Generic Name

Venetoclax

Mechanism

Venetoclax binds the BH3 pocket of BCL‑2 with high affinity, displacing pro‑apoptotic BH3‑only proteins (e.g., BIM, PUMA). This releases BAX/BAK, triggers mitochondrial outer membrane permeabilization, and activates the intrinsic apoptotic cascade. The drug’s specificity for BCL‑2 spares BCL‑XL, reducing platelet toxicity compared with earlier agents.

Pharmacokinetics

• Absorption: Oral, ~90 % bioavailability when taken with moderate‑fat meal.
• Distribution: Extensive tissue distribution; volume of distribution ≈ 50 L.
• Metabolism: Primarily CYP3A (≈ 60 %) and, to a lesser extent, CYP2B6. Concomitant CYP3A inhibitors/inducers necessitate dose adjustment.
• Elimination: Hepatic (major) and renal excretion of metabolites; ~70 % unchanged by feces.
• Half‑life: Mean t½ ≈ 13–19 h (steady‑state ~5 days).

Indications

• Chronic Lymphocytic Leukemia (CLL) with > 40 % lymphocytosis, 17p deletion, or mutated TP53.
• Acute Myeloid Leukemia (AML) in patients ≥ 75 y or with comorbidities precluding cytarabine/mitoxantrone.
• Relapsed/Refractory Multiple Myeloma (in combination with dexamethasone or other agents).
• Non‑Hodgkin Lymphoma (NHL) – approved for indolent subtypes with documented BCL‑2 dependence.

Contraindications

• Contraindications: Known hypersensitivity to venetoclax or excipients.
• Warnings:
• Tumor Lysis Syndrome (TLS): Require prophylactic allopurinol/rasburicase and a strict 5‑day dose ramp‑up.
• Severe myelosuppression → risk of febrile neutropenia.
• CYP3A modulators: Strong inhibitors (e.g., ketoconazole) → 25 % dose; strong inducers (e.g., rifampin) → cancel therapy.
• Cardiovascular: QTc prolongation in combination with other QT‑prolonging drugs.

Dosing

Tip: Always pause or reduce dose for CYP3A inhibitors and reactivate upon withdrawal.

Adverse Effects

• Common
• Neutropenia (up to 70 %)
• Anemia, thrombocytopenia
• Nausea, vomiting, diarrhea
• Fatigue
• Fever, chills, upper respiratory tract infections
• Serious
• Tumor Lysis Syndrome (TLS) – fatal if untreated
• Severe neutropenia → opportunistic infections
• Cardiac events: QTc prolongation, arrhythmias (rare)
• Fungal infections (Candida spp.)

Monitoring

• Baseline: CBC with diff, electrolytes, renal/hepatic panels, uric acid, QTc interval.
• During Therapy:
• CBC twice weekly (first month) → later monthly.
• Electrolytes, uric acid, renal function monthly.
• QTc interval at 2–3 days after first dose, then before each dose escalation.
• TLS‑Risk Stratification: Urate and lactate‑dehydrogenase levels monitored 24 h pre‑dose, and every 4 h during ramp‑up for high‑risk pts.

Clinical Pearls

• Ramping Is Key: A 5‑day incremental titration dramatically reduces TLS incidence; skip the 200 mg dose if patient presents ≥ 130 mmol/L creatinine or high tumor burden.
• Drug‑Drug Interaction Cheat Sheet:
• Strong CYP3A inhibitors → 25 % dose (e.g., clarithromycin).
• Strong inducers → stop therapy; re‑initiate only when inhibitor discontinued.
• Platelet‐Friendly: Institutional monitoring for thrombocytopenia can be less intensive than BCL‑XL inhibitors; focus on neutrophils.
• Elderly & AML: When combined with low‑dose cytarabine (“mini‑Hi–MAC”), consider a lower starting dose (50 mg) and observe early neutropenia with prompt G‑CSF.
• Reversible TLS: Administer rasburicase immediately once uric acid > 14 mg/dL or > ucrate levels rising > 25 %.
• Post‑Therapy Surveillance: Even after disease remission, patients should maintain CBCs monthly for 6 months, as delayed neutropenia can occur.

Reference-friendly Note: This card synthesizes current FDA labeling and NCCN guidelines (2024). For deeper pharmacodynamics and resistance mechanisms, consult the latest peer‑reviewed literature.