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Luspatercept Demonstrates Superior Efficacy in Frontline Treatment of Lower-Risk MDS

• Luspatercept gains FDA approval as a frontline treatment for anemia in lower-risk myelodysplastic syndrome (MDS) patients without prior erythropoiesis-stimulating agent (ESA) use. • The COMMANDS trial demonstrated that luspatercept achieved higher rates of red blood cell transfusion independence and hemoglobin increase compared to epoetin alfa. • In MDS patients with ring sideroblasts and SF3B1 mutations, luspatercept is emerging as the most effective frontline therapy, showing high overall response rates. • While luspatercept's use in non-ring sideroblast cases remains debated, it has revolutionized treatment for frontline MDS patients with SF3B1 mutations.

Luspatercept-aamt (Reblozyl) has received FDA approval for the treatment of anemia in patients with very low- to intermediate-risk myelodysplastic syndrome (MDS) who have not previously been treated with erythropoiesis-stimulating agents (ESAs) and may require regular red blood cell (RBC) transfusions. This approval marks a significant advancement in the treatment landscape for lower-risk MDS.
The approval was based on interim findings from the phase 3 COMMANDS trial (NCT03682536), which compared luspatercept to epoetin alfa. The results demonstrated that luspatercept led to superior rates of concurrent RBC transfusion independence (RBC-TI) and hemoglobin (Hb) increase, regardless of ring sideroblast status. Specifically, 58.5% of patients treated with luspatercept achieved the primary endpoint of RBC-TI for at least 12 weeks with a mean Hb increase of at least 1.5 g/dL within the first 24 weeks, compared to 31.2% of those given epoetin alfa (P < .0001).

Luspatercept's Impact on MDS with Ring Sideroblasts

According to Dr. David Sallman, luspatercept is the most effective frontline therapy for MDS patients with ring sideroblasts. The COMMANDS trial showed high overall response rates with luspatercept, particularly in transfusion-dependent patients. Dr. Sallman emphasizes the importance of performing a bone marrow biopsy and molecular testing for the SF3B1 mutation to ensure accurate diagnosis, as ring sideroblasts may be missed during staining.

Considerations for Non-Ring Sideroblast Cases

The use of luspatercept in non-ring sideroblast cases is more controversial. While outcomes with luspatercept were not inferior to epoetin alfa in these patients, the superiority was not as pronounced. Erythropoietin levels are a key consideration, as patients with levels greater than 200 U/L tend to respond less well to ESAs. This strengthens the argument for using luspatercept in this subgroup. Despite differing opinions on the universal application of luspatercept in MDS, it has undeniably transformed the treatment of frontline patients with MDS harboring SF3B1 mutations, with most achieving a favorable response.
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Reference News

[1]
Dr Sallman on the Significance of the FDA Approval of Luspatercept for Lower-Risk MDS
onclive.com · Oct 15, 2024

David Sallman, MD, discusses the 2023 FDA approval of luspatercept-aamt (Reblozyl) for anemia in very low– to intermedia...

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