eBulletin Newsletter

NCCN Flash Updates: NCCN Guidelines Updated for Acute Myeloid Leukemia

NCCN has published updates to the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines^®), the NCCN Radiation Therapy Compendium™, and the NCCN Imaging Appropriate Use Criteria (NCCN Imaging AUC™) for Acute Myeloid Leukemia. These NCCN Guidelines^® are currently available as Version 1.2024.

Link directly to the Updates section of the NCCN Guidelines: Acute Myeloid Leukemia

Global

• References updated throughout the guideline.
• Blood cell count measurements changed to "...x 10⁹/L" throughout the guidelines.

EVAL-1

• Evaluation
  • 6th bullet modified: Molecular analyses (ASXL1, c-KIT, FLT3 [ITD (internal tandem duplication) and TKD (tyrosine kinase domain)], NPM1, in-frame bZIP mutation in CEBPA [biallelic], IDH1, IDH2, RUNX1, TP53, and other mutations (AML-A)
  • 8th bullet added: Recommend additional molecular and genetic testing for heritable hematologic malignancy predisposition in a subset of patients, particularly in patients <50 years (see MDS-D and MDS-E from the NCCN Guidelines for Myelodysplastic Syndromes)
  • 11th bullet modified: Brain MRI with and without contrast, if leukemic meningitis suspected (AML-B)
  • 12th bullet modified: Consider FDG-PET/CT, if clinical suspicion forin individuals with extramedullary disease (See AML-B)

EVAL-2

• Diagnosis
  • AML modified: To appropriately stratify available intensive therapy options, expedite test results of molecular and cytogenetic analyses for immediately actionable mutations or chromosomal abnormalities (eg, core binding factor [CBF], FLT3 [ITD and TKD], NPM1, IDH1, IDH2)
    • 1st bullet modified: For patients with hyperleukocytosis uncontrolled with hydroxyurea or leukapheresis, one dose of intermediate-dose cytarabine (1–2 g) may be considered prior to receiving diagnostic results.

EVAL-2A

• Footnote b added: A heritable hematologic malignancy predisposition syndrome may account for cytopenias with or without MDS in some patients, whether presenting to pediatric or adult care centers (eg, GATA2 deficiency syndrome, Shwachman-Diamond syndrome, telomere biology disorders). Functional laboratory studies and constitutional (germline) genetic testing using large NGS panels to include genes listed on MDS-E in the NCCN Guidelines for Myelodysplastic Syndromes, whole exome or whole genome sequencing complemented within silico copy number variant (CNV) calling, and/or laboratory analysis for CNVs, such as microarray testing, is recommended for certain patients. See Genetic Familial High-Risk Assessment: Heritable Hematologic Malignancy Predisposition Syndromes (MDS-D) and Gene Mutations Associated with Heritable Hematologic Malignancy Predisposition Syndromes (MDS-E).
• Footnote g added: At the moment, there are discrepancies between two recognized classification systems (Khoury JD, et al. Leukemia 2022;36:1703-1719; Arber DA, et al. Blood 2022;140:1200-1228) for AML. The NCCN guidelines do not advocate for one over another. Providers should exercise their best clinical judgment related to these discrepancies, and the NCCN Panel recommends classification systems be written to allow for maximal clinical trial participation.

APL-1

• Footnote b added: For patients with APL being treated at a community center, collaboration with a center with expertise has been shown to reduce induction mortality. Jillella AP, et al. Blood 2022;140:1011-1013. (Also for APL-2A, APL-3A, APL-4A).

APL-2

• APL Treatment Induction (Low Risk), Preferred Regimens
  • Pathway 1 modified: ATRA 45 mg/m² in 2 divided doses daily + arsenic trioxide 0.15 mg/kg IV daily (category 1) See Principles of Supportive Care for APL (APL-A)
  • Pathway 2 modified: ATRA 45 mg/m² in 2 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)

APL-A

• 3rd bullet added: Hydroxyurea can be used to treat leukocytosis in individuals with low-risk disease who experience a rise in WBC count after treatment with an ATRA/arsenic trioxide based regimen.
• 4th bullet
  • 3rd sub bullet modified: The following cytoreduction strategies for leukocytosis may be used for differentiation syndrome that is difficult to treat: hydroxyurea, anthracycline, or gemtuzumab ozogamicin.Hydroxyurea can be used to treat leukocytosis associated with differentiation syndrome. In difficult-to-treat cases, an anthracycline (daunorubicin or idarubicin) or gemtuzumab ozogamicin can be used.
• Footnote a modified: Antiviral prophylaxis against varicella-zoster virus for duration of treatment may be appropriate. Freyer CW, et al. Leuk Lymphoma 2021;62:696-702; Glass JL, et al. Blood 2015;126:3752.126:Abstract 3752.

AML-1

• This page was extensively revised.

AML-2

• This page was extensively revised.

AML-2A

• Footnote a modified: Patients with elevated blast counts are at risk for tumor lysis and organ dysfunction secondary to leukostasis. Measures to rapidly reduce the WBC count include leukapheresis, hydroxyurea, and/or a single dose of cytarabine (1–2 g). Prompt institution of definitive therapy is essential. (Also for AML-4A)
• Footnote b modified by adding: Consider the use of geriatric assessment for patients with AML ≥60 years of age. Ritchie EK, et al. Blood Adv 2022;6:3812-3820; Min GJ, et al. Blood 2022;139:1646-1658; Saad M, et al. Blood 2020;136:2715-2719; Klepin HD, et al. Blood 2013;121:4287-4294. (Also for AML-4A)
• Footnote d modified by adding: Tarlock K, et al. Blood 2021;138:1137-1147. (Also for AML-6A)
• Footnote g modified: Consider referral to palliative care for consultation at the start of induction. LeBlanc TW, et al. Curr Hematol Malig Rep 2017;12:300-308 and LeBlanc TW, et al. J Oncol Pract 2017;13:589-590.El-Jawahri A, et al. JAMA Oncol 2021;7:238-245. See NCCN Guidelines for Palliative Care. (Also for AML-4A)
• Footnote q added: In times of fludarabine shortage, cladribine can be substituted for fludarabine. (Also for AML-6A)
• Footnote r modified: Consider dose adjustments for cytarabine based on age and renal function. Doses of cytarabine ≥2 g/m² should be used with caution in patients ≥60 years and patients with renal failure due to concern for neurotoxicity. See Principles of Systemic Therapy (AML-E). (Also for AML-3A)
• Footnote t added: Gemtuzumab ozogamicin may be beneficial in NPM1-mutated AML (Kapp-Schwoerer S, et al. Blood 2020;136:3041-3050). The role of gemtuzumab ozogamicin in CEBPA-mutated AML is not established.

AML-2B

• Footnote v modified: The RATIFY trial studied patients aged 18–60 y with FLT3-ITDmutated AML. An extrapolation of the data suggests that patients aged 61–70 years with FLT3-ITDmutated AML who are fit to receive 7+3 should be offered midostaurin since it seems to provide a survival benefit without undue toxicity. Schlenk RF, et al. Blood 2019;133:840-851. (Also added to AML-6A)
• Footnote x modified: There are limited data supporting the use of this regimen in patients aged <60 years. Lancet JE, et al. J Clin Oncol 2018;36:2684-2692. For patients with AML-MRC and previous hypomethylating agent (HMA) exposure, the benefit from standard induction did not differ from the benefit with CPX-351/dual-drug liposomal encapsulation of cytarabine and daunorubicin. Lancet JE, et al. J Clin Oncol 2018;36:2684-2692. While the mutational definition of AML-MRC as it applies to the use of CPX-351/dual-drug liposomal cytarabine and daunorubicin was not studied in the original trial, its use can be considered. (Also added to AML-6A)
• Footnote aa modified: The use of doses of cytarabine ≥2 g/m²HiDAC for induction outside the setting of a clinical trial is still controversial. While the remission rates are the same for doses of cytarabine >100 to 200 mg/m² and doses of cytarabine ≥2 g/m²HiDAC, two studies have shown more rapid BM blast clearance after one cycle of high-dose therapy. Kern W, Estey EH. Cancer 2006;107:116-124.
• Footnotes removed
  • Doses of cytarabine should be modified based on age and renal insufficiency as per protocol. DiNardo CD, et al. J Clin Oncol 2021;39:2768-2778.
  • Regimens that include gemtuzumab ozogamicin have limited benefit in poor-risk disease.

AML-3

• This page was extensively revised.

AML-3A

• Footnote cc added: When using a cytarabine-based induction regimen with doses of cytarabine >100 to 200 mg/m², consider delaying BM aspirate and biopsy to D21.
• Footnote ff modified: For re-induction, no data are available to show superiority with intermediate-dose cytarabine or HiDAC.1–2 g/m² of cytarabine compared to doses ≥2 g/m².
• Footnote ii added: When performed, BM aspirate and biopsy should include cytogenetic and molecular studies, as appropriate. For measurable (minimal) residual disease (MRD) assessment, see AML-H.
• Footnotes removed:
  • Consider referral to palliative care for consultation at the start of induction. LeBlanc TW, et al. Curr Hematol Malig Rep 2017;12:300-308 and LeBlanc TW, et al. J Oncol Pract 2017;13:589-590. See NCCN Guidelines for Palliative Care.
  • Begin alternate donor search (haploidentical, unrelated donor, or cord blood) if no appropriate matched sibling donor is available and the patient is a candidate for allogeneic HCT. For lack of response to induction, alternative therapy to achieve remission is encouraged prior to HCT. See NCCN Guidelines for Hematopoietic Cell Transplantation.
  • If ambiguous, consider repeat BM biopsy in 5–7 days before proceeding with therapy.

AML-4

• This page was extensively revised.

AML-4A

• Footnote jj added: For patients who decline induction chemotherapy and/or targeted therapy, best supportive care may include hydroxyurea and/or transfusion support.
• Footnote oo modified: In patients with AML with TP53 mutation, a 10-day course of decitabine may be considered (Welch JS, et al. N Engl J Med 2016;375:2023-2036). Response may not be evident before 3–4 cycles of treatment with HMAs (ie, azacitidine, decitabine). Continue HMA treatment until progression if patient is tolerating therapy. Similar delays in response are likely with novel agents in a clinical trial, but endpoints will be defined by the protocol.

AML-5

• Heading modified: Follow-up After Induction Therapy with Lower Intensity Therapy (Intensive Induction Ineligible or Declines)

AML-6

• This page was extensively revised.

AML-6A

• Footnote hh added: 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.
• Footnote tt modified: Alternate dosing of cytarabine for postremission therapy has been reported (Discussion). Jaramillo S, et al. Blood Cancer J 2017;7:e564. Doses of cytarabine ≥2 g/m² should be used with caution in patients ≥60 years and patients with renal failure due to concern for neurotoxicity. See Principles of Systemic Therapy (AML-E).
• Footnote ww modified: Patients may require at least one cycle of HiDACcytarabine-based 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.
• Footnote xx modified: There is no evidence that HiDAC is superior to intermediate doses (1.5 g/m2 daily x 5 days) ofcytarabine doses ≥2 g/m² are superior to doses 1–2 g/m² in patients with AML with intermediate-risk cytogenetics.
• Footnote yy added: Allogeneic transplant is recommended for patients with favorable-risk disease who are unable to complete consolidation or who have high-risk features such as MRD-positivity or KIT mutation.
• Footnote removed: Alternate administration of intermediate-dose cytarabine may also be used. Sperr WG, et al. Clin Cancer Res 2004;10:3965-3971.

AML-7

• 1st pathway
  • Risk group modified: Patient with intermediate or adverse risk diseasenon-CBF-AML
  • Treatment, 2nd bullet
    • 2nd sub bullet modified: Decitabine (category 2B)
• Footnote zz modified: This is not intended to replace consolidation chemotherapy. In addition, patients who are fit with AML with intermediate- and/or adverse-risk cytogenetics may benefit from HCT in first CR, and there are no data to suggest that maintenance therapy with oral azacitidine can replace HCT. The panel also notes that the trial did not include patients <55 years of age or those with CBF-AML; it was restricted to patients ≥55 years of age with AML with intermediate or adverse cytogenetics who were not felt to be candidates for HCT. Most patients received at least 1 cycle of consolidation prior to starting oral azacitidine. Wei AH, et al. N Engl J Med 2020;383:2526-2537.

AML-8

• Surveillance
  • 3rd bullet modified: Donor search should be initiated at first relapse in appropriate patients concomitant with institution of other therapy if no sibling donor has been identified
• Treatment options
  • 2nd pathway modified: Targeted therapy (AML-J) followed by matched sibling or alternative donor allogeneic HCT
  • 3rd pathway modified: Chemotherapy (see AML-J) followed by matched sibling or alternative donor allogeneic HCT

AML-A

• This section was extensively revised.

AML-C

• General Principles, 1st bullet modified: Patients who present with isolated extramedullary disease (myeloid sarcoma) should be treated with systemic therapy. Local therapy (RT or surgery [rare cases]) may be used for residual disease or for symptomatic disease.

AML-E

• This section was extensively revised.

AML-F

• 4th bullet modified: 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.

AML-G

• Induction
  • 1st bullet modified: CBC daily (differential daily or as clinically indicated during chemotherapy and every other day after recovery of WBC countANC >500/mcL0.5 x 10⁹/L until either normal differential or persistent leukemia is documented); platelets daily while in the hospital until platelet-transfusion independent.
  • 5th bullet modified: BM aspirate/biopsy 14–21 days after start of therapy to document hypoplasia. If hypoplasia is not documented or indeterminate, repeat biopsy within 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.

AML-I

• 1st bullet
  • 4th sub bullet modified: A BM biopsy/aspirate should be performed if spicules are absent from the aspirate sample.
• 2nd bullet, 3rd sub bullet
  • 1st sub-sub-bullet modified: If studied pretreatment, CR with negativity for a genetic marker by reverse transcriptase PCR (RT-PCR) or CR with negativity by MFC

AML-J 1 of 2

• Aggressive therapy for appropriate patients
  • 2nd bullet modified: CytarabineHiDAC (if not received previously in treatment) ± (idarubicin or daunorubicin or mitoxantrone)
• Footnote b added: Appropriate patients include those eligible for aggressive therapy and with relatively short first remission. For patients with long first remission, reinduction therapy may be appropriate.

AML-K 1 of 2

• General
  • 1st bullet added: Highly consider consultation with high-volume tertiary care/academic medical center.
  • 3rd bullet modified: Patients with disease in remission should takewill frequently require breaks between treatment, such as extending cycle length from 28-day to 42-day cycleson the order of 7–14 days to allow for hematological recovery.

AML-K 2 of 2

• 1st bullet
  • 1st sub bullet modified: If NED after cycle 1, consider repeat BM biopsy at 3- to 6-month intervals, assuming no unexpected changes in blood counts occur.
• Footnote removed: Recommend referral to tertiary care center/academic medical center if need to consider discontinuation of any agent, or to continue maintenance on single-agent venetoclax

BPDCN-1

• Evaluation/Workup
  • 3rd bullet
    • Last sub bullet modified: Molecular analysis (most common aberrations include: ASXL1, IDH1–2, IKZF1–3, NPM1, NRAS, TET1–2, TP53, U2AF1, ZEB2TET2, ASXL1, ZRSR2, SRSF2, TP53, NRAS, IDH2, and ETV6)
  • 5th bullet modified: All patients require a diagnostic LP at the time of initial diagnosis, at disease relapse, or any other time when there is a clinical suspicion for CNS involvement. Consider following with IT chemotherapy prophylaxis as clinically indicated (BPDCN-B).
• Footnote b added: Close collaboration with dermatology is recommended. For guidance on classification and measurement of skin lesions, see page MFSS-3 in the NCCN Guidelines for Primary Cutaneous Lymphomas.

BPDCN-B

• Without CNS disease
  • 1st bullet modified: Consider administering prophylactic CNS-directed IT chemotherapy strongly recommended to be administered prophylactically
• Footnote b added: Consider IT chemotherapy prophylaxis even in the absence of known CNS disease, given the high percentage (30%) of primary CNS involvement at relapse. Sullivan JM, Rizzieri DA. Hematology Am Soc Hematol Educ Program 2016;2016:16-23. Pemmaraju N, Kantarjian H, Sweet K, et al. Blood 2023;141:567-578.

MS-1

• Some sections of the discussion have been updated.