NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®)

Acute Myeloid Leukemia

Version 3.2026 — November 24, 2025

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Trials should be designed to maximize inclusiveness and broad representative enrollment.

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NCCN Guidelines Version 3.2026 NCCN Guidelines Index

Table of Contents
Acute Myeloid Leukemia (Age ≥18 years) Discussion

*Daniel A. Pollyea, MD, MS/Chair ‡ Þ † Gabriel Mannis, MD ‡ † Dinesh Rao, MD, PhD ≠
University of Colorado Cancer Center Stanford Cancer Institute UCLA Jonsson Comprehensive Cancer Center
*Jessica K. Altman, MD/Vice Chair ‡ Guido Marcucci, MD † Þ Farhad Ravandi, MD Þ ‡
Robert H. Lurie Comprehensive Cancer City of Hope National Medical Center The University of Texas
Center of Northwestern University Alice Mims, MD, MS † MD Anderson Cancer Center
Rita Assi, MD ‡ The Ohio State University Comprehensive Zaker Schwabkey, MD ‡
Indiana University Melvin and Bren Simon Cancer Center - James Cancer Hospital Huntsman Cancer Institute
Comprehensive Cancer Center and Solove Research Institute at the University of Utah
Kimo Bachiashvili, MD, MPH ‡ Kelsey Moriarty, MS, CGC Rory Shallis, MD ‡
O'Neil Comprehensive Cancer Center at UAB UT Southwestern Simmons Yale Cancer Center/Smilow Cancer Hospital
Vijaya Raj Bhatt, MBBS, MS ‡ ξ Comprehensive Cancer Center Richard M. Stone, MD ‡ †
Fred & Pamela Buffett Cancer Center Moaath Mustafa Ali, MD, MPH ‡ Dana-Farber/Brigham and
Amir T. Fathi, MD ‡ † Case Comprehensive Cancer Center/ Women’s Cancer Center
Mass General Cancer Center University Hospitals Seidman Cancer Center Swapna Thota, MD ‡ †
and Cleveland Clinic Taussig Cancer Institute St. Jude Children's Research Hospital/The
Kateryna Fedorov, MD ‡
Vanderbilt-Ingram Cancer Center Jadee Neff, MD, PhD ≠ University of Tennessee Health Science Center
Duke Cancer Institute Geoffrey L. Uy, MD † ‡ ξ
James M. Foran, MD †
Mayo Clinic Comprehensive Cancer Center Reza Nejati, MD ≠ Siteman Cancer Center at Barnes-
Fox Chase Cancer Center Jewish Hospital and Washington
Ivana Gojo, MD ‡ University School of Medicine
Johns Hopkins Kimmel Cancer Center Rebecca Olin, MD, MSCE ‡ ξ
UCSF Helen Diller Family Alison Walker, MD, MBA, MPH ‡
Aaron Goldberg, MD, PhD ‡ Þ Comprehensive Cancer Center Moffitt Cancer Center
Memorial Sloan Kettering Cancer Center
Anand Patel, MD ‡ Eunice Wang, MD ‡
Aric C. Hall, MD ‡ ξ The UChicago Medicine Roswell Park Comprehensive Cancer Center
University of Wisconsin Comprehensive Cancer Center
Carbone Cancer Center NCCN
Mary-Elizabeth Percival, MD, MS ‡ Ajibola Awotiwon, MBBS, MSc
Brian A. Jonas, MD, PhD ‡ Fred Hutchinson Cancer Center Sydney L. Roth, BS
UC Davis Comprehensive Cancer Center
Alexander Perl, MD † Katie Stehman, PA-C, MMS
Matthew R. Levine, MD Abramson Cancer Center
Patient Advocate at the University of Pennsylvania
ξ Bone marrow transplantation
James Mangan, MD, PhD ‡ Kristen Pettit, MD ‡ ‡ Hematology/Hematology oncology
UC San Diego Moores Cancer Center University of Michigan Rogel Cancer Center Þ Internal medicine
† Medical oncology
≠ Pathology
* Discussion Section Writing Committee Member
NCCN Guidelines Panel Disclosures
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NCCN Guidelines Version 3.2026 NCCN Guidelines Index

Table of Contents
Acute Myeloid Leukemia (Age ≥18 years) Discussion

NCCN Acute Myeloid Leukemia Panel Members

Summary of the Guidelines Updates Find an NCCN Member Institution:
Evaluation for AML (EVAL-1) • ELN Risk Stratification by Biological Disease [Link]
Factors for Patients with Non-APL AML Treated institutions.
APL with Intensive Induction Chemotherapy (AML-A) NCCN Categories of Evidence and
• Classification and Treatment Recommendations • Evaluation and Treatment of CNS Leukemia
Consensus: All recommendations
(APL-1) (AML-B)
• Low-Risk Treatment Induction and Consolidation • Principles of Radiation Therapy (AML-C) are category 2A unless otherwise
Therapy (APL-2) • General Considerations and Supportive Care for indicated.
• High-Risk Induction and Consolidation Therapy Patients with AML Who Prefer Not to Receive See NCCN Categories of Evidence
(APL-3) Blood Transfusions (AML-D) and Consensus.
• Post-Consolidation Therapy and Monitoring (APL-5) • Principles of Systemic Therapy for AML (AML-E)
• Therapy for Relapse (APL-6) • Principles of Supportive Care for AML (AML-F)
• Principles of Supportive Care for APL (APL-A) • Monitoring During Intensive Therapy (AML-G)
NCCN Categories of Preference:
• Principles of Systemic Therapy for APL (APL-B) • Measurable (Minimal) Residual Disease
Assessment (AML-H) All recommendations are considered
AML • Response Criteria Definitions for Acute Myeloid appropriate.
• Risk Group and Induction (Intensive Induction Leukemia (AML-I) See NCCN Categories of Preference.
Eligible) (AML-1) • Principles of Venetoclax Use with HMA or LDAC
• Follow-up and Reinduction After Cytarabine-Based (AML-J) • Abbreviations (ABBR-1)
Induction (AML-3)
• Risk Group and Induction (Intensive Induction BPDCN
Ineligible or Declines) (AML-4) • Introduction (BPDCN-INTRO)
• Follow-up After Induction Therapy with Lower • Evaluation/Workup (BPDCN-1)
Intensity Therapy (Intensive Induction Ineligible or • Treatment (BPDCN-2)
Declines) (AML-5) • Surveillance and Treatment for Relapsed/
• Consolidation Therapy (Intensive Induction Eligible) Refractory Disease (BPDCN-4)
(AML-6) • Principles of BPDCN (BPDCN-A)
• Maintenance Therapy (AML-7) • Evaluation and Treatment of CNS Disease
• AML Surveillance and Therapy for Relapsed/ (BPDCN-B)
Refractory Disease (AML-8) • Principles of Supportive Care for BPDCN
• Therapy for Relapsed/Refractory Disease (AML-9) (BPDCN-C)

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. ©2025.

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 PLEASE NOTE that use of this NCCN Content is governed by the End-User License Agreement, and you MAY NOT distribute this Content or use it with any artificial intelligence model or tool.
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NCCN Guidelines Version 3.2026 NCCN Guidelines Index

Table of Contents
Acute Myeloid Leukemia (Age ≥18 years) Discussion

Updates in Version 3.2026 of the NCCN Guidelines for Acute Myeloid Leukemia include:
AML-9
• Therapy For Relapsed/Refractory Disease
Targeted therapy: Therapy for AML with NPM1 mutation, ziftomenib added.
AML-E 8 of 14
• Principles of Systemic Therapy For AML; Therapy For Relapsed/Refractory Disease: Targeted therapy
Therapy added: Ziftomenib (NPM1 mutation)
Regimen added: 600 mg once daily on days 1-28 of a 28-day cycle
• Footnote v modified: Revumenib is FDA approved for the treatment of relapsed or refractory acute leukemia with a KMT2A translocation, as well as relapsed or
refractory AML with a susceptible NPM1 mutation with no satisfactory alternative treatment options, in adult and pediatric patients ≥1 year.
• Footnote x added: Ziftomenib is FDA approved for the treatment of adults with relapsed or refractory AML with a susceptible NPM1 mutation with no satisfactory
alternative treatment options.
AML-E 13 of 14
• Reference 64 added: Wang ES, Montesinos P, Foran J, et al. Ziftomenib in relapsed or refractory NPM1-mutated AML. J Clin Oncol 2025;43:3381–3390.
MS-1
• The discussion section has been updated to reflect the changes in the algorithm.

Updates in Version 2.2026 of the NCCN Guidelines for Acute Myeloid Leukemia include:
AML-E 9 OF 14
• Fludarabine + cytarabine + G-CSF + idarubicin + venetoclax regimen modified: Fludarabine 30 mg/m2 on days 2–6; cytarabine 1.5–2 g/m2 over 4 hours starting 4 hours
after fludarabine infusion on days 2–6; G-CSF SC daily on days 1–7; idarubicin 6 mg/m2 IV on days 4–5; venetoclax 400 mg on days 1–7 14. Corresponding reference
updated to DiNardo CD, Jen WY, Takahashi K, et al. Long term results of venetoclax combined with FLAG-IDA induction and consolidation for newly diagnosed and
relapsed or refractory acute myeloid leukemia. Leukemia 2025;39:854-863.
MS-1
• The discussion section has been updated to reflect the changes in the algorithm.

Updates in Version 1.2026 of the NCCN Guidelines for Acute Myeloid Leukemia include:
General
• References updated across the guidelines.
EVAL-1
• Evaluation For AML
5th bullet modified: Bone marrow (BM) core biopsy and aspirate analyses, including immunophenotyping by immunohistochemistry (IHC) stains + flow cytometry, and
the analysis of chromosomal structural variations by cytogenetics, fluorescence in situ hybridization (FISH), and or whole genome next generation sequencing (NGS)
(AML-A)
6th bullet modified: Molecular analyses for lesions that allow risk stratification as per ELN 2022 (ASXL1, BCOR, KIT, EZH2, FLT3 [internal tandem duplication (ITD)
and tyrosine kinase domain (TKD)], NPM1, in-frame bZIP mutation in CEBPA, IDH1, IDH2, RUNX1, SF3B1, SRSF2, STAG2, TP53, U2AF1, ZRSR2 and other
mutations) (AML-A)
8th bullet modified: Consider additional molecular and genetic testing for heritable hematologic malignancy predisposition in a subset of patients, particularly in
patients <50 years and those with a family history (see MDS-D and MDS-E in the NCCN Guidelines for Myelodysplastic Syndromes)
13th bullet modified: Lumbar puncture (LP), if symptomatic (category 2B for asymptomatic) (AML-B)

Continued
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NCCN Guidelines Version 3.2026 NCCN Guidelines Index

Table of Contents
Acute Myeloid Leukemia (Age ≥18 years) Discussion

Updates in Version 1.2026 of the NCCN Guidelines for Acute Myeloid Leukemia include:
EVAL-2
• Diagnosis
AML
◊ 1st bullet modified: For patients with hyperleukocytosis uncontrolled with hydroxyurea or leukapheresis, one dose of cytarabine (0.5 1–2 g) may be considered
prior to receiving diagnostic results. Leukapheresis may be considered for certain patients with symptomatic hyperleukocytosis, though data for benefit are limited
EVAL-2A
• Footnote a added: Refer to the NCCN Distress Thermometer and Problem List, which includes social determinants of health. See NCCN Guidelines for Distress
Management (DIS-A).
APL-3
• APL Treatment Induction (High Risk)
Preferred Regimens pathway modified: BM aspirate and biopsy at day 28 to document remission consider LP before proceeding with consolidation (Also Useful in
Certain Circumstances on APL-3 and Prolonged QTcF on APL-4)
Footnote g added: Begin prophylaxis with prednisone; the optimal duration of steroid prophylaxis is unknown. If differentiation syndrome develops, change to
dexamethasone. Lo-Coco F, et al. N Engl J Med 2013;369:111-121. See Principles of Supportive Care for APL (APL-A). (Also APL-4)
Footnote m added: For all patients with high-risk APL, consider LP before proceeding with consolidation. (Also APL-4)
APL-5
• Footnote n modified: PCR should be performed on a blood sample at completion of consolidation to document molecular remission. In patients receiving the ATRA/
arsenic regimen, consider earlier sampling at 3–4 months during consolidation. Prior practice guidelines have recommended monitoring blood by PCR every 3
mo for 2 y to detect molecular relapse. We continue to endorse this for patients with high-risk disease or those >60 y of age or who had long interruptions during
consolidation, or patients on regimens that use maintenance and are not able to tolerate maintenance. Clinical experience indicates that risk of relapse in patients with
low-risk disease who are in molecular remission at completion of consolidation is low and monitoring may not be necessary outside the setting of a clinical trial. While
long-term monitoring has been standard, with newer, more effective regimens, the value is less certain.
APL-A
• Principles of Supportive Care For APL
5th bullet, 2nd sub bullet modified: For patients at high risk (WBC count >10 x 109/L) for developing differentiation syndrome and for those receiving an ATRA/arsenic
trioxide-based regimen, initiate prophylaxis with corticosteroids, either prednisone 0.5 mg/kg day 1 or dexamethasone 10 mg every 12 hours (see NCCN Guidelines
for Prevention and Treatment of Cancer-Related Infections). Taper the steroid dose over a period of several days. If patient develops differentiation syndrome,
change prednisone to dexamethasone 10 mg every 12 hours until count recovery or risk of differentiation has abated.
6th bullet, 1st sub bullet, 2nd sub sub bullet modified: Serum electrolytes (Ca, K, Mg, phosphorus) and creatinine
APL-B 1 OF 6
• Principles of Systemic Therapy For APL
Footnote b added: The optimal dosing of arsenic trioxide for patients with obesity is unknown, though retrospective studies suggest there may be a role for dose
capping. Zacholski K, et al. J Oncol Pharm Pract 2022;28:1340-1349; Jen WY, et al. Leuk Lymphoma 2024;65:378-382. (Also APL-B 2 of 6, APL-B 3 of 6, APL-B 4A
of 6, APL-B 5 of 6)
AML-1
• Intensive Induction Eligible
1st pathway, Favorable-risk AML by cytogenetics (core binding factor [CBF]-AML)
◊ Other Recommended, regimen removed: 7 + 3 (mitoxantrone) (for age ≥60 y)
2nd pathway, Favorable-risk AML by molecular mutation profiled or Intermediate-risk AML per ELN (AML-A)
◊ Preferred, regimen removed: 7 + 3 (mitoxantrone) (for age ≥60 y) Continued
◊ Other Recommended, 4th regimen modified: CLAG-M (cladribine + cytarabine + G-CSF - mitoxantrone) (category 2B; use with caution in patients >60 y)

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NCCN Guidelines Version 3.2026 NCCN Guidelines Index

Table of Contents
Acute Myeloid Leukemia (Age ≥18 years) Discussion

Updates in Version 1.2026 of the NCCN Guidelines for Acute Myeloid Leukemia include:
AML-2
• Intensive Induction Eligible
Poor/Adverse-Risk Groups
◊ 1st pathway
– 3rd bullet modified: Cytogenetic or molecular changes consistent with MDS (previously classified as AML with myelodysplasia-related changes [AML-MRC])
• Intensive Induction Eligible
Treatment Induction,
◊ Principles of Venetoclax, see AML-J removed
◊ 1st pathway, Therapy-related AML other than CBF-AML; Antecedent MDS/chronic myelomonocytic leukemia (CMML); Cytogenetic or molecular changes
consistent with MDS (previously classified as AML with myelodysplasia-related changes [AML-MRC]), Other recommended
– 5th regimen added: CLIA (cladribine + idarubicin + cytarabine) + venetoclax (category 2B)
– 6th regimen added: FLAG-IDA + venetoclax (category 2B; use with caution in patients >60 y)
◊ 2nd pathway, Poor-risk AML without TP53 mutation or del(17p) abnormality, Other recommended
– 7th regimen added: CLIA + venetoclax (category 2B)
– 8th regimen added: FLAG-IDA + venetoclax (category 2B; use with caution in patients >60 y)
◊ 2nd pathway, Poor-risk AML without TP53 mutation or del(17p) abnormality, Useful in certain circumstances
– Regimen removed: 7 + 3 (mitoxantrone) (for age ≥60 y) (category 2B)
– Regimen removed: Cytarabine + (daunorubicin or idarubicin) + etoposide (category 2B for patients >45 y) (use with caution in patients >60 y)
AML-2A
• Footnote k modified: For CBF-AML with FLT3-TKD mutation, the Panel prefers gemtuzumab ozogamicin over an FLT3 inhibitor. For CBF-AML with FLT3-ITD, there is
insufficient data to recommend one as preferred over the other.
• Footnote r modified: There are limited data supporting the use of this regimen in patients aged <60 years. For patients with AML with cytogenetic changes consistent
with MDS (previously classified as AML-MRC) and previous hypomethylating agent (HMA) exposure, the benefit from standard induction did not differ from the benefit
with CPX-351/dual-drug liposomal encapsulation of cytarabine and daunorubicin. Lancet JE, et al. J Clin Oncol 2018;36:2684-2692. While the mutational definition of
AML-MRC as it applies to the use of CPX-351/dual-drug liposomal cytarabine and daunorubicin was not studied in the original trial, its use can be considered. There is
emerging data that CPX-351/dual-drug liposomal encapsulation of cytarabine and daunorubicin provides most benefit for patients with AML with mutations in SRSF2,
SF3B1, EZH2, U2AF1, ZRSR2, BCOR, STAG2, or ASXL1 (Shimony SO, et al. Blood 2024;144:60). (Also AML-6A)
• Footnote u modified: Patients with cytopenias with disease in remission should take breaks between cycles. For more details about cycle length, see Principles of
Venetoclax (AML-J). (Also AML-4A)
AML-3
• Follow-Up And Reinduction After Cytarabine-Based Induction
3rd column
◊ Regimen removed: 7 + 3 (mitoxantrone) (for age ≥60 y)
◊ 6th regimen added: HMA (azacitidine or decitabine) + venetoclax
◊ 7th bullet modified: CPX-351/dual-drug liposomal encapsulation of cytarabine and daunorubicin (therapy-related AML other than CBFAML, antecedent MDS/
CMML, or cytogenetic or molecular changes consistent with MDS AML-MRC) (preferred only if given in induction; BM aspirate and biopsy 14–21 days after start of
therapy)
◊ 8th bullet modified: Consider regimens for relapsed/refractory disease, including targeted therapies, if lack of response to induction (Response criteria, see AML-I).
Therapy for Relapsed/Refractory Disease (AML-9)
5th column, 1st pathway modified: Response CR (Screening LP, see AML-B) (Response criteria, see AML-I)
6th column
◊ 1st pathway modified: Consolidation (if received intensive re-induction Eligible) (AML-6) Continued
◊ 2nd pathway added: Continue lower intensity therapy (if received HMA + venetoclax reinduction) (AML-5)
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NCCN Guidelines Version 3.2026 NCCN Guidelines Index

Table of Contents
Acute Myeloid Leukemia (Age ≥18 years) Discussion

Updates in Version 1.2026 of the NCCN Guidelines for Acute Myeloid Leukemia include:
AML-3A
• Footnote s added: Venetoclax combination regimens may be continued for patients whose disease demonstrates clinical improvement (CR/CR with incomplete
hematologic recovery [CRi]), with consideration of subsequent transplant, where appropriate. DiNardo CD, et al. Lancet Oncol 2018;19:216-228; Wei A, et al. Blood
2017;130:890; DiNardo CD, et al. Blood 2019;133:7-17; DiNardo CD, et al. N Engl J Med 2020;383:617-629; Kadia TM, et al. J Clin Oncol 2022;40:3848-3857.
• Footnote t added: Patients whose disease has progressed to AML from MDS after significant exposure to HMAs (ie, azacitidine, decitabine) may be less likely to derive
benefit from continued treatment with HMAs compared to patients who are HMA-naïve. Alternative treatment strategies should be considered. DiNardo CD, et al.
Blood 2019;133:7-17.
• Footnote u added: Patients with cytopenias with disease in remission should take breaks between cycles. For more details about cycle length, see Principles of
Venetoclax (AML-J).
AML-4
• Lower Intensity Therapy (Intensive Induction Ineligible or Declines)
Treatment Induction, AML with IDH1 mutation
◊ Preferred
– Regimen moved here from Other Recommended: Decitabine + venetoclax
◊ Useful in Certain Circumstances
– 3rd regimen added: Olutasidenib (category 2B) (not eligible for preferred regimen and not eligible for ivosidenib due to prolonged QTcF)
AML-4A
• Footnote cc modified: Response to treatment with IDH inhibitors enasidenib or ivosidenib may take 3–5 months.
• Footnote dd modified: IDH inhibitors Enasidenib or ivosidenib increases the risk for differentiation syndrome and hyperleukocytosis that may require treatment with
hydroxyurea and steroids. Monitor closely for differentiation syndrome and initiate therapy to resolve symptoms according to indications. Note that differentiation
syndrome can occur later (up to several months after induction).
AML-8
• AML Surveillance And Therapy For Relapsed/Refractory Disease (After Completion Of Consolidation)
1st column, 4th bullet modified: Confirm molecular remission and monitor for molecular relapse, if applicable. See Measurable (Minimal) Residual Disease
Assessment (AML-H)
4th column, 2nd option modified: Targeted therapy alone or in combination (AML-9) followed by allogeneic HCT
• Footnote ww modified: Molecular and cytogenetic analyses Multi-gene molecular profiling/targeted NGS (including testing for IDH1/IDH2, FLT3 mutations, and KMT2A
rearrangements) are is suggested as it may assist with selection of therapy and appropriate clinical trials (Discussion). Molecular testing should be repeated at each
relapse or progression.
AML-9
• Therapy For Relapsed/Refractory Disease
Targeted therapy: Therapy for AML with NPM1 mutation, revumenib added.
• Footnote zz added: There have been trials conducted combining targeted therapies with other agents.
• Footnote aaa added: Best sequencing of targeted therapies is unknown at this time and depends on clinical context.
AML-B
• Evaluation And Treatment of CNS Leukemia
Footnote c modified: Screening LP should be considered at first remission before first intensive consolidation for asymptomatic patients with monocytic differentiation,
MPAL, WBC count >40 x 109/L at diagnosis, extramedullary disease, high-risk APL, intraparenchymal hemorrhage at diagnosis, or FLT3 mutations, MLLT3::KMT2A
fusion, monocytic differentiation, or MPAL. For further information regarding MPAL, see NCCN Guidelines for Acute Lymphoblastic Leukemia.

Continued

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 PLEASE NOTE that use of this NCCN Content is governed by the End-User License Agreement, and you MAY NOT distribute this Content or use it with any artificial intelligence model or tool.
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NCCN Guidelines Version 3.2026 NCCN Guidelines Index

Table of Contents
Acute Myeloid Leukemia (Age ≥18 years) Discussion

Updates in Version 1.2026 of the NCCN Guidelines for Acute Myeloid Leukemia include:
AML-E 1 OF 14
• Principles of Systemic Therapy For AML. Intensive Induction Eligible
Regimen removed: Standard 7 + 3 (mitoxantrone)
AML-E 1A of 14
• Footnote f added: Daunorubicin 60 mg/m2 is preferred over 90 mg/m2. Rollig C, et al. J Clin Oncol 2025;43:65-74.
• Footnote removed: For age ≥60 years
AML-E 2 OF 14
• Principles of Systemic Therapy For AML. Intensive Induction Eligible
4th regimen added: CLIA + venetoclax
5th regimen added: FLAG-IDA + venetoclax
Regimen removed: Cytarabine (HiDAC) + (daunorubicin or idarubicin) + etoposide
• Footnote g added: In times of fludarabine shortage, cladribine can be substituted for fludarabine.
• Footnote i modified: Patients with cytopenias with disease in remission should take breaks between cycles. For more details about cycle length, see AML-J. (Also
AML-E 4, AML-E 10)
• Footnote j added: Principles of Venetoclax Use With HMA or LDAC (AML-J). (Also AML-E 3A, AML-E 4, AML-E 10)
• Footnote k added: Use with caution in patients >60 years.
• Principles of Systemic Therapy For AML. Intensive Induction Eligible
The following footnotes were removed:
◊ The CR rates and 2-year OS in patients between 60 and 65 years of age treated with daunorubicin 90 mg/m2 is also comparable to the outcome for idarubicin 12
mg/m2; the higher-dose daunorubicin did not benefit patients >65 years of age (Löwenberg B, et al. N Engl J Med 2009;361:1235-1248).
◊ The use of doses of cytarabine ≥2 g/m2 for induction outside the setting of a clinical trial is still controversial. While the remission rates are the same for doses of
cytarabine >100 to 200 mg/m2 and doses of cytarabine ≥2 g/m2, two studies have shown more rapid BM blast clearance after one cycle of high-dose therapy. Kern
W, Estey EH. Cancer 2006;107:116-124.
AML-E 3 OF 14
• Principles of Systemic Therapy For AML. Reinduction In The Setting Of Residual Disease After Cytarabine-Based Induction
• Regimen added: HMA (azacitidine or decitabine) + venetoclax
• Regimen removed: Standard 7 + 3 (mitoxantrone)
AML-E 3A OF 14
• Footnote i added: Patients with cytopenias with disease in remission should take breaks between cycles. For more details about cycle length, see AML-J.
AML-E 4 OF 14
• Principles of Systemic Therapy For AML. Lower Intensity Therapy (Intensive Induction Ineligible or Declines)
8th regimen added: Olutasidenib
AML-E 8 OF 14
• Principles of Systemic Therapy For AML. Therapy For Relapsed/Refractory Disease: Targeted therapy
8th regimen modified: Revumenib (KMT2A rearrangement or NPM1 mutation)
AML-F
• Footnote a added: Refer to the NCCN Distress Thermometer and Problem List, which includes social determinants of health. See NCCN Guidelines for Distress
Management (DIS-A).
AML-G
• Heading modified: Monitoring During Intensive Therapy

Continued

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NCCN Guidelines Version 3.2026 NCCN Guidelines Index

Table of Contents
Acute Myeloid Leukemia (Age ≥18 years) Discussion

Updates in Version 1.2026 of the NCCN Guidelines for Acute Myeloid Leukemia include:
AML-H 1 OF 4
• Measurable (Minimal) Residual Disease Assessment
The following bullets were moved from Methods of Testing section to General section:
◊ There are commercially available tests that can be used for MRD assessments, as well as further testing methods at certain academic centers.
◊ The most frequently used methods for MRD assessment include quantitative molecular assays such as real-time quantitative PCR (RQ-PCR) and multicolor flow
cytometry (MFC) assays specifically designed to detect abnormal MRD immunophenotypes.
◊ The optimal sample for initial MRD assessment is a first, dedicated pull of the BM aspirate. The quality of the sample is of paramount importance to have reliable
evaluation. Once MRD-negative remission by BM is achieved, peripheral blood can be utilized for surveillance of MRD for PML:RAR alpha, NPM1, CBFB::MYH11,
and RUNX1::RUNX1T1.
◊ Mutations associated with clonal hematopoiesis of indeterminate potential (CHIP) and aging (ie, DNMT3A, TET2, potentially ASXL1) are not considered reliable
markers for MRD and are difficult to differentiate in routine practice.
AML-H 1 OF 4
• Measurable (Minimal) Residual Disease Assessment
Methods of Testing
◊ Flow Cytometry, 1st bullet modified: If using flow cytometry to assess MRD, it is recommended that a specific MRD assay that incorporates both different
from normal and leukemia-associated immunophenotypes (LAIPs) assessment is utilized, but, most importantly, that it is interpreted by an experienced
hematopathologist, preferably at the same laboratory as diagnostic flow cytometry for consistency. Utilization of an assay with minimum limit of detection of ≤10-3 is
recommended.
◊ Molecular, 1st bullet modified: The Panel recommends RQ-PCR for detection of PML::RAR alpha, NPM1, CBFB::MYH11, and RUNX1::RUNX1T1. Utilization of an
assay with minimum limit of detection of ≤10-4 is recommended.
AML-H 2 OF 4
• Measurable (Minimal) Residual Disease Assessment
Timing of MRD Assessment
◊ 1st bullet, 3rd sub bullet modified: For NPM1-mutated, CBFB::MYH11, and RUNX1::RUNX1T1 AML: after two cycles of intensive chemotherapy (eg, one cycle of
induction and one cycle of consolidation) and for serial monitoring every 6 to 12 weeks for 24 months.
◊ 2nd bullet, 2nd sub bullet added: NPM1 molecular MRD is strongly prognostic in patients receiving venetoclax-based low-intensity therapy. The Panel supports
monitoring NPM1 by RQ-PCR every 6 to 12 weeks in the BM or peripheral blood in patients receiving venetoclax-based low-intensity therapy.
Management of MRD Positivity
◊ 3rd bullet added: The Panel recommends post-transplant maintenance gilteritinib for patients with BM FLT3-ITD MRD ≥10-6 by a highly sensitive, NGS-based,
targeted, deep-sequencing assay with a sensitivity level of ≤10-5 pre- or post-allogeneic HCT.
◊ 4th bullet added: As there is no clear optimal management of MRD positivity, the Panel favors a clinical trial for MRD positivity if available. If a clinical trial,
allogeneic HCT, targeted therapy, or other consolidation strategies are not pursued, the Panel notes that venetoclax-based low-intensity therapy has demonstrated
high rates of MRD reduction in MRD and oligoblastic AML.
AML-I
• Response Criteria Definitions For Acute Myeloid Leukemia
2nd bullet, 1st sub bullet modified: Morphologic CR – transfusion independence
4th bullet, 1st sub bullet modified: Reappearance of leukemic blasts in the peripheral blood or the finding of ≥ > 5% blasts in the BM, not attributable to another cause
(eg, BM regeneration after consolidation therapy) or extramedullary relapse.
5th bullet, 1st sub bullet modified: Inability to attain CR, CRh, or CRi following exposure to at least 2 courses of intensive induction therapy.
6th bullet added: MRD relapse
◊ 1st sub bullet added: Conversion from MRD negativity to MRD positivity, independent of method of testing.
Continued

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Acute Myeloid Leukemia (Age ≥18 years) Discussion

Updates in Version 1.2026 of the NCCN Guidelines for Acute Myeloid Leukemia include:
AML-J 1 OF 4
• Principles of Venetoclax Use With HMA or LDAC
General, 5th bullet modified: Drug-drug interactions occur with strong or moderate CYP3A4 inhibitors and may require dose adjustment. Refer to venetoclax
prescribing information ([Link] and consult with a pharmacist for potential drug interactions. Strong or moderate
CYP3A4 inducers (eg, carbamazepine, phenytoin, rifampin) should be avoided.
Prognostic Risk Classification for Patients Ineligible for Intensive Therapy Treated with HMA/Venetoclax
◊ Intermediate benefit, Genetic Abnormality modified: Mutations in KRAS and/or NRAS and/or FLT3-ITD; negative for mutation in TP53
AML-J 2 OF 4
• Principles of Venetoclax Use With HMA or LDAC
New section added: Therapy for Patients with Substantial Comorbidities
AML-J 3 OF 4
• Principles of Venetoclax Use With HMA or LDAC
4th column, 2nd pathway, 1st bullet modified: G-CSF is encouraged may be added
6th column, 1st pathway
◊ 1st bullet added: Delay next cycle for up to 14 days to allow recovery of ANC >0.5 x 109/L and platelets >50 x 109/L
– 1st sub bullet added: G-CSF is encouraged
◊ 2nd bullet modified: Consider further reduction in venetoclax duration (eg, 14 days, 7 days, or 5 days) if cytopenias recur in subsequent cycles
BPDCN-1
• This page was extensively revised.
BPDCN-2
• This page was extensively revised.
BPDCN-3
• This page was extensively revised.
BPDCN-4
• Treatment For Relapsed/Refractory Disease
2nd bullet
◊ 2nd sub bullet modified: Tagraxofusp-erzs (preferred, if not already used)
◊ 6th sub bullet modified: HMA (azacitidine or decitabine) + venetoclax Venetoclax-based therapy, see BPDCN-2 AML-4
• Footnote removed: Consider CNS prophylaxis for patients with overt systemic disease.
BPDCN-A
• Principles of BPDCN. General Principles:
◊ 2nd bullet added: Diagnosis can be extremely challenging and whenever possible should involve an experienced hematopathologist.
◊ 7th bullet modified: Prognosis for BPDCN is poor and the median OS is approximately 8–12 months when patients are treated with chemotherapy without
consolidative allogeneic HCT.
◊ 9th bullet modified: For patients who are fit, current treatment options for BPDCN include tagraxofusp-erzs and chemotherapy, whereas those with low albumin
and/or comorbidities should receive non-intensive regimen options localized therapy or supportive care as shown in the algorithm (BPDCN-2).
BPDCN-B
• Evaluation And Treatment of CNS Disease
Without CNS disease, 1st bullet modified: Consider Administering prophylactic CNS-directed IT chemotherapy
MS-1
• The discussion section has been updated to reflect the changes in the algorithm.

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Acute Myeloid Leukemia (Age ≥18 years) Discussion

EVALUATION FOR AMLa

• History and physical (H&P)
• Complete blood count (CBC), platelets, differential, comprehensive metabolic panel
(CMP), uric acid, lactate dehydrogenase (LDH)
• B12 and folic acid evaluation
• Prothrombin time (PT), partial thromboplastin time (PTT), fibrinogen
• Bone marrow (BM) core biopsy and aspirate analyses, including immunophenotyping
by immunohistochemistry (IHC) stains + flow cytometry, and the analysis of
chromosomal structural variations by cytogenetics, fluorescence in situ hybridization
(FISH), and next generation sequencing (NGS) (AML-A)
• Molecular analyses for lesions that allow risk stratification as per ELN 2022b (AML-A)
• Comprehensive pathology report, including diagnosis of acute myeloid leukemia
(AML) within the context of the diagnostic system used,1,2,3 blast count, cellularity,
morphologic dysplasia, and mutation status if available
• Consider additional molecular and genetic testing for heritable hematologic
malignancy predisposition in a subset of patientsc (see MDS-D and MDS-E in the
Multidisciplinary diagnostic studies (EVAL-2)
NCCN Guidelines for Myelodysplastic Syndromes)
• Early referral to transplant center and/or human leukocyte antigen (HLA) typing for
patients with potential hematopoietic cell transplantation (HCT) in the future (except
for patients with a major contraindication to HCT)
• Brain CT without contrast, if central nervous system (CNS) hemorrhage suspectedd
(AML-B)
• Brain MRI with and without contrast, if leukemic meningitis suspectedd (AML-B)
• Consider FDG-PET/CT in individuals with extramedullary disease
• Lumbar puncture (LP), if symptomaticd (AML-B)
• Evaluate myocardial function (echocardiogram or multigated acquisition [MUGA]
scan) in patients with a history or symptoms of cardiac disease or prior/planned
exposure to cardiotoxic drugs or radiation therapy (RT) to thorax
• Counsel patients on infertility risk, with consideration of fertility preservation as
appropriate (see NCCN Guidelines for Adolescent and Young Adult (AYA) Oncology)
• Consider early integration of palliative care4 (see NCCN Guidelines for Palliative Care)

Footnotes and References on EVAL-2A

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

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Acute Myeloid Leukemia (Age ≥18 years) Discussion

DIAGNOSTIC DIAGNOSISe,f,g,2,3
STUDIES
Acute promyelocytic leukemia (APL):
In patients with clinical or pathologic features of APL, start all-trans retinoic APL Classification
acid (ATRA) upon first suspicion of APL.h Early initiation of ATRA may prevent and Treatment
the lethal complication of bleeding.h If cytogenetic and molecular testing do Recommendations
not confirm APL, discontinue ATRA and continue treatment as for AML (APL-1)

AML:
To appropriately stratify available intensive therapy options, expedite test
results of molecular and cytogenetic analyses for immediately actionable
mutations or chromosomal abnormalities
• For patients with hyperleukocytosis uncontrolled with hydroxyurea, Risk Group and
Multidisciplinary
cytarabine (0.5–2 g) may be considered prior to receiving diagnostic results. Induction (Intensive
diagnostic
Leukapheresis may be considered for certain patients with symptomatic Induction Eligible)
studiese,f,2,3
hyperleukocytosis, though data for benefit are limited.5,6 (AML-1)
• For patients who prefer not to receive blood transfusion(s), see AML-D for
general considerations and supportive care
For suspicion of blastic plasmacytoid dendritic cell neoplasm (BPDCN), see
BPDCN-INTRO

Myelodysplastic syndromes (MDS) See NCCN Guidelines for Myelodysplastic Syndromes

B-cell or T-cell lymphoblastic leukemia/lymphomaf See NCCN Guidelines for Acute Lymphoblastic Leukemia

Footnotes and References on EVAL-2A

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

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Acute Myeloid Leukemia (Age ≥18 years) Discussion

FOOTNOTES FOR EVALUATION FOR AML

a Refer to the NCCN Distress Thermometer and Problem List, which includes social determinants of health. See NCCN Guidelines for Distress Management (DIS-A).
b A variety of gene mutations are associated with specific prognoses (category 2A) and may guide medical decision-making (category 2B). Other genetic lesions may
have therapeutic significance. The field of genomics in myeloid malignancies and related implications in AML are evolving rapidly. Mutations should be tested in all
patients. Multiplex gene panels and targeted NGS analysis are recommended for the ongoing management of AML in various phases of treatment. (Papaemmanuil
E, et al. N Engl J Med 2016;374:2209-2221; Lindsley RC, et al. Blood 2015;125:1367-1376; Dohner H, et al. Blood 2022;140:1345-1377; Gardin C, et al. Blood Adv
2020;4:1942-1949; Tazi Y, Arango-Ossa JE, et al. Nat Commun 2022;13:4622). (Discussion). If a test is not available at your institution, consult the pathology team
(prior to performing the BM evaluation) about preserving material from the original diagnostic sample for future testing at an outside reference lab. Peripheral blood
may alternatively be used to detect molecular abnormalities in patients with disease with morphologically detectable, circulating leukemic blasts.
c A heritable hematologic malignancy predisposition syndrome may account for cytopenias with or without MDS in some patients, whether presenting to pediatric or
adult care centers (eg, GATA2 deficiency syndrome, Shwachman-Diamond syndrome, telomere biology disorders). Functional laboratory studies and constitutional
(germline) genetic testing using large NGS panels to include genes listed on MDS-E in the NCCN Guidelines for Myelodysplastic Syndromes, whole exome or whole
genome sequencing complemented within silico copy number variant (CNV) calling, and/or laboratory analysis for CNVs, such as microarray testing, is recommended
for certain patients. See Genetic Familial High-Risk Assessment: Hereditary Myeloid Malignancy Predisposition Syndromes (MDS-D) and Gene Mutations Associated
with Hereditary Myeloid Malignancy Predisposition Syndromes (MDS-E) in the NCCN Guidelines for Myelodysplastic Syndromes.
d Consider administration of one dose of intrathecal (IT) chemotherapy (methotrexate, cytarabine, or a combination of these agents) at time of diagnostic LP. See
Evaluation and Treatment of CNS Leukemia (AML-B).
e At the moment, there are discrepancies between two recognized classification systems (Khoury JD, et al. Leukemia 2022;36:1703-1719; Arber DA, et al. Blood
2022;140:1200-1228) for AML. The NCCN Guidelines do not advocate for one over another. Providers should exercise their best clinical judgment related to these
discrepancies, and the NCCN Panel recommends classification systems be written to allow for maximal clinical trial participation.
f When presented with rare cases such as acute leukemias of ambiguous lineage (ALAL), including mixed phenotype acute leukemias (MPAL) (according to 2022 WHO
classification), consultation with an experienced hematopathologist is strongly recommended.
g Patients with AML should preferably be cared for at experienced leukemia centers where clinical trials may be more available. Young adults may be eligible for
pediatric trials.
h ATRA should be available in all community hospitals, so appropriate therapy can be started promptly.

REFERENCES FOR EVALUATION FOR AML

1 Arber DA, Vardiman JW, Brunning RD, et al. Acute myeloid leukemia with recurrent genetic abnormalities. In: Swerdlow SH, Campo E, Harris NL, et al., eds. WHO
Classification of Tumours of Haematopoietic and Lymphoid Tissues (ed 4th). Lyon: IARC; 2008:110-123.
2 Khoury JD, Solary E, Abla O, et al. The 5th edition of the World Health Organization classification of haematolymphoid tumours: myeloid and histiocytic/dendritic
neoplasms. Leukemia 2022;36:1703-1719.
3 Arber DA, Orazi A, Hasserjian RP, et al. International Consensus Classification of myeloid neoplasms and acute leukemias: Integrating morphologic, clinical, and
genomic data. Blood 2022;140:1200-1228.
4 El-Jawahri A, LeBlanc TW, Kavanaugh A, et al. Effectiveness of integrated palliative and oncology care for patients with acute myeloid leukemia: a randomized clinical
trial. JAMA Oncol 2021;7:238-245.
5 Kim K, Konopleva M, DiNardo CD, et al. Urgent cytoreduction for newly diagnosed acute myeloid leukemia patients allows acquisition of pretreatment genomic data
and enrollment on investigational clinical trials. Am J Hematol 2022;97:885-894.
6 Bewersdorf JP, Giri S, Tallman MS, et al. Leukapheresis for the management of hyperleukocytosis in acute myeloid leukemia-A systematic review and meta-analysis.
Transfusion 2020;60:2360-2369.

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

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Acute Promyelocytic Leukemia (Age ≥18 years) Discussion

APL CLASSIFICATION AND TREATMENT RECOMMENDATIONS

Low risk (white blood cell [WBC] Treatment

count ≤10 x 109/L) Induction (APL-2)

Confirmed
APLa,b
Treatment
No cardiac issues Induction (APL-3)

High risk (WBC count >10 x 109/L)

Cardiac issues Treatment

(low ejection fraction [EF] or QTcF prolongationc) Induction (APL-4)

a Therapy-related APL is treated the same as de novo APL. FLT3 inhibitors are not recommended for FLT3-positive APL. Gale RE, et al. Blood 2005;106:3768-3776.
b For patients with APL being treated at a community center, collaboration with a center with expertise has been shown to reduce induction mortality. Jillella AP, et al.
JAMA Oncol 2025;11:400-407.
c Principles
of Supportive Care for APL (APL-A).

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

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Acute Promyelocytic Leukemia (Age ≥18 years) Discussion

APL TREATMENT INDUCTION (LOW RISK)b,c,d,e CONSOLIDATION THERAPYi,k

See references (APL-7) and APL-B 1 of 6 for details on regimens

Preferred Regimens
ATRA + daily arsenic trioxidef,g,1 If blood count recovery by
(category 1) day 28 (platelet >100 x 109/L,
absolute neutrophil count
Continue consolidaton as per
or [ANC] >1 x 109/L), proceed with
protocol (see references and
consolidation. BM aspirate
APL-B 1 of 6)
and biopsy may be considered
ATRA + intermittent arsenic trioxidef,g,2 to document <5% blasts and
(category 1) no abnormal promyelocytesh,i,j
Post-Consolidation
Therapy (APL-5)
Useful in Certain Circumstances (if arsenic is not available or contraindicated)

ATRA + idarubicinf,g,3 BM aspirate and biopsy

(category 1) days 28–35 to document Continue consolidaton as per
or <5% blasts and no abnormal protocol (see references and
promyelocytesi before APL-B 1 of 6)
ATRA + gemtuzumab ozogamicinf,4 proceeding with consolidationk

b For patients with APL being treated at a community center, collaboration with a center with expertise has been shown to reduce induction mortality. Jillella AP, et al. JAMA Oncol
2025;11:400-407.
c Principles of Supportive Care for APL (APL-A).
d Several groups have published large trials with excellent outcomes. However, to achieve the expected results, one needs to use the regimen consistently through all components and not
mix induction from one trial with consolidation from another.
e Early mortality is related to bleeding, differentiation syndrome, or infection. Persistent disease is rare.
f Data suggest that lower doses of ATRA (25 mg/m2) in divided doses until clinical remission may be used in children and adolescents. Kutny MA, et al. J Clin Oncol 2017;35:3021-3029.
g Begin prophylaxis with prednisone; the optimal duration of steroid prophylaxis is unknown. If differentiation syndrome develops, change to dexamethasone. Lo-Coco F, et al. N Engl J
Med 2013;369:111-121. See Principles of Supportive Care for APL (APL-A).
h If no evidence of morphologic disease (<5% blasts and no abnormal promyelocytes), discontinue ATRA and arsenic trioxide to allow for peripheral blood recovery since arsenic trioxide
can be associated with significant myelosuppression. If evidence of morphologic disease, continue ATRA and arsenic trioxide and repeat BM 1 week later.
i The presence of measurable cytogenetic and molecular markers post-induction does not carry prognostic or therapeutic implications.
j If full course of induction treatment is not given, or counts have not recovered by days 28–35, a BM aspirate and biopsy is recommended to document <5% blasts and no abnormal
promyelocytes before proceeding with consolidation.
k For regimens using high cumulative doses of cardiotoxic agents, consider reassessing cardiac function prior to each anthracycline/mitoxantrone-containing course.
References on APL-7
Note: All recommendations are category 2A unless otherwise indicated.

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APL TREATMENT INDUCTION (HIGH RISK)b,c,d,e,l,m CONSOLIDATION THERAPYk

(For patients with cardiac issues, see APL-4)
See references (APL-7), APL-B 2 of 6, and APL-B 3 of 6 for details on regimens
Preferred Regimens
ATRA + idarubicin + arsenic trioxidef,g,5
or
BM aspirate and biopsy at day
ATRA + daily arsenic trioxide + Continue consolidaton as
28 to document remissionh,i
gemtuzumab ozogamicinf,6 per protocol (see references
before proceeding with
and APL-B 2 of 6)
or consolidationk,9
ATRA + intermittent arsenic trioxide +
gemtuzumab ozogamicinf,g,2

Post-Consolidation
Useful in Certain Circumstances (if arsenic is not available or contraindicated during induction) Therapy (APL-5)
BM aspirate and biopsy at day Continue consolidaton as
ATRA + daunorubicin x 4 days + 28 to document remissionh
cytarabine f,7 per protocol (see references
before proceeding with and APL-B 3 of 6)
consolidation k,9
or
ATRA + daunorubicin x 3 days + BM aspirate and biopsy at day
cytarabinef,8 28 to document remissioni
Continue consolidaton as
or per protocol (see references
before proceeding with
ATRA + idarubicin f,3 and APL-B 3 of 6)
consolidationk,9

b For patients with APL being treated at a community center, collaboration with a center
with expertise has been shown to reduce induction mortality. Jillella AP, et al. JAMA Oncol
2025;11:400-407. h If no evidence of morphologic disease (<5% blasts and no abnormal promyelocytes),
c Principles of Supportive Care for APL (APL-A). discontinue ATRA and arsenic trioxide to allow for peripheral blood recovery since arsenic
d Several groups have published large trials with excellent outcomes. However, to achieve trioxide can be associated with significant myelosuppression. If evidence of morphologic
the expected results, one needs to use the regimen consistently through all components disease, continue ATRA and arsenic trioxide and repeat BM 1 week later.
and not mix induction from one trial with consolidation from another. i The presence of measurable cytogenetic and molecular markers post-induction does not
e Early mortality is related to bleeding, differentiation syndrome, or infection. Persistent carry prognostic or therapeutic implications.
disease is rare. k For regimens using high cumulative doses of cardiotoxic agents, consider reassessing
f Data suggest that lower doses of ATRA (25 mg/m2) in divided doses until clinical remission cardiac function prior to each anthracycline/mitoxantrone-containing course.
may be used in children and adolescents. Kutny MA, et al. J Clin Oncol 2017;35:3021-3029. l It is important for the management of APL that regimens containing ATRA and arsenic
g Begin prophylaxis with prednisone; the optimal duration of steroid prophylaxis is unknown. trioxide be administered unless there is a contraindication based on extenuating patient
If differentiation syndrome develops, change to dexamethasone. Lo-Coco F, et al. N Engl J circumstances.
Med 2013;369:111-121. See Principles of Supportive Care for APL (APL-A). m For all patients with high-risk APL, consider LP before proceeding with consolidation.

References on APL-7
Note: All recommendations are category 2A unless otherwise indicated.

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APL TREATMENT INDUCTION (HIGH RISK)b,c,d,e,m CONSOLIDATION THERAPYk

IN PATIENTS WITH CARDIAC ISSUES
(For patients without cardiac issues, see APL-3)
See references (APL-7) and APL-B 4 of 6 for details on regimens
Low EF
ATRA + daily arsenic trioxide + BM aspirate and
gemtuzumab ozogamicinf,g,6 biopsy at day 28 to Continue consolidaton as
or document remissionh,i per protocol (see references
ATRA + intermittent arsenic trioxide before proceeding with and APL-B 4 of 6)
+ gemtuzumab ozogamicinf,g,2 consolidation

Prolonged QTcF BM aspirate and

biopsy at day 28 to Continue consolidaton as
Post-Consolidation Therapy (APL-5)
ATRA + gemtuzumab ozogamicinf,4 document remissioni per protocol (see references
before proceeding with and APL-B 4 of 6)
or consolidation

ATRA + daunorubicin x 3 days BM aspirate and

+ cytarabinef,8 biopsy at day 28 to Continue consolidaton as
or document remissioni per protocol (see references
before proceeding with and APL-B 4 of 6)
ATRA + idarubicinf,3
consolidationk,9

b For patients with APL being treated at a community center, collaboration with a center with expertise has been shown to reduce induction mortality. Jillella AP, et al. JAMA Oncol
2025;11:400-407.
c Principles of Supportive Care for APL (APL-A).
d Several groups have published large trials with excellent outcomes. However, to achieve the expected results, one needs to use the regimen consistently through all components and not
mix induction from one trial with consolidation from another.
e Early mortality is related to bleeding, differentiation syndrome, or infection. Persistent disease is rare.
f Data suggest that lower doses of ATRA (25 mg/m2) in divided doses until clinical remission may be used in children and adolescents. Kutny MA, et al. J Clin Oncol 2017;35:3021-3029.
g Begin prophylaxis with prednisone; the optimal duration of steroid prophylaxis is unknown. If differentiation syndrome develops, change to dexamethasone. Lo-Coco F, et al. N Engl J
Med 2013;369:111-121. See Principles of Supportive Care for APL (APL-A).
h If no evidence of morphologic disease (<5% blasts and no abnormal promyelocytes), discontinue ATRA and arsenic trioxide to allow for peripheral blood recovery since arsenic trioxide
can be associated with significant myelosuppression. If evidence of morphologic disease, continue ATRA and arsenic trioxide and repeat BM 1 week later.
i The presence of measurable cytogenetic and molecular markers post-induction does not carry prognostic or therapeutic implications.
k For regimens using high cumulative doses of cardiotoxic agents, consider reassessing cardiac function prior to each anthracycline/mitoxantrone-containing course.
m For all patients with high-risk APL, consider LP before proceeding with consolidation.
References on APL-7
Note: All recommendations are category 2A unless otherwise indicated.

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Acute Promyelocytic Leukemia (Age ≥18 years) Discussion

APL POST- MONITORING

CONSOLIDATION
THERAPY

Monitor by
Polymerase PCRn for up PCR negative
Maintenance therapy if
chain reaction to 2 y after PCR negative
included in the initial
(PCR) completion of Repeat
treatment protocol
negative treatment PCR PCRn for
positiveo confirmation
within 4 wks
PCR positiveo
Document
molecular
remissionn,o First
after relapse10
consolidation Therapy
PCR negative for Relapse
Repeat (APL-6)
PCR positiveo PCRn for
confirmation
within 4 wks
PCR positiveo

n PCR should be performed on a blood sample at completion of consolidation to document molecular remission. Prior practice guidelines have recommended monitoring
blood by PCR every 3 mo for 2 y to detect molecular relapse. We continue to endorse this for patients with high-risk disease or those who had long interruptions during
consolidation. Clinical experience indicates that risk of relapse in patients with low-risk disease who are in molecular remission at completion of consolidation is low
and monitoring may not be necessary outside the setting of a clinical trial. While long-term monitoring has been standard, with newer, more effective regimens, the
value is less certain.
o To confirm PCR positivity, a second blood sample should be done in 2–4 weeks in a reliable laboratory. If molecular relapse is confirmed by a second positive test,
treat as first relapse (APL-6). If the second test is negative, frequent monitoring (every 3 mo for 2 y) is strongly recommended to confirm that the test remains negative.
The PCR testing lab should indicate the level of sensitivity of assay for positivity (most clinical labs have a sensitivity level of 10-4), and testing should be done in the
same lab to maintain the same level of sensitivity. Consider consultation with a physician experienced in molecular diagnostics if results are equivocal.
References on APL-7
Note: All recommendations are category 2A unless otherwise indicated.

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APL THERAPY FOR RELAPSE ADDITIONAL THERAPY

See references (APL-7) and APL-B 5 of 6 for details on regimens Transplant Autologous
candidate HCTt
PCR
Early relapse Anthracycline-based negative
(<6 mo) after ATRA regimen as per APL-3q,r (by BM) Not Arsenic trioxide
and arsenic trioxide or gemtuzumab transplant consolidation
(no anthracycline) ozogamicin12,13 Consider CNS candidate (total of 6 cycles)
prophylaxis
Second with
remission intrathecal (IT)
(morphologic) chemotherapy
No prior exposure (methotrexate Matched sibling
to arsenic trioxide or cytarabine) Transplant
or alternative
First relapse or early relapse Arsenic trioxide ± candidate
PCR donor HCTt,11
(morphologic (<6 mo) after ATRA ATRA11 ± gemtuzumab
positive
or molecular)p + anthracycline- ozogamicinq,r
(by BM) Not
containing
transplant Clinical trial
regimen11
candidate

Clinical trial
Arsenic trioxide ±
Late relapse (≥6 mo) or
ATRA ± (anthracycline No remission
after arsenic trioxide- Matched sibling or
or gemtuzumab
containing regimen alternative donor HCTt
ozogamicin)q,r,s

p Document molecular panel to verify relapsed APL versus therapy-related AML. r Outcomes
are uncertain in patients who received arsenic trioxide during initial
q Following the first cycle of consolidation, if the patient's disease is not in induction/consolidation therapy.
molecular remission (by quantitative PCR on BM sample), consider matched s There is a small randomized trial that suggests that the addition of ATRA does
sibling or alternative donor (haploidentical, unrelated donor, or cord blood) HCT not confer any benefit over arsenic trioxide alone. Raffoux E, et al. J Clin Oncol
or clinical trial. Testing is recommended at least 2–3 weeks after the completion of 2003;21:2326-2334.
arsenic trioxide to avoid false positives. t See NCCN Guidelines for Hematopoietic Cell Transplantation.
References on APL-7
Note: All recommendations are category 2A unless otherwise indicated.

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Acute Promyelocytic Leukemia (Age ≥18 years) Discussion

REFERENCES
1 Lo-Coco F, Avvisati G, Vignetti M, et al. Retinoic acid and arsenic trioxide for acute promyelocytic leukemia. N Engl J Med 2013;369:111-121.
2 Burnett AK, Russell NH, Hills RK, et al. Arsenic trioxide and all-trans retinoic acid treatment for acute promyelocytic leukaemia in all risk groups (AML17): results of a
randomised, controlled, phase 3 trial. Lancet Oncol 2015;16:1295-1305.
3 Sanz MA, Montesinos P, Rayón C, et al. Risk-adapted treatment of acute promyelocytic leukemia based on all-trans retinoic acid and anthracycline with addition of
cytarabine in consolidation therapy for high-risk patients: further improvements in treatment outcome. Blood 2010;115:5137-5146.
4 Estey E, Giles FJ, Beran M, et al. Experience with gemtuzumab ozogamycin ("mylotarg") and all-trans retinoic acid in untreated acute promyelocytic leukemia. Blood
2002;99:4222-4224.
5 Iland HJ, Bradstock K, Supple SG, et al. All-trans-retinoic acid, idarubicin, and IV arsenic trioxide as initial therapy in acute promyelocytic leukemia (APML4). Blood
2012;120:1570-1752.
6 Abaza Y, Kantarjian H, Garcia-Manero G, et al. Long-term outcome of acute promyelocytic leukemia treated with all-trans-retinoic acid, arsenic trioxide, and
gemtuzumab. Blood 2017;129:1275-1283.
7 Powell BL, Moser B, Stock W, et al. Arsenic trioxide improves event-free and overall survival for adults with acute promyelocytic leukemia: North American Leukemia
Intergroup Study C9710. Blood 2010;116:3751-3757.
8 Adès L, Sanz MA, Chevret S, et al. Treatment of newly diagnosed acute promyelocytic leukemia (APL): a comparison of French-Belgian-Swiss and PETHEMA results.
Blood 2008;111:1078-1084.
9 Breccia M, Carmosino I, Diverio D, et al. Early detection of meningeal localization in acute promyelocytic leukaemia patients with high presenting leucocyte count. Br J
Haematol 2003;120:266-270.
10 Grimwade D, Jovanovic JV, Hills RK, et al. Prospective minimal residual disease monitoring to predict relapse of acute promyelocytic leukemia and to direct pre-
emptive arsenic trioxide therapy. J Clin Oncol 2009;27:3650-3658.
11 Cicconi L, Breccia M, Franceschini L, et al. Prolonged treatment with arsenic trioxide (ATO) and all-trans-retinoic acid (ATRA) for relapsed acute promyelocytic
leukemia previously treated with ATRA and chemotherapy. Ann Hematol 2018;97:1797-1802.
12 Lo-Coco F, Cimino G, Breccia M, et al. Gemtuzumab ozogamicin (Mylotarg) as a single agent for molecularly relapsed acute promyelocytic leukemia. Blood
2004;104:1995-1999
13 Estey EH, Giles FJ, Beran M, et al. Experience with gemtuzumab ozogamycin ("mylotarg") and all-trans retinoic acid in untreated acute promyelocytic leukemia.
Blood 2002;99:4222-4224.

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

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Acute Promyelocytic Leukemia (Age ≥18 years) Discussion

PRINCIPLES OF SUPPORTIVE CARE FOR APLa

There are variations among institutions, but the following issues are important to consider in the management of APL.
• Early mortality is related to bleeding, differentiation syndrome, or infection.
• Clinical coagulopathy:
Management of clinical coagulopathy: Aggressive platelet transfusion support to maintain platelets ≥50 x 109/L; fibrinogen replacement with
cryoprecipitate and fresh frozen plasma to maintain a level >150 mg/dL and PT and PTT close to normal values. Monitor daily until coagulopathy
resolves.
Avoid use of tunneled catheter or port-a-cath.
• Leukapheresis1 is not routinely recommended in patients with a high WBC count in APL because of the difference in leukemia biology; however, in
life-threatening cases with leukostasis that is not responsive to other modalities, leukapheresis can be considered with caution.
• Hydroxyurea can be used to treat leukocytosis in individuals with low-risk disease who experience a rise in WBC count after treatment with an
ATRA/arsenic trioxide based regimen.
• APL differentiation syndrome:
Maintain a high index of suspicion of APL differentiation syndrome (ie, fever, often associated with increasing WBC count >10 x 109/L, usually
at initial diagnosis or relapse; shortness of breath; hypoxemia; pleural or pericardial effusions).2 Close monitoring of volume overload and
pulmonary status is indicated. Initiate dexamethasone at first signs or symptoms of respiratory compromise (ie, hypoxemia, pulmonary infiltrates,
pericardial or pleural effusions) (10 mg BID for 3–5 days with a taper over 2 weeks). Consider interrupting ATRA therapy until hypoxia resolves.
For patients at high risk (WBC count >10 x 109/L) for developing differentiation syndrome and for those receiving an ATRA/arsenic trioxide-
based regimen, initiate prophylaxis with corticosteroids, either prednisone 0.5 mg/kg day 1 or dexamethasone 10 mg every 12 hours (see NCCN
Guidelines for Prevention and Treatment of Cancer-Related Infections). Taper the steroid dose over a period of several days. If patient develops
differentiation syndrome, change prednisone to dexamethasone 10 mg every 12 hours until count recovery or risk of differentiation has abated.2,3
Hydroxyurea can be used to treat leukocytosis associated with differentiation syndrome. In difficult-to-treat cases, an anthracycline (daunorubicin
or idarubicin) or gemtuzumab ozogamicin can be used.
• Arsenic trioxide monitoring:
Prior to initiating therapy
◊ Electrocardiogram (ECG) for prolonged QTc interval assessment
◊ Serum electrolytes and creatinine
During therapy (weekly during induction therapy and before each course of post-remission therapy)
◊ Minimize use of drugs that may prolong QT interval.
◊ Maintain K and Mg concentrations within middle or upper range of normal.
◊ In patients with prolonged QTc interval >500 millisec, correct electrolytes and proceed with caution. QTcF is recommended; however, in settings
where QTcF corrections are unavailable, a cardiology consult may be appropriate for patients with prolonged QTc.4
• Myeloid growth factors should not be used during induction. They may be considered during consolidation in selected cases (ie, life-threatening
infections, signs/symptoms of sepsis); however, there are no outcomes data regarding the prophylactic use of growth factors in consolidation.
1 Daver N, et al. Br J Haematol 2015;168:646-653.
2 Lo-Coco F, et al. N Engl J Med 2013;369:111-121.
a Antiviral
prophylaxis against varicella-zoster virus for duration of treatment may 3 Sanz MA, et al. Blood 2010;115:5137-5146.
be appropriate. Glass JL, et al. Blood 2015;126:3752. 4 Sanz MA, et al. Blood 2019;133:1630-1643.

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

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PRINCIPLES OF SYSTEMIC THERAPY FOR APL

APL TREATMENT INDUCTION (LOW RISK)a,b (APL-2)
Preferred Regimens

Therapy Induction Consolidation

ATRA + daily ATRA 45 mg/m2 in 2 divided doses daily Arsenic trioxide 0.15 mg/kg/d IV 5 d/wk for 4 weeks every 8 weeks for
arsenic trioxidec,1 + arsenic trioxide 0.15 mg/kg IV daily a total of 4 cycles, and ATRA 45 mg/m2/d for 2 weeks every 4 weeks
(category 1) for a total of 7 cycles (category 1)
First 3 consolidation cycles = 56-day cycles:
ATRA 45 mg/m2/d PO in 2 divided doses daily on days 1–14 and 29–42
ATRA 45 mg/m2 in 2 divided doses daily
(2 weeks on followed by 2 weeks off) + arsenic trioxide 0.3 mg/kg on
for 60 days or until achievement of
ATRA + days 1–5 of week 1 followed by 0.25 mg/kg twice weekly during weeks
complete remission (CR) + arsenic trioxide
intermittent 2–4
0.3 mg/kg IV on days 1–5 of week 1 and
arsenic trioxidec,2 4th consolidation cycle = 28-day cycle:
0.25 mg/kg twice weekly during weeks 2–8
ATRA 45 mg/m2/d PO in 2 divided doses daily on days 1–14 + arsenic
(category 1)
trioxide 0.3 mg/kg on days 1–5 of week 1 followed by 0.25 mg/kg twice
weekly during weeks 2–4

Useful in Certain Circumstances (if arsenic is not available or contraindicated)

Therapy Induction Consolidation

ATRA + ATRA 45 mg/m2 in 2 divided doses daily ATRA 45 mg/m2 x 15 days + idarubicin 5 mg/m2 x 4 days x 1 cycle,
idarubicinc,3 + idarubicin 12 mg/m on days 2, 4, 6, 8
2
then ATRA x 15 days + mitoxantrone 10 mg/m2/d x 3 days x 1 cycle,
(category 1) or on days 2, 4, 6 for aged >70 y then ATRA x 15 days + idarubicin 12 mg/m2 x 1 day x 1 cycle
(category 1)
ATRA + ATRA 45 mg/m in 2 divided doses daily +
2
ATRA 45 mg/m2 in 2 divided doses daily during weeks 1–2, 5–6,
gemtuzumab a single dose of gemtuzumab ozogamicin 9–10, 13–14, 17–18, 21–22, and 25–26. A single dose of gemtuzumab
ozogamicin2,4 6 or 9 mg/m2 on day 5 ozogamicin 6 or 9 mg/m2 may be given monthly until achievement of
complete molecular remission
a Data suggest that lower doses of ATRA (25 mg/m2) in divided doses until clinical remission may be used in children and adolescents. Kutny MA, et al. J Clin Oncol 2017;35:3021-3029.
b The optimal dosing of arsenic trioxide for patients with obesity is unknown, though retrospective studies suggest there may be a role for dose capping. Zacholski K, et al. J Oncol Pharm
Pract 2022;28:1340-1349; Jen WY, et al. Leuk Lymphoma 2024;65:378-382.
c Begin prophylaxis with prednisone; the optimal duration of steroid prophylaxis is unknown. If differentiation syndrome develops, change to dexamethasone. Lo-Coco F, et al. N Engl J
Med 2013;369:111-121. See Principles of Supportive Care for APL (APL-A).
References on APL-B 6 of 6
Note: All recommendations are category 2A unless otherwise indicated.
APL-B
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Acute Promyelocytic Leukemia (Age ≥18 years) Discussion

PRINCIPLES OF SYSTEMIC THERAPY FOR APL

APL TREATMENT INDUCTION (HIGH RISK)a,b (APL-3)
(For patients with cardiac issues, see APL-B 4 of 6)
Preferred Regimens
Therapy Induction Consolidation
ATRA + ATRA 45 mg/m2 (days 1–36, 2 ATRA 45 mg/m2 x 28 days + arsenic trioxide 0.15 mg/kg/d x 28 days x 1 cycle,
idarubicin + divided doses daily) + age-adjusted then ATRA 45 mg/m2 x 7 days every 2 weeks x 3 + arsenic trioxide 0.15 mg/kg/d
arsenic trioxide5 idarubicin 6–12 mg/m2 on days 2, x 5 days for 5 weeks x 1 cycled,e
4, 6, 8 + arsenic trioxide 0.15 mg/kg
(days 9–36 as 2 h IV infusion)
ATRA + daily ATRA 45 mg/m2 in 2 divided doses Arsenic trioxide 0.15 mg/kg daily 5 d/wk for 4 weeks every 8 weeks for a total of
arsenic trioxide daily and arsenic trioxide 0.15 4 cycles + ATRA 45 mg/m2 for 2 weeks every 4 weeks for a total of 7 cycles.e,f
+ gemtuzumab mg/kg/d IV + a single dose of If ATRA or arsenic trioxide discontinued due to toxicity, a single dose of
ozogamicin2,6 gemtuzumab ozogamicin 6 or gemtuzumab ozogamicin 6 or 9 mg/m2 may be given every 4–5 weeks provided
9 mg/m2 may be given on day 1, or platelets and ANC recover to ≥100 x 109/L and ≥1 x 109/L, respectively, until
day 2, or day 3, or day 4 molecular CR
ATRA + ATRA 45 mg/m2 in 2 divided First 3 consolidation cycles = 56-day cyclesf:
intermittent doses daily for 60 days or until ATRA 45 mg/m2/d PO in 2 divided doses daily on days 1–14 and 29–42 (2 weeks
arsenic trioxide achievement of CR and arsenic on followed by 2 weeks off) + arsenic trioxide 0.3 mg/kg on days 1–5 of week 1
+ gemtuzumab trioxide 0.3 mg/kg IV on days 1–5 of followed by 0.25 mg/kg twice weekly during weeks 2–4
ozogamicin2,4 week 1 and 0.25 mg/kg twice weekly 4th consolidation cycle = 28-day cycle:
during weeks 2–8 (category 1) ATRA 45 mg/m2/d PO in 2 divided doses daily on days 1–14 + arsenic trioxide
+ a single dose of gemtuzumab 0.3 mg/kg on days 1–5 of week 1 followed by 0.25 mg/kg twice weekly during
ozogamicin 6 or 9 mg/m2 may be weeks 2–4.e (category 1)
given on day 1, or day 2, or day 3, If ATRA or arsenic trioxide discontinued due to toxicity, a single dose of
or day 4 gemtuzumab ozogamicin 6 or 9 mg/m2 may be given every 4–5 weeks provided
platelets and ANC recover to ≥100 x 109/L and ≥1 x 109/L, respectively, until
molecular CR
Continued
a Data suggest that lower doses of ATRA (25 mg/m2) in divided doses until clinical remission may be used in children and adolescents. Kutny MA, et al. J Clin Oncol 2017;35:3021-3029.
b The optimal dosing of arsenic trioxide for patients with obesity is unknown, though retrospective studies suggest there may be a role for dose capping. Zacholski K, et al. J Oncol Pharm
Pract 2022;28:1340-1349; Jen WY, et al. Leuk Lymphoma 2024;65:378-382.
d Although the original regimen included high-dose cytarabine (HiDAC) as second consolidation, some investigators recommend using HiDAC early for CNS prophylaxis, especially for
patients not receiving IT chemotherapy.
e Consider IT chemotherapy (eg, 2 doses for each consolidation cycle) as an option for CNS prophylaxis.
f Additional gemtuzumab ozogamicin may be considered during consolidation if PCR remains positive beyond 3 months of consolidation.
References on APL-B 6 of 6
Note: All recommendations are category 2A unless otherwise indicated.
APL-B
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Acute Promyelocytic Leukemia (Age ≥18 years) Discussion

PRINCIPLES OF SYSTEMIC THERAPY FOR APL

APL TREATMENT INDUCTION (HIGH RISK)a,b (APL-3)
(For patients with cardiac issues, see APL-B 4 of 6)
Useful in Certain Circumstances (if arsenic is not available or contraindicated during induction)

Therapy Induction Consolidation

ATRA + ATRA 45 mg/m2 in 2 divided doses daily + Arsenic trioxide 0.15 mg/kg/d x 5 days for 5 weeks every 7 weeks
daunorubicin daunorubicin 50 mg/m2 x 4 days (IV days for a total of 2 cycles, then ATRA 45 mg/m2 x 7 days +
x 4 days + 3–6) + cytarabine 200 mg/m2 x 7 days (IV daunorubicin 50 mg/m2 x 3 days for 2 cyclese
cytarabine7 days 3–9)
ATRA + ATRA 45 mg/m2 in 2 divided doses daily Daunorubicin 60 mg/m2 x 3 days + cytarabine 200 mg/m2 x 7 days
daunorubicin + daunorubicin 60 mg/m2 x 3 days + x 1 cycle, then cytarabine [2 g/m2 (aged <50 y) or 1.5 g/m2 (aged
x 3 days + cytarabine 200 mg/m2 x 7 days 50–60 y) every 12 h x 5 daysd,g or 1 g/m2 (aged >60 y) every 12 h
cytarabine8 x 4 days] + daunorubicin 45 mg/m2 x 3 days x 1 cycle + 5 doses
of IT chemotherapy
ATRA + ATRA 45 mg/m in 2 divided doses daily + ATRA 45 mg/m2 x 15 days + idarubicin 5 mg/m2 and cytarabine
2

idarubicin3 idarubicin 12 mg/m2 on days 2, 4, 6, 8 or on 1 g/m2 x 4 days x 1 cycle,h then ATRA x 15 days + mitoxantrone
days 2, 4, 6 for those aged >70 y 10 mg/m2/d x 5 daysi x 1 cycle, then ATRA x 15 days + idarubicin
12 mg/m2 x 1 day + cytarabine 150 mg/m2 every 8 hours x 4 days
x 1 cyclee,h

a Data suggest that lower doses of ATRA (25 mg/m2) in divided doses until clinical remission may be used in children and adolescents. Kutny MA, et al. J Clin Oncol
2017;35:3021-3029.
b The optimal dosing of arsenic trioxide for patients with obesity is unknown, though retrospective studies suggest there may be a role for dose capping. Zacholski K, et
al. J Oncol Pharm Pract 2022;28:1340-1349; Jen WY, et al. Leuk Lymphoma 2024;65:378-382.
d Although the original regimen included HiDAC as second consolidation, some investigators recommend using HiDAC early for CNS prophylaxis, especially for patients
not receiving IT chemotherapy.
e Consider IT chemotherapy (eg, 2 doses for each consolidation cycle) as an option for CNS prophylaxis.
g Dose adjustment of cytarabine may be needed for patients >60 years or patients with renal dysfunction.
h Patients with high-risk disease who are >60 years did not receive cytarabine in consolidation and were treated in the intermediate-risk group in the LPA2005 study.
i Mitoxantrone was reduced to 3 days in patients with intermediate-risk disease in the LPA2005 study.
References on APL-B 6 of 6
Note: All recommendations are category 2A unless otherwise indicated.
APL-B
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Acute Promyelocytic Leukemia (Age ≥18 years) Discussion

PRINCIPLES OF SYSTEMIC THERAPY FOR APL

APL TREATMENT INDUCTION (HIGH RISK) IN PATIENTS WITH CARDIAC ISSUESa,b (APL-4)
Low EF
Therapy Induction Consolidation
ATRA + daily ATRA 45 mg/m2 in 2 divided Arsenic trioxide 0.15 mg/kg daily 5 days/wk for 4 weeks every 8 weeks for a total of 4 cycles
arsenic trioxide doses daily + arsenic + ATRA 45 mg/m2 in 2 divided doses daily for 2 weeks every 4 weeks for a total of 7 cycles.e,f
+ gemtuzumab trioxide 0.15 mg/kg daily + a If ATRA or arsenic trioxide discontinued due to toxicity, a single dose of gemtuzumab
ozogamicin2,6 single dose of gemtuzumab ozogamicin 6 or 9 mg/m2 may be given every 4–5 weeks provided platelets and ANC recover
ozogamicin 6 or 9 mg/m2 on to ≥100 x 109/L and ≥1 x 109/L, respectively, until molecular CR
day 1
ATRA + ATRA 45 mg/m2 in 2 divided First 3 consolidation cycles = 56-day cyclesf:
intermittent doses daily for 60 days or ATRA 45 mg/m2/d PO in 2 divided doses daily on days 1–14 and 29–42 (2 weeks on followed
arsenic trioxide until achievement of CR + by 2 weeks off) + arsenic trioxide 0.3 mg/kg on days 1–5 of week 1 followed by 0.25 mg/kg
+ gemtuzumab arsenic trioxide 0.3 mg/kg twice weekly during weeks 2–4
ozogamicin2,4 on days 1–5 of week 1 and 4th consolidation cycle = 28-day cycle:
0.25 mg/kg twice weekly in ATRA 45 mg/m2/d PO in 2 divided doses daily on days 1–14 + arsenic trioxide 0.3 mg/kg on
weeks 2–8 (category 1) + a days 1–5 of week 1 followed by 0.25 mg/kg twice weekly during weeks 2–4.e (category 1)
single dose of gemtuzumab If ATRA or arsenic trioxide discontinued due to toxicity, a single dose of gemtuzumab
ozogamicin 6 or 9 mg/m2 on ozogamicin 6 or 9 mg/m2 may be given every 4–5 weeks provided platelets and ANC recover
day 1 to ≥100 x 109/L and ≥1 x 109/L, respectively, until molecular CR
Prolonged QTcF
Therapy Induction Consolidation
ATRA + ATRA 45 mg/m2 in 2 divided doses ATRA 45 mg/m2 in 2 divided doses daily during weeks 1–2, 5–6, 9–10, 13–14, 17–18,
gemtuzumab daily + a single dose of gemtuzumab 21–22, and 25–26. Gemtuzumab ozogamicin 6 or 9 mg/m2 may be given monthly
ozogamicin2,4 ozogamicin 6 or 9 mg/m2 on day 1 until molecular CR
ATRA + ATRA 45 mg/m2 in 2 divided doses Daunorubicin 60 mg/m2 x 3 days + cytarabine 200 mg/m2 x 7 days x 1 cycle, then
daunorubicin daily + daunorubicin 60 mg/m2 x cytarabine [2 g/m2 (aged <50 y) or 1.5 g/m2 (age 50–60 y) every 12 h x 5 daysd,g or
x 3 days + 3 days + cytarabine 200 mg/m2 x 1 g/m2 (aged >60 y) every 12 h x 4 days], + daunorubicin 45 mg/m2 x 3 days x 1 cycle
cytarabine8 7 days + 5 doses of IT chemotherapy
ATRA + ATRA 45 mg/m2 in 2 divided doses ATRA 45 mg/m2 x 15 days + idarubicin 5 mg/m2 and cytarabine 1 g/m2 x 4 days x 1
idarubicin3 daily + idarubicin 12 mg/m2 on days cycle,h then ATRA x 15 days + mitoxantrone 10 mg/m2/d x 5 daysi x 1 cycle, then
2, 4, 6, 8 or on days 2, 4, 6 for those ATRA x 15 days + idarubicin 12 mg/m2 x 1 day + cytarabine 150 mg/m2 every 8 hours
aged >70 y x 4 days x 1 cyclee,h
Footnotes on APL-B 4A References on APL-B 6 of 6

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

APL-B
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Acute Promyelocytic Leukemia (Age ≥18 years) Discussion

PRINCIPLES OF SYSTEMIC THERAPY FOR APL

FOOTNOTES FOR APL TREATMENT INDUCTION (HIGH RISK) IN PATIENTS WITH CARDIAC ISSUES
a Data suggest that lower doses of ATRA (25 mg/m2) in divided doses until clinical remission may be used in children and adolescents. Kutny MA, et al. J Clin Oncol
2017;35:3021-3029.
b The optimal dosing of arsenic trioxide for patients with obesity is unknown, though retrospective studies suggest there may be a role for dose capping. Zacholski K, et
al. J Oncol Pharm Pract 2022;28:1340-1349; Jen WY, et al. Leuk Lymphoma 2024;65:378-382.
d Although the original regimen included HiDAC as second consolidation, some investigators recommend using HiDAC early for CNS prophylaxis, especially for patients
not receiving IT chemotherapy.
e Consider IT chemotherapy (eg, 2 doses for each consolidation cycle) as an option for CNS prophylaxis.
f Additional gemtuzumab ozogamicin may be considered during consolidation if PCR remains positive beyond 3 months of consolidation.
g Dose adjustment of cytarabine may be needed for patients >60 years or patients with renal dysfunction.
h Patients with high-risk disease who are >60 years did not receive cytarabine in consolidation and were treated in the intermediate-risk group in the LPA2005 study.
i Mitoxantrone was reduced to 3 days in patients with intermediate-risk disease in the LPA2005 study.

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

APL-B
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Acute Promyelocytic Leukemia (Age ≥18 years) Discussion

PRINCIPLES OF SYSTEMIC THERAPY FOR APL

THERAPY FOR RELAPSEb (APL-6)

Therapy Regimen
Gemtuzumab ozogamicin9 6 mg/m2 IV for a maximum of 6 doses
Arsenic trioxide ± ATRA ± Arsenic trioxide 0.15 mg/kg dailyj,k ± ATRA 45 mg/m2 in 2 divided doses daily ± a single
gemtuzumab ozogamicin10 dose of gemtuzumab ozogamicin until count recovery with BM confirmation of remission
Arsenic trioxide ± ATRA ± Arsenic trioxide 0.15 mg/kg dailyj,k ± ATRA 45 mg/m2 in 2 divided doses dailyl ±
(anthracycline or gemtuzumab (anthracycline or a single dose of gemtuzumab ozogamicin) until count recovery with
ozogamicin)4 BM confirmation of remission
For anthracycline based-
regimens, see APL-3

b The optimal dosing of arsenic trioxide for patients with obesity is unknown, though retrospective studies suggest there may be a role for dose capping. Zacholski K, et
al. J Oncol Pharm Pract 2022;28:1340-1349; Jen WY, et al. Leuk Lymphoma 2024;65:378-382.
j Following the first cycle of consolidation, if the patient's disease is not in molecular remission (by quantitative PCR on BM sample), consider matched sibling or
alternative donor (haploidentical, unrelated donor, or cord blood) HCT or clinical trial. Testing is recommended at least 2–3 weeks after the completion of arsenic
trioxide to avoid false positives.
k Outcomes are uncertain in patients who received arsenic trioxide during initial induction/consolidation therapy.
l There is a small randomized trial that suggests that the addition of ATRA does not confer any benefit over arsenic trioxide alone. Raffoux E, et al. J Clin Oncol
2003;21:2326-2334.
References on APL-B 6 of 6
Note: All recommendations are category 2A unless otherwise indicated.
APL-B
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Acute Promyelocytic Leukemia (Age ≥18 years) Discussion

REFERENCES FOR PRINCIPLES OF SYSTEMIC THERAPY FOR APL

1 Lo-Coco F, Avvisati G, Vignetti M, et al. Retinoic acid and arsenic trioxide for acute promyelocytic leukemia. N Engl J Med 2013;369:111-121.
2 Burnett AK, Russell NH, Hills RK, et al. Arsenic trioxide and all-trans retinoic acid treatment for acute promyelocytic leukaemia in all risk groups (AML17): results of a
randomised, controlled, phase 3 trial. Lancet Oncol 2015;16:1295-1305.
3 Sanz MA, Montesinos P, Rayón C, et al. Risk-adapted treatment of acute promyelocytic leukemia based on all-trans retinoic acid and anthracycline with addition of
cytarabine in consolidation therapy for high-risk patients: further improvements in treatment outcome. Blood 2010;115:5137-5146.
4 Estey E, Giles FJ, Beran M, et al. Experience with gemtuzumab ozogamycin ("mylotarg") and all-trans retinoic acid in untreated acute promyelocytic leukemia. Blood
2002;99:4222-4224.
5 Iland HJ, Bradstock K, Supple SG, et al. All-trans-retinoic acid, idarubicin, and IV arsenic trioxide as initial therapy in acute promyelocytic leukemia (APML4). Blood
2012;120:1570-1752.
6 Abaza Y, Kantarjian H, Garcia-Manero G, et al. Long-term outcome of acute promyelocytic leukemia treated with all-trans-retinoic acid, arsenic trioxide, and
gemtuzumab. Blood 2017;129:1275-1283.
7 Powell BL, Moser B, Stock W, et al. Arsenic trioxide improves event-free and overall survival for adults with acute promyelocytic leukemia: North American Leukemia
Intergroup Study C9710. Blood 2010;116:3751-3757.
8 Adès L, Sanz MA, Chevret S, et al. Treatment of newly diagnosed acute promyelocytic leukemia (APL): a comparison of French-Belgian-Swiss and PETHEMA results.
Blood 2008;111:1078-1084.
9 Lo-Coco F, Cimino G, Breccia M, et al. Gemtuzumab ozogamicin (Mylotarg) as a single agent for molecularly relapsed acute promyelocytic leukemia. Blood
2004;104:1995-1999
10 Cicconi L, Breccia M, Franceschini L, et al. Prolonged treatment with arsenic trioxide (ATO) and all-trans-retinoic acid (ATRA) for relapsed acute promyelocytic
leukemia previously treated with ATRA and chemotherapy. Ann Hematol 2018;97:1797-1802.

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

APL-B
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Acute Myeloid Leukemia (Age ≥18 years) Discussion

INTENSIVE FAVORABLE/ TREATMENT INDUCTIONe,f,g,h,i

INDUCTION INTERMEDIATE-RISK
ELIGIBLE GROUPS (AML-A) Preferred:
• Standard 7 + 3 (daunorubicin or idarubicin)j + gemtuzumab ozogamicink,l
(CD33 positive)m

Favorable-risk AML Other Recommended:

by cytogenetics • Standard 7 + 3 (daunorubicin or idarubicin)j
(core binding factor • FLAG-IDA (fludarabinen + cytarabine + granulocyte colony-stimulating factor
[CBF]-AML)c [G-CSF] - idarubicin) + gemtuzumab ozogamicink,l (CD33 positive)m (category
2B; use with caution in patients >60 y)
Useful in Certain Circumstances:
• FLAGn + gemtuzumab ozogamicink,l (CD33 positive)m (for those ineligible for
an anthracycline) (category 2B) Follow-Up
and Re-
Induction
Preferred: After
• Standard 7 + 3 (daunorubicin or idarubicin)j (category 1) Cytarabine-
Intensive Based
induction Favorable-risk
AML by molecular Other Recommended: Induction
eligiblea,b (AML-3)
mutation profiled • Standard 7 + 3 (daunorubicin or idarubicin)j + gemtuzumab ozogamicinl,o
or (CD33 positive)m
Intermediate-risk • FLAG-IDAn (category 2B; use with caution in patients >60 y)
AML per ELN • FLAG-IDAn + gemtuzumab ozogamicinl,o (CD33 positive)m (category 2B; use
(AML-A) with caution in patients >60 y)
• CLAG-M (cladribine + cytarabine + G-CSF - mitoxantrone) (category 2B; use
with caution in patients >60 y)

• Standard 7 + 3 (daunorubicin or idarubicin)j + midostaurinp (FLT3-internal

AML with FLT3 tandem duplication [ITD] or tyrosine kinase domain [TKD]) (category 1)
mutation • Standard 7 + 3 (daunorubicin or idarubicin)j + quizartinib (FLT3-ITD only)
(category 1)

Poor/adverse risk
AML-2
groups AML-4 (Intensive Induction Ineligible)

Footnotes on AML-2A
Note: All recommendations are category 2A unless otherwise indicated.

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Acute Myeloid Leukemia (Age ≥18 years) Discussion

INTENSIVE POOR/ADVERSE- TREATMENT INDUCTIONe,f,g,h,i

INDUCTION RISK GROUPS
ELIGIBLE (AML-A)
• Therapy-related AML Preferred:
other than CBF-AML • CPX-351/dual-drug liposomal cytarabine and daunorubicinr
• Antecedent (category 1, preferred for age ≥60 y)
MDS/chronic • Standard 7 + 3 (daunorubicin or idarubicin)j (preferred for
myelomonocytic age <60 y)
leukemia (CMML) Other Recommended:
• Cytogenetic or • CPX-351/dual-drug liposomal cytarabine and daunorubicinr
molecular changes (for age <60 y)
consistent with • Standard 7 + 3 (daunorubicin or idarubicin)j (for age ≥60 y) Follow-up and Re-
MDS (previously • Decitabine (days 1–5) + venetoclaxs,t,u Induction After
classified as AML • Azacitidine + venetoclaxs,t,u Cytarabine-Based
with myelodysplasia- • CLIA (cladribine + idarubicin + cytarabine) + venetoclax Induction (AML-3)
related changes (category 2B) or
Intensive [AML-MRC]) • FLAG-IDAn + venetoclax (category 2B; use with caution in Follow-up After
induction patients >60 y) Induction Therapy with
eligiblea,b Lower Intensity Therapy
Preferred: (Intensive Induction
• No regimens are considered preferred, clinical trial is Ineligible or Declines)
recommended (AML-5)
Other Recommended:
• Standard 7 + 3 (daunorubicin or idarubicin)j
Poor-risk AML without • CPX-351/dual-drug liposomal cytarabine and daunorubicinr
TP53 mutation or (category 2B)
del(17p) abnormality • FLAG-IDAn (category 2B) (use with caution in patients >60 y)
• Decitabine (days 1–5) + venetoclaxs,u
• Azacitidine + venetoclaxs,u
• CLAG-M (category 2B)
• CLIA + venetoclax (category 2B)
• FLAG-IDAn + venetoclax (category 2B; use with caution in
patients >60 y)

Poor-risk AML with TP53

mutation or del(17p) Clinical trialq
abnormalityq
Footnotes on AML-2A
Note: All recommendations are category 2A unless otherwise indicated.

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Acute Myeloid Leukemia (Age ≥18 years) Discussion

FOOTNOTES FOR INTENSIVE INDUCTION ELIGIBLE

a Patients with elevated blast counts are at risk for tumor lysis and organ dysfunction secondary to leukostasis. Measures to rapidly reduce the WBC count include leukapheresis,
hydroxyurea, and/or a single dose of cytarabine. Prompt institution of definitive therapy is essential.
b Poor performance/functional status and a comorbid medical condition, in addition to age, are factors that influence ability to tolerate standard induction therapy. Web-based tools available
to evaluate the probability of CR and early death after standard induction therapy in patients aged ≥60 years with AML can be found at: Walter RB, et al. J Clin Oncol 2011;29:4417-4423;
Borlenghi E, et al. J Geriatr Oncol 2021;12:550-556. Consider the use of geriatric assessment for patients with AML ≥60 years of age. Ritchie EK, et al. Blood Adv 2022;6:3812-3820; Min
GJ, et al. Blood 2022;139:1646-1658; Saad M, et al. Blood 2020;136:2715-2719; Klepin HD, et al. Blood 2013;121:4287-4294. See NCCN Guidelines for Older Adult Oncology.
c Consider screening with FISH to identify translocations/abnormalities associated with CBF-AML.
d In-frame bZIP mutations in CEBPA are more predictive of favorable outcomes than double mutations. Taube F, et al. Blood 2022;139:87-103; Wakita S, et al. Blood Adv 2022;6:238-247;
Tarlock K, et al. Blood 2021;138:1137-1147.
e Principles of Supportive Care for AML (AML-F).
f Monitoring During Therapy (AML-G).
g Consider referral to palliative care for consultation at the start of induction. El-Jawahri A, et al. JAMA Oncol 2021;7:238-245. See NCCN Guidelines for Palliative Care.
h General Considerations and Supportive Care for Patients with AML Who Prefer Not to Receive Blood Transfusions (AML-D).
i Principles of Systemic Therapy for AML (AML-E).
j For patients who exceed anthracycline dose or have cardiac issues but are still able to receive intensive therapy, alternative non-anthracycline–containing regimens may be considered
(eg, FLAG, clofarabine-based regimens [category 3]). See Discussion.
k For CBF-AML with FLT3-TKD mutation, the Panel prefers gemtuzumab ozogamicin over an FLT3 inhibitor. For CBF-AML with FLT3-ITD, there is insufficient data to recommend one as
preferred over the other.
l Patients who receive transplant shortly following gemtuzumab ozogamicin administration may be at risk for developing sinusoidal obstruction syndrome (SOS). Wadleigh M, et al. Blood
2003;102:1578-1582. If transplant is planned, note that prior studies have used a 60- to 90-day interval between the last administration of gemtuzumab ozogamicin and HCT.
m Threshold for CD33 is not well-defined and may be ≥1% by flow cytometry.
n In times of fludarabine shortage, cladribine can be substituted for fludarabine.
o Gemtuzumab ozogamicin may be beneficial in NPM1-mutated AML (Kapp-Schwoerer S, et al. Blood 2020;136:3041-3050). The role of gemtuzumab ozogamicin in CEBPA-mutated AML
is not established.
p The RATIFY trial studied patients aged 18–60 years with FLT3-mutated AML. An extrapolation of the data suggests that patients aged 61–70 years with FLT3-mutated AML who are fit to
receive 7 + 3 should be offered midostaurin since it seems to provide a survival benefit without undue toxicity. Schlenk RF, et al. Blood 2019;133:840-851.
q Outcomes for patients with poor-risk AML with TP53 mutation remain poor with conventional induction chemotherapy (Rücker FG, et al. Blood 2012;119:2114-2121) and the Panel
prioritizes clinical trial enrollment in this setting. While conventional induction chemotherapy regimens can be given in the setting of a TP53 mutation, less intensive chemotherapy is
preferred for patients not enrolled in clinical trials (DiNardo CD, et al. N Engl J Med 2020;383:617-629; Welch JS, et al. N Engl J Med 2016;375:2023-2036).
r There are limited data supporting the use of this regimen in patients aged <60 years. For patients with AML with cytogenetic changes consistent with MDS (previously classified as
AML-MRC) and previous hypomethylating agent (HMA) exposure, the benefit from standard induction did not differ from the benefit with CPX-351/dual-drug liposomal encapsulation
of cytarabine and daunorubicin. Lancet JE, et al. J Clin Oncol 2018;36:2684-2692. While the mutational definition of AML-MRC as it applies to the use of CPX-351/dual-drug liposomal
cytarabine and daunorubicin was not studied in the original trial, its use can be considered. There is emerging data that CPX-351/dual-drug liposomal encapsulation of cytarabine and
daunorubicin provides most benefit for patients with AML with mutations in SRSF2, SF3B1, EZH2, U2AF1, ZRSR2, BCOR, STAG2, or ASXL1 (Shimony SO, et al. Blood 2024;144:60).
s Venetoclax combination regimens may be continued for patients whose disease demonstrates clinical improvement (CR/CR with incomplete hematologic recovery [CRi]), with
consideration of subsequent transplant, where appropriate. DiNardo CD, et al. Lancet Oncol 2018;19:216-228; Wei A, et al. Blood 2017;130:890; DiNardo CD, et al. Blood 2019;133:7-17;
DiNardo CD, et al. N Engl J Med 2020;383:617-629; Kadia TM, et al. J Clin Oncol 2022;40:3848-3857.
t Patients whose disease has progressed to AML from MDS after significant exposure to HMAs (ie, azacitidine, decitabine) may be less likely to derive benefit from continued treatment
with HMAs compared to patients who are HMA-naïve. Alternative treatment strategies should be considered. DiNardo CD, et al. Blood 2019;133:7-17.
u Patients with cytopenias with disease in remission should take breaks between cycles. For more details about cycle length, see Principles of Venetoclax (AML-J).

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

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Acute Myeloid Leukemia (Age ≥18 years) Discussion

FOLLOW-UP AND REINDUCTION AFTER CYTARABINE-BASED INDUCTIONi,v

RE-INDUCTION Consolidation (if
• Cytarabine received intensive
• Standard 7 + 3 (daunorubicin or Response re-induction)
idarubicin)z (Screening LP, (AML-6)
• 5 + 2 [(daunorubicin or see AML-B)
idarubicin) or (mitoxantrone for (Response
age ≥60 y)]z criteria, see Continue lower
• Standard 7 + 3 (daunorubicin AML-I) intensity therapy
or idarubicin) + midostaurinz (if received HMA
(FLT3 mutated [ITD or TKD]) + venetoclax re-
• Standard 7 + 3 or 5 + 2 BM aspirate and induction) (AML-5)
Residual (daunorubicin or idarubicin) + biopsy to document
disease (if quizartinibz (FLT3-ITD only) remission status
ambiguous, • HMA (azacitidine or decitabine)
repeat BM upon count
+ venetoclaxs,t,u recovery, or by • Allogeneic HCT (See
biopsy within • CPX-351/dual-drug liposomal NCCN Guidelines for
Consider 7 days before day 42 at the latest
encapsulation of cytarabine in the setting of Hematopoietic Cell
follow-up proceeding with Transplantation)
therapy) and daunorubicin (therapy- delayed count
BMf aspirate related AML other than CBF- • Cytarabine (if
and biopsy recoveryaa
AML, antecedent MDS/CMML, not previously
14–21 days or cytogenetic or molecular used as treatment
after start changes consistent with MDS) Lack of for persistent
of therapyw,x (preferred only if given in response to disease at day 15)
induction; BM aspirate and induction/ ± anthracycline
biopsy 14–21 days after start of Primary (daunorubicin or
therapy) refractory idarubicin)z if a
• Consider regimens for (Response clinical trial is not
relapsed/refractory disease, criteria, see available while
including targeted therapies, if AML-I) awaiting identification
lack of response to induction of a donor
(Response criteria, see • Therapy for Relapsed/
AML-I). Therapy for Relapsed/ Refractory Disease
Refractory Disease (AML-9) (AML-9)
• Best supportive care

Hypoplasiay Await recovery Footnotes on AML-3A

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

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FOOTNOTES FOR FOLLOW-UP AND REINDUCTION AFTER CYTARABINE-BASED INDUCTION

f Monitoring During Therapy (AML-G).
i Principles of Systemic Therapy for AML (AML-E).
s Venetoclax combination regimens may be continued for patients whose disease demonstrates clinical improvement (CR/CR with incomplete hematologic recovery
[CRi]), with consideration of subsequent transplant, where appropriate. DiNardo CD, et al. Lancet Oncol 2018;19:216-228; Wei A, et al. Blood 2017;130:890; DiNardo
CD, et al. Blood 2019;133:7-17; DiNardo CD, et al. N Engl J Med 2020;383:617-629; Kadia TM, et al. J Clin Oncol 2022;40:3848-3857.
t Patients whose disease has progressed to AML from MDS after significant exposure to HMAs (ie, azacitidine, decitabine) may be less likely to derive benefit from
continued treatment with HMAs compared to patients who are HMA-naïve. Alternative treatment strategies should be considered. DiNardo CD, et al. Blood 2019;133:7-
17.
u Patients with cytopenias with disease in remission should take breaks between cycles. For more details about cycle length, see Principles of Venetoclax (AML-J).
v Consider clinical trials for patients with disease with targeted molecular abnormalities.
w When using a cytarabine-based induction regimen with doses of cytarabine >100 to 200 mg/m2, consider delaying BM aspirate and biopsy to D21.
x There are limited prospective data to support this recommendation. Othus M, et al. Leukemia 2016;30:1779-1780.
y Hypoplasia is defined as cellularity <20% of which the residual blasts are <5% (ie, blast percentage of residual cellularity).
z For regimens using high cumulative doses of cardiotoxic agents, consider reassessing cardiac function prior to each anthracycline/mitoxantrone-containing course.
Karanes C, et al. Leuk Res 1999;23:787-794.
aa When performed, BM aspirate and biopsy should include cytogenetic and molecular studies, as appropriate. For measurable (minimal) residual disease (MRD)
assessment, see AML-H.

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

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Acute Myeloid Leukemia (Age ≥18 years) Discussion

LOWER RISK GROUPS TREATMENT INDUCTIONe,g,h,i

INTENSITY Principles of Venetoclax, see AML-J
THERAPY Preferred
(INTENSIVE • Azacitidine + venetoclax (category 1)s,t,u
INDUCTION • Azacitidine + ivosidenib (category 1)t,cc,dd,ee
INELIGIBLE • Decitabine + venetoclaxs,t,u
OR Other Recommended
DECLINES) • Ivosidenibcc,dd
AML with IDH1 Useful in Certain Circumstances
mutation
• Low-dose cytarabine (LDAC) + venetoclaxs,u (prior exposure
to HMA)
• Azacitidine or decitabinet,ff (contraindication to venetoclax)
• Olutasidenibcc,dd (category 2B) (not eligible for preferred
regimen and not eligible for ivosidenib due to prolonged
QTcF) Follow-up After
Not a Induction Therapy
candidate with Lower Intensity
for intensive Therapy (Intensive
induction Induction Ineligible
Preferred or Declines)
therapy or
• Azacitidine + venetoclax (category 1)s,t,u (AML-5)
declinesa,b,bb
• Decitabine + venetoclaxs,t,u
Other Recommended
• Cladribine + LDAC + venetoclaxs (category 2B)
Useful in Certain Circumstances
• LDAC + venetoclaxs,u (prior exposure to hypomethylating
agent [HMA])
AML without • Azacitidine or decitabinet,ff (contraindication to venetoclax)
IDH1 mutation • LDAC + glasdegibgg
• LDAC (prior exposure to HMA or contraindication to
venetoclax)
• Gilteritinib ± azacitidinet (FLT3-ITD or TKD, not eligible for
preferred regimen)
• Enasidenib ± azacitidinet,cc,dd (IDH2 mutation, not eligible
for preferred regimen)
• Gemtuzumab ozogamicinhh (CD33 positive, not eligible for
preferred regimen)m

Footnotes on AML-4A

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

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Acute Myeloid Leukemia (Age ≥18 years) Discussion

FOOTNOTES FOR LOWER INTENSITY THERAPY (INTENSIVE INDUCTION INELIGIBLE OR DECLINES)

a Patients with elevated blast counts are at risk for tumor lysis and organ dysfunction secondary to leukostasis. Measures to rapidly reduce the WBC count include
leukapheresis, hydroxyurea, and/or a single dose of cytarabine. Prompt institution of definitive therapy is essential.
b Poor performance/functional status and a comorbid medical condition, in addition to age, are factors that influence ability to tolerate standard induction therapy. Web-
based tools available to evaluate the probability of CR and early death after standard induction therapy in patients aged ≥60 years with AML can be found at: Walter
RB, et al. J Clin Oncol 2011;29:4417-4423; Borlenghi E, et al. J Geriatr Oncol 2021;12:550-556. Consider the use of geriatric assessment for patients with AML ≥60
years of age. Ritchie EK, et al. Blood Adv 2022;6:3812-3820; Min GJ, et al. Blood 2022;139:1646-1658; Saad M, et al. Blood 2020;136:2715-2719; Klepin H, et al.
Blood 2013;121:4287-4294. See NCCN Guidelines for Older Adult Oncology.
e Principles of Supportive Care for AML (AML-F).
g Consider referral to palliative care for consultation at the start of induction. El-Jawahri A, et al. JAMA Oncol 2021;7:238-245. See NCCN Guidelines for Palliative Care.
h General Considerations and Supportive Care for Patients Who Prefer Not to Receive Blood Transfusions (AML-D).
i Principles of Systemic Therapy for AML (AML-E).
m Threshold for CD33 is not well-defined and may be ≥1% by flow cytometry.
s Venetoclax combination regimens may be continued for patients whose disease demonstrates clinical improvement (CR/CRi), with consideration of subsequent
transplant, where appropriate. DiNardo CD, et al. Lancet Oncol 2018;19:216-228; Wei A, et al. Blood 2017;130:890; DiNardo CD, et al. Blood 2019;133:7-17; DiNardo
CD, et al. N Engl J Med 2020;383:617-629. Kadia TM, et al. J Clin Oncol 2022;40:3848-3857.
t Patients whose disease has progressed to AML from MDS after significant exposure to HMAs (ie, azacitidine, decitabine) may be less likely to derive benefit from
continued treatment with HMAs compared to patients who are HMA-naïve. Alternative treatment strategies should be considered. DiNardo CD, et al. Blood 2019;133:7-
17.
u Patients with cytopenias with disease in remission should take breaks between cycles. For more details about cycle length, see Principles of Venetoclax (AML-J).
bb For patients who decline induction chemotherapy and/or targeted therapy, best supportive care may include hydroxyurea and/or transfusion support.
cc Response to treatment with IDH inhibitors may take 3–5 months.
dd IDH inhibitors increase the risk for differentiation syndrome and hyperleukocytosis that may require treatment with hydroxyurea and steroids. Monitor closely for
differentiation syndrome and initiate therapy to resolve symptoms according to indications. Note that differentiation syndrome can occur later (up to several months
after induction).
ee This regimen is approved for patients with newly diagnosed AML with an IDH1 mutation who met at least one of the following criteria: aged >75 years, baseline
Eastern Cooperative Oncology Group (ECOG) performance status of 2, severe cardiac or pulmonary disease, hepatic impairment with bilirubin >1.5 times the upper
limit of normal, creatinine clearance (CrCl) <45 mL/min, or other comorbidity. Montesinos P, et al. N Engl J Med 2022;386:1519-1531.
ff Response may not be evident before 3–4 cycles of treatment with HMAs (ie, azacitidine, decitabine). Continue HMA treatment until progression if patient is tolerating
therapy. Similar delays in response are likely with novel agents in a clinical trial, but endpoints will be defined by the protocol.
gg This regimen is for treatment of newly diagnosed AML in patients who are ≥75 years of age, or who have significant comorbid conditions (ie, severe cardiac disease,
ECOG performance status ≥2, baseline creatinine >1.3 mg/dL) and has been associated with an improved overall survival (OS) in a randomized trial. Cortes JE, et al.
Leukemia 2019;33:379-389.
hh Regimens that include gemtuzumab ozogamicin have limited benefit in poor-risk disease.

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

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AML-4A
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Acute Myeloid Leukemia (Age ≥18 years) Discussion

FOLLOW-UP AFTER INDUCTION THERAPY WITH LOWER INTENSITY THERAPY (INTENSIVE INDUCTION INELIGIBLE OR DECLINES)i

Response
(Response • Allogeneic HCTii
Maintenance
criteria, • Continue on lower intensity regimen that
(AML-7)
see AML-I) was previously used for induction per AML-4
BM aspirate and
biopsy to document
remission status
Previous (timing is dependent
lower on agent). For
intensity measurable
therapy (minimal) residual
disease (MRD)
assessment, see
AML-H
No response
or Therapy for Relapsed/Refractory Disease (AML-9)
progression or
(Response Best supportive care (hydroxyurea, transfusion support)
criteria, see (See NCCN Guidelines for Palliative Care)
AML-I)

i Principles of Systemic Therapy for AML (AML-E).

ii Patients who are deemed as candidates for HCT and who have an available donor should be transplanted in first remission.

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

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AML-5
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Acute Myeloid Leukemia (Age ≥18 years) Discussion

CONSOLIDATION RISK GROUP TREATMENTi

THERAPYjj,kk (AML-A)
• Cytarabinemm ± gemtuzumab ozogamicinl (CD33 Consider
positive)m (only if gemtuzumab ozogamicin was given allogeneic HCTl,qq
Favorable-risk AML by during induction) or
cytogenetics (CBF-AML) • Cytarabinemm (5 or 7 days) ± ([daunorubicin or Maintenance
or by molecular mutation idarubicin] or [mitoxantrone for age ≥60 y])z (AML-7)
profile per ELN (AML-A)d,ll • Cytarabinemm + (daunorubicin or idarubicin) + or
gemtuzumab ozogamicinl,z,nn (CD33 positive)m (only if Surveillance
gemtuzumab ozogamicin was given during induction) (AML-8)

• Allogeneic HCT (preferred for FLT3-ITD)jj,kk,oo

AML with FLT3 mutation • Cytarabinemm + midostaurinp (FLT3-ITD or TKD)
Intensive • Cytarabinemm + quizartinib (FLT3-ITD only)
induction
eligible
• Cytarabinemm,pp Allogeneic HCTl
• Cytarabinemm + (daunorubicin or idarubicin) + (if not previously
Intermediate-risk AML gemtuzumab ozogamicinl,z,nn (CD33 positive)m (only if performed)
gemtuzumab ozogamicin was given during induction) or
• Allogeneic HCTjj,kk Maintenance
(AML-7)
or
• Poor-risk AML with and Surveillance
• Allogeneic HCTjj,kk (preferred) (AML-8)
without TP53 mutation or • Cytarabinemm
del(17p) abnormality • CPX-351/dual-drug liposomal encapsulation of
• Therapy-related AML other cytarabine and daunorubicinr (preferred only if given
than CBF-AML during induction)
• Antecedent MDS/CMML • FLAG-IDA (use with caution in patients >60 y)
• Cytogenetic changes (preferred only if given during induction)n,mm
consistent with MDS • Continuation of lower intensity regimen used for
(previously classified as induction (eg, HMA, [azacitidine or decitabine] +
AML-MRC) venetoclax) (AML-4)

Footnotes on AML-6A
Note: All recommendations are category 2A unless otherwise indicated.

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AML-6
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Acute Myeloid Leukemia (Age ≥18 years) Discussion

FOOTNOTES FOR CONSOLIDATION THERAPY (INTENSIVE INDUCTION ELIGIBLE)

d In-frame bZIP mutations in CEBPA are more predictive of favorable outcomes than double mutations. Taube F, et al. Blood 2022;139:87-103; Wakita S, et al. Blood
Adv 2022;6:238-247; Tarlock K, et al. Blood 2021;138:1137-1147.
i Principles of Systemic Therapy for AML (AML-E).
l Patients who receive transplant shortly following gemtuzumab ozogamicin administration may be at risk for developing SOS. Wadleigh M, et al. Blood 2003;102:1578-
1582. If transplant is planned, note that prior studies have used a 60- to 90-day interval between the last administration of gemtuzumab ozogamicin and HCT.
m Threshold for CD33 is not well-defined and may be ≥1% by flow cytometry.
n In times of fludarabine shortage, cladribine can be substituted for fludarabine.
p The RATIFY trial studied patients aged 18–60 years with FLT3-mutated AML. An extrapolation of the data suggests that patients aged 61–70 years with FLT3-
mutated AML who are fit to receive 7 + 3 should be offered midostaurin since it seems to provide a survival benefit without undue toxicity. Schlenk RF, et al. Blood
2019;133:840-851.
r There are limited data supporting the use of this regimen in patients aged <60 years. For patients with AML with cytogenetic changes consistent with MDS
(previously classified as AML-MRC) and previous HMA exposure, the benefit from standard induction did not differ from the benefit with CPX-351/dual-drug liposomal
encapsulation of cytarabine and daunorubicin. Lancet JE, et al. J Clin Oncol 2018;36:2684-2692. While the mutational definition of AML-MRC as it applies to the use of
CPX-351/dual-drug liposomal cytarabine and daunorubicin was not studied in the original trial, its use can be considered. There is emerging data that CPX-351/dual-
drug liposomal encapsulation of cytarabine and daunorubicin provides most benefit for patients with AML with mutations in SRSF2, SF3B1, EZH2, U2AF1, ZRSR2,
BCOR, STAG2, or ASXL1 (Shimony SO, et al. Blood 2024;144:60).
z For regimens using high cumulative doses of cardiotoxic agents, consider reassessing cardiac function prior to each anthracycline/mitoxantrone-containing course.
Karanes C, et al. Leuk Res 1999;23:787-794.
jj For appropriate patients, begin alternate donor search (haploidentical, unrelated donor, or cord blood) if no appropriate matched sibling donor is available and the
patient is a candidate for allogeneic HCT. For lack of response to induction, alternative therapy to achieve remission is encouraged prior to HCT. See NCCN Guidelines
for Hematopoietic Cell Transplantation.
kk Patients eligible for allogeneic HCT may require at least one cycle of consolidation while donor search is in progress or while awaiting collaboration with a transplant
center to maintain remission. Patients may proceed directly to transplant following achievement of remission if a donor is available.
ll See Measurable (Minimal) Residual Disease Assessment (AML-H) for additional guidance on MRD monitoring for patients with CBF-AML and NPM1-mutated AML.
mm Alternate dosing of cytarabine for postremission therapy has been reported (Discussion). Jaramillo S, et al. Blood Cancer J 2017;7:e564. Doses of cytarabine ≥2
g/m2 should be used with caution in patients ≥60 years and patients with renal failure due to concern for neurotoxicity. See Principles of Systemic Therapy for AML
(AML-E).
nn This regimen may also be used in patients with AML with KIT mutations because the outcomes are similar in patients with AML without KIT mutations.
oo Consider NPM1 molecular MRD status, if applicable.
pp There is no evidence that cytarabine doses ≥2 g/m2 are superior to doses 1–2 g/m2 in patients with AML with intermediate-risk cytogenetics.
qq Allogeneic transplant is recommended for patients with favorable-risk disease who are unable to complete consolidation or who have high-risk features such as MRD-
positivity or KIT mutation.

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

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AML-6A
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Acute Myeloid Leukemia (Age ≥18 years) Discussion

MAINTENANCE THERAPY TREATMENTi

Post Chemotherapy
• Patient with non–CBF-AML: • Consider oral azacitidine until progression
Received prior intensive chemotherapy or unacceptable toxicity (category 1 for
and disease is now in remission age ≥55 y)tt,uu
Completed no consolidation or some • Useful in Certain Circumstances:
consolidation Azacitidine or decitabine for a maximum
No allogeneic HCT is planned of 12 cycles (unable to receive oral
azacitidine) Surveillance
(AML-8)

• Patient with history of FLT3 mutation: • Quizartinib (FLT3-ITD only) (preferred for
Previously received FLT3 inhibitor FLT3-ITD)
No allogeneic HCT is planned • Midostaurin (FLT3-ITD or TKD)

Post Allogeneic HCT • Gilteritinib (FLT3-ITD or TKD) (preferred for

FLT3-ITD in CR1 without MRD negativity
Post allogeneic HCT, in remission, by ultrasensitive assay pre-transplant) Surveillance
and history of FLT3 mutation • Sorafenib (FLT3-ITD only) (AML-8)
• Midostaurin (FLT3-ITD or TKD)
• Quizartinib (FLT3-ITD only)

Post allogeneic HCT, in remission, with history Surveillance

• Low-dose decitabine + G-CSF (category 2B)
of AML with high-risk featuresrr,ss (AML-8)

tt This is not intended to replace consolidation chemotherapy. In addition, patients who are fit may benefit from HCT in first CR,
and there are no data to suggest that maintenance therapy with oral azacitidine can replace HCT. The Panel also notes that the
i Principles of Systemic Therapy for AML (AML-E). trial did not include patients <55 years of age or those with CBF-AML; it was restricted to patients ≥55 years of age with AML
rr ELN Risk Stratification by Biological Disease with intermediate or adverse cytogenetics who were not felt to be candidates for HCT. Most patients received at least 1 cycle of
Factors for Patients with Non-APL AML Treated with consolidation prior to starting oral azacitidine. Wei AH, et al. N Engl J Med 2020;383:2526-2537.
Intensive Induction Chemotherapy (AML-A). uu There are certain circumstances where oral azacitidine may be of benefit for those who have completed a recommended course
ss Gao L, et al. J Clin Oncol 2020;38:4249-4259. of consolidation. Dohner H, et al. Blood 2022;140:1674-1685.

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

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AML-7
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Acute Myeloid Leukemia (Age ≥18 years) Discussion

AML SURVEILLANCEvv AND THERAPY FOR RELAPSED/REFRACTORY DISEASE

(AFTER COMPLETION OF CONSOLIDATION)

• CBC, platelets every 1–3 mo for Options:

2 y, then every 3–6 mo up to 5 y Clinical trial (strongly preferred)
• BM aspirate and biopsy only if or
peripheral smear is abnormal or Targeted therapy alone or in combination
cytopenias develop (AML-9) followed by allogeneic HCT
• Donor search should be initiated Relapse Molecular profiling to or
at first relapse in appropriate (Response determine mutation Chemotherapy (AML-9) followed by allogeneic
patients concomitant with criteria, see status of actionable HCT
institution of other therapy AML-I) genesww or
• Confirm molecular remission Best supportive care
and monitor for molecular (See NCCN Guidelines for Palliative Care)
relapse, if applicable. See
Measurable (Minimal) Residual Useful in Certain Circumstances:
Disease Assessment (AML-H) Allogeneic HCTxx

vv Studies are ongoing to evaluate the role of molecular monitoring in the surveillance for early relapse in patients with AML (Discussion).
ww Molecular and cytogenetic analyses (including testing for IDH1/IDH2, FLT3 mutations, and KMT2A rearrangements) are suggested as they may assist with selection
of therapy and appropriate clinical trials (Discussion). Molecular testing should be repeated at each relapse or progression.
xx Allogeneic HCT may be considered for patients who did not achieve CR following first induction therapy or for those with first relapse who had previously been
scheduled for allogeneic HCT. Stelljes M, et al. Lancet Haematol 2024;11:e324-e335.

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

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THERAPY FOR RELAPSED/REFRACTORY DISEASEi,yy

Clinical trialyy Intensive therapy for appropriate patientsbbb,ccc:
Targeted therapyzz,aaa: • Cladribine + cytarabine + G-CSF ± (mitoxantrone or idarubicin)
• Therapy for AML with FLT3-ITD mutation • Cytarabine ± (daunorubicin or idarubicin or mitoxantrone)
Gilteritinib (category 1) • Fludarabine + cytarabine + G-CSF ± idarubicin ± venetoclaxddd
HMAs (azacitidine or decitabine) + sorafenib • Etoposide + cytarabine ± mitoxantrone
Quizartinib (category 2B) • Clofarabine ± cytarabine ± idarubicin
• Therapy for AML with FLT3-TKD mutation • CLIA (cladribine + idarubicin + cytarabine) + venetoclax (category 2B)
Gilteritinib (category 1)
• Therapy for AML with IDH2 mutation Less intensive therapy:
Enasidenib • HMAs (azacitidine or decitabine)t
• Therapy for AML with IDH1 mutation • LDAC (category 2B)
Ivosidenib • (HMA or LDAC) + venetoclaxt,ddd
Olutasidenib
• Therapy for CD33-positive AML
Gemtuzumab ozogamicin
• Therapy for AML with lysine methyltransferase 2A gene (KMT2A)
rearrangement
Revumenib
• Therapy for AML with NPM1 mutation
Revumenib
Ziftomenib

i Principles of Systemic Therapy for AML (AML-E).

t Patients whose disease has progressed to AML from MDS after significant bbb Appropriate patients include those eligible for intensive therapy and with
exposure to HMAs (ie, azacitidine, decitabine) may be less likely to derive benefit relatively short first remission. For patients with long first remission, reinduction
from continued treatment with HMAs compared to patients who are HMA-naïve. therapy may be appropriate.
Alternative treatment strategies should be considered. DiNardo CD, et al. Blood ccc Reinduction therapy may be appropriate in certain circumstances, such as in
2019;133:7-17. patients with long first remission (there are no data regarding re-induction with
yy There are promising ongoing clinical trials investigating targeted therapies based dual-drug liposomal encapsulation of cytarabine and daunorubicin). This strategy
on molecular mutations for relapsed/refractory disease. Molecular profiling should primarily applies to cytotoxic chemotherapy and excludes the re-use of targeted
be considered if not done at diagnosis, or repeated to determine clonal evolution. agents due to the potential development of resistance. Targeted therapies may
See Discussion. be retried if agents were not administered continuously and not stopped due to
zz There have been trials conducted combining targeted therapies with other agents. development of clinical resistance. If a second CR is achieved, then consolidation
aaa Best sequencing of targeted therapies is unknown at this time and depends on with allogeneic HCT should be considered.
clinical context. ddd Principles of Venetoclax Use with HMA or LDAC (AML-J).

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

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Acute Myeloid Leukemia (Age ≥18 years) Discussion

ELN RISK STRATIFICATION BY BIOLOGICAL DISEASE FACTORS FOR PATIENTS WITH NON-APL AML TREATED WITH INTENSIVE
INDUCTION CHEMOTHERAPY1
Risk Categorya,b Genetic Abnormality
Favorable t(8;21)(q22;q22.1)/RUNX1::RUNX1T1b,c
inv(16)(p13.1q22) or t(16;16)(p13.1;q22)/CBFB::MYH11b,c
Mutated NPM1b,d without FLT3-ITD
bZIP in-frame mutated CEBPAe
Intermediate Mutated NPM1b,d with FLT3-ITD
Wild-type NPM1 with FLT3-ITD (without adverse-risk genetic lesions)
t(9;11)(p21.3;q23.3)/MLLT3::KMT2Ab,f
Cytogenetic and/or molecular abnormalities not classified as favorable or adverse
Poor/Adverse t(6;9)(p23.3;q34.1)/DEK::NUP214
t(v;11q23.3)/KMT2A-rearrangedg
t(9;22)(q34.1;q11.2)/BCR::ABL1
t(8;16)(p11.2;p13.3)/KAT6A::CREBBP
inv(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2)/GATA2, MECOM(EVI1)
t(3q26.2;v)/MECOM(EVI1)-rearranged
-5 or del(5q); -7; -17/abn(17p)
Complex karyotype,h monosomal karyotypei
Mutated ASXL1, BCOR, EZH2, RUNX1, SF3B1, SRSF2, STAG2, U2AF1, and/or ZRSR2j
Mutated TP53k

a Frequencies, response rates, and outcome measures should be reported by risk category, and, if

sufficient numbers are available, by specific genetic lesions indicated.

b Mainly based on results observed in intensively treated patients. Initial risk assignment may change

during the treatment course based on the results from analyses of MRD. i Monosomal karyotype: presence of two or more distinct monosomies (excluding loss of X or Y),
c Concurrent KIT and/or FLT3 gene mutation does not alter risk categorization. or one single autosomal monosomy in combination with at least one structural chromosome
d AML with NPM1 mutation and adverse-risk cytogenetic abnormalities are categorized as adverse-risk. abnormality (excluding CBF-AML).
e Only in-frame mutations affecting the bZIP region of CEBPA, irrespective of whether they occur as j For the time being, these markers should not be used as an adverse prognostic marker if they co-

monoallelic or biallelic mutations, have been associated with favorable outcome. occur with favorable-risk AML subtypes.
f The presence of t(9;11)(p21.3;q23.3) takes precedence over rare, concurrent adverse-risk gene k TP53 mutation at a variant allele fraction of at least 10%, irrespective of the TP53 allelic status

mutations. (mono- or biallelic mutation); TP53 mutations are significantly associated with AML with complex and
g Excluding KMT2A partial tandem duplication (PTD). monosomal karyotype.
h Complex karyotype: ≥3 unrelated chromosome abnormalities in the absence of other class-defining 1 Dohner H, Wei AH, Appelbaum FR, et al. Diagnosis and management of AML in adults: 2022

recurring genetic abnormalities; excludes hyperdiploid karyotypes with three or more trisomies (or recommendations from an international expert panel on behalf of the ELN. Blood 2022;140:1345-
polysomies) without structural abnormalities. 1377.
NCCN Guidelines for Myelodysplastic Syndromes
Note: All recommendations are category 2A unless otherwise indicated.

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Acute Myeloid Leukemia (Age ≥18 years) Discussion

EVALUATION AND TREATMENT OF CNS LEUKEMIAa

Negative Observe and repeat LP if symptoms persist

Negative
LPd
mass effect
Positive by
CT/MRI to morphology or IT chemotherapyf 2x/wk until clear,
At diagnosis, immunotype by then weekly x 4–6 wksa
rule out
neurologic flow cytometrye
bleed or
symptomsb
mass effect Positive RTg followed by IT chemotherapyf 2x/wk until clear,
mass effect Consider fine-needle then weekly x 4–6 wksa
or increased aspiration (FNA) or or
intracranial biopsy Cytarabine-based therapy with doses ≥2 g/m2 +
pressure dexamethasone to reduce intracranial pressure

Negative Observe and repeat LP if symptoms present

First CR
screening, no
LP
neurologic
symptomsc IT chemotherapy 2x/wk until cleara
Cerebrospinal fluid (CSF) positive
±
by morphology or immunotype by
If patient is to receive doses of cytarabine ≥2 g/m2,
flow cytometrye
follow up with LP post completion of therapy to
document clearance

a Further CNS prophylaxis per institutional practice.

b For patients with major neurologic signs or symptoms at diagnosis, appropriate imaging studies should be performed to detect meningeal disease, chloromas, or CNS
bleeding. LP should be performed if no mass, lesion, or hemorrhage was detected on the imaging study with central shift making an LP relatively contraindicated.
c Screening LP should be considered at first remission for asymptomatic patients with WBC count >40 x 109/L at diagnosis, extramedullary disease, high-risk APL,
intraparenchymal hemorrhage at diagnosis, FLT3 mutations, MLLT3::KMT2A fusion, monocytic differentiation, or MPAL. For further information regarding MPAL, see
NCCN Guidelines for Acute Lymphoblastic Leukemia.
d In the presence of circulating blasts, administer IT chemotherapy with diagnostic LP.
e If equivocal, consider repeating LP with morphology or immunotype by flow cytometry to delineate involvement.
f Induction chemotherapy should be started concurrently. However, for patients receiving doses of cytarabine ≥2 g/m2, since this agent crosses the blood-brain barrier, IT
therapy can be deferred until induction is completed. IT chemotherapy may consist of methotrexate, cytarabine, or a combination of these agents.
g Concurrent use of CNS RT with doses of cytarabine ≥2 g/m2 or IT methotrexate may increase risk of neurotoxicity. See Principles of Radiation Therapy (AML-C).

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

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Acute Myeloid Leukemia (Age ≥18 years) Discussion

PRINCIPLES OF RADIATION THERAPY

General Principles
• Patients who present with isolated extramedullary disease (myeloid sarcoma) or leukemia cutis should be treated with systemic therapy.
Local therapy (RT or surgery [rare cases]) may be used for residual disease or for symptomatic disease.
General Treatment Information
• CNS leukemia: RTa followed by IT chemotherapyb 2x/wk until clear, then weekly x 4–6 weeksc

a Concurrent use of CNS RT with doses of cytarabine ≥2 g/m2 or IT methotrexate may increase risk of neurotoxicity.
b Induction chemotherapy should be started concurrently. However, for patients receiving doses of cytarabine ≥2 g/m2, since this agent crosses the blood-brain barrier, IT
therapy can be deferred until induction is completed. IT chemotherapy may consist of methotrexate, cytarabine, or a combination of these agents.
c Further CNS prophylaxis per institutional practice.

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

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Acute Myeloid Leukemia (Age ≥18 years) Discussion

GENERAL CONSIDERATIONS AND SUPPORTIVE CARE FOR PATIENTS WITH AML

WHO PREFER NOT TO RECEIVE BLOOD TRANSFUSIONS1-5
General Supportive Care
• There is no established treatment of AML that does not require the use of blood and blood products for supportive care.
• Discuss goals of care and understanding of complications without transfusion.
• For Jehovah’s Witnesses, the United States Branch of the Christian Congregation of Jehovah’s Witness has a Hospital Liaison Committee
that can provide helpful information about bloodless medicine: [Link]
contacts/united-states
• Clarify acceptance of certain blood products (eg, cryoprecipitate) under certain circumstances, including a discussion of whether stem cells
(donor or autologous) will be acceptable.
• Minimize blood loss (eg, use of pediatric collection tubes).
• Minimize risk of bleeding, including consideration for use of oral contraceptive pills or medroxyprogesterone acetate in menstruating
individuals; proton pump inhibitor, aggressive antiemetic prophylaxis, and stool softeners are advised to reduce risk of gastrointestinal (GI)
bleed; nasal saline sprays are advised to reduce epistaxis; and fall precautions are advised, particularly in patients with thrombocytopenia.
• Avoid concomitant medicines or procedures that can increase the risk of bleeding or myelosuppression.
• Consider using vitamin K (to potentially reverse coagulopathy) and aminocaproic acid or tranexamic acid in patients at risk of bleeding (eg,
when platelet count drops below 30 x 109/L) or for management of bleeding.
• Consider use of aminocaproic acid rinses for oral bleeding or significant mucositis that could result in bleeding.
• Consider using acetaminophen to manage fever.
• Consider iron, folate, and vitamin B12 supplementation if deficient. Iron supplementation may be avoided in someone with excess iron
levels.
• Consider use of erythropoiesis-stimulating agent (ESA), G-CSF, and thrombopoietin (TPO) mimetics after a thorough discussion of potential
risks, benefits, and uncertainties.
• Consider bed rest and supplemental oxygenation in patients with severe anemia.

Disease-Specific Considerations
• Test for actionable mutations and consider use of targeted agents instead of intensive chemotherapy, particularly in a non-curative setting.
• May consider use of less myelosuppressive induction including dose reduction of anthracyclines, and use of non-intensive chemotherapy.6
• Consider referring to centers with experience in bloodless autologous HCT.

1 Laszio D, Agazzi A, Goldhirsch A, et al. Tailored therapy of adult acute leukaemia 4 Beck A, Lin R, Rejali AR, et al. Safety of bloodless autologous stem cell
in Jehovah’s Witnesses: unjustified reluctance to treat. Eur J Haematol transplantation in Jehovah's Witness patients. Bone Marrow Transplant
2004;72:264-267. 2020;55:1059-1067.
2 El Chaer F, Ballen KK. Treatment of acute leukaemia in adult Jehovah's 5 Rubenstein M, Duvic M. Bone marrow transplantation in Jehovah's Witnesses.
Witnesses. Br J Haematol 2020;190:696-707. Leuk Lymphoma 2004;45:635-636.
3 Ballen KK, Becker PS, Yeap BY, et al. Autologous stem-cell transplantation 6 Bock AM, Pollyea DA. Venetoclax with azacitidine for two younger Jehovah's
can be performed safely without the use of blood-product support. J Clin Oncol Witness patients with high risk acute myeloid leukemia. Am J Hematol
2004;22:4087-4094. 2020;90:E269-E272.

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

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Acute Myeloid Leukemia (Age ≥18 years) Discussion

PRINCIPLES OF SYSTEMIC THERAPY FOR AMLa,b

INTENSIVE INDUCTION ELIGIBLE (AML-1, AML-2)
Therapy Regimen
Standard 7 + 3 (daunorubicin Cytarabine 200 mg/m2 continuous infusion x 7 days with daunorubicin 60 mg/m2 or
or idarubicin) + gemtuzumab idarubicin 12 mg/m2 x 3 days and a single dose of gemtuzumab ozogamicin 3 mg/m2
ozogamicin (CD33 positive) c,d,e,1-5 (up to one 4.5-mg vial) given on day 1, or day 2, or day 3, or day 4; alternatively, three
total doses may be given on days 1, 4, and 7
Standard 7 + 3 (daunorubicin or Cytarabine 100 or 200 mg/m2 continuous infusion x 7 days with daunorubicin 60f or
idarubicin)d,e,6,7,8,9 90 mg/m2 or idarubicin 12 mg/m2 x 3 days
FLAG-IDA + gemtuzumab Fludarabine 30 mg/m2 days 2–6, cytarabine 2 g/m2 over 4 hours starting 4 hours after
ozogamicin (CD33 positive) c,g,h,10 fludarabine infusion on days 2–6, idarubicin 8 mg/m2 IV on days 4–6, and G-CSF
subcutaneously (SC) daily days 1–7 plus a single dose of gemtuzumab ozogamicin
3 mg/m2 in first course
FLAG + gemtuzumab ozogamicin Fludarabine 30 mg/m2 days 1–5, cytarabine 2 g/m2 over 4 hours starting 3.5 hours after
(CD33 positive)c,g,h,11 fludarabine infusion on days 1–5, and G-CSF SC daily starting day 1 through recovery
of ANC to 1 × 109/L plus a single dose of gemtuzumab ozogamicin 3 mg/m2 on day 1
FLAG-IDAg,h,1,10 Fludarabine 30 mg/m2 days 2–6, cytarabine 2 g/m2 over 4 hours starting 4 hours after
fludarabine infusion on days 2–6, idarubicin 8 mg/m2 IV on days 4–6, and G-CSF SC
daily days 1–7
CLAG-M h,12,13 Cladribine 5 mg/m2 days 2–6, cytarabine 2 g/m2 over 4 hours starting 2 hours after
cladribine infusion on days 2–6, mitoxantrone 10 mg/m2 IV on days 2–4, and G-CSF SC
daily days 1–6
Standard 7 + 3 (daunorubicin or Cytarabine 100 or 200 mg/m2 continuous infusion x 7 days with daunorubicin 60 mg/m2
idarubicin) + midostaurin or idarubicin 12 mg/m2 x 3 days and oral midostaurin 50 mg every 12 hours, days 8–21
(FLT3-ITD or TKD) d,e,14,15,16

Standard 7 + 3 (daunorubicin or Cytarabine 100 or 200 mg/m2 continuous infusion x 7 days with daunorubicin 60 mg/m2
idarubicin) + quizartinib or idarubicin 12 mg/m2 x 3 days and quizartinib 35.4 mg PO daily, days 8–21
(FLT3-ITD only) d,e,17

Footnotes on AML-E 1A References on AML-E 11 of 14

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

AML-E
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PRINCIPLES OF SYSTEMIC THERAPY FOR AML

INTENSIVE INDUCTION ELIGIBLE
FOOTNOTES
a An FDA-approved biosimilar is an appropriate substitute for any recommended systemic biologic therapy in the NCCN Guidelines.
b Specific recommendations, Categories of Evidence and Consensus, and Categories of Preference vary based on patient and disease characteristics (see AML-1
through AML-9). The charts in this section delineate systemic therapy regimens that can be used and provide some additional details.
c A meta-analysis showing an advantage with gemtuzumab ozogamicin included other dosing schedules. Hills RK, et al. Lancet Oncol 2014;15:986-996.
d ECOG reported a significant increase in CR rates and OS using daunorubicin 90 mg/m2 x 3 days versus 45 mg/m2 x 3 days in patients <60 years of age. Fernandez
HF, et al. N Engl J Med 2009;361:1249-1259. If there is residual disease on days 12–14, the additional daunorubicin dose is 45 mg/m2 x 3 days. Burnett AK, et al.
Blood 2015;125:3878-3885.
e The CR rates and 2-year OS in patients between 60 and 65 years of age treated with daunorubicin 90 mg/m2 is also comparable to the outcome for idarubicin
12 mg/m2; the higher-dose daunorubicin did not benefit patients >65 years of age (Löwenberg B, et al. N Engl J Med 2009;361:1235-1248).
f Daunorubicin 60 mg/m2 is preferred over 90 mg/m2. Rollig C, et al. J Clin Oncol 2025;43:65-74.
g In times of fludarabine shortage, cladribine can be substituted for fludarabine.
h Consider dose adjustments for cytarabine based on age and renal function. Doses of cytarabine ≥2 g/m2 should be used with caution in patients ≥60 years and
patients with renal failure due to concern for neurotoxicity.

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

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PRINCIPLES OF SYSTEMIC THERAPY FOR AMLa,b

INTENSIVE INDUCTION ELIGIBLE (AML-1, AML-2)
Therapy Regimen
CPX-351/dual-drug liposomal cytarabine CPX-351/dual-drug liposomal cytarabine 100 mg/m2 and daunorubicin
and daunorubicin18 44 mg/m2 on days 1, 3, and 5 x 1 cycle
Decitabine (days 1–5) + venetoclaxi,j,19,20 Decitabine 20 mg/m2 IV (days 1–5 of each 28-day cycle) and venetoclax
PO once daily (100 mg day 1, 200 mg day 2, and 400 mg days 3 and
beyond)
Azacitidine + venetoclaxi,j,19,21 Azacitidine 75 mg/m2 SC or IV days 1–7 of each 28-day cycle and
venetoclax PO once daily (100 mg day 1, 200 mg day 2, and 400 mg days
3 and beyond)
CLIA + venetoclax22 Cladribine 5 mg/m2 on days 1–5, cytarabine 1–1.5 g/m2 over 2 hours
starting 3–6 hours after cladribine infusion on days 1–5, idarubicin
10 mg/m2 on days 1–3; venetoclax 400 mg on days 2–8
FLAG-IDA + venetoclaxg,h,k,23 Fludarabine 30 mg/m2 days 2–6, cytarabine 1.5 g/m2 over 4 hours starting
4 hours after fludarabine infusion on days 2–6, idarubicin 8 mg/m2 IV
on days 4–6, and G-CSF SC daily days 1–7 plus venetoclax PO once
daily on days 1–7 (100 mg day 1, 200 mg day 2, and 400 mg days 3 and
beyond)

a An FDA-approved biosimilar is an appropriate substitute for any recommended systemic biologic therapy in the NCCN Guidelines.
b Specific recommendations, Categories of Evidence and Consensus, and Categories of Preference vary based on patient and disease characteristics (see AML-1
through AML-9). The charts in this section delineate systemic therapy regimens that can be used and provide some additional details.
g In times of fludarabine shortage, cladribine can be substituted for fludarabine.
h Consider dose adjustments for cytarabine based on age and renal function. Doses of cytarabine ≥2 g/m2 should be used with caution in patients ≥60 years and
patients with renal failure due to concern for neurotoxicity.
i Patients with cytopenias with disease in remission should take breaks between cycles. For more details about cycle length, see AML-J.
j Principles of Venetoclax Use With HMA or LDAC (AML-J).
k Use with caution in patients >60 years.
References on AML-E 11 of 14
Note: All recommendations are category 2A unless otherwise indicated.
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PRINCIPLES OF SYSTEMIC THERAPY FOR AMLa,b

REINDUCTION IN THE SETTING OF RESIDUAL DISEASE AFTER CYTARABINE-BASED INDUCTION (AML-3)

Therapy Regimen
Cytarabinel • Cytarabine 2–3 g/m2 over 3 hours every 12 hours on days 1, 3, and 5, or days
• HiDACh 1, 2, and 3 for 1–2 cycles
• Intermediate-dose cytarabine • Cytarabine 1–2 g/m2 over 3 hours every 12 hours x 4–6 doses for 1–2 cycles
Standard 7 + 3 (daunorubicin or idarubicin)m,n,6,7,8 Cytarabine 100 or 200 mg/m2 continuous infusion x 7 days with daunorubicin
45–90 mg/m2 or idarubicin 12 mg/m2 x 3 days
Standard 5 + 2 (daunorubicin or idarubicin or Cytarabine 100 or 200 mg/m2 continuous infusion x 5 days with daunorubicin
mitoxantrone)m,n,o,24,25 45–60 mg/m2 or idarubicin 10–12 mg/m2 or mitoxantrone 12 mg/m2 x 2 days
Standard 7 + 3 (daunorubicin14 or idarubicin15) + Cytarabine 100 or 200 mg/m2 continuous infusion x 7 days with daunorubicin
midostaurin (FLT3-ITD or TKD)m,n 60 mg/m2 or idarubicin 12 mg/m2 x 3 days and oral midostaurin 50 mg every
12 hours, days 8–21
Standard 7 + 3 (daunorubicin or idarubicin) + Cytarabine 100 or 200 mg/m2 continuous infusion x 7 days with daunorubicin
quizartinib17 (FLT3-ITD only)m,n 60 mg/m2 or idarubicin 12 mg/m2 x 3 days and quizartinib 35.4 mg PO daily,
days 8–21
Standard 5 + 2 (daunorubicin or idarubicin) + Cytarabine 100 or 200 mg/m2 continuous infusion x 5 days with daunorubicin
quizartinib17 (FLT3-ITD only)m,n 45–60 mg/m2 or idarubicin 10–12 mg/m2 x 2 days and quizartinib 35.4 mg PO
daily, days 6–19
CPX-351/dual-drug liposomal cytarabine and CPX-351/dual-drug liposomal cytarabine 100 mg/m2 and daunorubicin 44 mg/m2
daunorubicinm,18 on days 1 and 3 x 1 cycle
Cytarabine (HiDAC)h + (daunorubicin or idarubicin)m Cytarabine 2 g/m2 every 12 hours x 6 days or 3 g/m2 every 12 hours x 4 days
with daunorubicin 50 mg/m2 or idarubicin 12 mg/m2 x 3 days
HMA (azacitidine or decitabine) + venetoclaxi,j,26 Azacitidine 75 mg/m2 SC or IV days 1–7 or decitabine 20 mg/m2 IV days 1–5 of
each 28-day cycle and venetoclax PO once daily (100 mg day 1, 200 mg day 2,
and 400 mg days 3 and beyond)

Footnotes on AML-E 3A References on AML-E 11 of 14

Note: All recommendations are category 2A unless otherwise indicated.
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Acute Myeloid Leukemia (Age ≥18 years) Discussion

PRINCIPLES OF SYSTEMIC THERAPY FOR AML

REINDUCTION IN THE SETTING OF RESIDUAL DISEASE AFTER CYTARABINE-BASED INDUCTION
FOOTNOTES
a An FDA-approved biosimilar is an appropriate substitute for any recommended systemic biologic therapy in the NCCN Guidelines.
b Specific recommendations, Categories of Evidence and Consensus, and Categories of Preference vary based on patient and disease characteristics (see AML-1
through AML-9). The charts in this section delineate systemic therapy regimens that can be used and provide some additional details.
h Consider dose adjustments for cytarabine based on age and renal function. Doses of cytarabine ≥2 g/m2 should be used with caution in patients ≥60 years and
patients with renal failure due to concern for neurotoxicity.
i Patients with cytopenias with disease in remission should take breaks between cycles. For more details about cycle length, see AML-J.
j Principles of Venetoclax Use With HMA or LDAC (AML-J).
l For re-induction, no data are available to show superiority with 1–2 g/m2 of cytarabine compared to doses ≥2 g/m2.
m For regimens using high cumulative doses of cardiotoxic agents, consider reassessing cardiac function prior to each anthracycline/mitoxantrone-containing course.
Karanes C, et al. Leuk Res 1999;23:787-794.
n If daunorubicin 90 mg/m2 was used in induction, the recommended dose for daunorubicin for reinduction prior to count recovery is 45 mg/m2 for no more than 2 doses.
Analogously, if idarubicin 12 mg/m2 was used for induction, the early reinduction dose should be limited to 10 mg/m2 for 1 or 2 doses.
o For age ≥60 years.

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

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PRINCIPLES OF SYSTEMIC THERAPY FOR AMLa,b

LOWER INTENSITY THERAPY (INTENSIVE INDUCTION INELIGIBLE OR DECLINES)
(AML-4)

Therapy Regimen
Azacitidine + venetoclaxi,j,20,23 Azacitidine 75 mg/m2 SC or IV days 1–7 of each 28-day cycle and venetoclax PO
once daily (100 mg day 1, 200 mg day 2, and 400 mg days 3 and beyond)
Azacitidine + ivosidenib (IDH1 mutation) p,27 Azacitidine 75 mg/m2 SC or IV (days 1–7 or days 1–5, 8, and 9 of each 28-day cycle)
and ivosidenib 500 mg PO once daily on days 1–28
Decitabine + venetoclax i,j,20,21,28 Decitabine 20 mg/m2 IV (days 1–5 or days 1–10) and venetoclax PO once daily
(100 mg day 1, 200 mg day 2, and 400 mg day 3 and beyond)
29
Ivosidenib (IDH1 mutation) 500 mg PO once daily on days 1–28 of a 28-day cycle
LDAC + venetoclax i,j,30 LDAC 20 mg/m2/day SC days 1–10 of each 28-day cycle and venetoclax PO once
daily (100 mg day 1, 200 mg day 2, 400 mg day 3 and 600 mg days 4 and beyond)
Azacitidine 31,32 75 mg/m2 SC or IV days 1–7 of each 28-day cycle
Decitabine33,34 20 mg/m2 IV days 1–5 of each 28-day cycle
Olutasidenib35,36 150 mg PO twice daily on days 1–28 of a 28-day cycle
Cladribine + LDAC + venetoclax 37 Induction: Cladribine 5 mg/m2 days 1–5 and LDAC 20 mg SC twice daily days 1–10
and venetoclax PO once daily (100 mg day 1, 200 mg day 2, and 400 mg days 3–21
of each 28-day cycle)q
Consolidation Courses 1, 4–5, 8–9, 12–13, 16–17: Cladribine 5 mg/m2 days 1–3 and
LDAC 20 mg SC twice daily days 1–10 and venetoclax PO 400 mg days 1–21 of a
28-day cycle
Consolidation Courses 2–3, 6–7, 10–11, 14–15: Azacitidine 75 mg/m2 SC or IV days
1–7 and venetoclax PO 400 mg days 1–21 of a 28-day cycle

a An FDA-approved biosimilar is an appropriate substitute for any recommended systemic biologic therapy in the NCCN Guidelines.
b Specific recommendations, Categories of Evidence and Consensus, and Categories of Preference vary based on patient and disease characteristics (see AML-1 through AML-9). The
charts in this section delineate systemic therapy regimens that can be used and provide some additional details.
i Patients with cytopenias with disease in remission should take breaks between cycles. For more details about cycle length, see AML-J.
j Principles of Venetoclax Use With HMA or LDAC (AML-J).
p This regimen is approved for patients with newly diagnosed AML with an IDH1 mutation who met at least one of the following criteria: aged >75 years, baseline ECOG performance
status of 2, severe cardiac or pulmonary disease, hepatic impairment with bilirubin >1.5 times the upper limit of normal, CrCl <45 mL/min, or other comorbidity. Montesinos P, et al. N Engl
J Med 2022;386:1519-1531.
q If CR/CRi not achieved following induction, a second course of induction can be administered.
References on AML-E 11 of 14
Note: All recommendations are category 2A unless otherwise indicated.
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Acute Myeloid Leukemia (Age ≥18 years) Discussion

PRINCIPLES OF SYSTEMIC THERAPY FOR AMLa,b

LOWER INTENSITY THERAPY (INTENSIVE INDUCTION INELIGIBLE OR DECLINES) (AML-4)

Therapy Regimen
LDAC + glasdegibr,38 LDAC 20 mg SC every 12 hours (days 1–10 of each 28-day cycle) +
glasdegib (100 mg PO daily on days 1–28)
LDAC33 20 mg/m2/day SC (days 1–10 of each 28-day cycle)
Gilteritinib (FLT3-ITD or TKD)39 Gilteritinib 120 mg PO once daily on days 1–28 of a 28-day cycle
Gilteritinib + azacitidine (FLT3-ITD or TKD)39 Gilteritinib 120 mg PO once daily on days 1–28 + azacitidine 75 mg/m2 SC
or IV on days 1–7 of each 28 day cycle
Azacitidine + enasidenib (IDH2 mutation)40 Azacitidine 75 mg/m2 SC or IV on days 1–7 of each 28-day cycle +
enasidenib 100 mg daily on days 1–28
Enasidenib41 (IDH2 mutation) 100 mg PO once daily on days 1–28 of a 28-day cycle
Gemtuzumab ozogamicin (CD33 positive)c,1,42 6 mg/m2 IV on day 1 and 3 mg/m2 IV on day 8
See AML-4 for other lower intensity regimens
that were previously used for induction

a An FDA-approved biosimilar is an appropriate substitute for any recommended systemic biologic therapy in the NCCN Guidelines.
b Specific recommendations, Categories of Evidence and Consensus, and Categories of Preference vary based on patient and disease characteristics (see AML-1
through AML-9). The charts in this section delineate systemic therapy regimens that can be used and provide some additional details.
c A meta-analysis showing an advantage with gemtuzumab ozogamicin included other dosing schedules. Hills RK, et al. Lancet Oncol 2014;15:986-996.
r This regimen is for treatment of newly diagnosed AML in patients who are ≥75 years of age, or who have significant comorbid conditions (ie, severe cardiac disease,
ECOG performance status ≥2, baseline creatinine >1.3 mg/dL) and has been associated with an improved OS in a randomized trial. Cortes JE, et al. Leukemia
2019;33:379-389.
References on AML-E 11 of 14
Note: All recommendations are category 2A unless otherwise indicated.
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PRINCIPLES OF SYSTEMIC THERAPY FOR AMLa,b

CONSOLIDATION THERAPY: INTENSIVE INDUCTION ELIGIBLE (AML-6)
Therapy Regimen
Cytarabines,t,43 • Cytarabine 1.5–3 g/m2 over 3 hours every 12 hours on days 1, 3, and 5 or days 1, 2,
• HiDAC and 3 x 3–4 cycles
• Intermediate-dose cytarabine • Cytarabine 1–1.5 g/m2 every 12 hours x 4–6 doses for 1–2 cycles
Cytarabine (HiDAC)s,43 + gemtuzumab Cytarabine 1.5–3 g/m2 over 3 hours every 12 hours on days 1, 3, and 5 or on days 1,
ozogamicin (CD33 positive)c,1 2, and 3 x 3–4 cycles with gemtuzumab ozogamicin 3 mg/m2 (maximum dose 4.5 mg)
on day 1 x 2 cycles
Cytarabine (standard dose) (7 days) ± Cytarabine 100 or 200 mg/m2 continuous infusion over 7 days x 1–2 cycles ±
([daunorubicin or idarubicin] or mitoxantrone )o m daunorubicin 45 mg/m2 or idarubicin 10 mg/m2 or mitoxantrone 12 mg/m2 x 3 days
Cytarabine (standard dose) (5 days) ± Cytarabine 100 or 200 mg/m2 continuous infusion over 5 days x 1–2 cycles ±
[(daunorubicin or idarubicin] or mitoxantrone )o m daunorubicin 45 mg/m2 or idarubicin 10 mg/m2 or mitoxantrone 12 mg/m2 x 2 days
Cytarabine (intermediate-dose cytarabine)r + Cytarabine 1–1.5 g/m2 every 12 hours on days 1–4 + daunorubicin 60 mg/m2 on day
daunorubicin + gemtuzumab ozogamicin (CD33 1 (first cycle) and days 1–2 (second cycle) + gemtuzumab ozogamicin 3 mg/m2
positive)c,m,1 (maximum dose 4.5 mg) on day 1 x 2 cycles
Cytarabine s,43 14
+ midostaurin (FLT3-ITD or TKD): • Cytarabine 1.5-3 g/m2 over 3 hours every 12 hours on days 1, 3, and 5 or days 1, 2,
• HiDAC + midostaurin and 3 x 3–4 cycles + midostaurin 50 mg twice daily on days 8–21 x 4 cycles
• Intermediate-dose cytarabine + midostaurin • Cytarabine 1–1.5 g/m2 over 3 hours every 12 hours on days 1, 3, and 5 or days 1, 2,
and 3 x 3–4 cycles + midostaurin 50 mg twice daily on days 8–21 x 4 cycles
Cytarabine s,43 17
+ quizartinib (FLT3-ITD only) • Cytarabine 3 g/m2 over 3 hours every 12 hours on days 1, 3, and 5 + quizartinib
• HiDAC + quizartinib 35.4 mg PO daily on days 6–19 for up to 4 cycles
• Intermediate-dose cytarabine + quizartinib • Cytarabine 1.5 g/m2 over 3 hours every 12 hours on days 1, 3, and 5 + quizartinib
35.4 mg PO daily on days 6–19 for up to 4 cycles
CPX-351/dual-drug liposomal cytarabine and CPX-351/dual-drug liposomal cytarabine 65 mg/m2 and daunorubicin 29 mg/m2 on
daunorubicin m,18 day 1 and 3 x 1–2 cycles
See AML-1 and AML-2 for FLAG-IDA
See AML-4 for continuation of lower intensity therapy

Footnotes on AML-E 6A References on AML-E 11 of 14

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

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Acute Myeloid Leukemia (Age ≥18 years) Discussion

PRINCIPLES OF SYSTEMIC THERAPY FOR AML

CONSOLIDATION THERAPY: INTENSIVE INDUCTION ELIGIBLE
FOOTNOTES
a An FDA-approved biosimilar is an appropriate substitute for any recommended systemic biologic therapy in the NCCN Guidelines.
b Specific recommendations, Categories of Evidence and Consensus, and Categories of Preference vary based on patient and disease characteristics (see AML-1
through AML-9). The charts in this section delineate systemic therapy regimens that can be used and provide some additional details.
c A meta-analysis showing an advantage with gemtuzumab ozogamicin included other dosing schedules. Hills RK, et al. Lancet Oncol 2014;15:986-996.
m For regimens using high cumulative doses of cardiotoxic agents, consider reassessing cardiac function prior to each anthracycline/mitoxantrone-containing course.

Karanes C, et al. Leuk Res 1999;23:787-794.

o For age ≥60 years.
s Alternate dosing of cytarabine for postremission therapy has been reported (Discussion). Jaramillo S, et al. Blood Cancer J 2017;7:e564. Doses of cytarabine ≥2 g/m2
should be used with caution in patients ≥60 years and patients with renal failure due to concern for neurotoxicity.
t There is no evidence that cytarabine doses ≥2 g/m2 are superior to doses 1–2 g/m2 in patients with AML with intermediate-risk cytogenetics.

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

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Acute Myeloid Leukemia (Age ≥18 years) Discussion

PRINCIPLES OF SYSTEMIC THERAPY FOR AMLa,b

MAINTENANCE THERAPY
(AML-7)
Therapy Regimen
Oral azacitidine44,45 300 mg PO daily on days 1–14 of each 28-day cycle
Azacitidine46 50 mg/m2 SC daily on days 1–5 of a 28-day cycle for a maximum of 12 cycles
Decitabine47,48 20 mg/m2 IV daily on days 1–5 of a 28- to 56-day cycle or days 1–3 of a 28-day cycle
for a maximum of 12 cycles
Gilteritinib49 (FLT3-ITD or TKD) 120 mg PO daily, days 1–28 of each 28-day cycle (up to 26 cycles)
Sorafenib50,51 (FLT3-ITD only) 200 mg PO twice daily on days 1–28 x 3 cycles, then 400 mg PO twice daily on
days 1–28 (based on tolerance, continue until 24 months of therapy have been
completed)
Midostaurin (FLT3-ITD or TKD)15,52 50 mg PO twice daily on days 1–28 of each 28-day cycle x 12 cycles
Quizartinibu,17 (FLT3-ITD only) 26.5 or 53 mg PO daily, days 1–28 of each 28-day cycle (up to 36 cycles)
Low-dose decitabine53 Decitabine 5 mg/m2 IV days 2–6 and G-CSF SC days 1–6

a An FDA-approved biosimilar is an appropriate substitute for any recommended systemic biologic therapy in the NCCN Guidelines.
b Specific recommendations, Categories of Evidence and Consensus, and Categories of Preference vary based on patient and disease characteristics (see AML-1
through AML-9). The charts in this section delineate systemic therapy regimens that can be used and provide some additional details.
u During cycle 1, quizartinib should be dosed at 26.5 mg PO once daily on days 1–14 if QTcF is ≤450 ms. If QTcF remains ≤450 ms on day 15, the dose should be
increased to 53 mg PO daily for the remainder of the 28-day cycle. The 26.5 mg dose should be maintained if QTcF was >500 ms at any point during induction or
consolidation.
References on AML-E 11 of 14
Note: All recommendations are category 2A unless otherwise indicated.
AML-E
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Acute Myeloid Leukemia (Age ≥18 years) Discussion

PRINCIPLES OF SYSTEMIC THERAPY FOR AMLa,b

THERAPY FOR RELAPSED/REFRACTORY DISEASE
(AML-9)
TARGETED THERAPY
Therapy Regimen
Gilteritinib (FLT3-ITD or TKD)54 120 mg PO once daily on days 1–28 of a 28-day cycle
Azacitidine or decitabine + (Azacitidine 75 mg/m2 SC or IV on days 1–7 or decitabine 20 mg/m2 IV on days
sorafenib (FLT3-ITD)55,56 1–10 of each 28-day cycle) and sorafenib 400 mg PO twice daily on days 1–28
Quizartinib (FLT3-ITD)u,57 26.5 or 53 mg PO daily on days 1–28 of each 28-day cycle
Enasidenib (IDH2)58 100 mg PO once daily on days 1–28 of a 28-day cycle
Ivosidenib (IDH1)59 500 mg PO once daily on days 1–28 of a 28-day cycle
Olutasidenib (IDH1)60 150 mg PO twice daily on days 1–28 of a 28-day cycle
Gemtuzumab ozogamicin 3 mg/m2 (up to one 4.5 mg vial) IV on days 1, 4, and 7
(CD33-positive)c,61
Revumenib (KMT2A 160 mg PO twice daily on days 1–28 of a 28-day cycle (with a strong cytochrome
rearrangement or NPM1 P450 inhibitor) or 270 mg PO twice daily on days 1–28 of a 28-day cycle (without
mutation)v,w,62,63 a strong cytochrome P450 inhibitor)
Ziftomenib (NPM1 mutation)x,64 600 mg once daily on days 1-28 of a 28-day cycle

a An FDA-approved biosimilar is an appropriate substitute for any recommended systemic biologic therapy in the NCCN Guidelines.
b Specific recommendations, Categories of Evidence and Consensus, and Categories of Preference vary based on patient and disease characteristics (see AML-1
through AML-9). The charts in this section delineate systemic therapy regimens that can be used and provide some additional details.
c A meta-analysis showing an advantage with gemtuzumab ozogamicin included other dosing schedules. Hills RK, et al. Lancet Oncol 2014;15:986-996.
u During cycle 1, quizartinib should be dosed at 26.5 mg PO once daily on days 1–14 if QTcF is ≤450 ms. If QTcF remains ≤450 ms on day 15, the dose should be
increased to 53 mg PO daily for the remainder of the 28-day cycle. The 26.5 mg dose should be maintained if QTcF was >500 ms at any point during induction or
consolidation.
v Revumenib is FDA approved for the treatment of relapsed or refractory acute leukemia with a KMT2A translocation, as well as relapsed or refractory AML with a
susceptible NPM1 mutation with no satisfactory alternative treatment options, in adult and pediatric patients ≥1 year.
w Refer to revumenib prescribing information for recommendations on weight-based dosing for patients weighing <40 kg ([Link]
daf/[Link]).
x Ziftomenib is FDA approved for the treatment of adults with relapsed or refractory AML with a susceptible NPM1 mutation with no satisfactory alternative treatment
options.
References on AML-E 11 of 14
Note: All recommendations are category 2A unless otherwise indicated.
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Acute Myeloid Leukemia (Age ≥18 years) Discussion

PRINCIPLES OF SYSTEMIC THERAPY FOR AMLa,b

THERAPY FOR RELAPSED/REFRACTORY DISEASE
(AML-9)
INTENSIVE THERAPY FOR APPROPRIATE PATIENTS
Therapy Regimen
Cladribine + cytarabine + G-CSF ± Cladribine 5 mg/m2 on days 2–6; cytarabine 2 g/m2 over 4 hours starting 2 hours after cladribine infusion
mitoxantrone or idarubicinh,65,66,67 on days 2–6; G-CSF SC daily on days 1–6 ± (mitoxantrone 10 mg/m2 or idarubicin 8 mg/m2 on days 2–4)
Cytarabine ± daunorubicin or Cytarabine 2 g/m2 every 12 hours on days 1–6 or 3 g/m2 every 12 hours x 4 days vs. days 1, 3, 5, 7 with
idarubicinh,68 (daunorubicin 50 mg/m2 or idarubicin 12 mg/m2 x 3 days)
Cytarabine ± mitoxantroneh,68 Cytarabine 1.5–3 g/m2 every 12 hours on days 1–6 ± mitoxantrone 10 mg/m2 on days 7–9
Fludarabine + cytarabine + G-CSF Fludarabine 30 mg/m2 on days 2–6; cytarabine 2 g/m2 over 4 hours starting 4 hours after fludarabine
± idarubicinh,69,70 infusion on days 2–6; G-CSF SC daily on days 1–5; ± idarubicin 10 mg/m2 IV on days 1–3
Fludarabine + cytarabine + G-CSF Fludarabine 30 mg/m2 on days 2–6; cytarabine 1.5–2 g/m2 over 4 hours starting 4 hours after fludarabine
+ idarubicin + venetoclaxh,23 infusion on days 2–6; G-CSF SC daily on days 1–7; idarubicin 6 mg/m2 IV on days 4–5; venetoclax
400 mg on days 1–7
Etoposide + cytarabineh,71 Etoposide 100 mg/m2 on days 1–5; cytarabine 3 g/m2 every 12 hours on days 1–4
Etoposide + cytarabine ± Etoposide 100 mg/m2 on days 1–5; cytarabine 1 g/m2 every 12 hours on days 1–5; mitoxantrone 8 mg/m2
mitoxantrone71 daily on days 1–5
Clofarabine72,73 Clofarabine 40 mg/m2 on days 1–5
Clofarabine + cytarabineh,72,73 Clofarabine 25 mg/m2 on days 1–5; cytarabine 2 g/m2 over 3 hours starting 4 hours after clofarabine
infusion on days 1–5
Clofarabine + cytarabine + Clofarabine 22.5 mg/m2 on days 1–5; cytarabine 750 mg/m2 over 3 hours starting 3–6 hours after
idarubicin72,73 clofarabine infusion on days 1–5; idarubicin 6 mg/m2 on days 1–3
Clofarabine + idarubicin72,73 Clofarabine 22.5 mg/m2 on days 1–5; idarubicin 10 mg/m2 daily on days 1–3
CLIA + venetoclax22 Cladribine 5 mg/m2 on days 1–5; cytarabine 1–1.5 g/m2 over 2 hours starting 3–6 hours after cladribine
infusion on days 1–5; idarubicin 10 mg/m2 on days 1–3; venetoclax 400 mg on days 2–8

a An FDA-approved biosimilar is an appropriate substitute for any recommended systemic biologic therapy in the NCCN Guidelines.
b Specific recommendations, Categories of Evidence and Consensus, and Categories of Preference vary based on patient and disease characteristics (see AML-1 through AML-9). The
charts in this section delineate systemic therapy regimens that can be used and provide some additional details.
h Consider dose adjustments for cytarabine based on age and renal function. Doses of cytarabine ≥2 g/m2 should be used with caution in patients ≥60 years and patients with renal failure
due to concern for neurotoxicity.
References on AML-E 11 of 14
Note: All recommendations are category 2A unless otherwise indicated.
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Acute Myeloid Leukemia (Age ≥18 years) Discussion

PRINCIPLES OF SYSTEMIC THERAPY FOR AMLa,b

THERAPY FOR RELAPSED/REFRACTORY DISEASE
(AML-9)
LESS INTENSIVE THERAPY
Therapy Regimen
Azacitidine or decitabine Azacitidine 75 mg/m2 SC or IV on days 1–7 or decitabine 20 mg/m2 IV on days 1–5 of a 28-day cycle
LDAC 20 mg/m2 SC on days 1–10 of a 28-day cycle
Azacitidine or decitabine Azacitidine 75 mg/m2 SC or IV on days 1–7 or decitabine 20 mg/m2 IV on days 1–5 or days 1–10 of
+ venetoclaxi,j,74 each 28-day cycle and venetoclax PO once daily (100 mg day 1, 200 mg day 2, and 400 mg day 3
and beyond)
LDAC + venetoclax i,j,75 LDAC 20 mg/m2 SC on days 1–10 of each 28-day cycle and venetoclax PO once daily (100 mg day 1,
200 mg day 2, 400 mg day 3, and 600 mg day 4 and beyond)

a An FDA-approved biosimilar is an appropriate substitute for any recommended systemic biologic therapy in the NCCN Guidelines.
b Specific recommendations, Categories of Evidence and Consensus, and Categories of Preference vary based on patient and disease characteristics (see AML-1
through AML-9). The charts in this section delineate systemic therapy regimens that can be used and provide some additional details.
i Patients with cytopenias with disease in remission should take breaks between cycles. For more details about cycle length, see AML-J.
j Principles of Venetoclax Use With HMA or LDAC (AML-J).
References on AML-E 11 of 14
Note: All recommendations are category 2A unless otherwise indicated.
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Acute Myeloid Leukemia (Age ≥18 years) Discussion

REFERENCES FOR PRINCIPLES OF SYSTEMIC THERAPY FOR AML

1 Burnett AK, 12 Wrzesien-Kus A, Robak T, Wierzbowska A, et al. A multicenter,
Hills RK, Milligan D, et al. Identification of patients with acute
myeloblastic leukemia who benefit from the addition of gemtuzumab ozogamicin: open, noncomparative, phase II study of the combination of cladribine
results of the MRC AML15 trial. J Clin Oncol 2011;29:369-377. (2-chlorodeoxyadenosine), cytarabine, granulocyte colony-stimulating factor and
2 Castaigne S, Pautas C, Terré C, et al. Effect of gemtuzumab ozogamicin on mitoxantrone as induction therapy in refractory acute myeloid leukemia: a report
survival of adult patients with de-novo acute myeloid leukaemia (ALFA-0701): a of the Polish Adult Leukemia Group. Ann Hematol 2005;84:557-564.
13 Wierzbowska A, Robak T, Pluta A, et al. Cladribine combined with high doses of
randomised, open-label, phase 3 study. Lancet 2012;379:1508-1516.
3 Hills RK, Castaigne S, Appelbaum FR, et al. Addition of gemtuzumab ozogamicin arabinoside cytosine, mitoxantrone, and G-CSF (CLAG-M) is a highly effective
to induction chemotherapy in adult patients with acute myeloid leukaemia: a meta- salvage regimen in patients with refractory and relapsed acute myeloid leukemia
analysis of individual patient data from randomised controlled trials. Lancet Oncol of the poor risk: a final report of the Polish Adult Leukemia Group. Eur J Haematol
2014;15:986-996. 2008;80:115-126.
4 Burnett AK, Russell NH, Hills RK, et al. Addition of gemtuzumab ozogamicin to 14 Stone RM, Mandrekar SJ, Sanford BL, et al. Midostaurin plus chemotherapy for
induction chemotherapy improves survival in older patients with acute myeloid acute myeloid leukemia with a FLT3 mutation. N Engl J Med 2017;377:454-464.
15 Azzi J, Cirrone F, Abdul-Hay M et al. Midostaurin in Combination with Idarubicin
leukemia. J Clin Oncol 2012;30:3924-3931.
5 Burnett A, Cavenagh J, Russell N, et al. Defining the dose of gemtuzumab and Cytarabine (3+7) Induction for FLT3 Positive AML - Very High Complete
ozogamicin in combination with induction chemotherapy in acute myeloid Response Rates and Transition to Allogeneic Transplantation. Blood 2018; 132:
leukemia: a comparison of 3 mg/m2 with 6 mg/m2 in the NCRI AML17 Trial. 5216; Lee JS, Wagner CB, Prelewicz S, et al. Efficacy and toxicity of midostaurin
Haematologica 2016;101:724-731. with idarubicin and cytarabine induction in FLT3-mutated acute myeloid leukemia.
6 Fernandez HF, Sun Z, Yao X, et al. Anthracycline dose intensification in acute Haematologica 2023;108:3460-3463.
16 Dohner H, Weber D, Krzykalla J, et al. Midostaurin plus intensive chemotherapy
myeloid leukemia. N Engl J Med 2009;361:1249-1259.
7 Burnett AK, Russell NH, Hills RK, et al. A randomized comparison of daunorubicin for younger and older patients with AML and FLT3 internal tandem duplications.
90 mg/m2 vs 60 mg/m2 in AML induction: results from the UK NCRI AML17 trial in Blood Adv 2022;6:5345-5355.
17 Erba HP, Montesinos P, Kim HJ, et al. Quizartinib plus chemotherapy in newly
1206 patients. Blood 2015;125:3878-3885.
8 Pautas C, Merabet F, Thomas X, et al. Randomized study of intensified diagnosed patients with FLT3-internal-tandem-duplication-positive acute myeloid
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18 Lancet JE, Uy GL, Cortes JE, et al. CPX-351 (cytarabine and daunorubicin)
study. J Clin Oncol 2010;28:808-814.
9 Rollig C, Steffen B, Schliemann C, et al. Single or double induction with 7 + 3 liposome for injection versus conventional cytarabine plus daunorubicin in older
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20 Welch JS, Petti AA, Miller CA, et al. TP53 and decitabine in acute myeloid
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11 Borthakur G, Cortes JE, Estey EE, et al. Gemtuzumab ozogamicin with leukemia and myelodysplastic syndromes. N Engl J Med 2016;375:2023-2036.
21 DiNardo CD, Jonas BA, Pullarkat V, et al. Azacitidine and venetoclax in
fludarabine, cytarabine, and granulocyte colony stimulating factor (FLAG-GO) as
front-line regimen in patients with core binding factor acute myelogenous leukemia. previously untreated acute myeloid leukemia. N Engl J Med 2020;383:617-629.
Am J Hematol 2014;89:964-968.

Continued

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

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REFERENCES FOR PRINCIPLES OF SYSTEMIC THERAPY FOR AML

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26 Jamy O, Lin K, Worth S, et al. Hypomethylating agent/venetoclax versus intensive cladribine plus low-dose cytarabine alternating with 5-azacitidine in older patients
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mutated acute myeloid leukemia. N Engl J Med 2022;386:1519-1531. myeloid leukemia or high-risk myelodysplastic syndrome. Leukemia 2019;33:379-
28 DiNardo CD, Maiti A, Rausch CR, et al. 10-day decitabine with venetoclax for 389.
newly diagnosed intensive chemotherapy ineligible, and relapsed or refractory 39 Wang ES, Montesinos P, Minden MD, et al. Phase 3 trial of gilteritinib plus
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29 Roboz GJ, DiNardo CD, Stein EM, et al. Ivosidenib induces deep durable 40 DiNardo CD, Schuh AC, Stein EM, et al. Enasidenib plus azacitidine versus
remissions in patients with newly diagnosed IDH1-mutant acute myeloid leukemia. azacitidine alone in patients with newly diagnosed, mutant-IDH2 acute myeloid
Blood 2020;135:463-471. leukaemia (AG221-AML-005): a single-arm, phase 1b and randomised, phase 2
30 Wei AH, Strickland SA Jr, Hou JZ, et al. Venetoclax combined with low-dose trial. Lancet Oncol 2021;22:1597-1608.
cytarabine for previously untreated patients with acute myeloid leukemia: Results 41 Stein EM, Shoben A, Borate U, et al. Enasidenib is highly active in previously
from a phase Ib/II study. J Clin Oncol 2019;37:1277-1284. untreated IDH2 mutant AML: Early results from the beat AML master trial
31 Fenaux P, Mufti GJ, Hellstrom-Lindberg E, et al. Azacitidine prolongs overall [abstract]. Blood 2018;132(Suppl):Abstract 287.
survival compared with conventional care regimens in elderly patients with low 42 Amadori S, Suciu S, Selleslag D, et al. Gemtuzumab ozogamicin versus best
bone marrow blast count acute myeloid leukemia. J Clin Oncol 2010;28:562-569. supportive care in older patients with newly diagnosed acute myeloid leukemia
32 Dombret H, Seymour JF, Butrym A, et al. International phase 3 study of unsuitable for intensive chemotherapy: Results of the randomized phase III
azacitidine vs conventional care regimens in older patients with newly diagnosed EORTC-GIMEMA AML-19 trial. J Clin Oncol 2016;34:972-979. Erratum in: J Clin
AML with >30% blasts. Blood 2015;126:291-299. Oncol 2022;40:525.
43 Jaramillo S, Benner A, Krauter J, et al. Condensed versus standard schedule
of high-dose cytarabine consolidation therapy with pegfilgrastim growth factor
support in acute myeloid leukemia. Blood Cancer J 2017;7:e564.
Continued

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

AML-E
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Acute Myeloid Leukemia (Age ≥18 years) Discussion

REFERENCES FOR PRINCIPLES OF SYSTEMIC THERAPY FOR AML

44 Wei AH, 55 Ravandi F, Alattar ML, Grunwald MR, et al. Phase 2 study of azacytidine plus
Döhner H, Pocock C, et al. Oral azacitidine maintenance therapy for
acute myeloid leukemia in first remission. N Engl J Med 2020;383:2526-2537. sorafenib in patients with acute myeloid leukemia and FLT3 internal tandem
45 Dohner H, Wei AH, Roboz GJ, et al. Prognostic impact of NPM1 and FLT3 duplication mutation. Blood 2013:121:4655-4662.
56 Muppidi MR, Portwood S, Griffiths EA, et al. Decitabine and sorafenib therapy
mutations in patients with AML in first remission treated with oral azacitidine. Blood
2022;140:1674-1685. in FLT3 ITD-mutant acute myeloid leukemia. Clin Lymphoma Myeloma Leuk
46 Huls G, Chitu DA, Havelange V, et al. Azacitidine maintenance after intensive 2015;15 Suppl:S73-S79.
57 Cortes JE, Khaled S, Martinelli G, et al. Quizartinib versus salvage
chemotherapy improves DFS in older AML patients. Blood 2019;133:1457-1464.
47 Boumber Y, Kantarjian H, Jorgensen J, et al. A randomized study of decitabine chemotherapy in relapsed or refractory FLT3-ITD acute myeloid leukaemia
versus conventional care for maintenance therapy in patients with acute myeloid (QuANTUM-R): a multicentre, randomised, controlled, open-label, phase 3 trial.
leukemia in complete remission. Leukemia 2012;26:2428-2431. Lancet Oncol 2019;20:984-997.
48 Tallman MS, Litzow M, Ofran Y, et al. Maintenance decitabine (DAC) improves 58 Stein EM, DiNardo CD, Pollyea DA, et al. Enasidenib in mutant IDH2 relapsed or
disease-free (DFS) and overall survival (OS) after intensive therapy for acute refractory acute myeloid leukemia. Blood 2017;130:722-731.
59 DiNardo CD, Stein EM, de Botton S, et al. Durable remissions with ivosidenib in
myeloid leukemia (AML) in older adults, particularly in FLT3-ITD-negative patients:
ECOG-ACRIN (E-A) E2906 randomized study [abstract]. Blood 2019;134:Abstract IDH1-mutated relapsed or refractory AML. N Eng J Med 2018;378:2386-2398.
60 Cortes J, Fenaux P, Yee K, et al. Olutasidenib (FT-2102) induces durable
115.
49 Pratz KW, Cherry M, Altman JK, et al. A Phase 1 Study of gilteritinib in complete remissions in patients with relapsed/refractory mIDH1 acute myeloid
combination with induction and consolidation chemotherapy in patients with newly leukemia. Results from a planned interim analysis of a phase 2 pivotal clinical trial
diagnosed AML: Final results. Blood 2020;136:16-17. [abstract] Blood 2022;140: Abstract 2757.
50 Xuan L, Wang Y, Yang K, et al. Sorafenib maintenance after allogeneic 61 Taksin AL, Legrand O, Raffoux E, et al. High efficacy and safety profile of
haemopoietic stem-cell transplantation in patients with FLT3-ITD acute myeloid fractionated doses of Mylotarg as induction therapy in patients with relapsed
leukaemia: long-term follow-up of an open-label, multicentre, randomised, phase 3 acute myeloblastic leukemia: a prospective study of the alfa group. Leukemia
trial. Lancet Haematol 2023;10:e600-e611. 2007;21:66-71.
51 Burchert A, Bug G, Fritz LV, et al. Sorafenib maintenance after allogeneic 62 Issa GC, Aldoss I, Thirman MJ, et al. Menin inhibition with revumenib for
hematopoietic stem cell transplantation for acute myeloid leukemia with FLT3- KMT2A-rearranged relapsed or refractory acute leukemia (AUGMENT-101). J Clin
internal tandem duplication mutation (SORMAIN). J Clin Oncol 2020;38:2993- Oncol 2024:JCO2400826.
63 Arellano ML, Thirman MJ, DiPersio JF, et al. Menin inhibition with revumenib for
3002.
52 Maziarz RT, Levis M, Patnaik MM, et al. Midostaurin after allogeneic stem cell NPM1-mutated relapsed or refractory acute myeloid leukemia: the AUGMENT-101
transplant in patients with FLT3-internal tandem duplication-positive acute myeloid study. Blood 2025;146:1065-1077.
64 Wang ES, Montesinos P, Foran J, et al. Ziftomenib in relapsed or refractory
leukemia. Bone Marrow Transplant 2021;56:1180-1189.
53 Gao L, Zhang Y, Wang S, et al. Effect of rhG-CSF combined with decitabine NPM1-mutated AML. J Clin Oncol 2025;43:3381–3390.
65 Robak T, Wrzesień-Kuś A, Lech-Marańda E, et al. Combination regimen of
prophylaxis on relapse of patients with high-risk MRD-negative AML after HSCT:
An open-label, multicenter, randomized controlled trial. J Clin Oncol 2020;38:4249- cladribine (2-chlorodeoxyadenosine), cytarabine and G-CSF (CLAG) as induction
4259. therapy for patients with relapsed or refractory acute myeloid leukemia. Leuk
54 Perl AE, Larson RA, Podoltsev NA, et al. Follow-up of patients with R/R FLT3- Lymphoma 2000;39:121-129.
mutation-positive AML treated with gilteritinib in the phase 3 ADMIRAL trial. Blood
2022;139:3366-3375.

Continued

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

AML-E
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Acute Myeloid Leukemia (Age ≥18 years) Discussion

REFERENCES FOR PRINCIPLES OF SYSTEMIC THERAPY FOR AML

66 Fridle C, Medinger M, Wilk MC, et al. Cladribine, cytarabine and idarubicin
(CLA-Ida) salvage chemotherapy in relapsed acute myeloid leukemia (AML). Leuk
Lymphoma 2017:1068-1075.
67 Wrzesien-Kus A, Robak T, Wierzbowska A, et al. A multicenter,
open, noncomparative, phase II study of the combination of cladribine
(2-chlorodeoxyadenosine), cytarabine, granulocyte colony-stimulating factor and
mitoxantrone as induction therapy in refractory acute myeloid leukemia: a report of
the Polish Adult Leukemia Group. Ann Hematol 2005;84:557-564.
68 Karanes C, Kopecky KJ, Head DR, et al. A phase III comparison of high dose
ARA-C (HIDAC) versus HIDAC plus mitoxantrone in the treatment of first relapsed
or refractory acute myeloid leukemia Southwest Oncology Group Study. Leuk Res
1999;23:787-794.
69 Montillo M, Mirto S, Petti MC, et al. Fludarabine, cytarabine, and G-CSF (FLAG)
for the treatment of poor risk acute myeloid leukemia. Am J Hematol 1998;58:105-
109.
70 Parker JE, Pagliuca A, Mijovic A, et al. Fludarabine, cytarabine, G-CSF and
idarubicin (FLAG-IDA) for the treatment of poor-risk myelodysplastic syndromes
and acute myeloid leukaemia. Br J Haematol 1997;99:939-944.
71 Nair G, Karmali G, Gregory SA, et al. Etoposide and cytarabine as an effective
and safe cytoreductive regimen for relapsed or refractory acute myeloid leukemia
[abstract]. J Clin Oncol 2011;29(Suppl):Abstract 6539.
72 Faderl S, Wetzler M, Rizzieri D, et al. Clorarabine plus cytarabine compared with
cytarabine alone in older patients with relapsed or refractory acute myelogenous
leukemia: results from the CLASSIC I Trial. J Clin Oncol 2012;30:2492-2499.
73 Faderl S, Ferrajoli A, Wierda W, et al. Clofarabine combinations as acute myeloid
leukemia salvage therapy. Cancer 2008;113:2090-2096.
74 Aldoss I, Yang D, Aribi A, et al. Efficacy of the combination of venetoclax
and hypomethylating agents in relapsed/refractory acute myeloid leukemia.
Haematologica 2018;103:e404-e407.
75 DiNardo CD, Rausch CR, Benton C, et al. Clinical experience with the BCL2-
inhibitor venetoclax in combination therapy for relapsed and refractory acute
myeloid leukemia and related myeloid malignancies. Am J Hematol 2018;93:401-
407.

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

AML-E
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Acute Myeloid Leukemia (Age ≥18 years) Discussion

PRINCIPLES OF SUPPORTIVE CARE FOR AMLa

There are variations among institutions, but the following issues are important to consider in the management of AML.
General • Patients receiving doses of cytarabine ≥2 g/m2 (particularly those
• Blood products: with impaired renal function), or doses of cytarabine 1–1.5 g/m2
Leukocyte-depleted products should be used for transfusion. in patients >60 years of age, are at risk for cerebellar toxicity.
All patients with AML are at risk for acute graft-versus-host disease Neurologic assessment, including tests for nystagmus, slurred
(aGVHD) and management should be based on institutional speech, and dysmetria, should be performed before each dose of
practice/preference. See NCCN Guidelines for Hematopoietic Cell cytarabine.
Transplantation. In patients exhibiting rapidly rising creatinine due to tumor
Transfusion thresholds: red blood cell (RBC) counts for hemoglobin lysis, doses of cytarabine ≥2 g/m2 should be discontinued until
≤7 to 8 g/dL or per institutional guidelines or symptoms of anemia; creatinine normalizes.
platelets for patients with platelets <10,000/mcL or with any signs of In patients who develop cerebellar toxicity, cytarabine should be
bleeding.b stopped. Rechallenge with doses of cytarabine ≥2 g/m2 in future
Cytomegalovirus (CMV) screening for potential HCT candidates may treatment cycles should not be attempted.1
be considered. • Steroid eye drops should be administered to both eyes 4 times
• Tumor lysis prophylaxis: hydration with diuresis, and allopurinol or daily for all patients undergoing cytarabine therapy at doses of
rasburicase. Rasburicase should be considered as initial treatment ≥2 g/m2 until 24 hours post completion of cytarabine.
in patients with rapidly increasing blast counts, high uric acid, or • Growth factors may be considered as a part of supportive care
evidence of impaired renal function. for post-remission therapy. Note that such use may confound
Glucose-6-phosphate dehydrogenase (G6PD) deficiency should interpretation of the BM evaluation. Patients should be off
be checked when possible. However, it is not always feasible to do granulocyte-macrophage colony-stimulating factor (GM-CSF) or
so rapidly. If there is high suspicion of G6PD deficiency, caution is G-CSF for a minimum of 7 days before obtaining BM to document
necessary; rasburicase may be contraindicated. remission.
• Unless a site-specific contraindication exists, a central venous access • Decisions regarding use and choice of antibiotics should be made
device (CVAD) with multiple lumens is recommended to allow the by the individual institutions based on the prevailing organisms
administration of peripherally contraindicated systemic therapies and and their drug resistance patterns. Posaconazole has been shown
possibly multiple infusions during higher risk periods of cytopenias to significantly decrease fungal infections when compared to
related to disease and/or myelosuppressive therapy. fluconazole and itraconazole.2 Outcomes with other azoles, such
CVAD routine care and maintenance should be provided as per as voriconazole, echinocandins, or amphotericin B, may produce
institutional policy. equivalent results. See the NCCN Guidelines for the Prevention and
CVAD removal and/or replacement should be determined based on Treatment of Cancer-Related Infections and commensurate with the
individual clinical circumstances. institutional practice for antibiotic stewardship.

a Refer to the NCCN Distress Thermometer and Problem List, which 1 Smith GA, Damon LE, Rugo HS, et al. High-dose cytarabine dose modification
includes social determinants of health. See NCCN Guidelines for Distress reduces the incidence of neurotoxicity in patients with renal insufficiency. J Clin Oncol
Management (DIS-A). 1997;15:833-839.
b Patients who are alloimmunized should receive cross-match–compatible 2 Cornely OA, Maertens J, Winston DJ, et al. Posaconazole vs. fluconazole or
and/or HLA-specific blood products. itraconazole prophylaxis in patients with neutropenia. N Engl J Med 2007;356:348-359.

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

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AML-F
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Acute Myeloid Leukemia (Age ≥18 years) Discussion

MONITORING DURING INTENSIVE THERAPY

Induction
• CBC daily (differential daily or as clinically indicated during chemotherapy and every other day after recovery of ANC >0.5 x 109/L until either
normal differential or persistent leukemia is documented); platelets daily while in the hospital until platelet-transfusion independent.
• Chemistry profile, including electrolytes, liver function test (LFT), blood urea nitrogen (BUN), creatinine, uric acid, and phosphorous, at least
daily during active treatment until risk of tumor lysis is past. If the patient is receiving nephrotoxic agents, closer monitoring is required
through the period of hospitalization.
• Consider reduced frequency of labs to 1–2 times per week following completion of chemotherapy based on individual circumstances, such
as degree of count recovery, intensity of induction, and/or patient preference.
• Coagulation panel 1–2 times per week.
For patients who have evidence of disseminated intravascular coagulation (DIC), coagulation parameters including fibrinogen should be
monitored daily until resolution of DIC.
• BM aspirate/biopsy 14–21 days after start of therapy to document hypoplasia. If hypoplasia is not documented or indeterminate, repeat biopsy
within 7 days to clarify persistence of leukemia. If hypoplasia, then repeat biopsy at time of hematologic recovery to document remission. If
cytogenetics were initially abnormal, include cytogenetics as part of the remission documentation.

Post-Remission Therapy
• CBC, platelets 2 times per week during chemotherapy.
• Chemistry profile, electrolytes daily during chemotherapy.
• Outpatient monitoring post chemotherapy: CBC, platelets, differential, and electrolytes 2–3 times per week until recovery.
• BM aspirate/biopsy only if peripheral blood counts are abnormal or if counts have not recovered within 5 weeks.
• Patients with AML with high-risk features, including poor-prognosis cytogenetics, therapy-related AML, prior MDS, or possibly 2 or more
inductions to achieve a CR are at increased risk for relapse and should be considered for early alternate donor search, as indicated on AML-6.

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

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AML-G
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Acute Myeloid Leukemia (Age ≥18 years) Discussion

MEASURABLE (MINIMAL) RESIDUAL DISEASE ASSESSMENT

General
• There is compelling evidence in both children and adults with AML that detectable MRD following achievement of remission is associated
with an increased risk of relapse.1
• MRD in AML refers to the presence of leukemic cells below the threshold of detection by conventional morphologic methods. Patients whose
disease achieved a CR by morphologic assessment alone can still harbor a large number of leukemic cells in the BM.2 After completion of
therapy, “molecular relapses” can predict hematologic relapses within a 3- to 6-month timeframe.1
• There are distinct differences between diagnostic threshold assessments and MRD assessments. Standard NGS diagnostic tests are not
designed for MRD assessment due to inferior sensitivity.
• With contemporary measurement techniques, the role of MRD in treatment decision-making is evolving.
• The threshold to define MRD+ and MRD- samples depends on the technique and subgroup of AML.
• There are commercially available tests that can be used for MRD assessments, as well as further testing methods at certain academic
centers.
• The most frequently used methods for MRD assessment include quantitative molecular assays such as real-time quantitative PCR (RQ-PCR)
and multicolor flow cytometry (MFC) assays specifically designed to detect abnormal MRD immunophenotypes.2
• The optimal sample for initial MRD assessment is a first, dedicated pull of the BM aspirate. The quality of the sample is of paramount
importance to have reliable evaluation. Once MRD-negative remission by BM is achieved, peripheral blood can be utilized for surveillance of
MRD for PML::RAR alpha, NPM1,3 CBFB::MYH11, and RUNX1::RUNX1T1.4
• Mutations associated with clonal hematopoiesis of indeterminate potential (CHIP) and aging (ie, DNMT3A, TET2, potentially ASXL1) are not
considered reliable markers for MRD and are difficult to differentiate in routine practice.5-7

Methods of Testing
Flow Cytometry
• If using flow cytometry to assess MRD, it is recommended that a specific MRD assay that incorporates both different from normal and
leukemia-associated immunophenotypes (LAIPs) assessment is utilized, but, most importantly, that it is interpreted by an experienced
hematopathologist, preferably at the same laboratory as diagnostic flow cytometry for consistency. Utilization of an assay with minimum
limit of detection of ≤10-3 is recommended.
Molecular
• The Panel recommends RQ-PCR for detection of PML::RAR alpha, NPM1,3 CBFB::MYH11, and RUNX1::RUNX1T1.4 Utilization of an assay
with minimum limit of detection of ≤10-4 is recommended.
• For detection of FLT3-ITD, the Panel recommends a highly sensitive, NGS-based, targeted, deep-sequencing assay with a sensitivity level of
≤10-5.
• The Panel does not routinely recommend other NGS–based assays to detect mutated genes (targeted sequencing, 20–50 genes per panel)5,6
for MRD assessment due to inferior sensitivity.
Continued
References on AML-H 4 of 4
Note: All recommendations are category 2A unless otherwise indicated.
AML-H
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MEASURABLE (MINIMAL) RESIDUAL DISEASE ASSESSMENT

Timing of MRD Assessment
• While there is a paucity of data regarding the optimal frequency of MRD monitoring, the Panel recommends monitoring at the following time
points:
Upon achievement of morphologic remission5-7
At the time of and following allogeneic HCT.8
For NPM1-mutated, CBFB::MYH11, and RUNX1::RUNX1T1 AML: after two cycles of intensive chemotherapy (eg, one cycle of induction and
one cycle of consolidation) and for serial monitoring every 6 to 12 weeks for 24 months.3,9,10,11
For PML:RAR alpha: every 3 months for at least 24 months for patients with APL.
• Additional time points should be guided by the regimen used.4
Patients receiving venetoclax-based low-intensity therapy may achieve MRD-negative remission at later time points, including a significant
minority after 4–6 cycles of therapy. Therefore, repeat testing may be obtained.
NPM1 molecular MRD is strongly prognostic in patients receiving venetoclax-based low-intensity therapy. The Panel supports monitoring
NPM1 by RQ-PCR every 6 to 12 weeks in the BM or peripheral blood in patients receiving venetoclax-based low-intensity therapy.12

Management of MRD Positivity

• It is recommended that repeat testing should be performed within a short interval (eg, 1 month) if there is no hematologic relapse and
a BM biopsy and aspirate should be performed. Confirmation of MRD positivity in this setting is an indicator of high risk of relapse and
consideration should be made for allogeneic HCT, clinical trial, consolidation strategies, targeted therapy where appropriate, or therapy for
relapsed/refractory disease as clinically indicated.
• For NPM1, CBFB::MYH11, and RUNX1::RUNX1T1-mutated AML, if MRD is persistently positive after induction and/or consolidation, consider
a clinical trial or alternative therapies, including allogeneic HCT.
• The Panel recommends post-transplant maintenance gilteritinib for patients with BM FLT3-ITD MRD ≥10-6 by a highly sensitive, NGS-based,
targeted, deep-sequencing assay with a sensitivity level of ≤10-5 pre- or post-allogeneic HCT.13
• As there is no clear optimal management of MRD positivity, the Panel favors a clinical trial for MRD positivity if available. If a clinical trial,
allogeneic HCT, targeted therapy, or other consolidation strategies are not pursued, the Panel notes that venetoclax-based low-intensity
therapy has demonstrated high rates of MRD reduction in MRD and oligoblastic AML.14

Continued
References on AML-H 4 of 4
Note: All recommendations are category 2A unless otherwise indicated.
AML-H
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MEASURABLE (MINIMAL) RESIDUAL DISEASE ASSESSMENT

Relevant Clinical Trial Results
• In a study of patients with NPM1-mutated AML, proceeding to allogeneic HCT in CR1 led to a significant improvement in overall survival (OS)
for patients with MRD-detectable disease but no benefit for patients with MRD-negative disease.15
• In a planned subgroup analysis of the MORPHO trial, post-transplant maintenance therapy with gilteritinib was found to improve relapse-free
survival (RFS) (P = .0105) and OS (P = .0731) for patients with BM FLT3-ITD MRD ≥10-6 by PCR-NGS pre- or post-allogeneic HCT.13
• The SORMAIN trial revealed that post-transplant sorafenib maintenance had the greatest impact for patients with FLT3-ITD AML who
achieved MRD negativity pre-transplant and those with detectable MRD post-transplant.16
• In a subgroup analysis of the QUAZAR AML-001 trial, oral azacitidine maintenance therapy significantly improved survival among patients
who were ineligible for allogeneic HCT with NPM1-mutated AML in CR1 following intensive chemotherapy, with either detectable or
undetectable MRD by MFC.17
• In an analysis of patients treated with azacitidine + venetoclax on the VIALE-A trial, those who achieved composite CR (CRc) with MRD
<10-3 by MFC had improvements in median duration of remission and event-free survival (EFS), as well as a significant improvement in OS
compared to patients with MRD ≥10-3.18

References on AML-H 4 of 4
Note: All recommendations are category 2A unless otherwise indicated.
AML-H
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MEASURABLE (MINIMAL) RESIDUAL DISEASE ASSESSMENT

REFERENCES
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2 Schuurhuis GJ, Heuser M, Freeman S, et al. Minimal/measurable residual disease in AML: a consensus document from the European LeukemiaNet MRD Working
Party. Blood 2018;131:1275-1291.
3 Ivey A, Hills RK, Simpson MA, et al. Assessment of minimal residual disease in standard-risk AML. N Engl J Med 2016;374:422-433.
4 Jourdan E, Boissel N, Chevret S, et al. Prospective evaluation of gene mutations and minimal residual disease in patients with core binding factor acute myeloid
leukemia. Blood 2013;121:2213-2223.
5 Jongen-Lavrencic M, Grob T, Hanekamp D, et al. Molecular minimal residual disease in acute myeloid leukemia. N Engl J Med 2018;378:1189-1199.
6 Klco JM, Miller CA, Griffith M, et al. Association between mutation clearance after induction therapy and outcomes in acute myeloid leukemia. JAMA 2015;314:811-
822.
7 Morita K, Kantarjian HM, Wang F, et al. Clearance of somatic mutations at remission and the risk of relapse in acute myeloid leukemia. J Clin Oncol 2018;36:1788-
1797.
8 Thol F, Gabdoulline R, Liebich A, et al. Measurable residual disease monitoring by NGS before allogeneic hematopoietic cell transplantation in AML. Blood
2018;132:1703-1713.
9 Puckrin R, Atenafu EG, Claudio JO, et al. Measurable residual disease monitoring provides insufficient lead-time to prevent morphologic relapse in the majority of
patients with core-binding factor acute myeloid leukemia. Haematologica 2021;106:56-63.
10 Willekens C, Blanchet O, Renneville A, et al. French AML Intergroup. Prospective long-term minimal residual disease monitoring using RQ-PCR in RUNX1-RUNX1T1-
positive acute myeloid leukemia: results of the French CBF-2006 trial. Haematologica 2016;101:328-35.
11 Rücker FG, Agrawal M, Corbacioglu A, et al. Measurable residual disease monitoring in acute myeloid leukemia with t(8;21)(q22;q22.1): results from the AML Study
Group. Blood 2019 Nov 7;134:1608-1618.
12 Othman J, Tiong IS, O'Nions J, et al. Molecular MRD is strongly prognostic in patients with NPM1-mutated AML receiving venetoclax-based nonintensive therapy.
Blood 2024;143:336-341.
13 Levis MJ, Hamadani M, Logan B, et al. Gilteritinib as post-transplant maintenance for acute myeloid leukemia with internal tandem duplication mutation of FLT3. J
Clin Oncol 2024;0:JCO2302474.
14 Tiong IS, Hiwase DK, Abro E, et al. Targeting molecular measurable residual disease and low-blast relapse in AML with venetoclax and low-dose cytarabine: A
prospective phase II study (VALDAC). J Clin Oncol 2024;42:2161-2173.
15 Othman J, Potter N, Ivey A, et al. Postinduction molecular MRD identifies patients with NPM1 AML who benefit from allogeneic transplant in first remission [abstract].
Blood 2024;143:1931-1936.
16 Burchert A, Bug G, Fritz LV, et al. Sorafenib maintenance after allogeneic hematopoietic stem cell transplantation for acute myeloid leukemia with FLT3-internal
tandem duplication mutation (SORMAIN). J Clin Oncol 2020;38:2993-3002.
17 Dohner H, Wei AH, Roboz GJ, et al. Prognostic impact of NPM1 and FLT3 mutations in patients with AML in first remission treated with oral azacitidine. Blood
2022;140:1674-1685.
18 Pratz KW, Jonas BA, Pullarkat V, et al. Measurable residual disease response and prognosis in treatment-naive acute myeloid leukemia with venetoclax and
azacitidine. J Clin Oncol 2022;40:855-865.

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

AML-H
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Acute Myeloid Leukemia (Age ≥18 years) Discussion

RESPONSE CRITERIA DEFINITIONS FOR ACUTE MYELOID LEUKEMIA1

These response criteria were defined in the context of intensive chemotherapy regimens, and may not be predictive of outcomes for patients
who receive other therapies.
• Morphologic leukemia-free state (MLFS)
BM <5% blasts in an aspirate with spicules; at least 200 cells must be enumerated
No blasts with Auer rods or persistence of extramedullary disease
If there is a question of residual leukemia, a BM aspirate/biopsy should be repeated in one week.
A BM biopsy/aspirate should be performed.
• CR
Morphologic CR
◊ ANC ≥1 x 109/L (blasts <5%)
◊ Platelets ≥100 x 109/L (blasts <5%)
CR without MRD (CRMRD-)
◊ If studied pretreatment, CR with negativity for a genetic marker by reverse transcriptase PCR (RT-PCR) or CR with negativity by MFCa
◊ Sensitivity varies by marker and method used; analyses should be done in experienced laboratories.
◊ Molecular CR – molecular studies negative
CR with partial hematologic recovery (CRh), defined as <5% blasts in the BM, no evidence of disease (NED), and partial recovery of
peripheral blood counts (platelets ≥50 × 109/L and ANC ≥0.5 × 109/L)2
CRi – All CR criteria and transfusion independence but with persistence of neutropenia
(<1 x 109/L) or thrombocytopenia (<100 x 109/L).
Responses less than CR may still be meaningful depending on the therapy.
• Partial remission (PR)b
Decrease of at least 50% in the percentage of blasts to 5% to 25% in the BM aspirate and meeting hematologic criteria for CR, as noted
above.
• Relapse following CR
Reappearance of leukemic blasts in the peripheral blood or the finding of ≥5% blasts in the BM, not attributable to another cause (eg, BM
regeneration after consolidation therapy) or extramedullary relapse.
• Primary refractory
Inability to attain CR, CRh, or CRi following exposure to at least 2 courses of intensive induction therapy.
• MRD relapse
Conversion from MRD negativity to MRD positivity, independent of method of testing.

a This is clinically relevant in APL and Ph+ leukemia, and inability to achieve a significant reduction (eg >3 log) in
molecular evidence of t(8;21) or inv(16) has a very high predictive value of relapse. Molecular remission for APL
should be performed after consolidation, not after induction as in non-APL AML. NPM1 is a target that can be
included in the molecular response assessment. Ivey A, et al. N Engl J Med 2016;374:422-433. 1 Dohner H, et al. Blood 2022;140:1345-1377.
b Partial remissions are useful in assessing potential activity of new investigational agents, usually in phase I trials. 2 Bloomfield CD, et al. Blood Rev 2018;32:416-425.

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

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Acute Myeloid Leukemia (Age ≥18 years) Discussion

PRINCIPLES OF VENETOCLAX USE WITH HMA OR LDAC

General
• Recommend consultation with a high-volume tertiary care/academic medical center throughout course of treatment.
• There are ongoing studies into the addition of a third agent to the combinations described in this section, and participation in clinical trials is
encouraged.
• The maximum number of cycles for these regimens is unknown, and treatment may continue as long as tolerated and effective.
• Consider antimicrobial prophylaxis per institutional protocol for patients with newly diagnosed disease.
• Drug-drug interactions occur with strong or moderate CYP3A4 inhibitors and may require dose adjustment. Refer to venetoclax prescribing
information ([Link] and consult with a pharmacist for potential drug interactions.
Strong or moderate CYP3A4 inducers (eg, carbamazepine, phenytoin, rifampin) should be avoided.

Prognostic Risk Classification for Patients Ineligible for Intensive Therapy Treated with HMA/Venetoclax1

Benefit with HMA/Venetoclax Genetic Abnormality

Higher benefit Negative for mutations in TP53, KRAS, NRAS, and FLT3-ITD
Intermediate benefit Mutations in KRAS and/or NRAS and/or FLT3-ITD; negative for mutation
in TP53
Lower benefit Mutation in TP53

References on AML-J 4 of 4
Note: All recommendations are category 2A unless otherwise indicated.
AML-J
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Acute Myeloid Leukemia (Age ≥18 years) Discussion

PRINCIPLES OF VENETOCLAX USE WITH HMA OR LDAC

Tumor Lysis Syndrome (TLS) Risk/Monitoring During Cycle 1
• To decrease the risk of severe TLS, aim to achieve WBC count of <25 x 109/L with hydroxyurea/leukapheresis prior to starting therapy.
• Inpatient treatment is strongly recommended during first cycle of treatment, especially through dose escalation.a
• Intrapatient dose escalation for venetoclax with HMA is 100 mg, 200 mg, and 400 mg daily on days 1–3; intrapatient dose escalation for
venetoclax with LDAC is 100 mg, 200 mg, 400 mg, and 600 mg daily on days 1–4. Concomitant interacting medications may require changes
to these dosages.b
• Recommend treatment with allopurinol or other uric acid–lowering agent until no further risk of TLS.
• Monitor blood chemistries every 6–8 hours after initiation for a total of 24 hours following maximum dose escalation; if within normal limits,
recheck once daily and continue monitoring until no further risk of TLS.
• Aggressively monitor and manage electrolyte imbalances.

Therapy for Patients with Substantial Comorbidities

• Consider initiating therapy with a reduced duration of venetoclax (eg, 7 days).2

Therapy for Patients with Relapsed/Refractory Disease

• Consider the same TLS and intrapatient dose escalation measures as described for “TLS Risk/Monitoring During Cycle 1.”
• Consider the same recommendations for early BM biopsy and cytopenia mitigation plan as per AML-J 3 of 4.
• Recommend antifungal prophylaxis if indicated3

a Patients may need hospitalization beyond first cycle, based on medical circumstances. Treatment in outpatient setting may be
considered per institutional practice or treatment preference.
b Refer to venetoclax prescribing information for further recommendations ([Link] References on AML-J 4 of 4

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

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Acute Myeloid Leukemia (Age ≥18 years) Discussion

PRINCIPLES OF VENETOCLAX USE WITH HMA OR LDAC4-10

CR
Start cycle 2 on day 29 or
(Response
laterc if marrow results
criteria,
not available on day 29
see AML-I)

Cycle 3 and beyond

• Delay next cycle for
Start cycle 2 up to 14 daysc to allow
Delay cycle 2 for up to 14
BM MLFS or CRi • Consider recovery of ANC >0.5 x
Cycle 1 daysc to allow recovery
aspirate (Response reduction of 109/L and platelets >50 x
Venetoclax + of ANC >0.5 x 109/L and
and biopsy criteria, see venetoclax 109/L
HMA or LDAC platelets >50 x 109/L
days 21–28 AML-I) duration to G-CSFd is encouraged
• G-CSFd is encouraged
21 days • Consider further
reduction in venetoclax
duration (eg, 14 days,
7 days, or 5 days) if
MLFS or cytopenias recur in
better subsequent cycles
response • Dose modifications
(Response to HMA, or LDAC may
criteria, also be considered in
see AML-I) accordance with their
BM
Start cycle 2 aspirate label
without delay and biopsy
Lack of days 21–28
response
(Response Lack of Continue therapy up to 4
criteria, response cyclese and if no response,
see AML-I) (Response see Therapy for Relapsed/
criteria, see Refractory Disease (AML-9)
Disease progression, see AML-I)
Therapy for Relapsed/
Refractory Disease (AML-9)
c Longer delays may be considered.
d An FDA-approved biosimilar is an appropriate substitute for any recommended systemic biologic therapy in the NCCN Guidelines.
e Decrease in blasts/response is most commonly seen following 2 cycles. While venetoclax + HMA or LDAC may be continued for up
to 4 cycles to monitor for delayed response, it is also reasonable to stop therapy after 2 cycles in the setting of lack of response. References on AML-J 4 of 4
Note: All recommendations are category 2A unless otherwise indicated.
AML-J
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Acute Myeloid Leukemia (Age ≥18 years) Discussion

PRINCIPLES OF VENETOCLAX USE WITH HMA OR LDAC

REFERENCES
1 Döhner H, Pratz KW, DiNardo CD, et al. Genetic risk stratification and outcomes among treatment-naive patients with AML treated with venetoclax and azacitidine.
Blood 2024;144:2211-2222.
2 Willekens C, Bazinet A, Chraibi S, et al. Reduced venetoclax exposure to 7 days vs standard exposure with hypomethylating agents in newly diagnosed AML patients.
Blood Cancer J 2025;15:68.
3 Bataller A, Bazinet A, DiNardo CD, et al. Prognostic risk signature in patients with acute myeloid leukemia treated with hypomethylating agents and venetoclax. Blood
Adv 2024;8:927-935.
4 DiNardo CD, Pratz K, Pullarkat V, et al. Venetoclax combined with decitabine or azacitidine in treatment-naive, elderly patients with acute myeloid leukemia. Blood
2019;133:7-17.
5 Jonas BA, Pollyea DA. How we use venetoclax with hypomethylating agents for the treatment of newly diagnosed patients with acute myeloid leukemia. Leukemia
2019;33:2795-2804.
6 DiNardo CD, Jonas BA, Pullarkat V, et al. Azacitidine and venetoclax in previously untreated acute myeloid leukemia. N Engl J Med 2020;383:617-629.
7 Pratz KW, DiNardo CD, Selleslag D, et al. Postremission cytopenia management in patients with acute myeloid leukemia treated with venetoclax and azacitidine in
VIALE-A. Am J Hematol 2022;97:E416-E419.
8 Jonas BA, Wei AH, Recher C, et al. Timing of response with venetoclax combination treatment in patients with newly diagnosed acute myeloid leukemia. Am J Hematol
2022;97:E299-E303.
9 Jonas BA, DiNardo C, Fracchiolla N, et al. Use of CYP3Ai and impact on outcomes in patients with acute myeloid leukemia treated with venetoclax plus azacitidine in
the VIALE-A study. Am J Hematol 2022;97:E422-E425.
10 Pratz KW, Jonas BA, Pullarkat V, et al. Measurable residual disease response and prognosis in treatment-naive acute myeloid leukemia with venetoclax and
azacitidine. J Clin Oncol 2022;40:855-865.

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

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Blastic Plasmacytoid Dendritic Cell Neoplasm Table of Contents
Discussion
(Age ≥18 years)
INTRODUCTION

Decisions about diagnosis and management for BPDCN

should involve multidisciplinary consultation at a
high-volume center with use of appropriate interventions.
Consider referral to an academic institution.

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

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Blastic Plasmacytoid Dendritic Cell Neoplasm Table of Contents
Discussion
(Age ≥18 years)
EVALUATION/WORKUP FOR BPDCNa,1,2 DIAGNOSIS4
• H&P
• CBC, platelets, differential, CMP
• Analysis of skin lesions Expression of
(collaboration with dermatology is CD4 and/or
recommended),3,b peripheral blasts, Stepwise CD56 plus
BM aspirate/biopsy, and lymph node immunophenotypic expression
biopsy (if indicated) including: evaluation: of CD123 and
Dendritic cell morphology • pDC markers: one other pDC Treatment
assessment CD123, TCF4, marker Induction
 IHC TCL1, CD303, • Eligible for
Immature cells
Flow cytometry CD304 OR BPDCN tagraxofusp-erzs
with blastoid
Cytogenetic analysis • Other markers: confirmedc (BPDCN-2)
morphology
Molecular analysis (most common CD4, CD56 Expression • Not eligible for
aberrations include: TET2, ASXL1, • Expected negative of any three tagraxofusp-erzs
ZRSR2, SRSF2, TP53, NRAS, IDH2, markers: CD3, pDC markers (BPDCN-3)
and ETV6)4,5 (RUNX1 mutations CD14, CD19, and absent
are rare in this entity) CD34, lysozyme, expression
• FDG-PET/CT scan of other sites, if myeloperoxidase of expected
clinical suspicion for extramedullary negative
disease and/or lymphadenopathy markers
• All patients require a diagnostic
LP with IT chemotherapy at the
time of initial diagnosis, at disease
relapse, or any other time when
there is a clinical suspicion for CNS
involvement (BPDCN-B).2

a Principles of BPDCN (BPDCN-A).

b Close collaboration with dermatology is recommended. For guidance on classification and measurement of skin lesions, see
page MFSS-3 in the NCCN Guidelines for Primary Cutaneous Lymphomas.
c Differential diagnoses may include certain similar entities, such as AML with plasmacytoid dendritic cell differentiation, but can
generally be ruled out by careful adherence to established diagnostic criteria. Xiao W, et al. Blood 2021;137:1377-1391. References on BPDCN-5

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

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Blastic Plasmacytoid Dendritic Cell Neoplasm Table of Contents
Discussion
(Age ≥18 years)
TREATMENT TREATMENT INDUCTION6
OF BPDCNd Preferred:
• Allogeneic
• Tagraxofusp-erzs (formerly SL-401) 12 mcg/kg HCT10,16,17,18 Surveillance
IV over 15 minutes once daily on days 1–5 of a CRf (BPDCN-4)
21-day cycle3,7,8 Other Recommended:
For management of adverse events, see • Autologous HCT
Supportive Care (BPDCN-C) • Tagraxofusp-erzs
• IT chemotherapy in patients with documented until progression Treatment for
CNS disease at diagnosis and as prophylaxis Relapsed/Refractory
for patients without documented CNS disease Disease (BPDCN-4)
(methotrexate, cytarabine)9 (BPDCN-B) Lack of response to induction12

Eligible for
tagraxofusp-erzse • ALL-type induction: Preferred:
HyperCVAD (hyperfractionated cyclophosphamide, • Allogeneic
vincristine, doxorubicin, dexamethasone, alternating with HCT10,16,17,18 Surveillance
high-dose methotrexate and cytarabine)10,11,12,13 CRf Other (BPDCN-4)
• AML-type induction: Recommended:
Standard-dose cytarabine 100 or 200 mg/m2 continuous • Autologous
infusion x 7 days with idarubicin 12 mg/m2 or daunorubicin HCT
Intensive 60–90 mg/m2 x 3 days10
• Lymphoma induction: Treatment
CHOP (cyclophosphamide, doxorubicin, vincristine, and for
prednisone)10 Lack of
Relapsed/
• IT chemotherapy in patients with documented CNS disease response to
Refractory
Other at diagnosis and as prophylaxis for patients without induction12
Disease
Recommended: documented CNS disease (methotrexate, cytarabine)9 (BPDCN-4)
Chemotherapy (BPDCN-B)

• HMA (azacitidine or decitabine) + venetoclax14,15

• IT chemotherapy in patients with documented CNS disease at diagnosis and as prophylaxis for patients
Lower without documented CNS disease (methotrexate, cytarabine)9 (BPDCN-B)
intensity • Palliative options include:
Systemic steroids
Supportive Care (BPDCN-C)

Footnotes on BPDCN-2A
References on BPDCN-5
Note: All recommendations are category 2A unless otherwise indicated.

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Blastic Plasmacytoid Dendritic Cell Neoplasm Table of Contents
Discussion
(Age ≥18 years)
FOOTNOTES
d Principles of Supportive Care for BPDCN (BPDCN-C).
e Albumin ≥3.2 g/dL, LVEF ≥ institutional lower limit of normal, creatinine ≤1.5 mg/dL, bilirubin ≤1.5 mg/dL, AST/ALT ≤2.5 x ULN and no clinically significant
cardiovascular disease. Pemmaraju N, et al. N Engl J Med 2019;380:1628-1637.
f CR in BPDCN has the same hematologic criteria as AML (AML-I), but it is also important to document resolution of any extramedullary sites including CNS and skin
lesions. If the skin still shows microscopic disease, consider continuing additional cycles (at least 4) of therapy before managing as relapsed/refractory disease. For
appropriate studies to assess CR, see Pemmaraju N, et al. N Engl J Med 2019;380:1628-1637.

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

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Blastic Plasmacytoid Dendritic Cell Neoplasm Table of Contents
Discussion
(Age ≥18 years)
TREATMENT TREATMENT INDUCTION6
OF BPDCNd

• Chemotherapy
ALL-type induction: Preferred:
HyperCVAD (hyperfractionated cyclophosphamide, • Allogeneic
vincristine, doxorubicin, dexamethasone, alternating with HCT10,16,17,18 Surveillance
high-dose methotrexate and cytarabine)10,11,12,13 CRf Other (BPDCN-4)
AML-type induction: Recommended:
Eligible Standard-dose cytarabine 100 or 200 mg/m2 continuous • Autologous
for infusion x 7 days with idarubicin 12 mg/m2 or daunorubicin HCT
intensive 60–90 mg/m2 x 3 days10
therapy Lymphoma induction: Treatment
CHOP (cyclophosphamide, doxorubicin, vincristine, and for
prednisone)10 Lack of
Relapsed/
• IT chemotherapy in patients with documented CNS disease response to
Refractory
Not eligible for at diagnosis and as prophylaxis for patients without induction12
Disease
tagraxofusp-erzs documented CNS disease (methotrexate, cytarabine)9 (BPDCN-4)
(BPDCN-B)

• Chemotherapy
HMA (azacitidine or decitabine) + venetoclax14
Not
• IT chemotherapy in patients with documented CNS disease at diagnosis and
eligible
as prophylaxis for patients without documented CNS disease (methotrexate,
for
cytarabine)9 (BPDCN-B)
intensive
• Palliative options include:
therapy or
Systemic steroids
declines
Supportive Care (BPDCN-C)

d Principles of Supportive Care for BPDCN (BPDCN-C).

f CR in BPDCN has the same hematologic criteria as AML (AML-I), but it is also important to document resolution of any extramedullary sites including CNS and skin
lesions. If the skin still shows microscopic disease, consider continuing additional cycles (at least 4) of therapy before managing as relapsed/refractory disease. For
appropriate studies to assess CR, see Pemmaraju N, et al. N Engl J Med 2019;380:1628-1637.
References on BPDCN-5
Note: All recommendations are category 2A unless otherwise indicated.

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Blastic Plasmacytoid Dendritic Cell Neoplasm Table of Contents
Discussion
(Age ≥18 years)
SURVEILLANCE TREATMENT FOR RELAPSED/REFRACTORY DISEASE

• Evaluate CNS for disease/prophylaxis9

• CBC, platelets every 1–3 mo for • Consider
2 y, then every 3–6 mo up to 5 y Clinical trial (preferred)
• BM aspirate and biopsy only if Tagraxofusp-erzs3,8 (if not already used)
peripheral smear is abnormal or For management of adverse events, see Supportive Care (BPDCN-C)
Relapsed/
cytopenias develop Chemotherapy (if not already used), see Treatment Induction (BPDCN-2)
refractory
• Repeat FDG-PET/CT scan for patients Local RT to isolated lesions/areas
BPDCN
with prior evidence of extramedullary Systemic steroids
disease HMA (azacitidine or decitabine) + venetoclax,15,19,20 see BPDCN-2
• Consider re-biopsy for any suspicious • Donor search should be initiated at first relapse in appropriate patients
skin or extramedullary lesions concomitant with institution of other therapy if no sibling donor has been
identified

References on BPDCN-5

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

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Blastic Plasmacytoid Dendritic Cell Neoplasm Table of Contents
Discussion
(Age ≥18 years)
REFERENCES
1 Khoury JD, Solary E, Abla O, et al. The 5th edition of the World Health 14 Lee BJ. Venetoclax and hypomethylating agents versus tagraxofusp in
Organization classification of haematolymphoid tumours: myeloid and histiocytic/ older patients with blastic plasmacytoid dendritic cell neoplasm. Ann Hematol
dendritic neoplasms. Leukemia 2022;36:1703-1719. 2025;104:2069-2071.
2 Pemmaraju N, Kantarjian H, Sweet K, et al. North American Blastic Plasmacytoid 15 DiNardo CD, Rausch CR, Benton C, et al. Clinical experience with the BCL2-
Dendritic Cell Neoplasm Consortium: position on standards of care and areas of inhibitor venetoclax in combination therapy for relapsed and refractory acute
need. Blood 2023;141:567-578. myeloid leukemia and related myeloid malignancies. Am J Hematol 2018;93:401-
3 Pemmaraju N, Lane AA, Sweet KL, et al. Tagraxofusp in blastic plasmacytoid 407.
dendritic-cell neoplasm. N Engl J Med 2019;380:1628-1637. 16 Kharfan-Dabaja MA, Al Malki MM, Deotare U, et al. Haematopoietic cell
4 Menezes J, Acquadro F, Wiseman M, et al. Exome sequencing reveals novel transplantation for blastic plasmacytoid dendritic cell neoplasm: a North American
and recurrent mutations with clinical impact in blastic plasmacytoid dendritic cell multicentre collaborative study. Br J Haematol 2017;179:781-789.
neoplasm. Leukemia 2014;28:823-829. 17 Roos-Weil D, Dietrich S, Boumendil A, et al. Stem cell transplantation can
5 Togami K, Chung SS, Madan V, et al. Sex-biased ZRSR2 mutations in myeloid provide durable disease control in blastic plasmacytoid dendritic cell neoplasm:
malignancies impair plasmacytoid dendritic cell activation and apoptosis. Cancer a retrospective study from the European Group for Blood and Marrow
Discov 2022;12:522-541. Transplantation. Blood 2013;121:440-446.
6 Pemmaraju N, Kantarjian HM, Khoury JD, et al. Blastic plasmacytoid dendritic 18 Aoki T, Suzuki R, Kuwatsuka Y, et al. Long-term survival following autologous
cell neoplasm (BPDCN) commonly presents in the setting of prior or concomitant and allogeneic stem cell transplantation for blastic plasmacytoid dendritic cell
hematologic malignancies (PCHM): Patient characteristics and outcomes in neoplasm. Blood 2015;125:3559-3562.
the rapidly evolving modern targeted therapy era [abstract]. Blood 2019;134 19 Montero J, Stephansky J, Cai T, et al. Blastic plasmacytoid dendritic cell
(Suppl):Abstract 2723. neoplasm is dependent on BCL2 and sensitive to venetoclax. Cancer Discov
7 Frankel AE, Woo JH, Ahn C, et al. Activity of SL-401, a targeted therapy directed 2017;7:156-164.
to interleukin-3 receptor, in blastic plasmacytoid dendritic cell neoplasm patients. 20 Rausch CR, DiNardo CD, Kadia T, et al. Results of off-label venetoclax use
Blood 2014;124:385-392. in combination with low-intensity chemotherapy in patients with relapsed and
8 Pemmaraju N, Sweet KL, Stein AS, et al. Long-term benefits of tagraxofusp refractory myeloid malignancies [abstract]. Blood 2017;130(Suppl):Abstract 1356.
for patients with blastic plasmacytoid dendritic cell neoplasm. J Clin Oncol
2022;40:3032-3036.
9 Martín-Martín L, Almeida J, Pomares H, et al. Blastic plasmacytoid dendritic
cell neoplasm frequently shows occult central nervous system involvement at
diagnosis and benefits from intrathecal therapy. Oncotarget 2016;7:10174-10181.
10 Pagano L, Valentini CG, Pulsoni A, et al. Blastic plasmacytoid dendritic cell
neoplasm with leukemic presentation: an Italian multicenter study. Haematologica
2013;98:239-246.
11 Reimer P, Rüdiger T, Kraemer D, et al. What is CD4+CD56+ malignancy and
how should it be treated? Bone Marrow Transplant 2003;32:637-646.
12 Deotare U, Yee KW, Le LW, et al. Blastic plasmacytoid dendritic cell neoplasm
with leukemic presentation: 10-Color flow cytometry diagnosis and HyperCVAD
therapy. Am J Hematol 2016;91:283-286.
13 Pemmaraju N, Wilson NR, Garcia-Manero G, et al. Characteristics and outcomes
of patients with blastic plasmacytoid dendritic cell neoplasm treated with frontline
HCVAD. Blood Adv 2022;6:3027-3035.

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

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Blastic Plasmacytoid Dendritic Cell Neoplasm Table of Contents
Discussion
(Age ≥18 years)
PRINCIPLES OF BPDCN
General Principles:
• BPDCN is a disorder of immature dendritic cells that regulate effector T-cell function.
• Diagnosis can be extremely challenging and whenever possible should involve an experienced hematopathologist.
• It constitutes only 0.44% of hematologic malignancies and <1% of acute leukemia presentations.1
• It occurs in all races and geographic areas.
• It is more common in adults (median age, 65–67 years) with an approximate male-to-female ratio of 3:1.
• It most commonly presents as asymptomatic skin lesions,a,2 cytopenias, circulating peripheral blasts (leukemic phase), lymphadenopathy,
and CNS manifestations.
• Prognosis for BPDCN is poor and the median OS is approximately 8–12 months when patients are treated with chemotherapy without
consolidative allogeneic HCT.3,4
• Studies suggest that being in first remission during receipt of allogeneic HCT significantly enhances the median OS.4-6 Reduced-intensity
conditioning may be considered in patients whose disease achieves CR but cannot tolerate myeloablative HCT.7
• For patients who are fit, current treatment options for BPDCN include tagraxofusp-erzs and chemotherapy, whereas those with low albumin
and/or comorbidities should receive non-intensive regimen options as shown in the algorithm (BPDCN-2).
Hypoalbuminemia and capillary leak syndrome are known, potentially serious adverse events associated with tagraxofusp-erzs treatment,8
and must be monitored closely during therapy (See Principles of Supportive Care for BPDCN [BPDCN-C]).

1 Bueno C, Almeida J, Lucio P, et al. Incidence and characteristics of CD4(+)/HLA DRhi dendritic
cell malignancies. Haematologica 2004;89:58-69.
2 Pemmaraju N, Lane AA, Sweet KL, et al. Tagraxofusp in blastic plasmacytoid dendritic-cell
neoplasm. N Engl J Med 2019;380:1628-1637.
3 Dalle S, Beylot-Barry M, Bagot M, et al. Blastic plasmacytoid dendritic cell neoplasm: is
transplantation the treatment of choice? Br J Dermatol 2010;162:74-79.
4 Pagano L, Valentini CG, Pulsoni A, et al. Blastic plasmacytoid dendritic cell neoplasm with
leukemic presentation: an Italian multicenter study. Haematologica 2013;98:239-246.
5 Deotare U, Yee KW, Le LW, et al. Blastic plasmacytoid dendritic cell neoplasm with leukemic
presentation: 10-Color flow cytometry diagnosis and HyperCVAD therapy. Am J Hematol
2016;91:283-286.
6 Roos-Weil D, Dietrich S, Boumendil A, et al. Stem cell transplantation can provide durable
disease control in blastic plasmacytoid dendritic cell neoplasm: a retrospective study from the
European Group for Blood and Marrow Transplantation. Blood 2013;121:440-446.
a Close collaboration with dermatology is recommended. For 7 Pagano L, Valentini CG, Grammatico S, Pulsoni A. Blastic plasmacytoid dendritic cell neoplasm:
guidance on classification and measurement of skin lesions, diagnostic criteria and therapeutical approaches. Br J Haematol 2016;174:188-202.
see page MFSS-3 in the NCCN Guidelines for Primary 8 Frankel AE, Woo JH, Ahn C, et al. Activity of SL-401, a targeted therapy directed to interleukin-3
Cutaneous Lymphomas. receptor, in blastic plasmacytoid dendritic cell neoplasm patients. Blood 2014;124:385-392.

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

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NCCN Guidelines Index
Blastic Plasmacytoid Dendritic Cell Neoplasm Table of Contents
Discussion
(Age ≥18 years)
EVALUATION AND TREATMENT OF CNS DISEASE

• CNS-directed IT chemotherapya
Twice weekly dosing until CSF is clear
With CNS disease Once the CSF is clear (negative on cytology) continue weekly IT treatments for at least 4 doses, then
twice per month for a total of at least 8 doses
Consider continuing IT treatments once or twice per month for ongoing prophylaxisb

• Administer prophylactic CNS-directed IT chemotherapya,c

Without CNS disease Twice per month for a total of at least 8 doses
Consider continuing IT treatment once or twice per month for ongoing prophylaxisb

a Chemotherapy regimens may follow institutional standards, but would preferably be aggressive including alternating cytarabine with methotrexate, or triple IT agents
(ie, cytarabine, methotrexate, steroid).
b Decision should be based on shared decision-making with patient after discussion of risks and benefits.
c Consider IT chemotherapy prophylaxis even in the absence of known CNS disease, given the high percentage (30%) of primary CNS involvement at relapse. Sullivan
JM, et al. Hematology Am Soc Hematol Educ Program 2016;2016:16-23. Pemmaraju N, et al. Blood 2023;141:567-578.

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

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NCCN Guidelines Index
Blastic Plasmacytoid Dendritic Cell Neoplasm Table of Contents
Discussion
(Age ≥18 years)
PRINCIPLES OF SUPPORTIVE CARE FOR BPDCN
Administration/Management of Toxicities Associated with Tagraxofusp-erzsa
• Patients must have a baseline serum albumin of 3.2 g/dL or higher to be able to start tagraxofusp-erzs.
Replace serum albumin if <3.5 g/dL or if there is a reduction of ≥0.5 from baseline.
• Capillary leak syndrome (life-threatening/fatal) can occur in patients receiving this drug.
• The first cycle of this drug should be administered in the inpatient setting. Closely monitor toxicity during and after drug administration. It is
recommended that patients remain in the hospital for at least 24 hours after completion of the first cycle.
Premedicate with an H1-histamine antagonist, acetaminophen, corticosteroid, and H2-histamine antagonist prior to each infusion.
Administer tagraxofusp-erzs at 12 mcg/kg IV over 15 minutes once daily on days 1–5 of a 21-day cycle. Alternately, 5 doses can be
administered over a 10-day period, if needed for dose delays.
• Prior to each dose of drug: Check vital signs, albumin, transaminases, and creatinine.
• Collaboration with a dermatologist for supportive care is essential.

Hold Tagraxofusp-erzs Dosing for the Following Reasons:

• Serum albumin <3.5 g/dL or a reduction from baseline of ≥0.5
• Body weight ≥1.5 kg over prior day
• Edema, fluid overload, and/or hypotension
• Alanine aminotransferase (ALT)/aspartate aminotransferase (AST) increase >5 times the upper limit of normal
• Serum creatinine >1.8 or CrCl ≤60 mL/min
• Systolic blood pressure (SBP) ≥160 or ≤80 mmHg
• Heart rate (HR) ≥130 bpm or ≤40 bpm
• Temperature ≥38°C
• Mild to severe hypersensitivity reaction

a See prescribing information for full details on administration and toxicity management ([Link]

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

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Table of Contents
Acute Myeloid Leukemia (Age ≥18 years) Discussion

ABBREVIATIONS

aGVHD acute graft-versus-host disease CRh complete remission with partial H&P history and physical
ALAL acute leukemia of ambiguous hematologic recovery HCT hematopoietic cell transplant
lineage CRi complete remission with HLA human leukocyte antigen
ALT alanine aminotransferase incomplete hematologic recovery
HMA hypomethylating agent
AML acute myeloid leukemia CRMRD- complete remission without
measurable (minimal) residual HR heart rate
ANC absolute neutrophil count disease
APL acute promyelocytic leukemia CSF cerebrospinal fluid IHC immunohistochemistry
AST aspartate aminotransferase CVAD central venous access device IT intrathecal
ATRA all-trans retinoic acid ITD internal tandem duplication
AYA adolescent and young adult DIC disseminated intravascular
coagulation LAIP leukemia-associated
BM bone marrow immunophenotype
BPDCN blastic plasmacytoid dendritic cell ECG electrocardiogram LDH lactate dehydrogenase
neoplasm ECOG Eastern Cooperative Oncology LFT liver function test
BUN blood urea nitrogen Group LP lumbar puncture
bZIP basic leucine zipper EF ejection fraction
EFS event-free survival MDS myelodysplastic syndrome
CBC complete blood count ESA erythropoiesis-stimulating agent MFC multicolor flow cytometry
CBF core binding factor MLFS morphologic leukemia-free state
CHIP clonal hematopoiesis of FDG fluorodeoxyglucose MPAL mixed phenotype acute leukemia
indeterminate potential FISH fluorescence in situ hybridization MPO myeloperoxidase
CMML chronic myelomonocytic leukemia FNA fine-needle aspiration MRC myelodysplasia-related changes
CMP comprehensive metabolic panel
MRD measurable (minimal) residual
CMV cytomegalovirus G6PD glucose-6-phosphate disease
CNS central nervous system dehydrogenase MUGA multigated acquisition
CNV copy number variant G-CSF granulocyte colony-stimulating
CR complete remission factor
NED no evidence of disease
CRc composite CR GI gastrointestinal
NGS next-generation sequencing
CrCl creatinine clearance GM-CSF granulocyte-macrophage colony-
stimulating factor

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Table of Contents
Acute Myeloid Leukemia (Age ≥18 years) Discussion

ABBREVIATIONS

OS overall survival

PCR polymerase chain reaction

PR partial remission
PT prothrombin time
PTD partial tandem duplication
PTT partial thromboplastin time

RBC red blood cell

RFS relapse-free survival
RQ-PCR real-time quantitative polymerase
chain reaction
RT-PCR reverse transcriptase polymerase
chain reaction

SBP systolic blood pressure

SOS sinusoidal obstruction syndrome

TKD tyrosine kinase domain

TLS tumor lysis syndrome
TPO thrombopoietin

WBC white blood cell

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Table of Contents
Acute Myeloid Leukemia (Age ≥18 years) Discussion

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

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Acute Myeloid Leukemia
Follow-up and Reinduction Therapy After Cytarabine-Based Induction .....................47
Discussion This discussion corresponds to the NCCN Guidelines for
Acute Myeloid Leukemia. Last updated November 24, 2025. Post-Remission or Consolidation Therapy in Patients Eligible for Intensive Induction
Therapy ....................................................................................................................48

Table of Contents AML Induction Therapy for Patients Ineligible for Intensive Induction ........................53

Overview ........................................................................................................................ 2 Post-Remission or Consolidation Therapy in Patients Ineligible for Intensive Induction
Therapy ....................................................................................................................60
Guidelines Update Methodology ..................................................................................... 2
Maintenance Therapy ...............................................................................................60
Literature Search Criteria................................................................................................ 3
Principles of Venetoclax Use with HMAs or Low-Dose Cytarabine-Based Treatment 63
Sensitive/Inclusive Language Usage .............................................................................. 3
Role of MRD Monitoring ............................................................................................65
Initial Evaluation ............................................................................................................. 3
Postremission Surveillance for AML ..........................................................................70
Workup ...................................................................................................................... 3
Management of Relapsed/Refractory AML ................................................................70
Diagnosis ................................................................................................................... 6
NCCN Recommendations .........................................................................................74
Risk Stratification by Biological Disease Factors ......................................................... 8
Supportive Care for Patients with AML ..........................................................................75
Familial Genetic Alterations in AML .......................................................................... 17
Supportive Care for Patients with AML Who Prefer Not to Receive Blood Transfusions .76
Principles of Acute Myeloid Leukemia Treatment .......................................................... 17
Evaluation and Treatment of CNS Leukemia .................................................................77
Management of Acute Promyelocytic Leukemia ............................................................ 18
Management of Blastic Plasmacytoid Dendritic Cell Neoplasm .....................................78
Induction Therapy for Patients with APL ................................................................... 19
Workup .....................................................................................................................79
Consolidation Therapy for Patients with APL ............................................................ 24
Induction Therapy for Patients with BPDCN ..............................................................79
Post-Consolidation or Maintenance for Patients with APL ......................................... 28
Postremission Surveillance for BPDCN .....................................................................84
Management of Relapsed APL ................................................................................. 30
Management of Relapsed/Refractory BPDCN ...........................................................84
Supportive Care for Patients with APL ...................................................................... 33
References ...................................................................................................................85
Management of Acute Myeloid Leukemia ..................................................................... 35

AML Induction Therapy for Patients Eligible for Intensive Induction Therapy ............ 36

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Overview purine analog fludarabine, has also been associated with therapy-related
Acute myeloid leukemia (AML) is a heterogeneous hematologic MDS/AML in patients with lymphoproliferative disorders, particularly when
malignancy characterized by the clonal expansion of myeloid blasts in the administered in combination with alkylating agents.11,12 Radiation therapy
peripheral blood, bone marrow (BM), and/or other tissues. It is the most (RT), especially in the context of myeloablative therapy (eg, total body
common form of acute leukemia among adults and accounts for the irradiation [TBI], radioimmunotherapy) given before autologous
largest number of annual deaths from leukemias in the United States.1 An hematopoietic cell transplantation (HCT) may also increase the risk for
estimated 22,020 people will be diagnosed with AML in 2025, and 11,090 therapy-related MDS/AML.13,14 The disease course of therapy-related
patients will die of the disease.1 According to the SEER Cancer Statistics MDS/AML is generally progressive and may be more resistant to
Review, the median age at diagnosis is 68 years, with approximately 60% conventional cytotoxic therapies than de novo cases of MDS/AML.9
of patients diagnosed at ≥65 years of age and approximately a third Importantly, clinical outcomes in patients with therapy-related AML have
diagnosed at ≥75 years of age.2 Other registries report the median age of been shown to be significantly inferior (both in terms of relapse-free
diagnosis at 71 years.3 Thus, as the population ages, the incidence of survival [RFS] and overall survival [OS]) compared with patients with de
AML, along with myelodysplastic syndromes (MDS), seems to be rising. novo cases,8,15 except those with the therapy-related acute promyelocytic
leukemia (APL) subtype.7,16 The proportion of patients with unfavorable
Environmental factors that have long been established to increase the cytogenetics tends to be higher in the population with therapy-related
risks of MDS and AML include prolonged exposure to petrochemicals; AML. Even among patients with core binding factor (CBF) translocations,
solvents such as benzene; pesticides; and ionizing radiation.4 which are associated with favorable outcomes, patients with therapy-
related CBF-AML tend to do less well.17
Therapy-related MDS/AML (secondary MDS/AML) is a well-recognized
consequence of cancer treatment in a proportion of patients receiving The Panel for the NCCN Clinical Practice Guidelines in Oncology (NCCN
cytotoxic therapy for solid tumors or hematologic malignancies. Reports Guidelines®) for Acute Myeloid Leukemia convenes annually to update
suggest that therapy-related MDS/AML may account for 5% to 20% of recommendations for the diagnosis and treatment of AML in adults. These
patients with MDS/AML.5-7 The rate of therapy-related MDS/AML is higher recommendations are based on a review of recently published clinical
among patients with certain primary tumors, including breast cancer, trials that have led to significant improvements in treatment or have
gynecologic cancers, and lymphomas (both non-Hodgkin lymphoma and yielded new information regarding biologic factors that may have
Hodgkin lymphoma), largely owing to the more leukemogenic cytotoxic prognostic importance.
agents that are commonly used in the treatment of these tumors.7-10 Two
well-documented categories of cytotoxic agents associated with the Guidelines Update Methodology
development of therapy-related MDS/AML are alkylating agents and The complete details of the Development and Update of the NCCN
topoisomerase inhibitors.5,8,9 Treatment with antimetabolites, such as the Guidelines are available at [Link].

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Literature Search Criteria continue to use the terms men, women, female, and male when citing
Prior to the update of the NCCN Guidelines® for AML, an electronic search statistics, recommendations, or data from organizations or sources that do
of the PubMed database was performed to obtain key literature in AML not use inclusive terms. Most studies do not report how sex and gender
published since the previous Guidelines update, using the following search data are collected and use these terms interchangeably or inconsistently.
terms: acute myeloid leukemia or acute promyelocytic leukemia or blastic If sources do not differentiate gender from sex assigned at birth or organs
plasmacytoid dendritic cell neoplasm. The PubMed database was chosen present, the information is presumed to predominantly represent cisgender
as it remains the most widely used resource for medical literature and individuals. NCCN encourages researchers to collect more specific data in
indexes peer-reviewed biomedical literature.18 Results were confined to future studies and organizations to use more inclusive and accurate
the following article types: Clinical Trial, Phase II, Clinical Trial, Phase III; language in their future analyses.
Clinical Trial, Phase IV; Guideline; Practice Guideline; Meta-Analysis;
Initial Evaluation
Randomized Controlled Trial; Systematic Reviews; and Validation Studies.
The initial evaluation of AML has two objectives. The first is to characterize
The data from key PubMed articles as well as articles from additional the disease process based on factors such as prior toxic exposure,
sources deemed as relevant to these Guidelines and discussed by the antecedent myelodysplasia, and karyotypic and molecular abnormalities,
Panel during the Guidelines update have been included in this version of which may provide prognostic information that can impact responsiveness
the Discussion section. Recommendations for which high-level evidence is to chemotherapy, risk of relapse, and appropriateness for the use of
lacking are based on the Panel’s review of lower-level evidence and targeted therapies. The second objective focuses on patient-specific
expert opinion. factors, including assessment of comorbid conditions, which may affect an
individual’s ability to tolerate therapy. Both disease-specific and individual
Sensitive/Inclusive Language Usage patient factors are taken into consideration when deciding on a treatment
NCCN Guidelines strive to use language that advances the goals of strategy.
equity, inclusion, and representation.19 NCCN Guidelines endeavor to use
language that is person-first; not stigmatizing; anti-racist, anti-classist, Workup
anti-misogynist, anti-ageist, anti-ableist, and anti-weight-biased; and The evaluation and initial workup for suspected AML consists of a
inclusive of individuals of all sexual orientations and gender identities. comprehensive medical history and physical examination. Laboratory
NCCN Guidelines incorporate non-gendered language, instead focusing evaluations include a comprehensive metabolic panel and a complete
on organ-specific recommendations. This language is both more accurate blood count (CBC), including platelets and a differential of white blood
and more inclusive and can help fully address the needs of individuals of cells (WBCs). Serum uric acid and lactate dehydrogenase (LDH) have
all sexual orientations and gender identities. NCCN Guidelines will prognostic relevance and should be evaluated.20,21 Vitamin B12 and folic

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NCCN Guidelines Version 3.2026

Acute Myeloid Leukemia

acid should also be assessed to rule out nutritional deficiencies that can, symptomatic hyperleukocytosis, though data for benefit are limited.27,28 A
in extreme circumstances, be mistaken for a diagnosis of AML. retrospective study of three clinical trials compared the use of
cytoreduction with hydroxyurea or cytarabine versus no cytoreduction.27
BM core biopsy and aspirate analyses (including immunophenotyping by There was no significant difference in OS between the two groups, with
immunohistochemistry [IHC] stains with flow cytometry) and the analysis 30- and 60-day mortality rates of 2% and 7% versus 2% (P = .978) and
of chromosomal structural variations by cytogenetics, fluorescence in situ 6% (P = .652), suggesting that urgent cytoreduction with hydroxyurea or
hybridization (FISH), and next generation sequencing (NGS) are cytarabine while awaiting complete diagnostic information is a safe
necessary for risk stratification and to potentially guide therapy of AML. approach that may provide a bridge to appropriate incorporation of
targeted therapies or clinical trial enrollment.27 For patients who prefer not
In addition, several gene mutations are associated with specific prognoses
to receive blood transfusions as part of therapy, see Supportive Care for
in a subset of patients (category 2A) and may guide treatment decisions
Patients with AML Who Prefer Not to Receive Blood Transfusions for
(category 2B). Molecular analyses for lesions that allow risk stratification
general considerations, although the committee believes that in most
per ELN 2022 are recommended for all patients at diagnosis (See ELN
cases, good outcomes from these strategies are rare. If blastic
Risk Stratification by Biological Disease Factors for Patients with Non-APL
plasmacytoid dendritic cell neoplasm (BPDCN) is suspected, see
AML Treated with Intensive Induction Chemotherapy in the algorithm).22
Management of Blastic Plasmacytoid Dendritic Cell Neoplasm for workup,
Other genetic lesions may have therapeutic significance. The field of
diagnosis, and treatment recommendations.
genomics in myeloid malignancies and related implications in AML are
evolving rapidly. All patients should be tested for mutations, and multiplex Studies have reported on the prognostic impact of a number of molecular
gene panels and targeted NGS analysis are recommended for the ongoing abnormalities in patients with AML (see Risk Stratification by Biological
management of AML in various phases of treatment.22-26 Additional Disease Factors). Adequate marrow should be available at the time of
molecular and genetic testing for heritable hematologic malignancy diagnosis or relapse for molecular studies as per the institutional practice.
predisposition may be considered in a subset of patients. See MDS-D and Local pathologists should be consulted to discuss ways to optimize
MDS-E in the NCCN Guidelines for Myelodysplastic Syndromes (available sample collection and preservation. If molecular testing is not available at
at [Link]). the patient’s treatment center, evaluation at an outside reference
laboratory or transfer to another institution is recommended prior to
To appropriately stratify therapy options, test results of molecular and
performing the BM evaluation. Circulating leukemic blasts from peripheral
cytogenetic analyses of immediately actionable genes or chromosomal
blood may alternatively be used to detect molecular abnormalities.
abnormalities should be expedited. For patients with hyperleukocytosis,
hydroxyurea or cytarabine (0.5–2 g) may be considered prior to initiation of Extramedullary presentation, including central nervous system (CNS)
therapy. Leukapheresis may be considered for certain patients with disease, is uncommon in patients with AML. However, if extramedullary

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disease is suspected, an FDG-PET/CT should be considered. Patients Coagulopathy is common at presentation in many leukemias; it is
with significant CNS signs or symptoms at presentation should be therefore standard clinical practice to screen for coagulopathy by
evaluated using appropriate imaging techniques, such as radiography, CT, evaluating prothrombin time (PT), partial thromboplastin time (PTT), and
or MRI for the detection of intracranial bleeding, leptomeningeal disease, fibrinogen activity as part of the initial evaluation and before performing
or mass lesions in either the brain or spinal cord. If CNS hemorrhage is any invasive procedure. The need for a cardiac evaluation (eg,
suspected, a CT of the brain without contrast is recommended. If leukemic echocardiogram or multigated acquisition [MUGA] scan) should be
meningitis is suspected, a brain MRI with and without contrast is determined based on individual risk factors. Patients with a history or
recommended. However, if symptoms persist, and bleeding and mass symptoms of cardiac disease, prior exposure to cardiotoxic drugs or
lesions are excluded, the patient should have a lumbar puncture (LP) for thoracic RT, or those of an older age, should have an echocardiogram. In
diagnostic purposes once coagulopathy has been corrected, adequate patients who are younger and are otherwise asymptomatic with no history
platelet support is available, and the circulating disease has been cleared of cardiac disease, an echocardiogram can be considered. In cases of
through the initiation of systemic therapy. One dose of intrathecal (IT) patients who are acutely ill, treatment should not be delayed for an
chemotherapy (methotrexate, cytarabine, or a combination of these echocardiogram. A small study of 76 patients with cancer who were
agents) can be considered at the time of diagnostic LP. Routine screening screened for cardiac disease identified only 4 patients with cardiac
LPs are not warranted at the time of diagnosis in patients with AML who abnormalities. Of these 4 patients, the presence of cardiac disease did not
lack neurologic symptoms. Screening LPs should be considered at first change the course of treatment.29
remission in asymptomatic patients with WBC count >40 x 109/L at
diagnosis, extramedullary disease, high-risk APL, intraparenchymal Early referral to a transplant center is recommended and human leukocyte
hemorrhage at diagnosis, AML with FLT3 mutations or MLLT3::KMT2A antigen (HLA) typing should be performed in all patients with newly
fusion, monocytic differentiation, or mixed phenotype acute leukemia diagnosed AML for whom allogeneic HCT would be considered. HLA
(MPAL), particularly in patients not receiving doses of cytarabine ≥2 g/m2 typing of family members is recommended for these patients and tissue
(ie, patients who are not fit for intensive induction therapy). For patients typing should be broadened to include alternative donor searches. In
who present with solitary extramedullary disease (currently referred to as patients with non-favorable-risk AML, a donor search should begin while
myeloid sarcoma, and historically as granulocytic sarcoma, or chloroma) the patient is undergoing induction chemotherapy rather than waiting for
without overt marrow disease, the initial treatment should still be based on remission to be achieved.
systemic induction chemotherapy. RT or surgical resection may be
All patients should be counseled on infertility risk. Fertility perseveration
incorporated with systemic chemotherapy in emergent situations;
may be considered for appropriate patients (see NCCN Guidelines for
however, these modalities, if needed at all, should be optimally deferred
AYA Oncology, available at [Link]).
until after count recovery to avoid excess toxicity.

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Early integration of palliative care should also be considered. See NCCN abnormalities with t(15;17), t(8;21), and inv(16) or t(16;16) regardless of
Guidelines for Palliative Care (available at [Link]). A randomized the percentage of marrow blasts.
trial of 160 patients with AML assessed patient-reported outcomes in
those receiving integrated palliative and oncology care compared to In 2003, the International Working Group for Diagnosis, Standardization of
patients assigned to usual care.30 Patients assigned to integrated palliative Response Criteria accepted the cytochemical and immunophenotypic
and oncology care reported better quality of life (P = .048), less WHO criteria as the standard for diagnosing AML, including the reporting
depression (P = .04), less anxiety (P = .04), and less post-traumatic stress of myelodysplasia according to morphology.32 However, no evidence
disorder (PTSD) symptoms (P = .002) during intensive chemotherapy and shows that myelodysplasia represents an independent risk factor, likely
for up to 24 weeks. because it is frequently linked to poor-risk cytogenetics.

Diagnosis In 2008, WHO revised the diagnostic and response criteria for AML to
include additional recurrent genetic abnormalities created by reciprocal
Originally, the classification system for AML was defined by the French
translocations/inversions, and a new provisional category for some of the
American British (FAB) system, which relied on cytochemical stains and
molecular markers that have been found to have a prognostic impact.33
morphology to separate AML from acute lymphoblastic leukemia (ALL)
Additionally, the category of AML with recurrent genetic abnormalities was
and to categorize the disease based on degree of myeloid and monocytic
expanded to include the following: t(9;11)(p22;q23), t(6;9)(p23;q34)
differentiation. In 1999, WHO developed a newer classification system,
(provisional entity), inv(3)(q21 q26.2) or inv(3;3)(q21;q26.2) (provisional
which incorporates information from cytogenetics and evidence of
entity), and t(1;22)(p13;q13) (provisional entity), in addition to the
antecedent myelodysplasia, to refine prognostic subgroups that may
previously recognized t(8;21)(q22;q22); inv(16)(p13;1q22) or
define treatment strategies.31 During this transition from the FAB system to
t(16;16)(p13.1;q22); and t(15;17)(q22;q12) [APL subtype]. Other
the WHO classification, the percent blasts threshold for defining
provisional entities included AML with molecular abnormalities such as
high-grade MDS and AML was lowered. The FAB classification had set
mutated NPM1 or CEBPA genes (further information on these genetic
the threshold between high-grade MDS and AML at 30% blasts, whereas
lesions is provided later).33
the WHO classification lowered the threshold for diagnosing AML to ≥20%
blasts. This change was based on the finding that the biologic behavior
In 2016, WHO expanded the recurrent genetic abnormalities to include
(and survival outcomes) of the FAB MDS subgroup of “refractory anemia
two provisional categories, AML with BCR::ABL1 rearrangement and AML
with excess blasts in transformation (RAEB-T),” defined as patients with
with RUNX1 mutation.34 AML with BCR::ABL1 rearrangement is a rare de
20% to 30% blasts, was similar compared with that of patients with >30%
novo AML that may benefit from therapies that entail tyrosine kinase
blasts. In an appropriate clinical setting, the WHO classification system
inhibitors. AML with RUNX1 mutation is associated with a poorer
further allowed AML to be diagnosed in patients with abnormal
prognosis in patients treated with intensive chemotherapy.
hematopoiesis and characteristic clonal structural cytogenetic

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update, ALAL/MPAL were separated into those with defining genetic

In 2022, WHO eliminated blast cutoffs for most types of AML with defining abnormalities and those defined based on immunophenotyping only.
genetical alterations (excluding AML with BCR::ABL1 and AML with Lineage assignment criteria were refined to highlight principles of intensity
CEBPA mutation), though the 20% blast cutoff to differentiate MDS from and pattern. In addition, MPAL with ZNF384 rearrangement and ALAL with
AML was retained.35 AML with defining genetic abnormalities (eg, AML BCL11B rearrangement were added as subtypes of ALAL with defining
with NPM1 mutation, AML with RUNX1::RUNX1T1 fusion) was also genetic alterations.35 Due to the rarity of ALAL/MPAL, consultation with an
separated from AML defined by differentiation (eg, AML with maturation, experienced hematopathologist should be sought.
AML with minimal differentiation), eliminating the term AML, not otherwise
specified (NOS).35 A new section on AML with other defined genetic Currently, there are discrepancies between two recognized classification
alterations was also added, with incorporation of subtypes of AML with systems for AML, WHO and the International Consensus Classification
rare genetic fusions.35 In addition, the term AML with (ICC).35,36 For example, as noted previously, WHO 2022 eliminated blast
myelodysplasia-related changes (AML-MRC) was replaced with the term cutoffs for most types of AML with genetical alterations, while the ICC
AML, myelodysplasia-related (AML-MR). Updates were made to the retains a blast cutoff of ≥10% for AML with recurrent genetic abnormalities.
defining cytogenetic criteria for this type of AML and a mutation-based In addition, ICC 2022 created a separate category of AML with mutated
definition was introduced based on the following 8 genes: SRSF2, SF3B1, TP53 that supersedes their classifications of AML with myelodysplasia-
U2AF1, ZRSR2, ASXL1, EZH2, BCOR, and STAG2.35 related gene mutations and cytogenetic abnormalities. ICC also
recognized a new category of MDS/AML in 2022 that requires 10% to 19%
The accurate classification of AML requires multidisciplinary diagnostic blasts while WHO 2022 has retained the classification of MDS-increased
studies including morphology, immunophenotyping (IHC and flow blasts.
cytometry), and molecular genetics analysis. The latter should include the
analysis of structural variations by cytogenetics, FISH, or whole-genome The NCCN Guidelines do not advocate for one over another. Providers
sequencing and advanced molecular analysis techniques, as needed, to should exercise their best clinical judgment related to these discrepancies,
specify both translocations and gene mutations. The NCCN AML Panel and the NCCN Panel recommends classification systems be written to
suggests that complementary diagnostic techniques can be used at the allow for maximal clinical trial participation.
discretion of the pathology department of the individual institution. Some
Aberrant expression of differentiation antigens present at diagnosis may
cases may still show evidence of both myeloid and lymphoid antigen
allow tracking of residual blasts through flow cytometry in follow-up
expression on the leukemic cells and are defined as acute leukemias of
samples that may appear normal according to conventional morphology.
ambiguous lineage (ALAL) and MPAL, which were grouped into a single
Ongoing research is moving MRD monitoring to the forefront for all
category with the WHO 2022 update to reflect their overlapping
patients with AML (see Role of MRD Monitoring).
immunophenotypic and clinical characteristics.35 With the WHO 2022

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Risk Stratification by Biological Disease Factors 11 trial had similar results with 5-year survival rates for those with AML
Although cytogenetic and molecular information are often unknown when with favorable-, intermediate-, and poor-risk cytogenetics of 34%, 13%,
treatment is initiated in patients with de novo AML, karyotypes and and 2%, respectively.40 This last study included a population of patients
molecular markers represent the most important prognostic factors for ≥55 years of age, which is believed to attribute to the overall lower percent
predicting remission rates, relapse risks, and OS outcomes. The NCCN survival in all groups.
AML Panel has adopted the European LeukemiaNet (ELN)
The importance of obtaining adequate samples of marrow or peripheral
recommendations for risk stratification,22 which were updated in 2022 (See
blood at diagnosis for full karyotyping and FISH cytogenetic analysis for
ELN Risk Stratification by Biological Disease Factors for Patients with
the most common abnormalities cannot be overemphasized. Although
Non-APL AML Treated with Intensive Induction Chemotherapy in the
FISH studies for common cytogenetic abnormalities may allow for rapid
algorithm). ELN risk categories are based on results observed in patients
screening to identify either favorable-, intermediate-, or poor/adverse-risk
treated with intensive induction chemotherapy; however, as use of
groups, additional tests are needed to provide a full picture of the genetic
venetoclax-based regimens in the upfront setting has increased, data has
factors that contribute to risk (see Molecular Markers).
emerged that certain genetic abnormalities that confer poor outcomes with
intensive chemotherapy are associated with improved survival in the The presence of autosomal chromosome monosomies in AML has
setting of lower intensity therapy with venetoclax. emerged as an important prognostic factor associated with extremely poor
prognosis.41-43 Data from three large studies have identified monosomal
Cytogenetics
karyotypes (defined as ≥2 autosomal monosomies, or a single monosomy
In an analysis of data from pediatric and adult patients with AML
with an additional structural abnormality) as a subset of unfavorable
(n = 1612) enrolled in the United Kingdom Medical Research Council (UK
cytogenetic prognosticators. Although complex karyotype (≥3 clonal
MRC) AML 10 trial, the 5-year survival rates for those with AML with
cytogenetic abnormalities) and either monosomy 5 or monosomy 7 are
favorable-, intermediate-, and unfavorable-risk cytogenetics were 65%,
categorized as high-risk/poor/adverse cytogenetics, the presence of a
41%, and 14%, respectively.37 In a review of data from adult patients
monosomal karyotype was found to confer further negative prognostic
treated in a phase III Southwest Oncology Group (SWOG)/Eastern
influence within the high-risk group. This high-risk subgroup was first
Cooperative Oncology Group (ECOG) intergroup study (n = 609), the
identified in a joint study conducted by the Dutch-Belgian-Swiss
5-year survival rates for those with AML with favorable-, intermediate-, and
cooperative groups (HOVON/SAKK), which evaluated the correlation
adverse-risk cytogenetics were 55%, 38%, and 11%, respectively.38
between cytogenetics and OS outcomes in patients ≥60 years of age with
Similarly, in a retrospective review of adult patients with AML treated on
AML (n = 1975). The 4-year OS rate in patients with AML with monosomal
Cancer and Leukemia Group B (CALGB) protocols (n = 1213), the 5-year
karyotype was 4% compared with 26% in those with AML with complex
survival rates for patients with AML with favorable-, intermediate-, and
karyotype (but without monosomal karyotype).41
poor-risk cytogenetics were 55%, 24%, and 5%, respectively.39 The AML

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These findings were confirmed in subsequent analyses from other large Molecular Markers
cooperative group studies. In an analysis of data from patients treated on The intermediate-risk cytogenetic category is the most heterogeneous
SWOG protocols (n = 1344; age 16–88 years), 13% of patients were group in AML, because it encompasses both normal karyotype AML
found to have monosomal karyotype; nearly all of these cases (98%) (NK-AML) without gross structural abnormalities and those with structural
occurred within the unfavorable cytogenetics category.42 The incidence of changes that are considered neither adverse risk nor favorable. Based on
monosomal karyotype increased with age, from 4% in patients ≥30 years retrospective analyses of data from large cooperative group studies, 40%
of age to 20% in patients >60 years of age. Among the unfavorable to 50% of patients with de novo AML have normal karyotype, which is
cytogenetics cohort, the 4-year OS rate in the setting of monosomal associated with intermediate risk as measured in terms of survival
karyotype was 3% compared with 13% in the subgroup without outcomes.37,39 However, even in patients with NK-AML, clinical outcome is
monosomal karyotype. In patients with AML with monosomy 7, heterogeneous.
monosomal karyotype did not appear to influence outcomes (4-year OS,
0%–3%); the 4-year OS rates for patients with AML with inv(3)/t(3;3) and Identification of mutations that carry prognostic and therapeutic impact is
t(6;9) and those with AML without monosomal karyotype were 0% and 9%, rendering molecular profiling for all AML cases a standard part of the
respectively.42 In a retrospective study that evaluated the prognostic diagnostic workup. In addition to basic cytogenetic analysis, new
impact of monosomal karyotype in patients >60 years of age (n = 186) molecular markers can help refine prognostics groups, particularly in the
with unfavorable cytogenetics treated in a GOELAMS trial, the 2-year OS setting of a normal karyotype. These markers include NPM1, FLT3,
rate was significantly decreased among patients with AML with CEBPA, IDH1/2, DNMT3A, and KIT, TP53, RUNX1, and ASXL1 gene
monosomal karyotype compared with patients with AML without this mutations.44-56 Tests for these molecular markers are now available in
abnormality (7% vs. 22%; P < .0001). Similar outcomes were observed commercial reference laboratories and in referral centers. Therefore, it is
within the subgroup of patients with AML with complex karyotype.43 important for physicians to confer with the local pathologist on how to
optimize sample collection from the time of diagnosis for subsequent
These studies show that monosomal karyotype, independent of other molecular diagnostic tests. Testing for additional mutations may also be
adverse cytogenetic factors, confers very poor prognosis. In the NCCN recommended.
Guidelines, the presence of monosomal karyotype is included in the
poor/adverse-risk category of AML based on cytogenetics (see ELN Risk NPM1 Mutations
Stratification by Biological Disease Factors for Patients with Non-APL AML The NPM1 gene encodes a shuttle protein within the nucleolus of cells.
Treated with Intensive Induction Chemotherapy in the algorithm). Mutations in this gene occur in 28% to 35% of AML cases.54,57,58 The
NPM1 mutation has been shown to be associated with NK-AML with a
reported frequency of 48% to 53%.46,52,59 Isolated NPM1 mutation, which
localizes to the cytoplasm, confers a higher complete remission (CR) rate

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and improved event-free survival (EFS) and OS compared with patients shorter remission durations (eg, decreased DFS) and decreased OS
who have NK-AML with wild-type NPM1, resulting in outcomes similar to outcomes in some studies,48,62,66,69 other studies have reported no impact
patients with CBF-AML.46,47,52,54,55 However, a meta-analysis revealed that of FLT3-TKD on prognosis59,70,71 or even a favorable outcome on OS with
when adverse-risk cytogenetics are present, NPM1 mutation is associated FLT3-TKD mutations.72 In the latter study from the UK MRC, the 5-year
with poor outcome.60 OS rates among patients with and without FLT3-TKD mutations were 53%
versus 37%, respectively. Patients with a higher level of FLT3-TKD
FLT3 Mutations mutations (>25%) had a significantly higher 5-year OS rate compared with
The FLT3 gene encodes a receptor tyrosine kinase involved in those with lower levels of mutations, which showed an OS rate similar to
hematopoiesis. Two major classes of activating FLT3 mutations have that of patients without FLT3-TKD mutations (71% vs. 37%; adjusted
been identified in AML, which include the ITD and TKD point mutations.61- P = .004).72
66 FLT3-ITD mutations occur in approximately 30% of cases and are more

common than FLT3-TKD mutations, which occur in approximately 10% of The discrepant findings from these studies may be a result of important
cases.44,48,59,65-69 differences such as patient baseline characteristics, presence of
concurrent genetic lesions (eg, NPM1, CEBPA mutations), or inclusion of
Numerous studies have shown the negative prognostic influence of the APL subtypes. Studies have shown that FLT3-TKD mutations can
FLT3-ITD in patients with AML, resulting in shorter remission durations occur in a subgroup of patients with the prognostically favorable NPM1 or
(eg, decreased disease-free survival [DFS] in patients who achieve a CR) CEBPA mutations.59,71 Moreover, FLT3-TKD mutations as the sole genetic
and poorer survival outcomes compared with patients who have wild-type aberration or occurring concurrently with t(15;17)/PML::RARA (underlying
FLT3 AML.44,48,62,63,65,67,68,70 Among patients with FLT3-ITD and NK-AML, lesion in the APL subtype) or with FLT3-ITD (FLT3 double mutation) have
median OS from the time of diagnosis ranged from 6 to 12 months.44,48,65,68 been associated with poorer outcomes.59,71

Interestingly, a study in patients with NK-AML showed that prognosis was CEBPA Mutations
worse among patients with AML with FLT3-ITD without wild-type FLT3, Another mutation associated with prognosis is the CEBPA gene, a
compared with those with FLT3-ITD with wild-type FLT3 in the second transcription factor that plays a key role in the differentiation of
allele. The median OS among patients with FLT3-ITD in the absence of a granulocytes.50 Mutations in CEBPA have been reported in 7% to 11% of
wild-type FLT3 was only 7 months compared with 46 months among cases of AML (or 13%–15% of NK-AML cases) and have been associated
patients with wild-type FLT3 with or without FLT3-ITD.65 The FLT3-TKD with a favorable outcome (similar to outcomes in the setting of CBF
mutations predominantly occur independently of FLT3-ITD, and most translocations) with regard to increased remission duration and OS
frequently involve mutations in the D835 residue of a TKD. Although the outcome compared with wild-type CEBPA.49,58,59,73-75 One caveat identified
presence of FLT3-TKD mutations has been shown to be associated with was that the OS benefit with CEBPA was observed in the setting of double

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mutations (biallelic) of CEBPA but not in the setting of a single mutation of An additional retrospective analysis evaluated prognosis in 1028 patients
the gene. The 8-year OS rates reported in this study for patients with with AML with CEBPA mutations.78 The presence of CEBPA-bZIP
double-mutant–positive, single-mutation, and wild-type CEBPA genes mutations was associated with higher CR rates compared to AML without
were 54%, 31%, and 34%, respectively.74 The revised 2016 WHO CEBPA-bZIP mutations (90.2% for all age groups, 92.7% for patients ≤70
classification of AML redefined mutated CEBPA to indicate that biallelic years of age; P < .001). AML with CEBPA-bZIP mutation was also
mutations (and not single CEBPA mutations) are associated with improved associated with longer OS than AML without CEBPA-bZIP mutation (not
prognosis.34 reached [NR] vs. 945 days for all age groups; P < .001 and NR vs. 1296
days for patients ≤70 years of age and in the setting of intermediate-risk
More recent studies have investigated the prognostic significance of karyotype; P < .001). Similarly, AML with CEBPA-bZIP mutation was
CEBPA mutations or insertions/deletions in the bZIP region, irrespective of associated with longer median time to relapse than AML without
biallelic status.76-78 In a report from the Children’s Oncology Group (COG), CEBPA-bZIP mutation (NR vs. 612 days for all age groups; P < .001 and
CEBPA mutations in 2958 children and young adults with newly diagnosed NR vs. 671 days for patients ≤70 years of age and in the setting of
AML were evaluated, including a cohort with a single CEBPA-bZIP intermediate-risk karyotype; P < .001). The favorable prognostic
mutation and a cohort harboring a second CEBPA mutation significance of CEBPA-bZIP mutations was also observed in the setting of
(CEBPA-double-mutated [CEBPA-dm]).76 EFS was identical between the single-mutated CEBPA-sm (OS for all patients, P = .008; OS for patients
two CEBPA cohorts (64%) and OS was similar, at 81% for the CEBPA-dm ≤70 years of age and in the setting of intermediate-risk karyotype, P =
cohort and 89% for the CEBPA-bZIP cohort (P = .259). Outcomes were .008; cumulative incidence of relapse for all patients, P = .063; cumulative
worse in the CEBPA wild-type cohort, with EFS of 46% and OS of 61% incidence of relapse for patients ≤70 years of age and in the setting of
(both P < .001). This study highlighted favorable outcomes in the setting of intermediate-risk karyotype, P = .026). Multivariate analysis revealed that
CEBPA-bZIP domain mutations, irrespective of monoallelic or biallelic in patients ≤70 years of age, the presence of a CEBPA-bZIP mutation was
status. found to be the strongest predictor of improved OS (hazard ratio [HR],
0.3287; 95% CI, 0.1852–0.5834; P < .001)
A retrospective analysis of 240 adult patients with AML with CEBPA
mutations revealed improved EFS in the setting of CEBPA-dm and IDH1/2 Mutations
CEBPA-bZIP mutations compared to CEBPA mutations affecting the
Mutations in IDH1 have been reported in 6% to 9% of AML cases, with a
N-terminal transactivation domains (CEBPAsmTAD), at 20.7, 17.1, and 5.7
higher frequency among patients with NK-AML (8%–16%).58,79-84 IDH1
months, respectively.77 Similarly, OS was significantly improved in the
mutations were found to occur concurrently with NK-AML and NPM1
setting of CEBPA-dm and CEBPA-bZIP mutations compared to
mutations.79-82,84 Additionally, these mutations have been associated with
CEBPAsmTAD mutations, at 103, 63, and 13 months, respectively.
wild-type CEBPA and the absence of FLT3 abnormalities.82

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Findings from published reports on the prognostic effects of IDH1 IDH2 mutations,79,80,84 whereas others have reported favorable outcomes
mutations have been inconsistent. Although some studies showed no with IDH2 mutations.58,85 In one study, an association was found between
prognostic effect of IDH1 mutations on OS when considering all IDH IDH2 mutations and poorer prognosis in the subgroup of patients with
mutations (IDH1 and IDH2 combined) or in the overall patient NK-AML and otherwise favorable risk (NPM1 mutation without
population,79-82 IDH1 mutations correlated with significantly worse FLT3-ITD).84 However, in another study, the IDH2 mutation (restricted to
outcomes in the subgroup of patients with NK-AML with favorable- or IDH2-R140) was associated with improved survival among the overall
intermediate-risk disease.79,82,84 In the subgroup of patients <60 years of study population, and among the subgroup of patients with favorable risk
age with favorable-risk AML (NPM1 mutation without FLT3-ITD), IDH1 (intermediate-risk AML with NPM1 mutation without FLT3-ITD).58 In this
mutations were associated with a significantly decreased 5-year DFS rate latter subgroup, the presence of IDH1 or IDH2 mutations was associated
(42% vs. 59%; P = .046) and a trend for decreased OS rate (50% vs. with a significantly increased 3-year OS rate compared with NPM1
63%) compared with wild-type IDH.82 In another study, IDH mutations mutation without FLT3-ITD and without IDH1 or IDH2 mutations (89% vs.
(IDH1 and IDH2 combined) were associated with significantly inferior 31%; P < .0001). These results seem to suggest that in patients with
5-year RFS rates (37% vs. 67%; P = .02) and OS rates (41% vs. 65%; NK-AML without FLT3-ITD, NPM1 mutations confer a survival benefit only
P = .03) in the subgroup of patients with favorable-risk AML (NK-AML with in the presence of concurrent IDH mutations.58
NPM1 mutation without FLT3-ITD).84 This prognostic significance was
observed when IDH1 and IDH2 mutations were separately analyzed, The prognosis of IDH1- or IDH2-mutated AML is more recently being
although patient numbers were small for each subgroup and statistical impacted by the increasingly use of lower-intensity treatment options
significance was reached only for the RFS analysis.84 IDH1 mutations including venetoclax-based regimens and IDH1/2 inhibitors. In a
were also associated with worse EFS and OS outcomes among the retrospective study that evaluated 556 patients with newly diagnosed AML
subgroup of patients with intermediate-risk NK-AML (wild-type NPM1 with IDH1, IDH2, or NPM1 mutations, IDH1 mutations were associated
without FLT3-ITD).79 Mutations in IDH2 have been reported in 8% to 12% with an increased risk of death compared to IDH2 mutations; however, this
of AML cases,58,79,80,84,85 with a higher frequency of 19% among those with risk was partially negated by treatment with lower intensity, venetoclax-
NK-AML.82 The presence of IDH2 mutations was mutually exclusive with based regimens.86 OS rates were similar between patients with IDH2-
IDH1 mutation in nearly all cases.79,80,82 Mutations have been identified in mutated/NPM1-wild type, IDH2-mutated/NPM1-wild type, and IDH-wild
R172 and R140 of the IDH2 gene, with the R140 mutation occurring more type/NPM1-mutated AML that were treated with venetoclax-based
frequently.82,84,85 Interestingly, the IDH2-R172 mutation seemed to be regimens. While there was a trend towards improved survival with
mutually exclusive with NPM1 mutations and FLT3-ITD.82,84,85 intensive chemotherapy in the setting of IDH2-mutated AML with co-
occurring NPM1 mutations compared to without NPM1 mutations (P =.77),
Reports on the prognostic effect of IDH2 mutations have also been there was a significant improvement in survival with venetoclax-based
inconsistent. Some studies have reported the lack of prognostic value of therapy in the setting of IDH1-mutated AML with concurrent NPM1

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mutations compared to without NPM1 mutations (P = .0056). In another patients <60 years of age with NK-AML, a DNMT3A mutation was
study including 81 patients (median age, 74 years) with newly diagnosed associated with significantly decreased DFS (3-year rate, 20% vs. 49%;
AML treated with venetoclax combined with a hypomethylating agent P = .007) and a trend toward decreased OS.94 In this latter study,
(HMA) or LDAC, CR was achieved in 82% of patients with IDH1-mutated non-R882 DNMT3A mutations were significantly associated with poorer
AML and in 100% of patients with IDH-2 mutated AML.87 IDH1/2 inhibitors outcomes in patients <60 years of age but not R882 mutations; in contrast,
used alone or in combination with venetoclax have also improved DNMT3A-R882 mutations (but not non-R882 mutations) in patients ≥60
outcomes for IDH-mutated AML, with remission rates of >40% to 50% years of age were associated with significantly decreased DFS (3-year
single agent and >60% to 70% when combined with venetoclax. 88-91 rate, 3% vs. 21%; P = .006) and OS (3-year rate, 4% vs. 24%; P = .01).94
The authors concluded that the prognostic relevance of DNMT3A
DNMT3A Mutations mutations may depend on age and mutation type. Currently, the
The DNMT3A mutations have been reported in 18% to 22% of AML interactions of IDH1 or IDH2 and DNMT3 mutations with other molecular
cases,58,92,93 with a frequency of 29% to 34% in those with NK-AML.94-96 changes require further investigation to determine the prognostic value in
R882 is the most commonly mutated residue. This mutation has also been patients with NK-AML. Although commercial testing is available for FLT3
observed in conjunction with NPM1 mutations and FLT3 mutations.93,95,96 and CEBPA, most of the other genetic mutations are not available for
Data concerning the prognostic significance of DNMT3A mutations have testing outside of the research setting. Other candidate genes that are
thus far been conflicting. Some studies in the overall AML population and associated with an adverse impact on outcome are TET2 and RUNX1.97,98
in patients with intermediate-risk disease reported no significant effect of
DNMT3A mutations on survival outcomes,58,95 whereas other studies have KIT Mutations
shown a negative prognostic effect in the overall population or specific KIT mutations have been reported in approximately 20% of patients with
subgroups.92-94,96 Studies have shown significantly decreased OS CBF-AML.51,99 Studies have shown that KIT mutations are associated with
outcomes among patients with DNMT3A-mutated AML compared with decreased remission duration (eg, EFS and RFS) and decreased OS in
patients with DNMT3A wild-type AML (median OS, 12–21 vs. 40–41 patients with AML with t(8;21).45,51,53,99 However, the association of KIT
months).92,93 Significantly decreased OS with DNMT3A mutations has also mutations on CBF-AML with inv(16) is less clear than the data for t(8;21),
been reported in the subgroup of patients with NK-AML who have with several studies showing no association.45,99,100 In an analysis from the
wild-type NPM1 with or without FLT3-ITD, or NPM1 mutation in the German-Austrian AML Study Group, the frequency and prognostic impact
presence of FLT3-ITD, but not in the favorable subgroup with NPM1 of secondary genetic lesions were evaluated in patients with CBF-AML
mutation without FLT3-ITD.93 A study reported that in patients <60 years of who were treated in prospective trials (n = 176).101 Secondary
age with NK-AML, the presence of DNMT3A mutations was associated chromosomal abnormalities were found in 39% of cases, with the most
with significantly decreased OS compared with the wild-type gene (5-year common abnormalities being trisomy 22 (18%), trisomy 8 (16%), and 7q
OS rate, 23% vs. 45%; P = .02).96 Another study also showed that in deletion (5%). Secondary genetic lesions were found in 84% of cases,

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including mutations in RAS (53%; NRAS in 45%; KRAS in 13%), KIT RUNX1 Mutations
(37%), and FLT3 (17%; FLT3-TKD in 14%; FLT3-ITD in 5%; both The RUNX1 gene, encoding a myeloid transcription factor, is mutated in
mutations present in 2%). In addition, 25% of cases had more than one of approximately 10% of de novo AML cases and is associated with
these mutations. Mutations in KIT and RAS were less likely to occur adverse prognoses.24,111,112 In a study of adult patients with newly
concurrently, whereas mutations in KIT and FLT3 occurred concurrently in diagnosed AML (n = 2439), RUNX1 mutations were associated with age
6% of cases.101 Of these secondary genetic lesions, KIT mutation and ≥60 years, male gender, more immature morphology, and secondary
trisomy 22 were significant independent factors predictive of RFS in AML evolving from MDS. 112 RUNX1 mutations frequently co-occurred
multivariable analysis; FLT3 mutations, trisomy 22, and trisomy 8 were with epigenetic modifiers ASXL1, IDH2, KMT2A, and EZH2.112 In a study
significant independent predictors for OS.101 These studies demonstrate examining the impact of multiple RUNX1 mutations and loss of wild-type
the importance of secondary genetic mutations in the prognostic RUNX1 in AML, both loss of wild-type RUNX1 (OS, 5 months) and
classification of patients with otherwise favorable-risk CBF-AML (see ELN having ≥1 RUNX1 mutation (14 months) had an adverse impact on
Risk Stratification by Biological Disease Factors for Patients with Non-APL prognosis compared to 1 RUNX1 mutation (22 months; P < .002 and
AML Treated with Intensive Induction Chemotherapy in the algorithm). .048, respectively). 113

KMT2A Rearrangements However, in a retrospective study comparing outcomes for patients who
The mixed lineage leukemia gene (MLL; also called HRX, ALL-1, or received intensive induction (n = 149) vs. venetoclax/azacitidine (n =
currently KMT2A), located on chromosome 11q23, was initially recognized 143), the presence of a RUNX1 mutation favored venetoclax/azacitidine
as a recurrent locus of chromosomal translocation in AML and ALL.102,103 over intensive chemotherapy for CR/complete remission with incomplete
In one series of 1897 AML cases, the incidence of 11q23/KMT2A hematologic recovery (CRi) rate (P = .0397) and, in those ≥65 years of
rearrangements was 2.8%, and they were significantly higher in age, OS (P = .0166).114 In a separate cohort propensity matched for ELN
therapy-related AML than in de novo AML (9.4% vs. 2.6%; P < .0001).104 risk group, HCT status, and age, RUNX1 mutation again favored
The frequency of KMT2A rearrangements was also significantly higher in venetoclax/azacitidine over intensive chemotherapy for OS (P = .0125).
patients <60 years of age (5.3% vs. 0.8%; P < .0001).104 Depending on the In another retrospective study of patients with newly diagnosed AML who
fusion partner, the 11q23/ KMT2A rearrangement is associated with received low-intensity therapy with venetoclax, RUNX1 mutation was
intermediate to poor prognosis.105-107 NK-AML can be characterized by associated with superior OS, with a median OS of 25.1 months vs. 11.3
partial tandem duplication in the KMT2A gene (KMT2A-PTD),108-110 and months for RUNX1 wild type and 2-year OS rates of 54% vs 33%,
KMT2A-PTD is associated with reduced OS.58 respectively (P = .12).115 In contrast, RUNX1 mutation was associated
with inferior OS among patients who received intensive chemotherapy (P
= .02) or low-intensity therapy without venetoclax (P = .03).

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ASXL Mutations are more frequently associated with monosomal karyotype, and with
The ASXL1 gene, located on chromosome band 20q11, encodes a abnormalities in chromosomes 5 and 7. 125 In therapy-related AML, the
protein in the ETP genes family, which has functions in frequency of TP53 mutations is approximately 23%. 24 In a large analysis
transcription.116,117 ASXL1 mutations have been reported in of different hematologic malignancies including 858 AML cases, TP53
approximately 5% to 36% of de novo AML cases,113,118-121 and are mutations or deletions were observed in 7% and 1%, respectively, of the
associated with poor outcomes. 58,117,120 In an analysis of peripheral blood AML cases, and both TP53 mutations and deletions were observed in
samples from adult patients with AML (n = 423), ASXL1-mutated AML 5% of the cases.126 TP53 mutations were significantly more frequently
was observed to be more common in patients ≥60 years of age seen in patients ≥60 years of age when compared to patients <60 years
compared to patients <60 years of age (16.2% vs. 3.2%, respectively; P of age (9% vs. 2%; P < .001).126 Interestingly, compared to TP53
< .001). In patients ≥60 years of age, ASXL1 mutations were significantly deletions, TP53 mutations negatively impacted survival in AML (36
associated with wild-type NPM1, FLT3-ITD mutations, mutated CEBPA, months vs. 9 months, respectively; P < .001), suggesting the importance
and lower survival. 117 A large series analyzing younger adult patients of evaluating both TP53 mutation and deletion status. 126
with AML (range, 18–61 years) also observed that ASXL1 mutations Classification and Prognostic Relevance of Gene Mutations
were associated with age >61 years (P = .0001) and decreased EFS and The NCCN AML Panel adopted the 2022 ELN recommendations for risk
OS.122 In this study, ASXL1 mutations were also significantly associated stratification.22 Therefore, both NCCN and the ELN classify patients with
with RUNX1 (P = .0001).122 In another study analyzing biological and NK-AML, CBF-AML, mutated NPM1 without FLT3-ITD, or bZIP in-frame
prognostic subgroups based on mutations in ASXL1, RUNX1, DNMT3A, mutated CEBPA as having favorable-risk disease (see ELN Risk
NPM1, FLT3, and TP53 in patients with AML-MRC (n = 125), ASXL1 (n = Stratification by Biological Disease Factors for Patients with Non-APL AML
26; 21%) and TP53 (n = 28; 22%) were independently associated with Treated with Intensive Induction Chemotherapy in the algorithm).22,127 In
shorter OS (HR, 2.53; 95% CI, 1.40–4.6; P = .002).123 A more recent the updated 2022 ELN guidelines, FLT3-ITD allelic ratio is no longer taken
meta-analysis of 10 studies, including 5816 patients with AML, also into consideration; thus, AML with FLT3-ITD and no adverse-risk genetic
revealed worse OS for patients ≥60 years with ASXL1-mutated AML lesions is categorized as intermediate-risk, regardless of NPM1 mutation
compared to patients <60 years (HR, 2.86; 95% CI, 1.34–6.08; P = status.22 The reasoning behind this change was multifactorial, in part due
.006).124 to standardization issues with the FLT3-ITD allelic ratio assay, the impact
of midostaurin-based therapy in AML with FLT3-ITD without NPM1
TP53 Mutations
mutation, and the increasing role of MRD in AML management.
TP53 mutations have been reported in approximately 12% to 13% of
AML cases, and are associated with adverse risk and poor The 2022 ELN guidelines also categorize AML-MR gene mutations
outcomes.23,125,126 TP53 mutations are also most common in AML with (pathologic variants in at ≥1 of the following genes: ASXL1, BCOR, EZH2,
complex karyotype.125 However, in therapy-related AML, TP53 mutations

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RUNX1, SF3B1, SRSF2, STAG2, U2AF1, and/or ZRSR2) as adverse favorable prognosis for NPM1 (HR, 0.56 and 0.37, respectively) and
risk.22 CEBPA (HR, 0.56 and 0.42, respectively).

AML with mutated NPM1 and adverse-risk cytogenetics has also been The clinical significance of FLT3 mutations in patients with APL remains
categorized as adverse-risk, based on a pooled analysis of 2426 patients controversial. FLT3-ITD is associated with a higher incidence of several
that revealed poorer outcomes in those with NPM1-mutated, FLT3-ITD– hematologic features associated with APL (eg, higher WBC count,
negative (or low allelic ratio) AML with concurrent karyotype decreased fibrogen levels, higher Sanz risk score).128,129 However, there
abnormalities.22,60 For instance, adverse-risk chromosomal abnormalities remains a paucity of data to support a correlation of FLT3-ITD on OS and
were associated with lower CR rates (87.7% for normal karyotype, 86.0% rate of relapse.128,130,131 Although mutation status alone may not reflect
for aberrant intermediate karyotype, and 66.3% for adverse karyotype; P < patient outcome, there was a trend for decreased OS and EFS with a
.001), worsened 5-year OS (52.4% vs. 44.8% vs. 19.5%, respectively; P < higher FLT3-ITD mutational load suggesting that further studies are
.001), inferior EFS (40.6% vs. 36.0% vs. 18.1%, respectively; P < .001), in necessary to elucidate the clinical significance of this mutation.131
addition to higher 5-year relapse rates (43.6% vs. 44.2% vs. 51.9%, Conversely, FLT3-TKD has not been associated with the hematologic
respectively; P = .0012).60 features of APL and studies do not show a correlation of FLT3-TKD on
outcome.128,129,131-133
As seen from the earlier discussions, patients with NK-AML may present
with multiple molecular abnormalities. NPM1 mutations can occur The molecular markers discussed provide prognostic information that aid
concurrently with FLT3-ITD, and patients who have both genetic lesions risk stratification of patients with AML and may influence subsequent
have an outcome more similar to those with isolated FLT3-ITD treatment decisions. Research into basic leukemia biology using banked
mutations.46,52 Thus, NPM1 mutation confers favorable prognosis only in samples from clinical trials may provide keys to altered cellular pathways,
the absence of FLT3-ITD.59 Similarly, the benefit in OS outcomes seen which may lead to new treatment options. Risk stratification incorporating
with CEBPA mutations seems to be lost in the presence of concurrent molecular data along with cytogenetics is summarized in the guidelines
FLT3-ITD.74 As previously mentioned, studies suggest that FLT3-TKD in (see ELN Risk Stratification by Biological Disease Factors for Patients with
the presence of FLT3-ITD is associated with poorer prognosis. In contrast, Non-APL AML Treated with Intensive Induction Chemotherapy in the
FLT3-TKD may be associated with an additional favorable prognosis in the algorithm). The NCCN AML Panel recognizes that molecular genetics is a
presence of NPM1 or CEBPA mutations.71 A systematic review and rapidly evolving field in AML; therefore, risk stratification should be
meta-analysis in patients <60 years of age with NK-AML further modified based on continuous evaluation of evolving research data. Again,
established the prognostic role of these markers.56 OS and RFS predicted it is important for physicians to confer with the local pathologist on how to
unfavorable prognosis for FLT3-ITD (HR, 1.86 and 1.75, respectively) and optimize sample collection from the time of diagnosis for future molecular

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diagnostics in patients who have NK-AML or in other situations where Principles of Acute Myeloid Leukemia Treatment
molecular analysis may refine the prognostic category. Treatment of acute leukemia has historically been divided into induction
chemotherapy and postremission (eg, consolidation) therapy. The
Familial Genetic Alterations in AML
induction strategy, intensive chemotherapy or lower-intensity
Relative to sporadic cases of AML and MDS, the prevalence of known chemotherapy is influenced by individual patient characteristics such as
familial acute leukemia and MDS syndromes is felt to be rare, but with fitness, presence of comorbid conditions affecting performance status,
increasing recognition of germline mutations associated with preexisting myelodysplasia, and disease characteristics. For those eligible
predisposition to developing AML/MDS, identifying these syndromes is for intensive chemotherapy, obtaining a remission is the first step in
important for optimal care of patients and their relatives.134-137 The NCCN controlling the disease; however, it is also important for patients to emerge
Panel recommends additional molecular and genetic testing for heritable from the induction phase in a condition to tolerate subsequent, more
hematologic malignancy predisposition in a subset of patients, particularly intensive treatments during consolidation to achieve durable disease
in patients <50 years of age and those with a family history. A heritable control.
hematologic malignancy predisposition syndrome may account for
cytopenias with or without MDS in some patients, whether presenting to In patients fit for intensive induction therapy, strategies for consolidation
pediatric or adult care centers (eg, GATA2 deficiency syndrome, are based on the potential risk of relapse, with patients with higher risk
Shwachman-Diamond syndrome, telomere biology disorders). Functional disease receiving more intensive therapy. Cytogenetic and molecular
laboratory studies and constitutional (germline) genetic testing using large abnormalities are the most significant prognostic indicators; however,
NGS panels to include genes listed on MDS-E in the NCCN Guidelines for failure to achieve remission after 1 cycle of induction therapy or high tumor
Myelodysplastic Syndromes (available at [Link]), whole exome burden, defined as a WBC count ≥40 x 109/L,138 are included as poor-risk
or whole genome sequencing complemented with in silico copy number factors for long-term remission. Therefore, response is assessed based on
variant (CNV) calling, and/or laboratory analysis for CNVs, such as BM morphology and cytogenetic and molecular responses taken at
microarray testing, is recommended for certain patients. See Genetic several points during the course of treatment (see Response Criteria
Familial High-Risk Assessment: Hereditary Myeloid Malignancy Definitions for Acute Myeloid Leukemia and Monitoring During Therapy in
Predisposition Syndromes (MDS-D) and Gene Mutations Associated with the algorithm for definitions of CR and partial remission [PR] and disease
Hereditary Myeloid Malignancy Predisposition Syndromes (MDS-E) in the relapse). The use of flow cytometry and/or molecular methods to assess
NCCN Guidelines for Myelodysplastic Syndromes (available at MRD is emerging as a novel determinant to assess the depth of
[Link]). therapeutic response at the time of morphologic remission in patients with
AML (see Role of MRD Monitoring).

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For patients who initiate treatment with lower intensity therapy, such as reaction (PCR) to document disease burden and to ultimately confirm
azacitidine plus venetoclax, and achieve response, allogeneic HCT or molecular remission. As further emphasis of the cytogenetic attribute of
continuation of the lower intensity treatment regimen are subsequent APL, the 2016 WHO classification of myeloid neoplasms and acute
options. leukemia changed the definition of APL from the cytogenetic criteria of
t(15;17) to the molecular definition of “APL with PML::RARA” to be
Additionally, best supportive care may be an appropriate choice for certain inclusive of complex or cryptic rearrangements that lead to a functional
patients based on performance status, patient wishes, and disease transcription factor.34
characteristics.
APL may be de novo or therapy-related. Some of the following attributes
In some cases, patients who either received postremission therapy or of therapy-related APL (t-APL) were highlighted in a systematic review: 1)
those who did not may experience relapse, usually within 6 to 9 months the average age of diagnosis is 47 years with a higher incidence in
females; 2) the risk significantly declines 2 years after completion of
Finally, all patients require attentive supportive care related to the
treatment for the primary antecedent disease; 3) breast cancer,
underlying leukemia (ie, tumor lysis syndrome [TLS]) and the adverse
hematologic malignancy, multiple sclerosis, and genitourinary malignancy
effects of chemotherapy (see Principles of Supportive Care in the
are the most common antecedent diseases; 4) topoisomerase II inhibitors
algorithm).
and RT have the highest risk associated with developing t-APL; 5) the
Management of Acute Promyelocytic Leukemia clinicopathology of t-APL is not different from de novo APL; 6) the single
mutation t(15;17) is most common; and 7) the remission rate of t-APL is
APL is a particularly aggressive subtype of AML, comprising
80%, which is comparable to de novo APL.144 Therefore, t-APL and de
approximately 10% of AML cases. APL has a distinct morphology and
novo APL are treated similarly.
clinical presentation that may be associated with a high early death rate
due to potentially fatal coagulopathy.139-141 In an analysis of data (from The incorporation of all-trans retinoic acid (ATRA) and the use of risk
1992–2007) from the National Cancer Institute SEER registry, the stratification (based on WBC counts) in the management of APL has
age-adjusted annual incidence rate of APL was 0.23 per 100,000 largely improved outcomes for patients with this subtype. The unique
persons.142 The median age of APL diagnosis was 44 years, which is ability of ATRA to produce differentiation in APL blasts can reverse the
younger than that of patients with AML (median age, 67 years).142,143 APL coagulopathy, which is the major cause of death during induction. To
is cytogenetically distinguished by the t(15;17) chromosomal translocation. minimize early induction mortality due to coagulopathy, patients with a
The translocation of the PML gene on chromosome 15 to the RARA gene presumptive diagnosis of APL based on morphology, immunophenotype,
on chromosome 17 [ie, t(15;17)(q24.1;q21.1)] produces a PML::RARA and/or coagulopathy with a positive disseminated intravascular
fusion gene that can be quantitatively monitored using polymerase chain coagulation screen should promptly start ATRA. It is not necessary to wait

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for molecular testing or BM with cytogenetics to confirm the diagnosis. The There is a high frequency of FLT3 mutations in APL. In a systematic
initial clinical diagnosis of APL may be confirmed by FISH or PCR ideally review including 11 studies, FLT3-ITD frequency in APL occurred in about
in the peripheral blood and if not confirmed, ATRA may be discontinued 12% to 38% of cases and FLT3-TKD occurred in 2% to 20% of cases.154
and standard AML therapy initiated. Data are inconsistent about whether FLT3-ITD in APL results in a negative
prognosis. Several studies support this association and further correlate
Studies have demonstrated the necessity of early recognition and prompt FLT3-ITD with higher WBC counts, lower platelet counts, and the
initiation of ATRA based on a presumed diagnosis of APL to reduce the expression of the bcr3 PML::RARA fusion transcript.154-158 However, data
rate of early mortality. This is evidenced by early death rates below 10% from other studies have not shown a correlation.67,159 It has been proposed
reported for patients enrolled in clinical trials145-149 compared to the general that the discrepancy between studies may be at least partially resolved by
population where early mortality rates are still in excess of 15%.142,150-152 incorporation of a FLT3-ITD/wild-type ratio to measure the effect on
Data from the SEER registry measured 2-year survival and 30-day prognosis.131,160 Data showed that a ratio of >0.66 resulted in a shorter
mortality from 1977 to 2007 and found a 61% improvement in 3-year 5-year RFS.160 Similarly, shorter EFS and OS were observed in patients
survival per decade (P = .001) but a consistent rate of 30-day mortality with a ≥0.5 ratio compared to patients with <0.5 (EFS, P = .029; OS,
averaging 20%.150 Education of heath care providers to identify the first P = .084).131 In a retrospective study evaluating survival outcomes in
suspicion of APL may extend the improved outcomes seen in clinical trials cases of de novo APL with FLT3-ITD mutation, the presence of FLT3-ITD
to the general population if treatment is not delayed. mutation did not significantly impact OS (86% vs. 70%; P = .32) or EFS
(86% vs. 70%; P = .33).158 While data may correlate with prognosis, there
For patients with APL being treated at a community center, collaboration
currently remains no change in treatment course depending on expression
with a center with expertise has been shown to reduce induction
of FLT3-ITD and no recommendation to utilize a FLT3 inhibitor.
mortality.153 In this prospective trial, seven physicians with an expertise in
APL at six academic lead centers created a simplified APL treatment Induction Therapy for Patients with APL
algorithm. When patients with suspected APL presented to community
The evolution of treatment strategies for APL, built on clinical observation
centers, the APL experts provided community center physicians with a
and well-constructed clinical trials, represents one of the most rewarding
plan for an initial workup and therapy and were available for 24/7 support
sagas of modern hematology. An early study by a group in Shanghai
in the setting of complications or need for treatment modification. A total of
reported a CR rate of 85% in response to single-agent ATRA.161 The first
202 patients (median age, 53 years; range, 18–91 years) were enrolled in
North American Intergroup study confirmed a 70% CR rate with
the study, 62 at academic lead centers and 140 at community centers.
single-agent ATRA, which was equivalent to rates obtained with
Induction survival and 1-year OS were the same between patients treated
conventional doses of cytarabine and daunorubicin.162,163 Induction
at academic lead centers or community centers, at 97% and 94.5%,
regimens with ATRA combined with anthracyclines (with or without
respectively.
cytarabine) are associated with CR rates >90%, as demonstrated in

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several large cooperative group trials.164-167 Using ATRA-based induction induction and the increased rates of relapse), in the PETHEMA LPA 94
regimens followed by consolidation with regimens containing either ATRA trials, Sanz et al171,172 devised a risk stratification study based solely on
with anthracyclines, or cytarabine with anthracyclines, >80% of patients WBC and platelet counts at presentation. In this study, the induction
with APL can be cured of their disease.164,166-168 ATRA with arsenic trioxide regimen remained the same (AIDA), but ATRA was added to consolidation
(ATO) has resulted in improved outcomes for patients with APL.169 Risk cycles 1 to 3 for all but patients with low-risk disease (ie, WBC ≤10 x 109/L
stratification is a major consideration in the treatment of APL (see APL: and platelets >40 x 109/L). The CR rate in this trial was 90%, with inability
Classification and Treatment Recommendation in the algorithm).167 to achieve CR in the remaining 10% mostly attributed to hemorrhage,
Although clinical trials may group patients into those with low-, infection, or differentiation syndrome. Factors predictive of death during
intermediate-, or high-risk disease, the NCCN Panel categorizes patients induction were a WBC count >10 x 109/L, age >60 years, creatinine ≥1.4,
with APL as having low-risk disease (WBC count ≤10 x 109/L) or high-risk and male sex.171,172 In 2006, Ades et al173 reported the outcome of the
disease (WBC count >10 x 109/L). Patients with low-risk disease are French APL 2000 trial (n = 340) in which patients <60 years of age with
typically treated with less intensive consolidation regimens compared with WBC counts <10 x 109/L were randomized to receive ATRA (45 mg/m2)
regimens used for high-risk disease. and daunorubicin (60 mg/m2/day for 3 days) as induction therapy with or
without cytarabine (200 mg/m2/day for 7 days). Those randomized to
The French APL 93 trial compared sequential therapy of ATRA followed cytarabine for induction also received cytarabine during consolidation. 173
by chemotherapy (cytarabine and daunorubicin) with concurrent ATRA Patients with WBC counts >10 x 109/L or age >60 years received
plus chemotherapy. CR rates were 92% in both arms, but the relapse rate cytarabine. While the CR rates were similar between the randomized
at 2 years was 6% in the combined ATRA plus chemotherapy group groups (99% with cytarabine and 94% without cytarabine), those receiving
versus 16% for the sequential group.146,170 Induction regimens were pared cytarabine had a lower 2-year cumulative incidence of relapse (5% with
down to ATRA and idarubicin (the AIDA schedule) in both the Italian cytarabine and 16% without cytarabine) that translated into an improved
GIMEMA 93 trial and the Spanish PETHEMA LPA 94 trial, which produced EFS rate (93% with cytarabine and 77% with no cytarabine) at 2 years.
CR rates of 89% to 95%, raising the question of whether there was a need The 2-year OS rate was 98% with cytarabine and 90% without cytarabine.
for cytarabine in APL induction.145,149 In these trials, 51% to 61% of Among patients with a WBC count >10 x 109/L, the CR rate was 97%; the
evaluable patients achieved PCR-negative status for PML::RARA 2-year EFS rate was 89% for those <60 years of age and 79% for those
following induction therapy; 93% to 98% were PCR-negative after >60 years of age.173 A report of a joint analysis of the outcomes in the
consolidation. The estimated 2-year EFS rate was 79% in both trials.145,149 PETHEMA 99 and the French APL 2000 trials in patients <65 years of age
In the PETHEMA trial, the 2-year OS rate was 82%.149 showed that in patients with a WBC count <10 x 109/L, CR rates were
similar, but the relapse rates at 3 years were lower in the PETHEMA trial,
Following observational data that correlated elevated WBC counts and
which used AIDA and no cytarabine during induction (with ATRA during
high-risk disease (based on both the higher number of deaths during
consolidation), than in the APL 2000 cytarabine-containing regimen (4%

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vs. 14%; P = .03).165 However, for patients with a WBC count >10 x 109/L, low- and high-risk APL. With a median follow-up of 47.6 months (range,
the cytarabine-containing protocol resulted in higher CR (95% vs. 84%; 2.7–159.7 months), the 5-year EFS, DFS, and OS rates for patients with
P = .018) and 3-year OS rates (91.5% vs. 81%; P = .026).165 The second low-risk disease were 87%, 99%, and 89%, respectively, and for the
North American Intergroup trial also used ATRA (45 mg/m2), daunorubicin patients with high-risk disease were 81%, 89%, and 86%, respectively.179
(50 mg/m2/day for 4 days), and cytarabine (200 mg/m2/day for 7 days) with These data suggested that ATRA and ATO combined with GO is feasible
a similar initial CR rate of 90%.166 Consolidation in this trial differed in that and elicits durable responses. In another study by Estey et al,180 patients
2 cycles of ATO were given following induction and prior to the final 2 with APL were treated with ATRA and GO (9 mg/m2 on day 1 or 5 of
cycles of anthracycline. induction therapy). Patients with WBC counts of >30 x 109/L also received
idarubicin (12 mg/m2/day on days 1–3). In this study (n = 19), the CR rate
ATO has been found to be a potent promoter of apoptosis in APL in all patients who received ATRA plus GO and idarubicin was 84%, and
cells.174,175 In 2004, Shen et al176 first published outcomes using 88% in patients who received ATRA plus GO.180 However, clinicians
single-agent ATRA, single-agent ATO, or the combination of both drugs.176 should be aware of possible adverse events associated with GO including
While CR rates exceeded 90% in all three treatment arms, the decline in sinusoidal obstruction syndrome (SOS) similar to which is described in the
quantity of PML::RARA fusion transcripts (as measured by quantitative transplant setting.181,182
PCR) was significantly higher with the combination. Time to hematologic
response was more rapid and RFS (after a median follow-up of 18 A phase II study (APML4) from Australia/New Zealand evaluated an
months) was improved with the combination regimen compared with the induction regimen with ATO added to a backbone of AIDA in patients with
monotherapy regimens.176 Subsequently, Estey et al177 used a similar previously untreated APL (n = 124; median age, 44 years).183 Patients
combination of ATRA and ATO to treat patients with low-risk APL.177 received 1 cycle of induction therapy with ATRA (45 mg/m2 days 1–36 in
Patients with high-risk disease in the same study were treated with ATRA divided doses), age-adjusted idarubicin (6–12 mg/m2 days 2, 4, 6, and 8),
and ATO combined with gemtuzumab ozogamicin (GO; 9 mg/m2 on day 1 and ATO (0.15 mg/kg days 9–36 as a 2-hour IV infusion). All patients
of induction therapy). In a report from this study (n = 82), the CR rate in all received prednisone (1 mg/kg/day for at least 10 days) regardless of initial
patients was 92% (95% for low-risk and 81% for high-risk disease) and the WBC count as prophylaxis for differentiation syndrome.183 The most
estimated 3-year OS rate was 85%.178 The authors suggested that ATRA common grade 3 or 4 non-hematologic adverse events during induction
combined with ATO, with or without GO, may be an alternative to included infections (76%; including febrile neutropenia), hepatic toxicity
conventional chemotherapy in patients with untreated APL. A subsequent (44%), gastrointestinal toxicity (28%), metabolic abnormalities (16%), and
study examined the long-term outcomes of patients with newly diagnosed prolonged QTc interval (14%); grade 3 or 4 differentiation syndrome
APL treated with ATRA and ATO with or without GO [9 mg/m2 on day 1 of occurred in 14% of patients. Patients with a CR to induction received
induction therapy for high-risk APL patients] (n = 187; median age, 50 consolidation with 2 cycles of ATRA and ATO. Maintenance therapy was
years; range, 18–84 years).179 The CR rate was 96% for patients with both administered for 2 years and consisted of eight 3-month cycles of

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treatment with ATRA, oral methotrexate, and 6-mercaptopurine.183 Grade and Arm B (100% vs. 95%). After a median follow-up period of 34.4
3 or 4 adverse events occurred primarily during induction (as above); the months, the 2-year EFS rate was significantly higher in Arm A compared
most common grade 3 or 4 events during consolidation (cycle 1) included with Arm B (97% vs. 86%; P < .001 for noninferiority; P = .02 for
infections (19%) and hepatic toxicity (12%), and no deaths occurred during superiority). The 2-year OS probability was also significantly higher in Arm
consolidation cycles. The hematologic CR rate after induction was 95%; A compared with Arm B (99% vs. 91%; P = .02). Four patients in Arm B
early death (during induction) occurred in 3% of patients. The 2-year DFS died during induction therapy (2 deaths were caused by differentiation
and failure-free survival rates were 97.5% and 88%, respectively. The syndrome). One patient in Arm A and 3 patients in Arm B died during
2-year OS rate was 93%.183 This trial enrolled 24 patients who were consolidation. Grade 3 or 4 neutropenia and thrombocytopenia lasting >15
considered to have high-risk disease per the Sanz criteria. OS was not days were significantly more frequent in Arm B compared with Arm A
affected by the Sanz risk group (P[trend] = .17), although a correlation was throughout induction and consolidation cycles. Grade 3 or 4 hepatic
made with the failure-free survival rate (P[trend] = .03). This association may toxicities also occurred more frequently in Arm A compared with Arm B
be attributed to the method of analysis that included patients who withdrew (63% vs. 6%; P < .001).169 Health-related quality-of-life outcomes were not
from the study due to declining treatment or excessive toxicity, as well as significantly different between treatment groups except for fatigue severity.
patients who had relapse, death, or who were unable to achieve a There was improvement in fatigue following induction in the ATRA plus
molecular CR. ATO group (P = .022), though the benefit was negligible by third
consolidation (P = .660).184 This randomized study showed noninferiority
In a phase III randomized trial of the Italian-German Cooperative Group, of an ATRA plus ATO regimen compared with AIDA, which may allow for
induction with ATRA combined with ATO was compared with the AIDA elimination of chemotherapy agents in the initial treatment of patients with
regimen in patients with newly diagnosed, low-, or intermediate-risk APL non–high-risk APL.
(n = 162; APL0406 study).169 Patients in Arm A received ATRA (45 mg/m2)
plus ATO (0.15 mg/kg) daily until CR, then ATO 5 days per week for 4 Data from the randomized phase III AML17 trial compared ATRA plus
weeks every 8 weeks for a total of 4 courses, and ATRA daily for 2 weeks ATO to AIDA in a cohort of 235 patients. ATRA was given to both groups
every 4 weeks for a total of 7 courses. Patients in Arm B received in daily divided oral doses (45 mg/m2) until remission or until day 60, after
standard AIDA induction followed by consolidation with 3 cycles of which patients were treated 2 weeks on then 2 weeks off.185 The AIDA
anthracycline-based consolidation combined with ATRA and then group received 4 cycles of consolidation consisting of 12 mg/m2 IV
maintenance comprising low-dose chemotherapy and ATRA.168 In idarubicin on days 2, 4, 6, and 8 in the first course; 5 mg/m2 IV idarubicin
addition, all patients received prednisone (0.5 mg/kg/day from day 1 until on days 1 through 4 in course 2; 10 mg/m2 mitoxantrone on days 1
the end of induction) as prophylaxis for differentiation syndrome. The through 4 in course 3; and 12 mg/m2 idarubicin on day 1 of the final
primary endpoint of this study was the 2-year EFS rate. Among patients course.185 The ATRA plus ATO treatment entailed 0.3 mg/kg IV ATO on
with evaluable data (n = 156), CR rates were not different between Arm A days 1 through 5 in the first week and 0.25 mg/kg twice weekly in weeks 2

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through 8 in course 1 and then twice weekly in weeks 2 through 4 during components of the protocol and not mix induction regimens from one trial
courses 2 through 5. Patients with high-risk disease could receive an initial with consolidation regimens from another trial. With the advances in
dose of GO (6 mg/m2 IV). Comparison between the ATRA plus ATO group treatment regimens, the Panel emphasizes the importance of receiving
and the AIDA group showed a higher 4-year EFS (91% vs. 70%; P = .002) treatment from an established treatment center for the monitoring and
and lower 4-year cumulative incidence of morphologic relapse (1% vs. treatment of adverse events, regardless of risk stratification. However, as
18%; P = .0007) for ATRA plus ATO compared to AIDA, though no previously noted, for patients with APL being treated at a community
statistically significant difference in 4-year survival was seen (93% vs. center, collaboration with a center with expertise has been shown to
89%; P = .25). Quality of life was equivalent in the treatment groups for reduce induction mortality.153 The recommendations within the guidelines
both patients with high- and low-risk disease as measured by the primary are broken down by: 1) risk classification using WBC count (cutoff of 10 x
outcome of global functioning (effect size, 2.17; 95% CI, -2.79 to 7.12; 109/L) at diagnosis; and 2) whether patients with high-risk disease have
P = .39).185 However, the data from the trial measured more supportive cardiac issues. It is important for the management of APL that regimens
care treatments and higher liver toxicity with AIDA. Treatment schedule containing ATRA and ATO be administered unless there is a
differed from previous trials by moving to a higher dose of ATO given at a contraindication based on extenuating patient circumstances.
lower frequency of twice weekly. Though data are limited to this single
trial, the NCCN AML Panel recognizes that this alternative dosing For patients with low-risk disease (WBC counts ≤10 x 109/L), for initial
schedule may be more manageable for patients who have difficulty getting induction the Panel recommends ATRA plus daily ATO (0.15 mg/kg)169; or
to the clinic. ATRA plus intermittent ATO (0.3 mg/kg)185 as category 1, preferred
regimen options. If ATO is contraindicated or not available, the Panel
All five induction regimens discussed above offer excellent outcomes. recommends AIDA (ATRA + idarubicin)167 (category 1); ATRA plus a
These regimens are ATRA plus ATO (0.15 mg/kg; with the addition of single dose of GO (6 or 9 mg/m2 on day 5)180,185; or enrollment in a clinical
idarubicin for patients with high-risk disease only); ATRA plus trial.
daunorubicin (50 mg/m2 daily for 4 days) plus cytarabine; ATRA plus
daunorubicin (60 mg/m2 daily for 3 days) plus cytarabine; AIDA; or ATRA For patients with high-risk disease (WBC counts >10 x 109/L), the NCCN
plus ATO (0.3 mg/kg). Choice of regimen will be influenced by risk group, AML Panel historically recommended a regimen that included cytarabine
fitness, and cardiovascular risks. along with ATRA plus daunorubicin (PETHEMA LPA 99 trial) over AIDA
(APL 2000 trial) because of higher CR and 3-year OS rates.165,167 To
NCCN Recommendations for Induction Therapy for Patients with APL improve patient outcome, the PETHEMA LPA 99 trial and the GIMEMA
The NCCN AML Panel recommends that patients with APL be treated AIDA-0493 study were modified to incorporate the combination of ATRA
according to one of the regimens established from the clinical trials; with cytarabine either during induction (LPA 2005)167 or during
importantly, one should use a regimen consistently through all consolidation (AIDA-2000).168 The improved outcomes in both of these

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studies suggest a supra-additive effect with ATRA plus cytarabine, tapering schedules. For patients who develop differentiation syndrome on
independent of the anthracycline. The APML4 trial has shown the benefit these regimens despite prednisone prophylaxis, prednisone should be
of induction that includes ATRA and ATO. Unlike the other regimens, the stopped and replaced with dexamethasone 10 mg twice daily (see
APML4 trial does not use cytarabine during induction. In light of these Principles of Supportive Care for APL in the algorithm). If using non-ATO
studies, the Panel recommends initial induction with these preferred regimens, either steroid regimen is acceptable although there may be a
regimens: ATRA and idarubicin and ATO,183 or ATRA and either daily or slight preference for dexamethasone for high-risk disease. While the Panel
intermittent ATO with a single dose of GO (9179 mg/m2 or 6185 mg/m2 that recommends the use of prophylactic corticosteroids, it is acknowledged
may be given on day 1, day 2, day 3, or day 4). Other recommended that corticosteroids may not be necessary in all patients and that the
regimens include ATRA plus daunorubicin and cytarabine163,165,166; AIDA optimal duration of steroid prophylaxis is unknown. Some institutions may
alone167; or enrollment in a clinical trial. advocate a low threshold for initiating corticosteroids instead of defaulting
to prophylaxis. Until more studies are done to address this issue,
In patients with high-risk disease with cardiac issues that include low consistency to the selected protocol should be sought.
ejection fraction, the Panel recommends initial induction with ATRA and
either daily or intermittent ATO with a single dose of GO (9 mg/m2 on day Consolidation Therapy for Patients with APL
1179 or 6 mg/m2 on day 1185). If the patient with high-risk disease develops Because the differentiating action of ATRA occurs over a longer time
a prolonged QTcF, the Panel recommends initial induction with ATRA and period than the cytoreduction of conventional chemotherapy, early marrow
a single dose of GO 9 mg/m2180 or 6 mg/m2185 on day 1; ATRA plus evaluations for hematologic response at days 7 to 14 post induction are
daunorubicin and cytarabine163,165; or AIDA alone.167 For cytarabine- misleading and may lead to overtreatment. Marrow evaluation is not
containing regimens, dose adjustments of cytarabine may be needed for recommended until recovery of blood counts, usually 4 to 6 weeks after
patients >60 years of age or those with renal dysfunction. induction. Cytogenetic analysis is usually normal by this point, but
molecular remission often requires at least 2 cycles of consolidation. Thus,
The sudden onset of differentiation syndrome and the severity of the
the first assessment of molecular remission should not be performed prior
complications have resulted in the frequent use of preemptive
to count recovery. At count recovery following induction therapy, patients
dexamethasone because there are no markers to predict its development.
should proceed with consolidation. For patients with low-risk disease, if a
The Panel recommends the prophylactic administration of corticosteroids
patient is cytopenic on days 28 to 35, BM biopsy and aspirate is
in patients with a WBC count >10 x 109/L (or in patients receiving induction
recommended to document <5% blasts and no abnormal promyelocytes
with both ATRA and ATO, regardless of WBC count) to prevent
and to assess whether the marrow is suppressed and to determine
differentiation syndrome. The ATRA plus ATO regimens defined by
whether ATRA and ATO should be held to allow count recovery. If,
Lo-Coco et al169 or Iland et al183,186 use prednisone 0.5 mg/kg as
however, blood counts have recovered by this time point, a BM biopsy
prophylaxis for differentiation syndrome but with differing durations and
may be considered to document <5% blasts and no abnormal

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promyelocytes, but is optional. For patients with high-risk disease, LP improved relapse and DFS rates, there were significant rates of relapse
should be considered at count recovery following induction therapy, before (26%) and 3-year DFS (77%). In the PETHEMA LPA 2005 study, both
proceeding with consolidation.187 Many consolidation regimens involve ATRA and cytarabine were included in the anthracycline-containing
high cumulative doses of cardiotoxic agents. It is therefore important to consolidation regimen for the patients with high-risk disease.167 In this
assess the cardiac function of patients prior to initiating each high-risk group, the 3-year relapse rate was reduced to 11% (compared
anthracycline- or mitoxantrone-containing consolidation cycle. with 26% from the LPA 99 study), and the 3-year DFS and OS rates were
Consolidation regimens using ATO will require monitoring of the QTc 82% and 79%, respectively. The LPA 2005 trial also began to approach
interval and optimizing electrolytes (see Principles of Supportive Care for the question of how to reduce toxicity during consolidation therapy in
APL in the algorithm and Supportive Care for Patients with APL in the patients with low- and intermediate-risk disease by dose reduction of
discussion). mitoxantrone (from 10 mg/m2/day for 5 days to 10 mg/m2/day for 3 days in
cycle 2) and a small reduction of idarubicin dose for low- and
According to the package insert, for QTc >450 msec for males and 460 intermediate-risk groups (from 7 mg/m2/day for 4 days to 5 mg/m2/day for
msec for females, corrective measures should be initiated and 4 days in cycle 1 and from 2 doses of 12 mg/m2/day to 1 dose of 12
reassessment with serial electrocardiograms (ECGs) should be performed mg/m2/day in cycle 3). Based on results in the low- and intermediate-risk
prior to ATO treatment. groups, lowering the dose of mitoxantrone resulted in reduction of toxicity
and hospital stay while maintaining the anti-leukemic activity (compared
The goal of consolidation therapy for APL is a durable molecular
with results in low- and intermediate-risk groups from the LPA 99 study).
remission. Data from the two sequential PETHEMA trials,149,171,172 which
With the consolidation regimens evaluated in the LPA 2005 study,
produced the current risk model, were used to construct subsequent trials
outcomes were similar between low-risk and intermediate-risk groups with
that intensify therapy for the high-risk groups. In the second PETHEMA
regard to the 3-year cumulative incidence of relapse (6% vs. 6%), the
trial (LPA 99), 15 days of ATRA (45 mg/m2) were added to each of 3
3-year DFS (93% vs. 94%), and the 3-year OS rate (96% vs. 93%).167
cycles of anthracycline-based consolidation therapy. Overall, relapse rates
were reduced from 20% to 9% with the incorporation of ATRA in the The AIDA-2000 trial of the Italian GIMEMA group has confirmed that
consolidation phase.171 For the low-risk group, there was no difference in inclusion of ATRA in consolidation significantly improved outcome, most
relapse rate (3%–6%) or in 3-year DFS rate (93%–97%) between the notably for patients with high-risk disease; the high-risk group received a
ATRA group compared with a similar consolidation without ATRA in the consolidation regimen containing ATRA and cytarabine along with
LPA 94 trial.171 Among patients with intermediate-risk disease, the relapse anthracyclines.168 In this study, the 6-year cumulative incidence of relapse
rate was reduced from 14% to 2.5% with the incorporation of ATRA; the was 9% for patients in the high-risk group; the 6-year DFS and OS rates in
3-year DFS rate was 97% with ATRA consolidation versus 82% in this group were 84.5% and 83%, respectively. In the AIDA-2000 study, the
historical controls.171 Although the addition of ATRA to the high-risk group low- and intermediate-risk groups were collapsed into a single category,

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and received the same consolidation regimen with ATRA, mitoxantrone, directly after achieving remission.166 In this trial, patients who were
and idarubicin (ATRA 45 mg/m2 for 15 days + idarubicin 5 mg/m2 for 4 randomized to receive 2 courses of 25 days of ATO (5 days a week for 5
days in cycle 1; ATRA for 15 days and mitoxantrone 10 mg/m2/day for 5 weeks) immediately after entering CR followed by the standard
days in cycle 2; and ATRA for 15 days and idarubicin 12 mg/m2 for 1 dose post-remission regimen with 2 more courses of ATRA plus daunorubicin,
in cycle 3). For patients in the low- and intermediate-risk group, the 6-year had a significantly higher 3-year EFS rate (80% vs. 63%; P < .0001) and
cumulative incidence of relapse was 11%; the 6-year DFS and OS rates in improved OS outcomes (3-year OS rate, 86% vs. 81%; P = .06) compared
this group were 86% and 89%, respectively.168 with those who received only the 2 courses of ATRA plus chemotherapy.
The 3-year DFS rate was also significantly improved with the addition of
In the European APL 2000 trial, which randomized daunorubicin with or ATO (90% vs. 70%; P < .0001). The favorable outcomes with the
without cytarabine for the consolidation phase (no ATRA during incorporation of ATO were observed in patients with low-/intermediate-risk
consolidation) for the low- and intermediate-risk (ie, “standard risk”) and high-risk disease.166 Notably, in the high-risk group, DFS outcomes
groups, the 2-year EFS rate was higher with the addition of cytarabine.173 with the addition of ATO were similar to the DFS rate observed for the
Long-term follow-up from this study showed that in patients with standard- low-/intermediate-risk group, suggesting that ATO may help to overcome
risk disease, the addition of cytarabine substantially reduced cumulative the negative prognostic influence of high-risk disease. The overall
incidence of relapse (7-year relapse rate, 13% vs. 29%; P = .0065) and outcomes do not appear to be superior to the less complex consolidation
increased 7-year EFS rates (83% vs. 65%; P = .0029) compared with the schedules used in either of the two most recent European trials for
regimen without cytarabine.188 A poorer response was seen in patients patients in the low- and intermediate-risk groups, but did appear to offer
who did not receive cytarabine despite maintenance treatment of improved survival for patients with high-risk disease. However, the
continuous 6-mercaptopurine plus methotrexate and intermittent ATRA. consolidation phase in the North American Intergroup protocol is longer
Furthermore, all patients with high-risk disease received cytarabine during and may be difficult for some patients to complete.
induction and consolidation resulting in a 7-year relapse rate, EFS rate,
and OS rate of 7.1%, 82.2%, and 87.6%, respectively, an outcome that The French APL 2006 randomized trial evaluated the role of ATO in
was slightly improved over patients with standard-risk disease treated consolidation therapy for previously untreated APL, both for patients with
without cytarabine. Although the results of the European APL 2000 trial standard-risk disease (WBC count <10 x 109/L; ATO vs. cytarabine vs.
are limited by the use of a single anthracycline in all study arms, the data ATRA, all in combination with idarubicin during consolidation) and patients
support the use of cytarabine in standard-risk APL with the anthracycline with high-risk disease (WBC >10 x 109/L; cytarabine vs. ATO + cytarabine,
daunorubicin. both in combination with idarubicin during consolidation).189,190 Based on
results from the interim analysis (median follow-up, 22–24 months), all
The North American Intergroup trial also focused on decreasing toxicity regimens resulted in CR rates exceeding 95% with low rates of relapse.
during consolidation by incorporating ATO into the consolidation schema However, the use of ATO in the consolidation phase was associated with

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NCCN Guidelines Version 3.2026

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longer durations of myelosuppression, which necessitated a protocol with no differences in 2-year DFS (97% vs. 90%; P = .11) or cumulative
amendment to further reduce the chemotherapy dose in patients receiving incidence of relapse (1% vs. 6%; P = .24) between treatment arms.169
ATO.189 In the second interim analysis, the only change was a decrease of
idarubicin during second consolidation. Data from this analysis show a In the French APL 93 trial, a 4% incidence of CNS relapse was reported in
99.4% CR across all groups encompassing a total of 347 patients.190 patients with WBC counts >10 x 109/L. In the APL 2000 trial, that high-risk
While the 2-year EFS and OS rates were >95% for all three groups, there population received five doses of IT chemotherapy using a combination of
was a reduction of myelosuppression in the group treated with AIDA methotrexate, cytarabine, and steroids, upon count recovery following
compared to idarubicin plus cytarabine and idarubicin plus ATO, which induction therapy. These patients also received a higher dose of
had similar durations.190 The potential benefits of the use of ATO or ATRA cytarabine (2 g/m2) during consolidation (in cycle 2) as compared with 1
in consolidation may rest in a lower risk for long-term cardiovascular g/m2 in the APL 93 trial. There were no cases of CNS relapse in the APL
complications and a lower risk for secondary myelodysplasia. 2000 trial, compared with 5 cases in the APL 93 trial. While the original
treatment protocol on APL 2000 used high-dose cytarabine (HiDAC) in the
In the phase II APML4 study from Australia/New Zealand, 2 cycles of ATO second cycle of consolidation, some investigators suggest the use of
and ATRA were used as consolidation in patients who achieved a CR after HiDAC earlier, particularly in those patients who are not receiving IT
a 3-drug induction with ATRA, idarubicin, and ATO.183 Among the patients therapy for CNS prophylaxis.
who proceeded to consolidation (n = 112), all achieved molecular
NCCN Recommendations for Consolidation Therapy for Patients with APL
remission, and the 2-year DFS rate was 97.5%. The 2-year OS rate in all
patients with evaluable data in this study (n = 124) was 93%.183 As For patients with low-risk disease, the NCCN AML Panel has positioned
discussed earlier, in the phase III randomized trial of ATRA combined with the ATRA plus ATO regimen first, based on results from the APL0406
ATO versus the AIDA regimen (APL0406 study) in patients with newly phase III randomized trial in comparison with the AIDA regimen.169 An
diagnosed, low-, or intermediate-risk APL (n = 162), patients in the ATRA additional ATRA plus ATO regimen based on the AML 17 trial185 is also a
plus ATO arm received consolidation with ATO 5 days per week for 4 preferred option. The GIMEMA AIDA-2000 regimen168 is an additional
weeks every 8 weeks for a total of 4 courses, and ATRA daily for 2 weeks option. However, all three of these regimens will yield excellent results. It
every 4 weeks for a total of 7 courses (Arm A).169 Patients in the AIDA arm is important to note that clinicians should use a regimen consistently
(Arm B) received 3 cycles of anthracycline-based consolidation combined through all components of the treatment protocol and not mix induction
with ATRA and then maintenance with low-dose chemotherapy and regimens from one trial with consolidation regimens from another trial. It is
ATRA.168 After a median follow-up period of 31 months, the 2-year EFS also important for the management of APL that regimens containing ATRA
rate was significantly longer in Arm A compared with Arm B (97% vs. 86%; and ATO be administered unless there is a contraindication based on
P < .001 for noninferiority; P = .02 for superiority of ATRA-ATO). In extenuating patient circumstances.
addition, the 2-year OS was also longer in Arm A (99% vs. 91%; P = .02),

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For patients with high-risk disease, preferred consolidation therapies For patients with high-risk APL, IT chemotherapy (eg, 2 doses for each
include ATRA plus ATO as used in the APML4 trial,183 or ATRA and ATO consolidation cycle) can be considered for CNS prophylaxis. IT
(plus a single dose of GO every 4–5 weeks until molecular CR if chemotherapy may include agents such as methotrexate alternating with
ATRA/ATO are discontinued due to toxicity, provided absolute neutrophil cytarabine either alone or combined with corticosteroids; the choice of
count [ANC] and platelets have recovered to >1.0 x 109/L and 100 x 109/L, single drug versus combinations may vary based on clinical situation and
respectively).179,185 Other recommended consolidation approaches include institutional practice. Usually IT chemotherapy is started at the completion
cytarabine with daunorubicin as used in the French APL 2000 trial173; of induction and then given at the start and at count recovery on
cytarabine with AIDA as used in the PETHEMA LPA 2005167; and 2 cycles subsequent consolidations. IT chemotherapy can be omitted during cycles
of ATO followed by 2 additional cycles of standard chemotherapy as used of higher dose cytarabine.
in the North American Intergroup trial.166 When using a
cytarabine-containing regimen, dose adjustments of cytarabine may be Post-Consolidation or Maintenance for Patients with APL
needed for patients >60 years of age or for patients with renal Following consolidation therapy, patients are assessed for molecular
dysfunction.165,166 In patients who could not tolerate anthracyclines and remission using RT-PCR techniques on BM samples. For patients who
who received ATRA and ATO for induction therapy, the reported trials achieve PCR negativity, a 1- to 2-year course of ATRA maintenance
continued with repeated cycles of these two agents following induction therapy, which may be combined with 6-mercaptopurine and
without anthracycline.177,178 methotrexate, may be a reasonable approach. The recommendations for
maintenance ATRA arose from several early trials that showed superior
For patients with high-risk disease and cardiac issues (eg, low ejection RFS for patients receiving ATRA alone or in combination as maintenance
fraction and prolonged QTcF), the NCCN AML Panel recommends ATO therapy. The French APL 93 trial randomized eligible patients (n = 289) to
(0.15 mg/kg or 0.3 mg/kg) with ATRA for consolidation.179,185 If ATRA or four different maintenance regimens: no maintenance, continuous
ATO are discontinued due to toxicity, a single dose of GO (6 mg/m2185 or 9 chemotherapy with 6-mercaptopurine and methotrexate, intermittent
mg/m2) may be considered once every 4 to 5 weeks, provided ANC and ATRA, and the combination of ATRA with 6-mercaptopurine and
platelets have recovered to >1.0 x 109/L and 100 x 109/L, respectively, methotrexate.146 Results showed decreased 2-year relapse rates with
until molecular CR is achieved. If the patient received ATRA and GO as continuous chemotherapy (11.5% vs. 27% with no chemotherapy) and
induction therapy, consolidation with ATRA and GO should follow.180 As with ATRA (13.5% vs. 25% with no ATRA). The estimated 2-year relapse
mentioned previously, the Panel suggests that a regimen should be used rate for patients who received maintenance with ATRA in combination with
consistently through all components and physicians should not mix chemotherapy was 7.4%, suggesting an additive benefit with the
induction therapy from one trial with consolidation therapy from another. combination. The 2-year EFS rate was also improved with continuous
chemotherapy (92% vs. 77% without chemotherapy) and with ATRA (87%
vs. 82% without ATRA); the 2-year EFS rate among patients who received

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ATRA in combination with chemotherapy was 93%.146 Results from the respectively.163 Thus, the incorporation of ATRA during induction and
long-term follow-up of the APL 93 study showed a beneficial effect of maintenance appeared to improve long-term remission durations. It should
maintenance treatment with intermittent ATRA and continuous be noted that in the above North American Intergroup trial, molecular
chemotherapy, with an additive effect of the two modalities. The 10-year remission status was not assessed prior to randomization to maintenance
cumulative relapse rates with no maintenance, ATRA alone, continuous treatment.
chemotherapy, and ATRA combined with chemotherapy were 43%, 33%,
23%, and 13%, respectively (P < .001).164 Patients considered to have The Japanese APL 97 randomized study evaluated the role of
high-risk disease (WBC count >5 x 109/L) appeared to derive the most maintenance with intensified chemotherapy compared with observation in
benefit from maintenance therapy. The 10-year cumulative relapse rate patients with APL who were in molecular remission following consolidation
among patients with high-risk disease with no maintenance, ATRA alone, (n = ).191 The estimated 6-year DFS was not significantly different between
continuous chemotherapy, and ATRA combined with chemotherapy was the chemotherapy maintenance and observation arms (63% vs. 80%). In
68%, 53%, 33%, and 21%, respectively (P < .001). No statistically fact, the estimated 6-year OS was significantly lower with maintenance
significant difference in the 10-year relapse rates was observed among (86% vs. 99%; P = .014), which the investigators attributed to possible
patients with lower risk disease, although the relapse rate dropped from effects of chemotherapy maintenance on the development of secondary
29% without maintenance to 11.5% with ATRA combined with malignancies and responses to subsequent (second-line) therapies.191
chemotherapy. Overall, the 10-year OS rates with no maintenance, ATRA
Data from the AIDA 0493 trial suggested that there was no long-term
alone, continuous chemotherapy, and ATRA combined with chemotherapy
benefit to maintenance therapy (ie, combination chemotherapy with
were 74%, 88%, 93%, and 94%, respectively (P < .001).164
6-mercaptopurine and methotrexate, ATRA alone, or ATRA in combination
The first North American Intergroup trial showed superior DFS outcomes with chemotherapy) in patients who had achieved molecular remission
for patients receiving maintenance ATRA compared with no (PCR negativity) at the end of consolidation therapy.192 In this trial, ATRA
maintenance.163 In this trial, patients were randomized to induction therapy was not given during consolidation. The above studies have not
with daunorubicin plus cytarabine or with ATRA alone, and subsequently demonstrated long-term benefit with the use of maintenance therapy in
underwent a second randomization to maintenance therapy with ATRA or patients who achieve molecular remission following consolidation therapy.
no maintenance (observation only). Consolidation therapy comprised the Further data from randomized trials are needed to address the question of
initial induction therapy regimen for course 1, and then daunorubicin and maintenance. A phase III cooperative group trial (SWOG 0521) is
HiDAC for course 2. The 5-year DFS rates for the four randomization designed to examine the need for maintenance therapy (using the
groups, chemotherapy induction plus observation, chemotherapy induction combination of ATRA, 6-mercaptopurine, and methotrexate) in patients
plus ATRA maintenance, ATRA induction plus observation, and ATRA with low-risk APL. In this trial, patients receive induction therapy with
induction plus ATRA maintenance, were 16%, 47%, 55%, and 74%, ATRA, daunorubicin, and cytarabine, followed by consolidation therapy

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NCCN Guidelines Version 3.2026

Acute Myeloid Leukemia

with ATO, ATRA, and daunorubicin. Patients are then randomized to RT-PCR monitoring was the strongest predictor of clinical relapse (P <
receive maintenance therapy or no further treatment (observation only). .0001) and RFS (P < .0001).194 If the second test was negative,
No benefit for maintenance was observed.193 The benefit of maintenance maintenance therapy and frequent monitoring (eg, every 2–3 months) for
therapy likely depends on the regimens used during induction and up to an additional 2 years is strongly recommended to ensure continued
consolidation therapies. Therefore, it is important to use maintenance PCR negativity. Testing should be done in the same laboratory to maintain
therapy in conjunction with the treatment protocols in which they have a consistent level of sensitivity. Most clinical labs have a sensitivity level of
been shown to confer benefit. 10-4. If results are equivocal, consultation with a physician experienced in
molecular diagnostics should be considered. For patients who develop
NCCN Recommendations for Post-Consolidation or Maintenance for
cytopenias and who have a negative RT-PCR, a BM aspirate is
Patients with APL
recommended to assess for new cytogenetic abnormalities, as secondary
RT-PCR should be performed on a blood sample at completion of
MDS and AML can occur following APL therapy.
consolidation to document molecular remission. It is at the discretion of the
treating physician to determine the appropriate frequency of monitoring for Management of Relapsed APL
individual patients.
ATO is recommended for patients who do not achieve molecular remission
While long-term monitoring has been standard, with newer, more effective at completion of consolidation or who subsequently demonstrate
regimens, the value is less certain. Periodic monitoring, often every 3 molecular or morphologic relapse. As a single agent, ATO produced CR
months, is recommended for up to 2 years after completion of treatment to rates of 80% to 90% in patients with hematologic relapse and achieved
detect molecular relapse in patients with high-risk disease or those who molecular remissions in 70% to 80% of those patients.175,195-197 In a
had long interruptions during consolidation. Clinical experience indicates retrospective analysis of patients with APL who experienced relapse after
that the risk of relapse in patients with low-risk disease who are in first-line therapy with ATRA combined with chemotherapy (n = 23),
molecular remission at completion of consolidation is low, and monitoring reinduction therapy with ATO-containing regimens (ATO monotherapy,
may not be necessary outside the setting of a clinical trial. At the current n = 20; ATO combined with ATRA and anthracycline, n = 2; ATO
level of test sensitivity/specificity, a change from PCR negative to positive combined with mitoxantrone, n = 1) resulted in hematologic CR in 95%
status should be confirmed in a blood sample by a reliable laboratory and molecular remission in 83% of patients.198 ATRA and ATO appear to
within 2 to 4 weeks. If molecular relapse is confirmed by a second positive be synergistic and one could consider using the combination in patients
test, the patient should be treated for relapsed disease (see APL: Therapy who have not received ATRA during consolidation.174-176 However, in a
for Relapse in the algorithm). A prospective study that analyzed 6727 small randomized study of patients with relapsed APL (n = 20), all patients
serial RT-PCR assays from patients with newly diagnosed APL receiving previously treated with ATRA-containing chemotherapy showed no
ATRA and anthracycline-based induction therapy found that sequential improvement in response by adding ATRA to ATO compared with ATO
alone.199 The role of retreatment with ATO for patients who experience

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NCCN Guidelines Version 3.2026

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relapse following therapy with ATO-containing regimens during initial voluntary withdrawal of the drug in 2010 was based on interim data from a
induction and/or consolidation therapy remains unknown. A retrospective randomized trial in adult patients (aged 18–60 years) with AML comparing
analysis in a small number of patients reported a second CR rate of 93% induction regimens of cytarabine and daunorubicin with or without GO in
(both for hematologic CR and molecular remission) among patients who which there was no improvement in outcomes and a small but significant
were retreated with ATO combined with ATRA (with or without increase in early mortality in the GO arm.202 Subsequent results of this trial
anthracyclines) after a relapse following first-line therapy with single-agent eventually showed no difference in overall mortality between the two
ATO (n = 14).198 A small multicenter study evaluated 22 patients with APL arms.203 Since its withdrawal from the market, studies have demonstrated
treated with prolonged ATRA-ATO at the time of relapse and reported that a significant benefit for GO in specific patient populations. Therefore, GO
90% of patients achieved molecular CR after 2 cycles.200 At a median has been re-approved for AML. One complication to evaluating the benefit
follow-up of 58 months, 4-year OS probability was 0.85 (95% CI, 0.61– of GO is that APL occurs in a small population of patients, and therefore
0.94), DFS was 0.74 (95% CI, 0.49–0.88), and EFS was 0.68 (95% CI, studies do not have the numbers to enroll for a suitable trial. The benefit of
0.45–0.83). GO must be weighed against the possibility for adverse events. Clinicians
should be advised of the possible complication of SOS when administering
For patients with APL who experience relapse early (<6 months) after an GO.
initial CR to first-line therapy with ATRA and ATO with no prior exposure to
anthracyclines, anthracycline-based regimens (ATRA plus daunorubicin For patients who experience an early relapse (<6 months) after an initial
and cytarabine163,165,166; and AIDA alone167) are recommended. Single- CR to ATRA and anthracycline-containing first-line regimens or with no
agent GO is another option. In a study of 16 patients with relapsed APL, prior exposure to ATO, it is recommended that the patient receive ATO
GO at a dose of 6 mg/m2 was administered for 2 doses, followed by a third with or without ATRA, and with or without a single dose of GO until count
dose for patients achieving a new molecular remission.201 Molecular recovery with marrow confirms remission.
remission was achieved in 6 of 7 patients tested after 1 dose, in 9 of 11
patients tested after 2 doses, and in 13 of 13 patients tested after 3 doses. For patients who experience a late relapse (≥6 months) to ATO-containing
Among the remaining 3 patients, 1 achieved molecular remission after regimens, ATO with or without ATRA, and with or without an anthracycline
dose 1 and received no additional doses due to hepatic toxicity and 2 or a single dose of GO, is recommended as first-line therapy after relapse.
experienced molecular relapse while receiving GO. Among patients who Following completion of the first cycle of consolidation, if the patient does
experienced response, molecular responses were sustained for a median not enter molecular remission, a matched sibling or alternative donor
of 15 months in 7 of 14 (50%) patients, while the remaining 50% (haploidentical, unrelated donor, or cord blood) HCT or clinical trial is
experienced relapse from a range of 3 to 15 months. Among patients who recommended. Testing is recommended at least 2 to 3 weeks after the
experienced relapse, 2 were retreated with GO and obtained new completion of ATO to avoid false positives.
molecular remissions. All patients experienced myelosuppression. The

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A small phase II trial in patients with relapsed APL evaluated ATO during autologous HCT recipients was 63% (range, 49%–75%) versus 50%
induction and consolidation followed by a peripheral blood hematopoietic (range, 44%–57%) in patients receiving allogeneic HCT. Although the DFS
cell harvest after HiDAC chemotherapy and autologous HCT.204 The study was not statistically significant (P = .1), the difference in OS did reach
enrolled 35 patients (26 with hematologic relapse and 9 with molecular statistical significance (P = .002). In the patients receiving autologous
relapse) between the ages of 18 and 65 years. The EFS after 1 year was HCT, OS was 75% (range, 63%–85%) versus 50% (range, 48%–61%).
77% (90% CI, 63%–86%). At a median follow-up of 4.9 years (range, 0.3– The authors attribute this benefit to the increased treatment-related
6.3 years), the 5-year EFS was 65% and the 5-year OS was 77% with an mortality seen with patients receiving allogeneic (30%) compared to
estimated 59% probability of failure-free survival.204 The data suggest that autologous HCT (2%).
this sequential treatment regimen may provide improved outcomes with
greater duration. It should be noted that only limited evidence from retrospective studies
exist regarding the role of autologous and allogeneic HCT following
A retrospective analysis conducted by the European APL Group showed relapse of APL in the era of ATO therapy. The optimal consolidation
that in patients who received HCT following a second hematologic strategy following therapy with ATO-containing regimens in patients with
remission (primarily with ATRA-containing regimens), outcomes were relapsed disease remains to be defined.207 In a small retrospective study
more favorable with autologous HCT (n = 50) compared with allogeneic of patients with relapsed APL treated with ATO-containing induction and
HCT (n = 23). The 7-year RFS (79% vs. 92%) and EFS (61% vs. 52%) consolidation therapy, outcome of further consolidation with autologous
rates did not reach statistical significance between patients who received HCT was compared with maintenance (without autologous HCT)
autologous versus allogeneic HCT; however, 7-year OS rates were consisting of ATO with or without ATRA.198 In this analysis, all patients had
significantly improved with autologous compared with allogeneic HCT achieved second molecular remission following induction and
(60% vs. 52%; P = .04).205 Among patients who received a PCR-negative consolidation therapy with the ATO-containing regimens; subsequently, 14
autograft, the 7-year RFS and OS rates were 87% and 75%, respectively. patients underwent autologous HCT and 19 patients opted for an
Although the relapse rates were low with allogeneic HCT, the reduced OS ATO-containing maintenance regimen. Consolidation with autologous HCT
with this procedure was accounted for by the higher treatment-related was associated with a significantly higher 5-year EFS rate (83% vs.
mortality observed in the allogeneic HCT group compared with the 34.5%; P = .001) and OS rate (100% vs. 38.5%; P = .001) compared with
autologous HCT group (39% vs. 6%).205 ATO-containing maintenance therapy.198 The authors concluded that
consolidation with autologous HCT was superior to ATO-containing
A second study also suggested that autologous HCT could have a survival maintenance alone in patients who achieved molecular remission after
advantage over allogeneic HCT in this population.206 Chakrabarty et al206 relapse. Outcome data from the ELN registry reported a 3-year OS after
looked at 294 patients who received either allogeneic (n = 232) or transplant in second CR of 80% compared with 59% in patients without
autologous HCT (n = 62) between 1995 and 2006. The 5-year DFS in the transplant (P = .03).208

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A small percentage of relapsed APL has a CNS component.209,210 93 and APL 2000 trials.214 A fundamental difference between these two
Therefore, for patients who are in second morphologic remission, the use trials was the use of dexamethasone (10 mg every 12 hours beginning on
of IT chemotherapy for CNS prophylaxis should be considered. Patients day 1) for patients on APL 2000. The early death rate from differentiation
who achieve a molecular remission after second-line therapy should be syndrome dropped from 8 in 139 patients (6%) in the APL 93 trial to 2 in
considered for autologous HCT if they do not have contraindications to 133 patients (1.5%) in the APL 2000 trial.
high-dose therapy. Allogeneic HCT should be reserved for patients who
have persistent disease despite therapy for relapsed disease. For patients There should be a high index of suspicion for differentiation syndrome in
in second CR who have contraindications to HCT, continued therapy with patients with APL who may be triggered by symptoms including fever, an
ATO for 6 cycles is recommended in the absence of a suitable clinical trial. increasing WBC count >10 x 109/L, shortness of breath, hypoxemia, and
pleural or pericardial effusion. Close monitoring of volume overload and
Supportive Care for Patients with APL pulmonary status is warranted in these patients and initiation of
Specific supportive care issues should be considered when treating dexamethasone should occur at the first signs or symptoms of respiratory
patients with APL. Therapy for APL is often associated with a constellation compromise (ie, hypoxia, pulmonary infiltrates, pericardial or pleural
of symptoms and physiologic abnormalities, including fluid retention, effusions). The NCCN AML Panel recommends treating with
dyspnea, episodic hypotension, pulmonary infiltrates, and pulmonary or dexamethasone 10 mg twice daily for 3 to 5 days, then tapering the dose
pericardial effusions now referred to as “differentiation syndrome.” over 2 weeks (see Principles of Supportive Care for APL in the algorithm).
Approximately 15% to 25% of patients who have not been previously ATRA may need to be withheld during the initial acute symptomatic period
treated receiving ATRA-containing therapy develop this syndrome.211,212 but may be resumed when symptoms resolve. Other factors that have
Patients may begin to develop evidence of differentiation syndrome early been reported to increase the risk of differentiation syndrome include a
in the treatment with either ATRA or ATO as single agents or in high body mass index and age >40 years. For patients at high risk (WBC
combination. These patients develop fever, often accompanied by rapidly count >10 x 109/L) of developing differentiation syndrome, initiate
rising WBC counts (>10 x 109/L). Patients should be closely monitored for prophylaxis with corticosteroids, either prednisone (0.5 mg/kg) from day 1
hypoxia and the development of pulmonary infiltrates or pleural effusion. or dexamethasone 10 mg every 12 hours (see Principles of Supportive
Differentiation syndrome along with hemorrhage are the leading causes of Care for APL in the algorithm). The steroid dose should be tapered over a
death during induction therapy. Early recognition and prompt initiation of period of several days. It is recommended that the prophylaxis regimen
corticosteroids are key components in the management of this follow the specific treatment protocol used. In the Australia/New Zealand
complication. In some studies, low mortality and morbidity rates were study that evaluated induction with ATO added to a backbone of AIDA
reported when corticosteroids were administered prophylactically in (phase II APML4 trial), all patients received prednisone (1 mg/kg/day for at
patients presenting with high WBC counts.171,213 Kelaidi et al214 assessed least 10 days) as prophylaxis for differentiation syndrome regardless of
the outcomes of patients with high WBC (>10 x 109/L) enrolled in the APL initial WBC count [see APL Treatment Induction (High Risk) in the

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algorithm].183 In the Italian-German Cooperative Group study that maintain platelet counts of ≥50 x 109/L, by fibrinogen replacement with
evaluated ATRA combined with ATO versus the AIDA regimen (phase III cryoprecipitate and fresh frozen plasma to maintain a level >150 mg/dL,
APL0406 trial), patients received prophylaxis with prednisone (0.5 and by maintenance of PT and PTT close to normal values. Patients with
mg/kg/day) from day 1 until the end of induction [see APL Treatment clinical coagulopathy need to be monitored daily until resolution. Given the
Induction (Low Risk) in the algorithm].169 The optimal duration of steroid risks of coagulopathy in APL at diagnosis, invasive procedures including
prophylax is unknown. If a patient develops differentiation syndrome, it is leukapheresis and/or central line placement should be avoided. If possible,
recommended that treatment be changed from prednisone to the diagnosis of APL may be made using peripheral blood samples, which
dexamethasone 10 mg every 12 hours until count recovery or risk of may minimize risk of bleeding complications until coagulopathy can be
differentiation has abated.167,169 Hydroxyurea can be used to treat adequately controlled.
leukocytosis associated with differentiation syndrome. In difficult-to-treat
cases, an anthracycline or GO can be used. ATO therapy may prolong the QT interval, making patients susceptible to
ventricular arrhythmias. Therefore, prior to initiation of therapy, an ECG is
Leukapheresis is not routinely recommended in the management of high recommended to assess the QT interval. Routine monitoring (eg, weekly)
WBC counts in APL because of the difference in leukemia biology. A during therapy is suggested for patients who are older. Serum electrolytes
retrospective study analyzed 242 patients with APL, 12% of whom had a (calcium, potassium, magnesium, and phosphorous) should also be
WBC >50 x 109/L at presentation.215 Of the 29 patients presenting with monitored prior to and during therapy to maintain electrolytes within the
hyperleukocytosis, 11 (38%) underwent leukapheresis. There was no middle or upper normal range. Other drugs that prolong the QT interval
significant difference in CR rate (82% vs. 78%; P = .79) or 3-year OS should be avoided during ATO therapy to minimize the risk of cardiac
(73% vs. 67%; P = .64) in patients who underwent leukapheresis arrhythmias. For patients with an absolute QTc interval >500 msec, the
compared to patients who did not undergo leukapheresis. However, in use of a QTcF (corrected QT interval by Fredericia) correction formula is
cases of potentially life-threatening leukostasis not responsive to other recommended and ECGs should be reassessed on a weekly basis during
modalities, leukapheresis can be considered with caution. Hydroxyurea induction therapy, and prior to each course of post-remission therapy. A
can be used to treat leukocytosis in individuals with low-risk disease who cardiology consult may be appropriate for patients with prolonged QTc and
experience a rise in WBC count after treatment with an ATRA/ATO-based when QTcF corrections are unavailable.216
regimen.
While ATO has not been classically associated with renal toxicity, a
Because coagulopathy is common in patients with APL, it is important to multivariate analysis of patients receiving ATO-based therapy found that
screen for this problem with evaluation of PT, PTT, and fibrinogen doses of ATO >15 mg were associated with significantly higher rates of
concentration during the initial workup and before any invasive procedure. significant, idiopathic acute kidney injury (AKI) compared to lower doses
Clinical coagulopathy is managed by aggressive transfusion support to

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(15.8% vs. 0%; P = .001), suggesting a capped dose of 15 mg may be optimizing treatment options based on this information may be ideal.219
reasonable, particularly for patients with obesity.217 Early in the process of developing a treatment plan, it is reasonable to
consider referral to palliative care for consultation.30
Growth factors are not recommended during induction for patients with
APL as they can complicate assessment of response and increase the risk With respect to induction chemotherapy for patients with newly diagnosed
of differentiation syndrome. There is no evidence for whether growth AML, NCCN now recommends consideration for intensive induction
factors have a positive or negative impact on long-term outcome if used therapy to be a function of overall fitness rather than age. Previously, age
during consolidation. However, growth factors may be considered during >60 years was considered the therapeutic divergence point to not pursue
consolidation in selected cases, including in the event of life-threatening intensive induction based on: a higher prevalence of unfavorable genetics
infections, or when signs/symptoms of sepsis are present, in an attempt to and antecedent myelodysplasia, a higher incidence of multidrug
shorten the duration of neutropenia. resistance, and an increased frequency of comorbid medical conditions
that resulted in higher treatment-related mortality.220,221 Now, adults who
Antiviral prophylaxis for herpes zoster (HZ) for the duration of treatment are older with intact functional status (ie, ECOG score 0–2), minimal
may be appropriate, given the association between ATO exposure and comorbidities, and de novo AML without unfavorable cytogenetics or
HZ.218 molecular markers, and especially those with favorable features, may
benefit from intensive cytarabine-based therapy regardless of chronologic
Management of Acute Myeloid Leukemia
age. Similarly, younger patients with the presence of high-risk factors with
The intent of traditional induction chemotherapy is to produce a major conventional intensive induction may be considered for non-conventional
reduction in the leukemic burden and to restore normal hematopoiesis. induction approaches. Overall, because (CR rates rarely exceed 70% in
Initial treatment decisions for AML are based on a variety of factors, younger patients and 50% in patients who are older, substantial
including functional/performance status and comorbid medical conditions opportunity exists for innovative clinical trials involving both patient
(factors that influence one’s ability to tolerate standard induction therapy), populations.
a history of antecedent hematological conditions, exposure to prior
chemotherapy or RT, and specific disease biology. Although these A treatment decision-making algorithm for previously untreated patients
biological factors, typically reflected by cytogenetic and molecular ≥60 years of age with AML who are medically fit was developed by the
markers, are powerful predictors of outcomes, initial therapeutic decisions German AML Cooperative Group. Based on data from a large study
must sometimes be made before this information is fully available. While (n = 1406), patient and disease factors significantly associated with
AML can present as a medical emergency that requires rapid initiation of response and/or early death were identified and risk scores were
therapy, it is becoming increasingly recognized in the field that it may be developed based on multivariate regression analysis.222 The predictive
possible to delay treatment to wait for this biological information; model was subsequently validated in an independent cohort of patients

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≥60 years of age (n = 801) treated with 2 courses of induction therapy with be independent predictors of survival, with median survival of 10.9 months
cytarabine and daunorubicin. The algorithm, with or without knowledge of for the fit for intensive chemotherapy group, 4.2 months for the unfit for
cytogenetic or molecular risk factors, predicts the probability of achieving a intensive chemotherapy group, and 1.8 months in the unfit for even
CR and the risk for an early death for patients who are older with nonintensive therapy group (P = .000). Additionally, in the unfit for even
untreated AML and considered eligible for standard intensive nonintensive therapy group, survival with any form of treatment was not
treatments.222 In addition, comprehensive geriatric assessments can be better than with best supportive care. For the unfit for intensive
complementary to the assessment of comorbid conditions and are chemotherapy group, nonintensive therapy was found to be as effective as
emerging as better predictive tools of functional status.223-227 intensive therapy and for the fit for intensive chemotherapy group,
intensive therapy was more effective than nonintensive therapy.
A comprehensive predictive model for early death following induction in
patients with newly diagnosed AML suggests that age may reflect other In a retrospective cohort study of adult patients with AML (n = 1100;
covariates, and the evaluation of these factors may provide a more range, 20–89 years), a composite predictive model examined the impact
accurate predictive model.221 The model includes performance score, age, of comorbidities on 1-year mortality following induction treatment.230 This
platelet count, serum albumin, presence or absence of secondary AML, analysis incorporated patient-specific (ie, age, comorbidities) and AML-
WBC count, peripheral blood blast percentage, and serum creatinine. specific (ie, cytogenetic and molecular risks) features, and resulted in a
These factors, when taken together, result in a predictive accuracy based predictive estimate of 0.76 based on AUC.230
on the area under the curve (AUC) of 0.82 (a perfect correlation is an AUC
of 1.0).221 This model is complex, and currently there is no tool available to AML Induction Therapy for Patients Eligible for Intensive Induction
Therapy
implement this model. A shortened form of the model was based on
covariates that include age, performance status, and platelet count. The Induction Therapy
simplified model provides an AUC of 0.71, which is less accurate than the Standard induction regimens used for patients eligible for intensive
complex model but may be more accurate than decision-making strategies induction therapy are based on a backbone of cytarabine plus an
based solely on age.221 anthracycline, and CR rates for patients who are ≤50 years of age have
consistently been in the range of 60% to 70% in most large cooperative
Another retrospective study used the fitness criteria originally proposed by group trials using this therapy. Historically, in most large cooperative group
Ferrera et al in 2013228 that included age >75 years, medical trials, daunorubicin has been the most commonly used anthracycline at
comorbidities, active resistant infection, and performance status ≥3 not doses of 60 to 90 mg/m2 daily for 3 days. Idarubicin, which has a longer
related to leukemia, to categorize patients into 3 categories: 1) fit for intracellular retention time, used at doses of 12 mg/m2 daily for 3 days, has
intensive chemotherapy; 2) unfit for intensive chemotherapy; and 3) unfit had comparable remission rates with fewer patients requiring additional
for even nonintensive therapy.229 These categories of fitness were found to therapy at day 15 to achieve remission.

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The randomized Acute Leukemia French Association (ALFA)-9801 study higher cure rate than daunorubicin despite the high dose (240 mg/m2 total
(n = 468) showed that idarubicin induction (using the standard 12 mg/m2 dose) of daunorubicin (27.4% vs. 15.9%; P = .049).233
daily for 3 days or intensified with 12 mg/m2 daily for 4 days) compared
with higher dose daunorubicin (≤80 mg/m2) yielded a significantly higher In a systematic review and meta-analysis of 29 randomized controlled
CR rate in patients aged 50 to 70 years (80% vs. 70%, respectively; trials (RCTs) comparing idarubicin to daunorubicin,234 idarubicin had a
P = .03).231 The median OS for all patients was 17 months. The estimated lower remission failure rate compared to daunorubicin (relative risk [RR],
2-year EFS and OS rates were 23.5% and 38%, respectively, and the 0.81; 95% CI, 0.66–0.99; P = .04), but no difference was observed in early
estimated 4-year EFS and OS rates were 18% and 26.5%, respectively; death or overall mortality. Furthermore, this benefit was only seen when
however, no significant differences were observed between treatment the dose ratio between daunorubicin and idarubicin was <5. Both
arms with regard to EFS, OS, and cumulative relapse rates.231 high-dose daunorubicin and idarubicin resulted in 5-year survival rates
between 40% and 50%.234
The ALFA-9803 study (n = 416) evaluated induction with idarubicin (9
mg/m2 daily for 4 days) compared with daunorubicin (45 mg/m2 daily for 4 In a HOVON trial, which randomized patients ≥60 years of age to induction
days) in patients ≥65 years of age.232 In this trial, the CR rate after therapy with standard-dose cytarabine combined with either
induction was 57% and induction death occurred in 10% of patients. The standard-dose daunorubicin (45 mg/m2 daily for 3 days; n = 411) or
median OS for all patients was 12 months; the estimated 2-year OS rate dose-escalated daunorubicin (90 mg/m2 daily for 3 days; n = 402), the CR
was 27%. No significant differences in these outcomes were seen rate was 54% and 64%, respectively (P = .002).235 No significant
between anthracycline treatment arms.232 Long-term outcomes based on a differences were observed in EFS, DFS, or OS outcomes between
combined analysis of data from the two ALFA trials above (9801 and 9803 treatment arms. Among the subgroup of patients aged 60 to 65 years
studies; n = 727) showed superior results with standard idarubicin (n = 299), an advantage with dose-escalated compared with
induction (36 mg/m2 total dose) compared with daunorubicin induction standard-dose daunorubicin was observed with regard to rates of CR
(240 mg/m2 total dose for patients <65 years of age; 180 mg/m2 total dose (73% vs. 51%), 2-year EFS (29% vs. 14%), and 2-year OS (38% vs. 23%).
for patients ≥65 years of age) in patients ≥50 years of age with AML.233 At These outcomes with dose-escalated daunorubicin seemed similar to
a median actuarial follow-up of 7.5 years, the median OS for all patients those with idarubicin (12 mg/m2 daily for 3 days) from the ALFA-9801
included in the analysis was 14.2 months. The estimated 5-year OS rate study, in which the 4-year EFS and OS rates were 21% and 32%,
was 15.3%, and the overall cure rate was 13.3%. Induction with standard respectively.231 In the HOVON trial, the benefit in OS outcomes for the
idarubicin was associated with a significantly higher cure rate compared dose-escalated daunorubicin group was observed only in patients ≤65
with daunorubicin (16.6% vs. 9.8%; P = .018). In the group of patients <65 years of age or in those with CBF translocations.235 It has been suggested
years of age, standard idarubicin was still associated with a significantly that a dose of 60 mg/m2 of daunorubicin may be equally as effective as 90
mg/m2 and have a lower toxicity. A study from Burnett et al236 compared

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these two doses in 1206 patients who were predominately <60 years of Risk-Stratified Treatment Strategies
age. There was no difference in CR (73% vs. 75%; odds ratio [OR], 1.07;
95% CI, 0.83–1.39; P = .60). The 60-day mortality was higher in the Favorable-Risk Genetics
patients receiving 90 mg/m2 (10% vs. 5%; HR, 1.98; 95% CI, 1.30–3.02; Cytarabine and anthracycline dose during induction: A large
P = .001), though the 2-year OS was similar (59% vs. 60%; HR, 1.16; 95% randomized phase III study (E1900) from the ECOG reported a significant
CI, 0.95–1.43; P = .15).234 It is worth noting that all patients received a increase in CR rate (71% vs. 57%; P < .001) and median OS (24 vs. 16
second course of chemotherapy that included additional daunorubicin (50 months; P = .003) using daunorubicin 90 mg/m2 daily for 3 days (n = 327)
mg/m2) on days 1, 3, and 5, which may potentially have mitigated the versus 45 mg/m2 daily for 3 days (n = 330) in patients <60 years of age
effects of a 90 mg/m2 daunorubicin dose. with previously untreated AML.244 Based on subgroup analyses, however,
the survival benefit with high-dose daunorubicin was shown to be
In a recent randomized controlled trial comparing doses of 60 mg/m2 of restricted to patients with favorable- and intermediate-risk cytogenetic
daunorubicin to 90 mg/m2 as part of 7 + 3 induction in patients with newly profiles (median OS, 34 vs. 21 months; P = .004) and those <50 years
diagnosed AML (n = 864; median age, 52 years), the higher dose was not (median OS, 34 vs. 19 months; P = .004). The survival outcome for
associated with statistically significant improvements in early response, 3- patients with unfavorable cytogenetics was poor, with a median OS of only
year RFS, or 3-year OS.237 10 months in both treatment arms.244

Although patients >75 years of age with significant comorbidities generally CD33-Positive AML: GO is a humanized anti-CD33 monoclonal antibody
do not benefit from conventional chemotherapy treatment, the rare patient conjugated with the cytotoxic agent calicheamicin,245 that was initially
with favorable-risk AML and no significant comorbidities might be an approved in the year 2000 as a monotherapy for AML based on data from
exception. single-arm phase II trials for adult patients who are older (median age, 61
years) in first relapse.246 The withdrawal of the drug in 2010 was based on
For patients who exceed anthracycline dose or have cardiac issues but
interim data from a randomized trial in adult patients (aged 18–60 years)
are still able to receive intensive therapy, alternative non–anthracycline-
with AML comparing induction regimens of cytarabine and daunorubicin
containing regimens (eg, FLAG, clofarabine-based regimens) may be
with or without GO in which there was no improvement in outcomes and a
considered.238-243
small but significant increase in early mortality in the GO arm.202
Recent studies have incorporated tailored strategies according to Subsequent results of this trial eventually showed no difference in overall
cytogenetics and molecular abnormalities, and the current NCCN mortality between the two arms.203 Since its withdrawal from the market,
Guidelines for AML outline treatment strategies according to specific risk studies have demonstrated a significant benefit for GO in specific patient
groups. populations. In the MRC AML 15 trial, the efficacy and safety of adding
GO (3 mg/m2 on day 1 of induction) to three induction regimens, including

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daunorubicin (50 mg/m2 on days 1, 3, and 5) and cytarabine (100 mg/m2 Patients in the daunorubicin and cytarabine and FLAG-IDA arms were
on days 1–10 every 12 hours), was evaluated in patients ≤60 years of age randomly assigned to a single dose of GO (3 mg/m2) during the first
with previously untreated AML (n = 1113).247 The addition of GO was well induction course.251 Patients with favorable- and intermediate-risk disease
tolerated and there were no differences in RFS or OS rates between arms who received two induction courses of FLAG-IDA with GO in course 1,
that received or did not receive GO. The patients predicted to derive followed by 2 courses of HiDAC had an 8-year survival rate from remission
significant benefit with the GO addition to chemotherapy included those of 72% (favorable risk, 95%; intermediate risk, 63%).251
with favorable-risk cytogenetics, with a trend towards benefit for those with
intermediate-risk cytogenetics. Patients with adverse risk cytogenetics A phase II trial evaluated the safety and efficacy of FLAG with GO in 45
were unlikely to derive benefit.247 A meta-analysis of five randomized trials patients ≥18 years of age (median, 48 years; age range, 19–76 years) with
(including adult patients ≥60 years of age) showed that adding GO newly diagnosed AML with CBF-AML [inversion 16, t(16;16), or t(8;21)].252
(including alternative dosing schedules) to conventional induction therapy For induction and post-remission therapy, patients received FLAG with GO
also provides survival benefit.248 3 mg/m2 on day 1, though fludarabine and cytarabine were given for 4 to 5
days with induction and for 3 days with post-remission therapy. Up to 6
In the AMLSG 09-09 trial, 588 patients with newly diagnosed NPM1- cycles of post-remission therapy were allowed, though only a total of 2
mutated AML were randomized to intensive chemotherapy plus ATRA, cycles of post-remission therapy could include GO. Overall response rate
with and without GO.249 While the study did not reach its primary endpoint (ORR) was 95%, with 91% of patients achieving CR and 4% of patients
of significant improvement in EFS (P = .10), the addition of GO was achieving CR with incomplete platelet recovery (CRp) with a median
associated with a significant reduction in cumulative incidence of relapse number of 5 post-remission cycles (range, 0–6 cycles). Three-year OS
in patients achieving CR or CRi (P = .005).249 In a follow-up landmark and RFS were 78% and 85%, respectively. The most common grade 3–4
analysis, the addition of GO was associated with significantly lower NPM1 non-hematologic adverse events were elevation of AST/ALT, respiratory
mutation transcript levels by real-time quantitative PCR (RQ-PCR) in both failure, renal insufficiency, and cardiac arrhythmias. There were no reports
BM and peripheral blood after the first cycle of induction, and this effect of SOS.
was sustained throughout all subsequent cycles.250 Four-year cumulative
incidence of relapse rates were also significantly lower in the GO arm There are conflicting data about the use of GO for patients who are older
(31.6% vs. 43.9%; P = .015) and 4-year RFS rates were superior (60.5% with AML. Three phase III randomized trials evaluated the efficacy and
vs. 48.9%; P = .028).250 In the MRC AML 15 trial, younger patients with safety of adding the anti-CD33 antibody-drug conjugate GO to induction
untreated AML (median age, 49 years) were randomized to two induction therapy with daunorubicin and cytarabine in patients who are older with
courses of: 1) daunorubicin and cytarabine with or without etoposide previously untreated AML.253-255 In the phase III ALFA-0701 trial, patients
(ADE; n = 1983); or 2) ADE versus fludarabine, cytarabine, granulocyte aged 50 to 70 years with de novo AML (n = 280) were randomized to
colony-stimulating factor (G-CSF), and idarubicin (FLAG-IDA; n = 1268).251 receive induction with daunorubicin (60 mg/m2 daily for 3 days) and

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cytarabine (200 mg/m2 continuous infusion for 7 days), with or without are older with previously untreated AML characterized by favorable- or
(control arm) fractionated GO 3 mg/m2 given on days 1, 4, and 7.255 intermediate-risk cytogenetics, not adverse-risk. A review of these studies
Patients with persistent marrow blasts at day 15 received additional led to the approval of GO in September 2017 for the treatment of adults
daunorubicin and cytarabine. Patients who achieved a CR/CRi after with newly diagnosed CD33-positive AML.
induction received two consolidation courses with daunorubicin and
cytarabine, with or without GO (3 mg/m2 on day 1). The CR/CRi after The third phase III trial combining GO with chemotherapy showed a
induction was similar between the GO and control arms (81% vs. 75%). different result than the other two. In this study, patients between the ages
The GO arm was associated with significantly higher estimated 2-year of 61 and 75 years were given chemotherapy consisting of mitoxantrone,
EFS (41% vs. 17%; P = .0003), RFS (50% vs. 23%; P = .0003), and OS cytarabine, and etoposide (n = 472).253 Half of the patients were given 6
(53% vs. 42%; P = .0368) rates compared with the control.255 The GO arm mg/m2 GO prior to chemotherapy on days 1 and 15. In remission,
was associated with a higher incidence of hematologic toxicity (16% vs. treatment included two courses of consolidation with or without 3 mg/m2
3%; P < .0001); this was not associated with an increase in the risk of GO on day 0. The OS between the two groups was similar (GO, 45% vs.
death from toxicity.255 no GO, 49%), but the induction and 60-day mortality rates were higher in
the patients given GO (17% vs. 12% and 22% vs. 18%, respectively). Only
In another multicenter, phase III, randomized trial from the UK and a small subgroup of patients <70 years of age with secondary AML
Denmark (AML-16 trial), patients >50 years of age with previously showed any benefit to treatment. Combined with the increased toxicity, the
untreated AML or high-risk MDS (n = 1115) were randomized to receive results of this study suggest that GO may not provide an advantage over
daunorubicin-based induction (daunorubicin combined with cytarabine or standard chemotherapy for some patients who are older with AML.253
clofarabine) with or without (control) GO (3 mg/m2 on day 1 of course 1 of
induction).254 The median age was 67 years (range, 51–84 years) and Conflicting studies have led to the publication of several systematic
98% of patients were ≥60 years of age; 31% were ≥70 years of age. The reviews and meta-analyses. A larger systematic review, inclusive of any
CR/CRi rate after induction was similar between the GO and control arms RCTs that investigated the benefit of anti-CD33 antibody therapy,
(70% vs. 68%). The GO arm was associated with significantly lower 3-year regardless of whether treatment was in de novo or secondary disease,
cumulative incidence of relapse (68% vs. 76%; P = .007) and higher concluded that the data from 11 trials showed increased induction deaths
3-year RFS (21% vs. 16%; P = .04) and OS (25% vs. 20%; P = .05) rates (P = .02) and reduced residual disease (P = .0009).256 Despite improved
compared with the control arm. The early mortality rates were not different RFS (HR, 0.90; 95% CI, 0.84–0.98; P = .01), no OS benefit was measured
between treatment arms (30-day mortality rate, 9% vs. 8%); in addition, no (HR, 0.96; 95% CI, 0.90–1.02; P = .2). Two other meta-analyses showed
major increase in adverse events was observed with GO.254 These two improved RFS, though induction death was elevated.257,258 Conversely, a
trials suggest that the addition of GO to standard induction regimens fourth meta-analysis evaluating 5 trials with 3325 patients ≥15 years of
reduced the risk of relapse and improved OS outcomes in patients who age showed a reduced risk of relapse (P = .0001) and improved 5-year

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OS (OR, 0.90; 95% CI, 0.82–0.98; P = .01) with the addition of GO to or death, 0.78; P = .002) compared with those on the placebo arm.261
conventional induction therapy.248 It was noted that the greatest survival These data may be extrapolated to suggest benefit in fit adults who are
benefit was seen in patients with favorable cytogenetics. Some benefit older.
was seen in patients with intermediate cytogenetics, but no benefit was
reported with the addition of GO in patients with adverse cytogenetics. A retrospective exploratory study found a consistent benefit from the
These studies underscore the need for further investigation that elucidates addition of midostaurin to standard chemotherapy in patients treated on
the benefits of GO for the treatment of AML. the RATIFY trial across different NPM1/FLT3-ITD genotypes categorized
according to the 2017 ELN risk groups (favorable, intermediate, and
Intermediate-Risk Genetics adverse).262 Five-year OS rates for patients treated in the midostaurin arm
FLT3-Positive AML: The majority of FLT3-mutated AML cases occur in compared to the placebo arm were 0.73 (95% CI, 0.60–0.89) versus 0.53
patients with intermediate-risk cytogenetics. Data have demonstrated (95% CI, 0.40–0.72) in the favorable-risk groups, 0.52 (95% CI, 0.40–0.67)
improved survival for patients with newly diagnosed FLT3-mutation– versus 0.34 (95% CI, 0.23–0.49) in the intermediate-risk groups, and 0.43
positive AML when midostaurin is added to standard chemotherapy as (95% CI, 0.32–0.56) versus 0.20 (95% CI, 0.12–0.35) in the adverse-risk
part of frontline treatment.259-261 This led to its breakthrough designation groups.
and approval by the U.S. Food and Drug Administration (FDA) in 2017. In
In the phase II AMLSG 16-10 trial in adult patients with previously
the CALGB 10603/RATIFY Alliance trial, patients aged 18 to 59 years,
untreated AML (n = 440; range, 18–70 years; 128 patients included
with newly diagnosed FLT3-mutation–positive AML (ITD or TKD) were
between the ages of 61–70 years), the efficacy and safety of midostaurin
randomized (n = 717) to receive standard cytarabine therapy (200 mg/m2
added to intensive chemotherapy, followed by allogeneic HCT and single-
daily for 7 days via continuous infusion) and daunorubicin (60 mg/m2 on
agent midostaurin maintenance therapy for a year was evaluated.263 All
days 1–3) with placebo or midostaurin (50 mg, twice daily on days 8–
patients were confirmed to have FLT3-ITD–positive disease. The CR/CRi
21).261 If residual disease in the BM was observed on day 21, patients
rate after induction therapy was 74.9% (age ≤60 years, 759%; age >60
were treated with a second blinded course. Patients who achieved CR
years, 72.4%). Forty-five percent of patients proceeded to transplant in
received four 28-day cycles of HiDAC (3 g/m2 every 12 hours on days 1, 3,
CR/CRi, and a subset initiated maintenance therapy (n = 163; 128 after
and 5) with placebo or midostaurin (50 mg, twice a day on days 8–21)
allogeneic HCT and 35 after HiDAC consolidation). The 2-year EFS and
followed by a year of maintenance therapy with placebo or midostaurin (50
OS rates were 59% and 59% in patients <60 years of age, and 41% and
mg twice a day).261 The median OS was 74.7 months (95% CI, 31.5–NR)
47% in patients >60 years of age.263 Multivariate analysis showed a
in the midostaurin group compared to 25.6 months (95% CI, 18.6–42.9) in
significant OS benefit for patients treated on AMLSG 16-10 trial compared
the placebo group (P = .009).261 Patients who received midostaurin with
to patients treated on the CALGB 10603/RATIFY Alliance trial (HR, 0.71;
standard induction and consolidation therapy experienced significant
P < .001).263
improvement in OS (HR for death, 0.78; P = .009) and EFS (HR for event

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The randomized phase 3 QuANTUM-First trial compared chemotherapy in Therapy-Related AML or Antecedent MDS/CMML or
combination with the FLT3 inhibitor quizartinib versus placebo in patients Cytogenetic Changes Consistent with MDS
(n = 539; age range, 20–75 years; median age, 56 years) with newly Although most cases of AML are de novo, secondary AML and therapy-
diagnosed FLT3-ITD mutated AML.264 For induction, quizartinib 40 mg related AML account for approximately 25% of all AML cases and are
daily versus placebo was administered on days 8 to 21 along with associated with poor outcomes.268,269 Data have demonstrated improved
standard 7 + 3 (cytarabine 100–200 mg/m2 for 7 days via continuous survival in patients with secondary AML who are older when a dual-drug
infusion and either daunorubicin 60 mg/m2 or idarubicin 12 mg/m2 on days liposomal formulation of cytarabine and daunorubicin in a 5:1 molar ratio
1–3). In the setting of persistent leukemia on BM biopsy at count recovery, (CPX-351) is used as frontline therapy.270-272 In a phase II trial, patients
reinduction with 7 + 3 or 5 + 2 plus quizartinib or placebo were treatment ≥60 years of age with newly diagnosed AML (n = 126) were randomized
options. For those achieving CR or CRi, consolidation therapy consisted of 2:1 to first-line CPX-351 or the conventional administration of cytarabine
cytarabine 1.5 to 3 mg/m2 combined with quizartinib versus placebo, and daunorubicin (7 + 3 regimen).271 Compared to the standard 7 + 3
allogeneic HCT, or both. Following consolidation, maintenance therapy regimen, CPX-351 produced higher response rates (CPX-351, 66.7% vs.
consisted of single-agent quizartinib versus placebo for ≤3 years. With a 7 + 3, 51.2%; P = .07); however, differences in EFS and OS were not
median follow-up of 39.2 months, OS was 31.9 months in the quizartinib statistically significant.271 A planned analysis of the secondary AML
arm compared to 15.1 months in the placebo arm (HR, 0.78; P = .032). subgroup demonstrated that CPX-351 was associated with a higher CR
There were similar amounts of adverse events between the two arms, rate (57.6% vs. 31.6%; P = .06).271
though neutropenia was more common in the quizartinib group.264
These results led to the development of a randomized phase III study
Some studies suggest that a higher dose of daunorubicin (90 mg/m2), comparing the efficacy and safety of CPX-351 to the conventional
compared to lower doses of either 45 or 60 mg/m2, is significantly administration of cytarabine and daunorubicin (control arm) in patients 60–
associated with increased CR and survival rates in patients with 75 years of age with newly diagnosed secondary AML (n = 309).272 With a
intermediate-risk cytogenetics and those who have FLT3-ITD mutation– median follow-up of 20.7 months, CPX-351 significantly improved OS
positive AML.265,266 A phase III study compared idarubicin (12 mg/m2 for 3 compared to the control arm (median, 9.56 vs. 5.95 months; HR, 0.69;
days) and high-dose daunorubicin (90 mg/m2 for 3 days) with standard 95% CI, 0.52–0.90; P = .003).272 CPX-351 was also associated with
cytarabine therapy during induction in young adults with newly diagnosed significantly higher overall remission (47.7% vs. 33.3%; P = .016) and CR
AML (age range, 15–65 years). It was determined that high-dose (37.3% vs. 25.6%; P = .04) rates. However, for patients with cytogenetic
daunorubicin was associated with higher OS and EFS rates in patients changes consistent with MDS (previously classified as AML-MRC) and
with FLT3-ITD mutation–positive AML.267 However, these studies did not previous HMA exposure, the benefit from standard induction did not differ
include midostaurin or quizartinib. from the benefit with CPX-351. The most frequently reported grade 3–5
adverse events in the CPX-351 and control groups were febrile

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neutropenia (68.0% vs. 70.9%), pneumonia (19.6% vs. 14.6%), and trial,274,275 patients <60 years of age were randomized (n = 301) to receive
hypoxia (13.1% vs. 15.2%).272 either HiDAC (3 g/m2 every 12 hours on days 1, 3, 5, and 7 for a total of 24
g/m2) or standard cytarabine therapy (100 mg/m2 daily for 7 days via
Other Regimens for Intermediate- or Poor-Risk continuous infusion); patients in both arms received daunorubicin (50
Cytogenetics mg/m2 on days 1–3) and etoposide (75 mg/m2 daily for 7 days). The CR
HiDAC-Containing Regimens: HiDAC as induction therapy is seldom rates were equivalent in both arms (71% and 74%, respectively), and a
used. The most recent study from the EORTC-GIMEMA AML-12 trial significantly higher 5-year RFS rate was observed in the HiDAC arm (48%
suggests that HiDAC (3 g/m2 every 12 hours on days 1, 2, 5, and 7) vs. 25%; P = .007).275 Patients in both treatment arms received only 2
improves outcome in patients who are <46 years of age.273 This study cycles of standard-dose cytarabine, daunorubicin, and etoposide for
randomized 1900 patients between the ages of 15 and 60 years into two consolidation therapy. Median remission duration was 45 months for the
treatment groups, HiDAC and standard-dose cytarabine (100 mg/m2/d by high-dose arm, compared with 12 months for the standard treatment
continuous infusion for 10 days). Both groups were also given arm.274 However, treatment-related morbidity and mortality were higher in
daunorubicin (50 mg/m2/d on days 1, 3, and 5) and etoposide (50 mg/m2/d the HiDAC arm; the 5-year OS rates were 33% in the high-dose arm
on days 1–5). Data from a median 6-year follow-up indicate an OS near compared with 25% in the standard-dose arm.275
statistical significance (HiDAC, 42.5% vs. SDAC, 38.7%; P = .06), and
when separated by age with a cutoff of 46 years, the benefit was relegated In a large SWOG study,276 patients <65 years of age (n = 665) with de
to the <46 years of age patient cohort (HiDAC, 51.9% vs. SDAC, 43.3%; novo or secondary AML were randomized to receive HiDAC (2 g/m2 every
P = .009) compared to patients ≥46 years of age (HiDAC, 32.9% vs. 12 hours for 6 days for a total of 24 g/m2; patients <50 years of age were
SDAC, 33.9%; P = .91). Other populations that benefited from HiDAC initially randomized to receive 3 g/m2 at the above schedule before the
were patients with high-risk disease, including patients with very poor-risk high-dose arm was redefined to 2 g/m2 because of toxicity concerns) or
cytogenetic abnormalities and/or FLT3-ITD mutation or with secondary standard-dose cytarabine (200 mg/m2 daily for 7 days); patients in both
AML. There was no significant increase in grade 3 or 4 toxicities except for treatment arms also received daunorubicin (45 mg/m2 daily for 3 days).
an increase in conjunctivitis (grade 2–3) with HiDAC (12.4%) versus Patients treated in the HiDAC arm received a second high-dose cycle for
SDAC (0.5%). The incidence of adverse events was equivalent (SDAC, consolidation, whereas patients in the standard-dose arm were
67.6% vs. HiDAC, 66.2%). Patients in CR received a single consolidation randomized to receive consolidation therapy with either 2 cycles of
cycle of daunorubicin and cytarabine (500 mg/m2 every 12 hours for 6 standard-dose cytarabine or 1 cycle of HiDAC plus daunorubicin. The CR
days) and subsequent HCT.273 rates were similar, with 55% for the high-dose arm compared with 58% for
the standard-dose arm for patients <50 years of age, and 45% for HiDAC
HiDAC therapy during induction was initially explored in the 1990s in two versus 53% for standard-dose therapy for patients 50 to 65 years of age.
large cooperative group trials. In an Australian Leukemia Study Group DFS rate (for patients with a CR) and OS rate (for all patients) at 4 years

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were not significantly different among treatment arms. Induction therapy course) experienced a 4-year DFS rate of 44%. Among all patients who
with HiDAC was associated with significantly higher rates of received consolidation with HiDAC, the rates of treatment-related deaths
treatment-related mortality (14% vs. 5% for patients <50 years of age; and serious neurotoxicity were 5% and 12%, respectively.277
20% vs. 12% for patients aged 50–64 years; P = .003) and grade 3 or
higher neurologic toxicity (8% vs. 2% for patients <50 years of age; 5% vs. Because the OS outcomes for the high-dose arm in the SWOG trial
0.5% for patients aged 50–64 years; P < .0001).276 For patients <50 years consisting of HiDAC induction and 2 cycles of HiDAC consolidation (4-year
of age, consolidation with HiDAC was associated with similar rates of OS rate of 52% for patients <50 years of age) were comparable to those
treatment-related mortality (2% vs. 0%) and grade 3 or higher neurologic of the CALGB trial with standard-dose infusional cytarabine induction and
toxicity (2% vs. 0%) compared with the standard dose. For the original 4 cycles of HiDAC consolidation (4-year OS rate of 52% for patients aged
cohort of patients <50 years of age who received 3 g/m2 HiDAC for ≤60 years), the use of HiDAC in the induction phase outside of a clinical
induction, the rates of treatment-related deaths (10% vs. 5%) and grade 3 trial remains controversial. A meta-analysis including 22 trials and 5945
or greater neurologic toxicity (16% vs. 2%) were higher than for those who patients with de novo AML <60 years of age demonstrated improved RFS
received the standard dose. Similarly, for patients <50 years of age who and reduced risk of relapse, particularly in the favorable-risk cytogenetics
received 3 g/m2 HiDAC for consolidation, the rates of treatment-related group, for patients receiving HiDAC versus standard chemotherapy.278
deaths (4% vs. 0%) and grade 3 or greater neurologic toxicity (16% vs. However, toxicity was a limiting factor and emphasis was placed on the
0%) were higher than for those who received the standard dose.276 importance of future studies to define the populations that would most
benefit from HiDAC and to optimize dosing recommendations. The
Patients <50 years of age who received HiDAC induction and decision to use high- versus standard-dose cytarabine for induction might
consolidation in the SWOG trial had the highest OS and DFS rates at 4 be influenced by consolidation strategies; fewer high-dose consolidation
years (52% and 34%, respectively) compared with those who received cycles may be needed for patients induced with HiDAC or for those who
standard-dose induction and consolidation (34% and 24%, respectively) or will undergo early autologous HCT. Although the remission rates are
standard induction with high-dose consolidation (23% and 14%, similar for high- and standard-dose cytarabine, two studies have shown
respectively).276 However, the percentage of patients achieving a CR who more rapid marrow blast clearance after 1 cycle of high-dose therapy and
did not proceed to consolidation was twice as high in the HiDAC induction a DFS advantage for patients ≤50 years of age who received the
arm.276 The risks for neurotoxicity and renal insufficiency are increased high-dose therapy.279 No data are available using >60 mg/m2 of
with HiDAC; therefore, both renal and neurologic function should be daunorubicin or 12 mg/m2 of idarubicin with HiDAC. With either high- or
closely monitored in patients receiving this treatment. In a CALGB trial,277 standard-dose cytarabine-based induction for younger patients, between
the subgroup of patients ≤60 years of age (n = 156) who received 20% and 45% of these patients will not enter remission. In a report of 122
standard-dose cytarabine-daunorubicin induction therapy and 4 courses of patients treated with HiDAC and daunorubicin, the remission rates were
HiDAC consolidation (3 g/m2 every 12 hours on days 1, 3, and 5, per

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strongly influenced by cytogenetics, with CR rates of 87%, 79%, and 62% initial ramp up. A cycle of reinduction was allowed from those not
for favorable-, intermediate-, and poor-risk groups, respectively.280 experiencing a response to induction. Consolidation consisted of FLAG
with abbreviated 3-day schedules of fludarabine and cytarabine, with or
As previously mentioned, in the MRC AML 15 trial, younger patients with without idarubicin for 2 consolidation cycles at provider’s discretion. ORR
untreated AML (median age, 49 years), were randomized to two induction was 97%, with a 95% composite CR (CRc) rate. Ninety percent of patients
courses of: 1) daunorubicin and cytarabine with or without etoposide achieved MRD negativity by flow cytometry and 64% of patients were
(ADE; n = 1983); or 2) ADE versus FLAG-IDA (n = 1268).251 In successfully bridged to allogeneic HCT. Three-year OS was 66% and 3-
consolidation, patients were randomized to amsacrine, cytarabine, year EFS was 64%. Grade 3–4 febrile neutropenia occurred in 78% of
etoposide, and then mitoxantrone/cytarabine, or HiDAC (3 g/m2; n = patients, though 30- and 60-day mortality rates were low and comparable
1445).251 Patients in the HiDAC arm received 1.5 g/m2 in consolidation, to other standard intensive induction regimens.
and were treated with or without a fifth course of cytarabine (n = 227).
There were no significant differences in the rate of CR between ADE and Venetoclax has also been studied in combination with cladribine,
FLAG-IDA (81% vs. 84%, respectively), but FLAG-IDA significantly idarubicin, and cytarabine (CLIA) as induction and consolidation in a
decreased relapse rates (FLAG-IDA, 38% vs. ADE, 55%; P < .001).251 A phase II study among patients with AML (n = 45) or high-risk MDS (n = 4)
randomized phase III study from the HOVON/SAKK groups compared who were eligible for intensive induction therapy.283 Thirty-five percent of
standard cytarabine/idarubicin induction with or without clofarabine (10 patients with AML met ELN adverse-risk criteria. Venetoclax was
mg/m2 on days 1–5) for patients with AML between the ages of 18 to 65 administered on days 2–8 without ramp up, though cytoreduction was
years.281 While there was no difference in the OS and EFS in the group as utilized prior to initiation of venetoclax if WBC was >20 x 109/L. ORR was
a whole, there was a decrease in relapse rate counter balanced by an 94%, with a CR rates of 84%. Eighty-two percent of patients achieved
increased rate of death in remission for the clofarabine arm. In a subset MRD negativity. With a median follow-up of 13.5 months, estimated 1-year
analysis, there was a significant improvement in OS and EFS for the ELN EFS and OS were 68% and 85%, respectively. Sixty-two percent of
intermediate I group, primarily in patients in the NPM1 wild-type/FLT3- patients were bridged to allogeneic HCT in remission, with a median of 2
ITD–negative subgroup with a 4-year EFS of 40% for the clofarabine arm cycles of therapy. Grade ≥3 febrile neutropenia occurred in 74% of
versus 18% for the control arm.281 patients. Grade ≥3 adverse events were otherwise infrequent, though
included elevated transaminases and bilirubin, rash, diarrhea, and
The combination of FLAG-IDA with the BCL-2 inhibitor venetoclax has infection.
been studied in a phase II trial among patients with newly diagnosed AML,
including those with secondary or therapy-related AML who were eligible The combination of cladribine, cytarabine, G-CSF, and mitoxantrone
for intensive induction chemotherapy (n = 77; age ≥18 years).282 Following (CLAG-M) has been studied as induction therapy for patients with AML in
protocol amendment, venetoclax was administered for 7 days following the relapsed/refractory (R/R) setting by the Polish Adult Leukemia

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Group.284,285 In a multicenter phase II study, 118 patients with R/R AML therapy options, such as an HMA combined with venetoclax, can still be
received induction therapy with cladribine 5 mg/m2, cytarabine 2 g/m2, considered. For more information on these options, see AML Induction
mitoxantrone 10 mg/m2, and G-CSF. For those who achieved PR with Therapy for Patients Ineligible for Intensive Induction.
induction, a second cycle of CLAG-M was given, while those who
NCCN Recommendations
achieved CR received consolidation with cytarabine and mitoxantrone,
with or without cladribine. CR rate was 58% following 1 to 2 cycles; one- The NCCN AML Panel strongly encourages enrollment in a clinical trial for
year OS and DFS rates were 43% and 68.6% for the entire cohort. One- treatment induction for patients with AML. Patients with AML with TP53
year OS rate was improved for patients who achieved CR, at 73%.284 mutation or del(17p) are groups with especially poor prognosis and should
Longer term follow-up revealed 4-year OS of 14% for the entire cohort and be considered for enrollment in clinical trials. For patients not enrolled in a
DFS of 30% among patients who had achieved CR.285 The most common clinical trial, genetics, overall functional status, and the risk status of the
adverse events were hematologic. Risk factors associated with worsened disease guide treatment strategies.
OS included increased age, WBC >10 x 109/L, and poor-risk karyotype,
For patients with favorable-risk AML by cytogenetics (CBF-AML),
while poor-risk karyotype was the only factor associated with worsened
infusional standard 7 + 3 (cytarabine 100–200 mg/m2 continuous infusion
DFS.
for 7 days combined with either idarubicin [12 mg/m2 for 3 days] or
CPX-351: In a post hoc analysis of a randomized phase III study daunorubicin [60–90 mg/m2 for 3 days]) combined with GO247,255 is a
assessing the efficacy and safety of CPX-351 versus 7 + 3 in patients 60 preferred recommendation. Other recommended regimens include
to 75 years of age with newly diagnosed secondary AML,272 patients were standard 7 + 3 without GO236,244 or FLAG-IDA combined with GO251
reclassified into risk groups according to the ELN 2017286 classification (should be used with caution in patients >60 years of age). FLAG with GO
system.287 Among patients with adverse-risk AML, remission rates with can be considered for patients ineligible for an anthracycline (category
CPX-351 were greater than with 7 + 3 (41% vs. 26%). Patients with TP53- 2B).252 Of note, the Panel prefers GO over FLT3 inhibitor-based regimens
mutated disease had similar remission rates with CPX-351 vs. 7 + 3 (33% for patients with CBF-AML with FLT3-TKD; however, for CBF-AML with
vs. 35%), though those without TP53-mutated disease had improved FLT3-ITD there is insufficient data to recommend one as preferred over
remission rates with CPX-351 (44% vs. 22%). Median OS and post- another.
transplant survival was also longer for patients with adverse-risk disease
For patients with favorable-risk AML by molecular mutation profile or
treated with CPX-351 compared to 7 + 3 (7.59 vs. 5.52 months and 43.14
intermediate-risk AML according to ELN risk stratification,22 the preferred
vs. 7.08 months, respectively).
regimen is standard 7 + 3 with either daunorubicin or idarubicin (category
Lower Intensity Therapy: For certain patients with poor-risk or 1 recommendation). Other recommended regimens include FLAG-IDA
secondary AML that are eligible for intensive induction, lower intensity (category 2B),251 CLAG-M (category 2B),284,285 or for CD33-positive

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disease, standard 7 + 3 with GO or FLAG-IDA with GO (category 2B). abnormalities and mutations including RUNX1, ASXL1, BCOR, EZH2,
FLAG and CLAG containing regimens should be used with caution in SF3B1, SRSF2, STAG2, U2AF1, ZRSR2, and/or TP53, are considered to
patients >60 years of age. have poor-risk disease in the context of intensive induction therapy.
Although all patients with AML are best managed within the context of an
For patients with FLT3-mutated AML, midostaurin (FLT3-ITD or TKD)261,288 appropriate clinical trial, it is particularly important that this group of
or quizartinib (FLT3-ITD only)264 are added to standard-dose cytarabine patients with poor-risk disease, particularly patients with TP53 mutation or
(200 mg/m2 continuous infusion) for 7 days combined with daunorubicin del(17p), should be entered into a clinical trial (incorporating either
(60 mg/m2 for 3 days) or idarubicin (12 mg/m2 for 3 days) (both category 1 chemotherapy or novel agents), if available, given that only 40% to 50% of
recommendations). these patients experience a CR (approximately 25% in patients who are
older with disease with poor-risk cytogenetics) with standard induction
For patients with therapy-related AML other than CBF-AML, antecedent
therapy. In addition, HLA testing should be performed promptly in those
MDS/chronic myelomonocytic leukemia (CMML), and/or cytogenetic or
who may be candidates for either fully ablative or reduced-intensity
molecular changes consistent with MDS, CPX-351 [cytarabine (100
conditioning (RIC) allogeneic HCT from a matched sibling or an alternative
mg/m2) and daunorubicin (44 mg/m2)] as an intravenous infusion over 90
donor, which constitutes the best option for long-term disease control.290
minutes on days 1, 3, and 5 of 1 cycle is a category 1, preferred
recommendation for patients ≥60 years of age. However, for patients <60 For patients with poor-risk AML not participating in clinical trials, other
years of age CPX-351 is an other recommended, category 2A recommended regimens include standard 7 + 3 (daunorubicin or
recommendation, because the trial did not include this patient idarubicin), CPX-351287 (category 2B recommendation), FLAG-IDA
population.272 For patients <60 years of age, standard 7 + 3 (daunorubicin (category 2B recommendation), CLAG-M (category 2B), and venetoclax
or idarubicin) is preferred, while for patients ≥60 years of age, standard 7 + combined with any of the following: decitabine (days 1–5), azacitidine,
3 (daunorubicin or idarubicin) is an other recommended regimen. FLAG-IDA, or CLIA (category 2B in combination with FLAG-IDA or CLIA).
Additional other recommended options include venetoclax combined with
any of the following: decitabine (days 1–5), azacitidine, FLAG-IDA, or Follow-up and Reinduction Therapy After Cytarabine-Based
CLIA (a category 2B in combination with FLAG-IDA or CLIA). There is Induction
emerging data that CPX-351 provides the most benefit for patients with To judge the efficacy of the induction therapy, a BM aspirate and biopsy
AML with mutations in SRSF2, SF3B1, EZH2, U2AF1, ZRSR2, BCOR, may be performed 14 to 21 days after start of therapy. In patients who
STAG2, or ASXL1.289 have received cytarabine-based induction and have residual disease
without hypoplasia (hypoplasia is defined as cellularity <20% of which the
Patients with unfavorable karyotypes, such as 11q23 abnormalities,
residual blasts are <5% [ie, blast percentage of residual cellularity]),
monosomy -5 or -7, monosomal karyotype, or complex cytogenetic
additional therapy with cytarabine 100 to 200 mg/m2 and anthracycline, or

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escalation to higher doses of cytarabine 1 to 3 g/m2 may be considered for Patients who have persistent disease following two courses of therapy
reinduction; no data are available to determine superiority of cytarabine (including a reinduction attempt based on mid-cycle marrow) are
100 to 200 mg/m2 versus 1 to 3 g/m2. After a BM biopsy on day 21, considered to have had a lack of response to primary induction, or primary
cytarabine 100 to 200 mg/m2 with anthracycline and midostaurin261 or refractory disease. Treatment options include clinical trial or use of
quizartinib264 should be considered for patients with FLT3-mutated AML chemotherapy regimens used for R/R disease (see Management of
(quizartinib only for FLT3-ITD AML). If dual-drug liposomal encapsulation Relapsed/Refractory AML). However, the likelihood of achieving a CR with
of cytarabine and daunorubicin was given during induction, after a BM a third chemotherapy regimen is low, at approximately 20%. If the patient
biopsy 14–21 days after induction, re-induction with CPX-351 [cytarabine did not receive cytarabine-based therapy for persistent disease at day 15,
(100 mg/m2) and daunorubicin (44 mg/m2)] as an intravenous infusion over cytarabine 2 to 3 g/m2 with or without anthracycline may be used if a
90 minutes on days 1 and 3 is recommended for patients with therapy- clinical trial is not available and a donor is not yet identified. If regimens
related AML other than CBF-AML, antecedent MDS/CMML, or cytogenetic used will result in high cumulative doses of cardiotoxic agents, consider
or molecular changes consistent with MDS.272 An HMA (azacitidine or reassessing the patient’s cardiac function before each
decitabine) combined with venetoclax may also be utilized in scenarios anthracycline/mitoxantrone-containing course.292
where less intensive consolidation is preferred.291 Additional regimens for
R/R disease, including targeted therapies, may also be considered. If the patient has an identified sibling or alternative donor available, a
transplant option should be explored, although the Panel encourages
If the marrow is hypoplastic, additional treatment selection is deferred until using alternative therapies to achieve remission prior to the transplant. For
the blood counts recover and remission status can be assessed. If there is patients whose clinical condition has deteriorated such that active
no evidence of hematologic recovery, all patients should have a repeat BM treatment is not an option, best supportive care should be continued.
aspirate and biopsy by day 42-post treatment, regardless of the degree of
hematologic recovery. Post-Remission or Consolidation Therapy in Patients Eligible for
Intensive Induction Therapy
If hypoplasia status is unclear, a repeat BM biopsy should be performed Although successful induction therapy clears the visible signs of leukemia
within 7 days before proceeding with post induction therapy. For patients in the marrow and restores normal hematopoiesis in patients with de novo
who achieve CR with the additional post induction therapy, consolidation AML, additional post-remission therapy (ie, consolidation) may be needed
therapy can be initiated upon count recovery. Screening LP should be to reduce the residual abnormal cells to a level that can be contained by
considered at first remission before first consolidation for patients with immune surveillance. For patients eligible for intensive induction therapy,
disease with monocytic differentiation, MPAL, WBC count >40 x 109/L at post-remission therapy is also based on risk status defined by
diagnosis, extramedullary disease, or FLT3 mutations. cytogenetics and molecular abnormalities (see Evaluation for AML in the
algorithm and Initial Evaluation in the Discussion).

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High-Dose Cytarabine: Since 1994, multiple (3–4) cycles of HiDAC cumulative incidence of relapse at 5 years (56% vs. 29%; P = .05) and a
therapy have been the standard consolidation regimen for patients <60 decreased 5-year OS rate (48% vs. 68%) compared with wild-type KIT; in
years of age with disease with either favorable- or intermediate-risk multivariate analysis, the presence of KIT mutations remained a significant
cytogenetics. This consolidation therapy is based on a CALGB trial predictor of decreased OS in the subgroup with inv(16). In patients with
comparing 100 mg/m2, 400 mg/m2, and 3 g/m2 doses of cytarabine.277 The t(8;21), KIT mutations were associated with a higher incidence of relapse
4-year DFS rate for patients receiving consolidation with 3 g/m2 of HiDAC at 5 years (70% vs. 36%; P = .017), but no difference was observed in
was 44%, with a 5% treatment-related mortality rate and a 12% incidence 5-year OS (42% vs. 48%).51 The CALGB trial also included 4 courses of
of severe neurologic toxicity. Although the initial report did not break down monthly maintenance chemotherapy with daunorubicin and subcutaneous
remission duration by cytogenetic groups, subsequent analysis showed a cytarabine after the consolidation phase; however, only 55% of patients in
5-year RFS (continuous CR measured from time of randomization) rate of CR received maintenance chemotherapy following HiDAC
50% for CBF-AML, 32% for patients with NK-AML, and 15% for patients in consolidation.277 Subsequent clinical trials have eliminated this form of
other cytogenetic categories (overall P < .001). Among the patients who maintenance therapy after post-remission therapy. However, the impact of
received HiDAC consolidation, the 5-year RFS rate was 78% for CBF- KIT mutations in CBF-AML is unclear. A meta-analysis of 11 studies
AML, 40% for NK-AML, and 21% for other cytogenetic categories.280 examining the effect of KIT mutations on CR, OS, and relapse rates of
CBF-AML determined that KIT mutations did not affect CR rates.293 In
In some studies, in patients with CBF-AML who received postremission patients with t(8;21) AML, KIT mutations were associated with an
therapy with HiDAC, the presence of KIT mutations resulted in poorer increased risk of relapse and shorter OS rates compared to inv(16)
outcomes, particularly in t(8;21).45,51 In a multicenter study, patients with AML.293
CBF-AML (n = 67) were enrolled in intensive chemotherapy protocols that
involved HiDAC postremission therapy.45 At 24 months, a KIT mutation in Some studies suggest that after induction, relative to KIT mutations, MRD
the TKD at codon 816 (TKD816) in patients with t(8;21) was associated with may be a more relevant prognostic factor for CBF-AML risk
a significantly higher incidence of relapse (90% vs. 35.3%; P = .002) and stratification.286,294-296 In a prospective study, adult patients with CBF-AML
lower OS (25% vs. 76.5%; P = .006) compared to wild-type KIT.45 In CBF- (aged 18–60 years; n = 198) were randomized to receive a reinforced
AML with inv(16), TKD816 did not result in a significant difference in relapse induction course (treatment arm A) or standard induction course
incidence and OS.45 The prognostic influence of TKD816 and other (treatment arm B), followed by 3 HiDAC consolidation courses.295
mutations in exon 17 (mutKIT17) versus other recurrent KIT mutations in Treatment arm A consisted of a first sequence with daunorubicin (60
CBF-AML, such as exon 8 (mutKIT8), have been investigated.51,100 In an mg/m2/day by a 30-minute IV infusion) on days 1 and 3 and cytarabine
analysis of adult patients <60 years of age with CBF-AML treated on (500 mg/m2 continuous infusion) from days 1 to 3, followed by a second
CALGB trials (n = 110), KIT mutations (mutKIT17 and mutKIT8) among sequence at day 8 with daunorubicin (35 mg/m2/day by a 30-minute IV
patients with disease with inv(16) were associated with a higher infusion) on days 8 and 9, and cytarabine (1000 mg/m2 every 12 hours by

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a 2-hour infusion) on days 8 and 10.295 Treatment arm B consisted of cytarabine; cycle 1: cytarabine, 1 g/m2 every 12 hours for 5 days +
cytarabine (200 mg/m2 continuous infusion) for 7 days combined with idarubicin, 12 mg/m2 daily for 3 days; cycle 2: cytarabine, 2 g/m2 every 12
daunorubicin (60 mg/m2 for 3 days). In treatment arm B, at day 15 a hours for 4 days + amsacrine, 120 mg/m2 daily for 3 days). Patients who
peripheral blood and BM evaluation was performed followed by a second experienced a CR after both treatment cycles were eligible to receive
sequence of chemotherapy in patients who reached CR.295 In addition, consolidation with a third cycle of chemotherapy or autologous or
MRD levels were serially monitored for RUNX1::RUNX1T1 and allogeneic HCT.298 A similar proportion of patients in each treatment arm
CBFB::MYH11 by RQ-PCR in BM samples before the first, second, and received consolidation, specifically 26% to 27% with a third chemotherapy
third consolidation courses. In this study, both treatment arms cycle, 10% to 11% with autologous HCT, and 27% to 29% with allogeneic
demonstrated similar efficacy. After first consolidation, higher WBC, KIT HCT. No significant differences were observed between the
gene mutations and/or FLT3 gene mutations, and a <3-log MRD reduction intermediate- and high-dose arms in rates of CR (80% vs. 82%), 5-year
were associated with a higher specific hazard of relapse, but MRD was the EFS (34% vs. 35%), or 5-year OS (40% vs. 42%).298 These results are
only prognostic factor in multivariate analysis.295 At 36 months, the comparable to those from the CALGB study with HiDAC.277 More than
cumulative incidence of relapse and RFS were 22% versus 54% (P < 50% of patients in each arm had already experienced a CR when they
.001) and 73% versus 44% (P < .001) in patients who achieved 3-log MRD received cycle 2. The 5-year cumulative rate of relapse risk was also
reduction versus other patients.295 A prospective study analyzed the effect similar between treatment arms (39% vs. 27%, respectively).298 Outcomes
of a condensed HiDAC consolidation therapy schedule given on days 1, 2, were poor for patients with disease with monosomal karyotype at baseline
and 3 versus the commonly used schedule of days 1, 3, and 5 in adult (n = 83), although the high-dose regimen was associated with significantly
patients (aged 18–60 years) with AML (n = 176), and found that there was improved rates of 5-year EFS (13% vs. 0%; P = .02) and OS (16% vs. 0%;
no cumulative hematologic toxicity and no change in survival.297 P = .02) compared with patients in this subgroup receiving the
intermediate-dose. The incidence of grade 3 or 4 toxicities after cycle 1
Intermittent shortages of several chemotherapy agents have raised the was higher in the high-dose arm than in the intermediate-dose arm (61%
question of how best to use cytarabine. The HOVON/SAKK study vs. 51%; P = .005), but the incidence of 30-day mortality was the same in
compared a double-induction concept using intermediate-dose cytarabine both arms (10%).298 This study suggests that 2 cycles of
or HiDAC as part of an induction/consolidation regimen in a phase III intermediate-dose cytarabine (1 g/m2 every 12 hours for 6 days; total dose
randomized study in patients (age 18–60 years) with newly diagnosed 12 g/m2 per cycle) for each consolidation cycle may be a feasible
AML (n = 860).298 Patients were randomized to treatment with an alternative to 3 cycles of HiDAC (3 g/m2 for 6 doses; total dose of 18 g/m2
“intermediate-dose” cytarabine regimen (12 g/m2 cytarabine; cycle 1: per cycle). This study as well as the MRC AML 15 study251 suggest that
cytarabine, 200 mg/m2 daily for 7 days + idarubicin, 12 mg/m2 daily for 3 doses of 3 g/m2 of cytarabine are not clearly more effective than lower
days; cycle 2: cytarabine, 1 g/m2 every 12 hours for 6 days + amsacrine, doses of 1.5–3 g/m2; in the MRC AML 15 trial, the cumulative incidence of
120 mg/m2 daily for 3 days) or a “high-dose” cytarabine regimen (26 g/m2

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relapse was statistically lower for higher dose cytarabine but this did not donor group (n = 61; 75% underwent HCT) and 48.5% for the no-donor
translate into better RFS.251 group (n = 104; 62.5% underwent HCT).300 The incidence of relapse was
35% and 47%, respectively, and the incidence of death in CR was 20%
Intermediate-Dose Cytarabine: The prospective CALGB trial277 and 5%, respectively. The 4-year OS rate among patients with
established the efficacy of HiDAC consolidation in patients ≤60 years of intermediate-risk disease was 53% for the donor group and 54% for the
age with AML.277 In this study, a subgroup of patients ≥60 years of age no-donor group.300
with AML who received standard-dose cytarabine-daunorubicin induction
therapy and more than one course of HiDAC consolidation (3 g/m2 every The SWOG/ECOG trial reported a 5-year survival rate (from time of CR) of
12 hours on days 1, 3, and 5, per course) experienced severe 44% with allogeneic HCT (n = 18; 61% underwent HCT) and 13% with
neurotoxicity and a 4-year DFS rate of <16%.277 Although the CALGB trial autologous HCT (n = 20; 50% underwent HCT) among the subgroup of
did not show an overall benefit for higher doses of cytarabine patients with unfavorable cytogenetics. Moreover, the 5-year survival rate
consolidation in patients ≥60 years of age,277 a subset of patients with a was similar between those allocated to autologous HCT and those
good performance status, normal renal function, and a normal or low-risk intended for chemotherapy consolidation alone (13% and 15%,
karyotype might be considered for a single cycle of cytarabine (1.0–1.5 respectively).38 The 5-year survival rates (from time of CR) for patients
g/m2 daily for 4–6 doses) without an anthracycline. In a study by Sperr et with disease with intermediate-risk cytogenetics were 52% for the
al, the CALGB consolidation was modified and given as intermediate-dose allogeneic HCT group (n = 47; 66% underwent HCT) and 36% for the
cytarabine at 1 g/m2 every 12 hours on days 1, 3, and 5, per course, for 4 autologous HCT group (n = 37; 59% underwent HCT).38
cycles in a group of AML patients >60 years of age.299 In this study, the
treatment was well-tolerated without neurotoxicity and 25 of 47 patients In the UK MRC AML 10 trial, significant benefit with allogeneic HCT was
received all 4 consolidation cycles. The median OS, DFS, and continuous observed for the subgroup of patients with disease with intermediate-risk
CR were 10.6, 15.5, and 15.9 months, respectively.299 The probability of cytogenetics (but not for those with disease with favorable or high-risk
OS, DFS, and continuous CR at 5 years was 18%, 22%, and 30%, cytogenetics). In this subgroup, the DFS (50% vs. 39%; P = .004) and OS
respectively.299 rates (55% vs. 44%; P = .02) were significantly higher among the donor
groups than the no-donor groups.301
Allogeneic Hematopoietic Transplantation: In the EORTC/GIMEMA
trial, a 43% 4-year DFS rate was reported in the donor group of patients The role of myeloablative allogeneic HCT is limited in patients who are
with disease with poor-risk cytogenetics (n = 64; 73% underwent HCT); older because of significant comorbidities; however, ongoing interest has
this was significantly higher than the 4-year DFS rate (18%; P = .008) been shown in RIC allogeneic HCT as consolidation therapy.302,303 Case
among the no-donor group (n = 94; 46% underwent HCT).300 The 4-year series and analysis of registry data have reported encouraging results,
DFS rate among patients with intermediate-risk AML was 45% for the with 40% to 60% 2-year OS rates and 20% non-relapse mortality for

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patients who underwent transplant in remission.302,303 In a retrospective in first CR was associated with a significantly lower 3-year cumulative
analysis comparing outcomes with RIC allogeneic HCT and autologous relapse rate (22% vs. 62%; P < .001) and a higher 3-year RFS rate (56%
HCT in patients ≥50 years of age based on large registry data, RIC vs. 29%; P < .001) compared with the non-HCT group. Although HCT was
allogeneic HCT was associated with lower risk for relapse and superior associated with a significantly higher rate of non-relapse mortality (21%
DFS and OS relative to autologous HCT.302 The authors also noted that a vs. 3%; P < .001), the 3-year OS rate showed a survival benefit with HCT
survival benefit was not observed in the subgroup of patients undergoing (62% vs. 51%; P = .012).306 Among the patients who underwent allogeneic
RIC allogeneic HCT in first CR because of an increased incidence of non- HCT, myeloablative conditioning was used in 37% of patients, whereas
relapse mortality. RIC was used in 61%. Survival outcomes between these groups were
similar, with 3-year OS rates of 63% and 61%, respectively.306
Estey et al304 prospectively evaluated a protocol in which patients ≥50
years of age with disease with unfavorable cytogenetics would be Another study evaluating treatment in patients 60 to 70 years of age
evaluated for a RIC allogeneic HCT.304 Of the 259 initial patients, 99 compared outcomes between RIC allogeneic HCT reported to the Center
experienced a CR and were therefore eligible for HCT evaluation. Of these for International Blood and Marrow Transplant Research (n = 94) and
patients, only 14 ultimately underwent transplantation because of illness, standard chemotherapy induction and postremission therapy from the
lack of donor, declining, or unspecified reasons. The authors compared CALGB studies (n = 96).307 Allogeneic HCT in first CR was associated with
the results of RIC allogeneic HCT with those from matched participants significantly lower 3-year relapse (32% vs. 81%; P < .001) and higher
receiving conventional-dose chemotherapy. This analysis suggested that 3-year leukemia-free survival rates (32% vs. 15%; P < .001) compared
RIC allogeneic HCT was associated with improved RFS, and the authors with the chemotherapy-only group. As would be expected, allogeneic HCT
concluded that this approach remains of interest.304 In an analysis of was associated with a significantly higher rate of non-relapse mortality
outcomes between two different strategies for matched-sibling allogeneic (36% vs. 4%; P < .001) at 3 years; the 3-year OS rate was not significantly
HCT, outcomes in patients ≤50 years of age (n = 35) receiving different between the groups (37% vs. 25%; P = .08), although there was
conventional myeloablative allogeneic HCT were compared with those in a trend favoring allogeneic HCT.307 A prospective multicenter phase II
patients >50 years of age (n = 39) receiving RIC allogeneic HCT.305 This study examined the efficacy of RIC allogeneic HCT in patients 60 to 74
study showed similar rates of 4-year non-relapse mortality (19% and 20%, years of age with AML in first CR (n = 114).308 After allogeneic HCT, DFS
respectively), and no difference was seen in relapse and OS rates.305 and OS at 2 years were 42% (95% CI, 33%–52%) and 48% (95% CI,
39%–58%), respectively, for the entire group.308 A time-dependent
A retrospective study based on data in patients 50 to 70 years of age with analysis of four successive prospective HOVON-SAKK AML trials
AML compared outcomes in patients who underwent allogeneic HCT examined data from patients ≥60 years of age who obtained a first CR
(either myeloablative conditioning or RIC; n = 152) with those who did not after induction chemotherapy (n = 640).309 For patients who received
receive HCT in first CR (chemotherapy only; n = 884).306 Allogeneic HCT

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allogeneic HCT as post-remission therapy (n = 97), a 5-year OS rate was For those with intermediate-risk AML, consolidation options include
35% (95% CI, 25%–44%).309 cytarabine or cytarabine with daunorubicin and GO for those with CD33-
positive disease. Allogeneic HCT is also an option for those who have
Collectively, these studies suggest that RIC allogeneic HCT is a feasible already achieved remission and have a donor available.
treatment option for patients ≥60 years of age, particularly those in first CR
with minimal comorbidities and who have an available donor. For this For those with poor-risk AML with and without TP53 mutation or del(17p)
strategy to be better used, potential transplant options should be abnormality, therapy-related AML (other than CBF-AML), antecedent
considered during induction therapy, and alternative donor MDS/CMML, and cytogenetic changes consistent with MDS, consolidative
options/searches should be explored earlier in the disease management. allogeneic HCT is preferred for those in remission with an available donor.
Other consolidation options include CPX-351/dual-drug liposomal
NCCN Recommendations
encapsulation of cytarabine and daunorubicin or FLAG-IDA (preferred for
Consolidation therapy options for patients with favorable-risk AML by those who received those agents during induction therapy). For patients
cytogenetics (CBF-AML) or by molecular mutation profile per ELN22 who received lower intensity regimens for induction, such as HMAs with
include cytarabine; cytarabine (5 or 7 days) combined with daunorubicin or venetoclax, these regimens can be continued as consolidation therapy.
idarubicin, or mitoxantrone for those ≥60 years of age; and cytarabine with
GO or cytarabine with daunorubicin or idarubicin and GO for those with For patients with FLT3-mutated disease, intermediate-risk, poor-risk, or
CD33-positive disease. GO regimens should only be given during secondary AML, maintenance therapy or allogeneic HCT (if not previously
consolidation if also utilized during induction. Consolidation should be performed) for those who are eligible are options following consolidation
followed by maintenance therapy for those eligible or by consideration of therapy.
allogeneic HCT for patients who are unable to complete consolidation or
who have high-risk disease features such as MRD positivity or KIT AML Induction Therapy for Patients Ineligible for Intensive
Induction
mutation. Of note, patients who receive transplant shortly following GO
administration may be at risk for developing SOS.310 If transplant is In patients who cannot tolerate intensive treatment strategies, low-intensity
planned, it should be noted that prior studies have used a 60- to 90-day approaches have been investigated, including use of HMAs alone or
interval between the last administration of GO and HCT. combined with venetoclax.

Options for consolidation therapy for patients with FLT3-mutated disease Hypomethylating Agents (HMAs)
include allogeneic HCT (preferred for FLT3-ITD), cytarabine combined An international, randomized, phase III study by Fenaux et al311 compared
with midostaurin (FLT3-ITD or TKD) or quizartinib (FLT3-ITD only). the HMA 5-azacitidine with conventional care (best supportive care,
low-dose cytarabine, or intensive chemotherapy) in patients with MDS
(n = 358). Although this study was designed for evaluation of treatment in

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patients with high-risk MDS (based on FAB criteria), 113 study patients 22% with a CR in 14% of patients across all dose levels.315 A phase II
(32%) fulfilled criteria for AML using the 2008 WHO classification, with study targeting patients ≥60 years of age with AML who were not
marrow-blast percentages between 20% and 30%.311,312 In the subgroup candidates for or declined intensive therapy, administered a decitabine
of these patients with AML, a significant survival benefit was found with dose of 20 mg/m2 for 10 days and demonstrated a CR rate of 47% (n =
5-azacitidine compared with conventional care regimens, with a median 25) after a median of 3 cycles of therapy.316 In a study aimed at identifying
OS of 24.5 months versus 16 months (HR, 0.47; 95% CI, 0.28–0.79; the relationship between molecular markers and clinical responses to
P = .005).312 The 2-year OS rates were 50% and 16%, respectively decitabine, adult patients with AML and MDS (n = 116; median age, 74
(P = .001). In a phase III study focused on adult patients ≥65 years of age, years; range, 29–88 years) were treated with decitabine (20 mg/m2 for 10
the efficacy and safety of azacitidine versus conventional care regimens days every 28 days).317 Response rates were higher among patients with
(standard induction chemotherapy, low-dose cytarabine, or supportive disease with unfavorable-risk cytogenetics compared to patients with
care) was evaluated in patients with newly diagnosed AML with >30% disease with favorable- or intermediate-risk cytogenetics (67% vs. 34%,
blasts.313 Compared to conventional care regimens, azacitidine was respectively; P < .001), and in the setting of TP53 mutations compared to
associated with an increase in median OS (6.5 vs.10.4 months; HR, 0.85; wild-type TP53 (100% vs. 41%; P < .001).317 A phase II study comparing a
95% CI, 0.69–1.03; stratified log-rank P = .1009).313 The 1-year survival 5-day versus 10-day treatment schedule for decitabine in patients ≥60
rates with azacitidine and conventional care regimens were 46.5% and years of age (n = 71) with newly diagnosed AML determined that the
34.2%, respectively. efficacy and safety of both schedules were not significantly different.318

Another HMA, decitabine, has also been evaluated as remission induction In an open-label, randomized, phase III study, decitabine (20 mg/m2 for 5
therapy for patients who are older with AML.314 In a phase II study in days every 28 days) was compared with physician’s choice (either
previously untreated patients ≥60 years of age (n = 55; median age, 74 low-dose cytarabine [20 mg/m2/day SC for 10 consecutive days every 28
years), the overall CR rate with this agent (20 mg/m2 for 5 days every 28 days] or supportive care) in patients ≥65 years of age with newly
days) was 24% (including 6 out of 25 patients [24%] with poor-risk diagnosed AML.319 Based on the protocol-specified final analysis of the
cytogenetics), and the median EFS and OS were 6 months and 8 months, primary endpoint (OS), decitabine was associated with a statistically
respectively.314 An earlier phase I study evaluated different dose nonsignificant trend for increased median OS compared with physician’s
schedules of decitabine in patients with R/R leukemias (n = 50; AML choice (7.7 vs. 5 months; HR, 0.85; 95% CI, 0.69–1.04; P = .108). A
diagnosis, n = 37).315 In this study decitabine was given at 5, 10, 15, or 20 subsequent post hoc analysis of OS with additional follow-up time showed
mg/m2 for 5 days per week for 2 to 4 consecutive weeks (ie, 10, 15, or 20 the same median OS with a statistically significant advantage associated
days). The decitabine dose of 15 mg/m2 for 10 days (n = 17) was with decitabine (HR, 0.82; 95% CI, 0.68–0.99; P = .037). The CR
associated with the highest response rates, with an ORR of 65% and CR (including CRi) rate was significantly higher with decitabine (18% vs. 8%;
rate of 35%. Among the patients with R/R AML (n = 37), the ORR was P = .001).319 The most common treatment-related adverse events with

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decitabine versus cytarabine included thrombocytopenia (27% vs. 26%), months) and median duration of follow-up of 15.1 months (range, 9.8–31.7
neutropenia (24% vs. 15%), febrile neutropenia (21% vs. 15%), and months), 67% of patients achieved CR/CRi.321 The median duration of
anemia (21% vs. 20%). The 30-day mortality rates were similar between CR/CRi and median OS was 11.3 months and 17.5 months,
the decitabine and cytarabine groups (9% vs. 8%).319 Both azacitidine and respectively.321 In a subgroup analysis, the CR/CRi rates of patients with
decitabine are approved by the FDA for the treatment of patients with disease with intermediate- and poor-risk cytogenetics were 74% and 60%,
MDS. with a median duration of 12.9 months (95% CI, 11.0 months–NR) versus
6.7 months (95% CI, 4.1–9.4 months), respectively.321 The CR/CRi rates in
Venetoclax-Containing Regimens
the setting of TP53, IDH1/2, and FLT3 mutations were 47%, 71%, and
Studies have evaluated the combination of HMAs with venetoclax, an oral 72%, respectively. In addition, patients with de novo AML and secondary
BCL2 inhibitor, as an induction therapy strategy for patients who are older AML, respectively, had the same CR/CRi rate of 67%, with a median
with AML.320-323 In a phase Ib study, patients ≥65 years of age with duration of CR/CRi of 9.4 months (95% CI, 7.2–11.7 months) versus NR
previously untreated AML (n = 57) were enrolled into 3 groups: group A (n (95% CI, 12.5 months–NR).321 In a phase 3 follow-up to this study, at a
= 23) received venetoclax and decitabine (20 mg/m2 daily for 5 days of median follow-up of 20.5 months, the median OS was 14.7 months in the
each 28-day cycle); group B (n = 22) received venetoclax and azacitidine group treated with azacitidine and venetoclax and 9.6 months in the group
(75 mg/m2 daily for 7 days of each 28-day cycle); and group C, a substudy treated with azacitidine only (control) (HR, 0.66; 95% CI, 0.52–0.85;
of venetoclax and decitabine (n = 12), received an oral CYP3A inhibitor, P = .001).322 The CR/CRi rate was also higher in the azacitidine and
posaconazole, to determine its effect on the pharmacokinetics of venetoclax group versus the control group (66.4% vs. 28.3%, respectively;
venetoclax.320 Daily target doses for venetoclax in different cohorts within P = .001).322
groups A and B were 400 mg, 800 mg, and 1200 mg. The most common
treatment-related adverse event in groups A and B was febrile neutropenia Another phase Ib/II study evaluated the efficacy of venetoclax combined
(30% and 32%, respectively), with an overall CR/CRi rate of 61% (95% CI, with low-dose cytarabine (20 mg/m2 daily for 10 days) in patients ≥60
47.6–74.0). In groups A and B, the CR/CRi rate was 60% (95% CI, 44.3– years of age with previously untreated AML ineligible for intensive
74.3).320 chemotherapy (n = 82; median age, 74 years).323 All patients received at
least one dose of venetoclax at 600 mg. The CR/CRi rate was 54% (95%
In a follow-up to this study, the efficacy of either 400 mg or 800 mg of CI, 42%–65%) with a median duration of remission of 8.1 months (95% CI,
venetoclax combined with either decitabine or azacitidine was evaluated in 5.3–14.9 months), and the median OS for all patients was 10.1 months
patients ≥65 years of age with previously untreated AML and who were (95% CI, 5.7–14.2 months).323 Patients with de novo AML, intermediate-
ineligible for intensive chemotherapy (n = 145; median age, 74 years).321 risk cytogenetic features, and no prior HMA exposure demonstrated
The venetoclax dose of 400 mg was found to be the recommended phase CR/CRi rates of 71%, 63%, and 62%, respectively.323 The average
II dose. With a median time on study of 8.9 months (range, 0.2–31.7 CR/CRi rates in the setting of NPM1 or IDH1/2 mutations were higher than

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in the setting of TP53 or FLT3 mutations (89% and 72% vs. 30% and 44%, A recent meta-analysis of four clinical trials with 440 patients with AML
respectively).323 who were ineligible for intensive chemotherapy revealed a pooled CR rate
of 40% and a pooled CR/CRi rate of 64% for venetoclax combined with
A randomized, placebo-controlled, phase III study also evaluated the HMAs or LDAC, respectively.325 Median OS for all patients was 11.7 (95%
efficacy of venetoclax combined with low-dose cytarabine at a dose of 20 CI, 10.15–14.18) months. Another meta-analysis comparing venetoclax
mg/m2 SC daily for 10 days in adults ≥18 years of age (median age, 76 with HMA or LDAC revealed significant improvements in OS with
years) deemed ineligible for intensive chemotherapy.324 Venetoclax dosing venetoclax with azacitidine compared to single-agent azacitidine (HR,
was ramped up over a 4-day period to a target dose of 600 mg daily. At 0.66), LDAC azacitidine (HR, 0.57), and best supportive care azacitidine
preplanned primary analysis (median follow-up, 12 months), no significant (HR, 0.37).326 Similarly, venetoclax with LDAC led to significant
difference in median OS was noted between the venetoclax/ low-dose improvements in OS compared with LDAC (HR, 0.70) and best supportive
cytarabine and placebo/ low-dose cytarabine arms (7.2 months vs. 4.1 care (HR, 0.46).
months, respectively, HR, 0.75; 95% CI, 0.52–1.07; P = .11) However, at
updated analysis, with an additional 6 months of follow-up, median OS Venetoclax has also been studied in triplet combinations, including with
was 8.4 months for the venetoclax/low-dose cytarabine arm versus 4.1 LDAC and cladribine. In a phase II study, the efficacy of
months for the placebo/ low-dose cytarabine arm (HR, 0.70; 95% CI, venetoclax/cladribine/LDAC alternating with venetoclax/azacitidine was
0.50–0.99; P = .04). CR/Cri rates were 48% for the venetoclax/ low-dose evaluated in 60 patients with newly diagnosed AML deemed ineligible for
cytarabine arm versus 13% in the placebo/low-dose cytarabine arm (P < intensive therapy (n = 60; median age, 68 years; range, 57–84 years).327
.001), and benefit was seen across all patient subgroups (including AML Patients received cladribine 5 mg/m2 IV on days 1 to 5, LDAC 20 mg SC
with baseline intermediate or poor cytogenetic risk, and AML with TP53-, twice daily days 1 to 10, and venetoclax 400 mg once daily days 1 to 21
IDH/1/2-, FLT3-, or NPM1-mutations). EFS was also improved in the following ramp up. Cytoreduction with either hydroxyurea, cytarabine, or
venetoclax/ low-dose cytarabine arm compared to the placebo/LDAC arm, ATRA was utilized prior to the start of therapy for patients with WBC >20 x
at 4.7 months and 2 months, respectively (HR, 0.58; 95% CI, 0.42–0.82; P 109/L. Patients not experiencing CR/CRi following induction were eligible
= .002). for a second induction cycle. Consolidation cycles alternated between
venetoclax/cladribine/LDAC and venetoclax with azacitidine 75 mg/m2 IV
Based on these studies, venetoclax in combination with HMAs, decitabine or SC days 1 to 7 up to 18 total cycles. Composite CR was 93%, with 84%
or azacitidine, or low-dose cytarabine are approved by the FDA for the of patients achieving MRD negativity. With a median follow-up of 22.1
treatment of newly diagnosed AML in adults ≥75 years, or in patients who months, neither median OS nor DFS were reached. Only one patient
have comorbidities that preclude use of intensive induction chemotherapy. experienced grade 4 TLS. Febrile neutropenia and pneumonia were the
most common nonhematologic grade 3–4 adverse events.

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Low-Dose Cytarabine-Containing Regimens pathway, and evaluated in patients ≥55 years of age with previously
Other approaches have evaluated low-dose cytarabine. The UK NCRI untreated AML or high-risk MDS ineligible for intensive chemotherapy (n =
AML 14 trial randomized 217 patients who were older (primarily aged >60 132).330 Criteria for unsuitability for intensive chemotherapy included being
years; de novo AML, n = 129; secondary AML, n = 58; high-risk MDS, ≥75 years of age, having serum creatinine >1.3 mg/dL, and having severe
n = 30) and unfit for intensive induction chemotherapy to receive either cardiac disease or ECOG score = 2. Patients were randomized 2:1 to
low-dose cytarabine subcutaneously (20 mg twice daily for 10 consecutive receive low-dose cytarabine alone (20 mg twice daily for 10 days every 28
days, every 4–6 weeks) or hydroxyurea (given to maintain target WBC days) or combined with oral glasdegib (100 mg daily). The addition of
counts <10 x 109/L).328 Patients were also randomized to receive ATRA or glasdegib to low-dose cytarabine also improved OS compared to low-dose
no ATRA. Low-dose cytarabine resulted in a CR rate of 18% (vs. 1% with cytarabine alone (8.8 months vs. 4.9 months, respectively), and the CR
hydroxyurea) and a survival benefit compared with hydroxyurea in patients rates were higher in the low-dose cytarabine and glasdegib arm (17%, n =
with favorable or NK-AML. No advantage was observed with the addition 15/88) compared to low-dose cytarabine alone (2.3%; n = 1/44).330 In the
of ATRA. The median DFS in patients who achieved a CR with low-dose glasdegib plus low-dose cytarabine arm, the benefit in CR was primarily
cytarabine was 8 months.328 Even with this “low-intensity” treatment seen in patients with disease with favorable-/intermediate-risk
approach, induction death occurred in 26% of patients, and overall cytogenetics (n = 10/52) when compared to patients with disease with
prognosis remained poor for patients who were older who could not poor-risk cytogenetics (n = 5/36).330 Glasdegib in combination with low-
tolerate intensive chemotherapy regimens. A phase II study evaluated a dose cytarabine is currently approved by the FDA for the treatment of
regimen with low-dose cytarabine (20 mg twice daily for 10 days) newly diagnosed AML in patients ≥75 years of age, or in patients who
combined with clofarabine (20 mg/m2 daily for 5 days) in patients ≥60 have comorbidities that preclude use of intensive induction chemotherapy.
years of age with previously untreated AML (n = 60; median age, 70
years; range, 60–81 years).329 Patients who achieved a response received CD33-Positive AML
consolidation (≤17 courses) with clofarabine plus low-dose cytarabine Single-agent GO has also been evaluated as an option for induction
alternated with decitabine. Among patients with evaluable data (n = 59), therapy for those not eligible for intensive induction. A randomized phase
the CR rate was 58% and median RFS was 14 months. The median OS III study evaluated the efficacy of single-agent GO (6 mg/m2 on day 1 and
for all patients was 12.7 months. The induction mortality rate was 7% at 8 3 mg/m2 on day 8) versus best supportive care as first-line therapy in
weeks.329 Although this regimen appeared to be active in patients who are patients ≥61 years of age with AML who were not eligible for intensive
older with AML, the authors noted that the benefits of prolonged chemotherapy (n = 237).331 Compared to best supportive care, GO alone
consolidation remain unknown. improved the 1-year OS rate (9.7% vs. 24.3%, respectively). In the GO
group, the median OS was 4.9 months (95% CI, 4.2–6.8 months) and 3.6
In a phase II trial, low-dose cytarabine was combined with glasdegib, a months (95% CI, 2.6–4.2 months) in the best supportive care group.331
selective inhibitor of the Smoothened protein in the Hedgehog signaling

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IDH Mutation-Positive AML was 41.2% (95% CI, 24.6%–59.3%), and the ORR was 58.8% (20/34;
Initially approved by the FDA for use in the R/R AML setting, IDH-targeted 95% CI, 40.7%–75.4%).90,332 Based on these data, ivosidenib was
inhibitors have demonstrated utility in the frontline setting.88,91,332-334 In a approved by the FDA in May 2019 as a first-line treatment option for AML
phase I/II study, the clinical activity and safety of enasidenib, an IDH2 with an IDH1 mutation in patients who are ≥75 years old or who have
mutant inhibitor, was evaluated in adult patients with IDH2-mutated comorbidities that preclude the use of intensive induction chemotherapy.
advanced AML including R/R disease.335 Approximately 19% of patients (n
= 34 of 176) with R/R AML achieved CR, with an OS of 19.7 months with a In a more recent phase III randomized study, the safety and efficacy of
median OS of 9.3 months.335 In patients ≥60 years with newly diagnosed azacitidine combined with ivosidenib versus placebo for newly diagnosed
AML, the efficacy of enasidenib was evaluated in a phase Ib/II sub-study IDH1-mutated AML in patients (n = 146) ineligible for intensive induction
within the Beat AML trial.88 Patients were treated with enasidenib (100 was assessed.91 With a median follow-up of 12.4 months, EFS was
mg/day) in continuous 28-day cycles. Azacitidine (75 mg/m2 days 1–7) significantly longer with azacitidine combined with ivosidenib compared to
was added to enasidenib for some patients who did not achieve CR/CRi placebo (P = .002). Similarly, median OS was improved in the
by cycle 5. Of 23 patients with evaluable data receiving enasidenib azacitidine/ivosidenib arm (24 vs. 7.9 months; P = .001). Rates of
monotherapy, CR/CRi was achieved in 43% of patients (7 CR/2 CRi).88 differentiation syndrome, grade ≥3 neutropenia, and bleeding were higher
in the azacitidine/ivosidenib arm, while rates of grade ≥3 febrile
In an ongoing phase I/II study, the safety and efficacy of enasidenib plus neutropenia and infection were higher in the azacitidine/placebo arm.
azacitidine was compared to azacitidine alone in 101 patients (median
age, 75 years) with newly diagnosed, IDH2-mutated AML.89 In the phase II The IDH1 inhibitor olutasidenib has also shown activity in the frontline
portion of the study, ORR was improved with enasidenib plus azacitidine setting. In a phase I/II study, patients with newly diagnosed or R/R IDH1-
compared to azacitidine alone (74% [50/68] vs. 36% [12/33], respectively; mutated AML arising from a myeloproliferative disorder (n = 15; median
P = .0003). age, 67 years; range, 48–83 years) were treated with either olutasidenib
monotherapy or olutasidenib in combination with azacitidine.333 In the
Ivosidenib, an IDH1-mutation inhibitor, demonstrated durable remissions newly diagnosed cohort, CRc was achieved in 53% of patients, including 3
in IDH1 R/R AML, with 30.2% of patients (n = 54 of 179) with R/R AML patients treated with olutasidenib monotherapy. CR was achieved in 40%
achieving CR/CR with partial hematologic recovery (CRh).336 As an of patients with a median duration of CR of 15.6 months. With a median
extension of this study, the safety and efficacy of ivosidenib in patients follow-up of 55.3 months, median OS was 20.9 months among those who
with untreated AML was evaluated (n = 34; median age, 76.5 years).90,332 achieved response and 13.8 months among the entire cohort of patients
In a phase I dose-escalation and expansion study, patients received with newly diagnosed disease. In a similar phase I/II study assessing the
ivosidenib once daily or twice daily in 28-day cycles, and a dose of 500 mg safety and efficacy of olutasidenib with or without azacitidine among 78
per day was selected as the dose for expansion groups. The CR/CRh rate

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adults with newly diagnosed or R/R IDH1-mutated AML, ORR was 77% treatment induction of patients with AML who are ineligible for intensive
with combination therapy and 25% with monotherapy.334 induction therapy. For patients not enrolled in a clinical trial, treatment
options include lower intensity therapy based on the presence or absence
Treatment with IDH inhibitors may induce differentiation syndrome and of an IDH1 mutation.
hyperleukocytosis, which may be managed with corticosteroids and
hydroxyurea.337-339 In the absence of an IDH1 mutation, preferred regimens include
venetoclax combined with HMAs (azacitidine [category 1] or decitabine).
Alternatively, as previously discussed emerging data suggest that patients Cladribine with LDAC and venetoclax is another recommended, category
with de novo AML characterized by IDH1/2-mutant AML may benefit from 2B recommendation. Other options that may be useful in certain
venetoclax/HMA-based therapy with reported remission rates of >70%, circumstances include low-dose cytarabine combined with venetoclax or
albeit in a relatively small number of patients.87,321 glasdegib. For patients with FLT3 mutations who are not eligible for a
preferred regimen, gilteritinib alone or combined with azacitidine (FLT3-
FLT3-Positive AML
ITD or TKD) is a treatment option. For patients with IDH2 mutations not
The phase III randomized LACEWING trial compared the safety and
eligible for a preferred regimen, enasidenib alone or in combination with
efficacy of azacitidine plus gilteritinib, a FLT3 inhibitor that has
azacitidine are treatment options. Patients not considered candidates for
demonstrated antileukemic activity in FLT3-positive R/R AML,340,341 to
preferred, combination, or targeted therapy may receive monotherapy with
azacitidine alone in patients (n = 123; median age, 78 years) with newly
HMA (azacitidine or decitabine), GO alone, or low-dose cytarabine alone.
diagnosed FLT3-mutated AML who were ineligible for intensive induction
Best supportive care with hydroxyurea and transfusion support should also
chemotherapy.342 Though OS was similar with gilteritinib/azacitidine
be considered and have been used as the comparator arm in several
compared to azacitidine alone (9.82 vs. 8.87 months; P = .753), CRc rates
clinical trials in patients who are older or unfit for intensive induction.
were significantly higher with gilteritinib/azacitidine (58.1% vs. 26.5%; P <
.001). Rates of adverse events were also similar between the two arms. For patients with IDH1-mutant AML, preferred treatment options include
azacitidine in combination with ivosidenib or venetoclax (both category 1
There is emerging evidence that venetoclax combined with azacitidine and
recommendations), or decitabine combined with venetoclax. Ivosidenib
gilteritinib may be beneficial in patients with FLT3-mutated AML who are
monotherapy is an other recommended treatment option. Other regimens
ineligible for intensive chemotherapy,343 though with careful dosing to
that may be useful in certain circumstances include venetoclax combined
reduce the incidence of significant cytopenias.
with low-dose cytarabine (for those with prior exposure to an HMA) or low-
NCCN Recommendations intensity therapy with azacitidine or decitabine (for those with a
Similar to recommendations for patients eligible for intensive induction contraindication to venetoclax). Given that olutasidenib is associated with
therapy, the NCCN AML Panel encourages enrollment in a clinical trial for less severe QTc prolongation compared to ivosidenib in clinical

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trials333,334,336, olutasidenib monotherapy may be useful for those not azacitidine once daily for 7 days per cycle (n = 3 at 200 mg; n = 4 at 300
eligible for a preferred regimen and not eligible for ivosidenib monotherapy mg), and 23 received oral azacitidine for 14 days per cycle (n = 4 at 150
due to a prolonged QTcF (a category 2B recommendation). mg; n = 19 at 200 mg [expansion cohort]).346 At 19 months of follow-up,
median OS was NR and estimated 1-year survival rates were 86% and
Post-Remission or Consolidation Therapy in Patients Ineligible for 81% in the 7-day and 14-day dosing cohorts, respectively.346
Intensive Induction Therapy
NCCN Recommendations In the international phase 3 trial, QUAZAR AML-001, investigators
Previous Lower Intensity Therapy: For patients who previously evaluated the efficacy of oral azacitidine as post-remission therapy in adult
received lower intensity therapy, a marrow to document remission status patients (≥55 years of age) who had newly diagnosed AML or secondary
upon hematologic recovery should be performed, with the timing AML, and had experienced CR or CRi after induction with intensive
dependent on the therapy used. If a response is observed, allogeneic HCT therapies but were ineligible for allogeneic HCT (n = 472; median age, 68
may be considered for select patients if a donor is available. Alternatively, years; range, 55–86 years).347 Within 4 months of attaining CR or CRi,
low-dose therapies used in induction with demonstrated efficacy may be patients were randomized to receive placebo (n = 234) or 300 mg of oral
continued until progression (see AML Induction Therapy for Patients azacitidine (n = 238) once daily on days 1 to 14 of repeated 28-day
Ineligible for Intensive Induction; NCCN Recommendations). Thereafter, treatment cycles. A 21-day dosing schedule was allowed for patients who
maintenance therapy can be considered for those who are eligible. experienced AML relapse with 5% of 15% blasts in blood or BM while
enrolled in the study. This treatment schedule could continue indefinitely
If no response or progression is seen, a clinical trial, therapies for R/R or until the presence of >15% blasts, unacceptable toxicity, or allogeneic
AML (see Management of Relapsed/Refractory AML), or best supportive HCT. At a median follow-up of 41.2 months, median OS was 24.7 months
care are recommended options. and 14.8 months in the oral azacitidine and placebo arms, respectively
(HR, 0.69; 95% CI, 0.55–0.86; P = .0009). In addition, the median RFS
Maintenance Therapy
was significantly prolonged in the oral azacitidine arm at 10.2 months
Hypomethylating Agents: To improve treatment outcomes, some compared to the placebo arm at 4.8 months (HR, 0.65; 95% CI, 0.52–0.81;
studies have evaluated the efficacy of maintenance therapy with HMAs P = .0001). Based on these data, in September 2020, the FDA approved
after induction or allogeneic HCT. CC-486 is a novel oral formulation of oral azacitidine for continued treatment of patients with AML who achieved
azacitidine that allows prolonged exposure in patients with hematologic first CR or CRi following intensive induction chemotherapy and are not
malignancies.344,345 In a phase I/II trial evaluating the efficacy of oral able to complete intensive postremission therapy. In a post hoc analysis,
azacitidine as maintenance therapy after allogeneic HCT in adult patients patients with NPM1-mutated AML had improvement in OS by 37% (HR,
(≥18 years) with AML or MDS, patients received 1 of 4 dosing schedules 0.63; 95% CI, 0.41–0.98) and RFS by 45% (HR, 0.55; 95% CI, 0.35–0.84)
per 28-day cycle for ≤12 cycles.346 Of 30 patients, 7 received oral with oral azacitidine compared to placebo.348 Oral azacitidine also led to a

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37% OS (HR, 0.63; 95% CI, 0.35–1.12) and 49% RFS benefit (HR, 0.51; .012) and OS (P = .06) in the entire cohort. A significant improvement in
95% CI, 0.27–0.95) in patients with FLT3-mutated AML compared to OS was noted in patients with FLT3-ITD-negative AML (P = .039).
placebo. For both patients with NPM1-mutated AML and FLT3-mutated
AML, median OS benefit was seen regardless of MRD status post A multicenter, phase II, randomized trial compared maintenance therapy
intensive chemotherapy. with low-dose decitabine to no intervention in patients with high-risk AML
who achieved MRD negativity post-allogeneic HCT (n = 202 with
In a phase 3 randomized trial, HOVON97, investigators evaluated the evaluable data).352 High risk was defined as AML with poor-risk
efficacy of maintenance therapy with azacitidine in patients with AML or cytogenetics per ELN, primary refractory or relapsed AML, or secondary
MDS with refractory anemia with excess of blasts (n = 116; aged ≥60 AML. Patients in the low-dose decitabine arm received decitabine 5
years) who were in CR or CRi after intensive chemotherapy.349 Patients mg/m2 IV days 2 to 6 combined with recombinant human G-CSF (rhG-
were randomized to either observation (n = 60) or treated with azacitidine CSF) SC on days 1 to 6 every 6 to 8 weeks for up to 6 cycles. Two-year
(n = 56) at 50 mg/m2 subcutaneously on days 1 to 5 every 4 weeks until cumulative incidence of relapse was significantly lower in the low-dose
relapse for a maximum of 12 cycles.349 Thirty-five patients received at decitabine arm (15% vs. 38.3%; P < .01). Two-year cumulative incidence
least 12 cycles of azacitidine and the estimated 12-month DFS for the of chronic GVHD was similar between the two groups (23% in the low-
azacitidine and observation groups was 64% and 42%, respectively (log dose decitabine arm vs. 21.7% in the control arm; P = .82). The most
rank, P = .04).349 common adverse events in the low-dose decitabine arm were
hematologic.
A randomized trial compared conventional care (low-dose cytarabine or
intensive chemotherapy) to decitabine 20 mg/m2 days 1 to 5 every 4 to 8 FLT3 Inhibitors: TKIs have been studied as maintenance therapy in
weeks in patients (n = 50 [45 with evaluable data]; median age, 57 years; patients with AML with FLT3 mutations.
range, 24–79) with AML in first or subsequent CR.350 With a median
follow-up of 44.9 months, fewer patients experienced relapse in the In a phase III study, patients (n = 202) with FLT3-ITD–mutated AML who
decitabine arm, though this was not statistically significant (50% vs. 60%; underwent allogeneic HCT with CRc before and after transplant were
P = .7). There was also no significant difference in OS (45% vs. 36%; P = assigned to maintenance sorafenib or control upon hematologic count
.9) or EFS (35% vs. 32%; P = .9). Another randomized phase II trial recovery between 30 to 60 days post-transplant.353 With a median follow-
compared the safety and efficacy of an abbreviated 3-day schedule of up of 60.4 months post-transplant, maintenance sorafenib was associated
decitabine 20 mg/m2 IV every 4 weeks for 1 year to observation in patients with improved OS (72% vs. 55.9%; P = .011), leukemia-free survival (70%
≥60 years of age (n = 120; median age 69 years) with AML treated with vs. 49%; P = .0007), and GVHD-free, RFS (58% vs. 39.2%; P = .003)
intensive induction therapy in the ECOG-ACRIN E2906 phase III trial.351 compared to control. Maintenance sorafenib was also associated with
Abbreviated decitabine was associated with improvement in DFS (P = lower cumulative incidence of relapse compared to control (15% vs.

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36.3%; P = .0003). There was no significant increase noted in non-relapse In a four-part phase I study, the safety and efficacy of the TKI gilteritinib
mortality or 5-year cumulative incidence of chronic GVHD with sorafenib was assessed in patients (n = 80; median age, 59 years; range, 23–77
maintenance. years) with newly diagnosed FLT3 mutation-positive AML.356 Patients
received standard 7 + 3 (daunorubicin or idarubicin) induction and HiDAC
In the phase II SORMAIN trial, patients (n = 83) in complete hematologic consolidation, both combined with gilteritinib, followed by gilteritinib
CR after allogeneic HCT were randomized to sorafenib or placebo for 24 maintenance. CRc was 81.8% among patients in all dose groups (40–200
months post-transplant.354 With a median follow-up of 41.8 months, HR for mg daily) and 81.6% among patients who received the recommended
relapse or death for the sorafenib arm compared to the placebo arm was expansion dose (120 mg daily). Median OS was NR at 35.8 months.
0.39 (95% CI, 0.18–0.85; log-rank P = .013) and the probability of RFS at Among patients with FLT3-ITD mutated disease who received a dose of
24 months was higher in the sorafenib arm (85% vs. 53.3%; P = .002). ≥120 mg daily and achieved CRc, 70% achieved mutational clearance.
Randomized trials are needed for further data.
In the previously discussed CALGB 10603/RATIFY Alliance trial (see
Induction Therapy, Risk-Stratified Treatment Strategies, and Intermediate- The efficacy of the TKI quizartinib was investigated in a phase III trial, in
Risk Genetics) patients with newly diagnosed FLT3-mutation–positive which patients with newly diagnosed FLT3-ITD–mutated AML (n = 539;
AML (ITD or TKD) were randomized to receive chemotherapy in median age, 56 years; range, 18–75 years) were randomized to quizartinib
combination with the TKI midostaurin or placebo during induction and versus placebo combined with standard 7 + 3 (daunorubicin or idarubicin)
consolidation, followed by post-chemotherapy maintenance with induction chemotherapy.264 Those who achieved Cr/CRi moved on to
midostaurin or placebo.261 Fifty-seven percent of patients on trial consolidation with either HiDAC plus quizartinib or placebo, allogeneic
underwent allogeneic HCT during their disease course. In a sensitivity HCT, or both. Consolidation was followed by maintenance quizartinib or
analysis that censored data at the time of transplant, 4-year OS was placebo. Rates of CRc following 1 to 2 cycles of induction were higher in
higher in the midostaurin arm, though not statistically significant (63.7% the quizartinib arm (72% vs. 65%). With a median follow-up of 39.2
vs. 55.7%; P = .08), although patients did not go on to receive post- months, there was a significant OS benefit for the quizartinib arm (31.9 vs.
transplant maintenance.261 In a phase II trial in patients aged 18 to 70 15.1 months; P = .032). OS was also improved in the quizartinib arm in a
years with FLT3-ITD–mutated AML in CR1 following allogeneic HCT, prespecified sensitivity analysis that censored for patients who proceeded
patients were randomized to standard treatment (chosen by treating to allogeneic HCT at any point in time.
provider) with or without midostaurin.355 Among 30 patients who completed
a full 12 cycles of therapy, both 18-month RFS (89% vs. 76%; P = .27)
and estimated 24-month OS (85% vs. 76%; P = .34) favored the
midostaurin arm, though not significantly so.

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NCCN Recommendations Throughout maintenance therapy patients should be reassessed for

appropriateness of their current regimens, treatment intensity, and
Post-chemotherapy
potential candidacy for allogeneic HCT.
For patients with non-CBF-AML in CR following intensive chemotherapy
who completed no consolidation or some consolidation and for whom no Principles of Venetoclax Use with HMAs or Low-Dose Cytarabine-
allogeneic HCT is planned, oral azacitidine until progression or Based Treatment
unacceptable toxicity is a category 1, preferred maintenance therapy With growing use of venetoclax-based therapies (eg, venetoclax with
option for those >55 years of age (category 2A recommendation for all HMAs or low-dose cytarabine), and the fact that these therapies may be
others). For patients unable to receive oral azacitidine, single-agent given for an indefinite duration as long as patients’ disease responds or
conventional HMA therapy with azacitidine or decitabine for a maximum of patients derive hematologic benefit from the therapies, the AML Panel
12 cycles may be considered. There are certain circumstances where oral reviewed the literature and emerging guidelines that can inform a
azacitidine may be of benefit for those who have completed a consensus on ways to optimize use of these therapies. The AML Panel
recommended course of consolidation.348 highly recommends consultation with a high-volume tertiary
care/academic medical center throughout the course of treatment for
For patients with FLT3-mutated AML who have previously received an
community centers utilizing venetoclax-based therapies.
FLT3 inhibitor and for whom no allogeneic HCT is planned, quizartinib
(FLT3-ITD only; preferred for FLT3-ITD) and midostaurin (FLT3-ITD or Given that ELN risk stratification is largely intended for patients treated
TKD) are maintenance therapy options. with intensive induction therapy, Döhner and colleagues analyzed data
from patients treated on the phase III VIALE-A trial322 and on a phase 1B
Post-allogeneic HCT
study321 to develop a prognostic risk classification system for patients
For patients with FLT3-ITD– or TKD-mutated AML in CR following
treated with venetoclax and an HMA. 357 Patients with TP53-mutated AML
allogeneic HCT, gilteritinib, midostaurin, and quizartinib are maintenance
were found to derive lower benefit; patients with AML with KRAS and/or
therapy options. For patients with FLT3-ITD–mutated AML in pre-
NRAS and/or FLT3-ITD mutations and without mutations in TP53 were
transplant CR1 without MRD negativity by ultrasensitive assay, gilteritinib
found to derive intermediate benefit; and those with AML without
is preferred. Sorafenib is another post-allogeneic HCT maintenance
mutations in TP53, KRAS, NRAS, or FLT3-ITD were found to derive
therapy option for patients with FLT3-ITD–mutated AML only.
higher benefit from venetoclax combined with an HMA.
For patients with a history of AML with poor-risk features in remission
For patients with newly diagnosed disease, venetoclax with HMA or low-
post-allogeneic HCT, low-dose decitabine + G-CSF is a recommended
dose cytarabine should be given concomitantly. There are ongoing studies
category 2B option for maintenance therapy.352
into the addition of a third agent to the combinations described in this

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NCCN Guidelines Version 3.2026

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section, and participation in clinical trials is encouraged. Prior to first cycle, the Panel recommends continuing treatment regardless of
administering therapy, it is important to achieve a WBC count of <25 x cytopenias until a response assessment is made,360 with aggressive
109/L with hydroxyurea or leukapheresis if needed.358 It is worth noting that transfusion support and supportive care as needed. The Panel also
the data supporting a beneficial role for leukapheresis in this context are recommends withholding growth factors until after the first cycle
limited.359 In addition, venetoclax is a substrate of CYP3A4, so dose response assessment.358 However, G-CSF is encouraged for
adjustments of venetoclax are recommended when concurrently using neutropenic patients who are in morphologic remission but whose counts
venetoclax with strong or moderate CYP3A4 inhibitors, most commonly have not recovered at the end of a treatment cycle. A BM biopsy is
the azole class of antifungal agents.360,361 The AML Panel recommends necessary for response assessment on days 21 to 28 of the first cycle,358
consulting with a pharmacist for potential drug interactions and referring to perhaps on the earlier end of this range for patients who receive the
venetoclax prescribing information. Strong or moderate CYP3A4 inducers combination of venetoclax and decitabine.
(eg, carbamazepine, phenytoin, rifampin) should be avoided. Initiating
therapy with a reduced duration of venetoclax (eg, 7 days) may be If there is no morphologic remission (blasts are ≥5%) at first cycle
considered for patients with substantial comorbidities.362 response assessment but evidence of efficacy exists, a second cycle
should proceed without interruption with the goal of achieving
To minimize the development of TLS—which is uncommon in this morphologic remission. A repeat BM biopsy should then be performed on
setting358—during the first cycle of treatment, inpatient treatment is days 21 to 28 of this cycle, or subsequent cycles, until morphologic
strongly recommended, especially through dose escalation. The remission is achieved.
intrapatient dose escalation for venetoclax with HMA is 100 mg, 200 mg,
and 400 mg given daily on days 1 to 3; and the intrapatient dose If blasts are <5% at first cycle response assessment and counts have
escalation for venetoclax with low-dose cytarabine is 100 mg, 200 mg, recovered (CR), a second cycle can proceed. If blasts are <5% at first
400 mg, and 600 mg given daily on days 1 to 4. 358 Concomitant cycle response assessment and cytopenias are present (morphologic
interacting medications may require changes to these dosages. To leukemia-free state [MLFS] or CRi), all treatment should be held and the
minimize and avert further risk of TLS, the Panel recommends following measures should be considered: growth factor support, if
aggressive monitoring of blood chemistries; monitoring and managing indicated; and a treatment-free interval for up to 14 days. Longer delays
electrolyte imbalances; and treatment with allopurinol or other uric acid- may also be considered. When counts have recovered to a clinically
lowering agent until there is no further risk of TLS.358 significant threshold (ANC >0.5 x 109/L and platelets >50 x 10 9/L), the
next cycle of treatment can begin. 358 If counts have not recovered to a
Venetoclax and HMAs have been shown to induce prolonged cytopenias clinically significant threshold, consider repeating the BM biopsy. If
even after achieving remission, and neutropenia is a dominant treatment- morphologic remission is ongoing, therapy can continue to be held or a
related toxicity associated with this combination of agents. 363 During the

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second cycle can proceed with adjustments to dose or schedule of leukemic cells below the threshold of detection by conventional
venetoclax and HMA or low-dose cytarabine.358 morphologic methods. Patients who have achieved a CR by morphologic
assessment alone can still harbor a large number of leukemic cells in the
During subsequent cycles of treatment, if remission was observed after BM.365 After completion of therapy, “molecular relapses” can predict
the first cycle, sequential cycles should continue with up to 14-day hematologic relapses within a 3- to 6-month timeframe.364 Due to the
interruptions between cycles for count recovery and/or growth factor rapidly evolving nature of this field and the undeniable need for monitoring,
support.358 If there is no evidence of disease after the first cycle and MRD is still under investigation, with NCCN recommendations as
assuming no unexpected changes in blood counts occur, consideration discussed below.
can be made to repeat the BM biopsy at 3- to 6-month intervals, or as
needed based on clinical suspicion for relapse, depending on the goals While morphologic assessment is the first step in a cure for AML, there
of the patient. If count recovery worsens over time, relapsed disease remains a level of MRD that currently lacks any standardized method of
should be ruled out with a repeat BM biopsy. 358 If morphologic remission monitoring. The threshold to define MRD+ and MRD- samples depends on
is ongoing with worsening blood counts, consider decreasing the the technique and subgroup of AML. There are commercially available
duration, and/or dose, of venetoclax and/or HMA or low-dose cytarabine. tests that can be used for MRD assessments, as well as further testing
However, if there is no morphologic remission after the second or third methods at certain academic centers. The most frequently used methods
cycle, the likelihood of response is decreased, and consideration should for MRD assessment include quantitative molecular assays such as
be made for enrollment in a clinical trial if available. If no clinical trial is RQ-PCR and multicolor flow cytometry assays. RQ-PCR amplifies
available, and there has been some disease response with manageable leukemia-associated genetic abnormalities, while flow cytometric profiling
toxicity, therapy may be continued as long as it is tolerated. detects leukemia-associated immunophenotypes (LAIPs).366-368 Both
methods have a higher sensitivity than conventional morphology. RQ-PCR
If venetoclax and HMA or low-dose cytarabine are being given to has a sensitivity of 10-3 to 10-5, while flow cytometry has a sensitivity
patients with R/R AML, the Panel recommends antifungal prophylaxis. 363 between 10-4 to 10-5. The challenge of incorporating these techniques into
Other recommendations for TLS, intrapatient dose escalation, BM routine practice is a lack of standardization and established cutoff values,
biopsies, and cytopenia mitigation plans are similar to considerations that though ongoing research is focused on addressing these limitations. Most
have been described. of what is known about MRD monitoring has been done in the APL
population369,370; however, these techniques are now expanding to include
Role of MRD Monitoring
other AML subtypes.371 Emerging technologies include digital PCR and
There is compelling evidence in both children and adults with AML that NGS.365 NGS-based assays can be used to detect mutated genes through
detectable MRD following achievement of remission is associated with an targeted sequencing gene panels,372,373 though their routine use is not
increased risk of relapse.364 MRD in AML refers to the presence of recommended for MRD assessment given higher sensitivities of PCR- and

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Acute Myeloid Leukemia

flow cytometry-based methods.365 A highly sensitive NGS-based, targeted, childhood non-APL AML cases, respectively.269,375 Mutations in AML
deep-sequencing assay with a sensitivity level of ≤10-5 is recommended include NPM1, DNMT3A, and FLT3-ITD mutations. NPM1 mutations are
for detection of FLT3-ITD, however. seen in approximately one-third of adult AML cases, while <10% of
childhood cases have this mutation.376,377 Similarly, the DMNT3A mutation
The data from these methods have been correlated with AML treatment is found at a higher percentage in adult (15%–20%) compared to
outcome and the preliminary results are promising. A systematic review childhood (2%) AML.92,378,379 The FLT3-ITD mutation is found in 25% of
and meta-analysis including 11,151 patients with AML reported significant adult and 15% of childhood AML.63,380 Two less well-studied mutations that
differences in estimated 5-year RFS and OS among patients who may serve as MRD markers include CEBPA and MLL-PTDs.381 Finally, the
achieved negative MRD compared to patients with residual MRD (64% vs. main target of gene overexpression in AML is the Wilms’ tumor (WT1)
25% and 68% vs. 34%, respectively).364 Refinement of these methods that gene. Taken together, these putative targets for MRD monitoring
take into account variables including the intrinsic nature of the transcript as encompass the majority of AML cases.
well as factors of the patient population, including age, disease severity,
and treatment, will make MRD monitoring in patients with AML a more A study of 29 patients with either RUNX1::RUNX1T1 or CBFB::MYH11
reliable tool. AML during postinduction and post-consolidation chemotherapy did not
observe a correlation with survival.382 However, the authors did correlate a
Because a high-quality sample is essential for reliable treatment ≥1 log rise in RQ-PCR transcript relative to the remission BM sample as
evaluation, the NCCN AML Panel recommends that the optimal sample for indicative of inferior leukemia-free survival and imminent morphologic
MRD assessment is a first dedicated pull of the BM. Once MRD-negative relapse.382 Another study evaluated BM from 53 patients during
remission by BM is achieved, peripheral blood can be utilized for consolidation therapy and was the first to establish clinically relevant MRD
surveillance of MRD for PML::RAR alpha, NPM1,374 CBFB::MYH11, and cut-off values for the CBFB::MYH11 transcript to stratify patients at
RUNX1::RUNX1T1.295 increased risk of relapse.294 PCR negativity in at least one BM sample
during consolidation therapy was predictive of a 2-year RFS of 79% as
Methods of Testing
compared to the 54% seen in the setting of PCR-positivity. Similarly, Yin et
Molecular al296 found that a <3-log reduction in RUNX1::RUNX1T1 transcript in BM
or a >10 CBFB::MYH11 copy number in peripheral blood after 1 course of
RQ-PCR induction chemotherapy was highly predictive of relapse.296 A study in 15
There are three classifications of RQ-PCR targets: leukemic fusion genes, patients with childhood AML showed that increased RUNX1::RUNX1T1
mutations, and gene overexpression. The most investigated leukemic transcript levels were predictive of relapse.383 MLL fusion transcripts for
fusion genes are RUNX1::RUNX1T1, CBFB::MYH11, and MLL (KMT2A) MRD monitoring have also been analyzed in 19 patients with
fusion transcripts. Gene fusions are found in 20% and 35% of adult and t(9;11)(q22;q23) AML. Eleven of these patients showed negative PCR for

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the MLL fusion transcripts, which were associated with a better outcome. relapse versus 53% for patients with a positive PCR.392 This correlation
While most studies have shown a correlation between transcript level and was also seen when taken after completion of therapy. In addition, an RQ-
outcome, a study of childhood AML showed RQ-PCR of PCR analysis of 2596 samples from 346 patients with NPM1-mutated AML
RUNX1::RUNX1T1 to be a poor marker for relapse and the method to be demonstrated that MRD was the only independent prognostic factor for
inferior to flow cytometry.384 The different outcomes of the studies highlight mortality (HR, 4.84; 95% CI, 2.57–9.15; P < .001) and persisting NPM1-
the need for standardization of these methods. It also may be an indication mutated transcripts were associated with relapse.374
of variability between adult and pediatric populations, a factor that must be
considered when establishing methods and cutoffs. CEBPA and MLL-PTDs are additional targets for MRD monitoring by
RQ-PCR.381,399 While data suggest both transcripts may be suitable MRD
The use of RQ-PCR in mutations is hampered by the inability to markers, the small sample sizes limit current use of these markers until
distinguish the number of cells containing transcripts, as each cell may data can be extrapolated to a larger population. Mutations associated with
have variable levels. Furthermore, these transcripts still may be detected clonal hematopoiesis of indeterminate potential (CHIP) and aging
in cells that have differentiated in response to treatment and are no longer including DNMT3A, TET2, and potentially ASXL1 are not considered
clonogenic, thereby giving a false positive.385,386 Another caveat is the reliable MRD markers.372,373,400
instability of mutations that may result in false negatives. This is
particularly true for FLT3-ITD387-389 and NPM1 mutations.390-392 Despite Gene overexpression studies have focused on WT1. Retrospective data
these complications, several studies have correlated NPM1 mutations and show that a lower level of WT1 after induction therapy is associated with
outcome.130,374,391,393-397 In a small study of 25 patients, the use of a higher long-term remission.401 A meta-analysis of 11 trials, encompassing 1297
sensitivity RQ-PCR was shown to circumvent transcript instability, patients, showed the poor prognostic significance of WT1 level.402 WT1
ultimately showing that FLT3-ITD MRD monitoring was predictive of was overexpressed in 86% of marrow and 91% of blood samples from 504
relapse.398 patients with AML when compared to 204 healthy donors.403 However,
when using the cutoff values of >100-fold detection, only 46% of blood and
In comparison to FLT3-ITD, data suggest that NPM1 mutations may be 13% of marrow samples in the cohort were positive.403 This reflects the
more stable.393 Schittger et al396 developed and tested primers for 17 outliers of the healthy population that have higher WT1 transcripts.
different mutations of NPM1.396 Serial analyses of 252 NPM1-mutated Furthermore, only 19% of childhood AML samples met this criterion in a
AML samples at 4 time points showed a strong correlation between the study.404 While WT1 is a strong candidate for MRD monitoring, early
level of NPM1mut and outcome. Kronke et al392 further modified this method studies show that there is variability in the detection of this transcript that
to show that NPM1mut levels after double induction and consolidation must first be addressed. In a retrospective study of AML patients who
therapy reflected OS and cumulative incidence of relapse.392 In 245 underwent allogeneic HCT (n = 74), a multigene MRD RQ-PCR array
patients, PCR negativity had a 6.5% 4-year cumulative incidence of predicted clinical relapses occurring in the first 100 days after allogeneic

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NCCN Guidelines Version 3.2026

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HCT compared with 57% sensitivity using WT1 RQ-PCR alone.405 Notably, threshold and only 100 of the 1215 samples (8%) with <5% myeloblasts
for patients in CR prior to allogeneic HCT, the presence of pre- fell into this category. The ability of MRD monitoring to predict an
transplantation MRD positivity in peripheral blood testing was associated unfavorable EFS was statistically significant (P < .0001).384 In a study of
with survival similar to patients with pathologist BM-based diagnosis of adult patients with AML who underwent allogeneic HCT from peripheral
active disease.405 blood or BM donor (n = 359), pre-transplant staging with flow cytometry
demonstrated similar outcomes in 3-year OS and PFS estimates between
Highly Sensitive NGS-Based Assays patients with MRD-positive morphologic remission and patients with active
In a retrospective observational study, among patients ≥18 years of age disease (26% vs. 23% and 12% vs. 13%, respectively) when compared to
with AML in first CR prior to allogeneic HCT, persistence of FLT3-ITD patients in MRD-negative remission (73% and 67%, respectively).409
variants at an allele fraction of ≥0.01% in peripheral blood by a highly
sensitive NGS-based, targeted, deep-sequencing assay was associated The most difficult issue facing flow cytometry as an effective method for
with a higher 3-year risk of relapse (68% vs. 21%; P < .001) and worsened MRD monitoring is standardization and training. Flow cytometry relies
3-year OS (39% vs. 64%; P < .001).406 heavily on the expertise of the technician who must take into account
variability in instruments, fluorochromes, analysis software, and individual
Flow Cytometry antigens. Variations in the treatment schedule, dosing, type of treatment,
Flow cytometry for the monitoring of AML measures the presence of and time of draw are also potential variables. Despite the issues with flow
tumor-specific antigens and abnormalities not found on normal BM cells. cytometry, research is focused on improving the method by defining
Several known markers identify abnormal cells or cell maturation, and threshold cutoff values410-413 as well as generating standards to equalize
when used as a panel these markers can define cell populations.407 data among different instruments and software programs. If using flow
Studies in both adult and childhood AML cases show a correlation cytometry to assess MRD, it is recommended that a specific MRD assay
between flow cytometry and relapse. Loken et al408 showed that 7 of 27 that incorporates both different from normal and LAIPs assessment is
patients who had not achieved morphologic remission had negative MRD utilized, but, most importantly, that it is interpreted by an experienced
by flow cytometry. All 7 patients were long-term survivors when compared hematopathologist, preferably at the same laboratory as diagnostic flow
with the remaining 20 patients. Conversely, in a separate study of 188 cytometry for consistency. Utilization of an assay with minimum limit of
patients in morphologic remission, <5% had high levels of MRD by flow detection of ≤10-3 is recommended.
cytometry.408 A larger study of 1382 follow-up BM samples from 202
A study by Feller et al414 further defined LAIPs and evaluated whether data
children with AML demonstrated MRD to be a predictor of relapse. In this
from an established MRD monitoring laboratory could be replicated in four
study 28 of the 38 samples (74%) with >15% myeloblasts had
centers with no significant prior experience. Increased success rates of
measurements of ≥0.1% by flow cytometry. In patients with 5% to 15%
defining LAIPs were seen in all four centers after extensive group
myeloblasts, 43 of the 129 patients (33%) were detected by the same

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discussion. The inexperienced laboratories had a success rate of 82% to alpha, MRD monitoring is recommended every 3 months for at least 24
93% for defining at least one LAIP in a sample from 35 evaluable samples. months. Patients receiving venetoclax-based low-intensity therapy may
The missed LAIPs would have resulted in 7% to 18% of the patients being achieve MRD-negative remission at later time points, including a
unevaluable by MRD in these centers. The number of samples incorrectly significant minority after 4 to 6 cycles of therapy. Therefore, repeat testing
evaluated increases if they included samples in which at least two LAIPs may be obtained. NPM1 molecular MRD is strongly prognostic in patients
were identified by the primary lab, but the other labs only detected one receiving venetoclax-based low-intensity therapy. The Panel supports
LAIP. This accounted for an additional 9% to 20% of cases that would monitoring NPM1 by RQ-PCR every 6 to 12 weeks in the BM or peripheral
have resulted in false negatives. LAIPs with high specificity and sensitivity blood in patients receiving venetoclax-based low-intensity therapy.420
(MRD levels of .01%) were very well-defined in the multicenter analysis.
Management of MRD Positivity
With regard to the missed LAIPs, the authors proposed the design of
redundant panels to account for immunophenotypic shift. Inconsistencies Following an MRD-positive result, it is recommended that repeat testing
in LAIPs with MRD of ≤0.1% may be resolved with the use of a greater should be performed within a short interval (eg, 1 month) if there is no
number of fluorochromes.415 Another important conclusion from this hematologic relapse, and a BM biopsy and aspirate should be performed.
publication was the ability of these methods to be applied to different Confirmation of MRD positivity in this setting is an indicator of high risk of
instruments; both the Beckman Coulter and the Becton Dickinson relapse and consideration should be made for allogeneic HCT, clinical
instruments were tested and obtained similar results. MRD monitoring is a trial, consolidation strategies, targeted therapy where appropriate, or
more feasible option if performed in core facilities until greater research is therapy for R/R disease as clinically indicated.
done on the method to eliminate variability. Enrollment in clinical trials that
For NPM1, CBFB::MYH11, and RUNX1::RUNX1T1-mutated AML, if MRD
provide MRD monitoring is encouraged.
is persistently positive after induction and/or consolidation, consideration
Timing of MRD Assessment should be made for a clinical trial or alternative therapies, including
The timing of MRD assessments will vary and depend on the regimen allogeneic HCT.
used,295,374 but may occur after achievement of morphologic
The Panel recommends post-transplant maintenance gilteritinib for
remission372,373,400 and at the time of and following allogeneic
patients with BM FLT3-ITD MRD ≥10-6 by a highly sensitive, NGS-based,
transplantation.416
targeted, deep-sequencing assay with a sensitivity level of ≤10-5 pre- or
For NPM1-mutated,CBFB::MYH11, and RUNX1::RUNX1T1 AML, MRD post-allogeneic HCT.421 As there is no clear optimal management of MRD
assessment is recommended after 2 cycles of intensive chemotherapy positivity, the Panel favors a clinical trial for MRD positivity if available. If a
(eg, 1 cycle of induction and 1 cycle of consolidation) and for serial clinical trial, allogeneic HCT, targeted therapy, or other consolidation
monitoring every 6 to 12 weeks for 24 months.374,417-419 For PML::RAR strategies are not pursued, the Panel notes that venetoclax-based low-

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intensity therapy has demonstrated high rates of MRD reduction in MRD rates but do not generate substantial CR duration.426 Currently, allogeneic
and oligoblastic AML.422 HCT at second CR is associated with relatively lower rates of relapse and
represents the only potentially curative option.286,423,427 Emerging data are
Postremission Surveillance for AML demonstrating the utility of targeted therapies in R/R AML, as discussed
Monitoring CBCs, including platelets, every 1 to 3 months for the first 2 below. At time of relapse or progression, molecular profiling should be
years after patients have completed consolidation therapy, then every 3 to considered if not done at diagnosis, or repeated to determine clonal
6 months thereafter up to 5 years, is recommended. Bone marrow evolution.
evaluation should be performed only if the peripheral smear becomes
abnormal or if cytopenias develop, rather than as routine surveillance at Targeted Therapy
fixed intervals, unless the bone marrow evaluation is being performed as FLT3-Positive AML
part of a clinical research protocol; however, molecular remission should In a phase I/II study, the safety and tolerability of gilteritinib, an FLT3
be confirmed following consolidation therapy and monitoring for molecular inhibitor, was assessed in adult patients with R/R AML (n = 252).428 In this
relapse is encouraged, if applicable. group, 58 patients had wild-type FLT3 and 194 patients had FLT3
mutations (FLT3-ITD, n = 162; FLT3-TKD/FLT3 D385, n = 16), and
A donor search should be initiated at first relapse in appropriate patients
received oral gilteritinib (20–450 mg) once daily in one of seven dose-
concomitant with initiation of therapy. At each relapse or progression, the
escalation or dose-expansion cohorts.428 Gilteritinib was well-tolerated in
Panel suggests conducting molecular and cytogenetic analyses using
this patient subpopulation and the most common grade 3 or 4 adverse
appropriate material to determine the status of actionable abnormalities
events were febrile neutropenia (39%), anemia (24%), thrombocytopenia
including FLT3 (ITD and TKD), IDH1/IDH2, and KMT2a rearrangements
(13%), sepsis (11%), and pneumonia (11%).428 The ORR in all patients
because it may guide selection of appropriate therapies (see Management
with R/R AML was 40%, which was improved to 52% in FLT3 mutation-
of Relapsed/Refractory AML) and enrollment in appropriate clinical trials.
positive AML patients treated with gilteritinib doses ≥80 mg/day.428
Ongoing studies are evaluating the role of molecular monitoring in the
surveillance for early relapse in patients with AML (see Role of MRD In a phase 3 trial, the efficacy of gilteritinib was compared to conventional
Monitoring). chemotherapy used to treat R/R AML (n = 371).340 In this study, the four
chemotherapy options included two high-intensity options (FLAG-IDA; and
Management of Relapsed/Refractory AML
mitoxantrone plus etoposide and cytarabine [MEC]) and two low-intensity
Treatment of R/R AML is challenging and outcomes are poor.286,423 Many options (low-dose cytarabine and azacitidine). Of the 371 patients with
studies have also demonstrated that lack of early blast clearance or lack of eligible data, 247 were randomly assigned to the gilteritinib group (120
response to the first induction cycle are major predictors for poor mg/day) or the chemotherapy group (n = 124). The percentage of patients
outcomes.286,424,425 Intensive regimens generally achieve high second CR

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who had CR with full or partial hematologic recovery was 34% and 15.3% chemotherapy arm (P = .02). There were similar rates of sepsis and septic
in the gilteritinib and chemotherapy groups, respectively.340 The median shock between the two arms. Grade 3 QT prolongation occurred in 4% of
OS was significantly longer in the gilteritinib group compared to the patients in the quizartinib arm by investigator report.
chemotherapy group (9.3 vs. 5.6 months; HR, 0.64; 95% CI, 0.49–0.83; P
< .001).340 In addition, the median EFS was longer in the gilteritinib group IDH Mutation-Positive AML
when compared to the chemotherapy group at 2.8 months versus 0.7
The studies evaluating the efficacy of ivosidenib336 and enasidenib335 in
months, respectively (HR for relapse or lack of remission or death, 0.79;
IDH1- and IDH2-mutation positive R/R AML, respectively, have been
95% CI, 0.58–1.09).340 Based on these data, gilteritinib was approved by
summarized in a previous section, AML Induction Therapy for Patients
the FDA in November 2018 for the treatment of adult patients who have
Ineligible for Intensive Induction, for patients who are not candidates for or
R/R AML with an FLT3 mutation. Longer term follow-up data revealed a 2-
decline intensive remission induction therapy.
year cumulative incidence of relapse of 75.5% for the gilteritinib arm,
though few relapses occurred after 18 months.341 Twenty six of 247 The IDH1 inhibitor olutasidenib was investigated among patients with R/R
patients in the gilteritinib arm remained alive for ≥2 years without relapse IHD1-mutated AML (n = 147; median age, 71 years; age range, 32–87
and 18 of these patients were able to proceed to allogeneic HCT. years) in a phase II trial.432 Thirty-five percent of patients achieved CR +
CRh, in a median time of 1.9 months (range, 0.9–5.6 months).
Emerging evidence suggests that gilteritinib in combination with
venetoclax may be beneficial for FLT3-mutated AML.429 CD33-Positive AML

In a phase II study, the efficacy of azacitidine and sorafenib, an FLT3 In a study by Taksin et al, adult patients with AML in first relapse (n = 57)
inhibitor, was evaluated in adult patients with R/R AML (n = 43; median received fractionated doses of GO, given at a dose of 3 mg/m2 on days 1,
age, 67 years; range, 24–87 months).430 The response rate was 46%, with 4, and 7 for one course.433 Fifteen patients achieved CR (26%) and 4
CR, CR/CRi, and PR rates of 16%, 27%, and 3%, respectively.430 In achieved CRp (7%). The median RFS was similar for patients who
addition, the degree of FLT3-ITD inhibition appeared to correlate with achieved CR and CRp and was 11 months.433 In addition, no veno-
plasma sorafenib concentrations. occlusive disease (sinusoidal obstructive syndromes) occurred after GO
treatment or after GO followed by HCT (n = 7), although the authors
In a phase III study, patients aged ≥18 years with relapsed or refractory
recommended a minimum delay of 90 days between GO treatment and
FLT3-ITD–mutated AML (n = 335) were randomized to receive the FLT3
HCT.433
inhibitor quizartinib versus chemotherapy (low-dose cytarabine, MEC, or
FLAG-IDA).431 With a median follow-up of 23.5 months, OS was 6.2
months in the quizartinib arm compared to 4.7 months in the

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KMT2A-Rearranged AML data evaluable for efficacy; median age: 63 years).435 Co-mutations were
common, including 31.0% with concurrent FLT3-ITD mutations, and 34.5%
In the ongoing phase II AUGMENT-101 study the safety and efficacy of of patients experienced progression on ≥3 prior lines of therapy. ORR was
the oral menin inhibitor revumenib was evaluated in adult and pediatric 46.9%, with 23.4% of patients achieving CR or CRh. Median EFS was 3.0
patients ≥30 days old (n = 94; 57 with efficacy-evaluable data) with months. Among the entire cohort, median OS was 4.0 months compared
primary refractory or relapsed KMT2Ar acute leukemia, including 78 to 23.3 months among those achieving CR or CRh. 5 patients (16.7%)
patients with AML.434 Many patients (43.6%) had received ≥3 prior lines of were successfully bridged to allogeneic HCT. Grade ≥3 treatment-related
therapy and 50% of patients had undergone prior allogeneic HCT. QTcF prolongation occurred in 21.4% of patients and grade ≥3
differentiation syndrome occurred in 13.1% of patients.
Patients received revumenib 163 mg (or 95 mg/m2 for those weighing <40
kg) every 12 hours in 28-day continuous cycles. Dose of revumenib could Based on this data, the FDA indication for revumenib was expanded to
be increased to 276 mg (or 160 mg/m2 if weight <40 kg) if no concomitant include R/R AML with a susceptible NPM1 mutation in adult and pediatric
strong CYP3A4 inhibitor was being utilized; however, this did not occur on patients ≥1 year old with no satisfactory alternative treatment options.
study and is rare in R/R acute leukemia, as most patients require fungal
prophylaxis with azoles. Among patients with evaluable data, the CR/CRh The safety and efficacy of a second oral menin inhibitor, ziftomenib, for
rate was 22.8%. ORR was 63.2% with 68.2% of patients achieving MRD adults ≥18 years with R/R AML with an NPM1 mutation, was evaluated in
negativity. Among those who achieved response, 38.9% were able to the phase I/II KOMET-001 trial (n = 112 in the pooled phase IB/II
proceed to allogeneic HCT and half of these patients receive revumenib population; median age 69 years).436 Patients had received a median of 2
maintenance therapy following HCT. prior lines of therapy (range, 1-7) and co-mutations, including FLT3 and
IDH mutations, were common. Patients received ziftomenib 600 mg once
The most common adverse effects were nausea/vomiting/diarrhea, febrile daily in a continuous fashion. CR/CRh rate was 22%, significantly higher
neutropenia (grade ≥3 in 37.2% of patients), and edema. Grade ≥3 than the 12% rate seen with historical standard regimens for this patient
differentiation syndrome occurred in 16% of patients and grade ≥3 QTc population (P = .0058). ORR rate was 33%. Median OS among patients
prolongation occurred in 13.8% of patients. experiencing response was 18.4 months compared to 6.6 months in the
entire cohort.
Based on this data, the FDA approved revumenib for R/R acute leukemia
with a KMT2A translocation in adult and pediatric patients ≥1 year. Grade ≥3 treatment-related AEs were common, occurring in 93% of
patients, and included febrile neutropenia in 26% of patients and
NPM1 Mutated AML
differentiation syndrome in 15% of patients.
The AUGMENT-101 study also evaluated the safety and efficacy of
revumenib for patients with R/R AML with an NPM1 mutation (n = 64 with

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Based on this data, the FDA approved ziftomenib for adults with R/R AML years of age and at 1 g/m2 for those ≥60 years of age. Venetoclax was
with a susceptible NPM1 mutation with no satisfactory alternative given on days 2 to 8 of a 28-day cycle at 400 mg daily without ramp up,
treatment options. though cytoreduction with hydroxyurea, cytarabine, or ATRA was given
prior to the start of treatment for patients with a WBC >20 x 109/L. ORR
Chemotherapy
rate was 94%. Among patients with available MRD assessments, 82%
The guidelines provide a list of several commonly used regimens for R/R achieved MRD negativity. Estimated 12-month OS and EFS rates were
disease that are grouped as either intensive or less intensive therapy (see 85% and 68%, respectively. Neutropenic fever, infection, and elevations of
AML: Therapy for Relapsed/Refractory Disease in the algorithm). The ALT were the most frequent grade ≥3 adverse events.
regimens grouped under intensive therapy represent purine analog (eg,
fludarabine, cladribine, clofarabine)–containing regimens, which have In a study of patients with resistant or relapsing AML (n = 38), patients
shown remission rates of approximately 30% to 45% in several clinical were treated with fludarabine, cytarabine, and G-CSF (FLAG), and overall
trials, and those that have been used as the comparator arms in U.S. 21 patients (55%) achieved CR.439 In a study by Parker et al, patients with
cooperative group trials in the past decade. high-risk MDS/AML (n = 19; including R/R AML, n = 7), treated with
fludarabine, cytarabine, G-CSF, and idarubicin responded to therapy, with
A study by Robak et al evaluated the efficacy of cladribine, cytarabine, and 12 patients (63%) achieving CR.440 In a more recent phase II study
G-CSF (CLAG) as reinduction therapy in patients with R/R AML (n = investigating the safety and efficacy of venetoclax combined with FLAG-
20).437 Ten patients (50%) achieved CR with a median duration of 22.5 IDA in 61 patients with R/R AML, ORR was 67% was a CRc rate of
weeks (range, 3.5–53 weeks). Two patients experienced a PR (10%) and 41%.282 Seventy-four percent of patients achieved MRD-negativity by flow
8 patients had disease that did not respond to therapy.437 In another study, cytometry and 57% of patients were successfully bridged to allogeneic
the efficacy of cladribine, cytarabine, and idarubicin was analyzed in HCT.
patients with R/R AML (n = 34).438 After at least one cycle of treatment, 18
patients (52.9%) achieved CR and 16 (47.1) received subsequent In a phase I study, a regimen with clofarabine, cytarabine, and idarubicin
allogeneic HCT.438 In a phase II study, CLAG-M was investigated in was evaluated in a subgroup of adult patients with R/R AML (n = 21) and
patients with refractory AML.284 After 1 or 2 cycles of treatment, 49% (n = 10 patients (48%) achieved CR.441 A regimen with clofarabine (40 mg/m2)
21) of patients achieved CR. One-year OS among patients who achieved combined with cytarabine (2 g/m2) was evaluated in a randomized,
CR was 73%. In a phase II study, the safety and efficacy of cladribine, placebo-controlled, phase III trial (CLASSIC I trial) in R/R AML, resulting in
idarubicin, and cytarabine (CLIA) combined with venetoclax as induction an ORR of 47% (CR rate, 35%) and a median OS of 6.6 months.442 A
and consolidation was evaluated in 50 patients ≤65 years with newly retrospective study compared clofarabine versus fludarabine in
diagnosed AML (n = 45), MPAL (n = 1), or MDS (n = 4) deemed eligible combination with HiDAC with or without G-CSF.443 Patients treated with a
for intensive therapy.283 Cytarabine was dosed at 1.5 g/m2 for patients <60 clofarabine-based regimen (n = 50) compared to a fludarabine-based

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regimen (n = 101) had a higher CR rate (OR, 9.57; P < .0001) and a 56 post-allogeneic HCT, defined as “treatment success.” In the intent-to-
longer survival (mortality HR, 0.43; P = .0002).443 treat population, 83% of patients in the immediate allogeneic group
achieved “treatment success,” compared to 79% in the remission induction
The regimens for R/R AML grouped under less intensive therapy include group (test for noninferiority, P = .036). A 3.4% difference in treatment
HMAs (azacitidine or decitabine), low-dose cytarabine, and venetoclax- success was estimated, which did not meet the predefined 2.5%
containing regimens. Emerging studies suggest that venetoclax in significance level. Patients in the immediate allogeneic HCT group did
combination with HMAs or low-dose cytarabine has demonstrated spend a median of 27 fewer days in the hospital setting, however (P <
antileukemic activity in R/R AML, MDS, and BPDCN.444 A study suggests .0001).
that azacitidine followed by donor lymphocyte infusions (DLIs) may be a
treatment option for therapy in patients who have AML that relapses after NCCN Recommendations
allogeneic HCT.445 These data are based on a prospective phase II trial of The NCCN AML Panel recommends enrollment in a clinical trial for the
28 patients with AML. In this study, 22 patients received DLIs and an ORR management of R/R AML as a strongly preferred option. Other options
of 30% was achieved. This included 7 CRs and 2 PRs. At publication, include targeted therapy or chemotherapy followed by allogeneic HCT. For
there were 5 patients still in CR with a median of 777 days (range, 461– targeted therapies, the guidelines provide a list of options including
888 days). Neutropenia and thrombocytopenia grade III/IV were the most gilteritinib for patients with FLT3 mutations (a category 1
common adverse events (65% and 63%, respectively). Acute and chronic recommendation). Quizartinib (a category 2B recommendation) or
graft-versus-host disease (GVHD) were seen in 37% and 17% of patients, sorafenib combined with an HMA (azacitidine or decitabine) are targeted
respectively. Correlations suggest a better response in patients with therapy options for patients with FLT3-ITD mutations. Other targeted
myelodysplasia-related changes (P = .011) and lower blast count therapy options include GO for patients with CD33-positive AML,
(P = .039) or patients with high-risk cytogenetics (P = .035). However, ivosidenib or olutasidenib for patients with IDH1 mutations, enasidenib for
interpretation of results is limited by the small size of the study.445 patients with IDH2 mutations, or revumenib for patients with KMT2Ar or
Allogeneic HCT NPM1-mutated AML. There have been trials conducted combining
In a randomized trial that investigated whether patients with AML in first targeted therapies with other agents.
untreated relapse or with poorly responsive disease required remission
The regimens for intensive therapy include: 1) CLAG, with or without
induction prior to allogeneic HCT (n = 281), patients were randomized to
mitoxantrone or idarubicin437,438; 2) cytarabine, if not previously received in
either disease control measures (LDAC or a single dose of mitoxantrone)
treatment, with or without anthracycline292; 3) FLAG with or without
followed by immediate allogeneic HCT or one cycle of high-dose
idarubicin or venetoclax282,439,440; 4) etoposide and cytarabine, with or
cytarabine and mitoxantrone in an effort to induce remission prior to
without mitoxantrone447,448; 5) clofarabine with or without cytarabine with or
allogeneic HCT.446 The primary endpoint was achievement of CR on day
without idarubicin441,442,449,450; or 6) CLIA with venetoclax.283 Less intensive

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treatment options may include: 1) HMAs alone (azacitidine or time of diagnosis. HLA typing is routinely used in many institutions to
decitabine)312,319,451; 2) low-dose cytarabine328,452 (a category 2B select platelet donors for patients who exhibit alloimmunization to
recommendation); or 3) venetoclax combined with HMAs or low-dose HLA-specific antigens.
cytarabine.444,453 Best supportive care is always an option for patients who
cannot tolerate or do not wish to pursue further intensive treatment. Standard tumor lysis prophylaxis includes hydration with diuresis, and
allopurinol administration or rasburicase treatment. Rasburicase is a
While more randomized trials are needed, allogeneic HCT may be genetically engineered recombinant form of urate oxidase enzyme.
considered for patients with R/R disease who did not achieve CR following Rasburicase should be considered as initial treatment in patients with
first induction therapy or for those who had previously been scheduled for rapidly increasing blast counts, high uric acid, or evidence of impaired
allogeneic HCT.446 renal function.454 When possible, patients should be evaluated for
glucose-6-phosphate dehydrogenase (G6PD) deficiency, as rasburicase
Supportive Care for Patients with AML use in these patients is contraindicated and is associated with an
Although variations exist between institutional standards and practices, increased risk of inducing hemolysis.455,456 Urine alkalinization was
several supportive care issues are important to consider in the treatment previously recommended as a means to increase uric acid solubility and
of patients with AML. In general, supportive care measures may include reduce the potential for uric acid precipitation in the tubules. However, this
the use of blood products for transfusion support and correction of method is not generally favored as there are no data to support this
coagulopathies, tumor lysis prophylaxis, anti-infective prophylaxis, and practice and similar effects could be seen with saline hydration alone.457
growth factor support. Monitoring for neurologic and cardiovascular Alkalinization can complicate care by increasing calcium phosphate
toxicities may be required for particular therapeutic agents (cytarabine or deposits in vital organs (eg, kidney, heart) as a result of
ATO) or because of patient-specific comorbidities. These supportive care hyperphosphatemia. Furthermore, in contrast to allopurinol, rasburicase
measures are tailored to address the specific needs and infection has the added benefit of rapid breakdown of serum uric acid, eliminating
susceptibility of each individual patient. the need for urine alkalinization.

When transfusion support is required, leukocyte-depleted blood products Unless a site-specific contraindication exists, a central venous access
should be used for transfusion. All patients with AML are at risk for acute device (CVAD) with multiple lumens is recommended to allow the
GVHD and management should be based on institutional practice or administration of peripherally contraindicated systemic therapies and
preference (see NCCN Guidelines for Hematopoietic Cell Transplantation, possibly multiple infusions during higher risk periods of cytopenias related
available at [Link]). Cytomegalovirus (CMV) screening for to disease and/or myelosuppressive therapy. Routine care and
potential HCT candidates is left to institutional policies regarding provision maintenance of a CVAD should be provided as per institutional policy.
of CMV-negative blood products to patients who are CMV-negative at the

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Removal and/or replacement of a CVAD should be determined based on of differentiation syndrome. However, in patients with AML (non-APL),
individual clinical circumstances. growth factors may be considered during induction for patients who are
septic and who have a life-threatening infection in an attempt to shorten
Patients who receive doses of cytarabine ≥2 g/m2, or patients >60 years of the duration of neutropenia. Some regimens such as FLAG incorporate
age who receive doses of cytarabine 1 to 1.5 g/m2, should be closely G-CSF into the regimen. However, the use of growth factors may
monitored for changes in renal function, because renal dysfunction is complicate the interpretation of marrow results. There is a
highly correlated with increased risk of cerebellar toxicity. Patients recommendation to discontinue colony-stimulating factors at least a week
receiving these doses of cytarabine should be monitored and assessed for before a planned marrow sample to assess remission status.
nystagmus, dysmetria, slurred speech, and ataxia before each dose;
patients exhibiting any neurologic signs should discontinue cytarabine, There is no evidence for whether growth factors have a positive or
and all subsequent doses of cytarabine must be restricted to 100 to 200 negative impact on long-term outcome if used during consolidation.
mg/m2. Patients who develop cerebellar toxicity should not be Growth factors may be considered as part of supportive care for
rechallenged with doses of cytarabine ≥2 g/m2 in future treatment postremission therapy. Growth factors are not routinely recommended in
cycles.458 Doses of cytarabine ≥2 g/m2 should also be discontinued in postremission therapy, except in life-threatening infections or when signs
patients with rapidly rising creatinine caused by tumor lysis. Steroid eye and symptoms of sepsis are present and the leukemia is believed to be in
drops should be administered to both eyes 4 times daily for all patients remission.
undergoing cytarabine therapy at this dose until 24 hours post completion
of cytarabine as prophylaxis for keratoconjuctivitis.459 Supportive Care for Patients with AML Who Prefer Not to
Receive Blood Transfusions
Decisions regarding the use and choice of antibiotics to prevent and treat There is no established treatment of AML that does not require use of
infections should be made by the individual institutions based on the blood and blood products for supportive care, and with limited data,
prevailing organisms and their drug resistance patterns.460 Greater detail providing guidelines or recommendations for AML management in this
regarding the prevention and treatment of cancer-related infections can be context is challenging. However, the AML Panel recognizes that this is a
found in the NCCN Guidelines for Prevention and Treatment of significant issue faced in a narrow spectrum of clinical settings. In this
Cancer-Related Infections (available at [Link]) and context, the Panel reviewed the existing literature and collective
commensurate with the institutional practice for antibiotic stewardship. experience with this issue and summarized some considerations to guide
treatment and supportive care. However, it is important to note that the
Growth factors (G-CSF or granulocyte macrophage colony-stimulating
Panel believes that in many cases, good outcomes from these strategies
factor [GM-CSF]) are not recommended during induction for patients with
are rare.
APL as they can complicate assessment of response and increase the risk

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At the outset, it is important to discuss the goals of care with the patient contraceptive pills or medroxyprogesterone acetate in menstruating
and establish an understanding of the complications that can arise individuals; or using proton pump inhibitors, as indicated.462,470 Vitamin K
without transfusions. In addition, it will be helpful to ascertain if the may be considered as an adjuvant to improve coagulopathy.462,470 In
patient will accept certain blood products (eg, cryoprecipitate) and stem patients at risk of bleeding (eg, when platelet counts drop below 30 x
cells (either autologous or from another donor source). To mobilize 10/9L), aminocaproic acid or tranexamic acid may be considered to
peripheral blood stem cells and/or bring up hemoglobin levels prior to manage bleeding.462,470 In patients with elemental or vitamin deficiencies,
peripheral blood stem cell transplantation, some treatment centers have consider iron, folate, and vitamin B12 supplementation if deficient.462,470 In
used erythropoiesis-stimulating agents (ESAs), G-CSF, and patients with severe anemia, consider bed rest and supplemental
thrombopoietin (TPO) mimetics. 461-463 However, before using this oxygenation.462,470
strategy, the potential risks, benefits, and uncertainties of using these
agents in this context should be thoroughly discussed. Consider referring For other general and supportive care considerations, see General
the patient to centers with expertise in bloodless autologous Considerations and Supportive Care for Patients with AML Who Prefer Not
transplant.462,463 In addition, for patients who are Jehovah’s Witnesses to Receive Blood Transfusions in the algorithm.
and for this reason refuse blood transfusions, the U.S. branch of the
Evaluation and Treatment of CNS Leukemia
Christian Congregation of Jehovah’s Witnesses has Hospital Liaison
Committees that may provide helpful information about bloodless Leptomeningeal involvement is much less frequent (<3%) in patients with
medicine.464 AML than in those with ALL; therefore, the Panel does not recommend LP
as part of the routine diagnostic workup. However, if neurologic symptoms
Regarding treatment options, the Panel recommends considering less (eg, headache, confusion, altered sensory input) are present at diagnosis,
myelosuppressive induction including dose reduction of anthracyclines an initial CT/MRI should be performed to rule out the possibility of
and use of nonintensive chemotherapy.465-469 Some of these options may meningeal disease, chloromas or other mass lesions, or CNS bleeding. If
include targeted agents guided by testing for actionable mutations instead no mass effect is seen, cerebrospinal fluid cytology should be sampled by
of intensive chemotherapy, especially in a noncurative setting. However, LP. If the LP is negative for leukemic cells, the patient can be followed with
the Panel notes that dose reductions in chemotherapy without transfusion a repeat LP if symptoms persist. If the LP is positive by morphology or
support in patients with AML is associated with a lower rate of remission, immunotype by flow cytometry, IT chemotherapy is recommended, given
high mortality by severe anemia, and is unlikely to result in durable concurrently with systemic induction therapy. If LP result is equivocal,
remissions.468 During treatment, measures should be taken to minimize consider repeating LP with morphology or immunotype by flow cytometry
blood loss and decrease the risk of bleeding, including: using pediatric to delineate involvement. IT therapy may include agents such as IT
collection tubes; avoiding concomitant medications or procedures that methotrexate or IT cytarabine either alone or combined. The selection of
increase the risk of bleeding or myelosuppression; using oral agents and dose schedules for IT therapy largely depend on the specific

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clinical situation (eg, extent of CNS leukemia, symptoms, systemic recommended evaluation and treatment of CNS leukemia, further CNS
therapies given concurrently) and institutional practices. Initially, IT therapy surveillance should be followed based on institutional practice.
is generally given twice weekly until the cytology shows no blasts, and
then weekly for 4 to 6 weeks. Importantly, IT therapy should only be Management of Blastic Plasmacytoid Dendritic Cell
administered by clinicians with experience and expertise in the delivery of Neoplasm
IT agents. Doses of cytarabine ≥2 g/m2 have significant penetration across BPDCN is a rare myeloid malignancy, representing only 0.44% of
the blood–brain barrier and may represent an alternative to repeated IT hematologic malignancies, with an incidence of 0.04 cases per 100,000
injections during induction therapy. The cerebrospinal fluid must then be people in the United States.471-473 BPDCN, which was formerly known as
reassessed after completion of induction therapy, and further IT therapy blastic natural killer cell lymphoma or granular CD4+/CD56+
should be given as appropriate. hematodermic neoplasm, was renamed in the 2008 WHO classification
with the evolving knowledge of its plasmacytoid dendritic cell (PDC)
If the initial CT/MRI identifies a mass effect or increased intracranial origin.474,475 In 2016, it was recognized as a unique myeloid malignancy.34
pressure due to a parenchymal lesion in the brain, a fine-needle aspiration Pathologically, it is characterized by aggressive proliferation of precursors
(FNA) or biopsy may be considered. If the results are positive, then RT is of PDCs.35,476 The etiology of BPDCN is unknown, but its association with
recommended, followed by IT therapy, as described earlier. IT therapy or MDS or CMML in some cases may suggest a related pathogenesis.35,477
doses of cytarabine ≥2 g/m2 should not be administered concurrently with BPDCN is associated with a poor prognosis, with median OS of
cranial RT because of the increased risks of neurotoxicity. Another option approximately 8 to 12 months when patients are treated with
for these patients includes therapy containing doses of cytarabine ≥2 g/m2 chemotherapy.476,478 Median age of presentation is in the sixth decade of
with dexamethasone to help reduce intracranial pressure. life, with an approximate male-to-female ratio of 3:1 up to 5:1.473,476 The
most frequent clinical presentation of typical BPDCN cases is
The Panel does not recommend routine screening for occult CNS disease
asymptomatic solitary or multiple skin lesions that can disseminate rapidly
in most patients with AML in remission. However, screening LP should be
without therapy.35,476 Peripheral blood and bone marrow involvement may
considered at for asymptomatic patients with WBC count >40 x 10/9L at
be minimal at presentation, but tend to develop as the disease progresses.
diagnosis, extramedullary disease, high-risk APL, intraparenchymal
Additional sites of involvement can include lymph nodes, spleen, and other
hemorrhage at diagnosis, AML with FLT3 mutations or MLLT3::KMT2A
extramedullary organs.35,475,479 Less commonly, patients may present with
fusion, monocytic differentiation, or MPAL. For patients with positive
features of an acute leukemia without skin manifestations.476 CNS
cerebrospinal fluid by morphology or immunotype by flow cytometry, the
involvement is not infrequent; approximately 10% of patients who present
Panel recommends either IT chemotherapy, as outlined earlier, or
with neurological symptoms at diagnosis have confirmed CNS
documenting clearance of CNS disease after the first cycle of
involvement480 and rates of CNS involvement, both at diagnosis and at
chemotherapy containing doses of cytarabine ≥2 g/m2. In addition to the

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Acute Myeloid Leukemia

relapse, have been found to be in the range of 9% to 26% in several The diagnosis of BPDCN can be difficult due to overlapping morphologic,
additional studies.476,481,482 immunophenotypic, and clinical features of other hematologic
malignancies, such as AML with plasmacytoid dendritic cell differentiation,
Workup but can generally be made by careful adherence to established diagnostic
The evaluation and initial workup for suspected BPDCN consists of a criteria.475,485 This is particularly true when BPDCN presents as isolated
comprehensive medical history and physical examination. Laboratory cutaneous lesions, as biopsy specimens from cutaneous lesions may not
evaluations include a comprehensive metabolic panel and a CBC yield sufficient cells for appropriate flow cytometric analysis.475
including platelets and a differential of WBCs. Analyses of peripheral Immunophenotypic evaluation should include PDC markers (CD123,
blasts, bone marrow biopsy and aspirate, biopsy of skin lesions and, if TCF4, TCL1, CD303, and CD304),35,475,486-488 other markers such as CD4
suspected to be involved, lymph nodes and other tissues are and CD56, as well as expected negative markers (CD3, CD14, CD19,
recommended. These analyses should include dendritic cell morphology CD34, lysozyme, and myeloperoxidase). A diagnosis of BPDCN requires
assessment, IHC, flow cytometry, cytogenetic analysis, and molecular expression of CD4 and/or CD56 plus expression of CD123 and one other
analyses. The most common molecular aberrations include TET2, ASXL1, PDC marker. Alternatively, a diagnosis can be made based on expression
ZRSR2, SRSF2, TP53, NRAS, IDH2, and ETV6.483,484 RUNX1 mutations of any three PDC markers and absent expression of expected negative
are rare in BPDCN. markers. 475,486-489 BPDCN must be distinguished from mature
plasmacytoid dendritic cell proliferation (MPDCP) in which PDCs are
Close collaboration with dermatology is recommended. It is essential to morphologically mature and CD56-negative.35
differentiate the skin lesions of BPDCN from other neoplastic and
non-neoplastic skin lesions and rashes, including leukemia cutis Induction Therapy for Patients with BPDCN
associated with AML, and analysis by experienced hematopathologists is Given the rarity of BPDCN, no standardized chemotherapy approach has
often required.475 For guidance on classification and measurement of skin been established.476 Historically, therapeutic approaches have varied
lesions, see the NCCN Guidelines for Primary Cutaneous Lymphomas widely and have included irradiation for localized skin lesions,
(available at [Link]). If extramedullary disease and/or lymphoma- or leukemia-type chemotherapy regimens, and HCT.490
lymphadenopathy is suspected, an FDG-PET/CT scan is recommended. Despite good initial responses to chemotherapy, with response rates of
All patients require a diagnostic LP with IT chemotherapy at the time of 40% to 90%,475 early relapse rates are high, even among those who
initial diagnosis, at disease relapse, or any other time when there is a achieve CR.475,476,490 CD123-targeted therapy with tagraxofusp-ersz is the
clinical suspicion for CNS involvement. Subsequent IT chemotherapy only FDA-approved treatment option for appropriate candidates.
prophylaxis should be considered, even in the absence of known CNS
disease given the high percentage (30%) of primary CNS involvement at Recently, a collaborative initiative, the North American BPDCN
relapse.473,475 Consortium (NABC), made up of a group of experts from multiple areas of

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expertise, has been formed to define the current standard of care for Hypoalbuminemia was the most consistent and early manifestation of
management of BPDCN and to identify future areas of research.473 capillary leak syndrome (grade 1 in 4 patients, grade 2 in 6 patients).
Symptoms of capillary leak syndrome were managed by the administration
CD123-Targeted Therapy
of parenteral albumin and diuretics. Though several patients experienced
CD123, or IL3Rα, overexpression is present in virtually all cases of grade 3 thrombocytopenia and neutropenia, myelosuppression was
BPDCN.479 Tagraxofusp (formerly SL-401) is a recombinant fusion protein generally modest and reversible, potentially reflecting the minimal
made up of the catalytic and translocation domains of diphtheria toxin expression of IL3R on normal myeloid progenitors. Many patients
fused to IL3 that has shown activity against BPDCN. experienced transaminitis without hyperbilirubinemia, with onset typically 5
to 10 days post-infusion and with full resolution typically 15 to 21 days
The first prospective study of treatment of patients with BPDCN included
following infusion.
11 patients with recurrent or refractory BPDCN or who were not
candidates for chemotherapy were treated with SL-401.491 Each cycle of In a multicohort study by Pemmaraju and colleagues, 84 patients with
SL-401 treatment was comprised of a 12.5 µg/kg dose administered over untreated or relapsed BPDCN were treated with an IV infusion of
a 15-minute infusion every day for up to 5 doses. Of 9 evaluable patients tagraxofusp at a dose of 12 µg/kg on days 1 to 5 of each 21-day cycle.492
who received treatment, 5 had a CR and 2 had a PR after 1 cycle of Treatment was given until disease progression or unacceptable adverse
SL-401 treatment (78% ORR). The median duration of response was 5 effects. Of the 84 patients, 65 received first-line treatment and 19 had
months (range, 1 to 20+ months), with responses occurring in all sites of received prior treatment. Among evaluable patients who received first-line
disease, including skin, bone marrow, and lymph nodes. Acute treatment of tagraxofusp, the primary outcome (CR and clinical CR) was
infusion-related adverse events such as fever, chills, and nausea were observed in 57% of patients, ORR was 75%, and median OS was 15.8
mild to moderate in severity and were most commonly seen within the first months. Of the patients who achieved CR or clinical CR following first-line
several hours after SL-401 infusion; however, these symptoms were treatment of tagraxofusp, 51% were successfully bridged to HCT
occasionally noted up to 4 to 8 hours following infusion. Premedications (allogeneic HCT, n = 13; autologous HCT, n = 6) while in remission and
including acetaminophen, diphenhydramine, methylprednisolone, and median OS in this subgroup was 38.4 months. Of the 18 patients who
famotidine were given, likely mitigating these events. Resulting symptoms achieved CR or clinical CR following first-line treatment who did not
following infusion responded to additional dosing of acetaminophen, proceed to HCT, 4 had duration of responses >6 months. Among the 19
meperidine, antiemetics, and/or H1- and H2-histamine antagonists. These patients who had received prior therapy, ORR was 58% with a median OS
acute infusion-related events may be related to cytokine release from of 8.2 months. Among this subgroup, 1 patient was successfully bridged to
necrotic cells and damaged BPDCN blasts. Most patients experienced one HCT. Based on earlier data from this trial,479 the FDA approved
or more symptoms suggestive of vascular or capillary leak syndrome, such tagraxofusp-erzs for the treatment of BPDCN in adults and pediatric
as hypoalbuminemia, edema, hypotension, and hyponatremia. patients ≥2 years of age in 2018.

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The most common adverse events noted in the Pemmaraju study were median OS was 8.7 months (range, 0.2–32.9), and patients who received
increased levels of alanine aminotransferase (ALT) and aspartate ALL-type chemotherapy appeared to have longer OS compared to
aminotransferase (AST), hypoalbuminemia, fatigue, fever, patients treated with AML-type chemotherapy (12.3 vs. 7.1 months,
thrombocytopenia, nausea, and peripheral edema.492 In addition, capillary respectively; P = .02). In addition, the median OS of patients who received
leak syndrome was observed in 21% of patients (8 of which were grade ≥3 transplant was significantly higher than non-transplanted patients (22.7 vs.
and 3 of which were grade 5 resulting in death), primarily in the first cycle 7.1 months, respectively; P = .03). Age was also noted to be a significant
of treatment. Median time to onset of capillary leak syndrome was 6 days prognostic factor, with a median OS of 12.6 months in patients <65 years
(range, 3–51 days), with a median duration of 6 days (range, 3–69 days). compared to 7.1 months for those >65 years (P = .04). Relapses occurred
Capillary leak syndrome was managed by withholding further doses of in 35% of patients at a median of 9.1 months.
tagraxofusp, administering IV albumin or glucocorticoids, and careful
management of volume status. An additional retrospective study analyzed the impact of 4 different
chemotherapeutic approaches: 1) local therapy or systemic regimens less
Chemotherapy intensive than CHOP; 2) CHOP and CHOP-like regimens; 3) acute
In a retrospective multicenter study, 41 patients with BPDCN received leukemia regimens; and 4) allogeneic or autologous HCT.490 Therapies
induction treatment with AML-type regimens (n = 26) and less intensive than CHOP were a heterogenous group, including local
ALL-type/lymphoma-type regimens (n = 15).476 The AML-type treatment radiation, systemic steroids, and supportive care, but were mostly
protocols included MEC; idarubicin, cytarabine, and etoposide (ICE); cyclophosphamide-based chemotherapy regimens. Though this group had
standard-dose cytarabine and anthracycline (7 + 3); FLAG; and a high ORR of 80% (68% CR), only 7% of patients had a sustained CR
FLAG-IDA. The ALL/lymphoma-type regimens included hyper-CVAD and the median OS for evaluable patients was 9 months. Patients in the
(alternative cycles of hyperfractionated cyclophosphamide, vincristine, CHOP and CHOP-like regimens arm had similar results despite therapy
doxorubicin, dexamethasone, methotrexate, and cytarabine), GIMEMA being more aggressive, with an ORR of 70% (55% CR) and only 1 case of
ALL trial therapy (association of doxorubicin, vincristine, prednisone, and sustained CR. Intensive acute leukemia regimens resulted in a CR rate of
asparaginase), CHOP (cyclophosphamide, doxorubicin, vincristine, and 94%, with approximately one-third of patients experiencing a sustained
prednisone), and CHOEP (CHOP plus etoposide). There were patients CR. There were 10 evaluable patients in the HCT arm (6 allogeneic, 4
who required additional therapy based on extramedullary disease (4 autologous). Median OS was 38.5 months in the allogeneic arm compared
patients received IT chemotherapy for CNS involvement and 2 patients to 16.5 months in the autologous arm. At the time of publication, all but
received RT for skin lesions). Fourteen percent of patients underwent one patient who had undergone allogeneic HCT in first remission
allogeneic HCT at some point in their course of therapy. After induction, remained disease-free.
the overall CR rate was 41%, with 7 patients achieving CR after AML-type
induction, and 10 patients achieving CR after ALL-type induction. The

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Another retrospective study evaluated the diagnostic flow cytometry those who are otherwise not candidates for intensive remission induction
pattern and outcome of nine patients with BPDCN after front-line treatment therapy. In vitro, BPDCN cells were found to be uniformly sensitive to
with hyper-CVAD.493 In this group, seven patients received induction venetoclax in a study that measured direct cytotoxicity, apoptosis assays,
treatment with hyper-CVAD and had a CR of 67% and ORR of 86%. Five and dynamic BH3 profiling.495
of the six patients who responded to therapy received planned allogeneic
HCT. With a median follow-up of 13.3 months, the 1-year DFS and OS A retrospective study assessed the efficacy of venetoclax combinations in
rates for all patients were 56% and 67%, respectively. The 1-year DFS for a total of 43 patients with R/R myeloid malignancies, including 2 patients
those who received allogeneic HCT was 80%. The 1-year OS for patients with BPDCN.444 The most common treatment regimens included
who received allogeneic HCT was 80%, compared to 50% in those who venetoclax with decitabine (53%), azacitidine (19%), and LDAC (19%).
received chemotherapy alone. The median OS was 7.9 months for those Patients had been previously treated with a median of 3 prior lines of
who received chemotherapy alone. therapy, including allogeneic HCT in 12% of patients. While ORR was
seen in 21% of patients, neither of the 2 patients with BPDCN who were
A more recent retrospective study compared outcomes of 100 patients evaluated achieved a response by formal criteria, though 1 patient had a
with BPDCN treated with frontline hyper-CVAD–based therapy (n = 35), major response by PET/CT, bone marrow blast reduction of >50%, and
tagraxofusp (n = 37), or other therapies (n = 28).494 The highest CR rates improvement in cutaneous lesions. The other patient with BPDCN also
were seen with hyper-CVAD–based therapy (80%), followed by had a significant improvement in cutaneous lesions. All patients who
tagraxofusp (59%), and finally other regimens (43%) (P = .01), though received venetoclax combination therapy experienced grade 3 or higher
there was no significant difference in OS (28.3 vs. 13.7 vs. 22.8 neutropenia and 72% developed a grade 3 or higher infection, most
months; P = .41) or remission duration probability (38.6 vs. NR vs. 10.2 commonly pneumonia, bacteremia, cellulitis, invasive fungal infections,
months; P = .24) noted between the 3 arms. Fifty-one percent of patients and urinary tract infections. All patients were given allopurinol for TLS
in the hyper-CVAD–based group were bridged to HCT, compared to 49% prophylaxis, and none developed hyperuricemia that required
of patients in the tagraxofusp group and 38% in the other regimens group, rasburicase.444
respectively (P = .455). This study suggests a continued role for
hyper-CVAD–based regimens in the targeted-therapy era. A larger retrospective, multicenter study assessed the outcomes of 71
patients ≥60 years of age with BPDCN, 32 who had received venetoclax
Venetoclax-Based Regimens combined with an HMA and 39 who received tagraxofusp.496 12-month OS
The antiapoptotic protein BCL2 is overexpressed in a majority of patients was comparable between venetoclax combined with an HMA and
with BPDCN.444 Venetoclax is an oral selective BCL2 inhibitor approved in tagraxofusp for the entire cohort, at 41.2% and 53%, respectively (P = .73)
combination with azacitidine, decitabine, or low dose cytarabine (LDAC) as well as a subset of patients ≥75 years of age (38.1% vs. 56.5%,
for the treatment of newly-diagnosed AML in patients ≥75 years or for respectively; P = .71).

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Hematopoietic Stem Cell Transplantation and outcomes were not impacted by conditioning type (MAC vs. RIC). The
Due to the rarity of BPDCN, there have been limited established 1-year OS for autologous HCT recipients was 11% (95% CI, 8%–50%).
standardized therapeutic approaches.497 HCT seems to generate durable
remissions, especially if given in first CR, as indicated by the studies A more recent retrospective study evaluated 162 adults with BPDCN that
discussed in the chemotherapy section, as well as others.474,476,490,493,497,498 underwent first HCT (allogeneic HCT, n = 146; autologous HCT, n = 16),
However, it is worth noting that data are limited to small case series and 78% of whom were in first CR.499 Among the allogeneic HCT group, 54%
retrospective registry studies, and larger prospective studies are needed received MAC, 46% received RIC, and 59% received in-vivo T-cell
to elucidate the role of HCT in BPDCN.498 depletion (TDC). TBI was used in 61% of MAC transplants and 26% of
RIC transplants. Comparable one-year OS and PFS rates were seen
A retrospective analysis from the Japan Society for Hematopoietic Cell following allogeneic and autologous HCT (OS, 66 vs. 70%; PFS, 62% vs.
Transplantation aimed to clarify the role of allogeneic HCT or autologous 66%). TBI as the conditioning backbone in allogeneic HCT led to
HCT in treating BPDCN.474 In this analysis, 25 patients were identified, significant improvements in OS and PFS compared to all other
with 14 patients having undergone allogeneic HCT and 11 patients having conditioning regimens. Adjusted 2-year PFS for MAC with TBI was 95%
undergone autologous HCT. All patients who underwent autologous HCT compared to 82% for MAC without TBI, 41% for RIC with TBI, and 60% for
were in first CR, while 12 of the 14 patients who underwent allogeneic RIC without TBI, respectively.
HCT were in first CR (2 were not in remission). With a median follow-up of
53.5 months, the OS rates at 4 years for patients who underwent NCCN Recommendations
autologous HCT and allogeneic HCT were 82% and 53%, respectively (P For patients who are eligible for tagraxofusp-ersz, the Panel recommends
= .11) and the PFS rates were 73% and 48%, respectively (P = .14). The either tagraxofusp-ersz or chemotherapy. Chemotherapy can be broken
data suggest that receiving autologous HCT in first CR may substantially down into intensive regimens such as AML-type (standard-dose
enhance survival. OS outcomes in the allogeneic HCT subgroup did not cytarabine plus anthracycline using 7 + 3), ALL-type (hyper-CVAD), and
differ significantly between myeloablative conditioning (MAC) and RIC lymphoma-type (CHOP) regimens or lower-intensity options such as an
regimens. HMA (azacitidine or decitabine) combined with venetoclax. Palliative
options include systemic steroids and supportive care. IT chemotherapy
A North American multicenter retrospective study analyzed the outcomes should be given in patients with CNS disease at diagnosis and as
of BPDCN patients treated with allogeneic HCT (n = 37) or autologous prophylaxis for patients without documented CNS disease. The same
HCT (n = 8).498 Allogeneic HCT recipients had a 1-year and 3-year OS of intensive and lower-intensity chemotherapy options and palliative options
68% (95% CI, 49%–81%) and 58% (95% CI, 38%–75%), respectively. are recommended for those who are not eligible for tagraxofusp-erzs.
Receiving allogeneic HCT in first CR yielded improved 3-year OS versus
allogeneic HCT not in first CR [74% (95% CI, 48%–89%) vs. 0, P < .0001],

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Tagraxofusp-ersz should be administered as an IV infusion at 12 µg/kg For patients with CNS disease, CNS-directed IT chemotherapy, preferably
over 15 minutes once daily on days 1 to 5 of each 21-day cycle. with alternating cytarabine with methotrexate, or triple IT agents
Alternatively, 5 doses can be administered over a 10-day period, if needed (cytarabine, methotrexate, steroid) is recommended twice weekly until
for dose delays. It is important to note that patients must have a baseline CSF cytology is negative. Once CSF cytology is negative, weekly IT
serum albumin of ≥3.2 g/dL to be able to start treatment with this agent. treatment should be continued for at least 4 doses, then twice per month
The most serious side effect associated with tagraxofusp is capillary leak for a total of at least 8 doses. Ongoing prophylaxis thereafter with IT
syndrome, which can occur during the first cycle of treatment and can be treatments once or twice per month may be considered.
life-threatening.479 A decrease in serum albumin during the first days of
treatment seems to be the most consistent predictor of capillary leak Postremission Surveillance for BPDCN
syndrome.479 Management includes delaying or withholding additional Following completion of consolidation therapy, it is recommended to
tagraxofusp doses, administering IV albumin according to pre-specified monitor a CBC, including platelets, every 1 to 3 months for the first 2
measures, administering glucocorticoids, and close management of years, then every 3 to 6 months thereafter for up to 5 years. Bone marrow
volume status.479 The Panel recommends replacing serum albumin if <3.5 evaluation should be performed only if cytopenias develop or if peripheral
g/dL or if there is a reduction of ≥0.5 from baseline. The Panel also smear is abnormal, rather than as routine surveillance at fixed intervals,
recommends premedication with an H1-histamine antagonist, unless the bone marrow evaluation is being performed as part of a clinical
acetaminophen, corticosteroid, and H2-histamine antagonist prior to each research protocol. For patients with prior evidence of extramedullary
infusion to help reduce the risk of hypersensitivity reaction. Other eligibility disease, a repeat FDG-PET/CT scan is recommended. In addition, routine
criteria for tagraxofusp-ersz include a left ventricular ejection fraction thorough skin exams with a re-biopsy should occur for any suspicious skin
(LVEF) ≥ institutional lower limit of normal, creatinine ≤1.5 mg/dL, bilirubin or extramedullary lesions.
≤1.5 mg/dL, AST/ALT ≤2.5 the upper limit of normal, and no clinically
significant cardiovascular disease.479 Management of Relapsed/Refractory BPDCN
Upon relapse, the NCCN AML Panel recommends evaluating for CNS
With all treatment options, if CR is observed, allogeneic HCT (preferred) or disease and administering IT chemotherapy prophylaxis.480 Management
autologous HCT should be considered for patients who are eligible. If options for R/R BPDCN include clinical trial (preferred), tagraxofusp-ersz
tagraxofusp-erzs was given as an initial treatment and HCT is not feasible, (if not already used), 479,492 chemotherapy (if not already given), local
additional cycles of tagraxofusp-erzs should be continued until disease radiation to isolated lesions, systemic steroids, or venetoclax-based
progression. If disease progresses or does not respond to induction regimens.444,495 During administration of any treatment option, a donor
therapy, patients should be considered for a clinical trial (preferred), or search should also be started at first relapse in appropriate patients if no
regimens used for R/R disease. sibling donor has been identified.

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Acute Myeloid Leukemia

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Acute Myeloid Leukemia

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Acute Myeloid Leukemia

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Acute Myeloid Leukemia

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Acute Myeloid Leukemia

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Acute Myeloid Leukemia

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Acute Myeloid Leukemia

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Acute Myeloid Leukemia

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Acute Myeloid Leukemia

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497. Roos-Weil D, Dietrich S, Boumendil A, et al. Stem cell

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