Luspatercept helps about half of transfusion-dependent lower-risk MDS patients become transfusion-free

Lower-risk myelodysplastic syndromes (LR-MDS) are bone marrow disorders in which anemia dominates the clinical picture. Many patients become dependent on red blood cell transfusions, which brings iron overload, a poorer quality of life, and shorter survival. Erythropoiesis-stimulating agents (ESAs) are the traditional first option, but most patients fail to respond or relapse. Luspatercept, a TGF-β superfamily ligand trap that promotes erythroid maturation, is approved in the US and Europe. Evidence has so far come from the MEDALIST and COMMANDS trials and a growing set of real-world reports, with no pooled synthesis.

The authors followed PRISMA and registered a PROSPERO protocol. They searched six databases through March 2025. They included trials, retrospective studies, and case series with more than 15 transfusion-dependent LR-MDS patients, and conference abstracts were allowed. Two reviewers screened studies and extracted data. Quality was rated with the Downs and Black checklist and Cochrane tools. Single-arm proportions were pooled with random-effects models, with subgroup analyses, meta-regression, and publication-bias testing. The primary endpoint was 8-week transfusion independence (TI).

Twenty studies (7 trials, 13 cohorts) with 3,455 patients were included. Pooled patients had a mean age of 73.6, 41.5% were female, about 90% had very low or low IPSS-R risk, 67% were RS+, and 76% had prior ESA exposure. The pooled 8-week TI rate was about 50% (reported as 50.2% in the results text and 51.2% in the abstract). Rates were significantly higher in RS+ than RS– studies (57.9% vs 43.0%). They were also higher in low-transfusion-burden than high-burden studies (72.9% vs 38.7%), although the low-burden estimate rests on only 45 patients. Twelve-week TI was 57.0%, and 24-week TI was 35.8%. ESA-naïve RS+ patients did best, with 70.2% at 8 weeks and 49.1% at 24 weeks. ESA-refractory RS– patients did worst, with 22.9% at 24 weeks. Studies with more than 90% prior ESA exposure had lower 12-week TI (43.1% vs 58%). Erythroid hematologic improvement occurred in 51.3% overall and 74.2% in ESA-naïve RS+ patients.

The most common adverse events were peripheral edema (17.8%), back pain (16.1%), diarrhea (15.6%), dizziness (12.3%), fatigue (11.4%), and headache (11.2%). Fatigue, dizziness, headache, and dyspnea were reported more often in clinical trials than in real-world studies. Serious adverse events were pooled at 28.0%, with no significant difference between trial and real-world settings. The authors conclude that luspatercept is effective and well tolerated, and that the data support frontline use, especially in ESA-naïve, RS+, low-burden patients.

Several caveats apply. Heterogeneity was very high (I² often above 80–90%), most data are single-arm and retrospective, and safety estimates rest on few studies. The lack of head-to-head comparisons also limits how far the results can guide treatment sequencing against other agents.