Mechanism of Action
- BCL-2 is overexpressed in AML blasts → prevents apoptosis.
- Venetoclax binds BCL-2 → releases pro-apoptotic proteins (BAX, BAK) → triggers mitochondrial apoptosis.
Approval: FDA-approved for:
- AML (in combination with hypomethylating agents/azacitidine or low-dose cytarabine in older/unfit patients).
- CLL/SLL (chronic lymphocytic leukemia/small lymphocytic lymphoma).
Key Features in AML
Target Population:
- Newly diagnosed AML in adults ≥75 years or unfit for intensive chemotherapy.
- Relapsed/refractory AML (investigational combinations).
Combination Regimens:
- Venetoclax + Azacitidine (most common, improves survival vs. azacitidine alone).
- Venetoclax + Low-Dose Cytarabine (LDAC).
- Venetoclax + HMA (hypomethylating agents).
Efficacy:
- Response rates: ~60-70% in newly diagnosed AML (CR/CRi).
- Overall survival: ~14.7 months (vs. 9.6 months with azacitidine alone).
Side Effects
- Myelosuppression (neutropenia, thrombocytopenia).
- Tumor Lysis Syndrome (TLS) (risk highest in first cycle, requires prophylaxis).
- Infections (due to neutropenia).
- GI effects (nausea, diarrhea).