Patients with myelodysplastic syndromes (MDS) develop iron overload due to their underlying ineffective erythropoiesis and chronic transfusion therapy. The TGF-β superfamily ligands trap luspatercept, despite lacking disease-modifying activity, has become first-line treatment in low-risk MDS thanks to its ability to improve anemia by promoting EPO-independent maturation of late-stage erythroid cells. Here we investigated the effect of a therapy combining luspatercept with the FPN inhibitor vamifeport in the preclinical NUP98-HOXD13 MDS mouse model, with the hypothesis that drug combo could have additive benefits for the disease. 

Vamifeport administration, either as single or combined treatment with luspatercept, corrected iron overload in MDS mice, by reducing serum iron, NTBI, and tissue iron loading. While both single agents ameliorated erythroid maturation and hematologic parameters, the combined therapy resulted in a further improvement of anemia and more effective erythropoiesis, as suggested by higher hemoglobin, hematocrit and RBCs, and decreased early erythroid precursors compared to single-drug treatments, effect likely resulting from improved progenitor survival and iron utilization. The HSPC pool and DNA damage were significantly ameliorated by vamifeport as single or combined treatment. Importantly, vamifeport, but not luspatercept, significantly attenuated myeloid expansion and myeloblasts in the MDS bone marrow, suggesting disease-modifying activity for this drug and revealing a major role of the iron status in myeloid skewing. 

Overall, these data prove that combo therapies aimed at restricting iron and boosting erythroid maturation have superior effects in improving MDS pathophysiology, providing pre-clinical evidence for their application, and suggest they may offer more effective strategies for MDS treatment.