Long-term Benefit of Luspatercept Therapy – Fresh Data from the MEDALIST Study
The goal of therapy for low-risk myelodysplastic syndrome (MDS) is to compensate for anemia, improve or maintain quality of life, and prolong the time to progression to higher-risk MDS (HR-MDS) or acute myeloid leukemia (AML). To manage anemia, we can resort to transfusion therapy or administer epoetins, lenalidomide, or luspatercept, the first representative of a class of drugs that support erythrocyte maturation. Last year's data from the follow-up of patients enrolled in the MEDALIST study pertain specifically to the latter.
Mechanism of Action of Luspatercept
Luspatercept is a recombinant fusion protein that binds to endogenous ligands, blocking the Smad2/3 signaling pathway, which slows down erythrocyte maturation and is pathologically active in diseases characterized by ineffective erythropoiesis. By doing so, luspatercept supports the normal maturation of erythroid cells in the bone marrow. In the context of MDS, it is used to treat adult patients with transfusion-dependent anemia due to very low, low, and intermediate-risk MDS with ring sideroblasts (MDS-RS), who are refractory to or intolerant of erythropoiesis-stimulating agents (ESA).
The MEDALIST Study and Subsequent Long-term Treatment
The double-blind, placebo-controlled phase III MEDALIST study included patients with very low, low, or intermediate-risk MDS-RS who showed refractoriness or intolerance to ESA or were unsuitable for this treatment and regularly received erythrocyte transfusions. They were randomized at a 2:1 ratio to the luspatercept group (1.0–1.75 mg/kg s.c. every 3 weeks) or the placebo group. The primary parameter was at least 8 weeks of transfusion independence during the first 24 weeks of treatment. After the study concluded, patients benefiting from luspatercept therapy were allowed to continue it during the long-term follow-up. Patients from the placebo group received supportive care during the follow-up.
Effect of Luspatercept on Transfusion Dependence
The follow-up analysis covers the period from November 2020 to January 2021 and includes data from 153 patients treated with luspatercept and 76 with placebo. The median follow-up time for patients on luspatercept was 40 months, compared to 38 months for placebo. During this period, 48.4% of patients on luspatercept achieved at least 8-week independence from transfusions compared to 15.8% with placebo. More than 16 weeks without the need for transfusions were achieved in 31.4% of patients with luspatercept and 7.9% with placebo. The cumulative duration of all periods during which the individual did not need a transfusion for at least 8 weeks, even if not continuous, was 80.7 weeks with luspatercept and 21.0 weeks with placebo.
Other results worth mentioning include that an average elevation in hemoglobin of > 15 g/l without transfusions was achieved in 41.8% of patients on luspatercept therapy compared to 3.9% with placebo.
Rate of Progression to HR-MDS and AML
Progression to high-risk MDS or acute myeloid leukemia was not high in either group: 5.9% of patients on luspatercept therapy progressed to HR-MDS and 2.6% to AML; in the placebo arm, 3.9% progressed to HR-MDS and another 3.9% to AML. The incidence of progression to HR-MDS per 100 patient-years adjusted for follow-up time was 2.22 with luspatercept, and 1.55 with placebo; for AML, it was 0.97 and 1.52, respectively.
Overall Survival
By the end of data collection, the median overall survival (OS) had not been reached in either study arm. Response to luspatercept therapy during the first 24 weeks of the MEDALIST study was associated with longer OS. Of 58 patients who achieved at least 8-week transfusion independence during luspatercept treatment in the primary study, 81% were alive at the end of extended follow-up (median OS not reached); of those who did not achieve this response in the primary study, 62.1% were alive (median OS 46.1 months). OS was longer in patients on luspatercept who achieved an increase in hemoglobin levels by at least 15 g/dl during the first 24 weeks of treatment.
Conclusion
Data from more than 3 years of follow-up of patients from the MEDALIST study show that long-term luspatercept treatment provides consistent clinical benefit with a predictable safety profile for patients with transfusion-dependent anemia due to lower-risk MDS-RS.
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Source: Platzbecker U., Santini V., Komrokji R. S. et al. Long-term utilization and benefit of luspatercept in transfusion-dependent, erythropoiesis-stimulating agent-refractory or -intolerant patients with lower-risk myelodysplastic syndromes with ring sideroblasts. Leukemia 2023 Nov; 37 (11): 2314−2318, doi: 10.1038/s41375-023-02031-7.
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2007-CZ-2400007
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