What is Acute Myeloid Leukemia (AML) and its treatment?

Acute Myeloid Leukemia (AML): Diagnosis, Classification, and Treatment

Acute myeloid leukemia (AML) is a heterogeneous hematologic malignancy characterized by the clonal expansion of myeloid blasts in the peripheral blood, bone marrow, and/or other tissues, with an annual incidence of 4-8 cases per 100,000 and a median age at diagnosis of 67-71 years. 1

Diagnosis and Classification

Diagnostic Criteria

• Presence of ≥20% myeloid blasts in bone marrow or peripheral blood
• Comprehensive workup should include:
  • Morphological examination
  • Cytochemistry
  • Immunophenotyping
  • Cytogenetic analysis
  • Molecular genetic testing 1

Risk Stratification

AML is classified into risk categories based on:

1. Patient-related factors:

   • Age (worse prognosis in patients ≥60 years)
   • Performance status
   • Comorbidities

2. Disease-related factors:

   • Cytogenetics:
     • Favorable: t(15;17), t(8;21), t(16;16)
     • Adverse: Complex karyotype, monosomal karyotype
   • Molecular markers:
     • Favorable: NPM1 mutation (without FLT3-ITD), CEBPA mutation
     • Adverse: FLT3-ITD, TP53 mutation, RUNX1 mutation 1

Treatment Approach

Induction Therapy

1. For patients eligible for intensive therapy (typically age <60-65 years with good performance status):

   • Standard "7+3" regimen:
     • Cytarabine 100-200 mg/m² continuous IV infusion for 7 days
     • Anthracycline (daunorubicin 60-90 mg/m² or equivalent) for 3 days 1, 2, 3
   • For FLT3-mutated AML: Add FLT3 inhibitor (midostaurin) 4
   • For APL (AML with t(15;17)): All-trans retinoic acid (ATRA) plus arsenic trioxide or anthracycline-based chemotherapy 1

2. For patients ineligible for intensive therapy (typically age ≥65-70 years or with significant comorbidities):

   • Hypomethylating agents (azacitidine or decitabine) with venetoclax 4, 5
   • Low-dose cytarabine with or without venetoclax
   • Targeted therapies for specific mutations (IDH1/2 inhibitors) 1, 5

Post-Remission (Consolidation) Therapy

1. Favorable-risk AML:

   • High-dose cytarabine-based chemotherapy (2-4 cycles) 1

2. Intermediate/adverse-risk AML:

   • Allogeneic hematopoietic stem cell transplantation (HSCT) in first complete remission if suitable donor available 1, 6
   • High-dose cytarabine-based chemotherapy if transplant not feasible

3. APL:

   • ATRA plus arsenic trioxide or anthracycline-based chemotherapy 1

Maintenance Therapy

• Oral azacitidine for patients who achieve remission but cannot complete intensive therapy 1
• ATRA-based maintenance for APL 1

Treatment of Relapsed/Refractory AML

1. Salvage chemotherapy options:

   • FLAG-IDA (fludarabine, cytarabine, G-CSF, idarubicin)
   • MEC (mitoxantrone, etoposide, cytarabine)
   • Targeted agents based on molecular profile

2. Allogeneic HSCT:

   • Consider for patients who achieve second remission 1, 6
   • Reduced-intensity conditioning for older patients or those with comorbidities 6

3. For relapsed APL:

   • Arsenic trioxide can induce remission even in patients refractory to ATRA 1

Special Considerations

Acute Promyelocytic Leukemia (APL)

• Immediate treatment with ATRA upon suspicion of APL, even before confirmation
• Monitor closely for differentiation syndrome and coagulopathy
• Maintain platelet counts ≥30-50 × 10⁹/L and fibrinogen in normal range 1

Supportive Care

• Aggressive management of infections during neutropenia
• Transfusion support for anemia and thrombocytopenia
• Tumor lysis syndrome prophylaxis, especially in patients with high white blood cell counts 1

Measurable Residual Disease (MRD)

• Increasingly important for response assessment and therapeutic decision-making
• Techniques include flow cytometry and molecular methods 1, 5

Common Pitfalls and Caveats

1. Delayed diagnosis: Symptoms may mimic other conditions; maintain high index of suspicion for unexplained cytopenias.

2. Inadequate diagnostic workup: Ensure comprehensive cytogenetic and molecular testing before starting treatment.

3. Overlooking APL: Failure to recognize and immediately treat APL can lead to fatal hemorrhagic complications.

4. Undertreatment of elderly patients: Age alone should not exclude patients from potentially curative approaches; consider fitness rather than chronological age.

5. Inadequate monitoring: Regular assessment for disease response and treatment toxicity is essential.

6. Neglecting clinical trials: NCCN strongly recommends clinical trial participation when available 1.

AML treatment has evolved significantly in recent years with the approval of multiple targeted therapies, offering new hope for improved outcomes in this historically challenging disease.