EHA 2025 | Interim efficacy analysis of azacitidine and venetoclax in previously untreated and HMA-failure MDS

Yes, thank you very much for having me. So I’m excited to present this study. Hypomethylating agents have been the cornerstone of therapy for higher-risk myelodysplastic syndrome, and there has been considerable interest in recent years looking at combination strategies to improve patient outcomes. The BCL2 inhibitor venetoclax improves response and survival in acute myeloid leukemia in combination with azacitidine compared to azacitidine alone. So we were very interested to investigate the safety and efficacy of azacitidine venetoclax in higher-risk MDS. We conducted a Phase I/II study here at MD Anderson in patients with IPSS intermediate 2 or high-risk MDS. We enrolled patients with MDS-CMML and MDS-MPN. Patients were eligible for a study if their bone marrow blasts were 5% or greater. The Phase I portion used a 3 plus 3 design to identify the Phase II dose of venetoclax at 400 milligrams daily for 14 days with azacitidine for 5 days. The Phase II portion had 2 cohorts, a first-line cohort and a hypomethylating agent failure cohort or HMA failure cohort. The primary objective was to estimate the overall response rate using the IWG 2023 criteria to reflect the more contemporary perspective. So we enrolled 50 patients, 42 were treated first line, and eight had HMA failure. Patients generally were older adults with significant comorbidities. The median age was 69 years. Most patients had very high risk disease, and TP53 mutations were among the most common mutations in the first line and HMA failure cohorts. So overall, this was a fairly high risk, older population. And despite this, we observed a very high overall response rate of 98% in the first line cohort. The composite complete remission rate was 83%, and the remaining 15% had marrow CR as the best response. The overall survival was 16.1 months, and the event-free survival was 9.6 months. Patients with DDX41 mutations had very encouraging outcomes. The response rate was 100%, and the overall survival was not reached. In the HMA failure cohort, 7 out of 8 patients responded for an overall response rate of 88%, and a composite complete remission rate of 63%, with the remaining 25% having marrow CRs. The median overall survival was 12.2 months, and the event-free survival was 4.3 months. So overall, despite having an older population with very high-risk disease, with a high prevalence and burden of TP53 mutations, the combination of azacitidine venetoclax produced high response rates and encouraging overall survival in patients with previously untreated and HMA-failure MDS. Despite the recent announcement that the Verona study was negative, which was a phase three trial that compared azacitidine venetoclax to azacitidine and placebo in newly diagnosed higher risk MDS, there likely are subsets of patients, such as those with DDX41 mutations, who do benefit from the addition of venetoclax.

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