Efficacy of Luspatercept in 1st Line Treatment of Anemia Due to Low-Risk Myelodysplastic Syndrome

Low-Risk MDS

MDS is a heterogeneous group of disorders of hematopoietic cells leading to inadequate hematopoiesis and cytopenias (primarily anemia) with a risk of progression to acute myeloid leukemia (AML). The aim of therapy in patients with low-risk MDS, which includes very low, low, and intermediate-risk according to the revised International Prognostic Scoring System (IPSS-R) from 2012, is to address anemia and improve quality of life. Treatment of anemia due to low-risk MDS often requires red blood cell transfusions, which are associated with increased morbidity, iron overload, and shorter overall survival. The standard treatment is the administration of ESA, such as epoetin alfa, although the therapeutic response is often uncertain and transient.

Indications for Luspatercept

Luspatercept is indicated in adults for the treatment of transfusion-dependent anemia due to very low, low, and intermediate-risk MDS. In the MEDALIST study, it reduced the severity of anemia with ring sideroblasts in patients with low-risk MDS who were transfusion-dependent and had shown refractoriness to ESA or had discontinued ESA due to adverse effects. The COMMANDS study is the first to evaluate the efficacy and safety of luspatercept compared to ESA in previously untreated patients with low-risk MDS.

Study Methodology and Course

The randomized controlled open-label COMMANDS study is ongoing at 142 centers in 26 countries. Adults with low-risk MDS who were untreated with ESA and required 2–6 units of red blood cell transfusions over 8 weeks for at least 8 weeks prior to randomization were included. Randomization was 1:1 to luspatercept or epoetin alfa and patients were stratified according to transfusion needs (</≥ 4 units/8 weeks), serum endogenous erythropoietin concentration (≤ 200/> 200 to < 500 U/L), and presence of ring sideroblasts. Luspatercept was administered subcutaneously every 3 weeks at an initial dose of 1 mg/kg, with possible titration up to 1.75 mg/kg. Epoetin alfa was administered subcutaneously once a week at an initial dose of 450 IU/kg, with possible titration up to 1050 IU/kg (maximum dose 80,000 IU).

The primary endpoint is red blood cell transfusion independence lasting at least 12 weeks with a concurrent average hemoglobin increase of at least 15 g/L (during the first 24 weeks). Safety is assessed in patients who received at least one dose of the study treatment.

Results

The COMMANDS study is ongoing. It randomized 356 patients with a median age of 74 years, of whom 56% were men. Results of a pre-specified interim analysis of 301 patients (147 with luspatercept and 154 with epoetin alfa) who completed 24 weeks of treatment or discontinued therapy have been published.

The primary endpoint was achieved in 59% of patients with luspatercept compared to 31% with epoetin alfa, a statistically significant difference (p < 0.0001). The median duration of treatment exposure was also longer in the luspatercept group (42 vs. 27 weeks).

The most common grade 3/4 adverse events (and affecting ≥ 3% of patients) with luspatercept were hypertension, anemia, dyspnea, neutropenia, thrombocytopenia, pneumonia, COVID-19, and syncope; and with epoetin alfa were anemia, pneumonia, neutropenia, hypertension, iron overload, and COVID pneumonia. The most common adverse events that were likely related to luspatercept treatment (none of which occurred with epoetin alfa in ≥ 3% of patients) included fatigue, asthenia, nausea, dyspnea, hypertension, and headache. One death occurred following AML diagnosis 44 days after starting luspatercept therapy, which was considered related to the treatment.

Conclusion

Results of this interim analysis of the COMMANDS study could alter the current approach to treating low-risk MDS. Luspatercept treatment in previously untreated patients was associated with a clinically and statistically significant reduction in transfusion dependency and longer maintenance of this independence compared to epoetin alfa. Therefore, luspatercept may benefit patients at earlier stages of MDS than it is currently administered and may reduce the number of transfusion-dependent patients and associated morbidity. Long-term evaluations, subgroup analyses (e.g., patients without SF3B1 mutation or without ring sideroblasts), and assessments of quality of life and pharmacoeconomics are needed for the future.

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Source: Platzbecker U., Della Porta M. G., Santini V. et al. Efficacy and safety of luspatercept versus epoetin alfa in erythropoiesis-stimulating agent-naive, transfusion-dependent, lower-risk myelodysplastic syndromes (COMMANDS): interim analysis of a phase 3, open-label, randomised controlled trial. Lancet 2023; 402 (10399): 373−385, doi: 10.1016/S0140-6736(23)00874-7.

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2007-CZ-2400011