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

Abstract

β-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 β-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 β-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 #NCT01749540 and #NCT02268409.

Graphical abstract

Figure 1.

Study design and cohorts. The analytic sample size for the primary study end point was 63 patients (non–transfusion dependent [NTD], n = 31; transfusion dependent [TD], n = 32); this included all patients who received 0.6 to 1.25 mg/kg of luspatercept in either the initial or extension stage of the study. Doses <0.6 mg/kg of luspatercept were not considered efficacious. *Patients assigned to the dose-escalation cohorts received luspatercept at dose levels of 0.2 to 1.25 mg/kg; patients were assigned to the following dose levels: 0.2 mg/kg (n = 6 patients; all NTD), 0.4 mg/kg (n = 6 patients; all NTD), 0.6 mg/kg (n = 5 NTD patients; n = 1 TD patient), 0.8 mg/kg (n = 3 NTD patients; n = 3 TD patients), 1.0 mg/kg (n = 2 NTD patients; n = 4 TD patients), and 1.25 mg/kg (n = 1 NTD patient; n = 4 TD patients). †Patients assigned to the expansion cohort and the extension stage received luspatercept at dose levels of 0.8 to 1.25 mg/kg; patients were assigned to the expansion cohort after review of adverse event (AE) and efficacy data for patients in the dose-escalation cohorts. ‡Patients entering the extension with treatment interruption were those who had finished the initial stage of treatment and had completed the end-of-study visit at least 28 days before receiving the first dose in the extension. §Patients enter the 2-month follow-up after discontinuing from or completing the extension stage; because of the treatment period of 60 months, no patients have yet entered the follow-up period.

Figure 2.

Mean (± 95% CI) change in hemoglobin level relative to baseline. (A) Non–transfusion-dependent patients with β-thalassemia treated with luspatercept at 0.2 to 0.4 mg/kg compared with 0.6 to 1.25 mg/kg during the initial stage of the study. (B) All non–transfusion-dependent patients with β-thalassemia treated with luspatercept at 0.6 to 1.25 mg/kg during the initial and/or extension stage of the study.

Figure 3.

Transfusion burden reduction vs baseline for patients with β-thalassemia treated with luspatercept (n = 32). (A) Percentage change in RBC transfusion burden over a continuous 12-week period post baseline vs the 12-week baseline period. Each bar represents 1 patient; the best recorded continuous 12-week period of transfusion burden reduction post baseline was used to calculate the percentage change for each patient. (B) Absolute change in RBC units on study vs baseline. Each circle represents 1 patient’s baseline RBC transfusion burden, as absolute number of transfused units in a 12-week period; each line represents the best recorded transfusion burden reduction for the patient over a continuous 12-week period post baseline. For both panels, only patients with a baseline transfusion burden of ≥2 RBC units and 12-week postbaseline transfusion data are shown.

Figure 4.

LIC change in non–transfusion-dependent (A) and transfusion-dependent β-thalassemia patients (B). Each filled circle represents 1 patient’s baseline LIC; each line represents the best recorded change in LIC post baseline. Only patients with ≥4 months postbaseline LIC are included. Patients noted to have received iron chelation therapy could have received it in the 84 days before treatment as well as on study. dw, dry weight.

Figure 5.

Leg ulcer healing in a patient with non–transfusion-dependent β-thalassemia treated with luspatercept. The patient received 0.4 mg/kg of luspatercept in the initial stage of the study and up to 1.25 mg/kg of luspatercept in the extension stage. The image example shown is representative of an ulcer that healed within 6 weeks.