Luspatercept Leads to Hemoglobin Increase in Patients With Non-Transfusion–Dependent Beta-Thalassemia

Ali Taher, MD

Without requiring red blood cell (RBC) transfusions, luspatercept-aamt (Reblozyl) led to a mean increase in hemoglobin (Hb) from baseline levels in 77.1% of patients compared with in 0% treated with placebo in patients with non-transfusion–dependent β-thalassemia (NTDT) in the phase 2 BEYOND trial (NCT03342404; EudraCT 2015-003225-33), according to a presentation during the European Hematology Association 2021 Virtual Congress.¹

Results showed that beyond the significant improvement of 1.0 g/dL or higher from baseline over a continuous 12-week interval during weeks 13 to 24 in the overall population (n = 145; P < .0001), the benefit with the agent was also observed regardless of baseline mean Hb level.

In patients whose baseline mean Hb was lower than 8.5 g/dL (n = 84), the mean Hb increase of 1.0 g/dL or higher from baseline was achieved in 72.7% of patients on luspatercept vs 0% of those on placebo (P < .0001). In those whose baseline mean Hb was 8.5 g/dL or greater (n = 61), these rates were 82.9% and 0%, respectively (P < .0001).

Additionally, luspatercept was found to be well tolerated over a prolonged period of time, and was associated with improvements in quality of life in this patient population.

“Treatment with luspatercept resulted in clinically significant and sustained improvements of anemia in adults with NTDT, as measured by hemoglobin levels, with more than 50% of patients [who received] luspatercept achieving and maintaining a hemoglobin increase of more than 1.5 g/dL or greater,” Ali Taher, MD, lead study author; and professor of medicine, hematology & oncology, at American University of Beirut Medical Center in Lebanon, said in a virtual presentation of the findings. “Clinical benefit of luspatercept treatment, previously observed in patients with transfusion-dependent thalassemias [TDTs] through significant reduction in RBC transfusion burden, has now also been observed in patients with NTDT, as measured by meaningful improvement of anemia.”

β-thalassemia is a hereditary blood disorder that is characterized by impaired hemoglobin production and chronic anemia of varying severity. Tailored RBC transfusions, iron chelation therapy, and novel treatments target the key pathophysiologic mechanisms in TDTs and NTDT. NTDT is made up of a diverse group of patients who do not require lifelong regular RBC transfusions as a means to survival but may require occasional transfusions during surgeries or infections.

Furthermore, patients with NTDT who have a baseline Hb of 10 g/dL or higher are known to have significantly longer morbidity-free survival vs those whose Hb is less than 10 g/dL (P < .001).² There is also a significant correlation between the improvement in Hb levels by 1 g/dL and decreased odds of developing morbidities in patients with NTDT whose baseline Hb was less than 10 g/dL.

Treatments that can improve anemia and disease complications in the NTDT population continue to represent an unmet need, Taher noted.

Luspatercept is a first-in-class erythroid maturation agent that binds select TGF-β superfamily ligands to diminish Smad2/3 signaling and enhance late-stage erythropoiesis. In 2019, the FDA approved luspatercept as a treatment of anemia in adult patients with TDT. The agent was subsequently approved by the European Medicines Agency for this indication in 2020.

The decision for those approvals came from the phase 3 BELIEVE trial (NCT02604433), in which 21.4% of patients with TDT who received luspatercept achieved at least a 33% reduction in RBC transfusion burden during weeks 13 to 24 compared with 4.5% for those who received placebo.³ Taher added that luspatercept may have clinical benefit to treat the anemia and improve outcomes in the NTDT patient population.

In the multicenter, double-blind, placebo-controlled BEYOND study, investigators sought to evaluate the safety and efficacy of luspatercept compared with placebo in adult patients with NTDT. Patients were randomized 2:1 to receive luspatercept subcutaneously at 1.0 mg/kg every 3 weeks (n = 100) or placebo subcutaneously every 3 weeks (n = 50). The study was then unblinded to include an open-label treatment period for patients on luspatercept, which is an estimated 15-month period.

The data cutoff date was September 14, 2020. The primary end point of the trial was achievement of at least 1.0 g/dL mean Hb increase from baseline over a continuous 12-week interval during weeks 13 to 24 in the absence of RBC transfusions. A key secondary end point was mean change from baseline in NTDT–patient-reported outcome (PRO) Tiredness/Weakness (T/W) domain score over a continuous 12-week interval during weeks 13 to 24.

Additional secondary end points included achievement of 1.5 g/dL or higher mean Hb increase from baseline over a continuous 12-week interval during weeks 13 to 24 in the absence of RBC transfusions; proportion of patients who remained RBC transfusion free over 24 weeks; mean change in NTDT-PRO T/W domain score by visit; achievement of 1.0 g/dL or higher mean Hb increase from baseline over a continuous 12-week interval during weeks 37 to 48 in the absence of RBC transfusions; duration of mean Hb increase from baseline of at least 1.0 g/dL during any 12-week interval; as well as safety and tolerability with luspatercept.

The baseline characteristics were similar between the luspatercept (n = 96) and placebo (n = 49) arms. Overall (n = 145), the median age was 40.0 years (range, 18.0-71.0) and 43.4% of patients were male. Moreover, 66.9% of patients had β-thalassemia, the median baseline Hb was 8.2 g/dL (range, 5.3-10.1), and 57.9% of patients’ baseline Hb were lower than 8.5 g/dL. The median baseline NTDT-PRO T/W score was 4.3 (0-9.5), and 69.7% of patients’ had a baseline NTDT-PRO T/W score that was 3 or higher. Furthermore, 86.2% of patients received 0 RBC transfusion units in the 24 weeks before the first luspatercept or placebo dose.

The mean serum ferritin level was 554.6 µg/L (standard deviation, 496.9), and the mean liver iron concentration was 6.0 mg/g.

Results also showed that the benefit with luspatercept with achievement of mean Hb increase from baseline to weeks 13 to 24 in the absence of RBC transfusions vs placebo was seen regardless of patients’ splenectomy status (yes, least squares [LS] mean difference 1.09; 95% CI, 0.72-1.45; P < .0001 vs no, LS mean difference 1.53; 95% CI, 1.20-1.86; P < .0001), sex (male, LS mean difference 1.39; 95% CI, 0.96-1.81; P < .0001 vs female, LS mean difference 1.42; 95% CI, 1.12-1.72), baseline Hb level (< 8.5 g/dL, LS mean difference, 1.46; 95% CI, 1.10-1.82; P < .0001 vs ≥ 8.5 g/dL, LS mean difference 1.36; 95% CI, 1.01-1.70; P < .0001), baseline NTDT-PRO T/W domain score (< 3 points, LS mean difference 1.30; 95% CI, 0.89-1.71; P < .0001 vs ≥ 3 points, LS mean difference 1.47; 95% CI, 1.15-1.78; P < .0001), and β-thalassemia genotype (without a-thalassemia, LS mean difference 1.45; 95% CI, 1.15-1.75; P < .0001 vs with a gene duplication, LS mean difference 1.48; 95% CI, 1.12-1.85; P < .0001).

Also, during weeks 13 to 24, 52.1% (n = 50) of patients on luspatercept achieved a mean Hb increase of 1.5 g/dL or higher from baseline. An improvement in NTDT-PRO T/W scores from baseline were also seen more frequently with luspatercept at -0.92 compared with -0.47 with placebo (LS mean difference -0.48; 95% CI, -1.03 to 0.08; P = .0924) in weeks 13 to 24. The improvement was also seen in weeks 37 to 48 with luspatercept (-1.0) over placebo (-0.16; LS mean difference -0.79; 95% CI, -1.58 to 0; P = .0510).

The NTDT-PRO T/W domain scores improved with luspatercept correlated with Hb increase Taher said, and added that the mean change from baseline in NTDT-PRO T/W score by visit showed a gradual and consistent improvement with luspatercept and was maintained through week 78.

Luspatercept also met the other secondary end points on the BEYOND study, including proportion of patients who stayed RBC transfusion-free over 24 weeks (89.6% with luspatercept vs 67.3% with placebo; P = .0013), achievement of 1.0 g/dL or more mean Hb increase from baseline over a continuous 12-week interval during weeks 37 to 48 in the absence of RBC transfusions (70.8% vs 2.0%, respectively; P < .0001), and total duration of the mean Hb increase from baseline 1.0 g/dL during any 12-week interval (243.3 days vs 132.9 days; P = N/A).

Regarding safety, at least 1 treatment-related treatment-emergent adverse event (TEAE) occurred in 76.0% and 36.7% of luspatercept- and placebo-treated patients, respectively; grade 3 or higher TEAEs occurred in 28.1% and 24.5% of patients, respectively. One or more serious TEAE occurred in 11.5% of those on luspatercept and 24.5% of patients on placebo. Thromboembolic events did not occur in any patients, and 2 malignant events were reported on the placebo arm; these included 1 case each of diffuse large B-cell lymphoma and hepatocellular carcinoma.

The most common, all-grade TEAEs reported in 5% or more of patients on luspatercept and placebo, respectively, included bone pain (36.5% vs 6.1%), headache (30.2% vs 20.4%) and arthralgia (29.2% vs 14.3%). No deaths occurred.

In April 2020, the FDA also approved luspatercept for the treatment of anemia failing an erythropoiesis stimulating agent and requiring 2 or more RBC units over 8 weeks in adult patients with very low- to intermediate-risk myelodysplastic syndromes with ring sideroblasts or with myelodysplastic/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis.

_References

_{1. Taher AT, Cappellini MD, Kattamis A, et al. The BEYOND study: results of a phase 2, double-blind, randomized, placebo-controlled multicenter study of luspatercept in adult patients with non-transfusion-dependent β-thalassemia. Presented at: European Hematology Association 2021 Virtual Congress; June 9-19, 2021; virtual. Abstract S101.}

_{2. Musallam KM, et al. Morbidity-free survival and hemoglobin level in non-transfusion-dependent β-thalassemia: a 10-year cohort study. Ann Hematol. Published online January 20, 2021. doi:10.1007/s00277-020-04370-2}

_{3. Reblozyl (luspatercept-aamt). Prescribing information. Bristol Myers Squibb; 2019. Accessed June 11, 2021.}