NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®)

Acute Myeloid Leukemia

Version 3.2022 — January 13, 2023

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Acute Myeloid Leukemia (Age ≥18 years) Discussion

*Daniel A. Pollyea, MD, MS/Chair ‡ Þ † Gabriel Mannis, MD ‡ Þ Rory Shallis, MD ‡

University of Colorado Cancer Center Stanford Cancer Institute Yale Cancer Center/Smilow Cancer Hospital
Jessica K. Altman, MD/Vice Chair ‡ Guido Marcucci, MD † Þ Paul J. Shami, MD ‡
Robert H. Lurie Comprehensive Cancer City of Hope National Medical Center Huntsman Cancer Institute
Center of Northwestern University Alice Mims, MD, MS † at the University of Utah
Vijaya Raj Bhatt, MBBS ‡ ξ The Ohio State University Comprehensive Eytan Stein, MD ‡
Fred & Pamela Buffett Cancer Center Cancer Center - James Cancer Hospital Memorial Sloan Kettering Cancer Center
Dale Bixby, MD, PhD ‡ † Þ and Solove Research Institute Richard M. Stone, MD ‡ †
University of Michigan Jadee Neff, MD, PhD ≠ Dana-Farber/Brigham and Women’s
Rogel Cancer Center Duke Cancer Institute Cancer Center
Hetty Carraway, MD, MBA † Reza Nejati, MD ≠ Stephen A. Strickland, MD, MSCI ‡
Case Comprehensive Cancer Center/University Fox Chase Cancer Center Vanderbilt-Ingram Cancer Center
Hospitals Seidman Cancer Center and Rebecca Olin, MD, MS ‡ ξ Kendra Sweet, MD, MS ‡ Þ †
Cleveland Clinic Taussig Cancer Institute UCSF Helen Diller Family Moffitt Cancer Center
Amir T. Fathi, MD ‡ † Comprehensive Cancer Center Swapna Thota, MD ‡
Massachusetts General Hospital Cancer Center Mary-Elizabeth Percival, MD, MS ‡ St. Jude Children's Research Hospital/The
James M. Foran, MD † Fred Hutchinson Cancer Research Center/ University of Tennessee Health Science Center
Mayo Clinic Cancer Center Seattle Cancer Care Alliance Geoffrey Uy, MD † ‡ ξ
Ivana Gojo, MD ‡ Alexander Perl, MD † Siteman Cancer Center at Barnes-Jewish
The Sidney Kimmel Comprehensive Abramson Cancer Center at the Hospital and Washington University School of
Cancer Center at Johns Hopkins University of Pennsylvania Medicine
Aric C. Hall, MD ‡ † ξ Amanda Przespolewski, DO ‡ Pankit Vachhani, MD ‡
University of Wisconsin Roswell Park Comprehensive Cancer Center O'Neil Comprehensive Cancer Center at UAB
Carbone Cancer Cente Dinesh Rao, MD, PhD ≠
Brian A. Jonas, MD, PhD ‡ UCLA Jonsson Comprehensive Cancer Center
NCCN
UC Davis Comprehensive Cancer Center Farhad Ravandi, MD Þ ‡ Deborah Freedman-Cass, PhD
Jeffrey Lancet, MD ‡ † The University of Texas Carly Cassara, MSc
Moffitt Cancer Center MD Anderson Cancer Center
James Mangan, MD ‡
UC San Diego Moores Cancer Center ξ Bone marrow transplantation
‡ Hematology/Hematology oncology
Þ Internal medicine
Continue † Medical oncology
≠ Pathology
NCCN Guidelines Panel Disclosures * Discussion Section Writing Committee Member

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Acute Myeloid Leukemia (Age ≥18 years) Discussion

NCCN Acute Myeloid Leukemia Panel Members

Summary of Guidelines Updates Clinical Trials: NCCN believes that
the best management for any patient
Evaluation for AML (EVAL-1) AML
APL • Risk Stratification by Genetics in Non-APL AML with cancer is in a clinical trial.
• Classification and Treatment Recommendations (AML-A) Participation in clinical trials is
(APL-1) • Evaluation and Treatment of CNS Leukemia especially encouraged.
• Low-Risk Treatment Induction and Consolidation (AML-B) Find an NCCN Member Institution:
Therapy (APL-2) • Principles of Radiation Therapy (AML-C) [Link]
• High-Risk Induction and Consolidation Therapy • General Considerations and Supportive Care for
institutions.
(APL-3) AML Patients Who Prefer Not to Receive Blood
• Post-Consolidation Therapy and Monitoring (APL- Transfusions (AML-D) NCCN Categories of Evidence and
5) • Principles of Supportive Care for AML (AML-E) Consensus: All recommendations
• Therapy for Relapse (APL-6) • Monitoring During Therapy (AML-F) are category 2A unless otherwise
• Principles of Supportive Care (APL-A) • Measurable (Minimal) Residual Disease indicated.
Assessment (AML-G)
AML See NCCN Categories of Evidence
• Response Criteria Definitions for Acute Myeloid
• (Age <60 y) Treatment Strategies and Induction Leukemia (AML-H) and Consensus.
(AML-1) • Therapy for Relapsed/Refractory Disease (AML-I)
• (Age <60 y) Risk Status and Consolidation Therapy • Principles of Venetoclax Use with HMA or LDAC
(AML-4) (AML-J) NCCN Categories of Preference:
• (Age ≥60 y) Treatment Strategies and Induction - All recommendations are considered
Candidates for Intensive Therapy (AML-5) BPDCN appropriate.
• (Age ≥60 y) Treatment Strategies and Induction - • Introduction (BPDCN-INTRO)
Non-Candidates for Intensive Therapy (AML-6) • Evaluation/Workup (BPDCN-1) See NCCN Categories of Preference.
• (Age ≥60 y) After Standard-Dose Cytarabine • Treatment (BPDCN-2)
Induction (AML-7) • Surveillance and Treatment for Relapsed/
• (Age ≥60 y) Post-Induction Therapy - Previous Refractory Disease (BPDCN-3)
Intensive Therapy (AML-8) • Principles of BPDCN (BPDCN-A)
• (Age ≥60 y) Post-Induction Therapy - Previous • Evaluation and Treatment of CNS Disease
Lower Intensity Therapy (AML-9) (BPDCN-B)
• Maintenance Therapy (AML-10) • Principles of Supportive Care for BPDCN
• AML Surveillance and Therapy for Relapsed/ (BPDCN-C)
Refractory Disease (AML-11)
The NCCN Guidelines® are a statement of evidence and consensus of the authors regarding their views of currently accepted approaches to treatment.
Any clinician seeking to apply or consult the NCCN Guidelines is expected to use independent medical judgment in the context of individual clinical
circumstances to determine any patient’s care or treatment. The National Comprehensive Cancer Network® (NCCN®) makes no representations or
warranties of any kind regarding their content, use or application and disclaims any responsibility for their application or use in any way. The NCCN
Guidelines are copyrighted by National Comprehensive Cancer Network®. All rights reserved. The NCCN Guidelines and the illustrations herein may not
be reproduced in any form without the express written permission of NCCN. ©2023.

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NCCN Guidelines Version 3.2022 NCCN Guidelines Index

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

Updates in Version 3.2022 of the NCCN Guidelines for Acute Myeloid Leukemia from Version 2.2022 include:
AML-I
• Targeted therapy for AML with IDH1 mutation, regimen added: Olutasidenib

Updates in Version 2.2022 of the NCCN Guidelines for Acute Myeloid Leukemia from Version 1.2022 include:
AML-6
• IDH1 or IDH2 Treatment Induction, preferred regimen added: Ivosidenib once daily (500mg) PO and azacitidine 75 mg/m2 SC or IV (days 1-7 or day 1-5, 8-9
of each 28-day cycle) (category 1) (IDH1 only)
AML-6A
• Footnote added: This regimen is approved for newly-diagnosed AML with an IDH1 mutation who met at least one of the following criteria: age >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 < 45 mL/min, or other comorbidity. Montesinos P, et al. N Engl J Med 2022;386:1519-1531.
Updates in Version 1.2022 of the NCCN Guidelines for Acute Myeloid Leukemia from Version 3.2021 include:
EVAL-1
• Evaluation
3rd bullet added: B12 and folic acid evaluation
14th bullet added: Consider early integration of palliative care (See NCCN Guidelines for Palliative Care)
• Diagnosis
APL revised: In patients with clinical and or pathologic features of APL....
AML, 1st sub-bullet revised: ...cytarabine (1-2 g) may be considered prior to receiving diagnostic results
EVAL-1A
• Footnote a revised: ...decision-making (category 2B) (See AML-A). Other genetic lesions, such as ASXL1, BCR-ABL, and PML-RAR alpha (See AML-A) may
have therapeutic implications significance... While the above Mutations should be tested in all patients...
• Footnote c added: El-Jawahri A, et al. JAMA Oncol 2021;7:238-245.

Acute Promyelocytic Leukemia (Age ≥18 years)

APL-2
• APL (Low Risk)
Treatment induction, Preferred Regimen, 1st and 2nd pathways revised: ATRA 45 mg/m2 in 2 divided doses daily + arsenic trioxide...
Consolidation therapy, 2nd row revised: First 3 consolidation cycles = 56 day cycles; ATRA 45 mg/m2/d PO divided into in 2 divided daily doses on...
Treatment induction, Useful in Certain Circumstances, 3rd pathway revised: ATRA 45 mg/m2 in 2 divided doses daily + idarubicin...
Consolidation therapy, 4th pathway revised: ATRA 45 mg/m2 in 2 divided doses daily.....may be given monthly until 28 weeks from complete response
(CR) until achievement of complete molecular response.
APL-3
• APL (High Risk), Treatment induction, ATRA regimen was clarified as appropriate: ATRA 45 mg/m2 in 2 divided doses daily...
APL-3A
• Footnote p added: It is important for the management of APL that regimens containing ATRA and arsenic trioxide be administered unless there is a
contraindication based on are extenuating patient circumstances. 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 s added: No arsenic is included in induction if unavailable or contraindicated.
• Footnote x revised: Consider 4–6 doses of IT chemotherapy (eg, 2 doses for each consolidation cycle) as an option for CNS prophylaxis. Continued
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Acute Myeloid Leukemia (Age ≥18 years) Discussion

Updates in Version 1.2022 of the NCCN Guidelines for Acute Myeloid Leukemia from Version 3.2021 include:
APL-4
• APL (High Risk) in Patients with Cardiac Issues
Treatment induction, ATRA regimen was clarified as appropriate: ATRA 45 mg/m2 in 2 divided doses daily
Consolidation Therapy, Prolonged QTc
◊ 1st pathway: ATRA 45 mg/m2 in 2 divided doses....until 28 weeks from CR until achievement of complete molecular response.
◊ 3rd pathway: ...+ cytarabine 150 mg/m2/8 h over 8h x 4 days x 1 cycle.
APL-4A
• Footnote removed: For patients who have prolonged QTc as their sole comorbidity, gemtuzumab ozogamicin could be substituted for anthracycline.
Acute Promyelocytic Leukemia (Age ≥18 years) (continued)
APL-5
• Footnote bb added: Grimwade D, et al. J Clin Oncol 2009;27:3650-3658.
APL-6
• Footnote dd added: Cicconi L. et al. Ann Hematol 2018;97:1797-1802.
APL-A
• Principles of Supportive Care for APL
3rd bullet, 2nd sub-bullet revised: ....dexamethasone 10 mg q 12 h (See NCCN Prevention and Treatment of Cancer-Related Infections).
Footnote 1 added: Antiviral prophylaxis zoster for duration of treatment may be appropriate. Freyer CW, et al. Leuk Lymphoma 2021;62:696-702; Glass
JL, et al. Blood 2015;126:3752–3752.
Footnote 2 added: Daver N, et al. Br J Haematol 2015;168:646-53.

Acute Myeloid Leukemia (Age ≥18 years)

AML-1
• General: Physiologic was removed from age throughout AML section
• Header clarified as: Age <60 y, Induction eligible
• Treatment Strategies
2nd qualifier revised: Intermediate-risk cytogenetics and FLT3-mutated (ITD or TKD) to FLT3/ITD/TKD with intermediate poor-risk genetics
AML-1A
• Footnote c revised: Patients with CBF-AML and core abnormalities may benefit from the addition of gemtuzumab ozogamicin....Gemtuzumab ozogamicin
is not beneficial in patients with adverse risk AML.
• Footnote d added: Borlenghi E, et al. J Geriatr Oncol 2021;12:550-556.
• Footnote e added: For CBF-AML leukemia with FLT3 mutation, the panel prefers gemtuzumab ozogamicin.
• Footnote f added: Gemtuzumab ozogamicin may be beneficial in NPM1-mutated AML (Kapp-Schwoerer S, et al. Blood 2020;136:3041-3050).
• Footnote p added: An FDA-approved biosimilar is an appropriate substitute for filgrastim.
• Footnote s added: Outcomes with unfavorable-risk cytogenetics and TP53-mutated AML remain poor with conventional induction chemotherapy (Rücker
FG, et al. Blood 2012;119:2114- 2121). Consider clinical trials, azacitidine/venetoclax (DiNardo CD, et al. N Engl J Med 2020;383:617-629), or a 10-day course
of decitabine (Welch JS, et al. N Engl J Med 2016;375:2023-2036).
• Footnote u revised by removing: However, one study showed that high-dose cytarabine may improve the outcome for younger patients. Willemze R, et al. J
Clin Oncol 2014;32:219-228.
AML-2 - AGE <60 y AFTER STANDARD-DOSE CYTARABINE INDUCTION/RE-INDUCTION
• Significant cytoreduction with low % residual blasts, 3rd bullet added: Intermediate or high-dose cytarabine Continued
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Acute Myeloid Leukemia (Age ≥18 years) Discussion

Updates in Version 1.2022 of the NCCN Guidelines for Acute Myeloid Leukemia from Version 3.2021 include:

AML-4
• Post-Remission/Maintenance Therapy header revised as Consolidation Therapy
CBF cytogenetic translocations, 1st bullet revised: ...on day 1 x 2 cycles (CD33-positive, NPM1 positive, FLT3 negative)
Intermediate-risk cytogenetics and Treatment-related disease other than CBF, moved maintenance therapy option to AML-10: Maintenance therapy with
oral azacitidine 300 mg PO once daily on days 1–14 of each 28-day cycle until progression or unacceptable toxicity (if patients decline or are not fit/
eligible for allogeneic HCT)
AML-5
• Treatment strategies, 2nd pathway revised: FLT3/ITD/TKD mutated (ITD or TKD) with intermediate/ poor-risk cytogenetics
• Footnote removed from page: 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.
AML-6 - AGE ≥60 y TREATMENT INDUCTION
• IDH1 or IDH2 mutation, for both preferred and other recommended, the venetoclax-based regimen moved to first bullet.
• Footnote eee added: DiNardo CD, et al. N Engl J Med 2020;383:617-629.
AML-8
• Post-Remission/Maintenance Therapy header revised as Post-Induction Therapy
• After complete response, the pathway was split by "Able to receive conventional consolidation" and "Not able to receive any or all of recommended
consolidation."
• Maintenance therapy options moved to not able to receive any or all of recommended consolidation.
Maintenance therapy with oral azacitidine 300 mg PO once daily on days 1–14 of each 28-day cycle until progression or unacceptable toxicity was
changed from a category 2A to a category 1, preferred recommendation.
Maintenance therapy with hypomethylating regimens every 4–6 weeks until progression, decitabine changed from a category 2A to a category 2B
recommendation.
AML-8A
• Footnote nnn was revised from, "This is a maintenance therapy and is not intended to replace consolidation chemotherapy, which can be curative in some
cases. In addition, fit patients 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 younger patients or those with with CBF-
AML; it was restricted to patients ≥55 years of age 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. Blood 2019;134 (Suppl_2):LBA-3 Wei AH, et al. N Engl J Med
2020;383:2526-2537."
• Footnote ooo was revised: An option for patients who had achieved a remission with a more intensive regimen but had regimen-related toxicity that
prevented them from receiving more conventional consolidation. Azacitidine: Huls G, et al. Blood 2019;133:1457-1464; Decitabine: Boumber Y, et al.
Leukemia 2012;26:2428–3241.
AML-10 MAINTENANCE THERAPY
• Added: Post allogeneic stem cell transplantation, in remission, and history of FLT3-ITD with the option of FLT3 inhibitor maintenance with sorafenib as a
category 2A recommendation.
• Clarified criteria for oral azacitidine as
Patient with intermediate or adverse risk disease:
◊ Who received prior intensive chemotherapy and is now in remission
◊ Completed no consolidation, some consolidation or a recommended course of consolidation and
◊ No allogeneic stem cell transplant is planned
• Added: Neither of the above scenarios is applicable with the recommendation for maintenance therapy as not recommended. Continued
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Acute Myeloid Leukemia (Age ≥18 years) Discussion

Updates in Version 1.2022 of the NCCN Guidelines for Acute Myeloid Leukemia from Version 3.2021 include:
AML-A 2 of 4 FAMILIAL GENETIC ALTERATIONS IN AML
• New page added related to predisposition to AML.
AML-H - RESPONSE CRITERIA DEFINITIONS FOR ACUTE MYELOID LEUKEMIA
• Statement added: 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.
AML-I - THERAPY FOR RELAPSED/REFRACTORY DISEASE
• Footnote 8 added: An FDA-approved biosimilar is an appropriate substitute for filgrastim.
AML-J - PRINCIPLES OF VENETOCLAX USE WITH HMA OR LDAC
• General, 2nd bullet revised from, "Reduction in duration of HMA and LDAC or venetoclax treatment can be considered, particularly when there are delays
in count recovery" to "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."
• Therapy for Newly Diagnosed Patients
Prior to therapy sub-bullets revised:
◊ To decrease the risk of severe tumor lysis syndrome (TLS), aim try to achieve WBC count of <25,000/mcL with hydroxyurea/leukapheresis if
necessary.
◊ Administer Initiate both therapies of the combination concomitantly.
◊ If azole antifungal prophylaxis or other CYP enzyme interacting medications are concurrently indicated, reduce venetoclax dose accordingly.
First Cycle Considerations
◊ TLS monitoring, 2nd sub-bullet revised by adding: Concomitant interacting medications may require changes to these dosages.
◊ TLS monitoring, 4th sub-bullet revised: 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.
◊ 3rd sub-bullet revised: If no morphologic remission (persistent marrow blasts above 5%)...
Cycle 2 and beyond
◊ 3rd sub-bullet added: If persistent disease after cycle 1, repeat marrow biopsy following cycle 2 (or subsequent cycles until NED or remission) to
again assess for cellularity and disease response, and determine timing of subsequent cycle.
◊ 6th sub-bullet revised: If no morphologic remission after cycle 2 or 3, the likelihood of response is decreased and patients could consider

Blastic Plasmacytoid Dendritic Cell Neoplasm

BPDCN-1
• Evaluation/Workup, 5th bullet revised from LP to rule out CNS disease; follow with IT prophylaxis if clinically indicated" to "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 prophylaxis as clinically indicated (see BPDCN-B)."

BPDCN-B - EVALUATION AND TREATMENT OF CNS DISEASE

• Recommendations added for treatment with and without CNS disease

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Acute Myeloid Leukemia (Age ≥18 years) Discussion

EVALUATION FOR AML DIAGNOSTIC DIAGNOSISd,e,f,g

STUDIES
(WHO 2016) Acute promyelocytic leukemia (APL):
• History and physical (H&P) In patients with clinical or pathologic features
• Complete blood count (CBC), platelets, differential, See APL
of APL, start all-trans retinoic acid (ATRA)
comprehensive metabolic panel, uric acid, lactate Classification
upon first suspicion of APL.h Early initiation of
dehydrogenase (LDH) and Treatment
ATRA may prevent the lethal complication of
• B12 and folic acid evaluation Recommendations
bleeding.h If cytogenetic and molecular testing
• Prothrombin time (PT), partial thromboplastin time (APL-1)
do not confirm APL, discontinue ATRA and
(PTT), fibrinogen continue treatment as for AML
• Bone marrow (BM) core biopsy and aspirate
analyses, including immunophenotyping by
immunohistochemistry (IHC) stains + flow cytometry Acute myeloid leukemia (AML):
and cytogenetic analyses (karyotype + FISH) (See To appropriately stratify available intensive
AML-A) therapy options, expedite test results
• Molecular analyses (ASXL1, c-KIT, FLT3 [ITD and of molecular and cytogenetic analyses
TKD], NPM1, CEBPA [biallelic], IDH1, IDH2, RUNX1, for immediately actionable mutations or
TP53, and other mutations)a (See AML-A) chromosomal abnormalities (eg, CBF, FLT3
See AML Risk
• Comprehensive pathology report, including diagnosis Multidisciplinary [ITD and TKD], NPM1, IDH1, IDH2)
Stratification and
of AML with recurrent cytogenetics vs. AML NOS, diagnostic • For patients with hyperleukocytosis
Treatment
blast count, cellularity, morphologic dysplasia, and studiesd,e uncontrolled with hydroxyurea or
Recommendations
mutation status if available leukapheresis, one dose of intermediate-dose
(AML-1)
• Human leukocyte antigen (HLA) typing for patient cytarabine (1–2 g) may be considered prior to
with potential hematopoietic cell transplantation receiving diagnostic results
(HCT) in the future (except for patients with a major • For patients who prefer not to receive
contraindication to HCT) and/or early referral to blood transfusion(s), see AML-D for general
transplant center considerations and supportive care
• Brain CT without contrast, if central nervous system For suspicion of blastic plasmacytoid dendritic
(CNS) hemorrhage suspectedb (See AML-B) cell neoplasm (BPDCN), see BPDCN-INTRO See NCCN
• Brain MRI with contrast, if leukemic meningitis Guidelines for
suspectedb (See AML-B) Myelodysplastic syndromes (MDS)
Myelodysplastic
• PET/CT, if clinical suspicion for extramedullary Syndromes
disease (See AML-B)
• Lumbar puncture (LP), if symptomaticb (category 2B See NCCN
for asymptomatic) B or T lymphoblastic Guidelines for Acute
• Evaluate myocardial function (echocardiogram or leukemia/lymphomae Lymphoblastic
MUGA scan) in patients with a history or symptoms Leukemia
of cardiac disease or prior/planned exposure to
cardiotoxic drugs or radiation to thorax
• Consider early integration of palliative carec (See See footnotes on EVAL-1A
NCCN Guidelines for Palliative Care) For the evaluation of BPDCN, see BPDCN-1

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.

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EVAL-1
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Acute Myeloid Leukemia (Age ≥18 years) Discussion

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 comprehensive 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 marrow 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 morphologically detectable, circulating leukemic blasts.
b Consider administration of one dose of 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 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 high-
grade MDS may allow enrollment of patients with AML-MDS.
e When presented with rare cases such as acute leukemias of ambiguous lineage including mixed phenotype acute leukemias (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. AML patients should preferably be managed at
experienced leukemia centers where clinical trials may be more available.
g Patients who present with isolated extramedullary disease (myeloid sarcoma) should be treated with systemic therapy. Local therapy (radiation therapy [RT] or surgery
[rare cases]) may be used for residual disease. See Principles of Radiation Therapy (AML-C).
h ATRA should be available in all community hospitals, so appropriate therapy can be started promptly.

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.

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EVAL-1A
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Acute Promyelocytic Leukemia (Age ≥18 years) Discussion

APL CLASSIFICATION AND TREATMENT RECOMMENDATIONS

See Treatment
Low risk (WBC 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.

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.

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Acute Promyelocytic Leukemia (Age ≥18 years) Discussion

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

Preferred Regimens • If blood count recovery by day 28
(platelet >100,000, ANC >1,000),
proceed with consolidation.
ATRAf 45 mg/m2 in 2 divided BM aspirate and biopsy may be
doses daily + arsenic considered to document morphologic
Arsenic trioxideg 0.15 mg/kg/d IV 5 d/wk for 4 weeks every
trioxideg 0.15 mg/kg IV remissionl,m but is optional.
8 weeks for a total of 4 cycles, and ATRA 45 mg/m2/d for 2
dailyh (category 1) See • If full course of induction treatment not
weeks every 4 weeks for a total of 7 cyclesh (category 1)
Principles of Supportive given, or counts have not recovered
Care for APL (APL-A) by day 28–35, a BM aspirate and
biopsy is recommended to document
morphologic remissionl,m before
or proceeding with consolidation
• If blood count recovery by day 28
(platelet >100,000, ANC >1,000), First 3 consolidation cycles = 56-day cycles:
ATRAf 45 mg/m2 in 2 divided proceed with consolidation. ATRA 45 mg/m2/d PO in 2 divided doses daily on days 1–14
doses daily + arsenic BM aspirate and biopsy may be and 29–42 (2 weeks on followed by 2 weeks off) + arsenic
trioxideg 0.3 mg/kg IV on considered to document morphologic trioxideg 0.3 mg/kg on days 1–5 of week 1 followed by 0.25
days 1–5 of week 1 and 0.25 remissionl,m but is optional. mg/kg twice weekly during weeks 2–4i
mg/kg twice weekly during • If full course of induction treatment not 4th consolidation cycle = 28-day cycle: See Post-
weeks 2–8i (category 1) See given, or counts have not recovered ATRA 45 mg/m2/d PO in 2 divided doses daily on days 1–14 Consolidation
Principles of Supportive by day 28–35, a BM aspirate and (2 weeks on followed by 2 weeks off) + arsenic trioxideg 0.3 Therapy
Care for APL (APL-A) biopsy is recommended to document mg/kg on days 1–5 of week 1 followed by 0.25 mg/kg twice (APL-5)
morphologic remissionl,m before weekly during weeks 2–4i
proceeding with consolidation
Useful in Certain Circumstances (if arsenic is not available or contraindicated)
ATRAf 45 mg/m2 in 2 divided ATRA 45 mg/m2 x 15 days + idarubicin 5 mg/m2 x 4 days x 1
At count recovery,
doses daily + idarubicin 12 cycle, then ATRA x 15 days + mitoxantrone 10 mg/m2/d x 3
proceed with
mg/m2 on days 2, 4, 6, 8j days x 1 cycle, then ATRA x 15 days + idarubicin 12 mg/m2 x
consolidationm,n
(category 1) 1 day x 1 cycle (category 1)j

BM aspirate and biopsy ATRA 45 mg/m2 in 2 divided doses daily during weeks 1–2,
ATRAf 45 mg/m2 in 2 divided 5–6, 9–10, 13–14, 17–18, 21–22, and 25–26. A single dose of
days 28–35 to document
doses daily + a single dose gemtuzumab ozogamicin 9 mg/m2 may be given monthlyk
morphologic remissionm
of gemtuzumab ozogamicin
before proceeding with until achievement of complete molecular response
9 mg/m2 on day 5k
consolidation

See footnotes on APL-2A

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.

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Acute Promyelocytic Leukemia (Age ≥18 years) Discussion

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 of 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).
h Lo-Coco F, et al. N Engl J Med 2013;369:111-121. Begin prophylaxis with prednisone through completion of induction. 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 (ie, absence of blasts and 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 marrow
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.

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.

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Acute Promyelocytic Leukemia (Age ≥18 years) Discussion

APL TREATMENT INDUCTION (HIGH RISK)b,c,d,o,p 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
6–12 mg/m2 on days 2, 4, 6, 8 + arsenic remission,l,m consider 28 days x 1 cycle, then ATRA 45 mg/m2 x 7 days every 2 weeks
trioxideg 0.15 mg/kg (days 9–36 as 2 h LP before proceeding x 3 + arsenic trioxide 0.15 mg/kg/d x 5 days for 5 weeks x 1
IV infusion)q with consolidationv cycleq,w,x
or
ATRAf 45 mg/m2 in 2 divided Arsenic trioxideg 0.15 mg/kg daily 5 d/wk for 4 weeks every
BM aspirate and biopsy
doses daily and arsenic trioxideg 8 weeks for a total of 4 cycles + ATRA 45 mg/m2 for 2 weeks
at day 28 to document
0.15 mg/kg/d IV + a single dose of every 4 weeks for a total of 7 cycles.r,x If ATRA or arsenic
remission,l,m consider
gemtuzumab ozogamicin 9 mg/m2 trioxide discontinued due to toxicity, a single dose of
LP before proceeding
may be given on day 1, or day 2, or gemtuzumab ozogamicin 9 mg/m2 may be given once every 4–5
with consolidationv
day 3, or day 4r weeks until 28 weeks from CR
or
ATRAf 45 mg/m2 in 2 divided doses ATRA 45 mg/m2 for 2 weeks every 4 weeks (or for 2 weeks on 2
daily and arsenic trioxideg 0.3 mg/kg IV BM aspirate and biopsy weeks off) in consolidation courses 1–4 + arsenic trioxideg 0.3
on days 1–5 of week 1 and 0.25 mg/kg at day 28 to document mg/kg on days 1–5 of week 1 in consolidation courses 1–4 and
twice weekly on weeks 2–8 (category remission,l,m consider 0.25 mg/kg twice weekly in weeks 2–4 in consolidation courses
1) + a single dose of gemtuzumab LP before proceeding 1–4 (category 1).i,x If ATRA or arsenic trioxide discontinued due
ozogamicin 6 mg/m2 may be given on with consolidationv to toxicity, a single dose of gemtuzumab ozogamicin 9 mg/m2 See Post-
day 1, or day 2, or day 3, or day 4i may be given once every 4–5 weeks until 28 weeks from CR Consolidation
Therapy (APL-5)
Other Recommended Regimenss
BM aspirate and biopsy
ATRAf 45 mg/m2 in 2 divided doses
at day 28 to document Arsenic trioxideg 0.15 mg/kg/d x 5 days for 5 weeks every 7
daily + daunorubicin 50 mg/m2 x 4
remission,l consider LP weeks for a total of 2 cycles, then ATRA 45 mg/m2 x 7 days +
days(IV days 3–6) + cytarabine 200
before proceeding with daunorubicin 50 mg/m2 x 3 days for 2 cyclest,x
mg/m2 x 7 days (IV days 3–9)t
consolidationv
or BM aspirate and biopsy
Daunorubicin 60 mg/m2 x 3 days + cytarabine 200 mg/m2 x 7
ATRAf 45 mg/m2 in 2 divided at day 28 to document
days x 1 cycle, then cytarabine 2 g/m2 (age <50) or 1.5 g/m2
doses daily + daunorubicin 60 remission,m consider
(age 50–60) every 12 h x 5 daysw,y + daunorubicin 45 mg/m2 x 3
mg/m2 x 3 days + cytarabine 200 LP before proceeding
days x 1 cycle + 5 doses of intrathecal (IT) chemotherapyu
mg/m2 x 7 daysu with consolidationv
or BM aspirate and biopsy ATRA 45 mg/m2 x 15 days + idarubicin 5 mg/m2 and cytarabine
ATRAf 45 mg/m2 in 2 divided doses daily at day 28 to document 1 g/m2 x 4 days x 1 cycle, then ATRA x 15 days + mitoxantrone
+ idarubicin 12 mg/m2 on days 2, 4, 6, 8j remission,m consider 10 mg/m2/d x 5 days x 1 cycle, then ATRA x 15 days +
LP before proceeding idarubicin 12 mg/m2 x 1 day + cytarabine 150 mg/m2/8 h x 4
See footnotes on APL-3A with consolidationv days x 1 cyclej,x

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.

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Acute Promyelocytic Leukemia (Age ≥18 years) Discussion

FOOTNOTES FOR APL TREATMENT INDUCTION AND CONSOLIDATION THERAPY (HIGH 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.
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).
i Burnett AK, et al. Lancet Oncol 2015;16:1295-1305.
j Sanz MA, et al. Blood 2010;115:5137-5146.
l If no evidence of morphologic disease (ie, absence of blasts and 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 marrow
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 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.
p 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. 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.
q Iland HJ, et al. Blood 2012;120:1570-1580.
r Abaza Y, et al. Blood 2017;129:1275-1283.
s No arsenic is included in induction if unavailable or contraindicated.
t Powell BL, et al. Blood 2010;116:3751-3757.
u Adès L, et al. Blood 2008;111:1078-1084.
v Breccia M, et al. Br J Haematol 2003;120:266-270.
w Although the original regimen included high-dose cytarabine as second consolidation, some investigators recommend using high-dose cytarabine early for CNS
prophylaxis, especially for patients not receiving IT chemotherapy.
x Consider IT chemotherapy (eg, 2 doses for each consolidation cycle) as an option for CNS prophylaxis.
y Dose adjustment of cytarabine may be needed for older patients or patients with renal dysfunction.

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.

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Acute Promyelocytic Leukemia (Age ≥18 years) Discussion

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

IN PATIENTS WITH CARDIAC ISSUES
(FOR PATIENTS WITHOUT CARDIAC ISSUES, SEE APL-3)

Low Ejection Fraction

BM aspirate and Arsenic trioxideg 0.15 mg/kg daily 5 days/wk for 4 weeks every 8
ATRAf 45 mg/m2 in 2 divided
biopsy at day weeks for a total of 4 cycles + ATRA 45 mg/m2 in 2 divided doses daily
doses daily + arsenic trioxideg
28 to document for 2 weeks every 4 weeks for a total of 7 cycles.r,x If ATRA or arsenic
0.15 mg/kg daily + a single dose
remissionl,m trioxide discontinued due to toxicity, a single dose of gemtuzumab
of gemtuzumab ozogamicin
before proceeding ozogamicin 9 mg/m2 may be given once every 4–5 weeks until 28
9 mg/m2 on day 1r
with consolidation weeks from CR
or
ATRAf 45 mg/m2 in 2 divided ATRA 45 mg/m2 in 2 divided doses daily for 2 weeks every 4 weeks (or
BM aspirate and
doses daily + arsenic trioxideg for 2 weeks on 2 weeks off) in consolidation courses 1–4 + arsenic
biopsy at day
0.3 mg/kg on days 1–5 of week 1 trioxideg 0.3 mg/kg on days 1–5 of week 1 in consolidation courses
28 to document
and 0.25 mg/kg twice weekly in 1–4 and 0.25 mg/kg twice weekly on weeks 2–4 in consolidation
remissionl,m before
weeks 2–8i (category 1) + a single courses 1–4 (category 1).i,x If ATRA or arsenic trioxide discontinued
proceeding with
dose of gemtuzumab ozogamicin due to toxicity, a single dose of gemtuzumab ozogamicin 9 mg/m2
consolidation
6 mg/m2 on day 1i may be given once every 4–5 weeks until 28 weeks from CR
See Post-
Consolidation
Prolonged QTc Therapy
BM aspirate and (APL-5)
ATRAf 45 mg/m2 in 2 divided
biopsy at day 28 to ATRA 45 mg/m2 in 2 divided doses daily during weeks 1–2, 5–6,
doses daily + a single dose of
document remissionm 9–10, 13–14, 17–18, 21–22, and 25–26. A single dose of gemtuzumab
gemtuzumab ozogamicin 9 mg/m2
on day 1k
before proceeding ozogamicin 9 mg/m2 may be given monthlyk until achievement of
with consolidation complete molecular response
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 at day 28 to document
cycle, then cytarabine 2 g/m2 (age <50) or 1.5 g/m2 (age 50–60) every
daily + daunorubicin 60 mg/m2 x 3 remission,m consider
12 h x 5 daysw,y + daunorubicin 45 mg/m2 x 3 days x 1 cycle +
days + cytarabine 200 mg/m2 x 7 LP before proceeding
5 doses of IT chemotherapyu
daysu with consolidationv
or BM aspirate and biopsy
ATRA 45 mg/m2 x 15 days + idarubicin 5 mg/m2 and cytarabine 1 g/m2
ATRAf 45 mg/m2 in 2 divided doses at day 28 to document
x 4 days x 1 cycle, then ATRA x 15 days + mitoxantrone 10 mg/m2/d x
daily + idarubicin 12 mg/m2 on days remission,m consider
5 days x 1 cycle, then ATRA x 15 days + idarubicin 12 mg/m2 x 1 day
2, 4, 6, 8j LP before proceeding
with consolidationv + cytarabine 150 mg/m2/8 h x 4 days x 1 cyclej,c

See footnotes on APL-4A

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.

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Acute Promyelocytic Leukemia (Age ≥18 years) Discussion

FOOTNOTES FOR APL TREATMENT INDUCTION AND CONSOLIDATION THERAPY (HIGH 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.
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).
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 (ie, absence of blasts and 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 marrow
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 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.
r Abaza Y, et al. Blood 2017;129:1275-1283.
u Adès L, et al. Blood 2008;111:1078-1084.
v Breccia M, et al. Br J Haematol 2003;120:266-270.
w Although the original regimen included high-dose cytarabine as second consolidation, some investigators recommend using high-dose cytarabine early for CNS
prophylaxis, especially for patients not receiving IT chemotherapy.
x Consider 4–6 doses of IT chemotherapy (eg, 2 doses for each consolidation cycle) as an option for CNS prophylaxis.
y Dose adjustment of cytarabine may be needed for older patients or patients with renal dysfunction.

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.

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APL POST- MONITORING

CONSOLIDATION
THERAPY

Monitor by
Polymerase PCRz 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 PCR PCRz for
therapy positiveaa confirmation
within 4 wks
Document PCR positiveaa
molecular
remissionz,aa First
after relapsebb
consolidation See
PCR negative
Repeat Therapy
PCRz for for Relapse
PCR positivez
confirmation (APL-6)
within 4 wks
PCR positiveaa

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

document molecular remission. In patients receiving the ATRA/arsenic regimen, aa To confirm PCR positivity, a second blood sample should be done in 2–4 weeks
consider earlier sampling at 3–4 months during consolidation. Prior practice in a reliable laboratory. If molecular relapse is confirmed by a second positive test,
guidelines have recommended monitoring blood by PCR every 3 mo for 2 y to treat as first relapse (APL-6). If the second test is negative, frequent monitoring
detect molecular relapse. We continue to endorse this for high-risk patients, those (every 3 mo for 2 y) is strongly recommended to confirm that the patient remains
>60 y of age or who had long interruptions during consolidation, or patients on negative. The PCR testing lab should indicate the level of sensitivity of assay for
regimens that use maintenance and are not able to tolerate maintenance. Clinical positivity (most clinical labs have a sensitivity level of 10-4), and testing should
experience indicates that risk of relapse in patients with low-risk disease who are be done in the same lab to maintain the same level of sensitivity. Consider
in molecular remission at completion of consolidation is low and monitoring may consultation with a physician experienced in molecular diagnostics if results are
not be necessary outside the setting of a clinical trial. While long-term monitoring equivocal.
has been standard, with newer, more effective regimens, the value is less certain. bb Grimwade D, et al. J Clin Oncol 2009;27:3650-3658.

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.

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APL THERAPY FOR RELAPSE ADDITIONAL THERAPY

Transplant Autologous
candidate HCT
PCR
Early relapse negative
(by BM) Not Arsenic trioxideg
(<6 mo) after ATRA Anthracycline-based
transplant consolidation
and arsenic trioxide regimen as per APL-3ee,ff
Consider CNS candidate (total of 6 cycles)
(no anthracycline)
prophylaxis
Second
with IT
remission
chemotherapy
(morphologic)
(methotrexate
Arsenic trioxide 0.15 mg/ or cytarabine) Matched sibling
No prior exposure kg dailyg,ee,ff ± ATRA 45 Transplant
or alternative
candidate
First relapse to arsenic trioxide mg/m2 in 2 divided doses PCR donor HCTdd
(morphologic or early relapse dailydd ± a single dose of positive
or molecular)cc (<6 mo) after ATRA gemtuzumab ozogamicin (by BM) Not
+ anthracycline- until count recovery with transplant Clinical trial
containing marrow confirmation of candidate
regimendd remission
Arsenic trioxide 0.15 mg/
kg dailyg,ee,ff ± ATRA 45 Clinical trial
mg/m2 in 2 divided doses or
No remission
Late relapse (≥6 mo) dailygg ± (anthracycline Matched sibling or
after arsenic trioxide- or a single dose of alternative donor HCT
containing regimen gemtuzumab ozogamicin)
until count recovery with
marrow confirmation of
ee Following the first cycle of consolidation, if the patient is not in molecular
remission
remission (by quantitative PCR on marrow sample), consider matched sibling or
alternative donor (haploidentical, unrelated donor, or cord blood) HCT or clinical
trial. Testing is recommended at least 2–3 weeks after the completion of arsenic
to avoid false positives.
g QTc and monitoring and optimizing electrolytes are important in safe ff Outcomes are uncertain in patients who received arsenic trioxide during initial
administration of arsenic trioxide. See Arsenic trioxide monitoring in Principles of induction/consolidation therapy.
Supportive Care for APL (APL-A). gg There is a small randomized trial that suggests that the addition of ATRA
cc Document molecular panel to verify relapsed APL versus therapy-related AML. does not confer any benefit over arsenic alone. Raffoux E, et al. J Clin Oncol
dd Cicconi L, et al. Ann Hematol 2018;97:1797-1802. 2003;21:2326-2334.

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.

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Acute Promyelocytic Leukemia (Age ≥18 years) Discussion

PRINCIPLES OF SUPPORTIVE CARE FOR APL1

There are variations among institutions, but the following issues are important to consider in the management of patients with 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.
• Leukapheresis2 is not recommended in the routine management of 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:
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 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.3,4
The following cytoreduction strategies for leukocytosis may be used for differentiation syndrome that is difficult to treat: hydroxyurea,
anthracycline, gemtuzumab ozogamicin.
• Arsenic trioxide monitoring:
Prior to initiating therapy
◊ Electrocardiogram (ECG) for prolonged QTc interval assessment
◊ Serum electrolytes (Ca, K, Mg) 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.5
• 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.
2 Daver N, et al. Br J Haematol 2015;168:646-53.
1 Antiviral
prophylaxis zoster for duration of treatment may be appropriate. 3 Lo-Coco F, et al. N Engl J Med 2013;369:111-121.
Freyer CW, et al. Leuk Lymphoma 2021;62:696-702; Glass JL, et al. Blood 4 Sanz MA, et al. Blood 2010;115:5137-5146.
2015;126:Abstract 3752. 5 Sanz MA, et al. Blood 2019;133:1630-1643.

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.

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Acute Myeloid Leukemia (Age ≥18 years) Discussion

AGE<60 y TREATMENT TREATMENT INDUCTIONg,h,i,j

INDUCTION STRATEGIES
ELIGIBLE Options:
• Standard-dose cytarabine 200 mg/m2 continuous infusion x 7 days with
daunorubicin 60 mg/m2 x 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,
Favorable-risk three total doses may be given on days 1, 4, and 7k,l (CD33-positive)m (preferred)
cytogenetics • Standard-dose cytarabine 100–200 mg/m2 continuous infusion x 7 days with
idarubicin 12 mg/m2 or daunorubicin 60–90 mg/m2 x 3 daysn,o (category 1)
• Fludarabine 30 mg/m2 days 2–6, high-dose cytarabine (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 granulocyte colony-stimulating factor (G-CSF)p subcutaneously (SC) daily days
1–7 plus a single dose of gemtuzumab ozogamicin 3 mg/m2 in first course (category 2B)q
FLT3/ITD/TKD with Standard-dose cytarabine 200 mg/m2 continuous infusion x 7 days with
intermediate/poor-risk daunorubicin 60 mg/m2 x 3 days and oral midostaurin 50 mg every 12 hours, days 8–21r
cytogeneticse (FLT3-mutated AML)
See
Agea,b,c Follow-up
<60 y Unfavorable-risk (AML-2)
induction cytogenetics and TP53- Alternative induction strategies should be considereds
eligibled mutated
• Therapy-related AML
other than CBF/AML Options:
• Antecedent • Standard-dose cytarabine 100–200 mg/m2 continuous infusion x 7 days with
MDS/CMML idarubicin 12 mg/m2 or daunorubicin 60–90 mg/m2 x 3 daysn,o (category 1)
• Cytogenetic changes • CPX-351/dual-drug liposomal encapsulation of cytarabine 100 mg/m2 and daunorubicin 44
consistent with MDS mg/m2 on days 1, 3, and 5 x 1 cyclet (category 2B)
(AML-MRC)
Options:
• Standard-dose cytarabine 100–200 mg/m2 continuous infusion x 7 days with
idarubicin 12 mg/m2 or daunorubicin 60–90 mg/m2 x 3 daysn,o (category 1)
• Standard-dose cytarabine 200 mg/m2 continuous infusion x 7 days with
daunorubicin 60 mg/m2 x 3 days and a single dose of gemtuzumab ozogamicin 3 mg/m2
Other recommended (up to one 4.5 mg vial) given on day 1, or day 2, or day 3, or day 4; alternatively, three
regimensf for
total doses may be given on days 1, 4, and 7k,l (CD33-positive)m (intermediate-risk AML)
intermediate- or
• HiDACo,u 2 g/m2 every 12 hours x 6 daysv or 3 g/m2 every 12 h x 4 daysw with
poor-risk disease
idarubicin 12 mg/m2 or daunorubicin 50 mg/m2 x 3 days,s and etoposide 50 mg/m2
days 1 to 5x (1 cycle) (category 1 for patients ≤45 y, category 2B for other age groups) See
• Fludarabine 30 mg/m2 on days 2–6, HiDAC 2 g/m2 over 4 hours starting 4 hours after Follow-up
fludarabine on days 2–6, idarubicin 8 mg/m2 IV on days 4–6, (AML-3)
See footnotes on AML-1A and G-CSF SC daily days 1–7 (category 2B)q

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.

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Acute Myeloid Leukemia (Age ≥18 years) Discussion

FOOTNOTES FOR TREATMENT INDUCTION ELIGIBLE (AGE <60 YEARS)

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
apheresis, hydroxyurea, and/or a single dose of cytarabine (1–2 g). Prompt institution of definitive therapy is essential.
b Poor performance status and a comorbid medical condition, in addition to age, are factors that influence ability to tolerate standard induction therapy.
c Patients with CBF-AML may benefit from the addition of gemtuzumab ozogamicin. Consider screening with fluorescence in situ hybridization (FISH) to identify
translocations/abnormalities associated with CBF-AML. Gemtuzumab ozogamicin is not beneficial in patients with adverse risk AML.
d Borlenghi E, et al. J Geriatr Oncol 2021;12:550-556.
e For CBF-AML leukemia with FLT3 mutation, the panel prefers gemtuzumab ozogamicin.
f Gemtuzumab ozogamicin may be beneficial in NPM1-mutated AML (Kapp-Schwoerer S, et al. Blood 2020;136:3041-3050).
g See Principles of Supportive Care for AML (AML-E).
h See Monitoring During Therapy (AML-F).
i 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.
j See General Considerations and Supportive Care for AML Patients Who Prefer Not to Receive Blood Transfusions (AML-D).
k Burnett AK, et al. J Clin Oncol 2011;29:369-377. Meta-analyses showing an advantage with gemtuzumab ozogamicin have included other dosing schedules; Hills RK,
et al. Lancet Oncol 2014;15:986-996.
l Patients who receive transplant shortly following gemtuzumab ozogamicin administration may be at risk for developing sinusoidal obstruction syndrome (SOS).
Wadleigh M, et al. Blood 2003;102:1578-1582. If transplant is planned, note that prior studies have used a 60- to 90-day interval between the last administration of
gemtuzumab ozogamicin and HCT.
m Threshold for CD33 is not well-defined and may be ≥1%.
n ECOG reported a significant increase in complete response rates and overall survival 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.
o For patients with impaired cardiac function, other cytarabine-based regimens alone or with other agents can be considered. See Discussion.
p An FDA-approved biosimilar is an appropriate substitute for filgrastim.
q Burnett AK, et al. J Clin Oncol 2013;31:3360-3368.
r This regimen is for FLT3 mutation-positive AML (both ITD and TKD mutations). While midostaurin was 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.
s Outcomes with unfavorable-risk cytogenetics and TP53-mutated AML remain poor with conventional induction chemotherapy (Rücker FG, et al. Blood 2012;119:2114-
2121). Consider clinical trials, azacitidine/venetoclax (DiNardo CD, et al. N Engl J Med 2020;383:617-629), or a 10-day course of decitabine (Welch JS, et al. N Engl J
Med 2016;375:2023-2036).
t 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.
u The use of high-dose cytarabine for induction outside the setting of a clinical trial is still controversial. While the remission rates are the same for standard- and high-
dose cytarabine, two studies have shown more rapid marrow blast clearance after one cycle of high-dose therapy. Kern W and Estey EH. Cancer 2006;107:116-124.
v Weick JK, et al. Blood 1996;88:2841-2851.
w Bishop JF, et al. Blood 1996;87:1710-1717.
x Willemze R, et al. J Clin Oncol 2014;32:219-228.

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.

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Acute Myeloid Leukemia (Age ≥18 years) Discussion

AGE <60 y
AFTER STANDARD-DOSE CYTARABINE INDUCTION/RE-INDUCTIONi,y,z

Options:
• Cytarabine 1.5–3 g/m2 every 12 hours x 6 daysdd
• Standard-dose cytarabine with idarubicin or
daunorubicinee,ff Complete response
• Standard-dose cytarabine with daunorubicin and (Screening LP, see Consolidation
Significant
oral midostaurinr,ee (BM aspirate and biopsy on (AML-4)
residual AML-B) (Response
day 21) (FLT3 mutated [ITD or TKD])
disease criteria, see AML-H)
• CPX-351/dual-drug liposomal encapsulation of BM aspirate and
without a
cytarabine 100 mg/m2 and daunorubicin 44 mg/ biopsy to document
hypocellular
m2 on days 1 and 3 x 1 cyclegg (therapy-related
BMbb,cc remission status
AML other than CBF-AML/APL, or patients with upon hematologic
antecedent MDS/CMML, or AML-MRC) (preferred recovery, including
only if given in induction; BM aspirate and biopsy cytogenetics and
14–21 days after start of therapy) molecular studies
Follow-up • See treatment for induction failure as appropriate.
BMh Options:
For measurable
aspirate (minimal) residual • Matched sibling or
and biopsy Significant disease (MRD) alternative donor HCTz
14–21 days cytoreductioncc Options: assessment, see • HiDAC (if not previously
after start with low % • Standard-dose cytarabine with idarubicin AML-G used as treatment for
of residual blasts or daunorubicinee,ff Induction persistent disease at
therapyaa (if ambiguous, • Standard-dose cytarabine with failure day 15) ± anthracycline
consider repeat daunorubicin and oral midostaurinr,ee (Response (daunorubicin or
BM biopsy in (BM aspirate and biopsy on day 21) (FLT3 criteria, idarubicin)ee if a clinical
5–7 days before mutated [ITD or TKD]) see AML-H) trial is not available while
proceeding with • Intermediate- or high-dose cytarabine awaiting identification of a
therapy) donor
• See Therapy for Relapsed/
Refractory Disease (AML-I)
Hypoplasiabb,cc Await recovery • Best supportive care

See footnotes on AML-2A

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.

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Acute Myeloid Leukemia (Age ≥18 years) Discussion

FOOTNOTES FOR TREATMENT AFTER STANDARD-DOSE CYTARABINE INDUCTION/RE-INDUCTION (AGE <60 YEARS)
h See Monitoring During Therapy (AML-F).
i 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.
r This regimen is for FLT3 mutation-positive AML (both ITD and TKD mutations). While midostaurin was 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.
y Consider clinical trials for patients with targeted molecular abnormalities.
z 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 induction failure, alternative therapy to achieve remission is encouraged prior to HCT.
aa There are limited prospective data to support this recommendation. Othus M, et al. Leukemia 2016;30:1779-1780.
bb If ambiguous, consider repeat BM biopsy in 5–7 days before proceeding with therapy.
cc Hypoplasia is defined as cellularity less than 20% of which the residual blasts are less than 5% (ie, blast percentage of residual cellularity).
dd For re-induction, no data are available to show superiority with intermediate or high-dose cytarabine.
ee 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.
ff 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.
gg Lancet JE, et al. J Clin Oncol 2018;36:2684-2692.

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.

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Acute Myeloid Leukemia (Age ≥18 years) Discussion

AGE <60 y
AFTER HIGH-DOSE CYTARABINE INDUCTIONi,y,z

Significant residual See Therapy for Relapsed/Refractory Disease (AML-I)

disease without a or
hypocellular BMbb,cc Best supportive care

Significant
cytoreductioncc
with low %
Follow-up BMh
residual blasts BM aspirate and
aspirate and Complete response
(if ambiguous, Await biopsy to document
biopsy 21–28 (Screening LP, see
consider repeat recovery remission status Consolidation (AML-4)
days after start AML-B) (Response
BM biopsy in upon hematologic
of therapy criteria, see AML-H)
5–7 days before recovery, including
proceeding with cytogenetics and
therapy) See Therapy for Relapsed/
molecular studies Refractory Disease (AML-I)
as appropriate. For Induction failure or
Await MRD assessment,
Hypoplasiabb,cc (Response criteria, Matched sibling or
recovery see AML-G see AML-H) alternative donor HCTz
or
Best supportive care

h See Monitoring During Therapy (AML-F).

i Consider referral to palliative care for consultationat 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.
y Consider clinical trials for patients with targeted molecular abnormalities.
z 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 induction failure, alternative therapy to achieve remission is encouraged prior to HCT.
bb If ambiguous, consider repeat BM biopsy in 5–7 days before proceeding with therapy.
cc Hypoplasia is defined as cellularity less than 20% of which the residual blasts are less than 5% (ie, blast percentage of residual cellularity).

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.

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Acute Myeloid Leukemia (Age ≥18 years) Discussion

AGE <60 y RISK STATUS CONSOLIDATION THERAPY

(See AML-A)

Options:
• HiDAC 3 g/m2 over 3 h every 12 h on days 1, 3, 5 (category 1) or days 1, 2, 3 x 3–4 cyclesii,jj
CBF cytogenetic
with or without gemtuzumab ozogamicin 3 mg/m2 (up to one 4.5 mg vial) on day 1 x 2
translocations and
MRD negative cyclesl,kk (CD33-positive, NPM1 positive, FLT3 negative)
(see AML-G) • Cytarabine 1000 mg/m2 every 12 hours on days 1–4 + daunorubicin 60 mg/m2 on day 1
(first cycle) or days 1–2 (second cycle) + gemtuzumab ozogamicin 3 mg/m2 (up to one 4.5
mg vial) on day 1 x 2 cyclesl,kk,ll(CD33-positive)

Options:
Intermediate-risk • Matched sibling or alternative donor HCTz,mm
cytogenetics and/ • HiDACnn 1.5–3 g/m2 over 3 h every 12 h on days 1, 3, 5 or days 1, 2, 3 x 3–4 cyclesii,jj
Age <60 y or molecular • HiDACnn 1.5–3 g/m2 over 3 h every 12 h on days 1, 3, 5 or days 1, 2, 3 with oral midostaurin See
abnormalities, 50 mg every 12 hours on days 8–21 x 4 cyclesr,ii,jj (FLT3-mutated AML) Maintenance
including MRD • Cytarabine 1000 mg/m2 every 12 hours on days 1–4 + daunorubicin 60 mg/m2 on day 1 (AML-10)
positive (see AML-G) (first cycle) or days 1–2 (second cycle) + gemtuzumab ozogamicin 3 mg/m2 (up to one 4.5
mg vial) on day 1 x 2 cyclesl,ll (CD33-positive)

Options:
Treatment-related • Matched sibling or alternative donor HCTz,mm (preferred)
disease other than • HiDAC 1.5–3 g/m2 over 3 h every 12 h on days 1, 3, 5 or days 1, 2, 3 x 3–4 cyclesii,jj
CBF and/or • HiDAC 1.5–3 g/m2 over 3 h every 12 h on days 1, 3, 5 or days 1, 2, 3 with oral midostaurin
unfavorable 50 mg every 12 hours on days 8–21 x 4 cyclesr,ii,jj (FLT3-mutated AML)
cytogenetics • CPX-351/dual-drug liposomal encapsulation of cytarabine 65 mg/m2 and daunorubicin 29
and/or molecular mg/m2 on days 1 and 3 x 1–2 cyclesoo (therapy-related AML or patients with antecedent
abnormalitiesz,hh MDS/CMML or AML-MRC) (preferred only if given in induction)

See footnotes on AML-4A

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.

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Acute Myeloid Leukemia (Age ≥18 years) Discussion

FOOTNOTES FOR CONSOLIDATION THERAPY (AGE <60 YEARS)

l Patients who receive transplant shortly following gemtuzumab ozogamicin administration may be at risk for developing SOS. Wadleigh M, et al. Blood 2003;102:1578-
1582. If transplant is planned, note that prior studies have used a 60- to 90-day interval between the last administration of gemtuzumab ozogamicin and HCT.
r This regimen is for FLT3 mutation-positive AML (both ITD and TKD mutations). While midostaurin was 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.
z 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 induction failure, alternative therapy to achieve remission is encouraged prior to HCT.
hh 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.
ii Mayer RJ, et al. N Engl J Med 1994;331:896-903; Jaramillo S, et al. Blood Cancer J 2017;7:e564.
jj Alternate dosing of cytarabine for postremission therapy has been reported (see Discussion). Jaramillo S, et al. Blood Cancer J 2017;7:e564.
kk Meta-analyses showing an advantage with gemtuzumab ozogamicin have included other dosing schedules. Hills RK, et al. Lancet Oncol 2014;15:986-996.
ll This regimen may also be used in patients with KIT mutations because the outcomes are similar in patients without KIT mutations.
mm Patients may require at least one cycle of high-dose cytarabine 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.
nn There is no evidence that HiDAC is superior to intermediate doses (1.5 g/m2 daily x 5 days) of cytarabine in patients with intermediate-risk cytogenetics.
oo Lancet JE, et al. J Clin Oncol 2018;36:2684-2692.

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.

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Acute Myeloid Leukemia (Age ≥18 years) Discussion

AGE ≥60 ya,pp TREATMENT TREATMENT INDUCTIONg,i,j

STRATEGIESqq
Options:
• Standard-dose cytarabine 200 mg/m2 continuous infusion x 7 days with
daunorubicin 60 mg/m2 x 3 days and three total doses of gemtuzumab ozogamicin
Favorable-risk 3 mg/m2 (up to one 4.5 mg vial) may be given on days 1, 4, and 7;rr alternatively, a single
cytogenetics dose may be given on day 1, or day 2, or day 3, or day 4l,kk (CD33-positive)m
• Standard-dose cytarabine (100–200 mg/m2 continuous infusion x 7 days) with idarubicinss
See Post-
12 mg/m2 or daunorubicintt 60–90 mg/m2 x 3 days or
Induction
mitoxantrone 12 mg/m2 x 3 days
Therapy
FLT3/ITD/TKD with (AML-7)
intermediate/poor-risk Standard-dose cytarabine 200 mg/m2 continuous infusion x 7 days with
cytogenetics daunorubicin 60 mg/m2 x 3 days and oral midostaurin 50 mg every 12 hours, days 8–21r,uu

• Therapy-related AML
CPX-351/dual-drug liposomal encapsulation of cytarabine 100 mg/m2 and daunorubicin 44
Candidate • Antecedent MDS/CMML
mg/m2 on days 1, 3, and 5 x 1 cycleoo (category 1)
for • AML-MRC
intensive
remission Options: (Principles of Venetoclax, see AML-J)
induction • Venetoclax once daily (100 mg day 1, 200 mg day 2, and 400 mg day 3 and beyond) PO
therapy and decitabine 20 mg/m2 IV (days 1–5 of each 28-day cycle)vv,ww
See Post-
Unfavorable-risk • Venetoclax once daily (100 mg day 1, 200 mg day 2, and 400 mg day 3 and beyond) PO
Induction
cytogenetics and azacitidine 75 mg/m2 SC or IV (days 1–7 of each 28-day cycle)vv,ww
Therapy
(exclusive of AML-MRC) • Venetoclax once daily (100 mg day 1, 200 mg day 2, 400 mg day 3, and 600 mg day 4 and
(AML-9)
beyond) PO and low-dose cytarabine (LDAC) 20 mg/m2/d SC (days 1–10 of each 28-day
cycle)vv,xx
• Low-intensity therapy (azacitidine [category 2B], decitabine)ww
Options:
• Standard-dose cytarabine (100–200 mg/m2 continuous infusion x 7 days) with
Other recommended idarubicinss 12 mg/m2 or daunorubicintt 60–90 mg/m2 x 3 days or mitoxantrone See Post-
regimens for intermediate- 12 mg/m2 x 3 days Induction
or poor-risk disease • Standard-dose cytarabine 200 mg/m2 continuous infusion x 7 days with daunorubicin Therapy
60 mg/m2 x 3 days and a single dose of gemtuzumab ozogamicin 3 mg/m2 (up to one 4.5 (AML-7)
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 7l,kk,yy (CD33-positive)m (intermediate-risk AML)
See footnotes on AML-5A
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.

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Acute Myeloid Leukemia (Age ≥18 years) Discussion

FOOTNOTES FOR TREATMENT INDUCTION (AGE ≥60 YEARS)

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
apheresis, hydroxyurea, and/or a single dose of cytarabine (1–2 g). Prompt institution of definitive therapy is essential.
g See Principles of Supportive Care for AML (AML-E).
i 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.
j See General Considerations and Supportive Care for Patients Who Prefer Not to Receive Blood Transfusions (AML-D).
l Patients who receive transplant shortly following gemtuzumab ozogamicin administration may be at risk for developing SOS. Wadleigh M, et al. Blood 2003;102:1578-
1582. If transplant is planned, note that prior studies have used a 60- to 90-day interval between the last administration of gemtuzumab ozogamicin and HCT.
m Threshold for CD33 is not well-defined and may be ≥1%.
r This regimen is for FLT3 mutation-positive AML (both ITD and TKD mutations). While midostaurin was 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.
kk Meta-analyses showing an advantage with gemtuzumab ozogamicin have included other dosing schedules. Hills RK, et al. Lancet Oncol 2014;15:986-996.
oo Lancet JE, et al. J Clin Oncol 2018;36:2684-2692.
pp There is a web-based scoring tool available to evaluate the probability of complete response and early death after standard induction therapy in elderly patients with
AML: [Link] Krug U, et al. Lancet 2010;376:2000-2008. A web-based tool to predict CR and early death can be found at: [Link]
[Link] and Walter RB, et al. J Clin Oncol 2011;29:4417-4423. Factors in decisions about fitness for induction chemotherapy include age, performance status,
functional status, and comorbid conditions. See NCCN Guidelines for Older Adult Oncology.
qq Patients with TP53 mutations are a group with poor prognosis, and should be considered for enrollment in clinical trials.
rr Castaigne S, et al. Lancet 2012;379:1508-1516.
ss For patients who exceed anthracycline dose or have cardiac issues but are still able to receive aggressive therapy, alternative non-anthracyline–containing regimens
may be considered (eg, FLAG, clofarabine-based regimens [category 3]).
tt The complete response rates and 2-year overall survival 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).
uu The RATIFY trial studied patients aged 18–60 y. An extrapolation of the data suggests that older patients 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.
vv This regimen may be continued for patients who demonstrate clinical improvement (CR/CRi), with consideration of subsequent transplant, where appropriate. DiNardo
CD, et al. Lancet Oncol 2018;19:216-228; Wei A, et al. Blood 2017;130:890; Wei A, et al. Haematologica 2017; Abstract S473; DiNardo CD, Blood 2019;133:7-17;
DiNardo CD, et al. N Engl J Med 2020;383:617-629.
ww Patients who have progressed to AML from MDS after significant exposure to hypomethylating agents (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.
xx Wei AH, et al. J Clin Oncol 2019;37:1277-1284.
yy Regimens that include gemtuzumab ozogamicin have limited benefit in patients with poor-risk disease.

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.

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Acute Myeloid Leukemia (Age ≥18 years) Discussion

AGE ≥60 ya,pp TREATMENT TREATMENT INDUCTIONg,i,j

STRATEGIES Principles of Venetoclax, see AML-J

Preferred
• Venetoclax once daily (100 mg day 1, 200 mg day 2, 400 mg day 3 and beyond) PO and
azacitidine 75 mg/m2 SC or IV (days 1–7 of each 28-day cycle)vv,ww,eee (category 1)
• Venetoclax once daily (100 mg day 1, 200 mg day 2, 400 mg day 3 and beyond) PO and
decitabine 20 mg/m2 IV (days 1–5 of each 28-day cycle)vv,ww
Other Recommended
AML without • Venetoclax once daily (100 mg day 1, 200 mg day 2, 400 mg day 3, and 600 mg day 4 and beyond)
actionable PO and LDAC 20 mg/m2/d SC (days 1–10 of each 28-day cycle)xx
mutations • Low-intensity therapy (azacitidine, decitabine)ww,zz
• Glasdegib (100 mg PO daily on days 1–28) + LDAC 20 mg SC every 12 hours (days 1–10 of each
28-day cycle)aaa
• Gemtuzumab ozogamicin 6 mg/m2 on day 1 and 3 mg/m2 on day 8bbb,ccc
(CD33-positive)m (category 2B)
• LDAC (category 3) 20 mg/m2/day SC for 10 consecutive days every 4 weeksddd
• Best supportive care (hydroxyurea, transfusion support)
See
Not a Preferred Post-Induction
candidate • Venetoclax-based therapy (same as above in combination with azacitidine or decitabine)vv,ww Therapy
for intensive (category 1 for combination with azacitidine)eee (AML-9)
remission IDH1 or IDH2 • Ivosidenibfff,ggg (IDH1 only)
induction mutation • Ivosidenib once daily (500mg) PO and azacitidine 75 mg/m2 SC or IV (days 1-7 or day 1-5, 8-9 of
therapy or each 28-day cycle)iii (category 1) (IDH1 only)
declines • Enasidenibggg,hhh (IDH2 only)
Other Recommended
• Venetoclax-based therapy (same as above in combination with LDACxx)
• Low-intensity therapy (azacitidine, decitabine)xx,aaa

Preferred
• Venetoclax-based therapy (same as above in combination with azacitidine or decitabine)vv,ww
FLT3 (category 1 for combination with azacitidine)eee
mutation Other Recommended
• Low-intensity therapy (azacitidine, decitabineww) + sorafenibjjj (FLT3-ITD–positive)
• Venetoclax-based therapy (same as above in combination with LDACxx)

See footnotes on AML-6A

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.

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Acute Myeloid Leukemia (Age ≥18 years) Discussion

FOOTNOTES FOR TREATMENT INDUCTION (AGE ≥60 YEARS)

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
apheresis, hydroxyurea, and/or a single dose of cytarabine (1–2 g). Prompt institution of definitive therapy is essential.
g See Principles of Supportive Care for AML (AML-E).
i 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.
j See General Considerations and Supportive Care for Patients Who Prefer Not to Receive Blood Transfusions (AML-D).
m Threshold for CD33 is not well-defined and may be ≥1%.
pp There is a web-based scoring tool available to evaluate the probability of complete response and early death after standard induction therapy in elderly patients with
AML: [Link] Krug U, et al. Lancet 2010;376:2000-2008. A web-based tool to predict CR and early death can be found at: [Link]
[Link] and Walter RB, et al. J Clin Oncol 2011;29:4417-4423. Factors in decisions about fitness for induction chemotherapy include age, performance status,
functional status, and comorbid conditions. See NCCN Guidelines for Older Adult Oncology.
vv This regimen may be continued for patients who demonstrate clinical improvement (CR/CRi), with consideration of subsequent transplant, where appropriate. DiNardo
CD, et al. Lancet Oncol 2018;19:216-228; Wei A, et al. Blood 2017;130:890; Wei A, et al. Haematologica 2017; Abstract S473; DiNardo CD, Blood 2019;133:7-17;
DiNardo CD, et al. N Engl J Med 2020;383:617-629.
ww Patients who have 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.
xx Wei AH, et al. J Clin Oncol 2019;37:1277-1284.
zz 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.
aaa 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.
bbb Amadori S, et al. J Clin Oncol 2016;34:972-979.
ccc Regimens that include gemtuzumab ozogamicin will not benefit patients with poor-risk disease.
ddd Kantarjian HM, et al. J Clin Oncol 2012;30:2670-2677.
eee DiNardo CD, et al. N Engl J Med 2020;383:617-629.
fff DiNardo CD, et al. Blood 2017;130:725; DiNardo CD, et al. Blood 2017;130:639; Roboz GJ, et al. Blood 2020;135:463-471.
ggg When using this agent, 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).
hhh Stein EM, et al. Blood 2015;126:323; DiNardo CD, et al. Blood 2017;130:639.
iii This regimen is approved for newly-diagnosed AML with an IDH1 mutation who met at least one of the following criteria: age >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 < 45 mL/min, or other
comorbidity. Montesinos P, et al. N Engl J Med 2022;386:1519-153.
jjj Ohanian M, et al. Am J Hematol 2018;93:1136-1141.

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.

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Acute Myeloid Leukemia (Age ≥18 years) Discussion

AGE ≥60 yz
AFTER STANDARD-DOSE CYTARABINE INDUCTIONi
Options:
• Additional standard-dose cytarabine with anthracycline (idarubicin or
daunorubicintt)ff or mitoxantroneee
• Standard-dose cytarabine with daunorubicin and oral midostaurinr,ee,uu
(FLT3 mutated [ITD or TKD])
Residual diseasebb
• Dual-drug liposomal encapsulation of cytarabine 100 mg/m2 and
(if ambiguous, consider See Post-
daunorubicin 44 mg/m2 on days 1 and 3 x 1–2 cyclesoo (therapy-related
repeat BM biopsy in 5–7 Induction
AML or patients with antecedent MDS/CMML or AML-MRC)
days before proceeding Therapy
(preferred only if given in induction)
Follow-up BMh with therapy)
• Intermediate-dose cytarabine (1–<2 g/m2)-containing regimens
(AML-8)
aspirate and • Consider allogeneic HCTkkk
biopsy 14–21 • See Therapy for Relapsed/Refractory Disease (AML-I)
days after start • Await recovery
of therapyaa • Best supportive care

Hypoplasiabb,cc Await recovery

ff 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
h See Monitoring During Therapy (AML-F). 2 doses. Analogously, if idarubicin 12 mg/m2 was used for induction, the early
i Consider referral to palliative care consultation at the start of induction. LeBlanc TW, reinduction dose should be limited to 10 mg/m2 for 1 or 2 doses.
et al. Curr Hematol Malig Rep 2017;12:300-308 and LeBlanc TW, et al. J Oncol Pract oo Lancet JE, et al. J Clin Oncol 2018;36:2684-2692.
2017;13:589-590. See NCCN Guidelines for Palliative Care. tt The complete response rate and 2-year overall survival in patients between 60 and 65
r This regimen is for FLT3 mutation-positive AML (both ITD and TKD mutations). While years of age treated with daunorubicin 90 mg/m2 are also comparable to the outcome
midostaurin was not FDA approved for maintenance therapy, the study was designed for idarubicin 12 mg/m2; the higher dose daunorubicin did not benefit patients >65
for consolidation and maintenance midostaurin for a total of 12 months. Stone RM, et years of age (Löwenberg B, et al. N Engl J Med 2009;361:1235-1248).
al. N Engl J Med 2017;377:454-464. uu The RATIFY trial studied patients aged 18–60 y. An extrapolation of the data
z Begin alternate donor search (haploidentical, unrelated donor, or cord blood) if no suggests that older patients who are fit to receive 7+3 should be offered midostaurin
appropriate matched sibling donor is available and the patient is a candidate for since it seems to provide a survival benefit without undue toxicity. Schlenk RF, et al.
allogeneic HCT. For induction failure, alternative therapy to achieve remission is Blood 2019;133:840-851.
encouraged prior to HCT. kkk Allogeneic transplant is a reasonable option in patients who experience failure after
aa There are limited prospective data to support this recommendation. Othus M, et al. re-induction with certain regimens (eg, intermediate- or high-dose cytarabine), and
Leukemia 2016;30:1779-1780. have identified donors available to start conditioning within 4–6 weeks from start of
bb If ambiguous, consider repeat BM biopsy in 5–7 days before proceeding with induction therapy. Patients without an identified donor would most likely need some
therapy. additional therapy as a bridge to transplant. HCT may be appropriate for patients
cc Hypoplasia is defined as cellularity less than 20% of which the residual blasts are with a low level of residual disease post-induction (eg, patients with prior MDS who
less than 5% (ie, blast percentage of residual cellularity). reverted back to MDS with <10% blasts). It is preferred that this approach be given
ee For regimens using high cumulative doses of cardiotoxic agents, consider in the context of a clinical trial. For patients with residual disease after 1 cycle of
reassessing cardiac function prior to each anthracycline/mitoxantrone-containing induction chemotherapy who would not tolerate another intensive salvage, consider a
course. Karanes C, et al. Leuk Res 1999;23:787-794. venetoclax-based regimen.

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.

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Acute Myeloid Leukemia (Age ≥18 years) Discussion

AGE ≥60 y Options

POST-INDUCTION THERAPY • Allogeneic HCTmmm
• Standard-dose cytarabine (100–200 mg/m2/d x 5–7 d x 1–2
cycles) ± anthracycline (idarubicin or daunorubicin)ee
• Consider intermediate-dose cytarabine 1–1.5 g/m2/d x 4–6
doses x 1–2 cycles for patients with good performance
status, normal renal function, and better-risk/normal
Able to receive karyotype with favorable molecular markers
• Intermediate-dose cytarabine 1–1.5 g/m2 over 3 h every 12 h See
conventional
Maintenance
consolidation on days 1, 3, and 5 or 1 g/m2 over 3 h every 12 h on days 1, 3,
(AML-10)
and 5 (total 6 doses) for a total of 4 planned cycles with oral
midostaurin 50 mg every 12 h on days 8–21r,nnn
• CPX-351/dual-drug liposomal encapsulation of cytarabine 65
mg/m2 and daunorubicin 29 mg/m2 on days 1 and 3 x 1–2
Complete cyclesoo (therapy-related AML or patients with antecedent
responselll MDS/CMML or AML-MRC) (preferred only if given in
(Response induction)
criteria, see • Cytarabine 1000 mg/m2 every 12 h on days 1–4 +
AML-H) daunorubicin 60 mg/m2 on day 1 (first cycle) or days 1–2
(second cycle) + gemtuzumab ozogamicin 3 mg/m2 (up to
BM aspirate one 4.5 mg vial) on day 1 x 2 cycleskk (CD33-positive)
and biopsy • Observation
to document
remission • Maintenance therapy with oral azacitidine 300 mg PO once daily on days
Previous
status upon Not able to 1–14 of each 28-day cycle until progression or unacceptable toxicity
intensive
hematologic receive any (category 1, preferred)ooo
therapy
recovery (4–6 or all of the • Maintenance therapy with hypomethylating regimens every 4–6 weeks until
weeks). For MRD
recommended progressionppp
assessment, see
AML-G consolidation Azacitidine
Decitabine (category 2B)
Induction Options
failure • Low-intensity therapy (azacitidine, decitabine)
(Response • Allogeneic HCT (preferably in clinical trial)
criteria, see • See Therapy for Relapsed/Refractory Disease (AML-I)
AML-H) • Best supportive care (See NCCN Guidelines for Palliative Care)

See footnotes on AML-8A

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.

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Acute Myeloid Leukemia (Age ≥18 years) Discussion

FOOTNOTES FOR POST-INDUCTION THERAPY (AGE ≥60 YEARS)

r This regimen is for FLT3 mutation-positive AML (both ITD and TKD mutations). While midostaurin was 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.
ee 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.
kk Meta-analyses showing an advantage with gemtuzumab ozogamicin have included other dosing schedules. Hills RK, et al. Lancet Oncol 2014;15:986-996.
oo Lancet JE, et al. J Clin Oncol 2018;36:2684-2692.
lll HLA typing should be used for patients considered to be strong candidates for allogeneic transplantation.
mmm Patients who are deemed as candidates for HCT and who have an available donor should be transplanted in first remission.
nnn Alternate administration of intermediate-dose cytarabine may also be used. Sperr WG, et al. Clin Cancer Res 2004;10:3965-3971. The RATIFY trial studied patients
aged 18–60 y. An extrapolation of the data suggests that older patients 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.
ooo This is not intended to replace consolidation chemotherapy. In addition, fit patients 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 younger
patients or those with CBF-AML; it was restricted to patients ≥55 years of age 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.
ppp Azacitidine: Huls G, et al. Blood 2019;133:1457-1464; Decitabine: Boumber Y, et al. Leukemia 2012;26:2428–3241.

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.

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Acute Myeloid Leukemia (Age ≥18 years) Discussion

AGE ≥60 y
POST-INDUCTION THERAPY
Options: (Principles of Venetoclax, see AML-J)
• Allogeneic HCTmmm
• Continue on lower-intensity regimen that was previously used per AML-6:
Hypomethylating regimens (azacitidine, decitabine) every 4–6 weeks until
progressionqq
Enasidenib until progression (IDH2-mutated AML)hhh,rrr or ivosidenibfff,rrr
Response (IDH1-mutated AML) until progression
Venetoclax once daily PO and decitabine 20 mg/m2 IV (days 1–5 of each 28-day See
(Response
cycle)qq,rr Maintenance
criteria, see Venetoclax once daily PO and azacitidine 75 mg/m2 SC or IV (days 1–7 of each (AML-10)
AML-H) 28-day cycle)qq,rr
BM aspirate and Venetoclax once daily PO and LDAC 20 mg/m2/d SC (days 1–10 of each 28-day
biopsy to document cycle)qq,xx
remission status Glasdegib (100 mg PO daily on days 1–28) + LDAC 20 mg SC every 12 hours
Previous (days 1–10 of each 28-day cycle)vv
upon hematologic
lower- Azacitidine or decitabine + sorafenib (FLT3-ITD-mutated AML)rr,jjj
recovery (timing
intensity
is dependent on • A single dose of gemtuzumab ozogamicin 2 mg/m2 on day 1 every 4 weeks for up to 8
therapy
agent)qqq For MRD continuation coursesbbb (CD33-positive) (category 2B)
assessment, see
AML-G
No response
or progression See Therapy for Relapsed/Refractory Disease (AML-I)
(Response or
criteria, see Best supportive care (See NCCN Guidelines for Palliative Care)
AML-H) vv 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). Cortes JE, et al.
qq This regimen may be continued for patients who demonstrate clinical Blood 2016;128:99-99.
improvement (CR/CRi), with consideration of subsequent transplant, where bbb Amadori S, et al. J Clin Oncol 2016;34:972-979.
appropriate. DiNardo CD, et al. Lancet Oncol 2018;19:216-228; Wei A, et al. fff DiNardo CD, et al. Blood 2017;130:725; DiNardo CD, et al. Blood 2017;130:639;
Blood 2017;130:890; Wei A, et al. Haematologica 2017; Abstract S473; DiNardo Roboz GJ, et al. Blood 2020;135:463-471.
CD, Blood 2019;133:7-17; DiNardo CD, et al. N Engl J Med 2020;383:617-629. hhh Stein EM, et al. Blood 2015;126:323; DiNardo CD, et al. Blood 2017;130:639.
rr Patients who have progressed to AML from MDS after significant exposure jjj Ohanian M, et al. Am J Hematol 2018;93:1136-1141.
to HMAs (ie, azacitidine, decitabine) may be less likely to derive benefit from mmm Patients who are deemed as candidates for HCT and who have an available
continued treatment with HMAs compared to patients who are HMA-naïve. donor should be transplanted in first remission.
Alternative treatment strategies should be considered. DiNardo CD, et al. Blood qqq Response to treatment with enasidenib or ivosidenib may take 3–5 months.
2019;133:7-17. rrr Enasidenib or ivosidenib increases the risk for differentiation syndrome and
xx Wei AH, et al. J Clin Oncol 2019;37:1277-1284. hyperleukocytosis that may require treatment with hydroxyurea and steroids.

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.

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Acute Myeloid Leukemia (Age ≥18 years) Discussion

MAINTENANCE THERAPY

• Patient with intermediate or adverse risk disease:

Who received prior intensive chemotherapy and
is now in remission Oral azacitidine 300 mg PO daily on
Completed no consolidation, some Days 1–14 of each 28-day cycle until
consolidation or a recommended course of progression or unacceptable toxicityooo
consolidation and
No allogeneic stem cell transplant is planned

See Surveillance (AML-11)

Post allogeneic stem cell
transplantation, in remission, and FLT3 inhibitor maintenance
history of FLT3-ITD • Sorafenibsss,ttt

Neither of the above scenarios is applicable Maintenance therapy not recommended

ooo This is not intended to replace consolidation chemotherapy. In addition, fit patients 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 younger
patients or those with CBF-AML; it was restricted to patients ≥55 years of age 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.
sss Xuan L, et al. Lancet Oncol 2020;21:1201-1212.
ttt Burchert A, et al. J Clin Oncol 2020;38:2993-3002.

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.

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AML SURVEILLANCEuuu 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-I) followed by
• BM aspirate and biopsy only if matched sibling or alternative donor HCT
peripheral smear is abnormal or Relapsevvv Comprehensive genomic or
cytopenias develop (Response profiling to determine Chemotherapy (see AML-I) followed by matched
• Donor search should be initiated criteria, see mutation status of sibling or alternative donor HCT
at first relapse in appropriate AML-H) actionable genes or
patients concomitant with Repeat initial successful induction regimenwww
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)

uuu Studies are ongoing to evaluate the role of molecular monitoring in the surveillance for early relapse in patients with AML (see Discussion).
vvv Comprehensive molecular profiling (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.
www 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 complete response is achieved, then consolidation with allogeneic HCT should be considered.

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.

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RISK STRATIFICATION BY GENETICS IN NON-APL AML1,2

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
Biallelic mutated CEBPA
Mutated NPM1 without FLT3-ITD or with FLT3-ITDlow†
Intermediate Mutated NPM1 and FLT3-ITDhigh†
Wild-type NPM1 without FLT3-ITD or with FLT3-ITDlow† (without adverse-risk genetic lesions)
t(9;11)(p21.3;q23.3); MLLT3-KMT2A‡
Cytogenetic abnormalities not classified as favorable or adverse
Poor/Adverse t(6;9)(p23;q34.1); DEK-NUP214
t(v;11q23.3); KMT2A rearranged
t(9;22)(q34.1;q11.2); BCR-ABL1
inv(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2); GATA2,MECOM(EVI1)
-5 or del(5q); -7; -17/abn(17p)
Complex karyotype,§ monosomal karyotype||
Wild-type NPM1 and FLT3-ITDhigh†
Mutated RUNX1¶
Mutated ASXL1¶
Mutated TP53#
Familial Genetic Alterations in AML, see AML-A 2 of 4
1 Dohner 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 Frequencies, response rates, and outcome measures should be reported by risk category, and, if sufficient numbers are available, by specific genetic lesions indicated.
* Prognostic impact of a marker is treatment-dependent and may change with new therapies.
† Low, low allelic ratio (<0.5); high, high allelic ratio (≥0.5); semiquantitative assessment of FLT3-ITD allelic ratio (using DNA fragment analysis) is determined as ratio of the area under
the curve “FLT3-ITD” divided by area under the curve “FLT3-wild type”; regardless of FLT3 allelic fractions, patients should be considered for HCT, though recent studies indicate that
AML with NPM1 mutation and FLT3-ITD low allelic ratio may also have a more favorable prognosis and patients should not routinely be assigned to allogeneic HCT. FLT3 allelic ratio is
not yet pervasively used, and IF not available, the presence of an FLT3 mutation should be considered high risk unless it occurs concurrently with an NPM1 mutation, in which case it is
intermediate risk. As data emerge, this measure will evolve.
‡ The presence of t(9;11)(p21.3;q23.3) takes precedence over rare, concurrent adverse-risk gene mutations.
§ Three or more unrelated chromosome abnormalities in the absence of 1 of the WHO-designated recurring translocations or inversions, that is, t(8;21), inv(16) or t(16;16), t(9;11), t(v;11)
(v;q23.3), t(6;9), inv(3) or t(3;3); AML with BCR-ABL1.
|| Defined by the presence of 1 single monosomy (excluding loss of X or Y) in association with at least 1 additional monosomy or structural chromosome abnormality (excluding CBF AML).
¶ These markers should not be used as an adverse prognostic marker if they co-occur with favorable-risk AML subtypes.
# TP53 mutations are significantly associated with AML with complex and monosomal karyotype.
Continued
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.
AML-A
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FAMILIAL GENETIC ALTERATIONS IN AML

• 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
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.

Kraft IL, Godley LA. Identifying potential germline variants from sequencing hematopoietic malignancies. Blood 2020;136:2498-2506.
Continued
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.
AML-A
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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 [Link].

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

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 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) recessive Skin hypopigmentation Telomere length studies
(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 [Link].
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.
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Acute Myeloid Leukemia (Age ≥18 years) Discussion

EVALUATION AND TREATMENT OF CNS LEUKEMIA1

Observe and repeat LP if

Negative
symptoms persist
Negative
mass effect LP4
Positive by
IT chemotherapy6 2x/wk until clear,
At CT/MRI to morphology or
then weekly x 4–6 wks1
diagnosis, rule out immunotype by
neurologic bleed or flow cytometry5
symptoms2 mass effect Positive RT7 followed by IT chemotherapy6 2x/wk until clear,
mass effect then weekly x 4–6 wks1
or increased Consider FNA or biopsy or
intracranial HiDAC-based therapy + dexamethasone to reduce
pressure intracranial pressure
Observe and repeat LP if
Negative symptoms present
First complete
response
screening, no LP
neurologic IT chemotherapy 2x/wk until clear1
symptoms3 Cerebrospinal fluid (CSF) positive
±
by morphology or immunotype by
If patient is to receive HiDAC, follow up with LP post
flow cytometry5
completion of therapy to document clearance

1 Further CNS prophylaxis per institutional practice.

2 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.
3 Screening LP should be considered at first remission before first consolidation for patients with monocytic differentiation, mixed phenotype acute leukemia (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.
4 In the presence of circulating blasts, administer IT chemotherapy with diagnostic LP.
5 If equivocal, consider repeating LP with morphology or immunotype by flow cytometry to delineate involvement.
6 Induction chemotherapy should be started concurrently. However, for patients receiving high-dose cytarabine, 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.
7 Concurrent use of CNS RT with high-dose cytarabine or IT methotrexate may increase risk of neurotoxicity. See Principles of Radiation Therapy (AML-C).

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.

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Acute Myeloid Leukemia (Age ≥18 years) Discussion

PRINCIPLES OF RADIATION THERAPY

General Principles
• Patients who present with isolated extramedullary disease (myeloid sarcoma) should be treated with systemic therapy. Local therapy
(radiation 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: RT1 followed by IT chemotherapy2 2x/wk until clear, then weekly x 4–6 weeks3

1 Concurrent use of CNS RT with high-dose cytarabine or IT methotrexate may increase risk of neurotoxicity.
2 Induction chemotherapy should be started concurrently. However, for patients receiving high-dose cytarabine, 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.
3 Further CNS prophylaxis per institutional practice.

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.

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Acute Myeloid Leukemia (Age ≥18 years) Discussion

GENERAL CONSIDERATIONS AND SUPPORTIVE CARE FOR AML PATIENTS

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 could provide helpful information about bloodless medicine: [Link]
contacts/united-states
• Clarify acceptance of certain blood products (eg, cryoprecipitate) under certain circumstances; including a discussion of whether stem cells
(donor or autologous) will be acceptable.
• Minimize blood loss (eg, use of pediatric collection tubes).
• Minimize risk of bleeding, including consideration for use of oral contraceptive pills or medroxyprogesterone acetate in menstruating
females; proton pump inhibitor, aggressive antiemetic prophylaxis, and stool softeners to reduce risk of 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. 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 transplant.

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 [published
online ahead of print, Jun 29].

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.

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Acute Myeloid Leukemia (Age ≥18 years) Discussion

PRINCIPLES OF SUPPORTIVE CARE FOR AML

There are variations among institutions, but the following issues are important to consider in the management of patients with AML.
General
• Blood products:
Leukocyte-depleted products used for transfusion.
All AML patients are at risk for acute graft-versus-host disease (aGVHD) and management should be based on institutional practice/
preference.
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.1
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. The patient should not be rechallenged with HiDAC in future
treatment cycles.2
• 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.3 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 Patients who are alloimmunized should receive cross-match–compatible and/or HLA-specific blood products.
2 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.
3 Cornely OA, Maertens J, Winston DJ, et al. Posaconazole vs. fluconazole or itraconazole prophylaxis in patients with neutropenia. N Engl J Med 2007;356:348-359.

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.

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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 PO4, 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 there is failure to recover counts within 5 weeks.
• Patients 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-4.

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.

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

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
patient 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 who 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 polymerase chain reaction (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.
For favorable-risk patients, if MRD is persistently positive after induction and/or consolidation, consider a clinical trial or alternative therapies, including
allogeneic transplantation.
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 transplantation.8 5 Klco JM, Miller CA, Griffith M, et al. Association between mutation clearance after
Additional time points should be guided by the regimen used.2,3
induction therapy and outcomes in acute myeloid leukemia. JAMA 2015;314:811-
1 Schuurhuis GJ, Heuser M, Freeman S, et al. Minimal/measurable residual 822.
disease in AML: consensus document from ELN MRD Working Party. Blood 6 Morita K, Kantarjian H, Wang F, et al. Clearance of somatic mutations at
2018;131:1275-1291. remission and the risk of relapse in acute myeloid leukemia J Clin Oncol 2018
2 Ivey A, Hills RK, Simpson MA, et al. Assessment of minimal residual disease in 36:1788-1797.
standard-risk AML. N Engl J Med 2016;374:422-433. 7 Short NJ, et al. Association of measurable residual disease with survival
3 Jourdan E, Boissel N, Chevret S, et al. Prospective evaluation of gene mutations outcomes in patients with acute myeloid leukemia: A systematic review and meta-
and minimal residual disease in patients with core binding factor acute myeloid analysis. JAMA Oncol 2020;6:1890-1899.
leukemia. Blood 2013;121:2213-2223. 8 Thol F, Gabdoulline R, Liebich A, et al. Measurable residual disease monitoring
4 Jongen-Lavrencic M, Grob T, Hanekamp D, et al. Molecular minimal residual by NGS before allogeneic hematopoietic cell transplantation in AML. Blood
disease in acute myeloid leukemia. N Engl J Med 2018;378:1189-1199. 2018;132:1703-1713.

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.

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Acute Myeloid Leukemia (Age ≥18 years) Discussion

RESPONSE CRITERIA DEFINITIONS FOR ACUTE MYELOID LEUKEMIA1

These response criteria were defined in the context of intensive chemotherapy regimens, and may not be predictive of outcomes for patients
who receive other therapies.
• Morphologic leukemia-free state
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 – patient independent of transfusions
Absolute neutrophil count >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
CRh - partial hematologic recovery, 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 remission4
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.
• Induction failure – Failure 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 failure to achieve a significant reduction (eg >3 log) in molecular evidence of t(8;21) or inv(16) has a very high
predictive value of relapse. Molecular remission for APL should be performed after consolidation, not after induction as in non-APL AML. NPM1 is a target that can be
included in the molecular response assessment. Ivey A, et al. N Engl J Med 2016;374:422-433.
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.

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.

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Acute Myeloid Leukemia (Age ≥18 years) Discussion

THERAPY FOR RELAPSED/REFRACTORY DISEASE1

Clinical trial1 • Therapy for CD33-positive AML
Gemtuzumab ozogamicin8
Targeted therapy:
Aggressive therapy for appropriate patients:
• Therapy for AML with FLT3-ITD mutation
• Cladribine + cytarabine + G-CSF9 ± mitoxantrone or idarubicin10,11
Gilteritinib2 (category 1)
• HiDAC (if not received previously in treatment) ± (idarubicin or
Hypomethylating agents (HMAs) (azacitidine or decitabine) +
daunorubicin or mitoxantrone)12
sorafenib3,4
• Fludarabine + cytarabine + G-CSF9 ± idarubicin13,14
• Therapy for AML with FLT3-TKD mutation
• Etoposide + cytarabine ± mitoxantrone15
Gilteritinib2 (category 1)
• Clofarabine ± cytarabine ± idarubicin16,17
• Therapy for AML with IDH2 mutation
Enasidenib5 Less aggressive therapy:
• Therapy for AML with IDH1 mutation • HMAs (azacitidine or decitabine)
Ivosidenib6 • LDAC (category 2B)
Olutasidenib7 • Venetoclax18 + HMA/LDAC19,20

1 There are promising ongoing clinical trials investigating targeted therapies based on molecular 11 Fridle C, Medinger M, Wilk MC, et al. Cladribine, cytarabine and idarubicin (CLA-Ida) salvage
mutations for relapsed/refractory disease. Molecular profiling should be considered if not done chemotherapy in relapsed acute myeloid leukemia (AML). Leuk Lymphoma 2017:1068-1075.
at diagnosis, or repeated to determine clonal evolution. See Discussion. 12 Karanes C, Kopecky KJ, Head DR, et al. A phase III comparison of high dose ARA-C (HIDAC)
2 Perl AE, Altman JK, Cortes J, et al. Selective inhibition of FLT3 by gilteritinib in relapsed or versus HIDAC plus mitoxantrone in the treatment of first relapsed or refractory acute myeloid
refractory acute myeloid leukaemia: a multicentre, first-in-human, open-label, phase 1-2 study. leukemia Southwest Oncology Group Study. Leuk Res 1999;23:787-794.
Lancet Oncol 2017;18:1061-1075. 13 Montillo M, Mirto S, Petti MC, et al. Fludarabine, cytarabine, and G-CSF (FLAG) for the
3 Ravandi F, Alattar ML, Grunwald MR, et al. Phase 2 study of azacytidine plus sorafenib in treatment of poor risk acute myeloid leukemia. Am J Hematol 1998;58:105-109.
patients with acute myeloid leukemia and FLT3 internal tandem duplication mutation. Blood 14 Parker JE, Pagliuca A, Mijovic A, et al. Fludarabine, cytarabine, G-CSF and idarubicin (FLAG-
[Link]-4662. IDA) for the treatment of poor-risk myelodysplastic syndromes and acute myeloid leukaemia. Br
4 Muppidi MR, Portwood S, Griffiths EA, et al. Decitabine and sorafenib therapy in FLT3 ITD- J Haematol 1997;99:939-944.
mutant acute myeloid leukemia. Clin Lymphoma Myeloma Leuk 2015;15 Suppl:S73-9. 15 Nair G, Karmali G, Gregory SA, et al. Etoposide and cytarabine as an effective and safe
5 Stein EM, DiNardo CD, Pollyea DA, et al. Enasidenib in mutant IDH2 relapsed or refractory cytoreductive regimen for relapsed or refractory acute myeloid leukemia. J Clin Oncol
acute myeloid leukemia. Blood 2017;130:722-731. 2011;29:15_suppl, 6539-6539.
6 DiNardo CD, Stein EM, de Botton S, et al. Durable remissions with ivosidenib in IDH1-mutated 16 Faderl S, Wetzler M, Rizzieri D, et al. Clorarabine plus cytarabine compared with cytarabine
relapsed or refractory AML. N Eng J Med 2018;378:2386-2398. alone in older patients with relapsed or refractory acute myelogenous leukemia: results from the
7 Cortes J, Fenaux P, Yee K, et al. Olutasidenib (FT-2102) induces durable complete remissions CLASSIC I Trial. J Clin Oncol 2012;30:2492-2499.
in patients with relapsed/refractory mIDH1 acute myeloid leukemia. Results from a planned 17 Faderl S, Ferrajoli A, Wierda W, et al. Clofarabine combinations as acute myeloid leukemia
interim analysis of a phase 2 pivotal clinical trial [abstract] Blood 2022;140: Abstract 2757. salvage therapy. Cancer 2008;113:2090-2096.
8 Taksin AL, Legrand O, Raffoux E, et al. High efficacy and safety profile of fractionated doses 18 See Principles of Venetoclax Use With HMA in AML Patients (AML-J).
of Mylotarg as induction therapy in patients with relapsed acute myeloblastic leukemia: a 19 Aldoss I, Yang D, Aribi A, et al. Efficacy of the combination of venetoclax and hypomethylating
prospective study of the alfa group. Leukemia 2007;21:66-71. agents in relapsed/refractory acute myeloid leukemia. Haematologica 2018;103:e404-e407.
9 An FDA-approved biosimilar is an appropriate substitute for filgrastim. 20 DiNardo CD, Rausch CR, Benton C, et al. Clinical experience with the BCL2-inhibitor
10 Robak T, Wrzesień-Kuś A, Lech-Marańda E, et al. Combination regimen of cladribine venetoclax in combination therapy for relapsed and refractory acute myeloid leukemia and
(2-chlorodeoxyadenosine), cytarabine and G-CSF (CLAG) as induction therapy for patients with related myeloid malignancies. Am J Hematol 2018;93:401-407.
relapsed or refractory acute myeloid leukemia. Leuk Lymphoma 2000;39:121-129.

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.

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Acute Myeloid Leukemia (Age ≥18 years) Discussion

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.
• 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.1
• Refer to prescribing information and consult with a pharmacist for potential drug interactions (eg, CYP3A4 inhibitors).
• 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 Newly Diagnosed Patients2
• 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.3
• First Cycle Considerations
TLS monitoring:
◊ In-patient treatment is strongly recommended during first cycle of treatment, especially through dose escalation.4
◊ 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.3
◊ 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 21–285
◊ If no morphologic remission (persistent marrow 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 next page

Continued
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.
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Acute Myeloid Leukemia (Age ≥18 years) Discussion

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

Therapy for Newly Diagnosed Patients (Continued)2
• 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 marrow biopsy following cycle 2 (or subsequent cycles until NED or remission) to again assess
for cellularity and disease response, and 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 has had any response with manageable toxicity, continue therapy as
tolerated.

Therapy for Relapsed/Refractory Patients

• Recommend antifungal prophylaxis if indicated.6
• 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."

1 Recommend referral to tertiary care center/academic medical center (AMC) if need to consider discontinuation of any agent, or to continue maintenance on single-
agent venetoclax.
2 Jonas BA, Pollyea DA. How we use venetoclax with hypomethylating agents for the treatment of newly diagnosed patients with acute myeloid leukemia. Leukemia
2019;33:2795-2804.
3 See venetoclax prescribing information: [Link]
4 Patients may need hospitalization beyond first cycle, based on medical circumstances. Treatment in outpatient setting may be considered per institutional practice or
treatment preference.
5 Combination of venetoclax + decitabine may favor an earlier assessment at day 21 (if blasts are reduced, but no morphologic remission).
6 Aldoss I, Dadwal S, Zhang J, et al. Invasive fungal infections in acute myeloid leukemia treated with venetoclax and hypomethylating agents. Blood Adv 2019;3:4043-
4049.

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

Decisions about diagnosis and management for BPDCN

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

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

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.

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Blastic Plasmacytoid Dendritic Cell Neoplasm Table of Contents
Discussion
(Age ≥18 years)
EVALUATION/WORKUP FOR BPDCNa,b DIAGNOSISd

• H&P
• CBC, platelets, differential, comprehensive metabolic panel
• Analysis of skin lesions (collaboration with dermatology is
recommended),c peripheral blasts, BM aspirate/biopsy, and lymph
node biopsy including: BPDCN diagnosis requires at
Dendritic cell morphology assessment least 4 of 6 BPDCN antigens:
Immunohistochemistry • CD123
Flow cytometry • CD4
BPDCN See Treatment
Cytogenetic analysis (karyotype and/or FISH) • CD56
confirmed Induction
Molecular analysis (most common aberrations include: ASXL1, • TCL-1
(BPDCN-2)
IDH1–2, IKZF1–3, NPM1, NRAS, TET1–2, TP53, U2AF1, ZEB2)d • CD2AP
• PET/CT scan of other sites, if clinical suspicion for extramedullary • CD303/BDCA-2
disease and/or lymphadenopathy without myeloid,e T or B
• All patients require a diagnostic LP at the time of initial diagnosis, lineage expression markers
at disease relapse, or any other time when there is a clinical
suspicion for CNS involvement. Follow with IT treatment
prophylaxis as clinically indicated (see BPDCN-B).

a See Principles of BPDCN (BPDCN-A).

b 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.
c 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 Lymphomas.
d Menezes J, et al. Leukemia 2014;28:823-829.
e Myeloid markers include MPO, lysozyme, CD14, CD34, CD116, and CD163.

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.

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Blastic Plasmacytoid Dendritic Cell Neoplasm Table of Contents
Discussion
(Age ≥18 years)
TREATMENT TREATMENT INDUCTIONj
OF BPDCNh
• Tagraxofusp-erzsi (formerly SL-401) (preferred) Consider See
12 mcg/kg IV over 15 minutes once daily on days 1–5 of a 21-day cyclek,l • Allogeneic HCTm,q,r,s Surveillance
For management of adverse events, see Supportive Care (BPDCN-C) • Autologous HCT (BPDCN-3)
• Chemotherapyi
AML-type induction chemotherapy:
CRp
Standard-dose cytarabine 100–200 mg/m2 continuous infusion x 7 days
Candidate for with idarubicin 12 mg/m2 or daunorubicin 60–90 mg/m2 x 3 daysm
ALL-type induction chemotherapy: Tagraxofusp-erzsi until progression
intensive remission
induction therapy HyperCVAD regimen (hyperfractionated cyclophosphamide, vincristine,
(AML-A) doxorubicin, dexamethasone, alternating with high-dose methotrexate Induction
See Treatment for
and cytarabine)m,n,o failure
Relapsed/Refractory Disease
Lymphoma induction: or less
(BPDC-3)
CHOP regimen (cyclophosphamide, doxorubicin, vincristine, and than CRo
prednisone)m
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 radiation
(ie, serum albumin <3.2
g/dL; not a candidate Options include:
for intensive remission Systemic disease • Venetoclax-based therapy,t see AML-6
induction therapy or (palliative intent) • Systemic steroids
tagraxofusp-erzsi) • Supportive Care (BPDCN-C)
p CR in BPDCN has the same hematologic criteria as AML (See AML-E), but it is also
important to document resolution of any extramedullary sites including CNS and
h See Principles of Supportive Care for BPDCN (BPDCN-C). skin lesions. If the skin still shows microscopic disease (CRc), consider continuing
i Consider CNS prophylaxis for patients with overt systemic disease. additional cycles (at least 4) of therapy before managing as relapsed/refractory
j Pemmaraju N, et al. Blood 2019;134(Supplement_1):2723. disease. For appropriate studies to assess CR, see Pemmaraju N, et al. N Engl J Med
k Frankel AE, et al. Blood 2014;124:385-392. 2019;380:1628-1637.
l Pemmaraju N, et al. N Engl J Med 2019;380:1628-1637. q Kharfan-Dabaja MA, et al. Br J Haematol 2017;179:781-789.
m Pagano L, et al. Haematologica 2013;98:239-246. r Roos-Weil D, et al. Blood 2013;121:440-446.
n Reimer P, et al. Bone Marrow Transplant 2003;32:637-646. s Aoki T, et al. Blood 2015;125:3559-3562.
o Deotare U, et al. Am J Hematol 2016;91:283-286. t DiNardo CD, et al. Am J Hematol 2018;93:401-407.

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.

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

• Evaluate CNS for disease/prophylaxisu

• Consider
• CBC, platelets every 1–3 mo for
Clinical trial (preferred)
2 y, then every 3–6 mo up to 5 y
Tagraxofusp-erzsi,l (preferred, if not already used)
• BM aspirate and biopsy only if peripheral
For management of adverse events, see Supportive Care (BPDCN-C)
smear is abnormal or cytopenias Relapsed/
Chemotherapy (if not already used), see Treatment Induction (BPDCN-2)
develop refractory
Local radiation to isolated lesions/areas
• Repeat PET/CT scan for patients with BPDCN
Systemic steroids
prior evidence of extramedullary disease
Venetoclax-based therapy,t,v,w see AML-6
• 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

i Consider CNS prophylaxis for patients with overt systemic disease.

l Pemmaraju N, et al. N Engl J Med 2019;380:1628-1637.
t DiNardo CD, et al. Am J Hematol 2018;93:401-407.
u Martin-Martin L, et al. Oncotarget 2016;7:10174-10181.
v Montero J, et al. Cancer Discovery 2017;7:156-164.
w Rausch CR, et al. Blood 2017;130:1356.

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.

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Blastic Plasmacytoid Dendritic Cell Neoplasm Table of Contents
Discussion
(Age ≥18 years)
PRINCIPLES OF BPDCN
General Principles:
• BPDCN is a disorder of immature dendritic cells that regulate effector T-cell function.
• 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,2 cytopenias, circulating peripheral blasts (leukemic phase), lymphadenopathy,
and CNS manifestations.
• Prognosis for BPDCN is poor and the median overall survival (OS) is approximately 8–12 months when patients are treated with
chemotherapy.3,4
• Studies suggest that being in first remission (CR1) during receipt of allogeneic HCT significantly enhances the median OS.4-6 Reduced-
intensity conditioning may be considered in patients who achieve CR but cannot tolerate myeloablative transplantation.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. 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.
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: diagnostic criteria and therapeutical approaches. Br J Haematol
2016;174:188-202.
8 Frankel AE, Woo JH, Ahn C, et al. Activity of SL-401, a targeted therapy directed to interleukin-3 receptor, in blastic plasmacytoid dendritic cell neoplasm patients.
Blood 2014;124:385-392.

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.

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NCCN Guidelines Version 3.2022 NCCN Guidelines Index

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

• CNS-directed IT chemotherapy1
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 chemotherapy1 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

1 Chemotherapy regimens may follow institutional standards, but would preferably be aggressive including alternating cytarabine with methotrexate, or triple
intrathecal agents (ie, cytarabine, methotrexate, steroid).

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.

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NCCN Guidelines Version 3.2022 NCCN Guidelines Index

Blastic Plasmacytoid Dendritic Cell Neoplasm Table of Contents
Discussion
(Age ≥18 years)
PRINCIPLES OF SUPPORTIVE CARE FOR BPDCN
Administration/Management of Toxicities Associated with Tagraxofusp-erzs1
• 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 creatinine clearance (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

1 For full details on administration and toxicity management, see: [Link]

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.

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

NCCN Categories of Evidence and Consensus

Category 1 Based upon high-level evidence, 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.

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Acute Myeloid Leukemia

Discussion This discussion corresponds to the NCCN Guidelines for Management of AML in Patients >60 Years ............................... MS-41
Acute Myeloid Leukemia. Last updated: November 12, 2020
Principles of Venetoclax Use with HMAs or LDAC-Based Treatment
................................................................................................. MS-53
Table of Contents
Role of MRD Monitoring ............................................................ MS-54
Overview ......................................................................................... MS-2
Postremission Surveillance for AML .......................................... MS-57
Literature Search Criteria and Guidelines Update Methodology........ MS-2
Management of Relapsed/Refractory AML................................. MS-58
Initial Evaluation .............................................................................. MS-3
Supportive Care for Patients with AML ...................................... MS-60
Workup ........................................................................................ MS-3
Supportive Care for Patients with AML Who Prefer Not to Receive
Diagnosis ..................................................................................... MS-5 Blood Transfusions ................................................................... MS-61

Cytogenetics and Risk Stratification ............................................. MS-6 Evaluation and Treatment of CNS Leukemia ............................. MS-62

Molecular Markers and Risk Stratification ..................................... MS-7 Management of Blastic Plasmacytoid Dendritic Cell Neoplasm ...... MS-63

Familial Genetic Alterations in AML ............................................ MS-13 Workup ..................................................................................... MS-63

Principles of Acute Myeloid Leukemia Treatment ........................... MS-13 Induction Therapy for Patients with BPDCN ............................... MS-64

Management of Acute Promyelocytic Leukemia ............................. MS-14 Postremission Surveillance for BPDCN...................................... MS-66

Induction Therapy for Patients with APL ..................................... MS-15 Management of Relapsed/Refractory BPDCN............................ MS-66

Consolidation Therapy for Patients with APL .............................. MS-20 References ................................................................................... MS-67

Post-Consolidation or Maintenance for Patients with APL ........... MS-23

Management of Relapsed APL ................................................... MS-25

Supportive Care for Patients with APL ........................................ MS-27

Management of Acute Myeloid Leukemia ....................................... MS-29

Management of AML in Patients Younger Than 60 Years ........... MS-29

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Acute Myeloid Leukemia

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

Acute myeloid leukemia (AML) is a heterogeneous hematologic especially in the context of myeloablative therapy (eg, total body irradiation
malignancy characterized by the clonal expansion of myeloid blasts in the or radioimmunotherapy) given before autologous hematopoietic cell
peripheral blood, bone marrow, and/or other tissues. It is the most transplantation (HCT) may also increase the risk for therapy-related
common form of acute leukemia among adults and accounts for the MDS/AML.13,14 The disease course of therapy-related MDS/AML is
largest number of annual deaths from leukemias in the United States. An generally progressive and may be more resistant to conventional cytotoxic
estimated 19,940 people will be diagnosed with AML in 2020, and 11,180 therapies than de novo cases of MDS/AML.9 Importantly, clinical outcomes
patients will die of the disease.1 According to the SEER Cancer Statistics in patients with therapy-related AML have been shown to be significantly
Review, the median age at diagnosis is 68 years;2 other registries report inferior (both in terms of relapse-free survival [RFS] and overall survival
71 years,3 with approximately 54% of patients diagnosed at ≥65 years of [OS]) compared with patients with de novo cases,8,15 except those with the
age (and approximately a third diagnosed at ≥75 years of age).2 Thus, as therapy-related acute promyelocytic leukemia (APL) subtype7,16 or the
the population ages, the incidence of AML, along with myelodysplastic favorable-risk core binding factor (CBF) translocations. The proportion of
syndromes (MDS), seems to be rising. patients with unfavorable cytogenetics tends to be higher in the population
with therapy-related AML. Even among the subgroup with favorable
Environmental factors that have long been established to increase the karyotypes, those with therapy-related AML tend to do less well.
risks of MDS and AML include prolonged exposure to petrochemicals;
solvents such as benzene; pesticides; and ionizing radiation.4 The AML Panel for the NCCN Clinical Practice Guidelines in Oncology
(NCCN Guidelines®) convenes annually to update recommendations for
Therapy-related MDS/AML (secondary MDS/AML) is a well-recognized the diagnosis and treatment of AML in adults. These recommendations
consequence of cancer treatment in a proportion of patients receiving are based on a review of recently published clinical trials that have led to
cytotoxic therapy for solid tumors or hematologic malignancies. Reports significant improvements in treatment or have yielded new information
suggest that therapy-related MDS/AML may account for 5% to 20% of regarding biologic factors that may have prognostic importance.
patients with MDS/AML.5-7 The rate of therapy-related MDS/AML is higher
among patients with certain primary tumors, including breast cancer, Literature Search Criteria and Guidelines Update
gynecologic cancers, and lymphomas (both non-Hodgkin lymphoma and
Methodology
Hodgkin lymphoma), largely owing to the more leukemogenic cytotoxic Prior to the update of this version of the NCCN Guidelines® for AML, an
agents that are commonly used in the treatment of these tumors.7-10 Two electronic search of the PubMed database was performed to obtain key
well-documented categories of cytotoxic agents associated with the literature in AML published since the previous Guidelines update using the
development of therapy-related MDS/AML are alkylating agents and following search terms: acute myeloid leukemia or acute promyelocytic
topoisomerase inhibitors.5,8,9 Treatment with antimetabolites, such as the leukemia. The PubMed database was chosen as it remains the most
purine analog fludarabine, has also been associated with therapy-related widely used resource for medical literature and indexes peer-reviewed
MDS/AML in patients with lymphoproliferative disorders, particularly when biomedical literature.17

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Acute Myeloid Leukemia

The search results were narrowed by selecting studies in humans Workup

published in English. Results were confined to the following article types: The evaluation and initial workup for suspected AML consists of a
Clinical Trial, Phase II; Clinical Trial, Phase III; Clinical Trial, Phase IV; comprehensive medical history and physical examination. Laboratory
Guideline; Meta-Analysis; Randomized Controlled Trial; Systematic evaluations include a comprehensive metabolic panel and a complete
Reviews; and Validation Studies. blood count (CBC) including platelets and a differential of white blood cells
(WBCs). Serum uric acid and lactate dehydrogenase (LDH) have
The data from key PubMed articles as well as articles from additional
prognostic relevance and should be evaluated.18,19 Bone marrow core
sources deemed as relevant to these Guidelines and discussed by the
biopsy and aspirate analyses (including immunophenotyping by
panel have been included in this version of the Discussion section (eg, e-
immunohistochemistry stains with flow cytometry) and cytogenetic
publications ahead of print, meeting abstracts). Recommendations for
analyses (karyotype with fluorescence in situ hybridization [FISH]) are
which high-level evidence is lacking are based on the panel’s review of
necessary for risk stratification and to potentially guide therapy of AML.
lower-level evidence and expert opinion.
Several gene mutations are associated with specific prognoses in a subset
NCCN recommendations have been developed to be inclusive of of patients (category 2A) and may guide treatment decisions (category
individuals of all sexual and gender identities to the greatest extent 2B). Presently, c-KIT, FLT3-ITD, FLT3-TKD, NPM1, CEBPA (biallelic),
possible. When citing published studies and recommendations from IDH1/IDH2, RUNX1, ASXL1, TP53, BCR-ABL, and PML-RAR alpha are
other organizations, the terms used (eg, male, female) reflect the cited included in this group. All patients should be tested for mutations in these
sources. genes, and multiplex gene panels and comprehensive next-generation
sequencing (NGS) analysis are recommended for the ongoing
The complete details of the Development and Update of the NCCN management of AML and various phases of treatment.20-22 To
Guidelines are available at [Link]. appropriately stratify therapy options, test results of molecular and
cytogenetic analyses of immediately actionable genes or chromosomal
Initial Evaluation abnormalities (eg, CBF, FLT3 [ITD or TKD], NPM1, IDH1, or IDH2) should
The initial evaluation of AML has two objectives. The first is to characterize be expedited. For patients with hyperleukocytosis uncontrolled with
the disease process based on factors such as prior toxic exposure, hydroxyurea or leukapheresis, one dose of intermediate-dose cytarabine
antecedent myelodysplasia, and karyotypic and molecular abnormalities, (1–2 grams)23 may be considered prior to receiving results. For patients
which may provide prognostic information that can impact responsiveness who prefer not to receive blood transfusions as part of therapy, see
to chemotherapy and risk of relapse. The second objective focuses on Supportive Care for Patients with AML Who Prefer Not to Receive Blood
patient-specific factors, including assessment of comorbid conditions, Transfusions for general considerations, although the committee believes
which may affect an individual’s ability to tolerate chemotherapy. Both that in many cases, good outcomes from this strategy are rare. If blastic
disease-specific and individual patient factors are taken into consideration plasmacytoid dendritic cell neoplasm (BPDCN) is suspected, see
when deciding treatment. Management of BPDCN for work up, diagnosis and treatment
recommendations.
© © ®
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Acute Myeloid Leukemia

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
CNS signs or symptoms at presentation should be evaluated using activity as part of the initial evaluation and before performing any invasive
appropriate imaging techniques, such as radiography, CT, or MRI for the procedure. The need for a cardiac evaluation (eg, echocardiogram or
detection of intracranial bleeding, leptomeningeal disease, or mass lesions multigated acquisition [MUGA] scan) should be determined based on
in either the brain or spinal cord. If CNS hemorrhage is suspected, a CT of individual risk factors. Patients with a history or symptoms of cardiac
brain without contrast is recommended. If leukemic meningitis is disease, prior exposure to cardiotoxic drugs or thoracic radiation, or those
suspected, a brain MRI with contrast is recommended. However, if of an older age, should have an echocardiogram. In younger patients who
symptoms persist, and bleeding and mass/lesions are excluded, the are otherwise asymptomatic with no history of cardiac disease, an
patient should have a lumbar puncture (LP) for diagnostic and possible echocardiogram can be considered. In the setting of acute illness,
therapeutic purposes once coagulopathy has been corrected, adequate treatment should not be delayed for an echocardiogram. A small study of
platelet support is available, and the circulating disease has been cleared 76 patients with cancer who were screened for cardiac disease identified
through the initiation of systemic therapy. Routine screening LPs are not only 4 patients with cardiac abnormalities. Of these 4 patients, the
warranted at the time of diagnosis in patients with AML. However, for presence of cardiac disease did not change the course of treatment.25
patients at high risk for CNS disease, such as those with monocytic
differentiation or high WBC count (>40,000/mcL)24 at presentation, a Human leukocyte antigen (HLA) typing should be performed in all patients
diagnostic LP should be considered as part of the documentation of with newly diagnosed AML for whom allogeneic HCT would be
remission status. Screening LPs should be considered at first remission considered. HLA typing of family members is recommended for patients
before first consolidation in the setting of monocytic differentiation, mixed up to age 80 years or per institutional practice who do not have

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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
strategies.26 During this transition from the FAB system to the WHO provisional entities include AML with molecular abnormalities such as
classification, the percent blasts threshold for defining high-grade MDS mutated nucleophosmin (NPM1) or CCAAT/enhancer-binding protein
and AML was lowered. The FAB classification had set the threshold alpha (CEBPA) genes (further information on these genetic lesions is
between high-grade MDS and AML at 30% blasts, whereas the WHO provided later).28 In 2016, WHO expanded the recurrent genetic
classification lowered the threshold for diagnosing AML to 20% or more abnormalities to include two provisional categories, AML with BCR-ABL1
blasts. This change was based on the finding that the biologic behavior rearrangement and AML with RUNX1 mutation. AML with BCR-ABL1
(and survival outcomes) of the FAB MDS subgroup of “refractory anemia rearrangement is a rare de novo AML that may benefit from therapies that
with excess blasts in transformation (RAEB-T),” defined as patients with entail tyrosine kinase inhibitors. AML with RUNX1 mutation is associated
20% to 30% blasts, was similar compared with that of patients with greater with a poorer prognosis.
than 30% blasts. In an appropriate clinical setting, the WHO classification
system further allowed AML to be diagnosed in patients with abnormal In accordance with the 2016 WHO classification, a diagnosis of AML is
hematopoiesis and in the setting of characteristic clonal structural made based on the presence of 20% or more blasts in the bone marrow or
cytogenetic abnormalities with t(15;17), t(8;21), and inv(16) or t(16;16) peripheral blood. In an appropriate clinical setting, a diagnosis of AML may
regardless of the percentage of marrow blasts. be made with <20% blasts in the setting of recurrent cytogenetic
abnormalities including t(15;17), t(8;21), t(16;16), or inv(16). The accurate
In 2003, the International Working Group for Diagnosis, Standardization of classification of AML requires multidisciplinary diagnostic studies including
Response Criteria accepted the cytochemical and immunophenotypic morphology, immunophenotyping (immunohistochemistry and flow

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cytometry), and molecular genetics analysis. The latter should include a Cytogenetics and Risk Stratification
complete cytogenetic analysis and advanced molecular analysis Although cytogenetic information is often unknown when treatment is
techniques, as needed, to specify both translocations and gene mutations. initiated in patients with de novo AML, karyotype represents the single
The NCCN AML Panel suggests that complementary diagnostic most important prognostic factor for predicting remission rates, relapse
techniques can be used at the discretion of the pathology department of risks, and OS outcomes. The cytogenetic risk categories adopted by these
the individual institution. Some cases may still show evidence of both guidelines are primarily based on analyses of large datasets from major
myeloid and lymphoid antigen expression on the leukemic cells and are cooperative group trials (see Risk Stratification by Genetics in Non-APL
defined as acute leukemias of ambiguous lineage. This is further AML in the algorithm).29-31 In an analysis of data from pediatric and adult
subgrouped into acute undifferentiated leukemia, MPAL with BCR-ABL1 patients with AML (n = 1612) enrolled in the United Kingdom Medical
rearrangement, MPAL with rearranged KMT2A, MPAL with B-cell/myeloid Research Council (UK MRC) AML 10 trial, the 5-year survival rates for
features not otherwise specified, and MPAL with T-cell/myeloid features those with favorable, intermediate, and unfavorable risk cytogenetics were
not otherwise specified. The expression of both cytochemical and/or 65%, 41%, and 14%, respectively.30 In a review of data from adult patients
immunophenotypic characteristics of both lineages on the same cells is treated in a phase III Southwest Oncology Group (SWOG)/Eastern
defined as biphenotypic, whereas expression of lineage-specific Cooperative Oncology Group (ECOG) intergroup study (n = 609), the
characteristics on different populations of leukemia cells is termed bilineal. 5-year survival rates in the setting of favorable, intermediate, and adverse
Due to the rarity of acute leukemias of ambiguous lineage (as defined by risk cytogenetics were 55%, 38%, and 11%, respectively.31 Similarly, in a
the 2016 WHO classification), consultation with an experienced retrospective review of adult patients with AML treated on Cancer and
hematopathologist should be sought. Leukemia Group B (CALGB) protocols (n = 1213), the 5-year survival
rates in the setting of favorable-, intermediate-, and poor-risk cytogenetics
Aberrant expression of differentiation antigens present at diagnosis may
were 55%, 24%, and 5%, respectively.29 The AML 11 trial had similar
allow tracking of residual blasts through flow cytometry in follow-up
results with 5-year survival rates in the setting of favorable-, intermediate-,
samples that may appear normal according to conventional morphology.
and poor-risk cytogenetics of 34%, 13%, and 2%, respectively.32 This last
The use of immunophenotyping and molecular markers to monitor
study included a population of patients ≥55 years of age, which is believed
measurable (also known as minimal) residual disease (MRD) in adult AML
to attribute to the overall lower percent survival in all groups.
has not yet been widely incorporated into postremission monitoring
strategies, except in some patient subgroups with APL, CBF-AML, and The importance of obtaining adequate samples of marrow or peripheral
NPM1-positive AML. However, ongoing research is moving MRD blood at diagnosis for full karyotyping and FISH cytogenetic analysis for
monitoring to the forefront for all patients with AML (see Role of MRD the most common abnormalities cannot be overemphasized. Although
Monitoring). FISH studies for common cytogenetic abnormalities may allow for rapid
screening to identify either favorable- or unfavorable-risk groups,
additional tests are needed to provide a full picture of the genetic factors
that contribute to risk (see Molecular Markers and Risk Stratification).

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The presence of autosomal chromosome monosomies in AML has 2-year OS rate was significantly decreased in the setting of monosomal
emerged as an important prognostic factor associated with extremely poor karyotype (7% vs. 22% without this abnormality; P < .0001). Similar
prognosis.33-35 Data from three large studies have identified monosomal outcomes were observed in the setting of complex karyotype.35
karyotypes (defined as ≥2 autosomal monosomies, or a single monosomy
with an additional structural abnormality) as a subset of unfavorable These studies show that monosomal karyotype, independent of other
cytogenetic prognosticators. Although complex karyotype (≥3 clonal unfavorable cytogenetic factors, confers very poor prognosis. In the NCCN
cytogenetic abnormalities) and either monosomy 5 or monosomy 7 are Guidelines, the presence of monosomal karyotype is included in the
categorized as high-risk/unfavorable cytogenetics, the presence of a unfavorable-risk category of AML based on cytogenetics (see Risk
monosomal karyotype was found to confer further negative prognostic Stratification by Genetics in Non-APL AML in the algorithm).
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
cooperative groups (HOVON/SAKK), which evaluated the correlation The intermediate-risk cytogenetic category is the most heterogeneous
between cytogenetics and OS outcomes in patients aged 60 years or group in AML, because it encompasses both normal karyotype AML
younger with AML (n = 1975). The 4-year OS rate in patients with (NK-AML) without gross structural abnormalities and those with structural
monosomal karyotype was 4% compared with 26% in those with complex changes that are considered neither poor risk nor favorable. Based on
karyotype (but without monosomal karyotype).33 retrospective analyses of data from large cooperative group studies, 40%
to 50% of patients with de novo AML have normal karyotype, which is
These findings were confirmed in subsequent analyses from other large associated with intermediate risk as measured in terms of survival
cooperative group studies. In an analysis of data from patients treated on outcomes.29,30 However, even in patients with NK-AML, clinical outcome is
SWOG protocols (n = 1344; age 16–88 years), 13% of patients were heterogeneous.
found to have monosomal karyotype; nearly all of these cases (98%)
occurred within the unfavorable cytogenetics category.34 The incidence of Identification of mutations that carry prognostic and therapeutic impact is
monosomal karyotype increased with age, from 4% in patients 30 years of rendering molecular profiling for all AML cases a standard part of the
age or younger to 20% in patients >60 years of age. Among patients with diagnostic workup. In addition to basic cytogenetic analysis, new
unfavorable cytogenetics, the 4-year OS rate in the setting of monosomal molecular markers can help refine prognostics groups, particularly in
karyotype was 3% compared with 13% without monosomal karyotype. In patients with a normal karyotype. These markers include NPM1, FMS-like
the setting of monosomy 7, monosomal karyotype did not appear to tyrosine kinase 3 (FLT3), CEBPA, isocitrate dehydrogenase 1 and 2
influence outcomes (4-year OS, 0%–3%); the 4-year OS rates in the (IDH1/2), DNA (cytosine-5)-methyltransferase 3A (DNMT3A), and KIT,
setting of inv(3)/t(3;3) and t(6;9) and without monosomal karyotype were TP53, RUNX1, and ASXL1 gene mutations.36-48 Tests for these molecular
0% and 9%, respectively.34 In a retrospective study that evaluated the markers are now available in commercial reference laboratories and in
prognostic impact of monosomal karyotype in patients >60 years of age referral centers. Therefore, it is important for physicians to confer with the
(n = 186) with unfavorable cytogenetics treated in a GOELAMS trial, the local pathologist on how to optimize sample collection from the time of

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NCCN Guidelines Version 3.2022

Acute Myeloid Leukemia

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
occur in the setting of prognostically favorable NPM1 or CEBPA
FLT3-ITD mutations occur in approximately 30% of cases and are more
mutations.51,62 Moreover, FLT3-TKD mutations as the sole genetic
common than FLT3-TKD mutations, which occur in approximately 10% of aberration or occurring concurrently with t(15;17)/promyelocytic leukemia
cases.36,40,51,56-60 Numerous studies have shown the negative prognostic (PML)-retinoic acid receptor alpha (RARA) (underlying lesion in the APL
influence of FLT3-ITD in patients with AML, resulting in shorter remission
subtype) or with FLT3-ITD (FLT3 double mutation) have been associated
durations (eg, decreased disease-free survival [DFS] in patients who with poorer outcomes.51,62
achieve a CR) and poorer survival outcomes compared with wild-type
FLT3.36,40,53,54,56,58,59,61 In the setting of FLT3-ITD and NK-AML, median OS CEBPA Mutations
from the time of diagnosis ranged from 6 to 12 months.36,40,56,59 Another mutation associated with prognosis is the CEBPA gene, a
transcription factor that plays a key role in the differentiation of
Interestingly, a study in patients with NK-AML showed that prognosis was granulocytes.42 Mutations in CEBPA have been reported in 7% to 11% of
worse in the setting of FLT3-ITD without wild-type FLT3, compared with cases of AML (or 13%–15% of cases of NK-AML) and have been
FLT3-ITD with wild-type FLT3 in the second allele. The median OS in the associated with a favorable outcome (similar to cases of CBF
setting of FLT3-ITD in the absence of a wild-type FLT3 was only 7 months translocations) with regard to increased remission duration and OS
compared with 46 months in the setting of wild-type FLT3 with or without outcome compared with wild-type CEBPA.41,50,51,64-66 One caveat identified
FLT3-ITD.56 The FLT3-TKD mutations predominantly occur independently

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NCCN Guidelines Version 3.2022

Acute Myeloid Leukemia

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
frequently.71,73,74 Interestingly, the IDH2-R172 mutation seemed to be
IDH1/2 Mutations
mutually exclusive with NPM1 mutations and FLT3-ITD.71,73,74
Mutations in IDH1 have been reported in 6% to 9% of AML cases, with a
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
mutations on OS when considering all IDH mutations (IDH1 and IDH2 FLT3-ITD).73 However, in another study, the IDH2 mutation (restricted to
combined) or in the overall patient population,68-71 IDH1 mutations IDH2-R140) was associated with improved survival among the overall
correlated with significantly worse outcomes in the subgroup of patients study population, and among the subgroup of patients with favorable risk
with NK-AML with favorable- or intermediate-risk disease.68,71,73 In the (intermediate-risk AML with NPM1 mutation without FLT3-ITD).50 In this
subgroup of patients younger than 60 years with favorable-risk AML latter subgroup, the presence of IDH1 or IDH2 mutations was associated
(NPM1 mutation without FLT3-ITD), IDH1 mutations were associated with with a significantly increased 3-year OS rate compared to the setting of
a significantly decreased 5-year DFS rate (42% vs. 59%; P = .046) and a NPM1 mutation without FLT3-ITD and without IDH1 or IDH2 mutations
trend for decreased OS rate (50% vs. 63%) compared with the setting of (89% vs. 31%; P < .0001). These results seem to suggest that in patients
wild-type IDH.71 In another study, IDH mutations (IDH1 and IDH2 with NK-AML without FLT3-ITD, NPM1 mutations confer a survival benefit
combined) were associated with significantly inferior 5-year RFS rates only in the presence of concurrent IDH mutations.50 The conflicting
(37% vs. 67%; P = .02) and OS rates (41% vs. 65%; P = .03) in the findings from the above studies require further investigation.
subgroup of patients with favorable-risk AML (NK-AML with NPM1
mutation without FLT3-ITD).73 This prognostic significance was observed DNMT3A Mutations
when IDH1 and IDH2 mutations were separately analyzed, although The DNMT3A mutations have been reported in 18% to 22% of cases of
patient numbers were small for each subgroup and statistical significance AML,50,75,76 with a frequency of 29% to 34% in cases of NK-AML.77-79 R882

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NCCN Guidelines Version 3.2022

Acute Myeloid Leukemia

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
KIT Mutations
thus far been conflicting. Some studies in the overall AML population and
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
45%; P = .02).79 Another study also showed that in younger patients (age (37%), and FLT3 (17%; FLT3-TKD in 14%; FLT3-ITD in 5%; both
<60 years) with NK-AML, a DNMT3A mutation was associated with mutations present in 2%). In addition, more than one of these mutations
significantly decreased DFS (3-year rate, 20% vs. 49%; P = .007) and a was found in 25% of cases. Mutations in KIT and RAS were less likely to
trend toward decreased OS.77 In this latter study, non-R882 DNMT3A occur concurrently, whereas mutations in KIT and FLT3 occurred
mutations were significantly associated with poorer outcomes in patients concurrently in 6% of cases.84 Of these secondary genetic lesions, KIT
younger than 60 years of age but not R882 mutations; in contrast, mutation and trisomy 22 were significant independent factors predictive of
DNMT3A-R882 mutations (but not non-R882 mutations) in patients ≥60 RFS in multivariable analysis; FLT3 mutations, trisomy 22, and trisomy 8
years of age were associated with significantly decreased DFS (3-year were significant independent predictors for OS.84 These studies
rate, 3% vs. 21%; P = .006) and OS (3-year rate, 4% vs. 24%; P = .01).77 demonstrate the importance of secondary genetic mutations in the
The authors concluded that the prognostic relevance of DNMT3A prognostic classification of patients with otherwise favorable-risk CBF AML
mutations may depend on age and mutation type. Currently, the (see Risk Stratification by Genetics in Non-APL AML in the algorithm).
interactions of IDH1 or IDH2 and DNMT3 mutations with other molecular KMT2A Rearrangements
changes require further investigation to determine the prognostic value in The mixed lineage leukemia gene (MLL; also called HRX, ALL-1, or
patients with NK-AML. Although commercial testing is available for FLT3 currently KMT2A), located on chromosome 11q23, was initially recognized
and CEBPA, most of the other genetic mutations are not available for

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NCCN Guidelines Version 3.2022

Acute Myeloid Leukemia

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
complex karyotype.105 However, in therapy-related AML, TP53 mutations
mutations frequently co-occurred with epigenetic modifiers ASXL1, IDH2,
are more frequently associated with monosomal karyotype, and with
KMT2A, and EZH2.95 In a study examining the impact of multiple RUNX1 abnormalities in chromosomes 5 and 7.105 In therapy-related AML, the
mutations and loss of wild-type RUNX1 in AML, both loss of wild-type frequency of TP53 mutations is approximately 23%.22 In a large analysis of
different hematologic malignancies including 858 AML cases, TP53
RUNX1 (OS, 5 months) and having ≥1 RUNX1 mutation (14 months) had
mutations or deletions were observed in 7% and 1%, respectively, of the
an adverse impact on prognosis compared to 1 RUNX1 mutation (22 AML cases, and both TP53 mutations and deletions were observed in 5%
months; P < .002 and .048, respectively).96 of the cases.106 TP53 mutations were significantly more frequently seen in
patients ≥60 years of age when compared to patients <60 years of age (9%
ASXL Mutations vs. 2%, P < .001).106 Interestingly, compared to TP53 deletions, TP53
mutations negatively impacted survival in AML (36 months vs. 9 months,
The additional sex combs-like 1 (ASXL1) gene, located on chromosome respectively; P < .001), suggesting the importance of evaluating both TP53
band 20q11, encodes a protein in the enhancer of trithorax and mutation and deletion status.106Classification and Prognostic Relevance of
polycomb (ETP) genes family, which have functions in transcription.97,98 Gene Mutations
ASXL1 mutations have been reported in approximately 5% to 36% of de The NCCN AML Panel adopted the 2017 European LeukemiaNet (ELN)
novo AML cases,96,99-102 and are associated with poor outcomes.50,98,101 recommendations for risk stratification.21 Therefore, both NCCN and the
In an analysis of peripheral blood samples from adult patients with AML ELN classify patients with NK-AML and mutated NPM1 or CEBPA (without
(n = 423), ASXL1 mutations were observed to be more common in FLT3-ITD) as having favorable risk.21,107 Specifically, patients with

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NCCN Guidelines Version 3.2022

Acute Myeloid Leukemia

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
younger (13.6 vs. 18.7 months, respectively); in patients >60 years, NPM1 or CEBPA mutations.62 A systematic review and meta-analysis in
median OS was similar between the two intermediate groups (9.5 vs. 9.2 patients younger than 60 years of age with NK-AML further established
months, respectively).107 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
In another study, patients in the intermediate I group who were younger prognosis for NPM1 (HR, 0.56 and 0.37, respectively) and CEBPA (HR,
than 60 years of age demonstrated longer OS than those in the 0.56 and 0.42, respectively).
intermediate II group; in patients >60 years of age, the OS was similar
between the two intermediate groups.109 Based on these data, the ELN The clinical significance of FLT3 mutations in patients with APL remains
simplified the intermediate risk group in the 2017 update.21 Both NCCN controversial. FLT3-ITD is associated with a higher incidence of several
and the ELN classify patients with NK-AML with both mutated NPM1 and a hematologic features associated with APL (eg, higher WBC count,
high allelic ratio (≥0.5) of FLT3-ITD (FLT3-ITDhigh), and those with decreased fibrinogen levels, higher Sanz risk score).110,111 However, there
wild-type NPM1 without FLT3-ITD or with FLT3-ITDlow (without adverse- remains a paucity of data to support a correlation of FLT3-ITD on OS and
risk genetic lesions) as having intermediate-risk AML. In addition, rate of relapse.110,112,113 Although mutation status alone may not reflect
t(9;11)(p21.3;q23.3), MLLT3-MLL, and other cytogenetic abnormalities outcome, there was a trend for decreased OS and EFS with a higher
that fall into neither the favorable nor adverse category are considered FLT3-ITD mutational load suggesting that further studies are necessary to
intermediate-risk. Both NCCN and the ELN classify wild-type NPM1 and elucidate the clinical significance of this mutation.113 Conversely,
FLT3-ITDhigh, mutated TP53, mutated RUNX1, or mutated ASXL1 as poor FLT3-TKD has not been associated with the hematologic features of APL
risk.21,107 However, mutated RUNX1 or ASXL1 should not be used as and studies do not show a correlation of FLT3-TKD on outcome.110,111,113-
115
poor-risk prognostic markers if they co-occur with favorable-risk AML

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NCCN Guidelines Version 3.2022

Acute Myeloid Leukemia

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
patients who have NK-AML or in other situations where molecular analysis Based on these emerging data, the AML panel recommends that patients
may refine the prognostic category. with a family history of leukemia, or of other hematologic cancers or
abnormalities, should be evaluated for an inherited predisposition
Familial Genetic Alterations in AML syndrome (see Familial Genetic Alterations in AML in the algorithm). The
Relative to sporadic cases of AML and MDS, the prevalence of known panel also strongly recommends that patients with a variant allele
familial acute leukemia and MDS syndromes is felt to be rare, but with frequency (VAF) of 40–60% of genes associated with a predisposition
increasing recognition of germline mutations associated with syndrome be referred for germline testing. However, there is no
predisposition to developing AML/MDS, identifying these syndromes is consensus on optimal management of individuals diagnosed with a
important for optimal care of patients and their relatives.116-119 Evaluation familial acute leukemia or MDS syndrome, so management must be
for an underlying familial syndrome in a patient with acute leukemia or individualized.116,120
MDS should involve a screening history, focused physical examination,
Principles of Acute Myeloid Leukemia Treatment
and diagnostic genetic testing.116,120 In particular, the screening
evaluation should determine if the patient has a family history of Treatment of acute leukemia has been divided into induction
hematologic malignancies (including AML, acute lymphoblastic leukemia chemotherapy and postremission (eg, consolidation) therapy. Although
[ALL], or aplastic leukemia) or unexplained leukopenia, anemia (eg, obtaining a remission is the first step in controlling the disease, it is also
aplastic anemia, macrocytic anemia) and/or thrombocytopenia within 2 important for patients to emerge from the induction phase in a condition to
generations.116,117,121,122 In addition, the Nordic Guidelines for germline tolerate subsequent, more intensive treatments during consolidation to
predisposition to myeloid neoplasms in adults recommend that the achieve durable disease control. In some cases, patients who either
screening evaluation should determine if the patient has signs or received postremission therapy or those who did not may experience
symptoms indicative of a hereditary condition (including Li Fraumeni relapse, usually within 6 to 9 months. Postremission therapy is

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NCCN Guidelines Version 3.2022

Acute Myeloid Leukemia

recommended for patients younger than 60 years and/or who are fit for Management of Acute Promyelocytic Leukemia
intensive therapy. However, there are trials that by design do not include APL is a particularly aggressive subtype of AML, comprising
postremission treatment for patients and the results have been promising; approximately 10% of AML cases. APL has a distinct morphology and
these trials are generally in older patients with AML. The induction strategy clinical presentation that may be associated with a high early death rate
is influenced by individual patient characteristics such as age, presence of due to potentially fatal coagulopathy.132-134 In an analysis of data (from
comorbid conditions affecting performance status, and preexisting 1992–2007) from the National Cancer Institute SEER registry, the
myelodysplasia. This is particularly true of patients who are older with age-adjusted annual incidence rate of APL was 0.23 per 100,000
AML. Patients whose performance status would make them poor persons.135 The median age of APL diagnosis was 44 years, which is
candidates for the standard antineoplastic regimens may still be able to younger than that of patients with AML (median age 67 years).2,135 APL is
participate in clinical trials or low-intensity therapy plus oral agents cytogenetically distinguished by the t(15;17) chromosomal translocation.
designed to target this underserved patient population. Supportive care The translocation of the PML gene on chromosome 15 to the RARA gene
may also be an appropriate choice. In younger patients, strategies for on chromosome 17 [ie, t(15;17)(q24.1;q21.1)] produces a PML-RARA
consolidation are based on the potential risk of relapse, with higher-risk fusion gene that can be quantitatively monitored using polymerase chain
patients receiving more aggressive therapy. Cytogenetic and molecular reaction (PCR) to document disease burden and to ultimately confirm
abnormalities are the most significant prognostic indicators; however, molecular remission. As further emphasis of the cytogenetic attribute of
failure to achieve remission after 1 cycle of induction therapy or high tumor APL, the most recent WHO classification of myeloid neoplasms and acute
burden, defined as a WBC count ≥40,000/mcL,24 are included as poor-risk leukemia changed the definition of APL from the cytogenetic criteria of
factors for long-term remission. Therefore, response is assessed based on t(15;17) to the molecular definition of “APL with PML-RARA” to be
bone marrow morphology and cytogenetic and molecular responses taken inclusive of complex or cryptic rearrangements that lead to a functional
at several points during the course of treatment (see Response Criteria transcription factor.67
Definitions for Acute Myeloid Leukemia and Monitoring During Therapy in
the algorithm for definitions of CR and partial response [PR] and disease APL may be de novo or therapy-related. Some of the following attributes
relapse). The use of flow cytometry and/or molecular methods to assess of therapy-related APL (t-APL) were highlighted in a systematic review: 1)
MRD is emerging as a novel determinant to assess the depth of the average age of diagnosis is 47 years with a higher incidence in
therapeutic response at the time of morphologic remission in patients with females; 2) the risk significantly declines 2 years after completion of
AML (see Role of MRD Monitoring). treatment for the primary antecedent disease; 3) breast cancer,
hematologic malignancy, multiple sclerosis, and genitourinary malignancy
Finally, all patients require attentive supportive care related to the are the most common antecedent diseases; 4) topoisomerase II inhibitors
underlying leukemia (ie, tumor lysis syndrome) and the adverse effects of and radiation have the highest risk associated with developing t-APL; 5)
chemotherapy (see Supportive Care in the algorithm). the clinicopathology of t-APL is not different from de novo APL; 6) the
single mutation t(15;17) is most common; and 7) the remission rate of

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NCCN Guidelines Version 3.2022

Acute Myeloid Leukemia

t-APL is 80%, which is comparable to de novo APL.136 Therefore, t-APL prognosis. Several studies support this association and further correlate
and de novo APL are treated similarly. FLT3-ITD with higher WBC counts, lower platelet counts, and the
expression of the bcr3 PML-RARA fusion transcript.145-148 However, data
The incorporation of all-trans retinoic acid (ATRA) and the use of risk from other studies have not shown a correlation.58,149 It has been proposed
stratification (based on WBC counts) in the management of APL has that the discrepancy between studies may be at least partially resolved by
largely improved outcomes for patients with this subtype. The unique incorporation of a FLT3-ITD/wild-type ratio to measure the effect on
ability of ATRA to produce differentiation in APL blasts can reverse the prognosis.113,150 Data showed that a ratio of greater than 0.66 resulted in a
coagulopathy, which is the major cause of death during induction. To shorter 5-year RFS.150 Similarly, shorter EFS and OS were observed in the
minimize early induction mortality due to coagulopathy, patients with a setting of equal to or greater than a 0.5 ratio compared to less than 0.5
presumptive diagnosis of APL based on morphology, immunophenotype, (EFS, P = .029; OS, P = .084).113 While data may correlate with prognosis,
and/or coagulopathy with a positive disseminated intravascular there currently remains no change in treatment course depending on
coagulation screen should promptly start ATRA. It is not necessary to wait expression of FLT3-ITD.
for molecular testing or bone marrow with cytogenetics to confirm the
diagnosis. The initial clinical diagnosis of APL may be confirmed by FISH Induction Therapy for Patients with APL
or PCR ideally in the peripheral blood and if not confirmed, ATRA may be The evolution of treatment strategies for APL, built on clinical observation
discontinued and standard AML therapy initiated. and well-constructed clinical trials, represents one of the most rewarding
sagas of modern hematology. An early study by a group in Shanghai
Studies have demonstrated the necessity of early recognition and prompt
reported a CR rate of 85% in response to single-agent ATRA.151 The first
initiation of ATRA based on a presumed diagnosis of APL to reduce the
North American Intergroup study confirmed a 70% CR rate with
rate of early mortality. This is evidenced by early death rates below 10%
single-agent ATRA, which was equivalent to rates obtained with
reported for patients enrolled in clinical trials137-141 compared to the general
conventional doses of cytarabine and daunorubicin.152,153 Induction
population where early mortality rates are still in excess of 15%.135,142-144
regimens with ATRA combined with anthracyclines (with or without
Data from the SEER registry measured 2-year survival and 30-day
cytarabine) are associated with CR rates exceeding 90%, as
mortality from 1977 to 2007 and found a 61% improvement in 3-year
demonstrated in several large cooperative group trials.154-157 Using
survival per decade (P = .001) but a consistent rate of 30-day mortality
ATRA-based induction regimens followed by consolidation with regimens
averaging 20%.142 Education of heath care providers to identify the first
containing either ATRA with anthracyclines, or cytarabine with
suspicion of APL may extend the improved outcomes seen in clinical trials
anthracyclines, more than 80% of patients with APL can be cured of their
to the general population if treatment is not delayed.
disease.154,156-158 ATRA with arsenic trioxide (ATO) has resulted in
There is a high frequency of FLT3 mutations in APL. In a systematic improved outcomes for patients with APL.159 Risk stratification is a major
review including 11 studies, FLT3-ITD frequency in APL occurred in about consideration in the treatment of APL (see APL: Classification and
12% to 38% of cases and FLT3-TKD occurred in 2% to 20% of cases.145 Treatment Recommendation in the algorithm).157 Although clinical trials
Data are inconsistent about whether FLT3-ITD in APL results in a negative may group patients into those with low-, intermediate-, or high-risk

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NCCN Guidelines Version 3.2022

Acute Myeloid Leukemia

disease, the NCCN Panel categorizes patients with APL as having low-risk outcome of the French APL 2000 trial (n = 340) in which patients younger
disease (WBC count ≤10,000/mcL) or high-risk disease (WBC than 60 years of age with WBC counts less than 10,000/mcL were
count >10,000/mcL). Patients with low-risk disease are typically treated randomized to receive ATRA (45 mg/m2) and daunorubicin (60 mg/m2/day
with less intensive consolidation regimens compared with regimens used for 3 days) as induction therapy with or without cytarabine (200 mg/m2/day
for patients with high-risk disease. for 7 days). Those randomized to cytarabine for induction also received
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
CR rates of 89% to 95%, raising the question of whether there was a need greater than 10,000/mcL, the CR rate was 97%; the 2-year EFS rate was
for cytarabine in APL induction.137,141 In these trials, 51% to 61% of 89% for those younger than 60 years of age and 79% for those >60 years
evaluable patients achieved PCR-negative status for PML-RARA following of age.163 A report of a joint analysis of the outcomes in the PETHEMA 99
induction therapy; 93% to 98% achieved PCR-negative status after and the French APL 2000 trials in patients younger than 65 years of age
consolidation. The estimated 2-year EFS rate was 79% in both trials.137,141 showed that in patients with a WBC count less than 10,000/mcL, CR rates
In the PETHEMA trial, the 2-year OS rate was 82%.141 were similar, but the relapse rates at 3 years were lower in the PETHEMA
trial, which used AIDA and no cytarabine during induction (with ATRA
Following observational data that correlated elevated WBC counts and
during consolidation), than in the APL 2000 cytarabine-containing regimen
high-risk disease (based on both the higher number of deaths during
(4% vs. 14%; P = .03).155 However, for patients with a WBC count greater
induction and the increased rates of relapse), in the PETHEMA LPA 94
than 10,000/mcL, the cytarabine-containing protocol resulted in higher CR
trials, Sanz et al161,162 devised a risk stratification study based solely on
(95% vs. 84%; P = .018) and 3-year OS rates (91.5% vs. 81%;
WBC and platelet counts at presentation. In this study, the induction
P = .026).155 The second North American Intergroup trial also used ATRA
regimen remained the same (AIDA), but ATRA was added to consolidation
(45 mg/m2), daunorubicin (50 mg/m2/day for 4 days), and cytarabine (200
cycles 1 to 3 for all but patients with low-risk disease (ie, WBC
mg/m2/day for 7 days) with a similar initial CR rate of 90%.156
≤10,000/mcL and platelets >40,000/mcL). The CR rate in this trial was
Consolidation in this trial differed in that two cycles of ATO were given
90% with almost all the failure attributed to hemorrhage, infection, or
following induction and prior to the final two cycles of anthracycline.
differentiation syndrome. Factors predictive of death during induction were
a WBC count greater than 10,000/mcL, age >60 years, creatinine of 1.4 or ATO has been found to be a potent promoter of apoptosis in APL
greater, and male gender.161,162 In 2006, Ades et al163 reported the cells.164,165 In 2004, Shen et al166 first published outcomes using

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NCCN Guidelines Version 3.2022

Acute Myeloid Leukemia

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
authors suggested that ATRA combined with ATO, with or without GO, (44%), gastrointestinal toxicity (28%), metabolic abnormalities (16%), and
may be an alternative to conventional chemotherapy in patients with prolonged QTc interval (14%); grade 3 or 4 differentiation syndrome
untreated APL. A subsequent study examined the long-term outcomes of occurred in 14% of patients. Patients who achieved CR following induction
patients with newly diagnosed APL treated with ATRA and ATO with or received consolidation with 2 cycles of ATRA and ATO. Maintenance
without GO [9 mg/m2 on day 1 of induction therapy for high-risk APL therapy was administered for 2 years and consisted of eight 3-month
patients] (n = 187; median age, 50 years; range, 18–84 years).169 The cycles of treatment with ATRA, oral methotrexate, and
complete remission rate was 96% for patients with both low- and high-risk 6-mercaptopurine.173 Grade 3 or 4 adverse events occurred primarily
APL. With a median follow-up of 47.6 months (range, 2.7–159.7 months), during induction (as above); the most common grade 3 or 4 events during
the 5-year EFS, DFS, and OS rates for patients with low-risk APL were consolidation (cycle 1) included infections (19%) and hepatic toxicity
87%, 99%, and 89%, respectively, and for patients with high-risk APL (12%), and no deaths occurred during consolidation cycles. The
were 81%, 89%, and 86%, respectively.169 These data suggested that hematologic CR rate after induction was 95%; early death (during
ATRA and ATO combined with GO is feasible and elicits durable induction) occurred in 3% of patients. The 2-year DFS and failure-free
responses. In another study by Estey et al,170 patients with APL were survival rates were 97.5% and 88%, respectively. The 2-year OS rate was
treated with ATRA and GO (9 mg/m2 on day 1 or 5 of induction therapy). 93%.173 This trial enrolled 24 patients that were defined as having high risk
Patients with WBC counts of >30,000/mcL also received idarubicin (12 disease based on the Sanz criteria. OS was not affected by the Sanz risk
mg/m2/day on days 1–3). In this study (n = 19), the CR rate in all patients group (P[trend] = .17), although a correlation was made with the failure-free
who received ATRA plus GO and idarubicin was 84%, and 88% in patients survival rate (P[trend] = .03). This association may be attributed to the
who received ATRA plus GO.170 However, clinicians should be aware of method of analysis that included patients who withdrew from the study due
possible adverse events associated with GO including sinusoidal

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NCCN Guidelines Version 3.2022

Acute Myeloid Leukemia

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
the end of induction) as prophylaxis for differentiation syndrome. The days 1 through 5 in the first week and 0.25 mg/kg twice weekly in weeks 2
primary endpoint of this study was the 2-year EFS rate. Among evaluable through 8 in course 1 and then twice weekly in weeks 2 through 4 during
patients (n = 156), CR rates were not different between Arm A and Arm B courses 2 through 5. Patients with high-risk disease could receive an initial
(100% vs. 95%). After a median follow-up period of 34.4 months, the dose of GO (6 mg/m2 IV). Comparison between the ATRA plus ATO group
2-year EFS rate was significantly higher in Arm A compared with Arm B and the AIDA group showed a higher 4-year EFS (91% vs. 70%; P = .002)
(97% vs. 86%; P < .001 for non-inferiority; P = .02 for superiority). The and lower 4-year cumulative incidence of morphologic relapse (1% vs.
2-year OS probability was also significantly higher in Arm A compared with 18%; P = .0007) for ATRA plus ATO compared to AIDA, though no
Arm B (99% vs. 91%; P = .02). Four patients in Arm B died during statistically significant difference in 4-year survival was seen (93% vs.
induction therapy (2 deaths were caused by differentiation syndrome). 89%; P = .25). Quality of life was equivalent in the treatment groups for
One patient in Arm A and 3 patients in Arm B died during consolidation. both patients with high- and low-risk disease as measured by the primary
Grade 3 or 4 neutropenia and thrombocytopenia lasting more than 15 outcome of global functioning (effect size, 2.17; 95% CI, -2.79–7.12;
days were significantly more frequent in Arm B compared with Arm A P = .39).175 However, the data from the trial measured more supportive
throughout induction and consolidation cycles. Grade 3 or 4 hepatic care treatments and higher liver toxicity with AIDA. Treatment schedule
toxicities also occurred more frequently in Arm A compared with Arm B differed from previous trials by moving to a higher dose of ATO given at a
(63% vs. 6%; P < .001).159 Health-related quality-of-life outcomes were not lower frequency of twice weekly. Though data are limited to this single
significantly different between treatment groups except for fatigue severity. trial, the NCCN AML Panel recognizes that this alternative dosing
There was improvement in fatigue following induction in the ATRA plus schedule may be more manageable for patients who have difficulty getting
ATO group (P = .022), though the benefit was negligible by third to the clinic.

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NCCN Guidelines Version 3.2022

Acute Myeloid Leukemia

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
monitoring and treatment of adverse events, regardless of risk single dose of GO (9 mg/m2 on day 1169 or 6 mg/m2 on day 1175). If the
stratification. The recommendations within the guidelines are broken down patient with high-risk disease exhibits signs of prolonged QTc, the panel
by: 1) risk classification using WBC count (cutoff of 10,000/mcL) at recommends initial induction with ATRA and a single dose of GO (9 mg/m2
diagnosis; and 2) whether patients with high-risk disease have cardiac on day 1)170; ATRA plus daunorubicin and cytarabine153,155; or AIDA
issues. alone.157

For patients with low-risk disease (WBC counts ≤10,000/mcL), for initial The sudden onset of differentiation syndrome and the severity of the
induction the panel recommends ATRA plus ATO (0.15 mg/kg)159 complications have resulted in the frequent use of preemptive
(category 1, preferred regimen); and ATRA plus ATO (0.3 mg/kg)175 dexamethasone, because there are no markers to predict its development.
(category 1, preferred regimen). If arsenic is contraindicated or not The panel recommends the prophylactic administration of corticosteroids
available, the panel recommends AIDA157 (category 1); ATRA plus a single in patients with a WBC count greater than 10,000/mcL (or in patients
dose of GO (9 mg/m2 on day 5)170; or enrollment in a clinical trial. receiving induction with both ATRA and ATO, regardless of WBC count) to
prevent differentiation syndrome. The ATRA plus ATO regimens defined
For patients with high-risk disease (WBC counts >10,000/mcL), the NCCN by Lo-Coco et al159 or Iland et al173,176 use prednisone 0.5 mg/kg as
AML Panel historically recommended a regimen that included cytarabine prophylaxis for differentiation syndrome but with differing durations and
along with ATRA plus daunorubicin (PETHEMA LPA 99 trial) over AIDA tapering schedules. For patients who develop differentiation syndrome on
(APL 2000 trial) because of higher CR and 3-year OS rates.155,157 To these regimens despite prednisone prophylaxis, prednisone should be
improve patient outcome, the PETHEMA LPA 99 trial and the GIMEMA stopped and replaced with dexamethasone 10 mg twice daily (see
AIDA-0493 study were modified to incorporate the combination of ATRA Supportive Care for APL in the algorithm). If using non-ATO regimens,

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NCCN Guidelines Version 3.2022

Acute Myeloid Leukemia

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
recommended until recovery of blood counts, usually 4 to 6 weeks after consolidation phase.161 For the low-risk group, there was no difference in
induction. Cytogenetic analysis is usually normal by this point, but relapse rate (3%–6%) or in 3-year DFS rate (93%–97%) between the
molecular remission often requires at least 2 cycles of consolidation. Thus, ATRA group compared with a similar consolidation without ATRA in the
the first assessment of molecular remission should not be performed prior LPA 94 trial.161 Among patients with intermediate risk disease, the relapse
to count recovery. At count recovery following induction therapy, patients rate was reduced from 14% to 2.5% with the incorporation of ATRA; the
should proceed with consolidation. For patients with low-risk disease, if a 3-year DFS rate was 97% with ATRA consolidation versus 82% in
patient is cytopenic on days 28–35, bone marrow biopsy and aspirate is historical controls.161 Although the addition of ATRA to the high-risk group
recommended to document blast clearance and to assess whether the improved relapse and DFS rates, there were significant rates of relapse
marrow is suppressed and to determine whether ATRA and ATO should (26%) and 3-year DFS (77%). In the PETHEMA LPA 2005 study, both
be held to allow count recovery. If, however, blood counts have recovered ATRA and cytarabine were included in the anthracycline-containing
by this time point, a bone marrow biopsy may be considered to consolidation regimen for patients with high-risk disease.157 In this
document remission but is optional. For patients with high-risk disease, high-risk group, the 3-year relapse rate was reduced to 11% (compared
LP should be considered at count recovery following induction therapy, with 26% from the LPA 99 study), and the 3-year DFS and OS rates were
before proceeding with consolidation.177 Many consolidation regimens 82% and 79%, respectively. The LPA 2005 trial also began to approach
involve high cumulative doses of cardiotoxic agents. It is therefore the question of how to reduce toxicity during consolidation therapy in
important to assess the cardiac function of patients prior to initiating each patients with low- and intermediate-risk disease by dose reduction of
anthracycline- or mitoxantrone-containing consolidation cycle. mitoxantrone (from 10 mg/m2/day for 5 days to 10 mg/m2/day for 3 days in
Consolidation regimens employing ATO will require monitoring of the QTc cycle 2) and a small reduction of idarubicin dose for low- and
interval and optimizing electrolytes (see Supportive Care for APL in the intermediate-risk groups (from 7 mg/m2/day for 4 days to 5 mg/m2/day for

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NCCN Guidelines Version 3.2022

Acute Myeloid Leukemia

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.
consolidation regimen containing ATRA and cytarabine along with
anthracyclines.158 In this study, the 6-year cumulative incidence of relapse The North American Intergroup trial also focused on decreasing toxicity
was 9% for patients in the high-risk group; the 6-year DFS and OS rates in during consolidation by incorporating ATO into the consolidation schema
this group were 84.5% and 83%, respectively. In the AIDA-2000 study, the directly after achieving remission.156 In this trial, patients who were
low- and intermediate-risk groups were collapsed into a single category, randomized to receive 2 courses of 25 days of ATO (5 days a week for 5
and received the same consolidation regimen with ATRA, mitoxantrone, weeks) immediately after entering CR followed by the standard
and idarubicin (ATRA 45 mg/m2 for 15 days + idarubicin 5 mg/m2 for 4 post-remission regimen with 2 more courses of ATRA plus daunorubicin,
days in cycle 1; ATRA for 15 days and mitoxantrone 10 mg/m2/day for 5 had a significantly higher 3-year EFS rate (80% vs. 63%; P < .0001) and
days in cycle 2; and ATRA for 15 days and idarubicin 12 mg/m2 for 1 dose improved OS outcomes (3-year OS rate 86% vs. 81%; P = .06) compared
in cycle 3). For patients in the low- and intermediate-risk group, the 6-year with those who received only the 2 courses of ATRA plus chemotherapy.
cumulative incidence of relapse was 11%; the 6-year DFS and OS rates in The 3-year DFS rate was also significantly improved with the addition of
this group were 86% and 89%, respectively.158 ATO (90% vs. 70%; P < .0001). The favorable outcomes with the
incorporation of ATO were observed in patients with low-/intermediate-risk
In the European APL 2000 trial, which randomized daunorubicin with or and high-risk disease.156 Notably, in the high-risk group, DFS outcomes
without cytarabine for the consolidation phase (no ATRA during with the addition of ATO were similar to the DFS rate observed for the
consolidation) for the low- and intermediate-risk (ie, “standard risk”) low-/intermediate-risk group, suggesting that ATO may help to overcome
groups, the 2-year EFS rate was higher with the addition of cytarabine.163 the negative prognostic influence of high-risk disease. The overall
Long-term follow-up from this study showed that in patients with standard outcomes do not appear to be superior to the less complex consolidation
risk disease, the addition of cytarabine substantially reduced cumulative schedules used in either of the two most recent European trials for

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NCCN Guidelines Version 3.2022

Acute Myeloid Leukemia

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 with no differences in 2-year DFS (97% vs. 90%; P = .11) or cumulative
associated with longer durations of myelosuppression, which necessitated incidence of relapse (1% vs. 6%; P = .24) between treatment arms.159
a protocol amendment to further reduce the chemotherapy dose in
patients receiving ATO.180 In the second interim analysis, the only change In the French APL 93 trial, a 4% incidence of CNS relapse was reported in
was a decrease of idarubicin during second consolidation. Data from this patients with WBC counts greater than 10,000/mcL. In the APL 2000 trial,
analysis show a 99.4% CR across all groups encompassing a total of 347 that high-risk population received five doses of IT chemotherapy using a
patients.181 While the two-year EFS and OS rates were above 95% for all combination of methotrexate, cytarabine, and steroids, upon count
three groups, there was a reduction of myelosuppression in the group recovery following induction therapy. These patients also received a
treated with AIDA compared to idarubicin plus cytarabine and idarubicin higher dose of cytarabine (2 g/m2) during consolidation (in cycle 2) as
plus ATO, which had similar durations.181 The potential benefits of the use compared with 1 g/m2 in the APL 93 trial. There were no cases of CNS
of ATO or ATRA in consolidation may rest in a lower risk for long-term relapse in the APL 2000 trial, compared with 5 cases in the APL 93 trial.
cardiovascular complications and a lower risk for secondary While the original treatment protocol on APL 2000 used HiDAC in the
myelodysplasia. second cycle of consolidation, some investigators suggest the use of
HiDAC earlier, particularly in those patients who are not receiving IT
In the phase II APML4 study from Australia/New Zealand, 2 cycles of ATO therapy for CNS prophylaxis.
and ATRA were used as consolidation in patients who achieved a CR after
a 3-drug induction with ATRA, idarubicin, and ATO.173 Among the patients For patients with low-risk disease, the NCCN AML Panel has positioned
who proceeded to consolidation (n = 112), all achieved molecular the ATRA plus ATO regimen first, based on results from the APL0406
remission, and the 2-year DFS rate was 97.5%. The 2-year OS rate in all phase III randomized trial in comparison with the AIDA regimen.159 An

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NCCN Guidelines Version 3.2022

Acute Myeloid Leukemia

additional ATRA plus ATO regimen based on the AML 17 trial175 is also a In general, it is recommended that 4 to 6 doses of intrathecal (IT)
preferred option. The GIMEMA AIDA-2000 regimen158 is an additional chemotherapy be given during consolidation for patients with high-risk
option. However, all three of these regimens will yield excellent results. It APL. IT chemotherapy may include agents such as methotrexate
is important to note that clinicians should use a regimen consistently alternating with cytarabine either alone or combined with corticosteroids;
through all components of the treatment protocol and not mix induction the choice of single drug versus combinations may vary based on clinical
regimens from one trial with consolidation regimens from another trial. situation and institutional practice. Usually the IT treatment is started at the
completion of induction and then given at the start and at count recovery
For patients with high-risk disease, preferred consolidation therapies on subsequent consolidations. IT chemotherapy can be omitted during
include ATRA plus ATO as used in the APML4 trial,173 or ATRA and ATO cycles of higher dose cytarabine.
(plus a single dose of GO if ATRA/ATO are discontinued due to
toxicity).169,175 Other recommended consolidation approaches include Post-Consolidation or Maintenance for Patients with APL
cytarabine with daunorubicin as used in the French APL 2000 trial163; Following consolidation therapy, patients are assessed for molecular
cytarabine with AIDA as used in the PETHEMA LPA 2005157; and 2 cycles remission using RT-PCR techniques on bone marrow samples. For
of ATO followed by 2 additional cycles of standard chemotherapy as used patients who have achieved PCR negative status, a 1- to 2-year course of
in the North American Intergroup trial.156 When using a ATRA maintenance therapy, which may be combined with
cytarabine-containing regimen, dose adjustments of cytarabine may be 6-mercaptopurine and methotrexate, may be a reasonable approach. The
needed for patients who are older or for patients with renal recommendations for maintenance ATRA arose from several early trials
dysfunction.155,156 In patients who could not tolerate anthracyclines and that showed superior RFS for patients receiving ATRA alone or in
who received ATRA and ATO for induction therapy, the reported trials combination as maintenance therapy. The French APL 93 trial randomized
continued with repeated cycles of these two agents following induction eligible patients (n = 289) to four different maintenance regimens: no
without anthracycline.167,168 For patients with high-risk disease and cardiac maintenance, continuous chemotherapy with 6-mercaptopurine and
issues (eg, low ejection fraction and prolonged QTc), the NCCN AML methotrexate, intermittent ATRA, and the combination of ATRA with
Panel recommends ATO (0.15 mg/kg or 0.3 mg/kg) with ATRA for 6-mercaptopurine and methotrexate.138 Results showed decreased 2-year
consolidation.169,175 If ATRA or ATO are discontinued due to toxicity, a relapse rates with continuous chemotherapy (11.5% vs. 27% with no
single dose of GO (9 mg/m2) may be considered once every 4 to 5 weeks chemotherapy) and with ATRA (13.5% vs. 25% with no ATRA). The
until 28 weeks from CR. If the patient received ATRA and GO as induction estimated 2-year relapse rate for patients who received maintenance with
therapy, consolidation with ATRA and GO should follow.170 As mentioned ATRA in combination with chemotherapy was 7.4%, suggesting an
previously, the panel suggests that a regimen should be used consistently additive benefit with the combination. The 2-year EFS rate was also
through all components and physicians should not mix induction therapy improved with continuous chemotherapy (92% vs. 77% without
from one trial with consolidation therapy from another. chemotherapy) and with ATRA (87% vs. 82% without ATRA); the 2-year
EFS rate among patients who received ATRA in combination with
chemotherapy was 93%.138 Results from the long-term follow-up of the

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NCCN Guidelines Version 3.2022

Acute Myeloid Leukemia

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
maintenance, ATRA alone, continuous chemotherapy, and ATRA The Japanese APL 97 randomized study evaluated the role of
combined with chemotherapy were 43%, 33%, 23%, and 13%, maintenance with intensified chemotherapy compared with observation in
respectively (P < .001).154 Patients considered to be at high risk (WBC patients with APL who achieved molecular remission following
count >5000/mcL) appeared to derive the most benefit from maintenance consolidation (n = 175).182 The estimated 6-year DFS was not significantly
therapy. The 10-year cumulative relapse rate among patients with different between the chemotherapy maintenance and observation arms
high-risk disease with no maintenance, ATRA alone, continuous (63% vs. 80%). In fact, the estimated 6-year OS was significantly lower
chemotherapy, and ATRA combined with chemotherapy was 68%, 53%, with maintenance (86% vs. 99%; P = .014), which the investigators
33%, and 21%, respectively (P < .001). No statistically significant attributed to possible effects of chemotherapy maintenance on the
difference in the 10-year relapse rates was observed among patients with development of secondary malignancies and responses to subsequent
lower-risk disease, although the relapse rate dropped from 29% without (second-line) therapies.182
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
chemotherapy, and ATRA combined with chemotherapy were 74%, 88%,
6-mercaptopurine and methotrexate, ATRA alone, or ATRA in combination
93%, and 94%, respectively (P < .001).154
with chemotherapy) in patients who achieved molecular remission (PCR
The first North American Intergroup trial showed superior DFS outcomes negative) at the end of consolidation therapy.183 In this trial, ATRA was not
for patients receiving maintenance ATRA compared with no given during consolidation. The above studies have not demonstrated
maintenance.153 In this trial, patients were randomized to induction therapy long-term benefit with the use of maintenance therapy in patients who
with daunorubicin plus cytarabine or with ATRA alone, and subsequently achieve molecular remission following consolidation therapy. Further data
underwent a second randomization to maintenance therapy with ATRA or from randomized trials are needed to address the question of
no maintenance (observation only). Consolidation therapy comprised the maintenance. A phase III cooperative group trial (SWOG 0521) is
initial induction therapy regimen for course 1, and then daunorubicin and designed to examine the need for maintenance therapy (using the
HiDAC for course 2. The 5-year DFS rates for the four randomization combination of ATRA, 6-mercaptopurine, and methotrexate) in patients
groups, chemotherapy induction plus observation, chemotherapy induction with low-risk APL. In this trial, patients receive induction therapy with
plus ATRA maintenance, ATRA induction plus observation, and ATRA ATRA, daunorubicin, and cytarabine, followed by consolidation therapy
induction plus ATRA maintenance, were 16%, 47%, 55%, and 74%, with ATO, ATRA, and daunorubicin. Patients are then randomized to
respectively.153 Thus, the incorporation of ATRA during induction and receive maintenance therapy or no further treatment (observation only).
maintenance appeared to improve long-term remission durations. It should No benefit for maintenance was observed.184 The benefit of maintenance
be noted that in the above North American Intergroup trial, molecular therapy likely depends on the regimens used during induction and

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NCCN Guidelines Version 3.2022

Acute Myeloid Leukemia

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
status should be confirmed in a blood sample by a reliable laboratory analysis in a small number of patients reported a second CR rate of 93%
within 2 to 4 weeks. If molecular relapse is confirmed by a second positive (both for hematologic CR and molecular remission) among patients who
test, the patient should be treated for relapsed disease (see APL: Therapy were retreated with ATO combined with ATRA (with or without
for Relapse in the algorithm). If the second test was negative, anthracyclines) after a relapse following first-line therapy with single-agent
maintenance therapy and frequent monitoring (eg, every 2–3 months) for ATO (n = 14).188
up to an additional 2 years may be considered to ensure that the PCR
remains negative. Testing should be done in the same laboratory to For patients with APL who experience relapse early (<6 months) after an
maintain a consistent level of sensitivity. For patients who develop initial CR to first-line therapy with ATRA and ATO with no prior exposure to
cytopenias and who have a negative RT-PCR, a bone marrow aspirate is anthracyclines, anthracycline-based regimens (ATRA plus daunorubicin
recommended to assess for new cytogenetic abnormalities, as secondary and cytarabine153,155,156; and AIDA alone157) are recommended. For
MDS and AML can occur following APL therapy. patients who experience an early relapse (<6 months) after an initial CR to
ATRA and anthracycline-containing first-line regimens or with no prior
Management of Relapsed APL exposure to ATO, it is recommended that the patient receive ATO with or
ATO is recommended for patients who do not achieve molecular remission without ATRA, and with or without a single dose of GO until count
at completion of consolidation or who subsequently demonstrate recovery with marrow confirms remission. For patients who experience a
molecular or morphologic relapse. As a single agent, ATO produced CR late relapse (≥6 months) to ATO-containing regimens, ATO with or without

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NCCN Guidelines Version 3.2022

Acute Myeloid Leukemia

ATRA, and with or without a single dose of GO/an anthracycline is mortality observed in the allogeneic HCT group compared with the
recommended as first-line therapy after relapse. Following completion of autologous HCT group (39% vs. 6%).191
the first cycle of consolidation, if the patient does not achieve molecular
remission, a matched sibling or alternative donor (haploidentical, unrelated A second study also suggested that autologous transplant could have a
donor, or cord blood) HCT or clinical trial is recommended. Testing is survival advantage over allogeneic transplant in this population.192
recommended at least 2 to 3 weeks after the completion of arsenic to Chakrabarty et al192 looked at 294 patients who received either allogeneic
avoid false positives. transplant (n = 232) or autologous transplant (n = 62) between 1995 and
2006. The 5-year DFS in the autologous transplant recipients was 63%
A small phase II trial in patients with relapsed APL evaluated ATO during (range, 49%–75%) versus 50% (range, 44%–57%) in patients receiving
induction and consolidation followed by a peripheral blood hematopoietic allogeneic transplant. Although the DFS was not statistically significant
cell harvest after HiDAC chemotherapy and autologous HCT.190 The study (P = .1), the difference in OS did reach statistical significance (P = .002).
enrolled 35 patients (16 who experienced hematologic relapse and 9 who In the patients receiving autologous transplant, OS was 75% (range, 63%–
experienced molecular relapse) between the ages of 18 and 65 years. The 85%) versus 50% (range, 48%–61%). The authors attribute this benefit to
EFS after 1 year was 77% (90% CI, 63%–86%). At a median follow-up of the increased treatment-related mortality seen with patients receiving
4.9 years (range, 0.3–6.3 years), the 5-year EFS was 65% and the 5-year allogeneic transplant (30%) compared to autologous transplant (2%).
OS was 77% with an estimated 59% probability of failure-free survival.190
The data suggest that this sequential treatment regimen may provide It should be noted that only limited evidence from retrospective studies
improved outcomes with greater duration. exist with regard to the role of autologous and allogeneic HCT following
relapse of APL in the era of ATO therapy. The optimal consolidation
A retrospective analysis conducted by the European APL Group showed strategy following therapy with ATO-containing regimens in patients with
that in patients who received HCT following a second hematologic relapsed disease remains to be defined.193 In a small retrospective study
remission (primarily with ATRA-containing regimens), outcomes were of patients with relapsed APL treated with ATO-containing induction and
more favorable with autologous HCT (n = 50) compared with allogeneic consolidation therapy, outcome of further consolidation with autologous
HCT (n = 23). The 7-year RFS (79% vs. 92%) and EFS (61% vs. 52%) HCT was compared with maintenance (without autologous HCT)
rates did not reach statistical significance between patients who received consisting of ATO with or without ATRA.188 In this analysis, all patients had
autologous HCT versus allogeneic HCT; however, 7-year OS rates were achieved second molecular remission following induction and
significantly improved with autologous compared with allogeneic HCT consolidation therapy with the ATO-containing regimens; subsequently, 14
(60% vs. 52%; P = .04).191 Among patients who received a PCR-negative patients underwent autologous HCT and 19 patients opted for an
autograft, the 7-year RFS and OS rates were 87% and 75%, respectively. ATO-containing maintenance regimen. Consolidation with autologous HCT
Although the relapse rates were low with allogeneic HCT, the reduced OS was associated with a significantly higher 5-year EFS rate (83% vs.
with this procedure was accounted for by the higher treatment-related 34.5%; P = .001) and OS rate (100% vs. 38.5%; P = .001) compared with
ATO-containing maintenance therapy.188 The authors concluded that

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NCCN Guidelines Version 3.2022

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consolidation with autologous HCT was superior to ATO-containing therapy with ATO for six cycles is recommended in the absence of a
maintenance alone in patients who achieved molecular remission after suitable clinical trial.
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 Supportive Care for Patients with APL
transplant (P = .03).194 Specific supportive care issues should be considered when treating
patients with APL. Therapy for APL is often associated with a constellation
In the context of a clinical trial or on compassionate use, GO is a potential of symptoms and physiologic abnormalities, including fluid retention,
treatment option for relapsed APL. The voluntary withdrawal of the drug in dyspnea, episodic hypotension, pulmonary infiltrates, and pulmonary or
2010 was based on interim data from a randomized trial in adult patients pericardial effusions now referred to as “differentiation syndrome.”
(aged 18–60 years) with AML comparing induction regimens of cytarabine Approximately 15% to 25% of previously untreated patients receiving
and daunorubicin with or without GO in which there was no improvement ATRA-containing therapy develop this syndrome.199,200 Patients may begin
in outcomes and a small but significant increase in early mortality in the to develop evidence of differentiation syndrome early in the treatment with
GO arm.195 Subsequent results of this trial eventually showed no either ATRA or ATO as single agents or in combination. These patients
difference in overall mortality between the two arms.196 Since its develop fever, often accompanied by rapidly rising WBC counts
withdrawal from the market, studies have demonstrated a significant (>10,000/mcL). Patients should be closely monitored for hypoxia and the
benefit for GO in specific patient populations. Therefore, GO has been re- development of pulmonary infiltrates or pleural effusion. Differentiation
approved for AML. One complication to evaluating the benefit of GO is that syndrome along with hemorrhage are the leading causes of death during
APL occurs in a small population of patients, and therefore studies do not induction therapy. Early recognition and prompt initiation of corticosteroids
have the numbers to enroll for a suitable trial. The benefit of GO must be are key components in the management of this complication. In some
weighed against the possibility for adverse events. Clinicians should be studies, low mortality and morbidity rates were reported when
advised of the possible complication of sinusoidal obstructive syndrome corticosteroids were administered prophylactically in patients presenting
when administering GO. with high WBC counts.161,201 Kelaidi et al202 assessed the outcomes of
patients with high WBC (>10,000/mcL) enrolled in the APL 93 and APL
A small percentage of relapsed APL has a CNS component.197,198
2000 trials.202 A fundamental difference between these two trials was the
Therefore, for patients who are in second morphologic remission, the use
use of dexamethasone (10 mg every 12 hours beginning on day 1) for
of IT therapy for CNS prophylaxis should be considered. Patients who
patients on APL 2000. The early death rate from differentiation syndrome
achieve a molecular remission after second-line therapy should be
dropped from 8 in 139 patients (6%) in the APL 93 trial to 2 in 133 patients
considered for autologous HCT if they do not have contraindications to
(1.5%) in the APL 2000 trial.
high-dose therapy. Allogeneic transplant should be reserved for patients
who have persistent disease despite therapy for relapsed disease. For There should be a high index of suspicion for differentiation syndrome in
patients in second CR who have contraindications to HCT, continued APL patients who may be triggered by symptoms including fever, an
increasing WBC count greater than 10,000/mcL, shortness of breath,

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NCCN Guidelines Version 3.2022

Acute Myeloid Leukemia

hypoxemia, and pleural or pericardial effusion. Close monitoring of volume Leukapheresis is not routinely recommended in the management of
overload and pulmonary status is warranted in these patients and initiation patients with high WBC counts in APL because of the difference in
of dexamethasone should occur at the first signs or symptoms of leukemia biology. However, in cases of potentially life-threatening
respiratory compromise (ie, hypoxia, pulmonary infiltrates, pericardial or leukostasis not responsive to other modalities, leukapheresis can be
pleural effusions). The NCCN AML Panel recommends treating with considered with caution.
dexamethasone 10 mg twice daily for 3 to 5 days, then tapering the dose
over 2 weeks (see Principles of Supportive Care for APL in the algorithm). Because coagulopathy is common in patients with APL, it is important to
ATRA may need to be withheld during the initial acute symptomatic period screen for this problem with evaluation of prothrombin time, partial
but may be resumed when symptoms resolve. Other factors that have thromboplastin time, and fibrinogen concentration during the initial workup
been reported to increase the risk of differentiation syndrome include a and before any invasive procedure. Clinical coagulopathy is managed by
high body mass index and age >40 years. For patients at high risk (WBC aggressive transfusion support to maintain platelet counts of 50,000/mcL
count >10,000/mcL) of developing differentiation syndrome, initiate or greater, by fibrinogen replacement with cryoprecipitate and frozen
prophylaxis with corticosteroids, either prednisone (0.5 mg/kg) from day 1 plasma to maintain a level of 150 mg/dL, and by maintenance of
or dexamethasone 10 mg every 12 hours (see Principles of Supportive prothrombin time and partial thromboplastin time close to normal. Patients
Care for APL in the algorithm). The steroid dose should be tapered over a with clinical coagulopathy need to be monitored daily until resolution.
period of several days. It is recommended that the prophylaxis regimen Given the risks of coagulopathy in APL at diagnosis, invasive procedures
follow the specific treatment protocol used. In the Australia/New Zealand including leukapheresis and/or central line placement should be avoided. If
study that evaluated induction with ATO added to a backbone of AIDA possible, the diagnosis of APL may be made using peripheral blood
(phase II APML4 trial), all patients received prednisone (1 mg/kg/day for at samples, which may minimize the risk of bleeding complications until
least 10 days) as prophylaxis for differentiation syndrome regardless of coagulopathy can be adequately controlled.
initial WBC count [see APL Treatment Induction (High Risk) in the
ATO therapy may prolong the QT interval, making patients susceptible to
algorithm].173 In the Italian-German Cooperative Group study that
ventricular arrhythmias. Therefore, prior to initiation of therapy, an ECG is
evaluated ATRA combined with ATO versus the AIDA regimen (phase III
recommended to assess the QT interval. Routine monitoring (eg, weekly)
APL0406 trial), patients received prophylaxis with prednisone (0.5
during therapy is suggested for patients who are older. Serum electrolytes
mg/kg/day) from day 1 until the end of induction [see APL Treatment
should also be monitored prior to and during therapy to maintain
Induction (Low Risk) in the algorithm].159 If a patient develops
electrolytes within the middle or upper normal range. Other drugs that
differentiation syndrome, it is recommended that treatment be changed
prolong the QT interval should be avoided during ATO therapy to minimize
from prednisone to dexamethasone 10 mg every 12 hours until count
the risk of cardiac arrhythmias. Patients with an absolute QTc interval
recovery or risk of differentiation has abated.157,159 In settings where
greater than 500 milliseconds should be reassessed on a weekly basis
differentiation syndrome is difficult to treat, the panel recommends the
during induction therapy, and prior to each course of post-remission
following cytoreduction strategies for leukocytosis: hydroxyurea,
anthracyclines, and GO.

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NCCN Guidelines Version 3.2022

Acute Myeloid Leukemia

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
to restore normal hematopoiesis. Early in the process of developing a Risk-Stratified Treatment Strategies
treatment plan, it is reasonable to consider referral to palliative care for Favorable-Risk Cytogenetics
consultation.204,205 Cytarabine and anthracycline dose during induction: A large
randomized phase III study (E1900) from the ECOG reported a significant
Recommendations for induction chemotherapy in patients with AML increase in CR rate (71% vs. 57%; P < .001) and median OS (24 vs. 16
consider age 60 years as a therapeutic divergence point. This is based on months; P = .003) using daunorubicin 90 mg/m2 daily for 3 days (n = 327)
the higher prevalence of unfavorable cytogenetics and antecedent versus 45 mg/m2 daily for 3 days (n = 330) in patients with previously
myelodysplasia, along with a higher incidence of multidrug resistance in untreated AML younger than 60 years.207 Based on subgroup analyses,
patients >60 years, and an increased frequency of comorbid medical however, the survival benefit with high-dose daunorubicin was shown to
conditions that affect the patient’s ability to tolerate intensive treatment.206 be restricted to patients with favorable- and intermediate-risk cytogenetic
Because complete remission rates rarely exceed 70% in younger patients profiles (median OS, 34 vs. 21 months; P = .004) and those younger than
and 50% in patients who are older, substantial opportunity exists for 50 years (median OS, 34 vs. 19 months; P = .004). The survival outcome
innovative clinical trials involving both patient populations. The guidelines for patients with unfavorable cytogenetics was poor, with a median OS of

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NCCN Guidelines Version 3.2022

Acute Myeloid Leukemia

only 10 months in both treatment arms.207 In an update of the E1900 trial, additional daunorubicin (50 mg/m2) on days 1, 3, and 5, which may
high-dose daunorubicin maintained a higher response than standard-dose potentially have mitigated the effects of a 90 mg/m2 daunorubicin dose.
daunorubicin in patients younger than 50 years of age (HR, 0.66;
P = .002).208 This benefit was seen regardless of cytogenetic risk profile. In CD33-Positive AML: GO is a humanized anti-CD33 monoclonal antibody
addition, patients with FLT3-ITD, DNMT3A, and NPM1 mutant AML had conjugated with the cytotoxic agent calicheamicin,212 that was initially
improved OS. Patients between 50 and 60 years of age with FLT3-ITD or approved in the year 2000 as a monotherapy for AML based on data from
NPM1mutant AML also benefitted from high-dose daunorubicin.208 High- single-arm phase II trials for older adult patients in first relapse.213 The
dose daunorubicin was previously evaluated in a European trial that voluntary withdrawal of the drug in 2010 was based on interim data from a
compared idarubicin 12 mg/m2 daily for 3 or 4 days versus daunorubicin randomized trial in adult patients (aged 18–60 years) with AML comparing
80 mg/m2 daily for 3 days in patients between ages 50 and 70 years; CR induction regimens of cytarabine and daunorubicin with or without GO in
rates were 83%, 78%, and 70%, respectively (P = .04).209 No difference which there was no improvement in outcomes and a small but significant
was seen in relapse rate, EFS, or OS outcomes between the treatment increase in early mortality in the GO arm.195 Subsequent results of this trial
arms. eventually showed no difference in overall mortality between the two
arms.196 Since its withdrawal from the market, studies have demonstrated
In a systematic review and meta-analysis of 29 randomized controlled a significant benefit for GO in specific patient populations. In the MRC
trials (RCTs) comparing idarubicin to daunorubicin,210 idarubicin had a AML 15 trial, the efficacy and safety of adding GO (3 mg/m2 on day 1 of
lower remission failure rate compared to daunorubicin (RR, 0.81; 95% CI, induction) to three induction regimens, including daunorubicin (50 mg/m2
0.66–0.99; P = .04), but no difference was observed in early death or on days 1, 3, and 5) and cytarabine (100 mg/m2 on days 1–10 every 12
overall mortality. Furthermore, this benefit was only seen when the dose hours), was evaluated in patients 60 years or younger with previously
ratio between daunorubicin and idarubicin was less than 5. Both high-dose untreated AML (n = 1,113).214 The addition of GO was well tolerated and
daunorubicin and idarubicin resulted in 5-year survival rates between 40% there were no differences in RFS or OS rates between arms that received
and 50%.210 or did not receive GO. The patients predicted to derive significant benefit
with the GO addition to chemotherapy included those with favorable-risk
It has been suggested that a dose of 60 mg/m2 daunorubicin may be cytogenetics, with a trend towards benefit for those with intermediate-risk
equally as effective as 90 mg/m2 and have a lower toxicity. A study from cytogenetics.214 A meta-analysis of five randomized trials (including adult
Burnett et al211 compared these two doses in 1206 patients who were patients ≥60 years) showed that adding GO (including alternative dosing
predominately younger than 60 years of age. There was no difference in schedules) to conventional induction therapy also provides survival
CR (73% vs. 75%; OR, 1.07; 95% CI, 0.83–1.39; P = .60). The 60-day benefit.215 A review of these and other studies (see Management of AML
mortality was higher in the patients receiving 90 mg/m2 (10% vs. 5%; HR, in Patients Older than 60 Years) led to the approval of GO in September
1.98; 95% CI, 1.30–3.02; P = .001), though the 2-year OS was similar 2017 for the treatment of adults with newly diagnosed CD33-positive AML.
(59% vs. 60%; HR, 1.16; 95% CI, 0.95–1.43; P = .15).210 It is worth noting
that all patients received a second course of chemotherapy that included

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NCCN Guidelines Version 3.2022

Acute Myeloid Leukemia

In the MRC AML 15 trial, younger patients with untreated AML (median 74.7 months (95% CI, 31.5–not reached [NR]) in the midostaurin group
age, 49 years), were randomized to two induction courses of: 1) compared to 25.6 months (95% CI, 18.6–42.9) in the placebo group (P =
daunorubicin and cytarabine (DA) with or without etoposide (ADE; n = .009).221 Patients who received midostaurin with standard induction and
1983); or 2) ADE versus fludarabine, cytarabine, granulocyte colony- consolidation therapy experienced significant improvement in OS (HR for
stimulating factor (G-CSF), and idarubicin (FLAG-Ida; n = 1268).216 death, 0.78; P = .009) and EFS (HR for event or death, 0.78; P = .002)
Patients in the DA and FLAG-Ida arms were randomly assigned to a single compared with those on the placebo arm.221
dose of GO (3 mg/m2) during the first induction course.216 Patients with
favorable- and intermediate-risk disease who received two induction Some studies suggest that a higher dose of daunorubicin (90 mg/m2),
courses of FLAG-Ida with GO in course 1, followed by 2 courses of HiDAC compared to lower doses of either 45 or 60 mg/m2, is significantly
had an 8-year survival rate from remission of 72% (favorable risk, 95%; associated with increased CR and survival rates in patients with
intermediate risk, 63%).216 intermediate-risk cytogenetics and those who have FLT3-ITD mutation–
positive AML.222,223 A phase III study compared idarubicin (12 mg/m2 for 3
KIT-Mutated AML: Emerging studies are evaluating the impact of adding days) and high-dose daunorubicin (90 mg/m2 for 3 days) with standard
dasatinib, a TKI, to AML therapy in CBF-AML with KIT mutations.217,218 cytarabine therapy during induction in young adults with newly diagnosed
AML (age range, 15–65 years). It was determined that high-dose
Intermediate-Risk Cytogenetics
daunorubicin was associated with higher OS and EFS rates in patients
FLT3-Positive AML: The majority of FLT3-mutated AML cases occur in with FLT3-ITD mutation–positive AML.224 However, these studies did not
patients with intermediate-risk cytogenetics. Data have demonstrated include midostaurin.
improved survival for patients with newly diagnosed FLT3-mutation–
positive AML when midostaurin is added to standard chemotherapy as Therapy-Related AML or Antecedent MDS/CMML or AML-MRC
part of frontline treatment.219-221 This led to its breakthrough designation Although most cases of AML are de novo, secondary AML and therapy-
and approval by the FDA in 2017. In the CALGB 10603/RATIFY Alliance related AML account for approximately 25% of all AML cases and are
trial, patients aged 18 to 59 years, with newly diagnosed FLT3-mutation– associated with poor outcomes.225,226 Emerging data have demonstrated
positive AML (ITD or TKD) were randomized (n = 717) to receive standard improved survival in patients who are older with secondary AML when a
cytarabine therapy (200 mg/m2 daily for 7 days via continuous infusion) dual-drug liposomal formulation of cytarabine and daunorubicin in a 5:1
and daunorubicin (60 mg/m2 on days 1–3) with placebo or midostaurin (50 molar ratio (CPX-351) is used as frontline therapy.227-229 In a phase II trial,
mg, twice daily on days 8–21).221 If residual disease in the bone marrow newly diagnosed patients ≥60 years of age with AML (n = 126), were
was observed on day 21, patients were treated with a second blinded randomized 2:1 to first-line CPX-351 or the conventional administration of
course. Patients who achieved CR received 4 28-day cycles of HiDAC (3 cytarabine and daunorubicin (7+3 regimen).228 Compared to the standard
g/m2 every 12 hours on days 1, 3, and 5) with placebo or midostaurin (50 7+3 regimen, CPX-351 produced higher response rates (CPX-351, 66.7%
mg, twice a day on days 8–21) followed by a year of maintenance therapy vs. 7+3, 51.2%; P = .07), however differences in EFS and OS were not
with placebo or midostaurin (50 mg twice a day).221 The median OS was statistically significant.228 A planned analysis of the secondary AML

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NCCN Guidelines Version 3.2022

Acute Myeloid Leukemia

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
younger than 46 years of age.230 This study randomized 1900 patients high-dose arm, compared with 12 months for the standard treatment
between the ages of 15 and 60 years into two treatment groups, HiDAC arm.231 However, treatment-related morbidity and mortality were higher in
and standard-dose cytarabine (SDAC; 100 mg/m2/d by continuous infusion the HiDAC arm; the 5-year OS rates were 33% in the high-dose arm
for 10 days). Both groups were also given daunorubicin (50 mg/m2/d on compared with 25% in the standard-dose arm.232
days 1, 3, and 5) and etoposide (50 mg/m2/d on days 1–5). Data from a
median 6-year follow-up indicate an OS near statistical significance In a large SWOG study,233 patients younger than 65 years (n = 665) with
(HiDAC, 42.5% vs. SDAC, 38.7%; P = .06), and when separated by age de novo or secondary AML were randomized to receive HiDAC (2 g/m2
with a cutoff of 46 years, the benefit was relegated to the younger patient every 12 hours for 6 days for a total of 24 g/m2; patients aged <50 years
cohort (HiDAC, 51.9% vs. SDAC, 43.3%; P = .009) compared to patients were initially randomized to receive 3 g/m2 at the above schedule before
≥46 years of age (HiDAC, 32.9% vs. SDAC, 33.9%; P = .91). Other the high-dose arm was redefined to 2 g/m2 because of toxicity concerns)
populations that benefited from HiDAC were patients with high-risk or standard-dose cytarabine (200 mg/m2 daily for 7 days); patients in both
disease, including patients with very poor-risk cytogenetic abnormalities treatment arms also received daunorubicin (45 mg/m2 daily for 3 days).
and/or FLT3-ITD mutation-positive AML or with secondary AML. There Patients treated in the HiDAC arm received a second high-dose cycle for

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NCCN Guidelines Version 3.2022

Acute Myeloid Leukemia

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
than for those who received the standard dose. Similarly, for patients favorable-risk cytogenetics, for patients receiving HiDAC versus standard
younger than 50 years who received 3 g/m2 HiDAC for consolidation, the chemotherapy.235 However, toxicity was a limiting factor and emphasis
rates of treatment-related deaths (4% vs. 0%) and grade 3 or greater was placed on the importance of future studies to define the populations
neurologic toxicity (16% vs. 0%) were higher than for those who received that would most benefit from HiDAC and to optimize dosing
the standard dose.233 recommendations. The decision to use high- versus standard-dose
cytarabine for induction might be influenced by consolidation strategies;
Younger patients (age <50 years) who received HiDAC induction and fewer high-dose consolidation cycles may be needed for patients induced
consolidation in the SWOG trial had the highest OS and DFS rates at 4 with HiDAC or for those who will undergo early autologous HCT. Although
years (52% and 34%, respectively) compared with those who received the remission rates are similar for high- and standard-dose cytarabine, 2
standard-dose induction and consolidation (34% and 24%, respectively) or studies have shown more rapid marrow blast clearance after 1 cycle of
standard induction with high-dose consolidation (23% and 14%, high-dose therapy and a DFS advantage for patients aged 50 years or
respectively).233 However, the percentage of patients achieving a CR who younger who received the high-dose therapy.236 No data are available
did not proceed to consolidation was twice as high in the HiDAC induction using more than 60 mg/m2 of daunorubicin or 12 mg/m2 of idarubicin with

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NCCN Guidelines Version 3.2022

Acute Myeloid Leukemia

HiDAC. With either high- or standard-dose cytarabine-based induction for NCCN Recommendations
younger patients, between 20% and 45% of these patients will not enter The NCCN AML Panel strongly encourages enrollment in a clinical trial for
remission. In a report of 122 patients treated with HiDAC and treatment induction of younger patients (aged <60 years) with AML. For
daunorubicin, the remission rates were strongly influenced by patients not enrolled in a clinical trial, cytogenetics and the risk status of
cytogenetics, with CR rates of 87%, 79%, and 62% for favorable-, the disease guide treatment strategies. For patients with favorable-,
intermediate-, and poor-risk groups, respectively.237 intermediate-, and poor-risk cytogenetics, infusional standard-dose
cytarabine (100–200 mg/m2 continuous infusion) for 7 days combined with
As previously mentioned, in the MRC AML 15 trial, younger patients with either idarubicin (12 mg/m2 for 3 days) or daunorubicin (60–90 mg/m2 for 3
untreated AML (median age, 49 years), were randomized to two induction days) is a category 1 recommendation.207
courses of: 1) daunorubicin and cytarabine with or without etoposide
(ADE; n = 1983); or 2) ADE versus fludarabine, cytarabine, G-CSF, and For patients with favorable-risk cytogenetics, other treatment options
idarubicin (FLAG-Ida; n = 1268).216 In consolidation, patients were include standard-dose cytarabine (200 mg/m2 continuous infusion) for 7
randomized to amsacrine, cytarabine, etoposide, and then days combined with daunorubicin (60 mg/m2 for 3 days) and GO for
mitoxantrone/cytarabine, or HiDAC (3 g/m2; n = 1445).216 Patients in the patients with CD33-positive AML (category 2A and preferred
HiDAC arm received 1.5 g/m2 in consolidation, and were treated with or recommendation);214 or, fludarabine (30 mg/m2 IV for days 2–6) plus
without a fifth course of cytarabine (n = 227). There were no significant HiDAC (2 g/m2) over 4 hours starting 4 hours after fludarabine in
differences in the rate of CR between ADE and FLAG-Ida (81% vs. 84%, combination with idarubicin (8 mg/m2 IV days 4–6) and G-CSF (SC daily
respectively), but FLAG-Ida significantly decreased relapse rates (FLAG- on days 1–7) plus a single dose of GO (category 2B recommendation).216
Ida, 38% vs. ADE, 55%; P < .001).216 A recent randomized phase III study
from the HOVON/SAKK groups compared standard cytarabine/idarubicin For patients with intermediate-risk cytogenetics and FLT3-mutated AML,
induction with or without clofarabine (10 mg/m2 on days 1–5) for patients midostaurin is added to standard-dose cytarabine (200 mg/m2 continuous
with AML between the ages of 18 to 65 years.238 While there was no infusion) for 7 days combined with daunorubicin (60 mg/m2 for 3 days)
difference in the OS and EFS in the group as a whole, there was a (category 2A recommendation).221
decrease in relapse rate counter balanced by an increased rate of death in
Patients with antecedent hematologic disease or treatment-related AML
remission for the clofarabine arm. In a subset analysis, there was a
are considered to have poor-risk disease, unless they have favorable
significant improvement in OS and EFS for the ELN intermediate I group,
cytogenetics such as t(8;21), inv(16), or t(16;16). In addition, patients with
primarily in patients in the NPM1 wild-type/FLT3-ITD–negative subgroup
unfavorable karyotypes, such as 11q23 abnormalities, monosomy -5 or -7,
with a 4-year EFS of 40% for the clofarabine arm versus 18% for the
monosomal karyotype, or complex cytogenetic abnormalities and
control arm.238
mutations including RUNX1, ASXL1, and TP53, are also considered to
have poor-risk disease. Although all patients with AML are best treated
within the context of an appropriate clinical trial, it is particularly important
that this group of patients with poor-risk disease should be entered into a

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NCCN Guidelines Version 3.2022

Acute Myeloid Leukemia

clinical trial (incorporating either chemotherapy or novel agents), if Postinduction Therapy

available, given that only 40% to 50% of these patients experience a CR After Standard-Dose Cytarabine Induction
(approximately 25% in adult patients who are older with poor-risk To judge the efficacy of the induction therapy, a bone marrow aspirate and
cytogenetics) with standard induction therapy. In addition, HLA testing biopsy should be performed 14 to 21 days after start of therapy. In patients
should be performed promptly in those who may be candidates for either who have received standard-dose cytarabine induction and have
fully ablative or reduced-intensity conditioning (RIC) allogeneic HCT from significant residual disease without hypoplasia (defined as cellularity less
a matched sibling or an alternative donor, which constitutes the best than 20% of which the residual blasts are less than 5% [ie, blast
option for long-term disease control.239 For younger patients (aged <60 percentage of residual cellularity]), additional therapy with standard-dose
years) with therapy-related AML other than CBF/APL, antecedent cytarabine and anthracycline or escalation to HiDAC (1.5–3 g/m2 every 12
MDS/chronic myelomonocytic leukemia (CMML), and cytogenetic changes hours for 6 days) may be considered for re-induction; no data are available
consistent with MDS (AML-MRC), CPX-351 [cytarabine (100 mg/m2) and to determine superiority of standard-dose cytarabine or HiDAC. After a
daunorubicin (44 mg/m2)] as an intravenous infusion over 90 minutes on bone marrow biopsy on day 21, standard-dose cytarabine with
days 1, 3, and 5 of 1 cycle is a category 2B recommendation, because the anthracycline and midostaurin should be considered for patients with
trial did not include this patient population.229 FLT3-mutated AML.221 If dual-drug liposomal encapsulation of cytarabine
and daunorubicin was given during induction, after a bone marrow biopsy
Other recommended induction regimens for intermediate- or poor-risk
14–21 days after induction, re-induction with CPX-351 [cytarabine (100
disease include: standard-dose cytarabine (200 mg/m2 continuous
mg/m2) and daunorubicin (44 mg/m2)] as an intravenous infusion over 90
infusion) for 7 days combined with daunorubicin (60 mg/m2 for 3 days) and
minutes on days 1 and 3 is recommended for patients with therapy-related
GO for patients with CD33-positive AML (intermediate-risk AML);214
AML other than CBF/APL, antecedent MDS/CMML, or AML-MRC.229
fludarabine (30 mg/m2 IV for days 2–6) plus HiDAC (2 g/m2) over 4 hours
Treatments for induction failure may also be considered.
starting 4 hours after fludarabine in combination with idarubicin (8 mg/m2
IV days 4–6) and G-CSF (SC daily on days 1–7) (category 2B For patients with significant (>50%) cytoreduction and a low percentage of
recommendation);216 or HiDAC plus an anthracycline and etoposide residual blasts (as defined above), standard-dose cytarabine with
(category 1 recommendation for patients 45 years of age or younger, but a idarubicin or daunorubicin, or standard-dose cytarabine with daunorubicin
category 2B recommendation for other age groups).230,231,233,236 The study and midostaurin is recommended for patients with for FLT3-mutated AML.
from Willemze et al230 that demonstrated improved OS for patients If daunorubicin (90 mg/m2) was used in induction, the recommended dose
between the ages of 15 and 45 years treated on this regimen was integral for reinduction of daunorubicin prior to count recovery is 45 mg/m2 for no
in the change of the recommendation to category 1 for this age group. For more than 2 doses. Similarly, if idarubicin (12 mg/m2) was used for
patients with impaired cardiac function, other cytarabine-based regimens induction, the early reinduction dose should be limited to 10 mg/m2 for 1 or
combined with non-cardiotoxic agents can be considered. For patients 2 doses. If the marrow is hypoplastic, additional treatment selection is
with unfavorable-risk cytogenetics and TP53-mutated AML, treatment deferred until the remission status can be assessed.
options are lacking, and alternative strategies should be considered.

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NCCN Guidelines Version 3.2022

Acute Myeloid Leukemia

If hypoplasia status is unclear, a repeat bone marrow biopsy should be therapy at this time is unlikely to induce remission in these cases. These
considered 5 to 7 days before proceeding with post induction therapy. For patients should be considered for a clinical trial or for use of regimens
patients who achieve CR with the additional post induction therapy, used for R/R disease (see Management of Relapsed/Refractory AML). If
consolidation therapy can be initiated upon count recovery. Screening LP an HLA-matched sibling or alternative donor has been identified, an
should be considered at first remission before first consolidation for allogeneic HCT may be effective in 25% to 30% of patients who have
patients with monocytic differentiation, MPAL, WBC count >40,000/mcL at experienced induction failure. If no donor is immediately available, patients
diagnosis, or extramedullary disease. should be considered for a clinical trial. If the patient’s clinical condition
has deteriorated to a point at which active therapy would be detrimental,
Patients who have persistent disease following two courses of therapy best supportive care may be the most appropriate option. If the patient has
(including a reinduction attempt based on midcycle marrow) are a significant cytoreduction following HiDAC with a small quantity of
considered to have experienced primary induction failure. Treatment residual blasts or hypoplasia, additional therapy should be delayed for an
options include clinical trial or use of chemotherapy regimens used for additional 10 to 14 days and the marrow status may be reassessed.
relapsed/refractory (R/R) disease (see Management of
Relapsed/Refractory AML). However, the likelihood of achieving a CR with Occasionally, patients with both myeloid and lymphoid markers at
a third chemotherapy regimen is low, at approximately 20%. If the patient diagnosis may experience response to ALL therapy if an AML induction
did not receive HiDAC for persistent disease at day 15, HiDAC with or regimen failed.4 Treatment decisions for patients with significant reduction
without anthracycline may be used if a clinical trial is not available and a without hypoplasia or those with hypoplasia are deferred until the blood
donor is not yet identified. If regimens used will result in high cumulative counts recover and a repeat marrow is performed to document remission
doses of cardiotoxic agents, consider reassessing the patient’s cardiac status. Response is then categorized as a CR or primary induction failure.
function before each anthracycline/mitoxantrone-containing course.240 If
Post-Remission or Consolidation Therapy
the patient has an identified sibling or alternative donor available, a
transplant option should be explored, although the panel encourages Although successful induction therapy clears the visible signs of leukemia
using alternative therapies to achieve remission prior to the transplant. For in the marrow and restores normal hematopoiesis in patients with de novo
patients whose clinical condition has deteriorated such that active AML, additional post-remission therapy (ie, consolidation) may be needed
treatment is not an option, best supportive care should be continued. to reduce the residual abnormal cells to a level that can be contained by
immune surveillance. For patients younger than 60 years of age, post-
After High-Dose Cytarabine Induction remission therapy is also based on risk status defined by cytogenetics and
Patients initially treated with HiDAC and who have significant residual molecular abnormalities (see Evaluation for Acute Leukemia in the
disease without a hypocellular marrow 21 to 28 days after start of therapy algorithm and Initial Evaluation in the Discussion).
are considered to have experienced induction failure. In the ELN
Guidelines, primary induction failure is defined as failure to achieve CR High-Dose Cytarabine: Since 1994, multiple (3–4) cycles of HiDAC
after two courses of intensive induction chemotherapy.21 Additional HiDAC therapy have been the standard consolidation regimen for patients
younger than 60 years with either good- or intermediate-risk cytogenetics.

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NCCN Guidelines Version 3.2022

Acute Myeloid Leukemia

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
and lower OS (25% vs. 76.5%, P = .006) compared to wild-type KIT.37 In Treatment arm A consisted of a first sequence with daunorubicin (60
CBF AML with inv(16), TKD816 did not result in a significant difference in mg/m2/day by a 30 minute IV infusion) on days 1 and 3 and cytarabine
relapse incidence and OS.37 The prognostic influence of TKD816 and other (500 mg/m2 continuous infusion) from days 1 to 3, followed by a second
mutations in exon 17 (mutKIT17) versus other recurrent KIT mutations in sequence at day 8 with daunorubicin (35 mg/m2/day by a 30 minute IV
CBF AML, such as exon 8 (mutKIT8), have been investigated.43,83 In an infusion) on days 8 and 9, and cytarabine (1000 mg/m2 every 12 hours by
analysis of adult patients younger than 60 years of age with CBF AML a 2-hour infusion) on days 8 and 10.243 Treatment arm B consisted of
treated on CALGB trials (n = 110), KIT mutations (mutKIT17 and mutKIT8) cytarabine (200 mg/m2 continuous infusion) for 7 days combined with
in the setting of inv(16) were associated with a higher cumulative daunorubicin (60 mg/m2 for 3 days. In treatment arm B, at day 15 a
incidence of relapse at 5 years (56% vs. 29%; P = .05) and a decreased peripheral blood and BM evaluation was performed followed by a second
5-year OS rate (48% vs. 68%) compared with wild-type KIT; in multivariate sequence of chemotherapy in patients who achieved CR.243 In addition,
analysis, the presence of KIT mutations remained a significant predictor of MRD levels were serially monitored for RUNX1-RUNX1T1 and CBFB-
decreased OS in the setting of inv(16). In the setting of t(8;21), KIT MYH11 by real-time quantitative polymerase chain reaction in BM samples
mutations were associated with a higher incidence of relapse at 5 years before the first, second, and third consolidation courses. In this study, both

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NCCN Guidelines Version 3.2022

Acute Myeloid Leukemia

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
AML (n = 860).23 Patients were randomized to treatment with an
well as the MRC AML 15 study216 suggest that doses of 3 g/m2 of
“intermediate-dose” cytarabine regimen (12 g/m2 cytarabine; cycle 1:
cytarabine are not clearly more effective than lower doses of 1.5–3 g/m2;
cytarabine, 200 mg/m2 daily for 7 days + idarubicin, 12 mg/m2 daily for 3
in the MRC AML 15 trial, the cumulative incidence of relapse was
days; cycle 2: cytarabine, 1 g/m2 every 12 hours for 6 days + amsacrine,
statistically lower for higher dose cytarabine but this did not translate into
120 mg/m2 daily for 3 days) or a “high-dose” cytarabine regimen (26 g/m2
better RFS.216
cytarabine; cycle 1: cytarabine, 1 g/m2 every 12 hours for 5 days +
idarubicin, 12 mg/m2 daily for 3 days; cycle 2: cytarabine, 2 g/m2 every 12 Allogeneic Hematopoietic Transplantation: In the EORTC/GIMEMA
hours for 4 days + amsacrine, 120 mg/m2 daily for 3 days). Patients who trial, a 43% 4-year DFS rate was reported in the donor group of patients
achieved a CR after both treatment cycles were eligible to receive with poor-risk cytogenetics (n = 64; 73% underwent HCT); this was
consolidation with a third cycle of chemotherapy or autologous or significantly higher than the 4-year DFS rate (18%; P = .008) among the
allogeneic HCT.23 A similar proportion of patients in each treatment arm no-donor group (n = 94; 46% underwent HCT).246 The 4-year DFS rate
received consolidation, specifically 26% to 27% of patients who received a among patients with intermediate-risk AML was 45% for the donor group
third chemotherapy cycle, 10% to 11% of patients who underwent (n = 61; 75% underwent HCT) and 48.5% for the no-donor group (n = 104;

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NCCN Guidelines Version 3.2022

Acute Myeloid Leukemia

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%; In the international phase 3 trial, QUAZAR AML-001, investigators
P = .02) were significantly higher among the donor groups than the evaluated the efficacy of oral azacitidine as post-remission therapy in adult
no-donor groups.247 patients (≥55 years of age) who had newly diagnosed AML or secondary
AML, and had experienced CR or CRi after induction with intensive
During the past decade, “normal” cytogenetics have been shown to therapies but were ineligible for allogeneic HCT (n = 472; median age, 68
encompass several molecular abnormalities with divergent risk years; range, 55–86 years).251 Within 4 months of attaining CR or CRi,
behaviors.38 The presence of an isolated NPM1 or biallelic CEBPA patients were randomized to receive placebo (n = 234) or 300 mg of oral
mutation improves prognosis to one only slightly less than that of AML with azacitidine (n = 238) once daily on days 1–14 of repeated 28-day
CBF translocations, placing these mutations in the favorable-risk treatment cycles.251 A 21-day dosing schedule was allowed for patients
molecular abnormalities category.38 In contrast, isolated FLT3-ITD who experienced AML relapse with 5% of 15% blasts in blood or bone
mutation and NK-AML have an outlook similar to poor-risk cytogenetics.45 marrow while enrolled in the study. This treatment schedule could
In a report that evaluated the ELN risk classification in a large cohort of continue indefinitely or until the presence of >15% blasts, unacceptable
patients, for those in the “Intermediate I” risk group (which includes toxicity, or allogeneic HCT.251 At a median follow-up of 41.2 months,
NK-AML with FLT3 abnormalities and those lacking both FLT3 and NPM1

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NCCN Guidelines Version 3.2022

Acute Myeloid Leukemia

median OS was 24.7 months and 14.8 months in the oral azacitidine and Intermediate-Risk Cytogenetics and/or Molecular Abnormalities Including
placebo arms, respectively (HR, 0.69; 95% CI, 0.55–0.86; P = .0009).251 In MRD Positive
addition, the median RFS was significantly prolonged in the oral The panel members agree that transplant-based options (either matched
azacitidine arm at 10.2 months compared to the placebo arm at 4.8 sibling or alternate donor allogeneic HCT) or 3 to 4 cycles of HiDAC
months (HR, 0.65; 95% CI, 0.52–0.81; P = .0001).251 Based on these data, affords a lower risk of relapse and a somewhat higher DFS when given as
in September 2020, the FDA approved oral azacitidine for continued consolidation for patients with intermediate-risk cytogenetics. While 2 to 3
treatment of patients with AML who achieved first CR or CRi following g/m2 HiDAC is preferred, a range of 1 to less than 2 g/m2 can be used to
intensive induction chemotherapy and are not able to complete intensive accommodate patients who are less fit. The role of autologous HCT in the
postremission therapy. intermediate-risk group outside of clinical trials is diminishing due to
improvements in allogeneic transplants, which are expanding the pool of
NCCN Recommendations potential donors outside the family setting. While autologous HCT is still
CBF Cytogenetic Translocations and MRD Negative incorporated into the clinical trial design in Europe, the consensus of the
The NCCN AML Panel recommends the following options for consolidation NCCN AML Panel was that autologous HCT should not be a
or maintenance therapy in this subgroup: 1) participation in a clinical trial; recommended consolidation therapy outside the setting of a clinical trial.
2) 3 to 4 cycles of HiDAC (category 1) alone or plus GO for patients with Clinical trial participation is encouraged. Another option for this group
CD33-positive AML; or 3) intermediate-dose cytarabine (1000 mg/m2) plus includes multiple courses (3–4) of HiDAC consolidation.253 If patients
daunorubicin and GO for patients with CD33-positive AML (category decline or are not fit/eligible for allogeneic HCT, maintenance therapy with
2A).214 There are insufficient data to evaluate the use of allogeneic HCT in oral azacitidine may be considered at 300 mg daily on days 1–14 of each
first remission for patients with AML who are MRD negative and have 28-day cycle until disease progression or unacceptable toxicity (a category
favorable-risk cytogenetics outside of a clinical trial.252 Data suggest that 2B option).251 The panel notes that this option is not intended to replace
the response to treatment is similar regardless of whether the consolidation chemotherapy.
favorable-risk cytogenetics are de novo and treatment-related.252
HiDAC (1.5–3 g/m2) with midostaurin may be considered for patients with
However, outcomes in the setting of t(8;21) with KIT mutations are less
FLT3-mutation–positive AML.254 Alternative regimens incorporating
favorable. These patients should be considered for either clinical trials
intermediate doses of cytarabine may be reasonable in patients with
targeted toward the molecular abnormality or allogeneic transplantation. In
intermediate-risk disease, including intermediate-dose cytarabine (1000
addition, for patients with favorable-risk cytogenetics who are persistently
mg/m2) plus daunorubicin and GO for patients with CD33-positive AML.214
MRD positive after induction and/or consolidation, alternative therapies
However, the panel notes that patients who receive a transplant shortly
including allogeneic transplantation, or a clinical trial should be
following GO administration may be at risk for developing sinusoidal
considered.
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
transplant.214 Comparable 5-year DFS rates were reported in patients

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NCCN Guidelines Version 3.2022

Acute Myeloid Leukemia

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

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NCCN Guidelines Version 3.2022

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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 [Link]
large study in patients ≥60 years (n = 1406), patient and disease factors [Link]/TRM/[Link]?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 [Link]
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.
[Link]
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
WBC count, peripheral blood blast percentage, and serum creatinine.
generally do not benefit from conventional chemotherapy treatment, the
These factors, when taken together, result in a predictive accuracy based
rare patient with favorable-risk or NK-AML and no significant comorbidities
on the area under the curve (AUC) of 0.82 (a perfect correlation is an AUC
might be the exception to this dogma. For patients with NK-AML, the
of 1.0).264 This model is complex, and currently there is not a tool available
remission rates are 40% to 50% with cytarabine combined with idarubicin,
to implement this model. A shortened form of the model was based on
daunorubicin, or mitoxantrone. The randomized study from the Acute
covariants that include age, PS, and platelet count. The simplified model
Leukemia French Association (ALFA)-9801 study (n = 468) showed that
provides an AUC of 0.71, which is less accurate than the complex model
idarubicin induction (the standard 12 mg/m2 daily for 3 days or intensified
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NCCN Guidelines Version 3.2022

Acute Myeloid Leukemia

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
daunorubicin induction (240 mg/m2 total dose for patients <65 years; 180 CD33-Positive AML: There are conflicting data about the use of GO for
mg/m2 total dose for patients ≥65 years) in patients ≥50 years with AML.267 patients who are older with AML. Three phase III randomized trials
At a median actuarial follow-up of 7.5 years, the median OS for all patients evaluated the efficacy and safety of adding the anti-CD33 antibody-drug
included in the analysis was 14.2 months. The estimated 5-year OS rate conjugate GO to induction therapy with daunorubicin and cytarabine in
was 15.3%, and the overall cure rate was 13.3%. Induction with standard patients who are older with previously untreated AML.274-276 In the phase III
idarubicin was associated with a significantly higher cure rate compared ALFA-0701 trial, patients aged 50 to 70 years with de novo AML (n = 280)
with daunorubicin (16.6% vs. 9.8%; P = .018). In the group of patients were randomized to receive induction with daunorubicin (60 mg/m2 daily
younger than age 65 years, standard idarubicin was still associated with a for 3 days) and cytarabine (200 mg/m2 continuous infusion for 7 days),
significantly higher cure rate than daunorubicin despite the high dose (240 with or without (control arm) fractionated GO 3 mg/m2 given on days 1, 4,
mg/m2 total dose) of daunorubicin (27.4% vs. 15.9%; P = .049).267 and 7.276 Patients with persistent marrow blasts at day 15 received
additional daunorubicin and cytarabine. Patients who achieved a CR/CRi
In the HOVON trial, which randomized patients ≥60 years to induction after induction received two consolidation courses with daunorubicin and
therapy with standard-dose cytarabine combined with either cytarabine, with or without GO (3 mg/m2 on day 1). The CR/CRi after

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Acute Myeloid Leukemia

induction was similar between the GO and control arms (81% vs. 75%). treatment included two courses of consolidation with or without 3 mg/m2
The GO arm was associated with significantly higher estimated 2-year GO on day 0. The OS between the two groups was similar (GO, 45% vs.
EFS (41% vs. 17%; P = .0003), RFS (50% vs. 23%; P = .0003), and OS no GO, 49%), but the induction and 60-day mortality rates were higher in
(53% vs. 42%; P = .0368) rates compared with the control.276 The GO arm the patients given GO (17% vs. 12% and 22% vs. 18%, respectively). Only
was associated with a higher incidence of hematologic toxicity (16% vs. a small subgroup of patients younger than 70 years of age with secondary
3%; P < .0001); this was not associated with an increase in the risk of AML showed any benefit to treatment. Combined with the increased
death from toxicity.276 toxicity, the results of this study suggest that GO may not provide an
advantage over standard chemotherapy for some patients who are older
In another multicenter, phase III, randomized trial from the UK and with AML.274
Denmark (AML-16 trial), patients >50 years with previously untreated AML
or high-risk MDS (n = 1115) were randomized to receive Conflicting studies have led to the publication of several systematic
daunorubicin-based induction (daunorubicin combined with cytarabine or reviews and meta-analyses. A larger systematic review, inclusive of any
clofarabine) with or without (control) GO (3 mg/m2 on day 1 of course 1 of RCTs that investigated the benefit of anti-CD33 antibody therapy,
induction).275 The median age was 67 years (range, 51–84 years) and regardless of whether treatment was in de novo or secondary disease,
98% of patients were ≥60 years; 31% were ≥70 years. The CR/CRi rate concluded that the data from 11 trials showed increased induction deaths
after induction was similar between the GO and control arms (70% vs. (P = .02) and reduced residual disease (P = .0009).277 Despite improved
68%). The GO arm was associated with significantly lower 3-year RFS (HR, 0.90; 95% CI, 0.84–0.98; P = .01), no OS benefit was measured
cumulative incidence of relapse (68% vs. 76%; P = .007) and higher (HR, 0.96; 95% CI, 0.90–1.02; P = .2). Two other meta-analyses showed
3-year RFS (21% vs. 16%; P = .04) and OS (25% vs. 20%; P = .05) rates improved RFS, though induction death was elevated.278,279 Conversely, a
compared with the control arm. The early mortality rates were not different fourth meta-analysis evaluating 5 trials with 3325 patients ≥15 years
between treatment arms (30-day mortality rate, 9% vs. 8%); in addition, no showed a reduced risk of relapse (P = .0001) and improved 5-year OS
major increase in adverse events was observed with GO.275 These two (OR, 0.90; 95% CI, 0.82–0.98; P = .01) with the addition of GO to
trials suggest that the addition of GO to standard induction regimens conventional induction therapy.215 It was noted that the greatest survival
reduced the risk of relapse and improved OS outcomes in patients who benefit was seen in patients with favorable cytogenetics. Some benefit
are older with previously untreated AML characterized by favorable or was seen in patients with intermediate cytogenetics, but no benefit was
intermediate-risk cytogenetics, not adverse risk. reported with the addition of GO in patients with adverse cytogenetics.
These studies underscore the need for further investigation that elucidates
The third phase III trial combining GO with chemotherapy showed a the benefits of GO for the treatment of AML.
different result than the other two. In this study, patients between the ages
of 61 and 75 years were given chemotherapy consisting of mitoxantrone, FLT3-Positive AML: The results of the CALGB 10603/RATIFY Alliance
cytarabine, and etoposide (n = 472).274 Half of the patients were given 6 trial221 have been described in an earlier section (See Management of
mg/m2 GO prior to chemotherapy on days 1 and 15. In remission, AML in Patients Younger Than 60 Years; Intermediate-Risk Cytogenetics)

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NCCN Guidelines Version 3.2022

Acute Myeloid Leukemia

and these data may be extrapolated to suggest benefit in fit adults who are months (HR, 0.47; 95% CI, 0.28–0.79; P = .005).282 The 2-year OS rates
older. In a phase II study in adult patients with previously untreated AML were 50% and 16%, respectively (P = .001). In a phase III study focused
(n = 284; range, 18–70 years; 86 patients included between the ages of on adult patients ≥65 years, the efficacy and safety of azacitidine versus
61–70 years), the efficacy and safety of midostaurin added to intensive conventional care regimens (standard induction chemotherapy, low-dose
chemotherapy, followed by allogeneic HCT and single-agent midostaurin cytarabine, or supportive care) was evaluated in patients with newly
maintenance therapy for a year was evaluated.280 All patients were diagnosed AML with >30% blasts.283 Compared to conventional care
confirmed to have FLT3-ITD–positive disease. The CR/CRi rate after regimens, azacitidine was associated with an increase in median OS (6.5
induction therapy was 76.4% (age <60 years, 75.8%; age >60 years, months vs.10.4 months; HR, 0.85; 95% CI, 0.69–1.03; stratified log-rank
77.9%). Many patients proceeded to transplant (72.4%), and a subset P = .1009).283 The 1-year survival rates with azacitidine and conventional
initiated maintenance therapy (n = 97; 75 after allogeneic HCT and 22 care regimens were 46.5% and 34.2%, respectively.
after HiDAC consolidation). The median time receiving maintenance
therapy was 9 months after allogeneic HCT and 10.5 months after HiDAC Another HMA, decitabine, has also been evaluated as remission induction
consolidation. The 2-year EFS and OS rates were 39% and 34% in therapy for patients who are older with AML.284 In a phase II study in
patients <60 years, and 53% and 46% in patients >60 years.280 previously untreated patients ≥60 years (n = 55; median age, 74 years),
the overall CR rate with this agent (20 mg/m2 for 5 days every 28 days)
Therapy-Related AML or Antecedent MDS/CMML or AML-MRC was 24% (including 6 out of 25 patients [24%] with poor-risk cytogenetics),
The studies evaluating the efficacy and safety of CPX-351 in patients aged and the median EFS and OS were 6 months and 8 months,
60 to 75 years with newly diagnosed secondary AML have been described respectively.284 An earlier phase I study evaluated different dose
(Management of AML in Patients Younger Than 60 Years; Therapy- schedules of decitabine in patients with R/R leukemias (n = 50; AML
Related AML or Antecedent MDS/CMML or AML-MRC).229 diagnosis, n = 37).285 In this study decitabine was given at 5, 10, 15, or 20
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
on FAB criteria), 113 study patients (32%) fulfilled criteria for AML using dose of 20 mg/m2 for 10 days and demonstrated a CR rate of 47% (n =
the 2008 WHO classification, with marrow-blast percentages between
25) after a median of three cycles of therapy.286 In a study aimed at
20% and 30%.281,282 In the subgroup of these patients with AML, a identifying the relationship between molecular markers and clinical
significant survival benefit was found with 5-azacitidine compared with responses to decitabine, adult patients with AML and MDS (n = 116;
conventional care regimens, with a median OS of 24.5 months versus 16 median age, 74 years; range, 29–88 years) were treated with decitabine

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Acute Myeloid Leukemia

(20 mg/m2 for 10 days every 28 days).287 Response rates were higher older with AML. In a phase Ib study, patients ≥65 years with previously
among patients with unfavorable-risk cytogenetics compared to patients untreated AML (n = 57) were enrolled into 3 groups: group A (n = 23)
with favorable- or intermediate-risk (67% vs. 34%, respectively; P < .001), received venetoclax and decitabine (20 mg/m2 daily for 5 days of each 28-
and in the setting of TP53 mutations compared to wild-type TP53 (100% day cycle); group B (n = 22) received venetoclax and azacitidine (75
vs. 41%; P < .001).287 A recent phase II study comparing a 5-day versus mg/m2 daily for 7 days of each 28-day cycle); and group C, a substudy of
10-day treatment schedule for decitabine in patients ≥60 years (n = 71) venetoclax and decitabine (n = 12), received an oral CYP3A inhibitor,
with newly diagnosed AML determined that the efficacy and safety of both posaconazole, to determine its effect on the pharmacokinetics of
schedules were not significantly different.288 venetoclax.290 Daily target doses for venetoclax in different cohorts within
groups A and B were 400 mg, 800 mg, and 1200 mg. The most common
In an open-label, randomized, phase III study, decitabine (20 mg/m2 for 5 treatment-related adverse event in groups A and B was febrile neutropenia
days every 28 days) was compared with physician’s choice (either (30% and 32%, respectively), with an overall CR/CRi rate of 61% (95% CI,
low-dose cytarabine [20 mg/m2/day SC for 10 consecutive days every 28 47.6–74.0).290 In groups A and B, the CR/CRi rate was 60% (95% CI,
days] or supportive care) in patients ≥65 years with newly diagnosed 44.3–74.3).290
AML.289 Based on the protocol-specified final analysis of the primary
endpoint (OS), decitabine was associated with a statistically nonsignificant In a follow-up to this study, the efficacy of either 400 mg or 800 mg of
trend for increased median OS compared with physician’s choice (7.7 venetoclax combined with either decitabine or azacitidine was evaluated in
months vs. 5 months; HR, 0.85; 95% CI, 0.69–1.04; P = .108). A patients ≥65 years with previously untreated AML and who were ineligible
subsequent post hoc analysis of OS with additional follow-up time showed for intensive chemotherapy (n = 145; median age, 74 years).291 The
the same median OS with a statistically significant advantage associated venetoclax dose of 400 mg was found to be the recommended phase II
with decitabine (HR, 0.82; 95% CI, 0.68–0.99; P = .037). The CR dose. With a median time on study of 8.9 months (range, 0.2–31.7
(including CRi) rate was significantly higher with decitabine (18% vs. 8%; months) and median duration of follow-up of 15.1 months (range, 9.8–31.7
P = .001).289 The most common treatment-related adverse events with months), 67% of patients achieved CR/CRi.291 The median duration of
decitabine versus cytarabine included thrombocytopenia (27% vs. 26%), CR/CRi and median OS was 11.3 months and 17.5 months,
neutropenia (24% vs. 15%), febrile neutropenia (21% vs. 15%), and respectively.291 In a subgroup analysis, the CR/CRi rates of patients with
anemia (21% vs. 20%). The 30-day mortality rates were similar between intermediate- and poor-risk cytogenetics were 74% and 60%, with a
the decitabine and cytarabine groups (9% vs. 8%).289 Both azacitidine and median duration of 12.9 months (95% CI, 11.0 months–NR) versus 6.7
decitabine are approved by the FDA for the treatment of patients with months (95% CI, 4.1–9.4 months), respectively.291 The CR/CRi rates in
MDS. with the setting of TP53, IDH1/2, and FLT3 mutations were 47%, 71%,
and 72%, respectively. In addition, patients with de novo AML and
Venetoclax-Containing Regimens: Emerging studies have evaluated secondary AML, respectively, had the same CR/CRi rate of 67%, with a
the combination of HMAs with venetoclax, an oral B-cell lymphoma 2 median duration of CR/CRi of 9.4 months (95% CI, 7.2–11.7 months)
(BCL2) inhibitor, as an induction therapy strategy for patients who are versus not reached (NR) (95% CI, 12.5 months–NR).291 In a phase 3

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NCCN Guidelines Version 3.2022

Acute Myeloid Leukemia

follow-up to this study, at a median follow-up of 20.5 months, the median Low-Dose Cytarabine-Containing Regimens: Other approaches have
OS was 14.7 months in the group treated with azacitidine and venetoclax evaluated low-dose cytarabine. The UK NCRI AML 14 trial randomized
and 9.6 months in the group treated with azacitidine only (control) (HR, 217 patients primarily aged >60 years (de novo AML, n = 129; secondary
0.66; 95% CI, 0.52–0.85; P = .001).292 The CR/CRi rate was also higher in AML, n = 58; high-risk MDS, n = 30) unfit for chemotherapy to receive
the azacitidine and venetoclax group versus the control group (66.4% vs. either low-dose cytarabine subcutaneously (20 mg twice daily for 10
28.3%, respectively; P = .001).292 consecutive days, every 4–6 weeks) or hydroxyurea (given to maintain
target WBC counts <10,000/mcL).294 Patients were also randomized to
Another phase Ib/II study evaluated the efficacy of venetoclax combined receive ATRA or no ATRA. Low-dose cytarabine resulted in a CR rate of
with low-dose cytarabine (20 mg/m2 daily for 10 days) in patients ≥60 18% (vs. 1% with hydroxyurea) and a survival benefit compared with
years with previously untreated AML ineligible for intensive chemotherapy hydroxyurea in patients with favorable or NK-AML. No advantage was
(n = 82; median age, 74 years).293 All patients received at least one dose observed with the addition of ATRA. The median DFS in patients who
of venetoclax at 600 mg. The CR/CRi rate was 54% (95% CI, 42%–65%) achieved a CR with low-dose cytarabine was 8 months.294 Even with this
with a median duration of remission of 8.1 months (95% CI, 5.3–14.9 “low-intensity” treatment approach, induction death occurred in 26% of
months), and the median OS for all patients was 10.1 months (95% CI, patients, and overall prognosis remained poor for patients who are older
5.7–14.2 months).293 Patients with de novo AML, intermediate-risk who cannot tolerate intensive chemotherapy regimens. A phase II study
cytogenetic features, and no prior HMA exposure demonstrated CR/CRi evaluated a regimen with low-dose cytarabine (20 mg twice daily for 10
rates of 71%, 63%, and 62%, respectively.293 The average CR/CRi rates in days) combined with clofarabine (20 mg/m2 daily for 5 days) in patients
the setting of NPM1 or IDH1/2 mutations were higher than in the setting of ≥60 years with previously untreated AML (n = 60; median age, 70 years;
TP53 or FLT3 mutations (89% and 72% vs. 30% and 44%, range, 60–81 years).295 Patients who experienced response received
respectively).293 Based on these studies, venetoclax in combination with consolidation (up to 17 courses) with clofarabine plus low-dose cytarabine
HMAs, decitabine or azacitidine, or low-dose cytarabine are approved by alternated with decitabine. Among evaluable patients (n = 59), the CR rate
the FDA for the treatment of newly diagnosed AML in adults ≥75 years, or was 58% and median RFS was 14 months. The median OS for all patients
in patients who have comorbidities that preclude use of intensive induction was 12.7 months. The induction mortality rate was 7% at 8 weeks.295
chemotherapy. Although this regimen appeared to be active in patients ≥60 years with
AML, the authors noted that the benefits of prolonged consolidation
Not a Candidate for or Declines Intensive Remission Induction Therapy
remain unknown.
AML Without Actionable Mutations
In adult patients who are older who cannot tolerate intensive treatment In a phase II trial, low-dose cytarabine was combined with glasdegib, a
strategies, low-intensity approaches have been investigated, including use selective inhibitor of the Smoothened protein in the Hedgehog signaling
of HMAs alone or combined with venetoclax (see Candidates for Intensive pathway, and evaluated in adult patients (age ≥55 years) with previously
Remission Induction Therapy, Hypomethylating Agents, and Venetoclax- untreated AML or high-risk MDS ineligible for intensive chemotherapy (n =
Containing regimens in the previous section). 132).296 Criteria for unsuitability for intensive chemotherapy included being

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Acute Myeloid Leukemia

≥75 years of age, having serum creatinine >1.3 mg/dL, and having severe AML achieved complete remission, with an OS of 19.7 months with a
cardiac disease or ECOG score = 2. Patients were randomized 2:1 to median OS of 9.3 months.300 In patients ≥60 years with newly diagnosed
receive low-dose cytarabine alone (20 mg twice daily for 10 days every 28 AML, the efficacy of enasidenib was evaluated in a phase Ib/II sub-study
days) or combined with oral glasdegib (100 mg daily). The addition of within the Beat AML trial.299 Patients were treated with enasidenib (100
glasdegib to low-dose cytarabine also improved OS compared to low-dose mg/day) in continuous 28-day cycles. Azacitidine (75 mg/m2 days 1–7)
cytarabine alone (8.8 months vs. 4.9 months, respectively), and the CR was added to enasidenib for some patients who did not achieve CR/CRi
rates were higher in the low-dose cytarabine and glasdegib arm (17%, n = by cycle 5. Of 23 evaluable patients receiving enasidenib monotherapy,
15/88) compared to low-dose cytarabine alone (2.3%; n = 1/44).296 In the CR/CRi was achieved in 43% of patients (7 CR/2 CRi).299
glasdegib plus low-dose cytarabine arm, the benefit in CR was primarily
seen in patients with favorable-/intermediate-risk cytogenetics (n = 10/52) Ivosidenib, an IDH1-mutation inhibitor, demonstrated durable remissions
when compared to patients with poor risk cytogenetics (n = 5/36).296 in IDH1 R/R AML, with 30.2% of patients (n = 54 of 179) with R/R AML
Glasdegib in combination with low-dose cytarabine is currently approved achieving CR/CRh.301 As an extension of this study, the safety and
by the FDA for the treatment of newly diagnosed AML in adults ≥75 years, efficacy of ivosidenib in patients with untreated AML was evaluated (n =
or in patients who have comorbidities that preclude use of intensive 34; median age, 76.5 years).298 In phase I dose-escalation and expansion,
induction chemotherapy. patients received ivosidenib once daily or twice daily in 28-day cycles, and
a dose of 500 mg per day was selected as the dose for expansion groups.
CD33-Positive AML: Single-agent GO has also been evaluated as an The CR/CRh rate was 41.2% (95% CI, 24.6%–59.3%), and the ORR was
option. A randomized phase III study evaluated the efficacy of single-agent 58.8% (20/34; 95% CI, 40.7%–75.4%).298 Based on these data, ivosidenib
GO (6 mg/m2 on day 1 and 3 mg/m2 on day 8) versus best supportive care was approved by the FDA in May 2019 as a first-line treatment option for
as first-line therapy in patients ≥61 years with AML who were not eligible AML with an IDH1 mutation in patients who are ≥75 years or who have
for intensive chemotherapy (n = 237).297 Compared to best supportive comorbidities that preclude the use of intensive induction chemotherapy.
care, GO alone improved the 1-year OS rate (9.7% vs. 24.3%, Treatment with both enasidenib and ivosidenib may induce differentiation
respectively). In the GO group, the median OS was 4.9 months (95% CI, syndrome and hyperleukocytosis, which may be managed with
4.2–6.8 months) and 3.6 months (95% CI, 2.6–4.2 months) in the best corticosteroids and hydroxyurea.302-304
supportive care group.297
Alternatively, emerging data suggest that patients with de novo AML
IDH Mutation-Positive AML: Initially approved by the FDA for use in the characterized by IDH1/2-mutant AML may benefit from venetoclax/HMA-
R/R AML setting, IDH-targeted inhibitors, enasidenib and ivosidenib, have based therapy with reported remission rates of greater than 70%, albeit in
demonstrated utility in the frontline setting.298,299 In a phase I/II study, the a relatively small number of patients.291
clinical activity and safety of enasidenib, an IDH2 mutant inhibitor, was
evaluated in adult patients with IDH2-mutated advanced AML including FLT3-Positive AML: In adult patients with newly diagnosed FLT3-
R/R disease.300 Approximately 19% of patients (n = 34 of 176) with R/R mutation-positive AML (n = 15; median age, 76 years; range, 65–86
years), an ongoing trial is evaluating the safety and tolerability of the

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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
NCCN Recommendations 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
anthracycline–containing regimens may be considered. Gemtuzumab (azacitidine [category 1] or decitabine). Other recommended options
ozogamicin (GO) may be added to standard-dose cytarabine combined include venetoclax combined with LDAC or low-intensity therapy with
with daunorubicin for patients with CD33-positive AML and who have HMAs (azacitidine or decitabine). For patients with FLT3-mutant AML, the
favorable- or intermediate-risk cytogenetics. Midostaurin is added to preferred treatment option is also venetoclax-based therapy combined
standard-dose cytarabine combined with daunorubicin for patients with with HMAs (azacitidine [category 1] or decitabine). Other treatment options
FLT3-mutated AML. For patients with therapy-related AML, antecedent for this category include HMAs in combination with sorafenib and
hematologic disorder, or AML-MRC, treatment with CPX-351 [cytarabine venetoclax combined with LDAC.
(100 mg/m2) and daunorubicin (44 mg/m2)] as intravenous infusion over 90
minutes on days 1, 3, and 5 of 1 cycle is recommended (a category 1
recommendation).

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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,
Many treatment strategies are designed to work more gradually using
or CPX-351 [cytarabine (100 mg/m2) and daunorubicin (44 mg/m2)], if
agents that may allow expression of tumor suppressor genes (eg, a
given during induction for patients with therapy-related AML, antecedent
methyltransferase inhibitor such as decitabine or 5-azacitidine) or increase
hematologic disorder, or AML-MRC. Alternatively, patients with FLT3-
apoptosis (eg, histone deacetylase inhibitors). Thus, success in these
mutation–positive AML may receive additional standard-dose cytarabine
trials may be assessed using indirect measures, such as hematologic
with daunorubicin and midostaurin. Additional treatment strategies for
improvement or decreased transfusion requirements and survival, without
these patients may include consideration of a clinical trial or use of
actually achieving CR. Frequently, in these trials, marrow examination is
regimens used for R/R disease (see Management of Relapsed/Refractory
not performed until completion of 1 to 2 cycles of therapy. However, the
AML).
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.
Postremission or Consolidation Therapy
Intermediate-dose cytarabine-containing regimens, allogeneic HCT, or
Patients who achieve a CR (including CRi) with standard induction
best supportive care are also treatment options. Allogeneic transplant is a
chemotherapy may receive further consolidation with these same agents.
reasonable option, preferably in the context of a clinical trial, in patients
who experience re-induction failure with certain regimens including Intermediate-Dose Cytarabine: The prospective CALGB trial234
intermediate-dose or HiDAC-containing regimens, and who have identified established the efficacy of HiDAC consolidation in patients with AML aged
donors available to start conditioning within 4 to 6 weeks from start of 60 years or younger.234 In this study, a subgroup of patients with AML ≥60
induction therapy. Patients without an identified donor would most likely years who received standard-dose cytarabine-daunorubicin induction
need some additional therapy as a bridge to transplant. Additionally, it is therapy and more than one course of HiDAC consolidation (3 g/m2 every
acceptable to await recovery in these patients as many will enter 12 hours on days 1, 3, and 5, per course) experienced severe

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NCCN Guidelines Version 3.2022

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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%
outcomes with RIC allogeneic HCT and autologous HCT in patients ≥50 vs. 3%; P < .001), the 3-year OS rate showed a survival benefit with HCT
years based on large registry data, RIC allogeneic HCT was associated (62% vs. 51%; P = .012).316 Among the patients who underwent allogeneic
with lower risk for relapse and superior DFS and OS relative to autologous HCT, myeloablative conditioning was used in 37% of patients, whereas
HCT.312 The authors also noted that a survival benefit was not observed in RIC was used in 61%. Survival outcomes between these groups were
the subgroup of patients undergoing RIC allogeneic HCT in first CR similar, with 3-year OS rates of 63% and 61%, respectively.316
because of an increased incidence of non-relapse mortality.
Another study evaluating treatment in patients aged 60–70 years compared
Estey et al prospectively evaluated a protocol in which patients ≥50
314
outcomes between RIC allogeneic HCT reported to the Center for
years with unfavorable cytogenetics would be evaluated for a RIC International Blood and Marrow Transplant Research (n = 94) and standard
allogeneic HCT.314 Of the 259 initial patients, 99 experienced a CR and chemotherapy induction and postremission therapy from the CALGB

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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
Collectively, these studies suggest that RIC allogeneic HCT is a feasible intensive therapy, a marrow to document remission status upon
treatment option for patients ≥60 years, particularly those in first CR with hematologic recovery should be performed after 4 to 6 weeks. If a CR is
minimal comorbidities and who have an available donor. For this strategy observed, a clinical trial is recommended. Other postremission or
to be better used, potential transplant options should be considered during maintenance therapy recommendations include: allogeneic HCT;
induction therapy, and alternative donor options/searches should be standard-dose cytarabine with or without an anthracycline;
explored earlier in the disease management. The guidelines note that RIC intermediate-dose cytarabine alone (for patients who are more fit) or plus
allogeneic HCT is considered an additional option for patients ≥60 years daunorubicin and GO for patients with CD33-positive AML; intermediate-
as postremission therapy in those experiencing a CR to induction therapy. dose cytarabine and midostaurin for patients with FLT3-mutation–positive
AML; or CPX-351 [cytarabine (65 mg/m2) and daunorubicin (29 mg/m2)],
Maintenance Therapy which is the preferred strategy if given during induction for patients with
Hypomethylating Agents: Preventing relapse in patients who are older therapy-related AML, antecedent hematologic disorder, or AML-MRC. If
with AML who have experienced first CR after intensive induction can be the patient received more intensive regimens in induction and achieved a
challenging. In a phase 3 randomized trial, HOVON97, investigators remission but had treatment-related toxicity that prevents the patient from
evaluated the efficacy of maintenance therapy with azacitidine in patients receiving conventional consolidation or is not eligible for allogeneic HCT,
≥60 years with AML or MDS with refractory anemia with excess of blasts maintenance therapy with HMAs may be appropriate.251,320 In some cases,

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NCCN Guidelines Version 3.2022

Acute Myeloid Leukemia

observation is recommended, as some patients have been able to addition of a third targeted agent to these combinations is not
maintain a CR without further treatment. recommended outside the context of a clinical trial. Prior to administering
therapy, it is important to achieve a WBC count of <25,000/mcL with
For patients who experience induction failure, a clinical trial, low-intensity hydroxyurea, or leukapheresis if needed.322 It is worth noting that the
therapy (azacitidine, decitabine), allogeneic HCT (preferably in the context data supporting a beneficial role for leukapheresis in this context is
of a clinical trial), therapies for R/R disease (see Management of limited.323 In addition, venetoclax is a substrate of CYP3A4, so dose
Relapsed/Refractory AML), or best supportive care are recommended adjustments of venetoclax are recommended when concurrently using
treatment options. venetoclax with strong CYP3A4 inhibitors, most commonly the azole
class of antifungal agents.324 Reductions in duration of venetoclax and
Previous Lower-Intensity Therapy: For patients who previously
HMAs or LDAC may be considered in the setting of cytopenias. If during
received lower-intensity therapy, a marrow to document remission status
treatment, there is a need to discontinue any of the agents or a
upon hematologic recovery should be performed, with the timing
consideration to continue maintenance on single-agent venetoclax, the
dependent on the therapy used. If a response is observed, allogeneic HCT
panel recommends referral to a tertiary cancer or academic medical
may be considered for select patients. Alternatively, low-dose therapies
center.
used in induction with demonstrated efficacy may be continued until
progression, including venetoclax plus HMAs; venetoclax plus low-dose To minimize the development of tumor lysis syndrome—which is
cytarabine; enasidenib (for IDH2-mutated AML); ivosidenib (for IDH1- uncommon in this setting322—during the first cycle of treatment, inpatient
mutated AML); glasdegib plus low-dose cytarabine; or HMAs alone or treatment is strongly recommended especially through dose-escalation.
combined with sorafenib (for FLT3-mutant AML); or GO alone (a category The intrapatient dose escalation for venetoclax with HMA is 100 mg, 200
2B recommendation). If no response or progression is seen, a clinical trial, mg, and 400 mg given daily on days 1 to 3; and the intrapatient dose
therapies for R/R AML (see Management of Relapsed/Refractory AML), or escalation for venetoclax with LDAC is 100 mg, 200 mg, 400 mg, and
best supportive care are recommended treatment options. 600 mg given daily on days 1 to 4.322 To minimize and avert further risk
of tumor lysis syndrome, the panel recommends aggressive monitoring
Principles of Venetoclax Use with HMAs or LDAC-Based Treatment
of blood chemistries; monitoring and managing electrolyte imbalances;
With growing use of venetoclax-based therapies (ie, venetoclax with and treatment with allopurinol or other uric acid lowering agent.322
HMAs or low-dose cytarabine), and the fact that these therapies may be
given for an indefinite duration as long as patients respond or derive Venetoclax and HMAs have been shown to induce prolonged cytopenias
hematologic benefit from the therapies, the AML Panel reviewed the even after achieving remission, and neutropenia is a dominant treatment-
literature and emerging guidelines that can inform a consensus on ways related toxicity associated with this combination of agents.321 During the
to optimize use of these therapies.321 first cycle, the panel recommends continuing treatment regardless of
cytopenias until a response assessment is made,324 with aggressive
For patients with newly-diagnosed disease, the panel notes that transfusion support and supportive care as needed. The panel also
venetoclax with HMA or LDAC should be given concomitantly. The

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recommends withholding growth factors until after the first cycle experienced some response with manageable toxicity, therapy may be
response assessment.322 However, granulocyte colony-stimulating continued as long as it is tolerated.
factors should be considered for patients who are neutropenic who have
achieved morphologic remission but whose counts have not recovered. A If venetoclax and HMA or LDAC are being given to patients with
bone marrow biopsy is necessary for response assessment on days 21– relapsed/refractory (R/R) AML, the panel recommends antifungal
28 of the first cycle,322 perhaps on the early end of this range for patients prophylaxis.321 Other recommendations for TLS, intrapatient dose
who receive the combination of venetoclax and decitabine. escalation, BM biopsies, and cytopenia mitigation plans are similar to
considerations that have been described.
If blasts are <5% during the first cycle, in the setting of cytopenias all
treatment should be held and the following measures should be Role of MRD Monitoring
considered: growth factor support, if indicated; and a treatment-free MRD in AML refers to the presence of leukemic cells below the threshold
interval for up to 14 days. When counts have recovered to a clinically of detection by conventional morphologic methods. Patients who have
significant threshold (ideally to CR or CRi), the next cycle of treatment achieved a CR by morphologic assessment alone can still harbor a large
can begin.322 If counts have not recovered to a clinically significant number of leukemic cells in the bone marrow.325 Due to the rapidly
threshold, consider repeating the BM biopsy. If morphological remission evolving nature of this field and the undeniable need for monitoring, MRD
is ongoing, therapy can continue to be held or a second cycle can is still under investigation, with NCCN recommendations as discussed
proceed with adjustments to dose or schedule of venetoclax and HMA or below.
LDAC.322
While morphologic assessment is the first step in a cure for AML, there
During the second and subsequent cycles of treatment, if remission was remains a level of MRD that currently lacks any standardized method of
observed after the first cycle, sequential cycles should continue with up monitoring. Two of the most commonly used techniques are real-time
to 14-day interruptions between cycles for count recover and/or growth quantitative PCR (RQ-PCR) and flow cytometry. RQ-PCR amplifies
factor support.322 If there is no evidence of disease after the first cycle leukemia-associated genetic abnormalities, while flow cytometric profiling
and assuming no unexpected changes in blood counts occur, the BM detects leukemia-associated immunophenotypes (LAIPs).326-328 Both
biopsy can be repeated at 3–6-month intervals, or as needed based on methods have a higher sensitivity than conventional morphology. RQ-PCR
clinical suspicion for relapse, depending on the goals of the patient. If has a detection range of 1 in 1000 to 1 in 100,000, while flow cytometry
count recovery worsens over time, relapsed disease should be ruled out has sensitivity between 10-4 to 10-5. The challenge of incorporating these
with a repeat BM biopsy.322 If morphological remission is ongoing with techniques into routine practice is a lack of standardization and
worsening blood counts, consider decreasing the duration, and/or dose, established cutoff values, though ongoing research is focused on
of venetoclax and/or HMA or LDAC. However, if there is no addressing these limitations. Most of what is known about MRD monitoring
morphological remission after the second cycle, consider enrollment in a has been done in the APL population;329,330 however, these techniques are
clinical trial if available. If no clinical trial is available, and patient has now expanding to include other AML subtypes.331 Emerging technologies

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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.
duplications.340 Finally, the main target of gene overexpression in AML is
the Wilms’ tumor (WT1) gene. Taken together, these putative targets for The use of RQ-PCR in mutations is hampered by the inability to
MRD monitoring encompass the majority of AML cases. distinguish the number of cells containing transcripts, as each cell may
have variable levels. Furthermore, these transcripts still may be detected
A study of 29 patients with either RUNX1-RUNX1T1 or CBFB-MYH11 in cells that have differentiated in response to treatment and are no longer
AML during postinduction and post-consolidation chemotherapy did not clonogenic, thereby giving a false positive.344,345 Another caveat is the
observe a correlation with survival.341 However, the authors did correlate a instability of mutations that may result in false negatives. This is
greater than or equal to 1 log rise in RQ-PCR transcript relative to the particularly true for FLT3-ITD346-348 and NPM1 mutations.349-351 Despite
remission bone marrow sample as indicative of inferior leukemia-free these complications, several studies have correlated NPM1 mutations and

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outcome.112,350,352-357 In a small study of 25 patients, the use of a higher when using the cutoff values of greater than 100-fold detection, only 46%
sensitivity RQ-PCR was shown to circumvent transcript instability, of blood and 13% of marrow samples in the cohort were positive.363 This
ultimately showing that FLT3-ITD MRD monitoring was predictive of reflects the outliers of the healthy population that have higher WT1
relapse.358 In comparison to FLT3-ITD, data suggest that NPM1 mutations transcripts. Furthermore, only 19% of childhood AML samples met this
may be more stable.352 Schittger et al356 developed and tested primers for criterion in a study.364 While WT1 is a strong candidate for MRD
17 different mutations of NPM1.356 Serial analyses of 252 NPM1-mutated monitoring, early studies show that there is variability in the detection of
AML samples at 4 time points showed a strong correlation between the this transcript that must first be addressed. In a retrospective study of
level of NPM1mut and outcome. Kronke et al351 further modified this method patients with AML who underwent allogeneic HCT (n = 74), a multigene
to show that NPM1mut levels after double induction and consolidation MRD RQ-PCR array predicted clinical relapses occurring in the first 100
therapy reflected OS and cumulative incidence of relapse.351 In 245 days after allogeneic HCT compared with 57% sensitivity using WTI RQ-
patients, PCR negativity had a 6.5% 4-year cumulative incidence of PCR alone.365 Notably, for patients who achieved CR prior to allogeneic
relapse versus 53% for PCR positivity.351 This correlation was also seen HCT, the presence of pre-transplantation MRD positivity in peripheral
when taken after completion of therapy. In addition, an RQ-PCR analysis blood testing was associated with survival similar to patients with
of 2596 samples from 346 patients with NPM1-mutated AML pathologist bone marrow-based diagnosis of active disease.365
demonstrated that MRD was the only independent prognostic factor for
Flow Cytometry
mortality (HR, 4.84; 95% CI, 2.57–9.15; P < .001) and persisting NPM1-
mutated transcripts were associated with relapse.353 Flow cytometry for the monitoring of AML measures the presence of
tumor-specific antigens and abnormalities not found on normal bone
CEBPA and MLL-partial tandem duplications are additional targets for marrow cells. Several known markers identify abnormal cells or cell
MRD monitoring by RQ-PCR.340,359 While data suggest both transcripts maturation, and when used as a panel these markers can define cell
may be suitable MRD markers, the small sample sizes limit current use of populations.366 Studies in both adult and childhood AML cases show a
these markers until data can be extrapolated to a larger population. correlation between flow cytometry and relapse. Loken et al367 showed
Mutations associated with clonal hematopoiesis of indeterminate potential that 7 of 27 patients who had not achieved morphologic remission had
(CHIP) and aging including DNMT3A, TET2, and potentially ASXL1, are negative MRD by flow cytometry. All 7 patients were long-term survivors
not considered reliable MRD markers.332,333,360 when compared with the remaining 20 patients. Conversely, in a separate
study of 188 patients who achieved morphologic remission, less than 5%
Gene overexpression studies have focused on WT1. Retrospective data had high levels of MRD by flow cytometry.367 A larger study of 1382
show that a lower level of WT1 after induction therapy is associated with follow-up bone marrow samples from 202 children with AML demonstrated
long-term remission.361 A meta-analysis of 11 trials, encompassing 1297 MRD to be a predictor of relapse. In this study 28 of the 38 samples (74%)
patients, showed the poor prognostic significance of WT1 level.362 WT1 with greater than 15% myeloblasts had measurements of 0.1% or greater
was overexpressed in 86% of marrow and 91% of blood samples from 504 by flow cytometry. In patients with 5% to 15% myeloblasts, 43 of the 129
patients with AML when compared to 204 healthy donors.363 However, patients (33%) were detected by the same threshold and only 100 of the

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NCCN Guidelines Version 3.2022

Acute Myeloid Leukemia

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 Postremission Surveillance for AML
with no significant prior experience. Increased success rates of defining Monitoring for CBCs, including platelets, every 1 to 3 months for the first 2
LAIPs were seen in all four centers after extensive group discussion. The years after patients have completed consolidation therapy, then every 3 to
inexperienced laboratories had a success rate of 82% to 93% for defining 6 months thereafter up to 5 years, is recommended. Bone marrow
at least one LAIP in a sample from 35 evaluable samples. The missed evaluation should be performed only if the hemogram becomes abnormal,
LAIPs would have resulted in 7% to 18% of the patients being unevaluable rather than as routine surveillance at fixed intervals, unless the bone
by MRD in these centers. The number of samples incorrectly evaluated marrow evaluation is being performed as part of a clinical research
increases if they included samples in which at least two LAIPs were protocol.
identified by the primary lab, but the other labs only detected one LAIP.
This accounted for an additional 9% to 20% of cases that would have If no sibling donor has been identified, a donor search should be initiated
resulted in false negatives. LAIPs with high specificity and sensitivity at first relapse in appropriate patients concomitant with initiation of

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NCCN Guidelines Version 3.2022

Acute Myeloid Leukemia

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
these data, gilteritinib was approved by the FDA in November 2018 for
Targeted Therapy the treatment of adult patients who have R/R AML with a FLT3 mutation.
FLT3-Positive AML: In a phase I/II study, the safety and tolerability of
gilteritinib, a FLT3 inhibitor, was assessed in adult patients with R/R AML In a phase II study, the efficacy of azacitidine and sorafenib, a FLT3
(n = 252).306 In this group, 58 patients had wild-type FLT3 AML and 194 inhibitor, was evaluated in adult patients with R/R AML (n = 43; median
patients had FLT3-mutated AML (FLT3-ITD, n = 162; FLT3-TKD/FLT3 age, 67 years; range, 24–87 months).382 The response rate was 46%, with
D385, n = 16), and received oral gilteritinib (20–450 mg) once daily in CR, CR/CRi, and PR rates of 16%, 27%, and 3%, respectively.382 In
one of seven dose-escalation or dose-expansion cohorts.306 Gilteritinib addition, the degree of FLT3-ITD inhibition appeared to correlate with
was well-tolerated in this patient subpopulation and the most common plasma sorafenib concentrations.
grade 3 or 4 adverse events were febrile neutropenia (39%), anemia
IDH Mutation-Positive AML: The studies evaluating the efficacy of
(24%), thrombocytopenia (13%), sepsis (11%) and pneumonia (11%).306
ivosidenib301 and enasidenib300 in IDH1- and IDH2-mutation positive R/R
The ORR in all patients with R/R AML was 40%, which was improved to
AML, respectively, have been summarized in a previous section under

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Management of AML in Patients >60 Years, for patients who are not In a study of patients with resistant or relapsing AML (n = 38), patients
candidates for or decline intensive remission induction therapy. were treated with fludarabine, cytarabine, and G-CSF, and overall 21
patients (55%) achieved CR.386 In a study by Parker et al, patients with
CD33-Positive AML: In a study by Taksin et al, adult patients with AML high-risk MDS/AML (n = 19; including R/R AML, n = 7), treated with
in first relapse (n = 57) received fractionated doses of GO, given at a fludarabine, cytarabine, G-CSF, and idarubicin experienced response to
dose of 3 mg/m2 on days 1, 4, and 7 for one course.383 Fifteen patients therapy, with 12 patients (63%) achieving CR.387
achieved CR (26%) and 4 achieved CRp (7%). The median RFS was
similar for patients who achieved CR and CRp and was 11 months.383 In In a phase I study, a regimen with clofarabine, cytarabine, and idarubicin
addition, no veno-occlusive disease (sinusoidal obstructive syndromes) was evaluated in a subgroup of adult patients with R/R AML (n = 21) and
occurred after GO treatment or after GO followed by HCT (n = 7), 10 patients (48%) achieved CR.388 A regimen with clofarabine (40 mg/m2)
although the authors recommended a minimum delay of 90 days combined with cytarabine (2 g/m2) was evaluated in a randomized,
between GO treatment and HCT.383 placebo-controlled, phase III trial (CLASSIC I trial) in R/R AML, resulting in
an ORR of 47% (CR rate, 35%) and a median OS of 6.6 months.389 A
Chemotherapy
retrospective study compared clofarabine versus fludarabine in
The guidelines provide a list of several commonly used regimens for R/R combination with HiDAC with or without G-CSF.390 Patients treated with a
disease that are grouped as either aggressive or less aggressive therapy clofarabine-based regimen (n = 50) compared to a fludarabine-based
(see AML: Therapy for Relapsed/Refractory Disease in the algorithm). The regimen (n = 101) had a higher CR rate (OR, 9.57; P < .0001) and a
regimens grouped under aggressive therapy represent purine analog (eg, longer survival (mortality HR, 0.43; P = .0002).390
fludarabine, cladribine, clofarabine)–containing regimens, which have
shown remission rates of approximately 30% to 45% in several clinical The regimens for R/R AML grouped under less aggressive or less
trials, and those that have been used as the comparator arms in U.S. intensive therapy include HMAs (azacitidine or decitabine), low-dose
cooperative group trials in the past decade. cytarabine, and venetoclax-containing regimens. Emerging studies
suggest that venetoclax in combination with HMAs or low-dose cytarabine
A study by Robak et al evaluated the efficacy of cladribine, cytarabine, and has demonstrated antileukemic activity in R/R AML, MDS, and BPDCN.391
G-CSF as re-induction therapy in patients with R/R AML (n = 20).384 Ten A study suggests that azacitidine followed by donor lymphocyte infusions
patients (50%) achieved CR with a median duration of 22.5 weeks (range, (DLIs) may be a treatment option for therapy in patients who have AML
3.5–53 weeks). Two patients experienced PR (10%) and 8 patients did not that relapses after allogeneic HCT.392 These data are based on a
have response to therapy.384 In another study, the efficacy of cladribine, prospective phase II trial of 28 patients with AML. In this study, 22 patients
cytarabine, and idarubicin was analyzed in patients with R/R AML (n = received DLIs and an ORR of 30% was achieved. This included 7 CRs
34).385 After at least one cycle of treatment, 18 patients (52.9%) achieved and 2 PRs. At publication, 5 patients remained in CR with a median of 777
CR and 16 (47.1) received subsequent allogeneic HCT.385 days (range, 461–888 days). Neutropenia and thrombocytopenia grade
III/IV were the most common adverse events (65% and 63%,

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NCCN Guidelines Version 3.2022

Acute Myeloid Leukemia

respectively). Acute and chronic graft-versus-host disease (GVHD) were In some cases, if a patient has experienced a long first remission (≥12
seen in 37% and 17% of patients, respectively. Correlations suggest a months), repeating treatment with a successful induction regimen may be
better response in patients with myelodysplasia-related changes considered. This strategy primarily applies to cytotoxic chemotherapy
(P = .011) and lower blast count (P = .039) or patients with high-risk regimens and excludes the use of dual-drug encapsulation of cytarabine
cytogenetics (P = .035). However, interpretation of results is limited by the and daunorubicin, and the re-use of targeted agents due to the potential
small size of the study.392 development of resistance. Targeted therapies may be retried if they were
NCCN Recommendations
not administered continuously and not stopped due to the development of
The NCCN AML Panel recommends enrollment in a clinical trial for the clinical resistance. If a second CR is achieved, consolidation with
management of R/R AML as a strongly preferred option. Other options allogeneic HCT should be considered.
include targeted therapy or chemotherapy followed by allogeneic HCT. For
Supportive Care for Patients with AML
targeted therapies, the guidelines provide a list of options including
Although variations exist between institutional standards and practices,
gilteritinib for patients with FLT3 mutations (a category 1
several supportive care issues are important to consider in the care of
recommendation). Sorafenib may be added to HMAs (azacitidine or
patients with AML. In general, supportive care measures may include the
decitabine) for patients with FLT3-ITD mutations. Other targeted therapy
use of blood products for transfusion support and correction of
options include GO for patients with CD33-positive AML, and ivosidenib or
coagulopathies, tumor lysis prophylaxis, anti-infective prophylaxis, and
enasidenib for patients with IDH1 or IDH2 mutations, respectively.
growth factor support. Monitoring for neurologic and cardiovascular
The regimens for aggressive therapy include: 1) cladribine, cytarabine, toxicities may be required for particular therapeutic agents (HiDAC or
and G-CSF, with or without mitoxantrone or idarubicin;384,385 2) HiDAC, if ATO) or because of patient-specific comorbidities. These supportive care
not previously received in treatment, with or without anthracycline240; 3) measures are tailored to address the specific needs and infection
fludarabine, cytarabine, and G-CSF (FLAG regimen) with or without susceptibility of each individual.
idarubicin;386,387 4) etoposide and cytarabine, with or without
When transfusion support is required, leukocyte-depleted blood products
mitoxantrone393,394; 5) clofarabine and cytarabine with or without
should be used for transfusion. All patients with AML are at risk for acute
idarubicin;388,389 or 6) clofarabine with or without idarubicin.395,396 Less
GVHD and management should be based on institutional practice or
aggressive or less intensive treatment options may include: 1) HMAs
preference. Cytomegalovirus (CMV) screening for potential HCT
alone (azacitidine or decitabine)282,289,397; 2) low-dose cytarabine294,398 (a
candidates is left to institutional policies regarding provision of
category 2B recommendation); or 3) venetoclax combined with HMAs or
CMV-negative blood products to patients who are CMV-negative at the
low-dose cytarabine.309,391 Best supportive care is always an option for
time of diagnosis. HLA typing is routinely used in many institutions to
patients who cannot tolerate or do not wish to pursue further intensive
select platelet donors for patients who exhibit alloimmunization to
treatment.
HLA-specific antigens.

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NCCN Guidelines Version 3.2022

Acute Myeloid Leukemia

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
each dose of HiDAC; patients exhibiting any neurologic signs should postremission therapy, except in life-threatening infections or when signs
discontinue HiDAC, and all subsequent cytarabine therapy must be and symptoms of sepsis are present and the leukemia is believed to be in
administered as standard dose. Patients who develop cerebellar toxicity remission.
should not be rechallenged with HiDAC in future treatment cycles.403
Supportive Care for Patients with AML Who Prefer Not to Receive
HiDAC should also be discontinued in patients with rapidly rising Blood Transfusions
creatinine caused by tumor lysis.
There is no established treatment of AML that does not require use of
Decisions regarding the use and choice of antibiotics to prevent and treat blood and blood products for supportive care, and with limited data,
infections should be made by the individual institutions based on the providing guidelines or recommendations for AML management in this
prevailing organisms and their drug resistance patterns.404 Greater detail context is challenging. However, the AML panel recognizes that this is a
significant issue faced in a narrow spectrum of clinical settings. In this
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NCCN Guidelines Version 3.2022

Acute Myeloid Leukemia

context, the panel reviewed the existing literature and collective remissions.411 During treatment, measures should be taken to minimize
experience with this issue and summarized some considerations to guide blood loss and decreased the risk of bleeding including: the use of
treatment and supportive care. However, it is important to note that the pediatric collection tubes; avoiding concomitant medications or procedures
panel believes that in many cases, good outcomes from these strategies that increase the risk of bleeding or myelosuppression; use of oral
are rare. contraceptive pills or medroxyprogesterone acetate in menstruating
individuals; or proton pump inhibitors, as indicated.406,413 Vitamin K may be
At the outset, it is important to discuss the goals of care with the patient considered as an adjuvant to improve coagulopathy.406,413 In patients at
and establish an understanding of the complications that can arise risk of bleeding (eg, when platelet counts drop below 30,000/mcL),
without transfusions. In addition, it will be helpful to ascertain if the aminocaproic acid or tranexamic acid may be considered to manage
patient will accept certain blood products (eg, cryoprecipitate) and stem bleeding.406,413 In patients with elemental or vitamin deficiencies, consider
cells (either autologous or from another donor source). To mobilize iron, folate, and vitamin B12 supplementation.406,413 In patients with severe
peripheral blood stem cells and/or bring up hemoglobin levels prior to anemia, consider bed rest and supplemental oxygenation.406,413
peripheral blood stem cell transplantation, some treatment centers have
used erythropoietin stimulating agents (ESAs), G-CSF, and Evaluation and Treatment of CNS Leukemia
thrombopoietin (TPO) mimetics.405-407 However, before using this Leptomeningeal involvement is much less frequent (<3%) in patients with
strategy, the potential risks, benefits and uncertainties of using these AML than in those with ALL; therefore, the panel does not recommend LP
agents in this context should be thoroughly discussed. Consider referring as part of the routine diagnostic workup. However, if neurologic symptoms
the patient to centers with expertise in bloodless autologous (eg, headache, confusion, altered sensory input) are present at diagnosis,
transplant.406,407 In addition, for patients who are Jehovah’s Witnesses an initial CT/MRI should be performed to rule out the possibility of
and for this reason decline blood transfusions, the U.S. branch of the intracranial hemorrhage or presence of a mass or lesion. If no mass effect
Christian Congregation of Jehovah’s Witness has Hospital Liaison is seen, cerebrospinal fluid cytology should be sampled by LP. If the LP is
Committees that may provide helpful information about bloodless negative for leukemic cells, the patient can be followed with a repeat LP if
medicine. symptoms persist. If the LP is positive by morphology or immunotype by
flow cytometry, IT chemotherapy is recommended, given concurrently with
Regarding treatment options, the panel recommends considering less
systemic induction therapy. If LP result is equivocal, consider repeating LP
myelosuppressive induction including dose reduction of anthracyclines
with morphology or immunotype by flow cytometry to delineate
and use of non-intensive chemotherapy.408-412 Some of these options may
involvement. IT therapy may include agents such as IT methotrexate or IT
include targeted agents guided by testing for actionable mutations instead
cytarabine either alone or combined. The selection of agents and dose
of intensive chemotherapy, especially in a noncurative setting. However,
schedules for IT therapy largely depend on the specific clinical situation
the panel notes that dose reductions in chemotherapy without transfusion
(eg, extent of CNS leukemia, symptoms, systemic therapies given
support in patients with AML is associated with a lower rate of remission,
concurrently) and institutional practices. Initially, IT therapy is generally
high mortality by severe anemia, and is unlikely to result in durable
given twice weekly until the cytology shows no blasts, and then weekly for

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NCCN Guidelines Version 3.2022

Acute Myeloid Leukemia

4 to 6 weeks. Importantly, IT therapy should only be administered by unknown but its association with MDS in some cases may suggest a
clinicians with experience and expertise in the delivery of IT agents. related pathogenesis.414 Median age of presentation is 65 to 67 years
HiDAC has significant penetration across the blood–brain barrier and may with an approximate male-to-female ratio of 3:1. The most frequent
represent an alternative to repeated IT injections during induction therapy. clinical presentation of typical BPDCN cases is asymptomatic solitary or
The cerebrospinal fluid must then be reassessed after completion of multiple skin lesions.414 Peripheral blood and bone marrow involvement
induction therapy, and further IT therapy should be given as appropriate. may be minimal at presentation, but tend to develop as the disease
progresses.414
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 Workup
biopsy may be considered. If the results are positive, then radiation The evaluation and initial workup for suspected BPDCN consists of a
therapy is recommended, followed by IT therapy, as described earlier. IT comprehensive medical history and physical examination. Laboratory
therapy or HiDAC should not be administered concurrently with cranial evaluations include a comprehensive metabolic panel and a CBC
radiation because of the increased risks of neurotoxicity. Another option including platelets and a differential of WBCs. Analyses of peripheral
for these patients includes HiDAC-containing therapy with dexamethasone blasts, bone marrow aspirate, and a lymph node biopsy is
to help reduce intracranial pressure. recommended. These analyses include dendritic cell morphology
assessment, immunohistochemistry, flow cytometry, cytogenetic analysis
The panel does not recommend routine screening for occult CNS disease
(including karyotyping and/or FISH), and molecular analyses. An
in most patients with AML in remission. The exceptions are patients with
analysis of skin lesions in collaboration with dermatology is also
extramedullary disease, monocytic differentiation, biphenotypic leukemia,
recommended because most presentations of BPDCN include skin
WBC count greater than 40,000/mcL at diagnosis, high-risk APL, or FLT3
manifestations including isolated purplish nodules, which account for
mutations. For patients with positive cerebrospinal fluid by morphology or
two-thirds of cases.414
immunotype by flow cytometry, the panel recommends either IT
chemotherapy, as outlined earlier, or documenting clearance of CNS A diagnosis of BPDCN requires the presence of at least 4 of these 6
disease after the first cycle of HiDAC chemotherapy. In addition to the antigens: CD123 (also interleukin-3 receptor-alpha [IL3Rα]), CD4, CD56,
recommended evaluation and treatment of CNS leukemia, further CNS TCL-1, CD2AP, and CD303/BDCA-2, in the absence of lineage-specific
surveillance should be followed based on institutional practice. markers.414,416 BPDCN must be distinguished from mature plasmacytoid
dendritic cell proliferation (MPDCP) in which PDCs are morphologically
Management of Blastic Plasmacytoid Dendritic Cell
mature and CD56-negative.414 In addition, recurrent mutations in the
Neoplasm
following genes have been described: ASXL1, IDH1, IDH2, IKZF1,
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare subtype IKZF2, IKZF3, NPM1, NRAS, TET1, TET2, TP53, U2AF1, and
of AML characterized by aggressive proliferation of precursors of ZEB2.414,416,417 If extramedullary disease and/or lymphadenopathy is
plasmacytoid dendritic cells (PDCs).414,415 The etiology of BPDCN is suspected, a PET/CT scan is recommended. An LP should also be

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NCCN Guidelines Version 3.2022

Acute Myeloid Leukemia

performed to rule out CNS disease, and if clinically indicated, follow the thrombocytopenia. In addition, capillary leak syndrome was observed in
LP with IT prophylaxis.416 19% of the patients and associated with one death in each of the dose
subgroups.419 Based on these data, in 2018 the FDA approved
Induction Therapy for Patients with BPDCN tagraxofusp-erzs for BPDCN in adults and pediatric patients at least 2
CD123-Targeted Therapy years of age.
Tagraxofusp (formerly SL-401) is a recombinant fusion protein made up
of the catalytic and translocation domains of diphtheria toxin (DT) fused Chemotherapy
to IL3. In pilot clinical study, 11 patients with recurrent or refractory Historically, therapeutic approaches for CD4+CD56+ malignancies have
BPDCN or who were not candidates for standard chemotherapy were varied widely and include irradiation for localized stages, lymphoma- or
treated with SL-401.418 Each cycle of SL-401 treatment was comprised of leukemia-type regimens, and myeloablative therapy.420 In a retrospective
a 12.5µg/kg dose administered over a 15-minute infusion every day for multicenter study, 41 patients with BPDCN received induction treatment
up to 5 doses.418 Of 9 evaluable patients who received treatment, 5 with AML-type regimens (n = 26) and ALL-type/lymphoma-type regimens
achieved a CR and 2 experienced a PR after one cycle of SL-401 (n = 15).415 The AML-type treatment protocols included MICE
treatment (78% response rate).418 The median duration of responses (mitoxantrone, cytarabine, etoposide), ICE (idarubicin, cytarabine,
was 5 months (range, 1–20+ months) with responses occurring in all etoposide), standard-dose cytarabine and anthracycline (7+3), FLAG,
sites of disease including skin, bone marrow, and lymph nodes.418 and FLAG-Ida. The ALL/lymphoma-type regimens included hyper-CVAD
Common adverse events including fever, chills, hypotension, edema, (alternative cycles of hyperfractionated cyclophosphamide, vincristine,
hypoalbuminemia, thrombocytopenia, and transaminasemia were doxorubicin, dexamethasone, methotrexate, and cytarabine), GIMEMA
transient.418 ALL trial therapy (association of doxorubicin, vincristine, prednisone, and
asparaginase), CHOP (cyclophosphamide, doxorubicin, vincristine, and
In a multicohort study, 47 patients with untreated or relapsed BPDCN prednisone), and CHOEP (CHOP plus etoposide).415 After induction, the
were treated with an intravenous (IV) infusion of tagraxofusp at a dose of overall CR rate was 41%, with 7 patients achieving CR after AML-type
7 or 12 µg/kg on days 1 to 5 of each 21-day cycle.419 Of the 47 patients, induction, and 10 patients achieving CR after ALL-type induction.415 The
32 received first-line treatment and 15 received previous treatment, median OS was 8.7 months (range, 0.2–32.9), and patients who received
which was given until disease progression or unacceptable toxic effects. ALL-type chemotherapy appeared to have longer OS compared to
Among 29 evaluable patients who received first-line treatment of patients treated with AML-type chemotherapy (12.3 vs. 7.1 months,
tagraxofusp at 12 µg/kg, the primary outcome (CR and clinical CR) was respectively; P = .02).415 In addition, the median OS of patients who
observed in 21 (71%) patients and the ORR was 90%.419 Among the 15 received transplant was significantly higher than non-transplanted
patients who were previously treated, the response rate was 67% with a patients (22.7 vs. 7.1 months, respectively; P = 0.03).
median OS of 8.5 months.419 The most common adverse events were
increased levels of alanine aminotransferase and aspartate Another retrospective study evaluated the diagnostic flow cytometry
aminotransferase, hypoalbuminemia, peripheral edema, and pattern and outcome of nine patients with BPDCN after front-line

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NCCN Guidelines Version 3.2022

Acute Myeloid Leukemia

treatment with hyper-CVAD.421 In this group, seven patients received having undergone autologous HCT. All patients who underwent
induction treatment with hyper-CVAD and had a CR of 67% and ORR of autologous HCT were in first CR.423 With a median follow-up of 53.5
86%. Five of the six patients who experienced response to therapy months, the OS rates at 4 years for patients who underwent autologous
received planned allogeneic stem cell transplantation. For a median HCT and allogeneic HCT were 82% and 53%, respectively (P = .11) and
follow-up of 13.3 months, the one-year DFS and OS rates for all patients the PFS rates were 73% and 48%, respectively (P = .14).423 The data
was 56% and 67%, respectively.421 For patients who received suggest that receiving autologous HCT in first CR may significantly
chemotherapy alone, the median OS was 7.9 months, but the median enhance survival.423
OS was not reached for patients who received transplantation.421
A North American multicenter retrospective study analyzed the outcomes
Hematopoietic Stem Cell Transplantation of patients with BPDCN treated with allogeneic HCT (n = 37) or
Due to the rarity of BPDCN, there have been limited established autologous HCT (n = 8).424 Allogeneic HCT recipients had a 1-year and
standardized therapeutic approaches.422 Hematopoietic cell 3-year OS of 68% (95% CI, 49%–81%) and 58% (95% CI, 38%–75%),
transplantation (HCT) seems to generate durable remissions, especially respectively.424 Receiving allogeneic HCT in first CR yielded improved 3-
if given in first CR.420,422-424 However, it is worth noting that data are year OS versus allogeneic HCT not in first CR [74% (95% CI, 48%–89%)
limited to small case series and retrospective registry studies, and larger vs. 0, P < .0001]. The 1-year OS for autologous HCT recipients was 11%
prospective studies are needed to elucidate the role of HCT in (95% CI, 8%–50%).424
BPDCN.424
NCCN Recommendations
In a retrospective study from the European Society for Blood and Marrow For patients who are candidates for intensive remission induction
Transplantation, an analysis was conducted to determine whether long- therapy, the panel recommends tagraxofusp-ersz as the preferred
term DFS could be achieved in patients with BPDCN who received option, and other options include AML-type (standard-dose cytarabine
allogeneic HCT or autologous HCT after high-dose chemotherapy (n = plus anthracycline using 7+3), ALL-type (hyper-CVAD), and lymphoma-
39).422 Nineteen patients received allogeneic HCT in first CR and in this type (CHOP) regimens.
group the 3-year cumulative incidence of relapse, DFS, and OS was
32%, 33%, and 41%, respectively.422 By univariate comparison, being in Tagraxofusp-ersz should be administered as an intravenous infusion at
first remission at allogeneic HCT significantly enhanced survival, 12 µg/kg over 15 minutes once daily on days 1 to 5 of each 21-day cycle.
whereas age, donor source, and GVHD did not significantly impact Alternatively, 5 doses can be administered over a 10-day period, if
survival.422 needed for dose delays. It is important to note that patients must have a
baseline serum albumin of 3.2 g/dL or higher to be able to start treatment
A retrospective analysis from the Japan Society for Hematopoietic Cell with this agent. The most serious side effect associated with tagraxofusp
Transplantation aimed to clarify the role of allogeneic HCT or autologous is capillary leak syndrome, which can occur during the first cycle of
HCT in treating BPDCN.423 In this analysis, 25 patients were identified, treatment and is life-threatening.419 A decrease in serum albumin during
with 14 patients having undergone allogeneic HCT and 11 patients the first days of treatment seems to be the most consistent predictor of

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NCCN Guidelines Version 3.2022

Acute Myeloid Leukemia

capillary leak syndrome.419 Management includes delaying or withholding disease, a repeat PET/CT scan is recommended. In addition, a re-biopsy
additional tagraxofusp doses, administering intravenous albumin should be considered for any suspicious skin or extramedullary lesions.
according to pre-specified measures, administering glucocorticoids, and
close management of volume status.419 The panel recommends Management of Relapsed/Refractory BPDCN
replacing serum albumin if <3.5 g/dL or if there is a reduction of ≥0.5 Upon relapse, the NCCN AML Panel recommends evaluating for CNS
from baseline. disease/prophylaxis.425 Management options for R/R BPDCN include
clinical trial (preferred), tagraxofusp-ersz (preferred, if not already
If CNS disease is documented at diagnosis or if clinically indicated, IT used),419 chemotherapy (if not already given), local radiation to isolated
chemotherapy should also be given. With all treatment options, if CR is lesions, systemic steroids, or venetoclax-based regimens.391,426 During
observed, allogeneic HCT or autologous HCT should be considered. If administration of any treatment option, a donor search should also be
tagraxofusp was given as an initial treatment, additional cycles of therapy started at first relapse in appropriate patients if no sibling donor has been
should be continued until disease progression. If disease progresses or identified.
does not respond to induction therapy, consideration should be made for
a clinical trial (preferred) or use of regimens used for R/R disease.

For patients with low performance and/or nutritional status (ie, serum
albumin <3.2 g/dL or are not a candidate for intensive remission
induction therapy or tagraxofusp-ersz), treatment options are limited. If
disease is localized or isolation to cutaneous involvement, palliative
treatment options include surgical excision or focal radiation. If the
disease is systemic, palliative options include low-intensity therapy with
venetoclax and HMAs, steroids, and supportive care.

Postremission Surveillance for BPDCN

Monitoring for CBCs, including platelets, every 1 to 3 months for the first
2 years after patients have completed consolidation therapy, then every
3 to 6 months thereafter up to 5 years, is recommended. Bone marrow
evaluation should be performed only if the hemogram becomes
abnormal, rather than as routine surveillance at fixed intervals, unless
the bone marrow evaluation is being performed as part of a clinical
research protocol. For patients with prior evidence of extramedullary

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NCCN Guidelines Version 3.2022

Acute Myeloid Leukemia

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NCCN Guidelines Version 3.2022

Acute Myeloid Leukemia

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Acute Myeloid Leukemia

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Acute Myeloid Leukemia

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Acute Myeloid Leukemia

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Acute Myeloid Leukemia

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Acute Myeloid Leukemia

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Acute Myeloid Leukemia

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