Luspatercept in Myelodysplastic Syndrome: A Review of Efficacy and Safety Data

INTRODUCTION. Transfusion-dependent anemia in myelodysplastic syndrome (MDS) is associated with severe complications and reduced survival, with up to 70% of patients being refractory to standard therapy with erythropoiesis-stimulating agents (ESAs). The approval of luspatercept, an inhibitor of the TGF-β signaling pathway, has introduced a novel approach to the pathogenesis-based treatment of anemia; however, accumulating real-world data necessitate a critical evaluation of the drug’s specific delayed risks and refinement of patient stratification algorithms.
AIM. To analyze clinical and postmarketing data on the efficacy, safety, and risks of luspatercept in MDS to refine clinical approaches to therapy and the safety profile of luspatercept.
DISCUSSION. Analysis of data from randomized controlled trials (MEDALIST, COMMANDS) and real-world clinical practice confirms a significant reduction in transfusion dependence and improvement in hemoglobin response
during luspatercept therapy in patients with lower-risk MDS, particularly in the presence of ring sideroblasts, SF3B1 mutations, and an erythropoietin level <500 mIU/mL. At the same time, ESAs remain the first-line agents
in patients without ring sideroblasts, and the routine use of luspatercept as initial therapy for all patients is premature due to insufficient data on long-term clinical benefits. The drug’s safety profile necessitates continuous
monitoring of adverse events: in addition to frequent complications (fatigue, arterial hypertension, and bone pain), special attention should be paid to the risks of nephrotoxicity, delayed remodeling of bone, cartilage, and muscle tissues, as well as the theoretical oncological risk arising from the dual role of the TGF-β signaling pathway in carcinogenesis. A promising direction for overcoming resistance to and incomplete response to monotherapy
is the combination of luspatercept with epoetin alfa, which enhances hematologic response.
CONCLUSIONS. Luspatercept is an effective and pathogenetically substantiated therapeutic option for anemia in patients with myelodysplastic syndrome with ring sideroblasts. However, its use requires strict patient stratification based on molecular genetic biomarkers (the presence of ring sideroblasts, SF3B1 mutations) and endogenous erythropoietin levels. The development of monitoring algorithms for luspatercept-specific adverse events (nephrotoxicity, changes in bone and cartilage tissue) and the justification of combination therapy strategies with ESAs will enhance the hematologic response and control the delayed risks of pharmacotherapy within the rational drug use.

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