azacitidine + luspatercept

**Azacitidine + luspatercept** is a combination therapy under investigation for higher-risk myelodysplastic syndromes (HR-MDS). Azacitidine is a cytidine nucleoside analog that incorporates into DNA and RNA, inhibiting DNA methyltransferases to induce hypomethylation and promote differentiation, apoptosis, and gene re-expression in malignant cells. Luspatercept is a recombinant fusion protein consisting of the extracellular domain of activin receptor type IIA fused to human IgG1 Fc, acting as a ligand trap to inhibit TGF-β superfamily signaling (SMAD2/3 pathway), thereby enhancing late-stage erythropoiesis and reducing ineffective hematopoiesis. Developed through clinical trials combining these agents, the regimen aims to improve outcomes in HR-MDS beyond azacitidine monotherapy, with azacitidine typically dosed at 75 mg/m² subcutaneously daily for 5 days every 28 days and luspatercept added for anemia management.