Luspatercept in Alpha-Thalassemia: a Preliminary Study

Alpha thalassemia is a genetic disorder of hemoglobin caused by mutations in the α-globin genes located on chromosome 16. The decreased synthesis of α-globin chains leads to an imbalance between α and β-globin, resulting in ineffective erythropoiesis, decreased red blood cell (RBC) survival, chronic hemolytic anemia, and related comorbidities. In the bone marrow microenvironment, certain TGF-β superfamily ligands act as negative regulators of late-stage erythroblast differentiation through the Smad 2/3 signaling pathway, which is hyperactivated in models characterized by ineffective erythropoiesis. Luspatercept, a recombinant fusion protein, mitigates ineffective erythropoiesis and enhances erythroid maturation by binding to TGF-β superfamily ligands, decreasing Smad 2/3 signaling in erythroid precursor cells. Luspatercept is the first disease-modifying drug approved by the US FDA in 2019 to treat transfusion-dependent β-thalassemia. Despite its efficacy in β-thalassemia, the mechanism of action in α-thalassemia is still not fully understood. This cross-sectional observational study compared hemoglobin (Hb), plasma GDF15, GDF11, hepcidin, and erythroferrone levels between healthy individuals and α-thalassemia patients and evaluated the potential effects of luspatercept treatment in α-thalassemia patients. The study included 12 subjects. Baseline hemoglobin levels were significantly different between healthy individuals and α-thalassemia patients (median values: 15.2 g/dl vs. 9.5 g/dl, p<0.0001). Although not statistically significant (p=0.0838), elevated baseline GDF15 levels in α-thalassemia patients (median values: 621.6 pg/ml vs. 261.9 pg/ml in healthy individuals) suggest its potential role as a marker for ineffective erythropoiesis and disease severity. Similarly, baseline GDF11 and hepcidin levels were higher in α-thalassemia patients compared to healthy controls (p=0.3320 and p=0.4149, respectively). The longitudinal effects of luspatercept/placebo treatment the studied patient showed a significant increase in Hb levels from 9.5 g/dl to 11.1 g/dl after the first drug administration, along with an increase in RBC number and reticulocyte count. Additionally, LDH and GDF15 values increased during the study, indicating potential drug-enhanced erythropoietic activity and stress. The increased erythropoietic activity was also reflected by the growth in erythropoietin (EPO) levels, from a baseline of 60.7 mU/ml to 67.4 mU/ml by the end of the study. Conversely, ferritin levels decreased from 806 ng/ml to 416 ng/ml, suggesting improved iron utilization. This analysis highlights significant differences in baseline hemoglobin and erythropoietic biomarkers between healthy individuals and α-thalassemia patients. Elevated baseline GDF15 and GDF11 levels in α-thalassemia may serve as markers for ineffective erythropoiesis and disease severity. The study also suggests that luspatercept may modulate late-stage erythroid maturation and early erythroid proliferation, leading to increased Hb levels, reduced anemia severity, and improved quality of life in α-thalassemia patients. Moreover, luspatercept treatment may increase erythropoietic stress, reflected by increased LDH and GDF15 levels in treated patients.