Venetoclax Combined with Three-Day Multi-Frequency Decitabine (DEC3-VEN) in the Treatment of Adult Patients with <i>De Novo</i> Acute Myeloid Leukemia

Background: Leukemia is one of the malignancies with a high mortality rate in China, with acute myeloid leukemia (AML) being the most common type, accounting for more than half of all cases. Venetoclax (VEN) is a selective small-molecule inhibitor of BCL-2, which has been shown to induce apoptosis in malignant cells that rely on BCL-2 for survival in preclinical studies. For de novo AML patients who are suitable for intensive chemotherapy, earlier research has indicated that VEN combined with intensive chemotherapy regimens (IA/DA/FLAG-I/CLAG-I) significantly improves complete remission (CR) and MRD negativity rates. To further explore the induction regimen for young, intensive chemotherapy-tolerant(fit), de novo AML patients, we have designed a protocol combining VEN with three-day multi-frequency decitabine（DEC）as induction therapy. This study aims to explore the safety and efficacy of the new protocol, venetoclax combined with a 3-day decitabine regimen, in de novo adult fit AML patients. Objective: To evaluate the efficacy and safety of venetoclax combined with three-day multi-frequency decitabine (DEC3-VEN) in de novo adult fit 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 &amp;gt;2 hours). For patients with FLT3/ITD positive, sorafenib is administered at 800 mg/day 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 June 30, 2024, 26 patients had been enrolled in the study, with a median age of 58 years (range 19-65) and 53.85% (14/26) being male. According to the European LeukemiaNet (ELN 2022) risk classification, five patients (19.23%) were in the favorable risk group, four (15.38%) in the intermediate risk group, and 17 (65.38%) in the adverse risk group. All patients received DEC3-VEN induction chemotherapy, with nine FLT3/ITD positive patients starting sorafenib on day 8. The cCR(CR+CRi) rate after one cycle of induction was 88.46% (23/26), with the CR rate was 80.77% (21/26). Among those who achieved cCR, the MRD negativity rate was 78.26% (18/23) by flow cytometry. The ORR were 100% (5/5) in the favorable risk group, 100% (4/4) in the intermediate risk group, and 82.35% (14/17) in the adverse risk group. During induction therapy, all patients experienced ≥ grade 3 hematologic toxicity, with common adverse reactions including febrile neutropenia. No patients died during induction. For those who achieved CR, the median time to white blood cell recovery (≥1.0 × 10⁹/L) was 14 days (range, 7-21), and to platelet recovery (≥20 × 10⁹/L) was 11.5 days (range, 0-19). As of June 30, 2024, the median follow-up is 74.5 days (range, 26-254), no enrolled patients have died. Conclusions: Venetoclax Combined with Three-Day Multi-frequency Decitabine has shown good efficacy and tolerability as an induction therapy for de novo adult fit 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