Multicenter phase 1-2 trial of all-oral treatment for acute myeloid leukemia in patients ineligible for intensive chemotherapy

For patients with acute myeloid leukemia (AML) who are 75 years of age or older, or who are ineligible for intensive induction therapy, azacitidine or decitabine plus venetoclax is the standard of care, but parenteral administration imposes a burden on patients and providers. Oral decitabine-cedazuridine has pharmacokinetic properties equivalent to those of intravenous decitabine but provides limited survival benefit as monotherapy. The multicenter phase 1-2 ASCERTAIN-V trial evaluated the all-oral therapy decitabine-cedazuridine plus venetoclax for these patients. To mitigate myelosuppression observed in phase 1, schedule adjustments were encouraged in phase 2b after bone marrow blast clearance. Primary endpoints were drug-drug interactions between decitabine-cedazuridine and vetenetoclax on days 5 and 15 of cycle 2 (phase 1-2a) and complete response (phase 2a-b). A total of 189 patients were enrolled (30 patients in phase 1, 58 in phase 2a, 101 in phase 2b). No drug-drug interactions were observed. In phase 2b, the percentage of patients with a complete response was 47% (95% CI 36-57) and the percentage of patients with complete response or complete response with incomplete hematologic recovery was 63% (53-73), and the median overall survival was 15.5 months (7.6-NE). Common grade 3 or higher adverse events in phase 2b were anemia (30% of patients), neutropenia (26%) and febrile neutropenia (25%). Mortality was 3% at 30 days and 10% at 60 days. The authors conclude that among patients with newly diagnosed AML who were ineligible for intensive chemotherapy, all-oral decitabine-cedazuridine plus venetoclax caused no drug-drug interactions and resulted in complete response in nearly half of the patients, with myelosuppressive effects.