Luspatercept Reduces Transfusion Burden in Transfusion-Dependent Patients With Beta-Thalassemia

Vip Viprakasit, MD, DPhil

A majority of adult patients with β-thalassemia who require regular red blood cell (RBC) transfusions experienced clinically meaningful and durable transfusion burden reduction associated with luspatercept (Reblozyl) in the phase III BELIEVE trial. There were no new safety signals. The incidence of adverse events (AE) was not associated with dose level, decreased over time, and did not affect treatment modification or continuation.

BELIEVE (NCT02604433) was a randomized, double-blind, study comparing luspatercept with placebo. Luspatercept is a first‑in‑class erythroid maturation agent binding select TGF-β superfamily ligands, reducing aberrant Smad2/3 signaling, and enhancing late-stage erythropoiesis.

This study enrolled adults with β-thalassemia or hemoglobin E/β‑thalassemia (including compound β-thalassemia mutation and/or multiplication of α-globin genes), who required regular transfusions of 6—20 RBC units in the 24 weeks prior to random assignment, with no transfusion-free period >35 days. Patients were randomly assigned 2:1 to luspatercept (n = 224) 1.0 mg/kg (up to 1.25 mg/kg), or placebo (n = 112), subcutaneously every 3 weeks for ≥48 wks. Patients in both treatment arms received RBC transfusions to maintain baseline hemoglobin levels as well as iron chelation therapy.

The primary end point was reduction of RBC transfusion burden by ≥33% from baseline, with a reduction of ≥2 units in weeks 13-24 versus the 12 weeks prior to randomization. After study unblinding, patients assigned to the placebo arm were allowed to crossover to luspatercept treatment (92 of 109 patients treated with placebo; 84.4%). Results for the luspatercept arm include only patients initially assigned to luspatercept.

Assessments using a data cutoff of January 7, 2019 including the number of response episodes, duration of clinical benefit, and safety in patients who experienced a response to luspatercept, were presented in a poster by Vip Viprakasit, MD, DPhil, Siriraj Hospital, Mahidol University, Bangkok, Thailand during the 2019 American Society of Hematology Annual Meeting.

Response episodes were defined as reduction in RBC transfusion from baseline over any consecutive 24 weeks and assessed at a median follow-up of 64.1 weeks. Duration of clinical benefit, defined as the time of first response (≥33% reduction in RBC transfusion over any 24 weeks) to discontinuation due to any cause at that episode, was also assessed. The open-label portion of the trial could continue up to 5 years followed by post-treatment follow-up of up to 3 years. Median duration of treatment was 95.7 weeks (1.7-128.1 weeks) with luspatercept (223 of 224 patients enrolled were treated); and 74.7 weeks (8.9-104.0 weeks) with placebo.

The primary end point, reduction of RBC transfusion burden by ≥33% from baseline, with a reduction of ≥2 units in weeks 13-24, was reached in 21.4% of patients in the luspatercept arm, and in 4.5% of patients in the placebo arm. Reduction of RBC transfusion burden by ≥33% over any 12-week period was reached in 76.3% of patients in the luspatercept arm and 34.8% in the placebo arm (P <.0001) and over any 24-week period was reached in 45.1% of patients in the luspatercept arm, and in 2.7% of patients in the placebo arm (P <.0001).

In patients receiving luspatercept who experienced a response, 73.3% experienced ≥2 separate response periods during any 24-week interval. Overall, 4.9% of patients receiving luspatercept experienced multiple episodes of response, defined as having ≥1 non-overlapping durations of response during any 24-week interval. There were no changes in pre-transfusion hemoglobin levels from pre-transfusion level over any fixed 12-week period throughout the study.

The median duration of clinical benefit for those with a response to luspatercept as 76.3 weeks, with 17.4% of patients having an ongoing clinical benefit response through out the entire study period from the time of the first dose.

AEs more frequently associated with luspatercept versus placebo included bone pain (20.2% vs 8.3%), arthralgia (21.1% vs 14.7%), and dizziness (12.1% vs 4.6%). These were primarily transient, grade 1-2, and not associated with dose level, treatment modification, or discontinuation. Discontinuations due to AE occurred only in the luspatercept arm, and included 2 patients due to arthralgia and 1 due to bone pain. The incidence of new onset AE decreased over time during the study in the luspatercept arm.

Monitoring for safety outcomes is ongoing. An ongoing phase 2 study, BEYOND (NCT03342404) is determining the efficacy and safety of luspatercept in patients with non-transfusion-dependent β-thalassemia. A phase IIa study (NCT04143724) is ongoing to determine the safety and pharmacokinetics in pediatric patients with transfusion-dependent β-thalassemia.

Viprakasit V, Taher AT, Hermine O, et al. Evaluating luspatercept responders in the phase 3, randomized, double-blind, placebo-controlled BELIEVE trial of luspatercept in adult -thalassemia patients who require regular red blood cell transfusions. Presented at: American Society of Hematology Annual Meeting; December 7-10, 2019; Orlando, FL. Abstract 3545. https://ash.confex.com/ash/2019/webprogram/Paper122685.html.

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