Extended Vs Standard Hypomethylating Agent Dosing in Combination with Venetoclax in Newly Diagnosed Acute Myeloid Leukemia

Background: The combination of a hypomethylating agent (HMA) and venetoclax (Ven) is considered first-line treatment in older/unfit patients with newly diagnosed AML (ND-AML). Standard of care HMA dosing (SOC) is azacitidine 75 mg/m² for 7 days (Aza-7) or decitabine 20 mg/m² for 5 days (Dec-5). Controversy remains on whether an extended duration of HMA (decitabine 20 mg/m² for 10 days) improves outcomes versus SOC dosing in combination with venetoclax. In a phase 2 trial, DiNardo et al evaluated a 10-day course of decitabine in combination with venetoclax (Dec-10/Ven) in older/unfit patients with ND-AML. With a median follow-up of 16 months, the overall response rate was 89% and the median overall survival (OS) was 18.1 months. Perez et al retrospectively compared Dec-10/Ven and Dec-5/Ven regimens in a single institution study. With a median follow-up of 12 months, they found no difference in rates of complete remission (CR)/complete remission with incomplete count recovery (CRi) (72% vs 69% in Dec-10/Ven and Dec-5/Ven, respectively) and a non-significant difference in median OS (26.6 months vs 13.5 months with Dec-10/Ven and Dec-5/Ven, respectively). We studied outcomes of SOC dosing and Dec-10/Ven across multiple institutions to further evaluate and compare the two regimens.

Methods: We retrospectively reviewed patients diagnosed with AML between June 2018 - June 2024 who received either an extended dosing regimen (Dec-10/Ven) or SOC dosing regimen (Aza-7/Ven or Dec-5/Ven) as front-line therapy. Three academic centers in the US participated. Prior HMA treatment was allowed if given for indications other than AML. Endpoints were CR/CRi, CR with negative measurable residual disease (MRD- CR), median OS, 30-day and 60-day mortality rates, infection and rehospitalization rates, number of cycles to response, and transplantation rate. Fisher's exact test and Pearson's Chi-squared test were used to compare the outcomes of the two cohorts and log-rank test was used to compare OS.

Results: A total of 142 patients were included in the study: 69 in the Dec-10/Ven cohort and 73 in the SOC cohort. Baseline characteristics were balanced between the Dec-10/Ven and SOC cohorts, including median age (71 years in both groups), the incidence of complex cytogenetics (29% vs 25%, p= 0.6), TP53 mutations (21% vs 23%, p= 0.7), secondary AML (32% vs 29%, p= 0.7), and risk groups based on the 2022 European LeukemiaNet (ELN) classification (with 63% poor risk in the Dec-10/Ven cohort vs 59% in the Dec-5/Ven).

With a median follow-up time of 25.5 months, there was no difference between Dec-10/Ven and SOC with regards to rates of CR/CRi (81% vs 74%, p= 0.3) or MRD-CR (30% vs 28%, p= 0.2). Similarly, when evaluating responses after the first induction cycle, we observed no difference in CR/CRi (61% vs 62%, p> 0.9), or MRD-CR (30% vs 43%, p=0.4). The median number of cycles to attain CR/CRi was not statistically different (2 cycles vs 1 cycle in Dec-10/Ven and Dec-5/Ven respectively, p= 0.7). The Dec-10/Ven cohort had a statistically significant improved median OS compared to SOC (21.4 months vs 12 months, p= 0.018). There were higher rates of 30-day and 60-day mortality in the SOC (8.2% vs 1.4%, p= 0.12, and 14 vs 4.3%, p=0.053). The Dec-10/Ven cohort had higher rates of documented infections (41% vs 21%, p= 0.009) and higher rates of rehospitalization (38% vs 18%, p= 0.008) during cycle 1. More patients in the Dec-10/Ven than the SOC cohort proceeded to allogeneic stem cell transplant (23% vs 8.2%, p=0.020).

Conclusion: Our study showed no difference in response rates in patients treated with either the SOC HMA duration or 10 days of decitabine in combination with venetoclax, which is congruous with findings from previous studies. Our study improved upon prior similar investigations of extended-versus-standard HMA + Ven dosing, by including multiple institutions and having a longer follow-up period. The significant improvement in OS with Dec-10/Ven vs SOC was unexpected given the similar rates of response and MRD- CR between the two groups. Possibilities for the difference in OS include a higher transplant rate in the Dec-10/Ven arm and an unexpectedly higher early mortality rate in the SOC cohort. Future analysis with an expanded number of patients and institutions will help to elaborate and clarify these findings.