On June 8, 2018, venetoclax (Venclexta) was granted regular approval for treatment of patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), with or without 17p deletion, who have received at least one prior therapy.^1,2

Supporting Efficacy Data

APPROVAL WAS BASED on findings from the open-label phase III MURANO trial, in which 389 patients with CLL who received at least 1 prior line of therapy were randomly assigned to treatment with venetoclax plus rituximab (Rituxan; n = 194) or bendamustine plus rituximab (n = 195).^2,3 Patients in the venetoclax group completed a 5-week ramp-up venetoclax schedule and then received venetoclax at 400 mg once daily for 24 months measured from the rituximab start date. Rituximab was initiated after venetoclax ramp up and given for 6 cycles (375 mg/m2 on cycle 1 day 1 and 500 mg/m2 on day 1 of cycles 2–6 in 28-day cycles). The comparator group received 6 cycles of the bendamustine combination (bendamustine at 70 mg/m2 on days 1 and 2 of each 28-day cycle and rituximab at the described dose and schedule).

After a median follow-up of 23 months, the median progression-free survival assessed by an independent review committee was not reached in the venetoclax group vs 18.1 months in the bendamustine group (hazard ratio = 0.19, P < .0001). The overall response rate was 92% vs 72%, respectively.

How It Works

VENETOCLAX IS a selective small-molecule inhibitor of the antiapoptotic protein BCL-2. BCL-2 has been found to be overexpressed in CLL cells, where it mediates tumor cell survival and has been associated with resistance to chemotherapeutics. Venetoclax acts to restore apoptosis by binding directly to the BCL-2 protein, displacing proapoptotic proteins such as BIM, and triggering mitochondrial outer membrane permeability and activation of caspases.

How It Is Used

PATIENTS MUST BE assessed for their level of risk for tumor-lysis syndrome and given prophylactic hydration and antihyperuricemics prior to the first dose of venetoclax to reduce the risk for tumor-lysis syndrome. Venetoclax is given via a weekly ramp-up schedule over 5 weeks to the recommended daily dose of 400 mg; the daily doses are 20, 50, 100, and 200 mg for weeks 1, 2, 3, and 4 and 400 mg for week 5 and thereafter. The ramp-up dosing schedule is designed to gradually reduce the tumor burden and decrease the risk for tumor-lysis syndrome.

For venetoclax combined with rituximab, rituximab should be started after completion of the 5-week ramp-up schedule and after the patient has received the 400-mg dose for 7 days. Rituximab is given on day 1 of each 28-day cycle for 6 cycles, at 375 mg/m2 in cycle 1 and at 500 mg/m2 in cycles 2 to 6. Patients should continue venetoclax at 400 mg once daily for 24 months from cycle 1 day 1 of rituximab. For venetoclax monotherapy, once-daily treatment should be continued until disease progression or unacceptable toxicity.

Venetoclax can cause rapid reduction in tumor and thus poses a risk for tumor-lysis syndrome in the initial 5-week ramp-up phase. Changes in blood chemistry consistent with tumor-lysis syndrome that require prompt management can occur as early as 6 to 8 hours after the first dose and at each dose increase. Product labeling provides detailed instructions on risk assessment and prophylaxis for tumor-lysis syndrome, as well as detailed instructions on dose interruption and modification for tumor-lysis syndrome, grade 3 or 4 nonhematologic toxicities, grade 3 or 4 neutropenia with infection or fever, and other grade 4 hematologic toxicity.

Concomitant use of venetoclax with strong CYP3A inhibitors (eg, ketoconazole, conivaptan, clarithromycin, indinavir, itraconazole) at initiation and during ramp up is contraindicated. For patients who have completed the ramp-up phase and are on a steady daily dose of venetoclax, the dose should be reduced by at least 75% when used concomitantly with strong CYP3A inhibitors. The venetoclax dose used prior to initiating the strong CYP3A inhibitor can be resumed 2 to 3 days after discontinuation of the inhibitor.

Concomitant use of moderate CYP3A inhibitors (eg, erythromycin, ciprofloxacin, diltiazem) as well as strong (eg, carbamazepine, phenytoin, rifampin, St. John’s wort) or moderate (eg, bosentan, efavirenz, etravirine, modafinil, nafcillin) CYP3A inducers, P-glycoprotein inhibitors (eg, amiodarone, captopril, cyclosporine), and P-glycoprotein substrates with a narrow therapeutic index should be avoided. Venetoclax dose modifications in concomitant use for some of these agents are provided in the product labeling.

Safety Profile

THE MOST COMMON adverse events (≥ 20%) with venetoclax in combination with rituximab were neutropenia, diarrhea, upper respiratory tract infection, fatigue, cough, and nausea. The most common (≥ 20%) adverse events with venetoclax in monotherapy studies were neutropenia, diarrhea, nausea, upper respiratory tract infection, anemia, fatigue, thrombocytopenia, musculoskeletal pain, edema, and cough.

In the MURANO trial, the most common adverse events of any grade occurring with an incidence of at least 5% in the venetoclax group vs the bendamustine group were neutropenia (65% vs 60%), diarrhea (40% vs 17%), upper respiratory tract infection (39% vs 23%), and musculoskeletal pain (19% vs 13%). In the venetoclax group, adverse events led to treatment discontinuation in 16% of patients, dose reduction in 15%, and dose interruption in 71%. Fatal adverse events in the absence of disease progression occurring within 30 days of the last venetoclax treatment and/or 90 days of the last rituximab treatment were reported in 4 patients (2%). The most common grade 3 or 4 laboratory abnormalities in the venetoclax group were neutropenia (64% vs 59% in the bendamustine group), lymphopenia (56% vs 55%), leukopenia (46% vs 35%), and hyperuricemia (36% vs 33%).

Venetoclax carries warnings/precautions for tumor-lysis syndrome, neutropenia, immunization, and embryofetal toxicity. Tumor-lysis syndrome should be anticipated, and risk should be assessed in all patients. Patients should be premedicated with antihyperuricemics, and adequate hydration should be ensured. More intensive measures should be employed as overall risk increases. Blood cell counts should be routinely monitored. No live attenuated vaccines should be given prior to, during, or after venetoclax treatment. Concomitant use of venetoclax with strong CYP3A inhibitors at initiation and during dose ramp up is contraindicated. Patients should discontinue breastfeeding when receiving venetoclax. ■

REFERENCES

1. U.S. Food and Drug Administration: FDA approves venetoclax for CLL or SLL, with or without 17p deletion, after one prior therapy. Available at www.fda.gov/Drugs/ InformationOnDrugs/ApprovedDrugs/ucm610308.htm. Accessed October 19, 2018.

2. Venclexta (venetoclax) tablets prescribing information, AbbVie Inc and Genentech Inc, June 2018. Available at www.accessdata.fda.gov/drugsatfda_docs/label/2018/208573s004s005lbl.pdf. Accessed October 19, 2018.

3. Seymour JF, et al: Venetoclax-rituximab in relapsed or refractory chronic lymphocytic leukemia. N Engl J Med 378:1107-1120, 2018.