The double edge of erythropoietic modulation in thalassaemia.

Luspatercept has emerged as a valuable therapeutic option for patients with transfusion-dependent β-thalassaemia, enabling significant reduction in transfusion requirements. In the report by Zaidel et al., a paradoxical clinical scenario is described in which treatment with luspatercept was associated with progressive splenomegaly, thrombocytopenia, increased haemolysis and a marked rise in reticulocytes and nucleated red blood cells, promptly reversible upon drug discontinuation. Luspatercept usually enhances late-stage erythroid maturation, but, in rare cases like this, seems to trigger or exacerbate extramedullary haematopoiesis (EMH) and/or splenic sequestration. The report underscores the importance of close monitoring and a deeper understanding of individual susceptibility to optimize the safe use of luspatercept in thalassaemia. Further studies are needed to clarify the underlying mechanisms and to identify patients at risk for EMH-related complications during luspatercept treatment. Commentary on: Zaidel et al. Acute splenomegaly, haemolysis, and thrombocytopenia following luspatercept initiation in a patient with transfusion-dependent thalassaemia: A case report. Br J Haematol 2025; 206:1806-1810.