On May 15, 2019, venetoclax was approved for the treatment of adult patients with previously untreated chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).^1,2

Supporting Efficacy Data

Approval was based on findings from the open-label phase III CLL14 trial (ClinicalTrials.gov identifier NCT02242942).² In the trial, 432 patients with previously untreated CLL with coexisting medical conditions (total Cumulative Illness Rating Scale [CIRS] score > 6 or creatinine clearance < 70 mL/min) were randomly assigned to receive venetoclax plus obinutuzumab (n = 216) or obinutuzumab plus chlorambucil (n = 216).

The median age of was 72 (range = 41–89 years); 89% were white; 67% were male; 36% and 43% had Binet stage B and C disease, respectively; 88% had an Eastern Cooperative Oncology Group performance status < 2; the median CIRS score was 8 (range = 0–28); and 58% had a creatinine clearance up to 70 mL/min. A 17p deletion was detected in 8% of patients; TP53 mutations, in 7%; 11q deletion, in 19%; and unmutated IgHV, in 57%.

The major efficacy outcome was progression-free survival assessed by independent review committee. The median progression-free survival was not reached in either group. After median follow-up of 28 months, progression-free survival events occurred in 13% of the venetoclax group vs 37% of the control group, demonstrating a significant improvement in the venetoclax group (hazard ratio = 0.33, P < .0001). Overall response rates were 85% in the venetoclax group vs 71% in the control group (P = .0007). The venetoclax group also had improvements in the rates of minimal residual disease negativity (less than 1 CLL cell/10⁴ leukocytes) in bone marrow (57% vs 17%) and peripheral blood (76% vs 35%). Overall survival data were not mature.

How It Works

Venetoclax is a selective small-molecule inhibitor of the antiapoptotic protein BCL2. BCL2 has been found to be overexpressed in CLL and acute myeloid leukemia cells, where it mediates tumor cell survival and has been associated with resistance to chemotherapeutics. Venetoclax helps to restore apoptosis by binding directly to the BCL2 protein, displacing proapoptotic proteins such as BIM, and triggering mitochondrial outer membrane permeability and activation of caspases. In preclinical studies, venetoclax showed cytotoxic activity in tumor cells that overexpress BCL2.

How It Is Used

Patients treated with venetoclax may develop tumor-lysis syndrome. Patient-specific factors for the level of risk of tumor-lysis syndrome must be assessed, and prophylactic hydration and antihyperuricemics must be provided to patients prior to the first dose to reduce the risk of tumor-lysis syndrome. Venetoclax dosing in CLL/SLL begins with a 5-week ramp-up to the recommended daily dose of 400 mg, with the dosing schedule designed to gradually reduce the tumor burden and decrease the risk of tumor-lysis syndrome. The dose schedule is 20 mg/d for week 1, 50 mg/d for week 2, 100 mg/d for week 3, 200 mg/d for week 4, and 400 mg/d for week 5 and beyond.

When venetoclax is used in combination with obinutuzumab, obinutuzumab administration begins at 100 mg on day 1 of cycle 1 followed by 900 mg on day 2 of cycle 1. A dose of 1,000 mg on days 8 and 15 of cycle 1 and on day 1 of each subsequent 28-day cycle is given for a total of 6 cycles. (Obinutuzumab prescribing information should be consulted for recommended obinutuzumab dosing information.) Venetoclax is started according to the 5-week ramp-up schedule on day 22 of cycle 1. After the ramp-up schedule is completed on day 28 of cycle 2, patients should continue venetoclax 400 mg once daily from day 1 of cycle 3 until the last day of cycle 12.

Product labeling provides detailed information on recommended tumor-lysis syndrome prophylaxis and monitoring during treatment based on tumor burden determination from clinical trial data. Product labeling provides detailed instructions on dose modifications. Product labeling provides instructions regarding the concomitant use of venetoclax with strong or moderate CYP3A inhibitors or P glycoprotein inhibitors, strong or moderate CYP3A inducers, and P glycoprotein substrates.

Safety Profile

In patients with CLL/SLL, the most common adverse events of any grade (≥ 20%) with venetoclax when administered with obinutuzumab, rituximab, or as monotherapy have been neutropenia, thrombocytopenia, anemia, diarrhea, nausea, upper respiratory tract infection, cough, musculoskeletal pain, fatigue, and edema. In addition to requiring a CIRS > 6 or a creatinine clearance < 70 mL/min, the CLL14 trial required hepatic transaminases and total bilirubin up to two times the upper limit of normal and excluded patients with any individual organ/system impairment score of 4 on CIRS except eye, ear, nose, and throat organ systems.

In the trial, the most common adverse events of any grade in the venetoclax/obinutuzumab group were neutropenia, diarrhea, fatigue, nausea, anemia, and upper respiratory tract infection. The most common grade ≥ 3 adverse events were neutropenia and anemia. The most common grade 3 or 4 laboratory abnormalities were neutropenia, lymphopenia, leukopenia, and hyperuricemia.

In the venetoclax group, serious adverse events were reported in 49% of patients, with the most common being febrile neutropenia and pneumonia. Adverse events led to treatment discontinuation in 16% of patients, dose reduction in 21%, and dose interruption in 74%. Neutropenia led to dose interruption in 41% of patients, dose reduction in 13%, and dose discontinuation in 2%. Fatal adverse events, most often infection, were reported in 2% of patients.

Concomitant use of venetoclax with strong CYP3A inhibitors at initiation and during the ramp-up phase in patients with CLL/SLL is contraindicated.

Venetoclax carries warnings/precautions for tumor-lysis syndrome, neutropenia, infections, 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 have adequate hydration. More intensive measures (intravenous hydration, frequent monitoring, hospitalization) should be employed as the overall risk of tumor-lysis syndrome increases. Patients should be monitored for blood cell counts and signs of infection. No live attenuated vaccines should be given prior to, during, or after venetoclax treatment. Patients should be advised not to breastfeed while receiving venetoclax. 

REFERENCES

1. U.S. Food and Drug Administration: FDA approves venetoclax for CLL and SLL. Available at www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-venetoclax-cll-and-sll. Accessed October 24, 2019.

2. Venclexta (venetoclax) tablets prescribing information, AbbVie Inc and Genentech Inc, May 2019. Available at www.accessdata.fda.gov/drugsatfda_docs/label/2019/208573s013lbl.pdf. Accessed October 24, 2019.