A Phase 3 Trial of Luspatercept in Patients with Transfusion-Dependent β-Thalassemia. N Engl J Med. 2020 Mar 26;382(13):1219–1230. doi:10.1056/NEJMoa1910182.
Clinical Question
In patients with transfusion-dependent β-thalassemia, does treatment with luspatercept reduce transfusion burden compared to placebo?
Background and Guidelines
- β-thalassemia is a hereditary hemoglobin disorder in which abnormal production of β-globin chains results in imbalanced ratio α-globin to β-globin, the two key components of adult hemoglobin.
- β-thalassemia is characterized by ineffective erythropoiesis and chronic anemia, often requiring lifelong regular red blood cell (RBC) transfusions. The need for blood transfusions couples without a physiologic method of removing excess iron results in iron overload that may result in end-organ failure and death in early adulthood.
- Standard management includes transfusion support (to reduce ineffective erythropoiesis) and iron chelation therapy; curative options are limited to allogeneic hematopoietic stem cell transplantation and gene therapy.
- Luspatercept is an erythroid maturation agent that enhances late-stage erythropoiesis by modulating TGF-β superfamily signaling.
- In an open-label, dose-ranging, phase 2 study, transfusion during any 12-week interval was reduced by at least 20% from baseline in 26 of 32 patients (81%) with transfusion-dependent β-thalassemia who received luspatercept at a dose of 0.60 to 1.25 mg per kilogram of body weight.1
Study Design
- Design: Randomized, double-blind, placebo-controlled, phase 3 trial with crossover
- Setting: 65 sites in 15 countries
- Randomization: 2:1 ratio to receive luspatercept or placebo.
- Duration of monitoring: Patients who completed the 48-week double-blind treatment period could continue to receive luspatercept or placebo in a double-blind manner until all the patients completed the initial 48-week period.
- Open-label extension phase: Patients still receiving luspatercept or placebo after study unblinding were eligible to receive luspatercept in an open-label extension phase until all patients originally randomized to luspatercept complete 5 years of treatment (or discontinue). All patients will be followed for 3 years after his/her last dose of treatment.2
Populations
- Population: 336 adults with transfusion-dependent β-thalassemi
- Transfusion dependence defined as 6 to 20 units of packed red cells, with no transfusion-free period of >35 days, within 24 weeks before randomization
- Key exclusion criteria:
- Hemoglobin S/β-thalassemia or α-thalassemia (hemoglobin H disease) or prior exposure to luspatercept or sotatercept, a pulmonary hypertension drug with a somewhat simlar MOA.
- Significant concomitant medical conditions such as HIV, active hepatitis B or C, poorly controlled diabetes mellitus, uncontrolled hypertension, recent deep vein thrombosis or stroke, major organ damage, or prior malignancy were also excluded.
- Patients receiving iron chelation therapy initiated ≤24 weeks prior to randomization were not eligible for inclusion
- Baseline characteristics
- Median age (range): 30 (18-66)
- Female sex: 58%
- Geographic region: North America/Europe 44.9%, Asia/Pacific 31.8%, Middle East/North Africa 23.2%
- Splenectomy: 58%
- Hemoglobin E/β thalassemia: 16%
- Β0/Β0 genotypeL: 31%
- Median pretransfusion Hgb (range): 9.3 g/dL (4.5-11.7)
- Median red cell transfusion units in 24 weeks (range): 14 (6-26)
- Median liver iron concentration (range): 5.69 mg/g of dry liver weight (0.2-125.0)
- Median myocardial iron deposition (range): 35.0 msec (3.0-205.9)
- Current iron-chelation therapy: 99.7%
Intervention
- Intervention: Luspatercept subcutaneous injection every 3 weeks (starting dose 1.0 mg/kg, titrated up to 1.25 mg/kg).
- All the patients also received best supportive care, including red-cell transfusion and iron-chelation therapy, according to local guidelines.
- Comparator: Placebo
- Dosing:
- Dose of study drug was increased from 1.0 to 1.25 mg/kg if the reduction in transfusion burden from baseline over ≥2 dose cycles was <33% or, at the investigator’s discretion, ≥33% but ≤50%. Maximum dose 120 mg.
- Dose delayed for grade ≥2 AEs until resolved to grade ≤1 or baseline; for grade ≥3 AEs, the dose was reduced by 25% when restarted.
- Dose reductions/delays for Hgb values, WBC values (until hematologic malignancy excluded in which case treatment discontinued)
Outcomes
- Primary Efficacy Outcome: 21.4% of luspatercept group achieved ≥33% reduction in transfusion burden from baseline (the 12-week period before the first dose of luspatercept or placebo) during weeks 13–24 plus a reduction of at least 2 red-cell units over this 12-week interval compared with 4.5% of placebo group (95% CI 2.24-14.97, p<0.001).
- Secondary Efficacy Outcomes:
- 21.4% of luspatercept group achieved ≥33% reduction in the transfusion burden from baseline during weeks 37 through 48 plus a reduction of at least 2 red-cell units over this 12-week interval compared with 3.6% of placebo group (p<0.001)
- 7.6% of luspatercept group achieved ≥50% reduction in the transfusion burden from baseline during weeks 13 through 24 plus a reduction of at least 2 red-cell units over this 12-week interval compared with 1.8% (p=0.03)
- 10.3% of luspatercept group achieved ≥50 reduction in the transfusion burden from baseline during weeks 37 through 48 plus a reduction of at least 2 red-cell units over this 12-week interval compared with 0.9% (p=0.002)
- Reductions in the transfusion burden of at least 33% and at least 50% from baseline were estimated to avoid the need for approximately 7 and 8 red-cell units, respectively, per patient over 6 months.
- Subgroup analysis suggested that the magnitude of response to luspatercept may be lower and that the time to response may be longer in patients with a β0/β0 genotype than in those with a non-β0/β0 genotype
- Serum ferritin levels were reduced from baseline in the luspatercept group whereas they increased from baseline in the placebo group. No clinically meaningful changes from baseline in liver iron concentration or myocardial iron deposition were observed during the assessment period.
- Pretransfusion hemoglobin levels did not decrease over the course of the trial.
- Safety:
- Discontinuation because of an adverse event that occurred during the treatment period was reported in 12 patients (5.4%) in the luspatercept group and in 1 patient (0.9%) in the placebo group
- Luspatercept was associated with bone pain, arthralgia, dizziness, hypertension, and hyperuricemia. Bone pain was generally of short duration and low grade.
- Rare thromboembolic events occurred in patients who had undergone splenectomy and had additional risk factors for thromboembolism.
Commentary:
Luspatercept was previously studied and approved the FDA for use in patients with low-risk myelodysplastic syndrome. The results of the multicenter, randomized, double-blind, placebo-controlled trial BELIEVE subsequently led to the FDA approval of luspatercept for treatment of anemia in adult patients with beta thalassemia who require regular red blood cell transfusions on November 8, 2019.
Beta-thalassemia is a multisystem disease that leads to chronic anemia, bone marrow suppression, and end-organ damage. Until recently, there were no FDA approved therapies aside from supportive care in the form of transfusions and iron chelation therapy. Although these supportive therapies are associated with improved prognosis and survival, there are many inherent challenges including access to transfusions in resource-limited areas as well as the lived experience of medication administration burden and adverse effects from iron chelation therapies.
Overall, luspatercept was associated with reduced transfusion burden during both prespecified 12-week intervals as well as during nonspecified intervals which reflects the potential benefit in real-world clinical practice when the medication would be used long-term. It is important to note that pretransfusion hemoglobin levels were maintained. From this, it is inferred that luspatercept’s effect of reducing transfusion burden was not due to variation in hemoglobin thresholds.
In recent years, several other therapeutic classes have been investigated for treatment of thalassemia and other erythrocyte disorders such as pyruvate kinase activators (e.g., mitapivat, etavopivat) and gene therapies. Long-term efficacy and safety data are needed to evaluate luspatercept’s use amongst a panoply of emerging therapeutics with various mechanisms of action, safety profiles, treatment durations, and modes of administration.
- Luspatercept significantly reduced transfusion requirements in adults with β-thalassemia, representing a major advance in supportive care.
- Clinical impact: Potential to decrease transfusion-related complications (iron overload, alloimmunization).
- Limitations: Long-term safety and durability of response remain uncertain; cost and access considerations.
- Future directions: Evaluation in non–transfusion-dependent thalassemia and pediatric populations.
References
1. Piga A, Perrotta S, Gamberini MR, et al. Luspatercept improves hemoglobin levels and blood transfusion requirements in a study of patients with β-thalassemia. Blood 2019;133:1279-1289.
2. Cappellini MD, Viprakasit V, Georgiev P, et al. Long-term efficacy and safety of luspatercept for the treatment of anaemia in patients with transfusion-dependent β-thalassaemia (BELIEVE): final results from a phase 3 randomised trial. Lancet Haematol. 2025 Mar;12(3):e180-e189.
Andrew Song, MD is a hematology fellow (ASH HFFTP) at the Dana-Farber / Mass General Brigham fellowship in Boston, MA. He received his MD from Harvard Medical School and completed Internal Medicine residency training at Massachusetts General Hospital. In 2026, he will be starting a faculty position as an adult classical hematologist at Mass General Brigham. His clinical research focuses on thrombosis/hemostasis with particular attention to platelet disorders and autoimmune disorders such as antiphosholipid syndrome.
