapy in adults with T-ALL (n = study from MDACC evaluated hyper-CVAD with or without rituximab in
23).284 With a median follow-up of 30.4 months (range, 2.4–69.2 months), patients with newly diagnosed Ph-negative B-lineage ALL (n = 282;
the CR rate for patients with T-ALL was 89%; however, a trend for inferior median age, 41 years; range, 13–83 years).163 Among the subgroup of
DFS and OS was observed for patients with ETP-ALL.284 After a median patients with CD20-positive ALL who were treated with hyper-CVAD
follow-up of 42.5 months, the 3-year complete remission duration and OS combined with rituximab, the 3-year CR duration and OS rates were 67%
rates were 66% (95% CI, 52%–77%) and 65% (95% CI, 51%–76%), and 61%, respectively. In addition, among patients <60 years of age with
respectively.285 These studies suggest that for patients with T-ALL, the CD20-positive disease, modified hyper-CVAD plus rituximab resulted in a
addition of nelarabine to frontline therapy may be a promising approach. significantly improved CR duration (70% vs. 38%; P < .001) and OS rate
(75% vs. 47%; P = .003) compared with the standard hyper-CVAD
Hyper-CVAD With or Without Rituximab or Blinatumomab
regimen without rituximab.163 No significant differences in outcomes with
The hyper-CVAD regimen constitutes another commonly used ALL the addition of rituximab were noted for the subgroup of patients with
treatment regimen for adults. A phase II study from MDACC evaluated CD20-negative disease. Notably, patients ≥60 years of age with
hyper-CVAD in adolescents and adults with previously untreated ALL (n = CD20-positive disease demonstrated higher rates of MRD negativity with
288; median age, 40 years; range, 15–92 years; Ph-positive in 17%).20 the inclusion of rituximab; however, this did not translate into a survival
The median OS for all patients was 32 months and the 5-year OS rate was benefit, again largely due to increased mortality in CR. It is worth noting
38%, with a median follow-up of 63 months. Among the patients with that this high rate of death in CR for patients ≥60 years of age may relate
Ph-negative ALL (n = 234), the 5-year OS rate was 42%.20 Among patients to anthracycline intensification as opposed to rituximab.288
who experienced a CR (92% of all patients), the 5-year CR duration rate
was 38%.20 Death during induction therapy occurred in 5% of patients, and

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Another phase II study from MDACC evaluated hyper-CVAD and evaluable cohort was 61%.292 Gökbuget et al293 examined the efficacy of
sequential blinatumomab in patients with newly diagnosed Ph-negative blinatumomab in an expanded cohort (n = 116) using a higher threshold
B-ALL (n = 38; median age, 37 years).289 Treatment consisted of 4 cycles for MRD positivity (hematologic CR with MRD ≥10-3). After one 28-day
of hyper-CVAD followed by 4 cycles of blinatumomab consolidation. cycle of blinatumomab, 88 of 113 patients with evaluable data achieved a
Maintenance consisted of 15 cycles of alternating POMP for 3 cycles and complete MRD response, and the RFS rate at 18 months was 54%.293 In
blinatumomab for 1 cycle. Three-year RFS was estimated at 73%, with no both of these trials, most patients achieving MRD negativity after
relapses >2 years from the start of therapy. Grade 3 CRS occurred in one blinatumomab proceeded to allogeneic HCT, establishing blinatumomab
patient (3%), while four patients (11%) had grade 3 neurological events as an effective “bridge to transplant” in patients with MRD-positive
related to blinatumomab. disease. Subsequent studies of blinatumomab evaluated its ability to
induce CR (including rapid MRD-negative responses) in patients with R/R
Linker 4-Drug Regimen
B-precursor ALL.294-296 In March 2018, the FDA approved blinatumomab
Linker et al290 evaluated an intensified chemotherapy regimen that use for the treatment of adult and pediatric patients with B-cell precursor
incorporated a 4-drug induction regimen (comprising vincristine, ALL in first or second CR with MRD defined as disease ≥0.1% (see
daunorubicin, prednisone, and asparaginase) with or without rituximab for Treatment of Relapsed Ph-Negative B-ALL for discussion of studies
CD-20 positive disease in adolescent and adult patients with ALL (n = 84; related to blinatumomab use in R/R B-ALL).
Ph-positive in 16%; median age, 27 years; range, 16–59 years). The
5-year EFS and OS rates for all patients were 48% and 47%, respectively. Initial Treatment in Adults with Ph-Negative ALL
Among the patients who experienced a CR (93% of all patients), the Hematopoietic Cell Transplant
5-year EFS rate was 52%. The 5-year EFS rate was 60% for the subgroup Studies evaluating HCT in first CR for AYA patients with Ph-negative ALL
of patients without high-risk features (n = 53).290 have generally been inclusive of adult patients and therefore have been
discussed previously (see Initial Treatment in AYA Patients with
Blinatumomab
Ph-Negative ALL). More aggressive therapies are being considered for
Blinatumomab has shown promising clinical efficacy as a means of
patients who are older or less fit. A retrospective study of 576 adults >45
eradicating persistent MRD following upfront chemotherapy. In a
years of age compared RIC or MAC allogeneic HCT from HLA-matched
multicenter, single-arm, phase II study, Topp et al291 evaluated the efficacy
siblings.198 Patients who received RIC (n = 127) versus MAC (n = 449) did
of blinatumomab in patients with MRD-positive Ph-negative B-ALL (n = 21;
not show any statistically significant difference in leukemia-free survival (P
age range, 20–77 years). Patients were considered to have MRD-positive
= .23; HR, 0.84), thereby supporting the incorporation of more aggressive
disease if they had never achieved MRD negativity before blinatumomab
treatments for this population.198
or had experienced a hematologic CR with MRD ≥10-4. After
blinatumomab treatment, 16 of 20 patients with evaluable data were CALGB 8811 Larson Regimen
determined to have achieved MRD negativity at a detection threshold of Typically, induction regimens for adult ALL are also based on a backbone
10-4.291 After a median follow-up of 33 months, the hematologic RFS of the of vincristine, corticosteroids, and anthracyclines. The CALGB 8811 trial

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NCCN Guidelines Version 2.2024

Acute Lymphoblastic Leukemia

evaluated a 5-drug induction regimen (comprising vincristine, non-significant increase in CR rate for those receiving G-CSF (81% vs.
daunorubicin, prednisone, L-asparaginase, and cyclophosphamide) as 55%; P = .1). For the entire group ≥60 years of age, median OS was
part of an intensive chemotherapy regimen for patients with previously improved to 12 months, but 3-year OS remained poor at 17%.297
untreated ALL (n = 197; Ph-positive in 29%; median age, 32 years; range,
GRAALL-2005 and 2014 Regimens
16–80 years).121 Patients >60 years of age received a dose-adjusted
regimen with a prednisone pulse for only 7 days and a 33% reduction of Studies evaluating the GRAALL-2003 regimen and GRAALL-2005
daunorubicin and cyclophosphamide doses. The median OS for all regimen with the addition of rituximab for CD20-positive disease included
patients was 36 months, after a median follow-up of 43 months. Among both AYA and adult patients.276,277 For discussion of these studies, refer to
patients who experienced a CR (85% of all patients), the median the previous section (see Initial Treatment in AYA Patients with
remission duration was 29 months. The estimated 3-year OS rate was Ph-Negative ALL). The role of standard-dose versus hyperfractionated
higher for the subgroup of patients <30 years of age compared with those cyclophosphamide during first induction and late intensification in adults
aged 30 to 59 years or patients ≥60 years of age (69% vs. 39% vs. 17%; P with newly diagnosed Ph-negative ALL was evaluated in a subsequent
< .001). This was largely due to high induction-related mortality (50%) in report from the GRAALL-2005 trial.298 After a median follow-up of 5.2
patients ≥60 years of age, contributing to a median OS of 1 month in this years, randomization to the hyperfractionated cyclophosphamide arm did
population.121 Among the subgroup of patients negative for the not increase the CR rate or prolong EFS or OS rates, and tolerability to
Philadelphia chromosome by both cytogenetics and molecular testing (n = this regimen was poor in patients ≥55 years of age.298
29), median OS was 39 months and the 3-year OS rate was 62%.121
The GRAALL-2014 study aimed to improve outcomes of the
The CALGB 9111 study evaluated the impact of adding granulocyte GRAALL-2005 by reducing chemotherapy intensity in patients aged 45 to
colony-stimulating factor (G-CSF) after intensive therapy (CALGB 8811 59 years and modifying the indication for HCT to only a post-induction
Larson regimen) on neutrophil recovery in adults with ALL (n = 198; MRD ≥10-3 and/or a post-consolidation MRD ≥10-4.299 Compared to
median age, 35 years; range, 16–83 years).297 Patients were randomized GRAALL-2005, induction death rate was significantly reduced in
to receive either placebo or G-CSF beginning 4 days after induction, and GRAALL-2014 among patients aged 45 to 59 years (3% vs. 11%; P =
the G-CSF group continued G-CSF treatment during consolidation. .001). CR rate was also higher in this age group in GRAALL-2014 (92%
Although the addition of G-CSF did not result in a significant impact in OS vs. 86%, P = .05), attributed to a higher need for second induction due to
or DFS, patients in the G-CSF group had significantly shorter durations of the reduced-intensity of first induction. In light of MRD-based HCT
neutropenia and thrombocytopenia, a higher CR rate, and lower induction indication, fewer patients proceeded to HCT on GRAALL-2014, leading to
mortality (P = .04) compared to patients in the placebo group.297 Among an increase in 3- year CIR (35% vs. 28%; P = .01), though a reduction in
the 41 patients >60 years of age randomized to G-CSF (n = 21) or placebo 3-year cumulative incidence of transplant related mortality (5% vs. 11%; P
(n = 20), G-CSF use was associated with lower induction mortality (10% < .001) and OS (71% vs. 64%; P = .002).
vs. 25%); however, this did not meet statistical significance. The reduction
In the phase II GRAALL-2014 T ATRIALL study of adult patients with
observed with induction mortality was accompanied by a similarly
T-ALL, patients were deemed to be at high risk based on the presence of
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Acute Lymphoblastic Leukemia

RAS/PTEN alterations or lack of NOTCH1/FBXW7 mutations.115,300 months, the 2- and 3-year EFS were 59%, and EFS was similar for B-ALL,
Patients in the high risk group were offered 2 cycles of nelarabine T-ALL, lymphoblastic lymphoma, Ph-negative B-ALL, and Ph-positive
combined with etoposide and cyclophosphamide during consolidation and B-ALL.301
another 3 cycles during maintenance, though some received standard of
MRC UKALL XII/ECOG E2993
care without nelarabine.300 Following 1 cycle, patients with MRD ≥10-3
and/or post-consolidation MRD ≥10-4 were eligible for HCT. When In one of the largest multicenter prospective trials conducted to date (MRC
censored at time of transplant, the addition of nelarabine was associated UKALL XII/ECOG E2993 study), adolescent and adult patients with newly
with a significant reduction in CIR (P = .045) and a non-significant diagnosed disease (n = 1521; aged 15–59 years) received induction
prolongation of DFS (P = .075). The benefit of nelarabine was similar in therapy consisting of vincristine, daunorubicin, prednisone, and
patients in the high risk group who were not eligible for transplant, with a L-asparaginase for 4 weeks (phase I) followed by cyclophosphamide,
significant reduction in CIR (P = .045) and a non-significant prolongation of cytarabine, oral 6-MP, and IT methotrexate for 4 weeks (phase II).111 After
DFS (P = .06). While patients with ETP-ALL did not benefit from completion of induction therapy, patients who experienced a CR received
nelarabine, the addition of nelarabine in patients with non-ETP ALL led to intensification therapy with 3 cycles of high-dose methotrexate (with
significant improvements in both CIR (P = .025) and DFS (P = .048). standard leucovorin rescue) and L-asparaginase. After intensification,
those <50 years of age who had an HLA-compatible sibling underwent
USC/MSKCC ALL Regimen Based on CCG-1882 Regimen allogeneic HCT; all others were randomized to receive autologous HCT or
Studies evaluating USC/MSKCC ALL regimen have included both AYA consolidation/maintenance treatment.111 For Ph-negative disease, high
and adult patients.278,279 For discussion of these studies, refer to the risk was defined as having any of the following factors: aged >35 years;
previous section (see Initial Treatment in AYA Patients with Ph-Negative time to CR >4 weeks; or elevated WBC count (>30 × 109/L for B-cell
ALL). lineage; >100 × 109/L for T-cell lineage). All other patients with
Ph-negative disease were considered to have standard-risk disease. The
Linker 4-Drug Regimen
5-year OS rate for all patients with Ph-negative ALL was 41%; the OS
The referenced study evaluating the Linker 4-drug regimen included both rates for the subgroups with standard-risk (n = 533) and high-risk disease
AYA and adult patients.290 For a summary of this study, refer to the (n = 590) were 54% and 29%, respectively.111 In the subgroup of patients
previous section (see Initial Treatment in AYA Patients with Ph-Negative with T-ALL (n = 356), the 5-year OS rate was 48%; the OS rate was
ALL). In a phase II study, Wieduwilt et al investigated whether the Linker improved to 61% for those with a matched sibling donor, primarily because
4-drug regimen could be safely intensified with the addition of PEG, of a lower incidence of cumulative relapse.302 Among the patients with
cyclophosphamide, rituximab, dasatinib, and IT liposomal cytarabine in T-ALL, those with disease with complex cytogenetic abnormalities had a
adults with ALL or lymphoblastic lymphoma (n = 29; median age, 28 poor 5-year OS outcome (19%).
years; range, 20–54 years).301 The CR rate for ALL was 88%. For
Ph-negative B-ALL (n = 16), the CR rate was 86%, and for Ph-positive
B-ALL (n = 7), the CR rate was 88%.301 With a median follow-up of 32

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NCCN Guidelines Version 2.2024

Acute Lymphoblastic Leukemia

Hyper-CVAD With or Without Rituximab or Blinatumomab consolidation (52% and 69%, respectively), and hyperglycemia (54%). 304
Studies evaluating hyper-CVAD with or without rituximab or blinatumomab In this study, SOS occurred in four patients (8%).
have included both AYA and adult patients.20,163,289 For discussion of these
studies, refer to the previous section (see Initial Treatment in AYA Patients A phase II study evaluated InO monotherapy in 26 patients (median age,
with Ph-Negative ALL). 46 years; range, 19–70 years) patients with B-cell ALL in CR1 or beyond
with positive MRD ( ≥1x10 -4).191 After a median of 3 cycles (range, 1-–
A separate phase II MDACC study evaluated the use of hyper-CVAD with cycles; 69% of patients achieved MRD negativity. Two-year RFS and OS
or without blinatumomab in patients ≥60 years of age with newly rates were 54% and 60%, respectively. Eight percent of patients
diagnosed Ph-negative B-ALL.303 Treatment consisted of 4 cycles of developed SOS and the remainder of adverse events were noted to be
mini-hyper-CVD followed by 4 cycles of blinatumomab consolidation. low grade.
Maintenance therapy consisted of 3 cycles of POMP alternating with 1
cycle of blinatumomab for a total of 12 cycles. Five-year PFS was 44%. In the ongoing phase II INITIAL-1 trial, InO combined with
The most common grade 3–4 events were hematological. Six patients dexamethasone is being investigated as an induction regimen for
(8%) developed SOS, four of which were fatal. patients ≥55 years of age (n = 43; median age, 64 years; age range, 56–
80 years) with newly diagnosed Ph-negative B-ALL.305 Up to 3 cycles of
Inotuzumab Ozogamicin InO/dexamethasone induction were given, followed by up to 6 cycles of
In a phase II study, the efficacy and safety of InO combined with GMALL consolidation adapted by age and maintenance therapy. All
low-intensity chemotherapy (mini-hyper-CVD) was evaluated in adults patients achieved CR/CRi following 2 to 3 cycles of InO/dex. Following
with a median age of 68 years with newly diagnosed Ph-negative ALL cycle 2, 53% of patients achieved MRD negativity, while 30% achieved
and an ECOG performance status ≤3 (n = 52; interquartile range, 64–72 MRD negativity following cycle 3. With a median follow-up of 2.7 years,
years).304 Compared to hyper-CVAD, mini-hyper-CVD has no 1-year EFS and OS were 88% and 91%, respectively. Three-year EFS
anthracycline and is composed of reduced doses of dexamethasone and OS were 55% and 73%, respectively.
(50% reduction), methotrexate (75% reduction), and cytarabine (given
every 12 hours at 0.5 g/m2 on days 2 and 3). In this study, InO was given In the ongoing phase II Alliance A041703 trial, the chemotherapy-free
on day 3 of the first 4 courses at 1.3–1.8 mg/m2 for cycle 1, followed by regimen of inotuzumab ozogamicin for induction followed by
1.0–1.3 mg/m2 for subsequent cycles. 304 In addition, maintenance blinatumomab consolidation is being investigated in patients ≥60 years of
therapy with dose-reduced POMP (6-MP, vincristine sulfate, age (n = 33; median age, 71 years; range, 60–84 years) with newly
methotrexate, and prednisone) was given for 3 years. With a median diagnosed Ph-negative B-ALL with no plans for allogeneic HCT. 306
follow-up of 29 months, the 2-year PFS was 59% (95% CI, 43%–72%).304 Induction course IA included InO at a dose of 0.8 mg/m 2 on day 1
Some of the most frequent grade 3 and 4 adverse events were followed by 0.5 mg/m 2 on days 8 and 15 of a 21-day cycle. Those with
prolonged thrombocytopenia (81%), infections during induction and adequate cytoreduction, defined as BM blasts ≥50% or cellularity ≤20%,
went on to receive either induction IB (InO 0.5 mg/m 2 on days 1, 8, and
15 of a 28-day cycle) if CR/CRi was achieved or induction IC (InO 0.8
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NCCN Guidelines Version 2.2024

Acute Lymphoblastic Leukemia

mg/m2 on days 1, 8, and 15 of a 28-day cycle) if having not achieved induction I (dexamethasone, vincristine, idarubicin) and induction II
CR/CRi. Those with inadequate cytoreduction to induction IA or those (cyclophosphamide, cytarabine), with rituximab added for patients with
without events in induction IA, IB, or IC began blinatumomab CD20-positive disease. The original treatment protocol (group 1) was
consolidation. Those achieving CR/CRi with InO received a total of three modified to evaluate CNS prophylaxis with liposomal cytarabine and
28-day cycles of blinatumomab, while all others received a total of 4 alternative consolidation with asparaginase (group 2); and after
cycles. The cumulative CR rate through induction InO courses was 85% induction, 1 cycle with 500 U/m2 PEG was scheduled to evaluate
and for blinatumomab consolidation was 97%. With a 22-month median feasibility (group 3). The reported overall CR rate was 76% (n = 203),
follow-up, 1-year EFS was 75% (95% CI, 61%–92%) and 1-year OS was and the CR rates in groups 1, 2, and 3 were 72%, 86%, and 82%,
84% (95% CI, 72%–98%). respectively.308 The 5-year OS rate was 23%, and the 2-year OS rates
observed in groups 1 and 2 were 33% and 52%, respectively.308 A major
GRAALL-SA1 Regimen
finding from this study included the importance of the ECOG
In an effort to decrease toxicity, the GRAALL-SA1 study compared the performance status before the onset of ALL (ECOGb) at predicting
efficacy and toxicity of pegylated liposomal doxorubicin (Peg-Dox) to induction mortality. Patients with an ECOGb score ≥2 correlated with
continuous infusion doxorubicin (CI-Dox) in patients ≥55 years of age higher induction mortality rates compared to those with an ECOGb score
with ALL.307 In this moderate-intensity regimen containing vincristine, of 0 to 1 (53% vs. 7%, respectively; P < .0001).308 In addition, the study
dexamethasone, and cyclophosphamide, patients were randomized to showed that consolidation with native Escherichia coli asparaginase and
receive either CI-Dox (n = 31; 12 mg/m2/day) or Peg-Dox (n = 29; 40 PEG was feasible and well tolerated, and was associated with
mg/m2).307 Compared to the CI-Dox arm, the Peg-Dox arm was improvements in CR rates and 2-year OS in this aged 55 to 85 years
significantly associated with reduced toxicity and fewer infections, but patient subset.308
there was no survival benefit: the induction mortality rate was 8%
(CI-Dox arm, 7% vs. Peg-Dox arm, 10%), the frequency of refractory PETHEMA-Based Regimen
disease after induction was 10% (CI-Dox arm, 17% vs. Peg-Dox arm, The Spanish PETHEMA group conducted phase II prospective studies in
3%; P = .1), and the CR rate was 82% (CI-Dox arm, 90% vs. Peg-Dox patients aged 56 to 79 years with Ph-negative ALL (ALLOLD07; n =
arm, 72%; P = .1).307 At 2 years, the estimated death in CR was 26.5% 56).309,310 The ALLOLD07 protocol was based on a protocol from
(CI-Dox arm, 37% vs. Peg-Dox arm, 19%), and the OS and EFS rates EWALL, and treatment comprised a 4-week induction with
were statistically similar at 35% and 24% in the CI-Dox and Peg-Dox dexamethasone, vincristine, idarubicin, cyclophosphamide, and
arms, respectively. 307 cytarabine, followed by consolidation with intermediate-dose
methotrexate and native E. coli asparaginase. The CR rate was 74%
GMALL Regimen
with an early death rate of 13%. The median DFS was 8 months with a
In a prospective trial, the GMALL group evaluated the efficacy of a median OS of 12 months. This trial included other adapted regimens for
moderate-intensity regimen in adults aged 55 to 85 years with Ph-positive ALL and mature B-ALL groups, but the outcomes were
Ph-negative ALL (n = 268).308 The induction therapy consisted of poorest in the Ph-negative ALL group.310

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Acute Lymphoblastic Leukemia

Modified DFCI 91-01 Protocol ECOG-ACRIN E1910 Regimen

A retrospective analysis examined the efficacy of a modified version of a In contrast to prior studies investigating blinatumomab as a means of
DFCI pediatric protocol, DFCI 91-01,269,311 in adults with newly diagnosed eradicating MRD during or after multiagent therapy, this phase III trial
ALL (n = 51; age range, 60–79 years).312 Induction consisted of investigated whether blinatumomab could improve outcomes in patients
dexamethasone (in place of prednisone), doxorubicin, cytarabine, and receiving chemotherapy who had achieved MRD negativity (<0.01%).318
reduced doses of methotrexate, vincristine, and native asparaginase. For Patients with newly diagnosed Ph-negative B-ALL between the ages of 30
patients who achieved CR, the median time to recurrence was 30 to 70 years initially received multiagent induction therapy with a BFM-like
months (range, 1–94 months).312 In patients with Ph-negative disease (n regimen adapted from E2993/UKALLXII. PEG was added for patients <55
= 35), the CR rate was 71%, with induction mortality and primary years of age and rituximab was added for CD20 positivity. Following
refractory rates of 20% and 9%, respectively. 312 The DFS rate amongst induction, patients who achieved a CR/CRi remained on study and
those achieving CR was 57.4% (95% CI, 32.8%–75.8%), while the proceeded to intensification with high dose methotrexate and
overall estimated 5-year OS was 40.5% (95% CI, 20%–60.2%).312 pegaspargase for CNS prophylaxis. Thereafter, MRD status was assessed
by 6-color flow cytometry. Patients were randomized to receive either 4
Low-Intensity Chemotherapy and Corticosteroids
cycles of consolidation chemotherapy or 2 cycles of blinatumomab
For adults who are older with ALL who may also have multiple followed by 3 cycles of consolidation chemotherapy, followed by a 3rd
comorbidities, the utility of traditional chemotherapy backbones based on cycle of blinatumomab, followed by another cycle of consolidation
vincristine, corticosteroids, and an anthracycline is limited largely due to chemotherapy, and finally a 4th cycle of blinatumomab. However, following
treatment-related toxicities.313 Attempts to identify optimal therapy in this the FDA approval of blinatumomab for patients with MRD positive disease,
population have included adaptations of palliative regimens including those with MRD positivity in the trial were no longer randomized and
vincristine and corticosteroids, and POMP.314-317 While these regimens are assigned to the blinatumomab arm. All patients received POMP
unlikely to generate cure, they can palliate the disease and extend maintenance therapy for a total of 2.5 years. Patients were referred for
survival, with clinical outcomes similar to those achieved with more allogeneic HCT at provider discretion. For the entire cohort, CR/CRi rate
intensive protocols. It is important to note that adults who are older with following induction was 81%. For those who achieved MRD negativity, the
ALL and multiple comorbidities have not typically qualified for clinical trials. addition of blinatumomab led to significant improvement on OS. Median
To improve clinical outcomes, trials designed specifically for this OS for the blinatumomab arm was not reached versus 71.4 months in the
population are needed. These should include novel, personalized consolidation chemotherapy arm (95% CI, 0.24–.075; P =.003).
approaches based on immunophenotype and/or genetic mutation status.
Based on this data, in June 2024, the FDA expanded the approval of
Blinatumomab
blinatumomab to include adult and pediatric patients ≥1 month
The referenced studies evaluating the efficacy of blinatumomab at Ph-negative B-ALL in the consolidation phase of multiphase
eradicating MRD during or after multiagent therapy included both AYA and chemotherapy.
adult patients.291-293 For a discussion of these studies, refer to the previous
section (see Initial Treatment in AYA Patients with Ph-Negative ALL).
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Acute Lymphoblastic Leukemia

Treatment of Relapsed Ph-Negative ALL extramedullary relapse. In a multivariate regression analysis, early bone
Despite major advances in the treatment of childhood ALL, approximately marrow and extramedullary relapse were independent predictors of poorer
20% of pediatric patients experience relapse after initial CR to frontline EFS outcomes.324
treatment regimens.319-321 Among those who experience relapse, only
Data from patients with disease relapse after frontline therapy in the MRC
approximately 30% experience long-term remission with subsequent
UKALL XII/ECOG E2993 study and PETHEMA studies showed that the
therapies.164,322,323 Based on a retrospective analysis of historical data from
median OS after relapse was only 4.5 to 6 months; the 5-year OS rate was
COG studies (for patients enrolled between 1998 and 2002; n = 9585),
7% to 10%.212,213 Approximately 20% to 30% of patients experience a
early relapse (<18 months from diagnosis) was associated with very poor
second CR with second-line therapies.213,215 Factors predictive of more
outcomes, with an estimated 5-year survival (from time of relapse) of
favorable outcomes after subsequent therapies included younger age and
21%.319 For cases of isolated bone marrow relapse, the 5-year survival
a first CR duration of more than 2 years.195,213 Among younger patients
estimates among early (n = 412), intermediate (n = 324), and late (n =
(aged <30 years) whose disease relapsed after experiencing a first CR
387) relapsing disease were 11.5%, 18.0%, and 43.5%, respectively (P <
duration longer than 2 years with frontline treatment in PETHEMA trials,
.0001). Intermediate relapse was defined as relapse occurring 18 to 36
the 5-year OS rate from the time of first relapse was 38%.213
months from time of diagnosis; late cases were defined as relapse
occurring ≥36 months from time of diagnosis. For cases of isolated CNS Hematopoietic Cell Transplant
relapse, the 5-year survival estimates among early (n = 175), intermediate HCT is the only potentially curative modality for R/R ALL. Based on
(n = 180), and late (n = 54) relapsing disease were 43.5%, 68.0%, and findings from evidence-based review of the published literature, the
78.0%, respectively (P < .0001).319 Based on multivariate analysis American Society for Blood and Marrow Transplantation guidelines
(adjusted for both timing and site of relapse), age (>10 years), presence of recommend HCT over chemotherapy alone for adults with ALL
CNS disease at diagnosis, male gender, and T-cell lineage disease were experiencing a second CR.325 Several studies have shown that for AYA
found to be significant independent predictors of decreased survival after patients in second CR, allogeneic HCT may improve outcomes,
relapse.319 In a separate analysis of data from one of the above COG particularly for patients who have early bone marrow relapse or have other
studies (CCG-1952), the timing and site of first relapse were significantly high-risk factors.322,323,326 Seemingly contradictory data were reported in
predictive of EFS and OS outcomes, even among the patients with the COG CCG-1952 study that showed prognosis after early bone marrow
standard-risk ALL (n = 347; based on NCI criteria: aged 1 to <10 years relapse in patients with standard-risk ALL (aged 1 to <10 years and WBC
and WBC count <50 × 109/L).324 Early bone marrow relapse (duration of count <50 × 109/L) remained poor with no apparent advantage of HCT,
first CR <36 months) was associated with significantly shorter estimated regardless of timing (ie, early or late) of bone marrow relapse.324 However,
3-year EFS (30% vs. 44.5%; P = .002) and OS (35% vs. 58%; P = .001) data were not available on the conditioning regimen used for HCT in this
rates compared with late bone marrow relapse.324 Similarly, early isolated study for comparison with other trials. The UKALLXII/ECOG2993 trial (n =
extramedullary relapse (duration of first CR <18 months) was associated 609; age range, 15–60 years) examined the efficacy of transplantation
with significantly shorter estimated 3-year EFS (37% vs. 71%; P = .01) after relapse in a subgroup of patients with relapsed ALL who had not
and OS (55% vs. 81.5%; P = .039) rates compared with late
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Acute Lymphoblastic Leukemia

received prior transplant.212 Patients treated with HCT demonstrated a prespecified subgroup analyses of patients with high bone marrow count
superior OS at 5 years compared to those treated with chemotherapy (≥50%) at relapse demonstrated lower blinatumomab-mediated median
alone.212 The CIBMTR group conducted an analysis of outcomes of survival and remission rates.294
patients with ALL (n = 582; median age, 29 years; range, <1 to 60 years)
who underwent transplant during relapse.327 At 3 years, OS rates were There are significant and unique side effects to blinatumomab treatment
16% (95% CI, 13%–20%).327 Response to therapy for relapsed/refractory compared to other established regimens. The most significant toxicities
disease prior to HCT may also predict outcome. One retrospective study noted in clinical studies are CNS events and cytokine release syndrome
has shown 3-year OS and EFS estimates of 69% and 62% (respectively) (CRS). Neurologic toxicities have been reported in 50% of patients
for patients in second or later MRD-negative remission at the time of HCT, (median onset, 7 days) and grade 3 or higher neurologic toxicities,
similar to the outcomes of those who underwent HCT in MRD-negative including encephalopathy, convulsions, and disorientation, have occurred
first remission at the same center.197 in 15% of patients.330 CRS typically occurs within the first 2 days following
initiation of blinatumomab infusion.330 Symptoms of CRS include pyrexia,
Blinatumomab headache, nausea, asthenia, hypotension, increased transaminases, and
A component of the growing arsenal of immunotherapies for cancer increased total bilirubin. The incidence of adverse events can be reduced
treatment, blinatumomab is a bispecific anti-CD3/CD19 monoclonal with monitoring for early intervention at onset of symptoms. However, the
antibody that showed high CR rates (69%; including rapid MRD-negative serious nature of these events underscores the importance of receiving
responses) in patients with R/R B-precursor ALL (n = 25).296,328 treatment in a specialized cancer center that has experience with
Blinatumomab was approved by the FDA based on data from a large blinatumomab.
phase II confirmatory study of 189 patients with R/R Ph-negative B-ALL
that demonstrated a CR or CR with incomplete platelet recovery (CRp) in Inotuzumab Ozogamicin
43% of patients within the first 2 cycles of treatment.295,329 In a follow-up Clinical studies described earlier include patients with relapsed or
prospective, multicenter, randomized, phase III trial, patients with R/R refractory Ph-positive and Ph-negative ALL.253,254 For discussion of these
B-cell precursor ALL (n = 405) were assigned to receive either studies, see Treatment of Relapsed Ph-Positive ALL.
blinatumomab (n = 271) or standard chemotherapy (n = 134).294 The OS
In a phase II study, the efficacy and safety of InO combined with
was longer in the blinatumomab group, with median OS at 7.7 months,
low-intensity chemotherapy (mini-hyper-CVD) was evaluated in adults with
compared to the standard chemotherapy group, with median OS at 4.0
R/R B-ALL (n = 59; median age, 35 years; range, 18–87 years).331 The
months (95% CI, 0.55–0.93; P = .01).294 Remission rates within 12 weeks
response rate was 78%, with 35 of these patients achieving CR (59%).331
after treatment initiation were significantly higher in the blinatumomab
The overall MRD negativity rate among responders was 82%. With a
group than in the standard chemotherapy group with respect to both CR
median follow-up of 24 months, the median RFS and OS were 8 and 11
with full hematologic recovery (CR, 34% vs. 16%; P < .001) and CR with
months, respectively. The 1-year RFS and OS rates were 40% and 46%,
full, partial, or incomplete hematologic recovery (CR, CR with partial
respectively. When using this regimen, the risk of SOS should be
hematologic recovery [CRh], or CRi, 44% vs. 25%; P < .001).294 Of note,

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NCCN Guidelines Version 2.2024

Acute Lymphoblastic Leukemia

considered in patients with previous liver damage and among transplant T cells to treat ALL is a significant advancement in the field.255,334,335 CAR
candidates. In this study, SOS occurred in 9 patients (15%).331 T-cell therapy relies on the genetic manipulation of a patient’s T cells to
generate a response against a leukemic cell-surface antigen, most
In a subsequent report, to reduce the risk of SOS and improve outcomes, commonly CD19.256 Briefly, T cells from the patient are harvested and
the investigators amended the protocol by lowering the weekly InO doses engineered with a receptor that targets a cell surface tumor-specific
and including 4 cycles of blinatumomab in the consolidation phase.332 In a antigen (eg, CD19 antigen on the surface of leukemic cells). The ability of
cohort of adults with Ph-negative B-ALL treated in first relapse (n = 48; CAR T cells to be reprogrammed to target any cell-surface antigen on
median age, 39 years; range, 18–87 years), the rates of SOS prior to the leukemic cells is advantageous and avoids the issue of tumor evasion of
protocol amendment and after the protocol amendment were 13% (n = 5 the immune system via receptor down regulation.256 The manufacture of
of 38) and 0% (n = 0 of 10), respectively.332 In addition, based on CAR T cells requires ex vivo viral transduction, activation, and expansion
propensity score matching, the combination of InO with mini-hyper-CVD over several days to produce a sufficient cell number to engender disease
with or without blinatumomab resulted in better outcomes than inotuzumab response.336 Following infusion, debulking of tumors occurs in less than a
alone or intensive chemotherapy for relapsed/refractory disease.332 week and these cells may remain in the body for extended periods of time
Long-term follow up data from a total of 96 patients revealed an ORR of to provide immunosurveillance against relapse.
80%, with 57% achieving a CR. Among responders, the overall MRD
negativity rate was 83%.333 Patients treated at first relapse had better There are several clinical trials using CAR T cells that differ in the receptor
outcomes than patients treated at second relapse or 3rd relapse and construct for patients with relapsed or refractory ALL. One of the first CAR
beyond, with ORR rates of 91%, 59%, and 57%, respectively. Similarly, constructs to be investigated, termed 19-28z—which links the CD19
rates of MRD negativity were higher among patients treated at first relapse binding receptor to the costimulatory protein CD28—demonstrated an
compared to those treated at second relapse or beyond, at 88% and 67%, overall CR in 14 out of 16 patients with relapsed or refractory B-ALL
respectively. Forty-six percent of patients ultimately went on to allogeneic following infusion with CAR T cells.337 This average remission rate is
HCT. Estimated 3-year OS was 33% in the entire cohort and 48% among significantly improved compared to the average remission rate for patients
patients who proceeded to allogeneic HCT. Sixteen percent of patients receiving standard-of-care chemotherapy following relapse (88% vs.
underwent allogeneic HCT developed SOS compared to 6% of patients approximately 30%).212,337-339 Furthermore, 7 out of 16 patients were able
who did not proceed to allogeneic HCT. to receive an allogeneic HCT, suggesting that CAR T cells may provide a
bridge to transplant.337 No relapse has been seen in patients who
CAR T Cells
underwent allogeneic HCT (follow-up, 2–24 months); however, 2 deaths
One of the early treatments for patients with advanced ALL included
occurred from transplant complications. Follow-up data of adults enrolled
adoptive cell therapy to induce a graft-versus-leukemia effect through
on this trial (n = 53) showed an 83% CR rate after the infusion and 32
allogeneic HCT or DLI. However, this method resulted in a significant risk
patients achieved an MRD-negative CR.340 At a median follow-up of 29
of GVHD. To circumvent this issue, current advances are focused on the
months (range, 1–65 months), the median OS was 12.9 months (95% CI,
use of the patient’s own T cells to target the tumor. The generation of CAR
8.7–23.4 months) and subsequent allogeneic HCT did not appear to
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NCCN Guidelines Version 2.2024

Acute Lymphoblastic Leukemia

improve survival.340 In contrast, data in children and young adults treated The single-arm, open-label, international multicenter phase 2 ZUMA-3
on another clinical trial at the National Institutes of Health/National Cancer clinical trial assessed the efficacy of the CAR T-cell product KTE X19
Institute with a similar CAR construct suggested consolidative allogeneic (brexucabtagene autoleucel) in 71 adults with R/R B-ALL.346 The primary
HCT post-CAR T-cell therapy might be associated with superior outcomes endpoint, the rate of overall CR or CRi by central assessment, was met
(2-year cumulative incidence of relapse post-transplant, 9.5%; 5-year EFS (71%; 95% CI, 57–82; P < .0001). Secondary endpoints were also met:
post-transplant, 62%).341 76% of patients experienced MRD-negative CR, the median duration of
remission was 12.8 months, the median RFS was 11.6 months, and the
Other CD19-targeted constructs have been investigated—some median OS was 18.2 months.346 Brexucabtagene autoleucel had a
comprising an alternative costimulatory protein, 4-1BB—have shown manageable safety profile. The most common grade 3 or higher adverse
similar results to the 19-28z CAR T cells in terms of overall CR.342 events were anemia (49%) and pyrexia (36%). It is also being evaluated in
Relevant in this context are data from the ELIANA trial of CTL019 children and young adults ≤21 years of age with R/R ALL in the ZUMA-4
(tisagenlecleucel) in 75 children and young adults with R/R B-ALL, which trial (NCT02625480).
demonstrated an overall remission rate of 81% within 3 months of infusion,
all of which were notably MRD negative.343 These results led to the
approval of CTL019 by the FDA in August 2017 for the treatment of As with blinatumomab, T-cell and CAR T-cell activation can be
patients <26 years of age with R/R precursor B-ALL. The efficacy of accompanied by severe CRS and neurologic toxicity (immune effector
CTL019 in children and young adults with R/R B-ALL in the non-trial cell-associated neurotoxicity syndrome or ICANS), as well as infectious
setting was recently confirmed using registry data from the CIBMTR. This risks—though treatment-related mortality remains low.343 While side
retrospective analysis showed morphologic CR in 85% of patients.344 MRD effects from CAR T cells can be severe, they are reversible in most cases.
negativity was reported in 99% of patients who had achieved a CR with CRS is clinically characterized by high fever, hypotension, tachycardia,
available data. A comparable proportion of patients experienced durable and hypoxia; ICANS includes delirium, aphasia, headaches, tremor, focal
responses at 12 months in the CIBMTR cohort compared to patients deficits, and cerebral edema. Higher CRS and ICANS severity have been
treated on the ELIANA clinical trial (61% and 67%, respectively). At the reported in patients with B-ALL compared to patients with NHL after CD19
last update of the ELIANA data at the 2019 American Society of CAR T-cell therapy.347 It is recommended to evaluate CRS and ICANS
Transplantation and Cellular Therapy (ASTCT) Annual Meeting (median severity using the ASTCT consensus criteria.348 Tocilizumab (interleukin-6
follow-up, 24 months), the median duration of remission and OS was NR receptor antagonist) and corticosteroids are the cornerstone of CRS and
and the 24-month RFS probability in responders was 62%. Survival ICANS management. An FDA-approved biosimilar is an appropriate
probability curves plateaued after 1 year. Consolidation with allo-HCT after substitute for tocilizumab. Expert consensus clinical guidelines were
CTL019 was reported in only 9% of patients who had achieved a CR. recently published by the Society of Immunotherapy of Cancer to guide
These updated results suggest treatment with CTL019 in children and toxicity management.349
young adults with R/R B-ALL could be curative in a subset of patients in
the absence of consolidative allo-HCT.345
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NCCN Guidelines Version 2.2024

Acute Lymphoblastic Leukemia

Nelarabine Augmented Hyper-CVAD

Nelarabine is a nucleoside analog that is currently approved for the A phase II study from the MDACC evaluated an augmented hyper-CVAD
treatment of patients with T-ALL who have unresponsive or relapsed regimen (that incorporated asparaginase, intensified vincristine, and
disease after at least two chemotherapy regimens. A phase II study of intensified dexamethasone) as therapy in adults with R/R ALL (n = 90;
nelarabine monotherapy in children and adolescents with R/R T-ALL or median age, 34 years; range, 14–70 years; median 1 prior regimen).352
T-cell NHL (n = 121) showed a 55% response rate among the subgroup Among patients with evaluable data (n = 88), the CR rate was 47%; an
with T-ALL with first bone marrow relapse (n = 34) and a 27% response additional 13% experienced a CRp and 5% experienced a partial
rate in the subgroup with a second or greater bone marrow relapse (n = remission. The 30-day mortality rate was 9% and median remission
36).164 Major toxicities included grade 3 or higher neurologic (both duration was 5 months. The median OS for all patients with evaluable data
peripheral and CNS) adverse events in 18% of patients. Nelarabine as was 6.3 months; median OS was 10.2 months for patients who
single-agent therapy was also evaluated in adults with R/R T-ALL or T-cell experienced a CR. In this study, 32% of patients were able to proceed to
lymphoblastic leukemia in a phase II study (n = 39; median age, 34 years; HCT.352
range, 16–66 years; median 2 prior regimens; T-ALL, n = 26).166 The CR
Clofarabine
rate (including CRi) was 31%; an additional 10% of patients experienced a
partial remission. The median DFS and OS were both 20 weeks and the Clofarabine is a nucleoside analog approved for the treatment of pediatric
1-year OS rate was 28%. Grade 3 or 4 myelosuppression was common, patients (aged 1–21 years) with ALL that is relapsed or refractory after at
but only one case of grade 4 CNS toxicity (reversible) was observed.166 least two prior regimens. In a phase II study of single-agent clofarabine in
pediatric patients who have undergone heavy pretreatment with R/R ALL
There are limited studies of nelarabine combination regimens in adults (n = 61; median age, 12 years; range, 1–20 years), the response rate (CR
with R/R T-ALL. In a study by Commander et al, pediatric patients with + CRp) was 20%.353 Single-agent clofarabine in this setting was
R/R T-ALL (n = 7; range, 1–19 years) were treated with nelarabine, associated with severe liver toxicities (generally reversible) and frequent
etoposide, and cyclophosphamide.350 In addition, all patients received IT febrile episodes including grade 3 or 4 infections and febrile
prophylaxis with methotrexate or triple IT therapy with methotrexate, neutropenia.353 Phase II studies evaluating the combination of clofarabine
cytarabine, and hydrocortisone. All patients experienced a CR after 1 or 2 with cyclophosphamide and etoposide in pediatric patients with R/R ALL
courses of therapy. The most common adverse events attributed to have resulted in response rates ranging from 44% to 52%.354,355 This
nelarabine were grade 2 and 3 sensory and motor neuropathy and combination has been associated with prolonged and severe
musculoskeletal pain.350 In phase I of the NECTAR trial, pediatric patients myelosuppression, febrile episodes, severe infections (including sepsis or
with R/R T-ALL and T-LL (range, 1–21 years) were also treated with septic shock), mucositis, and liver toxicities including fatal SOS (the latter
nelarabine, etoposide, and cyclophosphamide.351 Of nine patients with occurring in the post-allogeneic HCT setting).354
T-ALL with evaluable data, there were two CRs, one partial CR, and one
CR in the bone marrow/partial response (PR) in an extramedullary site for There are limited studies of clofarabine combination regimens in adults
a response rate of 44%.351 with R/R disease. In a study by Miano et al,356 pediatric patients with R/R

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NCCN Guidelines Version 2.2024

Acute Lymphoblastic Leukemia

ALL (n = 24; median age, 7.6 years; range, 1–20 years) were treated with 67%, respectively. 360 This regimen may be considered in patients who
clofarabine, etoposide, and cyclophosphamide, and 42% (10 of 24) of have received a maximal dose of anthracycline and have cardiac
patients experienced treatment response, with a 24-month OS rate of dysfunction and limited performance status.
25%.356 In a study from GRAALL, adults with R/R ALL (n = 55) were
TKIs
treated with clofarabine in combination with conventional chemotherapy
(cyclophosphamide [ENDEVOL cohort; median age, 53 years; range, 18– Studies evaluating other novel TKIs in targeting specific genetic subtypes
78 years], or a more intensive regimen with dexamethasone, have been evaluated for the treatment of R/R T-ALL disease. While
mitoxantrone, etoposide, and PEG [VANDEVOL cohort; median age, 34 daratumumab has efficacy in its application for MRD, it has been
years; range, 19–67 years]). Patients in the ENDEVOL cohort achieved a reported to have potential preclinical benefit in T-ALL with positive CD38
CR of 50% (9 of 18) and patients in the VANDEVOL cohort yielded a CR expression.361 The use of the selective BCL2 inhibitor, venetoclax, has
rate of 41% (15 of 37); the median OS was 6.5 months after a median been retrospectively analyzed in the treatment of R/R T-ALL. In this
follow-up of 6 months.357 The most common grade 3 or 4 toxicities analysis, 60% of patients receiving venetoclax plus various
included infection (58%) and liver toxicities (24%), with an early death rate chemotherapeutic agents such as hyper-CVAD, nelarabine, or
of 11%.357 Because the use of clofarabine-containing regimens require decitabine, achieved remission in marrow blasts, with the median OS of
close monitoring and intensive supportive care measures, patients should 7.7 months.362 Proteasome inhibition with the use of bortezomib in
only be treated in centers with expertise in the management of ALL, combination with chemotherapeutic agents has been suggested to
preferably in the context of a clinical trial. improved relapse response rates in patients with T-ALL. In a phase II
COG study, patients with ALL were treated with reinduction
MOpAD Regimen chemotherapy plus bortezomib. 363 Patients with relapsed T-ALL showed
A single-arm trial evaluating the efficacy of the MOAD regimen a CR rate of 68%, with end of induction MRD significantly predicting
(methotrexate, vincristine, L-asparaginase, and dexamethasone) in survival.363
adults with newly diagnosed ALL (n = 55) demonstrated a CR rate of
76% with a median CR duration of over 12 months. 358 A phase II trial NCCN Recommendations for Ph-Negative B-ALL
incorporated a new PEGylated formulation of L-asparaginase due to AYA Patients with Ph-Negative B-ALL
improved tolerability, 359 and examined the safety and efficacy of the The Panel recommends that AYA patients with Ph-negative B-ALL
MOpAD regimen (methotrexate, vincristine, PEG-L-asparaginase, and (regardless of risk group) be treated in a clinical trial, where possible. In
dexamethasone) in adults with relapsed or refractory ALL (n = 37). 360 For the absence of an appropriate clinical trial, the recommended induction
patients with Ph-positive ALL, TKIs (ie, imatinib, dasatinib, nilotinib) were therapy should comprise multiagent therapy regimens based on
added to the regimen and if patients had CD20-positive B-ALL, rituximab pediatric-inspired protocols and data from multi-institutional studies, such
was added to the regimen. The CR and ORR rates were 28% and 39%, as the PETHEMA ALL-96, GRAALL-2005 (with rituximab for
respectively, with a median duration of response of 4.3 months. 360 CD20-positive disease), DFCI-00-01 (preferred), or the CALGB 10403
Patients with Ph-positive ALL achieved CR and ORR rates of 50% and (preferred) and ECOG1910 regimens. Multiagent therapy protocols based

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NCCN Guidelines Version 2.2024

Acute Lymphoblastic Leukemia

on data from single-institution studies, including CCG-1882, the Linker monotherapy and the start of conditioning for allogeneic HCT to minimize
regimen, and hyper-CVAD (with or without rituximab), are also risk of SOS. SOS has been shown to occur less frequently when less
recommended. Treatment regimens should include adequate CNS alkylators are used as part of the conditioning regimen.259
prophylaxis for all patients. It is important to adhere to the treatment
regimens for a given protocol in its entirety. Testing for TPMT gene Adequate count recovery per protocol is necessary before transitioning to
polymorphism should be considered for patients receiving 6-MP as part of post remission therapy, even in the presence of MRD negativity. If count
maintenance therapy, especially in those who experience severe bone recovery is not achieved, additional follow up for MRD may be warranted.
marrow toxicities.
In all cases, the optimal timing of HCT is unclear. For patients who are fit,
For patients experiencing a CR following initial induction therapy, MRD additional therapy is recommended to eliminate MRD prior to transplant.
status should be assessed (see NCCN Recommendations for MRD Adequate count recovery per protocol is necessary before transitioning to
Assessment). If the resulting MRD status is negative or unavailable, post remission therapy, even in the presence of MRD negativity. If count
continuation of the multiagent therapy protocol or blinatumomab recovery is not achieved, additional follow up for MRD may be warranted.
monotherapy for consolidation followed by maintenance would be
For AYA patients experiencing less than a CR after initial induction
appropriate. Blinatumomab should be incorporated into frontline
therapy (ie, presence of primary refractory disease), the treatment
multiagent therapy regimens as a post-remission approach based on data
approach would be similar to that for patients with R/R ALL (see Patients
from ECOG1910.318 While ECOG1910 included patients aged 30 to 70
with Relapsed/Refractory Ph-Negative B-ALL).
years, multiagent therapy with blinatumomab as consolidation can be
considered in AYA patients. Consolidation with allogeneic HCT may also Adults with Ph-Negative B-ALL
be considered, especially in the setting of high-risk features. For patients For adults with Ph-negative B-ALL, the Panel recommends treatment in a
with negative MRD by flow cytometry but positive MRD by an clinical trial, where possible. In the absence of an appropriate clinical trial,
FDA-approved NGS assay, repeat testing before consolidation is started the recommended treatment approach would initially depend on the
should be considered to confirm MRD status. If MRD status is unavailable, patient’s age and/or presence of comorbid conditions. Treatment regimens
consideration should be made for retesting MRD at the first available should include adequate CNS prophylaxis for all patients, and a given
opportunity. treatment protocol should be followed in its entirety, from induction therapy
to consolidation/delayed intensification to maintenance therapy. Again,
If the MRD is persistent or rising, blinatumomab or inotuzumab ozogamicin
testing for TPMT gene polymorphism should be considered for patients
are recommended, though blinatumomab is preferred in this setting for
receiving 6-MP as part of maintenance therapy, especially in those who
those who have not previously received blinatumomab. Although
develop severe bone marrow toxicities.
long-term remission after blinatumomab monotherapy is possible,
allogeneic HCT can be considered as consolidative therapy. Although Although the age cutoff indicated in the guidelines has been set at 65
there is limited data, it is recommended to wait at least 4 weeks from InO years, it should be noted that chronologic age alone is not a sufficient

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NCCN Guidelines Version 2.2024

Acute Lymphoblastic Leukemia

surrogate for defining fitness; patients should be evaluated on an Patients with Relapsed/Refractory Ph-Negative B-ALL
individual basis to determine fitness for therapy based on factors such as For patients with R/R Ph-negative B-ALL, the approach to second-line
performance status, end-organ function, and end-organ reserve. treatment may depend on the duration of the initial response. For late
relapses (ie, relapses occurring ≥3 years from initial diagnosis),
For patients <65 years of age and without substantial comorbidities, the re-treatment with the same induction regimen is a reasonable option. For
recommended treatment approach is similar to that for AYA patients. other patients, participation in a clinical trial is preferred, when possible. In
Induction therapy should comprise multiagent therapy such as those the absence of an appropriate trial, for patients with R/R Ph-negative
based on protocols from the ECOG1910 regimen (preferred), CALGB precursor B-ALL, recommended category 1 options include blinatumomab
8811 study (Larson regimen), the Linker regimen, GRAALL-2005 (with or InO. As previously mentioned, InO is associated with increased
rituximab for CD20-positive disease), hyper-CVAD with or without hepatotoxicity, including fatal and life-threatening hepatic SOS, and
sequential blinatumomab (with or without rituximab), USC/MSKCC ALL increased risk of post-HCT non-relapse mortality.258
regimen (CCG-1882 regimen), the MRC UKALL XII/ECOG E2993
regimen, InO with mini-hyper-CVD with or without blinatumomab. Brexucabtagene autoleucel is an option for AYA and adult patients with
R/R Ph-negative B-ALL. Tisagenlecleucel is also an option for patients
For patients <65 years of age and without substantial comorbidities, the <26 years of age and with refractory disease or ≥2 relapses. Other options
MRD assessment and consolidation approach after initial treatment that may be considered include subsequent multiagent therapy, with
induction would be similar to that for AYA patients with Ph-B-ALL (see regimens containing clofarabine, InO with mini-hyper-CVD with or without
AYA Patients with Ph-Negative B-ALL); however, in the setting of blinatumomab, augmented hyper-CVAD, MOpAD regimen, or other
persistent/rising MRD blinatumomab or InO are consolidation therapy fludarabine-, cytarabine-, or alkylator-containing regimens.333,364-367 If
options prior to allogeneic HCT. Blinatumomab is strongly preferred in this patients who have not yet undergone transplant experience a second CR
setting for those who have not previously received blinatumomab. prior to transplant, consolidative allogeneic HCT should be strongly
considered. For patients with disease that relapses after an initial
For patients ≥65 years of age or patients with substantial comorbidities,
allogeneic HCT, other options may include a second allogeneic HCT
the recommended induction therapy includes multiagent therapy regimens
and/or DLI. However, the role of allogeneic HCT following treatment with
(including InO-containing regimens), InO monotherapy, or palliative
tisagenlecleucel is unclear. As previously discussed, persistence of
corticosteroids. Dose modifications may be required for systemic therapy
tisagenlecleucel in peripheral blood and persistent B-cell aplasia has been
agents, as needed. MRD assessment and consolidation approach after
associated with durable clinical responses without subsequent allogeneic
initial treatment induction would be similar to that for AYA patients with
HCT.260
Ph-B-ALL, with appropriate dose modifications (see AYA Patients with
Ph-Negative B-ALL).

For recommendations on the treatment of adults with mature B-ALL, refer

to the NCCN Guidelines for B-Cell Lymphomas.
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NCCN Guidelines Version 2.2024

Acute Lymphoblastic Leukemia

NCCN Recommendations for T-ALL approach would be similar to that for patients with R/R ALL (see Patients
AYA Patients with Ph-Negative T-ALL with Relapsed/Refractory Ph-Negative T-ALL).
The Panel recommends that AYA patients with T-ALL (regardless of risk
Adults with Ph-Negative T-ALL
group) be treated in a clinical trial, where possible. In the absence of an
For adults with T-ALL, the Panel recommends treatment in a clinical trial,
appropriate clinical trial, the recommended induction therapy should
where possible. In the absence of an appropriate clinical trial, the
comprise multiagent therapy regimens based on pediatric-inspired
recommended treatment approach would initially depend on the patient’s
protocols and data from multi-institutional studies, such as the COG
age and/or presence of comorbid conditions. Treatment regimens should
AALL0434 (preferred), PETHEMA ALL-96, GRAALL-2005, DFCI-00-01, or
include adequate CNS prophylaxis for all patients, and a given treatment
the CALGB 10403 (preferred) regimens. Multiagent therapy protocols
protocol should be followed in its entirety, from induction therapy to
based on data from single-institution studies, including CCG-1882, the
consolidation/delayed intensification to maintenance therapy. Again,
Linker regimen, and hyper-CVAD are also recommended.163 The addition
testing for TPMT gene polymorphism should be considered for patients
of nelarabine to COG AALL0434 and hyperCVAD may be beneficial.
receiving 6-MP as part of maintenance therapy, especially in those who
Treatment regimens should include adequate CNS prophylaxis for all
develop severe bone marrow toxicities.
patients. It is important to adhere to the treatment regimens for a given
protocol in its entirety. Testing for TPMT gene polymorphism should be Although the age cutoff indicated in the guidelines has been set at 65
considered for patients receiving 6-MP as part of maintenance therapy, years, it should be noted that chronologic age alone is not a sufficient
especially in those who experience severe bone marrow toxicities. surrogate for defining fitness; patients should be evaluated on an
individual basis to determine fitness for therapy based on factors such as
For patients experiencing a CR or CRi following initial induction therapy,
performance status, end-organ function, and end-organ reserve.
MRD status should be assessed (see NCCN Recommendations for MRD
Assessment). If the MRD status is positive and/or there are high-risk For patients <65 years of age and without substantial comorbidities, the
features such as ETP-phenotype or RAS/PTEN classifier, consolidation recommended treatment approach is similar to that for AYA patients.
with allogeneic HCT should be considered. Continuation of multiagent Induction therapy should comprise multiagent therapy such as those
therapy followed by maintenance therapy is another recommended based on protocols from the CALGB 8811 study (Larson regimen), the
consolidation option. For all other patients, continuation of multiagent Linker regimen, GRAALL-2005, GRAALL-2014, hyper-CVAD, or the MRC
therapy followed by maintenance therapy or consideration of consolidative UKALL XII/ECOG E2993 regimen. The addition of nelarabine to
allogeneic HCT are recommended. In all cases, the optimal timing of HCT GRALL-2014 and hyperCVAD may be beneficial. For patients <65 years
is unclear. For patients who are fit, additional therapy is recommended to of age and without substantial comorbidities, the MRD assessment and
eliminate MRD prior to transplant. consolidation approach after initial treatment induction would be similar to
that for AYA patients with T-ALL (see AYA Patients with T-ALL).
For AYA patients experiencing less than a CR or Cri after initial induction
therapy (ie, presence of primary refractory disease), the treatment

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Acute Lymphoblastic Leukemia

For patients ≥65 years of age or patients with substantial comorbidities, fractionated cyclophosphamide, vincristine, doxorubicin, and
the recommended induction therapy includes multiagent therapy regimens dexamethasone alternating with cycles of high-dose methotrexate and
or palliative corticosteroids. Dose modifications may be required for cytarabine) is also a common regimen used for lymphoblastic lymphoma.
systemic therapy agents, as needed. MRD assessment and consolidation A response rate of 100% was seen in a singular study, with 91% of
approach after initial treatment induction would be similar to that for AYA patients achieving a CR and a 3-year PFS of 66%.158 However, it should
patients with T-ALL, with appropriate dose modifications (see AYA be noted that 40% to 60% of adults experience relapse, suggesting that
Patients with T-ALL). other treatments including HCT may be warranted.

Patients with Relapsed/Refractory T-ALL Evaluation and Treatment of Extramedullary Disease

For patients with R/R T-ALL, the approach to second-line treatment may
CNS Involvement in ALL
depend on the duration of the initial response. For late relapses (ie,
Although the presence of CNS involvement at diagnosis is uncommon
relapses occurring ≥3 years from initial diagnosis), re-treatment with the
(approximately 3%–7% of cases), a substantial proportion of patients
same induction regimen is a reasonable option. For other patients,
(>50%) will eventually develop CNS leukemia in the absence of
participation in a clinical trial is preferred, when possible. In the absence of
CNS-directed therapy.1,50 CNS leukemia is defined by a WBC count of ≥5
an appropriate trial, the regimens listed for R/R Ph-negative B-ALL may be
leukocytes/mcL in the CSF with the presence of lymphoblasts.1,50 In
appropriate for R/R T-ALL; however, nelarabine166,368,369 in combination
children with ALL, CNS leukemia at diagnosis was associated with
with etoposide and cyclophosphamide is the preferred treatment
significantly decreased EFS rates.118,378,379 Factors associated with an
approach.350,351 Other recommended regimens that may be considered
increased risk for CNS relapse in children include T-cell
include HiDAC or regimens containing daratumumab,370-372 mitoxantrone-,
immunophenotype, high WBC counts at presentation, Ph-positive disease,
etoposide-, cytarabine,373 venetoclax,362,374 or bortezomib-containing
t(4;11) translocation, and presence of leukemic cells in the CSF.124 In
regimens.363
adults with ALL, CNS leukemia at diagnosis has been associated with a
Management of Lymphoblastic Lymphoma significantly higher risk for CNS relapse in large trials, although no
differences were observed in 5-year EFS or DFS rates compared with
As previously discussed, patients with lymphoblastic lymphoma generally
subgroups without CNS leukemia at presentation.380,381 CNS leukemia at
benefit from treatment with ALL-like regimens and should be treated in a
diagnosis was associated with a significantly decreased 5-year OS rate in
center that has experience with lymphoblastic lymphoma. Chemotherapy
one trial (29% vs. 38%; P = .03)380 but not in another trial (35% vs.
should be initiated as soon as possible; combination chemotherapy has
31%).381 Factors associated with an increased risk for CNS leukemia in
shown improved response though relapse is common.375 In patients with
adults include mature B-cell immunophenotype, T-cell immunophenotype,
lymphoblastic lymphoma, a 5-year DFS rate between 60% and 80% in
high WBC counts at presentation, and elevated serum LDH levels.43,380
children and between 55% and 95% in adults was seen following a
CNS-directed therapy may include cranial irradiation, IT therapy (eg,
regimen of cyclophosphamide, doxorubicin, vincristine, and prednisone
methotrexate, cytarabine, corticosteroids), and/or high-dose systemic
(CHOP) or other CHOP-like regimens.376,377 Hyper-CVAD (cycles of
chemotherapy (eg, methotrexate, cytarabine, 6-MP, asparaginase).1,50,124
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Acute Lymphoblastic Leukemia

Although cranial irradiation is an effective treatment modality for CNS and effective CNS-directed IT regimens, AYA patients can obtain
leukemia, it can be associated with serious adverse events, such as long-term EFS without the need for cranial irradiation or routine allogeneic
neurocognitive dysfunctions, secondary malignancies, and other long-term HCT.379,382
complications.1,124 With the increasing use of effective IT therapy and
high-dose systemic chemotherapy regimens, studies have examined the In adults with ALL who received IT therapy and intensive systemic
feasibility of eliminating cranial irradiation as part of CNS prophylaxis. In chemotherapy for CNS prophylaxis, the overall CNS relapse rate was 2%
studies of children with ALL who only received IT and/or intensive to 6%.20,126,383,384 Therefore, with the incorporation of adequate systemic
systemic chemotherapy for CNS prophylaxis, the 5-year cumulative chemotherapy (eg, high-dose methotrexate and cytarabine) and IT therapy
incidence of isolated CNS relapse or any CNS relapse was 3% to 4% and regimens (eg, methotrexate alone or with cytarabine and corticosteroid,
4% to 5%, respectively.116,379 which constitutes the triple IT regimen), the use of upfront cranial
irradiation can be avoided except in cases of overt CNS leukemia at
Data from the Total Therapy (XV) study by the St. Jude Children’s presentation, and the use of irradiation can be reserved for advanced
Research Hospital showed dramatic improvements in survival outcomes disease. CNS prophylaxis is typically given throughout the course of ALL
for the AYA population. In this study, patients were primarily risk-stratified therapy starting from induction to consolidation, to the maintenance
based on treatment response; patients were treated according to phases of treatment.
risk-adjusted intensive chemotherapy, with the incorporation of MRD
evaluation during induction (day 19) to determine the need for additional NCCN Recommendations for Evaluation and Treatment of
Extramedullary Involvement
doses of asparaginase.379,382 The 5-year EFS rate for the AYA population
(aged 15–18 years; n = 45) was 86% (95% CI, 72%–94%), which was not CNS involvement should be evaluated with LP at timing in accordance
significantly different from the 87% EFS rate (95% CI, 84%–90%; P = .61) with the specific treatment protocol used for each patient.
observed for patients <15 years of age (n = 448). The 5-year OS rates for Pediatric-inspired treatment regimens typically include LP at diagnostic
the AYA patients and patients <15 years of age were 88% and 94%, workup. The Panel recommends that IT therapy be administered with
respectively (P = not significant).379,382 The favorable EFS and OS initial LP. All patients being treated for ALL should receive adequate CNS
outcomes in AYA patients in this study were attributed partly to the use of prophylaxis with IT therapy and/or systemic therapy that incorporates
intensive dexamethasone, vincristine, and asparaginase, in addition to methotrexate.
early IT therapy (ie, triple IT therapy with cytarabine, hydrocortisone, and
The classification of CNS status includes the following: CNS-1 refers to no
methotrexate) for CNS-directed therapy. In addition, the use of
lymphoblasts in the CSF regardless of WBC count; CNS-2 is defined as a
prophylactic cranial irradiation was safely omitted in this study; the 5-year
WBC count <5 leukocytes/mcL in the CSF with the presence of blasts; and
cumulative incidence of isolated CNS relapse and any CNS relapse was
CNS-3 is defined as a WBC count of ≥5 leukocytes/mcL with the presence
3% and 4%, respectively, for the entire study population (n = 498).379
of blasts. If leukemic cells are present in the peripheral blood and the LP is
Moreover, all 11 patients with isolated CNS relapse were children <12
traumatic (containing ≥5 WBC/mcL in CSF with blasts), then the
years of age. This study showed that, with intensive risk-adjusted therapy
Steinherz-Bleyer algorithm can be used to determine the CNS
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NCCN Guidelines Version 2.2024

Acute Lymphoblastic Leukemia

classification (if the WBC/RBC ratio in the CSF is at least 2-fold greater Response Assessment and Surveillance
than the WBC/RBC ratio in the blood, then the classification would be Response Criteria
CNS-3; if not, the classification would be CNS-2). Flow cytometry may be
Response in Bone Marrow and Peripheral Blood
considered in the setting of CNS-1 status. Patients who have CNS-1
A CR requires the absence of circulating blasts and absence of
disease with leukemia detected only by flow cytometry may be at higher
extramedullary disease (ie, no lymphadenopathy, splenomegaly, skin/gum
risk but data are still forthcoming.
infiltration, testicular mass, CNS involvement, or other extramedullary
In general, patients with CNS involvement at diagnosis (ie, CNS-3 and/or involvement). A bone marrow assessment should show trilineage
cranial nerve involvement) or with CNS disease that does not clear after hematopoiesis and <5% blasts. For a CR, absolute neutrophil counts
induction IT chemotherapy should receive 18 Gy (in 1.8–2 Gy/fraction) of (ANCs) should be >1.0 × 109/L and platelet counts should be >100 ×
cranial irradiation. The entire brain and posterior half of the globe should 109/L. In addition, no recurrence should be observed for at least 4 weeks.
be included. The inferior border should include C2. Notably, areas of the A patient is considered to have achieved a CRi if all criteria for CR are met
brain targeted by the radiation field in the treatment of patients with ALL except the ANC remains <1.0 × 109/L or the platelet count remains <100 ×
are different from those targeted for brain metastases of solid tumors. In 109/L. A patient is considered to have achieved a CRh if all criteria for CR
addition, patients with CNS leukemia at diagnosis should receive are met and peripheral blood counts have partially recovered (ANC >0.5 ×
adequate systemic therapy as well as IT therapy containing methotrexate 109/L and platelet count >50 × 109/L.
throughout the treatment course. Adequate systemic therapy should also
Refractory disease is defined as having not achieved a CR at the end of
be given during the management of isolated CNS relapse.
induction therapy. PD is defined as an increase in the absolute number of
A testicular examination should be performed for all patients with testes at circulating blasts (in peripheral blood) or bone marrow blasts by at least
diagnostic workup; testicular involvement is especially common among 25%, or the development of extramedullary disease. Relapsed disease is
patients with T-ALL. Patients with clinical evidence of testicular disease at defined as the reappearance of blasts in the blood or bone marrow (>5%)
diagnosis that is not fully resolved by the end of induction therapy should or in any extramedullary site after achievement of a CR.
be considered for radiation to both testes in the scrotal sac. Radiation
Response in CNS Disease
therapy is typically performed concurrently with the first cycle of
Remission of CNS disease is defined as achievement of CNS-1 status (no
maintenance chemotherapy. Testicular total dose should be 24 Gy (in 2.0
lymphoblasts in CSF regardless of WBC count) in a patient with CNS-2 or
Gy/fraction).
CNS-3 at diagnosis. CNS relapse is defined as development of CNS-2 or
CNS-3 status or development of clinical signs of CNS leukemia (eg, facial
nerve palsy, brain/eye involvement, hypothalamic syndrome) without an
alternative explanation.

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NCCN Guidelines Version 2.2024

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Response in Lymphomatous Extramedullary Disease If relapse is suspected, a full workup should be considered. For
To assess treatment response, a CT of the neck/chest/abdomen/pelvis Ph-positive ALL, periodic quantification of the BCR::ABL1 transcript should
with IV contrast and PET/CT imaging should be performed. A CR in this be determined. During the second year after completion of therapy, a
context is defined as complete resolution of lymphomatous enlargement physical examination (including a testicular examination) and blood tests
by CT scan. For patients with a previous positive PET scan, a (CBC with differential) should be performed every 3 to 6 months. During
post-treatment residual mass of any size is considered a CR if it is PET the third year (and beyond) after completion of therapy, physical
negative. A PR is defined as a >50% decrease in the sum product of the examination (including a testicular examination) and blood tests (CBC with
greatest perpendicular diameters (SPD) of the lymphomatous differential) can be performed every 6 to 12 months or as clinically
enlargement. PD is defined as a >25% increase in the SPD. No response indicated. Recommendations for survivorship are available in the NCCN
indicates that neither criteria for a PR or PD (as defined earlier) are met. Guidelines for Adolescent and Young Adult (AYA) Oncology and NCCN
For patients with a previous positive PET scan, the post-treatment PET Guidelines for Survivorship.
must be positive in at least one previously involved site. Relapse is
defined as recurrence of mediastinal lymphomatous enlargement after The COG has published guidelines on long-term survivorship issues for
achieving CR. survivors of childhood cancers.385 These guidelines serve as a resource
for clinicians and family members/caretakers, and have the goal of
Surveillance providing screening and management recommendations for late effects
After completion of the ALL treatment regimen (including maintenance (those that may impact growth, cognitive function, emotional concerns,
therapy), the Panel recommends surveillance at regular intervals to reproductive health, risks for secondary malignancies, and other important
assess disease status. During the first year after completion of therapy, health issues) that may arise during the lifetime of an AYA cancer survivor
patients should undergo a complete physical examination (including a as a result of the therapeutic agents used during the course of antitumor
testicular examination) and blood tests (CBC with differential). Liver treatment.
function tests should be performed until normal values are achieved. An
assessment of bone marrow aspirate can be considered as clinically
Role of MRD Evaluation
indicated at a frequency of 3 to 6 months for the first 5 years; if a bone MRD in ALL refers to the presence of leukemic cells below the threshold
marrow aspirate is performed, flow cytometry with additional studies that of detection using conventional morphologic methods. Patients who
may include comprehensive cytogenetics, FISH, molecular tests, and experienced a CR according to morphologic assessment alone can
MRD assessments should be carried out. While there is insufficient potentially harbor a large number of leukemic cells in the bone marrow: up
evidence to guide MRD monitoring for patients with Ph-negative disease to 1010 malignant cells.36,386
following completion of maintenance therapy, the approval of
The most frequently used methods for MRD quantification include an
blinatumomab, and potentially future therapies for MRD-positive relapse,
FDA-approved NGS-based assay to detect fusion genes or clonal
may warrant testing in this regard.
rearrangements in Ig and T-cell receptor (TCR) loci (preferred; does not

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require patient-specific primers), multiparameter flow cytometry (eg, have detectable MRD based on sensitive assays (in which the threshold of
6-color or higher) to detect leukemia-associated immunophenotypes, MRD negativity is <1 x 10-4 bone marrow MNCs).400,401 An early study in
real-time quantitative PCR assays to detect fusion genes (eg, children with ALL (n = 178) showed that patients with detectable MRD
BCR::ABL1).387-394 after initial induction therapy (42% of patients) had significantly shorter
time to relapse than patients who achieved MRD-negative status (P <
Current multi-parameter flow cytometry or PCR methods can detect .001), defined by a PCR sensitivity level of <1.5 x 10-4.402 Patients with
leukemic cells at a sensitivity threshold of fewer than 10-4 (<0.01%) bone MRD after induction had a 10-fold increase in risk of death compared with
marrow mononuclear cells (MNCs), and NGS and some PCR methods those without detectable MRD. Moreover, the level of detectable MRD was
can detect leukemic cells at a sensitivity threshold of fewer than 10-6 found to correlate with relapse; patients with MRD of ≥1 x 10-2 had a
(<0.0001%) bone marrow MNCs.388,390,393,394 The concordance rate for 16-fold higher risk of relapse compared with those who had MRD levels <1
quantifying MRD between these methods is generally high at disease × 10-3.402 In another study in children with ALL (n = 158), patients with
burdens 10-4 (>0.01%), but NGS is able to detect MRD at lower detectable MRD (flow cytometry sensitivity level <1 x 10-4) at the end of
thresholds.389,391,394-398 In a study that analyzed MRD using both flow induction therapy had a significantly higher 3-year cumulative incidence of
cytometry and PCR techniques in 1375 samples from 227 patients with relapse than those who were MRD negative (33% vs. 7.5%; P < .001).403
ALL, the concordance rate for MRD assessment (based on a detection Subsequent studies have confirmed these findings. In a study of 165
threshold of <1 × 10-4 for both methods) was 97%.396 In another study, patients, the 5-year relapse rate was significantly higher among patients
both flow cytometry and high-throughput sequencing techniques were with MRD (flow cytometry sensitivity <1 x 10-4) versus those without
used to analyze MRD at a threshold of 0.01% in samples from 619 detectable disease (43% vs. 10%; P < .001).401 Persistence of MRD during
patients with pediatric B-ALL.394 At the 0.01% threshold, the concordance the course of therapy was associated with risk of relapse; the cumulative
between both methods was high, but high-throughput sequencing was rate of relapse was significantly higher among patients with MRD
able to detect MRD at lower thresholds.394 The combined or tandem use of persisting through week 14 of continued treatment compared with patients
both methods would allow for MRD monitoring in all patients, thereby who achieved MRD-negativity by 14 weeks (68% vs. 7%; P = .035).401
avoiding potential false-negative results.390,396,399 However, this practice MRD evaluation was shown to be a significant independent predictor of
could lead to an increase in cost without a clear directive in terms of outcome.
modification of treatment. Numerous studies in both childhood and adult
ALL have shown the prognostic importance of postinduction (and/or MRD assessments at an earlier time point in the course of treatment (eg,
post-consolidation) MRD measurements in predicting the likelihood of during induction therapy) have been shown to be highly predictive of
disease relapse. outcomes in children with ALL. In one study, nearly 50% of patients
achieved MRD clearance (MRD <1 × 10-4 by flow cytometry) before day 19
MRD Assessment in Childhood ALL of induction therapy (about 2–3 weeks from initiation of induction); the
Among children with ALL who achieve a CR according to morphologic 5-year cumulative incidence of relapse was significantly higher among
evaluation after induction therapy, approximately 25% to 50% may still patients with MRD at day 19 of treatment than those without detectable

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NCCN Guidelines Version 2.2024

Acute Lymphoblastic Leukemia

MRD (33% vs. 6%; P < .001).400 The prognostic significance of MRD with favorable cytogenetic/molecular markers such as the ETV6::RUNX1
detection at lower levels (sensitivity threshold, ≤1 × 10-5, or ≤0.001%, subtype or hyperdiploidy were either considered at standard risk or
according to PCR measurements) was evaluated in children with B-cell intermediate risk based on MRD evaluation.404 The 5-year EFS rate was
lineage ALL treated with contemporary regimens.393 At the end of 92% for patients categorized as at standard risk (n = 1348), 78% for
induction therapy, 58% of patients had undetectable disease based on intermediate risk (n = 1647), and 50% for high risk (n = 189), resulting in a
PCR values. Among the remaining patients with detectable MRD, 17% statistically significant difference among the groups (P < .001); the 5-year
had MRD of ≥0.01%, 14% had <0.01% (but ≥0.001%), and 11% had OS rates were 98%, 93%, and 60%, respectively. MRD-based risk
<0.001%. The 5-year cumulative incidence of relapse was significantly stratification significantly differentiated risks for relapse (between
higher among patients with MRD of ≥0.01% versus patients with <0.01% standard- and intermediate-risk subgroups) even among patient
or undetectable disease (23% vs. 6%; P < .001).393 Furthermore, the populations with disease with ETV6::RUNX1 or hyperdiploidy. Importantly,
5-year cumulative incidence of relapse was higher among the subgroup of in this large-scale study, MRD remained a significant and powerful
patients with MRD <0.01% (but ≥0.001%) versus those with MRD independent prognostic factor for relapse in the overall population.404
<0.001% or undetectable disease (13% vs. 5%; P < .05). MRD status at
the end of induction therapy strongly correlated with MRD levels (flow A randomized controlled trial in children and young adults with low-risk
cytometry sensitivity level <0.01%) at day 19 during induction; all patients ALL according to MRD compared treatment reduction to standard
who had MRD of ≥0.01% at the end of induction had MRD of ≥0.01% at induction (n = 521).405 Patients were randomized to receive either one or
day 19. Although this study showed that a higher risk of relapse was seen two delayed intensification courses consisting of PEG on day 4;
among patients with MRD below the generally accepted threshold level vincristine, dexamethasone (alternate weeks), and doxorubicin for 3
(<0.01% but ≥0.001%) compared with those with very low MRD (<0.001%) weeks; and 4 weeks of cyclophosphamide and cytarabine. The 5-year
or no detectable disease, further studies are warranted to determine EFS between the two cohorts was not statistically significant (94.4% vs.
whether this MRD threshold at day 19 should be used to risk stratify 95.5%; OR, 1; 95% CI, 0.43–2.31; two-sided P = .99). No statistical
patients or guide decisions surrounding treatment intensification.393 difference was seen regarding relapse or serious adverse events;
however, there was a singular treatment-related death in the second
In one of the largest collaborative studies conducted in Europe (the delayed intensification cohort and 74 episodes of grade 3 or 4 toxic
AIEOP-BFM ALL 2000 study), children with Ph-negative B-cell lineage events. The results suggest that treatment reduction is reasonable for
ALL (n = 3184 evaluable) were risk stratified according to MRD status children and young adults with ALL who have a low risk of relapse based
(PCR sensitivity level ≤0.01%) at two time points (days 33 and 78), which on MRD at the end of induction.
were used to guide postinduction treatment.404 Patients were considered
at standard risk if MRD negativity (≤0.01%) was achieved at both days 33 A randomized study investigated whether improved outcome could be
and 78, at intermediate risk if MRD was >0.01% (but <0.1%) on either day seen with augmented post-remission therapy for children and young adults
33 or 78 (the other time point being MRD-negative) or on both days 33 stratified by MRD.406 In this trial, 533 patients with a high risk of MRD
and 78, and at high risk if MRD was ≥0.1% on day 78. Nearly all patients (defined as clinical standard-risk and intermediate-risk with MRD of

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NCCN Guidelines Version 2.2024

Acute Lymphoblastic Leukemia

≥0.01% at day 29 of induction) were randomized to receive standard the application of this prognostic factor must be carefully evaluated on a
therapy or augmented post-remission therapy. The augmented treatment regimen-by-regimen basis.
regimen included 8 doses of PEG, 18 doses of vincristine, and escalated
dosing of intravenous methotrexate without folinic acid rescue during the Approximately 20% of children treated with intensive therapies for ALL will
interim maintenance courses. The 5-year EFS was higher in patients ultimately experience disease relapse.409 MRD assessment may play a
receiving the augmented regimen versus the standard treatment group prognostic role in the treatment of patients in the relapsed setting.410,411 In
(89.6% vs. 82.8%; OR, 0.61; 95% CI, 0.39–0.98; P = .04). However, it patients (n = 35) who experienced a second remission (morphologic CR)
should be noted that more adverse events were seen with the augmented after reinduction treatment, MRD (measured by flow cytometry with
regimen, and no statistically significant benefit was seen in OS at 5 years sensitivity level <0.01%) after reinduction (day 36) was significantly
(92.9% vs. 88.9%; OR, 0.67; 95% CI, 0.38–1.17; P = .16). associated with risks for relapse; the 2-year cumulative incidence of
relapse was 70% among patients with MRD of ≥0.01% versus 28% among
Stratification based on MRD may also indicate which patients should those with MRD <0.01% (P = .008).410 In addition, in the subgroup of
undergo allogeneic HCT versus continued chemotherapy. Children with an patients who experienced first relapse after cessation of treatment, the
intermediate risk of relapse based on MRD were stratified based on a 2-year cumulative incidence of second relapse was 49% in patients with
cutoff MRD level of 10-3.407 Patients with MRD of ≥10-3 were allocated to MRD of ≥0.01% versus 0% for those with MRD <0.01% (P = .014). Both
receive HCT (n = 99). In this group, 83% had donors and underwent HCT the presence of MRD at day 36 of reinduction therapy and at first relapse
versus 17% who had no suitable donor and therefore continued occurring during therapy were significant independent predictors of second
chemotherapy. The EFS was higher for patients receiving HCT (64% ± relapse based on multivariate analysis.410 In another study, MRD (PCR
5%) versus patients remaining on chemotherapy (24% ± 10%). Patients sensitivity level <0.01%) was evaluated in children with high-risk ALL (n =
who experienced a low level of MRD (<10-3) received continued 60) who experienced first relapse within 30 months from the time of
chemotherapy (n = 109). Within this cohort, 83 patients received either diagnosis.411 Categories based on MRD evaluation after the first
chemotherapy or radiotherapy alone and 22 patients received an allogenic chemotherapy cycle (3–5 weeks after initiation of reinduction treatment)
HCT. There was no significant difference in EFS between these two included MRD negative (undetectable MRD), MRD positive but
groups (66% ± 6% vs. 80% ± 9%; P = .45). Results indicate that MRD can unquantifiable (levels <0.01%), and MRD of ≥0.01%. The 3-year EFS
be useful to further risk stratify patients with intermediate risk of relapse to rates based on these MRD categories were 73%, 45%, and 19%,
the appropriate treatment regimen. However, the study acknowledges that respectively (P < .05).411 Thus, MRD assessment can identify patients with
MRD cutoff values are regimen dependent as indicated by the divergence a high probability of second relapse, which may offer an opportunity for
from the earlier ALL R3 trial. While the earlier trial advocated for the use of risk-adapted second-line treatment strategies.
MRD to stratify patients for HCT, a higher threshold for MRD level was
used (10-4), a difference that may reflect the more intensive induction Several studies suggest early assessment of MRD during induction
regimen.408 Therefore, MRD levels may influence treatment decisions, but treatment (eg, day 15 from initiation of treatment) may be highly predictive
of subsequent relapse in children with ALL.412,413 This raises the possibility

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NCCN Guidelines Version 2.2024

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of identifying patients with high-risk disease who may potentially benefit initial evaluation.415 Among patients who were initially classified as at
from earlier intensification or tailoring of treatment regimens, or for standard risk, those with MRD of <0.1% after induction had a significantly
potentially allowing less-intensive treatments to be administered in lower risk of relapse at 3 years compared with patients who had higher
patients at low risk for relapse based on early MRD measurements. Large levels of MRD (9% vs. 71%; P = .001). Interestingly, MRD measured
trials are warranted to address these possibilities, although serial MRD during post-consolidation within this protocol was not significantly
measurements may likely be needed to monitor leukemic cell kinetics predictive of outcomes.415 In the GMALL 06/99 study, patients with
during the long course of treatment. standard-risk disease (n = 148 evaluable) were monitored for MRD (PCR
sensitivity level <0.01%) at various time points during the first year of
MRD Assessment in Adult ALL treatment.414 Only patients with ALL who met all of the following criteria for
Studies in adults with ALL have shown the strong correlation between standard-risk disease were enrolled in this study: absence of t(4;11) MLL
MRD and risk for relapse, and the prognostic significance of MRD translocation or t(9;22) BCR::ABL translocation; WBC count <30 × 109/L
measurements during and after initial induction therapy.386,414-417 In an for B-cell lineage ALL or <100 × 109/L for T-cell lineage ALL; age 15 to 65
analysis of postinduction MRD (flow cytometry sensitivity level <0.05%) in years; and achievement of morphologic CR after phase I of induction
adult patients with ALL (n = 87), median RFS was significantly longer treatment. At the end of initial induction therapy (day 24), patients with
among patients with MRD <0.05% at day 35 compared with those with MRD of ≥0.01% had a 2.4-fold higher risk (95% CI, 1.3–4.2) of relapse
MRD of ≥0.05% (42 vs. 16 months; P = .001).417 A similar pattern emerged than those with MRD of <0.01%.414 Moreover, this study identified distinct
when only the subgroup of patients who achieved morphologic CR at day risk groups according to MRD status at various time points. Patients
35 was included in the MRD evaluation. Although patient numbers were categorized as at low risk (10% of study patients) had MRD of <0.01% on
limited, 90% of patients with MRD <0.03% at an earlier time point (day 14 days 11 and 24 (during and after initial induction), and had 3-year DFS
during induction therapy) remained relapse-free at 5 years.417 MRD after and OS rates of 100% (for both endpoints). Patients in the high-risk group
induction therapy was a significant predictor of relapse in a subgroup (23%) had MRD of ≥0.01% persisting through week 16, and 3-year DFS
analysis from the MRC UKALL/ECOG study of patients with Ph-negative and OS rates of 6% and 45%, respectively. All other patients (67%)
B-cell lineage ALL (n = 161).416 The 5-year RFS rate was significantly categorized as at intermediate risk had 3-year DFS and OS rates of 53%
higher in patients with MRD negativity versus those with MRD of ≥0.01% and 70%, respectively.414 Importantly, MRD was the only independently
(71% vs. 15%; P = .0002).416 significant predictor of outcome in a multivariate Cox regression analysis
that included gender, age, WBC count, B- or T-cell lineage, and MRD. In a
Postinduction MRD can serve as an independent predictor of relapse even prospective study from the MDACC, adult patients with B-ALL (n = 340;
among adult patients considered to be at standard risk based on median age, 52 years; range, 15–84 years) were monitored for MRD by
traditional prognostic factors. In a study of adult patients with Ph-negative multi-parameter flow cytometry (sensitivity level = 0.01%) at CR and at
ALL (n = 116), MRD status after induction therapy (flow cytometry approximately 3-month intervals after CR.418 MRD negative status at CR
sensitivity level <0.1%) was significantly predictive of relapse regardless of significantly correlated with improved DFS and OS, and was an
whether the patient was considered to be at standard risk or high risk at independent predictor of DFS (P < .05).418
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A prospective study (Japan ALL MRD2002) evaluated outcomes by MRD end of initial treatment) among the subgroup that experienced MRD
status in adult patients with Ph-negative ALL.419 Among the patients who positivity, whereas the median RFS has not yet been reached among
achieved a CR after induction/consolidation (n = 39), those who achieved patients who remained MRD-negative. The median time from MRD
MRD negativity (<0.1%) after induction had a significantly higher 3-year positivity (at any level, including non-quantifiable cases) to clinical relapse
DFS (69% vs. 31%; P = .004) compared with patients with MRD; 3-year was 9.5 months; the median time from quantitative MRD detection to
OS was higher among patients who achieved MRD-negative status after clinical relapse was only 4 months.421 Detection of post-consolidation MRD
induction, although the difference was not statistically significant (85% vs. was highly predictive of subsequent hematologic relapse and introduced
59%). Based on multivariate Cox regression analysis, age >35 years and the concept of molecular relapse in ALL.
MRD positivity after induction were significant independent factors
predictive of decreased DFS. WBC counts and MRD status after GMALL investigators evaluated the potential advantage of intensifying or
consolidation were not significant predictors of DFS outcomes.419 modifying treatment regimens (eg, incorporation of allogeneic HCT) based
on post-consolidation MRD status. In one of the largest studies to assess
MRD assessment after consolidation therapy has been shown to have the prognostic impact of MRD on treatment outcomes in adult patients with
prognostic significance, offering the possibility to adjust post-consolidation Ph-negative ALL (n = 580 with CR and evaluable MRD results; patients
treatment approaches. In a study that evaluated MRD (PCR sensitivity from GMALL 06/99 and 07/03 studies; age 15–55 years), molecular CR
level <0.01%) after consolidation therapy (weeks 16–22 from initiation of (defined as MRD <0.01%) after consolidation was associated with
induction) in adult patients with ALL (n = 142), patients with MRD of significantly higher probabilities of 5-year continuous CR (74% vs. 35%; P
<0.01% (n = 58) were primarily allotted to receive maintenance < .0001) and OS (80% vs. 42%; P = .0001) compared with persistent
chemotherapy for 2 years, whereas those with MRD of ≥0.01% (n = 54) quantifiable MRD positivity (MRD ≥10−4).422 Based on multivariate
were eligible to undergo allogeneic HCT after high-dose therapy.420 The analysis, molecular response status was a significant independent
5-year DFS rate was significantly higher among patients who achieved predictor of both 5-year continuous CR and OS outcomes. Among the
MRD negativity versus those with MRD of ≥0.01% (72% vs. 14%; P = patients with disease that did not result in a molecular CR, the subgroup
.001). Similarly, the 5-year OS rate was significantly higher for patients who underwent allogeneic HCT in clinical CR (n = 57) showed a
with MRD-negative status post-consolidation (75% vs. 33%; P = .001).420 significantly higher 5-year continuous CR (66% vs. 12%; P < .0001) and a
In a follow-up to the GMALL 06/99 study mentioned earlier, patients with trend for higher OS (54% vs. 33%; P = .06) compared with the subgroup
standard-risk ALL (as defined by Bruggemann et al414) who experienced without HCT (n = 63).422 In this latter subgroup of patients with disease
MRD negativity (PCR sensitivity <0.01% leukemic cells) during the first that did not result in a molecular CR and who did not undergo HCT, the
year of treatment underwent sequential MRD monitoring during median time from MRD detection to clinical relapse was approximately 8
maintenance therapy and follow-up.421 Among the patients included in this months.422 This analysis showed that MRD status following consolidation
analysis (n = 105), 28 (27%) experienced MRD-positivity after the first was an independent risk factor for poorer outcomes in adults with ALL,
year of therapy; MRD was detected before hematologic relapse in 17 of and may identify patients at high-risk who could potentially benefit from
these patients.421 The median RFS was 18 months (calculated from the allogeneic HCT.

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Acute Lymphoblastic Leukemia

Studies in children and adults with ALL suggest that differences may exist blinatumomab, InO, tisagenlecleucel, or brexucabtagene autoleucel), the
in the kinetics of leukemic cell eradication between these patient lab performing the MRD assessment should be notified.
populations. Among children treated on contemporary regimens, 60% to
75% experienced clearance of MRD at the end of induction therapy The timing of MRD assessment varies depending on the ALL treatment
(typically 5–6 weeks after initiation of induction).393,400-403,423 In one study, protocol used, and may occur during or after completion of initial induction
nearly 50% of children had MRD clearance (<0.01% by flow cytometry) at therapy. Therefore, it is recommended that the initial measurement be
day 19 of induction therapy.400 Adults seem to have a slower rate of performed on completion of induction therapy and end of consolidation;
leukemic cell clearance compared with children, with 30% to 50% of adults additional time points for MRD evaluation should be guided by the
achieving MRD negativity after initial induction.414,417 Approximately 50% of treatment protocol or regimen used and risk features.424,425 Importantly,
patients experienced persistent MRD positivity at 2 months after initiation both immunophenotype (B- vs. T-lineage) and genotype may impact the
of induction, with further reductions in the proportion of MRD-positive prognostic significance of various levels of MRD at different time points,
cases occurring beyond 3 to 5 months.386,414 Possible determinants for reflecting the influence of these variables on the kinetics of response to
differences in the kinetics of leukemic cell reduction in the bone marrow therapy.422,426-428 This further highlights the importance of referring to the
may be attributed to the therapeutic regimens, variations in the distribution protocol or regimen being used when interpreting MRD results. For some
of immunophenotypic or cytogenetic/molecular features, and other host techniques, a baseline sample (ie, prior to treatment) is needed to
factors. characterize the leukemic clone for subsequent MRD assessment.

NCCN Recommendations for MRD Assessment An increase in the frequency of serial monitoring of MRD may be useful in
patients experiencing molecular relapse and low-level disease429 or for
Collectively, studies show the high prognostic value of MRD in assessing
those with Ph-positive ALL discontinuing a TKI. In general, MRD positivity
risk for relapse in patients with ALL, and the role of MRD monitoring in
at the end of induction predicts high relapse rates and should prompt an
identifying subgroups of patients who may benefit from further intensified
evaluation for allogeneic HCT. When possible, therapy aimed at
therapies or alternative treatment strategies. The preferred sample for
eliminating MRD prior to allogeneic HCT is preferred.
MRD assessment is the first small-volume (up to 3 mL) pull or early pull of
the bone marrow aspirate, if feasible. If the patient is not treated at an Supportive Care for Patients with ALL
academic medical center, there are commercially available tests that
Given the highly complex and intensive treatment protocols used in the
should be used for MRD assessment. Six-color flow cytometry can detect
management of ALL, supportive care issues are important considerations
leukemic cells at a sensitivity threshold of <1 × 10-4 (<0.01%) bone marrow
to ensure that patients derive the most benefit from ALL therapy. Although
MNCs, and PCR or NGS methods can detect leukemic cells at a
differences may exist between institutional standards and practices,
sensitivity threshold of <1 × 10-6 (<0.0001%) bone marrow
supportive care measures for patients with ALL generally include the use
MNCs.388,390,424,425 If MRD is negative by flow cytometry, an FDA-approved
of antiemetics for prevention of nausea and vomiting, blood product
NGS assay should be considered to confirm negativity. For flow cytometric
transfusions or cytokine support for severe cytopenias, nutritional support
analysis of MRD, if immunotherapy has been used (eg, rituximab,
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for prevention of weight loss, gastroenterology support, pain management, Patients with ALL undergoing intensive chemotherapy or allogeneic HCT
prevention and management of infectious complications, and prophylaxis are highly susceptible to infections. Immunosuppression caused by the
for TLS. In addition, both short- and long-term consequences of potential underlying disease and therapeutic regimens can predispose patients to
toxicities associated with specific agents used in ALL regimens should be common bacterial and viral infections, and to various opportunistic
considered, such as with steroids (eg, risks for hyperglycemia or peptic infections (eg, candidiasis, invasive mold infections, Pneumocystis
ulcerations in the acute setting; risks for avascular necrosis with long-term jirovecii, CMV reactivation and infection), particularly during periods of
use) and asparaginase (risks for hypersensitivity reactions, hyperglycemia, prolonged neutropenia. Patients with ALL should be closely monitored for
coagulopathy, hepatotoxicity, and/or pancreatitis). Supportive care any signs or symptoms of infections. Cases of febrile neutropenia should
measures should be tailored to meet the individual needs of each patient be managed promptly with empiric anti-infectives and inpatient admission.
based on factors such as age, performance status, extent of cytopenias For recommendations for the prevention and management of infections in
before and during therapy, risks for infectious complications, disease patients with cancer, see the NCCN Guidelines for the Prevention and
status, and the specific agents used in the ALL treatment regimen. Treatment of Cancer-Related Infections.

NCCN Recommendations for Supportive Care High doses of methotrexate can result in toxic plasma methotrexate
Most chemotherapy regimens used in ALL contain agents that are at least concentrations in patients with significant renal dysfunction, large
moderately emetogenic, which may necessitate antiemetic support before effusions/ascites, and delayed methotrexate clearance (plasma
initiating emetogenic chemotherapy. Antiemesis prophylaxis may include methotrexate concentrations >2 SDs of the mean methotrexate excretion
the use of agents such as serotonin receptor antagonists, corticosteroids, curve specific for the dose of methotrexate administered). Toxic plasma
and/or neurokinin-1–receptor antagonists. Recommendations for methotrexate concentrations in patients may also be observed due to
antiemetic support for patients receiving chemotherapy are available in the other interacting medications. While this is more commonly seen in
NCCN Guidelines for Antiemesis. For patients with ALL, the routine use of osteosarcoma and soft-tissue tumors due to the higher dose of
corticosteroids as part of antiemetic therapy should be avoided given that methotrexate in treatment, the FDA has approved the use of glucarpidase
steroids constitute a major component of ALL regimens. For patients as a rescue product in patients with ALL. If a patient receiving high dose
experiencing >10% weight loss, enteral or parenteral nutritional support methotrexate experiences delayed elimination due to renal impairment,
should be considered. Regimens to maintain bowel movement and glucarpidase is strongly recommended either when plasma methotrexate
prevent the occurrence of constipation may need to be considered if concentrations are 2 SDs above the mean expected plasma concentration
receiving vincristine. For patients requiring transfusion support for severe as determined by [Link] or when plasma methotrexate level is >30
or prolonged cytopenias, only irradiated blood products should be used. μM at 36 hours, >10 μM at 42 hours, or >5 μM at 48 hours. Optimal
Growth factor support is recommended during blocks of myelosuppressive administration of glucarpidase is within 48 to 60 hours from the start of
therapy or as directed by the treatment protocol being followed for methotrexate infusion.430,431 Leucovorin should also be given as part of the
individual patients (see NCCN Guidelines for Hematopoietic Growth treatment of methotrexate toxicity and should be continued for at least 2
Factors). days following glucarpidase administration and should be administered at

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least 2 hours before or 2 hours after glucarpidase (see Supportive Care in Key components of the ALL treatment regimen, such as corticosteroids,
the algorithm). Drug interactions with trimethoprim-sulfamethoxazole immunotherapies, and asparaginase, are associated with unique toxicities
(TMP/SMX) and methotrexate can worsen methotrexate toxicity,432 so the that require close monitoring and management. Corticosteroids, such as
Panel recommends holding TMP/SMX when high-dose methotrexate is prednisone and dexamethasone, constitute a core component of nearly
administered, and re-starting when methotrexate clearance is achieved every ALL induction regimen, and are frequently incorporated into
per treatment protocol or institutional guidelines. consolidation and/or maintenance regimens. Acute side effects of steroids
may include hyperglycemia and steroid-induced diabetes mellitus. Patients
Patients with ALL may be at high risk for developing acute TLS, should be monitored for glucose control to minimize the risk of developing
particularly those with highly elevated WBC counts before induction infectious complications. Another acute side effect of steroid therapy
chemotherapy. TLS is characterized by metabolic abnormalities stemming includes peptic ulceration and dyspeptic symptoms; the use of histamine-2
from the sudden release of intracellular contents into the peripheral blood receptor antagonists or proton pump inhibitors should be considered
because of cellular disintegration induced by chemotherapy. If left during steroid therapy to reduce these risks. There may also be important
untreated, TLS can result in profound metabolic changes leading to drug interactions between proton pump inhibitors (PPIs) and methotrexate
cardiac arrhythmias, seizures, loss of muscle control, acute renal failure, that need to be considered prior to initiation of methotrexate-based
and even death. Recommendations for the management of TLS are therapy. Although uncommon, the use of high-dose corticosteroids can be
available in the Tumor Lysis Syndrome section of the NCCN Guidelines associated with mood alterations, psychosis, and other neuropsychiatric
for B-Cell Lymphomas. Standard prophylaxis for TLS includes hydration complications in patients with malignancies433-436; in this context, consider
with diuresis, alkalinization of the urine, and treatment with allopurinol or anti-psychotics. If no response, dose reductions may be required in these
rasburicase. Rasburicase should be considered as initial treatment in situations. A potential long-term side effect associated with steroid therapy
patients with rapidly increasing blast counts, high uric acid, or evidence of includes osteonecrosis/avascular necrosis.437,438 Osteonecrosis most often
impaired renal function. Although relatively uncommon in patients with affects weight-bearing joints, such as the hip and/or knee, and seems to
ALL, symptomatic hyperleukocytosis (leukostasis) constitutes a medical have a higher incidence among adolescents (presumably because of the
emergency and requires immediate treatment, as recommended in the period of skeletal growth) than younger children or adults.437,439-443 In
NCCN Guidelines for Acute Myeloid Leukemia. Leukostasis is children and adolescents (aged 1–21 years) with ALL evaluated in large
characterized by highly elevated WBC count (usually >100 × 109/L) and studies of the CCG, the cumulative incidence of symptomatic
symptoms of decreased tissue perfusion that often affect respiratory and osteonecrosis increased with age, from approximately 1% in patients <10
CNS function. Although leukapheresis is not typically recommended in the years of age, to 10% to 13.5% in patients between 10 and 15 years of
routine treatment of patients with high WBC counts, it can be considered age, to 18% to 20% in patients >16 years of age.439,440 In the Total XV
with caution in cases of leukostasis that is unresponsive to other study in children with ALL, symptomatic osteonecrosis occurred in 18% of
interventions. patients, with most cases occurring within 1 year of treatment initiation.437
Children >10 years of age had a significantly higher cumulative incidence
of osteonecrosis (45% vs. 10%; P < .001) compared with children ≤10
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years of age. In this study, factors such as age >10 years, lower serum during intensification phases may reduce the risks of osteonecrosis in
albumin levels, higher serum lipid levels, and higher exposure to adolescents.439 To monitor patients for risks of developing symptomatic
dexamethasone were associated with risks for osteonecrosis. Moreover, osteonecrosis, routine measurements for vitamin D and calcium levels
higher plasma exposure to dexamethasone (as measured by area under should be obtained, and periodic radiographic evaluation (using plain films
the concentration curve at Week 8 of therapy) and lower serum albumin or MRI) should be considered. In severe avascular necrosis cases,
were significant factors associated with the development of severe (grade consider withholding steroids from therapy.
3 or 4) osteonecrosis, even after adjusting for age and treatment arm.437
When patients are treated with InO, liver enzymes— especially bilirubin—
In a DFCI ALL Consortium study in children and adolescents that included should be closely monitored because SOS may occur.444 Ursodiol may be
randomization to postinduction therapy with dexamethasone versus considered for SOS prophylaxis.445,446 Defibrotide may be considered for
prednisone, dexamethasone was associated with a significantly increased patients who develop SOS related to InO toxicity.447,448 If InO is being
5-year EFS but, in children 10 to 18 years of age, the increased given as a bridge to allogeneic HCT, double alkylator conditioning is
cumulative incidence of osteonecrosis was comparable with prednisone.443 strongly discouraged, as SOS has been shown to occur less frequently
An earlier CCG study (CCG-1882) had reported a higher incidence of when alkylators are used as part of the conditioning regimen.445,446
symptomatic osteonecrosis among children randomized to receive an Although there is limited data, it is recommended to wait at least 4 weeks
augmented ALL regimen with 2 courses of dexamethasone compared with from InO monotherapy and the start of conditioning for allogeneic HCT to
those who received 1 course (23% vs. 16%; P = not significant).440 These minimize risk of SOS.
studies appeared to suggest that dexamethasone, particularly in higher
doses, may be associated with increased risks for osteonecrosis in Patients treated with blinatumomab and tisagenlecleucel should be
children who are older and adolescents. To further investigate these monitored for CRS and neurologic toxicity. For CRS (including refractory
findings, the CCG-1961 trial randomized patients (n = 2056; aged 1–21 CRS), tocilizumab should be considered.449 An FDA-approved biosimilar is
years) to postinduction intensification treatment with intermittent dose an appropriate substitute for tocilizumab. Upon development of CRS, the
scheduling of dexamethasone (10 mg/m2 daily on days 0–6 and days 14– Panel recommends holding blinatumomab infusions with consideration for
20) versus continuous doses of dexamethasone (10 mg/m2 daily on days steroids and/or vasopressors for patients with severe symptoms according
0–20).439 Among children and adolescents ≥10 years of age who to manufacturer guidelines and prescribing information. Signs and
experienced a rapid response to induction, use of intermittent symptoms neurologic toxicity include confusion, word-finding difficulty,
dexamethasone during the intensification phase was associated with somnolence, ataxia, tremor, seizure or syncope. Severe neurotoxicity
significantly decreased incidence of osteonecrosis compared with the related to blinatumomab. During the first month after tisagenlecleucel
standard continuous dose of dexamethasone (9% vs. 17%; P = .0005). infusion, prophylaxis with anti-seizure medication may be considered.450,451
The difference was particularly pronounced among adolescents >16 years A retrospective study investigating the safety of administering IT
of age (11% vs. 37.5%, respectively; P = .0003). This randomized trial chemotherapy during blinatumomab infusion in patients with ALL and
suggested that the use of intermittent (alternative week) dexamethasone found no statistically significant difference in incidence of neurotoxicity

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between patients treated or not treated with IT chemotherapy during pharmacokinetic and pharmacodynamic profiles of PEG and cal-PEG to
blinatumomab infusion (18.4% vs. 27.2%, respectively; P = .37).452 For be similar in patients with high-risk ALL (n = 165; age range, 1–30.99
additional information regarding guidelines for immunotherapy-related years), with the latter exhibiting a longer half-life.453 The DFCI ALL
toxicities, see NCCN Guidelines for Management of Consortium also evaluated whether calaspargase pegol could be
Immunotherapy-Related Toxicities. administered less frequently than PEG with similar toxicity profiles and
serum asparaginase activity (SAA). 468 In this study, patients with newly
Asparaginase is also a core component of ALL regimens, most often given diagnosed ALL (n = 230; age range, 1–21 years) were randomized to
during induction and consolidation for Ph-negative disease and should receive an intravenous dose (2500 IU/m 2) of either PEG or cal-PEG. The
only be used in specialized centers. In this context, patients should also be SAA was similar for both enzymes 18 days after the induction dose, but
closely monitored in the period during and after infusion for allergic the SAA was higher for cal-PEG 25 days after induction, suggesting the
response. Three different formulations of the enzyme are in clinical use: 1) potential for this enzyme to be given less frequently than PEG.
PEG; 2) calaspargase pegol-mknl (cal-PEG) (in patients ≤21 years); and Additionally, the two enzymes had similar efficacy. 99% of patients in the
3) asparaginase Erwinia chrysanthemi (recombinant)-rywn PEG arm achieved a CR compared to 95% in the cal-PEG arm (P = .12),
(ERW-rywn).These formulations differ in their pharmacologic properties, and there was no difference in the frequency of end of induction MRD
and may also differ in terms of immunogenicity.453-457 Asparaginase between the two groups. The 5-year EFS (± SE) of 84.9% (± 3.4%) was
products are associated with potentially severe hypersensitivity reactions for PEG and 88.1% (± 3.0%) for cal-PEG (P = .65).468 The FDA approved
(including anaphylaxis) due to anti-asparaginase or anti-PEG cal-PEG in December 2018 for use as part of multiagent therapy in
antibodies.458,459 PEG seems to be associated with a lower incidence of pediatric and AYA patients (aged ≤21 years) with ALL. PEG is
neutralizing antibodies compared with native asparaginase.460 However, substituted with Cal-PEG, an asparagine-specific enzyme, in AYA
cross-reactivity between neutralizing antibodies against native E. coli patients aged 15 to ≤21 years and adults aged 18 to ≤21 years for more
asparaginase and pegaspargase has been reported.461,462 Moreover, a sustained asparaginase activity. 453,469
high anti-asparaginase antibody level after initial therapy with native E. coli
asparaginase was associated with decreased asparaginase activity during Native E. coli asparaginase is no longer available; therefore, the NCCN
subsequent therapy with PEG.463 Therapeutic drug monitoring (TDM) can Panel recommends the use of PEG in the treatment of patients with ALL.
be considered for patients with low-grade systemic reactions to confirm For patients who develop severe hypersensitivity reactions during
efficacy and allow continuation of asparaginase. Patients who experience treatment with PEG, ERW-rywn, which has a more frequent administration
a grade 1 or 2 reaction but demonstrate adequate asparaginase activity schedule, should be substituted, and is currently approved by the FDA for
can be considered for rechallenge.464-467 patients with ALL who have developed hypersensitivity to E. coli-derived
asparaginase (see Supportive Care: Asparaginase Toxicity Management
Similar to PEG, cal-PEG is a newer asparaginase enzyme formulation in the algorithm). A phase 2/3 study457 supports a new intramuscular (IM)
with a different linker molecule that enhances its hydrolytic stability. 453 A dosing scheduling for ERW-rywn of 25 mg/m2 Monday/Wednesday, 50
multicenter, open-label, randomized study determined the mg/m2 Friday based on positive risk:benefit ratio.

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If the patient experiences grade 1 or grade 2 reactions including rash,

flushing, urticaria, and drug fever ≥38°C without bronchospasm,
hypotension, edema, or need for parenteral intervention, the asparaginase
that caused the reaction may be continued with consideration for
anti-allergy premedication (such as hydrocortisone, famotidine or
ranitidine, diphenhydramine or cetirizine, and acetaminophen). Measures
can be considered for preventing or limiting severity of infusion reactions
or hypersensitivity including slowing infusion to ≥2 hours, infusing normal
saline concurrently, and use of premedications. If anti-allergy medication is
used prior to PEG or ERW-rywn administration, TDM using commercially
available asparaginase activity assays is highly recommended, since
premedication may “mask” the systemic allergic reactions that can indicate
the development of neutralizing antibodies.464 However, if the patient
experiences anaphylaxis or other allergic reactions of grade 3 or 4 severity
(common terminology criteria for adverse events [CTCAE] 5.0470),
permanent discontinuation of the causative asparaginase is warranted.

Asparaginase can be associated with various toxicities, including

pancreatitis (ranging from asymptomatic cases with amylase or lipase
elevation, to symptomatic cases with vomiting or severe abdominal pain),
hepatotoxicity (eg, increased alanine or glutamine aminotransferase), and
coagulopathy (eg, thrombosis, hemorrhage). Detailed recommendations
for the management of asparaginase toxicity in AYA and adult patients
were published,456 and have been incorporated into the NCCN Guidelines
for ALL (see Supportive Care: Asparaginase Toxicity Management in the
algorithm).

Pain management should be used for patients with cancer, regardless of

disease stage. For discussion of the central principles of pain assessment
and management, see the NCCN Guidelines for Adult Cancer Pain.

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References 10. Gurgey A, Kara A, Tuncer M, et al. Acute lymphoblastic leukemia

associated with Klinefelter syndrome. Pediatr Hematol Oncol
1. Jabbour EJ, Faderl S, Kantarjian HM. Adult acute lymphoblastic 1994;11:227-229. Available at:
leukemia. Mayo Clin Proc 2005;80:1517-1527. Available at: [Link]
[Link]
11. Machatschek JN, Schrauder A, Helm F, et al. Acute lymphoblastic
2. Howlader N NA, Krapcho M, Miller D, et al. SEER Cancer Statistics leukemia and Klinefelter syndrome in children: two cases and review of
Review 1975-2018. National Cancer Institute 2021. Available at: the literature. Pediatr Hematol Oncol 2004;21:621-626. Available at:
[Link] [Link]
3. Siegel RL, Giaquinto AN, Jemal A. Cancer statistics, 2024. CA Cancer 12. Flatt T, Neville K, Lewing K, Dalal J. Successful treatment of fanconi
J Clin 2024;74:12-49. Available at: anemia and T-cell acute lymphoblastic leukemia. Case Rep Hematol
[Link] 2012;2012:396395. Available at:
[Link]
4. Esparza SD, Sakamoto KM. Topics in pediatric leukemia--acute
lymphoblastic leukemia. MedGenMed 2005;7:23. Available at: 13. Yetgin S, Tuncer M, Guler E, et al. Acute lymphoblastic leukemia in
[Link] Fanconi's anemia. Am J Hematol 1994;45:94. Available at:
[Link]
5. Hasle H. Pattern of malignant disorders in individuals with Down's
syndrome. Lancet Oncol 2001;2:429-436. Available at: 14. Strevens MJ, Lilleyman JS, Williams RB. Shwachman's syndrome
[Link] and acute lymphoblastic leukaemia. Br Med J 1978;2:18. Available at:
[Link]
6. Whitlock JA. Down syndrome and acute lymphoblastic leukaemia. Br J
Haematol 2006;135:595-602. Available at: 15. Woods WG, Roloff JS, Lukens JN, Krivit W. The occurrence of
[Link] leukemia in patients with the Shwachman syndrome. J Pediatr
1981;99:425-428. Available at:
7. Swaminathan M, Bannon SA, Routbort M, et al. Hematologic
[Link]
malignancies and Li-Fraumeni syndrome. Cold Spring Harb Mol Case
Stud 2019;5. Available at: [Link] 16. Passarge E. Bloom's syndrome: the German experience. Ann Genet
1991;34:179-197. Available at:
8. Stiller CA, Chessells JM, Fitchett M. Neurofibromatosis and childhood
[Link]
leukaemia/lymphoma: a population-based UKCCSG study. Br J Cancer
1994;70:969-972. Available at: 17. Taylor AM, Metcalfe JA, Thick J, Mak YF. Leukemia and lymphoma
[Link] in ataxia telangiectasia. Blood 1996;87:423-438. Available at:
[Link]
9. Shaw MP, Eden OB, Grace E, Ellis PM. Acute lymphoblastic leukemia
and Klinefelter's syndrome. Pediatr Hematol Oncol 1992;9:81-85. 18. Ma H, Sun H, Sun X. Survival improvement by decade of patients
Available at: [Link] aged 0-14 years with acute lymphoblastic leukemia: a SEER analysis.

MS-66
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Acute Lymphoblastic Leukemia

Sci Rep 2014;4:4227. Available at: 26. Tasian SK, Loh ML, Hunger SP. Philadelphia chromosome-like acute
[Link] lymphoblastic leukemia. Blood 2017;130:2064-2072. Available at:
[Link]
19. Pulte D, Gondos A, Brenner H. Improvement in survival in younger
patients with acute lymphoblastic leukemia from the 1980s to the early 27. PubMed Overview. Available at:
21st century. Blood 2009;113:1408-1411. Available at: [Link] Accessed February 7, 2023.
[Link]
28. Faderl S, O'Brien S, Pui CH, et al. Adult acute lymphoblastic
20. Kantarjian H, Thomas D, O'Brien S, et al. Long-term follow-up results leukemia: concepts and strategies. Cancer 2010;116:1165-1176.
of hyperfractionated cyclophosphamide, vincristine, doxorubicin, and Available at: [Link]
dexamethasone (Hyper-CVAD), a dose-intensive regimen, in adult acute
lymphocytic leukemia. Cancer 2004;101:2788-2801. Available at: 29. Amin HM, Yang Y, Shen Y, et al. Having a higher blast percentage in
[Link] circulation than bone marrow: clinical implications in myelodysplastic
syndrome and acute lymphoid and myeloid leukemias. Leukemia
21. Pulte D, Jansen L, Gondos A, et al. Survival of adults with acute 2005;19:1567-1572. Available at:
lymphoblastic leukemia in Germany and the United States. PLoS One [Link]
2014;9:e85554. Available at:
[Link] 30. Weinkauff R, Estey EH, Starostik P, et al. Use of peripheral blood
blasts vs bone marrow blasts for diagnosis of acute leukemia. Am J Clin
22. Sive JI, Buck G, Fielding A, et al. Outcomes in older adults with acute Pathol 1999;111:733-740. Available at:
lymphoblastic leukaemia (ALL): results from the international MRC [Link]
UKALL XII/ECOG2993 trial. Br J Haematol 2012;157:463-471. Available
at: [Link] 31. Alaggio R, Amador C, Anagnostopoulos I, et al. The 5th edition of the
World Health Organization Classification of Haematolymphoid Tumours:
23. Geyer MB, Hsu M, Devlin SM, et al. Overall survival among older US Lymphoid Neoplasms. Leukemia 2022;36:1720-1748. Available at:
adults with ALL remains low despite modest improvement since 1980: [Link]
SEER analysis. Blood 2017;129:1878-1881. Available at:
[Link] 32. Arber DA, Orazi A, Hasserjian R, et al. The 2016 revision to the
World Health Organization classification of myeloid neoplasms and acute
24. Wermann WK, Viardot A, Kayser S, et al. Comorbidities are frequent leukemia. Blood 2016;127:2391-2405. Available at:
in older patients with de novo acute lymphoblastic leukemia (ALL) and [Link]
correlate with induction mortality: Analysis of more than 1200 patients
from GMALL data bases. Blood 2018;132:660. Available at: 33. Den Boer ML, van Slegtenhorst M, De Menezes RX, et al. A subtype
[Link] of childhood acute lymphoblastic leukaemia with poor treatment
outcome: a genome-wide classification study. Lancet Oncol
25. Stock W. Adolescents and young adults with acute lymphoblastic 2009;10:125-134. Available at:
leukemia. Hematology Am Soc Hematol Educ Program [Link]
2010;2010:21-29. Available at:
[Link]
MS-67
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Acute Lymphoblastic Leukemia

34. Roberts KG, Gu Z, Payne-Turner D, et al. High frequency and poor lymphoblastic leukemia. Blood 2009;113:6330-6337. Available at:
outcome of Philadelphia chromosome-like acute lymphoblastic leukemia [Link]
in adults. J Clin Oncol 2017;35:394-401. Available at:
[Link] 43. Gokbuget N, Hoelzer D. Treatment of adult acute lymphoblastic
leukemia. Hematology Am Soc Hematol Educ Program 2006:133-141.
35. Harrison CJ, Moorman AV, Schwab C, et al. An international study of Available at: [Link]
intrachromosomal amplification of chromosome 21 (iAMP21): cytogenetic
characterization and outcome. Leukemia 2014;28:1015-1021. Available 44. Coustan-Smith E, Mullighan CG, Onciu M, et al. Early T-cell
at: [Link] precursor leukaemia: a subtype of very high-risk acute lymphoblastic
leukaemia. Lancet Oncol 2009;10:147-156. Available at:
36. Bassan R, Hoelzer D. Modern therapy of acute lymphoblastic [Link]
leukemia. J Clin Oncol 2011;29:532-543. Available at:
[Link] 45. Zhang J, Ding L, Holmfeldt L, et al. The genetic basis of early T-cell
precursor acute lymphoblastic leukaemia. Nature 2012;481:157-163.
37. Pui CH, Relling MV, Downing JR. Acute lymphoblastic leukemia. N Available at: [Link]
Engl J Med 2004;350:1535-1548. Available at:
[Link] 46. Schrauder A, Reiter A, Gadner H, et al. Superiority of allogeneic
hematopoietic stem-cell transplantation compared with chemotherapy
38. Bassan R, Gatta G, Tondini C, Willemze R. Adult acute alone in high-risk childhood T-cell acute lymphoblastic leukemia: results
lymphoblastic leukaemia. Crit Rev Oncol Hematol 2004;50:223-261. from ALL-BFM 90 and 95. J Clin Oncol 2006;24:5742-5749. Available at:
Available at: [Link] [Link]

39. Burmeister T, Meyer C, Schwartz S, et al. The MLL recombinome of 47. Khoury JD, Solary E, Abla O, et al. The 5th edition of the World
adult CD10-negative B-cell precursor acute lymphoblastic leukemia: Health Organization classification of haematolymphoid tumours: myeloid
results from the GMALL study group. Blood 2009;113:4011-4015. and histiocytic/dendritic neoplasms. Leukemia 2022;36:1703-1719.
Available at: [Link] Available at: [Link]

40. Gleissner B, Goekbuget N, Rieder H, et al. CD10- pre-B acute 48. Armstrong SA, Look AT. Molecular genetics of acute lymphoblastic
lymphoblastic leukemia (ALL) is a distinct high-risk subgroup of adult leukemia. J Clin Oncol 2005;23:6306-6315. Available at:
ALL associated with a high frequency of MLL aberrations: results of the [Link]
German Multicenter Trials for Adult ALL (GMALL). Blood
2005;106:4054-4056. Available at: 49. Moorman AV, Chilton L, Wilkinson J, et al. A population-based
[Link] cytogenetic study of adults with acute lymphoblastic leukemia. Blood
2010;115:206-214. Available at:
41. Borowitz MJ, Chan JKC. WHO Classification of Tumours of [Link]
Haematopoietic and Lymphoid Tissues (ed 4th). Lyon: IARC; 2008.
50. Seibel NL. Treatment of acute lymphoblastic leukemia in children and
42. Thomas DA, O'Brien S, Jorgensen JL, et al. Prognostic significance adolescents: peaks and pitfalls. Hematology Am Soc Hematol Educ
of CD20 expression in adults with de novo precursor B-lineage acute

MS-68
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NCCN Guidelines Version 2.2024

Acute Lymphoblastic Leukemia

Program 2008:374-380. Available at: 58. Roberts KG, Morin RD, Zhang J, et al. Genetic alterations activating
[Link] kinase and cytokine receptor signaling in high-risk acute lymphoblastic
leukemia. Cancer Cell 2012;22:153-166. Available at:
51. Paietta E, Roberts KG, Wang V, et al. Molecular classification [Link]
improves risk assessment in adult BCR-ABL1-negative B-ALL. Blood
2021;138:948-958. Available at: 59. Jain N, Roberts KG, Jabbour E, et al. Ph-like acute lymphoblastic
[Link] leukemia: a high-risk subtype in adults. Blood 2017;129:572-581.
Available at: [Link]
52. Burmeister T, Schwartz S, Bartram CR, et al. Patients' age and
BCR-ABL frequency in adult B-precursor ALL: a retrospective analysis 60. Roberts KG, Yang YL, Payne-Turner D, et al. Oncogenic role and
from the GMALL study group. Blood 2008;112:918-919. Available at: therapeutic targeting of ABL-class and JAK-STAT activating kinase
[Link] alterations in Ph-like ALL. Blood Adv 2017;1:1657-1671. Available at:
[Link]
53. Gleissner B, Gokbuget N, Bartram CR, et al. Leading prognostic
relevance of the BCR-ABL translocation in adult acute B-lineage 61. Heerema NA, Carroll AJ, Devidas M, et al. Intrachromosomal
lymphoblastic leukemia: a prospective study of the German Multicenter amplification of chromosome 21 is associated with inferior outcomes in
Trial Group and confirmed polymerase chain reaction analysis. Blood children with acute lymphoblastic leukemia treated in contemporary
2002;99:1536-1543. Available at: standard-risk children's oncology group studies: a report from the
[Link] children's oncology group. J Clin Oncol 2013;31:3397-3402. Available at:
[Link]
54. Pui C-H, Evans WE. Treatment of acute lymphoblastic leukemia. N
Engl J Med 2006;354:166-178. Available at: 62. Moorman AV, Robinson H, Schwab C, et al. Risk-directed treatment
[Link] intensification significantly reduces the risk of relapse among children
and adolescents with acute lymphoblastic leukemia and
55. Arico M, Valsecchi MG, Camitta B, et al. Outcome of treatment in intrachromosomal amplification of chromosome 21: a comparison of the
children with Philadelphia chromosome-positive acute lymphoblastic MRC ALL97/99 and UKALL2003 trials. J Clin Oncol 2013;31:3389-3396.
leukemia. N Engl J Med 2000;342:998-1006. Available at: Available at: [Link]
[Link]
63. Moorman AV, Richards SM, Robinson HM, et al. Prognosis of
56. Mullighan CG, Su X, Zhang J, et al. Deletion of IKZF1 and prognosis children with acute lymphoblastic leukemia (ALL) and intrachromosomal
in acute lymphoblastic leukemia. N Engl J Med 2009;360:470-480. amplification of chromosome 21 (iAMP21). Blood 2007;109:2327-2330.
Available at: [Link] Available at: [Link]

57. Roberts KG, Li Y, Payne-Turner D, et al. Targetable kinase-activating 64. Schultz KR, Pullen DJ, Sather HN, et al. Risk- and response-based
lesions in Ph-like acute lymphoblastic leukemia. N Engl J Med classification of childhood B-precursor acute lymphoblastic leukemia: a
2014;371:1005-1015. Available at: combined analysis of prognostic markers from the Pediatric Oncology
[Link] Group (POG) and Children's Cancer Group (CCG). Blood
2007;109:926-935. Available at:
[Link]
MS-69
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NCCN Guidelines Version 2.2024

Acute Lymphoblastic Leukemia

65. Holmfeldt L, Wei L, Diaz-Flores E, et al. The genomic landscape of 2018;36:1240-1249. Available at:
hypodiploid acute lymphoblastic leukemia. Nat Genet 2013;45:242-252. [Link]
Available at: [Link]
73. Beldjord K, Chevret S, Asnafi V, et al. Oncogenetics and minimal
66. Muhlbacher V, Zenger M, Schnittger S, et al. Acute lymphoblastic residual disease are independent outcome predictors in adult patients
leukemia with low hypodiploid/near triploid karyotype is a specific clinical with acute lymphoblastic leukemia. Blood 2014;123:3739-3749. Available
entity and exhibits a very high TP53 mutation frequency of 93%. Genes at: [Link]
Chromosomes Cancer 2014;53:524-536. Available at:
[Link] 74. Dupuis A, Gaub MP, Legrain M, et al. Biclonal and biallelic deletions
occur in 20% of B-ALL cases with IKZF1 mutations. Leukemia
67. Comeaux EQ, Mullighan CG. TP53 mutations in hypodiploid acute 2013;27:503-507. Available at:
lymphoblastic leukemia. Cold Spring Harb Perspect Med 2017;7. [Link]
Available at: [Link]
75. Mi JQ, Wang X, Yao Y, et al. Newly diagnosed acute lymphoblastic
68. Carroll AJ, Shago M, Mikhail FM, et al. Masked hypodiploidy: leukemia in China (II): prognosis related to genetic abnormalities in a
Hypodiploid acute lymphoblastic leukemia (ALL) mimicking hyperdiploid series of 1091 cases. Leukemia 2012;26:1507-1516. Available at:
ALL in children: A report from the Children's Oncology Group. Cancer [Link]
Genet 2019;238:62-68. Available at:
[Link] 76. Ribera J, Morgades M, Zamora L, et al. Prognostic significance of
copy number alterations in adolescent and adult patients with precursor
69. Boer JM, van der Veer A, Rizopoulos D, et al. Prognostic value of B acute lymphoblastic leukemia enrolled in PETHEMA protocols. Cancer
rare IKZF1 deletion in childhood B-cell precursor acute lymphoblastic 2015;121:3809-3817. Available at:
leukemia: an international collaborative study. Leukemia 2016;30:32-38. [Link]
Available at: [Link]
77. Martinelli G, Iacobucci I, Storlazzi CT, et al. IKZF1 (Ikaros) deletions
70. Mullighan CG, Miller CB, Radtke I, et al. BCR-ABL1 lymphoblastic in BCR-ABL1-positive acute lymphoblastic leukemia are associated with
leukaemia is characterized by the deletion of Ikaros. Nature short disease-free survival and high rate of cumulative incidence of
2008;453:110-114. Available at: relapse: a GIMEMA AL WP report. J Clin Oncol 2009;27:5202-5207.
[Link] Available at: [Link]

71. Caye A, Beldjord K, Mass-Malo K, et al. Breakpoint-specific multiplex 78. Iacobucci I, Storlazzi CT, Cilloni D, et al. Identification and molecular
polymerase chain reaction allows the detection of IKZF1 intragenic characterization of recurrent genomic deletions on 7p12 in the IKZF1
deletions and minimal residual disease monitoring in B-cell precursor gene in a large cohort of BCR-ABL1-positive acute lymphoblastic
acute lymphoblastic leukemia. Haematologica 2013;98:597-601. leukemia patients: on behalf of Gruppo Italiano Malattie Ematologiche
Available at: [Link] dell'Adulto Acute Leukemia Working Party (GIMEMA AL WP). Blood
2009;114:2159-2167. Available at:
72. Stanulla M, Dagdan E, Zaliova M, et al. IKZF1(plus) Defines a New [Link]
Minimal Residual Disease-Dependent Very-Poor Prognostic Profile in
Pediatric B-Cell Precursor Acute Lymphoblastic Leukemia. J Clin Oncol
MS-70
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NCCN Guidelines Version 2.2024

Acute Lymphoblastic Leukemia

79. van der Veer A, Waanders E, Pieters R, et al. Independent Blood 2017;129:3352-3361. Available at:
prognostic value of BCR-ABL1-like signature and IKZF1 deletion, but not [Link]
high CRLF2 expression, in children with B-cell precursor ALL. Blood
2013;122:2622-2629. Available at: 87. Behm FG, Raimondi SC, Frestedt JL, et al. Rearrangement of the
[Link] MLL gene confers a poor prognosis in childhood acute lymphoblastic
leukemia, regardless of presenting age. Blood 1996;87:2870-2877.
80. Mangum DS, Meyer JA, Mason CC, et al. Association of combined Available at: [Link]
focal 22q11.22 deletion and IKZF1 alterations with outcomes in
childhood acute lymphoblastic leukemia. JAMA Oncol 2021;7:1521-1528. 88. Pui CH, Chessells JM, Camitta B, et al. Clinical heterogeneity in
Available at: [Link] childhood acute lymphoblastic leukemia with 11q23 rearrangements.
Leukemia 2003;17:700-706. Available at:
81. Arber DA, Orazi A, Hasserjian RP, et al. International Consensus [Link]
Classification of myeloid neoplasms and acute leukemias: integrating
morphologic, clinical, and genomic data. Blood 2022;140:1200-1228. 89. Donadieu J, Auclerc MF, Baruchel A, et al. Prognostic study of
Available at: [Link] continuous variables (white blood cell count, peripheral blast cell count,
haemoglobin level, platelet count and age) in childhood acute
82. Smith M, Arthur D, Camitta B, et al. Uniform approach to risk lymphoblastic leukaemia. Analysis Of a population of 1545 children
classification and treatment assignment for children with acute treated by the French Acute Lymphoblastic Leukaemia Group (FRALLE).
lymphoblastic leukemia. J Clin Oncol 1996;14:18-24. Available at: Br J Cancer 2000;83:1617-1622. Available at:
[Link] [Link]

83. Brown P, Pieters R, Biondi A. How I treat infant leukemia. Blood 90. Romana SP, Mauchauffe M, Le Coniat M, et al. The t(12;21) of acute
2019;133:205-214. Available at: lymphoblastic leukemia results in a tel-AML1 gene fusion. Blood
[Link] 1995;85:3662-3670. Available at:
[Link]
84. Hunger SP, Loh ML, Whitlock JA, et al. Children's Oncology Group's
2013 blueprint for research: acute lymphoblastic leukemia. Pediatr Blood 91. Sutcliffe MJ, Shuster JJ, Sather HN, et al. High concordance from
Cancer 2013;60:957-963. Available at: independent studies by the Children's Cancer Group (CCG) and
[Link] Pediatric Oncology Group (POG) associating favorable prognosis with
combined trisomies 4, 10, and 17 in children with NCI Standard-Risk
85. Gadner H, Masera G, Schrappe M, et al. The Eighth International B-precursor Acute Lymphoblastic Leukemia: a Children's Oncology
Childhood Acute Lymphoblastic Leukemia Workshop ('Ponte di legno Group (COG) initiative. Leukemia 2005;19:734-740. Available at:
meeting') report: Vienna, Austria, April 27-28, 2005. Leukemia [Link]
2006;20:9-17. Available at:
[Link] 92. Boissel N, Auclerc M-F, Lheritier V, et al. Should adolescents with
acute lymphoblastic leukemia be treated as old children or young adults?
86. Reshmi SC, Harvey RC, Roberts KG, et al. Targetable kinase gene Comparison of the French FRALLE-93 and LALA-94 trials. J Clin Oncol
fusions in high-risk B-ALL: a study from the Children's Oncology Group. 2003;21:774-780. Available at:
[Link]
MS-71
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NCCN Guidelines Version 2.2024

Acute Lymphoblastic Leukemia

93. Ramanujachar R, Richards S, Hann I, et al. Adolescents with acute 99. Nachman J. Clinical characteristics, biologic features and outcome
lymphoblastic leukaemia: outcome on UK national paediatric (ALL97) for young adult patients with acute lymphoblastic leukaemia. Br J
and adult (UKALLXII/E2993) trials. Pediatr Blood Cancer Haematol 2005;130:166-173. Available at:
2007;48:254-261. Available at: [Link]
[Link]
100. Aguiar RC, Sohal J, van Rhee F, et al. TEL-AML1 fusion in acute
94. Zhang MJ, Hoelzer D, Horowitz MM, et al. Long-term follow-up of lymphoblastic leukaemia of adults. M.R.C. Adult Leukaemia Working
adults with acute lymphoblastic leukemia in first remission treated with Party. Br J Haematol 1996;95:673-677. Available at:
chemotherapy or bone marrow transplantation. The Acute Lymphoblastic [Link]
Leukemia Working Committee. Ann Intern Med 1995;123:428-431.
Available at: [Link] 101. Secker-Walker LM, Craig JM, Hawkins JM, Hoffbrand AV.
Philadelphia positive acute lymphoblastic leukemia in adults: age
95. Thomas X, Boiron JM, Huguet F, et al. Outcome of treatment in distribution, BCR breakpoint and prognostic significance. Leukemia
adults with acute lymphoblastic leukemia: analysis of the LALA-94 trial. J 1991;5:196-199. Available at:
Clin Oncol 2004;22:4075-4086. Available at: [Link]
[Link]
102. Neumann M, Heesch S, Gokbuget N, et al. Clinical and molecular
96. Goldstone AH, Richards SM, Lazarus HM, et al. In adults with characterization of early T-cell precursor leukemia: a high-risk subgroup
standard-risk acute lymphoblastic leukemia, the greatest benefit is in adult T-ALL with a high frequency of FLT3 mutations. Blood Cancer J
achieved from a matched sibling allogeneic transplantation in first 2012;2:e55. Available at:
complete remission, and an autologous transplantation is less effective [Link]
than conventional consolidation/maintenance chemotherapy in all
patients: final results of the International ALL Trial (MRC UKALL 103. Pieters R, Kaspers GJ, Klumper E, Veerman AJ. Clinical relevance
XII/ECOG E2993). Blood 2008;111:1827-1833. Available at: of in vitro drug resistance testing in childhood acute lymphoblastic
[Link] leukemia: the state of the art. Med Pediatr Oncol 1994;22:299-308.
Available at: [Link]
97. Vey N, Thomas X, Picard C, et al. Allogeneic stem cell
transplantation improves the outcome of adults with t(1;19)/E2A-PBX1 104. Raetz EA, Devidas M, Carroll AJ, et al. Cytogenetic and
and t(4;11)/MLL-AF4 positive B-cell acute lymphoblastic leukemia: early-response characteristics of adolescents and young adults with
results of the prospective multicenter LALA-94 study. Leukemia acute lymphoblastic leukemia (ALL): A Children's Oncology Group
2006;20:2155-2161. Available at: (COG) study [abstract]. J Clin Oncol 2010;28:Abstract 9509. Available at:
[Link] [Link]

98. Thiebaut A, Vernant JP, Degos L, et al. Adult acute lymphocytic 105. Bleyer A, Budd T, Montello M. Adolescents and young adults with
leukemia study testing chemotherapy and autologous and allogeneic cancer: the scope of the problem and criticality of clinical trials. Cancer
transplantation. A follow-up report of the French protocol LALA 87. 2006;107:1645-1655. Available at:
Hematol Oncol Clin North Am 2000;14:1353-1366, x. Available at: [Link]
[Link]

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NCCN Guidelines Version 2.2024

Acute Lymphoblastic Leukemia

106. Fern LA, Whelan JS. Recruitment of adolescents and young adults 113. Charrin C, Thomas X, Ffrench M, et al. A report from the LALA-94
to cancer clinical trials--international comparisons, barriers, and and LALA-SA groups on hypodiploidy with 30 to 39 chromosomes and
implications. Semin Oncol 2010;37:e1-8. Available at: near-triploidy: 2 possible expressions of a sole entity conferring poor
[Link] prognosis in adult acute lymphoblastic leukemia (ALL). Blood
2004;104:2444-2451. Available at:
107. Schmiegelow K, Heyman M, Gustafsson G, et al. The degree of [Link]
myelosuppression during maintenance therapy of adolescents with
B-lineage intermediate risk acute lymphoblastic leukemia predicts risk of 114. Pullarkat V, Slovak ML, Kopecky KJ, et al. Impact of cytogenetics
relapse. Leukemia 2010;24:715-720. Available at: on the outcome of adult acute lymphoblastic leukemia: results of
[Link] Southwest Oncology Group 9400 study. Blood 2008;111:2563-2572.
Available at: [Link]
108. Martin S, Ulrich C, Munsell M, et al. Delays in cancer diagnosis in
underinsured young adults and older adolescents. Oncologist 115. Trinquand A, Tanguy-Schmidt A, Ben Abdelali R, et al. Toward a
2007;12:816-824. Available at: NOTCH1/FBXW7/RAS/PTEN-based oncogenetic risk classification of
[Link] adult T-cell acute lymphoblastic leukemia: a Group for Research in Adult
Acute Lymphoblastic Leukemia study. J Clin Oncol 2013;31:4333-4342.
109. Hoelzer D, Thiel E, Loffler H, et al. Intensified therapy in acute Available at: [Link]
lymphoblastic and acute undifferentiated leukemia in adults. Blood
1984;64:38-47. Available at: 116. Kamps WA, Bokkerink JP, Hakvoort-Cammel FG, et al.
[Link] BFM-oriented treatment for children with acute lymphoblastic leukemia
without cranial irradiation and treatment reduction for standard risk
110. Hoelzer D, Thiel E, Loffler H, et al. Prognostic factors in a patients: results of DCLSG protocol ALL-8 (1991-1996). Leukemia
multicenter study for treatment of acute lymphoblastic leukemia in adults. 2002;16:1099-1111. Available at:
Blood 1988;71:123-131. Available at: [Link]
[Link]
117. Moricke A, Reiter A, Zimmermann M, et al. Risk-adjusted therapy of
111. Rowe JM, Buck G, Burnett AK, et al. Induction therapy for adults acute lymphoblastic leukemia can decrease treatment burden and
with acute lymphoblastic leukemia: results of more than 1500 patients improve survival: treatment results of 2169 unselected pediatric and
from the international ALL trial: MRC UKALL XII/ECOG E2993. Blood adolescent patients enrolled in the trial ALL-BFM 95. Blood
2005;106:3760-3767. Available at: 2008;111:4477-4489. Available at:
[Link] [Link]
112. Moorman AV, Harrison CJ, Buck GAN, et al. Karyotype is an 118. Schrappe M, Reiter A, Ludwig WD, et al. Improved outcome in
independent prognostic factor in adult acute lymphoblastic leukemia childhood acute lymphoblastic leukemia despite reduced use of
(ALL): analysis of cytogenetic data from patients treated on the Medical anthracyclines and cranial radiotherapy: results of trial ALL-BFM 90.
Research Council (MRC) UKALLXII/Eastern Cooperative Oncology German-Austrian-Swiss ALL-BFM Study Group. Blood
Group (ECOG) 2993 trial. Blood 2007;109:3189-3197. Available at: 2000;95:3310-3322. Available at:
[Link] [Link]

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Acute Lymphoblastic Leukemia

119. Seibel NL, Steinherz PG, Sather HN, et al. Early postinduction 2011;25:1232-1238. Available at:
intensification therapy improves survival for children and adolescents [Link]
with high-risk acute lymphoblastic leukemia: a report from the Children's
Oncology Group. Blood 2008;111:2548-2555. Available at: 126. Kantarjian HM, O'Brien S, Smith TL, et al. Results of treatment with
[Link] hyper-CVAD, a dose-intensive regimen, in adult acute lymphocytic
leukemia. J Clin Oncol 2000;18:547-561. Available at:
120. Stock W, La M, Sanford B, et al. What determines the outcomes for [Link]
adolescents and young adults with acute lymphoblastic leukemia treated
on cooperative group protocols? A comparison of Children's Cancer 127. Koller CA, Kantarjian HM, Thomas D, et al. The hyper-CVAD
Group and Cancer and Leukemia Group B studies. Blood regimen improves outcome in relapsed acute lymphoblastic leukemia.
2008;112:1646-1654. Available at: Leukemia 1997;11:2039-2044. Available at:
[Link] [Link]

121. Larson RA, Dodge RK, Burns CP, et al. A five-drug remission 128. Hoelzer D, Ludwig WD, Thiel E, et al. Improved outcome in adult
induction regimen with intensive consolidation for adults with acute B-cell acute lymphoblastic leukemia. Blood 1996;87:495-508. Available
lymphoblastic leukemia: cancer and leukemia group B study 8811. Blood at: [Link]
1995;85:2025-2037. Available at:
[Link] 129. Chrzanowska M, Kolecki P, Duczmal-Cichocka B, Fiet J.
Metabolites of mercaptopurine in red blood cells: a relationship between
122. Bostrom BC, Sensel MR, Sather HN, et al. Dexamethasone versus 6-thioguanine nucleotides and 6-methylmercaptopurine metabolite
prednisone and daily oral versus weekly intravenous mercaptopurine for concentrations in children with lymphoblastic leukemia. Eur J Pharm Sci
patients with standard-risk acute lymphoblastic leukemia: a report from 1999;8:329-334. Available at:
the Children's Cancer Group. Blood 2003;101:3809-3817. Available at: [Link]
[Link]
130. Lennard L, Lilleyman JS. Variable mercaptopurine metabolism and
123. Mitchell CD, Richards SM, Kinsey SE, et al. Benefit of treatment outcome in childhood lymphoblastic leukemia. J Clin Oncol
dexamethasone compared with prednisolone for childhood acute 1989;7:1816-1823. Available at:
lymphoblastic leukaemia: results of the UK Medical Research Council [Link]
ALL97 randomized trial. Br J Haematol 2005;129:734-745. Available at:
[Link] 131. McLeod HL, Relling MV, Crom WR, et al. Disposition of
antineoplastic agents in the very young child. Br J Cancer Suppl
124. Pui CH. Central nervous system disease in acute lymphoblastic 1992;18:S23-29. Available at:
leukemia: prophylaxis and treatment. Hematology Am Soc Hematol Educ [Link]
Program 2006:142-146. Available at:
[Link] 132. Hawwa AF, Collier PS, Millership JS, et al. Population
pharmacokinetic and pharmacogenetic analysis of 6-mercaptopurine in
125. Teuffel O, Kuster SP, Hunger SP, et al. Dexamethasone versus paediatric patients with acute lymphoblastic leukaemia. Br J Clin
prednisone for induction therapy in childhood acute lymphoblastic Pharmacol 2008;66:826-837. Available at:
leukemia: a systematic review and meta-analysis. Leukemia [Link]
MS-74
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Acute Lymphoblastic Leukemia

133. McLeod HL, Coulthard S, Thomas AE, et al. Analysis of thiopurine 141. Lennard L, Gibson BE, Nicole T, Lilleyman JS. Congenital
methyltransferase variant alleles in childhood acute lymphoblastic thiopurine methyltransferase deficiency and 6-mercaptopurine toxicity
leukaemia. Br J Haematol 1999;105:696-700. Available at: during treatment for acute lymphoblastic leukaemia. Arch Dis Child
[Link] 1993;69:577-579. Available at:
[Link]
134. Bhatia S, Landier W, Shangguan M, et al. Nonadherence to oral
mercaptopurine and risk of relapse in Hispanic and non-Hispanic white 142. McLeod HL, Lin JS, Scott EP, et al. Thiopurine methyltransferase
children with acute lymphoblastic leukemia: a report from the children's activity in American white subjects and black subjects. Clin Pharmacol
oncology group. J Clin Oncol 2012;30:2094-2101. Available at: Ther 1994;55:15-20. Available at:
[Link] [Link]

135. Grant DM, Tang BK, Kalow W. Variability in caffeine metabolism. 143. Collie-Duguid ES, Pritchard SC, Powrie RH, et al. The frequency
Clin Pharmacol Ther 1983;33:591-602. Available at: and distribution of thiopurine methyltransferase alleles in Caucasian and
[Link] Asian populations. Pharmacogenetics 1999;9:37-42. Available at:
[Link]
136. Grant DM, Tang BK, Campbell ME, Kalow W. Effect of allopurinol
on caffeine disposition in man. Br J Clin Pharmacol 1986;21:454-458. 144. Lennard L, Lilleyman JS. Individualizing therapy with
Available at: [Link] 6-mercaptopurine and 6-thioguanine related to the thiopurine
methyltransferase genetic polymorphism. Ther Drug Monit
137. Burton NK, Barnett MJ, Aherne GW, et al. The effect of food on the 1996;18:328-334. Available at:
oral administration of 6-mercaptopurine. Cancer Chemother Pharmacol [Link]
1986;18:90-91. Available at:
[Link] 145. Relling MV, Hancock ML, Rivera GK, et al. Mercaptopurine therapy
intolerance and heterozygosity at the thiopurine S-methyltransferase
138. Riccardi R, Balis FM, Ferrara P, et al. Influence of food intake on gene locus. J Natl Cancer Inst 1999;91:2001-2008. Available at:
bioavailability of oral 6-mercaptopurine in children with acute [Link]
lymphoblastic leukemia. Pediatr Hematol Oncol 1986;3:319-324.
Available at: [Link] 146. Relling MV, Gardner EE, Sandborn WJ, et al. Clinical
pharmacogenetics implementation consortium guidelines for thiopurine
139. Weinshilboum RM, Sladek SL. Mercaptopurine pharmacogenetics: methyltransferase genotype and thiopurine dosing: 2013 update. Clin
monogenic inheritance of erythrocyte thiopurine methyltransferase Pharmacol Ther 2013;93:324-325. Available at:
activity. Am J Hum Genet 1980;32:651-662. Available at: [Link]
[Link]
147. Relling MV, Gardner EE, Sandborn WJ, et al. Clinical
140. Evans WE, Horner M, Chu YQ, et al. Altered mercaptopurine Pharmacogenetics Implementation Consortium guidelines for thiopurine
metabolism, toxic effects, and dosage requirement in a thiopurine methyltransferase genotype and thiopurine dosing. Clin Pharmacol Ther
methyltransferase-deficient child with acute lymphocytic leukemia. J 2011;89:387-391. Available at:
Pediatr 1991;119:985-989. Available at: [Link]
[Link]
MS-75
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Acute Lymphoblastic Leukemia

148. Relling MV, Schwab M, Whirl-Carrillo M, et al. Clinical 155. Ottmann OG, Larson RA, Kantarjian HM, et al. Nilotinib in patients
Pharmacogenetics Implementation Consortium Guideline for Thiopurine (pts) with relapsed/refractory Philadelphia chromosome-positive acute
Dosing Based on TPMT and NUDT15 Genotypes: 2018 Update. Clin lymphoblastic leukemia (Ph+ ALL) who are resistant or intolerant to
Pharmacol Ther 2019;105:1095-1105. Available at: imatinib [abstract]. Blood 2007;110:Abstract 2815. Available at:
[Link] [Link]
/2815.
149. U.S. Food and Drug Administration. Prescribing information.
PURIXAN (mercaptopurine) oral suspension. 2014. Available at: 156. Ottmann OG, Pfeifer H, Cayuela JM, et al. Nilotinib (Tasigna®) and
[Link] low intensity chemotherapy for first-line treatment of elderly patients with
[Link]. Accessed September 29, 2016. BCR-ABL1- positive acute lymphoblastic leukemia: Final results of a
prospective multicenter trial (EWALL-PH02). Blood 2018;132:31.
150. Hanff LM, Mathot RA, Smeets O, et al. A novel 6-mercaptopurine Available at: [Link]
oral liquid formulation for pediatric acute lymphoblastic leukemia
patients - results of a randomized clinical trial. Int J Clin Pharmacol Ther 157. Talpaz M, Shah NP, Kantarjian H, et al. Dasatinib in
2014;52:653-662. Available at: imatinib-resistant Philadelphia chromosome-positive leukemias. N Engl J
[Link] Med 2006;354:2531-2541. Available at:
[Link]
151. Chessells JM, Harrison G, Lilleyman JS, et al. Continuing
(maintenance) therapy in lymphoblastic leukaemia: lessons from MRC 158. Thomas DA, O'Brien S, Cortes J, et al. Outcome with the
UKALL X. Medical Research Council Working Party in Childhood hyper-CVAD regimens in lymphoblastic lymphoma. Blood
Leukaemia. Br J Haematol 1997;98:945-951. Available at: 2004;104:1624-1630. Available at:
[Link] [Link]

152. Foa R, Vitale A, Vignetti M, et al. Dasatinib as first-line treatment for 159. Thomas DA, O'Brien SM, Faderl S, et al. Long-term outcome after
adult patients with Philadelphia chromosome-positive acute hyper-CVAD and imatinib (IM) for de novo or minimally treated
lymphoblastic leukemia. Blood 2011;118:6521-6528. Available at: Philadelphia chromosome-positive acute lymphoblastic leukemia
[Link] (Ph-ALL). J Clin Oncol 2010;28:6506. Available at:
[Link]
153. Jabbour E, Kantarjian H, Ravandi F, et al. Combination of
hyper-CVAD with ponatinib as first-line therapy for patients with 160. Wassmann B, Gokbuget N, Scheuring UJ, et al. A randomized
Philadelphia chromosome-positive acute lymphoblastic leukaemia: a multicenter open label phase II study to determine the safety and efficacy
single-centre, phase 2 study. Lancet Oncol 2015;16:1547-1555. of induction therapy with imatinib (Glivec, formerly STI571) in
Available at: [Link] comparison with standard induction chemotherapy in elderly (>55 years)
patients with Philadelphia chromosome-positive (Ph+/BCR-ABL+) acute
154. Ottmann OG, Druker BJ, Sawyers CL, et al. A phase 2 study of lymphoblastic leukemia (ALL) (CSTI571ADE 10). Ann Hematol
imatinib in patients with relapsed or refractory Philadelphia 2003;82:716-720. Available at:
chromosome-positive acute lymphoid leukemias. Blood [Link]
2002;100:1965-1971. Available at:
[Link]
MS-76
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Acute Lymphoblastic Leukemia

161. Di Gion P, Kanefendt F, Lindauer A, et al. Clinical pharmacokinetics 168. Schultz KR, Bowman WP, Aledo A, et al. Improved early event-free
of tyrosine kinase inhibitors: focus on pyrimidines, pyridines and pyrroles. survival with imatinib in Philadelphia chromosome-positive acute
Clin Pharmacokinet 2011;50:551-603. Available at: lymphoblastic leukemia: a children's oncology group study. J Clin Oncol
[Link] 2009;27:5175-5181. Available at:
[Link]
162. Thomas DA, Faderl S, O'Brien S, et al. Chemoimmunotherapy with
hyper-CVAD plus rituximab for the treatment of adult Burkitt and 169. Schultz KR, Carroll A, Heerema NA, et al. Long-term follow-up of
Burkitt-type lymphoma or acute lymphoblastic leukemia. Cancer imatinib in pediatric Philadelphia chromosome-positive acute
2006;106:1569-1580. Available at: lymphoblastic leukemia: Children's Oncology Group study AALL0031.
[Link] Leukemia 2014;28:1467-1471. Available at:
[Link]
163. Thomas DA, O'Brien S, Faderl S, et al. Chemoimmunotherapy with
a modified hyper-CVAD and rituximab regimen improves outcome in de 170. Slayton WB, Schultz KR, Kairalla JA, et al. Dasatinib plus intensive
novo Philadelphia chromosome-negative precursor B-lineage acute chemotherapy in children, adolescents, and young adults with
lymphoblastic leukemia. J Clin Oncol 2010;28:3880-3889. Available at: Philadelphia chromosome-positive acute lymphoblastic leukemia:
[Link] Results of Children's Oncology Group Trial AALL0622. J Clin Oncol
2018;36:2306-2314. Available at:
164. Berg SL, Blaney SM, Devidas M, et al. Phase II study of nelarabine [Link]
(compound 506U78) in children and young adults with refractory T-cell
malignancies: a report from the Children's Oncology Group. J Clin Oncol 171. Biondi A, Schrappe M, De Lorenzo P, et al. Imatinib after induction
2005;23:3376-3382. Available at: for treatment of children and adolescents with
[Link] Philadelphia-chromosome-positive acute lymphoblastic leukaemia
(EsPhALL): a randomised, open-label, intergroup study. Lancet Oncol
165. Cohen MH, Johnson JR, Justice R, Pazdur R. FDA drug approval 2012;13:936-945. Available at:
summary: nelarabine (Arranon) for the treatment of T-cell lymphoblastic [Link]
leukemia/lymphoma. Oncologist 2008;13:709-714. Available at:
[Link] 172. Biondi A, Gandemer V, De Lorenzo P, et al. Imatinib treatment of
paediatric Philadelphia chromosome-positive acute lymphoblastic
166. DeAngelo DJ, Yu D, Johnson JL, et al. Nelarabine induces leukaemia (EsPhALL2010): a prospective, intergroup, open-label,
complete remissions in adults with relapsed or refractory T-lineage acute single-arm clinical trial. Lancet Haematol 2018;5:e641-e652. Available at:
lymphoblastic leukemia or lymphoblastic lymphoma: Cancer and [Link]
Leukemia Group B study 19801. Blood 2007;109:5136-5142. Available
at: [Link] 173. Hunger SP, Saha V, Devidas M, et al. CA180-372: An international
collaborative phase 2 trial of dasatinib and chemotherapy in pediatric
167. Arico M, Schrappe M, Hunger SP, et al. Clinical outcome of children patients with newly diagnosed Philadelphia chromosome positive acute
with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). Blood 2017;130:98. Available at:
lymphoblastic leukemia treated between 1995 and 2005. J Clin Oncol [Link]
2010;28:4755-4761. Available at:
[Link]
MS-77
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Acute Lymphoblastic Leukemia

174. Foà R, Bassan R, Vitale A, et al. Dasatinib-Blinatumomab for Blood 2010;116:2070-2077. Available at:
Ph-Positive Acute Lymphoblastic Leukemia in Adults. N Engl J Med [Link]
2020;383:1613-1623. Available at:
[Link] 181. Jabbour E, Short NJ, Ravandi F, et al. Combination of hyper-CVAD
with ponatinib as first-line therapy for patients with Philadelphia
175. Assi R, Kantarjian H, Short NJ, et al. Safety and Efficacy of chromosome-positive acute lymphoblastic leukaemia: long-term
Blinatumomab in Combination With a Tyrosine Kinase Inhibitor for the follow-up of a single-centre, phase 2 study. Lancet Haematol
Treatment of Relapsed Philadelphia Chromosome-positive Leukemia. 2018;5:e618-e627. Available at:
Clin Lymphoma Myeloma Leuk 2017;17:897-901. Available at: [Link]
[Link]
182. de Labarthe A, Rousselot P, Huguet-Rigal F, et al. Imatinib
176. Couturier MA, Thomas X, Raffoux E, et al. combined with induction or consolidation chemotherapy in patients with
Blinatumomab + ponatinib for relapsed/refractory Philadelphia de novo Philadelphia chromosome-positive acute lymphoblastic
chromosome-positive acute lymphoblastic leukemia in adults. Leuk leukemia: results of the GRAAPH-2003 study. Blood
Lymphoma 2021;62:620-629. Available at: 2007;109:1408-1413. Available at:
[Link] [Link]

177. King AC, Pappacena JJ, Tallman MS, et al. Blinatumomab 183. Tanguy-Schmidt A, Rousselot P, Chalandon Y, et al. Long-term
administered concurrently with oral tyrosine kinase inhibitor therapy is a follow-up of the imatinib GRAAPH-2003 study in newly diagnosed
well-tolerated consolidation strategy and eradicates measurable residual patients with de novo Philadelphia chromosome-positive acute
disease in adults with Philadelphia chromosome positive acute lymphoblastic leukemia: a GRAALL study. Biol Blood Marrow Transplant
lymphoblastic leukemia. Leuk Res 2019;79:27-33. Available at: 2013;19:150-155. Available at:
[Link] [Link]

178. Short N, Kantarjian HM, Konopleva M, et al. Combination of 184. Bassan R, Rossi G, Pogliani EM, et al. Chemotherapy-phased
ponatinib and blinatumomab in Philadelphia chromosome-positive acute imatinib pulses improve long-term outcome of adult patients with
lymphoblastic leukemia: Early results from a phase II study [Abstract]. J Philadelphia chromosome-positive acute lymphoblastic leukemia:
Clin Oncol 2021;39:7001. Available at: Northern Italy Leukemia Group protocol 09/00. J Clin Oncol
[Link] 2010;28:3644-3652. Available at:
[Link]
179. Jabbour E, Short NJ, Jain N, et al. Ponatinib and blinatumomab for
Philadelphia chromosome-positive acute lymphoblastic leukaemia: a US, 185. Mizuta S, Matsuo K, Yagasaki F, et al. Pre-transplant
single-centre, single-arm, phase 2 trial [abstract]. Lancet Haematol imatinib-based therapy improves the outcome of allogeneic
2023;10:e24-e34. Available at: hematopoietic stem cell transplantation for BCR-ABL-positive acute
[Link] lymphoblastic leukemia. Leukemia 2011;25:41-47. Available at:
[Link]
180. Ravandi F, O'Brien S, Thomas D, et al. First report of phase 2 study
of dasatinib with hyper-CVAD for the frontline treatment of patients with 186. Yanada M, Takeuchi J, Sugiura I, et al. High complete remission
Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia. rate and promising outcome by combination of imatinib and
MS-78
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NCCN Guidelines Version 2.2024

Acute Lymphoblastic Leukemia

chemotherapy for newly diagnosed BCR-ABL-positive acute imatinib mesylate. Blood 2004;103:4396-4407. Available at:
lymphoblastic leukemia: a phase II study by the Japan Adult Leukemia [Link]
Study Group. J Clin Oncol 2006;24:460-466. Available at:
[Link] 193. Cornelissen JJ, Carston M, Kollman C, et al. Unrelated marrow
transplantation for adult patients with poor-risk acute lymphoblastic
187. Kim DY, Joo YD, Lim SN, et al. Nilotinib combined with multiagent leukemia: strong graft-versus-leukemia effect and risk factors
chemotherapy for newly diagnosed Philadelphia-positive acute determining outcome. Blood 2001;97:1572-1577. Available at:
lymphoblastic leukemia. Blood 2015;126:746-756. Available at: [Link]
[Link]
194. Esperou H, Boiron JM, Cayuela JM, et al. A potential
188. Wieduwilt MJ, Yin J, Wetzler M, et al. A phase II study of dasatinib graft-versus-leukemia effect after allogeneic hematopoietic stem cell
and dexamethasone as primary therapy followed by transplantation for transplantation for patients with Philadelphia chromosome-positive acute
adults with newly diagnosed Ph/BCR-ABL1-positive acute lymphoblastic lymphoblastic leukemia: results from the French Bone Marrow
leukemia (Ph+ ALL): Final results of Alliance/CALGB Study 10701. Blood Transplantation Society. Bone Marrow Transplant 2003;31:909-918.
2018;132:309. Available at: Available at: [Link]
[Link]
195. Fielding AK, Rowe JM, Richards SM, et al. Prospective outcome
189. Jabbour E, Kantarjian HM, Aldoss I, et al. First report of data on 267 unselected adult patients with Philadelphia
PhALLCON: A phase 3 study comparing ponatinib (pon) vs imatinib (im) chromosome-positive acute lymphoblastic leukemia confirms superiority
in newly diagnosed patients with Philadelphia chromosome-positive of allogeneic transplantation over chemotherapy in the pre-imatinib era:
acute lymphoblastic leukemia (Ph+ALL) [abstract]. J Clin Oncol results from the International ALL Trial MRC UKALLXII/ECOG2993.
2023;41:398868-398868. Available at: Blood 2009;113:4489-4496. Available at:
[Link] [Link]

190. FDA grants accelerated approval to ponatinib with chemotherapy 196. Bachanova V, Marks DI, Zhang MJ, et al. Ph+ ALL patients in first
for newly diagnosed Philadelphia chromosome-positive acute complete remission have similar survival after reduced intensity and
lymphoblastic leukemia. Available at: myeloablative allogeneic transplantation: impact of tyrosine kinase
[Link] inhibitor and minimal residual disease. Leukemia 2014;28:658-665.
nts-accelerated-approval-ponatinib-chemotherapy-newly-diagnosed-phila Available at: [Link]
delphia-chromosome. Accessed March 28, 2024.
197. Cassaday RD, Alan Potts D, Jr., Stevenson PA, et al. Evaluation of
191. Jabbour E, Haddad FG, Short NJ, et al. Phase 2 study of allogeneic transplantation in first or later minimal residual
inotuzumab ozogamicin for measurable residual disease in acute disease - negative remission following adult-inspired therapy for acute
lymphoblastic leukemia in remission. Blood 2024;143:417-421. Available lymphoblastic leukemia. Leuk Lymphoma 2016;57:2109-2118. Available
at: [Link] at: [Link]

192. Thomas DA, Faderl S, Cortes J, et al. Treatment of Philadelphia 198. Mohty M, Labopin M, Volin L, et al. Reduced-intensity versus
chromosome-positive acute lymphocytic leukemia with hyper-CVAD and conventional myeloablative conditioning allogeneic stem cell
transplantation for patients with acute lymphoblastic leukemia: a
MS-79
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Acute Lymphoblastic Leukemia

retrospective study from the European Group for Blood and Marrow Philadelphia chromosome-positive acute lymphoblastic leukemia. Blood
Transplantation. Blood 2010;116:4439-4443. Available at: 2017;130:99. Available at:
[Link] [Link]

199. Ribera JM, Oriol A, Gonzalez M, et al. Concurrent intensive 205. Chalandon Y, Thomas X, Hayette S, et al. First results of the
chemotherapy and imatinib before and after stem cell transplantation in GRAAPH-2005 study in younger adult patients with de novo Philadelphia
newly diagnosed Philadelphia chromosome-positive acute lymphoblastic positive acute lymphoblastic leukemia [abstract]. Blood
leukemia. Final results of the CSTIBES02 trial. Haematologica 2008;112:Abstract 12. Available at:
2010;95:87-95. Available at: [Link]
[Link]
206. Chalandon Y, Thomas X, Hayette S, et al. Is less chemotherapy
200. Larson RA. Management of acute lymphoblastic leukemia in older detrimental in adults with Philadelphia chromosome (Ph)-positive acute
patients. Semin Hematol 2006;43:126-133. Available at: lymphoblastic leukemia (ALL) treated with high-dose imatinib? Results of
[Link] the prospective randomized GRAAPH-2005 study [abstract]. Blood
2012;120:Abstract 138. Available at:
201. Ottmann OG, Wassmann B, Pfeifer H, et al. Imatinib compared with [Link]
chemotherapy as front-line treatment of elderly patients with Philadelphia
chromosome-positive acute lymphoblastic leukemia (Ph+ALL). Cancer 207. Chalandon Y, Thomas X, Hayette S, et al. Randomized study of
2007;109:2068-2076. Available at: reduced-intensity chemotherapy combined with imatinib in adults with
[Link] Ph-positive acute lymphoblastic leukemia. Blood 2015;125:3711-3719.
Available at: [Link]
202. Delannoy A, Delabesse E, Lheritier V, et al. Imatinib and
methylprednisolone alternated with chemotherapy improve the outcome 208. Rousselot P, Coude MM, Gokbuget N, et al. Dasatinib and
of elderly patients with Philadelphia-positive acute lymphoblastic low-intensity chemotherapy in elderly patients with Philadelphia
leukemia: results of the GRAALL AFR09 study. Leukemia chromosome-positive ALL. Blood 2016;128:774-782. Available at:
2006;20:1526-1532. Available at: [Link]
[Link]
209. Carpenter PA, Snyder DS, Flowers ME, et al. Prophylactic
203. Vignetti M, Fazi P, Cimino G, et al. Imatinib plus steroids induces administration of imatinib after hematopoietic cell transplantation for
complete remissions and prolonged survival in elderly Philadelphia high-risk Philadelphia chromosome-positive leukemia. Blood
chromosome-positive patients with acute lymphoblastic leukemia without 2007;109:2791-2793. Available at:
additional chemotherapy: results of the Gruppo Italiano Malattie [Link]
Ematologiche dell'Adulto (GIMEMA) LAL0201-B protocol. Blood
2007;109:3676-3678. Available at: 210. Chen H, Liu KY, Xu LP, et al. Administration of imatinib after
[Link] allogeneic hematopoietic stem cell transplantation may improve
disease-free survival for patients with Philadelphia chromosome-positive
204. Martinelli G, Piciocchi A, Papayannidis C, et al. First report of the acute lymphobla stic leukemia. J Hematol Oncol 2012;5:29. Available at:
Gimema LAL1811 phase II prospective study of the combination of [Link]
steroids with ponatinib as frontline therapy of elderly or unfit patients with
MS-80
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Acute Lymphoblastic Leukemia

211. Pfeifer H, Wassmann B, Bethge W, et al. Randomized comparison 218. Collins RH, Jr., Goldstein S, Giralt S, et al. Donor leukocyte
of prophylactic and minimal residual disease-triggered imatinib after infusions in acute lymphocytic leukemia. Bone Marrow Transplant
allogeneic stem cell transplantation for BCR-ABL1-positive acute 2000;26:511-516. Available at:
lymphoblastic leukemia. Leukemia 2013;27:1254-1262. Available at: [Link]
[Link]
219. Kolb HJ, Schattenberg A, Goldman JM, et al. Graft-versus-leukemia
212. Fielding AK, Richards SM, Chopra R, et al. Outcome of 609 adults effect of donor lymphocyte transfusions in marrow grafted patients. Blood
after relapse of acute lymphoblastic leukemia (ALL); an MRC 1995;86:2041-2050. Available at:
UKALL12/ECOG 2993 study. Blood 2007;109:944-950. Available at: [Link]
[Link]
220. Keil F, Kalhs P, Haas OA, et al. Relapse of Philadelphia
213. Oriol A, Vives S, Hernandez-Rivas JM, et al. Outcome after relapse chromosome positive acute lymphoblastic leukaemia after marrow
of acute lymphoblastic leukemia in adult patients included in four transplantation: sustained molecular remission after early and
consecutive risk-adapted trials by the PETHEMA Study Group. dose-escalating infusion of donor leucocytes. Br J Haematol
Haematologica 2010;95:589-596. Available at: 1997;97:161-164. Available at:
[Link] [Link]

214. Tavernier E, Boiron JM, Huguet F, et al. Outcome of treatment after 221. Matsue K, Tabayashi T, Yamada K, Takeuchi M. Eradication of
first relapse in adults with acute lymphoblastic leukemia initially treated residual bcr-abl-positive clones by inducing graft-versus-host disease
by the LALA-94 trial. Leukemia 2007;21:1907-1914. Available at: after allogeneic stem cell transplantation in patients with Philadelphia
[Link] chromosome-positive acute lymphoblastic leukemia. Bone Marrow
Transplant 2002;29:63-66. Available at:
215. Thomas DA, Kantarjian H, Smith TL, et al. Primary refractory and [Link]
relapsed adult acute lymphoblastic leukemia: characteristics, treatment
results, and prognosis with salvage therapy. Cancer 1999;86:1216-1230. 222. Yazaki M, Andoh M, Ito T, et al. Successful prevention of
Available at: [Link] hematological relapse for a patient with Philadelphia
chromosome-positive acute lymphoblastic leukemia after allogeneic
216. Ishida Y, Terasako K, Oshima K, et al. Dasatinib followed by bone marrow transplantation by donor leukocyte infusion. Bone Marrow
second allogeneic hematopoietic stem cell transplantation for relapse of Transplant 1997;19:393-394. Available at:
Philadelphia chromosome-positive acute lymphoblastic leukemia after [Link]
the first transplantation. Int J Hematol 2010;92:542-546. Available at:
[Link] 223. Tiribelli M, Sperotto A, Candoni A, et al. Nilotinib and donor
lymphocyte infusion in the treatment of Philadelphia-positive acute
217. Millot F, Cividin M, Brizard F, et al. Successful second allogeneic lymphoblastic leukemia (Ph+ ALL) relapsing after allogeneic stem cell
stem cell transplantation in second remission induced by dasatinib in a transplantation and resistant to imatinib. Leuk Res 2009;33:174-177.
child with Philadelphia chromosome positive acute lymphoblastic Available at: [Link]
leukemia. Pediatr Blood Cancer 2009;52:891-892. Available at:
[Link] 224. Yoshimitsu M, Fujiwara H, Ozaki A, et al. Case of a patient with
Philadelphia-chromosome-positive acute lymphoblastic leukemia
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Acute Lymphoblastic Leukemia

relapsed after myeloablative allogeneic hematopoietic stem cell 231. Pfeifer H, Wassmann B, Pavlova A, et al. Kinase domain mutations
transplantation treated successfully with imatinib and sequential donor of BCR-ABL frequently precede imatinib-based therapy and give rise to
lymphocyte infusions. Int J Hematol 2008;88:331-335. Available at: relapse in patients with de novo Philadelphia-positive acute
[Link] lymphoblastic leukemia (Ph+ ALL). Blood 2007;110:727-734. Available
at: [Link]
225. Branford S, Rudzki Z, Walsh S, et al. High frequency of point
mutations clustered within the adenosine triphosphate-binding region of 232. Bujassoum S, Rifkind J, Lipton JH. Isolated central nervous system
BCR/ABL in patients with chronic myeloid leukemia or Ph-positive acute relapse in lymphoid blast crisis chronic myeloid leukemia and acute
lymphoblastic leukemia who develop imatinib (STI571) resistance. Blood lymphoblastic leukemia in patients on imatinib therapy. Leuk Lymphoma
2002;99:3472-3475. Available at: 2004;45:401-403. Available at:
[Link] [Link]

226. Hu Y, Liu Y, Pelletier S, et al. Requirement of Src kinases Lyn, Hck 233. Leis JF, Stepan DE, Curtin PT, et al. Central nervous system failure
and Fgr for BCR-ABL1-induced B-lymphoblastic leukemia but not chronic in patients with chronic myelogenous leukemia lymphoid blast crisis and
myeloid leukemia. Nat Genet 2004;36:453-461. Available at: Philadelphia chromosome positive acute lymphoblastic leukemia treated
[Link] with imatinib (STI-571). Leuk Lymphoma 2004;45:695-698. Available at:
[Link]
227. Soverini S, Colarossi S, Gnani A, et al. Contribution of ABL kinase
domain mutations to imatinib resistance in different subsets of 234. Pfeifer H, Wassmann B, Hofmann WK, et al. Risk and prognosis of
Philadelphia-positive patients: by the GIMEMA Working Party on Chronic central nervous system leukemia in patients with Philadelphia
Myeloid Leukemia. Clin Cancer Res 2006;12:7374-7379. Available at: chromosome-positive acute leukemias treated with imatinib mesylate.
[Link] Clin Cancer Res 2003;9:4674-4681. Available at:
[Link]
228. Hofmann WK, Jones LC, Lemp NA, et al. Ph(+) acute lymphoblastic
leukemia resistant to the tyrosine kinase inhibitor STI571 has a unique 235. Takayama N, Sato N, O'Brien SG, et al. Imatinib mesylate has
BCR-ABL gene mutation. Blood 2002;99:1860-1862. Available at: limited activity against the central nervous system involvement of
[Link] Philadelphia chromosome-positive acute lymphoblastic leukaemia due to
poor penetration into cerebrospinal fluid. Br J Haematol
229. Jones D, Thomas D, Yin CC, et al. Kinase domain point mutations 2002;119:106-108. Available at:
in Philadelphia chromosome-positive acute lymphoblastic leukemia [Link]
emerge after therapy with BCR-ABL kinase inhibitors. Cancer
2008;113:985-994. Available at: 236. Redaelli S, Piazza R, Rostagno R, et al. Activity of bosutinib,
[Link] dasatinib, and nilotinib against 18 imatinib-resistant BCR/ABL mutants. J
Clin Oncol 2009;27:469-471. Available at:
230. Hofmann WK, Komor M, Wassmann B, et al. Presence of the [Link]
BCR-ABL mutation Glu255Lys prior to STI571 (imatinib) treatment in
patients with Ph+ acute lymphoblastic leukemia. Blood 237. Shah NP, Tran C, Lee FY, et al. Overriding imatinib resistance with
2003;102:659-661. Available at: a novel ABL kinase inhibitor. Science 2004;305:399-401. Available at:
[Link] [Link]
MS-82
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Acute Lymphoblastic Leukemia

238. Verstovsek S, Golemovic M, Kantarjian H, et al. AMN107, a novel 245. Gambacorti-Passerini C, Kantarjian HM, Kim DW, et al. Long-term
aminopyrimidine inhibitor of p190 Bcr-Abl activation and of in vitro efficacy and safety of bosutinib in patients with advanced leukemia
proliferation of Philadelphia-positive acute lymphoblastic leukemia cells. following resistance/intolerance to imatinib and other tyrosine kinase
Cancer 2005;104:1230-1236. Available at: inhibitors. Am J Hematol 2015;90:755-768. Available at:
[Link] [Link]

239. Kantarjian H, Giles F, Wunderle L, et al. Nilotinib in 246. Kantarjian HM, Cortes JE, Kim DW, et al. Bosutinib safety and
imatinib-resistant CML and Philadelphia chromosome-positive ALL. N management of toxicity in leukemia patients with resistance or
Engl J Med 2006;354:2542-2551. Available at: intolerance to imatinib and other tyrosine kinase inhibitors. Blood
[Link] 2014;123:1309-1318. Available at:
[Link]
240. Lilly MB, Ottmann OG, Shah NP, et al. Dasatinib 140 mg once daily
versus 70 mg twice daily in patients with Ph-positive acute lymphoblastic 247. Cortes JE, Kantarjian H, Shah NP, et al. Ponatinib in refractory
leukemia who failed imatinib: Results from a phase 3 study. Am J Philadelphia chromosome-positive leukemias. N Engl J Med
Hematol 2010;85:164-170. Available at: 2012;367:2075-2088. Available at:
[Link] [Link]

241. Ottmann OG, Larson RA, Kantarjian HM, et al. Phase II study of 248. Cortes JE, Kim DW, Pinilla-Ibarz J, et al. A phase 2 trial of ponatinib
nilotinib in patients with relapsed or refractory Philadelphia in Philadelphia chromosome-positive leukemias. N Engl J Med
chromosome--positive acute lymphoblastic leukemia. Leukemia 2013;369:1783-1796. Available at:
2013;27:1411-1413. Available at: [Link]
[Link]
249. Soverini S, Colarossi S, Gnani A, et al. Resistance to dasatinib in
242. Benjamini O, Dumlao TL, Kantarjian H, et al. Phase II trial of hyper Philadelphia-positive leukemia patients and the presence or the selection
CVAD and dasatinib in patients with relapsed Philadelphia chromosome of mutations at residues 315 and 317 in the BCR-ABL kinase domain.
positive acute lymphoblastic leukemia or blast phase chronic myeloid Haematologica 2007;92:401-404. Available at:
leukemia. Am J Hematol 2014;89:282-287. Available at: [Link]
[Link]
250. Soverini S, Martinelli G, Colarossi S, et al. Presence or the
243. Cortes JE, Kantarjian HM, Brummendorf TH, et al. Safety and emergence of a F317L BCR-ABL mutation may be associated with
efficacy of bosutinib (SKI-606) in chronic phase Philadelphia resistance to dasatinib in Philadelphia chromosome-positive leukemia. J
chromosome-positive chronic myeloid leukemia patients with resistance Clin Oncol 2006;24:e51-52. Available at:
or intolerance to imatinib. Blood 2011;118:4567-4576. Available at: [Link]
[Link]
251. Soverini S, Hochhaus A, Nicolini FE, et al. BCR-ABL kinase domain
244. Khoury HJ, Cortes JE, Kantarjian HM, et al. Bosutinib is active in mutation analysis in chronic myeloid leukemia patients treated with
chronic phase chronic myeloid leukemia after imatinib and dasatinib tyrosine kinase inhibitors: recommendations from an expert panel on
and/or nilotinib therapy failure. Blood 2012;119:3403-3412. Available at: behalf of European LeukemiaNet. Blood 2011;118:1208-1215. Available
[Link] at: [Link]
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Acute Lymphoblastic Leukemia

252. Martinelli G, Boissel N, Chevallier P, et al. Complete hematologic 259. Kantarjian H, Thomas D, Jorgensen J, et al. Results of inotuzumab
and molecular response in adult patients with relapsed/refractory ozogamicin, a CD22 monoclonal antibody, in refractory and relapsed
Philadelphia chromosome-positive B-precursor acute lymphoblastic acute lymphocytic leukemia. Cancer 2013;119:2728-2736. Available at:
leukemia following treatment with blinatumomab: Results from a phase [Link]
II, single-arm, multicenter study. J Clin Oncol 2017;35:1795-1802.
Available at: [Link] 260. Laetsch TW, Maude SL, Rives S, et al. Three-Year Update of
Tisagenlecleucel in Pediatric and Young Adult Patients With
253. Kantarjian H, Thomas D, Jorgensen J, et al. Inotuzumab Relapsed/Refractory Acute Lymphoblastic Leukemia in the ELIANA Trial.
ozogamicin, an anti-CD22-calecheamicin conjugate, for refractory and J Clin Oncol 2023;41:1664-1669. Available at:
relapsed acute lymphocytic leukaemia: a phase 2 study. Lancet Oncol [Link]
2012;13:403-411. Available at:
[Link] 261. de Bont JM, Holt B, Dekker AW, et al. Significant difference in
outcome for adolescents with acute lymphoblastic leukemia treated on
254. Kantarjian HM, DeAngelo DJ, Stelljes M, et al. Inotuzumab pediatric vs adult protocols in the Netherlands. Leukemia
ozogamicin versus standard therapy for acute lymphoblastic leukemia. N 2004;18:2032-2035. Available at:
Engl J Med 2016;375:740-753. Available at: [Link]
[Link]
262. Hallbook H, Gustafsson G, Smedmyr B, et al. Treatment outcome in
255. Grupp SA, Kalos M, Barrett D, et al. Chimeric antigen young adults and children >10 years of age with acute lymphoblastic
receptor-modified T cells for acute lymphoid leukemia. N Engl J Med leukemia in Sweden: a comparison between a pediatric protocol and an
2013;368:1509-1518. Available at: adult protocol. Cancer 2006;107:1551-1561. Available at:
[Link] [Link]

256. Sadelain M, Riviere I, Brentjens R. Targeting tumours with 263. Ribera JM, Oriol A, Bethencourt C, et al. Comparison of intensive
genetically enhanced T lymphocytes. Nat Rev Cancer 2003;3:35-45. chemotherapy, allogeneic or autologous stem cell transplantation as
Available at: [Link] post-remission treatment for adult patients with high-risk acute
lymphoblastic leukemia. Results of the PETHEMA ALL-93 trial.
257. Deeg HJ, Sandmaier BM. Who is fit for allogeneic transplantation? Haematologica 2005;90:1346-1356. Available at:
Blood 2010;116:4762-4770. Available at: [Link]
[Link]
264. Cornelissen JJ, van der Holt B, Verhoef GE, et al. Myeloablative
258. Kantarjian HM, DeAngelo DJ, Advani AS, et al. Hepatic adverse allogeneic versus autologous stem cell transplantation in adult patients
event profile of inotuzumab ozogamicin in adult patients with relapsed or with acute lymphoblastic leukemia in first remission: a prospective sibling
refractory acute lymphoblastic leukaemia: results from the open-label, donor versus no-donor comparison. Blood 2009;113:1375-1382.
randomised, phase 3 INO-VATE study. Lancet Haematol Available at: [Link]
2017;4:e387-e398. Available at:
[Link] 265. Marks DI, Perez WS, He W, et al. Unrelated donor transplants in
adults with Philadelphia-negative acute lymphoblastic leukemia in first

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NCCN Guidelines Version 2.2024

Acute Lymphoblastic Leukemia

complete remission. Blood 2008;112:426-434. Available at: 272. Ribera JM, Oriol A, Sanz MA, et al. Comparison of the results of the
[Link] treatment of adolescents and young adults with standard-risk acute
lymphoblastic leukemia with the Programa Espanol de Tratamiento en
266. Marks DI, Wang T, Perez WS, et al. The outcome of full-intensity Hematologia pediatric-based protocol ALL-96. J Clin Oncol
and reduced-intensity conditioning matched sibling or unrelated donor 2008;26:1843-1849. Available at:
transplantation in adults with Philadelphia chromosome-negative acute [Link]
lymphoblastic leukemia in first and second complete remission. Blood
2010;116:366-374. Available at: 273. DeAngelo DJ, Dahlberg S, Silverman LB, et al. A multicenter phase
[Link] II study using a dose intensified pediatric regimen in adults with
untreated acute lymphoblastic leukemia [abstract]. Blood
267. Ram R, Gafter-Gvili A, Vidal L, et al. Management of adult patients 2007;110:Abstract 587. Available at:
with acute lymphoblastic leukemia in first complete remission: systematic [Link]
review and meta-analysis. Cancer 2010;116:3447-3457. Available at:
[Link] 274. DeAngelo DJ, Stevenson KE, Dahlberg SE, et al. Long-term
outcome of a pediatric-inspired regimen used for adults aged 18-50
268. Yanada M, Matsuo K, Suzuki T, Naoe T. Allogeneic hematopoietic years with newly diagnosed acute lymphoblastic leukemia. Leukemia
stem cell transplantation as part of postremission therapy improves 2015;29:526-534. Available at:
survival for adult patients with high-risk acute lymphoblastic leukemia: a [Link]
metaanalysis. Cancer 2006;106:2657-2663. Available at:
[Link] 275. DeAngelo DJ, Stevenson K, Neuberg DS, et al. A multicenter phase
II study using a dose intensified pegylated-asparaginase pediatric
269. Barry E, DeAngelo DJ, Neuberg D, et al. Favorable outcome for regimen in adults with untreated acute lymphoblastic leukemia: A DFCI
adolescents with acute lymphoblastic leukemia treated on Dana-Farber ALL Consortium Trial. Blood 2015;126:80-80. Available at:
Cancer Institute Acute Lymphoblastic Leukemia Consortium Protocols. J [Link]
Clin Oncol 2007;25:813-819. Available at:
[Link] 276. Huguet F, Leguay T, Raffoux E, et al. Pediatric-inspired therapy in
adults with Philadelphia chromosome-negative acute lymphoblastic
270. Nachman JB, La MK, Hunger SP, et al. Young adults with acute leukemia: the GRAALL-2003 study. J Clin Oncol 2009;27:911-918.
lymphoblastic leukemia have an excellent outcome with chemotherapy Available at: [Link]
alone and benefit from intensive postinduction treatment: a report from
the children's oncology group. J Clin Oncol 2009;27:5189-5194. 277. Maury S, Chevret S, Thomas X, et al. Rituximab in B-Lineage Adult
Available at: [Link] Acute Lymphoblastic Leukemia. N Engl J Med 2016;375:1044-1053.
Available at: [Link]
271. Larsen EC, Devidas M, Chen S, et al. Dexamethasone and
high-dose methotrexate improve outcome for children and young adults 278. Douer D, Aldoss I, Lunning MA, et al. Pharmacokinetics-based
with high-risk B-acute lymphoblastic leukemia: A report from Children's integration of multiple doses of intravenous pegaspargase in a pediatric
Oncology Group Study AALL0232. J Clin Oncol 2016;34:2380-2388. regimen for adults with newly diagnosed acute lymphoblastic leukemia. J
Available at: [Link] Clin Oncol 2014;32:905-911. Available at:
[Link]
MS-85
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Acute Lymphoblastic Leukemia

279. Geyer MB, Ritchie EK, Rao AV, et al. Pediatric-inspired 286. O'Brien S, Thomas DA, Ravandi F, et al. Results of the
chemotherapy incorporating pegaspargase is safe and results in high hyperfractionated cyclophosphamide, vincristine, doxorubicin, and
rates of minimal residual disease negativity in adults up to age 60 with dexamethasone regimen in elderly patients with acute lymphocytic
Philadelphia chromosome-negative acute lymphoblastic leukemia. leukemia. Cancer 2008;113:2097-2101. Available at:
Haematologica 2021;106:2086-2094. Available at: [Link]
[Link]
287. Maury S, Huguet F, Leguay T, et al. Adverse prognostic
280. Stock W, Luger SM, Advani AS, et al. A pediatric regimen for older significance of CD20 expression in adults with Philadelphia
adolescents and young adults with acute lymphoblastic leukemia: results chromosome-negative B-cell precursor acute lymphoblastic leukemia.
of CALGB 10403. Blood 2019;133:1548-1559. Available at: Haematologica 2010;95:324-328. Available at:
[Link] [Link]

281. Winter SS, Dunsmore KP, Devidas M, et al. Safe integration of 288. Thomas D, O'Brien S, Faderl S, et al. Anthracycline dose
nelarabine into intensive chemotherapy in newly diagnosed T-cell acute intensification in adult acute lymphoblastic leukemia: lack of benefit in
lymphoblastic leukemia: Children's Oncology Group Study AALL0434. the context of the fractionated cyclophosphamide, vincristine,
Pediatr Blood Cancer 2015;62:1176-1183. Available at: doxorubicin, and dexamethasone regimen. Cancer 2010;116:4580-4589.
[Link] Available at: [Link]

282. Dunsmore KP, Winter S, Devidas M, et al. COG AALL0434: A 289. Jabbour E, Short NJ, Jain N, et al. Hyper-CVAD and sequential
randomized trial testing nelarabine in newly diagnosed t-cell malignancy blinatumomab for newly diagnosed Philadelphia chromosome-negative
[abstract]. J Clin Oncol 2018;36:10500. Available at: B-cell acute lymphocytic leukaemia: a single-arm, single-centre, phase 2
[Link] trial. Lancet Haematol 2022;9:e878-e885. Available at:
[Link]
283. Winter SS, Dunsmore KP, Devidas M, et al. Improved survival for
children and young adults with T-lineage acute lymphoblastic leukemia: 290. Linker C, Damon L, Ries C, Navarro W. Intensified and shortened
Results from the Children's Oncology Group AALL0434 Methotrexate cyclical chemotherapy for adult acute lymphoblastic leukemia. J Clin
Randomization. J Clin Oncol 2018;36:2926-2934. Available at: Oncol 2002;20:2464-2471. Available at:
[Link] [Link]

284. Jain P, Kantarjian H, Ravandi F, et al. The combination of 291. Topp MS, Kufer P, Gokbuget N, et al. Targeted therapy with the
hyper-CVAD plus nelarabine as frontline therapy in adult T-cell acute T-cell-engaging antibody blinatumomab of chemotherapy-refractory
lymphoblastic leukemia and T-lymphoblastic lymphoma: MD Anderson minimal residual disease in B-lineage acute lymphoblastic leukemia
Cancer Center experience. Leukemia 2014;28:973-975. Available at: patients results in high response rate and prolonged leukemia-free
[Link] survival. J Clin Oncol 2011;29:2493-2498. Available at:
[Link]
285. Abaza Y, H MK, Faderl S, et al. Hyper-CVAD plus nelarabine in
newly diagnosed adult T-cell acute lymphoblastic leukemia and 292. Topp MS, Gokbuget N, Zugmaier G, et al. Long-term follow-up of
T-lymphoblastic lymphoma. Am J Hematol 2018;93:91-99. Available at: hematologic relapse-free survival in a phase 2 study of blinatumomab in
[Link]
MS-86
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Acute Lymphoblastic Leukemia

patients with MRD in B-lineage ALL. Blood 2012;120:5185-5187. intensity and MRD-driven transplant indication significantly reduces
Available at: [Link] treatment-related mortality (TRM) and improves overall survival - Results
from the Graall-2014 Trial [abstract]. Blood 2022;140:112-114. Available
293. Gokbuget N, Dombret H, Bonifacio M, et al. Blinatumomab for at: [Link]
minimal residual disease in adults with B-cell precursor acute
lymphoblastic leukemia. Blood 2018;131:1522-1531. Available at: 300. Boissel N, Graux C, Huguet F, et al. Frontline consolidation with
[Link] nelarabine for adults with high-risk T-Cell acute lymphoblastic leukemia.
Results of the Graall-2014/T Atriall Phase 2 Study [abstract]. Blood
294. Kantarjian H, Stein A, Gokbuget N, et al. Blinatumomab versus 2023;142:962-962. Available at:
chemotherapy for advanced acute lymphoblastic leukemia. N Engl J Med [Link]
2017;376:836-847. Available at:
[Link] 301. Wieduwilt MJ, Jonas BA, Schiller GJ, et al. A phase II study of
pegylated asparaginase, cyclophosphamide, rituximab, and dasatinib
295. Topp MS, Gokbuget N, Stein AS, et al. Safety and activity of added to the UCSF 8707 (Linker 4-drug) regimen with liposomal
blinatumomab for adult patients with relapsed or refractory B-precursor cytarabine CNS prophylaxis for adults with newly diagnosed acute
acute lymphoblastic leukaemia: a multicentre, single-arm, phase 2 study. lymphoblastic leukemia (ALL) or lymphoblastic lymphoma (LBL):
Lancet Oncol 2015;16:57-66. Available at: University of California Hematologic Malignancies Consortium Study
[Link] (UCHMC) 1401. Blood 2018;132:4018-4018. Available at:
[Link]
296. Topp MS, Gokbuget N, Zugmaier G, et al. Phase II trial of the
anti-CD19 bispecific T cell-engager blinatumomab shows hematologic 302. Marks DI, Paietta EM, Moorman AV, et al. T-cell acute
and molecular remissions in patients with relapsed or refractory lymphoblastic leukemia in adults: clinical features, immunophenotype,
B-precursor acute lymphoblastic leukemia. J Clin Oncol cytogenetics, and outcome from the large randomized prospective trial
2014;32:4134-4140. Available at: (UKALL XII/ECOG 2993). Blood 2009;114:5136-5145. Available at:
[Link] [Link]
297. Larson RA, Dodge RK, Linker CA, et al. A randomized controlled 303. Jabbour E, Short NJ, Senapati J, et al. Mini-hyper-CVD plus
trial of filgrastim during remission induction and consolidation inotuzumab ozogamicin, with or without blinatumomab, in the subgroup
chemotherapy for adults with acute lymphoblastic leukemia: CALGB of older patients with newly diagnosed Philadelphia
study 9111. Blood 1998;92:1556-1564. Available at: chromosome-negative B-cell acute lymphocytic leukaemia: long-term
[Link] results of an open-label phase 2 trial. Lancet Haematol
2023;10:e433-e444. Available at:
298. Huguet F, Chevret S, Leguay T, et al. Intensified therapy of acute [Link]
lymphoblastic leukemia in adults: Report of the randomized
GRAALL-2005 clinical trial. J Clin Oncol 2018;36:2514-2523. Available 304. Kantarjian H, Ravandi F, Short NJ, et al. Inotuzumab ozogamicin in
at: [Link] combination with low-intensity chemotherapy for older patients with
Philadelphia chromosome-negative acute lymphoblastic leukaemia: a
299. Boissel N, Huguet F, Leguay T, et al. In adults with Ph-negative single-arm, phase 2 study. Lancet Oncol 2018;19:240-248. Available at:
acute lymphoblastic leukemia (ALL), age-adapted chemotherapy [Link]
MS-87
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Acute Lymphoblastic Leukemia

305. Stelljes M, Raffel S, Alakel N, et al. Inotuzumab Ozogamicin as 311. Storring JM, Minden MD, Kao S, et al. Treatment of adults with
Induction Therapy for Patients Older Than 55 Years With Philadelphia BCR-ABL negative acute lymphoblastic leukaemia with a modified
Chromosome-Negative B-Precursor ALL. J Clin Oncol 2024; 42:273-282. paediatric regimen. Br J Haematol 2009;146:76-85. Available at:
Available at: [Link] [Link]

306. Wieduwilt MJ, Yin J, Kour O, et al. Chemotherapy-free treatment 312. Martell MP, Atenafu EG, Minden MD, et al. Treatment of elderly
with inotuzumab ozogamicin and blinatumomab for older adults with patients with acute lymphoblastic leukaemia using a paediatric-based
newly diagnosed, Ph-negative, CD22-positive, B-cell acute lymphoblastic protocol. Br J Haematol 2013;163:458-464. Available at:
leukemia: Alliance A041703 [abstract]. J Clin Oncol 2023;41:7006-7006. [Link]
Available at:
[Link] 313. Kozlowski P, Lennmyr E, Ahlberg L, et al. Age but not Philadelphia
positivity impairs outcome in older/elderly patients with acute
307. Hunault-Berger M, Leguay T, Thomas X, et al. A randomized study lymphoblastic leukemia in Sweden. Eur J Haematol 2017;99:141-149.
of pegylated liposomal doxorubicin versus continuous-infusion Available at: [Link]
doxorubicin in elderly patients with acute lymphoblastic leukemia: the
GRAALL-SA1 study. Haematologica 2011;96:245-252. Available at: 314. Berry DH, Pullen J, George S, et al. Comparison of prednisolone,
[Link] vincristine, methotrexate, and 6-mercaptopurine vs. vincristine and
prednisone induction therapy in childhood acute leukemia. Cancer
308. Goekbuget N, Beck J, Brueggemann M, et al. Moderate intensive 1975;36:98-102. Available at:
chemotherapy including CNS-prophylaxis with liposomal cytarabine is [Link]
feasible and effective in older patients with Ph-negative acute
lymphoblastic leukemia (ALL): Results of a prospective trial from the 315. Hardisty RM, McElwain TJ, Darby CW. Vincristine and prednisone
German Multicenter Study Group for Adult ALL (GMALL). Blood for the induction of remissions in acute childhood leukaemia. Br Med J
2012;120:1493. Available at: 1969;2:662-665. Available at:
[Link] [Link]

309. Ribera JM, Garcia O, Fernandez-Abellan P, et al. Lack of negative 316. Hess CE, Zirkle JW. Results of induction therapy with vincristine
impact of Philadelphia chromosome in older patients with acute and prednisone alone in adult acute lymphoblastic leukemia: report of 43
lymphoblastic leukaemia in the thyrosine kinase inhibitor era: comparison patients and review of the literature. Am J Hematol 1982;13:63-71.
of two prospective parallel protocols. Br J Haematol 2012;159:485-488. Available at: [Link]
Available at: [Link]
317. Rodriguez V, Hart JS, Freireich EJ, et al. Pomp combination
310. Ribera JM, Garcia O, Oriol A, et al. Feasibility and results of chemotherapy of adult acute leukemia. Cancer 1973;32:69-75. Available
subtype-oriented protocols in older adults and fit elderly patients with at: [Link]
acute lymphoblastic leukemia: Results of three prospective parallel trials
from the PETHEMA group. Leuk Res 2016;41:12-20. Available at: 318. Litzow MR, Sun Z, Paietta E, et al. Consolidation therapy with
[Link] blinatumomab improves overall survival in newly diagnosed adult
patients with B-lineage acute lymphoblastic leukemia in measurable
residual disease negative remission: Results from the ECOG-ACRIN
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Acute Lymphoblastic Leukemia

E1910 randomized phase III National Cooperative Clinical Trials Network lymphoblastic leukemia in adults: an evidence-based review. Biol Blood
Trial. Blood 2022;140:LBA-1-LBA-1. Available at: Marrow Transplant 2006;12:1-30. Available at:
[Link] [Link]

319. Nguyen K, Devidas M, Cheng SC, et al. Factors influencing survival 326. Eapen M, Raetz E, Zhang MJ, et al. Outcomes after HLA-matched
after relapse from acute lymphoblastic leukemia: a Children's Oncology sibling transplantation or chemotherapy in children with B-precursor
Group study. Leukemia 2008;22:2142-2150. Available at: acute lymphoblastic leukemia in a second remission: a collaborative
[Link] study of the Children's Oncology Group and the Center for International
Blood and Marrow Transplant Research. Blood 2006;107:4961-4967.
320. Pui CH, Evans WE. Acute lymphoblastic leukemia. N Engl J Med Available at: [Link]
1998;339:605-615. Available at:
[Link] 327. Duval M, Klein JP, He W, et al. Hematopoietic stem-cell
transplantation for acute leukemia in relapse or primary induction failure.
321. Pui CH, Pei D, Sandlund JT, et al. Long-term results of St Jude J Clin Oncol 2010;28:3730-3738. Available at:
Total Therapy Studies 11, 12, 13A, 13B, and 14 for childhood acute [Link]
lymphoblastic leukemia. Leukemia 2010;24:371-382. Available at:
[Link] 328. Topp MS, Goekbuget N, Zugmaier G, et al. Anti-CD19 BiTE
blinatumomab induces high complete remission rate in adult patients
322. Einsiedel HG, von Stackelberg A, Hartmann R, et al. Long-term with relapsed B-precursor ALL: Updated results of an ongoing phase II
outcome in children with relapsed ALL by risk-stratified salvage therapy: trial [abstract]. Blood 2011;118:Abstract 252. Available at:
results of trial acute lymphoblastic leukemia-relapse study of the [Link]
Berlin-Frankfurt-Munster Group 87. J Clin Oncol 2005;23:7942-7950.
Available at: [Link] 329. Topp MS, Goekbuget N, Stein AS, et al. Confirmatory open-label,
single-arm, multicenter phase 2 study of the BiTE antibody
323. Tallen G, Ratei R, Mann G, et al. Long-term outcome in children blinatumomab in patients (pts) with relapsed/refractory B-precursor acute
with relapsed acute lymphoblastic leukemia after time-point and lymphoblastic leukemia (r/r ALL) [abstract]. J Clin Oncol
site-of-relapse stratification and intensified short-course multidrug 2014;32:Abstract 7005. Available at:
chemotherapy: results of trial ALL-REZ BFM 90. J Clin Oncol [Link]
2010;28:2339-2347. Available at:
[Link] 330. U.S. Food and Drug Administration. Prescribing information.
Blincyto® (blinatumomab) injection. 2014. Available at:
324. Malempati S, Gaynon PS, Sather H, et al. Outcome after relapse [Link]
among children with standard-risk acute lymphoblastic leukemia: f. Accessed September 29, 2016.
Children's Oncology Group study CCG-1952. J Clin Oncol
2007;25:5800-5807. Available at: 331. Jabbour E, Ravandi F, Kebriaei P, et al. Salvage
[Link] chemoimmunotherapy with inotuzumab ozogamicin combined with
mini-hyper-CVD for patients with relapsed or refractory Philadelphia
325. Hahn T, Wall D, Camitta B, et al. The role of cytotoxic therapy with chromosome-negative acute lymphoblastic leukemia: A phase 2 clinical
hematopoietic stem cell transplantation in the therapy of acute
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Acute Lymphoblastic Leukemia

trial. JAMA Oncol 2018;4:230-234. Available at: 338. Gokbuget N, Stanze D, Beck J, et al. Outcome of relapsed adult
[Link] lymphoblastic leukemia depends on response to salvage chemotherapy,
prognostic factors, and performance of stem cell transplantation. Blood
332. Jabbour E, Sasaki K, Ravandi F, et al. Chemoimmunotherapy with 2012;120:2032-2041. Available at:
inotuzumab ozogamicin combined with mini-hyper-CVD, with or without [Link]
blinatumomab, is highly effective in patients with Philadelphia
chromosome-negative acute lymphoblastic leukemia in first salvage. 339. O'Brien S, Schiller G, Lister J, et al. High-dose vincristine sulfate
Cancer 2018;124:4044-4055. Available at: liposome injection for advanced, relapsed, and refractory adult
[Link] Philadelphia chromosome-negative acute lymphoblastic leukemia. J Clin
Oncol 2013;31:676-683. Available at:
333. Jabbour E, Sasaki K, Short NJ, et al. Long-term follow-up of [Link]
salvage therapy using a combination of inotuzumab ozogamicin and
mini-hyper-CVD with or without blinatumomab in relapsed/refractory 340. Park JH, Riviere I, Gonen M, et al. Long-term follow-up of CD19
Philadelphia chromosome-negative acute lymphoblastic leukemia. CAR therapy in acute lymphoblastic leukemia. N Engl J Med
Cancer 2021;127:2025-2038. Available at: 2018;378:449-459. Available at:
[Link] [Link]

334. Brentjens RJ, Davila ML, Riviere I, et al. CD19-targeted T cells 341. Shah NN, Lee DW, Yates B, et al. Long-Term Follow-Up of
rapidly induce molecular remissions in adults with CD19-CAR T-Cell Therapy in Children and Young Adults With B-ALL. J
chemotherapy-refractory acute lymphoblastic leukemia. Sci Transl Med Clin Oncol 2021;39:1650-1659. Available at:
2013;5:177ra138. Available at: [Link]
[Link]
342. Grupp SA, Frey NV, Aplenc R, et al. T Cells engineered with a
335. Kochenderfer JN, Dudley ME, Feldman SA, et al. B-cell depletion chimeric antigen receptor (CAR) targeting CD19 (CTL019) produce
and remissions of malignancy along with cytokine-associated toxicity in a significant in vivo proliferation, complete responses and long-term
clinical trial of anti-CD19 chimeric-antigen-receptor-transduced T cells. persistence without GVHD in children and adults with relapsed,
Blood 2012;119:2709-2720. Available at: refractory ALL [abstract]. Blood 2013;122:Abstract 67. Available at:
[Link] [Link]

336. Hollyman D, Stefanski J, Przybylowski M, et al. Manufacturing 343. Maude SL, Laetsch TW, Buechner J, et al. Tisagenlecleucel in
validation of biologically functional T cells targeted to CD19 antigen for Children and Young Adults with B-Cell Lymphoblastic Leukemia. N Engl
autologous adoptive cell therapy. J Immunother 2009;32:169-180. J Med 2018;378:439-448. Available at:
Available at: [Link] [Link]

337. Davila ML, Riviere I, Wang X, et al. Efficacy and toxicity 344. Pasquini MC, Hu ZH, Curran K, et al. Real-world evidence of
management of 19-28z CAR T cell therapy in B cell acute lymphoblastic tisagenlecleucel for pediatric acute lymphoblastic leukemia and
leukemia. Sci Transl Med 2014;6:224ra225. Available at: non-Hodgkin lymphoma. Blood Adv 2020;4:5414-5424. Available at:
[Link] [Link]

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NCCN Guidelines Version 2.2024

Acute Lymphoblastic Leukemia

345. Grupp SA, Maude SL, Rives S, et al. Tisagenlecleucel for the 352. Faderl S, Thomas DA, O'Brien S, et al. Augmented hyper-CVAD
Treatment of Pediatric and Young Adult Patients with based on dose-intensified vincristine, dexamethasone, and asparaginase
Relapsed/Refractory Acute Lymphoblastic Leukemia: Updated Analysis in adult acute lymphoblastic leukemia salvage therapy. Clin Lymphoma
of the ELIANA Clinical Trial. Biology of Blood and Marrow Myeloma Leuk 2011;11:54-59. Available at:
Transplantation 2019;25:S126-S127. Available at: [Link]
[Link]
353. Jeha S, Gaynon PS, Razzouk BI, et al. Phase II study of clofarabine
346. Shah BD, Ghobadi A, Oluwole OO, et al. KTE-X19 for relapsed or in pediatric patients with refractory or relapsed acute lymphoblastic
refractory adult B-cell acute lymphoblastic leukaemia: phase 2 results of leukemia. J Clin Oncol 2006;24:1917-1923. Available at:
the single-arm, open-label, multicentre ZUMA-3 study. Lancet [Link]
2021;398:491-502. Available at:
[Link] 354. Hijiya N, Thomson B, Isakoff MS, et al. Phase 2 trial of clofarabine
in combination with etoposide and cyclophosphamide in pediatric
347. Sheth VS, Gauthier J. Taming the beast: CRS and ICANS after patients with refractory or relapsed acute lymphoblastic leukemia. Blood
CAR T-cell therapy for ALL. Bone Marrow Transplant 2021;56:552-566. 2011;118:6043-6049. Available at:
Available at: [Link] [Link]

348. Lee DW, Santomasso BD, Locke FL, et al. ASTCT Consensus 355. Locatelli F, Testi AM, Bernardo ME, et al. Clofarabine,
Grading for Cytokine Release Syndrome and Neurologic Toxicity cyclophosphamide and etoposide as single-course re-induction therapy
Associated with Immune Effector Cells. Biol Blood Marrow Transplant for children with refractory/multiple relapsed acute lymphoblastic
2019;25:625-638. Available at: leukaemia. Br J Haematol 2009;147:371-378. Available at:
[Link] [Link]

349. Maus MV, Alexander S, Bishop MR, et al. Society for 356. Miano M, Pistorio A, Putti MC, et al. Clofarabine, cyclophosphamide
Immunotherapy of Cancer (SITC) clinical practice guideline on immune and etoposide for the treatment of relapsed or resistant acute leukemia
effector cell-related adverse events. J Immunother Cancer 2020;8. in pediatric patients. Leuk Lymphoma 2012;53:1693-1698. Available at:
Available at: [Link] [Link]

350. Commander LA, Seif AE, Insogna IG, Rheingold SR. Salvage 357. Pigneux A, Sauvezie M, Vey N, et al. Clofarabine combinations in
therapy with nelarabine, etoposide, and cyclophosphamide in adults with refractory/relapsed acute lymphoblastic leukemia (ALL): A
relapsed/refractory paediatric T-cell lymphoblastic leukaemia and GRAALL Report. Blood 2011;118:2586-2586. Available at:
lymphoma. Br J Haematol 2010;150:345-351. Available at: [Link]
[Link]
358. Wiernik PH, Dutcher JP, Paietta E, et al. Long-term follow-up of
351. Whitlock J, dalla Pozza L, Goldberg JM, et al. Nelarabine in treatment and potential cure of adult acute lymphocytic leukemia with
combination with etoposide and cyclophosphamide is active in first MOAD: a non-anthracycline containing regimen. Leukemia
relapse of childhood T-acute lymphocytic leukemia (T-ALL) and 1993;7:1236-1241. Available at:
T-lymphoblastic lymphoma (T-LL). Blood 2014;124:795. Available at: [Link]
[Link]
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NCCN Guidelines Version 2.2024

Acute Lymphoblastic Leukemia

359. Wetzler M, Sanford BL, Kurtzberg J, et al. Effective asparagine 366. Specchia G, Pastore D, Carluccio P, et al. FLAG-IDA in the
depletion with pegylated asparaginase results in improved outcomes in treatment of refractory/relapsed adult acute lymphoblastic leukemia. Ann
adult acute lymphoblastic leukemia: Cancer and Leukemia Group B Hematol 2005;84:792-795. Available at:
Study 9511. Blood 2007;109:4164-4167. Available at: [Link]
[Link]
367. Weiss MA, Aliff TB, Tallman MS, et al. A single, high dose of
360. Kadia TM, Kantarjian HM, Thomas DA, et al. Phase II study of idarubicin combined with cytarabine as induction therapy for adult
methotrexate, vincristine, pegylated-asparaginase, and dexamethasone patients with recurrent or refractory acute lymphoblastic leukemia.
(MOpAD) in patients with relapsed/refractory acute lymphoblastic Cancer 2002;95:581-587. Available at:
leukemia. Am J Hematol 2015;90:120-124. Available at: [Link]
[Link]
368. Gokbuget N, Basara N, Baurmann H, et al. High single-drug activity
361. Bride KL, Vincent TL, Im SY, et al. Preclinical efficacy of of nelarabine in relapsed T-lymphoblastic leukemia/lymphoma offers
daratumumab in T-cell acute lymphoblastic leukemia. Blood curative option with subsequent stem cell transplantation. Blood
2018;131:995-999. Available at: 2011;118:3504-3511. Available at:
[Link] [Link]

362. Richard-Carpentier G, Jabbour E, Short NJ, et al. Clinical 369. Candoni A, Lazzarotto D, Ferrara F, et al. Nelarabine as salvage
experience with venetoclax combined with chemotherapy for relapsed or therapy and bridge to allogeneic stem cell transplant in 118 adult patients
refractory T-cell acute lymphoblastic leukemia. Clin Lymphoma Myeloma with relapsed/refractory T-cell acute lymphoblastic leukemia/lymphoma.
Leuk 2020;20:212-218. Available at: A CAMPUS ALL study. Am J Hematol 2020;95:1466-1472. Available at:
[Link]
370. Bonda A, Punatar S, Gokarn A, et al. Daratumumab at the frontiers
363. Horton TM, Whitlock JA, Lu X, et al. Bortezomib reinduction of post-transplant refractory T-acute lymphoblastic leukemia-a
chemotherapy in high-risk ALL in first relapse: a report from the worthwhile strategy? Bone Marrow Transplant 2018;53:1487-1489.
Children's Oncology Group. Br J Haematol 2019;186:274-285. Available Available at: [Link]
at: [Link]
371. Mirgh S, Ahmed R, Agrawal N, et al. Will daratumumab be the next
364. Giebel S, Krawczyk-Kulis M, Adamczyk-Cioch M, et al. Fludarabine, game changer in early thymic precursor-acute lymphoblastic leukaemia?
cytarabine, and mitoxantrone (FLAM) for the treatment of relapsed and Br J Haematol 2019;187:e33-e35. Available at:
refractory adult acute lymphoblastic leukemia. A phase study by the [Link]
Polish Adult Leukemia Group (PALG). Ann Hematol 2006;85:717-722.
Available at: [Link] 372. Ofran Y, Ringelstein-Harlev S, Slouzkey I, et al. Daratumumab for
eradication of minimal residual disease in high-risk advanced relapse of
365. Schiller G, Lee M, Territo M, et al. Phase II study of etoposide, T-cell/CD19/CD22-negative acute lymphoblastic leukemia. Leukemia
ifosfamide, and mitoxantrone for the treatment of resistant adult acute 2020;34:293-295. Available at:
lymphoblastic leukemia. Am J Hematol 1993;43:195-199. Available at: [Link]
[Link]

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NCCN Guidelines Version 2.2024

Acute Lymphoblastic Leukemia

373. Liedtke M, Dunn T, Dinner S, et al. Salvage therapy with from the international ALL trial MRC UKALL XII/ECOG E2993. Blood
mitoxantrone, etoposide and cytarabine in relapsed or refractory acute 2006;108:465-472. Available at:
lymphoblastic leukemia. Leuk Res 2014;38:1441-1445. Available at: [Link]
[Link]
381. Reman O, Pigneux A, Huguet F, et al. Central nervous system
374. Jain N, Stevenson KE, Winer ES, et al. A Multicenter Phase I Study involvement in adult acute lymphoblastic leukemia at diagnosis and/or at
Combining Venetoclax with Mini-Hyper-CVD in Older Adults with first relapse: results from the GET-LALA group. Leuk Res
Untreated and Relapsed/Refractory Acute Lymphoblastic Leukemia. 2008;32:1741-1750. Available at:
Blood 2019;134:3867-3867. Available at: [Link]
[Link]
382. Pui CH, Pei D, Campana D, et al. Improved prognosis for older
375. Bailey LC, Lange BJ, Rheingold SR, Bunin NJ. Bone-marrow adolescents with acute lymphoblastic leukemia. J Clin Oncol
relapse in paediatric acute lymphoblastic leukaemia. Lancet Oncol 2011;29:386-391. Available at:
2008;9:873-883. Available at: [Link]
[Link]
383. Annino L, Vegna ML, Camera A, et al. Treatment of adult acute
376. Hoelzer D, Gokbuget N, Digel W, et al. Outcome of adult patients lymphoblastic leukemia (ALL): long-term follow-up of the GIMEMA ALL
with T-lymphoblastic lymphoma treated according to protocols for acute 0288 randomized study. Blood 2002;99:863-871. Available at:
lymphoblastic leukemia. Blood 2002;99:4379-4385. Available at: [Link]
[Link]
384. Sancho JM, Ribera JM, Oriol A, et al. Central nervous system
377. Morel P, Lepage E, Brice P, et al. Prognosis and treatment of recurrence in adult patients with acute lymphoblastic leukemia:
lymphoblastic lymphoma in adults: a report on 80 patients. J Clin Oncol frequency and prognosis in 467 patients without cranial irradiation for
1992;10:1078-1085. Available at: prophylaxis. Cancer 2006;106:2540-2546. Available at:
[Link] [Link]

378. Burger B, Zimmermann M, Mann G, et al. Diagnostic cerebrospinal 385. Children’s Oncology Group. Long-term follow-up guidelines for
fluid examination in children with acute lymphoblastic leukemia: survivors of childhood, adolescent, and young adult cancers. 2018.
significance of low leukocyte counts with blasts or traumatic lumbar Available at:
puncture. J Clin Oncol 2003;21:184-188. Available at: [Link]
[Link] . Accessed January 31, 2019.

379. Pui CH, Campana D, Pei D, et al. Treating childhood acute 386. Mortuza FY, Papaioannou M, Moreira IM, et al. Minimal residual
lymphoblastic leukemia without cranial irradiation. N Engl J Med disease tests provide an independent predictor of clinical outcome in
2009;360:2730-2741. Available at: adult acute lymphoblastic leukemia. J Clin Oncol 2002;20:1094-1104.
[Link] Available at: [Link]

380. Lazarus HM, Richards SM, Chopra R, et al. Central nervous system 387. Carlson CS, Emerson RO, Sherwood AM, et al. Using synthetic
involvement in adult acute lymphoblastic leukemia at diagnosis: results templates to design an unbiased multiplex PCR assay. Nat Commun
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NCCN Guidelines Version 2.2024

Acute Lymphoblastic Leukemia

2013;4:2680. Available at: 395. Logan AC, Zhang B, Narasimhan B, et al. Minimal residual disease
[Link] quantification using consensus primers and high-throughput IGH
sequencing predicts post-transplant relapse in chronic lymphocytic
388. Denys B, van der Sluijs-Gelling AJ, Homburg C, et al. Improved flow leukemia. Leukemia 2013;27:1659-1665. Available at:
cytometric detection of minimal residual disease in childhood acute [Link]
lymphoblastic leukemia. Leukemia 2013;27:635-641. Available at:
[Link] 396. Neale GA, Coustan-Smith E, Stow P, et al. Comparative analysis of
flow cytometry and polymerase chain reaction for the detection of
389. Faham M, Zheng J, Moorhead M, et al. Deep-sequencing approach minimal residual disease in childhood acute lymphoblastic leukemia.
for minimal residual disease detection in acute lymphoblastic leukemia. Leukemia 2004;18:934-938. Available at:
Blood 2012;120:5173-5180. Available at: [Link]
[Link]
397. Wu D, Emerson RO, Sherwood A, et al. Detection of minimal
390. Gaipa G, Cazzaniga G, Valsecchi MG, et al. Time point-dependent residual disease in B lymphoblastic leukemia by high-throughput
concordance of flow cytometry and real-time quantitative polymerase sequencing of IGH. Clin Cancer Res 2014;20:4540-4548. Available at:
chain reaction for minimal residual disease detection in childhood acute [Link]
lymphoblastic leukemia. Haematologica 2012;97:1582-1593. Available
at: [Link] 398. Wu D, Sherwood A, Fromm JR, et al. High-throughput sequencing
detects minimal residual disease in acute T lymphoblastic leukemia. Sci
391. Ladetto M, Bruggemann M, Monitillo L, et al. Next-generation Transl Med 2012;4:134ra163. Available at:
sequencing and real-time quantitative PCR for minimal residual disease [Link]
detection in B-cell disorders. Leukemia 2014;28:1299-1307. Available at:
[Link] 399. Kerst G, Kreyenberg H, Roth C, et al. Concurrent detection of
minimal residual disease (MRD) in childhood acute lymphoblastic
392. Short NJ, Jabbour E, Albitar M, et al. Recommendations for the leukaemia by flow cytometry and real-time PCR. Br J Haematol
assessment and management of measurable residual disease in adults 2005;128:774-782. Available at:
with acute lymphoblastic leukemia: A consensus of North American [Link]
experts. Am J Hematol 2019;94:257-265. Available at:
[Link] 400. Coustan-Smith E, Sancho J, Behm FG, et al. Prognostic importance
of measuring early clearance of leukemic cells by flow cytometry in
393. Stow P, Key L, Chen X, et al. Clinical significance of low levels of childhood acute lymphoblastic leukemia. Blood 2002;100:52-58.
minimal residual disease at the end of remission induction therapy in Available at: [Link]
childhood acute lymphoblastic leukemia. Blood 2010;115:4657-4663.
Available at: [Link] 401. Coustan-Smith E, Sancho J, Hancock ML, et al. Clinical importance
of minimal residual disease in childhood acute lymphoblastic leukemia.
394. Wood B, Wu D, Crossley B, et al. Measurable residual disease Blood 2000;96:2691-2696. Available at:
detection by high-throughput sequencing improves risk stratification for [Link]
pediatric B-ALL. Blood 2018;131:1350-1359. Available at:
[Link]
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NCCN Guidelines Version 2.2024

Acute Lymphoblastic Leukemia

402. Cave H, van der Werff ten Bosch J, Suciu S, et al. Clinical 408. Parker C, Waters R, Leighton C, et al. Effect of mitoxantrone on
significance of minimal residual disease in childhood acute lymphoblastic outcome of children with first relapse of acute lymphoblastic leukaemia
leukemia. European Organization for Research and Treatment of (ALL R3): an open-label randomised trial. Lancet 2010;376:2009-2017.
Cancer--Childhood Leukemia Cooperative Group. N Engl J Med Available at: [Link]
1998;339:591-598. Available at:
[Link] 409. Ko RH, Ji L, Barnette P, et al. Outcome of patients treated for
relapsed or refractory acute lymphoblastic leukemia: a Therapeutic
403. Coustan-Smith E, Behm FG, Sanchez J, et al. Immunological Advances in Childhood Leukemia Consortium study. J Clin Oncol
detection of minimal residual disease in children with acute lymphoblastic 2010;28:648-654. Available at:
leukaemia. Lancet 1998;351:550-554. Available at: [Link]
[Link]
410. Coustan-Smith E, Gajjar A, Hijiya N, et al. Clinical significance of
404. Conter V, Bartram CR, Valsecchi MG, et al. Molecular response to minimal residual disease in childhood acute lymphoblastic leukemia after
treatment redefines all prognostic factors in children and adolescents first relapse. Leukemia 2004;18:499-504. Available at:
with B-cell precursor acute lymphoblastic leukemia: results in 3184 [Link]
patients of the AIEOP-BFM ALL 2000 study. Blood 2010;115:3206-3214.
Available at: [Link] 411. Paganin M, Zecca M, Fabbri G, et al. Minimal residual disease is an
important predictive factor of outcome in children with relapsed 'high-risk'
405. Vora A, Goulden N, Wade R, et al. Treatment reduction for children acute lymphoblastic leukemia. Leukemia 2008;22:2193-2200. Available
and young adults with low-risk acute lymphoblastic leukaemia defined by at: [Link]
minimal residual disease (UKALL 2003): a randomised controlled trial.
Lancet Oncol 2013;14:199-209. Available at: 412. Basso G, Veltroni M, Valsecchi MG, et al. Risk of relapse of
[Link] childhood acute lymphoblastic leukemia is predicted by flow cytometric
measurement of residual disease on day 15 bone marrow. J Clin Oncol
406. Vora A, Goulden N, Mitchell C, et al. Augmented post-remission 2009;27:5168-5174. Available at:
therapy for a minimal residual disease-defined high-risk subgroup of [Link]
children and young people with clinical standard-risk and
intermediate-risk acute lymphoblastic leukaemia (UKALL 2003): a 413. Panzer-Grumayer ER, Schneider M, Panzer S, et al. Rapid
randomised controlled trial. Lancet Oncol 2014;15:809-818. Available at: molecular response during early induction chemotherapy predicts a good
[Link] outcome in childhood acute lymphoblastic leukemia. Blood
2000;95:790-794. Available at:
407. Eckert C, Henze G, Seeger K, et al. Use of allogeneic [Link]
hematopoietic stem-cell transplantation based on minimal residual
disease response improves outcomes for children with relapsed acute 414. Bruggemann M, Raff T, Flohr T, et al. Clinical significance of
lymphoblastic leukemia in the intermediate-risk group. J Clin Oncol minimal residual disease quantification in adult patients with
2013;31:2736-2742. Available at: standard-risk acute lymphoblastic leukemia. Blood 2006;107:1116-1123.
[Link] Available at: [Link]

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Acute Lymphoblastic Leukemia

415. Holowiecki J, Krawczyk-Kulis M, Giebel S, et al. Status of minimal during and after maintenance treatment: data from the GMALL 06/99 and
residual disease after induction predicts outcome in both standard and 07/03 trials. Blood 2007;109:910-915. Available at:
high-risk Ph-negative adult acute lymphoblastic leukaemia. The Polish [Link]
Adult Leukemia Group ALL 4-2002 MRD Study. Br J Haematol
2008;142:227-237. Available at: 422. Gokbuget N, Kneba M, Raff T, et al. Adult patients with acute
[Link] lymphoblastic leukemia and molecular failure display a poor prognosis
and are candidates for stem cell transplantation and targeted therapies.
416. Patel B, Rai L, Buck G, et al. Minimal residual disease is a Blood 2012;120:1868-1876. Available at:
significant predictor of treatment failure in non T-lineage adult acute [Link]
lymphoblastic leukaemia: final results of the international trial UKALL
XII/ECOG2993. Br J Haematol 2010;148:80-89. Available at: 423. Dworzak MN, Froschl G, Printz D, et al. Prognostic significance and
[Link] modalities of flow cytometric minimal residual disease detection in
childhood acute lymphoblastic leukemia. Blood 2002;99:1952-1958.
417. Vidriales MB, Perez JJ, Lopez-Berges MC, et al. Minimal residual Available at: [Link]
disease in adolescent (older than 14 years) and adult acute
lymphoblastic leukemias: early immunophenotypic evaluation has high 424. Bruggemann M, Schrauder A, Raff T, et al. Standardized MRD
clinical value. Blood 2003;101:4695-4700. Available at: quantification in European ALL trials: proceedings of the Second
[Link] International Symposium on MRD assessment in Kiel, Germany, 18-20
September 2008. Leukemia 2010;24:521-535. Available at:
418. Ravandi F, Jorgensen JL, O'Brien SM, et al. Minimal residual [Link]
disease assessed by multi-parameter flow cytometry is highly prognostic
in adult patients with acute lymphoblastic leukaemia. Br J Haematol 425. Campana D. Minimal residual disease in acute lymphoblastic
2016;172:392-400. Available at: leukemia. Hematology Am Soc Hematol Educ Program 2010;2010:7-12.
[Link] Available at: [Link]

419. Nagafuji K, Miyamoto T, Eto T, et al. Monitoring of minimal residual 426. Borowitz MJ, Wood BL, Devidas M, et al. Prognostic significance of
disease (MRD) is useful to predict prognosis of adult patients with minimal residual disease in high risk B-ALL: a report from Children's
Ph-negative ALL: results of a prospective study (ALL MRD2002 Study). J Oncology Group study AALL0232. Blood 2015;126:964-971. Available at:
Hematol Oncol 2013;6:14. Available at: [Link]
[Link]
427. O'Connor D, Enshaei A, Bartram J, et al. Genotype-specific minimal
420. Bassan R, Spinelli O, Oldani E, et al. Improved risk classification for residual disease interpretation improves stratification in pediatric acute
risk-specific therapy based on the molecular study of minimal residual lymphoblastic leukemia. J Clin Oncol 2018;36:34-43. Available at:
disease (MRD) in adult acute lymphoblastic leukemia (ALL). Blood [Link]
2009;113:4153-4162. Available at:
[Link] 428. Wood BL, Winter SS, Dunsmore KP, et al. T-lymphoblastic
leukemia (T-ALL) shows excellent outcome, lack of significance of the
421. Raff T, Gokbuget N, Luschen S, et al. Molecular relapse in adult early thymic precursor (ETP) immunophenotype, and validation of the
standard-risk ALL patients detected by prospective MRD monitoring prognostic value of end-induction minimal residual disease (MRD) in
MS-96
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NCCN Guidelines Version 2.2024

Acute Lymphoblastic Leukemia

Children’s Oncology Group (COG) Study AALL0434. Blood 2014;124:1. reports. J Pain Symptom Manage 2000;19:309-317. Available at:
Available at: [Link] [Link]

429. Pemmaraju N, Kantarjian H, Jorgensen JL, et al. Significance of 436. Stiefel FC, Breitbart WS, Holland JC. Corticosteroids in cancer:
recurrence of minimal residual disease detected by multi-parameter flow neuropsychiatric complications. Cancer Invest 1989;7:479-491. Available
cytometry in patients with acute lymphoblastic leukemia in morphological at: [Link]
remission. Am J Hematol 2017;92:279-285. Available at:
[Link] 437. Kawedia JD, Kaste SC, Pei D, et al. Pharmacokinetic,
pharmacodynamic, and pharmacogenetic determinants of osteonecrosis
430. Ramsey LB, Balis FM, O'Brien MM, et al. Consensus guideline for in children with acute lymphoblastic leukemia. Blood
use of glucarpidase in patients with high-dose methotrexate induced 2011;117:2340-2347; quiz 2556. Available at:
acute kidney injury and delayed methotrexate clearance. Oncologist [Link]
2018;23:52-61. Available at:
[Link] 438. Patel B, Richards SM, Rowe JM, et al. High incidence of avascular
necrosis in adolescents with acute lymphoblastic leukaemia: a UKALL
431. Taylor ZL, Mizuno T, Punt NC, et al. [Link]: A clinical decision XII analysis. Leukemia 2008;22:308-312. Available at:
support tool evaluating high-dose methotrexate pharmacokinetics to [Link]
inform post-infusion care and use of glucarpidase. Clin Pharmacol Ther
2020;108:635-643. Available at: 439. Mattano LA, Jr., Devidas M, Nachman JB, et al. Effect of
[Link] alternate-week versus continuous dexamethasone scheduling on the risk
of osteonecrosis in paediatric patients with acute lymphoblastic
432. Hamid M, Lashari B, Ahsan I, et al. A deadly prescription: leukaemia: results from the CCG-1961 randomised cohort trial. Lancet
combination of methotrexate and trimethoprim-sulfamethoxazole. J Oncol 2012;13:906-915. Available at:
Community Hosp Intern Med Perspect 2018;8:149-151. Available at: [Link]
[Link]
440. Mattano LA, Jr., Sather HN, Trigg ME, Nachman JB. Osteonecrosis
433. Ducore JM, Waller DA, Emslie G, Bertolone SJ. Acute psychosis as a complication of treating acute lymphoblastic leukemia in children: a
complicating induction therapy for acute lymphoblastic leukemia. J report from the Children's Cancer Group. J Clin Oncol
Pediatr 1983;103:477-480. Available at: 2000;18:3262-3272. Available at:
[Link] [Link]

434. Friedenberg WR, Kyle RA, Knospe WH, et al. High-dose 441. te Winkel ML, Pieters R, Hop WC, et al. Prospective study on
dexamethasone for refractory or relapsing multiple myeloma. Am J incidence, risk factors, and long-term outcome of osteonecrosis in
Hematol 1991;36:171-175. Available at: pediatric acute lymphoblastic leukemia. J Clin Oncol 2011;29:4143-4150.
[Link] Available at: [Link]

435. Jenkins CA, Bruera E. Difficulties in diagnosing neuropsychiatric 442. Vora A. Management of osteonecrosis in children and young adults
complications of corticosteroids in advanced cancer patients: two case with acute lymphoblastic leukaemia. Br J Haematol 2011;155:549-560.
Available at: [Link]
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NCCN Guidelines Version 2.2024

Acute Lymphoblastic Leukemia

443. Vrooman LM, Stevenson KE, Supko JG, et al. Postinduction Hematol Educ Program 2016;2016:567-572. Available at:
dexamethasone and individualized dosing of Escherichia Coli [Link]
L-asparaginase each improve outcome of children and adolescents with
newly diagnosed acute lymphoblastic leukemia: results from a 450. Neelapu SS, Tummala S, Kebriaei P, et al. Chimeric antigen
randomized study--Dana-Farber Cancer Institute ALL Consortium receptor T-cell therapy - assessment and management of toxicities. Nat
Protocol 00-01. J Clin Oncol 2013;31:1202-1210. Available at: Rev Clin Oncol 2018;15:47-62. Available at:
[Link] [Link]

444. Kantarjian HM, DeAngelo DJ, Stelljes M, et al. Inotuzumab 451. Neelapu SS, Tummala S, Kebriaei P, et al. Toxicity management
ozogamicin versus standard of care in relapsed or refractory acute after chimeric antigen receptor T cell therapy: one size does not fit 'ALL'.
lymphoblastic leukemia: Final report and long-term survival follow-up Nat Rev Clin Oncol 2018;15:218. Available at:
from the randomized, phase 3 INO-VATE study. Cancer [Link]
2019;125:2474-2487. Available at:
[Link] 452. Ngo D, Otoukesh S, Stein AS, et al. The safety of concurrent
intrathecal chemotherapy during blinatumomab in adults with acute
445. George B, Kantarjian H, Jabbour E, Jain N. Role of inotuzumab lymphoblastic leukemia. Leuk Lymphoma 2022;63:2754-2756. Available
ozogamicin in the treatment of relapsed/refractory acute lymphoblastic at: [Link]
leukemia. Immunotherapy 2016;8:135-143. Available at:
[Link] 453. Angiolillo AL, Schore RJ, Devidas M, et al. Pharmacokinetic and
pharmacodynamic properties of calaspargase pegol Escherichia coli
446. Kebriaei P, Wilhelm K, Ravandi F, et al. Feasibility of allografting in L-asparaginase in the treatment of patients with acute lymphoblastic
patients with advanced acute lymphoblastic leukemia after salvage leukemia: results from Children's Oncology Group Study AALL07P4. J
therapy with inotuzumab ozogamicin. Clin Lymphoma Myeloma Leuk Clin Oncol 2014;32:3874-3882. Available at:
2013;13:296-301. Available at: [Link]
[Link]
454. Asselin BL. The three asparaginases. Comparative pharmacology
447. Kebriaei P, Cutler C, de Lima M, et al. Management of important and optimal use in childhood leukemia. Adv Exp Med Biol
adverse events associated with inotuzumab ozogamicin: expert panel 1999;457:621-629. Available at:
review. Bone Marrow Transplant 2018;53:449-456. Available at: [Link]
[Link]
455. Pieters R, Hunger SP, Boos J, et al. L-asparaginase treatment in
448. Giglio F, Xue E, Greco R, et al. Defibrotide Prophylaxis of acute lymphoblastic leukemia: a focus on Erwinia asparaginase. Cancer
Sinusoidal Obstruction Syndrome in Adults Treated With Inotuzumab 2011;117:238-249. Available at:
Ozogamicin Prior to Hematopoietic Stem Cell Transplantation. Front [Link]
Oncol 2022;12:933317. Available at:
[Link] 456. Stock W, Douer D, DeAngelo DJ, et al. Prevention and
management of asparaginase/pegasparaginase-associated toxicities in
449. Frey NV, Porter DL. Cytokine release syndrome with novel adults and older adolescents: recommendations of an expert panel. Leuk
therapeutics for acute lymphoblastic leukemia. Hematology Am Soc
MS-98
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NCCN Guidelines Version 2.2024

Acute Lymphoblastic Leukemia

Lymphoma 2011;52:2237-2253. Available at: ALL-BFM trials. Blood 2011;118:5774-5782. Available at:
[Link] [Link]

457. Maese L, Loh ML, Choi MR, et al. Recombinant erwinia 464. Bleyer A, Asselin BL, Koontz SE, Hunger SP. Clinical application of
asparaginase (JZP458) in acute lymphoblastic leukemia: Results from asparaginase activity levels following treatment with pegaspargase.
the phase 2/3 AALL1931 study. Blood 2023;141:704-712. Available at: Pediatr Blood Cancer 2015;62:1102-1105. Available at:
[Link] [Link]

458. Asselin B, Rizzari C. Asparaginase pharmacokinetics and 465. Burke MJ. How to manage asparaginase hypersensitivity in acute
implications of therapeutic drug monitoring. Leuk Lymphoma lymphoblastic leukemia. Future Oncol 2014;10:2615-2627. Available at:
2015;56:2273-2280. Available at: [Link]
[Link]
466. Burke MJ, Rheingold SR. Differentiating hypersensitivity versus
459. Salzer W, Bostrom B, Messinger Y, et al. Asparaginase activity infusion-related reactions in pediatric patients receiving intravenous
levels and monitoring in patients with acute lymphoblastic leukemia. asparaginase therapy for acute lymphoblastic leukemia. Leuk Lymphoma
Leuk Lymphoma 2018;59:1797-1806. Available at: 2017;58:540-551. Available at:
[Link] [Link]

460. Avramis VI, Sencer S, Periclou AP, et al. A randomized comparison 467. Marini BL, Brown J, Benitez L, et al. A single-center multidisciplinary
of native Escherichia coli asparaginase and polyethylene glycol approach to managing the global Erwinia asparaginase shortage. Leuk
conjugated asparaginase for treatment of children with newly diagnosed Lymphoma 2019;60:2854-2868. Available at:
standard-risk acute lymphoblastic leukemia: a Children's Cancer Group [Link]
study. Blood 2002;99:1986-1994. Available at:
[Link] 468. Vrooman LM, Blonquist TM, Stevenson KE, et al. Efficacy and
toxicity of pegaspargase and calaspargase pegol in childhood acute
461. Wang B, Relling MV, Storm MC, et al. Evaluation of immunologic lymphoblastic leukemia: Results of DFCI 11-001. J Clin Oncol
crossreaction of antiasparaginase antibodies in acute lymphoblastic 2021;39:3496-3505. Available at:
leukemia (ALL) and lymphoma patients. Leukemia 2003;17:1583-1588. [Link]
Available at: [Link]
469. Silverman LB, Blonquist TM, Hunt SK, et al. Randomized study of
462. Zalewska-Szewczyk B, Gach A, Wyka K, et al. The cross-reactivity pegasparagase (SS-PEG) and calaspargase pegol (SC-PEG) in pediatric
of anti-asparaginase antibodies against different L-asparaginase patients with newly diagnosed acute lymphoblastic leukemia or
preparations. Clin Exp Med 2009;9:113-116. Available at: lymphoblastic lymphoma: Results of DFCI ALL Consortium Protocol
[Link] 11-001. Blood 2016;128:175-175. Available at:
[Link]
463. Willer A, Gerss J, Konig T, et al. Anti-Escherichia coli asparaginase
antibody levels determine the activity of second-line treatment with 470. Common Terminology Criteria for Adverse Events (CTCAE). 2021.
pegylated E coli asparaginase: a retrospective analysis within the Available at:

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Acute Lymphoblastic Leukemia

[Link]
htm#ctc_50. Accessed February 1, 2024.

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