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Highlights from

American Society of Hematology

Annual meeting 2018

San Diego 1-4 December 2018

BELIEVE: Luspatercept significantly reduces transfusion burden versus placebo in patients with beta-thalassaemia

Take-home messages
  • Luspatercept achieved a reduction in transfusion burden across any 12- and 24-week analyses compared with placebo
  • AEs were mild to moderate and luspatercept was generally well tolerated
  • Luspatercept could provide a new treatment option for adult patients with beta-thalassaemia who require regular RBC transfusions
“… at this stage, we may say that luspatercept is a potential new therapy for adult patients with beta-thalassaemia who require regular RBC transfusions.”

Professor Maria Cappellini, Chief of Internal Medicine, Fondazione IRCCS Ca’ Granda Policlinico Hospital, University of Milan, Italy

“Luspatercept definitely met the primary endpoint, showing a statistically significant reduction in transfusion burden compared to placebo,” heard delegates at the American Society of Hematology (ASH) 60th Annual Meeting 2018. Professor Maria Cappellini, Chief of Internal Medicine, Fondazione IRCCS Ca’ Granda Policlinico Hospital, University of Milan, Italy, recounted the success of the BELIEVE trial.

Other than bone marrow transplantation, there are no curative treatments for beta-thalassaemia, and current management involves life-long red blood cell (RBC) transfusions and iron chelation therapy. For patients with this hereditary haemoglobinopathy, the need for frequent transfusions can have a significant effect on quality of life.

Ineffective erythropoiesis is a hallmark of beta-thalassaemia; a faulty beta-globin gene impairs haemoglobin (Hb) synthesis, and the subsequent aggregation of alpha-globin chains can cause RBC apoptosis.

Luspatercept is a first-in-class erythroid maturation agent in development for patients with myelodysplastic syndromes (MDS) and beta-thalassaemia. It acts by trapping TGF-beta ligands, which are negative regulators of RBC differentiation, thus restoring erythropoiesis and increasing levels of RBCs and Hb.

The investigational agent was tested in BELIEVE, a phase III, randomised, double-blind, placebo-controlled trial in adult patients with beta-thalassaemia, who required regular RBC transfusions (6-20 units in 24 weeks prior to randomisation with no transfusion-free period ≥35 days during that time).

A total of 336 patients from 65 different sites in 15 countries and were randomised in a 2:1 ratio to receive either luspatercept 1 mg/kg subcutaneously (SC) every 3 weeks (titration up to 1.25 mg/kg) + best supportive care (BSC), or placebo SC every 3 weeks + BSC. After a double-blind 48-week period, crossover was allowed post unblinding. BSC included RBC transfusions and iron chelation therapy to maintain baseline Hb level.

Mean age was 30, 58% of patients were female, and 58% of patients in each arm had undergone splenectomy. 30.4% (n=68) and 31.3% (n=35) of patients were genotype B0/B0 in the luspatercept and placebo arms, respectively.

The study met its primary endpoint: ≥33% reduction in transfusion burden from baseline (with a reduction of ≥2 RBC units) during weeks 13–24, showing a statistically significant difference between luspatercept (21.4%; n=48) and placebo (4.5%; n=5; odds ratio: 5.79; p<0.0001) in the intention-to-treat population.

The secondary endpoints of the trial were also met. At weeks 37-48, 19.6% (n=44) of patients receiving luspatercept achieved a ≥33% reduction in RBC transfusion burden, compared with 3.6% (n=4) receiving placebo (p<0.0001).

A ≥50% reduction in RBC transfusion burden was seen in 7.6% (n=17) and 10.3% (n=23) of patients receiving luspatercept at weeks 13-24 and 37-48, respectively, compared with 1.8% (n=2) and 0.9% (n=1) in patients receiving placebo (p=0.0303 and p=0.0017, luspatercept vs placebo, weeks 13-24 and 37-48). At weeks 13-24, the mean change in transfusion burden from baseline was -1.35

“[Versus placebo], luspatercept achieved a reduction in transfusion burden across any 12- or 24-week analysis - that’s the most important observation,” added Professor Cappellini.

Adverse events (AEs) were consistent with phase II data and were mild to moderate, without the need for dose modifications or interruptions. “[Luspatercept] is well tolerated in this population,” Professor Cappellini concluded, “so, at this stage, we may say that luspatercept is a potential new therapy for adult patients with beta-thalassaemia who require regular RBC transfusions.”

Luspatercept, which is not yet approved in any country, was certainly a focal point at ASH 2018. The results of MEDALIST, a randomised, double-blind, placebo-controlled, phase III trial, had similar success, as luspatercept significantly reduced transfusion burden compared with placebo in patients with MDS (very low to intermediate risk, with ring sideroblasts), who required RBC transfusions.

Based on Cappellini M D, Viprakasit V et al. The BELIEVE trial: results of a phase 3, randomized, double-blind, placebo-controlled study of luspatercept in adult beta-thalassemia patients who require regular red blood cell (RBC) transfusions (abstract 163). Presented on Saturday 1 December 2018.

Top image: © Racksuz

Article image: sciencephoto

The content and interpretation of these conference highlights are the views and comments of the speakers/authors.

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