Achieving transfusion independence with first-line luspatercept in a patient with LR-MDS–associated anaemia

Presentation and investigations
An 84-year-old man presented with a 2-year history of chronic anae­mia (haemoglobin [Hb], 10–11 g/dL) in December 2024. His anaemia progres­sively worsened, with Hb dropping to a nadir of 7.5 g/dL. He reported sta­ble angina and reduced exercise tol­erance, with an ability to walk only on level ground and inability to climb stairs. His medical history included ischaemic heart disease, hypertension, hypothy­roidism, and mild cytopenia.

Bone marrow examination con­firmed myelodysplastic syndrome (MDS). Molecular testing with next-gen­eration sequencing identified DNMT3A and EZH2 mutations, but he had no ring sideroblasts and was SF3B1-negative. His serum erythropoietin (EPO) was at 169 mU/mL. Revised International Prognostic Scoring System (IPSS-R) score was 1, indicating lower-risk (LR)–MDS.

In view of his pre-existing ischaemic heart disease, the Hb target for the pa­tient was set higher (>9 g/dL) and the transfusion threshold was lowered per our centre’s protocol. He received one unit of red blood cells (RBC) transfusion monthly to maintain Hb level and pre­vent exacerbation of myocardial isch­aemia. (Table)

Treatment and response
To avoid transfusion-related compli­cations (eg, iron overload), the patient chose first-line treatment with luspater­cept at a dose of 1.0 mg/kg Q3W in May 2025 after discussing the effica­cy and injection frequency of available treatment options. The dose was later uptitrated to 1.33 mg/kg.¹

The patient’s Hb level rose from 8.5 g/dL before luspatercept to 8.8 g/dL after the first dose and 9.9 g/ dL after the second dose, and further increased to 11.3 g/dL after the fifth dose. Notably, after the second dose, he achieved transfusion independence, with improvements in white blood cell and neutrophil counts. (Table)

The patient tolerated luspatercept well without experiencing any adverse events, and his blood pressure (BP) re­mained well controlled.

At the latest follow-up in Octo­ber 2025, he remained transfusion-independent with a Hb level of 11.3 g/ dL. He became angina-free and is able to climb three flights of stairs. (Table)

Discussion
Chronic anaemia is common in pa­tients with MDS, often requiring RBC transfusions.² Repeated transfusions require frequent hospital visits and can lead to iron overload.³

In transfusion‑dependent MDS, iron overload is associated with increased cardiac damage and worse survival.^2,4 In older patients with MDS and comor­bid cardiac disease, as in our case, the detrimental effects of iron overload are more pronounced and contribute sig­nificantly to mortality. RBC transfusion should be avoided whenever possible in these patients. Therefore, early inter­vention is needed to reduce the need for transfusions and subsequent risk of iron overload.

Following the success of the phase III MEDALIST trial in the second-line setting, the phase III, open-label, ran­domized, controlled COMMANDS trial compared the efficacy and safe­ty of luspatercept vs epoetin alfa (an erythropoiesis-stimulating agent [ESA]) as first-line treatment in 363 transfusion-dependent LR-MDS pa­tients, regardless of ring sideroblast status.^2,5

COMMANDS met its primary end­point. A greater proportion of patients treated with luspatercept achieved trans­fusion independence lasting ≥12 weeks with a concurrent mean Hb increase of ≥1.5 g/dL in weeks 1–24 vs epoetin alfa (60 vs 35 percent; risk difference, 25.4 percent; 95 percent confidence inter­val [CI], 15.8–35.0; p<0.0001) in the intention-to-treat population.²

Patients with high transfusion de­pendence and high serum EPO lev­els typically respond poorly to ESAs. However, subgroup analysis of COM­MANDS showed higher primary end­point response rates with luspatercept vs epoetin alfa across subgroups, regardless of baseline transfusion burden (<4 units per 8 weeks, 73 vs 56 percent; ≥4 units per 8 weeks, 47 vs 20 percent), serum EPO level (≤200 U/L, 71 vs 51 percent; >200 to <500 U/L, 35 vs 8 percent), SF3B1 mutation (present, 73 vs 42 percent; absent, 49 vs 40 percent), and ring sideroblast status (positive, 68 vs 39 percent; negative, 53 vs 50 percent).² Our patient with a high serum EPO lev­el (ie, a typical poor responder to ESAs) achieved and maintained transfusion independence after the second dose of luspatercept. (Table)