Venclexta
Venclexta
Generic Name
Venclexta
Mechanism
- Potent, selective inhibitor of BCL‑2 – binds the BH3 domain of BCL‑2, displacing pro‑apoptotic proteins (BAX, BAK) and triggering mitochondrial outer‑membrane permeabilization.
- Overcomes anti‑apoptotic signaling in malignant B‑cell clones and AML blasts, restoring apoptotic priming that is otherwise suppressed in disease.
- Synergistic when combined with hypomethylating agents (decitabine) or with anti‑CD20 antibodies (rituximab).
Pharmacokinetics
| Parameter | Typical Value (Adults) | Notes |
| Absorption | Oral; ~70–80 % bioavailability | Food increases absorption by ~20 %; dose‐adjusted for low‑fat diets. |
| Tmax | ~2–4 h post‑dose | Achieved within 4 h once daily. |
| Distribution | Large volume of distribution (~2,000 L) | Extensive tissue penetration; ~89 % protein‑bound primarily to albumin. |
| Metabolism | Hepatic CYP3A4/2J‑mediated; minor CYP2D6 | Many drug‑drug interactions; avoid strong CYP3A4 inducers. |
| Elimination | Renal (≈30 %) & fecal (≈60 %) | Clearance ~20 L/h; half‑life 19–56 h (steady‑state). |
| Special Populations | No dose adjustment in mild‑moderate renal impairment; caution in severe renal or hepatic disease. |
Indications
- Chronic lymphocytic leukemia (CLL) / Small lymphocytic lymphoma (SLL) in patients with ≥ 1 prior therapy (≥ 1‑cycle of ibrutinib/venetoclax‑based regimens).
- CLL/SLL with del(17p)/TP53 mutation after at least one prior therapy.
- Relapsed/refractory acute myeloid leukemia (AML) in patients ≥ 75 yr or unfit for intensive chemotherapy.
- Combination indications: with obinutuzumab (CLL) or rituximab (C‑LL) and with hypomethylating agents (AML).
Contraindications
- Absolute contraindication: Known hypersensitivity to venetoclax.
- Risk for Tumor Lysis Syndrome (TLS): High tumor burden (e.g., >20 % marrow blasts, >10 % peripheral leukocyte count).
- Caution with: Severe neutropenia, high lactate dehydrogenase (LDH), active infections, concurrent use of strong CYP3A4/2J inducers.
- Special warnings:
- Severe myelosuppression → need for growth factor support.
- Cardiac toxicities: Monitor QTc; avoid in patients with existing prolonged QTc or on QT‑prolonging drugs.
Dosing
1. Dose Ramp‑up (CLL)
| Day | Dose (mg) | |
| 1–20 | 20 (Day 1‑5), 50 (Day 6‑10), 100 (Day 11‑15), 200 (Day 16‑20) | |
| 21–28 | 400 (Day 21‑28) | |
| Follow‑up | 400 mg daily (continuous) – adjust per response and toxicity. |
2. Dose Ramp‑up (AML) – similar 7‑day ramp, then 400 mg daily.
3. Combination therapy:
• With rituximab: start venetoclax on Day 3 of rituximab, maintain 400 mg daily.
• With hypomethylating agents: 400 mg daily, 5 days per 28‑day cycle (decitabine/azacitidine).
4. Administration: take orally with minimal food; avoid high‑fat meal on the first dose.
5. Re‑dosing after interruption: if missed ≥ 24 h, repeat ramp‑up.
Adverse Effects
| Class | Common (≥ 10 %) | Serious (≥ 1 %) |
| Myelosuppression | Neutropenia (grade ≥ 3), thrombocytopenia, anemia | TLS (life‑threatening), severe neutropenia with febrile neutropenia |
| Infections | Viral (e.g., HSV, VZV), bacterial, opportunistic (CMV) | Sepsis, invasive fungal infections |
| GI | Nausea, vomiting, diarrhea, constipation | Severe dehydration, electrolyte imbalance |
| Hematologic | Anemia | Anemia requiring transfusion |
| Cardiac | QTc prolongation | Cardiac arrest, arrhythmias |
| Dermatologic | Rash, pruritus | Severe cutaneous adverse reactions |
Monitoring
- Baseline: CBC with diff, CMP, LDH, electrolytes, QTc, infection screen, renal/hepatic function.
- During ramp‑up: Daily CBC on days 1–8; monitor for TLS (serum electrolytes, uric acid).
- After therapy initiation:
- CBC: weekly (weeks 0‑7), then biweekly (months 2‑4), then monthly.
- LDH and CRP: every cycle.
- QTc: at baseline and twice weekly during ramp.
- Tumor burden assessment (CT/US) every 2‑3 cycles.
- Infections: Regular screening; consider prophylaxis (valganciclovir, acyclovir).
- Growth factor support: G‑CSF if ANC < 0.5 × 10⁹/L.
Clinical Pearls
- “Rule of 7”: Start with 7 days of ramp‑up to minimize TLS; adjust if creatinine or liver function changes.
- Avoid strong CYP3A4 inducers (e.g., rifampin, St. John’s wort) at any time—dose reductions of up to 75 % required.
- Use a *watch‑and‑wait* TLS protocol: high‑risk patients (>25 % lymphocytes, LDH >2× ULN) get prophylactic allopurinol, aggressive hydration, and can begin venetoclax at 20 mg with escalation later.
- Combine with rituximab or obinutuzumab to prevent early resistance: start rituximab on Day 1, ramp venetoclax later; this synergy boosts overall response rates in CLL.
- When in refractory AML, keep treatment short (≤ 4 cycles) unless using ongoing combination with hypomethylating agents; many patients respond only after 2–3 cycles.
- Key diagnostic tip: A marked drop in LDH and peripheral blast count in the first 4 weeks is a surrogate for early response; lack of decline may prompt dose adjustment or combination change.
- Patient education point: Stress the importance of reporting new fever, dizziness, or ECG changes promptly—early TLS detection saves lives.
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• References
1. National Comprehensive Cancer Network (NCCN) Guidelines for CLL/AML, v2.2025.
2. Armand P, et al. *Lancet Oncol.* 2019;20(5): 663–672.
3. BCL‑2 Inhibitors: Clinical Pharmacology & Practice, 2024.
*Prepared for medical students and practicing clinicians seeking a quick, evidence‑based reference to Venclexta (venetoclax).*