Abstract: S295

Type: Oral Presentation

Session title: New therapeutic approaches for thalassemia

Background
β-thalassemia is a genetic blood disorder caused by mutations that downregulate (β⁺) or silence (β⁰) expression of the gene (HBB) that encodes β-globin. Reduced expression of normal β-globin (β) leads to ineffective erythropoiesis, anemia and, in transfusion-dependent patients (pts), frequent and lifelong red blood cell (RBC) transfusions. Luspatercept, a first-in-class erythroid maturation agent approved for adult pts with β-thalassemia who require regular RBC transfusions, binds several TGF-β superfamily ligands to diminish Smad2/3 signaling and enhance late-stage erythropoiesis.

Aims
To explore the association between β-globin genotype and response to luspatercept in adult pts with β-thalassemia in the BELIEVE trial.

Methods
BELIEVE is a phase 3, double-blind, randomized, placebo (PBO)-controlled study evaluating the efficacy and safety of luspatercept in regularly transfused, adult pts with β-thalassemia (NCT02604433). Eligible pts were aged ≥18 years with β-thalassemia or hemoglobin (Hb) E/β‑thalassemia (compound β-thalassemia mutation and/or multiplication of α-globin genes was allowed) and required regular transfusions of 6–20 RBC units in the 24 weeks prior to randomization, with no transfusion-free period >35 days. All pts provided informed written consent. Pts were randomized 2:1 to luspatercept 1.0 mg/kg (up to 1.25 mg/kg allowed) or PBO administered subcutaneously every 3 weeks for ≥48 weeks. Pts in both treatment arms continued RBC transfusions to maintain target pretransfusion Hb levels, as well as iron chelation therapy.

Results
Of the 336 pts randomized as part of the BELIEVE trial, 103 had genotype β⁰/β⁰, 87 had genotype β⁰/β⁺, 84 had genotype β⁺/β⁺, 9 had ≥1 unmutated β (includes β/β, β⁺/β, β⁰/β), and 52 had HbE/β-thalassemia.

The primary endpoint (≥33% reduction in RBC transfusion burden in Weeks 13–24, with a reduction of ≥2 units) was achieved with luspatercept vs PBO treatment by 9/68 (13.2%) vs 2/35 (5.7%; P=0.271) β⁰/β⁰ pts, 15/59 (25.4%) vs 1/28 (3.6%; P=0.015) β⁰/β⁺ pts, 16/58 (27.6%) vs 0/26 (P=0.004) β⁺/β⁺ pts, and 6/31 (19.4%) vs 2/21 (9.5%; P=0.341) HbE/β-thalassemia pts.

In the luspatercept arm, ≥33% reduction in transfusion burden during any 24 weeks was achieved by 26/68 (38.2%) β⁰/β⁰ pts (vs 1/35 [2.9%] PBO; P<0.0001), 23/59 (39.0%) β⁰/β⁺ pts (vs 0/28 PBO; P=0.0001), 27/58 (46.6%) β⁺/β⁺ pts (vs 0/26 PBO; P<0.0001), and 12/31 (38.7%) HbE/β-thalassemia pts (vs 1/21 PBO [4.8%]; P=0.007) (May 11, 2018 cutoff). With luspatercept treatment, 7/68 (10.3%) β⁰/β⁰ pts (vs 1/35 [2.9%] PBO; P=0.193), 9/59 (15.3%) β⁰/β⁺ pts (vs 0/28 PBO; P=0.031), 10/58 (17.2%) β⁺/β⁺ pts (vs 0/26 PBO; P=0.028), and 8/31 (25.8%) HbE/β‑thalassemia pts (vs 0/21 PBO; P=0.013) achieved ≥50% reduction in transfusion burden during any 24 weeks.

Least squares mean change (standard error) in RBC units transfused from baseline in Weeks 13–24 in luspatercept vs PBO arms, respectively, were −0.48 (0.205) vs 0.85 (0.288) for β⁰/β⁰, −0.72 (0.273) vs 0.74 (0.395) for β⁰/β⁺, −0.90 (0.253) vs 0.71 (0.354) for β⁺/β⁺, and −0.69 (0.416) vs 0.26 (0.469) for HbE/β-thalassemia pts.

Grade ≥3 treatment-emergent adverse events (TEAEs; ≥1) were reported in 18/68 (26.5%), 17/58 (29.3%), 14/58 (24.1%), and 14/31 (45.2%) luspatercept-treated β⁰/β⁰, β⁰/β⁺, β⁺/β⁺, and HbE/β-thalassemia pts, respectively. The incidence of specific adverse events was consistent with the overall population.

Conclusion
Although response rates were lower in pts with the most severe disease (β⁰/β⁰), clinically meaningful reductions in transfusion burden were observed across genotypes.

Session topic: 27. Thalassemias

Keyword(s): Beta thalassemia, Clinical trial