Luspatercept Data Published in NEJM Highlight Benefit for Beta Thalassemia-Associated Anemia

Diane McDowell, MD

Results from the pivotal phase III BELIEVE trial, which supported the FDA approval of luspatercept-aamt (Reblozyl) for the treatment of anemia in adult patients with beta thalassemia who require regular red blood cell (RBC) transfusions, have been published in the New England Journal of Medicine.

Data from the study showed that treatment with luspatercept-aamt led to significant reductions in RBC transfusion burden in those with beta-thalassemia—associated anemia. Results specifically showed that 21.4% of patients who received luspatercept-aamt achieved a ≥33% reduction from baseline in RBC transfusion burden, with a reduction of ≥2 units, during weeks 13 to 24 after randomization compared with 4.5% of patients who received placebo (odds ratio, 5.79; 95% CI, 2.24-14.97; P <.001).

"These results published in the New England Journal of Medicine demonstrate the clinical benefit of Reblozyl, the first approved treatment for anemia in beta thalassemia in the US," Diane McDowell, MD, vice president, Hematology Global Medical Affairs, Bristol Myers Squibb," said in a press release. “Patients with beta thalassemia experience chronic anemia, often requiring life-long treatment with red blood cell transfusions, which are associated with multiple medical complications. The ability of Reblozyl to reduce the frequency and burden of regular red blood cell transfusions is clinically meaningful for these patients."

Beta thalassemia is a rare blood disorder that is caused by a genetic defect in hemoglobin; it is also associated with ineffective erythropoiesis, which leads to a production of fewer and less healthy RBCs and often leads to severe anemia. Luspatercept-aamt is a first-in-class erythroid maturation agent designed to regulate late-stage red blood cell maturation.

In the double-blind, placebo-controlled, multicenter, BELIEVE study (NCT02604433), investigators explored the safety and efficacy of luspatercept-aamt in adult patients with beta thalassemia who regularly required RBC transfusions. To be eligible for enrollment, patients had to be aged ≥18 years, had beta thalassemia or hemoglobin (Hb) E/beta thalassemia, and required regular transfusions of 6 to 20 RBC units in the 24 weeks prior to randomization with no transfusion-free period ≥35 days during that time.

A total 336 patients were randomized 2:1 to receive either luspatercept-aamt at a starting dose level of 1.0 mg/kg with titration up to 1.25 mg/kg (n = 224), or placebo (n = 112), subcutaneously every 3 weeks for ≥48 weeks; 332 patients were treated. Those in both arms continued to receive RBC transfusions and iron chelation therapy to maintain the same baseline Hb level.

The primary endpoint of the trial was a ≥33% reduction in transfusion burden, with a reduction of ≥2 RBC units, during weeks 13 to 24, when compared with a 12-week baseline period. Secondary endpoints included ≥33% reduction in RBC transfusion burden at weeks 37 to 48, ≥50% reduction in transfusion burden at weeks 13 to 24, ≥50% reduction in transfusion burden at weeks 37 to 48, and mean change in transfusion burden at weeks 13 to 24. Moreover, achievement of ≥33% reduction in RBC transfusion burden over any consecutive 12 weeks on study was also evaluated.

The median patient age was 30 years (range, 18-66) and 58% of patients were female. Additionally, patients received a median of 6 RBC units in the 12 weeks before treatment, and 58% of patients in each arm had undergone splenectomy. B0/B0 genotype was observed in 30.4% and 31.3% of patients in the luspatercept-aamt and placebo arms, respectively.

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

Regarding safety, thromboembolic events occurred in 3.6% of patients on the luspatercept-aamt arm. The most common AEs were headache (26% with luspatercept-aamt vs 24% with placebo), 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%).

The most common grade ≥3 AEs occurring with luspatercept were anemia (3.1% vs 0%), increased liver iron concentration (2.7% vs 0.9%) and hyperuricemia (2.7% vs 0%). Serious AEs occurred in 15.2% versus 5.5% of the luspatercept versus placebo arms, respectively. There was 1 death due to an unconfirmed case of acute myeloid leukemia.

Cappellini MD, Viprakasit V, Taher AT, et al. A phase 3 trial of luspatercept in patients with transfusion-dependent β-thalassemia. N Engl J Med. 2020;382(13):1219-1231. doi: 10.1056/NEJMoa1910182.