Introduction
Venclexta (venetoclax) is an oral targeted therapy that represents a significant advancement in the treatment of certain hematologic malignancies. As a first-in-class BCL-2 inhibitor, Venclexta specifically targets the apoptosis pathway, offering a novel mechanism for treating patients with specific types of leukemia and lymphoma. The drug received its initial FDA approval in April 2016 and has since expanded its indications through robust clinical trial data.
Mechanism of Action
Venclexta exerts its therapeutic effect through selective inhibition of B-cell lymphoma-2 (BCL-2) protein. BCL-2 is an anti-apoptotic protein that is overexpressed in many hematologic malignancies, allowing cancer cells to evade programmed cell death. Venetoclax binds directly to the BCL-2 protein, displacing pro-apoptotic proteins such as BIM. This restoration of apoptotic signaling triggers mitochondrial outer membrane permeabilization, cytochrome c release, and activation of caspases, ultimately leading to programmed cancer cell death.
The drug demonstrates high affinity for BCL-2 (Ki < 0.010 nM) with significantly less binding to other BCL-2 family proteins including BCL-xL (Ki > 48 nM) and BCL-w (Ki > 240 nM), contributing to its targeted therapeutic profile.
Indications
Venclexta is FDA-approved for:
- Chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) in adults:
- As monotherapy for patients with 17p deletion who have received at least one prior therapy - In combination with rituximab for patients who have received at least one prior therapy - In combination with obinutuzumab for previously untreated patients
- Acute myeloid leukemia (AML) in adults:
- In combination with azacitidine, decitabine, or low-dose cytarabine for newly diagnosed AML in adults who are age 75 years or older, or who have comorbidities that preclude intensive induction chemotherapy
Dosage and Administration
Dosing Regimen:Venclexta requires a 5-week ramp-up schedule to mitigate tumor lysis syndrome (TLS) risk:
- Week 1: 20 mg daily
- Week 2: 50 mg daily
- Week 3: 100 mg daily
- Week 4: 200 mg daily
- Week 5 onward: 400 mg daily (maintenance dose)
- Hepatic impairment: Reduce dose by 50% in patients with severe hepatic impairment (Child-Pugh Class C)
- Renal impairment: No dosage adjustment recommended for mild to moderate impairment; use caution in severe impairment (CrCl < 30 mL/min)
- CYP3A inhibitors: Avoid concomitant use with strong CYP3A inhibitors; if necessary, reduce Venclexta dose by at least 75% with moderate CYP3A inhibitors
- Take with food to enhance absorption
- Swallow tablets whole with water; do not chew, crush, or break
- Administer at approximately the same time each day
Pharmacokinetics
Absorption: Venetoclax absorption is enhanced by food, particularly high-fat meals. The mean Tmax is 5-8 hours post-dose. High-fat meal increases AUC by approximately 5-fold compared to fasting state. Distribution: Venetoclax is highly protein-bound (>99%) primarily to albumin. The mean steady-state volume of distribution is approximately 256-321 L. Metabolism: Primarily metabolized by CYP3A4/5. The major metabolite is M27 (formed via oxidation), which demonstrates significantly reduced pharmacological activity compared to the parent compound. Elimination: The elimination half-life is approximately 26 hours. Following a single 400 mg dose, mean apparent clearance is 9.45 L/h. Feces are the major route of elimination (approximately 100% of administered dose), with negligible renal excretion.Contraindications
- Concomitant use with strong CYP3A inhibitors at initiation and during ramp-up phase
- Patients with hypersensitivity to venetoclax or any component of the formulation
- Initiation in patients with white blood cell count ≥25,000/μL due to increased TLS risk (requires cytoreduction prior to initiation)
Warnings and Precautions
Tumor Lysis Syndrome (TLS): Venclexta carries a Black Box Warning for TLS, which can occur as early as 6-8 hours after the first dose. Risk factors include high tumor burden, renal impairment, and dehydration. Required precautions include:- TLS risk assessment before initiation
- Adequate hydration and antihyperuricemic agents
- Monitoring of blood chemistries (potassium, uric acid, calcium, phosphorus, creatinine)
- Gradual dose escalation according to ramp-up schedule
Drug Interactions
Strong CYP3A Inhibitors: (e.g., ketoconazole, clarithromycin) - Avoid concomitant use; if unavoidable, reduce Venclexta dose by at least 75% Moderate CYP3A Inhibitors: (e.g., fluconazole, verapamil) - Reduce Venclexta dose by at least 50% CYP3A Inducers: (e.g., rifampin, carbamazepine) - Avoid concomitant use as they may decrease venetoclax concentrations P-gp Inhibitors: (e.g., amiodarone, azithromycin) - Monitor for increased venetoclax exposure Warfarin: Venetoclax may increase warfarin exposure; monitor INR closelyAdverse Effects
Common (≥20%):- Neutropenia (41-51%)
- Diarrhea (29-35%)
- Nausea (28-35%)
- Anemia (18-28%)
- Upper respiratory tract infection (20-25%)
- Thrombocytopenia (22-27%)
- Fatigue (15-22%)
- Tumor lysis syndrome (including fatal cases)
- Neutropenia with infection (including sepsis)
- Pneumonia
- Febrile neutropenia
- Autoimmune hemolytic anemia
Monitoring Parameters
Prior to initiation:- Complete blood count with differential
- Comprehensive metabolic panel (including renal and hepatic function)
- TLS risk assessment
- Pregnancy test in women of reproductive potential
- Blood counts weekly during ramp-up, then monthly or as clinically indicated
- Electrolytes, creatinine, uric acid, calcium, phosphorus at pre-dose, 6-8 hours after first dose, and 24 hours after each dose increase during ramp-up
- Liver function tests periodically
- Signs/symptoms of infection
- TLS monitoring for at least 18 hours after first dose in high-risk patients
- Regular assessment of treatment response
- Monitoring for disease progression
- Assessment of residual cytopenias
Patient Education
- Take Venclexta exactly as prescribed with a meal
- Do not interrupt dosing without consulting your healthcare provider
- Maintain adequate hydration (6-8 glasses of water daily)
- Report immediately any signs of infection (fever, chills), unusual bleeding/bruising, fatigue, or yellowing of skin/eyes
- Use effective contraception during treatment and for at least 30 days after last dose
- Inform all healthcare providers about Venclexta use before starting any new medications
- Keep all scheduled laboratory appointments for safety monitoring
- Store medication at room temperature in original packaging
References
1. FDA Prescribing Information: Venclexta (venetoclax) tablets. Revised January 2023. 2. Roberts AW, et al. Targeting BCL2 with Venetoclax in Relapsed Chronic Lymphocytic Leukemia. N Engl J Med. 2016;374(4):311-322. 3. DiNardo CD, et al. Venetoclax combined with decitabine or azacitidine in treatment-naive, elderly patients with acute myeloid leukemia. Blood. 2019;133(1):7-17. 4. Seymour JF, et al. Venetoclax-rituximab in relapsed or refractory chronic lymphocytic leukemia. N Engl J Med. 2018;378(12):1107-1120. 5. Stilgenbauer S, et al. Venetoclax for patients with chronic lymphocytic leukemia with 17p deletion: results from the full population of a phase II pivotal trial. J Clin Oncol. 2018;36(19):1973-1980. 6. Anderson MA, et al. The BCL2 selective inhibitor venetoclax induces rapid onset apoptosis of CLL cells in patients via a TP53-independent mechanism. Blood. 2016;127(25):3215-3224.