Acute Myeloid Leukemia (AML)

Background:

• Proliferation of immature myeloid blasts with differentiation arrest

• The median age at diagnosis is late ~60s

• May present with pancytopenia, hyperleukocytosis (>100K), leukostasis, DIC, TLS

  • Symptoms of leukostasis:

    • Lung: SOB, DAH, respiratory failure

    • CNS: Confusion, coma, delirium, focal neurologic deficits

    • Eye: Impaired vision, retinal hemorrhage

    • Vascular: Priapism

Work up:

• Peripheral blood:

  • CBC with diff, PBS, coagulation panel (DIC risk in APL)

• BMBx:

  • A marrow or blood blast count of 20% or more is required, except for AML with t(15;17), t(8;21), inv(16) or t(16;16)

  • Myeloblasts, monoblasts, and megakaryoblasts are included in the blast count

• Flow cytometry:

  • Confirm myeloid lineage (CD13, CD33, CD34, MPO, etc.)

• Cytogenetics:

  • Karyotype is essential for risk stratification.

• Molecular panel:

  • FLT3, NPM1, CEBPA, IDH1/2, TP53

    • Two clinically important FLT3 mutations:

      • FLT3-ITD (Internal Tandem Duplication)

        • Most common, more aggressive

      • FLT3-TKD (Tyrosine Kinase Domain)

Risk classification:

• The European LeukemiaNet (ELN) 2022 classification categorizes AML based on cytogenetic and molecular abnormalities:

  • Favorable

    • t(8;21); RUNX1

    • inv(16) or t(16;16); CBFB–MYH11

    • Mutated NPM1 (without FLT3–ITD high)

    • bZIP in-frame mutated CEBPA

  • Intermediate

    • Mutated NPM1 with FLT3–ITD

    • Wild-type NPM1 with FLT3–ITD

    • t(9;11); MLLT3–KMT2A

    • Cytogenetic abnormalities not classified as favorable or adverse

  • Adverse

    • t(6;9); DEK–NUP214

    • t(v;11q23.3); KMT2A rearranged

    • t(9;22); BCR–ABL1

    • inv(3) or t(3;3); GATA2, MECOM (EVI1)

    • t(3q26.2;v); MECOM(EVI1) rearranged

    • −5 or del(5q); −7; −17/abn(17p)

    • Complex karyotype, monosomal karyotype

    • Mutated ASXL1, BCOR, EZH2, RUNX1, SF3B1, SRSF2, STAG2, U2AF1, or ZRSR2

    • Mutated TP53

Treatment:

Induction therapy:

• Fit/younger patients:

  • Preferred:

    • Cytarabine for 7 days + Idarubicin/daunorubicin for 3 days (7+3 regimen)

  • Alternative:

    • Cytarabine for 7 days + Mitoxantrone for 3 days

• Unfit/older patients:

  • Hypomethylating agents (azacitidine/decitabine) + venetoclax

  • Single agent

  • Reduced-intensity options

• Cardiac dysfunction/ anthracycline-ineligible:

  • Cytarabine for 7 days + Mitoxantrone for 3 days

• If FLT3-mutated:

  • 7+3 regimen + Midostaurin (FLT3 inhibitor)

    • FLT3 inhibitors:

      • FLT3-ITD and FLT3-TKD inhibitors:

        • Midostaurin

        • Gilteritinib

      • Selective FLT3-ITD inhibitors:

        • Sorafenib

        • Quizartinib

• If CD33+ and favorable-risk cytogenetics AML:

  • 7+3 regimen + Gemtuzumab ozogamicin

• Relapsed/refractory AML:

  • Hypomethylating agents (azacitidine/decitabine) + venetoclax

  • FLAG-IDA

    • Fludarabine, High-dose Cytarabine (Ara-C), G-CSF (filgrastim)- Idarubicin

  • CLAG-M

    • Cladribine, High-dose Cytarabine (Ara-C), G-CSF (filgrastim)- Mitoxantrone

• Follow up BMBx at 14-21 days to determine if in remission

  • Hypoplasia defined as <20% cellularity with <5% residual blasts

  • Repeat BMBx after recovery

• LP after remission:

  • Indications:

    • If neurologic symptoms

    • If asymptomatic but high risk for developing CNS disease

      • Monocytic differentiation (FAB M4/M5)

      • Mixed Phenotype Acute Leukemia (MPAL)

      • WBC >40,000 at diagnosis

      • Extramedullary disease (eg. gingival infiltration, leukemia cutis)

      • High-risk APL

      • FLT3 mutations

      • t(9;11) MLLT3:KMT2A fusion

  • If circulating blasts in the CSF (confirmed by flow cytometry) → Intrathecal (IT) chemotherapy

Consolidation therapy:

• Post-remission treatment given after induction achieves complete response (CR).

• Work up before starting consolidation therapy:

  • Bone marrow biopsy confirming CR

  • MRD assessment (flow cytometry ± molecular markers)

    • MRD positivity pushes toward allogeneic transplant

  • Review cytogenetic/molecular risk (ELN classification)

  • Assess:

    • Performance status

    • Organ function

    • Transplant eligibility

  • HLA typing if transplant is a possibility

• Regimens:

  • Favorable risk: 

    • HiDAC:

      • High Dose Cytarabine (Ara-C)

      • Only if transplant is not planned

      • Requires cerebellar exam before each dose

    • Allogeneic transplant NOT routinely recommended

      • Consider only for patients who are unable to complete consolidation therapy or who have high-risk features such as MRD-positivity or KIT mutation.

  • Intermediate Risk:

    • HiDAC

    • Cytarabine (Ara-C) + Idarubicin/daunorubicin + Gemtuzumab ozogamicin (if CD33+ and given during induction)

    • If FLT3-mutated:

      • Cytarabine + FLT3 inhibitor (Midostaurin or Quizartinib)

    • Allo-HSCT in CR1 only if:

      • MRD-positive

      • High-risk molecular features

  • Adverse Risk:

    • Allo-HSCT if young and achieved a CR (preferred)

      • Chemotherapy alone has high relapse rates

      • Consolidation chemo is usually a bridge to transplant, not definitive therapy

• Older/unfit patients:

  • Reduced-intensity consolidation

  • Continuation of lower intensity regimen used for induction

  • Hypomethylating agent-based approaches (if used in induction)

  • Some may go directly to maintenance rather than intensive consolidation

Maintenance therapy:

• Low-intensity, prolonged therapy given after induction ± consolidation in patients:

  • In complete response after induction therapy

  • Completed or cannot tolerate intensive consolidation

  • Not candidates for allo-HSCT

• Purpose:

  • Suppress MRD

  • Prolong relapse-free survival (RFS) (± OS depending on agent)

• Older adults:

  • Maintenance more commonly used due to inability to tolerate prolonged intensive consolidation

• MRD-positive but transplant-ineligible:

  • Maintenance may be used as disease suppression (not curative)

• Treatments:

  • Oral azacitidine is used for maintenance therapy in patients ineligible for allo-HSCT

    • Used regardless of cytogenetic risk

  • FLT3 inhibitors:

    • Only for FLT3-mutated AML and if FLT3 inhibitor was part of induction/consolidation

Patients ineligible for intensive induction:

• With IDH1 mutation:

  • Azacitidine/Decitabine + Venetoclax

  • Azacitidine + Ivosidenib

  • Ivosidenib

  • Low dose Ara-C + Venetoclax

  • Hypomethylating Agent Alone (Azacitidine/Decitabine)

• Without IDH1 mutation:

  • Azacitidine/Decitabine + Venetoclax (preferred)

  • Low dose Ara-C + Venetoclax +/- cladribine

  • Low dose Ara-C + glasdegib (Hedgehog pathway inhibitor)

  • Gilteritinib (if FLT3 mutated) +/- azacitidine

  • Enasidenib (if IDH2 mutated) +/- azacitidine

  • Gemtuzumab ozogamicin (if CD33 positive)

Acute Promyelocytic Leukemia (APL)

Background:

• AML subtype with t(15;17) → PML-RARA fusion

• Characterized by promyelocyte accumulation and severe coagulopathy

  • Associated with DIC on presentation

• Peripheral smear may shows Auer Rods

• High risk APL:

  • Classified as having >10,000 WBCs

  • Associated with increased risk of:

    • Early death

    • Hemorrhage

    • Differentiation syndrome

• Subtypes:

  • Microgranular

  • Hypergranular

    
    

Treatment:

• Start All-Trans-Retinoic Acid (ATRA) immediately if APL is suspected, before genetic confirmation

• Arsenic Trioxide (ATO) is relatively contraindicated in ventricular arrhythmia and prolonged QTc

• Induction Therapy:

  • Low risk APL:

    • ATRA + ATO

      • If arsenic is not available or contraindicated:

        • ATRA + Gemtuzumab ozogamicin

        • ATRA + Idarubicin

  • High risk APL:

    • ATRA + ATO + Gemtuzumab ozogamicin

    • ATRA + ATO + Idarubicin

      • If arsenic is not available or contraindicated:

        • ATRA + Gemtuzumab ozogamicin

        • ATRA + Idarubicin

        • ATRA + Daunorubicin + Cytarabine

• Requires BM assessment at day 28 to document remission before proceeding with consolidation

• Consolidation Therapy:

  • Low risk APL:

    • ATRA + ATO

    • If arsenic is not available or contraindicated:

      • ATRA + Gemtuzumab ozogamicin

      • ATRA + Idarubicin

  • High risk APL:

    • ATRA + ATO

    • If arsenic is not available or contraindicated:

      • ATRA + Gemtuzumab ozogamicin

      • ATRA + Idarubicin

      • Daunorubicin + Cytarabine

• If relapse/refractory:

  • If relapses >6 months after initial CR:

    • ATRA + ATO again

  • If relapses <6 months after initial CR:

    • ATRA + ATO + Gemtuzumab ozogamicin

    • ATRA + ATO + Idarubicin

    • If arsenic is not available or contraindicated:

      • ATRA + Gemtuzumab ozogamicin

      • ATRA + Idarubicin

      • Daunorubicin + Cytarabine

  • If 2nd remission achieved, consodilation:

    • If transplant candidate:

      • PCR negative in CR2 → auto-HSCT

      • If PCR positive in CR2 → allo-HSCT

    • If not transplant candidate → ATO consolidation x6 cycles

    • Consider CNS ppx with IT chemo