Luspatercept Increases Likelihood of Lasting Transfusion Independence in ESA-Naive, Lower-Risk MDS

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Luspatercept-aamt (Reblozyl) showed a durable improvement in the overall rate and cumulative duration of red blood cell transfusion independence (RBC-TI) for a period of at least 12 weeks vs epoetin alfa in patients with transfusion-dependent, erythropoiesis-stimulating agent (ESA)–naive, very low–, low-, or intermediate-risk myelodysplastic syndrome (MDS), according to data from the phase 3 COMMANDS trial (NCT03682536) that were presented at the 2025 ASCO Annual Meeting.1

The rate of RBC-TI for at least 12 weeks was 76.4% with luspatercept vs 55.8% with epoetin alfa (odds ratio [OR], 2.8; 95% CI, 1.7-4.5; P < .0001). The median duration of the longest 12-week or greater RBC-TI interval was 126.6 weeks (95% CI, 81.0-154.1) with luspatercept vs 86.7 weeks (95% CI, 55.9-105.9) with epoetin alfa (HR, 0.632; 95% CI, 0.434-0.919; P = .0156). The median cumulative duration of RBC-TI for at least weeks was 150.0 weeks (95% CI, 119.6-256.0) with luspatercept vs 95.1 weeks (95% CI, 74.9-180.1) with epoetin alfa (HR, 0.523; 95% CI, 0.353-0.777; P = .0011).

“These long-term results support luspatercept as the standard of care for anemia in first-line lower-risk MDS, providing prolonged responses and potential for extended survival,” Guillermo Garcia-Manero, MD, lead study author and chief of the Section of Myelodysplastic Syndromes and deputy chair of Translational Research in the Department of Leukemia at The University of Texas MD Anderson Cancer Center in Houston, said.

COMMANDS Background and Trial Design

Luspatercept is an erythroid maturation agent that improves erythropoiesis and in 2023, received an expanded FDA approval to include the treatment of anemia without prior ESA use in adult patients with very low– to intermediate-risk MDS who may require regular RBC transfusions.2

The expanded indication was based on data from the global, randomized, open-label COMMANDS trial, which enrolled patients at least 18 years of age with Revised International Prognostic Scoring System very low–, low-, or intermediate-risk MDS with or without ring sideroblasts (RS) by World Health Organization 2016 criteria, with less than 5% bone marrow blasts.1 Eligible patients were transfusion dependent and ESA naive, with an endogenous serum erythropoietin (EPO) level below 500 U/L.

Per the trial design patients were randomly assigned 1:1 to 1.0 mg/kg of subcutaneous luspatercept every 3 weeks, titrated up to 1.75 mg/kg (n = 182), or 450 IU/kg of subcutaneous epoetin alfa weekly, titrated up to 1050 IU/kg (n = 181). Treatment was continued until lack of clinical benefit or disease progression per International Working Group 2006 criteria.

The primary end point was RBC-TI for at least 12 weeks during the first 24 weeks of therapy with concurrent mean hemoglobin increase of at least 1.5 g/dL. Secondary end points included RBC-TI for at least 12 weeks during the first 24 weeks of therapy alone, duration of RBC-TI for 12 or more weeks, overall survival (OS), progression to acute myeloid leukemia (AML), and safety.

Taking Another Look With More Than Two Years of Follow-Up

Median follow-up was 30.6 months (range, 1-65) in the luspatercept arm and 28.8 months (range, 0-69) in the epoetin alfa arm. At data cutoff, the median duration of treatment was 71.5 (range, 3-276) and 44.0 weeks (range, 1-299) in the luspatercept and epoetin alfa arms, respectively. More than double the number of patients in the epoetin alfa arm were still on therapy in the luspatercept arm, at 10.1% vs 22.5%, respectively. Patients who received at least 1 dose escalation comprised the majority in the luspatercept (84.6%) and epoetin alfa (83.2%) arms.

The median OS was not reached in the luspatercept arm vs 46.0 months in the epoetin alfa arm (HR, 0.805; 95% CI, 0.565-1.146). Findings from the subgroup analysis indicated that luspatercept improved survival irrespective of baseline transfusion burden (<4 packed RBC U/8 weeks, HR, 0.830; 95% CI, 0.532-1.294; ≥4 packed RBC U/8 weeks, HR, 0.696; 95% CI, 0.395-1.227), RS status (RS positive, HR, 0.739; 95% CI, 0.484-1.130; RS negative, HR, 0.842; 95% CI, 0.454-1.561), and baseline serum EPO level (≤200 U/L, HR, 0.797; 95% CI, 0.530-1.197; >200 U/L, HR, 0.781; 95% CI, 0.396-1.540).

Treatment-emergent events of interest that occurred in at least 1 patient in the luspatercept (n = 182) and epoetin alfa (n = 179) arms, respectively, were asthenia (34.6%; 26.8%), hypertension (17.6%; 10.6%), malignancies (12.1%; 8.9%), fractures (11.0%; 12.8%), kidney toxicity (11.0%; 7.3%), premalignant disorders (7.1%; 7.8%), immunogenicity hypersensitivity-type reactions (5.5%; 1.7%), liver toxicity (3.8%; 3.4%), immunogenicity injection local-type reactions (2.7%; 0.6%), and extramedullary hematopoiesis masses (0.5%; 0%).

Progression to higher-risk MDS occurred in 2.2% of patients in the luspatercept arm vs 5.6% of patients in the epoetin alfa arm (HR, 0.388; 95% CI, 0.120-1.250; P = .1003). Progression to AML occurred in 4.9% and 4.4% of patients in the luspatercept and epoetin alfa arms, respectively (HR, 1.110; 95% CI, 0.420-2.932; P = .8326).

“Extended follow-up is ongoing; efforts to understand the impact of luspatercept TGF-β inhibition on survival are underway,” Garcia-Manero concluded.

Disclosures: No disclosures were listed for Garcia-Manero.

References

1. Garcia-Manero G, Giovanni Della Porta M, Zeidan A, et al. Overall survival (OS) and duration of response for transfusion independence (TI) in erythropoiesis stimulating agent (ESA)–naive patients (pts) with very low-, low-, or intermediate-risk myelodysplastic syndromes (MDS) treated with luspatercept (LUSPA) vs epoetin alfa (EA) in the COMMANDS trial. J Clin Oncol. 2025;43(suppl 16):6512. doi:10.1200/JCO.2025.43.16_suppl.6512
2. U.S. FDA approves Bristol Myers Squibb’s Reblozyl (luspatercept-aamt) as first-line treatment of anemia in adults with lower-risk myelodysplastic syndromes (MDS) who may require transfusions. News release. Bristol Myers Squibb. August 28, 2023. Accessed May 31, 2025. https://news.bms.com/news/details/2023/U.S.-FDA-Approves-Bristol-Myers-Squibbs-Reblozyl-luspatercept-aamt-as-First-Line-Treatment-of-Anemia-in-Adults-with-Lower-Risk-Myelodysplastic-Syndromes-MDS-Who-May-Require-Transfusions/default.aspx