Optimizing Venetoclax Duration in Combination with Hypomethylating Agents for Newly Diagnosed AML: Impact on Treatment Response and Survival Outcomes

Introduction: Venetoclax (ven), combined with hypomethylating agents (HMAs), is the preferred treatment for elderly/unfit patients with newly diagnosed acute myeloid leukemia (AML). There is increasing evidence that a shorter duration of ven may be non-inferior, mostly in combination with azacitidine, with the optimal treatment duration still uncertain. Our study evaluates treatment response and survival outcomes in newly diagnosed AML patients receiving shorter durations of ven, with most patients receiving decitabine Methods: This is a retrospective study of 85 newly diagnosed AML patients treated with HMA+ven at Norris Comprehensive Cancer Center between 2018-2024. Cytogenetic and molecular studies were performed using conventional karyotype and next-generation sequencing, respectively. The response was assessed according to the 2022 ELN criteria. The cumulative incidence of relapse (CIR) was evaluated using competing risk regression (Fine-Gray method), with death as a competing outcome. Overall survival (OS) was analyzed using the Cox proportional hazards model. Results: Our patients (median age 69 years, 63.5% male, 64.7% de novo) received a median of 3 cycles (range 1-28) of azacitidine (n=21) or decitabine (n=64) with ven. Ven duration varied: 14-day (n=11), 21-day (n=43), or 28-day course (n=31). ELN 2022 risk included favorable (19.0%, n=16), intermediate (19.0%, n=16), or adverse (61.9%, n=52). Nearly half of the patients had a normal karyotype (n=38, 48.1%) followed by complex (n=23, 29.1%) and monosomal (n=13, 16.5%), while the most common cytogenetic abnormalities were del(5q) (n=12, 18.8%), del(7q) (n=10, 12.5%), MLLT3::KMT2A (n=4, 6.2%), RUNX1::RUNX1T1 (n=4, 6.2%), and CBFB::MYH11 (n=3, 4.7%). Frequent mutations included TP53 (27.2%, n=22), TET2 (18.5%, n=15), K/NRAS (18.5%, n=15), NPM1 (17.3%, n=14), RUNX1 (16.0%, n=13), DNMT3A (16.0%, n=13), ASXL1 (14.8%, n=12), SRSF2 (14.8%, n=12), IDH2 (13.6%, n=11), U2AF1 (9.9%, n=8), WT1 (9.9%, n=8), PTPN11 (8.6%, n=7), BCOR (8.6%, n=7), KMT2A (7.4%, n=6), CEBPA (7.4%, n=6), JAK2 (7.4%, n=6), FLT3-ITD (4.9%, n=4), and IDH1 (2.5%, n=2). Complete remission (CR or CRi) occurred in 55.3% of patients, and 70.7% achieved MRD negativity at CR. Age at diagnosis, race, sex, ELN criteria, extramedullary disease, and CR rates did not differ with ven duration, but the diagnosis of de novo AML did (14 days: 27.3% vs. 21 days: 72.1% vs. 28 days: 67.7%, p=0.027). The 21-day cohort had the lowest refractory disease rate (14 days: 27.3% vs. 21 days: 14.0% vs. 28 days: 38.7%, p=0.045) and the shortest median time to MRD negativity (14 days: 1.1 months (mo) vs. 21 days: 0.8 mo vs. 28 days: 1.8 mo, p=0.029). Median OS was 15.7 mo (95% CI 13.1-25.1) with 43 deaths, and a 1-year CIR of 42.9% (29.0-56.1%). Compared to 21 days of ven, the 14-day group had shorter OS (HR 3.08, 95% CI 1.10-8.59, p=0.032, 6.1 mo vs. 17.6 mo) and increased CIR (HR 6.56, 95% CI 2.37-18.2, p0.001), while the 28-day group had similar OS (HR 1.31, p=0.41, 15.7 mo vs. 17.6 mo) and CIR (HR 1.39, p=0.40). Univariate analysis showed adverse ELN risk group (HR 4.37, 95% CI 1.5-12.7, p=0.007), complex karyotype (HR 2.50, 95% CI 1.26-4.98, p=0.009), positive MRD status at CR (HR 3.05, 95% CI 1.33-6.98, p=0.008), TP53 mutation (HR 2.50, 95% CI 1.28-4.89, p=0.008), and del(5q) (HR 2.36, 95% CI 1.04-5.35, p=0.040) as predictors of worse OS, while NPM1 mutation (HR 0.14, 95% CI 0.04-0.47, p=0.001) conferred improved OS. Predictors of worse CIR included positive MRD at CR (HR 3.26, 95% CI 1.34-7.93, p=0.009) and TP53 mutation (HR 3.27, 95% CI 1.40-7.63, p=0.006), while NPM1 mutations improved CIR (HR 0.16, 95% CI 0.05-0.59, p=0.006). Controlling for ELN and NPM1 mutations, 14-day ven continued to have worse CIR (HR 3.89, 95% CI 1.40-10.8, p=0.009) but not OS (HR 2.54, p=0.11). Conclusions: In our study, a 21-day venetoclax regimen was associated with lower rates of refractory disease, shorter time to MRD negativity, and improved CIR. Adverse ELN risk group, positive MRD status, and TP53 mutations were significant predictors of worse outcomes, while NPM1 mutations were associated with improved OS and CIR. These findings underscore the importance of tailoring venetoclax treatment duration and considering genetic and molecular profiles to optimize therapeutic efficacy in newly diagnosed AML patients.