Venetoclax combined with three-day multi-frequency decitabine (DEC3-VEN) VS venetoclax combined with azacitidine in elderly patients with Acute Myeloid Leukemia：a phase III, prospective, multicenter, randomized controlled trial

Abstract Background: Elderly patients with acute myeloid leukemia (AML) (≥60 years) have a poor prognosis and low long-term survival due to frequent adverse genomic mutations, poor tolerance to intensive chemotherapy, and suboptimal efficacy of conventional treatments. The combination of Venetoclax (VEN) with low-dose chemotherapy or hypomethylating agents (HMA) has demonstrated enhanced outcomes, yet it has not yet attained the optimal rates of remission and minimal residual disease (MRD) negativity. Other study has demonstrated that ten-day DEC combined with Ven can significantly improve the CR rate in newly diagnosed AML patients, albeit at the cost of a notably prolonged bone marrow suppression period. Based on previous research results and our clinical experience, we designed a regimen of VEN combined with three-day multi-frequency decitabine (DEC3-VEN) as induction therapy for elderly or unfit patients with de novo AML. We defined standard-dose venetoclax plus azacitidine as the control arm. Objective This study aims to explore the safety and efficacy of the DEC3-VEN in de novo AML patients who are elderly or unfit for intensive chemotherapy. Design, setting and participants This Phase III, prospective, multicenter, randomized controlled study is planned to be conducted in China Inter-Province Group of Blood Diseases (CPGBD). Eligible patients with de novo AML (excluding acute promyelocytic leukemia, etc) who are either ≥60 years old or unfit for intensive chemotherapy will be enrolled in the trial. Patients enrolled will be randomly allocated to either the experimental or control group. This trial has been registered on ClinicalTrials.gov (NCT06073730) and is currently continuing to recruit patients. Induction regimen Experimental Group(DEC3-VEN):VEN: 100 mg on Day 1, 200 mg on Day 2, 400 mg on Days 3-14; Decitabine: 20 mg/m² every 8 hours on Days 4-6 (infusion time >2 hours); Sorafenib: 600 mg/day on Days 8-14 (for FLT3/ITD positive patients) Control Group(VEN+AZA) : VEN: 100 mg on Day 1, 200 mg on Day 2, 400 mg on Days 3-28; Azacitidine (AZA): 75 mg/m²/day on Days 3-9 Main outcomes and measures The primary endpoint is whether DEC3-VEN improves event-free survival (EFS) compared to VEN+AZA in elderly or unfit adult AML patients. Results As of June 30, 2025, 120 patients were enrolled. There were no statistically significant differences in age and gender ratio between the experimental and control groups (P=0.742, P=0.460). According to ELN 2022 risk stratification, there were no statistically significant differences in the composition of patient risk categories between the experimental and control groups(P=0.266). Before starting of induction, three patients in the DEC3-VEN group and six in the VEN+AZA group withdrew voluntarily. During the first induction chemotherapy, two patients died in the DEC3-VEN group and six patients died in the VEN+AZA group. Currently, 52 patients in the DEC3-VEN group and 51 in the VEN+AZA group are evaluable for efficacy. The cCR(CR+CRi) was 76.9% (40/52) and the CR rate was 73.1% (38/52), with MRD negativity rate of 77.5% (31/40) in DEC3-VEN group by flow cytometry after the first cycle of induction therapy. In VEN+AZA group, the cCR(CR+CRi) was 60.8% (31/51) and the CR rate was 52.9% (27/51), MRD negativity rate of 51.6% (16/31). Compared to the VEN+AZA group, the DEC3+VEN group showed a significant improvement in CR and MRD negativity rate(χ²=4.484，P=0.034,χ²=5.230，P=0.022). As of June 30, 2025, the median follow-up was 182 days (range 11-605), OS, RFS, and EFS remain unreported due to the short follow-up duration. Conclusions DEC3+VEN shows good efficacy and tolerability as an induction therapy for de novo or unfit AML patients, compared with VEN+AZA. Keywords: Venetoclax; Decitabine; Acute Myeloid Leukemia; Elder