Venetoclax combined with three-day multi-frequency Decitabine (DEC3-VEN) in the treatment of adult patients with de novo Acute Myeloid Leukemia：updated results of a phase II trial

Abstract Background: Venetoclax (VEN), a selective small-molecule inhibitor of BCL-2, has shown significant improvements in remission rates among newly diagnosed AML patients when used in combination therapies. These include VEN combined with AZA, VEN combined with DEC, and VEN paired with IC (intensive chemotherapy). Our previous study showed that Ven combined with three-day multi-frequency DEC (DEC3-VEN) as induction therapy is a highly effective and safe induction therapy for adults with newly diagnosed AML (ASH 2024). To further validate the efficacy and safety of this induction regimen, the study continued to enroll patients with newly diagnosed AML. Now, we have updated the results of this phase 2, multicenter, single-arm trial. Objective: To further evaluate the efficacy and safety of venetoclax combined with three-day multi-frequency decitabine (DEC3-VEN) as induction therapy in adult patients with de novo AML patients. Design, setting and participants: A single-arm prospective clinical trial conducted in China Inter-Province Group of Blood Diseases (CPGBD). Eligible patients with de novo AML (excluding acute promyelocytic leukemia, etc) aged 16-65 years were enrolled in the trial. This trial has been registered on ClinicalTrials.gov (NCT06285136) and is currently ongoing with patient recruitment. Induction regimen: The regimen includes venetoclax administered at 100 mg on day 1, 200 mg on day 2, and 400 mg from days 3 to 14. Decitabine is administered at 20 mg/m² every 8 hours from days 4 to 6 (infusion time 2 hours). For patients with FLT3/ITD positive, sorafenib 800 mg/day or gilteritinib 80mg/day is administered at from days 8 to 14. Main outcomes and measures: The primary endpoint is the overall response rate (ORR) after one cycle of induction therapy, which includes complete remission (CR), complete remission with incomplete hematologic recovery (CRi), morphologic leukemia-free state (MLFS), and partial remission (PR). Results: By May 30, 2025, 101 patients had been enrolled in the study, six patients withdrew from the group before treatment, 95 patients received DEC3-VEN induction chemotherapy. The median age was 54 years (range 18-65) and 52.6% (50/95) being male. According to the European LeukemiaNet (ELN 2022) risk classification, 24 (25.3%), 25 (26.3%), and 46 (48.4%) patients were considered to belong to the favorable, intermediate, and adverse groups, respectively. The ORR(CR+CRi+MLF+PR) after one cycle of induction was 90.5% (86/95) with a cCR (CR + CRi) of 85.2% (CR 79/95, CRi 2/95). Among those who achieved cCR, the MRD negativity rate was 80.2% (65/81) by flow cytometry. The cCR rates were 100.0% (24/24) in the favorable risk group, 84.0% (21/25) in the intermediate risk group, and 78.3% (36/46) in the adverse risk group. Grade 3 or worse adverse effects included neutropenia, thrombocytopenia, and febrile neutropenia. No patients died during induction. For those who achieved cCR, the median white blood cell recovery (≥1.0 × 10⁹/L) and platelet recovery (≥20 × 10⁹/L) times were 15 days (range, 0-61), and 11 days (range, 0-48) days, respectively. As of June 30, 2025, the median follow-up is 245 days (range, 39-578), 13 patients proceed Allo-HSCT, the estimated 1-year OS, RFS, and EFS rates were 81.8% (95% CI 69.7%-89.4%)、79.4%(95% CI 65.9%-88.0%)、74.6%(95% CI 61.7%-83.7%), respectively. Conclusions: Venetoclax Combined with Three-Day Multi-frequency Decitabine has shown good efficacy and tolerability as an induction therapy for de novo adult AML patients. To the best of our knowledge, this is the first report about combination of Venetoclax Combined with Three-Day Multi-frequency Decitabine. Keywords: Venetoclax; Decitabine;AML; de novo