Luspatercept improves hemoglobin levels and blood transfusion requirements in a study of patients with β-thalassemia

Abstract

K E Y P O I N T S l A high percentage of patients with b-thalassemia had improvement in hemoglobin or transfusion burden after receiving luspatercept. l Findings support a randomized clinical trial to assess the efficacy and safety of luspatercept for treatment of b-thalassemia. b-thalassemia is a hereditary disorder with limited approved treatment options; patients experience anemia and its complications, including iron overload. The study aim was to determine whether luspatercept could improve anemia and disease complications in patients with b-thalassemia. This open-label, nonrandomized, uncontrolled study consisted of a 24-week dose-finding and expansion stage (initial stage) and a 5-year extension stage, currently ongoing. Sixty-four patients were enrolled; 33 were non-transfusion dependent (mean hemoglobin, <10.0 g/dL; <4 red blood cell [RBC] units transfused per 8 weeks), and 31 were transfusion dependent ( ‡4 RBC units per 8 weeks). Patients received 0.2 to 1.25 mg/kg luspatercept subcutaneously every 21 days for ‡5 cycles (dose-finding stage) and 0.8 to 1.25 mg/kg (expansion cohort and 5-year extension). The primary end point was erythroid response, defined as hemoglobin increase of ‡1.5 g/dL from baseline for ‡14 consecutive days (without RBC transfusions) for non-transfusion-dependent patients or RBC transfusion burden reduction ‡20% over a 12-week period vs the 12 weeks before treatment for transfusion-dependent patients. Eighteen non-transfusion-dependent patients (58%) receiving higher dose levels of luspatercept (0.6-1.25 mg/kg) achieved mean hemoglobin increase ‡1.5 g/dL over ‡14 days vs baseline. Twenty-six (81%) transfusion-dependent patients achieved ‡20% reduction in RBC transfusion burden. The most common grade 1 to 2 adverse events were bone pain, headache, and myalgia. As of the cutoff, 33 patients remain on study. In this study, a high percentage of b-thalassemia patients receiving luspatercept had hemoglobin or transfusion burden improvements. These findings support a randomized clinical trial to assess efficacy and safety. This study was registered at www.clinicaltrials.gov as

Switching from dispersible to film coated tablet formulation of deferasirox improves hemoglobin levels and transfusional interval in patients with transfusion‐dependent‐thalassemia

“…The use of erythropoiesis‐stimulating agents, such as erytropoietin, in beta‐thalassemia is not supported by controlled clinical trials (Fibach & Rachmilewitz, ). Recently, an open‐label, nonrandomized, uncontrolled study demonstrated an improvement in hemoglobin and transfusion burden in patients with beta‐thalassemia after the use of luspatercept (Piga et al , ). Therefore, iron chelation therapy (ICT) currently remains the main treatment for iron overload and for its complications in patients with thalassemia.…”

Early development of decreased β‐cell insulin secretion in children and adolescents with hemoglobin H disease and its relationship with levels of anemia

“…In conclusion, a high prevalence of decreased β‐cell insulin secretion was demonstrated among children and adolescents with Hb H disease, and this insulin secretory defect is likely to be related to the severity of anemia, independent of the type of Hb H disease. Whether or not increasing the functional Hb levels by blood transfusion or novel therapy on enhanced erythroid maturation will ameliorate insulin secretory defect has yet to be established. Further study is needed to prevent long‐term complications related to abnormal glucose metabolism in patients with Hb H disease.…”

Megakaryocyte TGFβ1 Partitions Hematopoiesis into Immature Progenitor/Stem Cells and Maturing Precursors

“…Accordingly, many causes of anemia are unresponsive to exogenous Epo. Recently, TGFβ superfamily activin receptor (Acvr2a/b) ligand traps have shown activity treating chronic Epo-unresponsive anemia in myelodysplastic syndrome (MDS) and beta-thalassemia and are thought to promote erythroid maturation after Epo signaling [22][23][24][25][26] . However, the molecular regulators of the Epo-unresponsive erythroid compartment are not well defined.…”