Venetoclax (Venclexta™)

What is venetoclax? Venetoclax is an oral, selective small molecule inhibitor of B-cell lymphoma-2 (BCL-2). How does venetoclax work? A commonly overexpressed survival protein, BCL-2 causes chronic lymphocytic leukemia (CLL) cells to become resistant to apoptosis. Venetoclax binds to BCL-2 and displaces pro-apoptotic proteins to restore programmed CLL cell death. What is this approved for? Venetoclax is approved in CLL patients with proven 17p deletion who have received at least one prior therapy. What is the basis for this approval? Venetoclax was granted accelerated approval based on the results of a phase II, open-label trial of 107 previously treated CLL patients with 17p deletion. Venetoclax was escalated to 400 mg daily until disease progression or unacceptable toxicity. A protocol specified analysis occurred after 70 patients completed a week 36 assessment. Overall response occurred in 77 percent (54/70) compared to a historical response of 40 percent (p < 0.0001). At approximately 12 months, the population overall response was 79 percent (85/107, 95% CI 70.5-86.6). Estimated 12-month progression-free and overall survival was 72 percent and 87 percent, respectively. Of note, patients who had poor prognostic factors or were refractory to prior therapy did not have inferior responses (Lancet Oncology 2016;17:768-778). How do you administer this drug? Venetoclax cycle 1 is dispensed in increasing weekly doses to mitigate tumor lysis syndrome (TLS) as follows: 20 mg/day Days 1-7, 50 mg/day Days 8-14, 100 mg/day Days 15-21, 200 mg/day Days 22-28. Subsequent cycles are 400 mg/day Days 1-28. Venetoclax should be taken with a meal at approximately the same time daily. Are any premedications needed? Assessment for tumor burden and TLS must be made prior to venetoclax administration. What are the common side effects associated with venetoclax (> or =10%)? The most common toxicities include peripheral edema, fatigue, headache, electrolyte abnormalities, diarrhea, neutropenia, thrombocytopenia, anemia, fever, and infections.TableWhat are the uncommon side effects associated with venetoclax (less than 10%)? Less common toxicities include TLS, febrile neutropenia, back pain, and pneumonia. Are there any important drug interactions I should be aware of? Venetoclax is metabolized by Cytochrome P450 3A4/5. Avoid concurrent use of venetoclax and strong CYP3A inducers due to potential decreased venetoclax efficacy. Venetoclax may increase the toxicity of warfarin and P-glycoprotein substrates with a narrow therapeutic index. Venetoclax dose reductions are recommended if coadministration with CYP3A inhibitors cannot be avoided (decrease venetoclax dose by 75% for strong inhibitors or 50% for moderate inhibitors/P-glycoprotein inhibitors). Dose reductions should only occur at steady state dosing (not cycle 1). How do I adjust the dose in the setting of renal insufficiency? Less than 0.1 percent of venetoclax is excreted in the urine; therefore, no dosage adjustment is needed. How do I adjust the dose in the setting of hepatic insufficiency? Venetoclax has not been studied in hepatic insufficiency. Given venetoclax is metabolized by Cytochrome P450 3A4/5 and eliminated (> 99%) via the biliary tract, there may be increased venetoclax toxicity in liver dysfunction. Practical tips Fatal cases of TLS have been reported in patients receiving venetoclax. Patients should receive prophylaxis and monitoring as per their assessed risk. Grade 3/4 neutropenia occurred in 41 percent of patients. Complete blood counts should be monitored and consideration given to antimicrobial prophylaxis with concomitant white blood cell growth factors. What should my patients know about venetoclax? Patients should contact their health care provider if they experience any of the following: Fever or chills Nausea or vomiting Shortness of breath Irregular heartbeat Dark or cloudy urine Unusual tiredness What else should I know about venetoclax? Patients should drink 6-8 glasses of water daily during cycle 1 of venetoclax. Store venetoclax at room temperature (below 86°F or 30°C). Live attenuated vaccines should not be administered. What useful links are available regarding venetoclax? https://www.venclexta.com/ https://www.fda.gov/drugs/informationondrugs/approveddrugs/ucm495351.htm Any ongoing clinical trials related to venetoclax? Studies evaluating the sequence of venetoclax with ibrutinib and idelalisib in CLL continue accrual. Venetoclax is also being evaluated in the CLL first-line setting in combination with ibrutinib, obinutuzumab, and rituximab/bendamustine. More information is available about the clinical trials at https://clinicaltrials.gov. HEIDI D. FINNES, PHARMD, BCOP, is Senior Manager, Pharmacy Cancer Research, and Assistant Professor of Pharmacy, College of Medicine, Mayo Clinic, Rochester, Minn. Oncology Times Clinical Advisory Editor RAMASWAMY GOVINDAN, MD, Co-Director, Section of Medical Oncology, Professor of Medicine, Washington University School of Medicine, Alvin J. Siteman Cancer Center, serves as the Pharmacy Forum column physician advisor. JANELLE E. MANN, PHARMD, BCOP, is an Investigational Drug Pharmacist, Washington University School of Medicine, Alvin J. Siteman Cancer Center, St. Louis, Mo., and serves as the Pharmacy Forum column co-editor. SARA K. BUTLER, PHARMD, BCPS, BCOP, is Clinical Oncology Pharmacy Supervisor, Barnes-Jewish Hospital, St. Louis, Mo., and also serves as a Pharmacy Forum column co-editor.Heidi D. Finnes, PHARMD, BCOP: Heidi D. Finnes, PHARMD, BCOPRamaswamy Govindan, MD: Ramaswamy Govindan, MD