Venetoclax with hypomethylating agents versus intensive chemotherapy as induction therapy in patients with newly diagnosed acute monocytic leukemia

Abstract Introduction Acute monocytic leukemia (AML-M5), a subtype of AML with poor prognosis, has traditionally been treated with intensive chemotherapy (IC) followed by hematopoietic stem cell transplantation (HSCT) in high-risk patients(1,2). Recently, venetoclax, a BCL-2 inhibitor, combined with hypomethylating agents (VEN+HMA), has shown promising efficacy in older and unfit AML patients and is increasingly considered for younger patients due to its favorable safety profile(3–5). However, resistance to venetoclax, has been demonstrated in monocytic leukemia stem cells (m-LSCs). Data comparing VEN+HMA to IC in AML-M5 subtype remain limited(6,7). Methods We conducted a retrospective cohort study of newly diagnosed AML-M5 patients at Shaanxi Provincial People's Hospital (2022–2024). Patients received either IC with the 7+3 regimen (IA group) or VEN+HMA (VEN group: venetoclax + azacitidine or decitabine). Venetoclax was administered off-label at 100mg day1, 200mg day2, 400 mg (days 1–7, 14, 21, or 28) without ramp-up. Standard prophylaxis and G-CSF were used. Outcomes included complete remission (CR), MRD negativity, overall survival (OS), disease-free survival (DFS), and cumulative incidence of relapse (CIR). Categorical and continuous variables were analyzed using Fisher's exact/Chi-squared and t-tests/Wilcoxon tests, respectively. Kaplan-Meier and cumulative incidence analyses assessed survival and relapse. Results Among 28 AML-M5 patients, 14 received IA and 14 received VEN+HMA. Baseline demographics and ELN risk categories were comparable between groups. CR rates post-induction were similar (71.4% in both, p=0.397). MRD-negative rates did not differ significantly (50% IA vs. 42.9% VEN, p=1.0). There was no significant difference in 1-year OS between the IA group and VEN group (100% vs 83.1%, p = 0.12). The VEN group has inferior DFS compared with the IA group (56.2% vs 83.3%, p = 0.045). The 1-year cumulative incidence of relapse in the VEN group was 43.6% compared with 18.1% in the IA group (p = 0.02). Conclusions VEN+HMA yielded similar initial complete remission rates compared to IC but was associated with inferior 1-year DFS and higher relapse in AML-M5 patients. These findings suggest suboptimal long-term efficacy of VEN-based induction in this subtype, potentially due to intrinsic venetoclax resistance linked to monocytic differentiation(8). Further studies are warranted to optimize induction strategies for AML-M5. References O'Dwyer K, Freyer DR, Horan JT. Treatment strategies for adolescent and young adult patients with acute myeloid leukemia. Blood. 2018 Jul 26;132(4):362–8. Liu L, Zhang A, Ruan M, Chang L, Liu F, Chen X, et al. Prognostic stratification of molecularly and clinically distinct subgroup in children with acute monocytic leukemia. Cancer Med. 2020 Jun;9(11):3647–55. Cherry EM, Abbott D, Amaya M, McMahon C, Schwartz M, Rosser J, et al. Venetoclax and azacitidine compared with induction chemotherapy for newly diagnosed patients with acute myeloid leukemia. Blood Adv. 2021 Dec 28;5(24):5565–73. Lu J, Xue S li, Wang Y, He X feng, Hu X hui, Miao M, et al. Venetoclax and decitabine vs intensive chemotherapy as induction for young patients with newly diagnosed AML. Blood. 2025 May 29;145(22):2645–55. DiNardo CD, Pratz K, Pullarkat V, Jonas BA, Arellano M, Becker PS, et al. Venetoclax combined with decitabine or azacitidine in treatment-naive, elderly patients with acute myeloid leukemia. Blood. 2019 Jan 3;133(1):7–17. Garciaz S, Hospital MA, Collette Y, Vey N. Venetoclax resistance in acute myeloid leukemia. Cancers. 2024 Mar 8;16(6):1091. Pei S, Shelton IT, Gillen AE, Stevens BM, Gasparetto M, Wang Y, et al. A novel type of monocytic leukemia stem cell revealed by the clinical use of venetoclax-based therapy. Cancer Discov. 2023 Sep 6;13(9):2032–49. Bruserud Ø, Selheim F, Hernandez-Valladares M, Reikvam H. Monocytic differentiation in acute myeloid leukemia cells: diagnostic criteria, biological heterogeneity, mitochondrial metabolism, resistance to and induction by targeted therapies. Int J Mol Sci. 2024 Jun 8;25(12):6356.