Diagnosis

• ≥ 20% blasts in blood or marrow (based on 200 nucleated cells from blood and 500 nucleated cells from bone marrow)
• clonal, recurring cytogenetic abnormalities (regardless of blast percentage)
• myeloid sarcoma (regardless of blast percentage)

Treatment

• For healthy fit patients <60 years age:

  • start induction chemotherapy with (“7+3”) which means 7 days of IV cytarabine and days 1-3 of daunorubicin
  • Formally: anthracycline plus cytarabine in "3 + 7" regimen, consisting of either daunorubicin 45-60 mg/m or idarubicin 12 mg/m IV once daily for 3 days plus standard dose cytarabine 100-200 mg/m/day by continuous IV for 7 days
  • Need echocardiogram prior to starting, often PICC placed with port placed later after induction in clinic

• For patients ≥ 60 years old PS 0-2 with de novo AML without antecedent hematologic disorder or therapy-related AML::

  • standard-dose cytarabine 100-200 mg/m/day continuous IV over 7 days plus any of idarubicin 12 mg/m (preferred), daunorubicin 45-90 mg/m, or mitoxantrone 12 mg/m IV once daily for 3 days
  • low-intensity therapy with either low-dose cytarabine subcutaneously, 5-azacytidine, or decitabine

• For patients PS > 2, if PS 0-3 with significant comorbidities, or patient aged ≥ 75 years:

  • Low-intensity therapy with either low-dose cytarabine subcutaneously, 5-azacytidine, or decitabine

• For patients with newly diagnosed therapy-related AML (t-AML) or AML with myelodysplasia-related changes (AML-MRC)

  • cytarabine and daunorubicin liposomal combination (Vyxeos) FDA approved recently in 2018.
  • https://ashpublications.org/blood/article/134/Supplement_1/1316/427266/Efficacy-and-Safety-of-CPX-351-Versus-7-3-in-a
  • Published online 2019 May 23. doi: 2147/IJN.S139450
  • fixed-combination of chemotherapy drugs in a liposome formulation
    • Infusion on days 1, 3, and 5
    • 2nd Induction (days 1 and 3)
    • Do a 14 day marrow but can be indeterminate and if is will do a 21 day marrow
  • Consolidation
    • Typically receive about two consolidation cycles
  • Failed induction therapy: FLAG: fludarabine, ara-C and G-CSF

  Monitoring

  • CBC with diff, CMP looking for tumor lysis syndrome (see below), LFT, Coagulation Panel on admission and every Monday,
  • Day 14 of cycle do a repeat bone marrow biopsy with hopeful goal of less < 5% blasts
    • If blasts > 5%, considered residual disease and will do a “5+2” cycle of IV cytarabine and daunorubicin
      • CR = Complete remission, CRi = Complete Remission with incomplete count recover, PR = persistent disease
    • If negative they await for count recovery which is defined as complete remission (CR):
      • bone marrow < 5% blasts in bone marrow aspirate
      • absolute neutrophil count (ANC) > 1,000/mcL
      • platelets ≥ 100,000/mcL
      • no residual evidence of extramedullary disease
      • Independence from red blood cell transfusions
    • CR with incomplete blood count recovery (CRi) defined as meeting all criteria for CR except ANC < 1,000/mcL or platelets < 100,000/mcL
    • Partial remission:
      • used in clinical trials, not a goal for standard therapy
      • defined as normalization of blood counts as defined in CR, with both decrease of ≥ 50% in percentage of blasts and bone marrow blast percentage 5%-25%
    • Relapse following complete response defined as any of
      • reappearance of leukemic blasts in peripheral blood

      • 5% blasts in bone marrow, not due to another cause (for instance, bone marrow regeneration after consolidation therapy)

      • extramedullary relapse
    • Next step depends on cytogenetics, if poor/intermediate prognosis based on cytogenetics, they are referred for bone marrow transplant
    • If relapse are referred for transplant

Consolidation Therapy

• In patients < 60 years old
  • High-dose cytarabine (HIDAC) 3 g/m IV every 12 hours on days 1, 3, and 5 for 3-4 cycles
    • 4 cycles associated with higher cure rate and longer 5 year survival rate so if fit and able to tolerate aim for 4 cycles
  • In patients with intermediate risk
    • Consider either HIDAC, matched sibling or alternative donor hematopoietic stem cell therapy
  • In patients with high risk
    • Matched sibling or alternative donor hematopoietic stem cell therapy
• In patients > 60 years old
  • standard-dose cytarabine (100-200 mg/m2/day for 5-7 days for 1-2 cycles) with or without either idarubicin or daunorubicin
  • **cytarabine 1-1.5 mg/m2/day for 4-6 doses for 1-2 cycles in patients with good performance status, normal renal function, or favorable risk status**
  • low-intensity therapy with 5-azacytidine or decitabine every 4-6 weeks until progression
• Therapy related or MDS progression to AML
  • Cpx-351 (liposomal cytarabine-daunorubicin, aka Vyxeos) >>>>> 7+3 with outcomes in this subpopulation
    • Induction therapy:
      • Infusion on days 1, 3, and 5
      • 2nd Induction (days 1 and 3)
      • Do a 14 day marrow but can be indeterminate and if is will do a 21 day marrow
    • Consolidation
      • Typically receive about two consolidation cycles
• Older patients

  • Acitabine (or decitabine) + venetoclax

    • More trials in support of actibaine than decitabine
    • FDA approved for newly diagnosed in AML >75 or comorbidities that prevent more aggressive induction therapy
    • oral venetoclax was administered at 400, 800, or 1200 mg daily in combination with either decitabine (20 mg/m2, days 1-5, intravenously [IV]) or azacitidine (75 mg/m2, days 1-7, IV or subcutaneously)
    • Prepublished online 2018 Oct 25. doi: 1182/blood-2018-08-868752
    • Don’t typically see nadir and count recovery like more aggressive chemotherapies (tend to be neutropenic for prolonged period of times (months)

  • LoDAC (low dose Cytarabine) + venetoclax

  • Special Targeted Therapies

    • FLT3+
      • SOME BIOCHEM (FUN INFO JUST FYI) doi: 1158/1535-7163.MCT-16-0876
        • receptor tyrosine kinase expressed on hematopoietic stem/progenitor cells → dimerizes and autophosphorylates then binds FTL3 ligand --> activating the intracellular tyrosine kinase domain (TKD) → phosphorylation of downstream molecules → activating signaling cascades that promote transcription of genes regulating survival, proliferation and differentiation
        • mutations result in constitutive activation of FLT3 signaling
      • FLT3 inhibitor midostaurin (RYDAPT) combined with 7+3 was able to triple overall survival (OS) in newly diagnosed FLT3+ AML patients
        • CALGB 10603 (“RATIFY”) Trial
      • Gilteritinib (inhibitor of AXL receptor tyrosine kinase) approved in 2018 for FTL3+ refractory AML
    • IDH1+
      • SOME BIOCHEM (FUN INFO BUT JUST FYI)
      • Ivosidenib
      • IDH2+