Dr Iyer on the Design of the COMMANDS Trial in Lower-Risk MDS With Anemia

Sunil Iyer, MD, assistant professor, medicine, Columbia University Irving Medical Center, Herbert Irving Pavilion, discusses the mechanism of action of luspatercept-aamt (Reblozyl), highlighting the design of the phase 3 COMMANDS trial (NCT03682536) in patients with lower-risk myelodysplastic syndrome (MDS) with anemia.

Luspatercept operates through a unique mechanism of action to address disease-related anemia in lower-risk MDS, Iyer begins. Traditionally, erythropoiesis-stimulating agents (ESAs) were the standard medication class used in this patient population, Iyer says. In MDS, cytopenia and ineffective erythropoiesis occur due to signaling from the TGFβ cytokine family, he says. Ligands such as activin and myostatin bind to the activin receptor on the surface of red blood cells (RBCs), leading to impaired erythropoiesis, Iyer explains, adding that this impairment results in immature RBCs that struggle to mature properly.

Luspatercept functions by resembling the extracellular domain of the activin receptor and then binding to TGFβ ligands, preventing them from engaging with the receptor, Iyer elucidates. This interference reduces signaling, facilitating RBC maturation and addressing anemia associated with MDS. The COMMANDS trial focused on evaluating luspatercept compared with ESAs in patients with lower-risk MDS and anemia requiring RBC transfusions, particularly those who had not previously received ESAs, he continues. Notably, this study design differed from previous trials that typically included patients who had already been treated with ESAs and were refractory to them, Iyer shares.

Luspatercept previously received FDA approval for patients with low-risk MDS with ring sideroblasts with or without the presence of an SF3B1 mutation who had progressed on ESA therapy, he expands. The unique aspect of the COMMANDS study was its examination of the efficacy and safety of luspatercept as a frontline treatment compared with ESAs in a broader patient cohort. This trial sought to provide valuable insights into the role of luspatercept in the initial management of anemia in lower-risk MDS, potentially impacting treatment strategies for this patient population, Iyer concludes.