Acute Myeloid Leukemia: NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines)

NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®)
Acute Myeloid Leukemia

Version 6.2023 — October 24, 2023
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NCCN Guidelines Version 6.2023 NCCN Guidelines Index

Table of Contents
Acute Myeloid Leukemia (Age ≥18 years) Discussion
*Daniel A. Pollyea, MD, MS/Chair ‡ Þ † Alice Mims, MD, MS † Paul J. Shami, MD ‡

University of Colorado Cancer Center The Ohio State University Comprehensive Huntsman Cancer Institute
*Jessica K. Altman, MD/Vice Chair ‡ Cancer Center - James Cancer Hospital at the University of Utah
Robert H. Lurie Comprehensive Cancer and Solove Research Institute Richard M. Stone, MD ‡ †
Center of Northwestern University Kelsey Moriarty, MS, CGC Dana-Farber/Brigham and Women’s
Rita Assi, MD, ‡ UT Southwestern Simmons Cancer Center
Indiana University Melvin and Bren Simon Comprehensive Cancer Center Stephen A. Strickland, MD, MSCI ‡
Comprehensive Cancer Center Moaath Mustafa Ali, MD, MPH ‡ Vanderbilt-Ingram Cancer Center
Amir T. Fathi, MD ‡ † Þ Case Comprehensive Cancer Center/ Swapna Thota, MD ‡
Mass General Cancer Center University Hospitals Seidman Cancer Center St. Jude Children's Research Hospital/The
and Cleveland Clinic Taussig Cancer Institute University of Tennessee Health Science Center
James M. Foran, MD †
Mayo Clinic Comprehensive Cancer Center Jadee Neff, MD, PhD ≠ Geoffrey Uy, MD † ‡ ξ
Duke Cancer Institute Siteman Cancer Center at Barnes-
Ivana Gojo, MD ‡
The Sidney Kimmel Comprehensive Reza Nejati, MD ≠ Jewish Hospital and Washington
Cancer Center at Johns Hopkins Fox Chase Cancer Center University School of Medicine
Aric C. Hall, MD ‡ † ξ Rebecca Olin, MD, MS ‡ ξ Pankit Vachhani, MD ‡

University of Wisconsin UCSF Helen Diller Family O'Neil Comprehensive Cancer Center at UAB
Carbone Cancer Center Comprehensive Cancer Center
Brian A. Jonas, MD, PhD ‡ Mary-Elizabeth Percival, MD, MS ‡
UC Davis Comprehensive Cancer Center Fred Hutchinson Cancer Center
Ashwin Kishtagari, MD ‡ Alexander Perl, MD †
Vanderbilt-Ingram Cancer Center Abramson Cancer Center at the
University of Pennsylvania
Jeffrey Lancet, MD ‡ †
Moffitt Cancer Center Amanda Przespolewski, DO ‡
Roswell Park Comprehensive Cancer Center
Lori Maness, MD ‡ NCCN
Fred & Pamela Buffett Cancer Center Dinesh Rao, MD, PhD ≠ Carly J. Cassara, MSc
UCLA Jonsson Comprehensive Cancer Center Katie Stehman, PA-C, MMS
James Mangan, MD, PhD ‡ ξ
UC San Diego Moores Cancer Center Farhad Ravandi, MD Þ ‡
The University of Texas
Gabriel Mannis, MD ‡ Þ MD Anderson Cancer Center
Stanford Cancer Institute ξ Bone marrow transplantation
Rory Shallis, MD ‡ ‡ Hematology/Hematology oncology
Guido Marcucci, MD † Þ Yale Cancer Center/Smilow Cancer Hospital Þ Internal medicine
City of Hope National Medical Center † Medical oncology
≠ Pathology
NCCN Guidelines Panel Disclosures

Continue * Discussion Section Writing Committee Member

Table of Contents
NCCN Acute Myeloid Leukemia Panel Members

Summary of Guidelines Updates Clinical Trials: NCCN believes that
Evaluation for AML (EVAL-1) • AML Surveillance and Therapy for Relapsed/ the best management for any patient
Refractory Disease (AML-10) with cancer is in a clinical trial.
APL • Risk Stratification by Biological Disease Factors for Participation in clinical trials is
• Classification and Treatment Recommendations Patients with Non-APL AML Treated with Intensive especially encouraged.
(APL-1) Induction Chemotherapy (AML-A)
• Low-Risk Treatment Induction and Consolidation • Evaluation and Treatment of CNS Leukemia Find an NCCN Member Institution:
Therapy (APL-2) (AML-B) https://www.nccn.org/home/member-
• High-Risk Induction and Consolidation Therapy • Principles of Radiation Therapy (AML-C) institutions.
(APL-3) • General Considerations and Supportive Care for
• Post-Consolidation Therapy and Monitoring (APL- Patients with AML Who Prefer Not to Receive NCCN Categories of Evidence and
5) Blood Transfusions (AML-D) Consensus: All recommendations
• Therapy for Relapse (APL-6) • Principles of Systemic Therapy (AML-E) are category 2A unless otherwise
• Principles of Supportive Care (APL-A) • Principles of Supportive Care for AML (AML-F) indicated.
• Monitoring During Therapy (AML-G)
AML • Measurable (Minimal) Residual Disease See NCCN Categories of Evidence
• Risk Group and Induction (Intensive Induction Assessment (AML-H) and Consensus.
Eligible) (AML-1) • Response Criteria Definitions for Acute Myeloid
• Follow-up and Reinduction After Standard-Dose Leukemia (AML-I)
Cytarabine Induction (AML-3) • Therapy for Relapsed/Refractory Disease (AML-J) NCCN Categories of Preference:
• Follow-up After High-Dose Cytarabine Induction for • Principles of Venetoclax Use with HMA or LDAC All recommendations are considered
Poor-Risk AML (AML-4) (AML-K) appropriate.
• Risk Group and Induction (Intensive Induction
Ineligible) (AML-5) BPDCN See NCCN Categories of Preference.
• Follow-Up After Induction Therapy with Lower • Introduction (BPDCN-INTRO) • Evaluation and Treatment of CNS Disease
Intensity Therapy (AML-6) • Evaluation/Workup (BPDCN-1) (BPDCN-B)
• (Age <60 y) ConsolidationTherapy (AML-7) • Treatment (BPDCN-2) • Principles of Supportive Care for BPDCN
• (Age ≥60 y) Consolidation Therapy (AML-8) • Surveillance and Treatment for Relapsed/ (BPDCN-C)
• Maintenance Therapy (AML-9) Refractory Disease (BPDCN-3)
• Principles of BPDCN (BPDCN-A) • Abbreviations (ABBR-1)
The NCCN Guidelines® are a statement of evidence and consensus of the authors regarding their views of currently accepted approaches to treatment.
Any clinician seeking to apply or consult the NCCN Guidelines is expected to use independent medical judgment in the context of individual clinical
circumstances to determine any patient’s care or treatment. The National Comprehensive Cancer Network® (NCCN®) makes no representations or
warranties of any kind regarding their content, use or application and disclaims any responsibility for their application or use in any way. The NCCN
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be reproduced in any form without the express written permission of NCCN. ©2023.

Table of Contents
Updates in Version 6.2023 of the NCCN Guidelines for Acute Myeloid Leukemia from Version 5.2023 include:
AML-9
• Erratum: 2nd pathway, maintenance therapy: FLT3 inhibitor maintenance treatment: Sorafenib (FLT3-ITD only or TKD) (Also for AML-E 9 of 9)
Global
• Terminologies in all NCCN Guidelines are being actively modified to advance the goals of equity, inclusion, and representation.
• References updated throughout the guideline.
AML-1
• Induction eligible, 2nd pathway, risk group modified: AML with FLT3-ITD/TKD mutation
• Induction eligible, 2nd pathway, treatment induction modified:
Standard 7+3 (daunorubicin or idarubicin) + midostaurin (FLT3-ITD or TKD)(category 1)
New regimen added: Standard 7 + 3 (daunorubicin or idarubicin) + quizartinib (FLT3-ITD only)(category 1)
AML-3
• 1st pathway, reinduction:
2nd bullet modified: Standard 7 + 3 (daunorubicin or idarubicin)
4th bullet modified: Standard 7 + 3 (daunorubicin or idarubicin) + midostaurin (BM aspirate and biopsy on day 21; FLT3-mutated [ITD or TKD])
New 5th bullet added: Standard 7 + 3 or 5 + 2 (daunorubicin or idarubicin) + quizartinib (FLT3-ITD only)
• 2nd pathway, reinduction:
1st bullet modified: Standard 7 + 3 (daunorubicin or idarubicin)
3rd bullet modified: Standard 7 + 3 (daunorubicin or idarubicin) + midostaurin (BM aspirate and biopsy on day 21; FLT3 mutated [ITD or TKD])
New 4th bullet added: Standard 7 + 3 or 5 + 2 (daunorubicin or idarubicin) + quizartinib (FLT3-ITD only)
AML-7
• 2nd pathway:
Risk group, 1st bullet modified: AML with FLT3-ITD/TKD mutation
Treatment (consolidation, age <60 y):
◊ 2nd bullet modified: HiDAC + midostaurin (FLT3 mutated-ITD or TKD)
◊ New 4th bullet added: HiDAC + quizartinib (FLT3-ITD only)
AML-8
• 2nd pathway:
Risk group modified: AML with FLT3-ITD/TKD mutation
Treatment (consolidation, age ≥60 y):
◊ 1st bullet modified: Intermediate-dose cytarabine + midostaurin (FLT3-ITD or TKD)
◊ New 2nd bullet added: Intermediate-dose cytarabine + quizartinib (FLT3-ITD only)
AML-8A
• Footnote removed: Alternate dosing of cytarabine for postremission therapy has been reported (see Discussion). Jaramillo S, et al. Blood Cancer J
2017;7:e564
Continued
UPDATES

Table of Contents
AML-9
• 2nd pathway, maintenance therapy
Qualifier modified: Post allogeneic HCT, in remission, and history of FLT3-ITD mutation
FLT3 inhibitor maintenance treatment modified
◊ 1st bullet modified: Sorafenib (FLT3-ITD or TKD)
◊ 2nd bullet modified: Midostaurin (FLT3-ITD or TKD) (category 2B)
◊ 3rd bullet modified: Gilteritinib (FLT3-ITD or TKD) (category 2B)
◊ New 4th bullet added: Quizartinib (FLT3-ITD only) (category 2B)
• 3rd pathway, maintenance therapy added:
Qualifier added: Patient with history of FLT3-ITD mutation, previously received quizartinib, no allogeneic HCT is planned
FLT3 inhibitor maintenance treatment added: Quizartinib (FLT3-ITD only)
• 4th pathway modified: If none Neither of the above scenarios is applicable
AML-E 1 of 9
• Therapy column, 6th row modified: Standard 7+3 (daunorubicin or idarubicin) + midostaurin (FLT3-ITD or TKD) (Also for AML-E 3 of 9)
• Regimen column, 6th row modified: Standard-dose cytarabine 100-200 mg/m2 continuous infusion x 7 days with daunorubicin 60 mg/m2 or idarubicin
12 mg/m2 x 3 days and oral midostaurin 50 mg every 12 hours, days 8–21 (Also for AML-E 3 of 9)
• New row added for Standard 7 + 3 (daunorubicin or idarubicin) + quizartinib (FLT3-ITD only)
AML-E 3 of 9
• New row added for Standard 7 + 3 (daunorubicin or idarubicin) + quizartinib (FLT3-ITD only)
• New row added for 5 + 2 (daunorubicin or idarubicin) + quizartinib (FLT3-ITD only)
AML-E 7 of 9
• Consolidation Age <60 Years table
Therapy column, 3rd row modified: HiDAC + midostaurin (FLT3-ITD or TKD)
New row added for HiDAC + quizartinib (FLT3-ITD only)
AML-E 8 of 9
• Therapy column, 4th row modified: Intermediate-dose cytarabine + midostaurin (FLT3-ITD or TKD)
• New row added for Intermediate-dose cytarabine + quizartinib (FLT3-ITD only)
AML-E 9 of 9
• Therapy column, 4th, 5th, and 6th rows modified by adding (FLT3-ITD or TKD) to Sorafenib, Midostaurin, and Giltertinib
• New row added for Quizartinib (FLT3-ITD only)
• Footnote f added: 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.
AML-J
• Targeted therapy for AML with FLT3-ITD mutation, new 3rd bullet added: Quizartinib (category 2B)
Continued
UPDATES

Table of Contents
AML-E 3 of 9
• Erratum: CPX-351/dual-drug liposomal cytarabine and daunorubicin, re-induction regimen modified: CPX-351/dual-drug liposomal cytarabine 100 mg/
m2 and daunorubicin 44 mg/m2 on days 1 and 3, and 5 x 1 cycle
MS-1
• The BPDCN section of the discussion has been updated.
AML-3
• Erratum: Re-induction for significant residual disease without a hypocellular BM, regimen added back after inadvertent removal: 7+3 (mitoxantrone) (for
age ≥60 y)
• Erratum: Re-induction for significant cytoreduction, regimen added back after inadvertent removal: 7+3 (mitoxantrone) (for age ≥60 y)
AML-E 1 of 9
• Erratum: FLAG-IDA + venetoclax regimen: HiDAC dosing modified from 2 g/m2 to 1.5 g/m2
• Global
• Terminologies modified to be more inclusive, including of all sexual orientations and gender identities.
EVAL-1
• Evaluation, bullet 5 modified: Bone marrow (BM) core biopsy and aspirate analyses, including immunophenotyping by immunohistochemistry (IHC)
stains + flow cytometry, and cytogenetic analyses (karyotype + FISH) the analysis of chromosomal structural variations by cytogenetics, fluorescence in
situ hybridization (FISH), or whole genome sequencing (See AML-A)
EVAL-1A
• Footnote a modified: 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 comprehensive targeted next-generation sequencing
(NGS) analysis are recommended for the ongoing management of AML and 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 2017;129:424-447) (see 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.
• Footnote removed: The WHO 2016 classification defines acute leukemia as ≥20% blasts in the marrow or blood. In an appropriate clinical setting, a
diagnosis of AML may be made with less than 20% in patients with the following cytogenetic abnormalities: t(15;17), t(8;21), t(16;16), inv(16). AML
evolving from MDS (AML-MDS) is often more resistant to cytotoxic chemotherapy than AML that arises without antecedent hematologic disorder and
may have a more indolent course. Some clinical trials designed for highgrade MDS may allow enrollment of patients with AML-MDS.
• Footnotes added:
d: Khoury JD, et al. Leukemia 2022;36:1703-1719.
j:Arber DA, et al. Blood 2022;140:1200-1228.
i: Kim K, et al. Am J Hematol. 2022;97:885-894. Continued
Version 6.2023, 10/24/2023 © 2023 National Comprehensive Cancer Network (NCCN ), All rights reserved. NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.
® ® ®
UPDATES

Table of Contents
Acute Promyelocytic Leukemia
APL-1
• Footnote a modified: 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.
APL-2
• APL Treatment Induction (Low-Risk), Preferred Regimens
Pathway 1 and Pathway 2, bullet 1 modified: If blood count recovery by day 28 (platelet >100,000, absolute neutrophil count (ANC) >1,000), proceed
with consolidation. BM aspirate and biopsy may be considered to document <5% blasts and no abnormal promyelocytes morphologic remission but is
optional
Pathway 1 and Pathway 2, bullet 2 modified: If full course of induction treatment not given, or counts have not recovered by day 28–35, a BM aspirate
and biopsy is recommended to document <5% blasts and no abnormal promyelocytes morphologic remission before proceeding with consolidation
but is optional
• APL Treatment Induction (Low-Risk), Useful in Certain Circumstances
Regimen 1 modified: ATRA 45 mg/m2 in 2 divided doses daily + idarubicin 12 mg/ m2 on days 2, 4, 6, 8 or on days 2, 4, 6 for aged >70 y (category 1)
Pathway 2 modified: BM aspirate and biopsy days 28–35 to document morphologic remission <5% blasts and no abnormal promyelocytes before
proceeding with consolidation
APL-2A
• Footnote g modified: QTc and monitoring and optimizing electrolytes are important in safe administration of arsenic trioxide. See Arsenic trioxide
monitoring in Principles of Supportive Care for APL (APL-A). Electrocardiogram (ECG) is recommended prior to initiating arsenic trioxide. During
therapy, if a patient presents with a prolonged QT interval, the use of QTcF correction formula is recommended. Interventions such as minimizing
concurrent QT-prolonging drugs and electrolyte correction are recommended prior to discontinuing arsenic trioxide.
• Footnote h modified: Lo-Coco F, et al. N Engl J Med 2013;369:111-121. Begin prophylaxis with prednisone; the optimal duration of steroid prophylaxis is
unknown. through completion of induction. If differentiation syndrome develops, change to dexamethasone. See Principles of Supportive Care for APL
(APL-A).
• Footnote l modified: If no evidence of morphologic disease (ie, absence of blasts and abnormal promyelocytes) (<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
• Footnote added: If full course of induction not given, BM biopsy should still be performed.
Continued
UPDATES

Table of Contents
APL-3
• APL Treatment Induction (High-Risk), Other Recommended Regimens, regimen 3 modified: ATRA 45 mg/m2 in 2 divided doses daily + idarubicin 12
mg/m2 on days 2, 4, 6, 8 or on days 2, 4, 6 for those aged >70 y
• Consolidation Therapy
Pathway 2 modified: Arsenic trioxide 0.15 mg/kg daily 5 d/wk for 4 weeks every 8 weeks for a total of 4 cycles + ATRA 45 mg/m2 for 2 weeks every
4 weeks for a total of 7 cycles. If ATRA or arsenic trioxide discontinued due to toxicity, a single dose of gemtuzumab ozogamicin 9 mg/m2 may be
given once every 4–5 weeks until 28 weeks from CR 4–5 weeks provided platelets and ANC recover to ≥100 and ≥1.0, respectively, until molecular
complete response (CR)
Pathway 3 modified: ATRA 45 mg/m2 for 2 weeks every 4 weeks (or for 2 weeks on 2 weeks off) in consolidation courses 1–4 + arsenic trioxide 0.3
mg/kg on days 1–5 of week 1 in consolidation courses 1–4 and 0.25 mg/kg twice weekly in weeks 2–4 in consolidation courses 1–4 (category 1). If
ATRA or arsenic trioxide discontinued due to toxicity, a single dose of gemtuzumab ozogamicin 9 mg/m2 may be given once every 4–5 weeks until 28
weeks from CR 4–5 weeks provided platelets and ANC recover to ≥100 and ≥1.0, respectively, until molecular CR
Pathway 5 modified: Daunorubicin 60 mg/m2 x 3 days + cytarabine 200 mg/m2 x 7 days x 1 cycle, then cytarabine 2 g/m2 (aged <50 y) or 1.5 g/
m2 (aged 50–60 y) every 12 h x 5 days or 1 g/m2 (aged >60 y) every 12 h x 4 days + daunorubicin 45 mg/m2 x 3 days x 1 cycle + 5 doses of IT
chemotherapy
APL-3A
• Footnote g modified by adding: ECG is recommended prior to initiating arsenic trioxide. During therapy, if a patient presents with a prolonged QT
interval, the use of QTcF correction formula is recommended. Interventions such as minimizing concurrent QT-prolonging drugs and electrolyte
correction are recommended prior to discontinuing arsenic trioxide.
• Footnote k added: Estey E, et al. Blood 2002;99:4222-4224.
• Footnote q modified by removing: It is important for regimens containing ATRA and arsenic trioxide to be administered for the management of APL. If
arsenic is not available or contraindicated, it may be omitted from induction.
• Footnote z modified: Dose adjustment of cytarabine may be needed for older patients >60 years or patients with renal dysfunction
• Footnote aa added: High-risk patients who are >60 years did not receive cytarabine in consolidation and were treated as intermediate-risk patients in
the LPA2005 study.
• Footnote bb added: Mitoxantrone was reduced to 3 days in intermediate-risk patients in the LPA2005 study.
APL-4
• Induction Therapy: Prolonged QTc, third regimen modified: ATRA 45 mg/m2 in 2 divided doses daily + idarubicin 12 mg/m2 on days 2, 4, 6, 8 or on days
2, 4, 6 for those aged >70 y
• Consolidation Therapy: Low EF
Sentence 2 in pathways 1 and 2 modified: If ATRA or arsenic trioxide discontinued due to toxicity, a single dose of gemtuzumab ozogamicin 9 mg/
m2 may be given once every 4–5 weeks until 28 weeks from CR 4–5 weeks provided platelets and ANC recover to ≥100 and ≥1.0, respectively, until
molecular CR
• Consolidation Therapy: Prolonged QTc
Pathway 1 modified: ATRA 45 mg/m2 in 2 divided doses daily during weeks 1–2, 5–6, 9–10, 13–14, 17–18, 21–22, and 25–26. A single dose of
gGemtuzumab ozogamicin 9 mg/m2 may be given monthly until achievement of complete molecular responseCR
Pathway 2 modified: Daunorubicin 60 mg/m2 x 3 days + cytarabine 200 mg/m2 x 7 days x 1 cycle, then cytarabine 2 g/m2 (aged <50 y) or 1.5 g/
m2 (age 50–60 y) every 12 h x 5 days or 1 g/m2 (aged >60 y) every 12 h x 4 days, + daunorubicin 45 mg/m2 x 3 days x 1 cycle + 5 doses of IT
chemotherapy Continued
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UPDATES

Table of Contents
APL-6
• Therapy for relapse, Early relapse (<6 mo) after ATRA and arsenic trioxide (no anthracycline) pathway modified: Anthracycline-based regimen as per
APL-3 or gemtuzumab ozogamicin
• Footnote kk added: See NCCN Guidelines for Hematopoietic Cell Transplantation.
APL-A
• APL differentiation syndrome, sub-bullet 1 modified: If steroids are not initiated at time of treatment with ATRA and arsenic, Maintain a high index of
suspicion of APL differentiation syndrome (ie, fever, often associated with increasing WBC count >10,000/mcL, usually at initial diagnosis or relapse;
shortness of breath; hypoxemia; pleural or pericardial effusions).3 Close monitoring of volume overload and pulmonary status is indicated. Initiate
dexamethasone at first signs or symptoms of respiratorycompromise (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.
AML-1 through AML-6
• Extensively revised by removing age as a determinant of induction treatment strategy, reclassification of certain risk groups, addition of new induction
treatment regimens. Clarification of parameters for and timing of BM aspirate and biopsy following induction were also revised.
AML-7 through AML-8
• Extensively revised to to provide recommendations for consolidation therapy based on age and risk group.
AML-9
• Maintenance Therapy
Patient with intermediate or adverse risk disease; treatment column, bullet 1 modified: Maintenance therapy with oral azacitidine 300 mg PO daily on
days 1–14 of each 28-day cycle until progression or unacceptable toxicity (category 1, preferred for age ≥55 y AML-
Patient with intermediate or adverse risk disease; treatment column, bullet 2 added: Maintenance therapy with HMA until progression or unacceptable
toxicity: Azacitidine, Decitabine (category 2B)
Post allogeneic HCT, in remission, and history of FLT3-ITD; treatment column, maintenance treatment options added: Midostaurin (category 2B) and
Gilteritinib (category 2B)
• References moved to the Principles of Systemic Therapy.
AML-10
• Footnote bbb modified: Comprehensive Multi-gene molecular profiling/targeted NGS (including IDH1/IDH2, FLT3 mutations) is suggested as it may
assist with selection of therapy and appropriate clinical trials (see Discussion). Molecular testing should be repeated at each relapse or progression.
AML-A 1 of 4
• Page revised by updating table to 2022 ELN recommendations
AML-A 4 of 4
• Name of syndrome modified: Telomere syndromes due to mutation in TERC or TERT (OMIM 127550, 613989, and 615190)
• Causative Gene(s) for telomere syndromes due to mutation in TERC or TERT (OMIM 127550, 613989, and 615190) modified: TERC/,TERT and RTEL1
AML-D
• General supportive care, bullet 11 modified: Consider iron, folate, and vitamin B12 supplementation if deficient. Iron supplementation may be avoided in
someone with excess iron levels.
Continued
UPDATES

Table of Contents
AML-E
• Principles of Systemic Therapy added
AML-F
• General, sub-bullet 7 modified: In patients who develop cerebellar toxicity, cytarabine should be stopped. The patient should not be rechallenged
Rechallenge with HiDAC in future treatment cycles should not be attempted
AML-K 1 of 2
• General
Bullet 2 added: Patients with disease in remission should take breaks between treatment, such as extending cycle length from 28-day to 42-day
cycles.
Bullet 4, sub-bullet 1 added: Strong CYP3A4 inhibitors (especially posaconazole) require significant dose reductions during initiation and ramp-up
phase followed by a reduced daily dose.
Bullet 4, sub-bullet 2 added: The use of strong or moderate CYP3A4 inducers (eg, carbamazepine, phenytoin, rifampin) should be avoided.
BPDCN-1
• Evaluation, bullet 5 modified: All patients require a diagnostic LP at the time of initial diagnosis, at disease relapse, or any other time when there is a
clinical suspicion for CNS involvement. Follow with IT treatment chemotherapy prophylaxis as clinically indicated
BPDCN-A
• Footnote a added: 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
UPDATES

Table of Contents
EVALUATION FOR AML DIAGNOSTIC DIAGNOSISd,e,f,j

• History and physical (H&P) STUDIES Acute promyelocytic leukemia (APL):
• Complete blood count (CBC), platelets, differential, In patients with clinical or pathologic
comprehensive metabolic panel (CMP), uric acid, lactate features of APL, start all-trans retinoic acid See APL
dehydrogenase (LDH) (ATRA) upon first suspicion of APL.h Early Classification
• B12 and folic acid evaluation initiation of ATRA may prevent the lethal and Treatment
• Prothrombin time (PT), partial thromboplastin time (PTT), complication of bleeding.h If cytogenetic Recommendations
fibrinogen and molecular testing do not confirm APL, (APL-1)
• Bone marrow (BM) core biopsy and aspirate analyses, discontinue ATRA and continue treatment
including immunophenotyping by immunohistochemistry as for AML
(IHC) stains + flow cytometry, and the analysis of AML:
chromosomal structural variations by cytogenetics, To appropriately stratify available intensive
fluorescence in situ hybridization (FISH), or whole genome therapy options, expedite test results
sequencing (See AML-A) of molecular and cytogenetic analyses
• Molecular analyses (ASXL1, c-KIT, FLT3 [ITD (internal tandem for immediately actionable mutations or
duplication) and TKD (tyrosine kinase domain)], NPM1, CEBPA See AML Risk
chromosomal abnormalities (eg, core
[biallelic], IDH1, IDH2, RUNX1, TP53, and other mutationsa binding factor [CBF], FLT3 [ITD and TKD],
Stratification and
(See AML-A) Multidisciplinary Treatment
NPM1, IDH1, IDH2) Recommendations
• Comprehensive pathology report, including diagnosis of AML diagnostic • For patients with hyperleukocytosis
(acute myeloid leukemia) with recurrent cytogenetics vs. studiesd,e,j Risk Group
uncontrolled with hydroxyurea or and Induction
AML not otherwise specified (NOS), blast count, cellularity, leukapheresis, one dose of intermediate-
morphologic dysplasia, and mutation status if available (Intensive
dose cytarabine (1–2 g) may be Induction Eligible)
• Human leukocyte antigen (HLA) typing for patient with considered prior to receiving diagnostic
potential hematopoietic cell transplantation (HCT) in the future (AML-1)
resultsi
(except for patients with a major contraindication to HCT) and/ • For patients who prefer not to receive
or early referral to transplant center blood transfusion(s), see AML-D for
• Brain CT without contrast, if central nervous system (CNS) general considerations and supportive
hemorrhage suspectedb (See AML-B) care
• Brain MRI with contrast, if leukemic meningitis suspectedb For suspicion of blastic plasmacytoid
(See AML-B) dendritic cell neoplasm (BPDCN), see
• PET/CT, if clinical suspicion for extramedullary disease (See BPDCN-INTRO
AML-B) See NCCN
• Lumbar puncture (LP), if symptomaticb (category 2B for Myelodysplastic syndromes (MDS)
Guidelines for
asymptomatic) Myelodysplastic
• Evaluate myocardial function (echocardiogram or MUGA scan) Syndromes
in patients with a history or symptoms of cardiac disease See NCCN
or prior/planned exposure to cardiotoxic drugs or radiation B-cell or T-cell
Guidelines for Acute
therapy (RT) to thorax lymphoblastic leukemia/
Lymphoblastic
• Consider early integration of palliative carec (See NCCN lymphomae
Leukemia
Guidelines for Palliative Care)
See footnotes on EVAL-1A
Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.
EVAL-1

Table of Contents
FOOTNOTES FOR EVALUATION FOR AML

a 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 next-generation sequencing (NGS) analysis are recommended for the ongoing management of AML and 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 2017;129:424-447)
(see 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.
b Consider administration of one dose of intrathecal (IT) chemotherapy (methotrexate or cytarabine) at time of diagnostic LP. See Evaluation and Treatment of CNS
Leukemia (AML-B).
c El-Jawahri A, et al. JAMA Oncol 2021;7:238-245.
d Khoury JD, et al. Leukemia 2022;36:1703-1719.
e When presented with rare cases such as acute leukemias of ambiguous lineage (ALAL) including mixed phenotype acute leukemias (MPAL) (according to 2016 WHO
classification), consultation with an experienced hematopathologist is strongly recommended.
f Young adults may be eligible for pediatric trials with more intensive induction regimens and transplant options. Patients with AML should preferably be cared for at
experienced leukemia centers where clinical trials may be more available.
h ATRA should be available in all community hospitals, so appropriate therapy can be started promptly.
i Kim K, et al. Am J Hematol 2022;97:885-894.
j Arber DA, et al. Blood 2022;140:1200-1228.

EVAL-1A

Table of Contents
Acute Promyelocytic Leukemia (Age ≥18 years) Discussion
APL CLASSIFICATION AND TREATMENT RECOMMENDATIONS
Low risk (white blood cell [WBC]) See Treatment

count ≤10,000/mcL) Induction (APL-2)
Confirmed APLa
See Treatment
No cardiac issues
Induction (APL-3)
High risk (WBC count >10,000/mcL)
Cardiac issues See Treatment

(low ejection fraction [EF] or QTc prolongation) 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.

APL-1

Table of Contents
APL TREATMENT INDUCTION (LOW RISK)b,c,d,e CONSOLIDATION THERAPYm,n

• If blood count recovery by day 28 (platelet
Preferred Regimens >100,000, absolute neutrophil count (ANC)
>1,000), proceed with consolidation. BM
aspirate and biopsy may be considered
ATRAf 45 mg/m2 in 2 divided
to document <5% blasts and no abnormal
doses daily + arsenic trioxideg Arsenic trioxideg 0.15 mg/kg/d IV 5 d/wk for 4 weeks every 8 weeks
promyelocytesl,m but is optional
0.15 mg/kg IV dailyh (category for a total of 4 cycles, and ATRA 45 mg/m2/d for 2 weeks every 4
• If full course of induction treatment not
1) See Principles of Supportive weeks for a total of 7 cyclesh (category 1)
given, or counts have not recovered by
Care for APL (APL-A)
day 28–35, a BM aspirate and biopsy is
recommended to document <5% blasts
and no abnormal promyelocytesl,m before
or
• If blood count recovery by day 28 (platelet
>100,000, ANC >1,000), proceed with First 3 consolidation cycles = 56-day cycles:
ATRAf 45 mg/m2 in 2 divided consolidation. BM aspirate and biopsy may ATRA 45 mg/m2/d PO in 2 divided doses daily on days 1–14 and
doses daily + arsenic trioxideg be considered to document <5% blasts 29–42 (2 weeks on followed by 2 weeks off) + arsenic trioxideg 0.3
0.3 mg/kg IV on days 1–5 of and no abnormal promyelocytesl,m but is mg/kg on days 1–5 of week 1 followed by 0.25 mg/kg twice weekly
week 1 and 0.25 mg/kg twice optional during weeks 2–4i
weekly during weeks 2–8i • If full course of induction treatment not 4th consolidation cycle = 28-day cycle:
See Post-
(category 1) See Principles given, or counts have not recovered by ATRA 45 mg/m2/d PO in 2 divided doses daily on days 1–14 (2
Consolidation
of Supportive Care for APL day 28–35, a BM aspirate and biopsy is weeks on followed by 2 weeks off) + arsenic trioxideg 0.3 mg/kg
Therapy
(APL-A) recommended to document <5% blasts on days 1–5 of week 1 followed by 0.25 mg/kg twice weekly during
(APL-5)
and no abnormal promyelocytesl,m before weeks 2–4i
Useful in Certain Circumstances (if arsenic is not available or contraindicated)

ATRA 45 mg/m2 x 15 days + idarubicin 5 mg/m2 x 4 days x 1 cycle,
doses daily + idarubicin 12 mg/ At count recovery,
then ATRA x 15 days + mitoxantrone 10 mg/m2/d x 3 days x 1
m2 on days 2, 4, 6, 8j (category proceed with
cycle, then ATRA x 15 days + idarubicin 12 mg/m2 x 1 day x 1 cycle
1) or on days 2, 4, 6 for aged consolidationm,n,o
(category 1)j
>70 yh,j
or BM aspirate and biopsy
ATRAf 45 mg/m2 in 2 divided days 28–35 to document ATRA 45 mg/m2 in 2 divided doses daily during weeks 1–2, 5–6,
doses daily + a single dose of <5% blasts and no 9–10, 13–14, 17–18, 21–22, and 25–26. A single dose of gemtuzumab
gemtuzumab ozogamicin 9 mg/ abnormal promyelocytesm ozogamicin 9 mg/m2 may be given monthlyk until achievement of
m2 on day 5k before proceeding with complete molecular response
consolidation
See footnotes on APL-2A

APL-2

Table of Contents
FOOTNOTES FOR APL TREATMENT INDUCTION AND CONSOLIDATION THERAPY (LOW RISK)
b 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.
c Monitor for APL differentiation syndrome and coagulopathy; see Principles of Supportive Care for APL (APL-A).
d Early mortality is related to bleeding, differentiation syndrome, or infection. Persistent disease is rare.
e Hydroxyurea should be considered to manage high WBC count (>10,000/mcL) during induction with ATRA/arsenic trioxide.
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 QTc and monitoring and optimizing electrolytes are important in safe administration of arsenic trioxide. See Arsenic trioxide monitoring in Principles of Supportive Care
for APL (APL-A). Electrocardiogram (ECG) is recommended prior to initiating arsenic trioxide. During therapy, if a patient presents with a prolonged QT interval, the use
of QTcF correction formula is recommended. Interventions such as minimizing concurrent QT-prolonging drugs and electrolyte correction are recommended prior to
discontinuing arsenic trioxide.
h Lo-Coco F, et al. N Engl J Med 2013;369:111-121. Begin prophylaxis with prednisone; the optimal duration of steroid prophylaxis is unknown. If differentiation
syndrome develops, change to dexamethasone. See Principles of Supportive Care for APL (APL-A).
i Burnett AK, et al. Lancet Oncol 2015;16:1295-1305.
j Sanz MA, et al. Blood 2010;115:5137-5146.
k Estey E, et al. Blood 2002;99:4222-4224.
l 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.
m The presence of measurable cytogenetic and molecular markers does not carry prognostic or therapeutic implications.
n For regimens using high cumulative doses of cardiotoxic agents, consider reassessing cardiac function prior to each anthracycline/mitoxantrone-containing course.
o If full course of induction not given, BM biopsy should still be performed.

APL-2A

Table of Contents
APL TREATMENT INDUCTION (HIGH RISK)b,c,d,p,q CONSOLIDATION THERAPYn

(For patients with cardiac issues, see APL-4) See references for details on regimens including maintenance therapy.
Preferred Regimens
ATRAf 45 mg/m2 (days 1–36, 2 divided BM aspirate and biopsy
doses daily) + age-adjusted idarubicin at day 28 to document ATRA 45 mg/m2 x 28 days + arsenic trioxideg 0.15 mg/kg/d x 28 days
6–12 mg/m2 on days 2, 4, 6, 8 + arsenic remission,l,m consider x 1 cycle, then ATRA 45 mg/m2 x 7 days every 2 weeks x 3 + arsenic
trioxideg 0.15 mg/kg (days 9–36 as 2 h IV LP before proceeding trioxide 0.15 mg/kg/d x 5 days for 5 weeks x 1 cycler,x,y
infusion)r with consolidationw
or
Arsenic trioxideg 0.15 mg/kg daily 5 d/wk for 4 weeks every 8 weeks
ATRAf 45 mg/m2 in 2 divided doses daily BM aspirate and biopsy for a total of 4 cycles + ATRA 45 mg/m2 for 2 weeks every 4 weeks
and arsenic trioxideg 0.15 mg/kg/d IV + a at day 28 to document for a total of 7 cycles.s,y If ATRA or arsenic trioxide discontinued
single dose of gemtuzumab ozogamicin remission,l,m consider due to toxicity, a single dose of gemtuzumab ozogamicin 9 mg/m2
9 mg/m2 may be given on day 1, or day 2, LP before proceeding may be given every 4–5 weeks provided platelets and ANC recover
or day 3, or day 4s with consolidationw to ≥100 and ≥1.0, respectively, until molecular complete response
or (CR)k
ATRA 45 mg/m2 for 2 weeks every 4 weeks (or for 2 weeks on 2
ATRAf 45 mg/m2 in 2 divided doses daily
weeks off) in consolidation courses 1–4 + arsenic trioxideg 0.3 mg/
and arsenic trioxideg 0.3 mg/kg IV on BM aspirate and biopsy
kg on days 1–5 of week 1 in consolidation courses 1–4 and 0.25
days 1–5 of week 1 and 0.25 mg/kg twice at day 28 to document
mg/kg twice weekly in weeks 2–4 in consolidation courses 1–4
weekly on weeks 2–8 (category 1) + a remission,l,m consider
(category 1).i,y If ATRA or arsenic trioxide discontinued due to
single dose of gemtuzumab ozogamicin LP before proceeding See Post-
toxicity, a single dose of gemtuzumab ozogamicin 9 mg/m2 may be
6 mg/m2 may be given on day 1, or day 2, with consolidationw
given every 4–5 weeks provided platelets and ANC recover to ≥100 Consolidation
or day 3, or day 4i
and ≥1.0, respectively, until molecular CRk Therapy
Other Recommended Regimenst (APL-5)
BM aspirate and biopsy
ATRAf 45 mg/m2 in 2 divided doses daily
at day 28 to document Arsenic trioxideg 0.15 mg/kg/d x 5 days for 5 weeks every 7 weeks
+ daunorubicin 50 mg/m2 x 4 days (IV
remission,l consider LP for a total of 2 cycles, then ATRA 45 mg/m2 x 7 days + daunorubicin
days 3–6) + cytarabine 200 mg/m2 x 7
before proceeding with 50 mg/m2 x 3 days for 2 cyclesu,y
days (IV days 3–9)u
consolidationw
or
BM aspirate and biopsy Daunorubicin 60 mg/m2 x 3 days + cytarabine 200 mg/m2 x 7 days x 1
ATRAf 45 mg/m2 in 2 divided doses daily at day 28 to document cycle, then cytarabine [2 g/m2 (aged <50 y) or 1.5 g/m2 (aged 50–60 y)
+ daunorubicin 60 mg/m2 x 3 days + remission,m consider every 12 h x 5 daysx,z or 1 g/m2 (aged >60 y) every
cytarabine 200 mg/m2 x 7 daysv LP before proceeding 12 h x 4 days] + daunorubicin 45 mg/m2 x 3 days x 1 cycle + 5 doses
with consolidationw of IT chemotherapyv
or BM aspirate and biopsy
ATRA 45 mg/m2 x 15 days + idarubicin 5 mg/m2 and cytarabine 1 g/
ATRAf 45 mg/m2 in 2 divided doses daily at day 28 to document
m2 x 4 days x 1 cycle,aa then ATRA x 15 days + mitoxantrone 10 mg/
+ idarubicin 12 mg/m2 on days 2, 4, 6, 8j remission,m consider
m2/d x 5 daysbb x 1 cycle, then ATRA x 15 days + idarubicin 12 mg/
or on days 2, 4, 6 for those aged >70 y LP before proceeding
m2 x 1 day + cytarabine 150 mg/m2/8 h x 4 days x 1 cyclej,y,aa
See footnotes on APL-3A with consolidationw

APL-3

Table of Contents
FOOTNOTES FOR APL TREATMENT INDUCTION AND CONSOLIDATION THERAPY (HIGH RISK)
2017;35:3021-3029.
for APL (APL-A). ECG is recommended prior to initiating arsenic trioxide. During therapy, if a patient presents with a prolonged QT interval, the use of QTcF correction
formula is recommended. Interventions such as minimizing concurrent QT-prolonging drugs and electrolyte correction are recommended prior to discontinuing arsenic
trioxide.
later.
p For patients with a high WBC count (>10,000/mcL), prophylactic steroids should be initiated to prevent differentiation syndrome (see Principles of Supportive Care for
APL [APL-A]). The use of prednisone versus dexamethasone is protocol dependent.
q It is important for the management of APL that regimens containing ATRA and arsenic trioxide be administered unless there is a contraindication based on extenuating
patient circumstances.
r Iland HJ, et al. Blood 2012;120:1570-1580.
s Abaza Y, et al. Blood 2017;129:1275-1283.
t No arsenic is included in induction if unavailable or contraindicated.
u Powell BL, et al. Blood 2010;116:3751-3757.
v Adès L, et al. Blood 2008;111:1078-1084.
w Breccia M, et al. Br J Haematol 2003;120:266-270.
x 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.
y Consider IT chemotherapy (eg, 2 doses for each consolidation cycle) as an option for CNS prophylaxis.
z Dose adjustment of cytarabine may be needed for patients >60 years or patients with renal dysfunction.
aa High-risk patients who are >60 years did not receive cytarabine in consolidation and were treated as intermediate-risk patients in the LPA2005 study.
bb Mitoxantrone was reduced to 3 days in intermediate-risk patients in the LPA2005 study.

APL-3A

Table of Contents
APL TREATMENT INDUCTION (HIGH RISK)b,c,d,p CONSOLIDATION THERAPYn

IN PATIENTS WITH CARDIAC ISSUES
(For patients without cardiac issues, see APL-3)
Low EF
BM aspirate and Arsenic trioxideg 0.15 mg/kg daily 5 days/wk for 4 weeks every 8 weeks
ATRAf 45 mg/m2 in 2 divided for a total of 4 cycles + ATRA 45 mg/m2 in 2 divided doses daily for 2
biopsy at day
doses daily + arsenic trioxideg weeks every 4 weeks for a total of 7 cycles.s,y If ATRA or arsenic trioxide
28 to document
0.15 mg/kg daily + a single dose
remissionl,m discontinued due to toxicity, a single dose of gemtuzumab ozogamicin 9
of gemtuzumab ozogamicin
before proceeding mg/m2 may be given every 4–5 weeks provided platelets and ANC recover
9 mg/m2 on day 1s
with consolidation to ≥100 and ≥1.0, respectively, until molecular CRk
or
ATRA 45 mg/m2 in 2 divided doses daily for 2 weeks every 4 weeks (or for
doses daily + arsenic trioxideg
BM aspirate and 2 weeks on 2 weeks off) in consolidation courses 1–4 + arsenic trioxideg
biopsy at day 0.3 mg/kg on days 1–5 of week 1 in consolidation courses 1–4 and 0.25 mg/
0.3 mg/kg on days 1–5 of week 1
and 0.25 mg/kg twice weekly in
28 to document kg twice weekly on weeks 2–4 in consolidation courses 1–4 (category 1).i,y
remissionl,m before
weeks 2–8i (category 1) + a single If ATRA or arsenic trioxide discontinued due to toxicity, a single dose of
proceeding with gemtuzumab ozogamicin 9 mg/m2 may be given every 4–5 weeks provided
dose of gemtuzumab ozogamicin
consolidation
6 mg/m2 on day 1i platelets and ANC recover to ≥100 and ≥1.0, respectively, until molecular
See Post-
CRk
Consolidation
Prolonged QTc Therapy
BM aspirate and (APL-5)
ATRAf 45 mg/m2 in 2 divided ATRA 45 mg/m2 in 2 divided doses daily during weeks 1–2, 5–6, 9–10,
biopsy at day 28 to
doses daily + a single dose of
document remissionm 13–14, 17–18, 21–22, and 25–26. Gemtuzumab ozogamicin 9 mg/m2 may
gemtuzumab ozogamicin 9 mg/m2
before proceeding be given monthlyk until molecular CR
on day 1k
with consolidation
or
ATRAf 45 mg/m2 in 2 divided doses Daunorubicin 60 mg/m2 x 3 days + cytarabine 200 mg/m2 x 7 days x 1
at day 28 to document cycle, then cytarabine [2 g/m2 (aged <50 y) or 1.5 g/m2 (age 50–60 y)
daily + daunorubicin 60 mg/m2 x 3
remission,m consider
days + cytarabine 200 mg/m2 x 7 every 12 h x 5 daysx,z or 1 g/m2 (aged >60 y) every 12 h x 4 days], +
LP before proceeding
daysv daunorubicin 45 mg/m2 x 3 days x 1 cycle + 5 doses of IT chemotherapyv
with consolidationw
or
ATRAf 45 mg/m2 in 2 divided doses ATRA 45 mg/m2 x 15 days + idarubicin 5 mg/m2 and cytarabine 1 g/m2 x
at day 28 to document 4 days x 1 cycle,aa then ATRA x 15 days + mitoxantrone 10 mg/m2/d x 5
daily + idarubicin 12 mg/m2 on days
remission,m consider daysbb x 1 cycle, then ATRA x 15 days + idarubicin 12 mg/m2 x 1 day +
2, 4, 6, 8 or on days 2, 4, 6 for those
LP before proceeding
aged >70 yj cytarabine 150 mg/m2/8 h x 4 days x 1 cyclej,y,aa
with consolidationw
See footnotes on APL-4A

APL-4

Table of Contents
FOOTNOTES FOR APL TREATMENT INDUCTION AND CONSOLIDATION THERAPY (HIGH RISK)
2017;35:3021-3029.
for APL (APL-A). ECG is recommended prior to initiating arsenic trioxide. During therapy, if a patient presents with a prolonged QT interval, the use of QTcF correction
formula is recommended. Interventions such as minimizing concurrent QT-prolonging drugs and electrolyte correction are recommended prior to discontinuing arsenic
trioxide.
later.
p For patients with a high WBC count (>10,000/mcL), prophylactic steroids should be initiated to prevent differentiation syndrome (see Principles of Supportive Care for
APL [APL-A]). The use of prednisone versus dexamethasone is protocol dependent.
s Abaza Y, et al. Blood 2017;129:1275-1283.
v Adès L, et al. Blood 2008;111:1078-1084.
w Breccia M, et al. Br J Haematol 2003;120:266-270.
x 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.
y Consider 4–6 doses of IT chemotherapy (eg, 2 doses for each consolidation cycle) as an option for CNS prophylaxis.
z Dose adjustment of cytarabine may be needed for patients >60 years or patients with renal dysfunction.
aa High-risk patients who are >60 years did not receive cytarabine in consolidation and were treated as intermediate-risk patients in the LPA2005 study.
bb Mitoxantrone was reduced to 3 days in intermediate-risk patients in the LPA2005 study.

APL-4A

Table of Contents
APL POST- MONITORING

CONSOLIDATION
THERAPY
Monitor by
Polymerase PCRcc 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 maintenance PCRcc for
therapy PCR
confirmation
positivedd
within 4 wks
Document
molecular PCR positive dd
remissioncc,dd First
after relapseee
consolidation See
PCR negative
Repeat Therapy
PCRcc for for Relapse
PCR positivecc
confirmation (APL-6)
within 4 wks
PCR positivedd
cc 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 dd To confirm PCR positivity, a second blood sample should be done in 2–4 weeks
guidelines have recommended monitoring blood by PCR every 3 mo for 2 y to in a reliable laboratory. If molecular relapse is confirmed by a second positive test,
detect molecular relapse. We continue to endorse this for patients with high-risk treat as first relapse (APL-6). If the second test is negative, frequent monitoring
disease, those >60 y of age or who had long interruptions during consolidation, (every 3 mo for 2 y) is strongly recommended to confirm that the test remains
or patients on regimens that use maintenance and are not able to tolerate negative. The PCR testing lab should indicate the level of sensitivity of assay for
maintenance. Clinical experience indicates that risk of relapse in patients with positivity (most clinical labs have a sensitivity level of 10-4), and testing should
low-risk disease who are in molecular remission at completion of consolidation be done in the same lab to maintain the same level of sensitivity. Consider
is low and monitoring may not be necessary outside the setting of a clinical consultation with a physician experienced in molecular diagnostics if results are
trial. While long-term monitoring has been standard, with newer, more effective equivocal.
regimens, the value is less certain. ee Grimwade D, et al. J Clin Oncol 2009;27:3650-3658.

APL-5

Table of Contents
APL THERAPY FOR RELAPSE ADDITIONAL THERAPY

Transplant Autologous
candidate HCTkk
PCR
Early relapse Anthracycline-based negative
(<6 mo) after ATRA regimen as per APL-3hh,ii (by BM) Not Arsenic trioxideg
and arsenic trioxide or gemtuzumab transplant consolidation
(no anthracycline) ozogamicinll Consider CNS candidate (total of 6 cycles)
prophylaxis
Second
with IT
remission
chemotherapy
Arsenic trioxide 0.15 mg/ (morphologic)
No prior exposure (methotrexate
kg dailyg,hh,ii ± ATRA 45 or cytarabine) Matched sibling
to arsenic trioxide Transplant
mg/m2 in 2 divided doses or alternative
or early relapse
First relapse dailygg ± a single dose of candidate
donor HCTgg,kk
(<6 mo) after ATRA PCR
(morphologic gemtuzumab ozogamicin
+ anthracycline- positive
or molecular)ff until count recovery (by BM)
containing Not
with BM confirmation of
regimengg transplant Clinical trial
remission candidate
Arsenic trioxide 0.15 mg/
kg dailyg,hh,ii ± ATRA 45
mg/m2 in 2 divided doses Clinical trial
Late relapse (≥6 mo) dailyjj ± (anthracycline No remission
or
after arsenic trioxide- or a single dose of Matched sibling or
containing regimen gemtuzumab ozogamicin) alternative donor HCTkk
until count recovery
with BM confirmation of hh Following
the first cycle of consolidation, if the patient's disease is not in
remission molecular remission (by quantitative PCR on BM sample), consider matched
sibling or alternative donor (haploidentical, unrelated donor, or cord blood) HCT
g QTc and monitoring and optimizing electrolytes are important in safe or clinical trial. Testing is recommended at least 2–3 weeks after the completion of
administration of arsenic trioxide. See Arsenic trioxide monitoring in Principles of arsenic trioxide to avoid false positives.
Supportive Care for APL (APL-A). ECG is recommended prior to initiating arsenic ii Outcomes are uncertain in patients who received arsenic trioxide during initial
trioxide. During therapy, if a patient presents with a prolonged QT interval, the use induction/consolidation therapy.
of QTcF correction formula is recommended. Interventions such as minimizing jj There is a small randomized trial that suggests that the addition of ATRA does
concurrent QT-prolonging drugs and electrolyte correction are recommended prior not confer any benefit over arsenic trioxide alone. Raffoux E, et al. J Clin Oncol
to discontinuing arsenic trioxide. 2003;21:2326-2334.
ff Document molecular panel to verify relapsed APL versus therapy-related AML. kk See NCCN Guidelines for Hematopoietic Cell Transplantation.
gg Cicconi L, et al. Ann Hematol 2018;97:1797-1802. ll Lo-Coco F, et al. Blood 2004;104:1995-1999.

APL-6

Table of Contents
PRINCIPLES OF SUPPORTIVE CARE FOR APLa

There are variations among institutions, but the following issues are important to consider in the management of APL.
• Clinical coagulopathy:
Management of clinical coagulopathy: Aggressive platelet transfusion support to maintain platelets ≥50,000/mcL; 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.
• APL differentiation syndrome:
Maintain a high index of suspicion of APL differentiation syndrome (ie, fever, often associated with increasing WBC count >10,000/mcL, 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 >10,000/mcL) for developing differentiation syndrome, initiate prophylaxis with corticosteroids, either
prednisone 0.5 mg/kg day 1 or dexamethasone 10 mg every 12 h (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 h until count recovery or risk of differentiation has abated.2,3
The following cytoreduction strategies for leukocytosis may be used for differentiation syndrome that is difficult to treat: hydroxyurea,
anthracycline, or gemtuzumab ozogamicin.
• Arsenic trioxide monitoring:
Prior to initiating therapy
◊ ECG for prolonged QTc interval assessment
◊ Serum electrolytes (Ca, K, Mg, phosphorus) 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.
a Antiviral prophylaxis zoster for duration of treatment may be appropriate. Freyer CW, et al. 2 Lo-Coco F, et al. N Engl J Med 2013;369:111-121.
Leuk Lymphoma 2021;62:696-702; Glass JL, et al. Blood 2015;126:Abstract 3752. 3 Sanz MA, et al. Blood 2010;115:5137-5146.
1 Daver N, et al. Br J Haematol 2015;168:646-653. 4 Sanz MA, et al. Blood 2019;133:1630-1643.

APL-A

Table of Contents
INTENSIVE RISK GROUP TREATMENT INDUCTIONe,f,g,h,t

INDUCTION Principles of Venetoclax, see AML-K
ELIGIBLE
Preferred:
• Standard 7+3 (daunorubicin)k,l,u,v + gemtuzumab ozogamicind,i (CD33
Favorable-risk AML
positive)j
(CBF-AML,c NPM1-
mutated/FLT3 wild-
Other Recommended:
type AML, in-frame
• Standard 7+3 (daunorubicin or idarubicin)k,l,u,v
basic leucine zipper
• 7+3 (mitoxantrone)k,l,u,v (for age ≥60 y)
[bZIP] mutation in
• FLAG-IDA (fludarabine + HiDACz + granulocyte colony-stimulating factor
CEBPA)y
[G-CSF]m - idarubicin) + gemtuzumab ozogamicind,i (category 2B; use with See Follow
caution in patients >60 y) -Up and Re-
Induction
• Standard 7+3 (daunorubicin or idarubicin)k,l,u,v + midostaurinn,w (FLT3-ITD or After
AML with FLT3 TKD) (category 1) Standard-
mutation • Standard 7+3 (daunorubicin or idarubicin)k,l,u,v + quizartinib (FLT3-ITD only) Dose
(category 1) Cytarabine
Induction Induction
eligiblea,b (AML-3)
Preferred:
• Standard 7+3 (daunorubicin or idarubicin)k,l,u,v (category 1)
Intermediate-risk
AML Other Recommended:
• Standard 7+3 (daunorubicin)k,l,u,v + gemtuzumab ozogamicini (CD33 positive)j
• FLAG-IDAm,z ± gemtuzumab ozogamicini (category 2B; use with caution in
patients >60 y)
• FLAG-IDAm,s + venetoclax (category 3)
See AML-5 (Intensive Induction Ineligible)

Poor risk groups See AML-2
See footnotes on AML-2A

AML-1

Table of Contents
INTENSIVE RISK GROUP TREATMENT INDUCTIONf,g,h,e,t

INDUCTION Principles of Venetoclax, see AML-K
ELIGIBLE
Favorable and
See AML-1
intermediate risk groups
• Standard 7+3 (idarubicin or daunorubicin)k,l,u,v (category 1)

• HiDACl,z,aa + idarubicin or daunorubicinu,v + etoposide (category 1 See Follow-
Poor-risk for patients ≤45 y, category 2B for other age groups) Up and
Induction AML with and without • FLAG-IDAm,z (category 2B) Re-Induction
eligiblea,b TP53 mutation or • FLAG-IDAm,s + venetoclax (category 3) After
• Decitabine (days 1–5) + venetoclaxq Standard-
del17p abnormalityo,x Dose
• Decitabine (days 1–10) + venetoclaxq (category 3)
• Azacitidine + venetoclaxq Cytarabine
• Low-dose cytarabine (LDAC) + venetoclaxq Induction
(AML-3)
• Low-intensity therapy (azacitidine [category 2B] or decitabine) or
• Therapy-related AML Follow-
other than CBF-AML Up After
• Antecedent • Standard 7+3 (daunorubicin or idarubicin)k,l,u,v (category 1) High-Dose
MDS/chronic • CPX-351/dual-drug liposomal cytarabine and daunorubicinp Cytarabine
myelomonocytic Induction for
(category 1 for ≥60 y, category 2B for <60 y) Poor-Risk
leukemia (CMML) • Decitabine (days 1–5) + venetoclaxq,r AML (AML-4)
• Cytogenetic changes • Azacitidine + venetoclaxq,r
consistent with • LDAC + venetoclaxq
MDS (AML with • Low-intensity therapy (azacitidine or decitabine)r
myelodysplasia-related
changes [AML-MRC])x

AML-2

Table of Contents
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 (1–2 g). 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. See NCCN Guidelines for Older Adult Oncology.
c Consider screening with FISH to identify translocations/abnormalities associated with CBF-AML.
d For CBF-AML with FLT3 mutation, the panel prefers gemtuzumab ozogamicin. 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.
e See Principles of Supportive Care for AML (AML-F).
f See Monitoring During Therapy (AML-G).
g Consider referral to palliative care for consultation at the start of induction. LeBlanc TW, et al. Curr Hematol Malig Rep 2017;12:300-308 and LeBlanc TW, et al. J
Oncol Pract 2017;13:589-590. See NCCN Guidelines for Palliative Care.
h See General Considerations and Supportive Care for Patients with AML Who Prefer Not to Receive Blood Transfusions (AML-D).
i 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.
j Threshold for CD33 is not well-defined and may be ≥1%.
k ECOG reported a significant increase in CR rates and overall survival (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.
l For patients with impaired cardiac function, other cytarabine-based regimens alone or with other agents can be considered. See Discussion.
m An FDA-approved biosimilar is an appropriate substitute for filgrastim.
n While midostaurin is not FDA approved for maintenance therapy, the study was designed for consolidation and maintenance midostaurin for a total of 12 months.
Stone RM, et al. N Engl J Med 2017;377:454-464.
o 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).
p There are limited data supporting the use of this regimen in patients aged <60 years. Lancet JE, et al. J Clin Oncol 2018;36:2684-2692. For patients with 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.
q Venetoclax with decitabine, azacitidine, or LDAC 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.
r 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.
s Doses of cytarabine should be modified based on age and renal insufficiency as per protocol. DiNardo CD, et al. J Clin Oncol 2021;39:2768-2778.
t See Principles of Systemic Therapy (AML-E).
Continued
AML-2A

Table of Contents
FOOTNOTES FOR INTENSIVE INDUCTION ELIGIBLE

u For patients who exceed anthracycline dose or have cardiac issues but are still able to receive aggressive therapy, alternative non-anthracycline–containing regimens
may be considered (eg, FLAG, clofarabine-based regimens [category 3]).
v 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).
w The RATIFY trial studied patients aged 18–60 y with FLT3-ITD AML. An extrapolation of the data suggests that patients aged 61–70 years with FLT3-ITD 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.
x Regimens that include gemtuzumab ozogamicin have limited benefit in poor-risk disease.
y 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.
z Consider dose adjustments for cytarabine based on age and renal function.
aa The use of HiDAC for induction outside the setting of a clinical trial is still controversial. While the remission rates are the same for standard-dose cytarabine and
HiDAC, two studies have shown more rapid BM blast clearance after one cycle of high-dose therapy. Kern W and Estey EH. Cancer 2006;107:116-124.

AML-2B

Table of Contents
FOLLOW-UP AND REINDUCTION AFTER STANDARD-DOSE CYTARABINE INDUCTIONg,t,bb,cc

RE-INDUCTION
• HiDACz,gg BM aspirate and
• Standard 7 + 3 (daunorubicin or idarubicin)hh,ii biopsy to document
• 7+3 (mitoxantrone)hh (for age ≥60 y) remission status after
• Standard 7 + 3 (daunorubicin or idarubicin) + ANC ≥1.0 and platelet
midostaurinn,hh,ii (FLT3 mutated [ITD or TKD]) count ≥100. If by day CR
Significant • Standard 7 + 3 or 5 + 2 (daunorubicin or 35 post-treatment (Screening Consolidation
residual idarubicin) + quizartinibhh,ii (FLT3-ITD only) there is no evidence LP, see
disease • CPX-351/dual-drug liposomal encapsulation of such hematologic <60 years (AML-7)
AML-B) ≥60 years (AML-8)
without a of cytarabine and daunorubicin (therapy- recovery, perform BM
(Response
hypocellular related AML other than CBF-AML/APL, aspirate and biopsy.
antecedent MDS/CMML, or AML-MRC) If by day 35 recovery criteria, see
BMee,ff
(preferred only if given in induction; BM is occurring but not AML-I)
aspirate and biopsy 14–21 days after start of yet to the level of
therapy) ANC ≥1.0 and platelet
• See treatment for lack of response to count ≥100, wait up
induction to one additional
Follow-up week to perform BM
BMf,gaspirate aspirate and biopsy. • Matched sibling or
and biopsy All patients should alternative donor HCTcc
14–21 days have BM aspirate and • HiDACz (if not previously
after start biopsy by day 42 post- used as treatment for
of therapydd treatment, regardless persistent disease at
Lack of
Significant • Standard 7 + 3 (daunorubicin or idarubicin)hh,ii of the degree of day 15) ± anthracycline
hematologic recovery. response
cytoreductionff • 7+3 (mitoxantrone)hh (for age ≥60 y) to (daunorubicin or
(<20% • Standard 7 + 3 (daunorubicin or idarubicin) + When performed, idarubicin)hh if a
induction
cellularity midostaurinn,hh,ii (FLT3 mutated [ITD or TKD]) BM aspirate and clinical trial is not
biopsy should include (Response
but >5% blasts • Standard 7 + 3 or 5 + 2 (daunorubicin or available while awaiting
or vice versa) idarubicin) + quizartinibhh,ii (FLT3-ITD only) cytogenetic and criteria, see
identification of a donor
(if ambiguous, • Intermediate-dose cytarabine molecular studies, AML-I) • See Therapy for
consider repeat • HiDACz,gg as appropriate. For Relapsed/Refractory
BM biopsy measurable (minimal) Disease (AML-J)
within 7 days) residual disease • Best supportive care
(MRD)
assessment, see
AML-H
Hypoplasiaee,ff Await recovery

AML-3

Table of Contents
FOOTNOTES FOR FOLLOW-UP AND REINDUCTION AFTER STANDARD-DOSE CYTARABINE INDUCTION

Oncol Pract 2017;13:589-590. See NCCN Guidelines for Palliative Care.
t See Principles of Systemic Therapy (AML-E).
z Consider dose adjustments for cytarabine based on age and renal function.
bb Consider clinical trials for patients with disease with targeted molecular abnormalities.
cc 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.
dd There are limited prospective data to support this recommendation. Othus M, et al. Leukemia 2016;30:1779-1780.
ee If ambiguous, consider repeat BM biopsy in 5–7 days before proceeding with therapy.
ff Hypoplasia is defined as cellularity less than 20% of which the residual blasts are less than 5% (ie, blast percentage of residual cellularity).
gg For re-induction, no data are available to show superiority with intermediate-dose cytarabine or HiDAC.
hh 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.
ii 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.

AML-3A

Table of Contents
FOLLOW-UP AFTER HIGH-DOSE CYTARABINE INDUCTION FOR POOR-RISK AMLg,bb,cc
Significant residual See Therapy for Relapsed/Refractory Disease (AML-J)

disease without a or
hypocellular BMee,ff Best supportive care
BM aspirate and biopsy to
document remission status after
Significant ANC ≥1.0 and platelet count
cytoreductionff ≥100. If by day 35 post-treatment
with low % there is no evidence of such CR
Follow-up BMf Consolidation
residual blasts hematologic recovery, perform (Screening LP,
aspirate and <60 years
(if ambiguous, Await BM aspirate and biopsy. If by see AML-B)
biopsy 21–28 (AML-7)
consider repeat recovery day 35 recovery is occurring but (Response
days after start ≥60 years
BM biopsy in not yet to the level of ANC ≥1.0 criteria, see
of therapy (AML-8)
5–7 days before and platelet count ≥100, wait AML-I)
proceeding with up to one additional week to
therapy) perform BM aspirate and biopsy.
All patients should have BM See Therapy for Relapsed/
Lack of Refractory Disease (AML-J)
aspirate and biopsy by day 42
response to
post-treatment, regardless of the induction or
Await
Hypoplasiaee,ff degree of hematologic recovery. (Response Matched sibling or
recovery alternative donor HCTcc
When performed, BM aspirate criteria, see
and biopsy should include AML-I) or
cytogenetic and molecular Best supportive care
studies, as appropriate. For MRD
assessment, see AML-H

g Consider referral to palliative care for consultation at the start of induction. LeBlanc TW, et al. Curr Hematol Malig Rep 2017;12:300-308 and LeBlanc TW, et al. J Oncol Pract 2017;13:589-590. See NCCN
Guidelines for Palliative Care.
bb Consider clinical trials for patients with disease with targeted molecular abnormalities.
cc 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.
ee If ambiguous, consider repeat BM biopsy in 5–7 days before proceeding with therapy.
ff Hypoplasia is defined as cellularity less than 20% of which the residual blasts are less than 5% (ie, blast percentage of residual cellularity).

AML-4

Table of Contents
LOWER RISK GROUPS TREATMENT INDUCTIONe,g,h,t

INTENSITY Principles of Venetoclax, see AML-K
THERAPY Preferred
(INTENSIVE • Azacitidine + venetoclax (category 1)q,r,oo
INDUCTION • Decitabine (days 1–5) + venetoclaxq,r,oo
INELIGIBLE)
Other Recommended
AML without
• LDAC + venetoclaxoo
actionable
• Azacitidine or decitabiner,jj
mutations
• Glasdegib + LDACkk
• Gemtuzumab ozogamicinll (CD33 positive)j (category 2B)
• LDAC (category 2B)
• Best supportive care (hydroxyurea, transfusion support)
Preferred
• Azacitidine + venetoclax (category 1)q,r,oo
• Ivosidenibmm,pp + azacitidinenn (category 1) (IDH1 only)
• Decitabine (days 1–5) + venetoclaxq,r,oo Follow-Up After Induction
Not a • Ivosidenibmm,pp (IDH1 only) Therapy With Lower
candidate • Enasidenibmm,pp (IDH2 only) Intensity Therapy (Intensive
for IDH1 or IDH2 Induction Ineligible) (AML-6)
intensive mutation Other Recommended
induction • LDAC + venetoclaxoo
therapya,b • Azacitidine, decitabiner,jj
Useful in Certain Circumstances

• Enasidenibmm,pp + azacitidine (IDH2 only) (category 2B)
Preferred
• Azacitidine + venetoclax (category 1)q,r,oo
• Decitabine (days 1–5) + venetoclaxq,r,oo
Other Recommended
FLT3
mutation • LDAC + venetoclaxoo
• Azacitidine or decitabiner,jj or sorafenib
• (Azacitidine or decitabine)r + sorafenib
Useful in Certain Circumstances

• Gilteritinib + azacitidine (category 2B) See footnotes on AML-5A

AML-5

Table of Contents
FOOTNOTES FOR LOWER INTENSITY THERAPY (INTENSIVE INDUCTION INELIGIBLE)

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 (1–2 g). 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. See NCCN Guidelines for Older Adult Oncology.
e See Principles of Supportive Care for AML (AML-F).
Oncol Pract.2017;13:589-590. See NCCN Guidelines for Palliative Care.
h See General Considerations and Supportive Care for Patients Who Prefer Not to Receive Blood Transfusions (AML-D).
q Venetoclax with decitabine, azacitidine, or LDAC 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.
r 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.
t See Principles of Systemic Therapy.
jj In patients with AML with TP53 mutation, a 10-day course of decitabine may be considered (Welch JS, et al. N Engl J Med 2016;375:2023-2036). 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.
kk 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. Blood
2016;128:99.
ll Regimens that include gemtuzumab ozogamicin have limited benefit in poor-risk disease.
mm 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).
nn 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, creatinine clearance (CrCl)
<45 mL/min, or other comorbidity. Montesinos P, et al. N Engl J Med 2022;386:1519-1531.
oo Patients with disease in remission should take breaks between cycles. For more details about cycle length, see AML-K.
pp Response to treatment with enasidenib or ivosidenib may take 3–5 months.

AML-5A

Table of Contents
FOLLOW-UP AFTER INDUCTION THERAPY WITH LOWER INTENSITY THERAPY (INTENSIVE INDUCTION INELIGIBLE)t
Response • Allogeneic HCTqq

• Continue on lower-intensity regimen that was
(Response previously used for induction per AML-5
criteria, • A single dose of gemtuzumab ozogamicin for up to
see AML-I) 8 continuation cycles (CD33-positive)j (category 2B)
BM aspirate and
biopsy to document
Previous See
remission status
lower- Maintenance
(timing is dependent
intensity (AML-9)
on agent) For MRD
therapy assessment, see
AML-H
No response
or See Therapy for Relapsed/Refractory Disease
progression (AML-J)
(Response or
criteria, see Best supportive care (hydroxyurea, transfusion
support) (See NCCN Guidelines for Palliative Care)
AML-I)

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

AML-6

Table of Contents
AGE <60 y RISK GROUP TREATMENTt

CONSOLIDATION (See AML-A)
THERAPY
Favorable-risk AML
(CBF-AML, NPM1- • HiDACtt ± gemtuzumab ozogamicini (CD33 positivej, NPM1-
mutated, FLT3 wild-type)
mutated/FLT3 wild-type AML, • Intermediate-dose cytarabine + daunorubicin + gemtuzumab
in-frame bZIP mutation in ozogamicini,uu (CD33 positive)j
CEBPA)xx
• Matched sibling or alternative donor HCTrr,vv

• HiDACtt,ww + midostaurinn (FLT3-ITD or TKD)
• HiDACtt,ww See
• AML with FLT3 mutationss
Age <60 y • HiDACtt,ww + quizartinib (FLT3-ITD only) Maintenance
• Intermediate-risk AMLrr
• Intermediate-dose cytarabine + daunorubicin + gemtuzumab (AML-9)
ozogamicini,uu (CD33 positive)j
• Poor risk AML with and

without TP53 mutation or
del17p abnormality • Matched sibling or alternative donor HCTrr,vv (preferred)
• HiDACtt
• Therapy-related AML other • CPX-351/dual-drug liposomal encapsulation of cytarabine and
than CBF-AML daunorubicin (preferred only if given during induction)
• Antecedent MDS/CMML • Continuation of lower intensity regimen used for induction
• Cytogenetic changes (eg, HMA, [azacitidine or decitabine] + venetoclax) See AML-5
consistent with MDS (AML-
MRC)

AML-7

Table of Contents
FOOTNOTES FOR CONSOLIDATION THERAPY (AGE <60 YEARS)

i 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.
rr 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.
ss FLT3-ITD mutation is a poor-risk feature in the setting of otherwise normal karyotype, and these patients should be considered for clinical trials where available.
tt Alternate dosing of cytarabine for postremission therapy has been reported (see Discussion). Jaramillo S, et al. Blood Cancer J 2017;7:e564.
uu 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.
vv Patients may require at least one cycle of HiDAC consolidation while donor search is in progress to maintain remission. Patients may proceed directly to transplant
following achievement of remission if a donor (sibling or alternative) is available.
ww There is no evidence that HiDAC is superior to intermediate doses (1.5 g/m2 daily x 5 days) of cytarabine in patients with AML with intermediate-risk cytogenetics.
xx 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.

AML-7A

Table of Contents
AGE ≥60 y RISK GROUP TREATMENTt

CONSOLIDATION (See AML-A)
THERAPY
Favorable-risk AML • Standard-dose cytarabine (5 or 7 days) ± (idarubicin or daunorubicin or

(CBF-AML, NPM1- mitoxantrone)hh
mutated/FLT3 wild- • Intermediate-dose cytarabine
type AML, in-frame • Intermediate-dose cytarabine + daunorubicin + gemtuzumab ozogamicin
bZIP mutation in (CD33 positive)j
CEBPA)xx • Allogeneic HCTqq
• Intermediate-dose cytarabine + midostaurinn,yy,zz (FLT3-ITD or TKD)

• AML with FLT3
• Intermediate-dose cytarabine + quizartinibyy (FLT3-ITD only)
mutation
• Allogeneic HCTqq See
Age ≥60 y Maintenance
(AML-9)
• Intermediate-dose cytarabine
• Intermediate-risk AML
• Allogeneic HCTqq
• Poor risk AML with

and without TP53
mutation or del17p • Allogeneic HCTqq
abnormality • Continuation of lower intensity regimen used for induction (eg, HMA
• Therapy-related AML [azacitidine or decitabine] + venetoclax) See AML-5
other than CBF-AML • CPX-351/dual-drug liposomal cytarabine and daunorubicin (preferred
• Antecedent MDS/ only if given during induction)
CMML • Intermediate-dose cytarabine-containing regimens (preferred only if
• Cytogenetic changes given during induction)
consistent with MDS
(AML-MRC)

AML-8

Table of Contents
FOOTNOTES FOR CONSOLIDATION THERAPY (AGE ≥60 YEARS)

hh 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.
qq Patients who are deemed as candidates for HCT and who have an available donor should be transplanted in first remission.
xx 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.
yy Alternate administration of intermediate-dose cytarabine may also be used. Sperr WG, et al. Clin Cancer Res 2004;10:3965-3971.
zz The RATIFY trial studied patients aged 18–60 y with FLT3-positive AML. An extrapolation of the data suggests that patients aged 61–70 years with FLT3-positive 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.

AML-8A

Table of Contents
MAINTENANCE THERAPY TREATMENTt
• Patient with intermediate or adverse risk disease: • Maintenance therapy with oral azacitidine until
Who received prior intensive chemotherapy and progression or unacceptable toxicity (category 1,
whose disease is now in remission preferred for age ≥55 y)zz
Completed no consolidation, some • Maintenance therapy with HMA until progression
consolidation or a recommended course of or unacceptable toxicity
consolidation and Azacitidine
No allogeneic HCT is planned Decitabine (category 2B)
See Surveillance
FLT3 inhibitor maintenance
(AML-10)
• Sorafenib (FLT3-ITD only)
Post allogeneic HCT, in remission,
• Midostaurin (FLT3-ITD or TKD) (category 2B)
and history of FLT3 mutation
• Gilteritinib (FLT3-ITD or TKD) (category 2B)
• Quizartinib (FLT3-ITD only) (category 2B)
• Patient with history of FLT3-ITD mutation:

Previously received quizartinib FLT3 inhibitor maintenance
No allogeneic HCT is planned • Quizartinib (FLT3-ITD only)
If none of the above scenarios is applicable Maintenance therapy not recommended

zz This is not intended to replace consolidation chemotherapy. In addition, fit patients with AML with intermediate- and/or adverse-risk cytogenetics 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 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 with intermediate or adverse cytogenetics who were not felt to be candidates for HCT. Most patients received at least 1
cycle of consolidation prior to starting oral azacitidine. Wei AH, et al. N Engl J Med 2020;383:2526-2537.

AML-9

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AML SURVEILLANCEaaa AND THERAPY FOR RELAPSED/REFRACTORY DISEASE

(AFTER COMPLETION OF CONSOLIDATION)
Options:
Clinical trial (strongly preferred)
• CBC, platelets every 1–3 mo for or
2 y, then every 3–6 mo up to 5 y Targeted therapy (see AML-J) followed by
• BM aspirate and biopsy only if matched sibling or alternative donor HCT
peripheral smear is abnormal or Relapsebbb Comprehensive genomic or
cytopenias develop (Response profiling to determine Chemotherapy (see AML-J) followed by
• Donor search should be initiated criteria, see mutation status of matched sibling or alternative donor HCT
at first relapse in appropriate AML-I) actionable genes or
patients concomitant with Repeat initial successful induction regimenccc
institution of other therapy if no if ≥12 months since induction regimen
sibling donor has been identified or
Best supportive care
(see NCCN Guidelines for Palliative Care)
aaa Studies are ongoing to evaluate the role of molecular monitoring in the surveillance for early relapse in patients with AML (see Discussion).
bbb Multi-gene molecular profiling/targeted NGS (including IDH1/IDH2, FLT3 mutations) is suggested as it may assist with selection of therapy and appropriate clinical trials (see
Discussion). Molecular testing should be repeated at each relapse or progression.
ccc Reinduction therapy may be appropriate in certain circumstances, such as in patients with long first remission (there are no data regarding re-induction with dual-drug liposomal
encapsulation of cytarabine and daunorubicin). This strategy primarily applies to cytotoxic chemotherapy and excludes the re-use of targeted agents due to the potential development of
resistance. Targeted therapies may be retried if agents were not administered continuously and not stopped due to development of clinical resistance. If a second CR is achieved, then
consolidation with allogeneic HCT should be considered.

AML-10

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RISK STRATIFICATION BY BIOLOGICAL DISEASE FACTORS FOR PATIENTS WITH NON-APL AML TREATED WITH INTENSIVE INDUCTION
CHEMOTHERAPY1,*
Risk Category*,† Genetic Abnormality
Favorable t(8;21)(q22;q22.1)/RUNX1::RUNX1T1†,‡
inv(16)(p13.1q22) or t(16;16)(p13.1;q22)/CBFB::MYH11†,‡
Mutated NPM1†,§ without FLT3-ITD
bZIP in-frame mutated CEBPA||
Intermediate Mutated NPM1†,§ with FLT3-ITD
Wild-type NPM1 with FLT3-ITD (without adverse-risk genetic lesions)
t(9;11)(p21.3;q23.3)/MLLT3::KMT2A†,¶
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-rearranged#
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,** monosomal karyotype††
Mutated ASXL1, BCOR, EZH2, RUNX1, SF3B1, SRSF2, STAG2, U2AF1, and/or ZRSR2‡‡
Mutated TP53a
† 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.
‡ Concurrent KIT and/or FLT3 gene mutation does not alter risk categorization
§ AML with NPM1 mutation and adverse-risk cytogenetic abnormalities are categorized as adverse-risk.
|| Only in-frame mutations affecting the bZIP region of CEBPA, irrespective of whether they occur as monoallelic or biallelic mutations, have been associated with favorable outcome.
¶ The presence of t(9;11)(p21.3;q23.3) takes precedence over rare, concurrent adverse-risk gene mutations.
# Excluding KMT2A partial tandem duplication (PTD).
** Complex karyotype: ≥3 unrelated chromosome abnormalities in the absence of other class-defining recurring genetic abnormalities; excludes hyperdiploid karyotypes with three or more trisomies (or
polysomies) without structural abnormalities.

†† Monosomal karyotype: presence of two or more distinct monosomies (excluding loss of X or Y), or one single autosomal monosomy in combination with at least one structural chromosome abnormality
(excluding CBF-AML).
‡‡ For the time being, these markers should not be used as an adverse prognostic marker if they co-occur with favorable-risk AML subtypes.
* Frequencies, response rates, and outcome measures should be reported by risk category, and, if sufficient numbers are available, by specific genetic lesions indicated.
a TP53 mutation at a variant allele fraction of at least 10%, irrespective of the TP53 allelic status (mono- or biallelic mutation); TP53 mutations are significantly associated with AML with complex and monosomal
karyotype.
1 Dohner H, Wei AH, Appelbaum FR, et al. Diagnosis and management of AML in adults: 2022 recommendations from an international expert panel on behalf of the ELN. Blood 2022;140:1345-1377.
For Familial Genetic Alterations in AML, see AML-A 2 of 4

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FAMILIAL GENETIC ALTERATIONS IN AML1

• Predisposition to AML is increasingly recognized. Referral for genetic counseling, germline tissue testing, and potential extension of these
services to appropriate family members should be considered in select patients (See the NCCN Guidelines for Genetic/Familial High-Risk
Assessment: Breast, Ovarian, and Pancreatic
• With a suggestive family history of leukemia, other hematologic cancers, or the associated conditions listed in the tables on the next
pages.
A diagnosis of MDS age <40 y or a personal history of ≥2 cancers (including those with therapy-related AML or MDS and at least one other
cancer).
In whom a high variant allele frequency (>30%) mutation associated with AML predisposition was detected at diagnosis, particularly if
it persists at high frequency in remission. These patients have a substantial risk of germline abnormalities and should be referred for
assessment.
• An expeditious evaluation for germline AML predisposition mutations is of particular importance to assist family donor selection prior to
allogeneic transplantation.
• Because commercial next-generation sequencing (NGS) panels for AML diagnostics sample neoplastic tissue and potentially lack
coverage of genes or mutation hotspots, they should not be used in isolation to assess for the presence or absence of AML predisposition
mutations. Germline mutation testing should only be performed on non-neoplastic tissues that do not carry a risk of blood contamination,
such as cultured skin fibroblasts from a skin biopsy. This is not typically available outside of academic referral centers and has a
prolonged turnaround time. Accordingly, it may be warranted to test the peripheral blood of family transplant donor candidates for suspect
gene mutations identified in AML diagnosis or remission specimens before final results are available from germline tissue samples. Still,
this testing should not replace referral for genetic counseling and germline assessment.
1 Kraft IL, Godley LA. Identifying potential germline variants from sequencing hematopoietic malignancies. Blood 2020;136:2498-2506.
Continued
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FAMILIAL GENETIC ALTERATIONS IN AML
Name of Syndrome Causative Pattern of Characteristic Other Other Associated Conditions Recommended
Gene(s) Inheritance Malignancy Hematopoietic Diagnostic Test
Abnormalities
Familial platelet RUNX1 Autosomal MDS Thrombocytopenia Exon sequencing and
disorder with dominant AML Platelet dysfunction gene rearrangement
propensity to myeloid T-cell ALL testing for RUNX1
malignancies (OMIM
601399)
Thrombocytopenia 2 ANKRD26 Autosomal MDS Thrombocytopenia 5’UTR and exon
(OMIM 188000) dominant AML Platelet dysfunction sequencing of
ANKRD26
Familial AML with CEBPA Autosomal AML Exon sequencing and
mutated CEBPA dominant gene rearrangement
(OMIM 116897) testing for CEBPA
Familial AML with DDX41 Autosomal MDS Monocytosis Solid tumor predisposition is Exon sequencing and
mutated DDX41 dominant AML likely [colon, bladder, stomach, gene rearrangement
(OMIM 608170) CMML pancreas, breast, and melanoma] testing for DDX41
Thrombocytopenia 5 ETV6 Autosomal MDS Thrombocytopenia Exon sequencing and
(OMIM 616216) dominant AML Platelet dysfunction gene rearrangement
CMML testing for ETV6
B-ALL
Myeloma
Familial MDS/AML GATA2 Autosomal MDS Monocytopenia Sensorineural deafness Exon sequencing,
with mutated GATA2 dominant AML Lymphopenia (NK Immunodeficiency intron 5 enhancer
(OMIM 137295) CMML cell, dendritic cell, Cutaneous warts region sequencing, and
B-cell, or CD4+ Pulmonary alveolar proteinosis gene rearrangement
T-cell) MonoMAC syndrome testing for GATA2
Emberger syndrome
Continued
Adapted with permission from: Churpek JE, Godley LA. Familial acute leukemia and myelodysplastic syndromes. In: UpToDate, Post TW (Ed), UpToDate, Waltham, MA.
(January 31, 2020) Copyright © 2020 UpToDate, Inc. For more information visit www.uptodate.com.

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FAMILIAL GENETIC ALTERATIONS IN AML
Name of Causative Pattern of Characteristic Other Other Associated Conditions Recommended Diagnostic
Syndrome Gene(s) Inheritance Malignancy Hematopoietic Test
Abnormalities
Familial AML with MBD4 Autosomal AML Colonic polyps Exon sequencing and gene
mutated MBD4 dominant rearrangement testing for
MBD4
MECOM-associated MECOM/EVI1 Autosomal MDS Bone marrow Radioulnar synostosis Exon sequencing and gene
syndrome (OMIM complex dominant AML failure Clinodactyly rearrangement testing for
165215 and B-cell deficiency Cardiac malformations MECOM/EVI1 complex
616738) Renal malformations
Hearing loss
Congenital SAMD9/ SAMD9 and Autosomal MDS Pancytopenia Normophosphatemic familial Full gene sequencing and
SAMD9L mutations SAMD9L dominant AML tumoral calcinosis gene rearrangement testing
MIRAGE syndrome for SAMD9 and SAMD9L
Ataxia
Telomere TERC,TERT Autosomal MDS Macrocytosis Idiopathic pulmonary fibrosis Full gene sequencing and
syndromes due to and RTEL1 dominant AML Cytopenias Hepatic cirrhosis gene rearrangement testing
mutation in TERC Aplastic anemia Nail dystrophy for TERT and TERC
or TERT (OMIM Autosomal Oral leukoplakia
127550, 613989, recessive Skin hypopigmentation Telomere length studies
and 615190) (TERT) Skin hyperpigmentation of lymphocyte subsets via
Premature gray hair FlowFISH
Cerebellar hypoplasia SNP array testing (No CLIA-
Immunodeficiency approved testing available)
Developmental delay
Myeloid neoplasms ATG2B and Autosomal AML Myelofibrosis SNP array testing (No CLIA-
with germline GSKIP dominant CMML approved testing available)
predisposition due ET
to duplications of
ATG2B and GSKIP
Adapted with permission from: Churpek JE, Godley LA. Familial acute leukemia and myelodysplastic syndromes. In: UpToDate, Post TW (Ed), UpToDate, Waltham, MA.
(January 31, 2020) Copyright © 2020 UpToDate, Inc. For more information visit www.uptodate.com.

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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 HiDAC-based therapy + dexamethasone to reduce
pressure 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 HiDAC, follow up with LP post
flow cytometrye
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 before first consolidation for patients with monocytic differentiation, MPAL, WBC count >40,000/mcL at diagnosis, extramedullary
disease, high-risk APL, or FLT3 mutations. 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 HiDAC, 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 HiDAC or IT methotrexate may increase risk of neurotoxicity. See Principles of Radiation Therapy (AML-C).

AML-B

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PRINCIPLES OF RADIATION THERAPY

General Principles
• Patients who present with isolated extramedullary disease (myeloid sarcoma) should be treated with systemic therapy. Local therapy
(RT or surgery [rare cases]) may be used for residual disease.
• In a small group of patients where extramedullary disease is causing nerve compressions, a small dose of RT may be considered to
decrease disease burden.
General Treatment Information
• Dosing prescription regimen
CNS leukemia: RTa followed by IT chemotherapyb 2x/wk until clear, then weekly x 4–6 weeksc
a Concurrent use of CNS RT with HiDAC or IT methotrexate may increase risk of neurotoxicity.
b Induction chemotherapy should be started concurrently. However, for patients receiving HiDAC, 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.

AML-C

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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: https://www.jw.org/en/medical-library/hospital-liaison-committee-hlc-
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 to reduce risk of gastrointestinal (GI) bleed; nasal
saline sprays to reduce epistaxis; and fall precautions 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 30,000/µL) 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-stimulation 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 in Jehovah’s Witnesses: unjustified reluctance to treat. Eur J Haematol 2004;72:264-267.
2 El Chaer F, Ballen KK. Treatment of acute leukaemia in adult Jehovah's Witnesses. Br J Haematol 2020;190:696-707.
3 Ballen KK, Becker PS, Yeap BY, et al. Autologous stem-cell cransplantation can be performed safely without the use of blood-product support. J Clin Oncol 2004;22:4087-4094.
4 Beck A, Lin R, Rejali AR, et al. Safety of bloodless autologous stem cell transplantation in Jehovah's Witness patients. Bone Marrow Transplant 2020;55:1059-1067.
5 Rubenstein M and Duvic M. Bone marrow transplantation in Jehovah's Witnesses. Leuk Lymphoma 2004;45:635-636.
6 Bock AM, Pollyea DA. Venetoclax with azacitidine for two younger Jehovah's Witness patients with high risk acute myeloid leukemia. Am J Hematol 2020;90:E269-E272

AML-D

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PRINCIPLES OF SYSTEMIC THERAPY

INTENSIVE INDUCTION ELIGIBLE (AML-1, AML-2)
Therapy Regimen
Standard 7+3 (daunorubicin) + gemtuzumab Standard-dose cytarabine 200 mg/m2 continuous infusion x 7 days with daunorubicin 60 mg/m2 x
ozogamicina,1,2 3 days and a single dose of gemtuzumab ozogamicin 3 mg/m2 (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 idarubicin) Standard-dose cytarabine 100–200 mg/m2 continuous infusion x 7 days with idarubicin 12 mg/m2or
daunorubicin 60 or 90 mg/m2 x 3 days
7+3 (mitoxantrone)b,c Standard-dose cytarabine 100-200 mg/m2 continuous infusion x 7 days with mitoxantrone 12 mg/m2
x 3 days
FLAG-IDAd,1 Fludarabine 30 mg/m2 days 2–6, HiDAC 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 subcutaneously (SC) daily
days 1–7
FLAG-IDA + gemtuzumab ozogamicina,d,3 Fludarabine 30 mg/m2 days 2–6, HiDAC 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 plus a single
dose of gemtuzumab ozogamicin 3 mg/m2 in first course
Standard 7+3 (daunorubicin4 or idarubicin5) + Standard-dose cytarabine 100-200 mg/m2 continuous infusion x 7 days with daunorubicin 60 mg/m2
midostaurin (FLT3-ITD or TKD) 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) + Standard-dose cytarabine 100-200 mg/m2 continuous infusion x 7 days with daunorubicin 60 mg/m2
quizartinib6 (FLT3-ITD only) or idarubicin 12 mg/m2 x 3 days and quizartinib 35.4 mg PO daily, days 8–21
FLAG-IDA3 + venetoclax7 Fludarabine 30 mg/m2 days 2–6, HiDACc 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 400 mg PO days 1–14
1 Burnett AK, et al. J Clin Oncol 2011;29:369-377.
2 Castaigne S et al. Lancet 2012;379:1508-1516.
a A meta-analysis showing an advantage with gemtuzumab ozogamicin included other 4 Stone RM, et al. N Engl J Med 2017;377:454-464.
dosing schedules. Hills RK, et al. Lancet Oncol 2014; 15:986-996 5 Jacques et al. Blood 2018; 132 (Supplement 1): 5216; Lee et al. Haematologica.
b For age ≥60 years 2023;10.3324/haematol.2022.281967.
c For regimens using high cumulative doses of cardiotoxic agents, consider reassessing 6 Erba HP, et al. Lancet 2023;401:1571-1583; Prescribing information for quizartinib
cardiac function prior to each anthracycline/mitoxantrone-containing course. Karanes C, et tablets, for oral use 2023. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/
al. Leuk Res 1999;23:787-794. label/2023/216993s000lbl.pdf.
d Use with caution in patients >60 years. 7 DiNardo CD, et al. Am J Hematol 2022;97:1035-1043.

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INTENSIVE INDUCTION ELIGIBLE (AML-1, AML-2)
Therapy Regimen
HiDAC + (daunorubicin or idarubicin) + HiDAC 2 g/m2 every 12 hours x 6 days or 3 g/m2 every 12 hours x 4 days
etoposide8-10 with daunorubicin 50 mg/m2 or idarubicin 12 mg/m2 x 3 days, and etoposide
50 mg/m2 days 1 to 5 (1 cycle)
Decitabine (days 1-5) + venetoclax 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 day 3 and beyond)
Decitabine (days 1-10) + venetoclax Decitabine 20 mg/m2 IV (days 1–10 of each 28-day cycle) and venetoclax PO
once daily (100 mg day 1, 200 mg day 2, and 400 mg day 3 and beyond)
Azacitidine + venetoclax 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)
LDAC + venetoclax11 LDAC 20 mg/m2/d 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)
Low-intensity therapy (azacitidine or Azacitidine 75 mg/m2 SC or IV days 1–7 of each 28-day cycle
decitabine) Decitabine 20 mg/m2/day IV (days 1–5 or days 1–10 of each 28-day cycle)
CPX-351/dual-drug liposomal cytarabine and CPX-351/dual-drug liposomal cytarabine 100 mg/m2 and daunorubicin 44
daunorubicin12 mg/m2 on days 1, 3, and 5 x 1 cycle
8 Weick JKK, et al. Blood 1996; 88:2841-2851.

9 Bishop JF et al. Blood 1996;87:1710-1717.
10 Willemze R et al. J Clin Oncol 2014;32:219-228.
11 Wei AH, et al. J Clin Oncol 2019;27:1277-1284.
12 Lancet JE, et al. J Clin Oncol 2018;36:2684-2692.

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FOLLOW-UP AND REINDUCTION AFTER STANDARD-DOSE CYTARABINE INDUCTION (AML-3)
Therapy Regimen
HiDAC Cytarabine 1.5–3 g/m2 over 3 hours every 12 hours on days 1, 3, and 5,
or days 1, 2, and 3 for 3–4 cycles
Standard 7+3 (daunorubicin or idarubicin) Standard-dose cytarabine 100–200 mg/m2 continuous infusion x 7 days
with daunorubicin 60–90 mg/m2 or idarubicin 12 mg/m2 x 3 days
Standard 7+3 (daunorubicin4 or Standard-dose cytarabine 100-200 mg/m2 continuous infusion x 7 days
idarubicin5) + midostaurin (FLT3-ITD or with daunorubicin 60 mg/m2 or idarubicin 12 mg/m2 x 3 days and oral
TKD) midostaurin 50 mg every 12 hours, days 8–21
Standard 7 + 3 (daunorubicin or Standard-dose cytarabine 100-200 mg/m2 continuous infusion x 7 days
idarubicin) + quizartinib6 (FLT3-ITD only) with daunorubicin 60 mg/m2 or idarubicin 12 mg/m2 x 3 days and
quizartinib 35.4 mg PO daily, days 8–21
5 + 2 (daunorubicin or idarubicin) + Standard-dose cytarabine 100-200 mg/m2 continuous infusion x 5 days
quizartinib6 (FLT3-ITD only) with daunorubicin 45-60 mg/m2 or idarubicin 10-12 mg/m2 x 2 days and
quizartinib 35.4 mg PO mg daily, days 6-19
CPX-351/dual-drug liposomal cytarabine CPX-351/dual-drug liposomal cytarabine 100 mg/m2 and daunorubicin
and daunorubicin12 44 mg/m2 on days 1 and 3 x 1 cycle
Intermediate-dose cytarabine Cytarabine 1 – 1.5 g/m2 over 3 hours every 12 hours x 4–6 doses for 1–2
cycles
HiDAC ± (daunorubicin or idarubicin) HiDAC 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
4 Stone RM, et al. N Engl J Med 2017;377:454-464.

5 Jacques et al. Blood 2018; 132 (Supplement 1): 5216; Lee et al. Haematologica. 2023;10.3324/haematol.2022.281967.
6 Erba HP, et al. Lancet 2023;401:1571-1583; Prescribing information for quizartinib tablets, for oral use 2023. Available at:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/216993s000lbl.pdf.
12 Lancet JE, et al. J Clin Oncol 2018;36:2684-2692.

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LOWER INTENSITY THERAPY (INTENSIVE INDUCTION INELIGIBLE) AML WITHOUT ACTIONABLE MUTATIONS
(AML-5)
Therapy Regimen
Azacitidine + venetoclax13 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)
Decitabine + venetoclax Decitabine 20 mg/m2 IV (days 1–5) and venetoclax PO once daily (100
mg day 1, 200 mg day 2, and 400 mg day 3 and beyond)
LDAC + venetoclax14 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 75 mg/m2 SC or IV days 1–7 of each 28-day cycle
Decitabine 20 mg/m2/day IV (days 1–5 of each 28-day cycle)
Glasdegib + LDACe Glasdegib (100 mg PO daily on days 1–28) + LDAC 20 mg SC every 12
hours (days 1–10 of each 28-day cycle)
Gemtuzumab ozogamicina,1,15 6 mg/m2 IV on day 1 and 3 mg/m2 IV on day 8
LDAC14 20 mg/m2/day SC (days 1–10 of each 28-day cycle)

Hydroxyurea (best supportive care) Adjust dose based on WBC count and tolerance
a A meta-analysis showing an advantage with gemtuzumab ozogamicin included

other dosing schedules. Hills RK, et al. Lancet Oncol 2014; 15:986-996
e 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 1 Burnett AK, et al. J Clin Oncol 2011;29:369-377.
disease, ECOG performance status ≥2, baseline creatinine >1.3 mg/dL) and has 13 DiNardo CD, et al. N Engl J Med 2020;383:617-629.
been associated with an improved OS in a randomized trial. Cortes JE, et al. 14 Kantarjian HM, et al. J Clin Oncol 2012;30:2670-2677.
Blood 2016;128:99. 15 Amadori S, et al. J Clin Oncol 2016;34:972-979.

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LOWER INTENSITY THERAPY (INTENSIVE INDUCTION INELIGIBLE) IDH1 OR IDH2 MUTATION (AML-5)
Therapy Regimen
Ivosidenib16 500 mg PO once daily on days 1–28 of a 28-day cycle
Ivosidenib + azacitidine Ivosidenib 500 mg PO once daily on days 1–28 and azacitidine 75 mg/
m2 SC or IV (days 1–7 or days 1–5, 8, and 9 of each 28-day cycle)
Enasidenib17 100 mg PO once daily on days 1–28 of a 28-day cycle
Enasidenib + azacitidine Enasidenib 100 mg daily on days 1-28 and azacitidine 75 mg/m2 SC or
IV on days 1-7 of each 28 day cycle
16 DiNardo CD, et al. Blood 2017;130:725; DiNardo CD, et al. Blood 2017;130:639; Roboz GJ, et al. Blood 2020;135:462-471.
17 Stein EM, et al. Blood 2015;126:323; DiNardo CD, et al. Blood 2017;130:639.

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LOWER INTENSITY THERAPY (INTENSIVE INDUCTION INELIGIBLE) FLT3 MUTATION (AML-5)
Therapy Regimen
Sorafenib 400 mg PO twice daily days 1–28 of each 28-day cycle
(Azacitidine or decitabine) + sorafenib18 Azacitidine 75 mg/m2 SC or IV days 1–7 of each 28-day cycle or
Decitabine 20 mg/m2 IV days 1–10 of each 28-day cycle + sorafenib
400 mg PO twice daily days 1–28 of each 28-day cycle
Gilteritinib + azacitidine Gilteritinib 120 mg daily on days 1-28 and azacitidine 75 mg/m2 SC or
IV on days 1-7 of each 28 day cycle
18 Ohanian M, et al. Am J Hematol 2018;93;1136-1141.

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FOLLOW-UP AFTER INDUCTION THERAPY WITH LOWER INTENSITY THERAPY (INTENSIVE INDUCTION INELIGIBLE)
(AML-6)
Therapy Regimen
Gemtuzumab ozogamicina,1,15 6 mg/m2 IV on day 1 and 3 mg/m2 IV on day 8
See AML-5 for other regimens
See AML-7 or AML-8 for consolidation
CONSOLIDATION AGE <60 YEARS
(AML-7)
Therapy Regimen
HiDAC19,20 + gemtuzumab ozogamicina,1 Cytarabine 3 g/m2 over 3 hours every 12 hours on days 1, 3, and 5 or
on days 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
Intermediate-dose cytarabine Cytarabine 1-1.5 g/m2 every 12 hours on days 1–4 + daunorubicin 60 mg/m2
+ daunorubicin + gemtuzumab on day 1 (first cycle) or days 1–2 (second cycle) + gemtuzumab ozogamicin
ozogamicina,1 3 mg/m2 (maximum dose 4.5 mg) on day 1 x 2 cycles
HiDAC19,20 + midostaurin4 (FLT3-ITD or Cytarabine 1.5–3 g/m2 over 3 hours every 12 hours on days 1, 3, and 5 or
TKD) days 1, 2, and 3 x 3–4 cycles + midostaurin 50 mg twice daily on days 8–21 x
4 cycles
HiDAC19,20 + quizartinib6 (FLT3-ITD only) Cytarabine 3 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
HiDAC19,20 Cytarabine 1.5–3 g/m2 over 3 hours every 12 hours on days 1, 3, and 5 or
days 1, 2, and 3 x 3–4 cycles
and daunorubicin12 29 mg/m2 on day 1 and 3 x 1 – 2 cycles
a A meta-analysis showing an advantage with gemtuzumab ozogamicin included other dosing
schedules. Hills RK, et al. Lancet Oncol 2014;15:986-996.
1 Burnett AK, et al. J Clin Oncol 2011;29:369-377. 12 Lancet JE, et al. J Clin Oncol 2018; 36:2684-2692.
4 Stone RM, et al. N Engl J Med 2017;377:454-464. 15 Amadori S, et al. J Clin Oncol 2016;34:972-979.
6 Erba HP, et al. Lancet 2023;401:1571-1583; Prescribing information for quizartinib tablets, for oral use 19 Mayer RJ, et al. N Engl J Med 1994;331:896-903
2023. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/216993s000lbl.pdf. 20 Jaramillo S, et al. Blood Cancer J 2017;7: e564

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CONSOLIDATION AGE ≥60 YEARS
(AML-8)
Therapy Regimen
Standard-dose cytarabine (5 or 7 Cytarabine (100–200 mg/m2 over 5–7 days x 1–2 cycles) +/- idarubicin
days) ± (idarubicin or daunorubicin or 10 mg/m2 or daunorubicin 45 mg/m2 or mitoxantrone 12 mg/m2 x 3 days
mitoxantrone)c
Intermediate-dose cytarabine Cytarabine 1–1.5 g/m2 x 4–6 doses for 1–2 cycles
Intermediate-dose cytarabine Cytarabine 1–1.5 g/m2 x 4–6 doses for 1–2 cycles + daunorubicin 60 mg/m2
+ daunorubicin + gemtuzumab on day 1 (first cycle) or days 1–2 (second cycle) + gemtuzumab ozogamicin
ozogamicina,1 3 mg/m2 (maximum dose 4.5 mg) on day 1 x 2 cycles
Intermediate-dose cytarabine + Cytarabine 1–1.5 g/m2 over 3 hours every 12 hours on days 1, 3, and 5 or
midostaurin4 (FLT3-ITD or TKD) days 1, 2, and 3 x 3–4 cycles + midostaurin 50 mg twice daily on days 8–21
x 4 cycles
Intermediate-dose cytarabine + Cytarabine 1.5 g/m2 over 3 hours every 12 hours on days 1, 3, and 5 +
6
quizartinib (FLT3-ITD only) quizartinib 35.4 mg PO daily on days 6–19 for up to 4 cycles
and daunorubicin12 29 mg/m2 on day 1 and 3 x 1–2 cycles
See AML-5 for continuation of of lower
intensity therapy

a A meta-analysis showing an advantage with gemtuzumab ozogamicin included 4 Stone RM, et al. N Engl J Med 2017;377:454-464.
other dosing schedules. Hills RK, et al. Lancet Oncol 2014;15:986-996. 6 Erba HP, et al. Lancet 2023;401:1571-1583; Prescribing information for
c For regimens using high cumulative doses of cardiotoxic agents, consider quizartinib tablets, for oral use 2023. Available at: https://www.accessdata.fda.
reassessing cardiac function prior to each anthracycline/mitoxantrone- gov/drugsatfda_docs/label/2023/216993s000lbl.pdf.
containing course. Karanes C, et al. Leuk Res 1999;23:787-794. 12 Lancet JE, et al. J Clin Oncol 2018; 36:2684-2692.

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MAINTENANCE THERAPY
(AML-9)
Therapy Regimen
Oral azacitidine 300 mg PO daily on days 1–14 of each 28-day cycle
Azacitidine21 75 mg/m2 IV daily on days 1–7 or days 1–5, 8, and 9 of a 28-day cycle
Decitabine22 20 mg/m2 IV daily on days 1–5 of a 28-day cycle
Sorafenib23, 24 (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) 50 mg PO twice daily on days 1–28 of each 28-day cycle x 12 cycles
Gilteritinib25 (FLT3-ITD or TKD) 120 mg PO daily, days 1–28 of each 28-day cycle (up to 26 cycles)
Quizartinib6 (FLT3-ITD only) 26.5-53 mgf PO daily, days 1-28 of each 28-day cycle (up to 36 cycles)
6 Erba HP, et al. Lancet 2023;401:1571-1583; Prescribing information for quizartinib

tablets, for oral use 2023. Available at: https://www.accessdata.fda.gov/drugsatfda_
docs/label/2023/216993s000lbl.pdf.
f During cycle 1, quizartinib should be dosed at 26.5 mg PO once daily on days 21 Huls G, et al. Blood 2019;133:1457-1464.
1-14 if QTcF is ≤450 ms. If QTcF remains ≤450 ms on day 15, the dose should 22 Boumber Y, et al. Leukemia 2012;26:2428-3241.
be increased to 53 mg PO daily for the remainder of the 28 day cycle. The 23 Xuan L, et al. Lancet Oncol 2020;21:1201-1212.
26.5 mg dose should be maintained if QTcF was >500 ms at any point during 24 Burchert A, et al. J Clin Oncol 2020;38:2993-3002.
induction or consolidation. 25 Pratz KW, et al. Blood 2020;136 (supplement 1):16-17.

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PRINCIPLES OF SUPPORTIVE CARE FOR AML

There are variations among institutions, but the following issues are important to consider in the management of AML.
General
• Blood products:
Leukocyte-depleted products should be used for transfusion.
All patients with AML are at risk for acute graft-versus-host disease (aGVHD) and management should be based on institutional practice/
preference. See NCCN Guidelines for Hematopoietic Cell Transplantation.
Transfusion thresholds: red blood cell (RBC) counts for hemoglobin ≤7–8 g/dL or per institutional guidelines or symptoms of anemia;
platelets for patients with platelets <10,000/mcL or with any signs of bleeding.a
Cytomegalovirus (CMV) screening for potential HCT candidates may be considered.
• Tumor lysis prophylaxis: hydration with diuresis, and allopurinol or rasburicase. Rasburicase should be considered as initial treatment in
patients with rapidly increasing blast counts, high uric acid, or evidence of impaired renal function.
Glucose-6-phosphate dehydrogenase (G6PD) deficiency should be checked when possible. However, it is not always feasible to do so
rapidly. If there is high suspicion of G6PD deficiency, caution is necessary; rasburicase may be contraindicated.
• Patients receiving HiDAC therapy (particularly those with impaired renal function), or intermediate-dose cytarabine in patients >60 years
of age, are at risk for cerebellar toxicity. Neurologic assessment, including tests for nystagmus, slurred speech, and dysmetria, should be
performed before each dose of cytarabine.
In patients exhibiting rapidly rising creatinine due to tumor lysis, HiDAC should be discontinued until creatinine normalizes.
In patients who develop cerebellar toxicity, cytarabine should be stopped. Rechallenge with HiDAC in future treatment cycles should not
be attempted.1
• Steroid (or equivalent) eye drops should be administered to both eyes 4 times daily for all patients undergoing HiDAC therapy until 24 hours
post completion of cytarabine.
• Growth factors may be considered as a part of supportive care for post-remission therapy. Note that such use may confound interpretation
of the BM evaluation. Patients should be off granulocyte-macrophage colony-stimulating factor (GM-CSF) or G-CSF for a minimum of 7 days
before obtaining BM to document remission.
• Decisions regarding use and choice of antibiotics should be made by the individual institutions based on the prevailing organisms and
their drug resistance patterns. Posaconazole has been shown to significantly decrease fungal infections when compared to fluconazole and
itraconazole.2 Outcomes with other azoles, such as voriconazole, echinocandins, or amphotericin B, may produce equivalent results. See
the NCCN Guidelines for the Prevention and Treatment of Cancer-Related Infections and commensurate with the institutional practice for
antibiotic stewardship.
1 Smith GA, Damon LE, Rugo HS, et al. High-dose cytarabine dose modification reduces the
incidence of neurotoxicity in patients with renal insufficiency. J Clin Oncol 1997;15:833-839.
a Patients who are alloimmunized should receive cross-match–compatible and/or HLA- 2 Cornely OA, Maertens J, Winston DJ, et al. Posaconazole vs. fluconazole or itraconazole
specific blood products prophylaxis in patients with neutropenia. N Engl J Med 2007;356:348-359.

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MONITORING DURING THERAPY

Induction
• CBC daily (differential daily or as clinically indicated during chemotherapy and every other day after recovery of WBC count >500/mcL 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 tests (LFTs), 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.
• LFTs 1–2 x/wk.
• Coagulation panel 1–2 x/wk.
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
in 7–14 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 2x/wk during chemotherapy.
• Chemistry profile, electrolytes daily during chemotherapy.
• Outpatient monitoring post chemotherapy: CBC, platelets, differential, and electrolytes 2–3 x/wk 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-7.

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MEASURABLE (MINIMAL) RESIDUAL DISEASE ASSESSMENT

• The role of MRD in prognosis and treatment is evolving. Participation in clinical trials is encouraged.
• MRD in AML refers to the presence of leukemic cells below the threshold of detection by conventional morphologic methods. MRD is a component
of disease evaluation over the course of sequential therapy. If the patient is not treated in an academic center, there are commercially available tests
available that can be used for MRD assessment. Patients whose disease achieved a CR by morphologic assessment alone can still harbor a large number
of leukemic cells in the BM.1 The points discussed below are relevant to intensive approaches (induction chemotherapy) but have not been validated for
other modalities of treatment.
• The most frequently employed methods for MRD assessment include real-time quantitative PCR (RQ-PCR) assays (ie, NPM1,2 CBFB::MYH11,
RUNX1::RUNX1T13) and multicolor flow cytometry (MFC) assays specifically designed to detect abnormal MRD immunophenotypes.1 The threshold to
define MRD+ and MRD- samples depends on the technique and subgroup of AML. NGS–based assays to detect mutated genes (targeted sequencing,
20–50 genes per panel)4,5 is not routinely used, as the sensitivity of PCR-based assays and flow cytometry is superior to what is achieved by conventional
NGS. Mutations associated with clonal hematopoiesis of indeterminate potential (CHIP) and aging (ie, DNMT3A, TET2, potentially ASXL1) are also not
considered reliable markers for MRD.4-6
There are distinct differences between diagnostic threshold assessments and MRD assessments. If using flow cytometry to assess MRD, it is
recommended that a specific MRD assay is utilized, but, most importantly, that it is interpreted by an experienced hematopathologist.
• Based on the techniques, the optimal sample for MRD assessment is either peripheral blood (NPM1 PCR-based techniques) or an early, dedicated pull of
the BM aspirate (ie, other PCR, flow cytometry, NGS). The quality of the sample is of paramount importance to have reliable evaluation.
• Studies in both children and adults with AML have demonstrated the correlation between MRD and risks for relapse, as well as the prognostic significance
of MRD measurements after initial induction therapy.7
MRD positivity is not proof of relapse. However, a persistently positive MRD result after induction, which depends on the technique used and the study, is
associated with an increased risk of relapse.
Forpatients with favorable-risk disease, if MRD is persistently positive after induction and/or consolidation, consider a clinical trial or alternative
therapies, including allogeneic HCT.
Some evidence suggests MRD testing may be more prognostic than KIT mutation status in CBF-AML, but this determination depends on the method
used to assess MRD and the trend of detectable MRD.
After completion of therapy, “Molecular relapses” can predict hematologic relapses within a 3- to 6-month timeframe.
• Timing of MRD assessment:
Upon completion of initial induction.4-6
Before allogeneic HCT.8
Additional time points should be guided by the regimen used.2,3
1 Schuurhuis GJ, Heuser M, Freeman S, et al. Minimal/measurable residual disease in AML: 5 Klco JM, Miller CA, Griffith M, et al. Association between mutation clearance after
consensus document from ELN MRD Working Party. Blood 2018;131:1275-1291. induction therapy and outcomes in acute myeloid leukemia. JAMA 2015;314:811-822.
2 Ivey A, Hills RK, Simpson MA, et al. Assessment of minimal residual disease in standard- 6 Morita K, Kantarjian H, Wang F, et al. Clearance of somatic mutations at remission and the
risk AML. N Engl J Med 2016;374:422-433. risk of relapse in acute myeloid leukemia J Clin Oncol 2018 36:1788-1797.
3 Jourdan E, Boissel N, Chevret S, et al. Prospective evaluation of gene mutations and 7 Short NJ, et al. Association of measurable residual disease with survival outcomes in
minimal residual disease in patients with core binding factor acute myeloid leukemia. Blood patients with acute myeloid leukemia: A systematic review and meta-analysis. JAMA Oncol
2013;121:2213-2223. 2020;6:1890-1899.
4 Jongen-Lavrencic M, Grob T, Hanekamp D, et al. Molecular minimal residual disease in 8 Thol F, Gabdoulline R, Liebich A, et al. Measurable residual disease monitoring by NGS
acute myeloid leukemia. N Engl J Med 2018;378:1189-1199. before allogeneic hematopoietic cell transplantation in AML. Blood 2018;132:1703-1713.

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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 should be performed if spicules are absent from the aspirate sample.
• Complete response (CR)
Morphologic CR – transfusion independence
ANC >1000/mcL (blasts <5%)
◊ Platelets ≥100,000/mcL (blasts <5%)
CR without MRD (CRMRD-)
◊ If studied pretreatment, CR with negativity for a genetic marker by RT-PCR or CR with negativity by MFC2
◊ Sensitivity varies by marker and method used; analyses should be done in experienced laboratories.
◊ Molecular CR – molecular studies negative
CR 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)3
CR with incomplete hematologic recovery (CRi) – All CR criteria and transfusion independence but with persistence of neutropenia (<1,000/
mcL) or thrombocytopenia (<100,000/mcL).
Responses less than CR may still be meaningful depending on the therapy.
• Partial remission (PR)4
Decrease of at least 50% in the percentage of blasts to 5% to 25% in the BM aspirate and the normalization of blood counts, as noted above.
• Relapse following CR is defined as reappearance of leukemic blasts in the peripheral blood or the finding of more than 5% blasts in the BM,
not attributable to another cause (eg, BM regeneration after consolidation therapy) or extramedullary relapse.
• Lack of response to induction – Inability to attain CR or CRi following exposure to at least 2 courses of intensive induction therapy.
1 Döhner H, Estey E, Grimwade D, et al. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood 2017;129:424-447.
2 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, Hills RK, Simpson MA,
et al. Assessment of minimal residual disease in standard-risk AML. N Engl J Med 2016;374:422-433.
3 Bloomfield CD, Estey E, Pleyer L, et al. Time to repeal and replace response criteria for acute myeloid leukemia? Blood Rev 2018;32:416-425.
4 Partial remissions are useful in assessing potential activity of new investigational agents, usually in phase I trials.

AML-I

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THERAPY FOR RELAPSED/REFRACTORY DISEASEa

Clinical triala Aggressive therapy for appropriate patients:
• Cladribine + cytarabine + G-CSFb ± mitoxantrone or idarubicin9,10
Targeted therapy:
• HiDAC (if not received previously in treatment) ± (idarubicin or
• Therapy for AML with FLT3-ITD mutation
daunorubicin or mitoxantrone)11
Gilteritinib1 (category 1)
• Fludarabine + cytarabine + G-CSFb ± idarubicin12,13
HMAs(azacitidine or decitabine) + sorafenib2,3
• Etoposide + cytarabine ± mitoxantrone14
Quizartinib4 (category 2B)
• Clofarabine ± cytarabine ± idarubicin15,16
• Therapy for AML with FLT3-TKD mutation
Gilteritinib1 (category 1) Less aggressive therapy:
• Therapy for AML with IDH2 mutation • HMAs (azacitidine or decitabine)
Enasidenib5 • LDAC (category 2B)
• Therapy for AML with IDH1 mutation • (HMA or LDAC)17,18 + venetoclaxc
Ivosidenib6
Olutasidenib7
8 Taksin AL, Legrand O, Raffoux E, et al. High efficacy and safety profile of fractionated doses of Mylotarg
as induction therapy in patients with relapsed acute myeloblastic leukemia: a prospective study of the
• Therapy for CD33-positive AML alfa group. Leukemia 2007;21:66-71.
Gemtuzumab ozogamicin8 9 Robak T, Wrzesień-Kuś A, Lech-Marańda E, et al. Combination regimen of cladribine
(2-chlorodeoxyadenosine), cytarabine and G-CSF (CLAG) as induction therapy for patients with
a There are promising ongoing clinical trials investigating targeted therapies based on molecular mutations
relapsed or refractory acute myeloid leukemia. Leuk Lymphoma 2000;39:121-129.
10 Fridle C, Medinger M, Wilk MC, et al. Cladribine, cytarabine and idarubicin (CLA-Ida) salvage
for relapsed/refractory disease. Molecular profiling should be considered if not done at diagnosis, or chemotherapy in relapsed acute myeloid leukemia (AML). Leuk Lymphoma 2017:1068-1075.
repeated to determine clonal evolution. See Discussion. 11 Karanes C, Kopecky KJ, Head DR, et al. A phase III comparison of high dose ARA-C (HIDAC) versus
b An FDA-approved biosimilar is an appropriate substitute for filgrastim.
HIDAC plus mitoxantrone in the treatment of first relapsed or refractory acute myeloid leukemia
c See Principles of Venetoclax Use With HMA in AML Patients with AML (AML-K).
Southwest Oncology Group Study. Leuk Res 1999;23:787-794.
1 Perl AE, Altman JK, Cortes J, et al. Selective inhibition of FLT3 by gilteritinib in relapsed or refractory 12 Montillo M, Mirto S, Petti MC, et al. Fludarabine, cytarabine, and G-CSF (FLAG) for the treatment of
acute myeloid leukaemia: a multicentre, first-in-human, open-label, phase 1-2 study. Lancet Oncol poor risk acute myeloid leukemia. Am J Hematol 1998;58:105-109.
2017;18:1061-1075. 13 Parker JE, Pagliuca A, Mijovic A, et al. Fludarabine, cytarabine, G-CSF and idarubicin (FLAG-IDA)
2 Ravandi F, Alattar ML, Grunwald MR, et al. Phase 2 study of azacytidine plus sorafenib in patients with
for the treatment of poor-risk myelodysplastic syndromes and acute myeloid leukaemia. Br J Haematol
acute myeloid leukemia and FLT3 internal tandem duplication mutation. Blood 2013:121:4655-4662. 1997;99:939-944.
3 Muppidi MR, Portwood S, Griffiths EA, et al. Decitabine and sorafenib therapy in FLT3 ITD-mutant acute 14 Nair G, Karmali G, Gregory SA, et al. Etoposide and cytarabine as an effective and safe cytoreductive
myeloid leukemia. Clin Lymphoma Myeloma Leuk 2015;15 Suppl:S73-9. regimen for relapsed or refractory acute myeloid leukemia. J Clin Oncol 2011;29:15_suppl, 6539-6539.
4 Cortes JE, Khaled S, Martinelli G, et al. Quizartinib versus salvage chemotherapy in relapsed or 15 Faderl S, Wetzler M, Rizzieri D, et al. Clorarabine plus cytarabine compared with cytarabine alone in
refractory FLT3-ITD acute myeloid leukaemia (QuANTUM-R): a multicentre, randomised, controlled, older patients with relapsed or refractory acute myelogenous leukemia: results from the CLASSIC I Trial.
open-label, phase 3 trial. Lancet Oncol 2019;20:984-997. J Clin Oncol 2012;30:2492-2499.
5 Stein EM, DiNardo CD, Pollyea DA, et al. Enasidenib in mutant IDH2 relapsed or refractory acute 16 Faderl S, Ferrajoli A, Wierda W, et al. Clofarabine combinations as acute myeloid leukemia salvage
myeloid leukemia. Blood 2017;130:722-731. therapy. Cancer 2008;113:2090-2096.

6 DiNardo CD, Stein EM, de Botton S, et al. Durable remissions with ivosidenib in IDH1-mutated relapsed 17 Aldoss I, Yang D, Aribi A, et al. Efficacy of the combination of venetoclax and hypomethylating agents in
or refractory AML. N Eng J Med 2018;378:2386-2398. relapsed/refractory acute myeloid leukemia. Haematologica 2018;103:e404-e407.
7 Cortes J, Fenaux P, Yee K, et al. Olutasidenib (FT-2102) induces durable complete remissions in 18 DiNardo CD, Rausch CR, Benton C, et al. Clinical experience with the BCL2-inhibitor venetoclax
patients with relapsed/refractory mIDH1 acute myeloid leukemia. Results from a planned interim in combination therapy for relapsed and refractory acute myeloid leukemia and related myeloid
analysis of a phase 2 pivotal clinical trial [abstract] Blood 2022;140: Abstract 2757. malignancies. Am J Hematol 2018;93:401-407.

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PRINCIPLES OF VENETOCLAX USE WITH HMA OR LDAC (1 OF 2)

General
• The maximum number of cycles for these regimens is unknown, and treatment may continue as long as tolerated and effective. As data become available,
additional insight and guidance about the recommended length of treatment will be provided.
• Patients with disease in remission should take breaks between treatment, such as extending cycle length from 28-day to 42-day cycles.
• Where there are delays in count recovery, reduction in duration of venetoclax and/or reduction in dose or duration of HMA or LDAC should be considered.a
• Refer to prescribing information and consult with a pharmacist for potential drug interactions (eg, CYP3A4 inhibitors).
Strong CYP3A4 inhibitors (especially posaconazole) require significant dose reductions during initiation and ramp-up phase followed by a reduced daily
dose.
The use of strong or moderate CYP3A4 inducers (eg, carbamazepine, phenytoin, rifampin) should be avoided.
• The addition of a third agent is not recommended to the combinations described in this section outside the context of a clinical trial.
Therapy for Patients with Newly Diagnosed Disease1

• Prior to Therapy
To decrease the risk of severe tumor lysis syndrome (TLS), aim to achieve WBC count of <25,000/mcL with hydroxyurea/leukapheresis if necessary.
Initiate both therapies of the combination concomitantly.
If azole antifungal prophylaxis or other CYP enzyme-interacting medications are concurrently indicated, reduce venetoclax dose accordingly.b
• First Cycle Considerations
TLS monitoring:
◊ In-patient treatment is strongly recommended during first cycle of treatment, especially through dose escalation.c
◊ 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 target dose 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.
◊ For patients with proliferative disease, monitor blood chemistries every 6–8 hours after initiation; if within normal limits, recheck once daily and
continue monitoring until no further risk of TLS.
◊ Aggressively monitor and manage electrolyte imbalances.
Continue treatment regardless of cytopenias; transfuse as needed and no growth factors until treatment cycle is complete.
BM biopsy for response assessment on days 21–28d
◊ If no morphologic remission (persistent BM blasts above 5%) but evidence of efficacy exists, proceed with a second cycle without interruption with the
goal of achieving morphologic remission, and repeat BM biopsy on days 21–28 of this cycle.
If blasts <5%, hold both therapies and consider the following measures:
◊ Administer growth factor support if indicated.
◊ Monitor blood counts for up to a 14-day period.
– If counts have recovered to a clinically significant threshold, resume the next cycle.
– If counts have not recovered to a clinically significant threshold, consider repeating the BM exam. If morphologic remission is ongoing, can continue
to hold therapy for count recovery or start the second cycle with adjustment in the dose or schedule of the HMA/LDAC and/or venetoclax.
Footnotes on AML-K 2 of 2
Continued
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Table of Contents
PRINCIPLES OF VENETOCLAX USE WITH HMA OR LDAC (2 OF 2)

Therapy for Patients with Newly Diagnosed Disease (Continued)1
• Cycle 2 and beyond
If NED after cycle 1, repeat BM biopsy at 3- to 6-month intervals, assuming no unexpected changes in blood counts occur.
If remission after cycle 1, continue sequential cycles with up to 14-day interruptions between cycles for count recovery and/or growth
factor support.
If persistent disease after cycle 1, repeat BM biopsy following cycle 2 (or subsequent cycles until NED or remission) to again assess for
cellularity and disease response, and to determine timing of subsequent cycle.
If count recovery worsens over time, rule out relapsed disease with repeat BM biopsy. If a morphologic remission is ongoing with
worsening blood counts, consider decreasing the dose/schedule of venetoclax and/or HMA/LDAC.
Repeat BM biopsy when concerned about relapse.
If no morphologic remission after cycle 2 or 3, the likelihood of response is decreased and patients could consider enrollment in a clinical
trial if available. In the absence of available clinical trials, if the patient's disease has had any response with manageable toxicity, continue
therapy as tolerated.
Therapy for Patients with Relapsed/Refractory Disease

• Recommend antifungal prophylaxis if indicated.2
• Consider the same TLS and intrapatient dose escalation measures as described under "First Cycle Considerations."
• Consider the same recommendations for early BM biopsy and cytopenia mitigation plan proposed under "First Cycle Considerations."
a Recommend referral to tertiary care center/academic medical center if need to consider discontinuation of
any agent, or to continue maintenance on single-agent venetoclax.
b See venetoclax prescribing information: https://www.accessdata.fda.gov/drugsatfda_docs/
label/2022/208573s027lbl.pdf 1 Jonas BA, Pollyea DA. How we use venetoclax with hypomethylating agents for
c Patients may need hospitalization beyond first cycle, based on medical circumstances. Treatment in the treatment of newly diagnosed patients with acute myeloid leukemia. Leukemia
outpatient setting may be considered per institutional practice or treatment preference. 2019;33:2795-2804.
d Combination of venetoclax + decitabine may favor an earlier assessment at day 21 (if blasts are reduced, 2 Aldoss I, Dadwal S, Zhang J, et al. Invasive fungal infections in acute myeloid leukemia
but no morphologic remission). treated with venetoclax and hypomethylating agents. Blood Adv 2019;3:4043-4049.

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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.

BPDCN-INTRO

Discussion
(Age ≥18 years)
EVALUATION/WORKUP FOR BPDCNa,1 DIAGNOSIS3
• H&P
• CBC, platelets, differential, CMP
• Analysis of skin lesions (collaboration with dermatology is
recommended),2 peripheral blasts, BM aspirate/biopsy, and lymph
BPDCN diagnosis requires at
node biopsy including:
least 4 of 6 BPDCN antigens:
Dendritic cell morphology assessment
• CD123
IHC
• CD4
Flow cytometry BPDCN See Treatment
• CD56
Cytogenetic analysis (karyotype and/or FISH) confirmed Induction
• TCL-1
Molecular analysis (most common aberrations include: ASXL1, (BPDCN-2)
• CD2AP
IDH1–2, IKZF1–3, NPM1, NRAS, TET1–2, TP53, U2AF1, ZEB2)3
• CD303/BDCA-2
• PET/CT scan of other sites, if clinical suspicion for extramedullary
without myeloid,b T or B
disease and/or lymphadenopathy
lineage expression markers
• All patients require a diagnostic LP at the time of initial diagnosis,
at disease relapse, or any other time when there is a clinical
suspicion for CNS involvement. Follow with IT chemotherapy
prophylaxis as clinically indicated (see BPDCN-B).
1 Facchetti F, Petrella T, Pileri SA. Blastic plasmacytoid dendritic cell neoplasm.

In: Swerdlow SH, Campo E, Harris NL, et al. WHO Classification of Tumours
of Haematopoietic and Lymphoid Tissues. Revised 4th ed. IARC Press: Lyon
2017:173-177.
2 Pemmaraju N, et al. N Engl J Med 2019;380:1628-1637. 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
a See Principles of BPDCN (BPDCN-A). Lymphomas.
b Myeloid markers include myeloperoxidase (MPO), lysozyme, CD14, CD34, CD116, and CD163. 3 Menezes J, et al. Leukemia 2014;28:823-829

BPDCN-1

Discussion
(Age ≥18 years)
TREATMENT TREATMENT INDUCTION4
OF BPDCNc • Tagraxofusp-erzsd (formerly SL-401) (preferred) Consider
• Allogeneic See
12 mcg/kg IV over 15 minutes once daily on days 1–5 of a 21-day cycle5,6
For management of adverse events, see Supportive Care (BPDCN-C) HCT7,10,11,12 Surveillance
• Autologous HCT (BPDCN-3)
• Chemotherapyd
AML-type induction chemotherapy:
Standard-dose cytarabine 100–200 mg/m2 continuous infusion x 7 days CRe
with idarubicin 12 mg/m2 or daunorubicin 60–90 mg/m2 x 3 days7
ALL-type induction chemotherapy: Tagraxofusp-erzsd until progression
Candidate for
intensive remission HyperCVAD regimen (hyperfractionated cyclophosphamide, vincristine,
induction therapy doxorubicin, dexamethasone, alternating with high-dose methotrexate
Lack of See Treatment for
and cytarabine)7,8,9
response to Relapsed/Refractory Disease
Lymphoma induction:
induction9 (BPDCN-3)
CHOP regimen (cyclophosphamide, doxorubicin, vincristine, and
prednisone)7
BPDCN • IT chemotherapy in patients with documented CNS disease at diagnosis/
if clinically indicated (methotrexate, cytarabine)
Patients with low Palliative options include:

performance and/or Localized/isolated
• Surgical excision
nutritional status cutaneous disease
• Focal RT
(ie, serum albumin <3.2
g/dL; not a candidate Options include:
for intensive remission Systemic disease • Venetoclax-based therapy,13 see AML-5
induction therapy or (palliative intent) • Systemic steroids
tagraxofusp-erzsd) • Supportive Care (BPDCN-C)
4 Pemmaraju N, et al. Blood 2019;134(Supplement_1):2723.
5 Frankel AE, et al. Blood 2014;124:385-392.
c See Principles of Supportive Care for BPDCN (BPDCN-C). 6 Pemmaraju N, et al. N Engl J Med 2019;380:1628-1637.
d Consider CNS prophylaxis for patients with overt systemic disease. 7 Pagano L, et al. Haematologica 2013;98:239-246.
e CR in BPDCN has the same hematologic criteria as AML (See AML-I), but it is 8 Reimer P, et al. Bone Marrow Transplant 2003;32:637-646.
also important to document resolution of any extramedullary sites including CNS 9 Deotare U, et al. Am J Hematol 2016;91:283-286.
and skin lesions. If the skin still shows microscopic disease , consider continuing 10 Kharfan-Dabaja MA, et al. Br J Haematol 2017;179:781-789.
additional cycles (at least 4) of therapy before managing as relapsed/refractory 11 Roos-Weil D, et al. Blood 2013;121:440-446.
disease. For appropriate studies to assess CR, see Pemmaraju N, et al. N Engl J Med 12 Aoki T, et al. Blood 2015;125:3559-3562.
2019;380:1628-1637. 13 DiNardo CD, et al. Am J Hematol 2018;93:401-407.

BPDCN-2

Discussion
(Age ≥18 years)
SURVEILLANCE TREATMENT FOR RELAPSED/REFRACTORY DISEASE
• Evaluate CNS for disease/prophylaxis14

• Consider
• CBC, platelets every 1–3 mo for
Clinical trial (preferred)
2 y, then every 3–6 mo up to 5 y
Tagraxofusp-erzsd,6 (preferred, if not already used)
• BM aspirate and biopsy only if
For management of adverse events, see Supportive Care (BPDCN-C)
peripheral smear is abnormal or Relapsed/
Chemotherapy (if not already used), see Treatment Induction (BPDCN-2)
cytopenias develop refractory
Local RT to isolated lesions/areas
• Repeat PET/CT scan for patients with BPDCN
Systemic steroids
prior evidence of extramedullary disease
Venetoclax-based therapy,13,15,16 see AML-5
• 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
6 Pemmaraju N, et al. N Engl J Med 2019;380:1628-1637.

13 DiNardo CD, et al. Am J Hematol 2018;93:401-407.
14 Martin-Martin L, et al. Oncotarget 2016;7:10174-10181.
15 Montero J, et al. Cancer Discovery 2017;7:156-164.
d Consider CNS prophylaxis for patients with overt systemic disease. 16 Rausch CR, et al. Blood 2017;130:1356.

BPDCN-3

Discussion
(Age ≥18 years)
PRINCIPLES OF BPDCN
General Principles:
• BPDCN is a disorder of immature dendritic cells that regulate effector T-cell function.
• 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.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 fit patients, current treatment options for BPDCN include tagraxofusp-erzs and chemotherapy, whereas those with low albumin and/or
comorbidities should receive localized therapy or supportive care as shown in the algorithm (see 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.
7 Pagano L, Valentini CG, Grammatico S, Pulsoni A. Blastic plasmacytoid dendritic cell neoplasm:
a Close collaboration with dermatology is recommended. For guidance on classification and diagnostic criteria and therapeutical approaches. Br J Haematol 2016;174:188-202.
measurement of skin lesions, see page MFSS-3 in the NCCN Guidelines for Primary Cutaneous 8 Frankel AE, Woo JH, Ahn C, et al. Activity of SL-401, a targeted therapy directed to interleukin-3
Lymphomas. receptor, in blastic plasmacytoid dendritic cell neoplasm patients. Blood 2014;124:385-392.

BPDCN-A

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
IT treatments may be continued once or twice per month, if desired
• CNS-directed IT chemotherapya strongly recommended to be administered prophylactically

Without CNS disease Twice per month for a total of at least 8 doses
IT treatment may be continued once or twice per month, if desired
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).

BPDCN-B

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 For full details on administration and toxicity management, see: https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/761116s007lbledt.pdf

BPDCN-C

Table of Contents
ABBREVIATIONS
aGVHD acute graft-versus-host disease CRi complete response with MDS myelodysplastic syndrome
ALAL acute leukemia of ambiguous incomplete hematologic recovery MFC multicolor flow cytometry
lineage CRMRD- CR without MRD MLFS morphologic leukemia-free state
ALT alanine aminotransferase CSF cerebrospinal fluid MPAL mixed phenotype acute leukemia
AMC academic medical center DIC disseminated intravascular MPO myeloperoxidase
AML acute myeloid leukemia coagulation
MRC myelodysplasia-related changes
ANC absolute neutrophil count ECG electrocardiogram
MRD measurable (minimal) residual
APL acute promyelocytic leukemia EF ejection fraction disease
AST aspartate aminotransferase ESA erythropoiesis-stimulation agent NED no evidence of disease
ATRA all-trans retinoic acide FISH fluorescence in situ hybridization NGS next-generation sequencing
BM bone marrow FNA fine-needle aspiration NOS not otherwise specified
BPDCN blastic plasmacytoid dendritic G6PD Glucose-6-phosphate OS overall survival
cell neoplasm dehydrogenase
PCR polymerase chain reaction
BUN blood urea nitrogen G-CSF granulocyte colony-stimulating
PR partial remission
bZIP basic leucine zipper factor
PT prothrombin time
CBC complete blood count GI gastrointestinal
PTD partial tandem duplication
CBF core binding factor GM-CSF granulocyte-macrophage colony-
stimulating factor PTT partial thromboplastin time
CHIP clonal hematopoiesis of RBC red blood cell
indeterminate potential HCT hematopoietic cell transplantation
HiDAC high-dose cytarabine RT radiation therapy
CMML chronic myelomonocytic
leukemia HLA human leukocyte antigen RQ-PCR real-time quantitative PCR
CMP comprehensive metabolic panel HMA hypomethylating agent RT-PCR real-time PCR
CMV Cytomegalovirus HP histroy and physical SBP systolic blood pressure
CNS central nervous system HR heart rate SC subcutaneously
CNV copy number variant IHC immunohistochemistry SOS sinusoidal obstruction syndrome
CR complete response IT intrathecal TKD tyrosine kinase domain
CR1 first complete response ITD internal tandem duplication TLS tumor lysis syndrome
CRc microscopic disease LDAC Low-dose cytarabine TPO thrombopoietin
CrCl creatinine clearance LDH lactate dehydrogenase WBC white blood cell
CRh complete response with partial LFT liver function tests
hematologic recovery
LP lumbar puncture
ABBR-1

Table of Contents
NCCN Categories of Evidence and Consensus

Category 1 Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate.
Category 2A Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate.
Category 2B Based upon lower-level evidence, there is NCCN consensus that the intervention is appropriate.
Category 3 Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate.
All recommendations are category 2A unless otherwise indicated.
NCCN Categories of Preference

Interventions that are based on superior efficacy, safety, and evidence; and, when appropriate,
Preferred intervention affordability.
Other recommended Other interventions that may be somewhat less efficacious, more toxic, or based on less mature data;
intervention or significantly less affordable for similar outcomes.
Useful in certain
Other interventions that may be used for selected patient populations (defined with recommendation).
circumstances
All recommendations are considered appropriate.
CAT-1
NCCN Guidelines Version 6.2023

Discussion This discussion corresponds to the NCCN Guidelines for Acute

Myeloid Leukemia. Discussion section for Blastic Plasmacytoid
Management of Acute Myeloid Leukemia ............................................. 29
Dendritic Cell Neoplasm was updated on April 5, 2023. Updates are Management of AML in Patients Younger Than 60 Years ................. 29
in progress for other discussion sections.
Table of Contents Management of AML in Patients >60 Years ...................................... 41
Principles of Venetoclax Use with HMAs or LDAC-Based Treatment . 53

Overview ............................................................................................... 2
Role of MRD Monitoring ................................................................... 54
Guidelines Update Methodology ............................................................ 2
Postremission Surveillance for AML ................................................. 58
Literature Search Criteria....................................................................... 2
Management of Relapsed/Refractory AML........................................ 58
Sensitive/Inclusive Language Usage ..................................................... 3
Supportive Care for Patients with AML ............................................. 60
Initial Evaluation .................................................................................... 3
Supportive Care for Patients with AML Who Prefer Not to Receive
Workup .............................................................................................. 3
Blood Transfusions .......................................................................... 62
Diagnosis ........................................................................................... 5
Evaluation and Treatment of CNS Leukemia .................................... 62
Cytogenetics and Risk Stratification ................................................... 6
Management of Blastic Plasmacytoid Dendritic Cell Neoplasm ............. 64
Molecular Markers and Risk Stratification ........................................... 7
Workup ............................................................................................ 64
Familial Genetic Alterations in AML .................................................. 13
Induction Therapy for Patients with BPDCN ...................................... 65
Principles of Acute Myeloid Leukemia Treatment ................................. 14
Postremission Surveillance for BPDCN............................................. 69
Management of Acute Promyelocytic Leukemia ................................... 14
Management of Relapsed/Refractory BPDCN................................... 69
Induction Therapy for Patients with APL ........................................... 16
References .......................................................................................... 70
Consolidation Therapy for Patients with APL .................................... 20
Post-Consolidation or Maintenance for Patients with APL ................. 23
Management of Relapsed APL ......................................................... 25
Supportive Care for Patients with APL .............................................. 27
Version 6.2023 © 2023 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.
MS-1

administered in combination with alkylating agents.11,12 Radiotherapy,

Overview
especially in the context of myeloablative therapy (eg, total body irradiation
Acute myeloid leukemia (AML) is a heterogeneous hematologic or radioimmunotherapy) given before autologous hematopoietic cell
malignancy characterized by the clonal expansion of myeloid blasts in the transplantation (HCT) may also increase the risk for therapy-related
peripheral blood, bone marrow, and/or other tissues. It is the most MDS/AML.13,14 The disease course of therapy-related MDS/AML is
common form of acute leukemia among adults and accounts for the generally progressive and may be more resistant to conventional cytotoxic
largest number of annual deaths from leukemias in the United States. An therapies than de novo cases of MDS/AML.9 Importantly, clinical outcomes
estimated 19,940 people will be diagnosed with AML in 2020, and 11,180 in patients with therapy-related AML have been shown to be significantly
patients will die of the disease.1 According to the SEER Cancer Statistics inferior (both in terms of relapse-free survival [RFS] and overall survival
Review, the median age at diagnosis is 68 years;2 other registries report [OS]) compared with patients with de novo cases,8,15 except those with the
71 years,3 with approximately 54% of patients diagnosed at ≥65 years of therapy-related acute promyelocytic leukemia (APL) subtype7,16 or the
age (and approximately a third diagnosed at ≥75 years of age).2 Thus, as favorable-risk core binding factor (CBF) translocations. The proportion of
the population ages, the incidence of AML, along with myelodysplastic patients with unfavorable cytogenetics tends to be higher in the population
syndromes (MDS), seems to be rising. with therapy-related AML. Even among the subgroup with favorable
karyotypes, those with therapy-related AML tend to do less well.
Environmental factors that have long been established to increase the
risks of MDS and AML include prolonged exposure to petrochemicals; The AML Panel for the NCCN Clinical Practice Guidelines in Oncology
solvents such as benzene; pesticides; and ionizing radiation.4 (NCCN Guidelines®) convenes annually to update recommendations for
the diagnosis and treatment of AML in adults. These recommendations
Therapy-related MDS/AML (secondary MDS/AML) is a well-recognized
are based on a review of recently published clinical trials that have led to
consequence of cancer treatment in a proportion of patients receiving
significant improvements in treatment or have yielded new information
cytotoxic therapy for solid tumors or hematologic malignancies. Reports
regarding biologic factors that may have prognostic importance.
suggest that therapy-related MDS/AML may account for 5% to 20% of
patients with MDS/AML.5-7 The rate of therapy-related MDS/AML is higher
Guidelines Update Methodology
among patients with certain primary tumors, including breast cancer,
gynecologic cancers, and lymphomas (both non-Hodgkin lymphoma and The complete details of the Development and Update of the NCCN
Hodgkin lymphoma), largely owing to the more leukemogenic cytotoxic Guidelines are available at www.NCCN.org.
agents that are commonly used in the treatment of these tumors.7-10 Two
Literature Search Criteria
well-documented categories of cytotoxic agents associated with the
development of therapy-related MDS/AML are alkylating agents and Prior to the update of the NCCN Guidelines® for AML, an electronic search
topoisomerase inhibitors.5,8,9 Treatment with antimetabolites, such as the of the PubMed database was performed to obtain key literature in AML
purine analog fludarabine, has also been associated with therapy-related published since the previous Guidelines update using the following search
MDS/AML in patients with lymphoproliferative disorders, particularly when terms: acute myeloid leukemia or acute promyelocytic leukemia. The
MS-2

PubMed database was chosen as it remains the most widely used present, the information is presumed to predominantly represent cisgender
resource for medical literature and indexes peer-reviewed biomedical individuals. NCCN encourages researchers to collect more specific data in
literature.17 future studies and organizations to use more inclusive and accurate
language in their future analyses.
The search results were narrowed by selecting studies in humans
published in English. Results were confined to the following article types: Initial Evaluation
Clinical Trial, Phase II; Clinical Trial, Phase III; Clinical Trial, Phase IV; The initial evaluation of AML has two objectives. The first is to characterize
Guideline; Meta-Analysis; Randomized Controlled Trial; Systematic the disease process based on factors such as prior toxic exposure,
Reviews; and Validation Studies. antecedent myelodysplasia, and karyotypic and molecular abnormalities,
which may provide prognostic information that can impact responsiveness
The data from key PubMed articles as well as articles from additional
to chemotherapy and risk of relapse. The second objective focuses on
sources deemed as relevant to these Guidelines and discussed by the
patient-specific factors, including assessment of comorbid conditions,
panel have been included in this version of the Discussion section (eg, e-
which may affect an individual’s ability to tolerate chemotherapy. Both
publications ahead of print, meeting abstracts). Recommendations for
disease-specific and individual patient factors are taken into consideration
which high-level evidence is lacking are based on the panel’s review of
when deciding treatment.
lower-level evidence and expert opinion.
Workup
Sensitive/Inclusive Language Usage
The evaluation and initial workup for suspected AML consists of a
NCCN Guidelines strive to use language that advances the goals of
comprehensive medical history and physical examination. Laboratory
equity, inclusion, and representation. NCCN Guidelines endeavor to use
evaluations include a comprehensive metabolic panel and a complete
language that is person-first; not stigmatizing; anti-racist, anti-classist, anti-
blood count (CBC) including platelets and a differential of white blood cells
misogynist, anti-ageist, anti-ableist, and anti-fat-biased; and inclusive of
(WBCs). Serum uric acid and lactate dehydrogenase (LDH) have
individuals of all sexual orientations and gender identities. NCCN
prognostic relevance and should be evaluated.18,19 Bone marrow core
Guidelines incorporate non-gendered language, instead focusing on
biopsy and aspirate analyses (including immunophenotyping by
organ-specific recommendations. This language is both more accurate
immunohistochemistry stains with flow cytometry) and cytogenetic
and more inclusive and can help fully address the needs of individuals of
analyses (karyotype with fluorescence in situ hybridization [FISH]) are
all sexual orientations and gender identities. NCCN Guidelines will
necessary for risk stratification and to potentially guide therapy of AML.
continue to use the terms men, women, female, and male when citing
Several gene mutations are associated with specific prognoses in a subset
statistics, recommendations, or data from organizations or sources that do
of patients (category 2A) and may guide treatment decisions (category
not use inclusive terms. Most studies do not report how sex and gender
2B). Presently, c-KIT, FLT3-ITD, FLT3-TKD, NPM1, CEBPA (biallelic),
data are collected and use these terms interchangeably or inconsistently.
IDH1/IDH2, RUNX1, ASXL1, TP53, BCR-ABL, and PML-RAR alpha are
If sources do not differentiate gender from sex assigned at birth or organs
included in this group. All patients should be tested for mutations in these
MS-3

genes, and multiplex gene panels and comprehensive next-generation CNS signs or symptoms at presentation should be evaluated using
sequencing (NGS) analysis are recommended for the ongoing appropriate imaging techniques, such as radiography, CT, or MRI for the
management of AML and various phases of treatment.20-22 To detection of intracranial bleeding, leptomeningeal disease, or mass lesions
appropriately stratify therapy options, test results of molecular and in either the brain or spinal cord. If CNS hemorrhage is suspected, a CT of
cytogenetic analyses of immediately actionable genes or chromosomal brain without contrast is recommended. If leukemic meningitis is
abnormalities (eg, CBF, FLT3 [ITD or TKD], NPM1, IDH1, or IDH2) should suspected, a brain MRI with contrast is recommended. However, if
be expedited. For patients with hyperleukocytosis uncontrolled with symptoms persist, and bleeding and mass/lesions are excluded, the
hydroxyurea or leukapheresis, one dose of intermediate-dose cytarabine patient should have a lumbar puncture (LP) for diagnostic and possible
(1–2 grams)23 may be considered prior to receiving results. For patients therapeutic purposes once coagulopathy has been corrected, adequate
who prefer not to receive blood transfusions as part of therapy, see platelet support is available, and the circulating disease has been cleared
Supportive Care for Patients with AML Who Prefer Not to Receive Blood through the initiation of systemic therapy. Routine screening LPs are not
Transfusions for general considerations, although the committee believes warranted at the time of diagnosis in patients with AML. However, for
that in many cases, good outcomes from this strategy are rare. If blastic patients at high risk for CNS disease, such as those with monocytic
plasmacytoid dendritic cell neoplasm (BPDCN) is suspected, see differentiation or high WBC count (>40,000/mcL)24 at presentation, a
Management of BPDCN for work up, diagnosis and treatment diagnostic LP should be considered as part of the documentation of
recommendations. remission status. Screening LPs should be considered at first remission
before first consolidation in the setting of monocytic differentiation, mixed
Recent studies have reported on the prognostic impact of a number of phenotype acute leukemia (MPAL), WBC count >40,000/mcL at diagnosis,
molecular abnormalities in patients with AML (see Molecular Markers and high-risk APL, FLT3 mutations, or extramedullary disease, particularly in
Risk Stratification). Adequate marrow should be available at the time of patients not receiving high-dose cytarabine (HiDAC) (ie, patients ≥60
diagnosis or relapse for molecular studies as per the institutional practice. years of age). For patients who present with solitary extramedullary
Local pathologists should be consulted to discuss ways to optimize disease (currently referred to as myeloid sarcoma, and historically as
sample collection and preservation. If molecular testing is not available at granulocytic sarcoma, or chloroma) without overt marrow disease, the
the patient’s treatment center, evaluation at an outside reference initial treatment should still be based on systemic induction chemotherapy.
laboratory or transfer to another institution is recommended prior to Radiation or surgical resection may be incorporated with systemic
performing the marrow evaluation. Circulating leukemic blasts from chemotherapy in emergent situations; however, these modalities, if
peripheral blood may alternatively be used to detect molecular needed at all, should be optimally deferred until after count recovery to
abnormalities. avoid excess toxicity.
Extramedullary presentation, including central nervous system (CNS) Coagulopathy is common at presentation in many leukemias; it is
disease, is uncommon in patients with AML. However, if extramedullary therefore standard clinical practice to screen for coagulopathy by
disease is suspected, a PET/CT is recommended. Patients with significant evaluating prothrombin time, partial thromboplastin time, and fibrinogen
MS-4

activity as part of the initial evaluation and before performing any invasive strategies.26 During this transition from the FAB system to the WHO
procedure. The need for a cardiac evaluation (eg, echocardiogram or classification, the percent blasts threshold for defining high-grade MDS
multigated acquisition [MUGA] scan) should be determined based on and AML was lowered. The FAB classification had set the threshold
individual risk factors. Patients with a history or symptoms of cardiac between high-grade MDS and AML at 30% blasts, whereas the WHO
disease, prior exposure to cardiotoxic drugs or thoracic radiation, or those classification lowered the threshold for diagnosing AML to 20% or more
of an older age, should have an echocardiogram. In younger patients who blasts. This change was based on the finding that the biologic behavior
are otherwise asymptomatic with no history of cardiac disease, an (and survival outcomes) of the FAB MDS subgroup of “refractory anemia
echocardiogram can be considered. In the setting of acute illness, with excess blasts in transformation (RAEB-T),” defined as patients with
treatment should not be delayed for an echocardiogram. A small study of 20% to 30% blasts, was similar compared with that of patients with greater
76 patients with cancer who were screened for cardiac disease identified than 30% blasts. In an appropriate clinical setting, the WHO classification
only 4 patients with cardiac abnormalities. Of these 4 patients, the system further allowed AML to be diagnosed in patients with abnormal
presence of cardiac disease did not change the course of treatment.25 hematopoiesis and in the setting of characteristic clonal structural
cytogenetic abnormalities with t(15;17), t(8;21), and inv(16) or t(16;16)
Human leukocyte antigen (HLA) typing should be performed in all patients regardless of the percentage of marrow blasts.
with newly diagnosed AML for whom allogeneic HCT would be
considered. HLA typing of family members is recommended for patients In 2003, the International Working Group for Diagnosis, Standardization of
up to age 80 years or per institutional practice who do not have Response Criteria accepted the cytochemical and immunophenotypic
favorable-risk cytogenetics, and tissue typing should be broadened to WHO criteria as the standard for diagnosing AML, including the reporting
include alternative donor searches. In patients with any non-favorable risk, of myelodysplasia according to morphology.27 However, no evidence
a donor search should begin while the patient is undergoing induction shows that myelodysplasia represents an independent risk factor, because
chemotherapy rather than waiting for remission to be achieved. Early it is frequently linked to poor-risk cytogenetics.
referral to a transplant center for patients with non-favorable risk AML is
recommended. In 2008, WHO revised the diagnostic and response criteria for AML to
include additional recurrent genetic abnormalities created by reciprocal
Diagnosis translocations/inversions, and a new provisional category for some of the
Originally, the classification system for AML was defined by the French molecular markers that have been found to have a prognostic impact.28
American British (FAB) system, which relied on cytochemical stains and Additionally, the category of AML with recurrent genetic abnormalities was
morphology to separate AML from acute lymphoblastic leukemia (ALL) expanded to include the following: t(9;11)(p22;q23), t(6;9)(p23;q34)
and to categorize the disease based on degree of myeloid and monocytic (provisional entity), inv(3)(q21 q26.2) or inv(3;3)(q21;q26.2) (provisional
differentiation. In 1999, WHO developed a newer classification system, entity), and t(1;22)(p13;q13) (provisional entity), in addition to the
which incorporates information from cytogenetics and evidence of previously recognized t(8;21)(q22;q22); inv(16)(p13;1q22) or
myelodysplasia, to refine prognostic subgroups that may define treatment t(16;16)(p13.1;q22); and t(15;17)(q22;q12) [APL subtype]. Other
MS-5

provisional entities include AML with molecular abnormalities such as Due to the rarity of acute leukemias of ambiguous lineage (as defined by
mutated nucleophosmin (NPM1) or CCAAT/enhancer-binding protein the 2016 WHO classification), consultation with an experienced
alpha (CEBPA) genes (further information on these genetic lesions is hematopathologist should be sought.
provided later).28 In 2016, WHO expanded the recurrent genetic
abnormalities to include two provisional categories, AML with BCR-ABL1 Aberrant expression of differentiation antigens present at diagnosis may
rearrangement and AML with RUNX1 mutation. AML with BCR-ABL1 allow tracking of residual blasts through flow cytometry in follow-up
rearrangement is a rare de novo AML that may benefit from therapies that samples that may appear normal according to conventional morphology.
entail tyrosine kinase inhibitors. AML with RUNX1 mutation is associated The use of immunophenotyping and molecular markers to monitor
with a poorer prognosis. measurable (also known as minimal) residual disease (MRD) in adult AML
has not yet been widely incorporated into postremission monitoring
In accordance with the 2016 WHO classification, a diagnosis of AML is strategies, except in some patient subgroups with APL, CBF-AML, and
made based on the presence of 20% or more blasts in the bone marrow or NPM1-positive AML. However, ongoing research is moving MRD
peripheral blood. In an appropriate clinical setting, a diagnosis of AML may monitoring to the forefront for all patients with AML (see Role of MRD
be made with <20% blasts in the setting of recurrent cytogenetic Monitoring).
abnormalities including t(15;17), t(8;21), t(16;16), or inv(16). The accurate
Cytogenetics and Risk Stratification
classification of AML requires multidisciplinary diagnostic studies including
morphology, immunophenotyping (immunohistochemistry and flow Although cytogenetic information is often unknown when treatment is
cytometry), and molecular genetics analysis. The latter should include a initiated in patients with de novo AML, karyotype represents the single
complete cytogenetic analysis and advanced molecular analysis most important prognostic factor for predicting remission rates, relapse
techniques, as needed, to specify both translocations and gene mutations. risks, and OS outcomes. The cytogenetic risk categories adopted by these
The NCCN AML Panel suggests that complementary diagnostic guidelines are primarily based on analyses of large datasets from major
techniques can be used at the discretion of the pathology department of cooperative group trials (see Risk Stratification by Genetics in Non-APL
the individual institution. Some cases may still show evidence of both AML in the algorithm).29-31 In an analysis of data from pediatric and adult
myeloid and lymphoid antigen expression on the leukemic cells and are patients with AML (n = 1612) enrolled in the United Kingdom Medical
defined as acute leukemias of ambiguous lineage. This is further Research Council (UK MRC) AML 10 trial, the 5-year survival rates for
subgrouped into acute undifferentiated leukemia, MPAL with BCR-ABL1 those with favorable, intermediate, and unfavorable risk cytogenetics were
rearrangement, MPAL with rearranged KMT2A, MPAL with B-cell/myeloid 65%, 41%, and 14%, respectively.30 In a review of data from adult patients
features not otherwise specified, and MPAL with T-cell/myeloid features treated in a phase III Southwest Oncology Group (SWOG)/Eastern
not otherwise specified. The expression of both cytochemical and/or Cooperative Oncology Group (ECOG) intergroup study (n = 609), the
immunophenotypic characteristics of both lineages on the same cells is 5-year survival rates in the setting of favorable, intermediate, and adverse
defined as biphenotypic, whereas expression of lineage-specific risk cytogenetics were 55%, 38%, and 11%, respectively.31 Similarly, in a
characteristics on different populations of leukemia cells is termed bilineal. retrospective review of adult patients with AML treated on Cancer and
MS-6

Leukemia Group B (CALGB) protocols (n = 1213), the 5-year survival These findings were confirmed in subsequent analyses from other large
rates in the setting of favorable-, intermediate-, and poor-risk cytogenetics cooperative group studies. In an analysis of data from patients treated on
were 55%, 24%, and 5%, respectively.29 The AML 11 trial had similar SWOG protocols (n = 1344; age 16–88 years), 13% of patients were
results with 5-year survival rates in the setting of favorable-, intermediate-, found to have monosomal karyotype; nearly all of these cases (98%)
and poor-risk cytogenetics of 34%, 13%, and 2%, respectively.32 This last occurred within the unfavorable cytogenetics category.34 The incidence of
study included a population of patients ≥55 years of age, which is believed monosomal karyotype increased with age, from 4% in patients 30 years of
to attribute to the overall lower percent survival in all groups. age or younger to 20% in patients >60 years of age. Among patients with
unfavorable cytogenetics, the 4-year OS rate in the setting of monosomal
The importance of obtaining adequate samples of marrow or peripheral karyotype was 3% compared with 13% without monosomal karyotype. In
blood at diagnosis for full karyotyping and FISH cytogenetic analysis for the setting of monosomy 7, monosomal karyotype did not appear to
the most common abnormalities cannot be overemphasized. Although influence outcomes (4-year OS, 0%–3%); the 4-year OS rates in the
FISH studies for common cytogenetic abnormalities may allow for rapid setting of inv(3)/t(3;3) and t(6;9) and without monosomal karyotype were
screening to identify either favorable- or unfavorable-risk groups, 0% and 9%, respectively.34 In a retrospective study that evaluated the
additional tests are needed to provide a full picture of the genetic factors prognostic impact of monosomal karyotype in patients >60 years of age
that contribute to risk (see Molecular Markers and Risk Stratification). (n = 186) with unfavorable cytogenetics treated in a GOELAMS trial, the
2-year OS rate was significantly decreased in the setting of monosomal
The presence of autosomal chromosome monosomies in AML has
karyotype (7% vs. 22% without this abnormality; P < .0001). Similar
emerged as an important prognostic factor associated with extremely poor
outcomes were observed in the setting of complex karyotype.35
prognosis.33-35 Data from three large studies have identified monosomal
karyotypes (defined as ≥2 autosomal monosomies, or a single monosomy These studies show that monosomal karyotype, independent of other
with an additional structural abnormality) as a subset of unfavorable unfavorable cytogenetic factors, confers very poor prognosis. In the NCCN
cytogenetic prognosticators. Although complex karyotype (≥3 clonal Guidelines, the presence of monosomal karyotype is included in the
cytogenetic abnormalities) and either monosomy 5 or monosomy 7 are unfavorable-risk category of AML based on cytogenetics (see Risk
categorized as high-risk/unfavorable cytogenetics, the presence of a Stratification by Genetics in Non-APL AML in the algorithm).
monosomal karyotype was found to confer further negative prognostic
influence within the high-risk group. This high-risk subgroup was first Molecular Markers and Risk Stratification
identified in a joint study conducted by the Dutch-Belgian-Swiss The intermediate-risk cytogenetic category is the most heterogeneous
cooperative groups (HOVON/SAKK), which evaluated the correlation group in AML, because it encompasses both normal karyotype AML
between cytogenetics and OS outcomes in patients aged 60 years or (NK-AML) without gross structural abnormalities and those with structural
younger with AML (n = 1975). The 4-year OS rate in patients with changes that are considered neither poor risk nor favorable. Based on
monosomal karyotype was 4% compared with 26% in those with complex retrospective analyses of data from large cooperative group studies, 40%
karyotype (but without monosomal karyotype).33 to 50% of patients with de novo AML have normal karyotype, which is
MS-7

associated with intermediate risk as measured in terms of survival FLT3-ITD mutations occur in approximately 30% of cases and are more
outcomes.29,30 However, even in patients with NK-AML, clinical outcome is common than FLT3-TKD mutations, which occur in approximately 10% of
heterogeneous. cases.36,40,51,56-60 Numerous studies have shown the negative prognostic
influence of FLT3-ITD in patients with AML, resulting in shorter remission
Identification of mutations that carry prognostic and therapeutic impact is durations (eg, decreased disease-free survival [DFS] in patients who
rendering molecular profiling for all AML cases a standard part of the achieve a CR) and poorer survival outcomes compared with wild-type
diagnostic workup. In addition to basic cytogenetic analysis, new FLT3.36,40,53,54,56,58,59,61 In the setting of FLT3-ITD and NK-AML, median OS
molecular markers can help refine prognostics groups, particularly in from the time of diagnosis ranged from 6 to 12 months.36,40,56,59
patients with a normal karyotype. These markers include NPM1, FMS-like
tyrosine kinase 3 (FLT3), CEBPA, isocitrate dehydrogenase 1 and 2 Interestingly, a study in patients with NK-AML showed that prognosis was
(IDH1/2), DNA (cytosine-5)-methyltransferase 3A (DNMT3A), and KIT, worse in the setting of FLT3-ITD without wild-type FLT3, compared with
TP53, RUNX1, and ASXL1 gene mutations.36-48 Tests for these molecular FLT3-ITD with wild-type FLT3 in the second allele. The median OS in the
markers are now available in commercial reference laboratories and in setting of FLT3-ITD in the absence of a wild-type FLT3 was only 7 months
referral centers. Therefore, it is important for physicians to confer with the compared with 46 months in the setting of wild-type FLT3 with or without
local pathologist on how to optimize sample collection from the time of FLT3-ITD.56 The FLT3-TKD mutations predominantly occur independently
diagnosis for subsequent molecular diagnostic tests. Testing for additional of FLT3-ITD, and most frequently involve mutations in the D835 residue of
mutations may also be recommended. a TKD. Although the presence of FLT3-TKD mutations has been shown to
be associated with shorter remission durations (eg, decreased DFS) and
NPM1 Mutations
decreased OS outcomes in some studies,40,53,57,60 other studies have
The NPM1 gene encodes a shuttle protein within the nucleolus of cells. reported no impact of FLT3-TKD on prognosis51,61,62 or even a favorable
Mutations in this gene occur in 28% to 35% of AML cases.46,49,50 The outcome on OS with FLT3-TKD mutations.63 In the latter study from the
NPM1 mutation has been shown to be associated with NK-AML with a UK MRC, the 5-year OS rates in the setting of FLT3-TKD mutations were
reported frequency of 48% to 53%.38,44,51 Isolated NPM1 mutation, which 53% versus 37% without FLT3-TKD mutations, respectively. The 5-year
localizes to the cytoplasm, confers a higher complete response (CR) rate OS rate was significantly higher in the setting of a higher level of
and improved event-free survival (EFS) and OS compared with NK-AML FLT3-TKD mutations (>25%) compared with lower levels of mutations, in
and wild-type NPM1, resulting in outcomes similar to cases with favorable which OS rate was similar to cases without FLT3-TKD mutations (71% vs.
cytogenetics (eg, CBF AML).38,39,44,46,47 37%; adjusted P = .004).63
FLT3 Mutations
The discrepant findings from these studies may be a result of important
The FLT3 gene encodes a receptor tyrosine kinase involved in differences such as patient baseline characteristics, presence of
hematopoiesis. Two major classes of activating FLT3 mutations have
concurrent genetic lesions (eg, NPM1, CEBPA mutations), or inclusion of
been identified in cases of AML, which include the internal tandem the APL subtypes. Studies have shown that FLT3-TKD mutations can
duplications (ITD) and tyrosine kinase domain (TKD) point mutations.52-57
MS-8

occur in the setting of prognostically favorable NPM1 or CEBPA mutations on OS when considering all IDH mutations (IDH1 and IDH2
mutations.51,62 Moreover, FLT3-TKD mutations as the sole genetic combined) or in the overall patient population,68-71 IDH1 mutations
aberration or occurring concurrently with t(15;17)/promyelocytic leukemia correlated with significantly worse outcomes in the subgroup of patients
(PML)-retinoic acid receptor alpha (RARA) (underlying lesion in the APL with NK-AML with favorable- or intermediate-risk disease.68,71,73 In the
subtype) or with FLT3-ITD (FLT3 double mutation) have been associated subgroup of patients younger than 60 years with favorable-risk AML
with poorer outcomes.51,62 (NPM1 mutation without FLT3-ITD), IDH1 mutations were associated with
a significantly decreased 5-year DFS rate (42% vs. 59%; P = .046) and a
CEBPA Mutations
trend for decreased OS rate (50% vs. 63%) compared with the setting of
Another mutation associated with prognosis is the CEBPA gene, a wild-type IDH.71 In another study, IDH mutations (IDH1 and IDH2
transcription factor that plays a key role in the differentiation of combined) were associated with significantly inferior 5-year RFS rates
granulocytes.42 Mutations in CEBPA have been reported in 7% to 11% of (37% vs. 67%; P = .02) and OS rates (41% vs. 65%; P = .03) in the
cases of AML (or 13%–15% of cases of NK-AML) and have been subgroup of patients with favorable-risk AML (NK-AML with NPM1
associated with a favorable outcome (similar to cases of CBF mutation without FLT3-ITD).73 This prognostic significance was observed
translocations) with regard to increased remission duration and OS when IDH1 and IDH2 mutations were separately analyzed, although
outcome compared with wild-type CEBPA.41,50,51,64-66 One caveat identified patient numbers were small for each subgroup and statistical significance
was that the OS benefit with CEBPA was observed in the setting of double was reached only for the RFS analysis.73 IDH1 mutations were also
mutations of CEBPA but not in the setting of a single mutation of the gene. associated with worse EFS and OS outcomes among the subgroup of
The 8-year OS rates reported in this study in the setting of patients with intermediate-risk NK-AML (wild-type NPM1 without
double-mutant-positive, single-mutation, and wild-type CEBPA genes were FLT3-ITD).68 Mutations in IDH2 have been reported in 8% to 12% of cases
54%, 31%, and 34%, respectively.65 The revised 2016 WHO classification of AML,50,68,69,73,74 with a higher frequency of 19% among those with
of AML has redefined mutated CEBPA to indicate that biallelic (double) NK-AML.71 The presence of IDH2 mutations was mutually exclusive with
mutations (and not single CEBPA mutations) are associated with improved IDH1 mutation in nearly all cases.68,69,71 Mutations have been identified in
prognosis.67 R172 and R140 of the IDH2 gene, with the R140 mutation occurring more
IDH1/2 Mutations
frequently.71,73,74 Interestingly, the IDH2-R172 mutation seemed to be
Mutations in IDH1 have been reported in 6% to 9% of AML cases, with a mutually exclusive with NPM1 mutations and FLT3-ITD.71,73,74
higher frequency among patients with NK-AML (8%–16%).50,68-73 IDH1 Reports on the prognostic effect of IDH2 mutations have also been
mutations were found to occur concurrently with NK-AML and NPM1
inconsistent. Some studies have reported the lack of prognostic value of
mutations.68-71,73 Additionally, these mutations have been associated with
IDH2 mutations,68,69,73 whereas others have reported favorable outcomes
wild-type CEBPA and the absence of FLT3 abnormalities.71 Findings from with IDH2 mutations.50,74 In one study, an association was found between
published reports on the prognostic effects of IDH1 mutations have been IDH2 mutations and poorer prognosis in the subgroup of patients with
inconsistent. Although some studies showed no prognostic effect of IDH1 NK-AML and otherwise favorable risk (NPM1 mutation without
MS-9

FLT3-ITD).73 However, in another study, the IDH2 mutation (restricted to 45%; P = .02).79 Another study also showed that in younger patients (age
IDH2-R140) was associated with improved survival among the overall <60 years) with NK-AML, a DNMT3A mutation was associated with
study population, and among the subgroup of patients with favorable risk significantly decreased DFS (3-year rate, 20% vs. 49%; P = .007) and a
(intermediate-risk AML with NPM1 mutation without FLT3-ITD).50 In this trend toward decreased OS.77 In this latter study, non-R882 DNMT3A
latter subgroup, the presence of IDH1 or IDH2 mutations was associated mutations were significantly associated with poorer outcomes in patients
with a significantly increased 3-year OS rate compared to the setting of younger than 60 years of age but not R882 mutations; in contrast,
NPM1 mutation without FLT3-ITD and without IDH1 or IDH2 mutations DNMT3A-R882 mutations (but not non-R882 mutations) in patients ≥60
(89% vs. 31%; P < .0001). These results seem to suggest that in patients years of age were associated with significantly decreased DFS (3-year
with NK-AML without FLT3-ITD, NPM1 mutations confer a survival benefit rate, 3% vs. 21%; P = .006) and OS (3-year rate, 4% vs. 24%; P = .01).77
only in the presence of concurrent IDH mutations.50 The conflicting The authors concluded that the prognostic relevance of DNMT3A
findings from the above studies require further investigation. mutations may depend on age and mutation type. Currently, the
interactions of IDH1 or IDH2 and DNMT3 mutations with other molecular
DNMT3A Mutations
changes require further investigation to determine the prognostic value in
The DNMT3A mutations have been reported in 18% to 22% of cases of patients with NK-AML. Although commercial testing is available for FLT3
AML,50,75,76 with a frequency of 29% to 34% in cases of NK-AML.77-79 R882 and CEBPA, most of the other genetic mutations are not available for
is the most commonly mutated residue. This mutation has also been testing outside of the research setting. Other candidate genes that are
observed in conjunction with NPM1 mutations and FLT3 mutations.76,78,79 associated with an adverse impact on outcome are TET2 and RUNX1.80,81
Data concerning the prognostic significance of DNMT3A mutations have
thus far been conflicting. Some studies in the overall AML population and KIT Mutations
in patients with intermediate risk reported no significant effect of DNMT3A KIT mutations have been reported in approximately 20% of patients with
mutations on survival outcomes,50,78 whereas other studies have shown a CBF AML.43,82 Studies have shown that KIT mutations are associated with
negative prognostic effect in the overall population or specific decreased remission duration (eg, EFS and RFS) and decreased OS in
subgroups.75-77,79 Studies have shown significantly decreased OS the setting of t(8;21).37,43,45,82 However, the association of KIT mutations on
outcomes in the setting of DNMT3A mutations compared with the CBF AML with inv(16) is less clear than the data for t(8;21), with several
wild-type gene (median OS, 12–21 months vs. 40–41 months).75,76 studies showing no association.37,82,83 In an analysis from the
Significantly decreased OS with DNMT3A mutations has also been German-Austrian AML Study Group, the frequency and prognostic impact
reported in the subgroup of patients with NK-AML with wild-type NPM1 of secondary genetic lesions were evaluated in patients with CBF AML
with or without FLT3-ITD, or NPM1 mutation in the presence of FLT3-ITD, who were treated in prospective trials (n = 176).84 Secondary
but not in the favorable subgroup with NPM1 mutation without FLT3-ITD.76 chromosomal abnormalities were found in 39% of cases, with the most
A study reported that in younger patients (age <60 years) with NK-AML, common abnormalities being trisomy 22 (18%), trisomy 8 (16%), and 7q
the presence of DNMT3A mutations was associated with significantly deletion (5%). Secondary genetic lesions were found in 84% of cases,
decreased OS compared with the wild-type gene (5-year OS rate, 23% vs. including mutations in RAS (53%; NRAS in 45%; KRAS in 13%), KIT
MS-10

(37%), and FLT3 (17%; FLT3-TKD in 14%; FLT3-ITD in 5%; both mutations frequently co-occurred with epigenetic modifiers ASXL1, IDH2,
mutations present in 2%). In addition, more than one of these mutations KMT2A, and EZH2.95 In a study examining the impact of multiple RUNX1
was found in 25% of cases. Mutations in KIT and RAS were less likely to mutations and loss of wild-type RUNX1 in AML, both loss of wild-type
occur concurrently, whereas mutations in KIT and FLT3 occurred RUNX1 (OS, 5 months) and having ≥1 RUNX1 mutation (14 months) had
concurrently in 6% of cases.84 Of these secondary genetic lesions, KIT an adverse impact on prognosis compared to 1 RUNX1 mutation (22
mutation and trisomy 22 were significant independent factors predictive of months; P < .002 and .048, respectively).96
RFS in multivariable analysis; FLT3 mutations, trisomy 22, and trisomy 8
ASXL Mutations
were significant independent predictors for OS.84 These studies
The additional sex combs-like 1 (ASXL1) gene, located on chromosome
demonstrate the importance of secondary genetic mutations in the
band 20q11, encodes a protein in the enhancer of trithorax and
prognostic classification of patients with otherwise favorable-risk CBF AML
polycomb (ETP) genes family, which have functions in transcription.97,98
(see Risk Stratification by Genetics in Non-APL AML in the algorithm).
ASXL1 mutations have been reported in approximately 5% to 36% of de
KMT2A Rearrangements novo AML cases,96,99-102 and are associated with poor outcomes.50,98,101
The mixed lineage leukemia gene (MLL; also called HRX, ALL-1, or In an analysis of peripheral blood samples from adult patients with AML
currently KMT2A), located on chromosome 11q23, was initially recognized (n = 423), ASXL1 mutations were observed to be more common in
as a recurrent locus of chromosomal translocation in AML and ALL.85,86 In patients ≥60 years compared to patients younger than 60 years (16.2%
one series of 1897 AML cases, the incidence of 11q23/KMT2A vs. 3.2%, respectively; P < .001). In patients ≥60 years of age, ASXL1
rearrangements was 2.8%, and they were significantly higher in therapy- mutations were significantly associated with wild-type NPM1, FLT3-ITD
related AML than in de novo AML (9.4% vs. 2.6%, P < .0001).87 The mutations, mutated CEBPA, and lower survival.98 A large series
frequency of KMT2A rearrangements was also significantly higher among analyzing younger adult patients with AML (range, 18–61 years) also
patients younger than 60 years (5.3% vs. 0.8%, P < .0001).87 Depending observed that ASXL1 mutations were associated with older age
on the fusion partner, the 11q23/ KMT2A rearrangement is associated with (P = .0001) and decreased EFS and OS.103 In this study, ASXL1
intermediate to poor prognosis.88-90 NK-AML can be characterized by mutations were also significantly associated with RUNX1 (P = .0001).103
partial tandem duplication in the KMT2A gene (KMT2A-PTD),91-93 and In another study analyzing biological and prognostic subgroups based on
KMT2A-PTD is associated with reduced OS.50 mutations in ASXL1, RUNX1, DNMT3A, NPM1, FLT3, and TP53 in
patients with AML with myelodysplasia-related changes (n = 125),
RUNX1 Mutations ASXL1 (n = 26; 21%) and TP53 (n = 28; 22%) were independently
The runt-related transcription factor 1 (RUNX1) gene, encoding a associated with shorter OS (HR, 2.53; 95% CI, 1.40–4.6; P = .002).104
myeloid transcription factor, is mutated in approximately 10% of de novo
AML cases and associated with adverse prognoses.22,94,95 In a study of TP53 Mutations
adult patients with newly diagnosed AML (n = 2439), RUNX1 mutations TP53 mutations have been reported in approximately 12%–13% of AML
were associated with age ≥60 years, male gender, more immature cases, and are associated with unfavorable risk and poor
morphology, and secondary AML evolving from MDS.95 RUNX1 outcomes.20,105,106 TP53 mutations are also most common in AML with
MS-11

complex karyotype.105 However, in therapy-related AML, TP53 mutations younger (13.6 vs. 18.7 months, respectively); in patients >60 years,
are more frequently associated with monosomal karyotype, and with median OS was similar between the two intermediate groups (9.5 vs. 9.2
abnormalities in chromosomes 5 and 7.105 In therapy-related AML, the months, respectively).107
frequency of TP53 mutations is approximately 23%.22 In a large analysis of
different hematologic malignancies including 858 AML cases, TP53 In another study, patients in the intermediate I group who were younger
mutations or deletions were observed in 7% and 1%, respectively, of the than 60 years of age demonstrated longer OS than those in the
AML cases, and both TP53 mutations and deletions were observed in 5% intermediate II group; in patients >60 years of age, the OS was similar
of the cases.106 TP53 mutations were significantly more frequently seen in between the two intermediate groups.109 Based on these data, the ELN
patients ≥60 years of age when compared to patients <60 years of age simplified the intermediate risk group in the 2017 update.21 Both NCCN
(9% vs. 2%, P < .001).106 Interestingly, compared to TP53 deletions, TP53 and the ELN classify patients with NK-AML with both mutated NPM1 and a
mutations negatively impacted survival in AML (36 months vs. 9 months, high allelic ratio (≥0.5) of FLT3-ITD (FLT3-ITDhigh), and those with
respectively; P < .001), suggesting the importance of evaluating both wild-type NPM1 without FLT3-ITD or with FLT3-ITDlow (without adverse-
TP53 mutation and deletion status.106 risk genetic lesions) as having intermediate-risk AML. In addition,
t(9;11)(p21.3;q23.3), MLLT3-MLL, and other cytogenetic abnormalities
Classification and Prognostic Relevance of Gene Mutations that fall into neither the favorable nor adverse category are considered
The NCCN AML Panel adopted the 2017 European LeukemiaNet (ELN) intermediate-risk. Both NCCN and the ELN classify wild-type NPM1 and
recommendations for risk stratification.21 Therefore, both NCCN and the FLT3-ITDhigh, mutated TP53, mutated RUNX1, or mutated ASXL1 as poor
ELN classify patients with NK-AML and mutated NPM1 or CEBPA (without risk.21,107 However, mutated RUNX1 or ASXL1 should not be used as
FLT3-ITD) as having favorable risk.21,107 Specifically, patients with poor-risk prognostic markers if they co-occur with favorable-risk AML
NK-AML with mutated NPM1 (without FLT3-ITD or with a low allelic ratio subtypes. (see Risk Stratification by Genetics in Non-APL AML in the
[<0.5] of FLT3-ITD [FLT3-ITDlow]) or with isolated biallelic CEBPA mutation algorithm).
are categorized as having favorable risk21 (see Risk Stratification by
Genetics in Non-APL AML in the algorithm). In the previous ELN As seen from the earlier discussions, patients with NK-AML may present
guidelines, a distinction was made between intermediate I and with multiple molecular abnormalities. NPM1 mutations can occur
intermediate II risk groups.108 An analysis that evaluated the prognostic concurrently with FLT3-ITD, and outcomes in the setting of both genetic
value of the ELN risk classification (based on data from the German lesions are similar to isolated FLT3-ITD mutations.38,44 Thus, NPM1
AML96 study) showed that for patients aged 60 years and younger, mutation confers favorable prognosis only in the absence of FLT3-ITD.51
median RFS was shorter for the Intermediate I than for the Intermediate II Similarly, the benefit in OS outcomes seen with CEBPA mutations seems
group (7.9 vs. 39.1 months, respectively). In patients >60 years, no major to be lost in the presence of concurrent FLT3-ITD.65 As previously
difference was observed (9.6 vs. 11.6 months, respectively).107 In this mentioned, studies suggest that FLT3-TKD in the presence of FLT3-ITD is
analysis, median OS between the Intermediate I and Intermediate II associated with poorer prognosis. In contrast, FLT3-TKD may be
groups was not as widely separated among patients aged 60 years and associated with an additional favorable prognosis in the presence of
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NPM1 or CEBPA mutations.62 A systematic review and meta-analysis in patients who have NK-AML or in other situations where molecular analysis
patients younger than 60 years of age with NK-AML further established may refine the prognostic category.
the prognostic role of these markers.48 OS and RFS predicted unfavorable
prognosis for FLT3-ITD (HR, 1.86 and 1.75, respectively) and favorable Familial Genetic Alterations in AML
prognosis for NPM1 (HR, 0.56 and 0.37, respectively) and CEBPA (HR, Relative to sporadic cases of AML and MDS, the prevalence of known
0.56 and 0.42, respectively). familial acute leukemia and MDS syndromes is felt to be rare, but with
increasing recognition of germline mutations associated with
The clinical significance of FLT3 mutations in patients with APL remains predisposition to developing AML/MDS, identifying these syndromes is
controversial. FLT3-ITD is associated with a higher incidence of several important for optimal care of patients and their relatives.116-119 Evaluation
hematologic features associated with APL (eg, higher WBC count, for an underlying familial syndrome in a patient with acute leukemia or
decreased fibrinogen levels, higher Sanz risk score).110,111 However, there MDS should involve a screening history, focused physical examination,
remains a paucity of data to support a correlation of FLT3-ITD on OS and and diagnostic genetic testing.116,120 In particular, the screening
rate of relapse.110,112,113 Although mutation status alone may not reflect evaluation should determine if the patient has a family history of
outcome, there was a trend for decreased OS and EFS with a higher hematologic malignancies (including AML, acute lymphoblastic leukemia
FLT3-ITD mutational load suggesting that further studies are necessary to [ALL], or aplastic leukemia) or unexplained leukopenia, anemia (eg,
elucidate the clinical significance of this mutation.113 Conversely, aplastic anemia, macrocytic anemia) and/or thrombocytopenia within 2
FLT3-TKD has not been associated with the hematologic features of APL generations.116,117,121,122 In addition, the Nordic Guidelines for germline
and studies do not show a correlation of FLT3-TKD on outcome.110,111,113- predisposition to myeloid neoplasms in adults recommend that the
115
screening evaluation should determine if the patient has signs or
symptoms indicative of a hereditary condition (including Li Fraumeni
The molecular markers discussed provide prognostic information that aid
syndrome) that predisposes them to developing myeloid neoplasms (eg,
risk stratification of patients with AML and may influence subsequent
AML or MDS).123Familial AML with mutated CEBPA is one of the most
treatment decisions. Research into basic leukemia biology using banked
common inherited syndromes associated with AML.116,124,125 Several
samples from clinical trials may provide keys to altered cellular pathways,
reports have noted that all individuals who carry this germline mutation
which may lead to new treatment options. Risk stratification incorporating
developed AML between 2–59 years of age.116,124,126,127 Other familial
molecular data along with cytogenetics is summarized in the guidelines
AML syndromes include: germline mutations in DDX41116,128,129 which are
(see Risk Stratification by Genetics in Non-APL AML in the algorithm). The
relatively common, and germline mutations in MBD4,130 which are rare;
NCCN AML Panel recognizes that molecular genetics is a rapidly evolving
or syndromes with platelet abnormalities, including familial platelet
field in AML; therefore, risk stratification should be modified based on
disorder with mutated RUNX1;116,120,131 or syndromes associated with
continuous evaluation of evolving research data. Again, it is important for
organ system manifestations, including familial MDS/AML with mutated
physicians to confer with the local pathologist on how to optimize sample
GATA2.116,120
collection from the time of diagnosis for future molecular diagnostics in
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Based on these emerging data, the AML panel recommends that patients consolidation are based on the potential risk of relapse, with higher-risk
with a family history of leukemia, or of other hematologic cancers or patients receiving more aggressive therapy. Cytogenetic and molecular
abnormalities, should be evaluated for an inherited predisposition abnormalities are the most significant prognostic indicators; however,
syndrome (see Familial Genetic Alterations in AML in the algorithm). The failure to achieve remission after 1 cycle of induction therapy or high tumor
panel also strongly recommends that patients with a variant allele burden, defined as a WBC count ≥40,000/mcL,24 are included as poor-risk
frequency (VAF) of 40–60% of genes associated with a predisposition factors for long-term remission. Therefore, response is assessed based on
syndrome be referred for germline testing. However, there is no bone marrow morphology and cytogenetic and molecular responses taken
consensus on optimal management of individuals diagnosed with a at several points during the course of treatment (see Response Criteria
familial acute leukemia or MDS syndrome, so management must be Definitions for Acute Myeloid Leukemia and Monitoring During Therapy in
individualized.116,120 the algorithm for definitions of CR and partial response [PR] and disease
relapse). The use of flow cytometry and/or molecular methods to assess
Principles of Acute Myeloid Leukemia Treatment MRD is emerging as a novel determinant to assess the depth of
Treatment of acute leukemia has been divided into induction therapeutic response at the time of morphologic remission in patients with
chemotherapy and postremission (eg, consolidation) therapy. Although AML (see Role of MRD Monitoring).
obtaining a remission is the first step in controlling the disease, it is also
important for patients to emerge from the induction phase in a condition to Finally, all patients require attentive supportive care related to the
tolerate subsequent, more intensive treatments during consolidation to underlying leukemia (ie, tumor lysis syndrome) and the adverse effects of
achieve durable disease control. In some cases, patients who either chemotherapy (see Supportive Care in the algorithm).
received postremission therapy or those who did not may experience
Management of Acute Promyelocytic Leukemia
relapse, usually within 6 to 9 months. Postremission therapy is
recommended for patients younger than 60 years and/or who are fit for APL is a particularly aggressive subtype of AML, comprising
intensive therapy. However, there are trials that by design do not include approximately 10% of AML cases. APL has a distinct morphology and
postremission treatment for patients and the results have been promising; clinical presentation that may be associated with a high early death rate
these trials are generally in older patients with AML. The induction strategy due to potentially fatal coagulopathy.132-134 In an analysis of data (from
is influenced by individual patient characteristics such as age, presence of 1992–2007) from the National Cancer Institute SEER registry, the
comorbid conditions affecting performance status, and preexisting age-adjusted annual incidence rate of APL was 0.23 per 100,000
myelodysplasia. This is particularly true of patients who are older with persons.135 The median age of APL diagnosis was 44 years, which is
AML. Patients whose performance status would make them poor younger than that of patients with AML (median age 67 years).2,135 APL is
candidates for the standard antineoplastic regimens may still be able to cytogenetically distinguished by the t(15;17) chromosomal translocation.
participate in clinical trials or low-intensity therapy plus oral agents The translocation of the PML gene on chromosome 15 to the RARA gene
designed to target this underserved patient population. Supportive care on chromosome 17 [ie, t(15;17)(q24.1;q21.1)] produces a PML-RARA
may also be an appropriate choice. In younger patients, strategies for fusion gene that can be quantitatively monitored using polymerase chain
MS-14

reaction (PCR) to document disease burden and to ultimately confirm or PCR ideally in the peripheral blood and if not confirmed, ATRA may be
molecular remission. As further emphasis of the cytogenetic attribute of discontinued and standard AML therapy initiated.
APL, the most recent WHO classification of myeloid neoplasms and acute
leukemia changed the definition of APL from the cytogenetic criteria of Studies have demonstrated the necessity of early recognition and prompt
t(15;17) to the molecular definition of “APL with PML-RARA” to be initiation of ATRA based on a presumed diagnosis of APL to reduce the
inclusive of complex or cryptic rearrangements that lead to a functional rate of early mortality. This is evidenced by early death rates below 10%
transcription factor.67 reported for patients enrolled in clinical trials137-141 compared to the general
population where early mortality rates are still in excess of 15%.135,142-144
APL may be de novo or therapy-related. Some of the following attributes Data from the SEER registry measured 2-year survival and 30-day
of therapy-related APL (t-APL) were highlighted in a systematic review: 1) mortality from 1977 to 2007 and found a 61% improvement in 3-year
the average age of diagnosis is 47 years with a higher incidence in survival per decade (P = .001) but a consistent rate of 30-day mortality
females; 2) the risk significantly declines 2 years after completion of averaging 20%.142 Education of heath care providers to identify the first
treatment for the primary antecedent disease; 3) breast cancer, suspicion of APL may extend the improved outcomes seen in clinical trials
hematologic malignancy, multiple sclerosis, and genitourinary malignancy to the general population if treatment is not delayed.
are the most common antecedent diseases; 4) topoisomerase II inhibitors
and radiation have the highest risk associated with developing t-APL; 5) There is a high frequency of FLT3 mutations in APL. In a systematic
the clinicopathology of t-APL is not different from de novo APL; 6) the review including 11 studies, FLT3-ITD frequency in APL occurred in about
single mutation t(15;17) is most common; and 7) the remission rate of 12% to 38% of cases and FLT3-TKD occurred in 2% to 20% of cases.145
t-APL is 80%, which is comparable to de novo APL.136 Therefore, t-APL Data are inconsistent about whether FLT3-ITD in APL results in a negative
and de novo APL are treated similarly. prognosis. Several studies support this association and further correlate
FLT3-ITD with higher WBC counts, lower platelet counts, and the
The incorporation of all-trans retinoic acid (ATRA) and the use of risk expression of the bcr3 PML-RARA fusion transcript.145-148 However, data
stratification (based on WBC counts) in the management of APL has from other studies have not shown a correlation.58,149 It has been proposed
largely improved outcomes for patients with this subtype. The unique that the discrepancy between studies may be at least partially resolved by
ability of ATRA to produce differentiation in APL blasts can reverse the incorporation of a FLT3-ITD/wild-type ratio to measure the effect on
coagulopathy, which is the major cause of death during induction. To prognosis.113,150 Data showed that a ratio of greater than 0.66 resulted in a
minimize early induction mortality due to coagulopathy, patients with a shorter 5-year RFS.150 Similarly, shorter EFS and OS were observed in the
presumptive diagnosis of APL based on morphology, immunophenotype, setting of equal to or greater than a 0.5 ratio compared to less than 0.5
and/or coagulopathy with a positive disseminated intravascular (EFS, P = .029; OS, P = .084).113 While data may correlate with prognosis,
coagulation screen should promptly start ATRA. It is not necessary to wait there currently remains no change in treatment course depending on
for molecular testing or bone marrow with cytogenetics to confirm the expression of FLT3-ITD.
diagnosis. The initial clinical diagnosis of APL may be confirmed by FISH
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Induction Therapy for Patients with APL CR rates of 89% to 95%, raising the question of whether there was a need
The evolution of treatment strategies for APL, built on clinical observation for cytarabine in APL induction.137,141 In these trials, 51% to 61% of
and well-constructed clinical trials, represents one of the most rewarding evaluable patients achieved PCR-negative status for PML-RARA following
sagas of modern hematology. An early study by a group in Shanghai induction therapy; 93% to 98% achieved PCR-negative status after
reported a CR rate of 85% in response to single-agent ATRA.151 The first consolidation. The estimated 2-year EFS rate was 79% in both trials.137,141
North American Intergroup study confirmed a 70% CR rate with In the PETHEMA trial, the 2-year OS rate was 82%.141
single-agent ATRA, which was equivalent to rates obtained with
Following observational data that correlated elevated WBC counts and
conventional doses of cytarabine and daunorubicin.152,153 Induction
high-risk disease (based on both the higher number of deaths during
regimens with ATRA combined with anthracyclines (with or without
induction and the increased rates of relapse), in the PETHEMA LPA 94
cytarabine) are associated with CR rates exceeding 90%, as
trials, Sanz et al161,162 devised a risk stratification study based solely on
demonstrated in several large cooperative group trials.154-157 Using
WBC and platelet counts at presentation. In this study, the induction
ATRA-based induction regimens followed by consolidation with regimens
regimen remained the same (AIDA), but ATRA was added to consolidation
containing either ATRA with anthracyclines, or cytarabine with
cycles 1 to 3 for all but patients with low-risk disease (ie, WBC
anthracyclines, more than 80% of patients with APL can be cured of their
≤10,000/mcL and platelets >40,000/mcL). The CR rate in this trial was
disease.154,156-158 ATRA with arsenic trioxide (ATO) has resulted in
90% with almost all the failure attributed to hemorrhage, infection, or
improved outcomes for patients with APL.159 Risk stratification is a major
differentiation syndrome. Factors predictive of death during induction were
consideration in the treatment of APL (see APL: Classification and
a WBC count greater than 10,000/mcL, age >60 years, creatinine of 1.4 or
Treatment Recommendation in the algorithm).157 Although clinical trials
greater, and male gender.161,162 In 2006, Ades et al163 reported the
may group patients into those with low-, intermediate-, or high-risk
outcome of the French APL 2000 trial (n = 340) in which patients younger
disease, the NCCN Panel categorizes patients with APL as having low-risk
than 60 years of age with WBC counts less than 10,000/mcL were
disease (WBC count ≤10,000/mcL) or high-risk disease (WBC
randomized to receive ATRA (45 mg/m2) and daunorubicin (60 mg/m2/day
count >10,000/mcL). Patients with low-risk disease are typically treated
for 3 days) as induction therapy with or without cytarabine (200 mg/m2/day
with less intensive consolidation regimens compared with regimens used
for 7 days). Those randomized to cytarabine for induction also received
for patients with high-risk disease.
cytarabine during consolidation.163 Patients with WBC counts greater than
The French APL 93 trial compared sequential therapy of ATRA followed 10,000/mcL or age >60 years received cytarabine. While the CR rates
by chemotherapy (cytarabine and daunorubicin) with concurrent ATRA were similar between the randomized groups (99% with cytarabine and
plus chemotherapy. CR rates were 92% in both arms, but the relapse rate 94% without cytarabine), those receiving cytarabine had a lower 2-year
at 2 years was 6% in the combined ATRA plus chemotherapy group cumulative incidence of relapse (5% with cytarabine and 16% without
versus 16% for the sequential group.138,160 Induction regimens were pared cytarabine) that translated into an improved EFS rate (93% with cytarabine
down to ATRA and idarubicin (the AIDA schedule) in both the Italian and 77% with no cytarabine) at 2 years. The 2-year OS rate was 98% with
GIMEMA 93 trial and the Spanish PETHEMA LPA 94 trial, which produced cytarabine and 90% without cytarabine. Among patients with a WBC count
MS-16

greater than 10,000/mcL, the CR rate was 97%; the 2-year EFS rate was authors suggested that ATRA combined with ATO, with or without GO,
89% for those younger than 60 years of age and 79% for those >60 years may be an alternative to conventional chemotherapy in patients with
of age.163 A report of a joint analysis of the outcomes in the PETHEMA 99 untreated APL. A subsequent study examined the long-term outcomes of
and the French APL 2000 trials in patients younger than 65 years of age patients with newly diagnosed APL treated with ATRA and ATO with or
showed that in patients with a WBC count less than 10,000/mcL, CR rates without GO [9 mg/m2 on day 1 of induction therapy for high-risk APL
were similar, but the relapse rates at 3 years were lower in the PETHEMA patients] (n = 187; median age, 50 years; range, 18–84 years).169 The
trial, which used AIDA and no cytarabine during induction (with ATRA complete remission rate was 96% for patients with both low- and high-risk
during consolidation), than in the APL 2000 cytarabine-containing regimen APL. With a median follow-up of 47.6 months (range, 2.7–159.7 months),
(4% vs. 14%; P = .03).155 However, for patients with a WBC count greater the 5-year EFS, DFS, and OS rates for patients with low-risk APL were
than 10,000/mcL, the cytarabine-containing protocol resulted in higher CR 87%, 99%, and 89%, respectively, and for patients with high-risk APL
(95% vs. 84%; P = .018) and 3-year OS rates (91.5% vs. 81%; were 81%, 89%, and 86%, respectively.169 These data suggested that
P = .026).155 The second North American Intergroup trial also used ATRA ATRA and ATO combined with GO is feasible and elicits durable
(45 mg/m2), daunorubicin (50 mg/m2/day for 4 days), and cytarabine (200 responses. In another study by Estey et al,170 patients with APL were
mg/m2/day for 7 days) with a similar initial CR rate of 90%.156 treated with ATRA and GO (9 mg/m2 on day 1 or 5 of induction therapy).
Consolidation in this trial differed in that two cycles of ATO were given Patients with WBC counts of >30,000/mcL also received idarubicin (12
following induction and prior to the final two cycles of anthracycline. mg/m2/day on days 1–3). In this study (n = 19), the CR rate in all patients
who received ATRA plus GO and idarubicin was 84%, and 88% in patients
ATO has been found to be a potent promoter of apoptosis in APL who received ATRA plus GO.170 However, clinicians should be aware of
cells.164,165 In 2004, Shen et al166 first published outcomes using possible adverse events associated with GO including sinusoidal
single-agent ATRA, single-agent ATO, or the combination of both drugs.166 obstruction syndrome similar to hepatic veno-occlusive disease described
While CR rates exceeded 90% in all three treatment arms, the decline in in the transplant setting.171,172
quantity of PML/RARA fusion transcripts (as measured by quantitative
PCR) was significantly higher with the combination. Time to hematologic A phase II study (APML4) from Australia/New Zealand evaluated an
response was more rapid and RFS (after a median follow-up of 18 induction regimen with ATO added to a backbone of AIDA in patients with
months) was improved with the combination regimen compared with the previously untreated APL (n = 124; median age, 44 years).173 Patients
monotherapy regimens.166 Subsequently, Estey et al167 used a similar received 1 cycle of induction therapy with ATRA (45 mg/m2 days 1–36 in
combination of ATRA and ATO to treat patients with low-risk APL.167 divided doses), age-adjusted idarubicin (6–12 mg/m2 days 2, 4, 6, and 8),
Patients with high-risk APL in the same study were treated with ATRA and and ATO (0.15 mg/kg days 9–36 as a 2-hour IV infusion). All patients
ATO combined with gemtuzumab ozogamicin (GO; 9 mg/m2 on day 1 of received prednisone (1 mg/kg/day for at least 10 days) regardless of initial
induction therapy). In a report from this study (n = 82), the CR rate in all WBC count as prophylaxis for differentiation syndrome.173 The most
patients was 92% (95% for patients with low-risk APL and 81% for patients common grade 3 or 4 non-hematologic adverse events during induction
with high-risk APL) and the estimated 3-year OS rate was 85%.168 The included infections (76%; including febrile neutropenia), hepatic toxicity
MS-17

(44%), gastrointestinal toxicity (28%), metabolic abnormalities (16%), and the end of induction) as prophylaxis for differentiation syndrome. The
prolonged QTc interval (14%); grade 3 or 4 differentiation syndrome primary endpoint of this study was the 2-year EFS rate. Among evaluable
occurred in 14% of patients. Patients who achieved CR following induction patients (n = 156), CR rates were not different between Arm A and Arm B
received consolidation with 2 cycles of ATRA and ATO. Maintenance (100% vs. 95%). After a median follow-up period of 34.4 months, the
therapy was administered for 2 years and consisted of eight 3-month 2-year EFS rate was significantly higher in Arm A compared with Arm B
cycles of treatment with ATRA, oral methotrexate, and (97% vs. 86%; P < .001 for non-inferiority; P = .02 for superiority). The
6-mercaptopurine.173 Grade 3 or 4 adverse events occurred primarily 2-year OS probability was also significantly higher in Arm A compared with
during induction (as above); the most common grade 3 or 4 events during Arm B (99% vs. 91%; P = .02). Four patients in Arm B died during
consolidation (cycle 1) included infections (19%) and hepatic toxicity induction therapy (2 deaths were caused by differentiation syndrome).
(12%), and no deaths occurred during consolidation cycles. The One patient in Arm A and 3 patients in Arm B died during consolidation.
hematologic CR rate after induction was 95%; early death (during Grade 3 or 4 neutropenia and thrombocytopenia lasting more than 15
induction) occurred in 3% of patients. The 2-year DFS and failure-free days were significantly more frequent in Arm B compared with Arm A
survival rates were 97.5% and 88%, respectively. The 2-year OS rate was throughout induction and consolidation cycles. Grade 3 or 4 hepatic
93%.173 This trial enrolled 24 patients that were defined as having high risk toxicities also occurred more frequently in Arm A compared with Arm B
disease based on the Sanz criteria. OS was not affected by the Sanz risk (63% vs. 6%; P < .001).159 Health-related quality-of-life outcomes were not
group (P[trend] = .17), although a correlation was made with the failure-free significantly different between treatment groups except for fatigue severity.
survival rate (P[trend] = .03). This association may be attributed to the There was improvement in fatigue following induction in the ATRA plus
method of analysis that included patients who withdrew from the study due ATO group (P = .022), though the benefit was negligible by third
to denial of treatment or excessive toxicity, as well as patients who consolidation (P = .660).174 This randomized study showed non-inferiority
experienced relapse, death, or failure to achieve a molecular CR. of an ATRA plus ATO regimen compared with AIDA, which may allow for
elimination of chemotherapy agents in the initial treatment of patients with
In a phase III randomized trial of the Italian-German Cooperative Group, non–high-risk APL.
induction with ATRA combined with ATO was compared with the AIDA
regimen in patients with newly diagnosed, low-, or intermediate-risk APL Data from the randomized phase III AML17 trial compared ATRA plus
(n = 162; APL0406 study).159 Patients in Arm A received ATRA (45 mg/m2) ATO to AIDA in a cohort of 235 patients. ATRA was given to both groups
plus ATO (0.15 mg/kg) daily until CR, then ATO 5 days per week for 4 in daily divided oral doses (45 mg/m2) until remission or until day 60, after
weeks every 8 weeks for a total of 4 courses, and ATRA daily for 2 weeks which patients were treated 2 weeks on then 2 weeks off.175 The AIDA
every 4 weeks for a total of 7 courses. Patients in Arm B received group received four cycles of consolidation consisting of 12 mg/m2 IV
standard AIDA induction followed by consolidation with 3 cycles of idarubicin on days 2, 4, 6, and 8 in the first course; 5 mg/m2 IV idarubicin
anthracycline-based consolidation combined with ATRA and then on days 1 through 4 in course 2; 10 mg/m2 mitoxantrone on days 1
maintenance comprising low-dose chemotherapy and ATRA.158 In through 4 in course 3; and 12 mg/m2 idarubicin on day 1 of the final
addition, all patients received prednisone (0.5 mg/kg/day from day 1 until course.175 The ATRA plus ATO treatment entailed 0.3 mg/kg IV ATO on
MS-18

days 1 through 5 in the first week and 0.25 mg/kg twice weekly in weeks 2 monitoring and treatment of adverse events, regardless of risk
through 8 in course 1 and then twice weekly in weeks 2 through 4 during stratification. The recommendations within the guidelines are broken down
courses 2 through 5. Patients with high-risk disease could receive an initial by: 1) risk classification using WBC count (cutoff of 10,000/mcL) at
dose of GO (6 mg/m2 IV). Comparison between the ATRA plus ATO group diagnosis; and 2) whether patients with high-risk disease have cardiac
and the AIDA group showed a higher 4-year EFS (91% vs. 70%; P = .002) issues.
and lower 4-year cumulative incidence of morphologic relapse (1% vs.
18%; P = .0007) for ATRA plus ATO compared to AIDA, though no For patients with low-risk disease (WBC counts ≤10,000/mcL), for initial
statistically significant difference in 4-year survival was seen (93% vs. induction the panel recommends ATRA plus ATO (0.15 mg/kg)159
89%; P = .25). Quality of life was equivalent in the treatment groups for (category 1, preferred regimen); and ATRA plus ATO (0.3 mg/kg)175
both patients with high- and low-risk disease as measured by the primary (category 1, preferred regimen). If arsenic is contraindicated or not
outcome of global functioning (effect size, 2.17; 95% CI, -2.79–7.12; available, the panel recommends AIDA157 (category 1); ATRA plus a single
P = .39).175 However, the data from the trial measured more supportive dose of GO (9 mg/m2 on day 5)170; or enrollment in a clinical trial.
care treatments and higher liver toxicity with AIDA. Treatment schedule
For patients with high-risk disease (WBC counts >10,000/mcL), the NCCN
differed from previous trials by moving to a higher dose of ATO given at a
AML Panel historically recommended a regimen that included cytarabine
lower frequency of twice weekly. Though data are limited to this single
along with ATRA plus daunorubicin (PETHEMA LPA 99 trial) over AIDA
trial, the NCCN AML Panel recognizes that this alternative dosing
(APL 2000 trial) because of higher CR and 3-year OS rates.155,157 To
schedule may be more manageable for patients who have difficulty getting
improve patient outcome, the PETHEMA LPA 99 trial and the GIMEMA
to the clinic.
AIDA-0493 study were modified to incorporate the combination of ATRA
All five induction regimens discussed above offer excellent outcomes. with cytarabine either during induction (LPA 2005)157 or during
These regimens are ATRA plus ATO (0.15 mg/kg; with the addition of consolidation (AIDA-2000).158 The improved outcomes in both of these
idarubicin for patients with high-risk disease only); ATRA plus studies suggest a supra-additive effect with ATRA plus cytarabine,
daunorubicin (50 mg/m2 daily for 4 days) plus cytarabine; ATRA plus independent of the anthracycline. The APML4 trial has shown the benefit
daunorubicin (60 mg/m2 daily for 3 days) plus cytarabine; AIDA; or ATRA of induction that includes ATRA and ATO. Unlike the other regimens, the
plus ATO (0.3 mg/kg). Choice of regimen will be influenced by risk group, APML4 trial does not use cytarabine during induction. In light of these
age, and cardiovascular risks. The NCCN AML Panel recommends that studies, the panel recommends initial induction with these preferred
patients with APL be treated according to one of the regimens established regimens: ATRA and ATO,173 or ATRA and ATO with a single dose of GO
from the clinical trials; importantly, one should use a regimen consistently (9 mg/m2169 or 6 mg/m2175 that may be given on day 1, day 2, day 3, or day
through all components of the protocol and not mix induction regimens 4). Other recommended regimens include ATRA plus daunorubicin and
from one trial with consolidation regimens from another trial. With the cytarabine153,155,156; AIDA alone157; or enrollment in a clinical trial. In
advances in treatment regimens, the panel emphasizes the importance of patients with high-risk disease with cardiac issues that include low ejection
receiving treatment from an established treatment center for the fraction, the panel recommends initial induction with ATRA and ATO with a
MS-19

single dose of GO (9 mg/m2 on day 1169 or 6 mg/m2 on day 1175). If the recommended until recovery of blood counts, usually 4 to 6 weeks after
patient with high-risk disease exhibits signs of prolonged QTc, the panel induction. Cytogenetic analysis is usually normal by this point, but
recommends initial induction with ATRA and a single dose of GO (9 mg/m2 molecular remission often requires at least 2 cycles of consolidation. Thus,
on day 1)170; ATRA plus daunorubicin and cytarabine153,155; or AIDA the first assessment of molecular remission should not be performed prior
alone.157 to count recovery. At count recovery following induction therapy, patients
should proceed with consolidation. For patients with low-risk disease, if a
The sudden onset of differentiation syndrome and the severity of the patient is cytopenic on days 28–35, bone marrow biopsy and aspirate is
complications have resulted in the frequent use of preemptive recommended to document blast clearance and to assess whether the
dexamethasone, because there are no markers to predict its development. marrow is suppressed and to determine whether ATRA and ATO should
The panel recommends the prophylactic administration of corticosteroids be held to allow count recovery. If, however, blood counts have recovered
in patients with a WBC count greater than 10,000/mcL (or in patients by this time point, a bone marrow biopsy may be considered to
receiving induction with both ATRA and ATO, regardless of WBC count) to document remission but is optional. For patients with high-risk disease,
prevent differentiation syndrome. The ATRA plus ATO regimens defined LP should be considered at count recovery following induction therapy,
by Lo-Coco et al159 or Iland et al173,176 use prednisone 0.5 mg/kg as before proceeding with consolidation.177 Many consolidation regimens
prophylaxis for differentiation syndrome but with differing durations and involve high cumulative doses of cardiotoxic agents. It is therefore
tapering schedules. For patients who develop differentiation syndrome on important to assess the cardiac function of patients prior to initiating each
these regimens despite prednisone prophylaxis, prednisone should be anthracycline- or mitoxantrone-containing consolidation cycle.
stopped and replaced with dexamethasone 10 mg twice daily (see Consolidation regimens employing ATO will require monitoring of the QTc
Supportive Care for APL in the algorithm). If using non-ATO regimens, interval and optimizing electrolytes (see Supportive Care for APL in the
either steroid regimen is acceptable although there may be a slight algorithm and Supportive Care for Patients with APL in the discussion).
preference for dexamethasone for high-risk disease. While the panel According to the package insert, for QTc greater than 450 msec for males
recommends the use of prophylactic corticosteroids, it is acknowledged and 460 msec for females, corrective measures should be initiated and
that corticosteroids may not be necessary in all patients. Some institutions reassessment with serial electrocardiograms (ECGs) should be performed
may advocate a low threshold for initiating corticosteroids instead of prior to ATO treatment.178
defaulting to prophylaxis. Until more studies are done to address this
issue, consistency to the selected protocol should be sought. The goal of consolidation therapy for APL is a durable molecular
remission. Data from the two sequential PETHEMA trials,141,161,162 which
Consolidation Therapy for Patients with APL produced the current risk model, were used to construct subsequent trials
Because the differentiating action of ATRA occurs over a longer time that intensify therapy for the high-risk groups. In the second PETHEMA
period than the cytoreduction of conventional chemotherapy, early marrow trial (LPA 99), 15 days of ATRA (45 mg/m2) were added to each of three
evaluations for hematologic response at days 7 to 14 post induction are cycles of anthracycline-based consolidation therapy. Overall, relapse rates
misleading and may lead to overtreatment. Marrow evaluation is not were reduced from 20% to 9% with the incorporation of ATRA in the
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consolidation phase.161 For the low-risk group, there was no difference in consolidation regimen containing ATRA and cytarabine along with
relapse rate (3%–6%) or in 3-year DFS rate (93%–97%) between the anthracyclines.158 In this study, the 6-year cumulative incidence of relapse
ATRA group compared with a similar consolidation without ATRA in the was 9% for patients in the high-risk group; the 6-year DFS and OS rates in
LPA 94 trial.161 Among patients with intermediate risk disease, the relapse this group were 84.5% and 83%, respectively. In the AIDA-2000 study, the
rate was reduced from 14% to 2.5% with the incorporation of ATRA; the low- and intermediate-risk groups were collapsed into a single category,
3-year DFS rate was 97% with ATRA consolidation versus 82% in and received the same consolidation regimen with ATRA, mitoxantrone,
historical controls.161 Although the addition of ATRA to the high-risk group and idarubicin (ATRA 45 mg/m2 for 15 days + idarubicin 5 mg/m2 for 4
improved relapse and DFS rates, there were significant rates of relapse days in cycle 1; ATRA for 15 days and mitoxantrone 10 mg/m2/day for 5
(26%) and 3-year DFS (77%). In the PETHEMA LPA 2005 study, both days in cycle 2; and ATRA for 15 days and idarubicin 12 mg/m2 for 1 dose
ATRA and cytarabine were included in the anthracycline-containing in cycle 3). For patients in the low- and intermediate-risk group, the 6-year
consolidation regimen for patients with high-risk disease.157 In this cumulative incidence of relapse was 11%; the 6-year DFS and OS rates in
high-risk group, the 3-year relapse rate was reduced to 11% (compared this group were 86% and 89%, respectively.158
with 26% from the LPA 99 study), and the 3-year DFS and OS rates were
82% and 79%, respectively. The LPA 2005 trial also began to approach In the European APL 2000 trial, which randomized daunorubicin with or
the question of how to reduce toxicity during consolidation therapy in without cytarabine for the consolidation phase (no ATRA during
patients with low- and intermediate-risk disease by dose reduction of consolidation) for the low- and intermediate-risk (ie, “standard risk”)
mitoxantrone (from 10 mg/m2/day for 5 days to 10 mg/m2/day for 3 days in groups, the 2-year EFS rate was higher with the addition of cytarabine.163
cycle 2) and a small reduction of idarubicin dose for low- and Long-term follow-up from this study showed that in patients with standard
intermediate-risk groups (from 7 mg/m2/day for 4 days to 5 mg/m2/day for risk disease, the addition of cytarabine substantially reduced cumulative
4 days in cycle 1 and from 2 doses of 12 mg/m2/day to 1 dose of 12 incidence of relapse (7-year relapse rate 13% vs. 29%; P = .0065) and
mg/m2/day in cycle 3). Based on results in the low- and intermediate-risk increased 7-year EFS rates (83% vs. 65%; P = .0029) compared with the
groups, lowering the dose of mitoxantrone resulted in reduction of toxicity regimen without cytarabine.179 A poorer response was seen in patients
and hospital stay while maintaining the anti-leukemic activity (compared who did not receive cytarabine despite maintenance treatment of
with results in low- and intermediate-risk groups from the LPA 99 study). continuous 6-mercaptopurine plus methotrexate and intermittent ATRA.
With the consolidation regimens evaluated in the LPA 2005 study, Furthermore, all patients with high-risk disease received cytarabine during
outcomes were similar between low-risk and intermediate-risk groups with induction and consolidation resulting in a 7-year relapse rate, EFS rate,
regard to the 3-year cumulative incidence of relapse (6% vs. 6%), the and OS rate of 7.1%, 82.2%, and 87.6%, respectively, an outcome that
3-year DFS (93% vs. 94%), and the 3-year OS rate (96% vs. 93%).157 was slightly improved over patients with standard-risk disease treated
without cytarabine. Although the results of the European APL 2000 trial
The AIDA-2000 trial of the Italian GIMEMA group has confirmed that are limited by the use of a single anthracycline in all study arms, the data
inclusion of ATRA in consolidation significantly improved outcome, most support the use of cytarabine in standard-risk APL with the anthracycline
notably for patients with high-risk disease; the high-risk group received a daunorubicin.
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The North American Intergroup trial also focused on decreasing toxicity associated with longer durations of myelosuppression, which necessitated
during consolidation by incorporating ATO into the consolidation schema a protocol amendment to further reduce the chemotherapy dose in
directly after achieving remission.156 In this trial, patients who were patients receiving ATO.180 In the second interim analysis, the only change
randomized to receive 2 courses of 25 days of ATO (5 days a week for 5 was a decrease of idarubicin during second consolidation. Data from this
weeks) immediately after entering CR followed by the standard analysis show a 99.4% CR across all groups encompassing a total of 347
post-remission regimen with 2 more courses of ATRA plus daunorubicin, patients.181 While the two-year EFS and OS rates were above 95% for all
had a significantly higher 3-year EFS rate (80% vs. 63%; P < .0001) and three groups, there was a reduction of myelosuppression in the group
improved OS outcomes (3-year OS rate 86% vs. 81%; P = .06) compared treated with AIDA compared to idarubicin plus cytarabine and idarubicin
with those who received only the 2 courses of ATRA plus chemotherapy. plus ATO, which had similar durations.181 The potential benefits of the use
The 3-year DFS rate was also significantly improved with the addition of of ATO or ATRA in consolidation may rest in a lower risk for long-term
ATO (90% vs. 70%; P < .0001). The favorable outcomes with the cardiovascular complications and a lower risk for secondary
incorporation of ATO were observed in patients with low-/intermediate-risk myelodysplasia.
and high-risk disease.156 Notably, in the high-risk group, DFS outcomes
with the addition of ATO were similar to the DFS rate observed for the In the phase II APML4 study from Australia/New Zealand, 2 cycles of ATO
low-/intermediate-risk group, suggesting that ATO may help to overcome and ATRA were used as consolidation in patients who achieved a CR after
the negative prognostic influence of high-risk disease. The overall a 3-drug induction with ATRA, idarubicin, and ATO.173 Among the patients
outcomes do not appear to be superior to the less complex consolidation who proceeded to consolidation (n = 112), all achieved molecular
schedules used in either of the two most recent European trials for remission, and the 2-year DFS rate was 97.5%. The 2-year OS rate in all
patients in the low- and intermediate-risk groups, but did appear to offer evaluable patients in this study (n = 124) was 93%.173 As discussed
improved survival for patients with high-risk disease. However, the earlier, in the phase III randomized trial of ATRA combined with ATO
consolidation phase in the North American Intergroup protocol is longer versus the AIDA regimen (APL0406 study) in patients with newly
and may be difficult for some patients to complete. diagnosed, low-, or intermediate-risk APL (n = 162), patients in the ATRA
plus ATO arm received consolidation with ATO 5 days per week for 4
The French APL 2006 randomized trial evaluated the role of ATO in weeks every 8 weeks for a total of 4 courses, and ATRA daily for 2 weeks
consolidation therapy for previously untreated APL, both for patients with every 4 weeks for a total of 7 courses (Arm A).159 Patients in the AIDA arm
standard-risk disease (WBC count <10,000/mcL; ATO vs. cytarabine vs. (Arm B) received 3 cycles of anthracycline-based consolidation combined
ATRA, all in combination with idarubicin during consolidation) and patients with ATRA and then maintenance with low-dose chemotherapy and
with high-risk disease (WBC >10,000/mcL; cytarabine vs. ATO + ATRA.158 After a median follow-up period of 31 months, the 2-year EFS
cytarabine, both in combination with idarubicin during consolidation).180,181 rate was significantly longer in Arm A compared with Arm B (97% vs. 86%;
Based on results from the interim analysis (median follow-up, 22–24 P < .001 for noninferiority; P = .02 for superiority of ATRA-ATO). In
months), all regimens resulted in CR rates exceeding 95% with low rates addition, the 2-year OS was also longer in Arm A (99% vs. 91%; P = .02),
of relapse. However, the use of ATO in the consolidation phase was
MS-22

with no differences in 2-year DFS (97% vs. 90%; P = .11) or cumulative in the North American Intergroup trial.156 When using a
incidence of relapse (1% vs. 6%; P = .24) between treatment arms.159 cytarabine-containing regimen, dose adjustments of cytarabine may be
needed for patients who are older or for patients with renal
In the French APL 93 trial, a 4% incidence of CNS relapse was reported in dysfunction.155,156 In patients who could not tolerate anthracyclines and
patients with WBC counts greater than 10,000/mcL. In the APL 2000 trial, who received ATRA and ATO for induction therapy, the reported trials
that high-risk population received five doses of IT chemotherapy using a continued with repeated cycles of these two agents following induction
combination of methotrexate, cytarabine, and steroids, upon count without anthracycline.167,168 For patients with high-risk disease and cardiac
recovery following induction therapy. These patients also received a issues (eg, low ejection fraction and prolonged QTc), the NCCN AML
higher dose of cytarabine (2 g/m2) during consolidation (in cycle 2) as Panel recommends ATO (0.15 mg/kg or 0.3 mg/kg) with ATRA for
compared with 1 g/m2 in the APL 93 trial. There were no cases of CNS consolidation.169,175 If ATRA or ATO are discontinued due to toxicity, a
relapse in the APL 2000 trial, compared with 5 cases in the APL 93 trial. single dose of GO (9 mg/m2) may be considered once every 4 to 5 weeks
While the original treatment protocol on APL 2000 used HiDAC in the until 28 weeks from CR. If the patient received ATRA and GO as induction
second cycle of consolidation, some investigators suggest the use of therapy, consolidation with ATRA and GO should follow.170 As mentioned
HiDAC earlier, particularly in those patients who are not receiving IT previously, the panel suggests that a regimen should be used consistently
therapy for CNS prophylaxis. through all components and physicians should not mix induction therapy
from one trial with consolidation therapy from another.
For patients with low-risk disease, the NCCN AML Panel has positioned
the ATRA plus ATO regimen first, based on results from the APL0406 In general, it is recommended that 4 to 6 doses of intrathecal (IT)
phase III randomized trial in comparison with the AIDA regimen.159 An chemotherapy be given during consolidation for patients with high-risk
additional ATRA plus ATO regimen based on the AML 17 trial175 is also a APL. IT chemotherapy may include agents such as methotrexate
preferred option. The GIMEMA AIDA-2000 regimen158 is an additional alternating with cytarabine either alone or combined with corticosteroids;
option. However, all three of these regimens will yield excellent results. It the choice of single drug versus combinations may vary based on clinical
is important to note that clinicians should use a regimen consistently situation and institutional practice. Usually the IT treatment is started at the
through all components of the treatment protocol and not mix induction completion of induction and then given at the start and at count recovery
regimens from one trial with consolidation regimens from another trial. on subsequent consolidations. IT chemotherapy can be omitted during
cycles of higher dose cytarabine.
For patients with high-risk disease, preferred consolidation therapies
include ATRA plus ATO as used in the APML4 trial,173 or ATRA and ATO Post-Consolidation or Maintenance for Patients with APL
(plus a single dose of GO if ATRA/ATO are discontinued due to
Following consolidation therapy, patients are assessed for molecular
toxicity).169,175 Other recommended consolidation approaches include
remission using RT-PCR techniques on bone marrow samples. For
cytarabine with daunorubicin as used in the French APL 2000 trial163;
patients who have achieved PCR negative status, a 1- to 2-year course of
cytarabine with AIDA as used in the PETHEMA LPA 2005157; and 2 cycles
ATRA maintenance therapy, which may be combined with
of ATO followed by 2 additional cycles of standard chemotherapy as used
MS-23

6-mercaptopurine and methotrexate, may be a reasonable approach. The chemotherapy, and ATRA combined with chemotherapy were 74%, 88%,
recommendations for maintenance ATRA arose from several early trials 93%, and 94%, respectively (P < .001).154
that showed superior RFS for patients receiving ATRA alone or in
combination as maintenance therapy. The French APL 93 trial randomized The first North American Intergroup trial showed superior DFS outcomes
eligible patients (n = 289) to four different maintenance regimens: no for patients receiving maintenance ATRA compared with no
maintenance, continuous chemotherapy with 6-mercaptopurine and maintenance.153 In this trial, patients were randomized to induction therapy
methotrexate, intermittent ATRA, and the combination of ATRA with with daunorubicin plus cytarabine or with ATRA alone, and subsequently
6-mercaptopurine and methotrexate.138 Results showed decreased 2-year underwent a second randomization to maintenance therapy with ATRA or
relapse rates with continuous chemotherapy (11.5% vs. 27% with no no maintenance (observation only). Consolidation therapy comprised the
chemotherapy) and with ATRA (13.5% vs. 25% with no ATRA). The initial induction therapy regimen for course 1, and then daunorubicin and
estimated 2-year relapse rate for patients who received maintenance with HiDAC for course 2. The 5-year DFS rates for the four randomization
ATRA in combination with chemotherapy was 7.4%, suggesting an groups, chemotherapy induction plus observation, chemotherapy induction
additive benefit with the combination. The 2-year EFS rate was also plus ATRA maintenance, ATRA induction plus observation, and ATRA
improved with continuous chemotherapy (92% vs. 77% without induction plus ATRA maintenance, were 16%, 47%, 55%, and 74%,
chemotherapy) and with ATRA (87% vs. 82% without ATRA); the 2-year respectively.153 Thus, the incorporation of ATRA during induction and
EFS rate among patients who received ATRA in combination with maintenance appeared to improve long-term remission durations. It should
chemotherapy was 93%.138 Results from the long-term follow-up of the be noted that in the above North American Intergroup trial, molecular
APL 93 study showed a beneficial effect of maintenance treatment with remission status was not assessed prior to randomization to maintenance
intermittent ATRA and continuous chemotherapy, with an additive effect of treatment.
the 2 modalities. The 10-year cumulative relapse rates with no
The Japanese APL 97 randomized study evaluated the role of
maintenance, ATRA alone, continuous chemotherapy, and ATRA
maintenance with intensified chemotherapy compared with observation in
combined with chemotherapy were 43%, 33%, 23%, and 13%,
patients with APL who achieved molecular remission following
respectively (P < .001).154 Patients considered to be at high risk (WBC
consolidation (n = 175).182 The estimated 6-year DFS was not significantly
count >5000/mcL) appeared to derive the most benefit from maintenance
different between the chemotherapy maintenance and observation arms
therapy. The 10-year cumulative relapse rate among patients with
(63% vs. 80%). In fact, the estimated 6-year OS was significantly lower
high-risk disease with no maintenance, ATRA alone, continuous
with maintenance (86% vs. 99%; P = .014), which the investigators
chemotherapy, and ATRA combined with chemotherapy was 68%, 53%,
attributed to possible effects of chemotherapy maintenance on the
33%, and 21%, respectively (P < .001). No statistically significant
development of secondary malignancies and responses to subsequent
difference in the 10-year relapse rates was observed among patients with
(second-line) therapies.182
lower-risk disease, although the relapse rate dropped from 29% without
maintenance to 11.5% with ATRA combined with chemotherapy. Overall, Data from the AIDA 0493 trial suggested that there was no long-term
the 10-year OS rates with no maintenance, ATRA alone, continuous benefit to maintenance therapy (ie, combination chemotherapy with
MS-24

6-mercaptopurine and methotrexate, ATRA alone, or ATRA in combination status should be confirmed in a blood sample by a reliable laboratory
with chemotherapy) in patients who achieved molecular remission (PCR within 2 to 4 weeks. If molecular relapse is confirmed by a second positive
negative) at the end of consolidation therapy.183 In this trial, ATRA was not test, the patient should be treated for relapsed disease (see APL: Therapy
given during consolidation. The above studies have not demonstrated for Relapse in the algorithm). If the second test was negative,
long-term benefit with the use of maintenance therapy in patients who maintenance therapy and frequent monitoring (eg, every 2–3 months) for
achieve molecular remission following consolidation therapy. Further data up to an additional 2 years may be considered to ensure that the PCR
from randomized trials are needed to address the question of remains negative. Testing should be done in the same laboratory to
maintenance. A phase III cooperative group trial (SWOG 0521) is maintain a consistent level of sensitivity. For patients who develop
designed to examine the need for maintenance therapy (using the cytopenias and who have a negative RT-PCR, a bone marrow aspirate is
combination of ATRA, 6-mercaptopurine, and methotrexate) in patients recommended to assess for new cytogenetic abnormalities, as secondary
with low-risk APL. In this trial, patients receive induction therapy with MDS and AML can occur following APL therapy.
ATRA, daunorubicin, and cytarabine, followed by consolidation therapy
with ATO, ATRA, and daunorubicin. Patients are then randomized to Management of Relapsed APL
receive maintenance therapy or no further treatment (observation only). ATO is recommended for patients who do not achieve molecular remission
No benefit for maintenance was observed.184 The benefit of maintenance at completion of consolidation or who subsequently demonstrate
therapy likely depends on the regimens used during induction and molecular or morphologic relapse. As a single agent, ATO produced CR
consolidation therapies. Therefore, it is important to use maintenance rates of 80% to 90% in patients with hematologic relapse and achieved
therapy in conjunction with the treatment protocols in which they have molecular remissions in 70% to 80% of those patients.165,185-187 In a
been shown to confer benefit. retrospective analysis of patients with APL who experienced relapse after
first-line therapy with ATRA combined with chemotherapy (n = 23),
RT-PCR should be performed on a blood sample at completion of reinduction therapy with ATO-containing regimens (ATO monotherapy,
consolidation to document molecular remission. It is at the discretion of the n = 20; ATO combined with ATRA and anthracycline, n = 2; ATO
treating physician to determine the appropriate frequency of monitoring for combined with mitoxantrone, n = 1) resulted in hematologic CR in 95%
individual patients. Periodic monitoring is recommended for up to 2 years and molecular remission in 83% of patients.188 ATRA and ATO appear to
during maintenance therapy to detect molecular relapse in patients with be synergistic and one could consider using the combination in patients
high-risk disease, patients >60 years of age or who had long interruptions who have not received ATRA during consolidation.164-166 However, in a
during consolidation, or patients on regimens that use maintenance and small randomized study of patients with relapsed APL (n = 20), all patients
are not able to tolerate maintenance. Clinical experience indicates that the previously treated with ATRA-containing chemotherapy showed no
risk of relapse in patients with low-risk disease who have achieved improvement in response by adding ATRA to ATO compared with ATO
molecular remission at completion of consolidation is low, and monitoring alone.189 The role of retreatment with ATO for patients who experience
may not be necessary outside the setting of a clinical trial. At the current relapse following therapy with ATO-containing regimens during initial
level of test sensitivity/specificity, a change from PCR negative to positive induction and/or consolidation therapy remains unknown. A retrospective
MS-25

analysis in a small number of patients reported a second CR rate of 93% The data suggest that this sequential treatment regimen may provide
(both for hematologic CR and molecular remission) among patients who improved outcomes with greater duration.
were retreated with ATO combined with ATRA (with or without
anthracyclines) after a relapse following first-line therapy with single-agent A retrospective analysis conducted by the European APL Group showed
ATO (n = 14).188 that in patients who received HCT following a second hematologic
remission (primarily with ATRA-containing regimens), outcomes were
For patients with APL who experience relapse early (<6 months) after an more favorable with autologous HCT (n = 50) compared with allogeneic
initial CR to first-line therapy with ATRA and ATO with no prior exposure to HCT (n = 23). The 7-year RFS (79% vs. 92%) and EFS (61% vs. 52%)
anthracyclines, anthracycline-based regimens (ATRA plus daunorubicin rates did not reach statistical significance between patients who received
and cytarabine153,155,156; and AIDA alone157) are recommended. For autologous HCT versus allogeneic HCT; however, 7-year OS rates were
patients who experience an early relapse (<6 months) after an initial CR to significantly improved with autologous compared with allogeneic HCT
ATRA and anthracycline-containing first-line regimens or with no prior (60% vs. 52%; P = .04).191 Among patients who received a PCR-negative
exposure to ATO, it is recommended that the patient receive ATO with or autograft, the 7-year RFS and OS rates were 87% and 75%, respectively.
without ATRA, and with or without a single dose of GO until count Although the relapse rates were low with allogeneic HCT, the reduced OS
recovery with marrow confirms remission. For patients who experience a with this procedure was accounted for by the higher treatment-related
late relapse (≥6 months) to ATO-containing regimens, ATO with or without mortality observed in the allogeneic HCT group compared with the
ATRA, and with or without a single dose of GO/an anthracycline is autologous HCT group (39% vs. 6%).191
recommended as first-line therapy after relapse. Following completion of
the first cycle of consolidation, if the patient does not achieve molecular A second study also suggested that autologous transplant could have a
remission, a matched sibling or alternative donor (haploidentical, unrelated survival advantage over allogeneic transplant in this population.192
donor, or cord blood) HCT or clinical trial is recommended. Testing is Chakrabarty et al192 looked at 294 patients who received either allogeneic
recommended at least 2 to 3 weeks after the completion of arsenic to transplant (n = 232) or autologous transplant (n = 62) between 1995 and
avoid false positives. 2006. The 5-year DFS in the autologous transplant recipients was 63%
(range, 49%–75%) versus 50% (range, 44%–57%) in patients receiving
A small phase II trial in patients with relapsed APL evaluated ATO during allogeneic transplant. Although the DFS was not statistically significant
induction and consolidation followed by a peripheral blood hematopoietic (P = .1), the difference in OS did reach statistical significance (P = .002).
cell harvest after HiDAC chemotherapy and autologous HCT.190 The study In the patients receiving autologous transplant, OS was 75% (range, 63%–
enrolled 35 patients (16 who experienced hematologic relapse and 9 who 85%) versus 50% (range, 48%–61%). The authors attribute this benefit to
experienced molecular relapse) between the ages of 18 and 65 years. The the increased treatment-related mortality seen with patients receiving
EFS after 1 year was 77% (90% CI, 63%–86%). At a median follow-up of allogeneic transplant (30%) compared to autologous transplant (2%).
4.9 years (range, 0.3–6.3 years), the 5-year EFS was 65% and the 5-year
OS was 77% with an estimated 59% probability of failure-free survival.190 It should be noted that only limited evidence from retrospective studies
exist with regard to the role of autologous and allogeneic HCT following
MS-26

relapse of APL in the era of ATO therapy. The optimal consolidation have the numbers to enroll for a suitable trial. The benefit of GO must be
strategy following therapy with ATO-containing regimens in patients with weighed against the possibility for adverse events. Clinicians should be
relapsed disease remains to be defined.193 In a small retrospective study advised of the possible complication of sinusoidal obstructive syndrome
of patients with relapsed APL treated with ATO-containing induction and when administering GO.
consolidation therapy, outcome of further consolidation with autologous
HCT was compared with maintenance (without autologous HCT) A small percentage of relapsed APL has a CNS component.197,198
consisting of ATO with or without ATRA.188 In this analysis, all patients had Therefore, for patients who are in second morphologic remission, the use
achieved second molecular remission following induction and of IT therapy for CNS prophylaxis should be considered. Patients who
consolidation therapy with the ATO-containing regimens; subsequently, 14 achieve a molecular remission after second-line therapy should be
patients underwent autologous HCT and 19 patients opted for an considered for autologous HCT if they do not have contraindications to
ATO-containing maintenance regimen. Consolidation with autologous HCT high-dose therapy. Allogeneic transplant should be reserved for patients
was associated with a significantly higher 5-year EFS rate (83% vs. who have persistent disease despite therapy for relapsed disease. For
34.5%; P = .001) and OS rate (100% vs. 38.5%; P = .001) compared with patients in second CR who have contraindications to HCT, continued
ATO-containing maintenance therapy.188 The authors concluded that therapy with ATO for six cycles is recommended in the absence of a
consolidation with autologous HCT was superior to ATO-containing suitable clinical trial.
maintenance alone in patients who achieved molecular remission after
Supportive Care for Patients with APL
relapse. Outcome data from the ELN registry reported a 3-year OS after
transplant in second CR of 80% compared with 59% in patients without Specific supportive care issues should be considered when treating
transplant (P = .03).194 patients with APL. Therapy for APL is often associated with a constellation
of symptoms and physiologic abnormalities, including fluid retention,
In the context of a clinical trial or on compassionate use, GO is a potential dyspnea, episodic hypotension, pulmonary infiltrates, and pulmonary or
treatment option for relapsed APL. The voluntary withdrawal of the drug in pericardial effusions now referred to as “differentiation syndrome.”
2010 was based on interim data from a randomized trial in adult patients Approximately 15% to 25% of previously untreated patients receiving
(aged 18–60 years) with AML comparing induction regimens of cytarabine ATRA-containing therapy develop this syndrome.199,200 Patients may begin
and daunorubicin with or without GO in which there was no improvement to develop evidence of differentiation syndrome early in the treatment with
in outcomes and a small but significant increase in early mortality in the either ATRA or ATO as single agents or in combination. These patients
GO arm.195 Subsequent results of this trial eventually showed no develop fever, often accompanied by rapidly rising WBC counts
difference in overall mortality between the two arms.196 Since its (>10,000/mcL). Patients should be closely monitored for hypoxia and the
withdrawal from the market, studies have demonstrated a significant development of pulmonary infiltrates or pleural effusion. Differentiation
benefit for GO in specific patient populations. Therefore, GO has been re- syndrome along with hemorrhage are the leading causes of death during
approved for AML. One complication to evaluating the benefit of GO is that induction therapy. Early recognition and prompt initiation of corticosteroids
APL occurs in a small population of patients, and therefore studies do not are key components in the management of this complication. In some
MS-27

studies, low mortality and morbidity rates were reported when least 10 days) as prophylaxis for differentiation syndrome regardless of
corticosteroids were administered prophylactically in patients presenting initial WBC count [see APL Treatment Induction (High Risk) in the
with high WBC counts.161,201 Kelaidi et al202 assessed the outcomes of algorithm].173 In the Italian-German Cooperative Group study that
patients with high WBC (>10,000/mcL) enrolled in the APL 93 and APL evaluated ATRA combined with ATO versus the AIDA regimen (phase III
2000 trials.202 A fundamental difference between these two trials was the APL0406 trial), patients received prophylaxis with prednisone (0.5
use of dexamethasone (10 mg every 12 hours beginning on day 1) for mg/kg/day) from day 1 until the end of induction [see APL Treatment
patients on APL 2000. The early death rate from differentiation syndrome Induction (Low Risk) in the algorithm].159 If a patient develops
dropped from 8 in 139 patients (6%) in the APL 93 trial to 2 in 133 patients differentiation syndrome, it is recommended that treatment be changed
(1.5%) in the APL 2000 trial. from prednisone to dexamethasone 10 mg every 12 hours until count
recovery or risk of differentiation has abated.157,159 In settings where
There should be a high index of suspicion for differentiation syndrome in differentiation syndrome is difficult to treat, the panel recommends the
APL patients who may be triggered by symptoms including fever, an following cytoreduction strategies for leukocytosis: hydroxyurea,
increasing WBC count greater than 10,000/mcL, shortness of breath, anthracyclines, and GO.
hypoxemia, and pleural or pericardial effusion. Close monitoring of volume
overload and pulmonary status is warranted in these patients and initiation Leukapheresis is not routinely recommended in the management of
of dexamethasone should occur at the first signs or symptoms of patients with high WBC counts in APL because of the difference in
respiratory compromise (ie, hypoxia, pulmonary infiltrates, pericardial or leukemia biology. However, in cases of potentially life-threatening
pleural effusions). The NCCN AML Panel recommends treating with leukostasis not responsive to other modalities, leukapheresis can be
dexamethasone 10 mg twice daily for 3 to 5 days, then tapering the dose considered with caution.
over 2 weeks (see Principles of Supportive Care for APL in the algorithm).
ATRA may need to be withheld during the initial acute symptomatic period Because coagulopathy is common in patients with APL, it is important to
but may be resumed when symptoms resolve. Other factors that have screen for this problem with evaluation of prothrombin time, partial
been reported to increase the risk of differentiation syndrome include a thromboplastin time, and fibrinogen concentration during the initial workup
high body mass index and age >40 years. For patients at high risk (WBC and before any invasive procedure. Clinical coagulopathy is managed by
count >10,000/mcL) of developing differentiation syndrome, initiate aggressive transfusion support to maintain platelet counts of 50,000/mcL
prophylaxis with corticosteroids, either prednisone (0.5 mg/kg) from day 1 or greater, by fibrinogen replacement with cryoprecipitate and frozen
or dexamethasone 10 mg every 12 hours (see Principles of Supportive plasma to maintain a level of 150 mg/dL, and by maintenance of
Care for APL in the algorithm). The steroid dose should be tapered over a prothrombin time and partial thromboplastin time close to normal. Patients
period of several days. It is recommended that the prophylaxis regimen with clinical coagulopathy need to be monitored daily until resolution.
follow the specific treatment protocol used. In the Australia/New Zealand Given the risks of coagulopathy in APL at diagnosis, invasive procedures
study that evaluated induction with ATO added to a backbone of AIDA including leukapheresis and/or central line placement should be avoided. If
(phase II APML4 trial), all patients received prednisone (1 mg/kg/day for at possible, the diagnosis of APL may be made using peripheral blood
MS-28

samples, which may minimize the risk of bleeding complications until to restore normal hematopoiesis. Early in the process of developing a
coagulopathy can be adequately controlled. treatment plan, it is reasonable to consider referral to palliative care for
consultation.204,205
ATO therapy may prolong the QT interval, making patients susceptible to
ventricular arrhythmias. Therefore, prior to initiation of therapy, an ECG is Recommendations for induction chemotherapy in patients with AML
recommended to assess the QT interval. Routine monitoring (eg, weekly) consider age 60 years as a therapeutic divergence point. This is based on
during therapy is suggested for patients who are older. Serum electrolytes the higher prevalence of unfavorable cytogenetics and antecedent
should also be monitored prior to and during therapy to maintain myelodysplasia, along with a higher incidence of multidrug resistance in
electrolytes within the middle or upper normal range. Other drugs that patients >60 years, and an increased frequency of comorbid medical
prolong the QT interval should be avoided during ATO therapy to minimize conditions that affect the patient’s ability to tolerate intensive treatment.206
the risk of cardiac arrhythmias. Patients with an absolute QTc interval Because complete remission rates rarely exceed 70% in younger patients
greater than 500 milliseconds should be reassessed on a weekly basis and 50% in patients who are older, substantial opportunity exists for
during induction therapy, and prior to each course of post-remission innovative clinical trials involving both patient populations. The guidelines
therapy. A cardiology consult may be appropriate for patients with consider recommendations for patients younger than or >60 years of age
prolonged QTc and when QTcF corrections are unavailable.203 separately.
Growth factors are not recommended during induction for patients with Management of AML in Patients Younger Than 60 Years
APL as they can complicate assessment of response and increase the risk Induction Therapy
of differentiation syndrome. There is no evidence for whether growth Standard induction regimens used for patients younger than age 60 years
factors have a positive or negative impact on long-term outcome if used are based on a backbone of cytarabine plus an anthracycline. Historically,
during consolidation. However, growth factors may be considered during in most large cooperative group trials, daunorubicin has been the most
consolidation in selected cases, including in the event of life-threatening commonly used anthracycline at doses of 45 to 60 mg/m2 daily for 3 days.
infections, or when signs/symptoms of sepsis are present, in an attempt to Idarubicin, which has a longer intracellular retention time, used at doses of
shorten the duration of neutropenia. 12 mg/m2 daily for 3 days, has had comparable remission rates with fewer
patients requiring additional therapy at day 15 to achieve remission. CR
Management of Acute Myeloid Leukemia rates for patients who are 50 years or younger have consistently been in
Most initial treatment decisions for AML are based on age, history of prior the range of 60% to 70% in most large cooperative group trials of
myelodysplasia or cytotoxic therapy, and performance status. Although infusional cytarabine and anthracycline. Recent studies have incorporated
karyotype and molecular markers are powerful predictors of DFS targeted strategies according to cytogenetics and molecular abnormalities,
outcomes, induction chemotherapy will be initiated before this information and the current NCCN Guidelines for AML outline treatment strategies
is available in most instances. The intent of traditional induction according to these cytogenetic risk groups.
chemotherapy is to produce a major reduction in the leukemic burden and
MS-29

Risk-Stratified Treatment Strategies ratio between daunorubicin and idarubicin was less than 5. Both high-dose
Favorable-Risk Cytogenetics daunorubicin and idarubicin resulted in 5-year survival rates between 40%
Cytarabine and anthracycline dose during induction: A large and 50%.210
randomized phase III study (E1900) from the ECOG reported a significant
It has been suggested that a dose of 60 mg/m2 daunorubicin may be
increase in CR rate (71% vs. 57%; P < .001) and median OS (24 vs. 16
equally as effective as 90 mg/m2 and have a lower toxicity. A study from
months; P = .003) using daunorubicin 90 mg/m2 daily for 3 days (n = 327)
Burnett et al211 compared these two doses in 1206 patients who were
versus 45 mg/m2 daily for 3 days (n = 330) in patients with previously
predominately younger than 60 years of age. There was no difference in
untreated AML younger than 60 years.207 Based on subgroup analyses,
CR (73% vs. 75%; OR, 1.07; 95% CI, 0.83–1.39; P = .60). The 60-day
however, the survival benefit with high-dose daunorubicin was shown to
mortality was higher in the patients receiving 90 mg/m2 (10% vs. 5%; HR,
be restricted to patients with favorable- and intermediate-risk cytogenetic
1.98; 95% CI, 1.30–3.02; P = .001), though the 2-year OS was similar
profiles (median OS, 34 vs. 21 months; P = .004) and those younger than
(59% vs. 60%; HR, 1.16; 95% CI, 0.95–1.43; P = .15).210 It is worth noting
50 years (median OS, 34 vs. 19 months; P = .004). The survival outcome
that all patients received a second course of chemotherapy that included
for patients with unfavorable cytogenetics was poor, with a median OS of
additional daunorubicin (50 mg/m2) on days 1, 3, and 5, which may
only 10 months in both treatment arms.207 In an update of the E1900 trial,
potentially have mitigated the effects of a 90 mg/m2 daunorubicin dose.
high-dose daunorubicin maintained a higher response than standard-dose
daunorubicin in patients younger than 50 years of age (HR, 0.66; CD33-Positive AML: GO is a humanized anti-CD33 monoclonal antibody
P = .002).208 This benefit was seen regardless of cytogenetic risk profile. In conjugated with the cytotoxic agent calicheamicin,212 that was initially
addition, patients with FLT3-ITD, DNMT3A, and NPM1 mutant AML had approved in the year 2000 as a monotherapy for AML based on data from
improved OS. Patients between 50 and 60 years of age with FLT3-ITD or single-arm phase II trials for older adult patients in first relapse.213 The
NPM1mutant AML also benefitted from high-dose daunorubicin.208 High- voluntary withdrawal of the drug in 2010 was based on interim data from a
dose daunorubicin was previously evaluated in a European trial that randomized trial in adult patients (aged 18–60 years) with AML comparing
compared idarubicin 12 mg/m2 daily for 3 or 4 days versus daunorubicin induction regimens of cytarabine and daunorubicin with or without GO in
80 mg/m2 daily for 3 days in patients between ages 50 and 70 years; CR which there was no improvement in outcomes and a small but significant
rates were 83%, 78%, and 70%, respectively (P = .04).209 No difference increase in early mortality in the GO arm.195 Subsequent results of this trial
was seen in relapse rate, EFS, or OS outcomes between the treatment eventually showed no difference in overall mortality between the two
arms. arms.196 Since its withdrawal from the market, studies have demonstrated
a significant benefit for GO in specific patient populations. In the MRC
In a systematic review and meta-analysis of 29 randomized controlled
AML 15 trial, the efficacy and safety of adding GO (3 mg/m2 on day 1 of
trials (RCTs) comparing idarubicin to daunorubicin,210 idarubicin had a
induction) to three induction regimens, including daunorubicin (50 mg/m2
lower remission failure rate compared to daunorubicin (RR, 0.81; 95% CI,
on days 1, 3, and 5) and cytarabine (100 mg/m2 on days 1–10 every 12
0.66–0.99; P = .04), but no difference was observed in early death or
hours), was evaluated in patients 60 years or younger with previously
overall mortality. Furthermore, this benefit was only seen when the dose
MS-30

untreated AML (n = 1,113).214 The addition of GO was well tolerated and and approval by the FDA in 2017. In the CALGB 10603/RATIFY Alliance
there were no differences in RFS or OS rates between arms that received trial, patients aged 18 to 59 years, with newly diagnosed FLT3-mutation–
or did not receive GO. The patients predicted to derive significant benefit positive AML (ITD or TKD) were randomized (n = 717) to receive standard
with the GO addition to chemotherapy included those with favorable-risk cytarabine therapy (200 mg/m2 daily for 7 days via continuous infusion)
cytogenetics, with a trend towards benefit for those with intermediate-risk and daunorubicin (60 mg/m2 on days 1–3) with placebo or midostaurin (50
cytogenetics.214 A meta-analysis of five randomized trials (including adult mg, twice daily on days 8–21).221 If residual disease in the bone marrow
patients ≥60 years) showed that adding GO (including alternative dosing was observed on day 21, patients were treated with a second blinded
schedules) to conventional induction therapy also provides survival course. Patients who achieved CR received 4 28-day cycles of HiDAC (3
benefit.215 A review of these and other studies (see Management of AML g/m2 every 12 hours on days 1, 3, and 5) with placebo or midostaurin (50
in Patients Older than 60 Years) led to the approval of GO in September mg, twice a day on days 8–21) followed by a year of maintenance therapy
2017 for the treatment of adults with newly diagnosed CD33-positive AML. with placebo or midostaurin (50 mg twice a day).221 The median OS was
74.7 months (95% CI, 31.5–not reached [NR]) in the midostaurin group
In the MRC AML 15 trial, younger patients with untreated AML (median compared to 25.6 months (95% CI, 18.6–42.9) in the placebo group (P =
age, 49 years), were randomized to two induction courses of: 1) .009).221 Patients who received midostaurin with standard induction and
daunorubicin and cytarabine (DA) with or without etoposide (ADE; n = consolidation therapy experienced significant improvement in OS (HR for
1983); or 2) ADE versus fludarabine, cytarabine, granulocyte colony- death, 0.78; P = .009) and EFS (HR for event or death, 0.78; P = .002)
stimulating factor (G-CSF), and idarubicin (FLAG-Ida; n = 1268).216 compared with those on the placebo arm.221
Patients in the DA and FLAG-Ida arms were randomly assigned to a single
dose of GO (3 mg/m2) during the first induction course.216 Patients with Some studies suggest that a higher dose of daunorubicin (90 mg/m2),
favorable- and intermediate-risk disease who received two induction compared to lower doses of either 45 or 60 mg/m2, is significantly
courses of FLAG-Ida with GO in course 1, followed by 2 courses of HiDAC associated with increased CR and survival rates in patients with
had an 8-year survival rate from remission of 72% (favorable risk, 95%; intermediate-risk cytogenetics and those who have FLT3-ITD mutation–
intermediate risk, 63%).216 positive AML.222,223 A phase III study compared idarubicin (12 mg/m2 for 3
days) and high-dose daunorubicin (90 mg/m2 for 3 days) with standard
KIT-Mutated AML: Emerging studies are evaluating the impact of adding cytarabine therapy during induction in young adults with newly diagnosed
dasatinib, a TKI, to AML therapy in CBF-AML with KIT mutations.217,218 AML (age range, 15–65 years). It was determined that high-dose
daunorubicin was associated with higher OS and EFS rates in patients
Intermediate-Risk Cytogenetics
with FLT3-ITD mutation–positive AML.224 However, these studies did not
FLT3-Positive AML: The majority of FLT3-mutated AML cases occur in
include midostaurin.
patients with intermediate-risk cytogenetics. Data have demonstrated
improved survival for patients with newly diagnosed FLT3-mutation–
positive AML when midostaurin is added to standard chemotherapy as
part of frontline treatment.219-221 This led to its breakthrough designation
MS-31

Therapy-Related AML or Antecedent MDS/CMML or AML-MRC younger than 46 years of age.230 This study randomized 1900 patients
Although most cases of AML are de novo, secondary AML and therapy- between the ages of 15 and 60 years into two treatment groups, HiDAC
related AML account for approximately 25% of all AML cases and are and standard-dose cytarabine (SDAC; 100 mg/m2/d by continuous infusion
associated with poor outcomes.225,226 Emerging data have demonstrated for 10 days). Both groups were also given daunorubicin (50 mg/m2/d on
improved survival in patients who are older with secondary AML when a days 1, 3, and 5) and etoposide (50 mg/m2/d on days 1–5). Data from a
dual-drug liposomal formulation of cytarabine and daunorubicin in a 5:1 median 6-year follow-up indicate an OS near statistical significance
molar ratio (CPX-351) is used as frontline therapy.227-229 In a phase II trial, (HiDAC, 42.5% vs. SDAC, 38.7%; P = .06), and when separated by age
newly diagnosed patients ≥60 years of age with AML (n = 126), were with a cutoff of 46 years, the benefit was relegated to the younger patient
randomized 2:1 to first-line CPX-351 or the conventional administration of cohort (HiDAC, 51.9% vs. SDAC, 43.3%; P = .009) compared to patients
cytarabine and daunorubicin (7+3 regimen).228 Compared to the standard ≥46 years of age (HiDAC, 32.9% vs. SDAC, 33.9%; P = .91). Other
7+3 regimen, CPX-351 produced higher response rates (CPX-351, 66.7% populations that benefited from HiDAC were patients with high-risk
vs. 7+3, 51.2%; P = .07), however differences in EFS and OS were not disease, including patients with very poor-risk cytogenetic abnormalities
statistically significant.228 A planned analysis of the secondary AML and/or FLT3-ITD mutation-positive AML or with secondary AML. There
subgroup demonstrated that CPX-351 was associated with a higher CR was no significant increase in grade 3 or 4 toxicities except for an increase
rate (57.6% vs. 31.6%; P = .06).228 These results led to the development in conjunctivitis (grade 2–3) with HiDAC (12.4%) versus SDAC (0.5%).
of a randomized phase III study comparing the efficacy and safety of CPX- Incidence of adverse events was equivalent (SDAC, 67.6% vs. HiDAC,
351 to the conventional administration of cytarabine and daunorubicin 66.2%). Patients in CR received a single consolidation cycle of
(control arm) in patients 60–75 years of age with newly diagnosed daunorubicin and cytarabine (500 mg/m2 every 12 hours for 6 days) and
secondary AML (n = 309).229 With a median follow-up of 20.7 months, subsequent HCT.230
CPX-351 significantly improved OS compared to the control arm (median,
9.56 vs. 5.95 months; HR, 0.69; 95% CI, 0.52-0.90; P = .003).229 CPX-351 HiDAC therapy during induction was initially explored two decades ago in
was also associated with significantly higher overall remission (47.7% vs. 2 large cooperative group trials. In an Australian Leukemia Study Group
33.3%; P = .016) and CR (37.3% vs. 25.6%; P = .04) rates. The most trial,231,232 patients younger than 60 years were randomized (n = 301) to
frequently reported grade 3 to 5 adverse events in the CPX-351 and receive either HiDAC (3 g/m2 every 12 hours on days 1, 3, 5, and 7 for a
control groups were febrile neutropenia (68.0% vs. 70.9%), pneumonia total of 24 g/m2) or standard cytarabine therapy (100 mg/m2 daily for 7
(19.6% vs. 14.6%), and hypoxia (13.1% vs. 15.2%).229 days via continuous infusion); patients in both arms received daunorubicin
(50 mg/m2 on days 1–3) and etoposide (75 mg/m2 daily for 7 days). The
Other Regimens for Intermediate- or Poor-risk Cytogenetics CR rates were equivalent in both arms (71% and 74%, respectively), and
HiDAC-Containing Regimens: The use of HiDAC as induction therapy a significantly higher 5-year RFS rate was observed in the HiDAC arm
continues to be a controversial approach. The most recent study from the (48% vs. 25%; P = .007).232 Patients in both treatment arms received only
EORTC-GIMEMA AML-12 trial suggests that HiDAC (3 g/m2 every 12 2 cycles of standard-dose cytarabine, daunorubicin, and etoposide for
hours on days 1, 2, 5, and 7) improves outcome in patients who are consolidation therapy. Median remission duration was 45 months for the
MS-32

high-dose arm, compared with 12 months for the standard treatment than for those who received the standard dose. Similarly, for patients
arm.231 However, treatment-related morbidity and mortality were higher in younger than 50 years who received 3 g/m2 HiDAC for consolidation, the
the HiDAC arm; the 5-year OS rates were 33% in the high-dose arm rates of treatment-related deaths (4% vs. 0%) and grade 3 or greater
compared with 25% in the standard-dose arm.232 neurologic toxicity (16% vs. 0%) were higher than for those who received
the standard dose.233
In a large SWOG study,233 patients younger than 65 years (n = 665) with
de novo or secondary AML were randomized to receive HiDAC (2 g/m2 Younger patients (age <50 years) who received HiDAC induction and
every 12 hours for 6 days for a total of 24 g/m2; patients aged <50 years consolidation in the SWOG trial had the highest OS and DFS rates at 4
were initially randomized to receive 3 g/m2 at the above schedule before years (52% and 34%, respectively) compared with those who received
the high-dose arm was redefined to 2 g/m2 because of toxicity concerns) standard-dose induction and consolidation (34% and 24%, respectively) or
or standard-dose cytarabine (200 mg/m2 daily for 7 days); patients in both standard induction with high-dose consolidation (23% and 14%,
treatment arms also received daunorubicin (45 mg/m2 daily for 3 days). respectively).233 However, the percentage of patients achieving a CR who
Patients treated in the HiDAC arm received a second high-dose cycle for did not proceed to consolidation was twice as high in the HiDAC induction
consolidation, whereas patients in the standard-dose arm were arm.233 The risks for neurotoxicity and renal insufficiency are increased
randomized to receive consolidation therapy with either 2 cycles of with HiDAC; therefore, both renal and neurologic function should be
standard-dose cytarabine or 1 cycle of HiDAC plus daunorubicin. The CR closely monitored in patients receiving this treatment. In a CALGB trial,234
rates were similar, with 55% for the high-dose arm compared with 58% for the subgroup of patients aged 60 years or younger (n = 156) who received
the standard-dose arm for patients younger than 50 years, and 45% for standard-dose cytarabine-daunorubicin induction therapy and 4 courses of
HiDAC versus 53% for standard-dose therapy for patients 50 to 65 years HiDAC consolidation (3 g/m2 every 12 hours on days 1, 3, and 5, per
of age. DFS rate (for patients who achieved a CR) and OS rate (for all course) experienced a 4-year DFS rate of 44%. Among all patients who
patients) at 4 years were not significantly different among treatment arms. received consolidation with HiDAC, the rates of treatment-related deaths
Induction therapy with HiDAC was associated with significantly higher and serious neurotoxicity were 5% and 12%, respectively.234
rates of treatment-related mortality (14% vs. 5% for patients aged <50
years; 20% vs. 12% for patients aged 50–64 years; P = .003) and grade 3 Because the OS outcomes for the high-dose arm in the SWOG trial
or higher neurologic toxicity (8% vs. 2% for patients aged <50 years; 5% consisting of HiDAC induction and 2 cycles of HiDAC consolidation (4-year
vs. 0.5% for patients aged 50–64 years; P < .0001).233 For patients OS rate of 52% for patients aged <50 years) were comparable to those of
younger than 50 years, consolidation with HiDAC was associated with the CALGB trial with standard-dose infusional cytarabine induction and 4
similar rates of treatment-related mortality (2% vs. 0%) and grade 3 or cycles of HiDAC consolidation (4-year OS rate of 52% for patients aged
higher neurologic toxicity (2% vs. 0%) compared with the standard dose. ≤60 years), the use of HiDAC in the induction phase outside of a clinical
For the original cohort of patients younger than 50 years who received 3 trial remains controversial. A meta-analysis including 22 trials and 5945
g/m2 HiDAC for induction, the rates of treatment-related deaths (10% vs. patients with de novo AML younger than 60 years of age demonstrated
5%) and grade 3 or greater neurologic toxicity (16% vs. 2%) were higher improved RFS and reduced risk of relapse, particularly in the setting of
MS-33

favorable-risk cytogenetics, for patients receiving HiDAC versus standard from the HOVON/SAKK groups compared standard cytarabine/idarubicin
chemotherapy.235 However, toxicity was a limiting factor and emphasis induction with or without clofarabine (10 mg/m2 on days 1–5) for patients
was placed on the importance of future studies to define the populations with AML between the ages of 18 to 65 years.238 While there was no
that would most benefit from HiDAC and to optimize dosing difference in the OS and EFS in the group as a whole, there was a
recommendations. The decision to use high- versus standard-dose decrease in relapse rate counter balanced by an increased rate of death in
cytarabine for induction might be influenced by consolidation strategies; remission for the clofarabine arm. In a subset analysis, there was a
fewer high-dose consolidation cycles may be needed for patients induced significant improvement in OS and EFS for the ELN intermediate I group,
with HiDAC or for those who will undergo early autologous HCT. Although primarily in patients in the NPM1 wild-type/FLT3-ITD–negative subgroup
the remission rates are similar for high- and standard-dose cytarabine, 2 with a 4-year EFS of 40% for the clofarabine arm versus 18% for the
studies have shown more rapid marrow blast clearance after 1 cycle of control arm.238
high-dose therapy and a DFS advantage for patients aged 50 years or
NCCN Recommendations
younger who received the high-dose therapy.236 No data are available
using more than 60 mg/m2 of daunorubicin or 12 mg/m2 of idarubicin with The NCCN AML Panel strongly encourages enrollment in a clinical trial for
HiDAC. With either high- or standard-dose cytarabine-based induction for treatment induction of younger patients (aged <60 years) with AML. For
younger patients, between 20% and 45% of these patients will not enter patients not enrolled in a clinical trial, cytogenetics and the risk status of
remission. In a report of 122 patients treated with HiDAC and the disease guide treatment strategies. For patients with favorable-,
daunorubicin, the remission rates were strongly influenced by intermediate-, and poor-risk cytogenetics, infusional standard-dose
cytogenetics, with CR rates of 87%, 79%, and 62% for favorable-, cytarabine (100–200 mg/m2 continuous infusion) for 7 days combined with
intermediate-, and poor-risk groups, respectively.237 either idarubicin (12 mg/m2 for 3 days) or daunorubicin (60–90 mg/m2 for 3
days) is a category 1 recommendation.207
As previously mentioned, in the MRC AML 15 trial, younger patients with
untreated AML (median age, 49 years), were randomized to two induction For patients with favorable-risk cytogenetics, other treatment options
courses of: 1) daunorubicin and cytarabine with or without etoposide include standard-dose cytarabine (200 mg/m2 continuous infusion) for 7
(ADE; n = 1983); or 2) ADE versus fludarabine, cytarabine, G-CSF, and days combined with daunorubicin (60 mg/m2 for 3 days) and GO for
idarubicin (FLAG-Ida; n = 1268).216 In consolidation, patients were patients with CD33-positive AML (category 2A and preferred
randomized to amsacrine, cytarabine, etoposide, and then recommendation);214 or, fludarabine (30 mg/m2 IV for days 2–6) plus
mitoxantrone/cytarabine, or HiDAC (3 g/m2; n = 1445).216 Patients in the HiDAC (2 g/m2) over 4 hours starting 4 hours after fludarabine in
HiDAC arm received 1.5 g/m2 in consolidation, and were treated with or combination with idarubicin (8 mg/m2 IV days 4–6) and G-CSF (SC daily
without a fifth course of cytarabine (n = 227). There were no significant on days 1–7) plus a single dose of GO (category 2B recommendation).216
differences in the rate of CR between ADE and FLAG-Ida (81% vs. 84%,
For patients with intermediate-risk cytogenetics and FLT3-mutated AML,
respectively), but FLAG-Ida significantly decreased relapse rates (FLAG-
midostaurin is added to standard-dose cytarabine (200 mg/m2 continuous
Ida, 38% vs. ADE, 55%; P < .001).216 A recent randomized phase III study
MS-34

infusion) for 7 days combined with daunorubicin (60 mg/m2 for 3 days) starting 4 hours after fludarabine in combination with idarubicin (8 mg/m2
(category 2A recommendation).221 IV days 4–6) and G-CSF (SC daily on days 1–7) (category 2B
recommendation);216 or HiDAC plus an anthracycline and etoposide
Patients with antecedent hematologic disease or treatment-related AML (category 1 recommendation for patients 45 years of age or younger, but a
are considered to have poor-risk disease, unless they have favorable category 2B recommendation for other age groups).230,231,233,236 The study
cytogenetics such as t(8;21), inv(16), or t(16;16). In addition, patients with from Willemze et al230 that demonstrated improved OS for patients
unfavorable karyotypes, such as 11q23 abnormalities, monosomy -5 or -7, between the ages of 15 and 45 years treated on this regimen was integral
monosomal karyotype, or complex cytogenetic abnormalities and in the change of the recommendation to category 1 for this age group. For
mutations including RUNX1, ASXL1, and TP53, are also considered to patients with impaired cardiac function, other cytarabine-based regimens
have poor-risk disease. Although all patients with AML are best treated combined with non-cardiotoxic agents can be considered. For patients
within the context of an appropriate clinical trial, it is particularly important with unfavorable-risk cytogenetics and TP53-mutated AML, treatment
that this group of patients with poor-risk disease should be entered into a options are lacking, and alternative strategies should be considered.
clinical trial (incorporating either chemotherapy or novel agents), if
available, given that only 40% to 50% of these patients experience a CR Postinduction Therapy
(approximately 25% in adult patients who are older with poor-risk After Standard-Dose Cytarabine Induction
cytogenetics) with standard induction therapy. In addition, HLA testing To judge the efficacy of the induction therapy, a bone marrow aspirate and
should be performed promptly in those who may be candidates for either biopsy should be performed 14 to 21 days after start of therapy. In patients
fully ablative or reduced-intensity conditioning (RIC) allogeneic HCT from who have received standard-dose cytarabine induction and have
a matched sibling or an alternative donor, which constitutes the best significant residual disease without hypoplasia (defined as cellularity less
option for long-term disease control.239 For younger patients (aged <60 than 20% of which the residual blasts are less than 5% [ie, blast
years) with therapy-related AML other than CBF/APL, antecedent percentage of residual cellularity]), additional therapy with standard-dose
MDS/chronic myelomonocytic leukemia (CMML), and cytogenetic changes cytarabine and anthracycline or escalation to HiDAC (1.5–3 g/m2 every 12
consistent with MDS (AML-MRC), CPX-351 [cytarabine (100 mg/m2) and hours for 6 days) may be considered for re-induction; no data are available
daunorubicin (44 mg/m2)] as an intravenous infusion over 90 minutes on to determine superiority of standard-dose cytarabine or HiDAC. After a
days 1, 3, and 5 of 1 cycle is a category 2B recommendation, because the bone marrow biopsy on day 21, standard-dose cytarabine with
trial did not include this patient population.229 anthracycline and midostaurin should be considered for patients with
FLT3-mutated AML.221 If dual-drug liposomal encapsulation of cytarabine
Other recommended induction regimens for intermediate- or poor-risk
and daunorubicin was given during induction, after a bone marrow biopsy
disease include: standard-dose cytarabine (200 mg/m2 continuous
14–21 days after induction, re-induction with CPX-351 [cytarabine (100
infusion) for 7 days combined with daunorubicin (60 mg/m2 for 3 days) and
mg/m2) and daunorubicin (44 mg/m2)] as an intravenous infusion over 90
GO for patients with CD33-positive AML (intermediate-risk AML);214
minutes on days 1 and 3 is recommended for patients with therapy-related
fludarabine (30 mg/m2 IV for days 2–6) plus HiDAC (2 g/m2) over 4 hours
MS-35

AML other than CBF/APL, antecedent MDS/CMML, or AML-MRC.229 function before each anthracycline/mitoxantrone-containing course.240 If
Treatments for induction failure may also be considered. the patient has an identified sibling or alternative donor available, a
transplant option should be explored, although the panel encourages
For patients with significant (>50%) cytoreduction and a low percentage of using alternative therapies to achieve remission prior to the transplant. For
residual blasts (as defined above), standard-dose cytarabine with patients whose clinical condition has deteriorated such that active
idarubicin or daunorubicin, or standard-dose cytarabine with daunorubicin treatment is not an option, best supportive care should be continued.
and midostaurin is recommended for patients with for FLT3-mutated AML.
If daunorubicin (90 mg/m2) was used in induction, the recommended dose After High-Dose Cytarabine Induction
for reinduction of daunorubicin prior to count recovery is 45 mg/m2 for no Patients initially treated with HiDAC and who have significant residual
more than 2 doses. Similarly, if idarubicin (12 mg/m2) was used for disease without a hypocellular marrow 21 to 28 days after start of therapy
induction, the early reinduction dose should be limited to 10 mg/m2 for 1 or are considered to have experienced induction failure. In the ELN
2 doses. If the marrow is hypoplastic, additional treatment selection is Guidelines, primary induction failure is defined as failure to achieve CR
deferred until the remission status can be assessed. after two courses of intensive induction chemotherapy.21 Additional HiDAC
therapy at this time is unlikely to induce remission in these cases. These
If hypoplasia status is unclear, a repeat bone marrow biopsy should be patients should be considered for a clinical trial or for use of regimens
considered 5 to 7 days before proceeding with post induction therapy. For used for R/R disease (see Management of Relapsed/Refractory AML). If
patients who achieve CR with the additional post induction therapy, an HLA-matched sibling or alternative donor has been identified, an
consolidation therapy can be initiated upon count recovery. Screening LP allogeneic HCT may be effective in 25% to 30% of patients who have
should be considered at first remission before first consolidation for experienced induction failure. If no donor is immediately available, patients
patients with monocytic differentiation, MPAL, WBC count >40,000/mcL at should be considered for a clinical trial. If the patient’s clinical condition
diagnosis, or extramedullary disease. has deteriorated to a point at which active therapy would be detrimental,
best supportive care may be the most appropriate option. If the patient has
Patients who have persistent disease following two courses of therapy
a significant cytoreduction following HiDAC with a small quantity of
(including a reinduction attempt based on midcycle marrow) are
residual blasts or hypoplasia, additional therapy should be delayed for an
considered to have experienced primary induction failure. Treatment
additional 10 to 14 days and the marrow status may be reassessed.
options include clinical trial or use of chemotherapy regimens used for
relapsed/refractory (R/R) disease (see Management of Occasionally, patients with both myeloid and lymphoid markers at
Relapsed/Refractory AML). However, the likelihood of achieving a CR with diagnosis may experience response to ALL therapy if an AML induction
a third chemotherapy regimen is low, at approximately 20%. If the patient regimen failed.4 Treatment decisions for patients with significant reduction
did not receive HiDAC for persistent disease at day 15, HiDAC with or without hypoplasia or those with hypoplasia are deferred until the blood
without anthracycline may be used if a clinical trial is not available and a counts recover and a repeat marrow is performed to document remission
donor is not yet identified. If regimens used will result in high cumulative status. Response is then categorized as a CR or primary induction failure.
doses of cardiotoxic agents, consider reassessing the patient’s cardiac
MS-36

Post-Remission or Consolidation Therapy and lower OS (25% vs. 76.5%, P = .006) compared to wild-type KIT.37 In
Although successful induction therapy clears the visible signs of leukemia CBF AML with inv(16), TKD816 did not result in a significant difference in
in the marrow and restores normal hematopoiesis in patients with de novo relapse incidence and OS.37 The prognostic influence of TKD816 and other
AML, additional post-remission therapy (ie, consolidation) may be needed mutations in exon 17 (mutKIT17) versus other recurrent KIT mutations in
to reduce the residual abnormal cells to a level that can be contained by CBF AML, such as exon 8 (mutKIT8), have been investigated.43,83 In an
immune surveillance. For patients younger than 60 years of age, post- analysis of adult patients younger than 60 years of age with CBF AML
remission therapy is also based on risk status defined by cytogenetics and treated on CALGB trials (n = 110), KIT mutations (mutKIT17 and mutKIT8)
molecular abnormalities (see Evaluation for Acute Leukemia in the in the setting of inv(16) were associated with a higher cumulative
algorithm and Initial Evaluation in the Discussion). incidence of relapse at 5 years (56% vs. 29%; P = .05) and a decreased
5-year OS rate (48% vs. 68%) compared with wild-type KIT; in multivariate
High-Dose Cytarabine: Since 1994, multiple (3–4) cycles of HiDAC analysis, the presence of KIT mutations remained a significant predictor of
therapy have been the standard consolidation regimen for patients decreased OS in the setting of inv(16). In the setting of t(8;21), KIT
younger than 60 years with either good- or intermediate-risk cytogenetics. mutations were associated with a higher incidence of relapse at 5 years
This consolidation therapy is based on a CALGB trial comparing 100 (70% vs. 36%: P = .017), but no difference was observed in 5-year OS
mg/m2, 400 mg/m2, and 3 g/m2 doses of cytarabine.234 The 4-year DFS (42% vs. 48%).43 The CALGB trial also included 4 courses of monthly
rate for patients receiving consolidation with 3 g/m2 of HiDAC was 44%, maintenance chemotherapy with daunorubicin and subcutaneous
with a 5% treatment-related mortality rate and a 12% incidence of severe cytarabine after the consolidation phase; however, only 55% of patients
neurologic toxicity. Although the initial report did not break down remission who achieved CR received maintenance chemotherapy following HiDAC
duration by cytogenetic groups, subsequent analysis showed a 5-year consolidation.234 Subsequent clinical trials have eliminated this form of
RFS (continuous CR measured from time of randomization) rate of 50% maintenance therapy after post-remission therapy. However, the impact of
for CBF AML, 32% for patients with NK-AML, and 15% for patients in other KIT mutations in CBF AML is unclear. A meta-analysis of 11 studies
cytogenetic categories (overall P < .001). Among the patients who examining the effect of KIT mutations on CR, OS, and relapse rates of
received HiDAC consolidation, the 5-year RFS rate was 78% for CBF CBF AML determined that KIT mutations did not affect CR rates.241 In the
AML, 40% for NK-AML, and 21% for other cytogenetic categories.237 setting of t(8;21) AML, KIT mutations were associated with an increased
risk of relapse and shorter OS rates compared to inv(16) AML.241
In some studies, in patients with CBF AML who received postremission
therapy with HiDAC, the presence of KIT mutations resulted in poorer Some studies suggest that after induction, relative to KIT mutations, MRD
outcomes, particularly in t(8;21).37,43 In a multicenter study, patients with may be a more relevant prognostic factor for CBF-AML risk
CBF AML (n = 67) were enrolled in intensive chemotherapy protocols that stratification.21,242-244 In a prospective study, adult patients with CBF AML
involved HiDAC postremission therapy.37 At 24 months, a KIT mutation in (aged 18–60 years; n = 198) were randomized to receive a reinforced
the TKD at codon 816 (TKD816) in the setting of t(8;21) was associated induction course (treatment arm A) or standard induction course
with a significantly higher incidence of relapse (90% vs. 35.3%, P = .002) (treatment arm B), followed by 3 HiDAC consolidation courses.243
MS-37

Treatment arm A consisted of a first sequence with daunorubicin (60 AML (n = 860).23 Patients were randomized to treatment with an
mg/m2/day by a 30 minute IV infusion) on days 1 and 3 and cytarabine “intermediate-dose” cytarabine regimen (12 g/m2 cytarabine; cycle 1:
(500 mg/m2 continuous infusion) from days 1 to 3, followed by a second cytarabine, 200 mg/m2 daily for 7 days + idarubicin, 12 mg/m2 daily for 3
sequence at day 8 with daunorubicin (35 mg/m2/day by a 30 minute IV days; cycle 2: cytarabine, 1 g/m2 every 12 hours for 6 days + amsacrine,
infusion) on days 8 and 9, and cytarabine (1000 mg/m2 every 12 hours by 120 mg/m2 daily for 3 days) or a “high-dose” cytarabine regimen (26 g/m2
a 2-hour infusion) on days 8 and 10.243 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 achieved a CR after both treatment cycles were eligible to receive
sequence of chemotherapy in patients who achieved CR.243 In addition, consolidation with a third cycle of chemotherapy or autologous or
MRD levels were serially monitored for RUNX1-RUNX1T1 and CBFB- allogeneic HCT.23 A similar proportion of patients in each treatment arm
MYH11 by real-time quantitative polymerase chain reaction in BM samples received consolidation, specifically 26% to 27% of patients who received a
before the first, second, and third consolidation courses. In this study, both third chemotherapy cycle, 10% to 11% of patients who underwent
treatment arms demonstrated similar efficacy. After first consolidation, autologous HCT, and 27% to 29% of patients who underwent allogeneic
higher WBC, KIT gene mutations and/or FLT3 gene mutations, and a less HCT. No significant differences were observed between the
than 3-log MRD reduction were associated with a higher specific hazard of intermediate- and high-dose arms in rates of CR (80% vs. 82%), 5-year
relapse, but MRD was the only prognostic factor in multivariate analysis.243 EFS (34% vs. 35%), or 5-year OS (40% vs. 42%).23 These results are
At 36 months, the cumulative incidence of relapse and RFS were 22% comparable to those from the CALGB study with HiDAC.234 More than
versus 54% (P < .001) and 73% versus 44% (P < .001) in patients who 50% of patients in each arm had already achieved a CR when they
achieved 3-log MRD reduction versus other patients.243 received cycle 2. The 5-year cumulative rate of relapse risk was also
similar between treatment arms (39% vs. 27%, respectively).23 Outcomes
A prospective study analyzed the effect of a condensed HiDAC were poor for patients with monosomal karyotype at baseline (n = 83),
consolidation therapy schedule given on days 1, 2, and 3 versus the although the high-dose regimen was associated with significantly
commonly used schedule of days 1, 3, and 5 in adult patients (aged 18–60 improved rates of 5-year EFS (13% vs. 0%; P = .02) and OS (16% vs. 0%;
years) with AML (n = 176), and found that there was no cumulative P = .02) compared with patients in this subgroup receiving the
hematologic toxicity and no change in survival.245 intermediate-dose. The incidence of grade 3 or 4 toxicities after cycle 1
was higher in the high-dose arm than in the intermediate-dose arm (61%
The recent shortages of several chemotherapy agents have raised the
vs. 51%; P = .005), but the incidence of 30-day mortality was the same in
question of how best to use cytarabine. The HOVON/SAKK study
both arms (10%).23 This study suggests that 2 cycles of intermediate-dose
compared a double-induction concept using intermediate-dose cytarabine
cytarabine (1 g/m2 every 12 hours for 6 days; total dose 12 g/m2 per cycle)
or HiDAC as part of an induction/consolidation regimen in a phase III
for each consolidation cycle may be a feasible alternative to 3 cycles of
randomized study in patients (age 18–60 years) with newly diagnosed
HiDAC (3 g/m2 for 6 doses; total dose of 18 g/m2 per cycle). This study as
MS-38

well as the MRC AML 15 study216 suggest that doses of 3 g/m2 of P = .02) were significantly higher among the donor groups than the
cytarabine are not clearly more effective than lower doses of 1.5–3 g/m2; no-donor groups.247
in the MRC AML 15 trial, the cumulative incidence of relapse was
statistically lower for higher dose cytarabine but this did not translate into During the past decade, “normal” cytogenetics have been shown to
better RFS.216 encompass several molecular abnormalities with divergent risk
behaviors.38 The presence of an isolated NPM1 or biallelic CEBPA
Allogeneic Hematopoietic Transplantation: In the EORTC/GIMEMA mutation improves prognosis to one only slightly less than that of AML with
trial, a 43% 4-year DFS rate was reported in the donor group of patients CBF translocations, placing these mutations in the favorable-risk
with poor-risk cytogenetics (n = 64; 73% underwent HCT); this was molecular abnormalities category.38 In contrast, isolated FLT3-ITD
significantly higher than the 4-year DFS rate (18%; P = .008) among the mutation and NK-AML have an outlook similar to poor-risk cytogenetics.45
no-donor group (n = 94; 46% underwent HCT).246 The 4-year DFS rate In a report that evaluated the ELN risk classification in a large cohort of
among patients with intermediate-risk AML was 45% for the donor group patients, for those in the “Intermediate I” risk group (which includes
(n = 61; 75% underwent HCT) and 48.5% for the no-donor group (n = 104; NK-AML with FLT3 abnormalities and those lacking both FLT3 and NPM1
62.5% underwent HCT).246 The incidence of relapse was 35% and 47%, mutations), RFS was more favorable with allogeneic HCT (94 vs. 7.9
respectively, and the incidence of death in CR was 20% and 5%, months without allogeneic HCT).107
respectively. The 4-year OS rate among patients with intermediate-risk
Maintenance Therapy
disease was 53% for the donor group and 54% for the no-donor group.246
Hypomethylating Agents (HMAs): To improve treatment outcomes,
The SWOG/ECOG trial reported a 5-year survival rate (from time of CR) of some studies have evaluated the efficacy of maintenance therapy with
44% with allogeneic HCT (n = 18; 61% underwent HCT) and 13% with HMAs after induction or allogeneic HCT. CC-486 is a novel oral
autologous HCT (n = 20; 50% underwent HCT) among the subgroup of formulation of azacitidine that allows prolonged exposure in patients with
patients with unfavorable cytogenetics. Moreover, the 5-year survival rate hematologic malignancies.248,249 In a phase I/II trial evaluating the efficacy
was similar between those allocated to autologous HCT and those of oral azacitidine as maintenance therapy after allogeneic HCT in adult
intended for chemotherapy consolidation alone (13% and 15%, patients (≥18 years) with AML or MDS, patients received 1 of 4 dosing
respectively).31 The 5-year survival rates (from time of CR) for patients schedules per 28-day cycle for up to 12 cycles.250 Of 30 patients, 7
with intermediate-risk cytogenetics were 52% for the allogeneic HCT received oral azacitidine once daily for 7 days per cycle (n = 3 at 200 mg;
group (n = 47; 66% underwent HCT) and 36% for the autologous HCT n = 4 at 300 mg), and 23 received oral azacitidine for 14 days per cycle (n
group (n = 37; 59% underwent HCT).31 = 4 at 150 mg; n = 19 at 200 mg [expansion cohort]).250 At 19 months of
follow-up, median OS was not reached and estimated 1-year survival rates
In the UK MRC AML 10 trial, significant benefit with allogeneic HCT was were 86% and 81% in the 7-day and 14-day dosing cohorts,
observed for the subgroup of patients with intermediate-risk cytogenetics respectively.250
(but not for those with favorable or high-risk cytogenetics). In this
subgroup, the DFS (50% vs. 39%; P = .004) and OS rates (55% vs. 44%;
MS-39

In the international phase 3 trial, QUAZAR AML-001, investigators favorable-risk cytogenetics outside of a clinical trial.252 Data suggest that
evaluated the efficacy of oral azacitidine as post-remission therapy in adult the response to treatment is similar regardless of whether the
patients (≥55 years of age) who had newly diagnosed AML or secondary favorable-risk cytogenetics are de novo and treatment-related.252
AML, and had experienced CR or CRi after induction with intensive However, outcomes in the setting of t(8;21) with KIT mutations are less
therapies but were ineligible for allogeneic HCT (n = 472; median age, 68 favorable. These patients should be considered for either clinical trials
years; range, 55–86 years).251 Within 4 months of attaining CR or CRi, targeted toward the molecular abnormality or allogeneic transplantation. In
patients were randomized to receive placebo (n = 234) or 300 mg of oral addition, for patients with favorable-risk cytogenetics who are persistently
azacitidine (n = 238) once daily on days 1–14 of repeated 28-day MRD positive after induction and/or consolidation, alternative therapies
treatment cycles.251 A 21-day dosing schedule was allowed for patients including allogeneic transplantation, or a clinical trial should be
who experienced AML relapse with 5% of 15% blasts in blood or bone considered.
marrow while enrolled in the study. This treatment schedule could
Intermediate-Risk Cytogenetics and/or Molecular Abnormalities Including
continue indefinitely or until the presence of >15% blasts, unacceptable
MRD Positive
toxicity, or allogeneic HCT.251 At a median follow-up of 41.2 months,
The panel members agree that transplant-based options (either matched
median OS was 24.7 months and 14.8 months in the oral azacitidine and
sibling or alternate donor allogeneic HCT) or 3 to 4 cycles of HiDAC
placebo arms, respectively (HR, 0.69; 95% CI, 0.55–0.86; P = .0009).251 In
affords a lower risk of relapse and a somewhat higher DFS when given as
addition, the median RFS was significantly prolonged in the oral
consolidation for patients with intermediate-risk cytogenetics. While 2 to 3
azacitidine arm at 10.2 months compared to the placebo arm at 4.8
g/m2 HiDAC is preferred, a range of 1 to less than 2 g/m2 can be used to
months (HR, 0.65; 95% CI, 0.52–0.81; P = .0001).251 Based on these data,
accommodate patients who are less fit. The role of autologous HCT in the
in September 2020, the FDA approved oral azacitidine for continued
intermediate-risk group outside of clinical trials is diminishing due to
treatment of patients with AML who achieved first CR or CRi following
improvements in allogeneic transplants, which are expanding the pool of
intensive induction chemotherapy and are not able to complete intensive
potential donors outside the family setting. While autologous HCT is still
postremission therapy.
incorporated into the clinical trial design in Europe, the consensus of the
NCCN Recommendations NCCN AML Panel was that autologous HCT should not be a
recommended consolidation therapy outside the setting of a clinical trial.
CBF Cytogenetic Translocations and MRD Negative
Clinical trial participation is encouraged. Another option for this group
The NCCN AML Panel recommends the following options for consolidation
includes multiple courses (3–4) of HiDAC consolidation.253 If patients
or maintenance therapy in this subgroup: 1) participation in a clinical trial;
decline or are not fit/eligible for allogeneic HCT, maintenance therapy with
2) 3 to 4 cycles of HiDAC (category 1) alone or plus GO for patients with
oral azacitidine may be considered at 300 mg daily on days 1–14 of each
CD33-positive AML; or 3) intermediate-dose cytarabine (1000 mg/m2) plus
28-day cycle until disease progression or unacceptable toxicity (a category
daunorubicin and GO for patients with CD33-positive AML (category
2B option).251 The panel notes that this option is not intended to replace
2A).214 There are insufficient data to evaluate the use of allogeneic HCT in
consolidation chemotherapy.
first remission for patients with AML who are MRD negative and have
MS-40

HiDAC (1.5–3 g/m2) with midostaurin may be considered for patients with for 1 cycle is recommended for patients with therapy-related AML other
FLT3-mutation–positive AML.254 Alternative regimens incorporating than CBF/APL, antecedent MDS/CMML, or AML-MRC.229 If patients
intermediate doses of cytarabine may be reasonable in patients with decline or are not fit/eligible for allogeneic HCT, maintenance therapy with
intermediate-risk disease, including intermediate-dose cytarabine (1000 oral azacitidine may be considered at 300 mg daily on days 1–14 of each
mg/m2) plus daunorubicin and GO for patients with CD33-positive AML.214 28-day cycle until disease progression or unacceptable toxicity.251 As
However, the panel notes that patients who receive a transplant shortly previously stated, the panel notes that this option is not intended to
following GO administration may be at risk for developing sinusoidal replace consolidation chemotherapy.
obstruction syndrome.255 If a transplant is planned, prior studies have used
a 60- to 90-day interval between the last administration GO and stem cell Management of AML in Patients >60 Years
transplant.214 Comparable 5-year DFS rates were reported in patients Induction Therapy
younger than 60 years with NK-AML after either 4 cycles of The creation of separate guidelines for patients >60 years recognizes the
intermediate-dose cytarabine or HiDAC (41%) or autologous HCT poor outcomes in this group treated with standard cytarabine and an
(45%).253 At this time, there is no evidence that HiDAC (2–3 g/m2) is anthracycline. In patients >60 years, the proportion of those with favorable
superior to intermediate-dose cytarabine in patients with intermediate-risk CBF translocations decreases, as does the number with isolated NPM1
AML. mutations, whereas the number of patients with unfavorable karyotypes
and mutations increases. However, it should be noted that although some
Treatment-Related Disease Other than CBF and/or Unfavorable studies have demonstrated that NPM1 mutations in patients who are older
Cytogenetics and/or Molecular Abnormalities
is a positive prognostic factor,256,257 other emerging studies suggest it may
The panel strongly recommends clinical trials as standard therapy for
predict unfavorable outcomes.258,259 In the UK NCRI AML 16 trial, similar to
patients with poor prognostic features, which include FLT3-ITD
younger patients, in patients who are older, only the combined wild-type
abnormalities in the setting of otherwise NK-AML, high WBC
FLT3 and NPM1 mutant group had improved survival.256 This same study
(>50,000/mcL) at diagnosis, or adverse cytogenetics/molecular markers
also demonstrated that the FLT3 mutation did not affect remission rates,
as well as secondary and therapy-related AML. If remission is observed,
though there was an association with inferior survival. Secondary AML,
consolidation therapy is recommended, and strong consideration should
either related to prior MDS or prior chemotherapy, also increases along
be given to allogeneic HCT with matched sibling or alternative donor
with a higher rate of multidrug resistance protein expression. Although
(including umbilical cord blood products) as part of consolidation strategy.
studies in the Swedish Acute Leukemia Registry documented
HiDAC-based consolidation with or without midostaurin for FLT3-
improvement in outcomes for patients younger than 60 years over the past
mutation–positive AML (as outlined for patients with intermediate-risk
3 decades, no similar improvement was observed for the population >60
AML) may be required to maintain remission while searching for a
years.206,260 Treatment-related mortality frequently exceeds any expected
potential matched donor. If CPX-351 was given during induction, an
transient response in this group, particularly in patients >75 years or in
additional treatment of CPX-351 [cytarabine (65 mg/m2) and daunorubicin
those who have significant comorbid conditions or ECOG performance
(29 mg/m2)] as an intravenous infusion over 90 minutes on days 1 and 3
status greater than 2.
MS-41

For patients >60 years with AML, the panel recommends using patient WBC count, peripheral blood blast percentage, and serum creatinine.
performance status, in addition to adverse features (eg, de novo AML These factors, when taken together, result in a predictive accuracy based
without favorable cytogenetics or molecular markers; therapy-related AML; on the area under the curve (AUC) of 0.82 (a perfect correlation is an AUC
antecedent hematologic disorder) and comorbid conditions, to select of 1.0).264 This model is complex, and currently there is not a tool available
treatment options rather than rely on a patient’s chronologic age alone. to implement this model. A shortened form of the model was based on
Comprehensive geriatric assessments are complementary to assessment covariants that include age, PS, and platelet count. The simplified model
of comorbid conditions and are emerging as better predictive tools of provides an AUC of 0.71, which is less accurate than the complex model
functional status.261,262 A treatment decision-making algorithm for but may be more accurate than decision-making strategies based solely
previously untreated, medically fit, patients ≥60 years with AML was on age.264 Based on this model, a Treatment Related Mortality calculator
developed by the German AML cooperative group. Based on data from a can be accessed online at https://www.fhcrc-
large study in patients ≥60 years (n = 1406), patient and disease factors research.org/TRM/Default.aspx?GUID=1358501B-C922-4422-84F0-
significantly associated with CR and/or early death were identified and risk 0E6C67D8F266.
scores were developed based on multivariate regression analysis.263 The
predictive model was subsequently validated in an independent cohort of In a retrospective cohort study of adult patients with AML (n = 1100;
patients ≥60 years (n = 801) treated with 2 courses of induction therapy range, 20–89 years), a composite predictive model examined the impact
with cytarabine and daunorubicin. The algorithm, with or without of comorbidities on 1-year mortality following induction treatment.265 This
knowledge of cytogenetic or molecular risk factors, predicts the probability analysis incorporated patient-specific (ie, age, comorbidities) and AML-
of achieving a CR and the risk for an early death for elderly patients with specific (ie, cytogenetic and molecular risks) features, and resulted in a
untreated AML who are medically fit and therefore considered eligible for predictive estimate of 0.76 based on AUC.265 This model can be accessed
standard treatments.263 The factors included in the algorithm are the online at http://www.amlcompositemodel.org/.
following: body temperature (≤38°C and >38 °C), hemoglobin levels (≤10.3
Adults who are older with intact functional status (ie, ECOG score 0–2),
and >10.3 g/dL), platelet counts (≤28K, >28K–≤53K, >53K–≤104K, and
minimal comorbidity, and de novo AML without unfavorable cytogenetics
>104K counts/mcL), fibrinogen levels (≤150 and >150 mg/dL), age at
or molecular markers, without antecedent hematologic disorder, and
diagnosis (60–64, >64–67, >67–72, and >72 years), and type of leukemia
without therapy-related AML may benefit from intensive cytarabine-based
(de novo and secondary). The algorithm can be accessed online at
therapy regardless of chronologic age.
http://www.aml-score.org/.
Candidates for Intensive Remission Induction Therapy
A comprehensive predictive model for early death following induction in
Favorable- or Intermediate-Risk Cytogenetics
patients with newly diagnosed AML suggests that age may reflect other
A reasonable treatment regimen for patients with favorable- or
covariants, and the evaluation of these factors may provide a more
intermediate-risk cytogenetics includes standard-dose cytarabine (100–
accurate predictive model. The model includes performance score, age,
200 mg/m2 by continuous infusion per day for 7 days) along with 3 days of
platelet count, serum albumin, presence or absence of secondary AML,
anthracycline. Although patients >75 years with significant comorbidities
MS-42

generally do not benefit from conventional chemotherapy treatment, the with daunorubicin (16.6% vs. 9.8%; P = .018). In the group of patients
rare patient with favorable-risk or NK-AML and no significant comorbidities younger than age 65 years, standard idarubicin was still associated with a
might be the exception to this dogma. For patients with NK-AML, the significantly higher cure rate than daunorubicin despite the high dose (240
remission rates are 40% to 50% with cytarabine combined with idarubicin, mg/m2 total dose) of daunorubicin (27.4% vs. 15.9%; P = .049).267
daunorubicin, or mitoxantrone. The randomized study from the Acute
Leukemia French Association (ALFA)-9801 study (n = 468) showed that In the HOVON trial, which randomized patients ≥60 years to induction
idarubicin induction (the standard 12 mg/m2 daily for 3 days or intensified therapy with standard-dose cytarabine combined with either
with 12 mg/m2 daily for 4 days) compared with high-dose daunorubicin (up standard-dose daunorubicin (45 mg/m2 daily for 3 days; n = 411) or
to 80 mg/m2) yielded a significantly higher CR rate in patients aged 50 to dose-escalated daunorubicin (90 mg/m2 daily for 3 days; n = 402), the CR
70 years (80% vs. 70%, respectively; P = .03).209 The median OS for all rate was 54% and 64%, respectively (P = .002).268 No significant
patients was 17 months. The estimated 2-year EFS and OS rates were differences were observed in EFS, DFS, or OS outcomes between
23.5% and 38%, respectively, and the estimated 4-year EFS and OS rates treatment arms. Among the subgroup of patients aged 60 to 65 years
were 18% and 26.5%, respectively; however, no significant differences (n = 299), an advantage with dose-escalated compared with
were observed between treatment arms with regard to EFS, OS, and standard-dose daunorubicin was observed with regard to rates of CR
cumulative relapse rates.209 (73% vs. 51%), 2-year EFS (29% vs. 14%), and 2-year OS (38% vs. 23%).
These outcomes with dose-escalated daunorubicin seemed similar to
The ALFA-9803 study (n = 416) evaluated (during first randomization) those with idarubicin (12 mg/m2 daily for 3 days) from the ALFA-9801
induction with idarubicin (9 mg/m2 daily for 4 days) compared with study, in which the 4-year EFS and OS rates were 21% and 32%,
daunorubicin (45 mg/m2 daily for 4 days) in patients ≥65 years.266 In this respectively.209 In the HOVON trial, the benefit in OS outcomes for the
trial, the CR rate after induction was 57% and induction death occurred in dose-escalated daunorubicin group was observed only in patients aged 65
10% of patients. The median OS for all patients was 12 months; the years and younger or in those with CBF translocations.268
estimated 2-year OS rate was 27%. No significant differences in these
outcomes were seen between anthracycline treatment arms.266 Long-term For patients who exceed anthracycline dose or have cardiac issues but
outcomes based on a combined analysis of data from the two ALFA trials are still able to receive intensive therapy, alternative non–anthracycline-
above (9801 and 9803 studies; n = 727) showed superior results with containing regimens, including clofarabine, may be considered.269-273
standard idarubicin induction (36 mg/m2 total dose) compared with
CD33-Positive AML: There are conflicting data about the use of GO for
daunorubicin induction (240 mg/m2 total dose for patients <65 years; 180
patients who are older with AML. Three phase III randomized trials
mg/m2 total dose for patients ≥65 years) in patients ≥50 years with AML.267
evaluated the efficacy and safety of adding the anti-CD33 antibody-drug
At a median actuarial follow-up of 7.5 years, the median OS for all patients
conjugate GO to induction therapy with daunorubicin and cytarabine in
included in the analysis was 14.2 months. The estimated 5-year OS rate
patients who are older with previously untreated AML.274-276 In the phase III
was 15.3%, and the overall cure rate was 13.3%. Induction with standard
ALFA-0701 trial, patients aged 50 to 70 years with de novo AML (n = 280)
idarubicin was associated with a significantly higher cure rate compared
were randomized to receive induction with daunorubicin (60 mg/m2 daily
MS-43

for 3 days) and cytarabine (200 mg/m2 continuous infusion for 7 days), The third phase III trial combining GO with chemotherapy showed a
with or without (control arm) fractionated GO 3 mg/m2 given on days 1, 4, different result than the other two. In this study, patients between the ages
and 7.276 Patients with persistent marrow blasts at day 15 received of 61 and 75 years were given chemotherapy consisting of mitoxantrone,
additional daunorubicin and cytarabine. Patients who achieved a CR/CRi cytarabine, and etoposide (n = 472).274 Half of the patients were given 6
after induction received two consolidation courses with daunorubicin and mg/m2 GO prior to chemotherapy on days 1 and 15. In remission,
cytarabine, with or without GO (3 mg/m2 on day 1). The CR/CRi after treatment included two courses of consolidation with or without 3 mg/m2
induction was similar between the GO and control arms (81% vs. 75%). GO on day 0. The OS between the two groups was similar (GO, 45% vs.
The GO arm was associated with significantly higher estimated 2-year no GO, 49%), but the induction and 60-day mortality rates were higher in
EFS (41% vs. 17%; P = .0003), RFS (50% vs. 23%; P = .0003), and OS the patients given GO (17% vs. 12% and 22% vs. 18%, respectively). Only
(53% vs. 42%; P = .0368) rates compared with the control.276 The GO arm a small subgroup of patients younger than 70 years of age with secondary
was associated with a higher incidence of hematologic toxicity (16% vs. AML showed any benefit to treatment. Combined with the increased
3%; P < .0001); this was not associated with an increase in the risk of toxicity, the results of this study suggest that GO may not provide an
death from toxicity.276 advantage over standard chemotherapy for some patients who are older
with AML.274
In another multicenter, phase III, randomized trial from the UK and
Denmark (AML-16 trial), patients >50 years with previously untreated AML Conflicting studies have led to the publication of several systematic
or high-risk MDS (n = 1115) were randomized to receive reviews and meta-analyses. A larger systematic review, inclusive of any
daunorubicin-based induction (daunorubicin combined with cytarabine or RCTs that investigated the benefit of anti-CD33 antibody therapy,
clofarabine) with or without (control) GO (3 mg/m2 on day 1 of course 1 of regardless of whether treatment was in de novo or secondary disease,
induction).275 The median age was 67 years (range, 51–84 years) and concluded that the data from 11 trials showed increased induction deaths
98% of patients were ≥60 years; 31% were ≥70 years. The CR/CRi rate (P = .02) and reduced residual disease (P = .0009).277 Despite improved
after induction was similar between the GO and control arms (70% vs. RFS (HR, 0.90; 95% CI, 0.84–0.98; P = .01), no OS benefit was measured
68%). The GO arm was associated with significantly lower 3-year (HR, 0.96; 95% CI, 0.90–1.02; P = .2). Two other meta-analyses showed
cumulative incidence of relapse (68% vs. 76%; P = .007) and higher improved RFS, though induction death was elevated.278,279 Conversely, a
3-year RFS (21% vs. 16%; P = .04) and OS (25% vs. 20%; P = .05) rates fourth meta-analysis evaluating 5 trials with 3325 patients ≥15 years
compared with the control arm. The early mortality rates were not different showed a reduced risk of relapse (P = .0001) and improved 5-year OS
between treatment arms (30-day mortality rate, 9% vs. 8%); in addition, no (OR, 0.90; 95% CI, 0.82–0.98; P = .01) with the addition of GO to
major increase in adverse events was observed with GO.275 These two conventional induction therapy.215 It was noted that the greatest survival
trials suggest that the addition of GO to standard induction regimens benefit was seen in patients with favorable cytogenetics. Some benefit
reduced the risk of relapse and improved OS outcomes in patients who was seen in patients with intermediate cytogenetics, but no benefit was
are older with previously untreated AML characterized by favorable or reported with the addition of GO in patients with adverse cytogenetics.
intermediate-risk cytogenetics, not adverse risk.
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These studies underscore the need for further investigation that elucidates on FAB criteria), 113 study patients (32%) fulfilled criteria for AML using
the benefits of GO for the treatment of AML. the 2008 WHO classification, with marrow-blast percentages between
20% and 30%.281,282 In the subgroup of these patients with AML, a
FLT3-Positive AML: The results of the CALGB 10603/RATIFY Alliance significant survival benefit was found with 5-azacitidine compared with
trial221 have been described in an earlier section (See Management of conventional care regimens, with a median OS of 24.5 months versus 16
AML in Patients Younger Than 60 Years; Intermediate-Risk Cytogenetics) months (HR, 0.47; 95% CI, 0.28–0.79; P = .005).282 The 2-year OS rates
and these data may be extrapolated to suggest benefit in fit adults who are were 50% and 16%, respectively (P = .001). In a phase III study focused
older. In a phase II study in adult patients with previously untreated AML on adult patients ≥65 years, the efficacy and safety of azacitidine versus
(n = 284; range, 18–70 years; 86 patients included between the ages of conventional care regimens (standard induction chemotherapy, low-dose
61–70 years), the efficacy and safety of midostaurin added to intensive cytarabine, or supportive care) was evaluated in patients with newly
chemotherapy, followed by allogeneic HCT and single-agent midostaurin diagnosed AML with >30% blasts.283 Compared to conventional care
maintenance therapy for a year was evaluated.280 All patients were regimens, azacitidine was associated with an increase in median OS (6.5
confirmed to have FLT3-ITD–positive disease. The CR/CRi rate after months vs.10.4 months; HR, 0.85; 95% CI, 0.69–1.03; stratified log-rank
induction therapy was 76.4% (age <60 years, 75.8%; age >60 years, P = .1009).283 The 1-year survival rates with azacitidine and conventional
77.9%). Many patients proceeded to transplant (72.4%), and a subset care regimens were 46.5% and 34.2%, respectively.
initiated maintenance therapy (n = 97; 75 after allogeneic HCT and 22
after HiDAC consolidation). The median time receiving maintenance Another HMA, decitabine, has also been evaluated as remission induction
therapy was 9 months after allogeneic HCT and 10.5 months after HiDAC therapy for patients who are older with AML.284 In a phase II study in
consolidation. The 2-year EFS and OS rates were 39% and 34% in previously untreated patients ≥60 years (n = 55; median age, 74 years),
patients <60 years, and 53% and 46% in patients >60 years.280 the overall CR rate with this agent (20 mg/m2 for 5 days every 28 days)
was 24% (including 6 out of 25 patients [24%] with poor-risk cytogenetics),
Therapy-Related AML or Antecedent MDS/CMML or AML-MRC
and the median EFS and OS were 6 months and 8 months,
The studies evaluating the efficacy and safety of CPX-351 in patients aged respectively.284 An earlier phase I study evaluated different dose
60 to 75 years with newly diagnosed secondary AML have been described schedules of decitabine in patients with R/R leukemias (n = 50; AML
(Management of AML in Patients Younger Than 60 Years; Therapy- diagnosis, n = 37).285 In this study decitabine was given at 5, 10, 15, or 20
Related AML or Antecedent MDS/CMML or AML-MRC).229 mg/m2 for 5 days per week for 2 to 4 consecutive weeks (ie, 10, 15, or 20
Unfavorable-Risk Cytogenetics (exclusive of AML-MRC)
days). The decitabine dose of 15 mg/m2 for 10 days (n = 17) was
Hypomethylating Agents (HMAs): An international, randomized, phase associated with the highest response rates, with an overall response rate
III study by Fenaux et al281 compared the HMA 5-azacitidine with (ORR) of 65% and CR rate of 35%. Among the patients with R/R AML
conventional care (best supportive care, low-dose cytarabine, or intensive (n = 37), the ORR was 22% with a CR in 14% across all dose levels.285 A
chemotherapy) in patients with MDS (n = 358). Although this study was phase II study targeting patients ≥60 years with AML who were not
designed for evaluation of treatment in patients with high-risk MDS (based candidates for or declined intensive therapy, administered a decitabine
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dose of 20 mg/m2 for 10 days and demonstrated a CR rate of 47% (n = decitabine are approved by the FDA for the treatment of patients with
25) after a median of three cycles of therapy.286 In a study aimed at MDS.
identifying the relationship between molecular markers and clinical
responses to decitabine, adult patients with AML and MDS (n = 116; Venetoclax-Containing Regimens: Emerging studies have evaluated
median age, 74 years; range, 29–88 years) were treated with decitabine the combination of HMAs with venetoclax, an oral B-cell lymphoma 2
(20 mg/m2 for 10 days every 28 days).287 Response rates were higher (BCL2) inhibitor, as an induction therapy strategy for patients who are
among patients with unfavorable-risk cytogenetics compared to patients older with AML. In a phase Ib study, patients ≥65 years with previously
with favorable- or intermediate-risk (67% vs. 34%, respectively; P < .001), untreated AML (n = 57) were enrolled into 3 groups: group A (n = 23)
and in the setting of TP53 mutations compared to wild-type TP53 (100% received venetoclax and decitabine (20 mg/m2 daily for 5 days of each 28-
vs. 41%; P < .001).287 A recent phase II study comparing a 5-day versus day cycle); group B (n = 22) received venetoclax and azacitidine (75
10-day treatment schedule for decitabine in patients ≥60 years (n = 71) mg/m2 daily for 7 days of each 28-day cycle); and group C, a substudy of
with newly diagnosed AML determined that the efficacy and safety of both venetoclax and decitabine (n = 12), received an oral CYP3A inhibitor,
schedules were not significantly different.288 posaconazole, to determine its effect on the pharmacokinetics of
venetoclax.290 Daily target doses for venetoclax in different cohorts within
In an open-label, randomized, phase III study, decitabine (20 mg/m2 for 5 groups A and B were 400 mg, 800 mg, and 1200 mg. The most common
days every 28 days) was compared with physician’s choice (either treatment-related adverse event in groups A and B was febrile neutropenia
low-dose cytarabine [20 mg/m2/day SC for 10 consecutive days every 28 (30% and 32%, respectively), with an overall CR/CRi rate of 61% (95% CI,
days] or supportive care) in patients ≥65 years with newly diagnosed 47.6–74.0).290 In groups A and B, the CR/CRi rate was 60% (95% CI,
AML.289 Based on the protocol-specified final analysis of the primary 44.3–74.3).290
endpoint (OS), decitabine was associated with a statistically nonsignificant
trend for increased median OS compared with physician’s choice (7.7 In a follow-up to this study, the efficacy of either 400 mg or 800 mg of
months vs. 5 months; HR, 0.85; 95% CI, 0.69–1.04; P = .108). A venetoclax combined with either decitabine or azacitidine was evaluated in
subsequent post hoc analysis of OS with additional follow-up time showed patients ≥65 years with previously untreated AML and who were ineligible
the same median OS with a statistically significant advantage associated for intensive chemotherapy (n = 145; median age, 74 years).291 The
with decitabine (HR, 0.82; 95% CI, 0.68–0.99; P = .037). The CR venetoclax dose of 400 mg was found to be the recommended phase II
(including CRi) rate was significantly higher with decitabine (18% vs. 8%; dose. With a median time on study of 8.9 months (range, 0.2–31.7
P = .001).289 The most common treatment-related adverse events with months) and median duration of follow-up of 15.1 months (range, 9.8–31.7
decitabine versus cytarabine included thrombocytopenia (27% vs. 26%), months), 67% of patients achieved CR/CRi.291 The median duration of
neutropenia (24% vs. 15%), febrile neutropenia (21% vs. 15%), and CR/CRi and median OS was 11.3 months and 17.5 months,
anemia (21% vs. 20%). The 30-day mortality rates were similar between respectively.291 In a subgroup analysis, the CR/CRi rates of patients with
the decitabine and cytarabine groups (9% vs. 8%).289 Both azacitidine and intermediate- and poor-risk cytogenetics were 74% and 60%, with a
median duration of 12.9 months (95% CI, 11.0 months–NR) versus 6.7
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months (95% CI, 4.1–9.4 months), respectively.291 The CR/CRi rates in Not a Candidate for or Declines Intensive Remission Induction Therapy
with the setting of TP53, IDH1/2, and FLT3 mutations were 47%, 71%, AML Without Actionable Mutations
and 72%, respectively. In addition, patients with de novo AML and In adult patients who are older who cannot tolerate intensive treatment
secondary AML, respectively, had the same CR/CRi rate of 67%, with a strategies, low-intensity approaches have been investigated, including use
median duration of CR/CRi of 9.4 months (95% CI, 7.2–11.7 months) of HMAs alone or combined with venetoclax (see Candidates for Intensive
versus not reached (NR) (95% CI, 12.5 months–NR).291 In a phase 3 Remission Induction Therapy, Hypomethylating Agents, and Venetoclax-
follow-up to this study, at a median follow-up of 20.5 months, the median Containing regimens in the previous section).
OS was 14.7 months in the group treated with azacitidine and venetoclax
and 9.6 months in the group treated with azacitidine only (control) (HR, Low-Dose Cytarabine-Containing Regimens: Other approaches have
0.66; 95% CI, 0.52–0.85; P = .001).292 The CR/CRi rate was also higher in evaluated low-dose cytarabine. The UK NCRI AML 14 trial randomized
the azacitidine and venetoclax group versus the control group (66.4% vs. 217 patients primarily aged >60 years (de novo AML, n = 129; secondary
28.3%, respectively; P = .001).292 AML, n = 58; high-risk MDS, n = 30) unfit for chemotherapy to receive
either low-dose cytarabine subcutaneously (20 mg twice daily for 10
Another phase Ib/II study evaluated the efficacy of venetoclax combined consecutive days, every 4–6 weeks) or hydroxyurea (given to maintain
with low-dose cytarabine (20 mg/m2 daily for 10 days) in patients ≥60 target WBC counts <10,000/mcL).294 Patients were also randomized to
years with previously untreated AML ineligible for intensive chemotherapy receive ATRA or no ATRA. Low-dose cytarabine resulted in a CR rate of
(n = 82; median age, 74 years).293 All patients received at least one dose 18% (vs. 1% with hydroxyurea) and a survival benefit compared with
of venetoclax at 600 mg. The CR/CRi rate was 54% (95% CI, 42%–65%) hydroxyurea in patients with favorable or NK-AML. No advantage was
with a median duration of remission of 8.1 months (95% CI, 5.3–14.9 observed with the addition of ATRA. The median DFS in patients who
months), and the median OS for all patients was 10.1 months (95% CI, achieved a CR with low-dose cytarabine was 8 months.294 Even with this
5.7–14.2 months).293 Patients with de novo AML, intermediate-risk “low-intensity” treatment approach, induction death occurred in 26% of
cytogenetic features, and no prior HMA exposure demonstrated CR/CRi patients, and overall prognosis remained poor for patients who are older
rates of 71%, 63%, and 62%, respectively.293 The average CR/CRi rates in who cannot tolerate intensive chemotherapy regimens. A phase II study
the setting of NPM1 or IDH1/2 mutations were higher than in the setting of evaluated a regimen with low-dose cytarabine (20 mg twice daily for 10
TP53 or FLT3 mutations (89% and 72% vs. 30% and 44%, days) combined with clofarabine (20 mg/m2 daily for 5 days) in patients
respectively).293 Based on these studies, venetoclax in combination with ≥60 years with previously untreated AML (n = 60; median age, 70 years;
HMAs, decitabine or azacitidine, or low-dose cytarabine are approved by range, 60–81 years).295 Patients who experienced response received
the FDA for the treatment of newly diagnosed AML in adults ≥75 years, or consolidation (up to 17 courses) with clofarabine plus low-dose cytarabine
in patients who have comorbidities that preclude use of intensive induction alternated with decitabine. Among evaluable patients (n = 59), the CR rate
chemotherapy. was 58% and median RFS was 14 months. The median OS for all patients
was 12.7 months. The induction mortality rate was 7% at 8 weeks.295
Although this regimen appeared to be active in patients ≥60 years with
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AML, the authors noted that the benefits of prolonged consolidation 4.2–6.8 months) and 3.6 months (95% CI, 2.6–4.2 months) in the best
remain unknown. supportive care group.297
In a phase II trial, low-dose cytarabine was combined with glasdegib, a IDH Mutation-Positive AML: Initially approved by the FDA for use in the
selective inhibitor of the Smoothened protein in the Hedgehog signaling R/R AML setting, IDH-targeted inhibitors, enasidenib and ivosidenib, have
pathway, and evaluated in adult patients (age ≥55 years) with previously demonstrated utility in the frontline setting.298,299 In a phase I/II study, the
untreated AML or high-risk MDS ineligible for intensive chemotherapy (n = clinical activity and safety of enasidenib, an IDH2 mutant inhibitor, was
132).296 Criteria for unsuitability for intensive chemotherapy included being evaluated in adult patients with IDH2-mutated advanced AML including
≥75 years of age, having serum creatinine >1.3 mg/dL, and having severe R/R disease.300 Approximately 19% of patients (n = 34 of 176) with R/R
cardiac disease or ECOG score = 2. Patients were randomized 2:1 to AML achieved complete remission, with an OS of 19.7 months with a
receive low-dose cytarabine alone (20 mg twice daily for 10 days every 28 median OS of 9.3 months.300 In patients ≥60 years with newly diagnosed
days) or combined with oral glasdegib (100 mg daily). The addition of AML, the efficacy of enasidenib was evaluated in a phase Ib/II sub-study
glasdegib to low-dose cytarabine also improved OS compared to low-dose within the Beat AML trial.299 Patients were treated with enasidenib (100
cytarabine alone (8.8 months vs. 4.9 months, respectively), and the CR mg/day) in continuous 28-day cycles. Azacitidine (75 mg/m2 days 1–7)
rates were higher in the low-dose cytarabine and glasdegib arm (17%, n = was added to enasidenib for some patients who did not achieve CR/CRi
15/88) compared to low-dose cytarabine alone (2.3%; n = 1/44).296 In the by cycle 5. Of 23 evaluable patients receiving enasidenib monotherapy,
glasdegib plus low-dose cytarabine arm, the benefit in CR was primarily CR/CRi was achieved in 43% of patients (7 CR/2 CRi).299
seen in patients with favorable-/intermediate-risk cytogenetics (n = 10/52)
when compared to patients with poor risk cytogenetics (n = 5/36).296 Ivosidenib, an IDH1-mutation inhibitor, demonstrated durable remissions
Glasdegib in combination with low-dose cytarabine is currently approved in IDH1 R/R AML, with 30.2% of patients (n = 54 of 179) with R/R AML
by the FDA for the treatment of newly diagnosed AML in adults ≥75 years, achieving CR/CRh.301 As an extension of this study, the safety and
or in patients who have comorbidities that preclude use of intensive efficacy of ivosidenib in patients with untreated AML was evaluated (n =
induction chemotherapy. 34; median age, 76.5 years).298 In phase I dose-escalation and expansion,
patients received ivosidenib once daily or twice daily in 28-day cycles, and
CD33-Positive AML: Single-agent GO has also been evaluated as an a dose of 500 mg per day was selected as the dose for expansion groups.
option. A randomized phase III study evaluated the efficacy of single-agent The CR/CRh rate was 41.2% (95% CI, 24.6%–59.3%), and the ORR was
GO (6 mg/m2 on day 1 and 3 mg/m2 on day 8) versus best supportive care 58.8% (20/34; 95% CI, 40.7%–75.4%).298 Based on these data, ivosidenib
as first-line therapy in patients ≥61 years with AML who were not eligible was approved by the FDA in May 2019 as a first-line treatment option for
for intensive chemotherapy (n = 237).297 Compared to best supportive AML with an IDH1 mutation in patients who are ≥75 years or who have
care, GO alone improved the 1-year OS rate (9.7% vs. 24.3%, comorbidities that preclude the use of intensive induction chemotherapy.
respectively). In the GO group, the median OS was 4.9 months (95% CI, Treatment with both enasidenib and ivosidenib may induce differentiation
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syndrome and hyperleukocytosis, which may be managed with anthracycline–containing regimens may be considered. Gemtuzumab
corticosteroids and hydroxyurea.302-304 ozogamicin (GO) may be added to standard-dose cytarabine combined
with daunorubicin for patients with CD33-positive AML and who have
Alternatively, emerging data suggest that patients with de novo AML favorable- or intermediate-risk cytogenetics. Midostaurin is added to
characterized by IDH1/2-mutant AML may benefit from venetoclax/HMA- standard-dose cytarabine combined with daunorubicin for patients with
based therapy with reported remission rates of greater than 70%, albeit in FLT3-mutated AML. For patients with therapy-related AML, antecedent
a relatively small number of patients.291 hematologic disorder, or AML-MRC, treatment with CPX-351 [cytarabine
(100 mg/m2) and daunorubicin (44 mg/m2)] as intravenous infusion over 90
FLT3-Positive AML: In adult patients with newly diagnosed FLT3-
minutes on days 1, 3, and 5 of 1 cycle is recommended (a category 1
mutation-positive AML (n = 15; median age, 76 years; range, 65–86
recommendation).
years), an ongoing trial is evaluating the safety and tolerability of the
combination of azacitidine and gilteritinib,305 a FLT3 inhibitor that has For patients with unfavorable-risk cytogenetics exclusive of AML-MRC,
demonstrated antileukemic activity in FLT3-positive R/R AML.306,307 Of 15 recommended options include: venetoclax combined with azacitidine,
evaluable patients, a CR/CRi rate of 67% was observed.305 Another study decitabine or low-dose cytarabine, or lower-intensity therapy with HMAs
evaluated the efficacy of azacitidine and sorafenib, a FLT3 inhibitor, as a (5-azacitidine [a category 2B recommendation] or decitabine).
front-line strategy in adult patients ≥60 years with FLT3-ITD mutation-
positive AML who cannot tolerate intensive induction (n = 27; median age, Not a Candidate for or Declines Intensive Remission Induction
74 years; range, 61–86 years).308 The ORR was 78%, with CR, CRi/CR Therapy: Treatment options include a clinical trial, or lower-intensity
with incomplete platelet recovery (CRp), and PR rates of 26%, 44%, and therapy based on the presence or absence of actionable mutations. The
7%, respectively.308 In addition, the median duration of CR/CRi/CRp was preferred regimens include venetoclax combined with HMAs (azacitidine
14.5 months, with a median OS of 8.3 months for the whole group.308 [category 1] or decitabine). Other recommended options include
venetoclax combined with low-dose cytarabine [LDAC] or glasdegib
combined with LDAC. Patients not considered candidates for combination
Similar to recommendations for adults younger than 60 years, the NCCN or targeted therapy may receive monotherapy with HMA (azacitidine or
AML Panel encourages enrollment in a clinical trial for treatment induction decitabine for either a 5- or 10-day course), GO alone (a category 2B
of patients aged ≥60 years with AML. For patients not enrolled in a clinical recommendation), or LDAC alone (a category 3 recommendation). Best
trial, cytogenetics, overall functional status, and the presence or absence supportive care with hydroxyurea and transfusion support should also be
of actionable mutations should guide treatment strategies. considered and have been used as the comparator arm in several clinical
trials in unfit patients who are older.
Candidates for Intensive Remission Induction Therapy: Standard
infusional cytarabine and anthracycline is recommended. For patients who For patients with IDH1- or IDH2-mutant AML, preferred treatment options
exceed anthracycline dose guidelines or have cardiac issues but who are include: ivosidenib or enasidenib for IDH1- or IDH2-mutant AML
still fit enough to receive aggressive therapy, alternative non- respectively; or venetoclax-based therapy combined with HMAs
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(azacitidine [category 1] or decitabine). Other recommended options best supportive care are also treatment options. Allogeneic transplant is a
include venetoclax combined with LDAC or low-intensity therapy with reasonable option, preferably in the context of a clinical trial, in patients
HMAs (azacitidine or decitabine). For patients with FLT3-mutant AML, the who experience re-induction failure with certain regimens including
preferred treatment option is also venetoclax-based therapy combined intermediate-dose or HiDAC-containing regimens, and who have identified
with HMAs (azacitidine [category 1] or decitabine). Other treatment options donors available to start conditioning within 4 to 6 weeks from start of
for this category include HMAs in combination with sorafenib and induction therapy. Patients without an identified donor would most likely
venetoclax combined with LDAC. need some additional therapy as a bridge to transplant. Additionally, it is
acceptable to await recovery in these patients as many will enter
Postinduction Therapy
remission without further treatment. Regardless of treatment, all patients
After Standard-Dose Cytarabine Induction receiving post-induction therapy after standard-dose cytarabine should
Similar to younger patients, patients ≥60 years who receive standard have a repeat bone marrow evaluation to document remission status.
cytarabine/anthracycline induction with or without midostaurin or GO, or a Because many patients who are older have some evidence of antecedent
dual-drug encapsulation of cytarabine and daunorubicin receive a bone myelodysplasia, full normalization of peripheral blood counts often does
marrow evaluation 14 to 21 days after start of therapy and are categorized not occur even if therapy clears the marrow blasts. Thus, many phase I/II
according to the presence of blasts or hypoplasia. Patients with hypoplasia trials for AML in patients who are older include categories such as CRi for
should await recovery of counts before continuing to post-remission patients who have fewer than 5% marrow blasts but mild residual
therapy. Patients with residual disease without hypoplasia may receive cytopenias.
additional standard-dose cytarabine with an anthracycline or mitoxantrone,
or CPX-351 [cytarabine (100 mg/m2) and daunorubicin (44 mg/m2)], if Many treatment strategies are designed to work more gradually using
given during induction for patients with therapy-related AML, antecedent agents that may allow expression of tumor suppressor genes (eg, a
hematologic disorder, or AML-MRC. Alternatively, patients with FLT3- methyltransferase inhibitor such as decitabine or 5-azacitidine) or increase
mutation–positive AML may receive additional standard-dose cytarabine apoptosis (eg, histone deacetylase inhibitors). Thus, success in these
with daunorubicin and midostaurin. Additional treatment strategies for trials may be assessed using indirect measures, such as hematologic
these patients may include consideration of a clinical trial or use of improvement or decreased transfusion requirements and survival, without
regimens used for R/R disease (see Management of Relapsed/Refractory actually achieving CR. Frequently, in these trials, marrow examination is
AML). not performed until completion of 1 to 2 cycles of therapy. However, the
Guidelines do not currently recommend post-induction HMAs. For patients
If daunorubicin (90 mg/m2) was used in induction, the recommended dose with residual disease after 1 cycle of induction chemotherapy who will not
for reinduction prior to count recovery is 45 mg/m2 for no more than 2 tolerate another intensive salvage, venetoclax-based regimens may be
doses. Similarly, if idarubicin (12 mg/m2) was used for induction, the early considered.309,310
reinduction dose should be limited to 10 mg/m2 for 1 or 2 doses.
Intermediate-dose cytarabine-containing regimens, allogeneic HCT, or
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Postremission or Consolidation Therapy outcomes with RIC allogeneic HCT and autologous HCT in patients ≥50
Patients who achieve a CR (including CRi) with standard induction years based on large registry data, RIC allogeneic HCT was associated
chemotherapy may receive further consolidation with these same agents. with lower risk for relapse and superior DFS and OS relative to autologous
HCT.312 The authors also noted that a survival benefit was not observed in
Intermediate-Dose Cytarabine: The prospective CALGB trial234 the subgroup of patients undergoing RIC allogeneic HCT in first CR
established the efficacy of HiDAC consolidation in patients with AML aged because of an increased incidence of non-relapse mortality.
60 years or younger.234 In this study, a subgroup of patients with AML ≥60
years who received standard-dose cytarabine-daunorubicin induction Estey et al314 prospectively evaluated a protocol in which patients ≥50
therapy and more than one course of HiDAC consolidation (3 g/m2 every years with unfavorable cytogenetics would be evaluated for a RIC
12 hours on days 1, 3, and 5, per course) experienced severe allogeneic HCT.314 Of the 259 initial patients, 99 experienced a CR and
neurotoxicity and a 4-year DFS rate of less than 16%.234 Although the were therefore eligible for HCT evaluation. Of these patients, only 14
CALGB trial did not show an overall benefit for higher doses of cytarabine ultimately underwent transplantation because of illness, lack of donor,
consolidation in patients ≥60 years,234 a subset of patients with a good declining transplantation, or unspecified reasons. The authors compared
performance status, normal renal function, and a normal or low-risk the results of RIC allogeneic HCT with those from matched subjects
karyotype might be considered for a single cycle of cytarabine (1.0–1.5 receiving conventional-dose chemotherapy. This analysis suggested that
g/m2 daily for 4–6 doses) without an anthracycline. In a study by Sperr et RIC allogeneic HCT was associated with improved RFS, and the authors
al, the CALGB consolidation was modified and given as intermediate-dose concluded that this approach remains of interest.314 In an analysis of
cytarabine at 1 g/m2 every 12 hours on days 1, 3, and 5, per course for 4 outcomes between two different strategies for matched-sibling allogeneic
cycles in a group of patients >60 years with AML.311 In this study, the HCT, outcomes in younger patients (aged ≤50 years; n = 35) receiving
treatment was well-tolerated without neurotoxicity and 25 of 47 patients conventional myeloablative allogeneic HCT were compared with those in
received all 4 consolidation cycles. The median OS, DFS, and continuous patients >50 years (n = 39) receiving RIC allogeneic HCT.315 This study
CR were 10.6, 15.5, and 15.9 months, respectively.311 The probability of showed similar rates of 4-year non-relapse mortality (19% and 20%,
OS, DFS, and continuous CR at 5 years were 18%, 22%, and 30%, respectively), and no difference was seen in relapse and OS rates.315
respectively.311
A retrospective study based on data in patients aged 50–70 years with
Allogeneic Hematopoietic Transplantation: The role of myeloablative AML compared outcomes in patients who underwent allogeneic HCT
allogeneic HCT is limited in patients who are older because of significant (either myeloablative conditioning or RIC; n = 152) with those who did not
comorbidities; however, ongoing interest has been shown in RIC receive HCT in first CR (chemotherapy only; n = 884).316 Allogeneic HCT
allogeneic HCT as consolidation therapy.312,313 Case series and analysis of in first CR was associated with a significantly lower 3-year cumulative
registry data have reported encouraging results, with 40% to 60% 2-year relapse rate (22% vs. 62%; P < .001) and a higher 3-year RFS rate (56%
OS rates and 20% non-relapse mortality for patients who underwent vs. 29%; P < .001) compared with the non-HCT group. Although HCT was
transplant in remission.312,313 In a retrospective analysis comparing associated with a significantly higher rate of non-relapse mortality (21%
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vs. 3%; P < .001), the 3-year OS rate showed a survival benefit with HCT explored earlier in the disease management. The guidelines note that RIC
(62% vs. 51%; P = .012).316 Among the patients who underwent allogeneic allogeneic HCT is considered an additional option for patients ≥60 years
HCT, myeloablative conditioning was used in 37% of patients, whereas as postremission therapy in those experiencing a CR to induction therapy.
RIC was used in 61%. Survival outcomes between these groups were
Maintenance Therapy
similar, with 3-year OS rates of 63% and 61%, respectively.316
Hypomethylating Agents: Preventing relapse in patients who are older
Another study evaluating treatment in patients aged 60–70 years compared with AML who have experienced first CR after intensive induction can be
outcomes between RIC allogeneic HCT reported to the Center for challenging. In a phase 3 randomized trial, HOVON97, investigators
International Blood and Marrow Transplant Research (n = 94) and standard evaluated the efficacy of maintenance therapy with azacitidine in patients
chemotherapy induction and postremission therapy from the CALGB ≥60 years with AML or MDS with refractory anemia with excess of blasts
studies (n = 96).317 Allogeneic HCT in first CR was associated with (n = 116) who achieved CR or CRi after intensive chemotherapy.320
significantly lower 3-year relapse (32% vs. 81%; P < .001) and higher 3-year Patients were randomized to either observation (n = 60) or treated with
leukemia-free survival rates (32% vs. 15%; P < .001) compared with the azacitidine (n = 56) at 50 mg/m2 subcutaneously on days 1–5 every 4
chemotherapy-only group. As would be expected, allogeneic HCT was weeks until relapse for a maximum of 12 cycles.320 Thirty-five patients
associated with a significantly higher rate of non-relapse mortality (36% vs. received at least 12 cycles of azacitidine and the estimated 12-month DFS
4%; P < .001) at 3 years; the 3-year OS rate was not significantly different for the azacitidine and observation groups were 64% and 42%,
between the groups (37% vs. 25%; P = .08), although there was a trend respectively (log rank, P = .04).320
favoring allogeneic HCT.317 A prospective multicenter phase II study
examined the efficacy of RIC allogeneic HCT in patients aged 60–74 years The studies evaluating the efficacy and safety of maintenance therapy with
with AML in first CR (n = 114).318 After allogeneic HCT, DFS and OS at 2 oral azacitidine or CC-486 in patients with newly diagnosed AML who
years were 42% (95% CI, 33%–52%) and 48% (95% CI, 39%–58%), have experienced first CR or CRi but are unable to continue with
respectively, for the entire group.318 A time-dependent analysis of four conventional consolidation have been described (See Management of
successive prospective HOVON-SAKK AML trials examined data from AML in Patients Younger Than 60 Years; sub-section: Maintenance
patients ≥60 years who obtained a first CR after induction chemotherapy (n Therapy).248,251
= 640).319 For patients who received allogeneic HCT as post-remission NCCN Recommendations
therapy (n = 97), a 5-year OS rate was 35% (95% CI, 25%–44%).319 Previous Intensive Therapy: For patients who had previously received
intensive therapy, a marrow to document remission status upon
Collectively, these studies suggest that RIC allogeneic HCT is a feasible
hematologic recovery should be performed after 4 to 6 weeks. If a CR is
treatment option for patients ≥60 years, particularly those in first CR with
observed, a clinical trial is recommended. Other postremission or
minimal comorbidities and who have an available donor. For this strategy
maintenance therapy recommendations include: allogeneic HCT;
to be better used, potential transplant options should be considered during
standard-dose cytarabine with or without an anthracycline;
induction therapy, and alternative donor options/searches should be
intermediate-dose cytarabine alone (for patients who are more fit) or plus
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daunorubicin and GO for patients with CD33-positive AML; intermediate- Principles of Venetoclax Use with HMAs or LDAC-Based Treatment
dose cytarabine and midostaurin for patients with FLT3-mutation–positive With growing use of venetoclax-based therapies (ie, venetoclax with
AML; or CPX-351 [cytarabine (65 mg/m2) and daunorubicin (29 mg/m2)], HMAs or low-dose cytarabine), and the fact that these therapies may be
which is the preferred strategy if given during induction for patients with given for an indefinite duration as long as patients respond or derive
therapy-related AML, antecedent hematologic disorder, or AML-MRC. If hematologic benefit from the therapies, the AML Panel reviewed the
the patient received more intensive regimens in induction and achieved a literature and emerging guidelines that can inform a consensus on ways
remission but had treatment-related toxicity that prevents the patient from to optimize use of these therapies.321
receiving conventional consolidation or is not eligible for allogeneic HCT,
maintenance therapy with HMAs may be appropriate.251,320 In some cases, For patients with newly-diagnosed disease, the panel notes that
observation is recommended, as some patients have been able to venetoclax with HMA or LDAC should be given concomitantly. The
maintain a CR without further treatment. addition of a third targeted agent to these combinations is not
recommended outside the context of a clinical trial. Prior to administering
For patients who experience induction failure, a clinical trial, low-intensity therapy, it is important to achieve a WBC count of <25,000/mcL with
therapy (azacitidine, decitabine), allogeneic HCT (preferably in the context hydroxyurea, or leukapheresis if needed.322 It is worth noting that the
of a clinical trial), therapies for R/R disease (see Management of data supporting a beneficial role for leukapheresis in this context is
Relapsed/Refractory AML), or best supportive care are recommended limited.323 In addition, venetoclax is a substrate of CYP3A4, so dose
treatment options. adjustments of venetoclax are recommended when concurrently using
venetoclax with strong CYP3A4 inhibitors, most commonly the azole
Previous Lower-Intensity Therapy: For patients who previously
class of antifungal agents.324 Reductions in duration of venetoclax and
received lower-intensity therapy, a marrow to document remission status
HMAs or LDAC may be considered in the setting of cytopenias. If during
upon hematologic recovery should be performed, with the timing
treatment, there is a need to discontinue any of the agents or a
dependent on the therapy used. If a response is observed, allogeneic HCT
consideration to continue maintenance on single-agent venetoclax, the
may be considered for select patients. Alternatively, low-dose therapies
panel recommends referral to a tertiary cancer or academic medical
used in induction with demonstrated efficacy may be continued until
center.
progression, including venetoclax plus HMAs; venetoclax plus low-dose
cytarabine; enasidenib (for IDH2-mutated AML); ivosidenib (for IDH1- To minimize the development of tumor lysis syndrome—which is
mutated AML); glasdegib plus low-dose cytarabine; or HMAs alone or uncommon in this setting322—during the first cycle of treatment, inpatient
combined with sorafenib (for FLT3-mutant AML); or GO alone (a category treatment is strongly recommended especially through dose-escalation.
2B recommendation). If no response or progression is seen, a clinical trial, The intrapatient dose escalation for venetoclax with HMA is 100 mg, 200
therapies for R/R AML (see Management of Relapsed/Refractory AML), or mg, and 400 mg given daily on days 1 to 3; and the intrapatient dose
best supportive care are recommended treatment options. escalation for venetoclax with LDAC is 100 mg, 200 mg, 400 mg, and
600 mg given daily on days 1 to 4.322 To minimize and avert further risk
MS-53

of tumor lysis syndrome, the panel recommends aggressive monitoring and assuming no unexpected changes in blood counts occur, the BM
of blood chemistries; monitoring and managing electrolyte imbalances; biopsy can be repeated at 3–6-month intervals, or as needed based on
and treatment with allopurinol or other uric acid lowering agent.322 clinical suspicion for relapse, depending on the goals of the patient. If
count recovery worsens over time, relapsed disease should be ruled out
Venetoclax and HMAs have been shown to induce prolonged cytopenias with a repeat BM biopsy.322 If morphological remission is ongoing with
even after achieving remission, and neutropenia is a dominant treatment- worsening blood counts, consider decreasing the duration, and/or dose,
related toxicity associated with this combination of agents.321 During the of venetoclax and/or HMA or LDAC. However, if there is no
first cycle, the panel recommends continuing treatment regardless of morphological remission after the second cycle, consider enrollment in a
cytopenias until a response assessment is made,324 with aggressive clinical trial if available. If no clinical trial is available, and patient has
transfusion support and supportive care as needed. The panel also experienced some response with manageable toxicity, therapy may be
recommends withholding growth factors until after the first cycle continued as long as it is tolerated.
response assessment.322 However, granulocyte colony-stimulating
factors should be considered for patients who are neutropenic who have If venetoclax and HMA or LDAC are being given to patients with
achieved morphologic remission but whose counts have not recovered. A relapsed/refractory (R/R) AML, the panel recommends antifungal
bone marrow biopsy is necessary for response assessment on days 21– prophylaxis.321 Other recommendations for TLS, intrapatient dose
28 of the first cycle,322 perhaps on the early end of this range for patients escalation, BM biopsies, and cytopenia mitigation plans are similar to
who receive the combination of venetoclax and decitabine. considerations that have been described.
If blasts are <5% during the first cycle, in the setting of cytopenias all Role of MRD Monitoring
treatment should be held and the following measures should be MRD in AML refers to the presence of leukemic cells below the threshold
considered: growth factor support, if indicated; and a treatment-free of detection by conventional morphologic methods. Patients who have
interval for up to 14 days. When counts have recovered to a clinically achieved a CR by morphologic assessment alone can still harbor a large
significant threshold (ideally to CR or CRi), the next cycle of treatment number of leukemic cells in the bone marrow.325 Due to the rapidly
can begin.322 If counts have not recovered to a clinically significant evolving nature of this field and the undeniable need for monitoring, MRD
threshold, consider repeating the BM biopsy. If morphological remission is still under investigation, with NCCN recommendations as discussed
is ongoing, therapy can continue to be held or a second cycle can below.
proceed with adjustments to dose or schedule of venetoclax and HMA or
LDAC.322 While morphologic assessment is the first step in a cure for AML, there
remains a level of MRD that currently lacks any standardized method of
During the second and subsequent cycles of treatment, if remission was monitoring. Two of the most commonly used techniques are real-time
observed after the first cycle, sequential cycles should continue with up quantitative PCR (RQ-PCR) and flow cytometry. RQ-PCR amplifies
to 14-day interruptions between cycles for count recover and/or growth leukemia-associated genetic abnormalities, while flow cytometric profiling
factor support.322 If there is no evidence of disease after the first cycle
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detects leukemia-associated immunophenotypes (LAIPs).326-328 Both duplications.340 Finally, the main target of gene overexpression in AML is
methods have a higher sensitivity than conventional morphology. RQ-PCR the Wilms’ tumor (WT1) gene. Taken together, these putative targets for
has a detection range of 1 in 1000 to 1 in 100,000, while flow cytometry MRD monitoring encompass the majority of AML cases.
has sensitivity between 10-4 to 10-5. The challenge of incorporating these
techniques into routine practice is a lack of standardization and A study of 29 patients with either RUNX1-RUNX1T1 or CBFB-MYH11
established cutoff values, though ongoing research is focused on AML during postinduction and post-consolidation chemotherapy did not
addressing these limitations. Most of what is known about MRD monitoring observe a correlation with survival.341 However, the authors did correlate a
has been done in the APL population;329,330 however, these techniques are greater than or equal to 1 log rise in RQ-PCR transcript relative to the
now expanding to include other AML subtypes.331 Emerging technologies remission bone marrow sample as indicative of inferior leukemia-free
include digital PCR and NGS.325 NGS-based assays can be used to detect survival and imminent morphologic relapse.341 Another study evaluated
mutated genes through targeted sequencing gene panels,332,333 though bone marrow from 53 patients during consolidation therapy and was the
higher sensitivities are observed in PCR- and flow cytometry-based first to establish clinically relevant MRD cut-off values for the
methods compared to conventional NGS.325 The data from these methods CBFB-MYH11 transcript to stratify patients with increased risk of
have been correlated with AML treatment outcome and the preliminary relapse.242 PCR negativity in at least one bone marrow sample during
results are promising. Refinement of these methods that take into account consolidation therapy was predictive of a 2-year RFS of 79% as compared
variables including the intrinsic nature of the transcript as well as factors of to the 54% seen in the setting of PCR-positivity. Similarly, Yin et al244
the patient population, including age, disease severity, and treatment, will found that a less than a 3-log reduction in RUNX1-RUNX1T1 transcript in
make MRD monitoring in patients with AML a more reliable tool. bone marrow or a greater than 10 CBFB-MYH11 copy number in
peripheral blood after 1 course of induction chemotherapy was highly
RQ-PCR predictive of relapse.244 A study in 15 patients with childhood AML showed
There are three classifications of RQ-PCR targets: leukemic fusion genes, that increased RUNX1-RUNX1T1 transcript levels were predictive of
mutations, and gene overexpression. The most investigated leukemic relapse.342 MLL fusion transcripts for MRD monitoring have also been
fusion genes are RUNX1-RUNX1T1, CBFB-MYH11, and MLL (KMT2A) analyzed in 19 patients with t(9;11)(q22;q23) AML. Eleven of these
fusion transcripts. Gene fusions are found in 20% and 35% of adult and patients showed negative PCR for the MLL fusion transcripts, which were
childhood non-APL AML cases, respectively.226,334 Mutations in AML associated with a better outcome. While most studies have shown a
include NPM1, DNMT3A, and FLT3-ITD mutations. NPM1 mutations are correlation between transcript level and outcome, a study of childhood
seen in approximately one-third of adult AML cases, while less than 10% AML showed RQ-PCR of RUNX1-RUNX1T1 to be a poor marker for
of childhood cases have this mutation.335,336 Similarly, the DMNT3A relapse and the method to be inferior to flow cytometry.343 The different
mutation is found at a higher percentage in adult (15%–20%) compared to outcomes of the studies highlight the need for standardization of these
childhood (2%) AML.75,337,338 The FLT3-ITD mutation is found in 25% of methods. It also may be an indication of variability between adult and
adult and 15% of childhood AML.54,339 Two less well-studied mutations that pediatric populations, a factor that must be considered when establishing
may serve as MRD markers include CEBPA and MLL-partial tandem methods and cutoffs.
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The use of RQ-PCR in mutations is hampered by the inability to (CHIP) and aging including DNMT3A, TET2, and potentially ASXL1, are
distinguish the number of cells containing transcripts, as each cell may not considered reliable MRD markers.332,333,360
have variable levels. Furthermore, these transcripts still may be detected
in cells that have differentiated in response to treatment and are no longer Gene overexpression studies have focused on WT1. Retrospective data
clonogenic, thereby giving a false positive.344,345 Another caveat is the show that a lower level of WT1 after induction therapy is associated with
instability of mutations that may result in false negatives. This is long-term remission.361 A meta-analysis of 11 trials, encompassing 1297
particularly true for FLT3-ITD346-348 and NPM1 mutations.349-351 Despite patients, showed the poor prognostic significance of WT1 level.362 WT1
these complications, several studies have correlated NPM1 mutations and was overexpressed in 86% of marrow and 91% of blood samples from 504
outcome.112,350,352-357 In a small study of 25 patients, the use of a higher patients with AML when compared to 204 healthy donors.363 However,
sensitivity RQ-PCR was shown to circumvent transcript instability, when using the cutoff values of greater than 100-fold detection, only 46%
ultimately showing that FLT3-ITD MRD monitoring was predictive of of blood and 13% of marrow samples in the cohort were positive.363 This
relapse.358 In comparison to FLT3-ITD, data suggest that NPM1 mutations reflects the outliers of the healthy population that have higher WT1
may be more stable.352 Schittger et al356 developed and tested primers for transcripts. Furthermore, only 19% of childhood AML samples met this
17 different mutations of NPM1.356 Serial analyses of 252 NPM1-mutated criterion in a study.364 While WT1 is a strong candidate for MRD
AML samples at 4 time points showed a strong correlation between the monitoring, early studies show that there is variability in the detection of
level of NPM1mut and outcome. Kronke et al351 further modified this method this transcript that must first be addressed. In a retrospective study of
to show that NPM1mut levels after double induction and consolidation patients with AML who underwent allogeneic HCT (n = 74), a multigene
therapy reflected OS and cumulative incidence of relapse.351 In 245 MRD RQ-PCR array predicted clinical relapses occurring in the first 100
patients, PCR negativity had a 6.5% 4-year cumulative incidence of days after allogeneic HCT compared with 57% sensitivity using WTI RQ-
relapse versus 53% for PCR positivity.351 This correlation was also seen PCR alone.365 Notably, for patients who achieved CR prior to allogeneic
when taken after completion of therapy. In addition, an RQ-PCR analysis HCT, the presence of pre-transplantation MRD positivity in peripheral
of 2596 samples from 346 patients with NPM1-mutated AML blood testing was associated with survival similar to patients with
demonstrated that MRD was the only independent prognostic factor for pathologist bone marrow-based diagnosis of active disease.365
mortality (HR, 4.84; 95% CI, 2.57–9.15; P < .001) and persisting NPM1-
Flow Cytometry
mutated transcripts were associated with relapse.353
Flow cytometry for the monitoring of AML measures the presence of
CEBPA and MLL-partial tandem duplications are additional targets for tumor-specific antigens and abnormalities not found on normal bone
MRD monitoring by RQ-PCR.340,359 While data suggest both transcripts marrow cells. Several known markers identify abnormal cells or cell
may be suitable MRD markers, the small sample sizes limit current use of maturation, and when used as a panel these markers can define cell
these markers until data can be extrapolated to a larger population. populations.366 Studies in both adult and childhood AML cases show a
Mutations associated with clonal hematopoiesis of indeterminate potential correlation between flow cytometry and relapse. Loken et al367 showed
that 7 of 27 patients who had not achieved morphologic remission had
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negative MRD by flow cytometry. All 7 patients were long-term survivors LAIPs were seen in all four centers after extensive group discussion. The
when compared with the remaining 20 patients. Conversely, in a separate inexperienced laboratories had a success rate of 82% to 93% for defining
study of 188 patients who achieved morphologic remission, less than 5% at least one LAIP in a sample from 35 evaluable samples. The missed
had high levels of MRD by flow cytometry.367 A larger study of 1382 LAIPs would have resulted in 7% to 18% of the patients being unevaluable
follow-up bone marrow samples from 202 children with AML demonstrated by MRD in these centers. The number of samples incorrectly evaluated
MRD to be a predictor of relapse. In this study 28 of the 38 samples (74%) increases if they included samples in which at least two LAIPs were
with greater than 15% myeloblasts had measurements of 0.1% or greater identified by the primary lab, but the other labs only detected one LAIP.
by flow cytometry. In patients with 5% to 15% myeloblasts, 43 of the 129 This accounted for an additional 9% to 20% of cases that would have
patients (33%) were detected by the same threshold and only 100 of the resulted in false negatives. LAIPs with high specificity and sensitivity
1215 samples (8%) with less than 5% myeloblasts fell into this category. (MRD levels of .01%) were very well-defined in the multicenter analysis.
The ability of MRD monitoring to predict an unfavorable EFS was With regard to the missed LAIPs, the authors proposed the design of
statistically significant (P < .0001).343 In a study of adult patients with AML redundant panels to account for immunophenotypic shift. Inconsistencies
who underwent allogeneic HCT from peripheral blood or bone marrow in LAIPs with MRD of 0.1% or lower may be resolved with the use of a
donor (n = 359), pre-transplant staging with flow cytometry demonstrated greater number of fluorochromes.374 Another important conclusion from
similar outcomes in 3-year OS and PFS estimates between patients this publication was the ability of these methods to be applied to different
experiencing MRD-positive morphologic remission and patients with active instruments; both the Beckman Coulter and the Becton Dickinson
disease (26% vs. 23% and 12% vs. 13%, respectively) when compared to instruments were tested and obtained similar results. MRD monitoring is a
patients who achieved MRD-negative remission (73% and 67%, more feasible option if performed in core facilities until greater research is
respectively).368 done on the method to eliminate variability. Enrollment in clinical trials that
provide MRD monitoring is encouraged.
The most difficult issue facing flow cytometry as an effective method for
MRD monitoring is standardization and training. Flow cytometry relies Because a high-quality sample is essential for reliable treatment
heavily on the expertise of the technician who must take into account evaluation, the NCCN AML Panel recommends that the optimal sample for
variability in instruments, fluorochromes, analysis software, and individual MRD assessment is either peripheral blood for NPM1 PCR-based
antigens. Variations in the treatment schedule, dosing, type of treatment, techniques or the first pull/early pull of the bone marrow aspirate for other
and time of draw are also potential variables. Despite the issues with flow PCR-, flow cytometry- and NGS-based assays. The timing of MRD
cytometry, research is focused on improving the method by defining assessments will vary and depend on the regimen used,243,353 but may
threshold cutoff values369-372 as well as generating standards to equalize occur after completion of initial induction332,333,360 and before allogeneic
data among different instruments and software programs. A study by transplantation.375
Feller et al373 further defined LAIPs and evaluated whether data from an
established MRD monitoring laboratory could be replicated in four centers
with no significant prior experience. Increased success rates of defining
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Postremission Surveillance for AML Targeted Therapy
Monitoring for CBCs, including platelets, every 1 to 3 months for the first 2 FLT3-Positive AML: In a phase I/II study, the safety and tolerability of
years after patients have completed consolidation therapy, then every 3 to gilteritinib, a FLT3 inhibitor, was assessed in adult patients with R/R AML
6 months thereafter up to 5 years, is recommended. Bone marrow (n = 252).306 In this group, 58 patients had wild-type FLT3 AML and 194
evaluation should be performed only if the hemogram becomes abnormal, patients had FLT3-mutated AML (FLT3-ITD, n = 162; FLT3-TKD/FLT3
rather than as routine surveillance at fixed intervals, unless the bone D385, n = 16), and received oral gilteritinib (20–450 mg) once daily in
marrow evaluation is being performed as part of a clinical research one of seven dose-escalation or dose-expansion cohorts.306 Gilteritinib
protocol. was well-tolerated in this patient subpopulation and the most common
grade 3 or 4 adverse events were febrile neutropenia (39%), anemia
If no sibling donor has been identified, a donor search should be initiated (24%), thrombocytopenia (13%), sepsis (11%) and pneumonia (11%).306
at first relapse in appropriate patients concomitant with initiation of The ORR in all patients with R/R AML was 40%, which was improved to
reinduction therapy. At relapse, the panel suggests conducting 52% in patients with FLT3-mutated AML treated with gilteritinib doses
comprehensive molecular profiling using appropriate material to determine ≥80 mg/day.306
the mutation status of actionable genes including FLT3 (ITD and TKD),
IDH1, and IDH2 because it may guide selection of appropriate therapies In a phase 3 trial, the efficacy of gilteritinib was compared to
(see Management of Relapsed/Refractory AML) and enrollment in conventional chemotherapy used to treat R/R AML (n = 371).307 In this
appropriate clinical trials. Ongoing studies are evaluating the role of study, the four chemotherapy options included two high-intensity options
molecular monitoring in the surveillance for early relapse in patients with (FLAG-Ida; and mitoxantrone plus etoposide and cytarabine [MEC]) and
AML (see Role of MRD Monitoring). two low-intensity options (low-dose cytarabine and azacitidine). Of the
371 eligible patients, 247 were randomly assigned to the gilteritinib group
Management of Relapsed/Refractory AML (120 mg/day) or the salvage chemotherapy group (n = 124). The
Treatment of R/R AML is challenging and outcomes are poor.21,376 Many percentage of patients who had CR with full or partial hematologic
studies have also demonstrated that lack of early blast clearance or lack of recovery was 34% and 15.3% in the gilteritinib and chemotherapy
response to the first induction cycle are major predictors for poor groups, respectively.307 The median OS was significantly longer in the
outcomes.21,377,378 Intensive regimens generally achieve high second CR gilteritinib group compared to the chemotherapy group (9.3 months vs.
rates but do not generate substantial CR duration.379 Currently, allogeneic 5.6 months; HR, 0.64; 95% CI, 0.49–0.83; P < .001).307 In addition, the
HCT at second CR is associated with relatively lower rates of relapse and median EFS was longer in the gilteritinib group when compared to the
represents the only potentially curative option.21,376,380 Emerging data are chemotherapy group at 2.8 months versus 0.7 months, respectively (HR
demonstrating the utility of targeted therapies in R/R AML.381 for treatment failure or death, 0.79; 95% CI, 0.58–1.09).307 Based on
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these data, gilteritinib was approved by the FDA in November 2018 for trials, and those that have been used as the comparator arms in U.S.
the treatment of adult patients who have R/R AML with a FLT3 mutation. cooperative group trials in the past decade.
In a phase II study, the efficacy of azacitidine and sorafenib, a FLT3 A study by Robak et al evaluated the efficacy of cladribine, cytarabine, and
inhibitor, was evaluated in adult patients with R/R AML (n = 43; median G-CSF as re-induction therapy in patients with R/R AML (n = 20).384 Ten
age, 67 years; range, 24–87 months).382 The response rate was 46%, with patients (50%) achieved CR with a median duration of 22.5 weeks (range,
CR, CR/CRi, and PR rates of 16%, 27%, and 3%, respectively.382 In 3.5–53 weeks). Two patients experienced PR (10%) and 8 patients did not
addition, the degree of FLT3-ITD inhibition appeared to correlate with have response to therapy.384 In another study, the efficacy of cladribine,
plasma sorafenib concentrations. cytarabine, and idarubicin was analyzed in patients with R/R AML (n =
34).385 After at least one cycle of treatment, 18 patients (52.9%) achieved
IDH Mutation-Positive AML: The studies evaluating the efficacy of CR and 16 (47.1) received subsequent allogeneic HCT.385
ivosidenib301 and enasidenib300 in IDH1- and IDH2-mutation positive R/R
AML, respectively, have been summarized in a previous section under In a study of patients with resistant or relapsing AML (n = 38), patients
Management of AML in Patients >60 Years, for patients who are not were treated with fludarabine, cytarabine, and G-CSF, and overall 21
candidates for or decline intensive remission induction therapy. patients (55%) achieved CR.386 In a study by Parker et al, patients with
high-risk MDS/AML (n = 19; including R/R AML, n = 7), treated with
CD33-Positive AML: In a study by Taksin et al, adult patients with AML fludarabine, cytarabine, G-CSF, and idarubicin experienced response to
in first relapse (n = 57) received fractionated doses of GO, given at a therapy, with 12 patients (63%) achieving CR.387
dose of 3 mg/m2 on days 1, 4, and 7 for one course.383 Fifteen patients
achieved CR (26%) and 4 achieved CRp (7%). The median RFS was In a phase I study, a regimen with clofarabine, cytarabine, and idarubicin
similar for patients who achieved CR and CRp and was 11 months.383 In was evaluated in a subgroup of adult patients with R/R AML (n = 21) and
addition, no veno-occlusive disease (sinusoidal obstructive syndromes) 10 patients (48%) achieved CR.388 A regimen with clofarabine (40 mg/m2)
occurred after GO treatment or after GO followed by HCT (n = 7), combined with cytarabine (2 g/m2) was evaluated in a randomized,
although the authors recommended a minimum delay of 90 days placebo-controlled, phase III trial (CLASSIC I trial) in R/R AML, resulting in
between GO treatment and HCT.383 an ORR of 47% (CR rate, 35%) and a median OS of 6.6 months.389 A
retrospective study compared clofarabine versus fludarabine in
Chemotherapy
combination with HiDAC with or without G-CSF.390 Patients treated with a
The guidelines provide a list of several commonly used regimens for R/R clofarabine-based regimen (n = 50) compared to a fludarabine-based
disease that are grouped as either aggressive or less aggressive therapy regimen (n = 101) had a higher CR rate (OR, 9.57; P < .0001) and a
(see AML: Therapy for Relapsed/Refractory Disease in the algorithm). The longer survival (mortality HR, 0.43; P = .0002).390
regimens grouped under aggressive therapy represent purine analog (eg,
fludarabine, cladribine, clofarabine)–containing regimens, which have The regimens for R/R AML grouped under less aggressive or less
shown remission rates of approximately 30% to 45% in several clinical intensive therapy include HMAs (azacitidine or decitabine), low-dose
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cytarabine, and venetoclax-containing regimens. Emerging studies idarubicin;386,387 4) etoposide and cytarabine, with or without
suggest that venetoclax in combination with HMAs or low-dose cytarabine mitoxantrone393,394; 5) clofarabine and cytarabine with or without
has demonstrated antileukemic activity in R/R AML, MDS, and BPDCN.391 idarubicin;388,389 or 6) clofarabine with or without idarubicin.395,396 Less
A study suggests that azacitidine followed by donor lymphocyte infusions aggressive or less intensive treatment options may include: 1) HMAs
(DLIs) may be a treatment option for therapy in patients who have AML alone (azacitidine or decitabine)282,289,397; 2) low-dose cytarabine294,398 (a
that relapses after allogeneic HCT.392 These data are based on a category 2B recommendation); or 3) venetoclax combined with HMAs or
prospective phase II trial of 28 patients with AML. In this study, 22 patients low-dose cytarabine.309,391 Best supportive care is always an option for
received DLIs and an ORR of 30% was achieved. This included 7 CRs patients who cannot tolerate or do not wish to pursue further intensive
and 2 PRs. At publication, 5 patients remained in CR with a median of 777 treatment.
days (range, 461–888 days). Neutropenia and thrombocytopenia grade
III/IV were the most common adverse events (65% and 63%, In some cases, if a patient has experienced a long first remission (≥12
respectively). Acute and chronic graft-versus-host disease (GVHD) were months), repeating treatment with a successful induction regimen may be
seen in 37% and 17% of patients, respectively. Correlations suggest a considered. This strategy primarily applies to cytotoxic chemotherapy
better response in patients with myelodysplasia-related changes regimens and excludes the use of dual-drug encapsulation of cytarabine
(P = .011) and lower blast count (P = .039) or patients with high-risk and daunorubicin, and the re-use of targeted agents due to the potential
cytogenetics (P = .035). However, interpretation of results is limited by the development of resistance. Targeted therapies may be retried if they were
small size of the study.392 not administered continuously and not stopped due to the development of
clinical resistance. If a second CR is achieved, consolidation with
allogeneic HCT should be considered.
The NCCN AML Panel recommends enrollment in a clinical trial for the
management of R/R AML as a strongly preferred option. Other options Supportive Care for Patients with AML
include targeted therapy or chemotherapy followed by allogeneic HCT. For Although variations exist between institutional standards and practices,
targeted therapies, the guidelines provide a list of options including several supportive care issues are important to consider in the care of
gilteritinib for patients with FLT3 mutations (a category 1 patients with AML. In general, supportive care measures may include the
recommendation). Sorafenib may be added to HMAs (azacitidine or use of blood products for transfusion support and correction of
decitabine) for patients with FLT3-ITD mutations. Other targeted therapy coagulopathies, tumor lysis prophylaxis, anti-infective prophylaxis, and
options include GO for patients with CD33-positive AML, and ivosidenib or growth factor support. Monitoring for neurologic and cardiovascular
enasidenib for patients with IDH1 or IDH2 mutations, respectively. toxicities may be required for particular therapeutic agents (HiDAC or
ATO) or because of patient-specific comorbidities. These supportive care
The regimens for aggressive therapy include: 1) cladribine, cytarabine,
measures are tailored to address the specific needs and infection
and G-CSF, with or without mitoxantrone or idarubicin;384,385 2) HiDAC, if
susceptibility of each individual.
not previously received in treatment, with or without anthracycline240; 3)
fludarabine, cytarabine, and G-CSF (FLAG regimen) with or without
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When transfusion support is required, leukocyte-depleted blood products each dose of HiDAC; patients exhibiting any neurologic signs should
should be used for transfusion. All patients with AML are at risk for acute discontinue HiDAC, and all subsequent cytarabine therapy must be
GVHD and management should be based on institutional practice or administered as standard dose. Patients who develop cerebellar toxicity
preference. Cytomegalovirus (CMV) screening for potential HCT should not be rechallenged with HiDAC in future treatment cycles.403
candidates is left to institutional policies regarding provision of HiDAC should also be discontinued in patients with rapidly rising
CMV-negative blood products to patients who are CMV-negative at the creatinine caused by tumor lysis.
time of diagnosis. HLA typing is routinely used in many institutions to
select platelet donors for patients who exhibit alloimmunization to Decisions regarding the use and choice of antibiotics to prevent and treat
HLA-specific antigens. infections should be made by the individual institutions based on the
prevailing organisms and their drug resistance patterns.404 Greater detail
Standard tumor lysis prophylaxis includes hydration with diuresis, and regarding the prevention and treatment of cancer-related infections can be
allopurinol administration or rasburicase treatment. Rasburicase is a found in the NCCN supportive care guidelines (see NCCN Clinical
genetically engineered recombinant form of urate oxidase enzyme. Practice Guidelines for Prevention and Treatment of Cancer-Related
Rasburicase should be considered as initial treatment in patients with Infections) and commensurate with the institutional practice for antibiotic
rapidly increasing blast counts, high uric acid, or evidence of impaired stewardship.
renal function.399 When possible, patients should be evaluated for glucose-
6-phosphate dehydrogenase (G6PD) deficiency, as rasburicase use in Growth factors (G-CSF or granulocyte macrophage colony-stimulating
these patients is contraindicated and is associated with an increased risk factor [GM-CSF]) are not recommended during induction for patients with
of inducing hemolysis.400,401 Urine alkalinization was previously APL as they can complicate assessment of response and increase the risk
recommended as a means to increase uric acid solubility and reduce the of differentiation syndrome. However, in patients with AML (non-APL),
potential for uric acid precipitation in the tubules. However, this method is growth factors may be considered during induction for patients who are
not generally favored as there are no data to support this practice and septic and who have a life-threatening infection in an attempt to shorten
similar effects could be seen with saline hydration alone.402 Alkalinization the duration of neutropenia. Some regimens such as FLAG incorporate G-
can complicate care by increasing calcium phosphate deposits in vital CSF into the regimen. However, the use of growth factors may complicate
organs (eg, kidney, heart) as a result of hyperphosphatemia. Furthermore, the interpretation of marrow results. There is a recommendation to
in contrast to allopurinol, rasburicase has the added benefit of rapid discontinue colony-stimulating factors at least a week before a planned
breakdown of serum uric acid, eliminating the need for urine alkalinization. marrow sample to assess remission status.
Patients who receive HiDAC should be closely monitored for changes in There is no evidence for whether growth factors have a positive or
renal function, because renal dysfunction is highly correlated with negative impact on long-term outcome if used during consolidation.
increased risk of cerebellar toxicity. Patients should be monitored and Growth factors may be considered as part of supportive care for
assessed for nystagmus, dysmetria, slurred speech, and ataxia before postremission therapy. Growth factors are not routinely recommended in
postremission therapy, except in life-threatening infections or when signs
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and symptoms of sepsis are present and the leukemia is believed to be in Committees that may provide helpful information about bloodless
remission. medicine.
Supportive Care for Patients with AML Who Prefer Not to Receive Regarding treatment options, the panel recommends considering less
Blood Transfusions myelosuppressive induction including dose reduction of anthracyclines
There is no established treatment of AML that does not require use of and use of non-intensive chemotherapy.408-412 Some of these options may
blood and blood products for supportive care, and with limited data, include targeted agents guided by testing for actionable mutations instead
providing guidelines or recommendations for AML management in this of intensive chemotherapy, especially in a noncurative setting. However,
context is challenging. However, the AML panel recognizes that this is a the panel notes that dose reductions in chemotherapy without transfusion
significant issue faced in a narrow spectrum of clinical settings. In this support in patients with AML is associated with a lower rate of remission,
context, the panel reviewed the existing literature and collective high mortality by severe anemia, and is unlikely to result in durable
experience with this issue and summarized some considerations to guide remissions.411 During treatment, measures should be taken to minimize
treatment and supportive care. However, it is important to note that the blood loss and decreased the risk of bleeding including: the use of
panel believes that in many cases, good outcomes from these strategies pediatric collection tubes; avoiding concomitant medications or procedures
are rare. that increase the risk of bleeding or myelosuppression; use of oral
contraceptive pills or medroxyprogesterone acetate in menstruating
At the outset, it is important to discuss the goals of care with the patient individuals; or proton pump inhibitors, as indicated.406,413 Vitamin K may be
and establish an understanding of the complications that can arise considered as an adjuvant to improve coagulopathy.406,413 In patients at
without transfusions. In addition, it will be helpful to ascertain if the risk of bleeding (eg, when platelet counts drop below 30,000/mcL),
patient will accept certain blood products (eg, cryoprecipitate) and stem aminocaproic acid or tranexamic acid may be considered to manage
cells (either autologous or from another donor source). To mobilize bleeding.406,413 In patients with elemental or vitamin deficiencies, consider
peripheral blood stem cells and/or bring up hemoglobin levels prior to iron, folate, and vitamin B12 supplementation.406,413 In patients with severe
peripheral blood stem cell transplantation, some treatment centers have anemia, consider bed rest and supplemental oxygenation.406,413
used erythropoietin stimulating agents (ESAs), G-CSF, and
thrombopoietin (TPO) mimetics.405-407 However, before using this Evaluation and Treatment of CNS Leukemia
strategy, the potential risks, benefits and uncertainties of using these Leptomeningeal involvement is much less frequent (<3%) in patients with
agents in this context should be thoroughly discussed. Consider referring AML than in those with ALL; therefore, the panel does not recommend LP
the patient to centers with expertise in bloodless autologous as part of the routine diagnostic workup. However, if neurologic symptoms
transplant.406,407 In addition, for patients who are Jehovah’s Witnesses (eg, headache, confusion, altered sensory input) are present at diagnosis,
and for this reason decline blood transfusions, the U.S. branch of the an initial CT/MRI should be performed to rule out the possibility of
Christian Congregation of Jehovah’s Witness has Hospital Liaison intracranial hemorrhage or presence of a mass or lesion. If no mass effect
is seen, cerebrospinal fluid cytology should be sampled by LP. If the LP is
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negative for leukemic cells, the patient can be followed with a repeat LP if immunotype by flow cytometry, the panel recommends either IT
symptoms persist. If the LP is positive by morphology or immunotype by chemotherapy, as outlined earlier, or documenting clearance of CNS
flow cytometry, IT chemotherapy is recommended, given concurrently with disease after the first cycle of HiDAC chemotherapy. In addition to the
systemic induction therapy. If LP result is equivocal, consider repeating LP recommended evaluation and treatment of CNS leukemia, further CNS
with morphology or immunotype by flow cytometry to delineate surveillance should be followed based on institutional practice
involvement. IT therapy may include agents such as IT methotrexate or IT
cytarabine either alone or combined. The selection of agents and dose
schedules for IT therapy largely depend on the specific clinical situation
(eg, extent of CNS leukemia, symptoms, systemic therapies given
concurrently) and institutional practices. Initially, IT therapy 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 administered by
clinicians with experience and expertise in the delivery of IT agents.
HiDAC has significant penetration across the blood–brain barrier and may
represent an alternative to repeated IT injections during induction therapy.
The cerebrospinal fluid must then be reassessed after completion of
induction therapy, and further IT therapy should be given as appropriate.
If the initial CT/MRI identifies a mass effect or increased intracranial

pressure due to a parenchymal lesion in the brain, a needle aspiration or
biopsy may be considered. If the results are positive, then radiation
therapy is recommended, followed by IT therapy, as described earlier. IT
therapy or HiDAC should not be administered concurrently with cranial
radiation because of the increased risks of neurotoxicity. Another option
for these patients includes HiDAC-containing therapy with dexamethasone
to help reduce intracranial pressure.
The panel does not recommend routine screening for occult CNS disease
in most patients with AML in remission. The exceptions are patients with
extramedullary disease, monocytic differentiation, biphenotypic leukemia,
WBC count greater than 40,000/mcL at diagnosis, high-risk APL, or FLT3
mutations. For patients with positive cerebrospinal fluid by morphology or
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Workup
Management of Blastic Plasmacytoid Dendritic Cell
Neoplasm The evaluation and initial workup for suspected BPDCN consists of a
BPDCN is a rare myeloid malignancy, representing only 0.44% of comprehensive medical history and physical examination. Laboratory
hematologic malignancies, with an incidence of 0.04 cases per 100,000 evaluations include a comprehensive metabolic panel and a CBC
people in the United States.414,415 BPDCN, which was formerly known as including platelets and a differential of WBCs. Analyses of peripheral
blastic natural killer cell lymphoma or granular CD4+/CD56+ hematodermic blasts, bone marrow biopsy and aspirate, biopsy of skin lesions and, if
neoplasm, was renamed in the 2008 WHO classification with the evolving suspected to be involved, lymph nodes and other tissues are
knowledge of its plasmacytoid dendritic cell (PDC) origin.416,417 In 2016, it recommended. These analyses should include dendritic cell morphology
was recognized as a unique myeloid malignancy.67 Pathologically, it is assessment, immunohistochemistry, flow cytometry, cytogenetic analysis
characterized by aggressive proliferation of precursors of PDCs.418,419 The (including karyotyping and/or FISH), and molecular analyses. Analysis of
etiology of BPDCN is unknown, but its association with MDS or CMML in skin lesions often occurs in collaboration with dermatology. It is essential
some cases may suggest a related pathogenesis.418,420 BPDCN is to differentiate the skin lesions of BPDCN from other neoplastic and non-
associated with a poor prognosis, with median OS of approximately 8-12 neoplastic skin lesions and rashes, including leukemia cutis associated
months when patients are treated with chemotherapy.419,421 Median age of with AML, and analysis by experienced hematopathologists is often
presentation is 65 to 67 years, with an approximate male-to-female ratio of required.417 If extramedullary disease and/or lymphadenopathy is
3:1. The most frequent clinical presentation of typical BPDCN cases is suspected, a PET/CT scan is recommended. A lumbar puncture is highly
asymptomatic solitary or multiple skin lesions that can disseminate rapidly recommended at initial diagnosis to rule out CNS disease, and
without therapy.418,419 Peripheral blood and bone marrow involvement may subsequent IT prophylaxis is strongly encouraged even in the absence of
be minimal at presentation, but tend to develop as the disease progresses. known CNS disease.417
Additional sites of involvement can include lymph nodes, spleen, and other
The diagnosis of BPDCN can be difficult due to overlapping
extramedullary organs.417,418,422 Less commonly, patients may present with
morphological, immunophenotypic, and clinical features of other
features of an acute leukemia without skin manifestations.419 CNS
hematologic malignancies, such as AML.417 This is particularly true when
involvement is not infrequent; approximately 10% of patients who present
BPDCN presents as isolated cutaneous lesions, as biopsy specimens
with neurological symptoms at diagnosis have confirmed CNS
from cutaneous lesions may not yield sufficient cells for appropriate flow
involvement423 and rates of CNS involvement, both at diagnosis and at
cytometric analysis.417 A diagnosis of BPDCN requires expression of at
relapse, have been found to be in the range of 9-26% in several additional
least 4 of these 6 antigens on malignant cells: CD123 (also referred to as
studies.419,424,425
interleukin-3 receptor-alpha [IL3Rα]), CD4, CD56, TCL-1, CD2AP, and
CD303/BDCA-2, in the absence of lineage-specific markers.417,418
TCF4/CD123 coexpression has also been found to be a sensitive and
specific diagnostic marker for BPDCN.426,427 CD303 is emerging as
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another marker useful in the diagnosis of BPDCN and may serve as a 15-minute infusion every day for up to 5 doses. Of 9 evaluable patients
potential marker for further directed therapy.428 BPDCN must be who received treatment, 5 had a CR and 2 had a PR after one cycle of SL-
distinguished from mature plasmacytoid dendritic cell proliferation 401 treatment (78% ORR). The median duration of response was 5
(MPDCP) in which PDCs are morphologically mature and CD56- months (range, 1–20+ months), with responses occurring in all sites of
negative.418 In addition, recurrent mutations in the following genes have disease, including skin, bone marrow, and lymph nodes. Acute infusion-
been described: ASXL1, IDH1, IDH2, IKZF1, IKZF2, IKZF3, NPM1, NRAS, related adverse events such as fever, chills, and nausea were mild to
TET1, TET2, TP53, U2AF1, and ZEB2.417,418,429,430 moderate in severity and were most commonly seen within the first several
hours after SL-401 infusion; however, these symptoms were occasionally
Induction Therapy for Patients with BPDCN noted up to 4-8 hours following infusion. Premedications including
Given the rarity of BPDCN, no standardized chemotherapy approach has acetaminophen, diphenhydramine, methylprednisolone, and famotidine
been established.419 Historically, therapeutic approaches have varied were given, likely mitigating these events. Resulting symptoms following
widely and have included irradiation for localized skin lesions, lymphoma- infusion responded to additional dosing of acetaminophen, meperidine,
or leukemia-type chemotherapy regimens, and HCT.431 Despite good initial antiemetics, and/or H1- and H2-histamine antagonists. These acute
responses to chemotherapy, with response rates of 40-90%417, early infusion-related events may be related to cytokine release from necrotic
relapse rates are high, even among those who achieve CR.417,419,431 cells and damaged BPDCN blasts. Most patients experienced one or more
CD123-targeted therapy with tagraxofusp-ersz has more recently emerged symptoms suggestive of vascular or capillary leak syndrome, such as
as the preferred treatment option in appropriate candidates. hypoalbuminemia, edema, hypotension, and hyponatremia.
Hypoalbuminemia was the most consistent and early manifestation of
Recently, a collaborative initiative, the North American BPDCN capillary leak syndrome (grade 1 in 4 patients, grade 2 in 6 patients).
Consortium (NABC), made up of a group of experts from multiple areas of Symptoms of capillary leak syndrome were managed by the administration
expertise, has been formed to define the current standard of care for of parenteral albumin and diuretics. Though several patients experienced
management of BPDCN and to identify future areas of research.432 grade 3 thrombocytopenia and neutropenia, myelosuppression was
CD123-Targeted Therapy
generally modest and reversible, potentially reflecting the minimal
expression of IL3R on normal myeloid progenitors. Many patients
CD123, or IL3Rα, overexpression is present in virtually all cases of
experienced transaminitis without hyperbilirubinemia, with onset typically
BPDCN.422 Tagraxofusp (formerly SL-401) is a recombinant fusion protein
5-10 days post-infusion and with full resolution typically 15-21 days
made up of the catalytic and translocation domains of diphtheria toxin
following infusion.
fused to IL3 that has shown activity against BPDCN.
In a multicohort study by Pemmaraju and colleagues, 84 patients with
The first prospective study of treatment of patients with BPDCN included
untreated or relapsed BPDCN were treated with an IV infusion of
11 patients with recurrent or refractory BPDCN or who were not
tagraxofusp at a dose of 12 µg/kg on days 1 to 5 of each 21-day cycle.434
candidates for chemotherapy were treated with SL-401.433 Each cycle of
Treatment was given until disease progression or unacceptable adverse
SL-401 treatment was comprised of a 12.5µg/kg dose administered over a
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effects. Of the 84 patients, 65 received first-line treatment and 19 had protocols included MEC (mitoxantrone, cytarabine, etoposide), ICE
received prior treatment. Among evaluable patients who received first-line (idarubicin, cytarabine, etoposide), standard-dose cytarabine and
treatment of tagraxofusp, the primary outcome (CR and clinical CR) was anthracycline (7+3), FLAG, and FLAG-Ida. The ALL/lymphoma-type
observed in 57% of patients, ORR was 75%, and median OS was 15.8 regimens included hyper-CVAD (alternative cycles of hyperfractionated
months. Of the patients who achieved CR or clinical CR following first-line cyclophosphamide, vincristine, doxorubicin, dexamethasone,
treatment of tagraxofusp, 51% were successfully bridged to HCT methotrexate, and cytarabine), GIMEMA ALL trial therapy (association of
(allogeneic HCT, n = 13; autologous HCT, n = 6) while in remission and doxorubicin, vincristine, prednisone, and asparaginase), CHOP
median OS in this subgroup was 38.4 months. Of the 18 patients who (cyclophosphamide, doxorubicin, vincristine, and prednisone), and
achieved CR or clinical CR following first-line treatment who did not CHOEP (CHOP plus etoposide). There were patients who required
proceed to HCT, 4 had duration of responses >6 months. Among the 19 additional therapy based on extramedullary disease (4 patients received IT
patients who had received prior therapy, ORR was 58% with a median OS chemotherapy for CNS involvement and 2 patients received radiation
of 8.2 months. Among this subgroup, 1 patient was successfully bridged to therapy for skin lesions). 14% of patients underwent allogeneic HCT at
HCT. Based on earlier data from this trial422, the FDA approved some point in their course of therapy. After induction, the overall CR rate
tagraxofusp-erzs for the treatment of BPDCN in adults and pediatric was 41%, with 7 patients achieving CR after AML-type induction, and 10
patients >2 years of age in 2018. patients achieving CR after ALL-type induction. The median OS was 8.7
months (range, 0.2–32.9), and patients who received ALL-type
The most common adverse events noted in the Pemmaraju study were chemotherapy appeared to have longer OS compared to patients treated
increased levels of alanine aminotransferase (ALT) and aspartate with AML-type chemotherapy (12.3 vs. 7.1 months, respectively; P = .02).
aminotransferase (AST), hypoalbuminemia, fatigue, fever, In addition, the median OS of patients who received transplant was
thrombocytopenia, nausea, and peripheral edema.434 In addition, capillary significantly higher than non-transplanted patients (22.7 vs. 7.1 months,
leak syndrome was observed in 21% of patients (8 of which were grade >3 respectively; P = .03). Age was also noted to be a significant prognostic
and 3 of which were grade 5 resulting in death), primarily in the first cycle factor, with a median OS of 12.6 months in patients <65 years compared
of treatment. Median time to onset of capillary leak syndrome was 6 days to 7.1 months for those >65 years (P = .04). Relapses occurred in 35% of
(range 3-51 days), with a median duration of 6 days (range 3-69 days). patients at a median of 9.1 months.
Capillary leak syndrome was managed by withholding further doses of
tagraxofusp, administering IV albumin or glucocorticoids, and careful An additional retrospective study analyzed the impact of 4 different
management of volume status. chemotherapeutic approaches: 1) local therapy or systemic regimens less
aggressive than CHOP, 2) CHOP and CHOP-like regimens, 3) acute
Chemotherapy
leukemia regimens, and 4) allogeneic or autologous HCT.431 Therapies
In a retrospective multicenter study, 41 patients with BPDCN received less intensive than CHOP were a heterogenous group, including local
induction treatment with AML-type regimens (n = 26) and ALL- radiation, systemic steroids, and supportive care, but were mostly
type/lymphoma-type regimens (n = 15).419 The AML-type treatment cyclophosphamide-based chemotherapy regimens. Though this group had
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a high ORR of 80% (68% CR), only 7% of patients had a sustained CR group were bridged to HCT, compared to 49% of patients in the
and the median OS for evaluable patients was 9 months. Patients in the tagraxofusp group and 38% in the other regimens group, respectively (P =
CHOP and CHOP-like regimens arm had similar results despite therapy .455). This study suggests a continued role for hyper-CVAD based
being more aggressive, with an ORR of 70% (55% CR) and only 1 case of regimens in the targeted-therapy era.
sustained CR. Intensive acute leukemia regimens resulted in a CR rate of
Venetoclax-Based Regimens
94%, with approximately 1/3 of patients experiencing a sustained CR.
There were 10 evaluable patients in the HCT arm (6 allogeneic, 4 The antiapoptotic protein B-cell leukemia/lymphoma-2 (BCL2) is
autologous). Median OS was 38.5 months in the allogeneic arm compared overexpressed in a majority of patients with BPDCN.391 Venetoclax is an
to 16.5 months in the autologous arm. At the time of publication, all but oral selective BCL2 inhibitor approved in combination with azacitidine,
one patient who had undergone allogeneic HCT in first remission decitabine, or low dose cytarabine (LDAC) for the treatment of newly-
remained disease-free. diagnosed AML in patients > 75 years or for those who are otherwise not
candidates for intensive remission induction therapy.437 In vitro, BPDCN
Another retrospective study evaluated the diagnostic flow cytometry cells were found to be uniformly sensitive to venetoclax in a study that
pattern and outcome of nine patients with BPDCN after front-line treatment measured direct cytotoxicity, apoptosis assays, and dynamic BH3
with hyper-CVAD.435 In this group, seven patients received induction profiling.438
treatment with hyper-CVAD and had a CR of 67% and ORR of 86%. Five
of the six patients who responded to therapy received planned allogeneic A retrospective study assessed the efficacy of venetoclax combinations in
HCT. With a median follow-up of 13.3 months, the one-year DFS and OS a total of 43 patients with R/R myeloid malignancies, including 2 patients
rates for all patients were 56% and 67%, respectively. The 1-year DFS for with BPDCN.391 The most common treatment regimens included
those who received allogeneic HCT was 80%. The 1-year OS for patients venetoclax with decitabine (53%), azacitidine (19%), and LDAC (19%).
who received allogeneic HCT was 80%, compared to 50% in those who Patients had been previously treated with a median of 3 prior lines of
received chemotherapy alone. The median OS was 7.9 months for those therapy, including allogeneic HCT in 12% of patients. While ORR was
who received chemotherapy alone. seen in 21% of patients, neither of the 2 patients with BPDCN that were
evaluated achieved a response by formal criteria, though one patient had
A more recent retrospective study compared outcomes of 100 patients a major response by PET/CT, bone marrow blast reduction of >50%, and
with BPDCN treated with frontline hyper-CVAD-based therapy (n= 35), improvement in cutaneous lesions. The other patient with BPDCN also
tagraxofusp (n = 37) or other therapies (n = 28.436 The highest CR rates had a significant improvement in cutaneous lesions. All patients who
were seen with hyper-CVAD based therapy (80%), followed by received venetoclax combination therapy experienced grade 3 or higher
tagraxofusp (59%), and finally other regimens (43%) (P = .01), though neutropenia and 72% developed a grade 3 or higher infection, most
there was no significant difference in OS (28.3 vs 13.7 vs 22.8 mo; P = commonly pneumonia, bacteremia, cellulitis, invasive fungal infections,
.41) or remission duration probability (38.6 vs not reached vs 10.2 mo; P = and urinary tract infections. All patients were given allopurinol for tumor
.24) noted between the 3 arms. 51% of patients in the hyper-CVAD based lysis syndrome prophylaxis, and none developed hyperuricemia that
MS-67

required rasburicase.391 Venetoclax in combination with hypomethylating allogeneic HCT not in first CR [74% (95% CI, 48%–89%) vs. 0, P < .0001],
agents appears to have efficacy in BPDCN, but larger and more and outcomes were not impacted by conditioning type (MAC vs RIC). The
formalized studies are necessary to confirm these observations. 1-year OS for autologous HCT recipients was 11% (95% CI, 8%–50%).
Hematopoietic Stem Cell Transplantation A more recent retrospective study evaluated 162 adults with BPDCN that
Due to the rarity of BPDCN, there have been limited established underwent first HCT (allogeneic HCT, n = 146; autologous HCT, n = 16),
standardized therapeutic approaches.439 HCT seems to generate durable 78% of whom were in first CR.441 Among the allogeneic HCT group, 54%
remissions, especially if given in first CR, as indicated by the studies received MAC, 46% received RIC, and 59% received in-vivo T-cell
discussed in the chemotherapy section, as well as others.416,419,431,435,439,440 depletion (TDC). Total body irradiation (TBI) was used in 61% of MAC
However, it is worth noting that data are limited to small case series and transplants and 26% of RIC transplants. Comparable one-year OS and
retrospective registry studies, and larger prospective studies are needed PFS rates were seen following allogeneic and autologous HCT (OS: 66 vs
to elucidate the role of HCT in BPDCN.440 70%; PFS: 62% vs 66%). TBI as the conditioning backbone in allogeneic
HCT led to significant improvements in OS and PFS compared to all other
A retrospective analysis from the Japan Society for Hematopoietic Cell conditioning regimens. Adjusted 2-year PFS for MAC with TBI was 95%
Transplantation aimed to clarify the role of allogeneic HCT or autologous compared to 82% for MAC without TBI, 41% for RIC with TBI, and 60% for
HCT in treating BPDCN.416 In this analysis, 25 patients were identified, RIC without TBI, respectively.
with 14 patients having undergone allogeneic HCT and 11 patients having
undergone autologous HCT. All patients who underwent autologous HCT NCCN Recommendations
were in first CR, while 12 of the 14 patients who underwent allogeneic For patients who are candidates for intensive remission induction therapy,
HCT were in first CR (2 were not in remission). With a median follow-up of the panel recommends tagraxofusp-ersz as the preferred option, and other
53.5 months, the OS rates at 4 years for patients who underwent options include AML-type (standard-dose cytarabine plus anthracycline
autologous HCT and allogeneic HCT were 82% and 53%, respectively (P using 7+3), ALL-type (hyper-CVAD), and lymphoma-type (CHOP)
= .11) and the PFS rates were 73% and 48%, respectively (P = .14). The regimens. If CNS disease is documented at diagnosis, IT chemotherapy
data suggest that receiving autologous HCT in first CR may substantially should also be given. If CNS disease is not present at diagnosis,
enhance survival. OS outcomes in the allogeneic HCT subgroup did not prophylactic IT chemotherapy is strongly encouraged.
differ significantly between myeloablative conditioning (MAC) and RIC
regimens. Tagraxofusp-ersz should be administered as an IV infusion at 12 µg/kg
over 15 minutes once daily on days 1 to 5 of each 21-day cycle.
A North American multicenter retrospective study analyzed the outcomes Alternatively, 5 doses can be administered over a 10-day period, if needed
of BPDCN patients treated with allogeneic HCT (n = 37) or autologous for dose delays. It is important to note that patients must have a baseline
HCT (n = 8).440 Allogeneic HCT recipients had a 1-year and 3-year OS of serum albumin of 3.2 g/dL or higher to be able to start treatment with this
68% (95% CI, 49%–81%) and 58% (95% CI, 38%–75%), respectively. agent. The most serious side effect associated with tagraxofusp is
Receiving allogeneic HCT in first CR yielded improved 3-year OS versus capillary leak syndrome, which can occur during the first cycle of treatment
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and can be life-threatening.422 A decrease in serum albumin during the first Postremission Surveillance for BPDCN
days of treatment seems to be the most consistent predictor of capillary Following completion of consolidation therapy, it is recommended to
leak syndrome.422 Management includes delaying or withholding additional monitor a CBC, including platelets, every 1 to 3 months for the first 2
tagraxofusp doses, administering IV albumin according to pre-specified years, then every 3 to 6 months thereafter for up to 5 years. Bone marrow
measures, administering glucocorticoids, and close management of evaluation should be performed only if cytopenias develop or if peripheral
volume status.422 The panel recommends replacing serum albumin if <3.5 smear is abnormal, rather than as routine surveillance at fixed intervals,
g/dL or if there is a reduction of ≥0.5 from baseline. The panel also unless the bone marrow evaluation is being performed as part of a clinical
recommends premedication with an H1-histamine antagonist, research protocol. For patients with prior evidence of extramedullary
acetaminophen, corticosteroid, and H2-histamine antagonist prior to each disease, a repeat PET/CT scan is recommended. In addition, routine
infusion to help reduce the risk of hypersensitivity reaction. thorough skin exams with a re-biopsy should occur for any suspicious skin
or extramedullary lesions.
With all treatment options, if CR is observed, allogeneic HCT or
autologous HCT should be considered. If tagraxofusp-erzs was given as Management of Relapsed/Refractory BPDCN
an initial treatment and HCT is not feasible, additional cycles of
Upon relapse, the NCCN AML Panel recommends evaluating for CNS
tagraxofusp-erzs should be continued until disease progression. If disease
disease and administering IT chemotherapy prophylaxis.423 Management
progresses or does not respond to induction therapy, patients should be
options for R/R BPDCN include clinical trial (preferred), tagraxofusp-ersz
considered for a clinical trial (preferred), or regimens used for R/R
(preferred, if not already used),422 chemotherapy (if not already given),
disease.
local radiation to isolated lesions, systemic steroids, or venetoclax-based
For patients with low performance and/or nutritional status (ie, serum regimens.391,438 During administration of any treatment option, a donor
albumin <3.2 g/dL) or for those who are not candidates for intensive search should also be started at first relapse in appropriate patients if no
remission induction therapy or tagraxofusp-ersz, treatment options are sibling donor has been identified.
limited. If disease is localized or isolated to cutaneous involvement,
palliative treatment options include surgical excision or focal radiation. If
disease is systemic, palliative options include low-intensity therapy with
venetoclax-based regimens, steroids, and supportive care.
MS-69

9. Larson RA. Etiology and management of therapy-related myeloid

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Acute Myeloid Leukemia: NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines)

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NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®)

Acute Myeloid Leukemia

NCCN Guidelines for Patients® available at www.nccn.org/patients

NCCN Guidelines Version 6.2023 NCCN Guidelines Index

*Daniel A. Pollyea, MD, MS/Chair ‡ Þ † Alice Mims, MD, MS † Paul J. Shami, MD ‡

Aric C. Hall, MD ‡ † ξ Rebecca Olin, MD, MS ‡ ξ Pankit Vachhani, MD ‡

NCCN Guidelines Panel Disclosures

NCCN Guidelines Version 6.2023 NCCN Guidelines Index

NCCN Acute Myeloid Leukemia Panel Members

NCCN Guidelines Version 6.2023 NCCN Guidelines Index

NCCN Guidelines Version 6.2023 NCCN Guidelines Index

NCCN Guidelines Version 6.2023 NCCN Guidelines Index

NCCN Guidelines Version 6.2023 NCCN Guidelines Index

NCCN Guidelines Version 6.2023 NCCN Guidelines Index

NCCN Guidelines Version 6.2023 NCCN Guidelines Index

NCCN Guidelines Version 6.2023 NCCN Guidelines Index

NCCN Guidelines Version 6.2023 NCCN Guidelines Index

EVALUATION FOR AML DIAGNOSTIC DIAGNOSISd,e,f,j

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

NCCN Guidelines Version 6.2023 NCCN Guidelines Index

FOOTNOTES FOR EVALUATION FOR AML

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

NCCN Guidelines Version 6.2023 NCCN Guidelines Index

APL CLASSIFICATION AND TREATMENT RECOMMENDATIONS

Low risk (white blood cell [WBC]) See Treatment

High risk (WBC count >10,000/mcL)

Cardiac issues See Treatment

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

NCCN Guidelines Version 6.2023 NCCN Guidelines Index

APL TREATMENT INDUCTION (LOW RISK)b,c,d,e CONSOLIDATION THERAPYm,n

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

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

NCCN Guidelines Version 6.2023 NCCN Guidelines Index

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

NCCN Guidelines Version 6.2023 NCCN Guidelines Index

APL TREATMENT INDUCTION (HIGH RISK)b,c,d,p,q CONSOLIDATION THERAPYn

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

NCCN Guidelines Version 6.2023 NCCN Guidelines Index

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

NCCN Guidelines Version 6.2023 NCCN Guidelines Index

APL TREATMENT INDUCTION (HIGH RISK)b,c,d,p CONSOLIDATION THERAPYn

See footnotes on APL-4A

NCCN Guidelines Version 6.2023 NCCN Guidelines Index

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

NCCN Guidelines Version 6.2023 NCCN Guidelines Index

APL POST- MONITORING

cc PCR should be performed on a blood sample at completion of consolidation to

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

NCCN Guidelines Version 6.2023 NCCN Guidelines Index

APL THERAPY FOR RELAPSE ADDITIONAL THERAPY

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

NCCN Guidelines Version 6.2023 NCCN Guidelines Index

PRINCIPLES OF SUPPORTIVE CARE FOR APLa

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

NCCN Guidelines Version 6.2023 NCCN Guidelines Index

INTENSIVE RISK GROUP TREATMENT INDUCTIONe,f,g,h,t

See AML-5 (Intensive Induction Ineligible)

See footnotes on AML-2A