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

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

Version 1.2022 — December 2, 2021
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NCCN Guidelines Version 1.2022 NCCN Guidelines Index

Table of Contents
Acute Myeloid Leukemia (Age ≥18 years) Discussion
*Daniel A. Pollyea, MD, MS/Chair ‡ Þ † Jeffrey Lancet, MD ‡ † Amanda Przespolewski, DO ‡

University of Colorado Cancer Center Moffitt Cancer Center Roswell Park Comprehensive Cancer Center
Jessica K. Altman, MD/Vice Chair ‡ James Mangan, MD ‡ Dinesh Rao, MD, PhD ≠
Robert H. Lurie Comprehensive Cancer UC San Diego Moores Cancer Center UCLA Jonsson Comprehensive Cancer Center
Center of Northwestern University Gabriel Mannis, MD ‡ Þ Farhad Ravandi, MD Þ ‡
Vijaya Raj Bhatt, MBBS ‡ ξ Stanford Cancer Institute The University of Texas
Fred & Pamela Buffett Cancer Center Guido Marcucci, MD † Þ MD Anderson Cancer Center
Dale Bixby, MD, PhD ‡ † Þ City of Hope National Medical Center Paul J. Shami, MD ‡
University of Michigan Alice Mims, MD, MS † Huntsman Cancer Institute
Rogel Cancer Center The Ohio State University Comprehensive at the University of Utah
Hetty Carraway, MD, MBA † Cancer Center - James Cancer Hospital Richard M. Stone, MD ‡ †
Case Comprehensive Cancer Center/University and Solove Research Institute Dana-Farber/Brigham and Women’s
Hospitals Seidman Cancer Center and Jadee Neff, MD, PhD ≠ Cancer Center
Cleveland Clinic Taussig Cancer Institute Duke Cancer Institute Stephen A. Strickland, MD, MSCI ‡
Amir T. Fathi, MD ‡ † Reza Nejati, MD ≠ Vanderbilt-Ingram Cancer Center
Massachusetts General Hospital Cancer Center Fox Chase Cancer Center Kendra Sweet, MD, MS ‡ Þ †
James M. Foran, MD † Rebecca Olin, MD, MS ‡ ξ Moffitt Cancer Center
Mayo Clinic Cancer Center UCSF Helen Diller Family Martin Tallman, MD ‡
Ivana Gojo, MD ‡ Comprehensive Cancer Center Memorial Sloan Kettering Cancer Center
The Sidney Kimmel Comprehensive Prapti Patel, MD ‡ Swapna Thota, MD ‡
Cancer Center at Johns Hopkins UT Southwestern Simmons St. Jude Children's Research Hospital/The
Aric C. Hall, MD ‡ † ξ Comprehensive Cancer Center University of Tennessee Health Science Center
University of Wisconsin Mary-Elizabeth Percival, MD, MS ‡ Pankit Vachhani, MD ‡
Carbone Cancer Center Fred Hutchinson Cancer Research Center/ O'Neil Comprehensive Cancer Center at UAB
Meagan Jacoby, MD, PhD ‡ † ξ Seattle Cancer Care Alliance
NCCN
Siteman Cancer Center at Barnes- Alexander Perl, MD † Mallory Campbell, PhD
Jewish Hospital and Washington Abramson Cancer Center at the Kristina Gregory, RN, MSN, OCN
University School of Medicine University of Pennsylvania Mary Dwyer, MS
Brian A. Jonas, MD, PhD ‡
UC Davis Comprehensive 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

Table of Contents
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) https://www.nccn.org/home/member-
• 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
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be reproduced in any form without the express written permission of NCCN. ©2021.

Table of Contents
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.
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.
Continued
Version 1.2022, 12/02/21 © 2021 National Comprehensive Cancer Network (NCCN ), All rights reserved. NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.
® ® ®
UPDATES

Table of Contents
Acute Promyelocytic Leukemia (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
UPDATES

Table of Contents
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
® ® ®
UPDATES

Table of Contents
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
UPDATES

Table of Contents
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.
EVAL-1

Table of Contents
FOOTNOTES FOR EVALUATION FOR AML

a A variety of gene mutations are associated with specific prognoses (category 2A) and may guide medical decision-making (category 2B). Other genetic lesions
may have therapeutic significance. The field of genomics in myeloid malignancies and related implications in AML are evolving rapidly. Mutations should be tested
in all patients. Multiplex gene panels and 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.

EVAL-1A

Table of Contents
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.

APL-1

Table of Contents
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

APL-2

Table of Contents
FOOTNOTES FOR APL TREATMENT INDUCTION AND CONSOLIDATION THERAPY (LOW RISK)
b Several groups have published large trials with excellent outcomes. However, to achieve the expected results, one needs to use the regimen consistently through all
components and not mix induction from one trial with consolidation from another.
c Monitor for APL differentiation syndrome and coagulopathy; see Principles of Supportive Care for APL (APL-A).
d Early mortality is related to bleeding, differentiation syndrome, or infection. Persistent disease is rare.
e Hydroxyurea should be considered to manage high WBC count (>10,000/mcL) during induction 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.

APL-2A

Table of Contents
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

APL-3

Table of Contents
FOOTNOTES FOR APL TREATMENT INDUCTION AND CONSOLIDATION THERAPY (HIGH RISK)
2017;35:3021-3029.
for APL (APL-A).
1 week later.
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.

APL-3A

Table of Contents
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
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
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

APL-4

Table of Contents
FOOTNOTES FOR APL TREATMENT INDUCTION AND CONSOLIDATION THERAPY (HIGH RISK)
2017;35:3021-3029.
for APL (APL-A).
k Estey E, et al. Blood 2002;99:4222-4224.
1 week later.
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.

APL-4A

Table of Contents
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.

APL-5

Table of Contents
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.

APL-6

Table of Contents
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.

APL-A

Table of Contents
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)
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

AML-1

Table of Contents
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.

AML-1A

Table of Contents
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

AML-2

Table of Contents
FOOTNOTES FOR TREATMENT AFTER STANDARD-DOSE CYTARABINE INDUCTION/RE-INDUCTION (AGE <60 YEARS)
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.

AML-2A

Table of Contents
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

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
y Consider clinical trials for patients with targeted molecular abnormalities.
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).

AML-3

Table of Contents
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)

AML-4

Table of Contents
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.
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.

AML-4A

Table of Contents
AGE ≥60 ya,pp TREATMENT TREATMENT INDUCTIONg,i,j

STRATEGIESqq
Options:
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)
AML-5

Table of Contents
FOOTNOTES FOR TREATMENT INDUCTION (AGE ≥60 YEARS)

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.
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: http://www.aml-score.org/. Krug U, et al. Lancet 2010;376:2000-2008. A web-based tool to predict CR and early death can be found at: https://trmcalculator.
fredhutch.org 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.

AML-5A

Table of Contents
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 • Enasidenibggg,hhh (IDH2 only)
therapy or Other Recommended
declines • 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) + sorafenibiii (FLT3-ITD–positive)
• Venetoclax-based therapy (same as above in combination with LDACxx)

AML-6

Table of Contents
FOOTNOTES FOR TREATMENT INDUCTION (AGE ≥60 YEARS)

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).
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: http://www.aml-score.org/. Krug U, et al. Lancet 2010;376:2000-2008. A web-based tool to predict CR and early death can be found at: https://trmcalculator.
fredhutch.org 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 Ohanian M, et al. Am J Hematol 2018;93:1136-1141.

AML-6A

Table of Contents
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 HCTjjj
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. jjj 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.

AML-7

Table of Contents
AGE ≥60 y Options

POST-INDUCTION THERAPY • Allogeneic HCTlll
• 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,mmm
• 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
responsekkk 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)nnn
therapy
recovery (4–6 or all of the • Maintenance therapy with hypomethylating regimens every 4–6 weeks until
weeks). For MRD
recommended progressionooo
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)

AML-8

Table of Contents
FOOTNOTES FOR POST-INDUCTION THERAPY (AGE ≥60 YEARS)
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.
kkk HLA typing should be used for patients considered to be strong candidates for allogeneic transplantation.
lll Patients who are deemed as candidates for HCT and who have an available donor should be transplanted in first remission.
mmm 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.
nnn 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.
ooo Azacitidine: Huls G, et al. Blood 2019;133:1457-1464; Decitabine: Boumber Y, et al. Leukemia 2012;26:2428–3241.

AML-8A

Table of Contents
AGE ≥60 y
POST-INDUCTION THERAPY
Options: (Principles of Venetoclax, see AML-J)
• Allogeneic HCTlll
• 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,qqq or ivosidenibfff,qqq
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,iii
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)ppp 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 iii Ohanian M, et al. Am J Hematol 2018;93:1136-1141.
to HMAs (ie, azacitidine, decitabine) may be less likely to derive benefit from lll Patients who are deemed as candidates for HCT and who have an available donor
continued treatment with HMAs compared to patients who are HMA-naïve. should be transplanted in first remission.
Alternative treatment strategies should be considered. DiNardo CD, et al. Blood ppp Response to treatment with enasidenib or ivosidenib may take 3–5 months.
2019;133:7-17. qqq 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.

AML-9

Table of Contents
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 toxicitynnn
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 • Sorafenibrrr,sss
Neither of the above scenarios is applicable Maintenance therapy not recommended
nnn 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.
rrr Xuan L, et al. Lancet Oncol 2020;21:1201-1212.
sss Burchert A, et al. J Clin Oncol 2020;38:2993-3002.

AML-10

Table of Contents
AML SURVEILLANCEttt 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 Relapseuuu 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 regimenvvv
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)
ttt Studies are ongoing to evaluate the role of molecular monitoring in the surveillance for early relapse in patients with AML (see Discussion).
uuu 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.
vvv 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.

AML-11

Table of Contents
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
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
AML-A
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Table of Contents
Name of Syndrome Causative Pattern of Characteristic Other Other Associated Conditions Recommended
Gene(s) Inheritance Malignancy Hematopoietic Diagnostic Test
Abnormalities
Familial platelet RUNX1 Autosomal MDS Thrombocytopenia Exon sequencing and
disorder with dominant AML Platelet dysfunction gene rearrangement
propensity to myeloid T-cell ALL testing for RUNX1
malignancies (OMIM
601399)
Thrombocytopenia 2 ANKRD26 Autosomal MDS Thrombocytopenia 5’UTR and exon
(OMIM 188000) dominant AML Platelet dysfunction sequencing of
ANKRD26
Familial AML with CEBPA Autosomal AML Exon sequencing and
mutated CEBPA dominant gene rearrangement
(OMIM 116897) testing for CEBPA
Familial AML with DDX41 Autosomal MDS Monocytosis Solid tumor predisposition is Exon sequencing and
mutated DDX41 dominant AML likely [colon, bladder, stomach, gene rearrangement
(OMIM 608170) CMML pancreas, breast, and melanoma] testing for DDX41
Thrombocytopenia 5 ETV6 Autosomal MDS Thrombocytopenia Exon sequencing and
(OMIM 616216) dominant AML Platelet dysfunction gene rearrangement
CMML testing for ETV6
B-ALL
Myeloma
Familial MDS/AML GATA2 Autosomal MDS Monocytopenia Sensorineural deafness Exon sequencing,
with mutated GATA2 dominant AML Lymphopenia (NK Immunodeficiency intron 5 enhancer
(OMIM 137295) CMML cell, dendritic cell, Cutaneous warts region sequencing, and
B-cell, or CD4+ Pulmonary alveolar proteinosis gene rearrangement
T-cell) MonoMAC syndrome testing for GATA2
Emberger syndrome
Continued
Adapted with permission from: Churpek JE, Godley LA. Familial acute leukemia and myelodysplastic syndromes. In: UpToDate, Post TW (Ed), UpToDate, Waltham, MA.
(January 31, 2020) Copyright © 2020 UpToDate, Inc. For more information visit www.uptodate.com.

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Table of Contents
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 www.uptodate.com.
AML-A
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Table of Contents
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).

AML-B

Table of Contents
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.

AML-C

Table of Contents
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: https://www.jw.org/en/medical-library/hospital-liaison-committee-hlc-
contacts/united-states
• Clarify acceptance of certain blood products (eg, cryoprecipitate) under certain circumstances; including a discussion of whether stem cells
(donor or autologous) will be acceptable.
• Minimize blood loss (eg, use of pediatric collection tubes).
• Minimize risk of bleeding, including consideration for use of oral contraceptive pills or medroxyprogesterone acetate in menstruating
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].

AML-D

Table of Contents
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.

AML-E

Table of Contents
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.

AML-F

Table of Contents
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.

AML-G

Table of Contents
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.

AML-H

Table of Contents
THERAPY FOR RELAPSED/REFRACTORY DISEASE1

Clinical trial1 Aggressive therapy for appropriate patients:
• Cladribine + cytarabine + G-CSF8 ± mitoxantrone or idarubicin9,10
Targeted therapy:
• HiDAC (if not received previously in treatment) ± (idarubicin or
• Therapy for AML with FLT3-ITD mutation
daunorubicin or mitoxantrone)11
Gilteritinib2 (category 1)
• Fludarabine + cytarabine + G-CSF8 ± idarubicin12,13
Hypomethylating agents (HMAs) (azacitidine or decitabine) +
• Etoposide + cytarabine ± mitoxantrone14
sorafenib3,4
• Clofarabine ± cytarabine ± idarubicin15,16
• Therapy for AML with FLT3-TKD mutation
Gilteritinib2 (category 1) Less aggressive therapy:
• Therapy for AML with IDH2 mutation • HMAs (azacitidine or decitabine)
Enasidenib5 • LDAC (category 2B)
• Therapy for AML with IDH1 mutation • Venetoclax17 + HMA/LDAC18,19
Ivosidenib6
• Therapy for CD33-positive AML
Gemtuzumab ozogamicin7 10 Fridle C, Medinger M, Wilk MC, et al. Cladribine, cytarabine and idarubicin (CLA-Ida)
salvage chemotherapy in relapsed acute myeloid leukemia (AML). Leuk Lymphoma
2017:1068-1075.
11 Karanes C, Kopecky KJ, Head DR, et al. A phase III comparison of high dose ARA-C
1 There are promising ongoing clinical trials investigating targeted therapies based on (HIDAC) versus HIDAC plus mitoxantrone in the treatment of first relapsed or refractory
molecular mutations for relapsed/refractory disease. Molecular profiling should be considered acute myeloid leukemia Southwest Oncology Group Study. Leuk Res 1999;23:787-794.
if not done at diagnosis, or repeated to determine clonal evolution. See Discussion. 12 Montillo M, Mirto S, Petti MC, et al. Fludarabine, cytarabine, and G-CSF (FLAG) for the
2 Perl AE, Altman JK, Cortes J, et al. Selective inhibition of FLT3 by gilteritinib in relapsed or treatment of poor risk acute myeloid leukemia. Am J Hematol 1998;58:105-109.
refractory acute myeloid leukaemia: a multicentre, first-in-human, open-label, phase 1-2 13 Parker JE, Pagliuca A, Mijovic A, et al. Fludarabine, cytarabine, G-CSF and idarubicin
study. Lancet Oncol 2017;18:1061-1075. (FLAG-IDA) for the treatment of poor-risk myelodysplastic syndromes and acute myeloid
3 Ravandi F, Alattar ML, Grunwald MR, et al. Phase 2 study of azacytidine plus sorafenib in leukaemia. Br J Haematol 1997;99:939-944.
patients with acute myeloid leukemia and FLT3 internal tandem duplication mutation. Blood 14 Nair G, Karmali G, Gregory SA, et al. Etoposide and cytarabine as an effective and safe
2013:121:4655-4662. cytoreductive regimen for relapsed or refractory acute myeloid leukemia. J Clin Oncol
4 Muppidi MR, Portwood S, Griffiths EA, et al. Decitabine and sorafenib therapy in FLT3 ITD- 2011;29:15_suppl, 6539-6539.
mutant acute myeloid leukemia. Clin Lymphoma Myeloma Leuk 2015;15 Suppl:S73-9. 15 Faderl S, Wetzler M, Rizzieri D, et al. Clorarabine plus cytarabine compared with cytarabine
5 Stein EM, DiNardo CD, Pollyea DA, et al. Enasidenib in mutant IDH2 relapsed or refractory alone in older patients with relapsed or refractory acute myelogenous leukemia: results from
acute myeloid leukemia. Blood 2017;130:722-731. the CLASSIC I Trial. J Clin Oncol 2012;30:2492-2499.
6 DiNardo CD, Stein EM, de Botton S, et al. Durable remissions with ivosidenib in IDH1- 16 Faderl S, Ferrajoli A, Wierda W, et al. Clofarabine combinations as acute myeloid leukemia
mutated relapsed or refractory AML. N Eng J Med 2018;378:2386-2398. salvage therapy. Cancer 2008;113:2090-2096.
7 Taksin AL, Legrand O, Raffoux E, et al. High efficacy and safety profile of fractionated doses 17 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 18 Aldoss I, Yang D, Aribi A, et al. Efficacy of the combination of venetoclax and
prospective study of the alfa group. Leukemia 2007;21:66-71. hypomethylating agents in relapsed/refractory acute myeloid leukemia. Haematologica
8 An FDA-approved biosimilar is an appropriate substitute for filgrastim. 2018;103:e404-e407.
9 Robak T, Wrzesień-Kuś A, Lech-Marańda E, et al. Combination regimen of cladribine 19 DiNardo CD, Rausch CR, Benton C, et al. Clinical experience with the BCL2-inhibitor
(2-chlorodeoxyadenosine), cytarabine and G-CSF (CLAG) as induction therapy for patients venetoclax in combination therapy for relapsed and refractory acute myeloid leukemia and
with relapsed or refractory acute myeloid leukemia. Leuk Lymphoma 2000;39:121-129. related myeloid malignancies. Am J Hematol 2018;93:401-407.

AML-I

Table of Contents
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
AML-J
® ® ®
1 OF 2

Table of Contents
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: https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/208573s026lbl.pdf
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.

AML-J
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2 OF 2

Blastic Plasmacytoid Dendritic Cell Neoplasm Table of Contents
Discussion
(Age ≥18 years)
INTRODUCTION
Decisions about diagnosis and management for BPDCN

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

BPDCN-INTRO

Discussion
(Age ≥18 years)
EVALUATION/WORKUP FOR BPDCNa,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.

BPDCN-1

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.

BPDCN-2

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.

BPDCN-3

Discussion
(Age ≥18 years)
PRINCIPLES OF BPDCN
General Principles:
• BPDCN is a disorder of immature dendritic cells that regulate effector T-cell function.
• It constitutes only 0.44% of hematologic malignancies and <1% of acute leukemia presentations.1
• It occurs in all races and geographic areas.
• It is more common in adults (median age, 65–67 years) with an approximate male-to-female ratio of 3:1.
• It most commonly presents as asymptomatic skin lesions,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.

BPDCN-A

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).

BPDCN-B

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: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/761116s000lbl.pdf

BPDCN-C

Table of Contents
NCCN Categories of Evidence and Consensus

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

Interventions that are based on superior efficacy, safety, and evidence; and, when appropriate,
Preferred intervention affordability.
Other recommended Other interventions that may be somewhat less efficacious, more toxic, or based on less mature data;
intervention or significantly less affordable for similar outcomes.
Useful in certain
Other interventions that may be used for selected patient populations (defined with recommendation).
circumstances
All recommendations are considered appropriate.
CAT-1
NCCN Guidelines Version 1.2022

Discussion This discussion corresponds to the NCCN Guidelines for Management of AML in Patients Older Than 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-57
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-14 Induction Therapy for Patients with BPDCN ............................... MS-63
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
Version 1.2022 © 2021 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.
MS-1

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 or [OS]) compared with patients with de novo cases,8,15 except those with the
older (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
MS-2

The search results were narrowed by selecting studies in humans (WBCs). Serum uric acid and lactate dehydrogenase (LDH) have
published in English. Results were confined to the following article types: prognostic relevance and should be evaluated.18,19 Bone marrow core
Clinical Trial, Phase II; Clinical Trial, Phase III; Clinical Trial, Phase IV; biopsy and aspirate analyses (including immunophenotyping by
Guideline; Meta-Analysis; Randomized Controlled Trial; Systematic immunohistochemistry stains with flow cytometry) and cytogenetic
Reviews; and Validation Studies. analyses (karyotype with fluorescence in situ hybridization [FISH]) are
necessary for risk stratification and to potentially guide therapy of AML.
The data from key PubMed articles as well as articles from additional Several gene mutations are associated with specific prognoses in a subset
sources deemed as relevant to these Guidelines and discussed by the of patients (category 2A) and may guide treatment decisions (category
panel have been included in this version of the Discussion section (eg, e- 2B). Presently, c-KIT, FLT3-ITD, FLT3-TKD, NPM1, CEBPA (biallelic),
publications ahead of print, meeting abstracts). Recommendations for IDH1/IDH2, RUNX1, ASXL1, TP53, BCR-ABL, and PML-RAR alpha are
which high-level evidence is lacking are based on the panel’s review of included in this group. All patients should be tested for mutations in these
lower-level evidence and expert opinion. 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 www.NCCN.org.
appropriately stratify therapy options, test results of molecular and
Initial Evaluation cytogenetic analyses of immediately actionable genes or chromosomal
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
Workup recommendations.
The evaluation and initial workup for suspected AML consists of a Recent studies have reported on the prognostic impact of a number of
comprehensive medical history and physical examination. Laboratory molecular abnormalities in patients with AML (see Molecular Markers and
evaluations include a comprehensive metabolic panel and a complete Risk Stratification). Adequate marrow should be available at the time of
blood count (CBC) including platelets and a differential of white blood cells diagnosis or relapse for molecular studies as per the institutional practice.
MS-3

Local pathologists should be consulted to discuss ways to optimize referred to as myeloid sarcoma, and historically as granulocytic sarcoma,
sample collection and preservation. If molecular testing is not available at or chloroma) without overt marrow disease, the initial treatment should still
the patient’s treatment center, evaluation at an outside reference be based on systemic induction chemotherapy. Radiation or surgical
laboratory or transfer to another institution is recommended prior to resection may be incorporated with systemic chemotherapy in emergent
performing the marrow evaluation. Circulating leukemic blasts from situations; however, these modalities, if needed at all, should be optimally
peripheral blood may alternatively be used to detect molecular deferred until after count recovery to avoid excess toxicity.
abnormalities in patients.
Coagulopathy is common at presentation in many leukemias; it is
Extramedullary presentation, including central nervous system (CNS) therefore standard clinical practice to screen for coagulopathy by
disease, is uncommon in patients with AML. However, if extramedullary evaluating prothrombin time, partial thromboplastin time, and fibrinogen
disease is suspected, a PET/CT is recommended. Patients with significant activity as part of the initial evaluation and before performing any invasive
CNS signs or symptoms at presentation should be evaluated using procedure. The need for a cardiac evaluation (eg, echocardiogram or
appropriate imaging techniques, such as radiography, CT, or MRI for the multigated acquisition [MUGA] scan) should be determined based on
detection of intracranial bleeding, leptomeningeal disease, or mass lesions individual risk factors. Patients with a history or symptoms of cardiac
in either the brain or spinal cord. If CNS hemorrhage is suspected, a CT of disease, prior exposure to cardiotoxic drugs or thoracic radiation, or those
brain without contrast is recommended. If leukemic meningitis is of an older age, should have an echocardiogram. In younger patients who
suspected, a brain MRI with contrast is recommended. However, if are otherwise asymptomatic with no history of cardiac disease, an
symptoms persist, and bleeding and mass/lesions are excluded, the echocardiogram can be considered. In cases of acutely ill patients,
patient should have a lumbar puncture (LP) for diagnostic and possible treatment should not be delayed for an echocardiogram. A small study of
therapeutic purposes once coagulopathy has been corrected, adequate 76 patients with cancer who were screened for cardiac disease identified
platelet support is available, and the circulating disease has been cleared only 4 patients with cardiac abnormalities. Of these 4 patients, the
through the initiation of systemic therapy. Routine screening LPs are not presence of cardiac disease did not change the course of treatment.25
warranted at the time of diagnosis in patients with AML. However, for
patients at high risk for CNS disease, such as those with monocytic Human leukocyte antigen (HLA) typing should be performed in all patients
differentiation or high WBC count (>40,000/mcL)24 at presentation, a with newly diagnosed AML for whom allogeneic HCT would be
diagnostic LP should be considered as part of the documentation of considered. HLA typing of family members is recommended for patients
remission status. Screening LPs should be considered at first remission up to age 80 years or per institutional practice who do not have
before first consolidation in patients with monocytic differentiation, mixed favorable-risk cytogenetics, and tissue typing should be broadened to
phenotype acute leukemia (MPAL), WBC count >40,000/mcL at diagnosis, include alternative donor searches. In patients with any non-favorable risk,
high-risk APL, FLT3 mutations, or extramedullary disease, particularly in a donor search should begin while the patient is undergoing induction
patients not receiving high-dose cytarabine (HiDAC) (ie, older patients). chemotherapy rather than waiting for remission to be achieved. Early
For patients who present with solitary extramedullary disease (currently
MS-4

referral to a transplant center for patients with non-favorable risk is In 2008, WHO revised the diagnostic and response criteria for AML to
recommended. include additional recurrent genetic abnormalities created by reciprocal
translocations/inversions, and a new provisional category for some of the
Diagnosis molecular markers that have been found to have a prognostic impact.28
Originally, the classification system for AML was defined by the French Additionally, the category of AML with recurrent genetic abnormalities was
American British (FAB) system, which relied on cytochemical stains and expanded to include the following: t(9;11)(p22;q23), t(6;9)(p23;q34)
morphology to separate AML from acute lymphoblastic leukemia (ALL) (provisional entity), inv(3)(q21 q26.2) or inv(3;3)(q21;q26.2) (provisional
and to categorize the disease based on degree of myeloid and monocytic entity), and t(1;22)(p13;q13) (provisional entity), in addition to the
differentiation. In 1999, WHO developed a newer classification system, previously recognized t(8;21)(q22;q22); inv(16)(p13;1q22) or
which incorporates information from cytogenetics and evidence of t(16;16)(p13.1;q22); and t(15;17)(q22;q12) [APL subtype]. Other
myelodysplasia, to refine prognostic subgroups that may define treatment provisional entities include AML with molecular abnormalities such as
strategies.26 During this transition from the FAB system to the WHO mutated nucleophosmin (NPM1) or CCAAT/enhancer-binding protein
classification, the percent blasts threshold for defining high-grade MDS alpha (CEBPA) genes (further information on these genetic lesions is
and AML was lowered. The FAB classification had set the threshold provided later).28 In 2016, WHO expanded the recurrent genetic
between high-grade MDS and AML at 30% blasts, whereas the WHO abnormalities to include two provisional categories, AML with BCR-ABL1
classification lowered the threshold for diagnosing AML to 20% or more rearrangement and AML with RUNX1 mutation. AML with BCR-ABL1
blasts. This change was based on the finding that the biologic behavior rearrangement is a rare de novo AML that may benefit from therapies that
(and survival outcomes) of the FAB MDS subgroup of “refractory anemia entail tyrosine kinase inhibitors. AML with RUNX1 mutation is associated
with excess blasts in transformation (RAEB-T),” defined as patients with with a poorer prognosis.
20% to 30% blasts, was similar compared with that of patients with greater
than 30% blasts. In an appropriate clinical setting, the WHO classification In accordance with the 2016 WHO classification, a diagnosis of AML is
system further allowed AML to be diagnosed in patients with abnormal made based on the presence of 20% or more blasts in the bone marrow or
hematopoiesis and characteristic clonal structural cytogenetic peripheral blood. In an appropriate clinical setting, a diagnosis of AML may
abnormalities with t(15;17), t(8;21), and inv(16) or t(16;16) regardless of be made with <20% blasts in patients with recurrent cytogenetic
the percentage of marrow blasts. abnormalities including t(15;17), t(8;21), t(16;16), or inv(16). The accurate
classification of AML requires multidisciplinary diagnostic studies including
In 2003, the International Working Group for Diagnosis, Standardization of morphology, immunophenotyping (immunohistochemistry and flow
Response Criteria accepted the cytochemical and immunophenotypic cytometry), and molecular genetics analysis. The latter should include a
WHO criteria as the standard for diagnosing AML, including the reporting complete cytogenetic analysis and advanced molecular analysis
of myelodysplasia according to morphology.27 However, no evidence techniques, as needed, to specify both translocations and gene mutations.
shows that myelodysplasia represents an independent risk factor, because The NCCN AML Panel suggests that complementary diagnostic
it is frequently linked to poor-risk cytogenetics. techniques can be used at the discretion of the pathology department of
MS-5

the individual institution. Some cases may still show evidence of both AML in the algorithm).29-31 In an analysis of data from pediatric and adult
myeloid and lymphoid antigen expression on the leukemic cells and are patients with AML (n = 1612) enrolled in the United Kingdom Medical
defined as acute leukemias of ambiguous lineage. This is further Research Council (UK MRC) AML 10 trial, the 5-year survival rates for
subgrouped into acute undifferentiated leukemia, MPAL with BCR-ABL1 those with favorable, intermediate, and unfavorable risk cytogenetics were
rearrangement, MPAL with rearranged KMT2A, MPAL with B-cell/myeloid 65%, 41%, and 14%, respectively.30 In a review of data from adult patients
features not otherwise specified, and MPAL with T-cell/myeloid features treated in a phase III Southwest Oncology Group (SWOG)/Eastern
not otherwise specified. The expression of both cytochemical and/or Cooperative Oncology Group (ECOG) intergroup study (n = 609), the
immunophenotypic characteristics of both lineages on the same cells is 5-year survival rates for those with favorable, intermediate, and adverse
defined as biphenotypic, whereas expression of lineage-specific risk cytogenetics were 55%, 38%, and 11%, respectively.31 Similarly, in a
characteristics on different populations of leukemia cells is termed bilineal. retrospective review of adult patients with AML treated on Cancer and
Due to the rarity of acute leukemias of ambiguous lineage (as defined by Leukemia Group B (CALGB) protocols (n = 1213), the 5-year survival
the 2016 WHO classification), consultation with an experienced rates for patients with favorable-, intermediate-, and poor-risk cytogenetics
hematopathologist should be sought. were 55%, 24%, and 5%, respectively.29 The AML 11 trial had similar
results with 5-year survival rates of the favorable-, intermediate-, and
Aberrant expression of differentiation antigens present at diagnosis may poor-risk cytogenetics of 34%, 13%, and 2%, respectively.32 This last
allow tracking of residual blasts through flow cytometry in follow-up study included an older population of patients, which is believed to
samples that may appear normal according to conventional morphology. attribute to the overall lower percent survival in all groups.
The use of immunophenotyping and molecular markers to monitor
measurable (also known as minimal) residual disease (MRD) in adult AML The importance of obtaining adequate samples of marrow or peripheral
has not yet been widely incorporated into postremission monitoring blood at diagnosis for full karyotyping and FISH cytogenetic analysis for
strategies, except in some patient subgroups with APL, CBF-AML, and the most common abnormalities cannot be overemphasized. Although
NPM1-positive AML. However, ongoing research is moving MRD FISH studies for common cytogenetic abnormalities may allow for rapid
monitoring to the forefront for all patients with AML (see Role of MRD screening to identify either favorable- or unfavorable-risk groups,
Monitoring). additional tests are needed to provide a full picture of the genetic factors
that contribute to risk (see Molecular Markers and Risk Stratification).
Cytogenetics and Risk Stratification
Although cytogenetic information is often unknown when treatment is The presence of autosomal chromosome monosomies in AML has
initiated in patients with de novo AML, karyotype represents the single emerged as an important prognostic factor associated with extremely poor
most important prognostic factor for predicting remission rates, relapse prognosis.33-35 Data from three large studies have identified monosomal
risks, and OS outcomes. The cytogenetic risk categories adopted by these karyotypes (defined as ≥2 autosomal monosomies, or a single monosomy
guidelines are primarily based on analyses of large datasets from major with an additional structural abnormality) as a subset of unfavorable
cooperative group trials (see Risk Stratification by Genetics in Non-APL cytogenetic prognosticators. Although complex karyotype (≥3 clonal
MS-6

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

NPM1 Mutations involve mutations in the D835 residue of a TKD. Although the presence of
The NPM1 gene encodes a shuttle protein within the nucleolus of cells. FLT3-TKD mutations has been shown to be associated with shorter
Mutations in this gene occur in 28% to 35% of AML cases.46,49,50 The remission durations (eg, decreased DFS) and decreased OS outcomes in
NPM1 mutation has been shown to be associated with NK-AML with a some studies,40,53,57,60 other studies have reported no impact of FLT3-TKD
reported frequency of 48% to 53%.38,44,51 Isolated NPM1 mutation, which on prognosis51,61,62 or even a favorable outcome on OS with FLT3-TKD
localizes to the cytoplasm, confers a higher complete response (CR) rate mutations.63 In the latter study from the UK MRC, the 5-year OS rates
and improved event-free survival (EFS) and OS compared with patients among patients with and without FLT3-TKD mutations were 53% versus
who are NK-AML and wild-type NPM1, resulting in outcomes similar to 37%, respectively. Patients with a higher level of FLT3-TKD mutations
patients with favorable cytogenetics (eg, CBF AML).38,39,44,46,47 (>25%) had a significantly higher 5-year OS rate compared with those with
lower levels of mutations, which showed an OS rate similar to that of
FLT3 Mutations
patients without FLT3-TKD mutations (71% vs. 37%; adjusted P = .004).63
The FLT3 gene encodes a receptor tyrosine kinase involved in
hematopoiesis. Two major classes of activating FLT3 mutations have The discrepant findings from these studies may be a result of important
been identified in patients with AML, which include the internal tandem differences such as patient baseline characteristics, presence of
duplications (ITD) and tyrosine kinase domain (TKD) point mutations.52-57 concurrent genetic lesions (eg, NPM1, CEBPA mutations), or inclusion of
FLT3-ITD mutations occur in approximately 30% of cases and are more the APL subtypes. Studies have shown that FLT3-TKD mutations can
common than FLT3-TKD mutations, which occur in approximately 10% of occur in a subgroup of patients with the prognostically favorable NPM1 or
patients.36,40,51,56-60 Numerous studies have shown the negative prognostic CEBPA mutations.51,62 Moreover, FLT3-TKD mutations as the sole genetic
influence of FLT3-ITD in patients with AML, resulting in shorter remission aberration or occurring concurrently with t(15;17)/promyelocytic leukemia
durations (eg, decreased disease-free survival [DFS] in patients with a (PML)-retinoic acid receptor alpha (RARA) (underlying lesion in the APL
CR) and poorer survival outcomes compared with patients who have subtype) or with FLT3-ITD (FLT3 double mutation) have been associated
wild-type FLT3.36,40,53,54,56,58,59,61 Among patients with FLT3-ITD and with poorer outcomes.51,62
NK-AML, median OS from the time of diagnosis ranged from 6 to 12
months.36,40,56,59 CEBPA Mutations
Another mutation associated with prognosis is the CEBPA gene, a
Interestingly, a study in patients with NK-AML showed that prognosis was transcription factor that plays a key role in the differentiation of
worse among patients with FLT3-ITD without wild-type FLT3, compared granulocytes.42 Mutations in CEBPA have been reported in 7% to 11% of
with those with FLT3-ITD with wild-type FLT3 in the second allele. The patients with AML (or 13%–15% of those with NK-AML) and have been
median OS among patients with FLT3-ITD in the absence of a wild-type associated with a favorable outcome (similar to patients with CBF
FLT3 was only 7 months compared with 46 months among wild-type FLT3 translocations) with regard to increased remission duration and OS
patients with or without FLT3-ITD.56 The FLT3-TKD mutations outcome compared with wild-type CEBPA.41,50,51,64-66 One caveat identified
predominantly occur independently of FLT3-ITD, and most frequently was that the OS benefit with CEBPA was observed for patients with
MS-8

double mutations of CEBPA but not for those with a single mutation of the associated with worse EFS and OS outcomes among the subgroup of
gene. The 8-year OS rates reported in this study for patients with 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
54%, 31%, and 34%, respectively.65 The revised 2016 WHO classification patients with AML,50,68,69,73,74 with a higher frequency of 19% among those
of AML has redefined mutated CEBPA to indicate that biallelic (double) with NK-AML.71 The presence of IDH2 mutations was mutually exclusive
mutations (and not single CEBPA mutations) are associated with improved with IDH1 mutation in nearly all cases.68,69,71 Mutations have been
prognosis.67 identified in R172 and R140 of the IDH2 gene, with the R140 mutation
occurring more frequently.71,73,74 Interestingly, the IDH2-R172 mutation
IDH1/2 Mutations
seemed to be mutually exclusive with NPM1 mutations and
Mutations in IDH1 have been reported in 6% to 9% of AML cases, with a FLT3-ITD.71,73,74
higher frequency among patients with NK-AML (8%–16%).50,68-73 IDH1
mutations were found to occur concurrently with NK-AML and NPM1 Reports on the prognostic effect of IDH2 mutations have also been
mutations.68-71,73 Additionally, these mutations have been associated with inconsistent. Some studies have reported the lack of prognostic value of
wild-type CEBPA and the absence of FLT3 abnormalities.71 Findings from IDH2 mutations,68,69,73 whereas others have reported favorable outcomes
published reports on the prognostic effects of IDH1 mutations have been with IDH2 mutations.50,74 In one study, an association was found between
inconsistent. Although some studies showed no prognostic effect of IDH1 IDH2 mutations and poorer prognosis in the subgroup of patients with
mutations on OS when considering all IDH mutations (IDH1 and IDH2 NK-AML and otherwise favorable risk (NPM1 mutation without
combined) or in the overall patient population,68-71 IDH1 mutations FLT3-ITD).73 However, in another study, the IDH2 mutation (restricted to
correlated with significantly worse outcomes in the subgroup of NK-AML IDH2-R140) was associated with improved survival among the overall
patients with favorable- or intermediate-risk disease.68,71,73 In the subgroup study population, and among the subgroup of patients with favorable risk
of patients younger than 60 years with favorable-risk AML (NPM1 mutation (intermediate-risk AML with NPM1 mutation without FLT3-ITD).50 In this
without FLT3-ITD), IDH1 mutations were associated with a significantly latter subgroup, the presence of IDH1 or IDH2 mutations was associated
decreased 5-year DFS rate (42% vs. 59%; P = .046) and a trend for with a significantly increased 3-year OS rate compared with patients with
decreased OS rate (50% vs. 63%) compared with patients who had NPM1 mutation without FLT3-ITD and without IDH1 or IDH2 mutations
wild-type IDH.71 In another study, IDH mutations (IDH1 and IDH2 (89% vs. 31%; P < .0001). These results seem to suggest that in patients
combined) were associated with significantly inferior 5-year RFS rates with NK-AML without FLT3-ITD, NPM1 mutations confer a survival benefit
(37% vs. 67%; P = .02) and OS rates (41% vs. 65%; P = .03) in the only in the presence of concurrent IDH mutations.50 The conflicting
subgroup of patients with favorable-risk AML (NK-AML with NPM1 findings from the above studies require further investigation.
mutation without FLT3-ITD).73 This prognostic significance was observed
when IDH1 and IDH2 mutations were separately analyzed, although DNMT3A Mutations
patient numbers were small for each subgroup and statistical significance The DNMT3A mutations have been reported in 18% to 22% of patients
was reached only for the RFS analysis.73 IDH1 mutations were also with AML,50,75,76 with a frequency of 29% to 34% in those with NK-AML.77-79
MS-9

R882 is the most commonly mutated residue. This mutation has also been genetic mutations are not available for testing outside of the research
observed in conjunction with NPM1 mutations and FLT3 mutations.76,78,79 setting. Other candidate genes that are associated with an adverse impact
Data concerning the prognostic significance of DNMT3A mutations have on outcome are TET2 and RUNX1.80,81
thus far been conflicting. Some studies in the overall AML population and
KIT Mutations
in patients with intermediate risk reported no significant effect of DNMT3A
mutations on survival outcomes,50,78 whereas other studies have shown a KIT mutations have been reported in approximately 20% of patients with
negative prognostic effect in the overall population or specific CBF AML.43,82 Studies have shown that KIT mutations are associated with
subgroups.75-77,79 Studies have shown significantly decreased OS decreased remission duration (eg, EFS and RFS) and decreased OS in
outcomes among patients with DNMT3A mutations compared with patients with t(8;21).37,43,45,82 However, the association of KIT mutations on
patients who have the wild-type gene (median OS, 12–21 months vs. 40– CBF AML with inv(16) is less clear than the data for t(8;21), with several
41 months).75,76 Significantly decreased OS with DNMT3A mutations has studies showing no association.37,82,83 In an analysis from the
also been reported in the subgroup of patients with NK-AML who have German-Austrian AML Study Group, the frequency and prognostic impact
wild-type NPM1 with or without FLT3-ITD, or NPM1 mutation in the of secondary genetic lesions were evaluated in patients with CBF AML
presence of FLT3-ITD, but not in the favorable subgroup with NPM1 who were treated in prospective trials (n = 176).84 Secondary
mutation without FLT3-ITD.76 A study reported that in younger patients chromosomal abnormalities were found in 39% of patients, with the most
(age <60 years) with NK-AML, the presence of DNMT3A mutations was common abnormalities being trisomy 22 (18%), trisomy 8 (16%), and 7q
associated with significantly decreased OS compared with the wild-type deletion (5%). Secondary genetic lesions were found in 84% of patients,
gene (5-year OS rate, 23% vs. 45%; P = .02).79 Another study also including mutations in RAS (53%; NRAS in 45%; KRAS in 13%), KIT
showed that in younger patients (age <60 years) with NK-AML, a (37%), and FLT3 (17%; FLT3-TKD in 14%; FLT3-ITD in 5%; both
DNMT3A mutation was associated with significantly decreased DFS mutations present in 2%). In addition, 25% of patients had more than one
(3-year rate, 20% vs. 49%; P = .007) and a trend toward decreased OS.77 of these mutations. Mutations in KIT and RAS were less likely to occur
In this latter study, non-R882 DNMT3A mutations were significantly concurrently, whereas mutations in KIT and FLT3 occurred concurrently in
associated with poorer outcomes in patients younger than 60 years of age 6% of patients.84 Of these secondary genetic lesions, KIT mutation and
but not R882 mutations; in contrast, DNMT3A-R882 mutations (but not trisomy 22 were significant independent factors predictive of RFS in
non-R882 mutations) in patients aged 60 years and older were associated multivariable analysis; FLT3 mutations, trisomy 22, and trisomy 8 were
with significantly decreased DFS (3-year rate, 3% vs. 21%; P = .006) and significant independent predictors for OS.84 These studies demonstrate
OS (3-year rate, 4% vs. 24%; P = .01).77 The authors concluded that the the importance of secondary genetic mutations in the prognostic
prognostic relevance of DNMT3A mutations may depend on age and classification of patients with otherwise favorable-risk CBF AML (see Risk
mutation type. Currently, the interactions of IDH1 or IDH2 and DNMT3 Stratification by Genetics in Non-APL AML in the algorithm).
mutations with other molecular changes require further investigation to
determine the prognostic value in patients with NK-AML. Although
commercial testing is available for FLT3 and CEBPA, most of the other
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KMT2A Rearrangements novo AML cases,96,99-102 and are associated with poor outcomes.50,98,101
The mixed lineage leukemia gene (MLL; also called HRX, ALL-1, or In an analysis of peripheral blood samples from adult patients with AML
currently KMT2A), located on chromosome 11q23, was initially recognized (n = 423), ASXL1 mutations were observed to be more common in older
as a recurrent locus of chromosomal translocation in AML and ALL.85,86 In adult patients (≥60 years) compared to patients younger than 60 years
one series of 1897 AML cases, the incidence of 11q23/KMT2A (16.2% vs. 3.2%, respectively; P < .001). In older patients, 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 in 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 older age, 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
mutations frequently co-occurred with epigenetic modifiers ASXL1, IDH2, complex karyotype.105 However, in therapy-related AML, TP53 mutations
KMT2A, and EZH2.95 In a study examining the impact of multiple RUNX1 are more frequently associated with monosomal karyotype, and with
mutations and loss of wild-type RUNX1 in AML, both loss of wild-type abnormalities in chromosomes 5 and 7.105 In therapy-related AML, the
RUNX1 (OS, 5 months) and having ≥1 RUNX1 mutation (14 months) had frequency of TP53 mutations is approximately 23%.22 In a large analysis
an adverse impact on prognosis compared to 1 RUNX1 mutation (22 of different hematologic malignancies including 858 AML cases, TP53
months; P < .002 and .048, respectively).96 mutations or deletions were observed in 7% and 1%, respectively, of the
AML cases, and both TP53 mutations and deletions were observed in
ASXL Mutations
5% of the cases.106 TP53 mutations were significantly more frequently
The additional sex combs-like 1 (ASXL1) gene, located on chromosome
seen in older adult patients (≥60 years) when compared to patients <60
band 20q11, encodes a protein in the enhancer of trithorax and
years of age (9% vs. 2%, P < .001).106 Interestingly, compared to TP53
polycomb (ETP) genes family, which have functions in transcription.97,98
deletions, TP53 mutations negatively impacted survival in AML (36
ASXL1 mutations have been reported in approximately 5% to 36% of de
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months vs. 9 months, respectively; P < .001), suggesting the importance with wild-type NPM1 without FLT3-ITD or with FLT3-ITDlow (without
of evaluating both TP53 mutation and deletion status.106 adverse-risk genetic lesions) as having intermediate-risk AML. In addition,
patients with t(9;11)(p21.3;q23.3), MLLT3-MLL, and other cytogenetic
Classification and Prognostic Relevance of Gene Mutations abnormalities that fall into neither the favorable nor adverse category are
The NCCN AML Panel adopted the 2017 European LeukemiaNet (ELN) considered to have intermediate-risk disease. Both NCCN and the ELN
recommendations for risk stratification.21 Therefore, both NCCN and the classify patients with wild-type NPM1 and FLT3-ITDhigh, mutated TP53,
ELN classify patients with NK-AML and mutated NPM1 or CEBPA (without mutated RUNX1, or mutated ASXL1 as having poor risk.21,107 However,
FLT3-ITD) as having favorable risk.21,107 Specifically, patients with mutated RUNX1 or ASXL1 should not be used as poor-risk prognostic
NK-AML with mutated NPM1 (without FLT3-ITD or with a low allelic ratio markers if they co-occur with favorable-risk AML subtypes. (see Risk
[<0.5] of FLT3-ITD [FLT3-ITDlow]) or with isolated biallelic CEBPA mutation Stratification by Genetics in Non-APL AML in the algorithm).
are categorized as having favorable risk21 (see Risk Stratification by
As seen from the earlier discussions, patients with NK-AML may present
Genetics in Non-APL AML in the algorithm). In the previous ELN
with multiple molecular abnormalities. NPM1 mutations can occur
guidelines, a distinction was made between intermediate I and
concurrently with FLT3-ITD, and patients who have both genetic lesions
intermediate II risk groups.108 An analysis that evaluated the prognostic
have an outcome more similar to those with isolated FLT3-ITD
value of the ELN risk classification (based on data from the German
mutations.38,44 Thus, NPM1 mutation confers favorable prognosis only in
AML96 study) showed that for patients aged 60 years and younger,
the absence of FLT3-ITD.51 Similarly, the benefit in OS outcomes seen
median RFS was shorter for the Intermediate I than for the Intermediate II
with CEBPA mutations seems to be lost in the presence of concurrent
group (7.9 vs. 39.1 months, respectively). In patients older than 60 years,
FLT3-ITD.65 As previously mentioned, studies suggest that FLT3-TKD in
no major difference was observed (9.6 vs. 11.6 months, respectively).107 In
the presence of FLT3-ITD is associated with poorer prognosis. In contrast,
this analysis, median OS between the Intermediate I and Intermediate II
FLT3-TKD may be associated with an additional favorable prognosis in the
groups was not as widely separated among patients aged 60 years and
presence of NPM1 or CEBPA mutations.62 A systematic review and
younger (13.6 vs. 18.7 months, respectively); in patients older than 60
meta-analysis in patients younger than 60 years of age with NK-AML
years, median OS was similar between the two intermediate groups (9.5
further established the prognostic role of these markers.48 OS and RFS
vs. 9.2 months, respectively).107
predicted unfavorable prognosis for FLT3-ITD (HR, 1.86 and 1.75,
In another study, patients in the intermediate I group who were younger respectively) and favorable prognosis for NPM1 (HR, 0.56 and 0.37,
than 60 years of age demonstrated longer OS than those in the respectively) and CEBPA (HR, 0.56 and 0.42, respectively).
intermediate II group; in patients older than 60 years of age, the OS was
The clinical significance of FLT3 mutations in patients with APL remains
similar between the two intermediate groups.109 Based on these data, the
controversial. FLT3-ITD is associated with a higher incidence of several
ELN simplified the intermediate risk group in the 2017 update.21 Both
hematologic features associated with APL (eg, higher WBC count,
NCCN and the ELN classify patients with NK-AML with both mutated
decreased fibrogen levels, higher Sanz risk score).110,111 However, there
NPM1 and a high allelic ratio (≥0.5) of FLT3-ITD (FLT3-ITDhigh), and those
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remains a paucity of data to support a correlation of FLT3-ITD on OS and examination, and diagnostic genetic testing.116,120 In particular, the
rate of relapse.110,112,113 Although mutation status alone may not reflect screening evaluation should determine if the patient has a family history
patient outcome, there was a trend for decreased OS and EFS with a of hematologic malignancies (including AML, acute lymphoblastic
higher FLT3-ITD mutational load suggesting that further studies are leukemia [ALL], or aplastic leukemia) or unexplained leukopenia, anemia
necessary to elucidate the clinical significance of this mutation.113 (eg, aplastic anemia, macrocytic anemia) and/or thrombocytopenia within
Conversely, FLT3-TKD has not been associated with the hematologic 2 generations.116,117,121,122 In addition, the Nordic Guidelines for germline
features of APL and studies do not show a correlation of FLT3-TKD on predisposition to myeloid neoplasms in adults recommend that the
outcome.110,111,113-115 screening evaluation should determine if the patient has signs or
symptoms indicative of a hereditary condition (including Li Fraumeni
The molecular markers discussed provide prognostic information that aid syndrome) that predisposes them to developing myeloid neoplasms (eg,
risk stratification of patients with AML and may influence subsequent AML or MDS).123Familial AML with mutated CEBPA is one of the most
treatment decisions. Research into basic leukemia biology using banked common inherited syndromes associated with AML.116,124,125 Several
samples from clinical trials may provide keys to altered cellular pathways, reports have noted that all individuals who carry this germline mutation
which may lead to new treatment options. Risk stratification incorporating developed AML between 2–59 years of age.116,124,126,127 Other familial
molecular data along with cytogenetics is summarized in the guidelines AML syndromes include: germline mutations in DDX41116,128,129 which are
(see Risk Stratification by Genetics in Non-APL AML in the algorithm). The relatively common, and germline mutations in MBD4,130 which are rare;
NCCN AML Panel recognizes that molecular genetics is a rapidly evolving or syndromes with platelet abnormalities, including familial platelet
field in AML; therefore, risk stratification should be modified based on disorder with mutated RUNX1;116,120,131 or syndromes associated with
continuous evaluation of evolving research data. Again, it is important for organ system manifestations, including familial MDS/AML with mutated
physicians to confer with the local pathologist on how to optimize sample GATA2.116,120
collection from the time of diagnosis for future molecular diagnostics in
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 management of patients and their relatives.116-119 familial acute leukemia or MDS syndrome, so management must be
Evaluation for an underlying familial syndrome in a patient with acute individualized.116,120
leukemia or MDS should involve a screening history, focused physical
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Principles of Acute Myeloid Leukemia Treatment MRD is emerging as a novel determinant to assess the depth of
Treatment of acute leukemia has been divided into induction therapeutic response at the time of morphologic remission in AML patients
chemotherapy and postremission (eg, consolidation) therapy. Although (see Role of MRD Monitoring).
obtaining a remission is the first step in controlling the disease, it is also
Finally, all patients require attentive supportive care related to the
important for patients to emerge from the induction phase in a condition to
underlying leukemia (ie, tumor lysis syndrome) and the adverse effects of
tolerate subsequent, more intensive treatments during consolidation to
chemotherapy (see Supportive Care in the algorithm).
achieve durable disease control. In some cases, patients who either
received postremission therapy or those who did not may experience Management of Acute Promyelocytic Leukemia
relapse, usually within 6 to 9 months. Postremission therapy is
APL is a particularly aggressive subtype of AML, comprising
recommended for patients younger than 60 years and/or who are fit for
approximately 10% of AML cases. APL has a distinct morphology and
intensive therapy. However, there are trials that by design do not include
clinical presentation that may be associated with a high early death rate
postremission treatment for patients and the results have been promising;
due to potentially fatal coagulopathy.132-134 In an analysis of data (from
these trials are generally in older patients with AML. The induction strategy
1992–2007) from the National Cancer Institute SEER registry, the
is influenced by individual patient characteristics such as age, presence of
age-adjusted annual incidence rate of APL was 0.23 per 100,000
comorbid conditions affecting performance status, and preexisting
persons.135 The median age of APL diagnosis was 44 years, which is
myelodysplasia. This is particularly true of elderly patients with AML.
younger than that of patients with AML (median age 67 years).2,135 APL is
Patients whose performance status would make them poor candidates for
cytogenetically distinguished by the t(15;17) chromosomal translocation.
the standard antineoplastic regimens may still be able to participate in
The translocation of the PML gene on chromosome 15 to the RARA gene
clinical trials or low-intensity therapy plus oral agents designed to target
on chromosome 17 [ie, t(15;17)(q24.1;q21.1)] produces a PML-RARA
this underserved patient population. Supportive care may also be an
fusion gene that can be quantitatively monitored using polymerase chain
appropriate choice. In younger patients, strategies for consolidation are
reaction (PCR) to document disease burden and to ultimately confirm
based on the potential risk of relapse, with higher-risk patients receiving
molecular remission. As further emphasis of the cytogenetic attribute of
more aggressive therapy. Cytogenetic and molecular abnormalities are the
APL, the most recent WHO classification of myeloid neoplasms and acute
most significant prognostic indicators; however, failure to achieve
leukemia changed the definition of APL from the cytogenetic criteria of
remission after 1 cycle of induction therapy or high tumor burden, defined
t(15;17) to the molecular definition of “APL with PML-RARA” to be
as a WBC count ≥40,000/mcL,24 are included as poor-risk factors for
inclusive of complex or cryptic rearrangements that lead to a functional
long-term remission. Therefore, response is assessed based on bone
transcription factor.67
marrow morphology and cytogenetic and molecular responses taken at
several points during the course of treatment (see Response Criteria APL may be de novo or therapy-related. Some of the following attributes
Definitions for Acute Myeloid Leukemia and Monitoring During Therapy in of therapy-related APL (t-APL) were highlighted in a systematic review: 1)
the algorithm for definitions of CR and partial response [PR] and disease the average age of diagnosis is 47 years with a higher incidence in
relapse). The use of flow cytometry and/or molecular methods to assess
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women; 2) the risk significantly declines 2 years after completion of averaging 20%.142 Education of heath care providers to identify the first
treatment for the primary antecedent disease; 3) breast cancer, suspicion of APL may extend the improved outcomes seen in clinical trials
hematologic malignancy, multiple sclerosis, and genitourinary malignancy to the general population if treatment is not delayed.
are the most common antecedent diseases; 4) topoisomerase II inhibitors
and radiation have the highest risk associated with developing t-APL; 5) There is a high frequency of FLT3 mutations in APL. In a systematic
the clinicopathology of t-APL is not different from de novo APL; 6) the review including 11 studies, FLT3-ITD frequency in APL occurred in about
single mutation t(15;17) is most common; and 7) the remission rate of 12% to 38% of cases and FLT3-TKD occurred in 2% to 20% of cases.145
t-APL is 80%, which is comparable to de novo APL.136 Therefore, t-APL Data are inconsistent about whether FLT3-ITD in APL results in a negative
and de novo APL are treated similarly. prognosis. Several studies support this association and further correlate
FLT3-ITD with higher WBC counts, lower platelet counts, and the
The incorporation of all-trans retinoic acid (ATRA) and the use of risk expression of the bcr3 PML-RARA fusion transcript.145-148 However, data
stratification (based on WBC counts) in the management of APL has from other studies have not shown a correlation.58,149 It has been proposed
largely improved outcomes for patients with this subtype. The unique that the discrepancy between studies may be at least partially resolved by
ability of ATRA to produce differentiation in APL blasts can reverse the incorporation of a FLT3-ITD/wild-type ratio to measure the effect on
coagulopathy, which is the major cause of death during induction. To prognosis.113,150 Data showed that a ratio of greater than 0.66 resulted in a
minimize early induction mortality due to coagulopathy, patients with a shorter 5-year RFS.150 Similarly, shorter EFS and OS were observed in
presumptive diagnosis of APL based on morphology, immunophenotype, patients with equal to or greater than a 0.5 ratio compared to patients with
and/or coagulopathy with a positive disseminated intravascular less than 0.5 (EFS, P = .029; OS, P = .084).113 While data may correlate
coagulation screen should promptly start ATRA. It is not necessary to wait with prognosis, there currently remains no change in treatment course
for molecular testing or bone marrow with cytogenetics to confirm the depending on expression of FLT3-ITD.
diagnosis. The initial clinical diagnosis of APL may be confirmed by FISH
or PCR ideally in the peripheral blood and if not confirmed, ATRA may be Induction Therapy for Patients with APL
discontinued and standard AML therapy initiated. The evolution of treatment strategies for APL, built on clinical observation
and well-constructed clinical trials, represents one of the most rewarding
Studies have demonstrated the necessity of early recognition and prompt sagas of modern hematology. An early study by a group in Shanghai
initiation of ATRA based on a presumed diagnosis of APL to reduce the reported a CR rate of 85% in response to single-agent ATRA.151 The first
rate of early mortality. This is evidenced by early death rates below 10% North American Intergroup study confirmed a 70% CR rate with
reported for patients enrolled in clinical trials137-141 compared to the general single-agent ATRA, which was equivalent to rates obtained with
population where early mortality rates are still in excess of 15%.135,142-144 conventional doses of cytarabine and daunorubicin.152,153 Induction
Data from the SEER registry measured 2-year survival and 30-day regimens with ATRA combined with anthracyclines (with or without
mortality from 1977 to 2007 and found a 61% improvement in 3-year cytarabine) are associated with CR rates exceeding 90%, as
survival per decade (P = .001) but a consistent rate of 30-day mortality demonstrated in several large cooperative group trials.154-157 Using
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ATRA-based induction regimens followed by consolidation with regimens WBC and platelet counts at presentation. In this study, the induction
containing either ATRA with anthracyclines, or cytarabine with regimen remained the same (AIDA), but ATRA was added to consolidation
anthracyclines, more than 80% of patients with APL can be cured of their cycles 1 to 3 for all but low-risk patients (ie, WBC ≤10,000/mcL and
disease.154,156-158 ATRA with arsenic trioxide (ATO) has resulted in platelets >40,000/mcL). The CR rate in this trial was 90% with almost all
improved outcomes for patients with APL.159 Risk stratification is a major the failure attributed to hemorrhage, infection, or differentiation syndrome.
consideration in the treatment of APL (see APL: Classification and Factors predictive of death during induction were a WBC count greater
Treatment Recommendation in the algorithm).157 Although clinical trials than 10,000/mcL, age older than 60 years, creatinine of 1.4 or greater, and
may group patients into those with low-, intermediate-, or high-risk male sex.161,162 In 2006, Ades et al163 reported the outcome of the French
disease, the NCCN Panel categorizes patients with APL as having low-risk APL 2000 trial (n = 340) in which patients younger than 60 years of age
disease (WBC count ≤10,000/mcL) or high-risk disease (WBC with WBC counts less than 10,000/mcL were randomized to receive ATRA
count >10,000/mcL). Patients with low-risk disease are typically treated (45 mg/m2) and daunorubicin (60 mg/m2/day for 3 days) as induction
with less intensive consolidation regimens compared with regimens used therapy with or without cytarabine (200 mg/m2/day for 7 days). Those
for high-risk patients. randomized to cytarabine for induction also received cytarabine during
consolidation.163 Patients with WBC counts greater than 10,000/mcL or
The French APL 93 trial compared sequential therapy of ATRA followed age older than 60 years received cytarabine. While the CR rates were
by chemotherapy (cytarabine and daunorubicin) with concurrent ATRA similar between the randomized groups (99% with cytarabine and 94%
plus chemotherapy. CR rates were 92% in both arms, but the relapse rate 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 older than
evaluable patients achieved PCR-negative status for PML-RARA following 60 years of age.163 A report of a joint analysis of the outcomes in the
induction therapy; 93% to 98% were PCR-negative after consolidation. PETHEMA 99 and the French APL 2000 trials in patients younger than 65
The estimated 2-year EFS rate was 79% in both trials.137,141 In the years of age showed that in patients with a WBC count less than
PETHEMA trial, the 2-year OS rate was 82%.141 10,000/mcL, CR rates were similar, but the relapse rates at 3 years were
lower in the PETHEMA trial, which used AIDA and no cytarabine during
Following observational data that correlated elevated WBC counts and
induction (with ATRA during consolidation), than in the APL 2000
high-risk disease (based on both the higher number of deaths during
cytarabine-containing regimen (4% vs. 14%; P = .03).155 However, for
induction and the increased rates of relapse), in the PETHEMA LPA 94
patients with a WBC count greater than 10,000/mcL, the
trials, Sanz et al161,162 devised a risk stratification study based solely on
cytarabine-containing protocol resulted in higher CR (95% vs. 84%;
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P = .018) and 3-year OS rates (91.5% vs. 81%; P = .026).155 The second suggested that ATRA and ATO combined with GO is feasible and elicits
North American Intergroup trial also used ATRA (45 mg/m2), daunorubicin durable responses. In another study by Estey et al,170 patients with APL
(50 mg/m2/day for 4 days), and cytarabine (200 mg/m2/day for 7 days) with were treated with ATRA and GO (9 mg/m2 on day 1 or 5 of induction
a similar initial CR rate of 90%.156 Consolidation in this trial differed in that therapy). Patients with WBC counts of >30,000/mcL also received
two cycles of ATO were given following induction and prior to the final two idarubicin (12 mg/m2/day on days 1–3). In this study (n = 19), the CR rate
cycles of anthracycline. in all patients who received ATRA plus GO and idarubicin was 84%, and
88% in patients who received ATRA plus GO.170 However, clinicians
ATO has been found to be a potent promoter of apoptosis in APL should be aware of possible adverse events associated with GO including
cells.164,165 In 2004, Shen et al166 first published outcomes using sinusoidal obstruction syndrome similar to hepatic veno-occlusive disease
single-agent ATRA, single-agent ATO, or the combination of both drugs.166 described in the transplant setting.171,172
While CR rates exceeded 90% in all three treatment arms, the decline in
quantity of PML/RARA fusion transcripts (as measured by quantitative A phase II study (APML4) from Australia/New Zealand evaluated an
PCR) was significantly higher with the combination. Time to hematologic induction regimen with ATO added to a backbone of AIDA in patients with
response was more rapid and RFS (after a median follow-up of 18 previously untreated APL (n = 124; median age, 44 years).173 Patients
months) was improved with the combination regimen compared with the received 1 cycle of induction therapy with ATRA (45 mg/m2 days 1–36 in
monotherapy regimens.166 Subsequently, Estey et al167 used a similar divided doses), age-adjusted idarubicin (6–12 mg/m2 days 2, 4, 6, and 8),
combination of ATRA and ATO to treat patients with low-risk APL.167 and ATO (0.15 mg/kg days 9–36 as a 2-hour IV infusion). All patients
High-risk patients in the same study were treated with ATRA and ATO received prednisone (1 mg/kg/day for at least 10 days) regardless of initial
combined with gemtuzumab ozogamicin (GO; 9 mg/m2 on day 1 of WBC count as prophylaxis for differentiation syndrome.173 The most
induction therapy). In a report from this study (n = 82), the CR rate in all common grade 3 or 4 non-hematologic adverse events during induction
patients was 92% (95% for low-risk and 81% for high-risk patients) and the included infections (76%; including febrile neutropenia), hepatic toxicity
estimated 3-year OS rate was 85%.168 The authors suggested that ATRA (44%), gastrointestinal toxicity (28%), metabolic abnormalities (16%), and
combined with ATO, with or without GO, may be an alternative to prolonged QTc interval (14%); grade 3 or 4 differentiation syndrome
conventional chemotherapy in patients with untreated APL. A subsequent occurred in 14% of patients. Patients with a CR to induction received
study examined the long-term outcomes of patients with newly diagnosed consolidation with 2 cycles of ATRA and ATO. Maintenance therapy was
APL treated with ATRA and ATO with or without GO [9 mg/m2 on day 1 of administered for 2 years and consisted of eight 3-month cycles of
induction therapy for high-risk APL patients] (n = 187; median age, 50 treatment with ATRA, oral methotrexate, and 6-mercaptopurine.173 Grade
years; range, 18–84 years).169 The complete remission rate was 96% for 3 or 4 adverse events occurred primarily during induction (as above); the
patients with both low- and high-risk APL. With a median follow-up of 47.6 most common grade 3 or 4 events during consolidation (cycle 1) included
months (range, 2.7–159.7 months), the 5-year EFS, DFS, and OS rates infections (19%) and hepatic toxicity (12%), and no deaths occurred during
for low-risk patients were 87%, 99%, and 89%, respectively, and for the consolidation cycles. The hematologic CR rate after induction was 95%;
high-risk patients were 81%, 89%, and 86%, respectively.169 These data early death (during induction) occurred in 3% of patients. The 2-year DFS
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and failure-free survival rates were 97.5% and 88%, respectively. The throughout induction and consolidation cycles. Grade 3 or 4 hepatic
2-year OS rate was 93%.173 This trial enrolled 24 patients that were toxicities also occurred more frequently in Arm A compared with Arm B
defined as high risk based on the Sanz criteria. OS was not affected by (63% vs. 6%; P < .001).159 Health-related quality-of-life outcomes were not
the Sanz risk group (P[trend] = .17), although a correlation was made with significantly different between treatment groups except for fatigue severity.
the failure-free survival rate (P[trend] = .03). This association may be There was improvement in fatigue following induction in the ATRA plus
attributed to the method of analysis that included patients who withdrew ATO group (P = .022), though the benefit was negligible by third
from the study due to refusal of treatment or excessive toxicity, as well as consolidation (P = .660).174 This randomized study showed non-inferiority
patients who had 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. High-risk patients could receive an initial dose of GO
(100% vs. 95%). After a median follow-up period of 34.4 months, the (6 mg/m2 IV). Comparison between the ATRA plus ATO group and the
2-year EFS rate was significantly higher in Arm A compared with Arm B AIDA group showed a higher 4-year EFS (91% vs. 70%; P = .002) and
(97% vs. 86%; P < .001 for non-inferiority; P = .02 for superiority). The lower 4-year cumulative incidence of morphologic relapse (1% vs. 18%;
2-year OS probability was also significantly higher in Arm A compared with P = .0007) for ATRA plus ATO compared to AIDA, though no statistically
Arm B (99% vs. 91%; P = .02). Four patients in Arm B died during significant difference in 4-year survival was seen (93% vs. 89%; P = .25).
induction therapy (2 deaths were caused by differentiation syndrome). Quality of life was equivalent in the treatment groups for both high- and
One patient in Arm A and 3 patients in Arm B died during consolidation. low-risk patients as measured by the primary outcome of global
Grade 3 or 4 neutropenia and thrombocytopenia lasting more than 15 functioning (effect size, 2.17; 95% CI, -2.79–7.12; P = .39).175 However,
days were significantly more frequent in Arm B compared with Arm A the data from the trial measured more supportive care treatments and
MS-18

higher liver toxicity with AIDA. Treatment schedule differed from previous ATRA plus daunorubicin (PETHEMA LPA 99 trial) over AIDA (APL 2000
trials by moving to a higher dose of ATO given at a lower frequency of trial) because of higher CR and 3-year OS rates.155,157 To improve patient
twice weekly. Though data are limited to this single trial, the NCCN AML outcome, the PETHEMA LPA 99 trial and the GIMEMA AIDA-0493 study
Panel recognizes that this alternative dosing schedule may be more were modified to incorporate the combination of ATRA with cytarabine
manageable for patients who have difficulty getting to the clinic. either during induction (LPA 2005)157 or during consolidation
(AIDA-2000).158 The improved outcomes in both of these studies suggest
All five induction regimens discussed above offer excellent outcomes. a supra-additive effect with ATRA plus cytarabine, independent of the
These regimens are ATRA plus ATO (0.15 mg/kg; with the addition of anthracycline. The APML4 trial has shown the benefit of induction that
idarubicin for high-risk patients only); ATRA plus daunorubicin (50 mg/m2 includes ATRA and ATO. Unlike the other regimens, the APML4 trial does
daily for 4 days) plus cytarabine; ATRA plus daunorubicin (60 mg/m2 daily not use cytarabine during induction. In light of these studies, the panel
for 3 days) plus cytarabine; AIDA; or ATRA plus ATO (0.3 mg/kg). Choice recommends initial induction with these preferred regimens: ATRA and
of regimen will be influenced by risk group, age, and cardiovascular risks. ATO,173 or ATRA and ATO with a single dose of GO (9 mg/m2169 or 6
The NCCN AML Panel recommends that patients with APL be treated mg/m2175 that may be given on day 1, day 2, day 3, or day 4). Other
according to one of the regimens established from the clinical trials; recommended regimens include ATRA plus daunorubicin and
importantly, one should use a regimen consistently through all cytarabine153,155,156; AIDA alone157; or enrollment in a clinical trial. In high-
components of the protocol and not mix induction regimens from one trial risk patients with cardiac issues that include low ejection fraction, the
with consolidation regimens from another trial. With the advances in panel recommends initial induction with ATRA and ATO with a single dose
treatment regimens, the panel emphasizes the importance of receiving of GO (9 mg/m2 on day 1169 or 6 mg/m2 on day 1175). If the high-risk patient
treatment from an established treatment center for the monitoring and exhibits signs of prolonged QTc, the panel recommends initial induction
treatment of adverse events, regardless of risk stratification. The with ATRA and a single dose of GO (9 mg/m2 on day 1)170; ATRA plus
recommendations within the guidelines are broken down by: 1) risk daunorubicin and cytarabine153,155; or AIDA alone.157
classification using WBC count (cutoff of 10,000/mcL) at diagnosis; and 2)
whether high-risk patients have cardiac issues. The sudden onset of differentiation syndrome and the severity of the
complications have resulted in the frequent use of preemptive
For low-risk patients (WBC counts ≤10,000/mcL), for initial induction the dexamethasone, because there are no markers to predict its development.
panel recommends ATRA plus ATO (0.15 mg/kg)159 (category 1, preferred The panel recommends the prophylactic administration of corticosteroids
regimen); and ATRA plus ATO (0.3 mg/kg)175 (category 1, preferred in patients with a WBC count greater than 10,000/mcL (or in patients
regimen). If arsenic is contraindicated or not available, the panel receiving induction with both ATRA and ATO, regardless of WBC count) to
recommends AIDA157 (category 1); ATRA plus a single dose of GO (9 prevent differentiation syndrome. The ATRA plus ATO regimens defined
mg/m2 on day 5)170; or enrollment in a clinical trial. by Lo-Coco et al159 or Iland et al173,176 use prednisone 0.5 mg/kg as
prophylaxis for differentiation syndrome but with differing durations and
For high-risk patients (WBC counts >10,000/mcL), the NCCN AML Panel
tapering schedules. For patients who develop differentiation syndrome on
historically recommended a regimen that included cytarabine along with
MS-19

these regimens despite prednisone prophylaxis, prednisone should be anthracycline- or mitoxantrone-containing consolidation cycle.
stopped and replaced with dexamethasone 10 mg twice daily (see Consolidation regimens employing ATO will require monitoring of the QTc
Supportive Care for APL in the algorithm). If using non-ATO regimens, interval and optimizing electrolytes (see Supportive Care for APL in the
either steroid regimen is acceptable although there may be a slight algorithm and Supportive Care for Patients with APL in the discussion).
preference for dexamethasone for high-risk disease. While the panel According to the package insert, for QTc greater than 450 msec for men
recommends the use of prophylactic corticosteroids, it is acknowledged and 460 msec for women, 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, the relapse rate was
to count recovery. At count recovery following induction therapy, patients reduced from 14% to 2.5% with the incorporation of ATRA; the 3-year DFS
should proceed with consolidation. For patients with low-risk disease, if a rate was 97% with ATRA consolidation versus 82% in historical
patient is cytopenic on days 28–35, bone marrow biopsy and aspirate is controls.161 Although the addition of ATRA to the high-risk group improved
recommended to document blast clearance and to assess whether the relapse and DFS rates, there were significant rates of relapse (26%) and
marrow is suppressed and to determine whether ATRA and ATO should 3-year DFS (77%). In the PETHEMA LPA 2005 study, both ATRA and
be held to allow count recovery. If, however, blood counts have recovered cytarabine were included in the anthracycline-containing consolidation
by this time point, a bone marrow biopsy may be considered to regimen for the high-risk patients.157 In this high-risk group, the 3-year
document remission but is optional. For patients with high-risk disease, relapse rate was reduced to 11% (compared with 26% from the LPA 99
LP should be considered at count recovery following induction therapy, study), and the 3-year DFS and OS rates were 82% and 79%,
before proceeding with consolidation.177 Many consolidation regimens respectively. The LPA 2005 trial also began to approach the question of
involve high cumulative doses of cardiotoxic agents. It is therefore how to reduce toxicity during consolidation therapy in low- and
important to assess the cardiac function of patients prior to initiating each intermediate-risk patients by dose reduction of mitoxantrone (from 10
MS-20

mg/m2/day for 5 days to 10 mg/m2/day for 3 days in cycle 2) and a small groups, the 2-year EFS rate was higher with the addition of cytarabine.163
reduction of idarubicin dose for low- and intermediate-risk groups (from 7 Long-term follow-up from this study showed that in patients with standard
mg/m2/day for 4 days to 5 mg/m2/day for 4 days in cycle 1 and from 2 risk, the addition of cytarabine substantially reduced cumulative incidence
doses of 12 mg/m2/day to 1 dose of 12 mg/m2/day in cycle 3). Based on of relapse (7-year relapse rate 13% vs. 29%; P = .0065) and increased
results in the low- and intermediate-risk groups, lowering the dose of 7-year EFS rates (83% vs. 65%; P = .0029) compared with the regimen
mitoxantrone resulted in reduction of toxicity and hospital stay while without cytarabine.179 A poorer response was seen in patients who did not
maintaining the anti-leukemic activity (compared with results in low- and receive cytarabine despite maintenance treatment of continuous
intermediate-risk groups from the LPA 99 study). With the consolidation 6-mercaptopurine plus methotrexate and intermittent ATRA. Furthermore,
regimens evaluated in the LPA 2005 study, outcomes were similar all high-risk patients received cytarabine during induction and
between low-risk and intermediate-risk groups with regard to the 3-year consolidation resulting in a 7-year relapse rate, EFS rate, and OS rate of
cumulative incidence of relapse (6% vs. 6%), the 3-year DFS (93% vs. 7.1%, 82.2%, and 87.6%, respectively, an outcome that was slightly
94%), and the 3-year OS rate (96% vs. 93%).157 improved over standard-risk patients treated without cytarabine. Although
the results of the European APL 2000 trial are limited by the use of a
The AIDA-2000 trial of the Italian GIMEMA group has confirmed that single anthracycline in all study arms, the data support the use of
inclusion of ATRA in consolidation significantly improved outcome, most cytarabine in standard-risk APL with the anthracycline daunorubicin.
notably for high-risk patients; the high-risk group received a consolidation
regimen containing ATRA and cytarabine along with anthracyclines.158 In The North American Intergroup trial also focused on decreasing toxicity
this study, the 6-year cumulative incidence of relapse was 9% for patients during consolidation by incorporating ATO into the consolidation schema
in the high-risk group; the 6-year DFS and OS rates in this group were directly after achieving remission.156 In this trial, patients who were
84.5% and 83%, respectively. In the AIDA-2000 study, the low- and randomized to receive 2 courses of 25 days of ATO (5 days a week for 5
intermediate-risk groups were collapsed into a single category, and weeks) immediately after entering CR followed by the standard
received the same consolidation regimen with ATRA, mitoxantrone, and post-remission regimen with 2 more courses of ATRA plus daunorubicin,
idarubicin (ATRA 45 mg/m2 for 15 days + idarubicin 5 mg/m2 for 4 days in had a significantly higher 3-year EFS rate (80% vs. 63%; P < .0001) and
cycle 1; ATRA for 15 days and mitoxantrone 10 mg/m2/day for 5 days in improved OS outcomes (3-year OS rate 86% vs. 81%; P = .06) compared
cycle 2; and ATRA for 15 days and idarubicin 12 mg/m2 for 1 dose in cycle with those who received only the 2 courses of ATRA plus chemotherapy.
3). For patients in the low- and intermediate-risk group, the 6-year The 3-year DFS rate was also significantly improved with the addition of
cumulative incidence of relapse was 11%; the 6-year DFS and OS rates in ATO (90% vs. 70%; P < .0001). The favorable outcomes with the
this group were 86% and 89%, respectively.158 incorporation of ATO were observed in patients with low-/intermediate-risk
and high-risk disease.156 Notably, in the high-risk group, DFS outcomes
In the European APL 2000 trial, which randomized daunorubicin with or with the addition of ATO were similar to the DFS rate observed for the
without cytarabine for the consolidation phase (no ATRA during low-/intermediate-risk group, suggesting that ATO may help to overcome
consolidation) for the low- and intermediate-risk (ie, “standard risk”) the negative prognostic influence of high-risk disease. The overall
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outcomes do not appear to be superior to the less complex consolidation remission, and the 2-year DFS rate was 97.5%. The 2-year OS rate in all
schedules used in either of the two most recent European trials for evaluable patients in this study (n = 124) was 93%.173 As discussed
patients in the low- and intermediate-risk groups, but did appear to offer earlier, in the phase III randomized trial of ATRA combined with ATO
improved survival for patients with high-risk disease. However, the versus the AIDA regimen (APL0406 study) in patients with newly
consolidation phase in the North American Intergroup protocol is longer diagnosed, low-, or intermediate-risk APL (n = 162), patients in the ATRA
and may be difficult for some patients to complete. plus ATO arm received consolidation with ATO 5 days per week for 4
weeks every 8 weeks for a total of 4 courses, and ATRA daily for 2 weeks
The French APL 2006 randomized trial evaluated the role of ATO in every 4 weeks for a total of 7 courses (Arm A).159 Patients in the AIDA arm
consolidation therapy for previously untreated APL, both for standard-risk (Arm B) received 3 cycles of anthracycline-based consolidation combined
patients (WBC count <10,000/mcL; ATO vs. cytarabine vs. ATRA, all in with ATRA and then maintenance with low-dose chemotherapy and
combination with idarubicin during consolidation) and high-risk patients ATRA.158 After a median follow-up period of 31 months, the 2-year EFS
(WBC >10,000/mcL; cytarabine vs. ATO + cytarabine, both in combination rate was significantly longer in Arm A compared with Arm B (97% vs. 86%;
with idarubicin during consolidation).180,181 Based on results from the P < .001 for noninferiority; P = .02 for superiority of ATRA-ATO). In
interim analysis (median follow-up, 22–24 months), all regimens resulted addition, the 2-year OS was also longer in Arm A (99% vs. 91%; P = .02),
in CR rates exceeding 95% with low rates of relapse. However, the use of with no differences in 2-year DFS (97% vs. 90%; P = .11) or cumulative
ATO in the consolidation phase was associated with longer durations of incidence of relapse (1% vs. 6%; P = .24) between treatment arms.159
myelosuppression, which necessitated a protocol amendment to further
reduce the chemotherapy dose in patients receiving ATO.180 In the second In the French APL 93 trial, a 4% incidence of CNS relapse was reported in
interim analysis, the only change was a decrease of idarubicin during patients with WBC counts greater than 10,000/mcL. In the APL 2000 trial,
second consolidation. Data from this analysis show a 99.4% CR across all that high-risk population received five doses of IT chemotherapy using a
groups encompassing a total of 347 patients.181 While the two-year EFS combination of methotrexate, cytarabine, and steroids, upon count
and OS rates were above 95% for all three groups, there was a reduction recovery following induction therapy. These patients also received a
of myelosuppression in the group treated with AIDA compared to higher dose of cytarabine (2 g/m2) during consolidation (in cycle 2) as
idarubicin plus cytarabine and idarubicin plus ATO, which had similar compared with 1 g/m2 in the APL 93 trial. There were no cases of CNS
durations.181 The potential benefits of the use of ATO or ATRA in relapse in the APL 2000 trial, compared with 5 cases in the APL 93 trial.
consolidation may rest in a lower risk for long-term cardiovascular While the original treatment protocol on APL 2000 used HiDAC in the
complications and a lower risk for secondary 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 low-risk patients, the NCCN AML Panel has positioned the ATRA plus
who proceeded to consolidation (n = 112), all achieved molecular ATO regimen first, based on results from the APL0406 phase III
MS-22

randomized trial in comparison with the AIDA regimen.159 An additional In general, it is recommended that 4 to 6 doses of intrathecal (IT)
ATRA plus ATO regimen based on the AML 17 trial175 is also a preferred chemotherapy be given during consolidation for high-risk patients with
option. The GIMEMA AIDA-2000 regimen158 is an additional option. APL. IT chemotherapy may include agents such as methotrexate
However, all three of these regimens will yield excellent results. It is alternating with cytarabine either alone or combined with corticosteroids;
important to note that clinicians should use a regimen consistently through the choice of single drug versus combinations may vary based on clinical
all components of the treatment protocol and not mix induction regimens situation and institutional practice. Usually the IT treatment is started at the
from one trial with consolidation regimens from another trial. completion of induction and then given at the start and at count recovery
on subsequent consolidations. IT chemotherapy can be omitted during
For patients with high-risk disease, preferred consolidation therapies cycles of higher dose cytarabine.
include ATRA plus ATO as used in the APML4 trial,173 or ATRA and ATO
(plus a single dose of GO if ATRA/ATO are discontinued due to Post-Consolidation or Maintenance for Patients with APL
toxicity).169,175 Other recommended consolidation approaches include Following consolidation therapy, patients are assessed for molecular
cytarabine with daunorubicin as used in the French APL 2000 trial163; remission using RT-PCR techniques on bone marrow samples. For
cytarabine with AIDA as used in the PETHEMA LPA 2005157; and 2 cycles patients who are PCR negative, a 1- to 2-year course of ATRA
of ATO followed by 2 additional cycles of standard chemotherapy as used maintenance therapy, which may be combined with 6-mercaptopurine and
in the North American Intergroup trial.156 When using a methotrexate, may be a reasonable approach. The recommendations for
cytarabine-containing regimen, dose adjustments of cytarabine may be maintenance ATRA arose from several early trials that showed superior
needed for older patients or for patients with renal dysfunction.155,156 In RFS for patients receiving ATRA alone or in combination as maintenance
patients who could not tolerate anthracyclines and who received ATRA therapy. The French APL 93 trial randomized eligible patients (n = 289) to
and ATO for induction therapy, the reported trials continued with repeated four different maintenance regimens: no maintenance, continuous
cycles of these two agents following induction without anthracycline.167,168 chemotherapy with 6-mercaptopurine and methotrexate, intermittent
For patients with high-risk disease and cardiac issues (eg, low ejection ATRA, and the combination of ATRA with 6-mercaptopurine and
fraction and prolonged QTc), the NCCN AML Panel recommends ATO methotrexate.138 Results showed decreased 2-year relapse rates with
(0.15 mg/kg or 0.3 mg/kg) with ATRA for consolidation.169,175 If ATRA or continuous chemotherapy (11.5% vs. 27% with no chemotherapy) and
ATO are discontinued due to toxicity, a single dose of GO (9 mg/m2) may with ATRA (13.5% vs. 25% with no ATRA). The estimated 2-year relapse
be considered once every 4 to 5 weeks until 28 weeks from CR. If the rate for patients who received maintenance with ATRA in combination with
patient received ATRA and GO as induction therapy, consolidation with chemotherapy was 7.4%, suggesting an additive benefit with the
ATRA and GO should follow.170 As mentioned previously, the panel combination. The 2-year EFS rate was also improved with continuous
suggests that a regimen should be used consistently through all chemotherapy (92% vs. 77% without chemotherapy) and with ATRA (87%
components and physicians should not mix induction therapy from one vs. 82% without ATRA); the 2-year EFS rate among patients who received
trial with consolidation therapy from another. ATRA in combination with chemotherapy was 93%.138 Results from the
long-term follow-up of the APL 93 study showed a beneficial effect of
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maintenance treatment with intermittent ATRA and continuous remission status was not assessed prior to randomization to maintenance
chemotherapy, with an additive effect of the 2 modalities. The 10-year treatment.
cumulative relapse rates with no maintenance, ATRA alone, continuous
chemotherapy, and ATRA combined with chemotherapy were 43%, 33%, The Japanese APL 97 randomized study evaluated the role of
23%, and 13%, respectively (P < .001).154 Patients considered to be at maintenance with intensified chemotherapy compared with observation in
high risk (WBC count >5000/mcL) appeared to derive the most benefit patients with APL who were in molecular remission following consolidation
from maintenance therapy. The 10-year cumulative relapse rate among (n = 175).182 The estimated 6-year DFS was not significantly different
high-risk patients with no maintenance, ATRA alone, continuous between the chemotherapy maintenance and observation arms (63% vs.
chemotherapy, and ATRA combined with chemotherapy was 68%, 53%, 80%). In fact, the estimated 6-year OS was significantly lower with
33%, and 21%, respectively (P < .001). No statistically significant maintenance (86% vs. 99%; P = .014), which the investigators attributed
difference in the 10-year relapse rates was observed among patients with to possible effects of chemotherapy maintenance on the development of
lower-risk disease, although the relapse rate dropped from 29% without secondary malignancies and responses to subsequent (second-line)
maintenance to 11.5% with ATRA combined with chemotherapy. Overall, therapies.182
the 10-year OS rates with no maintenance, ATRA alone, continuous
Data from the AIDA 0493 trial suggested that there was no long-term
chemotherapy, and ATRA combined with chemotherapy were 74%, 88%,
benefit to maintenance therapy (ie, combination chemotherapy with
93%, and 94%, respectively (P < .001).154
6-mercaptopurine and methotrexate, ATRA alone, or ATRA in combination
The first North American Intergroup trial showed superior DFS outcomes with chemotherapy) in patients who were in molecular remission (PCR
for patients receiving maintenance ATRA compared with no negative) at the end of consolidation therapy.183 In this trial, ATRA was not
maintenance.153 In this trial, patients were randomized to induction therapy given during consolidation. The above studies have not demonstrated
with daunorubicin plus cytarabine or with ATRA alone, and subsequently long-term benefit with the use of maintenance therapy in patients who
underwent a second randomization to maintenance therapy with ATRA or achieve molecular remission following consolidation therapy. Further data
no maintenance (observation only). Consolidation therapy comprised the from randomized trials are needed to address the question of
initial induction therapy regimen for course 1, and then daunorubicin and maintenance. A phase III cooperative group trial (SWOG 0521) is
HiDAC for course 2. The 5-year DFS rates for the four randomization designed to examine the need for maintenance therapy (using the
groups, chemotherapy induction plus observation, chemotherapy induction combination of ATRA, 6-mercaptopurine, and methotrexate) in patients
plus ATRA maintenance, ATRA induction plus observation, and ATRA with low-risk APL. In this trial, patients receive induction therapy with
induction plus ATRA maintenance, were 16%, 47%, 55%, and 74%, ATRA, daunorubicin, and cytarabine, followed by consolidation therapy
respectively.153 Thus, the incorporation of ATRA during induction and with ATO, ATRA, and daunorubicin. Patients are then randomized to
maintenance appeared to improve long-term remission durations. It should receive maintenance therapy or no further treatment (observation only).
be noted that in the above North American Intergroup trial, molecular No benefit for maintenance was observed.184 The benefit of maintenance
therapy likely depends on the regimens used during induction and
MS-24

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 relapsed after first-line
therapy with ATRA combined with chemotherapy (n = 23), reinduction
RT-PCR should be performed on a blood sample at completion of therapy with ATO-containing regimens (ATO monotherapy, n = 20; ATO
consolidation to document molecular remission. It is at the discretion of the combined with ATRA and anthracycline, n = 2; ATO combined with
treating physician to determine the appropriate frequency of monitoring for mitoxantrone, n = 1) resulted in hematologic CR in 95% and molecular
individual patients. Periodic monitoring is recommended for up to 2 years remission in 83% of patients.188 ATRA and ATO appear to be synergistic
during maintenance therapy to detect molecular relapse in patients with and one could consider using the combination in patients who have not
high-risk disease, patients older than 60 years or who had long received ATRA during consolidation.164-166 However, in a small randomized
interruptions during consolidation, or patients on regimens that use study of patients with relapsed APL (n = 20), all patients previously treated
maintenance and are not able to tolerate maintenance. Clinical experience with ATRA-containing chemotherapy showed no improvement in response
indicates that the risk of relapse in patients with low-risk disease who are by adding ATRA to ATO compared with ATO alone.189 The role of
in molecular remission at completion of consolidation is low, and retreatment with ATO for patients who relapse following therapy with
monitoring may not be necessary outside the setting of a clinical trial. At ATO-containing regimens during initial induction and/or consolidation
the current level of test sensitivity/specificity, a change from PCR negative therapy remains unknown. A retrospective analysis in a small number of
to positive status should be confirmed in a blood sample by a reliable patients reported a second CR rate of 93% (both for hematologic CR and
laboratory within 2 to 4 weeks. If molecular relapse is confirmed by a molecular remission) among patients who were retreated with ATO
second positive test, the patient should be treated for relapsed disease combined with ATRA (with or without anthracyclines) after a relapse
(see APL: Therapy for Relapse in the algorithm). If the second test was following first-line therapy with single-agent ATO (n = 14).188
negative, maintenance therapy and frequent monitoring (eg, every 2–3
months) for up to an additional 2 years may be considered to ensure that For patients with APL who relapse early (<6 months) after an initial CR to
the patient remains PCR negative. Testing should be done in the same first-line therapy with ATRA and ATO with no prior exposure to
laboratory to maintain a consistent level of sensitivity. For patients who anthracyclines, anthracycline-based regimens (ATRA plus daunorubicin
develop cytopenias and who have a negative RT-PCR, a bone marrow and cytarabine153,155,156; and AIDA alone157) are recommended. For
aspirate is recommended to assess for new cytogenetic abnormalities, as patients who experience an early relapse (<6 months) after an initial CR to
secondary MDS and AML can occur following APL therapy. ATRA and anthracycline-containing first-line regimens or with no prior
exposure to ATO, it is recommended that the patient receive ATO with or
Management of Relapsed APL without ATRA, and with or without a single dose of GO until count
ATO is recommended for patients who do not achieve molecular remission recovery with marrow confirms remission. For patients who experience a
at completion of consolidation or who subsequently demonstrate late relapse (≥6 months) to ATO-containing regimens, ATO with or without
molecular or morphologic relapse. As a single agent, ATO produced CR ATRA, and with or without a single dose of GO/an anthracycline is
MS-25

recommended as first-line therapy after relapse. Following completion of A second study also suggested that autologous transplant could have a
the first cycle of consolidation, if the patient does not enter molecular survival advantage over allogeneic transplant in this population.192
remission, a matched sibling or alternative donor (haploidentical, unrelated Chakrabarty et al192 looked at 294 patients who received either allogeneic
donor, or cord blood) HCT or clinical trial is recommended. Testing is transplant (n = 232) or autologous transplant (n = 62) between 1995 and
recommended at least 2 to 3 weeks after the completion of arsenic to 2006. The 5-year DFS in the autologous transplant recipients was 63%
avoid false positives. (range, 49%–75%) versus 50% (range, 44%–57%) in patients receiving
allogeneic transplant. Although the DFS was not statistically significant
A small phase II trial in patients with relapsed APL evaluated ATO during (P = .1), the difference in OS did reach statistical significance (P = .002).
induction and consolidation followed by a peripheral blood hematopoietic In the patients receiving autologous transplant, OS was 75% (range, 63%–
cell harvest after HiDAC chemotherapy and autologous HCT.190 The study 85%) versus 50% (range, 48%–61%). The authors attribute this benefit to
enrolled 35 patients (16 with hematologic relapse and 9 with molecular the increased treatment-related mortality seen with patients receiving
relapse) between the ages of 18 and 65 years. The EFS after 1 year was allogeneic transplant (30%) compared to autologous transplant (2%).
77% (90% CI, 63%–86%). At a median follow-up of 4.9 years (range, 0.3–
6.3 years), the 5-year EFS was 65% and the 5-year OS was 77% with an It should be noted that only limited evidence from retrospective studies
estimated 59% probability of failure-free survival.190 The data suggest that exist with regard to the role of autologous and allogeneic HCT following
this sequential treatment regimen may provide improved outcomes with relapse of APL in the era of ATO therapy. The optimal consolidation
greater duration. strategy following therapy with ATO-containing regimens in patients with
relapsed disease remains to be defined.193 In a small retrospective study
A retrospective analysis conducted by the European APL Group showed of patients with relapsed APL treated with ATO-containing induction and
that in patients who received HCT following a second hematologic consolidation therapy, outcome of further consolidation with autologous
remission (primarily with ATRA-containing regimens), outcomes were HCT was compared with maintenance (without autologous HCT)
more favorable with autologous HCT (n = 50) compared with allogeneic consisting of ATO with or without ATRA.188 In this analysis, all patients had
HCT (n = 23). The 7-year RFS (79% vs. 92%) and EFS (61% vs. 52%) achieved second molecular remission following induction and
rates did not reach statistical significance between patients who received consolidation therapy with the ATO-containing regimens; subsequently, 14
autologous HCT versus allogeneic HCT; however, 7-year OS rates were patients underwent autologous HCT and 19 patients opted for an
significantly improved with autologous compared with allogeneic HCT ATO-containing maintenance regimen. Consolidation with autologous HCT
(60% vs. 52%; P = .04).191 Among patients who received a PCR-negative was associated with a significantly higher 5-year EFS rate (83% vs.
autograft, the 7-year RFS and OS rates were 87% and 75%, respectively. 34.5%; P = .001) and OS rate (100% vs. 38.5%; P = .001) compared with
Although the relapse rates were low with allogeneic HCT, the reduced OS ATO-containing maintenance therapy.188 The authors concluded that
with this procedure was accounted for by the higher treatment-related consolidation with autologous HCT was superior to ATO-containing
mortality observed in the allogeneic HCT group compared with the maintenance alone in patients who achieved molecular remission after
autologous HCT group (39% vs. 6%).191 relapse. Outcome data from the ELN registry reported a 3-year OS after
MS-26

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 syndromes
corticosteroids were administered prophylactically in patients presenting
when administering GO.
with high WBC counts.161,201 Kelaidi et al202 assessed the outcomes of
A small percentage of relapsed APL has a CNS component.197,198 patients with high WBC (>10,000/mcL) enrolled in the APL 93 and APL
Therefore, for patients who are in second morphologic remission, the use 2000 trials.202 A fundamental difference between these two trials was the
of IT therapy for CNS prophylaxis should be considered. Patients who use of dexamethasone (10 mg every 12 hours beginning on day 1) for
achieve a molecular remission after second-line therapy should be patients on APL 2000. The early death rate from differentiation syndrome
considered for autologous HCT if they do not have contraindications to dropped from 8 in 139 patients (6%) in the APL 93 trial to 2 in 133 patients
high-dose therapy. Allogeneic transplant should be reserved for patients (1.5%) in the APL 2000 trial.
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
therapy with ATO for six cycles is recommended in the absence of a
increasing WBC count greater than 10,000/mcL, shortness of breath,
suitable clinical trial.
hypoxemia, and pleural or pericardial effusion. Close monitoring of volume
overload and pulmonary status is warranted in these patients and initiation
of dexamethasone should occur at the first signs or symptoms of
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respiratory compromise (ie, hypoxia, pulmonary infiltrates, pericardial or leukemia biology. However, in cases of potentially life-threatening
pleural effusions). The NCCN AML Panel recommends treating with leukostasis not responsive to other modalities, leukapheresis can be
dexamethasone 10 mg twice daily for 3 to 5 days, then tapering the dose considered with caution.
over 2 weeks (see Principles of Supportive Care for APL in the algorithm).
ATRA may need to be withheld during the initial acute symptomatic period Because coagulopathy is common in patients with APL, it is important to
but may be resumed when symptoms resolve. Other factors that have screen for this problem with evaluation of prothrombin time, partial
been reported to increase the risk of differentiation syndrome include a thromboplastin time, and fibrinogen concentration during the initial workup
high body mass index and age older than 40 years. For patients at high and before any invasive procedure. Clinical coagulopathy is managed by
risk (WBC count >10,000/mcL) of developing differentiation syndrome, aggressive transfusion support to maintain platelet counts of 50,000/mcL
initiate prophylaxis with corticosteroids, either prednisone (0.5 mg/kg) from or greater, by fibrinogen replacement with cryoprecipitate and frozen
day 1 or dexamethasone 10 mg every 12 hours (see Principles of plasma to maintain a level of 150 mg/dL, and by maintenance of
Supportive Care for APL in the algorithm). The steroid dose should be prothrombin time and partial thromboplastin time close to normal. Patients
tapered over a period of several days. It is recommended that the with clinical coagulopathy need to be monitored daily until resolution.
prophylaxis regimen follow the specific treatment protocol used. In the Given the risks of coagulopathy in APL at diagnosis, invasive procedures
Australia/New Zealand study that evaluated induction with ATO added to a including leukapheresis and/or central line placement should be avoided. If
backbone of AIDA (phase II APML4 trial), all patients received prednisone possible, the diagnosis of APL may be made using peripheral blood
(1 mg/kg/day for at least 10 days) as prophylaxis for differentiation samples, which may minimize risk bleeding complications until
syndrome regardless of initial WBC count [see APL Treatment Induction coagulopathy can be adequately controlled.
(High Risk) in the algorithm].173 In the Italian-German Cooperative Group
ATO therapy may prolong the QT interval, making patients susceptible to
study that evaluated ATRA combined with ATO versus the AIDA regimen
ventricular arrhythmias. Therefore, prior to initiation of therapy, an ECG is
(phase III APL0406 trial), patients received prophylaxis with prednisone
recommended to assess the QT interval. Routine monitoring (eg, weekly)
(0.5 mg/kg/day) from day 1 until the end of induction [see APL Treatment
during therapy is suggested for older patients. Serum electrolytes should
Induction (Low Risk) in the algorithm].159 If a patient develops
also be monitored prior to and during therapy to maintain electrolytes
differentiation syndrome, it is recommended that treatment be changed
within the middle or upper normal range. Other drugs that prolong the QT
from prednisone to dexamethasone 10 mg every 12 hours until count
interval should be avoided during ATO therapy to minimize the risk of
recovery or risk of differentiation has abated.157,159 In settings where
cardiac arrhythmias. Patients with an absolute QTc interval greater than
differentiation syndrome is difficult to treat, the panel recommends the
500 milliseconds should be reassessed on a weekly basis during induction
following cytoreduction strategies for leukocytosis: hydroxyurea,
therapy, and prior to each course of post-remission therapy. A cardiology
anthracyclines, and GO.
consult may be appropriate for patients with prolonged QTc and when
Leukapheresis is not routinely recommended in the management of QTcF corrections are unavailable.203
patients with high WBC counts in APL because of the difference in
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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 older than 60 years, and an increased frequency of comorbid however, the survival benefit with high-dose daunorubicin was shown to
medical conditions that affect the patient’s ability to tolerate intensive be restricted to patients with favorable- and intermediate-risk cytogenetic
treatment.206 Because complete remission rates rarely exceed 70% in profiles (median OS, 34 vs. 21 months; P = .004) and those younger than
younger patients and 50% in older patients, substantial opportunity exists 50 years (median OS, 34 vs. 19 months; P = .004). The survival outcome
for innovative clinical trials involving both patient populations. The for patients with unfavorable cytogenetics was poor, with a median OS of
guidelines consider recommendations for patients older or younger than only 10 months in both treatment arms.207 In an update of the E1900 trial,
60 years of age separately. high-dose daunorubicin maintained a higher response than standard-dose
daunorubicin in patients younger than 50 years of age (HR, 0.66;
MS-29

P = .002).208 This benefit was seen regardless of cytogenetic risk profile. In approved in the year 2000 as a monotherapy for AML based on data from
addition, patients with FLT3-ITD, DNMT3A, and NPM1 mutant AML had single-arm phase II trials for older adult patients in first relapse.213 The
improved OS. Patients between 50 and 60 years of age with FLT3-ITD or voluntary withdrawal of the drug in 2010 was based on interim data from a
NPM1 also benefitted from high-dose daunorubicin.208 High-dose randomized trial in adult patients (aged 18–60 years) with AML comparing
daunorubicin was previously evaluated in a European trial that compared induction regimens of cytarabine and daunorubicin with or without GO in
idarubicin 12 mg/m2 daily for 3 or 4 days versus daunorubicin 80 mg/m2 which there was no improvement in outcomes and a small but significant
daily for 3 days in patients between ages 50 and 70 years; CR rates were increase in early mortality in the GO arm.195 Subsequent results of this trial
83%, 78%, and 70%, respectively (P = .04).209 No difference was seen in eventually showed no difference in overall mortality between the two
relapse rate, EFS, or OS outcomes between the treatment arms. arms.196 Since its withdrawal from the market, studies have demonstrated
a significant benefit for GO in specific patient populations. In the MRC
In a systematic review and meta-analysis of 29 randomized controlled AML 15 trial, the efficacy and safety of adding GO (3 mg/m2 on day 1 of
trials (RCTs) comparing idarubicin to daunorubicin,210 idarubicin had a induction) to three induction regimens, including daunorubicin (50 mg/m2
lower remission failure rate compared to daunorubicin (RR, 0.81; 95% CI, on days 1, 3, and 5) and cytarabine (100 mg/m2 on days 1–10 every 12
0.66–0.99; P = .04), but no difference was observed in early death or hours), was evaluated in patients 60 years or younger with previously
overall mortality. Furthermore, this benefit was only seen when the dose untreated AML (n = 1,113).214 The addition of GO was well tolerated and
ratio between daunorubicin and idarubicin was less than 5. Both high-dose there were no differences in RFS or OS rates between arms that received
daunorubicin and idarubicin resulted in 5-year survival rates between 40% or did not receive GO. The patients predicted to derive significant benefit
and 50%.210 with the GO addition to chemotherapy included those with favorable-risk
cytogenetics, with a trend towards benefit for those with intermediate-risk
It has been suggested that a dose of 60 mg/m2 daunorubicin may be
cytogenetics.214 A meta-analysis of five randomized trials (including adult
equally as effective as 90 mg/m2 and have a lower toxicity. A study from
patients ≥60 years) showed that adding GO (including alternative dosing
Burnett et al211 compared these two doses in 1206 patients who were
schedules) to conventional induction therapy also provides survival
predominately younger than 60 years of age. There was no difference in
benefit.215 A review of these and other studies (see Management of AML
CR (73% vs. 75%; OR, 1.07; 95% CI, 0.83–1.39; P = .60). The 60-day
in Patients Older than 60 Years) led to the approval of GO in September
mortality was higher in the patients receiving 90 mg/m2 (10% vs. 5%; HR,
2017 for the treatment of adults with newly diagnosed CD33-positive AML.
1.98; 95% CI, 1.30–3.02; P = .001), though the 2-year OS was similar
(59% vs. 60%; HR, 1.16; 95% CI, 0.95–1.43; P = .15).210 It is worth noting In the MRC AML 15 trial, younger patients with untreated AML (median
that all patients received a second course of chemotherapy that included age, 49 years), were randomized to two induction courses of: 1)
additional daunorubicin (50 mg/m2) on days 1, 3, and 5, which may daunorubicin and cytarabine (DA) with or without etoposide (ADE; n =
potentially have mitigated the effects of a 90 mg/m2 daunorubicin dose. 1983); or 2) ADE versus fludarabine, cytarabine, granulocyte colony-
stimulating factor (G-CSF), and idarubicin (FLAG-Ida; n = 1268).216
CD33-Positive AML: GO is a humanized anti-CD33 monoclonal antibody
Patients in the DA and FLAG-Ida arms were randomly assigned to a single
conjugated with the cytotoxic agent calicheamicin,212 that was initially
MS-30

dose of GO (3 mg/m2) during the first induction course.216 Patients with Some studies suggest that a higher dose of daunorubicin (90 mg/m2),
favorable- and intermediate-risk disease who received two induction compared to lower doses of either 45 or 60 mg/m2, is significantly
courses of FLAG-Ida with GO in course 1, followed by 2 courses of HiDAC associated with increased CR and survival rates in patients with
had an 8-year survival rate from remission of 72% (favorable risk, 95%; intermediate-risk cytogenetics and those who have FLT3-ITD mutation–
intermediate risk, 63%).216 positive AML.222,223 A phase III study compared idarubicin (12 mg/m2 for 3
days) and high-dose daunorubicin (90 mg/m2 for 3 days) with standard
KIT-Mutated AML: Emerging studies are evaluating the impact of adding cytarabine therapy during induction in young adults with newly diagnosed
dasatinib, a TKI, to AML therapy in CBF-AML with KIT mutations.217,218 AML (age range, 15–65 years). It was determined that high-dose
daunorubicin was associated with higher OS and EFS rates in patients
Intermediate-Risk Cytogenetics
with FLT3-ITD mutation–positive AML.224 However, these studies did not
FLT3-Positive AML: The majority of FLT3-mutated AML cases occur in
include midostaurin.
patients with intermediate-risk cytogenetics. Data have demonstrated
improved survival for patients with newly diagnosed FLT3-mutation– Therapy-Related AML or Antecedent MDS/CMML or AML-MRC
positive AML when midostaurin is added to standard chemotherapy as Although most cases of AML are de novo, secondary AML and therapy-
part of frontline treatment.219-221 This led to its breakthrough designation related AML account for approximately 25% of all AML cases and are
and approval by the FDA in 2017. In the CALGB 10603/RATIFY Alliance associated with poor outcomes.225,226 Emerging data have demonstrated
trial, patients aged 18 to 59 years, with newly diagnosed FLT3-mutation– improved survival in older patients with secondary AML when a dual-drug
positive AML (ITD or TKD) were randomized (n = 717) to receive standard liposomal formulation of cytarabine and daunorubicin in a 5:1 molar ratio
cytarabine therapy (200 mg/m2 daily for 7 days via continuous infusion) (CPX-351) is used as frontline therapy.227-229 In a phase II trial, newly
and daunorubicin (60 mg/m2 on days 1–3) with placebo or midostaurin (50 diagnosed older patients (age ≥60 years) with AML (n = 126), were
mg, twice daily on days 8–21).221 If residual disease in the bone marrow randomized 2:1 to first-line CPX-351 or the conventional administration of
was observed on day 21, patients were treated with a second blinded cytarabine and daunorubicin (7+3 regimen).228 Compared to the standard
course. Patients who achieved CR received 4 28-day cycles of HiDAC (3 7+3 regimen, CPX-351 produced higher response rates (CPX-351, 66.7%
g/m2 every 12 hours on days 1, 3, and 5) with placebo or midostaurin (50 vs. 7+3, 51.2%; P = .07), however differences in EFS and OS were not
mg, twice a day on days 8–21) followed by a year of maintenance therapy statistically significant.228 A planned analysis of the secondary AML
with placebo or midostaurin (50 mg twice a day).221 The median OS was subgroup demonstrated that CPX-351 was associated with a higher CR
74.7 months (95% CI, 31.5–not reached [NR]) in the midostaurin group rate (57.6% vs. 31.6%; P = .06).228 These results led to the development
compared to 25.6 months (95% CI, 18.6–42.9) in the placebo group (P = of a randomized phase III study comparing the efficacy and safety of CPX-
.009).221 Patients who received midostaurin with standard induction and 351 to the conventional administration of cytarabine and daunorubicin
consolidation therapy experienced significant improvement in OS (HR for (control arm) in patients 60–75 years of age with newly diagnosed
death, 0.78; P = .009) and EFS (HR for event or death, 0.78; P = .002) secondary AML (n = 309).229 With a median follow-up of 20.7 months,
compared with those on the placebo arm.221 CPX-351 significantly improved OS compared to the control arm (median,
MS-31

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 or older (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 high-risk patients including or standard-dose cytarabine (200 mg/m2 daily for 7 days); patients in both
patients with very poor-risk cytogenetic abnormalities and/or FLT3-ITD treatment arms also received daunorubicin (45 mg/m2 daily for 3 days).
mutation or with secondary AML. There was no significant increase in Patients treated in the HiDAC arm received a second high-dose cycle for
grade 3 or 4 toxicities except for an increase in conjunctivitis (grade 2–3) consolidation, whereas patients in the standard-dose arm were
with HiDAC (12.4%) versus SDAC (0.5%). Incidence of adverse events randomized to receive consolidation therapy with either 2 cycles of
was equivalent (SDAC, 67.6% vs. HiDAC, 66.2%). Patients in CR received standard-dose cytarabine or 1 cycle of HiDAC plus daunorubicin. The CR
a single consolidation cycle of daunorubicin and cytarabine (500 mg/m2 rates were similar, with 55% for the high-dose arm compared with 58% for
every 12 hours for 6 days) and subsequent HCT.230 the standard-dose arm for patients younger than 50 years, and 45% for
HiDAC versus 53% for standard-dose therapy for patients 50 to 65 years
of age. DFS rate (for patients with a CR) and OS rate (for all patients) at 4
MS-32

years were not significantly different among treatment arms. Induction received consolidation with HiDAC, the rates of treatment-related deaths
therapy with HiDAC was associated with significantly higher rates of and serious neurotoxicity were 5% and 12%, respectively.234
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 or higher Because the OS outcomes for the high-dose arm in the SWOG trial
neurologic toxicity (8% vs. 2% for patients aged <50 years; 5% vs. 0.5% consisting of HiDAC induction and 2 cycles of HiDAC consolidation (4-year
for patients aged 50–64 years; P < .0001).233 For patients younger than 50 OS rate of 52% for patients aged <50 years) were comparable to those of
years, consolidation with HiDAC was associated with similar rates of the CALGB trial with standard-dose infusional cytarabine induction and 4
treatment-related mortality (2% vs. 0%) and grade 3 or higher neurologic cycles of HiDAC consolidation (4-year OS rate of 52% for patients aged
toxicity (2% vs. 0%) compared with the standard dose. For the original ≤60 years), the use of HiDAC in the induction phase outside of a clinical
cohort of patients younger than 50 years who received 3 g/m2 HiDAC for trial remains controversial. A meta-analysis including 22 trials and 5945
induction, the rates of treatment-related deaths (10% vs. 5%) and grade 3 patients with de novo AML younger than 60 years of age demonstrated
or greater neurologic toxicity (16% vs. 2%) were higher than for those who improved RFS and reduced risk of relapse, particularly in the
received the standard dose. Similarly, for patients younger than 50 years favorable-risk cytogenetics, for patients receiving HiDAC versus standard
who received 3 g/m2 HiDAC for consolidation, the rates of chemotherapy.235 However, toxicity was a limiting factor and emphasis
treatment-related deaths (4% vs. 0%) and grade 3 or greater neurologic was placed on the importance of future studies to define the populations
toxicity (16% vs. 0%) were higher than for those who received the that would most benefit from HiDAC and to optimize dosing
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
arm.233 The risks for neurotoxicity and renal insufficiency are increased HiDAC. With either high- or standard-dose cytarabine-based induction for
with HiDAC; therefore, both renal and neurologic function should be younger patients, between 20% and 45% of these patients will not enter
closely monitored in patients receiving this treatment. In a CALGB trial,234 remission. In a report of 122 patients treated with HiDAC and
the subgroup of patients aged 60 years or younger (n = 156) who received daunorubicin, the remission rates were strongly influenced by
standard-dose cytarabine-daunorubicin induction therapy and 4 courses of cytogenetics, with CR rates of 87%, 79%, and 62% for favorable-,
HiDAC consolidation (3 g/m2 every 12 hours on days 1, 3, and 5, per intermediate-, and poor-risk groups, respectively.237
course) experienced a 4-year DFS rate of 44%. Among all patients who
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As previously mentioned, in the MRC AML 15 trial, younger patients with For patients with favorable-risk cytogenetics, other treatment options
untreated AML (median age, 49 years), were randomized to two induction include standard-dose cytarabine (200 mg/m2 continuous infusion) for 7
courses of: 1) daunorubicin and cytarabine with or without etoposide days combined with daunorubicin (60 mg/m2 for 3 days) and GO for
(ADE; n = 1983); or 2) ADE versus fludarabine, cytarabine, G-CSF, and patients with CD33-positive AML (category 2A and preferred
idarubicin (FLAG-Ida; n = 1268).216 In consolidation, patients were recommendation);214 or, fludarabine (30 mg/m2 IV for days 2–6) plus
randomized to amsacrine, cytarabine, etoposide, and then HiDAC (2 g/m2) over 4 hours starting 4 hours after fludarabine in
mitoxantrone/cytarabine, or HiDAC (3 g/m2; n = 1445).216 Patients in the combination with idarubicin (8 mg/m2 IV days 4–6) and G-CSF (SC daily
HiDAC arm received 1.5 g/m2 in consolidation, and were treated with or on days 1–7) plus a single dose of GO (category 2B recommendation).216
without a fifth course of cytarabine (n = 227). There were no significant
differences in the rate of CR between ADE and FLAG-Ida (81% vs. 84%, For patients with intermediate-risk cytogenetics and FLT3-mutated AML,
respectively), but FLAG-Ida significantly decreased relapse rates (FLAG- midostaurin is added to standard-dose cytarabine (200 mg/m2 continuous
Ida, 38% vs. ADE, 55%; P < .001).216 A recent randomized phase III study infusion) for 7 days combined with daunorubicin (60 mg/m2 for 3 days)
from the HOVON/SAKK groups compared standard cytarabine/idarubicin (category 2A recommendation).221
induction with or without clofarabine (10 mg/m2 on days 1–5) for patients
Patients with antecedent hematologic disease or treatment-related AML
with AML between the ages of 18 to 65 years.238 While there was no
are considered poor-risk, unless they have favorable cytogenetics such as
difference in the OS and EFS in the group as a whole, there was a
t(8;21), inv(16), or t(16;16). In addition, patients with unfavorable
decrease in relapse rate counter balanced by an increased rate of death in
karyotypes, such as 11q23 abnormalities, monosomy -5 or -7, monosomal
remission for the clofarabine arm. In a subset analysis, there was a
karyotype, or complex cytogenetic abnormalities and mutations including
significant improvement in OS and EFS for the ELN intermediate I group,
RUNX1, ASXL1, and TP53, are also considered to have poor risk.
primarily in patients in the NPM1 wild-type/FLT3-ITD–negative subgroup
Although all patients with AML are best managed within the context of an
with a 4-year EFS of 40% for the clofarabine arm versus 18% for the
appropriate clinical trial, it is particularly important that this poor-risk group
control arm.238
of patients should be entered into a clinical trial (incorporating either
NCCN Recommendations chemotherapy or novel agents), if available, given that only 40% to 50% of
The NCCN AML Panel strongly encourages enrollment in a clinical trial for these patients experience a CR (approximately 25% in older adult patients
treatment induction of younger patients (aged <60 years) with AML. For with poor-risk cytogenetics) with standard induction therapy. In addition,
patients not enrolled in a clinical trial, cytogenetics and the risk status of HLA testing should be performed promptly in those who may be
the disease guide treatment strategies. For patients with favorable-, candidates for either fully ablative or reduced-intensity conditioning (RIC)
intermediate-, and poor-risk cytogenetics, infusional standard-dose allogeneic HCT from a matched sibling or an alternative donor, which
cytarabine (100–200 mg/m2 continuous infusion) for 7 days combined with constitutes the best option for long-term disease control.239 For younger
either idarubicin (12 mg/m2 for 3 days) or daunorubicin (60–90 mg/m2 for 3 patients (aged <60 years) with therapy-related AML other than CBF/APL,
days) is a category 1 recommendation.207 antecedent MDS/chronic myelomonocytic leukemia (CMML), and
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cytogenetic changes consistent with MDS (AML-MRC), CPX-351 cytarabine and anthracycline or escalation to HiDAC (1.5–3 g/m2 every 12
[cytarabine (100 mg/m2) and daunorubicin (44 mg/m2)] as an intravenous hours for 6 days) may be considered for re-induction; no data are available
infusion over 90 minutes on days 1, 3, and 5 of 1 cycle is a category 2B to determine superiority of standard-dose cytarabine or HiDAC. After a
recommendation, because the trial did not include this patient bone marrow biopsy on day 21, standard-dose cytarabine with
population.229 anthracycline and midostaurin should be considered for patients with
FLT3-mutated AML.221 If dual-drug liposomal encapsulation of cytarabine
Other recommended induction regimens for intermediate- or poor-risk and daunorubicin was given during induction, after a bone marrow biopsy
disease include: standard-dose cytarabine (200 mg/m2 continuous 14–21 days after induction, re-induction with CPX-351 [cytarabine (100
infusion) for 7 days combined with daunorubicin (60 mg/m2 for 3 days) and mg/m2) and daunorubicin (44 mg/m2)] as an intravenous infusion over 90
GO for patients with CD33-positive AML (intermediate-risk AML);214 minutes on days 1 and 3 is recommended for patients with therapy-related
fludarabine (30 mg/m2 IV for days 2–6) plus HiDAC (2 g/m2) over 4 hours AML other than CBF/APL, antecedent MDS/CMML, or AML-MRC.229
starting 4 hours after fludarabine in combination with idarubicin (8 mg/m2 Treatments for induction failure may also be considered.
IV days 4–6) and G-CSF (SC daily on days 1–7) (category 2B
recommendation);216 or HiDAC plus an anthracycline and etoposide For patients with significant (>50%) cytoreduction and a low percentage of
(category 1 recommendation for patients 45 years of age or younger, but a residual blasts (as defined above), standard-dose cytarabine with
category 2B recommendation for other age groups).230,231,233,236 The study idarubicin or daunorubicin, or standard-dose cytarabine with daunorubicin
from Willemze et al230 that demonstrated improved OS for patients and midostaurin for FLT3-mutated AML patients is recommended. If
between the ages of 15 and 45 years treated on this regimen was integral daunorubicin (90 mg/m2) was used in induction, the recommended dose
in the change of the recommendation to category 1 for this age group. For for reinduction of daunorubicin prior to count recovery is 45 mg/m2 for no
patients with impaired cardiac function, other cytarabine-based regimens more than 2 doses. Similarly, if idarubicin (12 mg/m2) was used for
combined with non-cardiotoxic agents can be considered. For patients induction, the early reinduction dose should be limited to 10 mg/m2 for 1 or
with unfavorable-risk cytogenetics and TP53-mutated AML, treatment 2 doses. If the marrow is hypoplastic, additional treatment selection is
options are lacking, and alternative strategies should be considered. deferred until the remission status can be assessed.
Postinduction Therapy If hypoplasia status is unclear, a repeat bone marrow biopsy should be
After Standard-Dose Cytarabine Induction considered 5 to 7 days before proceeding with post induction therapy. For
To judge the efficacy of the induction therapy, a bone marrow aspirate and patients who achieve CR with the additional post induction therapy,
biopsy should be performed 14 to 21 days after start of therapy. In patients consolidation therapy can be initiated upon count recovery. Screening LP
who have received standard-dose cytarabine induction and have should be considered at first remission before first consolidation for
significant residual disease without hypoplasia (defined as cellularity less patients with monocytic differentiation, MPAL, WBC count >40,000/mcL at
than 20% of which the residual blasts are less than 5% [ie, blast diagnosis, or extramedullary disease.
percentage of residual cellularity]), additional therapy with standard-dose
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Patients who have persistent disease following two courses of therapy may be the most appropriate option. If the patient has a significant
(including a reinduction attempt based on midcycle marrow) are cytoreduction following HiDAC with a small quantity of residual blasts or
considered primary induction failures. Treatment options include clinical hypoplasia, additional therapy should be delayed for an additional 10 to 14
trial or use of salvage chemotherapy regimens used for relapsed/refractory days and the marrow status may be reassessed.
(R/R) disease (see Management of Relapsed/Refractory AML). However,
the likelihood of achieving a CR with a third chemotherapy regimen is low, Occasionally, patients with both myeloid and lymphoid markers at
at approximately 20%. If the patient did not receive HiDAC for persistent diagnosis may experience response to ALL therapy if an AML induction
disease at day 15, HiDAC with or without anthracycline may be used if a regimen failed.4 Treatment decisions for patients with significant reduction
clinical trial is not available and a donor is not yet identified. If regimens without hypoplasia or those with hypoplasia are deferred until the blood
used will result in high cumulative doses of cardiotoxic agents, consider counts recover and a repeat marrow is performed to document remission
reassessing the patient’s cardiac function before each status. Response is then categorized as a CR or primary induction failure.
anthracycline/mitoxantrone-containing course.240 If the patient has an
Post-Remission or Consolidation Therapy
identified sibling or alternative donor available, a transplant option should
Although successful induction therapy clears the visible signs of leukemia
be explored, although the panel encourages using alternative therapies to
in the marrow and restores normal hematopoiesis in patients with de novo
achieve remission prior to the transplant. For patients whose clinical
AML, additional post-remission therapy (ie, consolidation) may be needed
condition has deteriorated such that active treatment is not an option, best
to reduce the residual abnormal cells to a level that can be contained by
supportive care should be continued.
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
High-Dose Cytarabine: Since 1994, multiple (3–4) cycles of HiDAC
Guidelines, primary induction failure is defined as failure to achieve CR
therapy have been the standard consolidation regimen for patients
after two courses of intensive induction chemotherapy.21 Additional HiDAC
younger than 60 years with either good- or intermediate-risk cytogenetics.
therapy at this time is unlikely to induce remission in these cases. These
This consolidation therapy is based on a CALGB trial comparing 100
patients should be considered for a clinical trial or salvage regimens used
mg/m2, 400 mg/m2, and 3 g/m2 doses of cytarabine.234 The 4-year DFS
for R/R disease (see Management of Relapsed/Refractory AML). If an
rate for patients receiving consolidation with 3 g/m2 of HiDAC was 44%,
HLA-matched sibling or alternative donor has been identified, an
with a 5% treatment-related mortality rate and a 12% incidence of severe
allogeneic HCT may be effective in 25% to 30% of patients with induction
neurologic toxicity. Although the initial report did not break down remission
failure. If no donor is immediately available, patients should be considered
duration by cytogenetic groups, subsequent analysis showed a 5-year
for a clinical trial. If the patient’s clinical condition has deteriorated to a
RFS (continuous CR measured from time of randomization) rate of 50%
point at which active therapy would be detrimental, best supportive care
for CBF AML, 32% for patients with NK-AML, and 15% for patients in other
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cytogenetic categories (overall P < .001). Among the patients who analysis of 11 studies examining the effect of KIT mutations on CR, OS,
received HiDAC consolidation, the 5-year RFS rate was 78% for CBF and relapse rates of CBF AML determined that KIT mutations did not
AML, 40% for NK-AML, and 21% for other cytogenetic categories.237 affect CR rates.241 In patients with t(8;21) AML, KIT mutations were
associated with an increased risk of relapse and shorter OS rates
In some studies, in patients with CBF AML who received postremission compared to inv(16) AML.241
therapy with HiDAC, the presence of KIT mutations resulted in poorer
outcomes, particularly in t(8;21).37,43 In a multicenter study, patients with Some studies suggest that after induction, relative to KIT mutations, MRD
CBF AML (n = 67) were enrolled in intensive chemotherapy protocols that may be a more relevant prognostic factor for CBF-AML risk
involved HiDAC postremission therapy.37 At 24 months, a KIT mutation in stratification.21,242-244 In a prospective study, adult patients with CBF AML
the TKD at codon 816 (TKD816) in patients with t(8;21) was associated with (aged 18–60 years; n = 198) were randomized to receive a reinforced
a significantly higher incidence of relapse (90% vs. 35.3%, P = .002) and induction course (treatment arm A) or standard induction course
lower OS (25% vs. 76.5%, P = .006) compared to patients with wild-type (treatment arm B), followed by 3 HiDAC consolidation courses.243
KIT.37 In CBF AML with inv(16), TKD816 did not result in a significant Treatment arm A consisted of a first sequence with daunorubicin (60
difference in relapse incidence and OS.37 The prognostic influence of mg/m2/day by a 30 minute IV infusion) on days 1 and 3 and cytarabine
TKD816 and other mutations in exon 17 (mutKIT17) versus other recurrent (500 mg/m2 continuous infusion) from days 1 to 3, followed by a second
KIT mutations in CBF AML, such as exon 8 (mutKIT8), have been sequence at day 8 with daunorubicin (35 mg/m2/day by a 30 minute IV
investigated.43,83 In an analysis of adult patients younger than 60 years of infusion) on days 8 and 9, and cytarabine (1000 mg/m2 every 12 hours by
age with CBF AML treated on CALGB trials (n = 110), KIT mutations a 2-hour infusion) on days 8 and 10.243 Treatment arm B consisted of
(mutKIT17 and mutKIT8) among patients with inv(16) were associated cytarabine (200 mg/m2 continuous infusion) for 7 days combined with
with a higher cumulative incidence of relapse at 5 years (56% vs. 29%; daunorubicin (60 mg/m2 for 3 days. In treatment arm B, at day 15 a
P = .05) and a decreased 5-year OS rate (48% vs. 68%) compared with peripheral blood and BM evaluation was performed followed by a second
wild-type KIT; in multivariate analysis, the presence of KIT mutations sequence of chemotherapy in patients who reached CR.243 In addition,
remained a significant predictor of decreased OS in the subgroup with MRD levels were serially monitored for RUNX1-RUNX1T1 and CBFB-
inv(16). In patients with t(8;21), KIT mutations were associated with a MYH11 by real-time quantitative polymerase chain reaction in BM samples
higher incidence of relapse at 5 years (70% vs. 36%: P = .017), but no before the first, second, and third consolidation courses. In this study, both
difference was observed in 5-year OS (42% vs. 48%).43 The CALGB trial treatment arms demonstrated similar efficacy. After first consolidation,
also included 4 courses of monthly maintenance chemotherapy with higher WBC, KIT gene mutations and/or FLT3 gene mutations, and a less
daunorubicin and subcutaneous cytarabine after the consolidation phase; than 3-log MRD reduction were associated with a higher specific hazard of
however, only 55% of patients in CR received maintenance chemotherapy relapse, but MRD was the only prognostic factor in multivariate analysis.243
following HiDAC consolidation.234 Subsequent clinical trials have At 36 months, the cumulative incidence of relapse and RFS were 22%
eliminated this form of maintenance therapy after post-remission therapy. versus 54% (P < .001) and 73% versus 44% (P < .001) in patients who
However, the impact of KIT mutations in CBF AML is unclear. A meta- achieved 3-log MRD reduction versus other patients.243
MS-37

also similar between treatment arms (39% vs. 27%, respectively).23

Outcomes were poor for patients with monosomal karyotype at baseline
A prospective study analyzed the effect of a condensed HiDAC (n = 83), although the high-dose regimen was associated with significantly
consolidation therapy schedule given on days 1, 2, and 3 versus the improved rates of 5-year EFS (13% vs. 0%; P = .02) and OS (16% vs. 0%;
commonly used schedule of days 1, 3, and 5 in adult patients (aged 18–60 P = .02) compared with patients in this subgroup receiving the
years) with AML (n = 176), and found that there was no cumulative intermediate-dose. The incidence of grade 3 or 4 toxicities after cycle 1
hematologic toxicity and no change in survival.245 was higher in the high-dose arm than in the intermediate-dose arm (61%
vs. 51%; P = .005), but the incidence of 30-day mortality was the same in
The recent shortages of several chemotherapy agents have raised the
both arms (10%).23 This study suggests that 2 cycles of intermediate-dose
question of how best to use cytarabine. The HOVON/SAKK study
cytarabine (1 g/m2 every 12 hours for 6 days; total dose 12 g/m2 per cycle)
compared a double-induction concept using intermediate-dose cytarabine
for each consolidation cycle may be a feasible alternative to 3 cycles of
or HiDAC as part of an induction/consolidation regimen in a phase III
HiDAC (3 g/m2 for 6 doses; total dose of 18 g/m2 per cycle). This study as
randomized study in patients (age 18–60 years) with newly diagnosed
well as the MRC AML 15 study216 suggest that doses of 3 g/m2 of
AML (n = 860).23 Patients were randomized to treatment with an
cytarabine are not clearly more effective than lower doses of 1.5–3 g/m2;
“intermediate-dose” cytarabine regimen (12 g/m2 cytarabine; cycle 1:
in the MRC AML 15 trial, the cumulative incidence of relapse was
cytarabine, 200 mg/m2 daily for 7 days + idarubicin, 12 mg/m2 daily for 3
statistically lower for higher dose cytarabine but this did not translate into
days; cycle 2: cytarabine, 1 g/m2 every 12 hours for 6 days + amsacrine,
better RFS.216
120 mg/m2 daily for 3 days) or a “high-dose” cytarabine regimen (26 g/m2
cytarabine; cycle 1: cytarabine, 1 g/m2 every 12 hours for 5 days + Allogeneic Hematopoietic Transplantation: In the EORTC/GIMEMA
idarubicin, 12 mg/m2 daily for 3 days; cycle 2: cytarabine, 2 g/m2 every 12 trial, a 43% 4-year DFS rate was reported in the donor group of patients
hours for 4 days + amsacrine, 120 mg/m2 daily for 3 days). Patients who with poor-risk cytogenetics (n = 64; 73% underwent HCT); this was
experienced a CR after both treatment cycles were eligible to receive significantly higher than the 4-year DFS rate (18%; P = .008) among the
consolidation with a third cycle of chemotherapy or autologous or no-donor group (n = 94; 46% underwent HCT).246 The 4-year DFS rate
allogeneic HCT.23 A similar proportion of patients in each treatment arm among patients with intermediate-risk AML was 45% for the donor group
received consolidation, specifically 26% to 27% of third chemotherapy (n = 61; 75% underwent HCT) and 48.5% for the no-donor group (n = 104;
cycle patients, 10% to 11% of autologous HCT patients, and 27% to 29% 62.5% underwent HCT).246 The incidence of relapse was 35% and 47%,
of allogeneic HCT patients. No significant differences were observed respectively, and the incidence of death in CR was 20% and 5%,
between the intermediate- and high-dose arms in rates of CR (80% vs. respectively. The 4-year OS rate among intermediate-risk patients was
82%), 5-year EFS (34% vs. 35%), or 5-year OS (40% vs. 42%).23 These 53% for the donor group and 54% for the no-donor group.246
results are comparable to those from the CALGB study with HiDAC.234
More than 50% of patients in each arm had already experienced a CR The SWOG/ECOG trial reported a 5-year survival rate (from time of CR) of
when they received cycle 2. The 5-year cumulative rate of relapse risk was 44% with allogeneic HCT (n = 18; 61% underwent HCT) and 13% with
MS-38

autologous HCT (n = 20; 50% underwent HCT) among the subgroup of HMAs after induction or allogeneic HCT. CC-486 is a novel oral
patients with unfavorable cytogenetics. Moreover, the 5-year survival rate formulation of azacitidine that allows prolonged exposure in patients with
was similar between those allocated to autologous HCT and those hematologic malignancies.248,249 In a phase I/II trial evaluating the efficacy
intended for chemotherapy consolidation alone (13% and 15%, of oral azacitidine as maintenance therapy after allogeneic HCT in adult
respectively).31 The 5-year survival rates (from time of CR) for patients patients (≥18 years) with AML or MDS, patients received 1 of 4 dosing
with intermediate-risk cytogenetics were 52% for the allogeneic HCT schedules per 28-day cycle for up to 12 cycles.250 Of 30 patients, 7
group (n = 47; 66% underwent HCT) and 36% for the autologous HCT received oral azacitidine once daily for 7 days per cycle (n = 3 at 200 mg;
group (n = 37; 59% underwent HCT).31 n = 4 at 300 mg), and 23 received oral azacitidine for 14 days per cycle (n
= 4 at 150 mg; n = 19 at 200 mg [expansion cohort]).250 At 19 months of
In the UK MRC AML 10 trial, significant benefit with allogeneic HCT was follow-up, median OS was not reached and estimated 1-year survival rates
observed for the subgroup of patients with intermediate-risk cytogenetics were 86% and 81% in the 7-day and 14-day dosing cohorts,
(but not for those with favorable or high-risk cytogenetics). In this respectively.250
subgroup, the DFS (50% vs. 39%; P = .004) and OS rates (55% vs. 44%;
P = .02) were significantly higher among the donor groups than the In the international phase 3 trial, QUAZAR AML-001, investigators
no-donor groups.247 evaluated the efficacy of oral azacitidine as post-remission therapy in adult
patients (≥55 years of age) who had newly diagnosed AML or secondary
During the past decade, “normal” cytogenetics have been shown to AML, and had experienced CR or CRi after induction with intensive
encompass several molecular abnormalities with divergent risk therapies but were ineligible for allogeneic HCT (n = 472; median age, 68
behaviors.38 The presence of an isolated NPM1 or biallelic CEBPA years; range, 55–86 years).251 Within 4 months of attaining CR or CRi,
mutation improves prognosis to one only slightly less than that of patients patients were randomized to receive placebo (n = 234) or 300 mg of oral
with CBF translocations, placing these patients in the favorable-risk azacitidine (n = 238) once daily on days 1–14 of repeated 28-day
molecular abnormalities category.38 In contrast, patients with an isolated treatment cycles.251 A 21-day dosing schedule was allowed for patients
FLT3-ITD mutation and NK-AML have an outlook similar to those with who experienced AML relapse with 5% of 15% blasts in blood or bone
poor-risk cytogenetics.45 In a report that evaluated the ELN risk marrow while enrolled in the study. This treatment schedule could
classification in a large cohort of patients, for those in the “Intermediate I” continue indefinitely or until the presence of >15% blasts, unacceptable
risk group (which includes all patients with NK-AML with FLT3 toxicity, or allogeneic HCT.251 At a median follow-up of 41.2 months,
abnormalities and those lacking both FLT3 and NPM1 mutations), RFS median OS was 24.7 months and 14.8 months in the oral azacitidine and
was more favorable with allogeneic HCT (94 vs. 7.9 months without placebo arms, respectively (HR, 0.69; 95% CI, 0.55–0.86; P = .0009).251 In
allogeneic HCT).107 addition, the median RFS was significantly prolonged in the oral
azacitidine arm at 10.2 months compared to the placebo arm at 4.8
Maintenance Therapy
months (HR, 0.65; 95% CI, 0.52–0.81; P = .0001).251 Based on these data,
Hypomethylating Agents (HMAs): To improve treatment outcomes,
in September 2020, the FDA approved oral azacitidine for continued
some studies have evaluated the efficacy of maintenance therapy with
MS-39

treatment of patients with AML who achieved first CR or CRi following improvements in allogeneic transplants, which are expanding the pool of
intensive induction chemotherapy and are not able to complete intensive potential donors outside the family setting. While autologous HCT is still
postremission therapy. incorporated into the clinical trial design in Europe, the consensus of the
NCCN AML Panel was that autologous HCT should not be a
NCCN Recommendations
recommended consolidation therapy outside the setting of a clinical trial.
CBF Cytogenetic Translocations and MRD Negative Clinical trial participation is encouraged. Another option for this group
The NCCN AML Panel recommends the following options for consolidation includes multiple courses (3–4) of HiDAC consolidation.253 If patients
or maintenance therapy in this subgroup: 1) participation in a clinical trial; decline or are not fit/eligible for allogeneic HCT, maintenance therapy with
2) 3 to 4 cycles of HiDAC (category 1) alone or plus GO for patients with oral azacitidine may be considered at 300 mg daily on days 1–14 of each
CD33-positive AML; or 3) intermediate-dose cytarabine (1000 mg/m2) plus 28-day cycle until disease progression or unacceptable toxicity (a category
daunorubicin and GO for patients with CD33-positive AML (category 2B option).251 The panel notes that this option is not intended to replace
2A).214 There are insufficient data to evaluate the use of allogeneic HCT in consolidation chemotherapy.
first remission for patients with AML who are MRD negative and have
favorable-risk cytogenetics outside of a clinical trial.252 Data suggest that HiDAC (1.5–3 g/m2) with midostaurin may be considered for patients with
the response to treatment is similar regardless of whether the FLT3-mutation–positive AML.254 Alternative regimens incorporating
favorable-risk cytogenetics are de novo and treatment-related.252 intermediate doses of cytarabine may be reasonable in patients with
However, outcomes for patients with t(8;21) with KIT mutations are less intermediate-risk disease, including intermediate-dose cytarabine (1000
favorable. These patients should be considered for either clinical trials mg/m2) plus daunorubicin and GO for patients with CD33-positive AML.214
targeted toward the molecular abnormality or allogeneic transplantation. In However, the panel notes that patients who receive a transplant shortly
addition, for patients with favorable-risk cytogenetics who are persistently following GO administration may be at risk for developing sinusoidal
MRD positive after induction and/or consolidation, alternative therapies obstruction syndrome.255 If a transplant is planned, prior studies have used
including allogeneic transplantation, or a clinical trial should be a 60- to 90-day interval between the last administration GO and stem cell
considered. transplant.214 Comparable 5-year DFS rates were reported in patients
younger than 60 years with NK-AML after either 4 cycles of
Intermediate-Risk Cytogenetics and/or Molecular Abnormalities Including intermediate-dose cytarabine or HiDAC (41%) or autologous HCT
MRD Positive
(45%).253 At this time, there is no evidence that HiDAC (2–3 g/m2) is
The panel members agree that transplant-based options (either matched
superior to intermediate-dose cytarabine in patients with intermediate-risk
sibling or alternate donor allogeneic HCT) or 3 to 4 cycles of HiDAC
AML.
affords a lower risk of relapse and a somewhat higher DFS when given as
consolidation for patients with intermediate-risk cytogenetics. While 2 to 3 Treatment-Related Disease Other than CBF and/or Unfavorable
g/m2 HiDAC is preferred, a range of 1 to less than 2 g/m2 can be used to Cytogenetics and/or Molecular Abnormalities
accommodate patients who are less fit. The role of autologous HCT in the The panel strongly recommends clinical trials as standard therapy for
intermediate-risk group outside of clinical trials is diminishing due to patients with poor prognostic features, which include FLT3-ITD
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abnormalities in the setting of otherwise NK-AML, high WBC only the combined wild-type FLT3 and NPM1 mutant group had improved
(>50,000/mcL) at diagnosis, or adverse cytogenetics/molecular markers survival.256 This same study also demonstrated that the FLT3 mutation did
as well as secondary and therapy-related AML. If remission is observed, not affect remission rates, though there was an association with inferior
consolidation therapy is recommended, and strong consideration should survival. Secondary AML, either related to prior MDS or prior
be given to allogeneic HCT with matched sibling or alternative donor chemotherapy, also increases along with a higher rate of multidrug
(including umbilical cord blood products) as part of consolidation strategy. resistance protein expression. Although studies in the Swedish Acute
HiDAC-based consolidation with or without midostaurin for FLT3- Leukemia Registry documented improvement in outcomes for patients
mutation–positive AML (as outlined for patients with intermediate-risk younger than 60 years over the past 3 decades, no similar improvement
AML) may be required to maintain remission while searching for a was observed for the older population.206,260 Treatment-related mortality
potential matched donor. If CPX-351 was given during induction, an frequently exceeds any expected transient response in this group,
additional treatment of CPX-351 [cytarabine (65 mg/m2) and daunorubicin particularly in patients older than 75 years or in those who have significant
(29 mg/m2)] as an intravenous infusion over 90 minutes on days 1 and 3 comorbid conditions or ECOG performance status greater than 2.
for 1 cycle is recommended for patients with therapy-related AML other
than CBF/APL, antecedent MDS/CMML, or AML-MRC.229 If patients For older patients (age >60 years) with AML, the panel recommends using
decline or are not fit/eligible for allogeneic HCT, maintenance therapy with patient performance status, in addition to adverse features (eg, de novo
oral azacitidine may be considered at 300 mg daily on days 1–14 of each AML without favorable cytogenetics or molecular markers; therapy-related
28-day cycle until disease progression or unacceptable toxicity.251 As AML; antecedent hematologic disorder) and comorbid conditions, to select
previously stated, the panel notes that this option is not intended to treatment options rather than rely on a patient’s chronologic age alone.
replace consolidation chemotherapy. Comprehensive geriatric assessments are complementary to assessment
of comorbid conditions and are emerging as better predictive tools of
Management of AML in Patients Older Than 60 Years functional status.261,262 A treatment decision-making algorithm for
Induction Therapy previously untreated, medically fit, elderly patients (age ≥60 years) with
The creation of separate guidelines for patients older than 60 years AML was developed by the German AML cooperative group. Based on
recognizes the poor outcomes in this group treated with standard data from a large study in elderly patients (n = 1406), patient and disease
cytarabine and an anthracycline. In patients older than 60 years, the factors significantly associated with CR and/or early death were identified
proportion of those with favorable CBF translocations decreases, as does and risk scores were developed based on multivariate regression
the number with isolated NPM1 mutations, whereas the number of analysis.263 The predictive model was subsequently validated in an
patients with unfavorable karyotypes and mutations increases. However, it independent cohort of elderly patients (n = 801) treated with 2 courses of
should be noted that although some studies have demonstrated that induction therapy with cytarabine and daunorubicin. The algorithm, with or
NPM1 mutations in older patients is a positive prognostic factor,256,257 other without knowledge of cytogenetic or molecular risk factors, predicts the
emerging studies suggest it may predict unfavorable outcomes.258,259 In probability of achieving a CR and the risk for an early death for elderly
the UK NCRI AML 16 trial, similar to younger patients, in older patients, patients with untreated AML who are medically fit and therefore
MS-41

considered eligible for standard treatments.263 The factors included in the predictive estimate of 0.76 based on AUC.265 This model can be accessed
algorithm are the following: body temperature (≤38°C and >38 °C), online at http://www.amlcompositemodel.org/.
hemoglobin levels (≤10.3 and >10.3 g/dL), platelet counts (≤28K, >28K–
≤53K, >53K–≤104K, and >104K counts/mcL), fibrinogen levels (≤150 and Older adults with intact functional status (ie, ECOG score 0–2), minimal
>150 mg/dL), age at diagnosis (60–64, >64–67, >67–72, and >72 years), comorbidity, and de novo AML without unfavorable cytogenetics or
and type of leukemia (de novo and secondary). The algorithm can be molecular markers, without antecedent hematologic disorder, and without
accessed online at http://www.aml-score.org/. therapy-related AML may benefit from intensive cytarabine-based therapy
regardless of chronologic age.
A comprehensive predictive model for early death following induction in
Candidates for Intensive Remission Induction Therapy
patients with newly diagnosed AML suggests that age may reflect other
covariants, and the evaluation of these factors may provide a more Favorable- or Intermediate-Risk Cytogenetics
accurate predictive model. The model includes performance score, age, A reasonable treatment regimen for patients with favorable- or
platelet count, serum albumin, presence or absence of secondary AML, intermediate-risk cytogenetics includes standard-dose cytarabine (100–
WBC count, peripheral blood blast percentage, and serum creatinine. 200 mg/m2 by continuous infusion per day for 7 days) along with 3 days of
These factors, when taken together, result in a predictive accuracy based anthracycline. Although patients older than 75 years with significant
on the area under the curve (AUC) of 0.82 (a perfect correlation is an AUC comorbidities generally do not benefit from conventional chemotherapy
of 1.0).264 This model is complex, and currently there is not a tool available treatment, the rare patient with favorable-risk or NK-AML and no
to implement this model. A shortened form of the model was based on significant comorbidities might be the exception to this dogma. For
covariants that include age, PS, and platelet count. The simplified model patients with NK-AML, the remission rates are 40% to 50% with cytarabine
provides an AUC of 0.71, which is less accurate than the complex model combined with idarubicin, daunorubicin, or mitoxantrone. The randomized
but may be more accurate than decision-making strategies based solely study from the Acute Leukemia French Association (ALFA)-9801 study
on age.264 Based on this model, a Treatment Related Mortality calculator (n = 468) showed that idarubicin induction (the standard 12 mg/m2 daily for
can be accessed online at https://www.fhcrc- 3 days or intensified with 12 mg/m2 daily for 4 days) compared with
research.org/TRM/Default.aspx?GUID=1358501B-C922-4422-84F0- high-dose daunorubicin (up to 80 mg/m2) yielded a significantly higher CR
0E6C67D8F266. rate in patients aged 50 to 70 years (80% vs. 70%, respectively;
P = .03).209 The median OS for all patients was 17 months. The estimated
In a retrospective cohort study of adult patients with AML (n = 1100; 2-year EFS and OS rates were 23.5% and 38%, respectively, and the
range, 20–89 years), a composite predictive model examined the impact estimated 4-year EFS and OS rates were 18% and 26.5%, respectively;
of comorbidities on 1-year mortality following induction treatment.265 This however, no significant differences were observed between treatment
analysis incorporated patient-specific (ie, age, comorbidities) and AML- arms with regard to EFS, OS, and cumulative relapse rates.209
specific (ie, cytogenetic and molecular risks) features, and resulted in a
The ALFA-9803 study (n = 416) evaluated (during first randomization)
induction with idarubicin (9 mg/m2 daily for 4 days) compared with
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daunorubicin (45 mg/m2 daily for 4 days) in patients aged 65 years or study, in which the 4-year EFS and OS rates were 21% and 32%,
older.266 In this trial, the CR rate after induction was 57% and induction respectively.209 In the HOVON trial, the benefit in OS outcomes for the
death occurred in 10% of patients. The median OS for all patients was 12 dose-escalated daunorubicin group was observed only in patients aged 65
months; the estimated 2-year OS rate was 27%. No significant differences years and younger or in those with CBF translocations.268
in these outcomes were seen between anthracycline treatment arms.266
Long-term outcomes based on a combined analysis of data from the two For patients who exceed anthracycline dose or have cardiac issues but
ALFA trials above (9801 and 9803 studies; n = 727) showed superior are still able to receive intensive therapy, alternative non–anthracycline-
results with standard idarubicin induction (36 mg/m2 total dose) compared containing regimens, including clofarabine, may be considered.269-273
with daunorubicin induction (240 mg/m2 total dose for patients <65 years;
CD33-Positive AML: There are conflicting data about the use of GO for
180 mg/m2 total dose for patients ≥65 years) in older patients with AML
older patients with AML. Three phase III randomized trials evaluated the
(age ≥50 years).267 At a median actuarial follow-up of 7.5 years, the
efficacy and safety of adding the anti-CD33 antibody-drug conjugate GO
median OS for all patients included in the analysis was 14.2 months. The
to induction therapy with daunorubicin and cytarabine in older patients with
estimated 5-year OS rate was 15.3%, and the overall cure rate was
previously untreated AML.274-276 In the phase III ALFA-0701 trial, patients
13.3%. Induction with standard idarubicin was associated with a
aged 50 to 70 years with de novo AML (n = 280) were randomized to
significantly higher cure rate compared with daunorubicin (16.6% vs.
receive induction with daunorubicin (60 mg/m2 daily for 3 days) and
9.8%; P = .018). In the group of patients younger than age 65 years,
cytarabine (200 mg/m2 continuous infusion for 7 days), with or without
standard idarubicin was still associated with a significantly higher cure rate
(control arm) fractionated GO 3 mg/m2 given on days 1, 4, and 7.276
than daunorubicin despite the high dose (240 mg/m2 total dose) of
Patients with persistent marrow blasts at day 15 received additional
daunorubicin (27.4% vs. 15.9%; P = .049).267
daunorubicin and cytarabine. Patients with a CR/CRi after induction
In the HOVON trial, which randomized patients aged 60 years and older to received two consolidation courses with daunorubicin and cytarabine, with
induction therapy with standard-dose cytarabine combined with either or without GO (3 mg/m2 on day 1). The CR/CRi after induction was similar
standard-dose daunorubicin (45 mg/m2 daily for 3 days; n = 411) or between the GO and control arms (81% vs. 75%). The GO arm was
dose-escalated daunorubicin (90 mg/m2 daily for 3 days; n = 402), the CR associated with significantly higher estimated 2-year EFS (41% vs. 17%;
rate was 54% and 64%, respectively (P = .002).268 No significant P = .0003), RFS (50% vs. 23%; P = .0003), and OS (53% vs. 42%;
differences were observed in EFS, DFS, or OS outcomes between P = .0368) rates compared with the control.276 The GO arm was
treatment arms. Among the subgroup of patients aged 60 to 65 years associated with a higher incidence of hematologic toxicity (16% vs. 3%;
(n = 299), an advantage with dose-escalated compared with P < .0001); this was not associated with an increase in the risk of death
standard-dose daunorubicin was observed with regard to rates of CR from toxicity.276
(73% vs. 51%), 2-year EFS (29% vs. 14%), and 2-year OS (38% vs. 23%).
In another multicenter, phase III, randomized trial from the UK and
These outcomes with dose-escalated daunorubicin seemed similar to
Denmark (AML-16 trial), patients older than 50 years with previously
those with idarubicin (12 mg/m2 daily for 3 days) from the ALFA-9801
untreated AML or high-risk MDS (n = 1115) were randomized to receive
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daunorubicin-based induction (daunorubicin combined with cytarabine or Conflicting studies have led to the publication of several systematic
clofarabine) with or without (control) GO (3 mg/m2 on day 1 of course 1 of reviews and meta-analyses. A larger systematic review, inclusive of any
induction).275 The median age was 67 years (range, 51–84 years) and RCTs that investigated the benefit of anti-CD33 antibody therapy,
98% of patients were aged 60 years or older; 31% were aged 70 years or regardless of whether treatment was in de novo or secondary disease,
older. The CR/CRi rate after induction was similar between the GO and concluded that the data from 11 trials showed increased induction deaths
control arms (70% vs. 68%). The GO arm was associated with significantly (P = .02) and reduced residual disease (P = .0009).277 Despite improved
lower 3-year cumulative incidence of relapse (68% vs. 76%; P = .007) and RFS (HR, 0.90; 95% CI, 0.84–0.98; P = .01), no OS benefit was measured
higher 3-year RFS (21% vs. 16%; P = .04) and OS (25% vs. 20%; P = .05) (HR, 0.96; 95% CI, 0.90–1.02; P = .2). Two other meta-analyses showed
rates compared with the control arm. The early mortality rates were not improved RFS, though induction death was elevated.278,279 Conversely, a
different between treatment arms (30-day mortality rate, 9% vs. 8%); in fourth meta-analysis evaluating 5 trials with 3325 patients aged 15 years
addition, no major increase in adverse events was observed with GO.275 and older showed a reduced risk of relapse (P = .0001) and improved
These two trials suggest that the addition of GO to standard induction 5-year OS (OR, 0.90; 95% CI, 0.82–0.98; P = .01) with the addition of GO
regimens reduced the risk of relapse and improved OS outcomes in older to conventional induction therapy.215 It was noted that the greatest survival
patients with previously untreated AML characterized by favorable or benefit was seen in patients with favorable cytogenetics. Some benefit
intermediate-risk cytogenetics, not adverse risk. was seen in patients with intermediate cytogenetics, but no benefit was
reported with the addition of GO in patients with adverse cytogenetics.
The third phase III trial combining GO with chemotherapy showed a These studies underscore the need for further investigation that elucidates
different result than the other two. In this study, patients between the ages the benefits of GO for the treatment of AML.
of 61 and 75 years were given chemotherapy consisting of mitoxantrone,
cytarabine, and etoposide (n = 472).274 Half of the patients were given 6 FLT3-Positive AML: The results of the CALGB 10603/RATIFY Alliance
mg/m2 GO prior to chemotherapy on days 1 and 15. In remission, trial221 have been described in an earlier section (See Management of
treatment included two courses of consolidation with or without 3 mg/m2 AML in Patients Younger Than 60 Years; Intermediate-Risk Cytogenetics)
GO on day 0. The OS between the two groups was similar (GO, 45% vs. and these data may be extrapolated to suggest benefit in fit older adults.
no GO, 49%), but the induction and 60-day mortality rates were higher in In a phase II study in adult patients with previously untreated AML (n =
the patients given GO (17% vs. 12% and 22% vs. 18%, respectively). Only 284; range, 18–70 years; 86 older patients included [age range, 61–70
a small subgroup of patients younger than 70 years of age with secondary years]), the efficacy and safety of midostaurin added to intensive
AML showed any benefit to treatment. Combined with the increased chemotherapy, followed by allogeneic HCT and single-agent midostaurin
toxicity, the results of this study suggest that GO may not provide an maintenance therapy for a year was evaluated.280 All patients were
advantage over standard chemotherapy for some older patients with confirmed to have FLT3-ITD–positive disease. The CR/CRi rate after
AML.274 induction therapy was 76.4% (age <60 years, 75.8%; age >60 years,
77.9%). Many patients proceeded to transplant (72.4%), and a subset
initiated maintenance therapy (n = 97; 75 after allogeneic HCT and 22
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after HiDAC consolidation). The median time receiving maintenance Another HMA, decitabine, has also been evaluated as remission induction
therapy was 9 months after allogeneic HCT and 10.5 months after HiDAC therapy for older patients with AML.284 In a phase II study in previously
consolidation. The 2-year EFS and OS rates were 39% and 34% in untreated patients aged 60 years and older (n = 55; median age, 74
patients <60 years, and 53% and 46% in patients >60 years.280 years), the overall CR rate with this agent (20 mg/m2 for 5 days every 28
days) was 24% (including 6 out of 25 patients [24%] with poor-risk
Therapy-Related AML or Antecedent MDS/CMML or AML-MRC
cytogenetics), and the median EFS and OS were 6 months and 8 months,
The studies evaluating the efficacy and safety of CPX-351 in patients aged respectively.284 An earlier phase I study evaluated different dose
60 to 75 years with newly diagnosed secondary AML have been described schedules of decitabine in patients with R/R leukemias (n = 50; AML
(Management of AML in Patients Younger Than 60 Years; Therapy- diagnosis, n = 37).285 In this study decitabine was given at 5, 10, 15, or 20
Related AML or Antecedent MDS/CMML or AML-MRC).229 mg/m2 for 5 days per week for 2 to 4 consecutive weeks (ie, 10, 15, or 20
Unfavorable-Risk Cytogenetics (exclusive of AML-MRC)
days). The decitabine dose of 15 mg/m2 for 10 days (n = 17) was
Hypomethylating Agents (HMAs): An international, randomized, phase associated with the highest response rates, with an overall response rate
III study by Fenaux et al281 compared the HMA 5-azacitidine with (ORR) of 65% and CR rate of 35%. Among the patients with R/R AML
conventional care (best supportive care, low-dose cytarabine, or intensive (n = 37), the ORR was 22% with a CR in 14% across all dose levels.285 A
chemotherapy) in patients with MDS (n = 358). Although this study was phase II study targeting older patients (age ≥60 years) with AML who were
designed for evaluation of treatment in patients with high-risk MDS (based not candidates for or refused 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
months (HR, 0.47; 95% CI, 0.28–0.79; P = .005).282 The 2-year OS rates (20 mg/m2 for 10 days every 28 days).287 Response rates were higher
were 50% and 16%, respectively (P = .001). In a phase III study focused among patients with unfavorable-risk cytogenetics compared to patients
on older adult patients (≥65 years), the efficacy and safety of azacitidine with favorable- or intermediate-risk (67% vs. 34%, respectively; P < .001),
versus conventional care regimens (standard induction chemotherapy, and among patients with TP53 mutations compared to patients with wild-
low-dose cytarabine, or supportive care) was evaluated in patients with type TP53 (100% vs. 41%; P < .001).287 A recent phase II study comparing
newly diagnosed AML with >30% blasts.283 Compared to conventional a 5-day versus 10-day treatment schedule for decitabine in older patients
care regimens, azacitidine was associated with an increase in median OS (age ≥60 years; n = 71) with newly diagnosed AML determined that the
(6.5 months vs.10.4 months; HR, 0.85; 95% CI, 0.69–1.03; stratified log- efficacy and safety of both schedules were not significantly different.288
rank P = .1009).283 The 1-year survival rates with azacitidine and In an open-label, randomized, phase III study, decitabine (20 mg/m2 for 5
conventional care regimens were 46.5% and 34.2%, respectively. days every 28 days) was compared with physician’s choice (either
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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 older patients (age ≥65 years) with newly 44.3–74.3).290
diagnosed AML.289 Based on the protocol-specified final analysis of the
primary endpoint (OS), decitabine was associated with a statistically In a follow-up to this study, the efficacy of either 400 mg or 800 mg of
nonsignificant trend for increased median OS compared with physician’s venetoclax combined with either decitabine or azacitidine was evaluated in
choice (7.7 months vs. 5 months; HR, 0.85; 95% CI, 0.69–1.04; P = .108). older patients with previously untreated AML and who were ineligible for
A subsequent post hoc analysis of OS with additional follow-up time intensive chemotherapy (n = 145; age, ≥65 years; median age, 74
showed the same median OS with a statistically significant advantage years).291 The venetoclax dose of 400 mg was found to be the
associated with decitabine (HR, 0.82; 95% CI, 0.68–0.99; P = .037). The recommended phase II dose. With a median time on study of 8.9 months
CR (including CRi) rate was significantly higher with decitabine (18% vs. (range, 0.2–31.7 months) and median duration of follow-up of 15.1 months
8%; P = .001).289 The most common treatment-related adverse events with (range, 9.8–31.7 months), 67% of patients achieved CR/CRi.291 The
decitabine versus cytarabine included thrombocytopenia (27% vs. 26%), median duration of CR/CRi and median OS was 11.3 months and 17.5
neutropenia (24% vs. 15%), febrile neutropenia (21% vs. 15%), and months, respectively.291 In a subgroup analysis, the CR/CRi rates of
anemia (21% vs. 20%). The 30-day mortality rates were similar between patients with intermediate- and poor-risk cytogenetics were 74% and 60%,
the decitabine and cytarabine groups (9% vs. 8%).289 Both azacitidine and with a median duration of 12.9 months (95% CI, 11.0 months–NR) versus
decitabine are approved by the FDA for the treatment of patients with 6.7 months (95% CI, 4.1–9.4 months), respectively.291 The CR/CRi rates in
MDS. patients with TP53, IDH1/2, and FLT3 mutations were 47%, 71%, and
72%, respectively. In addition, patients with de novo AML and secondary
Venetoclax-Containing Regimens: Emerging studies have evaluated AML, respectively, had the same CR/CRi rate of 67%, with a median
the combination of HMAs with venetoclax, an oral B-cell lymphoma 2 duration of CR/CRi of 9.4 months (95% CI, 7.2–11.7 months) versus not
(BCL2) inhibitor, as an induction therapy strategy for older patients with reached (NR) (95% CI, 12.5 months–NR).291 In a phase 3 follow-up to this
AML. In a phase Ib study, older patients (≥65 years) with previously study, at a median follow-up of 20.5 months, the median OS was 14.7
untreated AML (n = 57) were enrolled into 3 groups: group A (n = 23) months in the group treated with azacitidine and venetoclax and 9.6
received venetoclax and decitabine (20 mg/m2 daily for 5 days of each 28- months in the group treated with azacitidine only (control) (HR, 0.66; 95%
day cycle); group B (n = 22) received venetoclax and azacitidine (75 CI, 0.52–0.85; P = .001).292 The CR/CRi rate was also higher in the
mg/m2 daily for 7 days of each 28-day cycle); and group C, a substudy of azacitidine and venetoclax group versus the control group (66.4% vs.
venetoclax and decitabine (n = 12), received an oral CYP3A inhibitor, 28.3%, respectively; P = .001).292
posaconazole, to determine its effect on the pharmacokinetics of
venetoclax.290 Daily target doses for venetoclax in different cohorts within Another phase Ib/II study evaluated the efficacy of venetoclax combined
groups A and B were 400 mg, 800 mg, and 1200 mg. The most common with low-dose cytarabine (20 mg/m2 daily for 10 days) in older patients
treatment-related adverse event in groups A and B was febrile neutropenia (≥60 years) with previously untreated AML ineligible for intensive
(30% and 32%, respectively), with an overall CR/CRi rate of 61% (95% CI, chemotherapy (n = 82; median age, 74 years).293 All patients received at
MS-46

least one dose of venetoclax at 600 mg. The CR/CRi rate was 54% (95% observed with the addition of ATRA. The median DFS in patients who
CI, 42%–65%) with a median duration of remission of 8.1 months (95% CI, achieved a CR with low-dose cytarabine was 8 months.294 Even with this
5.3–14.9 months), and the median OS for all patients was 10.1 months “low-intensity” treatment approach, induction death occurred in 26% of
(95% CI, 5.7–14.2 months).293 Patients with de novo AML, intermediate- patients, and overall prognosis remained poor for older patients who
risk cytogenetic features, and no prior HMA exposure demonstrated cannot tolerate intensive chemotherapy regimens. A phase II study
CR/CRi rates of 71%, 63%, and 62%, respectively.293 The average evaluated a regimen with low-dose cytarabine (20 mg twice daily for 10
CR/CRi rates in patients with NPM1 or IDH1/2 mutations were higher than days) combined with clofarabine (20 mg/m2 daily for 5 days) in patients
those with TP53 or FLT3 mutations (89% and 72% vs. 30% and 44%, aged 60 years or older with previously untreated AML (n = 60; median
respectively).293 Based on these studies, venetoclax in combination with age, 70 years; range, 60–81 years).295 Patients with a response received
HMAs, decitabine or azacitidine, or low-dose cytarabine are approved by consolidation (up to 17 courses) with clofarabine plus low-dose cytarabine
the FDA for the treatment of newly diagnosed AML in older adults at least alternated with decitabine. Among evaluable patients (n = 59), the CR rate
75 years or older, or in patients who have comorbidities that preclude use was 58% and median RFS was 14 months. The median OS for all patients
of intensive induction chemotherapy. was 12.7 months. The induction mortality rate was 7% at 8 weeks.295
Although this regimen appeared to be active in older patients with AML,
Not a Candidate for or Declines Intensive Remission Induction Therapy
the authors noted that the benefits of prolonged consolidation remain
AML Without Actionable Mutations unknown.
In older adult patients who cannot tolerate intensive treatment strategies,
low-intensity approaches have been investigated, including use of HMAs In a phase II trial, low-dose cytarabine was combined with glasdegib, a
alone or combined with venetoclax (see Candidates for Intensive selective inhibitor of the Smoothened protein in the Hedgehog signaling
Remission Induction Therapy, Hypomethylating Agents, and Venetoclax- pathway, and evaluated in adult patients (age ≥55 years) with previously
Containing regimens in the previous section). untreated AML or high-risk MDS ineligible for intensive chemotherapy (n =
132).296 Criteria for unsuitability for intensive chemotherapy included being
Low-Dose Cytarabine-Containing Regimens: Other approaches have at least 75 years of age, having serum creatinine >1.3 mg/dL, and having
evaluated low-dose cytarabine. The UK NCRI AML 14 trial randomized severe cardiac disease or ECOG score = 2. Patients were randomized 2:1
217 older patients (primarily aged >60 years; de novo AML, n = 129; to receive low-dose cytarabine alone (20 mg twice daily for 10 days every
secondary AML, n = 58; high-risk MDS, n = 30) unfit for chemotherapy to 28 days) or combined with oral glasdegib (100 mg daily). The addition of
receive either low-dose cytarabine subcutaneously (20 mg twice daily for glasdegib to low-dose cytarabine also improved OS compared to low-dose
10 consecutive days, every 4–6 weeks) or hydroxyurea (given to maintain cytarabine alone (8.8 months vs. 4.9 months, respectively), and the CR
target WBC counts <10,000/mcL).294 Patients were also randomized to rates were higher in the low-dose cytarabine and glasdegib arm (17%, n =
receive ATRA or no ATRA. Low-dose cytarabine resulted in a CR rate of 15/88) compared to low-dose cytarabine alone (2.3%; n = 1/44).296 In the
18% (vs. 1% with hydroxyurea) and a survival benefit compared with glasdegib plus low-dose cytarabine arm, the benefit in CR was primarily
hydroxyurea in patients with favorable or NK-AML. No advantage was seen in patients with favorable-/intermediate-risk cytogenetics (n = 10/52)
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when compared to patients with poor risk cytogenetics (n = 5/36).296 achieving CR/CRh.301 As an extension of this study, the safety and
Glasdegib in combination with low-dose cytarabine is currently approved efficacy of ivosidenib in patients with untreated AML was evaluated (n =
by the FDA for the treatment of newly diagnosed AML in older adults at 34; median age, 76.5 years).298 In phase I dose-escalation and expansion,
least 75 years or older, or in patients who have comorbidities that preclude patients received ivosidenib once daily or twice daily in 28-day cycles, and
use of intensive induction chemotherapy. a dose of 500 mg per day was selected as the dose for expansion groups.
The CR/CRh rate was 41.2% (95% CI, 24.6%–59.3%), and the ORR was
CD33-Positive AML: Single-agent GO has also been evaluated as an 58.8% (20/34; 95% CI, 40.7%–75.4%).298 Based on these data, ivosidenib
option. A randomized phase III study evaluated the efficacy of single-agent was approved by the FDA in May 2019 as a first-line treatment option for
GO (6 mg/m2 on day 1 and 3 mg/m2 on day 8) versus best supportive care AML with an IDH1 mutation in patients who are at least 75 years old or
as first-line therapy in older patients (age ≥61 years) with AML who were who have comorbidities that preclude the use of intensive induction
not eligible for intensive chemotherapy (n = 237).297 Compared to best chemotherapy. Treatment with both enasidenib and ivosidenib may induce
supportive care, GO alone improved the 1-year OS rate (9.7% vs. 24.3%, differentiation syndrome and hyperleukocytosis, which may be managed
respectively). In the GO group, the median OS was 4.9 months (95% CI, with corticosteroids and hydroxyurea.302-304
4.2–6.8 months) and 3.6 months (95% CI, 2.6–4.2 months) in the best
supportive care group.297 Alternatively, emerging data suggest that patients with de novo AML
characterized by IDH1/2-mutant AML may benefit from venetoclax/HMA-
IDH Mutation-Positive AML: Initially approved by the FDA for use in the based therapy with reported remission rates of greater than 70%, albeit in
R/R AML setting, IDH-targeted inhibitors, enasidenib and ivosidenib, have a relatively small number of patients.291
demonstrated utility in the frontline setting.298,299 In a phase I/II study, the
clinical activity and safety of enasidenib, an IDH2 mutant inhibitor, was FLT3-Positive AML: In adult patients with newly diagnosed FLT3-
evaluated in adult patients with IDH2-mutated advanced AML including mutation-positive AML (n = 15; median age, 76 years; range, 65–86
R/R disease.300 Approximately 19% of patients (n = 34 of 176) with R/R years), an ongoing trial is evaluating the safety and tolerability of the
AML achieved complete remission, with an OS of 19.7 months with a combination of azacitidine and gilteritinib,305 a FLT3 inhibitor that has
median OS of 9.3 months.300 In older patients (≥60 years) with newly demonstrated antileukemic activity in FLT3-positive R/R AML.306,307 Of 15
diagnosed AML, the efficacy of enasidenib was evaluated in a phase Ib/II evaluable patients, a CR/CRi rate of 67% was observed.305 Another study
sub-study within the Beat AML trial.299 Patients were treated with evaluated the efficacy of azacitidine and sorafenib, a FLT3 inhibitor, as a
enasidenib (100 mg/day) in continuous 28-day cycles. Azacitidine (75 front-line strategy in older adult patients with FLT3-ITD mutation-positive
mg/m2 days 1–7) was added to enasidenib for some patients who did not AML who cannot tolerate intensive induction (n = 27; median age, 74
achieve CR/CRi by cycle 5. Of 23 evaluable patients receiving enasidenib years; range, 61–86 years).308 The ORR was 78%, with CR, CRi/CR with
monotherapy, CR/CRi was achieved in 43% of patients (7 CR/2 CRi).299 incomplete platelet recovery (CRp), and PR rates of 26%, 44%, and 7%,
respectively.308 In addition, the median duration of CR/CRi/CRp was 14.5
Ivosidenib, an IDH1-mutation inhibitor, demonstrated durable remissions months, with a median OS of 8.3 months for the whole group.308
in IDH1 R/R AML, with 30.2% of patients (n = 54 of 179) with R/R AML
MS-48

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 older patients aged ≥60 years with AML. For patients not enrolled in a recommendation), or LDAC alone (a category 3 recommendation). Best
clinical trial, cytogenetics, overall functional status, and the presence or supportive care with hydroxyurea and transfusion support should also be
absence of actionable mutations should guide treatment strategies. considered and have been used as the comparator arm in several clinical
trials in older unfit patients.
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 Postinduction Therapy
recommendation). After Standard-Dose Cytarabine Induction
Similar to younger patients, older patients who receive standard
For patients with unfavorable-risk cytogenetics exclusive of AML-MRC, cytarabine/anthracycline induction with or without midostaurin or GO, or a
recommended options include: venetoclax combined with azacitidine, dual-drug encapsulation of cytarabine and daunorubicin receive a bone
decitabine or low-dose cytarabine, or lower-intensity therapy with HMAs marrow evaluation 14 to 21 days after start of therapy and are categorized
(5-azacitidine [a category 2B recommendation] or decitabine). according to the presence of blasts or hypoplasia. Patients with hypoplasia
should await recovery of counts before continuing to post-remission
Not a Candidate for or Declines Intensive Remission Induction
therapy. Patients with residual disease without hypoplasia may receive
Therapy: Treatment options include a clinical trial, or lower-intensity
additional standard-dose cytarabine with an anthracycline or mitoxantrone,
therapy based on the presence or absence of actionable mutations. The
or CPX-351 [cytarabine (100 mg/m2) and daunorubicin (44 mg/m2)], if
preferred regimens include venetoclax combined with HMAs (azacitidine
given during induction for patients with therapy-related AML, antecedent
[category 1] or decitabine). Other recommended options include
hematologic disorder, or AML-MRC. Alternatively, patients with FLT3-
venetoclax combined with low-dose cytarabine [LDAC] or glasdegib
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mutation–positive AML may receive additional standard-dose cytarabine apoptosis (eg, histone deacetylase inhibitors). Thus, success in these
with daunorubicin and midostaurin. Additional treatment strategies for trials may be assessed using indirect measures, such as hematologic
these patients may include consideration of a clinical trial or salvage improvement or decreased transfusion requirements and survival, without
regimens used for R/R disease (see Management of Relapsed/Refractory actually achieving CR. Frequently, in these trials, marrow examination is
AML). not performed until completion of 1 to 2 cycles of therapy. However, the
Guidelines do not currently recommend post-induction HMAs. For patients
If daunorubicin (90 mg/m2) was used in induction, the recommended dose with residual disease after 1 cycle of induction chemotherapy who will not
for reinduction prior to count recovery is 45 mg/m2 for no more than 2 tolerate another intensive salvage, venetoclax-based regimens may be
doses. Similarly, if idarubicin (12 mg/m2) was used for induction, the early considered.309,310
reinduction dose should be limited to 10 mg/m2 for 1 or 2 doses.
Intermediate-dose cytarabine-containing regimens, allogeneic HCT, or Postremission or Consolidation Therapy
best supportive care are also treatment options. Allogeneic transplant is a Patients who achieve a CR (including CRi) with standard induction
reasonable option, preferably in the context of a clinical trial, in patients chemotherapy may receive further consolidation with these same agents.
who experience re-induction failure with certain regimens including
intermediate-dose or HiDAC-containing regimens, and who have identified Intermediate-Dose Cytarabine: The prospective CALGB trial234
donors available to start conditioning within 4 to 6 weeks from start of established the efficacy of HiDAC consolidation in patients with AML aged
induction therapy. Patients without an identified donor would most likely 60 years or younger.234 In this study, a subgroup of patients with AML
need some additional therapy as a bridge to transplant. Additionally, it is aged 60 years or older who received standard-dose
acceptable to await recovery in these patients as many will enter cytarabine-daunorubicin induction therapy and more than one course of
remission without further treatment. Regardless of treatment, all patients HiDAC consolidation (3 g/m2 every 12 hours on days 1, 3, and 5, per
receiving post-induction therapy after standard-dose cytarabine should course) experienced severe neurotoxicity and a 4-year DFS rate of less
have a repeat bone marrow evaluation to document remission status. than 16%.234 Although the CALGB trial did not show an overall benefit for
Because many older patients have some evidence of antecedent higher doses of cytarabine consolidation in older patients,234 a subset of
myelodysplasia, full normalization of peripheral blood counts often does patients with a good performance status, normal renal function, and a
not occur even if therapy clears the marrow blasts. Thus, many phase I/II normal or low-risk karyotype might be considered for a single cycle of
trials for AML in the older patient include categories such as CRi for cytarabine (1.0–1.5 g/m2 daily for 4–6 doses) without an anthracycline. In
patients who have fewer than 5% marrow blasts but mild residual a study by Sperr et al, the CALGB consolidation was modified and given
cytopenias. as intermediate-dose cytarabine at 1 g/m2 every 12 hours on days 1, 3,
and 5, per course for 4 cycles in a group of AML patients older than 60
Many treatment strategies are designed to work more gradually using years of age.311 In this study, the treatment was well-tolerated without
agents that may allow expression of tumor suppressor genes (eg, a neurotoxicity and 25 of 47 patients received all 4 consolidation cycles. The
methyltransferase inhibitor such as decitabine or 5-azacitidine) or increase median OS, DFS, and continuous CR were 10.6, 15.5, and 15.9 months,
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respectively.311 The probability of OS, DFS, and continuous CR at 5 years 20%, respectively), and no difference was seen in relapse and OS
were 18%, 22%, and 30%, respectively.311 rates.315
Allogeneic Hematopoietic Transplantation: The role of myeloablative A retrospective study based on data in older patients (range, 50–70 years)
allogeneic HCT is limited in older patients because of significant with AML compared outcomes in patients who underwent allogeneic HCT
comorbidities; however, ongoing interest has been shown in RIC (either myeloablative conditioning or RIC; n = 152) with those who did not
allogeneic HCT as consolidation therapy.312,313 Case series and analysis of receive HCT in first CR (chemotherapy only; n = 884).316 Allogeneic HCT
registry data have reported encouraging results, with 40% to 60% 2-year in first CR was associated with a significantly lower 3-year cumulative
OS rates and 20% non-relapse mortality for patients who underwent relapse rate (22% vs. 62%; P < .001) and a higher 3-year RFS rate (56%
transplant in remission.312,313 In a retrospective analysis comparing vs. 29%; P < .001) compared with the non-HCT group. Although HCT was
outcomes with RIC allogeneic HCT and autologous HCT in patients aged associated with a significantly higher rate of non-relapse mortality (21%
50 years and older based on large registry data, RIC allogeneic HCT was vs. 3%; P < .001), the 3-year OS rate showed a survival benefit with HCT
associated with lower risk for relapse and superior DFS and OS relative to (62% vs. 51%; P = .012).316 Among the patients who underwent allogeneic
autologous HCT.312 The authors also noted that a survival benefit was not HCT, myeloablative conditioning was used in 37% of patients, whereas
observed in the subgroup of patients undergoing RIC allogeneic HCT in RIC was used in 61%. Survival outcomes between these groups were
first CR because of an increased incidence of non-relapse mortality. similar, with 3-year OS rates of 63% and 61%, respectively.316
Estey et al314 prospectively evaluated a protocol in which patients aged 50 Another study evaluating treatment in older patients (range, 60–70 years)
years and older with unfavorable cytogenetics would be evaluated for a compared outcomes between RIC allogeneic HCT reported to the Center
RIC allogeneic HCT.314 Of the 259 initial patients, 99 experienced a CR for International Blood and Marrow Transplant Research (n = 94) and
and were therefore eligible for HCT evaluation. Of these patients, only 14 standard chemotherapy induction and postremission therapy from the
ultimately underwent transplantation because of illness, lack of donor, CALGB studies (n = 96).317 Allogeneic HCT in first CR was associated with
refusal, or unspecified reasons. The authors compared the results of RIC significantly lower 3-year relapse (32% vs. 81%; P < .001) and higher 3-year
allogeneic HCT with those from matched subjects receiving leukemia-free survival rates (32% vs. 15%; P < .001) compared with the
conventional-dose chemotherapy. This analysis suggested that RIC chemotherapy-only group. As would be expected, allogeneic HCT was
allogeneic HCT was associated with improved RFS, and the authors associated with a significantly higher rate of non-relapse mortality (36% vs.
concluded that this approach remains of interest.314 In an analysis of 4%; P < .001) at 3 years; the 3-year OS rate was not significantly different
outcomes between two different strategies for matched-sibling allogeneic between the groups (37% vs. 25%; P = .08), although there was a trend
HCT, outcomes in younger patients (aged ≤50 years; n = 35) receiving favoring allogeneic HCT.317 A prospective multicenter phase II study
conventional myeloablative allogeneic HCT were compared with those in examined the efficacy of RIC allogeneic HCT in older patients (range, 60–
older patients (aged >50 years; n = 39) receiving RIC allogeneic HCT.315 74 years) with AML in first CR (n = 114).318 After allogeneic HCT, DFS and
This study showed similar rates of 4-year non-relapse mortality (19% and OS at 2 years were 42% (95% CI, 33%–52%) and 48% (95% CI, 39%–
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58%), respectively, for the entire group.318 A time-dependent analysis of four have experienced first CR or CRi but are unable to continue with
successive prospective HOVON-SAKK AML trials examined data from conventional consolidation have been described (See Management of
patients aged 60 years and older who obtained a first CR after induction AML in Patients Younger Than 60 Years; sub-section: Maintenance
chemotherapy (n = 640).319 For patients who received allogeneic HCT as Therapy).248,251
post-remission therapy (n = 97), a 5-year OS rate was 35% (95% CI, 25%–
NCCN Recommendations
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 aged 60 years and older, particularly those in hematologic recovery should be performed after 4 to 6 weeks. If a CR is
first CR with minimal comorbidities and who have an available donor. For observed, a clinical trial is recommended. Other postremission or
this strategy to be better used, potential transplant options should be maintenance therapy recommendations include: allogeneic HCT;
considered during induction therapy, and alternative donor standard-dose cytarabine with or without an anthracycline;
options/searches should be explored earlier in the disease management. intermediate-dose cytarabine alone (for patients who are more fit) or plus
The guidelines note that RIC allogeneic HCT is considered an additional daunorubicin and GO for patients with CD33-positive AML; intermediate-
option for patients aged 60 years and older as postremission therapy in dose cytarabine and midostaurin for patients with FLT3-mutation–positive
those experiencing a CR to induction therapy. AML; or CPX-351 [cytarabine (65 mg/m2) and daunorubicin (29 mg/m2)],
which is the preferred strategy if given during induction for patients with
Maintenance Therapy therapy-related AML, antecedent hematologic disorder, or AML-MRC. If
Hypomethylating Agents: Preventing relapse in older patients with the patient received more intensive regimens in induction and achieved a
AML who have experienced first CR after intensive induction can be remission but had treatment-related toxicity that prevents the patient from
challenging. In a phase 3 randomized trial, HOVON97, investigators receiving conventional consolidation or is not eligible for allogeneic HCT,
evaluated the efficacy of maintenance therapy with azacitidine in patients maintenance therapy with HMAs may be appropriate.251,320 In some cases,
with AML or MDS with refractory anemia with excess of blasts (n = 116; observation is recommended, as some patients have been able to
aged ≥60 years) who were in CR or CRi after intensive chemotherapy.320 maintain a CR without further treatment.
Patients were randomized to either observation (n = 60) or treated with
azacitidine (n = 56) at 50 mg/m2 subcutaneously on days 1–5 every 4 For patients in induction failure, a clinical trial, low-intensity therapy
weeks until relapse for a maximum of 12 cycles.320 Thirty-five patients (azacitidine, decitabine), allogeneic HCT (preferably in the context of a
received at least 12 cycles of azacitidine and the estimated 12-month DFS clinical trial), therapies for R/R disease (see Management of
for the azacitidine and observation groups were 64% and 42%, Relapsed/Refractory AML), or best supportive care are recommended
respectively (log rank, P = .04).320 treatment options.
The studies evaluating the efficacy and safety of maintenance therapy with Previous Lower-Intensity Therapy: For patients who previously
oral azacitidine or CC-486 in patients with newly diagnosed AML who received lower-intensity therapy, a marrow to document remission status
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upon hematologic recovery should be performed, with the timing treatment, there is a need to discontinue any of the agents or a
dependent on the therapy used. If a response is observed, allogeneic HCT consideration to continue maintenance on single-agent venetoclax, the
may be considered for select patients. Alternatively, low-dose therapies panel recommends referral to a tertiary cancer or academic medical
used in induction with demonstrated efficacy may be continued until center.
progression, including venetoclax plus HMAs; venetoclax plus low-dose
cytarabine; enasidenib (for IDH2-mutated AML); ivosidenib (for IDH1- To minimize the development of tumor lysis syndrome—which is
mutated AML); glasdegib plus low-dose cytarabine; or HMAs alone or uncommon in this setting322—during the first cycle of treatment, inpatient
combined with sorafenib (for FLT3-mutant AML); or GO alone (a category treatment is strongly recommended especially through dose-escalation.
2B recommendation). If no response or progression is seen, a clinical trial, The intrapatient dose escalation for venetoclax with HMA is 100 mg, 200
therapies for R/R AML (see Management of Relapsed/Refractory AML), or mg, and 400 mg given daily on days 1 to 3; and the intrapatient dose
best supportive care are recommended treatment options. escalation for venetoclax with LDAC is 100 mg, 200 mg, 400 mg, and
600 mg given daily on days 1 to 4.322 To minimize and avert further risk
Principles of Venetoclax Use with HMAs or LDAC-Based Treatment of tumor lysis syndrome, the panel recommends aggressive monitoring
With growing use of venetoclax-based therapies (ie, venetoclax with of blood chemistries; monitoring and managing electrolyte imbalances;
HMAs or low-dose cytarabine), and the fact that these therapies may be and treatment with allopurinol or other uric acid lowering agent.322
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
For patients with newly-diagnosed disease, the panel notes that cytopenias until a response assessment is made,324 with aggressive
venetoclax with HMA or LDAC should be given concomitantly. The transfusion support and supportive care as needed. The panel also
addition of a third targeted agent to these combinations is not recommends withholding growth factors until after the first cycle
recommended outside the context of a clinical trial. Prior to administering response assessment.322 However, granulocyte colony-stimulating
therapy, it is important to achieve a WBC count of <25,000/mcL with factors should be considered for neutropenic patients who are in
hydroxyurea, or leukapheresis if needed.322 It is worth noting that the morphologic remission but whose counts have not recovered. A bone
data supporting a beneficial role for leukapheresis in this context is marrow biopsy is necessary for response assessment on days 21–28 of
limited.323 In addition, venetoclax is a substrate of CYP3A4, so dose the first cycle,322 perhaps on the early end of this range for patients who
adjustments of venetoclax are recommended when concurrently using receive the combination of venetoclax and decitabine.
venetoclax with strong CYP3A4 inhibitors, most commonly the azole
If blasts are <5% during the first cycle, in the setting of cytopenias all
class of antifungal agents.324 Reductions in duration of venetoclax and
treatment should be held and the following measures should be
HMAs or LDAC may be considered in the setting of cytopenias. If during
considered: growth factor support, if indicated; and a treatment-free
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interval for up to 14 days. When counts have recovered to a clinically Role of MRD Monitoring
significant threshold (ideally to CR or CRi), the next cycle of treatment MRD in AML refers to the presence of leukemic cells below the threshold
can begin.322 If counts have not recovered to a clinically significant of detection by conventional morphologic methods. Patients who have
threshold, consider repeating the BM biopsy. If morphological remission achieved a CR by morphologic assessment alone can still harbor a large
is ongoing, therapy can continue to be held or a second cycle can number of leukemic cells in the bone marrow.325 Due to the rapidly
proceed with adjustments to dose or schedule of venetoclax and HMA or evolving nature of this field and the undeniable need for monitoring, MRD
LDAC.322 is still under investigation, with NCCN recommendations as discussed
below.
During the second and subsequent cycles of treatment, if remission was
observed after the first cycle, sequential cycles should continue with up While morphologic assessment is the first step in a cure for AML, there
to 14-day interruptions between cycles for count recover and/or growth remains a level of MRD that currently lacks any standardized method of
factor support.322 If there is no evidence of disease after the first cycle monitoring. Two of the most commonly used techniques are real-time
and assuming no unexpected changes in blood counts occur, the BM quantitative PCR (RQ-PCR) and flow cytometry. RQ-PCR amplifies
biopsy can be repeated at 3–6-month intervals, or as needed based on leukemia-associated genetic abnormalities, while flow cytometric profiling
clinical suspicion for relapse, depending on the goals of the patient. If detects leukemia-associated immunophenotypes (LAIPs).326-328 Both
count recovery worsens over time, relapsed disease should be ruled out methods have a higher sensitivity than conventional morphology. RQ-PCR
with a repeat BM biopsy.322 If morphological remission is ongoing with has a detection range of 1 in 1000 to 1 in 100,000, while flow cytometry
worsening blood counts, consider decreasing the duration, and/or dose, has sensitivity between 10-4 to 10-5. The challenge of incorporating these
of venetoclax and/or HMA or LDAC. However, if there is no techniques into routine practice is a lack of standardization and
morphological remission after the second cycle, consider enrollment in a established cutoff values, though ongoing research is focused on
clinical trial if available. If no clinical trial is available, and patient has had addressing these limitations. Most of what is known about MRD monitoring
some response with manageable toxicity, therapy may be continued as has been done in the APL population;329,330 however, these techniques are
long as it is tolerated. now expanding to include other AML subtypes.331 Emerging technologies
include digital PCR and NGS.325 NGS-based assays can be used to detect
If venetoclax and HMA or LDAC are being given to patients with
mutated genes through targeted sequencing gene panels,332,333 though
relapsed/refractory (R/R) AML, the panel recommends antifungal
higher sensitivities are observed in PCR- and flow cytometry-based
prophylaxis.321 Other recommendations for TLS, intrapatient dose
methods compared to conventional NGS.325 The data from these methods
escalation, BM biopsies, and cytopenia mitigation plans are similar to
have been correlated with AML treatment outcome and the preliminary
considerations that have been described.
results are promising. Refinement of these methods that take into account
variables including the intrinsic nature of the transcript as well as factors of
the patient population, including age, disease severity, and treatment, will
make MRD monitoring in patients with AML a more reliable tool.
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RQ-PCR relapse.244 A study in 15 patients with childhood AML showed that

There are three classifications of RQ-PCR targets: leukemic fusion genes, 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
survival and imminent morphologic relapse.341 Another study evaluated outcome.112,350,352-357 In a small study of 25 patients, the use of a higher
bone marrow from 53 patients during consolidation therapy and was the sensitivity RQ-PCR was shown to circumvent transcript instability,
first to establish clinically relevant MRD cut-off values for the ultimately showing that FLT3-ITD MRD monitoring was predictive of
CBFB-MYH11 transcript to stratify patients with increased risk of relapse.358 In comparison to FLT3-ITD, data suggest that NPM1 mutations
relapse.242 PCR negativity in at least one bone marrow sample during may be more stable.352 Schittger et al356 developed and tested primers for
consolidation therapy was predictive of a 2-year RFS of 79% as compared 17 different mutations of NPM1.356 Serial analyses of 252 NPM1-mutated
to the 54% seen in PCR-positive patients. Similarly, Yin et al244 found that AML samples at 4 time points showed a strong correlation between the
a less than a 3-log reduction in RUNX1-RUNX1T1 transcript in bone level of NPM1mut and outcome. Kronke et al351 further modified this method
marrow or a greater than 10 CBFB-MYH11 copy number in peripheral to show that NPM1mut levels after double induction and consolidation
blood after 1 course of induction chemotherapy was highly predictive of therapy reflected OS and cumulative incidence of relapse.351 In 245
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patients, PCR negativity had a 6.5% 4-year cumulative incidence of alone.365 Notably, for patients in CR prior to allogeneic HCT, the presence
relapse versus 53% for patients with a positive PCR.351 This correlation of pre-transplantation MRD positivity in peripheral blood testing was
was also seen when taken after completion of therapy. In addition, an RQ- associated with survival similar to patients with pathologist bone marrow-
PCR analysis of 2596 samples from 346 patients with NPM1-mutated AML 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 in morphologic remission, less than 5% had high
Gene overexpression studies have focused on WT1. Retrospective data levels of MRD by flow cytometry.367 A larger study of 1382 follow-up bone
show that a lower level of WT1 after induction therapy is associated with marrow samples from 202 children with AML demonstrated MRD to be a
long-term remission.361 A meta-analysis of 11 trials, encompassing 1297 predictor of relapse. In this study 28 of the 38 samples (74%) with greater
patients, showed the poor prognostic significance of WT1 level.362 WT1 than 15% myeloblasts had measurements of 0.1% or greater by flow
was overexpressed in 86% of marrow and 91% of blood samples from 504 cytometry. In patients with 5% to 15% myeloblasts, 43 of the 129 patients
patients with AML when compared to 204 healthy donors.363 However, (33%) were detected by the same threshold and only 100 of the 1215
when using the cutoff values of greater than 100-fold detection, only 46% samples (8%) with less than 5% myeloblasts fell into this category. The
of blood and 13% of marrow samples in the cohort were positive.363 This ability of MRD monitoring to predict an unfavorable EFS was statistically
reflects the outliers of the healthy population that have higher WT1 significant (P < .0001).343 In a study of adult patients with AML who
transcripts. Furthermore, only 19% of childhood AML samples met this underwent allogeneic HCT from peripheral blood or bone marrow donor (n
criterion in a study.364 While WT1 is a strong candidate for MRD = 359), pre-transplant staging with flow cytometry demonstrated similar
monitoring, early studies show that there is variability in the detection of outcomes in 3-year OS and PFS estimates between patients with MRD-
this transcript that must first be addressed. In a retrospective study of AML positive morphologic remission and patients with active disease (26% vs.
patients who underwent allogeneic HCT (n = 74), a multigene MRD RQ- 23% and 12% vs. 13%, respectively) when compared to patients in MRD-
PCR array predicted clinical relapses occurring in the first 100 days after negative remission (73% and 67%, respectively).368
allogeneic HCT compared with 57% sensitivity using WTI RQ-PCR
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The most difficult issue facing flow cytometry as an effective method for Because a high-quality sample is essential for reliable treatment
MRD monitoring is standardization and training. Flow cytometry relies evaluation, the NCCN AML Panel recommends that the optimal sample for
heavily on the expertise of the technician who must take into account MRD assessment is either peripheral blood for NPM1 PCR-based
variability in instruments, fluorochromes, analysis software, and individual techniques or the first pull/early pull of the bone marrow aspirate for other
antigens. Variations in the treatment schedule, dosing, type of treatment, PCR-, flow cytometry- and NGS-based assays. The timing of MRD
and time of draw are also potential variables. Despite the issues with flow assessments will vary and depend on the regimen used,243,353 but may
cytometry, research is focused on improving the method by defining occur after completion of initial induction332,333,360 and before allogeneic
threshold cutoff values369-372 as well as generating standards to equalize transplantation.375
data among different instruments and software programs. A study by
Feller et al373 further defined LAIPs and evaluated whether data from an Postremission Surveillance for AML
established MRD monitoring laboratory could be replicated in four centers Monitoring for CBCs, including platelets, every 1 to 3 months for the first 2
with no significant prior experience. Increased success rates of defining years after patients have completed consolidation therapy, then every 3 to
LAIPs were seen in all four centers after extensive group discussion. The 6 months thereafter up to 5 years, is recommended. Bone marrow
inexperienced laboratories had a success rate of 82% to 93% for defining evaluation should be performed only if the hemogram becomes abnormal,
at least one LAIP in a sample from 35 evaluable samples. The missed rather than as routine surveillance at fixed intervals, unless the bone
LAIPs would have resulted in 7% to 18% of the patients being unevaluable marrow evaluation is being performed as part of a clinical research
by MRD in these centers. The number of samples incorrectly evaluated protocol.
increases if they included samples in which at least two LAIPs were
identified by the primary lab, but the other labs only detected one LAIP. If no sibling donor has been identified, a donor search should be initiated
This accounted for an additional 9% to 20% of cases that would have at first relapse in appropriate patients concomitant with initiation of
resulted in false negatives. LAIPs with high specificity and sensitivity reinduction therapy. At relapse, the panel suggests conducting
(MRD levels of .01%) were very well-defined in the multicenter analysis. comprehensive molecular profiling using appropriate material to determine
With regard to the missed LAIPs, the authors proposed the design of the mutation status of actionable genes including FLT3 (ITD and TKD),
redundant panels to account for immunophenotypic shift. Inconsistencies IDH1, and IDH2 because it may guide selection of appropriate therapies
in LAIPs with MRD of 0.1% or lower may be resolved with the use of a (see Management of Relapsed/Refractory AML) and enrollment in
greater number of fluorochromes.374 Another important conclusion from appropriate clinical trials. Ongoing studies are evaluating the role of
this publication was the ability of these methods to be applied to different molecular monitoring in the surveillance for early relapse in patients with
instruments; both the Beckman Coulter and the Becton Dickinson AML (see Role of MRD Monitoring).
instruments were tested and obtained similar results. MRD monitoring is a
Management of Relapsed/Refractory AML
more feasible option if performed in core facilities until greater research is
done on the method to eliminate variability. Enrollment in clinical trials that Treatment of R/R AML is challenging and outcomes are poor.21,376 Many
provide MRD monitoring is encouraged. studies have also demonstrated that lack of early blast clearance or lack of
MS-57

response to the first induction cycle are major predictors for poor 5.6 months; HR, 0.64; 95% CI, 0.49–0.83; P < .001).307 In addition, the
outcomes.21,377,378 Intensive regimens generally achieve high second CR median EFS was longer in the gilteritinib group when compared to the
rates but do not generate substantial CR duration.379 Currently, allogeneic chemotherapy group at 2.8 months versus 0.7 months, respectively (HR
HCT at second CR is associated with relatively lower rates of relapse and for treatment failure or death, 0.79; 95% CI, 0.58–1.09).307 Based on
represents the only potentially curative option.21,376,380 Emerging data are these data, gilteritinib was approved by the FDA in November 2018 for
demonstrating the utility of targeted therapies in R/R AML.381 the treatment of adult patients who have R/R AML with a FLT3 mutation.
Targeted Therapy In a phase II study, the efficacy of azacitidine and sorafenib, a FLT3
FLT3-Positive AML: In a phase I/II study, the safety and tolerability of inhibitor, was evaluated in adult patients with R/R AML (n = 43; median
gilteritinib, a FLT3 inhibitor, was assessed in adult patients with R/R AML age, 67 years; range, 24–87 months).382 The response rate was 46%, with
(n = 252).306 In this group, 58 patients had wild-type FLT3 and 194 CR, CR/CRi, and PR rates of 16%, 27%, and 3%, respectively.382 In
patients had FLT3 mutations (FLT3-ITD, n = 162; FLT3-TKD/FLT3 D385, addition, the degree of FLT3-ITD inhibition appeared to correlate with
n = 16), and received oral gilteritinib (20–450 mg) once daily in one of plasma sorafenib concentrations.
seven dose-escalation or dose-expansion cohorts.306 Gilteritinib was
well-tolerated in this patient subpopulation and the most common grade IDH Mutation-Positive AML: The studies evaluating the efficacy of
3 or 4 adverse events were febrile neutropenia (39%), anemia (24%), ivosidenib301 and enasidenib300 in IDH1- and IDH2-mutation positive R/R
thrombocytopenia (13%), sepsis (11%) and pneumonia (11%).306 The AML, respectively, have been summarized in a previous section under
ORR in all patients with R/R AML was 40%, which was improved to 52% Management of AML in Patients Older Than 60 Years, for patients who
in FLT3-mutation positive AML patients treated with gilteritinib doses ≥80 are not candidates for or decline intensive remission induction therapy.
mg/day.306
CD33-Positive AML: In a study by Taksin et al, adult patients with AML
In a phase 3 trial, the efficacy of gilteritinib was compared to in first relapse (n = 57) received fractionated doses of GO, given at a
conventional chemotherapy used to treat R/R AML (n = 371).307 In this dose of 3 mg/m2 on days 1, 4, and 7 for one course.383 Fifteen patients
study, the four chemotherapy options included two high-intensity options achieved CR (26%) and 4 achieved CRp (7%). The median RFS was
(FLAG-Ida; and mitoxantrone plus etoposide and cytarabine [MEC]) and similar for patients who achieved CR and CRp and was 11 months.383 In
two low-intensity options (low-dose cytarabine and azacitidine). Of the addition, no veno-occlusive disease (sinusoidal obstructive syndromes)
371 eligible patients, 247 were randomly assigned to the gilteritinib group occurred after GO treatment or after GO followed by HCT (n = 7),
(120 mg/day) or the salvage chemotherapy group (n = 124). The although the authors recommended a minimum delay of 90 days
percentage of patients who had CR with full or partial hematologic between GO treatment and HCT.383
recovery was 34% and 15.3% in the gilteritinib and chemotherapy
Chemotherapy
groups, respectively.307 The median OS was significantly longer in the
The guidelines provide a list of several commonly used regimens for R/R
gilteritinib group compared to the chemotherapy group (9.3 months vs.
disease that are grouped as either aggressive or less aggressive therapy
MS-58

(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
respond 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, there were 5 patients still in CR with a median
CR and 16 (47.1) received subsequent allogeneic HCT.385 of 777 days (range, 461–888 days). Neutropenia and thrombocytopenia
grade III/IV were the most common adverse events (65% and 63%,
In a study of patients with resistant or relapsing AML (n = 38), patients respectively). Acute and chronic graft-versus-host disease (GVHD) were
were treated with fludarabine, cytarabine, and G-CSF, and overall 21 seen in 37% and 17% of patients, respectively. Correlations suggest a
patients (55%) achieved CR.386 In a study by Parker et al, patients with better response in patients with myelodysplasia-related changes
high-risk MDS/AML (n = 19; including R/R AML, n = 7), treated with (P = .011) and lower blast count (P = .039) or patients with high-risk
fludarabine, cytarabine, G-CSF, and idarubicin responded to therapy, with cytogenetics (P = .035). However, interpretation of results is limited by the
12 patients (63%) achieving CR.387 small size of the study.392
In a phase I study, a regimen with clofarabine, cytarabine, and idarubicin NCCN Recommendations
was evaluated in a subgroup of adult patients with R/R AML (n = 21) and The NCCN AML Panel recommends enrollment in a clinical trial for the
10 patients (48%) achieved CR.388 A regimen with clofarabine (40 mg/m2) management of R/R AML as a strongly preferred option. Other options
combined with cytarabine (2 g/m2) was evaluated in a randomized, include targeted therapy or chemotherapy followed by allogeneic HCT. For
placebo-controlled, phase III trial (CLASSIC I trial) in R/R AML, resulting in targeted therapies, the guidelines provide a list of options including
an ORR of 47% (CR rate, 35%) and a median OS of 6.6 months.389 A gilteritinib for patients with FLT3 mutations (a category 1
retrospective study compared clofarabine versus fludarabine in recommendation). Sorafenib may be added to HMAs (azacitidine or
combination with HiDAC with or without G-CSF.390 Patients treated with a decitabine) for patients with FLT3-ITD mutations. Other targeted therapy
clofarabine-based regimen (n = 50) compared to a fludarabine-based options include GO for patients with CD33-positive AML, and ivosidenib or
enasidenib for patients with IDH1 or IDH2 mutations, respectively.
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The regimens for aggressive therapy include: 1) cladribine, cytarabine, (HiDAC or ATO) or because of patient-specific comorbidities. These
and G-CSF, with or without mitoxantrone or idarubicin;384,385 2) HiDAC, if supportive care measures are tailored to address the specific needs and
not previously received in treatment, with or without anthracycline240; 3) infection susceptibility of each individual patient.
fludarabine, cytarabine, and G-CSF (FLAG regimen) with or without
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.
In some cases, if a patient has experienced a long first remission (≥12 Standard tumor lysis prophylaxis includes hydration with diuresis, and
months), repeating treatment with a successful induction regimen may be allopurinol administration or rasburicase treatment. Rasburicase is a
considered. This strategy primarily applies to cytotoxic chemotherapy genetically engineered recombinant form of urate oxidase enzyme.
regimens and excludes the use of dual-drug encapsulation of cytarabine Rasburicase should be considered as initial treatment in patients with
and daunorubicin, and the re-use of targeted agents due to the potential rapidly increasing blast counts, high uric acid, or evidence of impaired
development of resistance. Targeted therapies may be retried if they were renal function.399 When possible, patients should be evaluated for glucose-
not administered continuously and not stopped due to the development of 6-phosphate dehydrogenase (G6PD) deficiency, as rasburicase use in
clinical resistance. If a second CR is achieved, consolidation with these patients is contraindicated and is associated with an increased risk
allogeneic HCT should be considered. of inducing hemolysis.400,401 Urine alkalinization was previously
recommended as a means to increase uric acid solubility and reduce the
Supportive Care for Patients with AML potential for uric acid precipitation in the tubules. However, this method is
Although variations exist between institutional standards and practices, not generally favored as there are no data to support this practice and
several supportive care issues are important to consider in the similar effects could be seen with saline hydration alone.402 Alkalinization
management of patients with AML. In general, supportive care measures can complicate care by increasing calcium phosphate deposits in vital
may include the use of blood products for transfusion support and organs (eg, kidney, heart) as a result of hyperphosphatemia. Furthermore,
correction of coagulopathies, tumor lysis prophylaxis, anti-infective in contrast to allopurinol, rasburicase has the added benefit of rapid
prophylaxis, and growth factor support. Monitoring for neurologic and breakdown of serum uric acid, eliminating the need for urine alkalinization.
cardiovascular toxicities may be required for particular therapeutic agents
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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
HiDAC should also be discontinued in patients with rapidly rising Supportive Care for Patients with AML Who Prefer Not to Receive
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
regarding the prevention and treatment of cancer-related infections can be significant issue faced in a narrow spectrum of clinical settings. In this
found in the NCCN supportive care guidelines (see NCCN Clinical context, the panel reviewed the existing literature and collective
Practice Guidelines for Prevention and Treatment of Cancer-Related experience with this issue and summarized some considerations to guide
Infections) and commensurate with the institutional practice for antibiotic treatment and supportive care. However, it is important to note that the
stewardship. panel believes that in many cases, good outcomes from these strategies
are rare.
Growth factors (G-CSF or granulocyte macrophage colony-stimulating
factor [GM-CSF]) are not recommended during induction for patients with At the outset, it is important to discuss the goals of care with the patient
APL as they can complicate assessment of response and increase the risk and establish an understanding of the complications that can arise
of differentiation syndrome. However, in patients with AML (non-APL), without transfusions. In addition, it will be helpful to ascertain if the
growth factors may be considered during induction for patients who are patient will accept certain blood products (eg, cryoprecipitate) and stem
septic and who have a life-threatening infection in an attempt to shorten cells (either autologous or from another donor source). To mobilize
the duration of neutropenia. Some regimens such as FLAG incorporate G- peripheral blood stem cells and/or bring up hemoglobin levels prior to
CSF into the regimen. However, the use of growth factors may complicate peripheral blood stem cell transplantation, some treatment centers have
the interpretation of marrow results. There is a recommendation to used erythropoietin stimulating agents (ESAs), G-CSF, and
discontinue colony-stimulating factors at least a week before a planned thrombopoietin (TPO) mimetics.405-407 However, before using this
marrow sample to assess remission status. strategy, the potential risks, benefits and uncertainties of using these
agents in this context should be thoroughly discussed. Consider referring
MS-61

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 refuse 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 unlikely to result in durable given twice weekly until the cytology shows no blasts, and then weekly for
remissions.411 During treatment, measures should be taken to minimize 4 to 6 weeks. Importantly, IT therapy should only be administered by
blood loss and decreased the risk of bleeding including: the use of clinicians with experience and expertise in the delivery of IT agents.
pediatric collection tubes; avoiding concomitant medications or procedures HiDAC has significant penetration across the blood–brain barrier and may
that increase the risk of bleeding or myelosuppression; use of oral represent an alternative to repeated IT injections during induction therapy.
contraceptive pills or medroxyprogesterone acetate in menstruating The cerebrospinal fluid must then be reassessed after completion of
women; or proton pump inhibitors, as indicated.406,413 Vitamin K may be induction therapy, and further IT therapy should be given as appropriate.
considered as an adjuvant to improve coagulopathy.406,413 In patients at
risk of bleeding (eg, when platelet counts drop below 30,000/mcL), If the initial CT/MRI identifies a mass effect or increased intracranial
aminocaproic acid or tranexamic acid may be considered to manage pressure due to a parenchymal lesion in the brain, a needle aspiration or
bleeding.406,413 In patients with elemental or vitamin deficiencies, consider biopsy may be considered. If the results are positive, then radiation
iron, folate, and vitamin B12 supplementation.406,413 In patients with severe therapy is recommended, followed by IT therapy, as described earlier. IT
anemia, consider bed rest and supplemental oxygenation.406,413 therapy or HiDAC should not be administered concurrently with cranial
radiation because of the increased risks of neurotoxicity. Another option
Evaluation and Treatment of CNS Leukemia for these patients includes HiDAC-containing therapy with dexamethasone
Leptomeningeal involvement is much less frequent (<3%) in patients with to help reduce intracranial pressure.
AML than in those with ALL; therefore, the panel does not recommend LP
as part of the routine diagnostic workup. However, if neurologic symptoms
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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
unknown but its association with MDS in some cases may suggest a performed to rule out CNS disease, and if clinically indicated, follow the
related pathogenesis.414 Most patients are elderly with a median age of LP with IT prophylaxis.416
presentation of 65 to 67 years with an approximate male-to-female ratio
Induction Therapy for Patients with BPDCN
of 3:1. The most frequent clinical presentation of typical BPDCN cases is
asymptomatic solitary or multiple skin lesions.414 Peripheral blood and CD123-Targeted Therapy
bone marrow involvement may be minimal at presentation, but tend to Tagraxofusp (formerly SL-401) is a recombinant fusion protein made up
develop as the disease progresses.414 of the catalytic and translocation domains of diphtheria toxin (DT) fused
to IL3. In pilot clinical study, 11 patients with recurrent or refractory
Workup BPDCN or who were not candidates for standard chemotherapy were
The evaluation and initial workup for suspected BPDCN consists of a treated with SL-401.418 Each cycle of SL-401 treatment was comprised of
comprehensive medical history and physical examination. Laboratory a 12.5µg/kg dose administered over a 15-minute infusion every day for
evaluations include a comprehensive metabolic panel and a CBC up to 5 doses.418 Of 9 evaluable patients who received treatment, 5 had
including platelets and a differential of WBCs. Analyses of peripheral a CR and 2 had a PR after one cycle of SL-401 treatment (78% response
blasts, bone marrow aspirate, and a lymph node biopsy is rate).418 The median duration of responses was 5 months (range, 1–20+
recommended. These analyses include dendritic cell morphology months) with responses occurring in all sites of disease including skin,
assessment, immunohistochemistry, flow cytometry, cytogenetic analysis bone marrow, and lymph nodes.418 Common adverse events including
MS-63

fever, chills, hypotension, edema, hypoalbuminemia, thrombocytopenia, doxorubicin, dexamethasone, methotrexate, and cytarabine), GIMEMA
and transaminasemia were 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
thrombocytopenia. In addition, capillary leak syndrome was observed in treatment with hyper-CVAD.421 In this group, seven patients received
19% of the patients and associated with one death in each of the dose induction treatment with hyper-CVAD and had a CR of 67% and ORR of
subgroups.419 Based on these data, in 2018 the FDA approved 86%. Five of the six patients who responded to therapy received planned
tagraxofusp-erzs for BPDCN in adults and pediatric patients at least 2 allogeneic stem cell transplantation. For a median follow-up of 13.3
years of age. months, the one-year DFS and OS rates for all patients was 56% and
67%, respectively.421 For patients who received chemotherapy alone, the
Chemotherapy
median OS was 7.9 months, but the median OS was not reached for
Historically, therapeutic approaches for CD4+CD56+ malignancies have patients who received transplantation.421
varied widely and include irradiation for localized stages, lymphoma- or
leukemia-type regimens, and myeloablative therapy.420 In a retrospective Hematopoietic Stem Cell Transplantation
multicenter study, 41 patients with BPDCN received induction treatment Due to the rarity of BPDCN, there have been limited established
with AML-type regimens (n = 26) and ALL-type/lymphoma-type regimens standardized therapeutic approaches.422 Hematopoietic cell
(n = 15).415 The AML-type treatment protocols included MICE transplantation (HCT) seems to generate durable remissions, especially
(mitoxantrone, cytarabine, etoposide), ICE (idarubicin, cytarabine, if given in first CR.420,422-424 However, it is worth noting that data are
etoposide), standard-dose cytarabine and anthracycline (7+3), FLAG, limited to small case series and retrospective registry studies, and larger
and FLAG-Ida. The ALL/lymphoma-type regimens included hyper-CVAD prospective studies are needed to elucidate the role of HCT in
(alternative cycles of hyperfractionated cyclophosphamide, vincristine, BPDCN.424
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In a retrospective study from the European Society for Blood and Marrow NCCN Recommendations
Transplantation, an analysis was conducted to determine whether long- For patients who are candidates for intensive remission induction
term DFS could be achieved in patients with BPDCN who received therapy, the panel recommends tagraxofusp-ersz as the preferred
allogeneic HCT or autologous HCT after high-dose chemotherapy (n = option, and other options include AML-type (standard-dose cytarabine
39).422 Nineteen patients received allogeneic HCT in first CR and in this plus anthracycline using 7+3), ALL-type (hyper-CVAD), and lymphoma-
group the 3-year cumulative incidence of relapse, DFS, and OS was type (CHOP) regimens.
32%, 33%, and 41%, respectively.422 By univariate comparison, being in
first remission at allogeneic HCT significantly enhanced survival, Tagraxofusp-ersz should be administered as an intravenous infusion at
whereas age, donor source, and GVHD did not significantly impact 12 µg/kg over 15 minutes once daily on days 1 to 5 of each 21-day cycle.
survival.422 Alternatively, 5 doses can be administered over a 10-day period, if
needed for dose delays. It is important to note that patients must have a
A retrospective analysis from the Japan Society for Hematopoietic Cell baseline serum albumin of 3.2 g/dL or higher to be able to start treatment
Transplantation aimed to clarify the role of allogeneic HCT or autologous with this agent. The most serious side effect associated with tagraxofusp
HCT in treating BPDCN.423 In this analysis, 25 patients were identified, is capillary leak syndrome, which can occur during the first cycle of
with 14 patients having undergone allogeneic HCT and 11 patients treatment and is life-threatening.419 A decrease in serum albumin during
having undergone autologous HCT. All patients who underwent the first days of treatment seems to be the most consistent predictor of
autologous HCT were in first CR.423 With a median follow-up of 53.5 capillary leak syndrome.419 Management includes delaying or withholding
months, the OS rates at 4 years for patients who underwent autologous additional tagraxofusp doses, administering intravenous albumin
HCT and allogeneic HCT were 82% and 53%, respectively (P = .11) and according to pre-specified measures, administering glucocorticoids, and
the PFS rates were 73% and 48%, respectively (P = .14).423 The data close management of volume status.419 The panel recommends
suggest that receiving autologous HCT in first CR may significantly replacing serum albumin if <3.5 g/dL or if there is a reduction of ≥0.5
enhance survival.423 from baseline.
A North American multicenter retrospective study analyzed the outcomes If CNS disease is documented at diagnosis or if clinically indicated, IT
of BPDCN patients treated with allogeneic HCT (n = 37) or autologous chemotherapy should also be given. With all treatment options, if CR is
HCT (n = 8).424 Allogeneic HCT recipients had a 1-year and 3-year OS of observed, allogeneic HCT or autologous HCT should be considered. If
68% (95% CI, 49%–81%) and 58% (95% CI, 38%–75%), respectively.424 tagraxofusp was given as an initial treatment, additional cycles of therapy
Receiving allogeneic HCT in first CR yielded improved 3-year OS versus should be continued until disease progression. If disease progresses or
allogeneic HCT not in first CR [74% (95% CI, 48%–89%) vs. 0, P < does not respond to induction therapy, these patients should be
.0001]. The 1-year OS for autologous HCT recipients was 11% (95% CI, considered for a clinical trial (preferred) or salvage regimens used for
8%–50%).424 R/R disease.
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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
disease, a repeat PET/CT scan is recommended. In addition, a re-biopsy
should be considered for any suspicious skin or extramedullary lesions.
Management of Relapsed/Refractory BPDCN

Upon relapse, the NCCN AML Panel recommends evaluating for CNS
disease/prophylaxis.425 Management options for R/R BPDCN include
clinical trial (preferred), tagraxofusp-ersz (preferred, if not already
used),419 chemotherapy (if not already given), local radiation to isolated
lesions, systemic steroids, or venetoclax-based regimens.391,426 During
administration of any treatment option, a donor search should also be
started at first relapse in appropriate patients if no sibling donor has been
identified.
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Acute Myeloid Leukemia: NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines)

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

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NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®)

Acute Myeloid Leukemia

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

NCCN Guidelines Version 1.2022 NCCN Guidelines Index

*Daniel A. Pollyea, MD, MS/Chair ‡ Þ † Jeffrey Lancet, MD ‡ † Amanda Przespolewski, DO ‡

NCCN Guidelines Version 1.2022 NCCN Guidelines Index

NCCN Acute Myeloid Leukemia Panel Members

NCCN Guidelines Version 1.2022 NCCN Guidelines Index

Acute Promyelocytic Leukemia (Age ≥18 years)

NCCN Guidelines Version 1.2022 NCCN Guidelines Index

Acute Myeloid Leukemia (Age ≥18 years)

NCCN Guidelines Version 1.2022 NCCN Guidelines Index

NCCN Guidelines Version 1.2022 NCCN Guidelines Index

Blastic Plasmacytoid Dendritic Cell Neoplasm

BPDCN-B - EVALUATION AND TREATMENT OF CNS DISEASE

NCCN Guidelines Version 1.2022 NCCN Guidelines Index

EVALUATION FOR AML DIAGNOSTIC DIAGNOSISd,e,f,g

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

NCCN Guidelines Version 1.2022 NCCN Guidelines Index

FOOTNOTES FOR EVALUATION FOR AML

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

NCCN Guidelines Version 1.2022 NCCN Guidelines Index

APL CLASSIFICATION AND TREATMENT RECOMMENDATIONS

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

Cardiac issues See Treatment

a Therapy-related APL is treated the same as de novo APL.

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

NCCN Guidelines Version 1.2022 NCCN Guidelines Index

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

See footnotes on APL-2A

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

NCCN Guidelines Version 1.2022 NCCN Guidelines Index

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

NCCN Guidelines Version 1.2022 NCCN Guidelines Index

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

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

NCCN Guidelines Version 1.2022 NCCN Guidelines Index

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

NCCN Guidelines Version 1.2022 NCCN Guidelines Index

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

Low Ejection Fraction

See footnotes on APL-4A

NCCN Guidelines Version 1.2022 NCCN Guidelines Index

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

NCCN Guidelines Version 1.2022 NCCN Guidelines Index

APL POST- MONITORING

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

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

NCCN Guidelines Version 1.2022 NCCN Guidelines Index

APL THERAPY FOR RELAPSE ADDITIONAL THERAPY

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

NCCN Guidelines Version 1.2022 NCCN Guidelines Index

PRINCIPLES OF SUPPORTIVE CARE FOR APL1

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

NCCN Guidelines Version 1.2022 NCCN Guidelines Index

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

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

NCCN Guidelines Version 1.2022 NCCN Guidelines Index

FOOTNOTES FOR TREATMENT INDUCTION ELIGIBLE (AGE <60 YEARS)

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

NCCN Guidelines Version 1.2022 NCCN Guidelines Index

See footnotes on AML-2A

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