All-Oral Treatment of Newly Diagnosed Acute Myeloid Leukemia

BACKGROUND: For patients with acute myeloid leukemia (AML) who are 75 years of age or older or who are ineligible for intensive induction chemotherapy, azacitidine or decitabine plus venetoclax is the standard of care, but parenteral administration imposes a burden on patients and providers. Oral decitabine-cedazuridine, approved in Europe for AML, has pharmacokinetic properties equivalent to those of intravenous decitabine but provides limited survival benefit as monotherapy. METHODS: In this phase 1-2, open-label, multicenter, nonrandomized trial, we assigned patients with newly diagnosed AML who were 75 years of age or older or who were ineligible for intensive chemotherapy to receive oral decitabine-cedazuridine plus oral venetoclax. To mitigate myelosuppression observed in phase 1, schedule adjustments were encouraged in phase 2b after bone marrow blast clearance. The primary end points were the venetoclax area under the curve from 0 to 24 hours and maximum observed concentration with or without decitabine-cedazuridine (measures of drug interaction) on days 5 and 15 of cycle 2 (phase 1-2a) and complete response (phase 2a-b). RESULTS: A total of 189 patients were enrolled (30 patients in phase 1, 58 patients in phase 2a, and 101 patients in phase 2b). No drug-drug interactions were observed between decitabine-cedazuridine and venetoclax. In the pivotal phase 2b, the percentage of patients with a complete response was 47% (95% confidence interval [CI], 36 to 57), the percentage with a complete response or complete response with incomplete hematologic recovery was 63% (95% CI, 53 to 73), and median overall survival was 15.5 months (95% CI, 7.6 to could not be estimated). Common adverse events of grade 3 or higher in phase 2b were anemia (in 30% of the patients), neutropenia (in 26%), and febrile neutropenia (in 25%). Mortality was 3% at 30 days and 10% at 60 days. CONCLUSIONS: Among patients with newly diagnosed AML who were ineligible for intensive chemotherapy, all-oral decitabine-cedazuridine plus venetoclax caused no drug interactions and resulted in a complete response in nearly half the patients, with myelosuppressive effects. (Funded by Taiho Oncology; ASCERTAIN-V ClinicalTrials.gov number, NCT04657081.).