Acute Myeloid Leukemia (AML)

Background

• AML is a collection of malignant heterogeneous hematopoietic stem cell disorders caused by clonal expansion of myeloid blasts in bone marrow, peripheral blood, and other tissues.
• There are several types of AML recognized in the 2016 World Health Organization classification:
  • AML with recurrent genetic abnormalities
  • AML with myelodysplasia (MDS)-related changes
  • therapy-related myeloid neoplasms
  • AML, not otherwise specified
  • myeloid sarcoma
  • myeloid proliferations related to Down syndrome
  • acute leukemias of ambiguous lineage
• AML represented about 1.2% of all cancer cases in the United States in 2019.
• AML most commonly affects older adults (more than half of cases are in patients ≥ 65 years old).
• Risk factors for AML include
  • cytotoxic therapy (particularly 5-7 years after alkylating agents and 1-3 years after topoisomerase II inhibitors);
  • prior hematologic disorders, including myeloproliferative neoplasms;
  • germline genetic abnormalities such as Down Syndrome or cancer predisposition syndromes such as Fanconi anemia;
  • long-term exposure to petrochemicals or organizing solvent such as benzene;
  • smoking;
  • exposure to ionizing radiation.
• Patients generally have poor outcomes, with 5-year relative survival of 28.3% in the United States in 2009-2015. Prognosis is heavily influenced by both patient and leukemia characteristics such as age, patient performance status, comorbidities, genetics of leukemic cells, and other pre- and post-treatment factors.

Evaluation

• Patients with AML can present with anemia (causing fatigue), neutropenia (causing severe infections), and/or thrombocytopenia (causing hemorrhage) due to ineffective hematopoiesis. Patients can also present with leukostasis, tumor lysis syndrome, or disseminated intravascular coagulation as manifestations of the proliferation of malignant blasts.
• Diagnose patients according to the World Health Organization (WHO) diagnostic criteria, which define AML as any 1 of the following:
  • ≥ 20% myeloid blasts (myeloblasts, monoblasts, or megakaryoblasts) in peripheral blood or bone marrow (based on 200 leukocytes from blood smear and 500 nucleated cells from spiculated bone marrow smear);
  • any ≥ 1 of the following clonal, recurring cytogenetic abnormalities, regardless of myeloid blast percentage
    • t(8;21)(q22;q22.1), corresponding to RUNX1-RUNX1T1 fusion
    • inv(16)(p13.1q22) or t(16;16)(p13.1;q22), corresponding to CBFB-MYH11 fusion
    • t(15;17)(q22;q12), corresponding to acute promyelocytic leukemia (APL) with PML-RARA fusion
  • myeloid sarcoma (isolated extramedullary disease), regardless of myeloid blast percentage
• Classify AML into subtypes based on combination of history, histopathology with immunophenotyping by immunohistochemistry plus flow cytometry, and cytogenetic and molecular genetic testing of bone marrow.

Management

Initial Management

• For the treatment of acute promyelocytic leukemia (APL), see the Acute Promyelocytic Leukemia (APL) topic.
• While waiting for findings of cytogenetic and molecular genetic analyses, in patients with elevated blast count at risk of tumor lysis syndrome and leukostasis, consider management of hyperleukocytosis with leukapheresis, hydroxyurea, or cytarabine 1-2 g single dose (if hyperleukocytosis is not controlled with hydroxyurea or leukapheresis) (Weak recommendation).
• Induction chemotherapy:
  • Consider enrollment in a clinical trial as the preferred management strategy for all patients (Weak recommendation). See a list of ongoing trials in patients with AML at clinicaltrials.gov.
  • In patients who are eligible for intensive induction chemotherapy:
    • As the standard option, offer anthracycline or anthracenedione (either daunorubicin or idarubicin [or mitoxantrone also as an option for patients aged ≥ 60 years]) plus standard-dose cytarabine in "7+3 regimen" ("3+7 regimen") (Strong recommendation for patients < 60 years old; Weak recommendation for patients ≥ 60 years old).
    • Consider additions to "7+3 regimen" ("3+7 regimen") depend on cytogenetic risks and specific patient characteristics.
      • In patients with FLT3/internal tandem duplications (ITD)/tyrosine kinase domain (TKD) mutations (FLT3/TKD/IDT) and intermediate/poor-risk cytogenetics, offer addition of midostaurin to "7+3 regimen" ("3+7 regimen") (Strong recommendation).
      • In patients with favorable- or intermediate-risk cytogenetics and CD33-positive disease, consider addition of gemtuzumab ozogamicin to "7+3 regimen" ("3+7 regimen") (Weak recommendation).
    • In patients with therapy-related AML, AML with myelodysplasia-related changes, or history of myelodysplastic syndrome/chronic myelomonocytic leukemia (excluding CBF-AML),
      • offer liposomal encapsulation of daunorubicin and cytarabine for patients ≥ 60 years old, which improves survival compared to "7+3 regimen" ("3+7 regimen") (Strong recommendation).
      • consider liposomal encapsulation of daunorubicin and cytarabine for patients < 60 years old (Weak recommendation).
    • In patients < 60 years old with intermediate- or poor-risk cytogenetics, anthracycline plus high-dose cytarabine is also an option (Strong recommendation for patients ≤ 45 years old; Weak recommendation for patients aged 46-60 years).
  • In patients ≥ 60 years old who are ineligible or refuse intensive remission induction therapy,
    • Offer venetoclax plus azacitidine as preferred option for all patients regardless of actionable mutations (Strong recommendation); patients who received hypomethylating agents previously for myelodysplastic syndrome may be less likely to benefit from continued treatment with hypomethylating agents.
    • Consider venetoclax plus decitabine as alternative for all patients regardless of actionable mutations(Weak recommendation);patients who received hypomethylating agents previously for myelodysplastic syndrome may be less likely to benefit from continued treatment with hypomethylating agents.
• Postinduction therapy:
  • Follow-up bone marrow assessment is typically performed 21-28 days (after high-dose cytarabine) after start of therapy. A bone marrow biopsy is also performed around day 14 (with standard "7+3 regimen" ["3+7 regimen"]) to determine the need for reinduction.
  • For patients < 60 years old:
    • After standard-dose cytarabine induction:
      • If there is significant residual disease without hypocellular marrow, consider either further therapy to attempt induction of remission or management as primary refractory disease (Weak recommendation), and follow with postremission therapy if there is complete remission. Otherwise, consider managing as primary refractory disease.
      • If there is significant cytoreduction with low percentage of residual blasts, consider further therapy to attempt induction of remission (Weak recommendation), and follow with postremission therapy if there is complete remission. Otherwise, consider managing as primary refractory disease.
      • If there is hypoplasia (cellularity < 20% and residual blasts < 5%), consider waiting for bone marrow recovery (Weak recommendation) and follow with postremission therapy.
    • After high-dose cytarabine induction:
      • If there is significant residual disease without hypocellular marrow, consider managing as primary refractory disease (Weak recommendation).
      • If there is hypoplasia or significant cytoreduction with low proportion of residual blasts, consider waiting for bone marrow recovery (Weak recommendation). If there is complete remission, follow with postremission therapy. Otherwise, consider managing as primary refractory disease.
  • For patients ≥ 60 years old:
    • After standard-dose cytarabine induction:
      • If there is residual disease:
        • Consider further therapy to attempt induction of remission, or allogeneic hematopoietic stem cell transplantation (Weak recommendation), and follow with postremission therapy if there is complete remission. Otherwise, consider managing as primary refractory disease.
        • Other management options include awaiting bone marrow recovery, best supportive care only, or management as primary refractory disease (Weak recommendation).
      • If there is hypoplasia, consider waiting for bone marrow recovery (Weak recommendation) and follow with postremission therapy.
    • After venetoclax-based therapy, low-intensity azacitidine or decitabine, or mutation-targeted therapy:
      • If there is response, proceed with postremission therapy.
      • If there is progression or no remission or no clinical response after 4-6 cycles, consider managing as primary refractory disease.
• Postremission therapy:
  • Consider enrollment in a clinical trial (Weak recommendation). See a list of ongoing trials in patients with AML at clinicaltrials.gov.
  • For patients < 60 years old with complete remission after induction therapy, consider consolidation therapy according to risk status:
    • For patients with core binding factor (CBF) cytogenetic translocations and negative minimal residual disease (MRD), options include
      • high-dose cytarabine (with possible addition of gemtuzumab ozogamicin for CD33-positive disease) (Strong recommendation if given on days 1, 3, and 5 of cycle; Weak recommendation if given on days 1, 2, and 3 of cycle);
      • intermediate-dose cytarabine (with possible addition of gemtuzumab ozogamicin for CD33-positive disease) (Weak recommendation);
      • for CD33-positive disease, daunorubicin, intermediate-dose cytarabine, and gemtuzumab ozogamicin (Weak recommendation).
    • For other patients with favorable-risk cytogenetics, consider intermediate-dose cytarabine (with possible addition of gemtuzumab ozogamicin for CD33-positive disease, or addition of midostaurin for patients with FLT3 mutation).
    • For patients with intermediate-risk cytogenetics and/or molecular abnormalities, offer allogeneic hematopoietic stem cell transplant (HSCT) from matched-related or unrelated donor (Strong recommendation), or consider other high- or low-intensity chemotherapy options or autologous HSCT.
    • For patients with poor-risk cytogenetic and/or therapy-related AML, offer allogeneic HSCT from matched-related or unrelated donor as the preferred option (Strong recommendation), or consider other high- or low-intensity chemotherapy options.
    • Consider maintenance therapy with azacitidine until progression or toxicity (Weak recommendation) in patients with intermediate or adverse-risk disease with any of the following: are in remission after receiving prior intensive chemotherapy; completed no consolidation, some consolidation, or a recommended course of consolidation; for whom no allogeneic stem cell transplantation is planned.
  • For patients ≥ 60 years old with complete remission from previous intensive induction therapy, consider consolidation therapy according to risk status, fitness, and comorbidities.
    • Offer or consider allogeneic HSCT in fit patients (Strong recommendation for patients ≤ 75 years old with intermediate- or adverse-risk cytogenetics; Weak recommendation for patients with favorable-risk cytogenetics).
    • Consider or offer high- or low-intensity chemotherapy options, depending on risk status, actionable somatic abnormalities or immunophenotype, fitness, and comorbidities
    • Offer maintenance therapy for patients who are not able to receive any or all of the recommended consolidation therapy with either
      • azacitidine on days 1-14 (28-day cycles) until progression or toxicity as preferred option (Strong recommendation)
      • azacitidine or decitabine every 4-6 weeks until progression (Weak recommendation).

Management of Relapsed or Refractory Disease

• Consider enrollment in a clinical trial as the preferred management strategy (Weak recommendation). See list of ongoing trials in patients with AML at clinicaltrials.gov.
• Management of primary refractory disease:
  • In fit patients amenable to intensive therapy, management options include
    • allogeneic hematopoietic stem cell transplant (HSCT) (preferably in the context of a clinical trial for patients ≥ 60 years old) (Weak recommendation);
    • high-dose cytarabine with or without either daunorubicin or idarubicin (only if high-dose cytarabine has not been used previously for initial induction or reinduction for persistent disease) (Weak recommendation);
    • any intensive therapy options used for relapsed disease.
  • In unfit patients, consider lower-intensity therapy (with or without venetoclax), such as low-intensity azacitidine or decitabine, or low-dose cytarabine (Weak recommendation).
• Management of relapsed disease:
  • In fit patients amenable to intensive therapy, consider targeted therapy or intensive chemotherapy, followed by allogeneic hematopoietic stem cell transplant (HSCT) (Weak recommendation). Targeted therapy options depend on actionable mutations or receptor expression, such as FLT3-internal tandem duplication (ITD) or tyrosine kinase domain (TKD) mutations, IDH1 or IDH2 mutations, or CD33 expression.
  • If intensive therapy is not tolerable, consider targeted therapy or lower-intensity chemotherapy. Targeted therapy options depend on actionable mutations, such as FLT3-ITD or TKD mutation, or IDH1 or IDH2 mutations.
  • In patients with long duration of first remission (≥ 12 months since successful induction), as an alternative to the options mentioned above, consider reuse of the same regimens from initial induction chemotherapy (Weak recommendation), followed by allogeneic HSCT.
  • In patients not tolerating or not pursuing any further therapy options, consider best supportive care (Weak recommendation).