What is venetoclax (Venetoclax) used for in the treatment of cancer?

Venetoclax in Cancer Treatment

Venetoclax is primarily used for treating acute myeloid leukemia (AML) in adults who are ≥75 years or have comorbidities that preclude intensive chemotherapy, and for chronic lymphocytic leukemia (CLL), by targeting the anti-apoptotic B-cell lymphoma-2 (BCL-2) protein to induce programmed cell death in malignant cells. 1, 2

Mechanism of Action and Pharmacology

• Venetoclax is a BH3-mimetic that specifically blocks the anti-apoptotic BCL-2 protein, resulting in programmed cell death of cancer cells that overexpress BCL-2 1
• Overexpression of BCL-2 contributes to both lymphoid and myeloid malignancies by preventing apoptosis of cancer cells 3
• Venetoclax is primarily metabolized through the CYP3A4/5 enzyme pathway, making drug interactions with CYP3A inhibitors clinically significant 1

Approved Clinical Applications

• In AML, venetoclax is approved in combination with hypomethylating agents (azacitidine or decitabine) for newly diagnosed patients who are ineligible for intensive chemotherapy 3, 2
• In CLL, venetoclax is approved:
  • In combination with obinutuzumab for treatment-naive patients 2
  • In combination with rituximab for relapsed/refractory CLL 2, 4
• Response rates in AML vary based on genetic profile:
  • 74% complete remission (CR) or CR with incomplete count recovery (CRi) in intermediate-risk cytogenetics 5
  • 60% CR/CRi in poor-risk cytogenetics 5
  • 71% CR/CRi in IDH1/2 mutations 5
  • 47% CR/CRi in TP53 mutations 5

Dosing Considerations

• For AML, standard dosing is 400 mg daily in combination with hypomethylating agents 1, 5
• For CLL, a gradual dose ramp-up is essential to mitigate tumor lysis syndrome (TLS) risk:
  • Starting dose of 20 mg with weekly escalation over 5 weeks to reach target dose of 400 mg daily 1, 5
• Dose adjustments are required with certain concomitant medications:
  • 75% dose reduction when combined with posaconazole or other strong CYP3A inhibitors 3, 1
  • Dose adjustments needed with antibacterial agents such as ciprofloxacin or macrolides 3

Adverse Effects and Management

• Hematologic toxicities:

  • Neutropenia is common (40% grade 3-4) and may require growth factor support and/or dose adjustments 1
  • Febrile neutropenia occurs in 31-61% of patients depending on combination therapy 3
  • Infections of any grade occurred in 84% of patients on azacitidine-venetoclax combination vs 67% on azacitidine monotherapy 3

• Tumor lysis syndrome (TLS):

  • Significant risk during rapid tumor reduction, especially in CLL patients with high tumor burden 6, 5
  • Prevention strategies include gradual dose ramp-up, aggressive hydration, and prophylactic uric acid-lowering agents 6
  • High-risk patients may require hospitalization during dose escalation 6, 5

• Management recommendations:

  • Consider dose interruptions to allow for hematologic recovery in patients with good response 3
  • Early bone marrow assessment after completion of cycle 1 is crucial to evaluate response 3, 5
  • If TLS develops, temporarily hold venetoclax and manage electrolyte abnormalities aggressively 6
  • Consider prophylactic granulocyte colony-stimulating factor if dose reduction is ineffective for neutropenia 3, 1

Drug Interactions

• Venetoclax is metabolized by CYP3A4/5, requiring dose adjustments with CYP3A inhibitors 3, 1
• Specific interactions to monitor:
  • Posaconazole: Reduce venetoclax dose by 75% 3
  • Antibacterial agents (ciprofloxacin, macrolides): Ensure proper venetoclax dose adjustments 3
  • Coadministration with venetoclax at initiation and during ramp-up phase is contraindicated in CLL/SLL patients due to increased TLS risk 7

Emerging Applications

• Venetoclax is being studied in pediatric patients with relapsed or refractory AML, showing promising response rates when combined with intensive chemotherapy 8
• Combinations with other agents are being explored in myelodysplastic syndromes (MDS) and therapy-related MDS/AML 8, 9
• Multiple myeloma with t(11;14) translocation shows high BCL-2/MCL-1 ratio and may be particularly suited for venetoclax-based therapy 10

Clinical Pearls

• Despite effectiveness, venetoclax treatment is not curative, and clonal evolution and disease relapse appear to be common over time 10
• Serial molecular studies can help identify new prognostically significant mutations and guide treatment decisions 10
• Alternative antifungals such as echinocandins may be preferred when venetoclax is used, to avoid strong CYP3A inhibition 3, 1