The current study is an open-label, phase 1b dual-stage (dose escalation and expansion) trial that is evaluating the safety and preliminary efficacy of the oral small-molecule BCL-2 inhibitor venetoclax in combination with decitabine or azacitidine in patients aged ≥65 years with previously untreated acute myeloid leukemia (AML) who were ineligible for intensive chemotherapy.
In this study, patients who had previously received hypomethylating agents or chemotherapy; had favorable risk cytogenetics; known central nervous system involvement; and white blood cell (WBC) count >25 × 109/L were excluded from the study. Venetoclax was administered with a short ramp-up during cycle 1 from 20 mg (escalation stage) or 100 mg (expansion stage) to a final dose of 400, 800, or 1200 mg daily; decitabine 20 mg/m2 was administered intravenously on days 1 through 5 or azacitidine 75 mg/m2 intravenously or subcutaneously on days 1 through 7, every 28 days. The data cutoff date was February 17, 2017.
The study population included 145 patients, of which 60 were treated with venetoclax 400 mg (azacitidine = 29 patients; decitabine = 31 patients), and 74 with venetoclax 800 mg (azacitidine = 37 patients; decitabine = 37 patients), and 11 with venetoclax 1200 mg (azacitidine = 5 patients; decitabine = 6 patients). The median age among the total cohort was 74 years (range, 65-86 years), and the majority were male (64%). Moreover, 74 (51%) patients had intermediate risk, 71 (49%) showed poor-risk features, and 36 (25%) had secondary AML.
Safety analysis showed that adverse events (AEs) possibly related to venetoclax, occurring in ≥15% of patients, included nausea (43%), decreased WBC count (28%), fatigue (24%), decreased platelet count (22%), decreased neutrophil count (21%), diarrhea (20%), vomiting (17%), decreased appetite (17%), febrile neutropenia (17%), and neutropenia (15%). Nausea was an AE that was possibly related to azacitabine and decitabine, occurring in ≥20% of patients (azacitidine = 26%; decitabine = 23%).
In the intent-to-treat population (N = 145), the composite complete response rate was 67%, including 37% complete remission (CR) and 30% CR with incomplete blood count recovery (CRi), whereas the overall leukemia response rate (CR + CRi + partial remission + morphologic leukemia-free state) was 83%. Responses achieved by the 2 venetoclax combinations were similar. The median duration of CR/CRi was 11.3 months (95% confidence interval [CI], 8.9 months to not reached [NR]) for all treated patients, with 75% of patients showing sustained response for >6 months. The median overall survival (OS) in intent-to-treat patients was 17.5 months (95% CI, 12.3 months to NR), and the estimated 6-month, 1-year, and 2-year OS rates were 80%, 59%, and 46%, respectively.
Subgroup analysis by cytogenetic risk showed that patients with intermediate risk achieved a CR/CRi rate of 74%, whereas the response rate in the poor-risk group was 60%. Patients with secondary AML achieved a CR/CRi of 67%; those with IDH1/2, FLT3, and TP53 mutations achieved CR/CRi rates of 68%, 64%, and 56%, respectively.
These results demonstrate that the combination therapy of venetoclax 400 mg with decitabine or azacitidine had promising efficacy and a tolerable safety profile in elderly, treatment-naïve patients with AML. Based on these encouraging results, a phase 3 study is currently evaluating the combination of venetoclax 400 mg combined with azacitidine in this patient population.
