Luspatercept reduces red blood cell transfusion burden in beta-thalassemia
SAN DIEGO — Adults with transfusion-dependent beta-thalassemia experienced significant reductions in red blood cell transfusion burden with luspatercept, according to results of a randomized, double-blind, placebo-controlled phase 3 study presented at ASH Annual Meeting and Exposition.
Treatment with luspatercept (ACE-536; Acceleron Pharma, Celgene) also appeared well tolerated.
“Beta-thalassemia is an inherited hemoglobinopathy due to reduced or absent beta-globin chain synthesis leading to ineffective erythropoiesis and anemia,” Maria Domenica Cappellini, MD, professor at University of Milan in Italy, told HemOnc Today. “The standard of care for patients with beta-thalassemia is blood transfusion and iron chelation to remove the iron accumulated by transfusion. In spite of iron chelation treatment, many patients still experience multi morbidities due to iron toxicity and increased mortality. Therefore, there is a need to find new therapeutic approaches to improve the treatment of these patients.”
Luspatercept is a first-in-class erythroid maturation agent under development for adults with anemia from beta-thalassemia or myelodysplastic syndrome.
“Luspatercept enhances late-stage erythropoiesis, improving the anemia-neutralizing select transforming growth factor-superfamily ligands,” Cappellini told HemOnc Today. “The reduction of transfusion burden will be very meaningful for the patients and it may positively impact on their quality of lives.”
The analysis included 336 patients (median age, 30 years; range, 18-66; 58% women) — 332 of whom were treated — who had received a median of six red blood cell units in the 12 weeks prior to treatment. Fifty-eight percent of patients had undergone splenectomy.
Researchers randomly assigned patients 2:1 to receive a 1-mg/kg starting dose of luspatercept (n = 224) — with titration up to 1.25 mg/kg — or placebo (n = 112) every 3 weeks for at least 48 weeks. Patients in both groups continued to receive red blood cell transfusions and iron chelation therapy to maintain their baseline hemoglobin level.
According to HbVar database classification, 68 patients (30.4%) in the luspatercept arm and 35 patients (31.3%) in the placebo arm had the B0/B0 disease genotype.
A 33% or greater reduction in transfusion burden — with a reduction of at least two red blood cell units — during weeks 13 to 24 compared with a 12-week baseline period served as the study’s primary endpoint.
Key secondary endpoints included a 33% or greater reduction in red blood cell transfusion at weeks 37 to 48, a 50% or greater reduction in transfusion burden at weeks 13 to 24 and at weeks 37 to 48, and mean change in transfusion burden at weeks 13 to 24.
Overall, a greater proportion of patients in the luspatercept arm than the placebo arm achieved the primary endpoint (21.4% vs. 4.5%; OR = 5.79; OR = 5.79; P < .0001), as well as the secondary endpoints of a 33% or greater reduction in red blood cell transfusion burden at weeks 37 to 48 (19.6% vs. 3.6%; P < .0001), and a 50% or greater reduction in transfusion burden at weeks 13 to 24 (7.6% vs. 1.8%; P = .0303) and at weeks 37 to 48 (10.3% vs. 0.9%; P = .0017).
“We have to keep in mind that these are young adult patients, transfusing three units of blood every 3 weeks for their whole life, so this treatment really has a substantial impact,” Cappellini said during a press conference.
The difference of mean change from baseline in transfusion burden from week 13 to week 24 was –1.35 units (P < .0001).
Also, 70.5% of patients assigned luspatercept achieved at least a 33% reduction in transfusion burden over any 12 consecutive weeks compared with only 29.5% of patients assigned placebo (P < .0001).
Cappellini noted that this outcome may more accurately describe patient benefit than the primary endpoint used in the study design.
“It is much better to follow patients with the rolling methodology, because patients are different one by one, so they may respond at a different time and not necessarily in a fixed period,” she said during the press conference. “We added this endpoint to this phase 3 study and, in the future, this will definitely be a way to prove efficacy and the reduction of transfusion burden and to use it in real life. These are quite complicated and heterogenous patients who might start with a different level of ineffective erythropoiesis, so their response can be different.”
Treatment-related adverse events leading to dose delay or reduction appeared similar between the groups. Researchers reported no patient deaths among those treated with luspatercept.
“Beta thalassemia is a very demanding disease,” Cappellini said in a press release. “This new approach can totally change the quality of life for the patient. In addition, even for those who don’t become completely transfusion independent, reducing transfusions can reduce associated comorbidities.”
These data also should be put into context with gene therapy, which is emerging as an alternative treatment for beta-thalassemia, with many data presented at ASH this year, Cappellini said.
“In my opinion, gene therapy must be a cure to be really efficacious,” she said during the press conference. “You are not going to perform gene therapy to reduce the transfusion burden, that’s not what it is for. I think that still there is a way to go to achieve this goal.
“The other issue is probably the cost,” she added. “We have to wait and see whether there will be other new approaches alternative to gene therapy; luspatercept is definitely the most advanced.” – by Alexandra Todak
Domencia Cappellini M, et al. Abstract 163. Presented at: ASH Annual Meeting and Exposition; Dec. 1-4, 2018; San Diego.
Disclosures: Cappellini reports board of directors or advisory roles with Celgene, Sanofi/Genzyme and Vifor, and honoraria from Novartis. Please see the abstract for all other authors’ relevant financial disclosures.