Adding venetoclax to hypomethylating agents (HMAs) significantly improved response rates in participants with higher-risk myelodysplastic syndrome (MDS) in a retrospective analysis.
HMAs are the current standard-of-care treatment for patients with higher-risk MDS; however, response rates are low. Phase 1 data showed promising results when venetoclax combined with HMA was used to treat higher-risk MDS (NCT04160052).1 The response criteria for MDS have recently been updated for improved reflection of patient-centred and clinically relevant outcomes in higher-risk MDS.2 The study presented by Mihir Shukla, MD, New York University Grossman School of Medicine, New York, retrospectively assessed treatment outcomes for HMA plus venetoclax compared with HMA alone in participants (n=188, 2018–2023) with higher-risk MDS using the updated International Working Group 2023 response criteria.3
Participants in the combination therapy group presented with more aggressive disease, including higher proportions of TP53 mutations (30% vs 12%) and elevated Revised International Prognostic Scoring System (IPSS-R) risk scores (77% vs 45%), than those who received HMA only. Despite this, the combination group achieved significantly higher overall response rates (61% vs 33%) with notable improvements in complete response rates (49% vs 18%).
Among patients with IPSS-R scores higher than 5, event-free survival was nearly twice that of the HMA plus venetoclax group (27 months vs 14 months). Although overall survival showed a favorable trend (35 vs 26 months; an HMA alone vs combined therapy), the difference did not reach statistical significance, possibly due to the study’s limited sample size and short follow-up period. Notably, 38% of the HMA plus venetoclax group proceeded to allogeneic stem cell transplantation compared with 1.6% in the HMA-only cohort.
This study demonstrates the potential of HMA plus venetoclax combination therapy to achieve higher response rates and improve event-free survival in patients with higher-risk MDS, particularly those with high-risk disease features. The findings align with preliminary efficacy data from the earlier phase 1 trial, despite the limitation of the retrospective design and small cohort. Further studies are needed to confirm the combination’s clinical utility.
REFERENCES
- Bazinet A, Darcaniyan F, JabbourE, et al. Azacitidine plus venetoclax in patients with high-risk myelodysplastic syndromes or chronic myelomonocytic leukaemia: phase 1 results of a single-centre, dose-escalation, dose-expansion, phase 1–2 study. Lancet Haematol. 2022;9(10):e756–e765. doi: 10.1016/S2352-3026(22)00216-2
- Zeidan AM, Platzbecker U, Bewersdorf J, et al. Consensus proposal for revised International Working Group 2023 response criteria for higher-risk myelodysplastic syndromes. Blood. 2023;141(17):2047–2061. doi: 10.1182/blood.2022018604
- Shukla M, Okpara C, Xiang E, et al. A retrospective cohort study evaluating outcomes of higher risk MDS treated with hypomethylating agents with or without venetoclax using International Working Group 2023 response criteria. Abstract #4602. Presented at the American Society of Hematology Annual Meeting; December 7-10, 2024; San Diego, California.