European Commission Approves Luspatercept for Transfusion-Dependent Anemia in MDS or Beta-Thalassemia

The European Commission has approved luspatercept-aamt (Reblozyl) as a treatment for patients with transfusion-dependent anemia from very low-, low-, and intermediate-risk myelodysplastic syndromes (MDS) with ring sideroblasts who had unsatisfactory response or are not candidates for erythropoietin-based therapy, and patients with transfusion-dependent anemia linked with beta thalassemia.¹

“Across the EU, 25 million blood transfusions occur every year, some of which are needed by patients with anemia due to hematologic diseases like MDS and beta thalassemia,” said Diane McDowell, MD, vice president of Hematology Global Medical Affairs at Bristol Myers Squibb. “[Luspatercept] has the potential to address the ineffective erythropoiesis associated with MDS and beta thalassemia, decrease patients’ dependence on red blood cell transfusions and impact the underlying consequences of the high burden of anemia for these patients.”

Luspatercept marks the first and only approval of an erythroid maturation agent for use in the European Union, thus opening the opportunity for eligible patients to benefit from a new class of therapy. The decision was based on findings from the pivotal phase 3 MEDALIST and BELIEVE trials, which examined the novel agent in patients with anemia associated with MDS and beta thalassemia, respectively.

In the double-blinded, placebo-controlled, phase 3 MEDALIST trial, 229 patients categorized per the International Prognostic Scoring System-Revised criteria as either very low-, low-, or intermediate-risk MDS with ring sideroblasts and required red blood cell (RBC) transfusions were randomized to receive either luspatercept (n = 153) or placebo (n = 76) delivered subcutaneously every 3 weeks.

The median age of the participants included on the study was 71 years and more than half, or 63%, of patients were male. Additionally, SF3B1 mutations were detected in 93% of those on the investigational arm versus 86% of those on the placebo arm. The majority of the overall study population (95%) had received prior treatment with erythropoietin-stimulating agents (ESAs), and just under half (48%) had received prior iron chelation treatment.

Results showed that 38% of patients who received luspatercept achieved RBC-transfusion independence (RBC-TI) for ≥8 weeks versus just 13% of patients who were given the placebo (P <.001), thus meeting the primary end point of the trial.²

Additionally, the key secondary trial end point of RBC-TI for ≥12 weeks was met by a higher percentage of patients in the luspatercept arm than in the placebo arm at 28% versus 8%, respectively, for weeks 1 through 24, and 33% versus 12%, respectively, for weeks 1 through 48 (P <.001 for both). In an analysis that applied the International Working Group (IWG) 2018 criteria, 19% of patients who received luspatercept versus 4% of patients who were given placebo had RBC-TI for ≥16 weeks during weeks 1 through 24; these rates were 28% and 7%, respectively, during weeks 1 through 48.

Furthermore, the study met an additional secondary end point, which was hematologic improvement-erythroid (HI-E) for ≥8 weeks, as assessed by IWG 2006 criteria. Results showed that in weeks 1 through 24, HI-E responses were observed in 53% of patients on the luspatercept arm versus 12% of those on the placebo arm. Moreover, 59% versus 17% of patients on the luspatercept and placebo arms, respectively, experienced an HI-E response in weeks 1 through 48. Notably, no significant changes in neutrophil or platelet counts were reported during the double-blind period of the trial.

Fifty-two patients (90%) on the luspatercept arm who experienced a response had their first response at the starting dose of 1.00 mg/kg. Seven percent of patients responded to the treatment following dose increases: 2 patients when the dose was raised to 1.33 mg/kg and 2 patients when the dose was 1.75 mg/kg.

RBC-TI for ≥8 weeks was observed in 80% of those who received luspatercept at <4 units per 8 weeks, in 37% of patients who received 4 to 6 units per 8 weeks, and in 9% of those who were given ≥6 units per 8 weeks. The RBC-TI rates on the placebo arm were 40%, 4%, and 3%, respectively. Additionally, the RBC-TI rates with the investigational agent at ≥8 weeks during weeks through 24 were found to be comparable, regardless of the number of baseline mutations: 1 (36.4%), 2 (34.9%), 3 (42.4%), and 4 or 5 (33.3%).³

With regard to safety, the most common adverse events (AEs) reported in ≥10% of the luspatercept and placebo arms included fatigue (27% vs 13%, respectively), diarrhea (22% vs 9%), asthenia (20% vs 12%), nausea (20% vs 8%), dizziness (20% vs 5%), and back pain (19% vs 7%).

Grade ≥3 AEs were reported in 42% and 45% of those who received luspatercept and placebo, respectively; the most common toxicities were fatigue and injury (5% and 3% each, respectively). Additionally, 31% of patients on the luspatercept arm versus 30% of those on the placebo arm experienced ≥1 serious AE.

Updated data from the trial indicated that at a data cutoff of July 1, 2019, the RBC-TI at ≥8 weeks was 47.7% with luspatercept versus 15.8% with placebo (odds ratio [OR], 5.978; 95% CI, 2.840-12.581; P <.0001).⁴ At ≥6 units per 8 weeks, the RBC-TI was 21.2% in the luspatercept arm compared with 6.1% in the placebo arm (OR, 4.17; 95% CI, 0.89-19.60; P = .0547). In those who were administered 4 to 6 units per 8 weeks, the RBC-TI was 48.8% with luspatercept and 8.7% with placebo, respectively (OR, 10.00; 95% CI, 2.07-48.28; P = .0013). In those who were given <4 units per 8 weeks, the RBC-TI was 84.8% with luspatercept and 40.0% with placebo (OR, 8.36; 95% CI, 2.51-27.83; P = .0002).

Furthermore, 73 patients on the luspatercept arm achieved RBC-TI ≥8 weeks during the entire treatment period, 69.9% had ≥2 separate response periods, 38.4% of patients experienced ≥3 separate response periods, and 20.5% had ≥4 separate response periods.

“Dependence on blood transfusions caused by anemia in hematologic malignancies like MDS can often mean frequent and lengthy hospital visits, which can pose additional health risks and affect patients’ quality of life,” Uwe Platzbecker, MD, lead investigator of the MEDALIST trial, head of Clinic and Policlinic for Hematology and Cell Therapy, at Leipzig University Hospital. “Today’s approval of [luspatercept] provides healthcare professionals with a new therapy that has been shown to significantly reduce the number of red blood cell transfusions needed by [patients with] MDS and, in some cases, helped them to achieve transfusion independence.”

The double-blind, placebo-controlled, multicenter BELIEVE trial examined the safety and effectiveness of luspatercept in patients with beta thalassemia who regularly needed RBC transfusions. In the trial, 336 patients were randomized 2:1 to receive either luspatercept at a starting dose of 1.0 mg/kg with titration up to 1.25 mg/kg (n = 224) or placebo (n = 112) delivered subcutaneously every 3 weeks for ≥48 weeks. Throughout the study, patients in both arms continued to receive RBC transfusions and iron chelation treatment to maintain the same baseline Hb level.

The median age of the participants was 30 years and 58% were female. Additionally, patients received a median of 6 RBC units in the 12 weeks prior treatment, and more than half, or 58%, of patients in each arm had undergone splenectomy. B0/B0 genotype was detected in 30.4% and 31.3% of patients in the luspatercept and placebo arms, respectively.

Results demonstrated that 21.4% of patients who received luspatercept experienced a ≥33% reduction from baseline in RBC transfusion burden, with a reduction of ≥2 units during weeks 13 to 24 after randomization versus 4.5% of patients who were given placebo (risk difference, 17.0; 95% CI, 10.4-23.6; P <.0001).⁵

Additional results showed that 19.6% patients who received luspatercept achieved a ≥33% reduction in RBC transfusion burden at weeks 37 to 48 versus 3.6% of patients who received placebo (P <.0001). Furthermore, 7.6% and 10.3% of patients who received luspatercept achieved a ≥50% reduction in RBC transfusion burden at weeks 13 through 24 and 37 through 48, respectively, versus 1.8% and 0.9% of those who received placebo (P = .0303 and P = .0017, respectively).

With regard to safety, thromboembolic events were reported in 3.6% of patients who received luspatercept. Hypertension was observed in 10.7% of those who received luspatercept across the clinical development program. Serious AEs were reported in 3.6% of patients who were given luspatercept. One death due to an unconfirmed case of acute myeloid leukemia was reported.

The most common AEs reported included headache (26% with luspatercept vs 24% with placebo, respectively), bone pain (20% vs 8%, respectively), arthralgia (19% vs 12%), fatigue (14% vs 13%), cough (14% vs 11%), abdominal pain (14% vs 12%), diarrhea (12% vs 10%), and dizziness (11% vs 5%) .

Based on earlier data from the MEDALIST trial, in April 2020, luspatercept received regulatory approval from the FDA for the treatment of anemia failing an ESA and requiring 2 or more RBC units over 8 weeks in patients with very low- to intermediate-risk myelodysplastic syndromes with ring sideroblasts or with myelodysplastic/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis.

The agent had previously been approved in November 2019 for the treatment of anemia in adult patients with beta thalassemia who require regular RBC transfusions based on data from the BELIEVE trial.

References

1. European Commission approves Roblozyl (luspatercept) for the treatment of transfusion-dependent anemia in adult patients with myelodysplastic syndromes or beta thalassemia. News release. Bristol Myers Squibb. June 26, 2020. Accessed June 26, 2020. bit.ly/2Bc73SM.
2. Fenaux P, Platzbecker U, Mufti GJ, et al. Luspatercept in patients with lower-risk myelodysplastic syndromes. N Eng J Med. 2020;382(2):140-151. doi:10.1056/NEJMoa1908892
3. Fenaux P, Platzbecker U, Mufti GJ, et al. Luspatercept in patients with lower-risk myelodysplastic syndromes [supplementary appendix]. N Engl J Med. 2020;382(2):140-151. doi:10.1056/NEJMoa1908892
4. Fenaux P, Mufti GJ, Buckstein R, et al. Assessment of longer-term efficacy and safety in the phase 3, randomized, double-blind, placebo-controlled medalist trial of luspatercept to treat anemia in patients (pts) with revised International Prognostic Scoring System (IPSS-R) very low-, low-, or intermediate-risk myelodysplastic syndromes (MDS) with ring sideroblasts (RS) who require red blood cell (RBC) transfusions. Blood. 2019;134(suppl 1):841. doi: 10.1182/blood-2019-123064
5. FDA approves first therapy to treat patients with rare blood disorder. News release. FDA. November 8, 2019. Accessed June 26, 2020. bit.ly/2JZQeLZ.