Dr Komrokji on the Expanded Indication for Luspatercept in Lower-Risk MDS

“The FDA expanded the label for luspatercept, not just based on the MEDALIST [trial] for post-ESA [progression], but now as upfront [therapy for anemia in patients with lower-risk MDS].”

Rami Komrokji, MD, vice chair of the Malignant Hematology Department and a senior member of the Malignant Hematology and Experimental Therapeutics Program at the Moffitt Cancer Center; as well as a professor in medicine & oncologic sciences in the College of Medicine at the University of South Florida, discussed the evolution of research supporting the FDA approval of luspatercept-aamt (Reblozyl) for the treatment of anemia in patients with lower-risk myelodysplastic syndromes (MDS).

Luspatercept is a recombinant fusion protein that acts as a ligand trap targeting TGF-β ligands, Zeidan began. Its initial FDA approval for the treatment of anemia in patients with MDS with ring sideroblasts (RS) was based on data from the phase 3 MEDALIST trial (NCT02631070), which enrolled patients with lower-risk RS-positive MDS harboring SF3B1 mutations who were transfusion dependent and had progressed on prior erythropoiesis-stimulating agent (ESA) therapy. In this study, patients were randomly assigned to receive either luspatercept or placebo, and the trial demonstrated a transfusion independence rate of 38% for at least 8 weeks in the luspatercept arm.

Building on the findings from MEDALIST, the phase 3 COMMANDS trial (NCT03682536) evaluated luspatercept in the frontline setting compared with ESAs in patients with lower-risk, transfusion-dependent MDS, regardless of RS status, Komrokji explained. The primary end point was transfusion independence for at least 12 consecutive weeks combined with a hemoglobin level increase of at least 1.5 g/dL, he noted, adding that this end point was more rigorous than that of previous studies. The study population included both RS-positive and RS-negative patients; however, it was enriched for those with RS-positive disease, he stated.

In COMMANDS, luspatercept demonstrated superior efficacy compared with ESAs, particularly in the RS-positive subgroup, according to Komrokji. Notably, the findings suggested comparable, if not more durable, responses with luspatercept in patients with RS-positive disease vs those with RS-negative disease, he reported.

These findings led to an expanded FDA indication for luspatercept, allowing its use in patients with ESA-naive, lower-risk MDS. Furthermore, updated National Comprehensive Cancer Network guidelines now list luspatercept as the preferred first-line therapy for RS-positive MDS, although they also recognize it as a valid option for RS-negative patients, Komrokji concluded.