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NCCN Guidelines for Patients

available at www.nccn.org/patients

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines

)

Acute Myeloid Leukemia

Version 3.2021 — March 2, 2021

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*Martin S. Tallman, MD/Chair ‡

Memorial Sloan Kettering Cancer Center

*Daniel A. Pollyea, MD, MS/Vice Chair ‡ Þ †

University of Colorado Cancer Center

Jessica K. Altman, MD ‡

Robert H. Lurie Comprehensive Cancer

Center of Northwestern University

Frederick R. Appelbaum, MD † Þ

Fred Hutchinson Cancer Research Center/

Seattle Cancer Care Alliance

Vijaya Raj Bhatt, MBBS ‡ ξ

Fred & Pamela Buffett Cancer Center

Dale Bixby, MD, PhD ‡ † Þ

University of Michigan

Rogel Cancer Center

Marcos de Lima, MD ‡

Case Comprehensive Cancer Center/

University Hospitals Seidman Cancer Center

and Cleveland Clinic Taussig Cancer Institute

Amir T. Fathi, MD ‡ †

Massachusetts General Hospital Cancer Center

James M. Foran, MD †

Mayo Clinic Cancer Center

Ivana Gojo, MD ‡

The Sidney Kimmel Comprehensive

Cancer Center at Johns Hopkins

Aric C. Hall, MD ‡ † ξ

University of Wisconsin

Carbone Cancer Center

Meagan Jacoby, MD, PhD ‡ † ξ

Siteman Cancer Center at Barnes-

Jewish Hospital and Washington

University School of Medicine

Jeffrey Lancet, MD ‡ †

Moffitt Cancer Center

Gabriel Mannis, MD ‡ Þ

Stanford Cancer Institute

Guido Marcucci, MD † Þ

City of Hope National Medical Center

Michael G. Martin, MD †

St. Jude Children’s Research Hospital/

The University of Tennessee

Health Science Center

Alice Mims, MD, MS †

The Ohio State University Comprehensive

Cancer Center - James Cancer Hospital

and Solove Research Institute

Jadee Neff, MD, PhD ≠

Duke Cancer Institute

Reza Nejati, MD ≠

Fox Chase Cancer Center

Rebecca Olin, MD, MS ‡ ξ

UCSF Helen Diller Family

Comprehensive Cancer Center

Mary-Elizabeth Percival, MD, MS ‡

Fred Hutchinson Cancer Research Center/

Seattle Cancer Care Alliance

Alexander Perl, MD †

Abramson Cancer Center at the

University of Pennsylvania

Thomas Prebet, MD, PhD ‡

Yale Cancer Center/Smilow Cancer Hospital

Amanda Przespolewski, DO ‡

Roswell Park Comprehensive Cancer Center

Dinesh Rao, MD, PhD ≠

UCLA Jonsson Comprehensive Cancer Center

Farhad Ravandi, MD Þ ‡

The University of Texas

MD Anderson Cancer Center

Paul J. Shami, MD ‡

Huntsman Cancer Institute

at the University of Utah

Richard M. Stone, MD ‡ †

Dana-Farber/Brigham and Women’s

Cancer Center

Stephen A. Strickland, MD, MSCI ‡

Vanderbilt-Ingram Cancer Center

Kendra Sweet, MD, MS ‡ Þ †

Moffitt Cancer Center

Pankit Vachhani, MD ‡

O'Neal Comprehensive Cancer Center at UAB

Matthew Wieduwilt, MD, PhD ‡ ξ

UC San Diego Moores Cancer Center

NCCN

Kristina Gregory, RN, MSN, OCN

Ndiya Ogba, PhD

Continue

NCCN Guidelines Panel Disclosures

Bone marrow transplantation

‡

Hematology/Hematology oncology

Internal medicine

†

Medical oncology

≠

Pathology

Discussion Section Writing Committee Member

NCCN Guidelines Version 3.2021

Acute Myeloid Leukemia (Age ≥18 years)

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and this illustration may not be reproduced in any form without the express written permission of NCCN.

NCCN Guidelines Index

Table of Contents

Discussion

Clinical Trials: NCCN believes that the

best management for any patient with

cancer is in a clinical trial.

Participation in clinical trials is especially

encouraged.

To nd clinical trials online at NCCN

Member Institutions, click here:

nccn.org/clinical_trials/member_

institutions.aspx.

NCCN Categories of Evidence and

Consensus: All recommendations are

category 2A unless otherwise indicated.

See NCCN Categories of Evidence

and Consensus.

NCCN Categories of Preference:

All recommendations are considered

appropriate.

See NCCN Categories of Preference.

Evaluation for Acute Leukemia (EVAL-1)

APL

• Classication and Treatment Recommendations

(APL-1)

• Low-Risk Treatment Induction and Consolidation

Therapy (APL-2)

• High-Risk Induction and Consolidation Therapy

(APL-3)

• Post-Consolidation Therapy and Monitoring (APL-

• Therapy for Relapse (APL-6)

• Principles of Supportive Care (APL-A)

AML

• (Age <60 y) Treatment Strategies and Induction

(AML-1)

• (Age <60 y) Risk Status and Post-Remission

Therapy (AML-4)

• (Age ≥60 y) Treatment Strategies and Induction -

Candidates for Intensive Therapy (AML-5)

• (Age ≥60 y) Treatment Strategies and Induction -

Non-Candidates for Intensive Therapy (AML-6)

• (Age ≥60 y) Post-Remission Therapy - Previous

Intensive Therapy (AML-8)

• (Age ≥60 y) Post-Induction Therapy - Previous

Lower Intensity Therapy (AML-9)

• Surveillance and Therapy for Relapsed/Refractory

Disease (AML-10)

AML

• Risk Stratication by Genetics in Non-APL AML

(AML-A)

• Evaluation and Treatment of CNS Leukemia

(AML-B)

• Principles of Radiation Therapy (AML-C)

• General Considerations and Supportive Care

for Patients Who Prefer Not to Receive Blood

Transfusions (AML-D)

• Principles of Supportive Care for AML (AML-E)

• Monitoring During Therapy (AML-F)

• Measurable (Minimal) Residual Disease

Assessment (AML-G)

• Response Criteria Denitions for Acute Myeloid

Leukemia (AML-H)

• Therapy for Relapsed/Refractory Disease (AML-I)

• Principles of Venetoclax Use with HMA or LDAC-

Based Treatment (AML-J)

BPDCN

• Introduction (BPDCN-INTRO)

• Workup/Evaluation (BPDCN-1)

• Treatment (BPDCN-2)

• Surveillance and Relapse/Refractory Disease

(BPDCN-3)

• Principles of Blastic Plasmacytoid Dendritic Cell

Neoplasm (BPDCN-A)

• Principles of Supportive Care for Blastic

Plasmacytoid Dendritic Cell Neoplasm (BPDCN-B)

The NCCN Guidelines

are a statement of evidence and consensus of the authors regarding their views of currently accepted approaches to treatment.

Any clinician seeking to apply or consult the NCCN Guidelines is expected to use independent medical judgment in the context of individual clinical

circumstances to determine any patient’s care or treatment. The National Comprehensive Cancer Network

(NCCN

) makes no representations or

warranties of any kind regarding their content, use or application and disclaims any responsibility for their application or use in any way. The NCCN

Guidelines are copyrighted by National Comprehensive Cancer Network

NCCN Acute Myeloid Leukemia Panel Members

Summary of Guidelines Updates

NCCN Guidelines Version 3.2021

Acute Myeloid Leukemia (Age ≥18 years)

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

NCCN Guidelines Index

Table of Contents

Discussion

UPDATES

Continued

Updates in Version 1.2021 of the NCCN Guidelines for Acute Myeloid Leukemia from Version 4.2020 include:

EVAL-1

• Evaluation for Acute Leukemia

Bullet 4 modied: Bone marrow (BM) core biopsy and aspirate analyses, including immunophenotyping and cytochemistry by

immunohistochemistry (IHC) stains + ow cytometry

Bullet 6 modied: Molecular analyses (ASXL1, c-KIT, FLT3 [ITD and TKD], NPM1, CEBPA (biallelic), IDH1, IDH2, RUNX1, TP53, and other

mutations.

• Diagnosis; AML

To appropriately stratify available intensive therapy options, expedite test results of molecular and cytogenetic analyses (maximum 3-5

days) for immediately actionable mutations

Bullet 1 modied: For patients with highly proliferative cancers hyperleukocytosis uncontrolled with hydroxyurea or leukapheresis, one

dose of intermediate-dose cytarabine (1–2 gm) may be considered prior to receiving results.

Bullet added: For patients who prefer not to receive blood transfusion(s), see AML-D for general considerations and supportive care

Bullet removed: Appropriate management of leukocytosis is recommended while awaiting cytogenetic and molecular test results

Updates in Version 2.2021 of the NCCN Guidelines for Acute Myeloid Leukemia from Version 1.2021 include:

EVAL-1

• Diagnosis; AML

To appropriately stratify available intensive therapy options, expedite test results of molecular and cytogenetic analyses for immediately

actionable mutations or chromosomal abnormalities.

AML-A 2 of 3

• Bullet 1 modied: Patients with a family history of leukemia, or of hematologic cancer or abnormalities, together with the presence

of genetic mutations outlined in the table below should be considered for germline testing or and genetic counseling. It is strongly

recommended that patients with a germline variant allele frequency (VAF) of 40%–60% of genes associated with a predisposition syndrome

be referred for germline testing

MS-1

• The Discussion section has been updated to reect the changes in the algorithm.

Updates in Version 3.2021 of the NCCN Guidelines for Acute Myeloid Leukemia from Version 2.2021 include:

AML-H

• Complete response

4th sub-bullet revised, "CR with incomplete hematologic recovery (CRi)- All CR criteria and transfusion independence but with persistence

of neutropenia (<1,000/mcL) and or thrombocytopenia (<100,000/mcL)."

NCCN Guidelines Version 3.2021

Acute Myeloid Leukemia (Age ≥18 years)

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

NCCN Guidelines Index

Table of Contents

Discussion

Continued

UPDATES

EVAL-1A

• Footnote a modied; second and fourth sentences: Other mutations genetic lesions, such as ASXL1, BCR-ABL, and PML-RAR alpha (See

AML-A) may have therapeutic implications. The eld of genomics in myeloid malignancies and related implications in AML are evolving

rapidly. While the above mutations should be tested in all patients, multiplex gene panels and comprehensive next-generation sequencing

analysis are recommended for a comprehensive prognostic assessment the ongoing management of AML and various phases of treatment.

• Footnote b modied with removal of the following (already represented on AML-B): For patients with major neurologic signs or symptoms

at diagnosis, appropriate imaging studies should be performed to detect meningeal disease, chloromas, or CNS bleeding. LP should be

performed if no mass lesion is detected on the imaging study with central shift making an LP relatively contraindicated. Screening LP should

be considered at rst remission before rst consolidation for patients with monocytic dierentiation, mixed phenotype acute leukemia

(MPAL), WBC count >40,000/mcL at diagnosis, extramedullary disease, or high-risk APL

APL-2

• After induction with preferred regimens, monitoring recommendations modied:

If blood count recovery by day 28 (platelet >100,000, ANC >1,000), proceed with consolidation. BM aspirate and biopsy day 28–35 (if

cytopenic) may be considered to document morphologic remission but is optional.

If full course of induction treatment not given, or counts have not recovered by day 28–35, a BM aspirate and biopsy is recommended to

document morphologic remission before proceeding with consolidation.

• Consolidation Therapy modied for 2nd preferred regimen:

ATRA 45 mg/m

for 2 weeks every 4 weeks (or for 2 weeks on 2 weeks o) in consolidation courses 1–4 + arsenic trioxide 0.3 mg/kg IV on

days 1–5 of week one in consolidation courses 1–4 and 0.25 mg/kg twice weekly in weeks 2–4 in consolidation courses 1–4 (category 1)

replaced with

First 3 consolidation cycles = 56-day cycles:

ATRA 45 mg/m

/d PO divided into 2 daily doses on days 1–14 and 29–42 (2 weeks on followed by 2 weeks o) + arsenic trioxide 0.3 mg/kg

on days 1–5 of week 1 followed by 0.25 mg/kg twice weekly during weeks 2–4

4th consolidation cycle = 28 day cycle:

ATRA 45 mg/m

/d PO divided into 2 daily doses on days 1–14 (2 weeks on followed by 2 weeks o) + arsenic trioxide 0.3 mg/kg on days 1–5

of week 1 followed by 0.25 mg/kg twice weekly during weeks 2–4

• Other Recommended changed to Useful in Certain Circumstances (if contraindications to arsenic is not available or contraindicated)

Regimen added

◊ Induction: ATRA 45 mg/m

in 2 divided doses daily + a single dose of gemtuzumab ozogamicin 9 mg/m

on day 5

◊ Consolidation: ATRA 45 mg/m

in divided doses daily during weeks 1–2, 5–6, 9–10, 13–14, 17–18, 21–22, and 25–26. A single dose of

gemtuzumab ozogamicin 9 mg/m

may be given monthly until 28 weeks from CR

APL-2A

• Footnote k added: Estey et al. Blood 2002;99:4222-4224.

Updates in Version 1.2021 of the NCCN Guidelines for Acute Myeloid Leukemia from Version 4.2020 include:

NCCN Guidelines Version 3.2021

Acute Myeloid Leukemia (Age ≥18 years)

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

NCCN Guidelines Index

Table of Contents

Discussion

Continued

UPDATES

Updates in Version 1.2021 of the NCCN Guidelines for Acute Myeloid Leukemia from Version 4.2020 include:

APL-4

• APL Treatment Induction (High Risk) in Patients with Cardiac Issues; Prolonged QTc

• Regimens added

Induction: ATRA 45 mg/m

in 2 divided doses + daunorubicin 60 mg/m

x 3 days + cytarabine 200 mg/m

x 7 days

Consolidation: Daunorubicin 60 mg/m

x 3 days + cytarabine 200 mg/m

x 7 days x 1 cycle, then cytarabine 2 g/m

(age <50) or 1.5 g/m

(age

50–60) every 12 h x 5 days + daunorubicin 45 mg/m

x 3 days x 1 cycle + 5 doses of intrathecal (IT) chemotherapy

Induction: ATRA

45 mg/m

in 2 divided doses + idarubicin 12 mg/m

on days 2, 4, 6, 8

Consolidation: ATRA 45 mg/m

x 15 days + idarubicin 5 mg/m

and cytarabine 1 g/m

x 4 days x 1 cycle, then ATRA x 15 days + mitoxantrone

10 mg/m

/d x 5 days x 1 cycle, then ATRA x 15 days + idarubicin 12 mg/m

x 1 day + cytarabine 150 mg/m

over 8 h x 4 days x 1 cycle

APL-A

• APL dierentiation syndrome; sub-bullet 3 modied: The following cytoreduction strategies for leukocytosis may be used for dierentiation

syndrome that is dicult to treat: cytoreduction, hydroxyurea, anthracycline, gemtuzumab ozogamicin.

• Arsenic trioxide monitoring; sub-bullet 2, diamond 3 added: 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.

• Reference 3 added: Sanz MA, Fenaux P, Tallman MS, et al. Management of acute promyelocytic leukemia: updated recommendations from an

expert panel of the European LeukemiaNet. Blood 2019;133:1630-1643.

AML-1

• Age claried as physiologic age (applies throughout AML section)

• Favorable-risk cytogenetics

Preferred noted for standard-dose cytarabine with daunorubicin and gemtuzumab ozogamicin (CD33-positive)

Regimen added: Fludarabine 30 mg/m

IV days 2–6, HiDAC 2 g/m

over 4 hours starting 4 hours after udarabine IV on days 2–6, idarubicin

8 mg/m

IV on days 4–6, and granulocyte colony-stimulating factor (G-CSF) subcutaneously (SC) daily days 1–7 plus a single dose of

gemtuzumab ozogamicin 3 mg/m

in rst course (category 2B)

• Category added for Unfavorable risk cytogenetics and TP53-mutated

Alternative induction strategies should be considered

• Other recommended regimens for intermediate- or poor-risk disease

Regimen removed: Standard dose cytarabine with daunorubicin and cladribine

HiDAC regimen modied with a dose change for daunorubicin from 60 to 50 mg and the addition of etoposide 50 mg/m

days 1–5

AML-1A

• Footnote f added: Consider referral to palliative care for consultation at the start of induction. LeBlanc T, et al. Curr Hematol Malig Rep.

2017;12:300-308 and LeBlanc T, et al. J Oncol Pract. 2017;13:589-590. See NCCN Guidelines for Palliative Care. (also applies to AML-2A, AML-

3, AML-5A, AML-6A, AML-7)

• Footnote g added: See General Considerations and Supportive Care for AML Patients who Prefer not to receive Blood Transfusions (AML-D).

(also applies to AML-6A)

NCCN Guidelines Version 3.2021

Acute Myeloid Leukemia (Age ≥18 years)

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

NCCN Guidelines Index

Table of Contents

Discussion

UPDATES

Continued

Updates in Version 1.2021 of the NCCN Guidelines for Acute Myeloid Leukemia from Version 4.2020 include:

• Footnote o modied: 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.

• Footnote s added: Willemze R, et al. J Clin Oncol 2014;32:219-228.

• Footnote removed: Holowiecki J, et al. J Clin Oncol 2012;30:2441-2448. Although this trial showed an advantage for the addition of cladribine

to standard 7+3, BM aspirates were not performed after the rst cycle of induction until either counts recovered or blasts reappeared in the

peripheral blood, which would delay administration of a second cycle of induction compared to standard practice in the United States

AML-2A

• Footnote v added: There are limited prospective data to support this recommendation. Othus M, et al. Leukemia 2016;30:1779-1780. (also

applies to AML-7)

• Footnote removed: For patients with residual blasts after induction with standard-dose cytarabine with daunorubicin and cladribine, a

second cycle of the same induction regimen can be given if >50% cytoreduction.

AML-4

• Risk status categories modied

CBF cytogenetic translocations without KIT mutation and MRD negative

Intermediate-risk cytogenetics and/or molecular abnormalities, including MRD positive

AML-4A

• Footnote  modied: 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. (also applies to AML-5A, AML-8A)

AML-5A

• Footnote ll modied: 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://www.fhcrc-research.org/TRM/Default.aspx?GUID=1358501B-C922-4422-84F0-

0E6C67D8F266 and Walter RB, et al. J Clin Oncol. 2011;29:4417-4423. Factors in decisions about tness for induction chemotherapy include

age, performance status, functional status, and comorbid conditions. See NCCN Guidelines for Older Adult Oncology. (also applies to AML-

6A)

• Footnote mm added: Patients with TP53 mutations are a group with poor prognosis, and should be considered for enrollment in clinical

trials.

• Footnote nn added: Castaigne S, et al. Lancet 2012;379:1508-1516.

• Footnote rr modied: 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. (also applies to

AML-6A, AML-9)

• Footnote tt added: Wei AH, et al. J Clin Oncol 2019;37:1277-1284. (added to AML-6A, AML-9)

• Footnote vv added: Regimens that include gemtuzumab ozogamicin have limited benet in patients with poor-risk disease.

NCCN Guidelines Version 3.2021

Acute Myeloid Leukemia (Age ≥18 years)

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

NCCN Guidelines Index

Table of Contents

Discussion

UPDATES

Continued

Updates in Version 1.2021 of the NCCN Guidelines for Acute Myeloid Leukemia from Version 4.2020 include:

AML-6

• Regimens noted as preferred or other recommended

• AML without actionable mutations

Venetoclax and azacitidine noted as category 1 and preferred

Venetoclax and decitabine noted as preferred

LDAC dosing added: 20 mg/m

/day SC for 10 consecutive days every 4 weeks

• IDH1 of IDH2 mutation or FLT3 mutation

Venetoclax-based therapy with azacitidine noted as category 1 and preferred

Venetoclax-based therapy with decitabine noted as preferred

AML-6A

• Footnote ww modied: 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.

• Footnote yy added: Regimens that include gemtuzumab ozogamicin will not benet patients with poor-risk disease.

• Footnote zz added: Kantarjian HM, et al. J Clin Oncol 2012;30:2670-2677.

• Footnote aaa modied: 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. (also appiles to AML-9)

• Footnote ddd added: Ohanian M, et al. Am J Hematol 2018;93:1136-1141. (also applies to AML-9)

• Footnote removed: Ravandi F, et al. Blood 2013;121:4655-4662. (also applies to AML-9)

AML-7

• Treatment option modied: Reduced-intensity Consider allogeneic HCT

• Footnote eee modied: Reduced-intensity Allogeneic transplant is a reasonable option in patients who experience failure after re-induction

with certain regimens (eg, intermediate- or high-dose cytarabine), and have with identied donors available to start conditioning within 4–6

weeks from start of induction therapy. Patients without an identied donor would most likely need some additional therapy as a bridge to

transplant. Reduced-intensity HCT may be appropriate for patients with a low level of residual disease post-induction (eg, patients with prior

MDS who reverted back to MDS with <10% blasts). It is preferred that this approach be given in the context of a clinical trial. For patients

with residual disease after 1 cycle of induction chemotherapy who would not tolerate another intensive salvage, consider a venetoclax-

based regimen.

AML-8

• Complete response

Treatment option modied: Intermediate-dose cytarabine 1–1.5 g/m

over 3 h every 12 h on days 1, 3, and 5 or 1 g/m

over 3 h every 12 h on

days 1, 3, 5 (total 6 doses) for a total of 4 planned cycles with oral midostaurin 50 mg every 12 h on days 8–21

NCCN Guidelines Version 3.2021

Acute Myeloid Leukemia (Age ≥18 years)

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

NCCN Guidelines Index

Table of Contents

Discussion

UPDATES

Continued

Updates in Version 1.2021 of the NCCN Guidelines for Acute Myeloid Leukemia from Version 4.2020 include:

AML-8A

• Footnote iii modied: 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 t

to receive 7+3 should be oered midostaurin since it seems to provide a survival benet without undue toxicity. Schlenk RF, et al. Blood

2019;133:840-851.

• Footnote jjj modied: 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. Huls G, et al. Blood. 2019;133:1457-1464.

• Footnote removed: An excellent outcome was reported for outpatient consolidation that provides another option for elderly patients. Gardin

C, et al. Blood 2007;109:5129-5135.

AML-9

• Guidance modied: Continue on lower-intensity regimen that was previously used per AML-6

AML-10

• Testing recommendations at relapse modied

Determine mutation status of actionable genes: FLT3 (ITD or TKD); IDH1; IDH2

changed to

Comprehensive genomic proling to determine mutation status of actionable genes

• Footnote nnn modied: Comprehensive molecular proling (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.

• Footnote ooo modied: Reinduction therapy may be appropriate in certain circumstances, such as in patients with long rst remission (an

exception is 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-A 2 of 3

• Table added for Familial Genetic Alterations in AML (continues on AML-A 3 of 3)

AML-B

• Footnote 2 modied: 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.

• Footnote 3 modied: Screening LP should be considered at rst remission before rst consolidation for patients with monocytic

dierentiation, 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.

NCCN Guidelines Version 3.2021

Acute Myeloid Leukemia (Age ≥18 years)

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

NCCN Guidelines Index

Table of Contents

Discussion

UPDATES

Continued

Updates in Version 1.2021 of the NCCN Guidelines for Acute Myeloid Leukemia from Version 4.2020 include:

AML-D

• New section added: General Considerations and Supportive Care for AML Patients Who Prefer Not to Receive Blood Transfusions

AML-E

• General; Blood products

Sub-bullet 2 modied: Irradiated blood products for patients receiving immunosuppressive therapy (ie, udarabine, HCT). All AML patients

are at risk for acute graft-versus-host disease (aGVHD) and management should be based on institutional practice/preference.

• General; Tumor lysis prophylaxis

Sub-bullet added: Glucose-6-phosphate dehydrogenase (G6PD) deciency should be checked when possible. However, it is not always

feasible to do so rapidly. If there high suspicion of G6PD deciency, caution is necessary; rasburicase may be contraindicated.

AML-G

• Bullet 3 modied: The most frequently employed methods for MRD assessment include real-time quantitative polymerase chain reaction

(RQ-PCR) assays (ie, NPM1, CBFB-MYH11, RUNX1-RUNX1T1), next-generation sequencing (NGS)–based assays to detect mutated genes

(targeted sequencing, 20–50 genes per panel), and multicolor ow cytometry (MFC) assays specically designed to detect abnormal MRD

immunophenotypes. The threshold to dene MRD+ and MRD- samples depends on the technique and subgroup of AML. Next-generation

sequencing (NGS)–based assays to detect mutated genes (targeted sequencing, 20–50 genes per panel) is not routinely used, as the

sensitivity of PCR-based assays and ow 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.

Sub-bullet 1 modied: There are distinct dierences between diagnostic threshold assessments and MRD assessments. If using ow

cytometry to assess MRD, it is recommended that a standard specic MRD assay is utilized, but, most importantly, that it is interpreted by

an experienced hematopathologist.

• Bullet 4 modied: 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, ow cytometry, NGS). The quality of the sample is of paramount

importance to have reliable evaluation.

• Bullet 5

Sub-bullet removed: A negative MRD result after induction, which depends on the technique used and the study, predicts a lower incidence

of relapse.

Sub-bullet 2 modied: For favorable-risk patients, if MRD is persistently positive after induction and/or consolidation, consider a clinical

trial or alternative therapies, (eg, including allogeneic transplantation, consolidation).

◊ Diamond 1 removed: Patients with t(8;21) AML in remission may have a persistently positive PCR result, which may not indicate relapse.

Sub-bullet 3 added: Some evidence suggest 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.

• Reference 6 added: Morita K, Kantarjian H, Wang F, et al. Clearance of somatic mutations at remission and the risk of relapse in acute

myeloid leukemia J Clin Oncol 2018;36:1788-1797.

NCCN Guidelines Version 3.2021

Acute Myeloid Leukemia (Age ≥18 years)

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

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Discussion

UPDATES

Updates in Version 1.2021 of the NCCN Guidelines for Acute Myeloid Leukemia from Version 4.2020 include:

AML-H

• Bullet 1; Morphologic leukemia-free state

Sub-bullet 1 modied: BM <5% blasts in an aspirate with spicules; at least 200 cells must be enumerated

• Bullet 2: Complete response;

Morphologic CR; Diamond 3 modied: No residual evidence of extramedullary diseaseNo blasts with Auer rods or persistence of

extramedullary disease

Sub-bullet 2 added: CR without MRD (CR

MRD-

◊ Diamond 1 added: If studied pretreatment, CR with negativity for a genetic marker by RQ-PCR or CR with negativity by MFC

◊ Diamond 2 added: Sensitivity varies by marker and method used; analyses should be done in experienced laboratories

Sub-bullet removed: Cytogenetic CR - cytogenetics normal (in those with previously abnormal cytogenetics)

Sub-bullet 4 added: CRh - partial hematologic recovery, dened as < 5% blasts in the bone marrow, no evidence of disease, and partial

recovery of peripheral blood counts (platelets > 50 × 10

/L and ANC > 0.5 × 10

/L)

Sub-bullet 4 modied: CR with incomplete hematologic recovery (CRi) - There are some clinical trials that include a variant of CR referred

to as CRi. This has been dened as <5% marrow blasts, either ANC <1000/mcL or platelets <100,000/mcLAll CR criteria and transfusion

independence but with persistence of cytopenia (usually neutropenia (<1,000/mcL) and thrombocytopenia (<100,000/mcL).

• Bullet 5 modied: Induction failure - Failure to attain CR or CRi following exposure to at least 2 courses of intensive induction therapy (2

cycles of 7+3 or one cycle of 7+3 and one cycle of HiDAC).

• Footnote 1 modied: Cheson BD, Bennett JM, Kopecky KJ, et al. Revised recommendations of the international working group for diagnosis,

standardization of response criteria, treatment outcomes, and reporting standards for therapeutic trials in acute myeloid leukemia. J Clin

Oncol 2003;21:4642-4649. 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.

• Footnote 2 modied: This is clinically relevant only in APL and Ph+ leukemia, and failure to achieve a signicant reduction (eg >3 log) in

molecular evidence of t(8;21) or inv(16) has a very high predictive value of relapse at the present time. 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.

• Footnote 3 added: Bloomeld CD, Estey E, Pleyer L, et al. Time to repeal and replace response criteria for acute myeloid leukemia? Blood

Rev 2018;32:416-425.

• Footnote removed: 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.

Continued

NCCN Guidelines Version 3.2021

Acute Myeloid Leukemia (Age ≥18 years)

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and this illustration may not be reproduced in any form without the express written permission of NCCN.

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Discussion

Updates in Version 1.2021 of the NCCN Guidelines for Acute Myeloid Leukemia from Version 4.2020 include:

AML-I

• Aggressive therapy for appropriate patients

Regimen modied: Clofarabine ± cytarabine + G-CSF ± idarubicin

• Footnote 8 modied: Wierzbowska A, Robak T, Pluta A, et al. Cladribine combined with high doses of arabinoside cytosine, mitoxantrone,

and G-CSF (CLAG-M) is a highly eective salvage regimen in patients with refractory and relapsed acute myeloid leukemia of the poor

risk: a nal report of the Polish Adult Leukemia Group. Eur J Haematol 2008;80:115-126. Robak T, Wrzesień-Kuś A, Lech-Marańda E, et al.

Combination regimen of cladribine (2-chlorodeoxyadenosine), cytarabine and G-CSF (CLAG) as induction therapy for patients with relapsed

or refractory acute myeloid leukemia. Leuk Lymphoma 2000;39:121-129.

• Footnote 10 added: Karanes C, Kopecky KJ, Head DR, et al. A phase III comparison of high dose ARA-C (HIDAC) versus HIDAC plus

mitoxantrone in the treatment of rst relapsed or refractory acute myeloid leukemia Southwest Oncology Group Study. Leuk Res

1999;23:787-794.

• Footnote 13 modied: Amadori S, Arcese W, Isacchi G, et al. Mitoxantrone, etoposide, and intermediate-dose cytarabine: an eective and

tolerable regimen for the treatment of refractory acute myeloid leukemia. J Clin Oncol 1991;9:1210-1214. Nair G, Karmali G, Gregory SA, et

al. Etoposide and cytarabine as an eective and safe cytoreductive regimen for relapsed or refractory acute myeloid leukemia. J Clin Oncol

2011; 29:15_suppl, 6539-6539.

AML-J 1 of 2

• New section added: Principles of Venetoclax Use With HMA or LDAC-Based Treatement (continues on AML-J 2 of 2)

BPDCN-2

• Candidate for intensive remission induction therapy; Treatment Induction

Tagraxofusp-erzs noted as preferred (also applies to BPDCN-3)

Chemotherapy: AML and ALL induction claried as AML- and ALL-type induction chemotherapy.

• Patients with low performance and/or nutritional status

Localized/isolated cutaneous disease

◊ Treatment options claried as palliative

Systemic disease

◊ Treatment option added: Venetoclax-based therapy

• Footnote i added: Pemmaraju N, et al. Blood 2019;134(Supplement_1):2723.

• Footnote s added: DiNardo CD, et al. Am J Hematol 2018;93:401-407. (also applies to BPDCN-3)

BPDCN-B

• Administration/management of toxicities associated with tagraxofusp-erzs

Bullet 3; sub-bullet 2 modied: 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.

UPDATES

NCCN Guidelines Version 3.2021

Acute Myeloid Leukemia (Age ≥18 years)

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Discussion

EVALUATION FOR ACUTE LEUKEMIA DIAGNOSTIC

STUDIES

(WHO 2016)

DIAGNOSIS

c,d,e,f

• History and physical (H&P)

• Complete blood count (CBC), platelets, dierential,

comprehensive metabolic panel, uric acid, lactate

dehydrogenase (LDH)

• Prothrombin time (PT), partial thromboplastin time

(PTT), brinogen

• Bone marrow (BM) core biopsy and aspirate

analyses, including immunophenotyping by

immunohistochemistry (IHC) stains + ow

cytometryCytogenetic analyses (karyotype + FISH)

(See AML-A)

• Molecular analyses (ASXL1,c-KIT, FLT3 [ITD and TKD],

NPM1, CEBPA [biallelic], IDH1, IDH2, RUNX1,TP53,

and other mutations)

(See AML-A)

• Comprehensive pathology report, including diagnosis

of AML with recurrent cytogenetics vs. AML NOS,

blast count, cellularity, morphologic dysplasia, and

mutation status if available.

• Human leukocyte antigen (HLA) typing for patient

with potential hematopoietic cell transplantation

(HCT) in the future (except for patients with a major

contraindication to HCT) and/or early referral to

transplant center

• Brain CT without contrast, if CNS hemorrhage

suspected

(See AML-B)

• Brain MRI with contrast, if leukemic meningitis

suspected

(See AML-B)

• PET/CT, if clinical suspicion for extramedullary

disease (See AML-B)

• Lumbar puncture (LP), if symptomatic

(category 2B

for asymptomatic)

• Evaluate myocardial function (echocardiogram or

MUGA scan) in patients with a history or symptoms

of cardiac disease or prior/planned exposure to

cardiotoxic drugs or radiation to thorax

Multidisciplinary

diagnostic

studies

c,d

Acute promyelocytic leukemia (APL):

In patients with clinical and pathologic features

of APL, start all-trans retinoic acid (ATRA)

upon rst suspicion of APL.

Early initiation of

ATRA may prevent the lethal complication of

bleeding.

If cytogenetic and molecular testing

do not conrm APL, discontinue ATRA and

continue treatment as for AML

Acute myeloid leukemia (AML):To appropriately

stratify available intensive therapy options,

expedite test results of molecular and

cytogenetic analyses for immediately

actionable mutations or chromosomal

abnormalities (eg, CBF, FLT3 [ITD and TKD],

NPM1, IDH1, IDH2)

• For patients with hyperleukocytosis

uncontrolled with hydroxyurea or

leukapheresis, one dose of intermediate-dose

cytarabine (1–2 gm) may be considered prior

to receiving results

• For patients who prefer not to receive

blood transfusion(s), seeAML-D for general

considerations and supportive care

For suspicion of blastic plasmacytoid dendritic

cell neoplasm (BPDCN),see BPDCN-INTRO

Myelodysplastic syndromes (MDS)

B or T lymphoblastic

leukemia/lymphoma

See APL

Classication

and Treatment

Recommendations

(APL-1)

See AML Risk

Stratication and

Treatment

Recommendations

(AML-1)

See NCCN

Guidelines for

Myelodysplastic

Syndromes

See NCCN

Guidelines for Acute

Lymphoblastic

Leukemia

See footnotes on EVAL-1A

EVAL-1

For the evaluation of BPDCN, see BPDCN-1

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

NCCN Guidelines Version 3.2021

Acute Myeloid Leukemia (Age ≥18 years)

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.

NCCN Guidelines Index

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Discussion

A variety of gene mutations are associated with specific prognoses (category 2A) and may guide medical 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. The field of genomics in myeloid malignancies

and related implications in AML are evolving rapidly. While the above mutations should be tested in all patients, multiplex gene panels and comprehensivenext-

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.

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).

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.

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.

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.

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).

ATRA should be available in all community hospitals, so appropriate therapy can be started promptly.

FOOTNOTES FOR EVALUATION FOR ACUTE LEUKEMIA

EVAL-1A

(NCCN

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NCCN Guidelines Version 3.2021

Acute Myeloid Leukemia (Age ≥18 years)

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.

NCCN Guidelines Index

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Discussion

APL-1

APL CLASSIFICATION AND TREATMENT RECOMMENDATIONS

Conrmed APL

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

Low risk (WBC count ≤10,000/mcL)

No cardiac issues

Cardiac issues

(low ejection fraction [EF] or QTc prolongation)

See Treatment

Induction (APL-3)

See Treatment

Induction (APL-2)

See Treatment

Induction (APL-4)

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

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

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

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

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Acute Promyelocytic Leukemia (Age ≥18 years)

NCCN Guidelines Index

Table of Contents

Discussion

APL-2

APL TREATMENT INDUCTION (LOW RISK)

b,c,d,e

CONSOLIDATION THERAPY

ATRA

45 mg/m

in divided

doses daily + arsenic

trioxide

0.15 mg/kg IV

daily

(category 1) See

Principles of Supportive

Care for APL (APL-A)

• If blood count recovery by day 28

(platelet >100,000, ANC >1,000),

proceed with consolidation.

BM aspirate and biopsy may be

considered to document morphologic

remission

l,m

but is optional.

• If full course of induction treatment not

given, or counts have not recovered

by day 28–35, a BM aspirate and

biopsy is recommended to document

morphologic remission

l,m

before

proceeding with consolidation

Arsenic trioxide

0.15 mg/kg/d IV 5 d/wk for 4 weeks every

8 weeks for a total of 4 cycles, and ATRA 45 mg/m

/d for 2

weeks every 4 weeks for a total of 7 cycles

(category 1)

See Post-

Consolidation

Therapy

(APL-5)

ATRA

45 mg/m

in divided

doses daily + arsenic

trioxide

0.3 mg/kg IV

on days 1–5 of week 1

and 0.25 mg/kg twice

weekly during weeks

2–8

(category 1) See

Principles of Supportive

Care for APL (APL-A)

First 3 consolidation cycles = 56-day cycles:

ATRA 45 mg/m

/d PO divided into 2 daily doses on days 1–14

and 29–42 (2 weeks on followed by 2 weeks o) + arsenic

trioxide

0.3 mg/kg on days 1–5 of week 1 followed by 0.25

mg/kg twice weekly during weeks 2–4

4th consolidation cycle = 28-day cycle:

ATRA 45 mg/m

/d PO divided into 2 daily doses on days 1–14

(2 weeks on followed by 2 weeks o) + arsenic trioxide

0.3

mg/kg on days 1–5 of week 1 followed by 0.25 mg/kg twice

weekly during weeks 2–4

Preferred Regimens

ATRA

45 mg/m

in divided

doses daily + idarubicin

12 mg/m

on days 2, 4, 6,

(category 1)

At count recovery,

proceed with

consolidation

m,n

ATRA 45 mg/m

x 15 days + idarubicin 5 mg/m

x 4 days x 1

cycle, then ATRA x 15 days + mitoxantrone 10 mg/m

/d x 3

days x 1 cycle, then ATRA x 15 days + idarubicin 12 mg/m

1 day x 1 cycle (category 1)

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

ATRA

45 mg/m

in 2

divided doses daily

+ a single dose of

gemtuzumab ozogamicin

9 mg/m

on day 5

ATRA 45 mg/m

in divided doses daily during weeks 1–2,

5–6, 9–10, 13–14, 17–18, 21–22, and 25–26. A single dose of

gemtuzumab ozogamicin 9 mg/m

may be given monthly

until 28 weeks from complete response (CR)

BM aspirate and biopsy

days 28–35 to document

morphologic remission

before proceeding with

consolidation

• If blood count recovery by day 28

(platelet >100,000, ANC >1,000),

proceed with consolidation.

BM aspirate and biopsy may be

considered to document morphologic

remission

l,m

but is optional.

• If full course of induction treatment not

given, or counts have not recovered

by day 28–35, a BM aspirate and

biopsy is recommended to document

morphologic remission

l,m

before

proceeding with consolidation

See footnotes on APL-2A

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

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.

NCCN Guidelines Version 3.2021

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NCCN Guidelines Index

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Discussion

APL-2A

FOOTNOTES FOR APL TREATMENT INDUCTION AND CONSOLIDATION THERAPY (LOW RISK)

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.

Monitor for APL differentiation syndrome and coagulopathy; see Principles of Supportive Care for APL (APL-A).

Early mortality is related to bleeding, differentiation syndrome, or infection. Persistent disease is rare.

Hydroxyurea should be considered to manage high WBC count (>10,000/mcL) during induction of ATRA/arsenic trioxide.

Data suggest that lower doses of ATRA (25 mg/m

) in divided doses until clinical remission may be used in children and adolescents. Kutny MA, et al. J Clin Oncol

2017;35:3021-3029.

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).

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).

Burnett AK, et al. Lancet Oncol 2015;16:1295-1305.

Sanz MA, et al. Blood 2010;115:5137-5146.

Estey E, et al. Blood 2002;99:4222-4224.

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.

The presence of measurable cytogenetic and molecular markers does not carry prognostic or therapeutic implications.

For regimens using high cumulative doses of cardiotoxic agents, consider reassessing cardiac function prior to each anthracycline/mitoxantrone-containing course.

(NCCN

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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.

NCCN Guidelines Index

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Discussion

APL-3

APL TREATMENT INDUCTION (HIGH RISK)

b,c,d,o

CONSOLIDATION THERAPY

See references for details on regimens including maintenance therapy.

ATRA

45 mg/m

in divided doses

+ daunorubicin 60 mg/m

x 3 days

+ cytarabine 200 mg/m

x 7 days

ATRA

45 mg/m

in divided doses +

idarubicin 12 mg/m

on days 2, 4, 6, 8

ATRA

45 mg/m

(days 1–36, divided) +

age-adjusted idarubicin 6–12 mg/m

days 2, 4, 6, 8 + arsenic trioxide

0.15

mg/kg (days 9–36 as 2 h IV infusion)

Daunorubicin 60 mg/m

x 3 days + cytarabine 200 mg/m

x 7

days x 1 cycle, then cytarabine 2 g/m

(age <50) or 1.5 g/m

(age 50–60) every 12 h x 5 days

u,w

+ daunorubicin 45 mg/m

x 3

days x 1 cycle + 5 doses of intrathecal (IT) chemotherapy

ATRA 45 mg/m

x 15 days + idarubicin 5 mg/m

and cytarabine

1 g/m

x 4 days x 1 cycle, then ATRA x 15 days + mitoxantrone

10 mg/m

/d x 5 days x 1 cycle, then ATRA x 15 days +

idarubicin 12 mg/m

x 1 day + cytarabine 150 mg/m

/8 h x 4

days x 1 cycle

j,v

ATRA 45 mg/m

x 28 days + arsenic trioxide

0.15 mg/kg/d x 28

days x 1 cycle, then ATRA 45 mg/m

x 7 days every 2 weeks x 3

+ arsenic trioxide 0.15 mg/kg/d x 5 days for 5 weeks x 1 cycle

p,u

See Post-

Consolidation

Therapy (APL-5)

Other Recommended Regimens

Arsenic trioxide

0.15 mg/kg daily 5 d/wk for 4 weeks every

8 weeks for a total of 4 cycles + ATRA 45 mg/m

for 2 weeks

every 4 weeks for a total of 7 cycles.

q,v

If ATRA or arsenic

trioxide discontinued due to toxicity, a single dose of

gemtuzumab ozogamicin 9 mg/m

may be given once every 4–5

weeks until 28 weeks from CR

ATRA

45 mg/m

in divided doses

+ arsenic trioxide

0.15 mg/kg/d

IV + a single dose of gemtuzumab

ozogamicin 9 mg/m

may be given on

day 1, or day 2, or day 3, or day 4

See footnotes on APL-3A

Preferred Regimens

BM aspirate and biopsy

at day 28 to document

remission,

l,m

consider

LP before proceeding

with consolidation

ATRA

45 mg/m

in divided doses +

arsenic trioxide

0.3 mg/kg IV on days

1–5 of week 1 and 0.25 mg/kg twice

weekly on weeks 2–8 (category 1) + a

single dose of gemtuzumab ozogamicin

6 mg/m

may be given on day 1, or day

2, or day 3, or day 4

ATRA 45 mg/m

for 2 weeks every 4 weeks (or for 2 weeks on 2

weeks o) in consolidation courses 1–4 + arsenic trioxide

0.3

mg/kg on days 1–5 of week 1 in consolidation courses 1–4 and

0.25 mg/kg twice weekly in weeks 2–4 in consolidation courses

1–4 (category 1).

i,v

If ATRA or arsenic trioxide discontinued due

to toxicity, a single dose of gemtuzumab ozogamicin 9 mg/m

may be given once every 4–5 weeks until 28 weeks from CR

BM aspirate and biopsy

at day 28 to document

remission,

l,m

consider

LP before proceeding

with consolidation

ATRA

45 mg/m

in divided doses

+ daunorubicin 50 mg/m

x 4 days

(IV days 3–6) + cytarabine 200 mg/m

x 7 days (IV days 3–9)

Arsenic trioxide

0.15 mg/kg/d x 5 days for 5 weeks every 7

weeks for a total of 2 cycles, then ATRA 45 mg/m

x 7 days +

daunorubicin 50 mg/m

x 3 days for 2 cycles

r,v

BM aspirate and biopsy

at day 28 to document

remission,

l,m

consider

LP before proceeding

with consolidation

BM aspirate and biopsy

at day 28 to document

remission,

consider LP

before proceeding with

consolidation

BM aspirate and biopsy

at day 28 to document

remission,

consider

LP before proceeding

with consolidation

BM aspirate and biopsy

at day 28 to document

remission,

consider

LP before proceeding

with consolidation

(FOR PATIENTS WITH CARDIAC ISSUES, SEE APL-4)

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

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.

NCCN Guidelines Version 3.2021

Acute Promyelocytic Leukemia (Age ≥18 years)

NCCN Guidelines Index

Table of Contents

Discussion

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.

Monitor for APL differentiation syndrome and coagulopathy; see Principles of Supportive Care for APL (APL-A).

Early mortality is related to bleeding, differentiation syndrome, or infection. Persistent disease is rare.

Data suggest that lower doses of ATRA (25 mg/m

) in divided doses until clinical remission may be used in children and adolescents. Kutny MA, et al. J Clin Oncol

2017;35:3021-3029.

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).

Burnett AK, et al. Lancet Oncol 2015;16:1295-1305.

Sanz MA, et al. Blood 2010;115:5137-5146.

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.

The presence of measurable cytogenetic and molecular markers does not carry prognostic or therapeutic implications.

For regimens using high cumulative doses of cardiotoxic agents, consider reassessing cardiac function prior to each anthracycline/mitoxantrone-containing course.

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.

Iland HJ, et al. Blood 2012;120:1570-1580.

Abaza Y, et al. Blood 2017;129:1275-1283.

Powell BL, et al. Blood 2010;116:3751-3757.

Adès L, et al. Blood 2008;111:1078-1084.

Breccia M, et al. Br J Haematol 2003;120:266-270.

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.

Consider 4–6 doses of IT chemotherapy (eg, 2 doses for each consolidation cycle) as an option for CNS prophylaxis.

Dose adjustment of cytarabine may be needed for older patients or patients with renal dysfunction.

APL-3A

FOOTNOTES FOR APL TREATMENT INDUCTION AND CONSOLIDATION THERAPY (HIGH RISK)

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and this illustration may not be reproduced in any form without the express written permission of NCCN.

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

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Discussion

CONSOLIDATION THERAPY

ATRA

45 mg/m

in 2 divided

doses daily + arsenic trioxide

0.15 mg/kg daily + a single dose

of gemtuzumab ozogamicin

9 mg/m

on day 1

Arsenic trioxide

0.15 mg/kg daily 5 days/wk for 4 weeks every 8

weeks for a total of 4 cycles + ATRA 45 mg/m

in divided doses daily

for 2 weeks every 4 weeks for a total of 7 cycles.

q,v

If ATRA or arsenic

trioxide discontinued due to toxicity, a single dose of gemtuzumab

ozogamicin 9 mg/m

may be given once every 4–5 weeks until 28

weeks from CR

See Post-

Consolidation

Therapy

(APL-5)

APL TREATMENT INDUCTION (HIGH RISK)

b,c,d,o

IN PATIENTS WITH CARDIAC ISSUES

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

ATRA 45 mg/m

in divided doses daily for 2 weeks every 4 weeks (or

for 2 weeks on 2 weeks o) in consolidation courses 1–4 + arsenic

trioxide

0.3 mg/kg on days 1–5 of week 1 in consolidation courses

1–4 and 0.25 mg/kg twice weekly on weeks 2–4 in consolidation

courses 1–4 (category 1).

i,v

If ATRA or arsenic trioxide discontinued

due to toxicity, a single dose of gemtuzumab ozogamicin 9 mg/m

may be given once every 4–5 weeks until 28 weeks from CR

ATRA 45 mg/m

in divided doses daily during weeks 1–2, 5–6, 9–10,

13–14, 17–18, 21–22, and 25–26. A single dose of gemtuzumab

ozogamicin 9 mg/m

may be given monthly until 28 weeks from CR

ATRA

45 mg/m

in 2 divided

doses daily + a single dose of

gemtuzumab ozogamicin 9 mg/m

on day 1

ATRA

45 mg/m

in 2 divided

doses daily + arsenic trioxide

0.3 mg/kg on days 1–5 of week 1

and 0.25 mg/kg twice weekly in

weeks 2–8

(category 1) + a single

dose of gemtuzumab ozogamicin

6 mg/m

on day 1

APL-4

BM aspirate and

biopsy at day

28 to document

remission

l,m

before proceeding

with consolidation

BM aspirate and

biopsy at day

28 to document

remission

l,m

before

proceeding with

consolidation

BM aspirate and

biopsy at day 28 to

document remission

before proceeding

with consolidation

Low Ejection Fraction

Prolonged QTc

ATRA

45 mg/m

in 2 divided doses

+ daunorubicin 60 mg/m

x 3 days

+ cytarabine 200 mg/m

x 7 days

ATRA

45 mg/m

in 2 divided doses

+ idarubicin 12 mg/m

on days 2, 4,

6, 8

Daunorubicin 60 mg/m

x 3 days + cytarabine 200 mg/m

x 7 days x 1

cycle, then cytarabine 2 g/m

(age <50) or 1.5 g/m

(age 50–60) every

12 h x 5 days

u,w

+ daunorubicin 45 mg/m

x 3 days x 1 cycle +

5 doses of IT chemotherapy

ATRA 45 mg/m

x 15 days + idarubicin 5 mg/m

and cytarabine 1 g/m

x 4 days x 1 cycle, then ATRA x 15 days + mitoxantrone 10 mg/m

/d x

5 days x 1 cycle, then ATRA x 15 days + idarubicin 12 mg/m

x 1 day

+ cytarabine 150 mg/m

over 8 h x 4 days x 1 cycle

j,v

BM aspirate and biopsy

at day 28 to document

remission,

consider

LP before proceeding

with consolidation

BM aspirate and biopsy

at day 28 to document

remission,

consider

LP before proceeding

with consolidation

See footnotes on APL-4A

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

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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.

Monitor for APL differentiation syndrome and coagulopathy; see Principles of Supportive Care for APL (APL-A).

Early mortality is related to bleeding, differentiation syndrome, or infection. Persistent disease is rare.

Data suggest that lower doses of ATRA (25 mg/m

) in divided doses until clinical remission may be used in children and adolescents. Kutny MA, et al. J Clin Oncol

2017;35:3021-3029.

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).

Burnett AK, et al. Lancet Oncol 2015;16:1295-1305.

Sanz MA, et al. Blood 2010;115:5137-5146.

Estey E, et al. Blood 2002;99:4222-4224.

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.

The presence of measurable cytogenetic and molecular markers does not carry prognostic or therapeutic implications.

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.

Abaza Y, et al. Blood 2017;129:1275-1283.

Adès L, et al. Blood 2008;111:1078-1084.

Breccia M, et al. Br J Haematol 2003;120:266-270.

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.

Consider 4–6 doses of IT chemotherapy (eg, 2 doses for each consolidation cycle) as an option for CNS prophylaxis.

Dose adjustment of cytarabine may be needed for older patients or patients with renal dysfunction.

For patients who have prolonged QTc as their sole comorbidity, gemtuzumab ozogamicin could be substituted for anthracycline.

APL-4A

FOOTNOTES FOR APL TREATMENT INDUCTION AND CONSOLIDATION THERAPY (HIGH RISK)

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

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

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Discussion

APL-5

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

document molecular remission. In patients receiving the ATRA/arsenic regimen,

consider earlier sampling at 3–4 months during consolidation. Prior practice

guidelines have recommended monitoring blood by PCR every 3 mo for 2 y to

detect molecular relapse. We continue to endorse this for high-risk patients, those

>60 y of age or who had long interruptions during consolidation, or patients on

regimens that use maintenance and are not able to tolerate maintenance. Clinical

experience indicates that risk of relapse in patients with low-risk disease who are

in molecular remission at completion of consolidation is low and monitoring may

not be necessary outside the setting of a clinical trial. While long-term monitoring

has been standard, with newer, more effective regimens, the value is less certain.

To confirm PCR positivity, a second blood sample should be done in 2–4 weeks

in a reliable laboratory. If molecular relapse is confirmed by a second positive

test, treat as first relapse (APL-6). If the second test is negative, frequent

monitoring (every 3 mo for 2 y) is strongly recommended to confirm that the

patient remains negative. The PCR testing lab should indicate the level of

sensitivity of assay for positivity (most clinical labs have a sensitivity level of

-4

), and testing should be done in the same lab to maintain the same level

of sensitivity. Consider consultation with a physician experienced in molecular

diagnostics if results are equivocal.

APL POST-

CONSOLIDATION

THERAPY

MONITORING

First relapse

See Therapy

for Relapse

(APL-6)

Document

molecular

remission

y,z

after

consolidation

Polymerase

chain reaction

(PCR)

negative

PCR positive

Maintenance therapy if

included in the initial

treatment protocol

Monitor by

PCR

for up

to 2 y after

completion of

maintenance

therapy

Repeat

PCR

for

conrmation

within 4 wks

PCR negative

PCR

positive

Repeat

PCR

for

conrmation

within 4 wks

PCR negative

PCR positive

PCR negative

PCR positive

(NCCN

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

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

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Discussion

APL-6

APL THERAPY FOR RELAPSE ADDITIONAL THERAPY

First relapse

(morphologic

or molecular)

Early relapse

(<6 mo) after ATRA

and arsenic trioxide

(no anthracycline)

Anthracycline-based

regimen as per APL-3

bb,cc

No prior exposure

to arsenic trioxide

or early relapse

(<6 mo) after ATRA

+ anthracycline-

containing regimen

Arsenic trioxide 0.15 mg/

kg daily

g,bb,cc

± ATRA 45

mg/m

in 2 divided doses

daily

± a single dose of

gemtuzumab ozogamicin

until count recovery with

marrow conrmation of

remission

Second

remission

(morphologic)

No remission

Consider CNS

prophylaxis

with IT

chemotherapy

(methotrexate

or cytarabine)

Transplant

candidate

Autologous

HCT

Arsenic trioxide

consolidation

(total of 6 cycles)

Not

transplant

candidate

PCR

negative

(by BM)

PCR

positive

(by BM)

Transplant

candidate

Not

transplant

candidate

Matched sibling

or alternative

donor HCT

Clinical trial

Matched sibling or

alternative donor HCT

Late relapse (≥6 mo)

after arsenic trioxide-

containing regimen

Arsenic trioxide 0.15 mg/

kg daily

g,bb,cc

± ATRA 45

mg/m

in 2 divided doses

daily

± (anthracycline

or a single dose of

gemtuzumab ozogamicin)

until count recovery with

marrow conrmation of

remission

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).

Document molecular panel to verify relapsed APL versus therapy-related AML.

Following the first cycle of consolidation, if the patient is not in molecular

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.

Outcomes are uncertain in patients who received arsenic trioxide during initial

induction/consolidation therapy.

There is a small randomized trial that suggests that the addition of ATRA

does not confer any benefit over arsenic alone. Raffoux E, et al. J Clin Oncol

2003;21:2326-2334.

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

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

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

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Discussion

APL-A

PRINCIPLES OF SUPPORTIVE CARE FOR APL

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; brinogen 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.

• Leukapheresis is not recommended in the routine management of patients with a high WBC count in APL because of the dierence in leukemia

biology; however, in life-threatening cases with leukostasis that is not responsive to other modalities, leukapheresis can be considered with

caution.

• APL dierentiation syndrome:

If steroids are not initiated at time of treatment with ATRA and arsenic, maintain a high index of suspicion of APL dierentiation 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 eusions).

Close monitoring of volume overload and pulmonary status is indicated. Initiate dexamethasone at rst signs or symptoms

of respiratory compromise (ie, hypoxemia, pulmonary inltrates, pericardial or pleural eusions) (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 dierentiation syndrome, initiate prophylaxis with corticosteroids, either

prednisone 0.5 mg/kg day 1 or dexamethasone 10 mg q 12 h. Taper the steroid dose over a period of several days. If patient develops

dierentiation syndrome, change prednisone to dexamethasone 10 mg every 12 h until count recovery or risk of dierentiation has abated.

1,2

The following cytoreduction strategies for leukocytosis may be used for dierentiation syndrome that is dicult 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.

• 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.

Lo-Coco F, Avvisati G, Vignetti M, et al. Retinoic acid and arsenic trioxide for acute promyelocytic leukemia. N Engl J Med 2013;369:111-121.

Sanz MA, Montesinos P, Rayón C, et al. Risk-adapted treatment of acute promyelocytic leukemia based on all-trans retinoic acid and anthracycline with addition of

cytarabine in consolidation therapy for high-risk patients: further improvements in treatment outcome. Blood 2010;115:5137-5146.

Sanz MA, Fenaux P, Tallman MS, et al. Management of acute promyelocytic leukemia: updated recommendations from an expert panel of the European LeukemiaNet.

Blood 2019;133:1630-1643.

(NCCN

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

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Discussion

TREATMENT INDUCTION

d,e,f,g

Physiologic

age

a,b,c

<60 y

Favorable-risk

cytogenetics

Intermediate-risk

cytogenetics and FLT3-

mutated (ITD or TKD)

• Therapy-related AML

other than CBF/AML

• Antecedent

MDS/CMML

• Cytogenetic changes

consistent with MDS

(AML-MRC)

Other recommended

regimens for

intermediate- or

poor-risk disease

Options:

• Standard-dose cytarabine 200 mg/m

continuous infusion x 7 days with

daunorubicin 60 mg/m

x 3 days and a single dose of gemtuzumab ozogamicin 3 mg/m

(up to one 4.5 mg vial) given on day 1, or day 2, or day 3, or day 4; alternatively,

three total doses may be given on days 1, 4, and 7

h,i

(CD33-positive)

(preferred)

• Standard-dose cytarabine 100–200 mg/m

continuous infusion x 7 days with

idarubicin 12 mg/m

or daunorubicin 60–90 mg/m

x 3 days

k,l

(category 1)

• Fludarabine 30 mg/m

days 2–6, high-dose cytarabine (HiDAC) 2 g/m

over 4 hours

starting 4 hours after udarabine infusion on days 2–6, idarubicin 8 mg/m

IV on days

4–6, and granulocyte colony-stimulating factor (G-CSF) subcutaneously (SC) daily days

1–7 plus a single dose of gemtuzumab ozogamicin 3 mg/m

in rst course (category 2B)

Standard-dose cytarabine 200 mg/m

continuous infusion x 7 days with

daunorubicin 60 mg/m

x 3 days and oral midostaurin 50 mg every 12 hours, days 8–21

(FLT3-mutated AML)

Options:

• Standard-dose cytarabine 100–200 mg/m

continuous infusion x 7 days with

idarubicin 12 mg/m

or daunorubicin 60–90 mg/m

x 3 days

k,l

(category 1)

• Dual-drug liposomal encapsulation of cytarabine 100 mg/m

and daunorubicin 44 mg/m

on days 1, 3, and 5 x 1 cycle

(category 2B)

Options:

• Standard-dose cytarabine 100–200 mg/m

continuous infusion x 7 days with

idarubicin 12 mg/m

or daunorubicin 60–90 mg/m

x 3 days

k,l

(category 1)

• Standard-dose cytarabine 200 mg/m

continuous infusion x 7 days with

daunorubicin 60 mg/m

x 3 days and a single dose of gemtuzumab ozogamicin 3 mg/m

(up to one 4.5 mg vial) given on day 1, or day 2, or day 3, or day 4; alternatively, three

total doses may be given on days 1, 4, and 7

h,i

(CD33-positive)

(intermediate-risk AML)

• HiDAC

l,p

2 g/m

every 12 hours x 6 days

or 3 g/m

every 12 h x 4 days

with

idarubicin 12 mg/m

or daunorubicin 50 mg/m

x 3 days,

and etoposide 50 mg/m

days 1 to 5

(1 cycle) (category 1 for patients ≤45 y, category 2B for other age groups)

• Fludarabine 30 mg/m

on days 2–6, HiDAC 2 g/m

over 4 hours starting 4 hours after

udarabine on days 2–6, idarubicin 8 mg/m

IV on days 4–6,

and G-CSF SC daily days 1–7 (category 2B)

AML-1

TREATMENT

STRATEGIES

See

Follow-up

(AML-2)

See

Follow-up

(AML-3)

See footnotes on AML-1A

AML

PHYSIOLOGIC

AGE<60 y

Unfavorable risk

cytogenetics and

TP53-mutated

Alternative induction strategies should be considered

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Discussion

AML-1A

FOOTNOTES FOR TREATMENT INDUCTION (PHYSIOLOGICAGE <60 YEARS)

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.

Poor performance status and a comorbid medical condition, in addition to age, are factors that influence ability to tolerate standard induction therapy.

Patients with CBF-AML and core abnormalities may benefit from the addition of gemtuzumab ozogamicin. Consider screening with fluorescence in situ hybridization

(FISH) to identify translocations/abnormalities associated with CBF-AML.

See Principles of Supportive Care for AML (AML-E).

See Monitoring During Therapy (AML-F).

Consider referral to palliative care for consultation at the start of induction. LeBlanc T, et al. Curr Hematol Malig Rep 2017;12:300-308 and LeBlanc T, et al. J Oncol

Pract.2017;13:589-590. See NCCN Guidelines for Palliative Care.

See General Considerations and Supportive Care for AML Patients Who Prefer Not to Receive Blood Transfusions (AML-D)

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.

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.

Threshold for CD33 is not well-defined and may be ≥1%.

ECOG reported a significant increase in complete response rates and overall survival using daunorubicin 90 mg/m

x 3 days versus 45 mg/m

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/m

x 3 days.

Burnett AK, et al. Blood 2015;125:3878-3885.

For patients with impaired cardiac function, other cytarabine-based regimens alone or with other agents can be considered. See Discussion.

Burnett AK, et al. J Clin Oncol 2013;31:3360-3368.

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.

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.

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.

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.

Weick JK, et al. Blood 1996;88:2841-2851.

Bishop JF, et al. Blood 1996;87:1710-1717.

Willemze R, et al. J Clin Oncol 2014;32:219-228.

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Discussion

AML-2

AML PHYSIOLOGICAGE <60 y

AFTER STANDARD-DOSE CYTARABINE INDUCTION/RE-INDUCTION

f,t,u

Follow-up

aspirate

and biopsy

14–21 days

after start

of therapy

Signicant

residual

disease

without a

hypocellular

w,x

Signicant

cytoreduction

with low %

residual blasts

(if ambiguous,

consider repeat

BM biopsy in

5–7 days before

proceeding with

therapy)

Hypoplasia

w,x

Options:

• Cytarabine 1.5–3 g/m

every 12 hours x 6 days

• Standard-dose cytarabine with idarubicin or

daunorubicin

z,aa

• Standard-dose cytarabine with daunorubicin and

oral midostaurin

n,z

(BM aspirate and biopsy on

day 21) (FLT3 mutated [ITD or TKD])

• Dual-drug liposomal encapsulation of cytarabine

100 mg/m

and daunorubicin 44 mg/m

on days

1 and 3 x 1 cycle

(therapy-related AML other

than CBF-AML/APL, or patients with antecedent

MDS/CMML, or AML-MRC) (preferred only if given

in induction; BM aspirate and biopsy 14–21 days

after start of therapy)

• See treatment for induction failure

Options:

• Standard-dose cytarabine with idarubicin

or daunorubicin

z,aa

• Standard-dose cytarabine with

daunorubicin and oral midostaurin

n,z

(BM aspirate and biopsy on day 21) (FLT3

mutated [ITD or TKD])

Await recovery

BM aspirate and

biopsy to document

remission status

upon hematologic

recovery, including

cytogenetics and

molecular studies

as appropriate.

For measurable

(minimal) residual

disease (MRD)

assessment, see

AML-G

Complete response

(Screening LP, see

AML-B) (Response

criteria, see AML-H)

Induction

failure

(Response

criteria,

see AML-H)

Consolidation See

Post-Remission

Therapy (AML-4)

Options:

• Matched sibling or

alternative donor HCT

• HiDAC (if not previously

used as treatment for

persistent disease at

day 15) ± anthracycline

(daunorubicin or

idarubicin)

if a clinical

trial is not available while

awaiting identication of a

donor

• See Therapy for Relapsed/

Refractory Disease (AML-I)

• Best supportive care

See footnotes on AML-2A

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

NCCN Guidelines Version 3.2021

Acute Myeloid Leukemia (Age ≥18 years)

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

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

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Table of Contents

Discussion

AML-2A

FOOTNOTES FOR TREATMENT AFTER STANDARD-DOSE CYTARABINE INDUCTION/RE-INDUCTION (PHYSIOLOGIC AGE <60 YEARS)

See Monitoring During Therapy (AML-F).

Consider referral to palliative care for consultation at the start of induction. LeBlanc T, et al. Curr Hematol Malig Rep 2017;12:300-308 and LeBlanc T, et al. J Oncol Pract

2017;13:589-590. See NCCN Guidelines for Palliative Care.

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.

Consider clinical trials for patients with targeted molecular abnormalities.

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.

There are limited prospective data to support this recommendation. Othus M, et al. Leukemia 2016;30:1779-1780.

If ambiguous, consider repeat BM biopsy in 5–7 days before proceeding with therapy.

Hypoplasia is defined as cellularity less than 20% of which the residual blasts are less than 5% (ie, blast percentage of residual cellularity).

For re-induction, no data are available to show superiority with intermediate or high-dose cytarabine.

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.

If daunorubicin 90 mg/m

was used in induction, the recommended dose for daunorubicin for reinduction prior to count recovery is 45 mg/m

for no more than 2 doses.

Analogously, if idarubicin 12 mg/m

was used for induction, the early reinduction dose should be limited to 10 mg/m

for 1 or 2 doses.

Lancet JE, et al. J Clin Oncol 2018;36:2684-2692.

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

NCCN Guidelines Version 3.2021

Acute Myeloid Leukemia (Age ≥18 years)

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

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

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Table of Contents

Discussion

AML-3

AML PHYSIOLOGICAGE <60 y

AFTER HIGH-DOSE CYTARABINE INDUCTION

f,t,u

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

Best supportive care

Await

recovery

Await

recovery

BM aspirate and

biopsy to document

remission status

upon hematologic

recovery, including

cytogenetics and

molecular studies

as appropriate. For

MRD assessment,

see AML-G

Complete response

(Screening LP, see

AML-B) (Response

criteria, see AML-H)

Induction failure

(Response criteria,

see AML-H)

Consolidation See Post-

Remission Therapy (AML-4)

See Therapy for Relapsed/

Refractory Disease (AML-I)

Matched sibling or

alternative donor HCT

Best supportive care

Signicant residual

disease without a

hypocellular BM

w,x

Hypoplasia

w,x

Signicant

cytoreduction

with low %

residual blasts

(if ambiguous,

consider repeat

BM biopsy in

5–7 days before

proceeding with

therapy)

See Monitoring During Therapy (AML-F).

Consider referral to palliative care for consultation at the start of induction. LeBlanc T, et al. Curr Hematol Malig Rep 2017;12:300-308 and LeBlanc T, et al. J Oncol Pract

2017;13:589-590. See NCCN Guidelines for Palliative Care.

Consider clinical trials for patients with targeted molecular abnormalities.

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.

If ambiguous, consider repeat BM biopsy in 5–7 days before proceeding with therapy.

Hypoplasia is defined as cellularity less than 20% of which the residual blasts are less than 5% (ie, blast percentage of residual cellularity).

Follow-up BM

aspirate and

biopsy 21–28

days after start

of therapy

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

NCCN Guidelines Version 3.2021

Acute Myeloid Leukemia (Age ≥18 years)

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

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

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Table of Contents

Discussion

AML-4

RISK STATUS

(See AML-A)

Physiologic

age <60 y

CBF cytogenetic

translocations and

MRD negative

(see AML-G)

Intermediate-risk

cytogenetics and/

or molecular

abnormalities,

including MRD

positive (see AML-G)

Treatment-related

disease other than

CBF and/or

unfavorable

cytogenetics

and/or molecular

abnormalities

u,cc

Options:

• HiDAC 3 g/m

over 3 h every 12 h on days 1, 3, 5 (category 1) or days 1, 2, 3 x 3–4

cycles

dd,ee

with or without gemtuzumab ozogamicin 3 mg/m

(up to one 4.5 mg vial) on

day 1 x 2 cycles

i,

(CD33-positive)

• Cytarabine 1000 mg/m

every 12 hours on days 1–4 + daunorubicin 60 mg/m

on day 1

(rst cycle) or days 1–2 (second cycle) + gemtuzumab ozogamicin 3 mg/m

(up to one 4.5

mg vial) on day 1 x 2 cycles

i,,gg

(CD33-positive)

Options:

• Matched sibling or alternative donor HCT

u,ii

• HiDAC

1.5–3 g/m

over 3 h every 12 h on days 1, 3, 5 or days 1, 2, 3 x 3–4 cycles

dd,ee

• HiDAC

1.5–3 g/m

over 3 h every 12 h on days 1, 3, 5 or days 1, 2, 3 with oral midostaurin

50 mg every 12 hours on days 8–21 x 4 cycles

n,dd,ee

(FLT3-mutated AML)

• Cytarabine 1000 mg/m

every 12 hours on days 1–4 + daunorubicin 60 mg/m

on day 1

(rst cycle) or days 1–2 (second cycle) + gemtuzumab ozogamicin 3 mg/m

(up to one 4.5

mg vial) on day 1 x 2 cycles

i,gg

(CD33-positive)

• 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 t/

eligible for allogeneic HCT)

(category 2B)

See

Surveillance

(AML-10)

Options:

• Matched sibling or alternative donor HCT

u,ii

(preferred)

• HiDAC 1.5–3 g/m

over 3 h every 12 h on days 1, 3, 5 or days 1, 2, 3 x 3–4 cycles

dd,ee

• HiDAC 1.5–3 g/m

over 3 h every 12 h on days 1, 3, 5 or days 1, 2, 3 with oral midostaurin

50 mg every 12 hours on days 8–21 x 4 cycles

n,dd,ee

(FLT3-mutated AML)

• Dual-drug liposomal encapsulation of cytarabine 65 mg/m

and daunorubicin 29 mg/m

days 1 and 3 x 1–2 cycles

(therapy-related AML or patients with antecedent MDS/CMML

or AML-MRC) (preferred only if given in induction)

• 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 t/

eligible for allogeneic HCT)

AML

PHYSIOLOGIC

AGE <60 y

See footnotes on AML-4A

POST-REMISSION/MAINTENANCE THERAPY

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

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Acute Myeloid Leukemia (Age ≥18 years)

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

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

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Discussion

AML-4A

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.

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.

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.

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.

Mayer RJ, et al. N Engl J Med 1994;331:896-903; Jaramillo S, et al. Blood Cancer J 2017;7:e564.

Alternate dosing of cytarabine for postremission therapy has been reported (see Discussion). Jaramillo S, et al. Blood Cancer J 2017;7:e564.

Meta-analyses showing an advantage with gemtuzumab ozogamicin have included other dosing schedules. Hills RK, et al. Lancet Oncol 2014;15:986-996.

This regimen may also be used in patients with KIT mutations because the outcomes are similar in patients without KIT mutations.

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 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.

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.

There is no evidence that HiDAC is superior to intermediate doses (1.5 g/m

daily x 5 days) of cytarabine in patients with intermediate-risk cytogenetics.

Lancet JE, et al. J Clin Oncol 2018;36:2684-2692.

FOOTNOTES FOR POST-REMISSION/MAINTENANCE THERAPY (PHYSIOLOGIC AGE <60 YEARS)

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

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Acute Myeloid Leukemia (Age ≥18 years)

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

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

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Table of Contents

Discussion

AML

a,ll

PHYSIOLOGIC

AGE

≥60 y (See

NCCN Guidelines

for Older Adult

Oncology)

Candidate

for

intensive

remission

induction

therapy

TREATMENT INDUCTION

d,f,g

AML-5

Other recommended

regimens for intermediate-

or poor-risk disease

Options:

• Standard-dose cytarabine (100–200 mg/m

continuous infusion x 7 days) with

idarubicin

12 mg/m

or daunorubicin

60–90 mg/m

x 3 days or mitoxantrone

12 mg/m

x 3 days

• Standard-dose cytarabine 200 mg/m

continuous infusion x 7 days with daunorubicin

60 mg/m

x 3 days and a single dose of gemtuzumab ozogamicin 3 mg/m

(up to one 4.5

mg vial) given on day 1, or day 2, or day 3, or day 4; alternatively, three total doses may

be given on days 1, 4, and 7

i,,vv

(CD33-positive)

(intermediate-risk AML)

Unfavorable-risk

cytogenetics

(exclusive of AML-MRC)

Options: (Principles of Venetoclax, see AML-J)

• Venetoclax once daily (100 mg day 1, 200 mg day 2, and 400 mg day 3 and beyond) PO

and decitabine 20 mg/m

IV (days 1–5 of each 28-day cycle)

rr,ss

• Venetoclax once daily (100 mg day 1, 200 mg day 2, and 400 mg day 3 and beyond) PO

and azacitidine 75 mg/m

SC or IV (days 1–7 of each 28-day cycle)

rr,ss

• Venetoclax once daily (100 mg day 1, 200 mg day 2, 400 mg day 3, and 600 mg day 4 and

beyond) PO and low-dose cytarabine (LDAC) 20 mg/m

/d SC (days 1–10 of each 28-day

cycle)

rr,tt

• Low-intensity therapy (azacitidine [category 2B], decitabine)

ss,uu

Favorable-risk

cytogenetics

Options:

• Standard-dose cytarabine 200 mg/m

continuous infusion x 7 days with

daunorubicin 60 mg/m

x 3 days and three total doses of gemtuzumab ozogamicin

3 mg/m

(up to one 4.5 mg vial) may be given on days 1, 4, and 7;

alternatively, a single

dose may be given on day 1, or day 2, or day 3, or day 4

i,

(CD33-positive)

• Standard-dose cytarabine (100–200 mg/m

continuous infusion x 7 days) with

idarubicin

12 mg/m

or daunorubicin

60–90 mg/m

x 3 days or

mitoxantrone 12 mg/m

x 3 days

FLT3-mutated (ITD or TKD)

Standard-dose cytarabine 200 mg/m

continuous infusion x 7 days with

daunorubicin 60 mg/m

x 3 days and oral midostaurin 50 mg every 12 hours, days 8–21

n,qq

• Therapy-related AML

• Antecedent MDS/CMML

• AML-MRC

Dual-drug liposomal encapsulation of cytarabine 100 mg/m

and daunorubicin 44 mg/m

on days 1, 3, and 5 x 1 cycle

(category 1)

See Post-

Induction

Therapy

(AML-7)

See Post-

Induction

Therapy

(AML-9)

See Post-

Induction

Therapy

(AML-7)

TREATMENT

STRATEGIES

See footnotes on AML-5A

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

NCCN Guidelines Version 3.2021

Acute Myeloid Leukemia (Age ≥18 years)

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

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

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Table of Contents

Discussion

AML-5A

FOOTNOTES FOR TREATMENT INDUCTION (PHYSIOLOGICAGE ≥60 YEARS)

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.

See Principles of Supportive Care for AML (AML-E).

Consider referral to palliative care for consultation at the start of induction. LeBlanc T, et al. Curr Hematol Malig Rep 2017;12:300-308 and LeBlanc T, et al. J Oncol Pract

2017;13:589-590. See NCCN Guidelines for Palliative Care.

See General Considerations and Supportive Care for Patients Who Prefer Not to Receive Blood Transfusions (AML-D).

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.

Threshold for CD33 is not well-defined and may be ≥1%.

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.

Meta-analyses showing an advantage with gemtuzumab ozogamicin have included other dosing schedules. Hills RK, et al. Lancet Oncol 2014;15:986-996.

Lancet JE, et al. J Clin Oncol 2018;36:2684-2692.

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://www.fhcrc-

research.org/TRM/Default.aspx?GUID=1358501B-C922-4422-84F0-0E6C67D8F266 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.

Patients with TP53 mutations are a group with poor prognosis, and should be considered for enrollment in clinical trials.

Castaigne S, et al. Lancet 2012;379:1508-1516.

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]).

The complete response rates and 2-year overall survival in patients between 60 and 65 years of age treated with daunorubicin 90 mg/m

is also comparable to the

outcome for idarubicin 12 mg/m

; the higher-dose daunorubicin did not benefit patients >65 years of age (Löwenberg B, et al. N Engl J Med 2009;361:1235-1248).

The 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.

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.

Patients who have progressed to AML from MDS after signicant exposure to hypomethylating agents (HMAs) (ie, azacitidine, decitabine) may be less likely to derive

benet from continued treatment with HMAs compared to patients who are HMA-naïve. Alternative treatment strategies should be considered.

Wei AH, et al. J Clin Oncol 2019;37:1277-1284.

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.

Regimens that include gemtuzumab ozogamicin have limited benefit in patients with poor-risk disease.

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

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Acute Myeloid Leukemia (Age ≥18 years)

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.

NCCN Guidelines Index

Table of Contents

Discussion

AML

a,ll

PHYSIOLOGIC

AGE ≥60 y (See

NCCN Guidelines

for Older Adult

Oncology)

TREATMENT INDUCTION

d,f,g

Principles of Venetoclax, see AML-J

Not a

candidate

for intensive

remission

induction

therapy or

declines

AML-6

IDH1 or IDH2

mutation

Preferred

• Ivosidenib

aaa,bbb

(IDH1 only)

• Enasidenib

bbb,ccc

(IDH2 only)

• Venetoclax-based therapy (same as above in combination with azacitidine,

rr,ss

or decitabine

rr,ss

)

(category 1 for combination with azacitidine)

Other Recommended

• Low-intensity therapy (azacitidine, decitabine)

ss,uu

• Venetoclax-based therapy (same as above in combination with LDAC

)

FLT3

mutation

Preferred

• Venetoclax-based therapy (same as above in combination with azacitidine,

rr,ss

or decitabine

rr,ss

)

(category 1 for combination with azacitidine)

Other Recommended

• Low-intensity therapy (azacitidine, decitabine) + sorafenib

ss,ddd

(FLT3-ITD–positive)

• Venetoclax-based therapy (same as above in combination with LDAC

)

AML without

actionable

mutations

Preferred

• Venetoclax once daily (100 mg day 1, 200 mg day 2, 400 mg day 3 and beyond) PO and

azacitidine 75 mg/m

SC or IV (days 1–7 of each 28-day cycle)

rr,ss

(category 1)

• Venetoclax once daily (100 mg day 1, 200 mg day 2, 400 mg day 3 and beyond) PO and

decitabine 20 mg/m

IV (days 1–5 of each 28-day cycle)

rr,ss

Other Recommended

• Venetoclax once daily (100 mg day 1, 200 mg day 2, 400 mg day 3, and 600 mg day 4 and beyond)

PO and LDAC 20 mg/m

/d SC (days 1–10 of each 28-day cycle)

,tt

• Low-intensity therapy (azacitidine, decitabine)

ss,uu

• Glasdegib (100 mg PO daily on days 1–28) + LDAC 20 mg SC every 12 hours (days 1–10 of each

28-day cycle)

• Gemtuzumab ozogamicin 6 mg/m

on day 1 and 3 mg/m

on day 8

xx,yy

(CD33-positive)

(category 2B)

• LDAC (category 3) 20 mg/m

/day SC for 10 consecutive days every 4 weeks

• Best supportive care (hydroxyurea, transfusion support)

See

Post-Induction

Therapy

(AML-9)

TREATMENT

STRATEGIES

See footnotes on AML-6A

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

NCCN Guidelines Version 3.2021

Acute Myeloid Leukemia (Age ≥18 years)

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

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

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Discussion

AML-6A

FOOTNOTES FOR TREATMENT INDUCTION (PHYSIOLOGICAGE ≥60 YEARS)

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.

See Principles of Supportive Care for AML (AML-E).

Consider referral to palliative care for consultation at the start of induction. LeBlanc T, et al. Curr Hematol Malig Rep 2017;12:300-308 and LeBlanc T, et al. J Oncol

Pract.2017;13:589-590. See NCCN Guidelines for Palliative Care.

See General Considerations and Supportive Care for Patients Who Prefer Not to Receive Blood Transfusions (AML-D)

Threshold for CD33 is not well-defined and may be ≥1%.

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://www.fhcrc-

research.org/TRM/Default.aspx?GUID=1358501B-C922-4422-84F0-0E6C67D8F266 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.

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.

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.

Wei AH, et al. J Clin Oncol 2019;37:1277-1284.

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 dened by the protocol.

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.

Amadori S, et al. J Clin Oncol 2016;34:972-979.

Regimens that include gemtuzumab ozogamicin will not benefit patients with poor-risk disease.

Kantarjian HM, et al. J Clin Oncol 2012;30:2670-2677.

aaa

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.

bbb

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).

ccc

Stein EM, et al. Blood 2015;126:323; DiNardo CD, et al. Blood 2017;130:639.

ddd

Ohanian M, et al. Am J Hematol 2018;93:1136-1141.

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

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Acute Myeloid Leukemia (Age ≥18 years)

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.

NCCN Guidelines Index

Table of Contents

Discussion

AML-7

AML PHYSIOLOGICAGE ≥60 y

AFTER STANDARD-DOSE CYTARABINE INDUCTION

Options:

• Additional standard-dose cytarabine with anthracycline (idarubicin or

daunorubicin

)

or mitoxantrone

• Standard-dose cytarabine with daunorubicin and oral midostaurin

n,z,qq

(FLT3 mutated [ITD or TKD])

• Dual-drug liposomal encapsulation of cytarabine 100 mg/m

and

daunorubicin 44 mg/m

on days 1 and 3 x 1–2 cycles

(therapy-related

AML or patients with antecedent MDS/CMML or AML-MRC)

(preferred only if given in induction)

• Intermediate-dose cytarabine (1–<2 g/m

)-containing regimens

• Consider allogeneic HCT

eee

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

• Await recovery

• Best supportive care

Residual disease

(if ambiguous, consider

repeat BM biopsy in 5–7

days before proceeding

with therapy)

Hypoplasia

w,x

Await recovery

Follow-up BM

aspirate and

biopsy 14–21

days after start

of therapy

See Post-

Remission

Therapy

(AML-8)

See Monitoring During Therapy (AML-F).

Consider referral to palliative care consultation at the start of induction. LeBlanc T,

et al. Curr Hematol Malig Rep 2017;12:300-308 and LeBlanc T, et al. J Oncol Pract

2017;13:589-590. See NCCN Guidelines for Palliative Care.

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.

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.

There are limited prospective data to support this recommendation. Othus M, et al.

Leukemia 2016;30:1779-1780.

If ambiguous, consider repeat BM biopsy in 5–7 days before proceeding with therapy.

Hypoplasia is defined as cellularity less than 20% of which the residual blasts are less

than 5% (ie, blast percentage of residual cellularity).

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.

If daunorubicin 90 mg/m

was used in induction, the recommended dose for

daunorubicin for reinduction prior to count recovery is 45 mg/m

for no more than

2 doses. Analogously, if idarubicin 12 mg/m

was used for induction, the early

reinduction dose should be limited to 10 mg/m

for 1 or 2 doses.

Lancet JE, et al. J Clin Oncol 2018;36:2684-2692.

The complete response rate and 2-year overall survival in patients between 60

and 65 years of age treated with daunorubicin 90 mg/m

are also comparable to the

outcome for idarubicin 12 mg/m

; the higher dose daunorubicin did not benefit patients

>65 years of age (Löwenberg B, et al. N Engl J Med 2009;361:1235-1248).

The 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.

eee

Allogeneic transplant is a reasonable option in patients who experience failure after

re-induction with certain regimens (eg, intermediate- or high-dose cytarabine), and

have identified donors available to start conditioning within 4–6 weeks from start of

induction therapy. Patients without an identified donor would most likely need some

additional therapy as a bridge to transplant. HCT may be appropriate for patients

with a low level of residual disease post-induction (eg, patients with prior MDS who

reverted back to MDS with <10% blasts). It is preferred that this approach be given

in the context of a clinical trial. For patients with residual disease after 1 cycle of

induction chemotherapy who would not tolerate another intensive salvage, consider a

venetoclax-based regimen.

(NCCN

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

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Table of Contents

Discussion

AML-8

AML PHYSIOLOGIC AGE ≥60 y

POST-REMISSION/MAINTENANCE THERAPY

Options

• Allogeneic HCT

hhh

• Standard-dose cytarabine (100–200 mg/m

/d x 5–7 d x 1–2 cycles) ±

anthracycline (idarubicin or daunorubicin)

• Consider intermediate-dose cytarabine 1–1.5 g/m

/d x 4–6 doses x 1–2 cycles

for patients with good performance status, normal renal function, and better-

risk / normal karyotype with favorable molecular markers

• Intermediate-dose cytarabine 1–1.5 g/m

over 3 h every 12 h on days 1, 3, and

5 or 1 g/m

over 3 h every 12 h on days 1, 3, 5 (total 6 doses) for a total of 4

planned cycles with oral midostaurin 50 mg every 12 h on days 8–21

n,iii

• Dual-drug liposomal encapsulation of cytarabine 65 mg/m

and daunorubicin

29 mg/m

on days 1 and 3 x 1–2 cycles

(therapy-related AML or patients with

antecedent MDS/CMML or AML-MRC) (preferred only if given in induction)

• Cytarabine 1000 mg/m

every 12 h on days 1–4 + daunorubicin 60 mg/m

on day

1 (rst cycle) or days 1–2 (second cycle) + gemtuzumab ozogamicin 3 mg/m

(up to one 4.5 mg vial) on day 1 x 2 cycles



(CD33-positive)

• Maintenance therapy with hypomethylating regimens (azacitidine, decitabine)

every 4–6 weeks until progression

jjj

• Maintenance therapy with oral azacitidine 300 mg PO once daily on days 1–14

of each 28-day cycle until progression or unacceptable toxicity

• Observation

Complete

response

f,ggg

(Response

criteria, see

AML-H)

Induction

failure

(Response

criteria, see

AML-H)

BM aspirate

and biopsy

to document

remission

status upon

hematologic

recovery (4–6

weeks) For MRD

assessment, see

AML-G

Options

• Low-intensity therapy (azacitidine, decitabine)

• Allogeneic HCT (preferably in clinical trial)

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

• Best supportive care (See NCCN Guidelines for Palliative Care)

See

Surveillance

(AML-10)

intensive

therapy

See footnotes on AML-8A

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Discussion

AML-8A

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.

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.

Meta-analyses showing an advantage with gemtuzumab ozogamicin have included other dosing schedules. Hills RK, et al. Lancet Oncol 2014;15:986-996.

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 is 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.

Lancet JE, et al. J Clin Oncol 2018;36:2684-2692.

fff

Patients in remission may be screened with LP if initial WBC count >40,000/mcL or monocytic histology. See Evaluation and Treatment of CNS Leukemia (AML-B).

ggg

HLA typing should be used for patients considered to be strong candidates for allogeneic transplantation.

hhh

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

iii

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.

jjj

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. Huls G, et al. Blood 2019;133:1457-1464.

FOOTNOTES FOR POST-REMISSION/MAINTENANCE THERAPY (PHYSIOLOGIC AGE ≥60 YEARS)

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Discussion

AML PHYSIOLOGIC AGE ≥60 y

POST-INDUCTION THERAPY

lower-

intensity

therapy

Options: (Principles of Venetoclax, see AML-J)

• Allogeneic HCT

hhh

• Continue on lower-intensity regimen that was previously used per AML-6:

Hypomethylating regimens (azacitidine, decitabine) every 4–6 weeks until

progression

Enasidenib

until progression (IDH2-mutated AML)

ccc,lll

or ivosidenib

aaa,lll

(IDH1-mutated AML) until progression

Venetoclax once daily PO and decitabine 20 mg/m

IV (days 1–5 of each 28-day

cycle)

rr,ss

Venetoclax once daily PO and azacitidine 75 mg/m

SC or IV (days 1–7 of each

28-day cycle)

rr,ss

Venetoclax once daily PO and LDAC 20 mg/m

/d SC (days 1–10 of each 28-day

cycle)

rr,tt

Glasdegib (100 mg PO daily on days 1–28) + LDAC 20 mg SC every 12 hours

(days 1–10 of each 28-day cycle)

Azacitidine or decitabine + sorafenib (FLT3-ITD-mutated AML)

ss,ddd

• A single dose of gemtuzumab ozogamicin 2 mg/m

on day 1 every 4 weeks for up to 8

continuation courses

(CD33-positive) (category 2B)

BM aspirate and

biopsy to document

remission status

upon hematologic

recovery (timing

is dependent on

agent)

kkk

For MRD

assessment, see

AML-G

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

Best supportive care (See NCCN Guidelines for Palliative Care)

Response

(Response

criteria, see

AML-H)

No response

or progression

(Response

criteria, see

AML-H)

See

Surveillance

(AML-10)

AML-9

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.

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.

Wei AH, et al. J Clin Oncol 2019;37:1277-1284.

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. Blood

2016;128:99-99.

Amadori S, et al. J Clin Oncol 2016;34:972-979.

aaa

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.

ccc

Stein EM, et al. Blood 2015;126:323; DiNardo CD, et al. Blood 2017;130:639.

ddd

Ohanian M, et al. Am J Hematol 2018;93:1136-1141.

hhh

Patients who are deemed as candidates for HCT and who have an available donor should

be transplanted in first remission.

kkk

Response to treatment with enasidenib or ivosidenib may take 3–5 months.

lll

Enasidenib or ivosidenib increases the risk for differentiation syndrome and

hyperleukocytosis that may require treatment with hydroxyurea and steroids.

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

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Acute Myeloid Leukemia (Age ≥18 years)

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

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Discussion

AML-10

AML SURVEILLANCE

mmm

AND THERAPY FOR RELAPSED/REFRACTORY DISEASE

(AFTER COMPLETION OF CONSOLIDATION)

mmm

Studies are ongoing to evaluate the role of molecular monitoring in the surveillance for early relapse in patients with AML (see Discussion).

nnn

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.

ooo

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.

• CBC, platelets every 1–3 mo for

2 y, then every 3–6 mo up to 5 y

• BM aspirate and biopsy only if

peripheral smear is abnormal or

cytopenias develop

• Donor search should be initiated

at rst relapse in appropriate

patients concomitant with

institution of other therapy if no

sibling donor has been identied

Relapse

nnn

(Response

criteria, see

AML-H)

Comprehensive genomic

proling to determine

mutation status of

actionable genes

Options:

Clinical trial (strongly preferred)

Targeted therapy (see AML-I) followed by

matched sibling or alternative donor HCT

Chemotherapy (see AML-I) followed by matched

sibling or alternative donor HCT

Repeat initial successful induction regimen

ooo

if ≥12 months since induction regimen

Best supportive care

(see NCCN Guidelines for Palliative Care)

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Discussion

RISK STRATIFICATION BY GENETICS IN NON-APL AML

1,2

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.

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.

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-ITD

low

†

Intermediate Mutated NPM1 and FLT3-ITD

high

†

Wild-type NPM1 without FLT3-ITD or with FLT3-ITD

low

†

(without adverse-risk genetic lesions)

t(9;11)(p21.3;q23.3); MLLT3-KMT2A

‡

Cytogenetic abnormalities not classied 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-ITD

high

†

Mutated RUNX1

Mutated ASXL1

Mutated TP53

AML-A

1 OF 3

Familial Genetic Alterations in AML, see AML-A 2 of 3

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Discussion

FAMILIAL GENETIC ALTERATIONS IN AML

AML-A

2 OF 3

• Patients with a family history of leukemia, or of hematologic cancer or abnormalities, together with the presence of genetic mutations

outlined in the table below should be considered for germline testing and genetic counseling. It is strongly recommended that patients with

a variant allele frequency (VAF) of 40%–60% of genes associated with a predisposition syndrome be referred for germline testing.

Name of Syndrome Causative

Gene(s)

Pattern of

Inheritance

Characteristic

Malignancy

Other

Hematopoietic

Abnormalities

Other Associated Conditions Recommended

Diagnostic Test

Familial platelet

disorder with

propensity to myeloid

malignancies (OMIM

601399)

RUNX1 Autosomal

dominant

MDS

AML

T-cell ALL

Thrombocytopenia

Platelet dysfunction

Exon sequencing and

gene rearrangement

testing for RUNX1

Thrombocytopenia 2

(OMIM 188000)

ANKRD26 Autosomal

dominant

MDS

AML

Thrombocytopenia

Platelet dysfunction

5’UTR and exon

sequencing of

ANKRD26

Familial AML with

mutated CEBPA

(OMIM 116897)

CEBPA Autosomal

dominant

AML Exon sequencing and

gene rearrangement

testing for CEBPA

Familial AML with

mutated DDX41

(OMIM 608170)

DDX41 Autosomal

dominant

MDS

AML

CMML

Monocytosis Solid tumor predisposition is

likely [colon, bladder, stomach,

pancreas, breast, and melanoma]

Exon sequencing and

gene rearrangement

testing for DDX41

Thrombocytopenia 5

(OMIM 616216)

ETV6 Autosomal

dominant

MDS

AML

CMML

B-ALL

Myeloma

Thrombocytopenia

Platelet dysfunction

Exon sequencing and

gene rearrangement

testing for ETV6

Familial MDS/AML

with mutated GATA2

(OMIM 137295)

GATA2 Autosomal

dominant

MDS

AML

CMML

Monocytopenia

Lymphopenia (NK

cell, dendritic cell,B-

cell, or CD4+ T-cell)

Sensorineural deafness

Immunodeciency

Cutaneous warts

Pulmonary alveolar proteinosis

MonoMAC syndrome

Emberger syndrome

Exon sequencing,

intron 5 enhancer

region sequencing, and

gene rearrangement

testing for GATA2

Adapted with permission from: Churpek JE, Godley LA. Familial acute leukemia and myelodysplastic syndromes. In: UpToDate, Post TW (Ed), UpToDate, Waltham, MA.

Continued

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Discussion

Name of

Syndrome

Causative

Gene(s)

Pattern of

Inheritance

Characteristic

Malignancy

Other

Hematopoietic

Abnormalities

Other Associated Conditions Recommended Diagnostic

Test

Familial AML with

mutated MBD4

MBD4 Autosomal

dominant

AML Colonic polyps Exon sequencing and gene

rearrangement testing for

MBD4

MECOM-associated

syndrome (OMIM

165215 and

616738)

MECOM/EVI1

complex

Autosomal

dominant

MDS

AML

Bone marrow

failure

B-cell deciency

Radioulnar synostosis

Clinodactyly

Cardiac malformations

Renal malformations

Hearing loss

Exon sequencing and gene

rearrangement testing for

MECOM/EVI1 complex

Congenital SAMD9/

SAMD9L mutations

SAMD9 and

SAMD9L

Autosomal

dominant

MDS

AML

Pancytopenia Normophosphatemic familial

tumoral calcinosis

MIRAGE syndrome

Ataxia

Full gene sequencing and

gene rearrangement testing

for SAMD9 and SAMD9L

Telomere

syndromes due to

mutation in TERC

or TERT (OMIM

127550)

TERC/TERT Autosomal

dominant

Autosomal

recessive

(TERT)

MDS

AML

Macrocytosis

Cytopenias

Aplastic anemia

Idiopathic pulmonary brosis

Hepatic cirrhosis

Nail dystrophy

Oral leukoplakia

Skin hypopigmentation

Skin hyperpigmentation

Premature gray hair

Cerebellar hypoplasia

Immunodeciency

Developmental delay

Full gene sequencing and

gene rearrangement testing

for TERT and TERC

Telomere length studies

of lymphocyte subsets via

FlowFISH

SNP array testing (No CLIA-

approved testing available)

Myeloid neoplasms

with germline

predisposition due

to duplications of

ATG2B and GSKIP

ATG2B and

GSKIP

Autosomal

dominant

AML

CMML

Myelobrosis SNP array testing (No CLIA-

approved testing available)

AML-A

3 OF 3

FAMILIAL GENETIC ALTERATIONS IN AML

Adapted with permission from: Churpek JE, Godley LA. Familial acute leukemia and myelodysplastic syndromes. In: UpToDate, Post TW (Ed), UpToDate, Waltham, MA.

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Discussion

AML-B

Further CNS prophylaxis per institutional practice.

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.

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

In the presence of circulating blasts, administer IT chemotherapy with diagnostic LP.

If equivocal, consider repeating LP with morphology or immunotype by flow cytometry to delineate involvement.

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.

Concurrent use of CNS RT with high-dose cytarabine or IT methotrexate may increase risk of neurotoxicity. See Principles of Radiation Therapy (AML-C).

EVALUATION AND TREATMENT OF CNS LEUKEMIA

diagnosis,

neurologic

symptoms

First complete

response

screening, no

neurologic

symptoms

CT/MRI to

rule out

bleed or

mass eect

Negative

mass eect

Positive

mass eect

or increased

intracranial

pressure

Consider FNA or biopsy

Negative

Observe and repeat LP if

symptoms persist

IT chemotherapy

2x/wk until clear,

then weekly x 4–6 wks

followed by IT chemotherapy

2x/wk until clear,

then weekly x 4–6 wks

HiDAC-based therapy + dexamethasone to reduce

intracranial pressure

Negative

Observe and repeat LP if

symptoms present

IT chemotherapy 2x/wk until clear

If patient is to receive HiDAC, follow up with LP post

completion of therapy to document clearance

Cerebrospinal uid (CSF) positive

by morphology or immunotype by

ow cytometry

Positive by

morphology or

immunotype by

ow cytometry

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Acute Myeloid Leukemia (Age ≥18 years)

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.

NCCN Guidelines Index

Table of Contents

Discussion

AML-C

PRINCIPLES OF RADIATION THERAPY

I. General Principles

A. 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.

B. 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.

II. General Treatment Information

A. Dosing prescription regimen

1. CNS leukemia: RT

followed by IT chemotherapy

2x/wk until clear, then weekly x 4–6 weeks

Concurrent use of CNS RT with high-dose cytarabine or IT methotrexate may increase risk of neurotoxicity.

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.

Further CNS prophylaxis per institutional practice.

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Acute Myeloid Leukemia (Age ≥18 years)

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

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Discussion

AML-D

GENERAL CONSIDERATIONS AND SUPPORTIVE CARE FOR AML PATIENTS

WHO PREFER NOT TO RECEIVE BLOOD TRANSFUSIONS

1-5

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 if 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 women,

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 signicant 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, benets, and uncertainties.

• Consider bed rest and supplemental oxygenation in patients with severe anemia.

Disease-Specic 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.

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.

El Chaer F, Ballen KK. Treatment of acute leukaemia in adult Jehovah's Witnesses. Br J Haematol 2020;190:696-707.

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.

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.

Rubenstein M and Duvic M. Bone marrow transplantation in Jehovah's Witnesses. Leuk Lymphoma 2004;45:635-636.

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].

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Discussion

AML-E

Patients who are alloimmunized should receive cross-match–compatible and/or HLA-specific blood products.

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.

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.

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.

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) deciency should be checked when possible. However, it is not always feasible to do so

rapidly. If there is high suspicion of G6PD deciency, 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.

• 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 o 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 signicantly decrease fungal infections when compared to uconazole and

itraconazole.

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.

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

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Discussion

AML-F

MONITORING DURING THERAPY

Induction:

• CBC daily (dierential daily or as clinically indicated during chemotherapy and every other day after recovery of WBC count >500/mcL until

either normal dierential or persistent leukemia is documented); platelets daily while in the hospital until platelet-transfusion independent.

• Chemistry prole, including electrolytes, liver function tests (LFTs), blood urea nitrogen (BUN), creatinine, uric acid, and PO

, 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 brinogen 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 prole, electrolytes daily during chemotherapy

• Outpatient monitoring post chemotherapy: CBC, platelets, dierential, and electrolytes 2–3 x/wk until recovery

• BMaspirate/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.

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Acute Myeloid Leukemia (Age ≥18 years)

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

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

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Discussion

• 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.

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,

CBFB-

MYH11, RUNX1-RUNX1T1

) and multicolor ow cytometry (MFC) assays specically designed to detect abnormal MRD immunophenotypes.

The threshold

to dene MRD+ and MRD- samples depends on the technique and subgroup of AML. Next-generation sequencing (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 ow 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 alsonot considered reliable markers for MRD.

4-6

There are distinct dierences between diagnostic threshold assessments and MRD assessments. If using ow cytometry to assess MRD, it is

recommended that a specicMRD 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, ow 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 signicance

of MRD measurements after initial induction therapy.

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, (eg,

including allogeneic transplantation.

Some evidence suggest 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” canpredict hematologic relapses within a 3- to 6-month timeframe.

• Timing of MRD assessment:

Upon completion of initial induction.

4-6

Before allogeneic transplantation.

Additional time points should be guided by the regimen used.

2,3

MEASURABLE (MINIMAL) RESIDUAL DISEASE ASSESSMENT

Schuurhuis GJ, Heuser M, Freeman S, et al. Minimal/measurable residual disease in

AML: consensus document from ELN MRD Working Party. Blood 2018;131:1275-1291.

Ivey A, Hills RK, Simpson MA, et al. Assessment of minimal residual disease in standard-

risk AML. N Engl J Med 2016;374:422-433.

Jourdan E, Boissel N, Chevret S, et al. Prospective evaluation of gene mutations and

minimal residual disease in patients with core binding factor acute myeloid leukemia.

Blood 2013;121:2213-2223.

Jongen-Lavrencic M, Grob T, Hanekamp D, et al. Molecular minimal residual disease in

acute myeloid leukemia. N Engl J Med 2018;378:1189-1199.

Klco JM, Miller CA, Griffith M, et al. Association between mutation clearance after

induction therapy and outcomes in acute myeloid leukemia. JAMA 2015;314:811-822.

Morita K, Kantarjian H, Wang F, et al. Clearance of somatic mutations at remission and

the risk of relapse in acute myeloid leukemia J Clin Oncol 2018 36:1788-1797.

Thol F,

Gabdoulline R, Liebich A, et al. Measurable residual disease monitoring by NGS before

allogeneic hematopoietic cell transplantation in AML. Blood 2018;132:1703-1713.

AML-G

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and this illustration may not be reproduced in any form without the express written permission of NCCN.

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Acute Myeloid Leukemia (Age ≥18 years)

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.

NCCN Guidelines Index

Table of Contents

Discussion

AML-H

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.

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.

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.

Partial remissions are useful in assessing potential activity of new investigational agents, usually in phase I trials.

RESPONSE CRITERIA DEFINITIONS FOR ACUTE MYELOID LEUKEMIA

• 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 (CR

MRD-

)

◊ If studied pretreatment, CR with negativity for a genetic marker by RQ-PCR or CR with negativity by MFC

◊ Sensitivity varies by marker and method used; analyses should be done in experienced laboratoriesMolecular CR - molecular studies

negative

CRh - partial hematologic recovery, dened as <5% blasts in the BM, no evidence of disease, and partial recovery of peripheral blood

counts (platelets > 50 × 10

/L and ANC > 0.5 × 10

/L)

CR with incomplete hematologic recovery (CRi)- All CR criteria and transfusion independence but with persistence of neutropenia (<1,000/

mcL) or thrombocytopenia (<100,000/mcL).

Responses less than CR may still be meaningful depending on the therapy.

• Partial remission

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 dened as reappearance of leukemic blasts in the peripheral blood or the nding 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 CRifollowing exposure to at least 2 courses of intensive induction therapy.

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Acute Myeloid Leukemia (Age ≥18 years)

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

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Discussion

AML-I

There are promising ongoing clinical trials investigating targeted therapies based on molecular

mutations for relapsed/refractory disease. Molecular profiling should be considered if not done

at diagnosis, or repeated to determine clonal evolution. See Discussion.

Perl AE, Altman JK, Cortes J, et al. Selective inhibition of FLT3 by gilteritinib in relapsed or

refractory acute myeloid leukaemia: a multicentre, first-in-human, open-label, phase 1-2 study.

Lancet Oncol 2017;18:1061-1075.

Ravandi F, Alattar ML, Grunwald MR, et al. Phase 2 study of azacytidine plus sorafenib in

patients with acute myeloid leukemia and FLT-3 internal tandem duplication mutation. Blood

2013:121:4655-4662.

Muppidi MR, Portwood S, Griffiths EA, et al. Decitabine and sorafenib therapy in FLT3 ITD-

mutant acute myeloid leukemia. Clin Lymphoma Myeloma Leuk 2015;15 Suppl:S73-9.

Stein EM, DiNardo CD, Pollyea DA, et al. Enasidenib in mutant IDH2 relapsed or refractory

acute myeloid leukemia. Blood 2017;130:722-731.

DiNardo CD, Stein EM, de Botton S, et al. Durable remissions with ivosidenib in IDH1-mutated

relapsed or refractory AML. N Eng J Med 2018;378:2386-2398.

Taksin AL, Legrand O, Raffoux E, et al. High efficacy and safety profile of fractionated doses

of Mylotarg as induction therapy in patients with relapsed acute myeloblastic leukemia: a

prospective study of the alfa group. Leukemia 2007;21:66-71.

Robak T, Wrzesień-Kuś A, Lech-Marańda E, et al. Combination regimen of cladribine

(2-chlorodeoxyadenosine), cytarabine and G-CSF (CLAG) as induction therapy for patients with

relapsed or refractory acute myeloid leukemia. Leuk Lymphoma 2000;39:121-129.

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.

Karanes C, Kopecky KJ, Head DR, et al. A phase III comparison of high dose ARA-C (HIDAC)

versus HIDAC plus mitoxantrone in the treatment of first relapsed or refractory acute myeloid

leukemia Southwest Oncology Group Study. Leuk Res 1999;23:787-794.

Montillo M, Mirto S, Petti MC, et al. Fludarabine, cytarabine, and G-CSF (FLAG) for the

treatment of poor risk acute myeloid leukemia. Am J Hematol 1998;58:105-109.

Parker JE, Pagliuca A, Mijovic A, et al. Fludarabine, cytarabine, G-CSF and idarubicin (FLAG-

IDA) for the treatment of poor-risk myelodysplastic syndromes and acute myeloid leukaemia. Br

J Haematol 1997;99:939-944.

Nair G, Karmali G, Gregory SA, et al. Etoposide and cytarabine as an effective and safe

cytoreductive regimen for relapsed or refractory acute myeloid leukemia. J Clin Oncol

2011;29:15_suppl, 6539-6539.

Faderl S, Wetzler M, Rizzieri D, et al. Clorarabine plus cytarabine compared with

cytarabine alone in older patients with relapsed or refractory acute myelogenous leukemia:

results from the CLASSIC I Trial. J Clin Oncol 2012;30:2492-2499

Faderl S, Ferrajoli A, Wierda W, et al. Clofarabine combinations as acute myeloid leukemia

salvage therapy. Cancer 2008;113:2090-2096.

See Principles of Venetoclax Use With HMA in AML Patients (AML-J).

Aldoss I, Yang D, Aribi A, et al. Efficacy of the combination of venetoclax and hypomethylating

agents in relapsed/refractory acute myeloid leukemia. Haematologica 2018;103:e404-e407.

DiNardo CD, Rausch CR, Benton C, et al. Clinical experience with the BCL2-inhibitor

venetoclax in combination therapy for relapsed and refractory acute myeloid leukemia and

related myeloid malignancies. Am J Hematol 2018;93:401-407.

THERAPY FOR RELAPSED/REFRACTORY DISEASE

Clinical trial

Targeted therapy:

• Therapy for AML with FLT3-ITD mutation

Gilteritinib

(category 1)

Hypomethylating agents (azacitidine or decitabine) + sorafenib

3,4

• Therapy for AML with FLT3-TKD mutation

Gilteritinib

(category 1)

• Therapy for AML with IDH2 mutation

Enasidenib

• Therapy for AML with IDH1 mutation

Ivosidenib

• Therapy for CD33-positive AML

Gemtuzumab ozogamicin

Aggressive therapy for appropriate patients:

• Cladribine + cytarabine + G-CSF ± mitoxantrone or idarubicin

8,9

• HiDAC (if not received previously in treatment) ± (idarubicin or

daunorubicin or mitoxantrone)

• Fludarabine + cytarabine + G-CSF ± idarubicin

11,12

• Etoposide + cytarabine ± mitoxantrone

• Clofarabine ± cytarabine ± idarubicin

14,15

Less aggressive therapy:

• Hypomethylating agents (azacitidine or decitabine)

• LDAC (category 2B)

• Venetoclax

+ HMA/LDAC

17,18

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Acute Myeloid Leukemia (Age ≥18 years)

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

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Discussion

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

AML-J

1 of 2

General

• The maximum number of cycles for these regimens is unknown, and treatment may continue as long as tolerated and eective. As data

become available, additional insight and guidance about the recommended length of treatment will be provided.

• Reduction in duration of HMA and LDAC or venetoclax treatment can be considered, particularly when there are delays in count recovery.

• Refer to prescribing information and consult with a pharmacist for potential drug interactions (eg, CYP3A4 or CYP2D6 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 Patients

• Prior to Therapy

Try to achieve WBC count of <25,000/mcL with hydroxyurea/leukapheresis if necessary

Administer both therapies concomitantly

If antifungal prophylaxis is indicated, reduce venetoclax dose accordingly

• First Cycle Considerations

Tumor lysis syndrome (TLS) monitoring:

◊ In-patient treatment is strongly recommended during rst cycle of treatment, especially through dose escalation

◊ 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

◊ Recommend treatment with allopurinol or other uric acid lowering agent until no further risk of TLS

◊ Monitor blood chemistries every 6 hours after initiation; 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 21–28

◊ If no morphologic remission but evidence of ecacy exists, proceed with a second cycle without therapeutic 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 signicant threshold (ideally to CR or CRi status) resume the next cycle

– If counts have not recovered to a clinically signicant 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.

Recommend referral to tertiary care center/AMC if need to consider discontinuation

of any agent, or to continue maintenance on single-agent venetoclax.

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.

Patients may need hospitalization beyond first cycle, based on medical

circumstances. Treatment in outpatient setting may be considered per institutional

practice or treatment preference.

Combination of venetoclax + decitabine may favor an earlier assessment at day 21

(if blasts are reduced, but no morphologic remission).

Continued

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Acute Myeloid Leukemia (Age ≥18 years)

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NCCN Guidelines Index

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Discussion

PRINCIPLES OF VENETOCLAX USE WITH HMA OR LDAC-BASED TREATMENT (2 OF 2)

AML-J

2 of 2

Therapy for Newly Diagnosed Patients (Continued)

• Cycle 2 and beyond

If no evidence of disease (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 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, 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.

• 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."

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.

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.

(NCCN

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NCCN Guidelines Version 3.2021

Acute Myeloid Leukemia (Age ≥18 years)

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.

NCCN Guidelines Index

Table of Contents

Discussion

BPDCN-INTRO

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.

INTRODUCTION

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NCCN Guidelines Version 3.2021

Blastic Plasmacytoid Dendritic Cell Neoplasm

(Age ≥18 years)

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.

NCCN Guidelines Index

Table of Contents

Discussion

BPDCN-1

EVALUATION/WORKUP FOR BPDCN

a,b

DIAGNOSIS

• H&P

• CBC, platelets, dierential, comprehensive metabolic panel

• Analysis of skin lesions (collaboration with dermatology is

recommended),

peripheral blasts, BM aspirate/biopsy, and lymph

node biopsy including:

Dendritic cell morphology assessment

Immunohistochemistry

Flow cytometry

Cytogenetic analysis (karyotype and/or FISH)

Molecular analysis (most common abberations include: ASXL1,

IDH1–2, IKZF1–3, NPM1, NRAS, TET1–2, TP53, U2AF1, ZEB2)

• PET/CT scan for other sites, if clinical suspicion for extramedullary

disease and/or lymphadenopathy

• LP to rule out CNS disease; follow with IT prophylaxis

if clinically

indicated

See Treatment

Induction

(BPDCN-2)

BPDCN diagnosis requires at

least 4 of 6 BPDCN antigens:

• CD123

• CD4

• CD56

• TCL-1

• CD2AP

• CD303/BDCA-2

without myeloid,

T or B

lineage expression markers

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

NCCN Guidelines Version 3.2021

Blastic Plasmacytoid Dendritic Cell Neoplasm

(Age ≥18 years)

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.

NCCN Guidelines Index

Table of Contents

Discussion

BPDCN

conrmed

See Principles of BPDCN (BPDCN-A).

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.

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.

Menezes J, et al. Leukemia 2014;28:823-829.

Sullivan JM, Rizzieri DA. Hematology Am Soc Hematol Educ Program 2016;2016:16-23.

Myeloid markers include MPO, lysozyme, CD14, CD34, CD116, and CD163.

BPDCN-2

TREATMENT

OF BPDCN

Patients with low

performance and/or

nutritional status

(ie, serum albumin <3.2

g/dL; not a candidate

for intensive remission

induction therapy or

tagraxofusp-erzs

)

Candidate for

intensive remission

induction therapy

(AML-A)

TREATMENT INDUCTION

Localized/isolated

cutaneous disease

• Tagraxofusp-erzs

(formerly SL-401)(preferred)

12 mcg/kg IV over 15 minutes once daily on days 1–5 of a 21-day cycle

j,k

For management of adverse events, see Supportive Care (BPDCN-B)

• Chemotherapy

AML-type induction chemotherapy:

Standard-dose cytarabine 100–200 mg/m

continuous infusion x 7 days

with idarubicin 12 mg/m

or daunorubicin 60–90 mg/m

x 3 days

ALL-type induction chemotherapy:

HyperCVAD regimen (hyperfractionated cyclophosphamide, vincristine,

doxorubicin, dexamethasone, alternating with high-dose methotrexate

and cytarabine)

l,m,n

Lymphoma induction:

CHOP regimen (cyclophosphamide, doxorubicin, vincristine, and

prednisone)

• IT chemotherapy in patients with documented CNS disease at diagnosis/

if clinically indicated (methotrexate, cytarabine)

Palliative options include:

• Surgical excision

• Focal radiation

Induction

failure

or less

than CR

Consider

• Allogeneic HCT

l,p,q,r

• Autologous HCT

See Treatment for

Relapsed/Refractory Disease

(BPDCN-3)

Tagraxofusp-erzs

until progression

See

Surveillance

(BPDCN-3)

Systemic disease

(palliative intent)

Options include:

• Venetoclax-based therapy,

see AML-6

• Systemic steroids

• Supportive Care (BPDCN-B)

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

NCCN Guidelines Version 3.2021

Blastic Plasmacytoid Dendritic Cell Neoplasm

(Age ≥18 years)

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.

NCCN Guidelines Index

Table of Contents

Discussion

BPDCN

See Principles of Supportive Care for BPDCN (BPDCN-B).

Consider CNS prophylaxis for patients with overt systemic disease.

Pemmaraju N, et al. Blood 2019;134(Supplement_1):2723.

Frankel AE, et al. Blood 2014;124:385-392.

Pemmaraju N, et al. N Engl J Med 2019;380:1628-1637.

Pagano L, et al. Haematologica 2013;98:239-246.

Reimer P, et al. Bone Marrow Transplant 2003;32:637-646.

Deotare U, et al. Am J Hematol 2016;91:283-286.

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

skin lesions. If the skin still shows microscopic disease (CRc), consider continuing

additional cycles (at least 4) of therapy before managing as relapsed/refractory

disease. For appropriate studies to assess CR, see Pemmaraju N, et al. N Engl J Med

2019;380:1628-1637.

Kharfan-Dabaja MA, et al. Br J Haematol 2017;179:781-789.

Roos-Weil D, et al. Blood 2013;121:440-446.

Aoki T, et al. Blood 2015;125:3559-3562.

DiNardo CD, et al. Am J Hematol 2018;93:401-407.

BPDCN-3

• CBC, platelets every 1–3 mo for

2 y, then every 3–6 mo up to 5 y

• BM aspirate and biopsy only if peripheral

smear is abnormal or cytopenias

develop

• Repeat PET/CT scan for patients with

prior evidence of extramedullary disease

• Consider re-biopsy for any suspicious

skin or extramedullary lesions

Relapsed/

refractory

BPDCN

SURVEILLANCE

• Evaluate CNS for disease/prophylaxis

• Consider

Clinical trial (preferred)

Tagraxofusp-erzs

h,k

(preferred, if not already used)

For management of adverse events, see Supportive Care (BPDCN-B)

Chemotherapy (if not already used), see Treatment Induction (BPDCN-2)

Local radiation to isolated lesions/areas

Systemic steroids

Venetoclax-based therapy,

s,u,v

see AML-6

• Donor search should be initiated at rst relapse in appropriate patients

concomitant with institution of other therapy if no sibling donor has been

identied

TREATMENT FOR RELAPSED/REFRACTORY DISEASE

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

NCCN Guidelines Version 3.2021

Blastic Plasmacytoid Dendritic Cell Neoplasm

(Age ≥18 years)

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.

NCCN Guidelines Index

Table of Contents

Discussion

Consider CNS prophylaxis for patients with overt systemic disease.

Pemmaraju N, et al. N Engl J Med 2019;380:1628-1637.

DiNardo CD, et al. Am J Hematol 2018;93:401-407.

Martin-Martin L, et al. Oncotarget 2016;7:10174-10181.

Montero J, et al. Cancer Discovery 2017;7:156-164.

Rausch CR, et al. Blood 2017;130:1356.

BPDCN-A

PRINCIPLES OF BPDCN

General Principles:

• BPDCN is a disorder of immature dendritic cells that regulate eector T-cell function.

• It constitutes only 0.44% of hematologic malignancies and <1% of acute leukemia presentations.

• 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,

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 rst remission (CR1) during receipt of allogeneic HCT signicantly enhances the median OS.

4-6

Reduced-

intensity conditioning may be considered in patients who achieve CR but cannot tolerate myeloablative transplantation.

• For t 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,

and must be monitored closely during therapy (see Principles of Supportive Care for BPDCN [BPDCN-B]).

Bueno C, Almeida J, Lucio P, et al. Incidence and characteristics of CD4(+)/HLA DRhi dendritic cell malignancies. Haematologica 2004;89:58-69.

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.

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.

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.

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.

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.

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.

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.

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

NCCN Guidelines Version 3.2021

Blastic Plasmacytoid Dendritic Cell Neoplasm

(Age ≥18 years)

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.

NCCN Guidelines Index

Table of Contents

Discussion

BPDCN-B

PRINCIPLES OF SUPPORTIVE CARE FOR BPDCN

Administration/Management of Toxicities Associated with Tagraxofusp-erzs

• 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 rst 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 rst 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, uid 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

For full details on administration and toxicity management, see: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/761116s000lbl.pdf

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

NCCN Guidelines Version 3.2021

Blastic Plasmacytoid Dendritic Cell Neoplasm

(Age ≥18 years)

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.

NCCN Guidelines Index

Table of Contents

Discussion

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NCCN Guidelines Version 3.2021

Acute Myeloid Leukemia (Age ≥18 years)

NCCN Guidelines Index

Table of Contents

Discussion

NCCN Categories of Evidence and Consensus

Category 1 Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate.

Category 2A Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate.

Category 2B Based upon lower-level evidence, there is NCCN consensus that the intervention is appropriate.

Category 3 Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate.

All recommendations are category 2A unless otherwise indicated.

NCCN Categories of Preference

Preferred intervention

Interventions that are based on superior ecacy, safety, and evidence; and, when appropriate,

aordability.

Other recommended

intervention

Other interventions that may be somewhat less ecacious, more toxic, or based on less mature data;

or signicantly less aordable for similar outcomes.

Useful in certain

circumstances

Other interventions that may be used for selected patient populations (dened with recommendation).

All recommendations are considered appropriate.

CAT-1