Acute Myeloid Leukemia

1. Pathophysiology & Causes

AML arises from genetic mutations in myeloid progenitor cells, leading to:

• Uncontrolled proliferation of immature blast cells (>20% in bone marrow).
• Impaired differentiation (cells fail to mature into functional WBCs, RBCs, or platelets).

Key Mutations & Risk Factors:

2. Classification (WHO & FAB Systems)

A. WHO Classification (2016, based on genetics)

• AML with recurrent genetic abnormalities (e.g., PML-RARA, *RUNX1-RUNX1T1*).
• AML with myelodysplasia-related changes.
• Therapy-related AML.
• AML not otherwise specified (NOS).

B. FAB Classification (Morphology-based, older but still referenced)

3. Clinical Presentation

• Bone marrow failure: Anemia (fatigue), thrombocytopenia (bleeding), neutropenia (infections).
• Organ infiltration: Splenomegaly, gum hypertrophy (monocytic AML), CNS involvement (rare).
• DIC (Disseminated Intravascular Coagulation): Especially in APL (M3) due to granule release.

4. Diagnosis

Essential Tests:

1. CBC & Peripheral Smear: Blasts, cytopenias.
2. Bone Marrow Biopsy (>20% blasts).
3. Flow Cytometry (CD13, CD33, CD117 markers).
4. Cytogenetics & Molecular Testing (e.g., FLT3, NPM1, CEBPA).
5. Coagulation Panel (for APL/DIC).

5. Treatment Approach

1. Induction Therapy

Primary Treatment Goals

• Achieve complete remission (CR) by eradicating leukemic blasts from the bone marrow.
• Restore normal hematopoiesis (ANC > 1000/μL, platelets > 100,000/μL, <5% blasts in marrow).

Commonly Used Regimens

• Standard “7+3” Regimen:
  • Cytarabine: 100–200 mg/m²/day continuous IV infusion for 7 days
  • Anthracycline (commonly Daunorubicin 60–90 mg/m²/day or Idarubicin 12 mg/m²/day) IV push for 3 days
• Alternative in older or unfit patients:
  • Venetoclax + Hypomethylating agents:
    • Venetoclax (ramp-up to 400 mg daily)
    • Azacitidine 75 mg/m² SC/IV D1–7 or
    • Decitabine 20 mg/m² IV D1–5

Typical Duration

• One cycle (4–6 weeks including cytopenic recovery)
• Repeatable if remission is not achieved after the first cycle

Patient Selection

• 7+3: Fit adults < 60–65 years old without adverse comorbidities
• Venetoclax + HMA: Older adults (≥ 75) or those with comorbidities

Pharmacologic & Supportive Care Considerations

• Myelosuppression: Neutropenic precautions; G-CSF not routinely used during induction
• Tumor Lysis Syndrome (TLS): Especially with high WBC or Venetoclax; pre-hydration, allopurinol or rasburicase
• Cardiotoxicity: Anthracyclines; monitor LVEF
• Antimicrobial prophylaxis:
  • Fluconazole or posaconazole for antifungal
  • Levofloxacin for antibacterial
  • Acyclovir for viral prophylaxis
• Hydration and Uric Acid Management: 2–3 L/day IV fluids, monitor uric acid
• Mucositis and GI Toxicities: Frequent with cytarabine; manage with supportive care

2. Consolidation Therapy

Primary Treatment Goals

• Eliminate residual disease (MRD) and prolong disease-free survival (DFS)
• Prevent relapse

Common Regimens

• High-Dose Cytarabine (HiDAC):
  • Cytarabine 1.5–3 g/m² IV q12h on Days 1, 3, 5
  • Usually 2–4 cycles
• Intermediate-Dose Cytarabine (especially in older adults): 500–1000 mg/m² q12h
• Allogeneic Stem Cell Transplantation (allo-HSCT): Preferred for high-risk disease or MRD+ after induction

Typical Duration

• Each cycle: ~28 days (including count recovery)
• Number of cycles: 3–4

Patient Selection

• Given to patients achieving CR after induction
• Intensity and duration depend on cytogenetic/molecular risk stratification:
  • Favorable risk: consolidation only
  • Intermediate/poor risk: consolidation ± HSCT

Pharmacologic & Supportive Care Considerations

• Neurotoxicity: Cytarabine can cause cerebellar toxicity; monitor with neurologic assessments, especially in elderly
• Ocular toxicity: Use steroid eye drops (e.g., dexamethasone) prophylactically
• Renal monitoring: Adjust cytarabine dose in renal impairment
• Antimicrobial prophylaxis: Continue due to prolonged neutropenia
• Growth factors (G-CSF): May be used to support neutrophil recovery

3. Maintenance Therapy

Primary Treatment Goals

• Prolong remission, delay relapse
• Particularly used in patients ineligible for transplant or with targetable mutations

Common Regimens

• Oral Azacitidine (CC-486): 300 mg orally daily on Days 1–14 of a 28-day cycle
  • Approved for patients in CR/CRi after intensive induction
• FLT3-mutated AML:
  • Midostaurin (during consolidation) or
  • Gilteritinib for maintenance post-HSCT
• IDH1/IDH2-mutated AML:
  • Ivosidenib (IDH1) or Enasidenib (IDH2) in selected settings

Typical Duration

• Oral azacitidine: until disease progression or unacceptable toxicity (often 12+ cycles)
• Maintenance post-HSCT: 1–2 years depending on agent and patient response

Patient Selection

• Post-remission, transplant-ineligible patients
• Targeted therapy maintenance guided by mutation profiling (FLT3, IDH1/2)
• Post-transplant patients at high risk of relapse

Pharmacologic & Supportive Care Considerations

• Oral adherence critical for azacitidine and targeted agents
• Hepatic monitoring: IDH inhibitors can cause transaminitis
• Differentiation syndrome: With IDH inhibitors; treat with steroids
• QT prolongation: Common with midostaurin and others—ECG monitoring required
• GI toxicity: Nausea, vomiting with oral azacitidine—pre-treat with antiemetics

Summary Table

A. Induction Therapy (7+3 Protocol)

• Cytarabine (Ara-C) + Anthracycline (e.g., daunorubicin).
• APL (M3): ATRA (All-Trans Retinoic Acid) + Arsenic Trioxide (ATO)

B. Consolidation Therapy

• High-dose cytarabine (for favorable-risk AML).
• Allogeneic Stem Cell Transplant (SCT) for high-risk cases (e.g., *FLT3-ITD+, TP53+*)

C. Targeted Therapies (FDA-Approved)

D. Relapsed/Refractory AML

• Salvage chemo (e.g., FLAG-IDA).
• CAR-T cells (experimental).
• Clinical trials (e.g., menin inhibitors for *KMT2A-rearranged AML*).

6. Prognosis (5-Year Survival)

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