Venetoclax combined with three-day multi-frequency decitabine (DEC3-VEN) as induction treatment in newly diagnosed Acute Myeloid Leukemia with TP53-mutantion

Abstract Background: AML associated with TP53 mutations (TP53mut) often exhibits a complex karyotype, demonstrates a poor response to intensive chemotherapy, and typically presents with dismal outcomes, including a short median overall survival (OS). TP53mut are observed in 5-10% of de novo AML cases. Leukemia is a malignancy characterized by a notably high mortality rate. The selection of induction therapy for AML patients with TP53 mutations is still being explored. Our preliminary findings suggest that a combination of VEN with three-day multi-frequency Decitabine (DEC3-VEN) demonstrates both notable safety and significant effectiveness in newly diagnosed elderly patients with acute myeloid leukemia. To further explore the induction regimen for de novo AML patients with TP53mut. We investigated outcomes of patients with TP53mut AML treated with DEC3-VEN. METHODS Objective: To evaluate the efficacy and safety of venetoclax combined with three-day multi-frequency decitabine (DEC3-VEN) in de novo AML with TP53 Mutation patients. Induction regimen The induction regimen consisted of oral Ven (100mg Day 1; 200mg Day 2; 400mg Day 3-9 or 3-14). Decitabine is administered at 20 mg/m² every 8 hours from days 4 to 6 (infusion time >2 hours). Allogeneic hematopoietic stem-cell transplantation (allo-HSCT) were recommended for patients who achieved CR or CRi. Patients who could not proceed allo-HSCT received consolidation and maintenance therapy. 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). The secondary objectives were to evaluate overall survival (OS) and event-free survival (EFS). Results From Sep 2023 to May 2025, a total of 23 de novo AML patients with TP53mut were enrolled and treated with VEN with three-day multi-frequency Decitabine as induction therapy, with a median age of 69 years (range 46-91) and 47.8% (11/23) being male. TP53-altered subgroups included single mutation only without deletion of TP53 (n = 3/23, 13.0%) and multi-hit alterations (n=20/23, 86.9%) including multiple mutations without chromosomal deletion involving the TP53 locus (n =1/23, 4.3%), or TP53 mutation(s) with concomitant deletion noted on karyotype, array CGH or FISH (n = 19/23, 82.6%). The ORR(CR+CRi+MLFS) after one cycle of induction was 78.26% (18/23)with a composite complete response rate (CR + CRi) of 73.9% (CR 14/23, CRi 3/23). Moreover, 64.7% (11/17) of the patients reached CR with undetectable MRD assessed by flow cytometry. During induction therapy, all patients experienced ≥ grade 3 hematologic toxicity, with common adverse reactions including febrile neutropenia. No patients died during induction. As of July 15, 2025, with a median follow-up of 8(1-18) months, 2(8.7%) patients underwent allo-HSCT. The median OS in patients with TP53mut AML was 8(1-18) months. Conclusions Venetoclax Combined with Three-Day Multi-frequency Decitabine (DEC3-VEN) has shown good efficacy and tolerability as an induction therapy for de novo AML patients with TP53 mutation. Keywords Venetoclax; Decitabine;AML; de novo; TP53-mutation