Luspatercept shows real-world promise for lower-risk MDS anemia in 26-patient study

Myelodysplastic syndromes, a group of clonal disorders of the blood-forming stem cells, leave patients short of working red cells even when their bone marrow appears crowded with immature precursors. A retrospective single-center study from the hematology department of the Archet I hospital at Nice University Hospital now offers a snapshot of how luspatercept, an erythroid maturation agent, performed in routine practice among 26 adults treated between July 5, 2021 and July 3, 2024.

The study, published in Blood Research, examined patients with low- or intermediate-risk disease as defined by the Revised International Prognostic Scoring System, excluding those in the high or very high categories and anyone whose medical records were incomplete. Most participants had received luspatercept as a second-line therapy after erythropoiesis-stimulating agents had failed. The investigators collected data retrospectively from the ORBIS and CLINICOM electronic record systems, entered the variables into a standardized Microsoft Excel database, and analyzed them with SPSS software, comparing categorical variables with chi-square and Fisher exact tests and treating a p value below 0.05 as significant.

The cohort was elderly, with a median age of 74 years and a male-to-female sex ratio of 0.85. Roughly 80.77 percent of the group fell into the low-risk stratum of the IPSS-R. Baseline transfusion burden was categorized as low, moderate or high, corresponding to fewer than one, one to two, or more than two red cell units per month.

Dosing reflected the realities of clinical practice rather than a fixed protocol. Luspatercept was administered subcutaneously every three weeks. Ten patients, or 38.46 percent, began at the maximum dose of 1.75 mg/kg, while the remaining sixteen started at the standard 1 mg/kg. Of those sixteen, four continued without modification, whereas twelve required gradual escalation, six reaching 1.75 mg/kg and six stabilizing at an intermediate dose of 1.33 mg/kg. The authors note that the considerable proportion starting at 1.75 mg/kg from the first cycle reflected real-world practice driven by disease severity and high transfusion burden, with the aim of achieving a faster response in selected patients.

The headline result concerns efficacy. According to the updated 2023 International Working Group response criteria, 53.84 percent of the 26 patients achieved a complete erythroid response, while 30.77 percent had no response and 15.39 percent had no usable clinical documentation. The mean duration of response was 53.82 weeks, spanning a range of 2 to 152 weeks.

Subgroup analyses, which the authors explicitly label exploratory because of the limited sample size and statistical power, yielded intriguing but statistically inconclusive signals. Among the fifteen patients with ring sideroblasts, half achieved a complete response, yet the comparison with patients without ring sideroblasts showed no significant difference, with a chi-square value of 0.04 and a p value of 0.84 and an odds ratio of 1.17. Among the ten patients carrying the SF3B1 mutation, 70 percent achieved a complete response compared with 43.75 percent of the sixteen patients without the mutation, but this difference also failed to reach significance, with a chi-square value of 1.39, a p value of 0.24 and an odds ratio of 3. The two treatment-naive patients both responded completely, while ten of the eighteen second-line patients after ESA failure did so, a difference that likewise was not significant with a p value of 0.45.

Safety data were reassuring in outline but demand careful reading. Adverse events were reported in 34.62 percent of patients, nine of twenty-six, mostly grade 1 and manageable, with no treatment discontinuations or dose reductions observed. Just over half the cohort, 53.85 percent, experienced no adverse events at all, while for the remaining 11.53 percent, three patients, clinical documentation was insufficient to assess tolerance. The most frequently reported events were asthenia in 26.92 percent of patients and nervous system disorders in 11.53 percent. The authors caution that the retrospective design and possible under-reporting of adverse events mean the safety profile should be interpreted with caution.

To understand why these real-world numbers matter, it helps to trace the drug’s clinical development. Luspatercept is a recombinant fusion protein that binds endogenous ligands such as GDF-11 and activin B, members of the transforming growth factor-beta superfamily. By inhibiting the Smad2/3 signaling pathway, it facilitates terminal maturation of erythroid precursors, the normoblasts, in the bone marrow. Phase II data from the PACE-MDS trial in 2017 first demonstrated dose-dependent hematologic improvement. The pivotal MEDALIST trial in 2020 then showed superiority over placebo in lower-risk MDS with ring sideroblasts, with response rates of 38 percent versus 13 percent and a p value below 0.001.

The COMMANDS trial extended the evidence base further. On the strength of these results, the US Food and Drug Administration approved luspatercept, marketed as Reblozyl, in August 2023 for the treatment of anemia in patients with lower-risk MDS who may require red cell transfusions and have not previously received ESAs. The recommended initial dose is 1.0 mg/kg subcutaneously every three weeks, and the drug is also indicated for transfusion-associated anemia in beta-thalassemia.

Set against this backdrop, the Nice findings carry both weight and caveats. The authors conclude that luspatercept appears to be an effective treatment option in real-world practice, with erythroid efficacy broadly consistent with the pivotal trials and an acceptable safety profile, while stressing that the results should be interpreted with caution owing to the retrospective design, potential under-reporting of adverse events and incomplete data. The main limitation was the relatively short follow-up for a subset of patients, which prevented robust assessment of long-term outcomes such as overall survival and progression-free survival. Transfusion independence at the standardized eight- and twelve-week time points could not be systematically evaluated because transfusion records were incomplete or non-standardized, limiting direct comparison with MEDALIST and COMMANDS. The absence of baseline erythropoietin values and incomplete clinical documentation in some patients may also have affected the efficacy assessment.

Subject of Research: Real-world efficacy and safety of luspatercept for anemia in lower-risk myelodysplastic syndromes

Article Title: Interest of luspatercept in treatment of anemia in lower-risk of myelodysplastic syndrome anemia: a single center study of 26 patients

Article References: Elalaoui, A., Girault, C., & Cluzeau, T. (2026). Interest of luspatercept in treatment of anemia in lower-risk of myelodysplastic syndrome anemia: a single center study of 26 patients. Blood Research, 61(1), Article 62. https://doi.org/10.1007/s44313-026-00170-1

Image Credits: AI Generated

DOI: 10.1007/s44313-026-00170-1

Keywords: luspatercept, myelodysplastic syndromes, anemia, lower-risk MDS, erythroid response, SF3B1 mutation, ring sideroblasts, IWG 2023 criteria, COMMANDS trial, MEDALIST trial, retrospective study, drug safety