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NCCN Guidelines for Acute Lymphoblastic Leukemia

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NCCN Guidelines for Acute Lymphoblastic Leukemia

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NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®)

Acute Lymphoblastic Leukemia

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.

NCCN Guidelines for Patients® available at [Link]/patients

Continue

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NCCN Guidelines Version 2.2024 NCCN Guidelines Index

Table of Contents
Acute Lymphoblastic Leukemia Discussion

*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

NCCN Guidelines Version 2.2024 NCCN Guidelines Index

Table of Contents
Acute Lymphoblastic Leukemia Discussion

NCCN Acute Lymphoblastic Leukemia Panel Members

Find an NCCN Member Institution:
Summary of the Guidelines Updates [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)

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
Guidelines are copyrighted by National Comprehensive Cancer Network®. All rights reserved. The 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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NCCN Guidelines Version 2.2024 NCCN Guidelines Index

Table of Contents
Acute Lymphoblastic Leukemia Discussion

Terminologies in all NCCN Guidelines are being actively modified to advance the goals of equity, inclusion, and representation.
Updates in Version 2.2024 of the NCCN Guidelines for Acute Lymphoblastic Leukemia from Version 1.2024 include:
MS-41
• The following correction was made to the discussion section text on September 24, 2024:
Patients were randomized to receive either 4 cycles of consolidation chemotherapy or 2 cycles of blinatumomab followed by 3 2 cycles of
consolidation chemotherapy, followed by a 3rd cycle of blinatumomab, followed by another cycle of consolidation chemotherapy, and finally a 4th cycle
of blinatumomab.
MS-1
• The discussion section has been updated to reflect the changes in the algorithm.

Updates in Version 1.2024 of the NCCN Guidelines for Acute Lymphoblastic Leukemia from Version 4.2023 include:
Global Changes
• References updated throughout Guideline
ALL-1
• Classification
Bullet modified: Together, these studies allow determination of the World Health Organization (WHO) and International Consensus Criteria (ICC) ALL
subtypes and cytogenetic and clinical risk groups.
ALL-1A
• Footnote c modified: 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.
ALL-4
• Workup
5th bullet modified: Hepatitis B/C, human immunodeficiency virus (HIV), cytomegalovirus (CMV) Ab testing
ALL-5
• Treatment Induction
Adolescents and young adults (AYAs) and adults <65 years without substantial comorbidities
◊ New therapy option added: TKI + blinatumomab
Adults ≥65 years or with substantial comorbidities
◊ New therapy option added: TKI + blinatumomab
• Consolidation Therapy, Persistent/Rising MRD:
New therapy option added: Inotuzumab ozogamicin ± TKI
Top pathway modified: Consider allogeneic hematopoietic cell transplantation (HCT)

Continued
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Table of Contents
Acute Lymphoblastic Leukemia Discussion

Updates in Version 1.2024 of the NCCN Guidelines for Acute Lymphoblastic Leukemia from Version 4.2023 include:
ALL-5A
• Footnote gg added: Prior to blinatumomab initiation, cytoreduce with TKI + corticosteroid to peripheral WBC count of <10 x 109/L. Foà R, et al. N Engl J
Med 2020;383:1613-1623.
• Footnote ll modified: Although long-term remission after blinatumomab + TKI monotherapy is possible, allogeneic HCT can should be considered as
consolidative therapy
• Footnote mm added: Blinatumomab + TKI is preferred in consolidation regardless of MRD status for those who have not previously received
blinatumomab.
• Footnote nn added: 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. (Also for ALL-6A)
• Footnote pp modified: 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. (Also for ALL-6A, ALL-7)
• Footnote uu modified: Consider sequential periodic MRD monitoring (no more than every 3 months) for patients with complete molecular remission
(undetectable levels). Increased frequency may be indicated for detectable levels or for those discontinuing TKI.
• Footnote removed: For patients who are not candidates for multiagent therapy.
ALL-6
• Page extensively revised
ALL-6A
• Footnote ww modified: If MRD is unavailable, consider retesting for MRD at first available opportunity.
• Footnote yy added: Blinatumomab is preferred for those with persistent or rising MRD who have not previously received blinatumomab.
• Footnote zz modified: ECOG1910 included patients aged 30–70 years, but multiagent therapy with blinatumomab as consolidation can be considered in
AYA patients. Blinatumomab should be incorporated into frontline therapy as a post-remission approach based on data from ECOG1910.
• Footnote aaa modified: Although long-term remission after blinatumomab monotherapy is possible, allogeneic HCT can should be considered as
consolidative therapy
ALL-9A
• Footnote fff modified: Isolated extramedullary relapse (including both 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.
• Footnote kkk modified: The role of allogeneic HCT following cellular therapy tisagenlecleucel is unclear. Persistence of tisagenlecleucel in peripheral
blood and persistent B-cell aplasia has been associated with durable clinical responses without subsequent HCT. In the global registration trial, relapse-
free survival was 59% at 12 months, with only 9% of patients proceeding to HCT.
• Footnote lll modified: 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; for Treatment of Adults ≥65 years or Adults with Substantial Comorbidities, see ALL-D 4 of
9).

NCCN Guidelines Version 2.2024 NCCN Guidelines Index

Table of Contents
Acute Lymphoblastic Leukemia Discussion

Updates in Version 1.2024 of the NCCN Guidelines for Acute Lymphoblastic Leukemia from Version 4.2023 include:
ALL-C 1 of 4
• Best Supportive Care
6th bullet removed and moved to ALL-C 2 of 4: Consider defibrotide for patients who develop veno-occlusive disease (VOD) related to inotuzumab
ozogamicin toxicity.
ALL-C 3 of 4
• Asparaginase Toxicity Management
4th bullet modified: All toxicity grades refer to CTCAE v5.0 4.03.
6th bullet added: Consider anticoagulation prophylaxis if no contraindications.
• Hypersensitivity, Allergy, and Anaphylaxis
1st bullet modified: ERW-rywn should may be used as a second-line agent in patients who have developed a systemic allergic reaction or anaphylaxis
due to PEG hypersensitivity.
2nd bullet modified: Anaphylaxis or other allergic reactions of Grade 3–4 severity (CTCAE v5.0 4.03) merit permanent discontinuation of the type of
asparaginase that caused the reaction.
• Footnote a added: In the setting of AYA/Adult ALL, Cal-PEG is substituted for PEG in patients aged 15 to ≤21 years for more sustained asparaginase
activity.
• Footnote c modified: National Institutes of Health; National Cancer Institute. Common Terminology Criteria for Adverse Events (CTCAE) version 5.0
2017 4.03 2010. Available at: [Link]
ALL-C 4 of 4
• Non-CNS Thromboembolism
1st bullet modified: For Grade 2 or greater thromboembolic event, hold asparaginase until resolved and treat with appropriate antithrombotic therapy.
Upon resolution of symptoms and antithrombotic therapy stable or completed, consider resuming asparaginase.
ALL-D
• Section extensively revised
ALL-E 1 of 2
• Page extensively revised

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Table of Contents
Acute Lymphoblastic Leukemia Discussion

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: All recommendations are category 2A unless otherwise indicated.

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ALL-1
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Acute Lymphoblastic Leukemia Discussion

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: All recommendations are category 2A unless otherwise indicated.

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Acute Lymphoblastic Leukemia Discussion

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: All recommendations are category 2A unless otherwise indicated.

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ALL-2
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Acute Lymphoblastic Leukemia Discussion

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: All recommendations are category 2A unless otherwise indicated.

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Acute Lymphoblastic Leukemia Discussion

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: All recommendations are category 2A unless otherwise indicated.

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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: 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
or (HCT)ll,pp,qq,rr
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: 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: All recommendations are category 2A unless otherwise indicated.

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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: 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: 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: 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: 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
Note: 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.

Note: 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.

Note: All recommendations are category 2A unless otherwise indicated.

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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.

Note: All recommendations are category 2A unless otherwise indicated.

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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: All recommendations are category 2A unless otherwise indicated.
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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: All recommendations are category 2A unless otherwise indicated.
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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.
a In the setting of AYA/Adult ALL, Cal-PEG is substituted for PEG in patients aged 15 to
≤21 years for more sustained asparaginase activity.
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 4 Maese LD, Loh ML, Choi MR, et al. Recombinant erwinia asparaginase (JZP458) in acute

for Adverse Events (CTCAE) version 5.0 2017. Available at: [Link] lymphoblastic leukemia: Results from the phase 2/3 AALL1931 study. Blood 2023;141:704-712.
5 Hu Z, Persaud Y, Ahuja S. A systematic review and meta-analysis of the effectiveness of
protocoldevelopment/electronic_applications/[Link]
3 For more detailed information, refer to Stock W, Douer D, DeAngelo DJ, et al. primary thromboprophylaxis in acute lymphoblastic leukemia during early-phase therapy
Prevention and management of asparaginase/pegasparaginase-associated toxicities in 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
adults and older adolescents: recommendations of an expert panel. Leuk Lymphoma
2011:52:2237-2253. following treatment with pegaspargase. Pediatr Blood Cancer 2015;62:1102-1105.
Continued
Note: All recommendations are category 2A unless otherwise indicated.
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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.

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: All recommendations are category 2A unless otherwise indicated.

Note: All recommendations are category 2A unless otherwise indicated.

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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.

Note: All recommendations are category 2A unless otherwise indicated.

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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: All recommendations are category 2A unless otherwise indicated.

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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

Note: All recommendations are category 2A unless otherwise indicated.

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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: All recommendations are category 2A unless otherwise indicated.

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Ph-NEGATIVE B-ALL CONSOLIDATION COMPONENTS (MRD NEGATIVE/UNAVAILABLE) FOOTNOTES
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: All recommendations are category 2A unless otherwise indicated.

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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

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: All recommendations are category 2A unless otherwise indicated.

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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: All recommendations are category 2A unless otherwise indicated.

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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: All recommendations are category 2A unless otherwise indicated.

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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

Regimen components on ALL-D 20 of 28

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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

Note: All recommendations are category 2A unless otherwise indicated.

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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: All recommendations are category 2A unless otherwise indicated.

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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: All recommendations are category 2A unless otherwise indicated.

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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.

Note: 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: All recommendations are category 2A unless otherwise indicated.

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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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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 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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NCCN Guidelines Version 2.2024

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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NCCN Guidelines Version 2.2024

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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NCCN Guidelines Version 2.2024

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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NCCN Guidelines Version 2.2024

Acute Lymphoblastic Leukemia

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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Acute Lymphoblastic Leukemia

(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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NCCN Guidelines Version 2.2024

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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NCCN Guidelines Version 2.2024

Acute Lymphoblastic Leukemia

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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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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NCCN Guidelines Version 2.2024

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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NCCN Guidelines Version 2.2024

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

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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NCCN Guidelines Version 2.2024

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

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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NCCN Guidelines Version 2.2024

Acute Lymphoblastic Leukemia

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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NCCN Guidelines Version 2.2024

Acute Lymphoblastic Leukemia

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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Acute Lymphoblastic Leukemia

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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NCCN Guidelines Version 2.2024

Acute Lymphoblastic Leukemia

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NCCN Guidelines Version 2.2024

Acute Lymphoblastic Leukemia

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NCCN Guidelines Version 2.2024

Acute Lymphoblastic Leukemia

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NCCN Guidelines Version 2.2024

Acute Lymphoblastic Leukemia

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Acute Lymphoblastic Leukemia

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Acute Lymphoblastic Leukemia

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Acute Lymphoblastic Leukemia

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Acute Lymphoblastic Leukemia

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Acute Lymphoblastic Leukemia

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Acute Lymphoblastic Leukemia

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Acute Lymphoblastic Leukemia

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Acute Lymphoblastic Leukemia

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NCCN Guidelines Version 2.2024

Acute Lymphoblastic Leukemia

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MS-88
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MS-89
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NCCN Guidelines Version 2.2024

Acute Lymphoblastic Leukemia

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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
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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
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367. Weiss MA, Aliff TB, Tallman MS, et al. A single, high dose of
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368. Gokbuget N, Basara N, Baurmann H, et al. High single-drug activity
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363. Horton TM, Whitlock JA, Lu X, et al. Bortezomib reinduction of post-transplant refractory T-acute lymphoblastic leukemia-a
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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
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MS-93
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Acute Lymphoblastic Leukemia

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MS-97
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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:
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NCCN Guidelines Version 2.2024

Acute Lymphoblastic Leukemia

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Acute Lymphoblastic Leukemia

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