EHA 2025 | A Phase II trial of three-day decitabine, three-day azacitidine, or five-day azacitidine in LR-MDS

Yes, thank you very much. So, hypomethylating agents such as decitabine and azacitidine are the cornerstone of therapy in higher-risk myelodysplastic syndrome, but their efficacy and safety in lower-risk myelodysplastic syndrome is unclear. In the United States, five-day decitabine and seven-day azacitidine are the approved durations of hypomethylating agents. We previously published that three-day decitabine and three-day azacitidine are safe and effective in lower risk MDS, but the doses are not equivalent in those schedules, meaning that patients treated with three-day decitabine get 60% of the approved dose, while patients treated with three-day azacitidine get closer to 40% of the approved dose. Therefore, five-day azacitidine, which would be about 70% of the approved dose, may be a more appropriate comparison to three-day decitabine. So our goal was to determine the relative efficacy and optimal dosing schedule in a prospective trial of three-day decitabine, three-day azacitidine, and five-day azacitidine in lower-risk MDS. So we conducted a Bayesian randomized multi-center phase 2 study involving patients with lower-risk MDS treated at six centers. The protocol split patients into transfusion-dependent and transfusion-independent cohorts. Patients in either cohort could be randomized to any dosing schedule of the hypomethylating agents, and transfusion-independent patients could also be randomized to a best supportive care arm. So in other words, transfusion dependent patients could get three-day azacitidine, three-day decitabine, or five-day azacitidine. Transfusion independent patients could get three-day azacitidine, three-day decitabine, five-day azacitidine, or a best supportive care. Patients had to have IPSS low or intermediate at one risk disease. The primary endpoint was event-free survival, and our secondary endpoints were estimating overall response rate and overall survival. We randomized 247 patients, 241 of whom were treated. Most patients were older adults with a median age of 71 years. Baseline characteristics were well-balanced to cross-treatment arms. We did not observe any differences in overall response rates between any hypomethylating agent dosing schedule in transfusion-dependent or transfusion- independent patients. Transfusion independence was similar across all three dosing schedules, ranging from 40 to 44%. Among transfusion-dependent patients, there was no significant difference in event-free survival, but in a multivariate analysis, the overall survival of five-day azacitidine was better than three-day decitabine. Among transfusion-independent patients, five-day azacitidine had the best event-free survival. And in a multivariate analysis, the overall survival of five-day azacitidine was better than three-day decitabine and best supportive care. So taken together, shorter courses of hypomethylating agents appear safe and effective in lower risk MDS. And five-day azacitidine produces the most consistent event-free survival and overall survival benefit, which I don’t think is surprising because we are getting more of the drug. So the question we are wanting to know now is, how does this data compare to newer drugs for lower risk MDS, such as luspatercept and imetelstat, and how should we best sequence them. In addition, we’re also working on oral azacitidine, cesaridine here at MD Anderson, and this data will be tremendously helpful with determining the optimal duration for patients with lower-risk MDS. Thank you very much.

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