Maria Domenica Cappellini, MD, FRCP, FACP
Long-term treatment with luspatercept-aamt (Reblozyl) elicited the longest duration of reduced red blood cell (RBC) transfusion dependence among patients with β-thalassemia, according to updated data from the phase 3 BELIEVE trial (NCT02604433), presented at the 2022 EHA Congress.1
Response was assessed as reduction of RBC transfusion burden by at least 33% from baseline and by at least 50% from baseline among patients who received luspatercept vs placebo during any rolling 12- or 24-week interval. With a long-term data cutoff of January 5, 2021, among the 224 patients in the luspatercept arm, 173 patients (77.2%) had at least 33% response during any 12-week interval and 116 (51.8%) had a response during any 24-week interval. A transfusion burden reduction of at least 50% was reported among 112 patients (50%) and 53 patients (23.7%) during any 12- and 24-week interval, respectively.1
These outcomes were compared with prior data cutoff landmarks: May 11, 2018 (primary data cutoff) and January 7, 2019 (intermediate data cutoff). In the primary analysis, 70.5% and 41.1% of patients had at least a 33% reduction in transfusion burden at the 12- and 24-week intervals. These rates were 76.3% and 45.1% in the intermediate analysis, respectively. Reduction of at least 50% were reported at any 12- and 24-week intervals among 40.2% and 16.5% of patients, respectively, in the primary analysis and 44.6% and 20.5% in the intermediate analysis.1
“In terms of transfusion independence, at the cutoff of 3 years 12% of patients [who received] luspatercept, achieved transfusion independence, equal to or more than  weeks. And that, of course, implies the longest interval of this condition of transfusion in dependence,” said Maria Domenica Cappellini, MD, FRCP, FACP, professor of internal medicine at the University of Milan and chief of the Rare Diseases Centre at the Fondazione IRCCS Policlinico Hospital in Italy, during a presentation of the data.
The median longest duration of RBC transfusion independence was 72 days (95% CI, 62-103) with longer-term luspatercept treatment. At the primary and intermediate analysis cutoffs, the rates of RBC transfusion independence lasting at least 8 weeks were 10.7% and 11.2%, respectively, compared with 12.1% in the longer-term analysis.
“Continuous treatment with the luspatercept allowed for more patients to experience a reduction in RBC transfusion burden, with longer durations of responses compared [with] the previous cutoff,” Cappellini said. “We are confident that these [benefits] will be even more clear with longer follow-up and patients with transfusion dependent β-thalassemia treated in the BELIEVE study will continue to benefit from luspatercept with over 3 years of treatment.”
Additional data showed that the median duration of RBC transfusion burden reduction was 114 days (95% CI, 107-137) and 99 days (95% CI, 95-104) for those with 33% reduction and 50% reduction, respectively, at the long-term analysis cutoff. In the primary data cutoff analysis, the median duration of RBC transfusion burden reduction was 104 days (95% CI, 84-588) for those with at least 33% reduction and 97.5 days (95% CI, 84-588) for those with at least 50% reduction. In the intermediate analysis the median duration was 105 days (95% CI, 84-825) and 99 days (95% CI, 84-825), respectively.
The median treatment duration during the primary, intermediate, and long-term landmark analyses were 64.1 days (95% CI, 3-97), 95.7 days (95% CI, 1.7-128.1), and 153.6 days (95% CI, 1.7-215).
Further, the mean cumulative duration of RBC transfusion burden reduction during any rolling 12-week interval was 627.3 (standard deviation, 390.5) for patients who received luspatercept.1
In terms of RBC transfusion burden change from baseline, Cappellini noted that patients receiving luspatercept required fewer units of blood over time. The mean change in RBC units every 48 weeks from baseline was –4.8 (weeks 1-48), –5.6 (weeks 49-96), –6.2 (weeks 97-144), and –6.4 (weeks 145-192) compared with a 1.1 unit increase reported in weeks 1-48 with placebo.
Cappellini also highlighted that patients achieving an RBC transfusion burden reduction of 50% or higher experienced a greater interval between the transfusions compared with the baseline over time at a mean of +9.9 days (standard deviation, 22.0).1
Luspatercept, an erthyroid maturation agent, is approved for the treatment of anemia in patients with β-thalassemia who require regular red blood cell (RBC) transfusions. Additionally, it received an indication for patients who require 2 or more RBC units over 8 weeks for patients with very low- to intermediate-risk myelodysplastic syndromes (MDS) with ring sideroblasts or with MDS/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis.2
BELIEVE was a randomized, double-blind, study comparing luspatercept with placebo.1,3 Investigators enrolled adults with β-thalassemia who required regular transfusions of 6 to 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) plus best supportive care or placebo plus best supportive care (n = 112). Luspatercept was administered subcutaneously 1.0 mg/kg (up to a maximum dose of 1.25 mg/kg) every 3 weeks. Best supportive care included RBC transfusions to maintain baseline hemoglobin levels and iron chelation therapy.1,3
The primary end point was reduction of RBC transfusion burden by at least 33% from baseline with a reduction of at least 2 units in weeks 13 to 24 compared with the 12 weeks prior to randomization.3
Baseline characteristics between the experimental and control arm were well balanced. The median age was 30 years (range, 18-66). Median hemoglobin levels at 24 weeks were 9.31 g/dL (range, 4.5-11.4) and 9.15 g/dL (range, 5.8-11.7) in the luspatercept arm and placebo arm, respectively. The median RBC transfusion burden was 6.12 units (range, 3-14) every 12 weeks in the luspatercept arm and 6.27 (range, 3-12) in the placebo arm. The median burden every 24 weeks was 14 units (range, 6-24) and 15 (range, 6-26), respectively. Further, over half of patients (57.6% and 58.0%, respectively) had a splenectomy.
In terms of liver iron concentration (LIC), at baseline the median LIC in the luspatercept arm was 6.4 mg/g dry weight (range, 0.8-125.0) and 5.05 mg/g dry weight (range, 0.2-53.2) in the placebo arm. An analysis of LIC is ongoing, according to Cappellini.
At data cutoff 127 patients (56.7%) remained on study treatment and 2.7% (n = 6) have completed 192 weeks of treatment. Of the 224 patients in the luspatercept arm, 96 (42.9%) discontinued treatment. The most common reasons for discontinuation were physician decision (23.7%), adverse event (10.3%), or other (5.4%).
- Cappellini MD, Taher AT, Porter JB, et al. Longer-term analysis of efficacy of luspatercept in patients with transfusion-dependent β-thalassemia enrolled in the BELIEVE study. Presented at: 2022 EHA Congress; June 9-17, 2022; Vienna, Austria. Abstract S270.
- Reblozyl. Prescribing information. Celegene; 2020. Accessed June 11, 2022. bit.ly/3c0E2sj
- An efficacy and safety study of luspatercept (ACE-536) versus placebo in adults who require regular red blood cell transfusions due to beta (β) thalassemia (BELIEVE). ClinicalTrials.gov. Updated January 25, 2022. Accessed June 11, 2022. https://clinicaltrials.gov/ct2/show/NCT02604433