Phase 1b data previously showed that venetoclax (VEN), a selective small-molecule inhibitor of B-cell lymphoma 2, combined with azacitidine (AZA), was effective, with an acceptable safety profile in patients with acute myeloid leukemia (AML) who are ineligible for intensive therapy. This phase 3, randomized, double-blind, multicenter, placebo-controlled study (VIALE-A) assessed the efficacy of AZA + VEN versus AZA + placebo (PBO) in treatment-naïve patients with AML ineligible for intensive therapy.
Patients had confirmed AML and were ineligible for intensive induction therapy because of medical comorbidities and/or older age (≥75 years). Patients who received a prior hypomethylating agent were excluded. Randomization was performed 2:1 to AZA + VEN (AZA 75 mg/m2 subcutaneously or intravenously on days 1-7 per 28-day cycle and once-daily 400-mg VEN orally on days 1-28, with a 3-day ramp-up in cycle 1; N = 286) or AZA + PBO (AZA 75 mg/m2 on days 1-7 per each 28-day cycle and once-daily PBO orally on days 1-28; N = 145). The primary end point was overall survival (OS); secondary end points were composite complete remission (CR; CR + CR with incomplete hematologic recovery [CRi]), CR + CRi by the start of cycle 2, CR, transfusion independence (red blood cells or platelets), as well as CR + CRi and OS by various molecular subgroups, and event-free survival.
The median age was 76 years. The median OS was 14.7 months and 9.6 months in the AZA + VEN and AZA + PBO arms, respectively, at a median follow-up of 20.5 months (hazard ratio, 0.66; 95% confidence interval [CI], 0.52-0.85; P <.001), representing a 34% reduction in the risk for death. The median number of cycles was 7.0 and 4.5 in the AZA + VEN and AZA + PBO arms, respectively. CR + CRi was achieved by 66% and 28% of patients in the AZA + VEN versus AZA + PBO arms, respectively (P <.001). In the AZA + VEN arm, the median time to first CR or CRi was 1.3 months (95% CI, 0.6-9.9) and the duration of CR + CRi was 17.5 months; for the AZA + PBO arm, the median time to first CR or CRi was 2.8 months (95% CI, 0.8-13.2) and the duration of CR + CRi was 13.4 months. In the AZA + VEN arm, rates of CR + CRi in patients with poor and intermediate cytogenetic risk were 53% and 74%, respectively, whereas in patients with de novo and secondary AML, these rates were 66% and 67%, respectively. In the AZA + PBO arm, rates of CR + CRi in patients with poor and intermediate cytogenetic risk were 23% and 32%, respectively, whereas in patients with de novo and secondary AML, these rates were 30% and 23%, respectively.
Grade ≥3 hematologic adverse events (AEs) in the AZA + VEN versus AZA + PBO arms, respectively, included thrombocytopenia in 45% versus 38%, neutropenia in 42% versus 29%, febrile neutropenia in 42% versus 19%, anemia in 26% versus 20%, and leukopenia in 21% versus 12% of patients. Gastrointestinal AEs of all grades were common in both the AZA + VEN and AZA + PBO arms, including nausea in 44% and 35%, constipation in 43% and 39%, diarrhea in 41% and 33%, and vomiting in 30% and 23% of patients, respectively. Grade ≥3 AEs of note in the AZA + VEN versus AZA + PBO arms were febrile neutropenia in 30% versus 10% and pneumonia in 16% versus 22% of patients, respectively. Laboratory tumor lysis syndrome was observed in only 1% of patients in the AZA + VEN arm. The 30-day mortality rates were 7% (N = 21) and 6% (N = 9) for AZA + VEN and AZA + PBO, respectively.
The addition of VEN to AZA in treatment-naïve patients with AML ineligible for intensive therapy because of medical comorbidities and/or advanced age (≥75 years) produced statistically significantly greater response rates and OS versus AZA alone, with an acceptable safety profile.
Reference
DiNardo C, Jonas B, Pullarkat V, et al. A Randomized, Double-Blind, Placebo-Controlled Study of Venetoclax with Azacitidine vs Azacitidine in Treatment-Naïve Patients with Acute Myeloid Leukemia Ineligible for Intensive Therapy-VIALE-A. Presented at: 25th European Hematology Association Congress Virtual; June 11-21, 2020. Abstract LB2601.