Luspatercept safe, efficacious compared to ESAs for lower-risk myelodysplastic syndromes

A new study shows that Luspatercept was found to be safe and improved RBC transfusion independence and erythroid response, as well as the duration of response, compared to epoetin alfa in a clinically relevant and statistically significant way in the erythropoiesis-stimulating agent (ESA)‑naive transfusion-dependent (TD) patients with lower‑risk myelodysplastic syndromes (LR-MDS). The trial results were published in the journal American Society of Clinical Oncology. 

Lower-risk myelodysplastic syndromes (MDS) are characterized by the presence of dysplasia, low bone marrow blast percentage, low number and depth of cytopenia(s), and relatively good-risk karyotypic and molecular abnormalities. Erythropoiesis-stimulating agents (ESA) are usually used as first-line therapy in these patients. As most patients with LR-MDS have poor responses to ESAs, there is an unmet need to treat anemia and minimize TD. Hence researchers conducted an open-label, randomized phase 3 COMMANDS trial, which compared the effectiveness and safety of luspatercept vs epoetin alfa in ESA-naive patients with LR-MDS. 

Eligible patients who were ≥ 18 years old with IPSS-R-defined LR-MDS with or without RS, < 5% bone marrow blasts, sEPO levels < 500 U/L, required RBC transfusions (defined as 2–6 RBC units/8 weeks [wk] for ≥ 8 wk immediately before randomization), and were ESA naive were included in the study. Pts were randomly divided into 1:1 to receive subcutaneous Luspatercept at a starting dose of 1.0 mg/kg, titration up to 1.75 mg/kg) once every 3 wk or epoetin alfa (starting dose 450 IU/kg, titration up to 1050 IU/kg) weekly for ≥ 24 wk. The primary endpoint was the achievement of RBC transfusion independence (TI) ≥ 12 wk within the first 24 wk, with a mean hemoglobin increase ≥ 1.5 g/dL. Secondary endpoints included achievement of hematologic improvement-erythroid (HI-E) response ≥ 8 wk per IWG 2006 criteria, RBC-TI 24 wk and ≥ 12 wk, and safety. 

Results:

• About 178 pts received luspatercept and 176 epoetin alfa, with median treatment durations of 41.6 and 27.0 wk, respectively.
• The baseline characteristics of the patients were balanced between treatment groups. 
• The primary endpoint of RBC-TI 12 wk with concomitant mean Hb rise ≥1.5 g/dL during the first 24 wk was achieved by 86 (58.5%) pts receiving luspatercept versus 48 (31.2%) pts receiving epoetin alfa (P 0.0001) among 301 patients included in the efficacy analysis. 
• HI-E ≥ 8 wk was achieved by 109 (74.1%) luspatercept and 79 (51.3%) epoetin alfa pts (P< 0.0001).
• RBC-TI 24 wk and ≥12 wk were obtained by 70 (47.6%) and 98 (66.7%) luspatercept pts, respectively, vs 45 (29.2%) and 71 (46.1%) epoetin alfa pts, respectively, within the first 24 wk of therapy. (P = 0.0006 and 0.0002).
• About 164 (92.1%) luspatercept and 150 (85.2%) epoetin alfa pts reported treatment-emergent adverse events (TEAEs; any grade); 8 (4.5%) and 4 (2.3%) pts discontinued due to TEAEs.
• Treatment-related AEs were reported by 54 (30.3%) luspatercept and 31 (17.6%) epoetin alfa pts. AML progression was reported in 4 (2.2%) luspatercept and 5 (2.8%) epoetin alfa pts.
• About 32 [18.0%] patients from the luspatercept group and 32 [18.2%] epoetin alfa pts reported death and overall rates of death were comparable between arms during treatment and post-treatment. 

Thus, for the first time luspatercept which was found to be safe and showed clinically significant improvements proved to be superior over ESAs. 

Further reading: Garcia-Manero G, et al "Efficacy and safety results from the COMMANDS trial: A phase 3 study evaluating luspatercept vs epoetin alfa in the erythropoiesis-stimulating agent (ESA)-naive transfusion-dependent (TD) patients (pts) with lower-risk myelodysplastic syndromes (LR-MDS)" ASCO 2023; Abstract 7003.