Abstract
Luspatercept, an erythroid maturation agent, treats anemia in lower-risk myelodysplastic syndromes (MDS) by inhibiting SMAD2/3 signaling. However, its efficacy may be limited in immune-mediated erythroid suppression. We present two lower-risk MDS cases (per the Revised International Prognostic Scoring System) that developed red cell aplasia and poor response to luspatercept alone. Bone marrow showed near absence of erythroid precursors with multilineage dysplasia. Neither patient achieved hematologic improvement with luspatercept monotherapy. Cyclosporine A (Cy-A) was added, leading to hemoglobin improvement, transfusion independence, and marrow erythropoiesis recovery. These cases indicate red cell aplasia may reflect immune-mediated suppression, limiting luspatercept efficacy. The response to Cy-A highlights the potential role of immunosuppressive therapy. Combining luspatercept with Cy-A may offer a strategy for selected patients with lower-risk MDS and erythroid aplasia. Bone marrow reassessment should be considered in patients who fail to respond to luspatercept or who develop recurrent anemia after an initial response.