On October 16, 2020, venetoclax was granted regular approval for use in combination with azacitidine, decitabine, or low-dose cytarabine for the treatment of newly diagnosed acute myeloid leukemia (AML) in adults aged 75 years or older or those with comorbidities precluding intensive induction chemotherapy.^1,2

Venetoclax was initially granted accelerated approval for this indication in November 2018 on the basis of two single-arm studies, M14-358 (ClinicalTrials.gov identifier NCT02203773) and M14-387 (NCT02287233), which evaluated venetoclax in combination with azacitidine or decitabine and in combination with low-dose cytarabine, respectively.

Supporting Efficacy Data

Regular approval was supported by two confirmatory phase III double-blind trials in patients with AML aged 75 years or older or those with comorbidities precluding intensive induction chemotherapy.

In VIALE-A (NCT02993523),³ patients were randomly assigned 2:1 to receive venetoclax plus azacitidine (n = 286) or placebo plus azacitidine (n = 145). Efficacy was established based on an improvement in overall survival. Median overall survival was 14.7 months (95% confidence interval [CI] = 11.9–18.7 months) in the venetoclax/azacitidine group vs 9.6 months (95% CI = 7.4–12.7 months) in the placebo/azacitidine group (hazard ratio [HR] = 0.66, 95% CI = 0.52–0.85, P < .001). Complete remission was achieved in 37% vs 18% of patients (P < .001), with a median duration of complete remission of 18.0 vs 13.4 months.

In VIALE-C (NCT03069352), patients were randomly assigned 2:1 to receive venetoclax plus low-dose cytarabine (n = 143) or placebo plus low-dose cytarabine (n = 68). Efficacy was based on complete remission rate and duration of complete remission. Complete remission was achieved in 27% vs 7.4% of patients, with a median duration of complete remission of 11.1 months (95% CI = 6.1 months to not reached) vs 8.3 months (95% CI = 3.1 months to not reached). Venetoclax/low-dose cytarabine was not associated with an improvement in overall survival, with a median duration of 7.2 months (95% CI = 5.6–10.1 months) vs 4.1 months (95% CI = 3.1–8.8 months), yielding a hazard ratio of 0.75 (95% CI = 0.52–1.07, P = .114).

How It Works

Venetoclax is a selective small-molecule inhibitor of the antiapoptotic protein BCL2. BCL2 has been found to be overexpressed in chronic lymphocytic leukemia and AML 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 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 and continued during the dose ramp-up phase to reduce the risk of tumor-lysis syndrome.

In the current indication, venetoclax dosing is given in a ramp-up phase consisting of 100 mg, 200 mg, and 400 mg daily on the first 3 days of cycle 1 and at 400 mg daily thereafter. When used in combination with azacitidine or decitabine, it is given at 400 mg daily in each 28-day cycle with either azacitidine at 75 mg/m² intravenously (IV) or subcutaneously (SC) once daily on days 1 to 7 of each 28-day cycle or decitabine at 20 mg/m² IV once daily on days 1 to 5 of each 28-day cycle. When given in combination with low-dose cytarabine, after the ramp-up in cycle 1, it is given at 600 mg once daily in each 28-day cycle with low-dose cytarabine at 20 mg/m² SC once daily on days 1 to 10 of each 28-day cycle.

Treatment should be continued until disease progression or unacceptable toxicity. The dose of venetoclax should be reduced by 50% in patients with severe hepatic impairment.

Product labeling provides detailed information on recommended tumor-lysis syndrome prophylaxis and monitoring during treatment for AML. Product labeling provides instructions on dose modifications and management of adverse reactions in AML, including grade 4 neutropenia with or without fever or infection and grade 4 thrombocytopenia and grade 3 or 4 nonhematologic toxicities.

Concomitant use of venetoclax with strong or moderate CYP3A inducers (eg, apalutamide, carbamazepine, phenobarbital) should be avoided. Product labeling provides instructions on venetoclax dose reductions during ramp-up and for steady use after ramp-up for concomitant use with posaconazole and other strong CYP3A inhibitors (eg, ketoconazole, clarithromycin, nefazodone) and on dose reduction during concomitant use with moderate CYP3A inhibitors (eg, amiodarone, erythromycin, fluconazole) and P-glycoprotein inhibitors (eg, omeprazole, nifedipine, verapamil). P-glycoprotein substrates (eg, cyclosporin, digoxin, loperamide) should be taken at least 6 hours before venetoclax administration.

Safety Profile

The most common adverse events of any grade observed with venetoclax in combination with azacitidine, decitabine, or low-dose cytarabine (≥ 30% in any trial) were nausea, diarrhea, thrombocytopenia, constipation, neutropenia, febrile neutropenia, fatigue, vomiting, edema, pyrexia, pneumonia, dyspnea, hemorrhage, anemia, rash, abdominal pain, sepsis, musculoskeletal pain, dizziness, cough, oropharyngeal pain, and hypotension.

Among patients receiving venetoclax/azacitidine in VIALE-A, the most common grade 3 or 4 adverse events (≥ 10%) were febrile neutropenia (42%) and sepsis (excluding fungal; 22%). Grade 3 or 4 hematologic toxicity included decreased neutrophils (98%), platelets (88%), lymphocytes (71%), and hemoglobin (57%). Serious adverse events were reported in 83% of patients, the most common being febrile neutropenia (30%), pneumonia (22%), sepsis (excluding fungal; 19%), and hemorrhage (6%).

In VIALE-A, adverse events led to permanent discontinuation of venetoclax in 24% of patients, the most common causes being sepsis (excluding fungal; 3%) and pneumonia (2%). Adverse events led to dose interruption in 72%, the most common being febrile neutropenia (20%), neutropenia (20%), pneumonia (14%), sepsis (excluding fungal; 11%), and thrombocytopenia (10%). Fatal adverse events occurred in 23% of patients, the most common being pneumonia (4%), sepsis (excluding fungal; 3%), and hemorrhage (2%).

Among patients receiving venetoclax/low-dose cytarabine in VIALE-C, the most common grade 3 or 4 adverse events (≥ 10%) were febrile neutropenia (32%) and pneumonia (19%). Grade 3 or 4 hematologic adverse events included decreased platelets (95%), neutrophils (92%), lymphocytes (69%), and hemoglobin (57%). Serious adverse events were reported in 65% of patients, the most common being pneumonia (17%), febrile neutropenia (16%), and sepsis (excluding fungal; 12%).

In VIALE-C, adverse events led to dose interruption in 63%, the most common causes being neutropenia (20%), thrombocytopenia (15%), pneumonia (8%), febrile neutropenia (6%), and sepsis (excluding fungal; 6%). Treatment was permanently discontinued due to adverse events in 25%, the most common cause being pneumonia (6%). Fatal adverse events occurred in 23% of patients, the most common being sepsis (excluding fungal; 7%) and pneumonia (6%).

Venetoclax has warnings/precautions for tumor-lysis syndrome, neutropenia, infections, immunization, and embryofetal toxicity. Treatment of patients with multiple myeloma with venetoclax in combination with bortezomib plus dexamethasone is not recommended outside of controlled clinical trials. Tumor-lysis syndrome should be anticipated and risk should be assessed in all patients. In addition to premedication with antihyperuricemics and adequate hydration, more intensive measures (IV 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 until B-cell recovery. Patients should be advised not to breastfeed while receiving venetoclax. 

REFERENCES

1. U.S. Food and Drug Administration: FDA grants regular approval to venetoclax in combination for untreated acute myeloid leukemia. Available at https://www.fda.gov/drugs/drug-approvals-and-databases/fda-grants-regular-approval-venetoclax-combination-untreated-acute-myeloid-leukemia. Accessed October 30, 2020.

2. Venclexta prescribing information, AbbVie Inc and Genentech Inc, 2020. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/208573s020s021lbl.pdf. Accessed October 30, 2020.

3. DiNardo CD, Jonas BA, Pullarkat V, et al: Azacitidine and venetoclax in previously untreated acute myeloid leukemia. N Engl J Med 383:617-629, 2020.