A Study of Iron Metabolism in a Cohort of Beta Thalassemia Patients treated with Luspatercept

Background Iron is an essential biological catalyst whose serum levels are regulated by hepcidin, hypoxia and inflammation. β-thalassemia is characterized by iron overload which is the result of two factors: regular blood transfusions and increased duodenal iron absorption as a consequence of ineffective erythropoiesis which stimulates erythroferrone production and thus hepcidin inhibition. Objective The objective of this observational cross-sectional study was to examine the effects on various iron metabolism biochemical parameters of Luspatercept, a recombinant fusion protein which stimulates late-stage erythropoiesis by binding transforming growth factor β superfamily (TGF-β) ligands, to gain insight into the underlying molecular mechanisms of this recently approved drug. To our knowledge, this is the first study to try to characterize the response to Luspatercept in β-thalassemia patients in a non-clinical trial context. Method Fifty-one adult subjects were enrolled and divided into six different groups: healthy subjects, β-thalassemia carriers, non-transfusion-dependent patients (NTDT) treated with standard of care or with Luspatercept and transfusion-dependent patients (TDT) treated with standard therapy alone or in combination with Luspatercept. Peripheral blood samples were collected to analyze complete blood count and biomarkers of iron metabolism, including hepcidin, an experimental marker. Results Baseline hepcidin levels are statistically significantly higher in NTDT Luspatercept treated patients than in untreated NTDT patients (p = 0.029). When normalized to ferritin, baseline hepcidin-to-ferritin ratio is significantly lower in the Luspatercept NTDT group compared to untreated NTDT (p = 0.0140). These data are consistent with the results obtained from the comparative analysis of hepcidin at baseline and one week after the Luspatercept injection: hepcidin level decreases in a statistically significant way after the administration of the drug (p = 0.04). On the other hand, in TDT patients both hemoglobin and hepcidin levels are higher one week after the transfusion compared to baseline, in a statistically significant manner. The hepcidin-to-ferritin ratio is significantly lower also in TDT patients treated with Luspatercept compared to TDT patients treated with the standard of care (p = 0.0177). In TDT patients treated with Luspatercept hemoglobin levels are significantly increased from baseline to one week after the transfusion, however, unlike in NTDT patients, hepcidin increase is not statistically significant, probably given the interference given by blood transfusion. Conclusion In conclusion, according to our data, Luspatercept, which acts by stimulating erythropoiesis, is associated with reduced hepcidin, with the consequence that more iron is available for the enhanced erythropoiesis. The reduction of hepcidin could be related to the binding of Luspatercept to BMP6, a member of the binding transforming growth factor β superfamily (TGFβ), leading to BMP6-hepcidin axis suppression. One limitation of this study is the small number of patients, indeed increasing the number of participants in future studies may enable us to identify additional changes that may not have been apparent in this preliminary evaluation.