Background: beta-thalassemia is a hereditary blood disorder resulting in ineffective erythropoiesis and anemia. Management of anemia with regular blood transfusions is associated with complications including iron overload. Here, we report long-term safety and efficacy results of the first clinical study of luspatercept in beta-thalassemia, initiated in 2013, enrolling adults with both nontransfusion-dependent (NTD) and transfusion-dependent (TD) beta-thalassemia. Objectives: The objective was to report long-term safety data, for up to 5years of treatment, for 64 patients with TD or NTD beta-thalassemia, and long-term efficacy data for a subset of 63 patients with beta-thalassemia who received high-dose luspatercept (0.6-1.25mg/kg): 31 NTD and 32 TD patients. Design: The study was a phase 2, noncontrolled, open-label trial comprising a dose-finding base phase and a 5-year extension phase. Methods: Endpoints include safety; erythroid response over a continuous 12-week period [NTD: hemoglobin increase from baseline 1.0 or 1.5 g/dl; TD: red blood cell (RBC) transfusion burden reduction, 20%, 33%, or 50%]; and changes in biomarkers of ineffective erythropoiesis, iron metabolism parameters, Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F) scores, and 6-min walking distance. Results: Median duration of luspatercept exposure for NTD and TD patients was 910days (range, 40-1850) and 433days (range, 21-1790), respectively. Seventeen of 31 (54.8%) NTD patients achieved a mean hemoglobin increase of 1.5g/dl and 19 of 32 (59.4%) TD patients achieved 50% reduction in RBC transfusion burden, during any continuous 12-week period. Median cumulative duration of response was 1126days (range, 127-1790) for NTD patients and 909days (range, 87-1734) for TD patients. The most common treatment-related adverse events of any grade were bone pain, headache, and myalgia. Conclusion: Long-term assessment of patients with beta-thalassemia showed luspatercept was associated with sustained increases in hemoglobin levels in NTD patients and sustained transfusion burden reductions in TD patients. Trial registration: (ClinicalTrials.gov Identifiers: NCT01749540 and NCT02268409). Plain Language Summary Long-term safety and erythroid response with luspatercept treatment in patients with beta-thalassemia Background: beta-thalassemia is a genetic blood disorder caused by mutations in the beta-globin gene, which encodes one of the proteins that comprise hemoglobin, a key constituent of red blood cells. Patients with beta-thalassemia experience anemia, the main treatment for which is blood transfusions. Long-term repeated blood transfusions lower patients' quality of life, use hospital resources, and the resulting accumulation of excess iron can cause organ failure and decrease life expectancy. The severity of the anemia experienced by patients with beta-thalassemia varies; patients with transfusion-dependent beta-thalassemia require regular blood transfusions, compared with those with nontransfusion-dependent beta-thalassemia who require infrequent transfusions, or even none at all, to manage their symptoms. Luspatercept (Reblozyl((R))) is an agent that stimulates the production of red blood cells and is used to treat anemia caused by beta-thalassemia. However, the long-term effects of luspatercept treatment on patients with beta-thalassemia are not known. Objective: In this study, we report the long-term safety of luspatercept in 64 adult patients with either transfusion-dependent or nontransfusion-dependent beta-thalassemia, and the long-term efficacy of high-dose luspatercept (0.6-1.25mg/kg) in a subset of 63 patients. Results: The average time period that patients were treated with luspatercept was 910days for nontransfusion-dependent beta-thalassemia and 433days for transfusion-dependent beta-thalassemia. We report that in patients with nontransfusion-dependent beta-thalassemia, luspatercept treatment was associated with sustained increases, just over 3years, in hemoglobin levels. Likewise, in transfusion-dependent beta-thalassemia, luspatercept treatment was associated with a sustained reduction, 2.5years, in the amount of blood transfusion required to manage their anemia. Long-term treatment with luspatercept was not associated with any new side effects compared with previous short-term treatment studies. The most common side effects were headache (27 patients), bone pain (20 patients), and muscle pain (14 patients) with more than 90% of these patients experiencing these side effects as mild severity. Conclusion: The results of this study show that in patients with either transfusion-dependent or nontransfusion-dependent beta-thalassemia, luspatercept provides lasting reduction in anemia with mostly mild and predictable side effects.
