Luspatercept Reduces the Need for Transfusions in Patients With Beta Thalassemia and MDS

In two separate phase III trials presented at the 2018 ASH Annual Meeting, luspatercept, a first-in-class recombinant fusion protein, was found to be safe and effective at reducing transfusion burden in patients with myelodysplastic syndromes (MDS) and beta thalassemia, when compared with patients receiving placebo.

Alan F. List, MD, presents results from the MEDALIST trial.


In the MEDALIST trial, which enrolled patients with lower-risk MDS who were anemic, required regular red blood cell (RBC) transfusions, and had ring sideroblasts, more than half of participants treated with luspatercept had a reduction in transfusion burden. More than one-third (38%) of patients achieved the study’s primary endpoint of at least eight weeks without the need for a transfusion, coauthor Alan F. List, MD, from the Moffitt Cancer Center in Tampa, Florida, noted during his presentation of the findings during a Plenary Scientific Session.

Luspatercept works by binding to select TGF-beta superfamily ligands to reduce aberrant Smad2/3 signaling and enhance late-stage erythropoiesis, Dr. List explained. By interfering with the signals that suppress RBC production, the drug improves patients’ ability to manufacture their own RBCs – therefore reducing the need for transfusions.

“This is an agent that targets the pathobiology of anemia in MDS,” Dr. List told ASH Clinical News. “We’ve known for years that the TGF-beta signaling pathway was implicated in the pathogenesis of the anemia in lower-risk MDS, but we didn’t have any agents that could target that. Luspatercept does just that.”

The trial included 229 patients with MDS with ring sideroblasts classified as very low-, low-, or intermediate-risk disease per the Revised International Prognostic Scoring System scale. Dr. List explained that the MEDALIST trial included patients with MDS with ring sideroblasts based on results from a previous phase II trial in which luspatercept yielded a high frequency of transfusion reduction or transfusion independence in this patient population.

All patients either had not responded to or were ineligible to receive erythropoiesis-stimulating agents (ESAs) and required an average of at least two RBC transfusions every eight weeks. ESA-naïve patients had a low probability of benefit from ESAs, “by virtue of RBC transfusion dependence and serum erythropoietin levels greater than 200 U/L,” Dr. List noted.

Patients were randomized 2:1 to receive either luspatercept 1 mg/kg every 21 days (titrated up to 1.75 mg/kg; n=153) or placebo (n=76). Patient characteristics were well balanced between the luspatercept and placebo arms: Forty-three percent of patients in each group were “heavily transfused” (defined as requiring ≥6 units every eight weeks) and the median hemoglobin (Hb) level at baseline was 7.6 g/dL.

As of May 8, 2018 (data cutoff), 70 luspatercept-treated patients (45.8%) and six placebo-treated patients (7.9%) were still receiving treatment. The most common reason for treatment discontinuation in both groups was lack of clinical benefit (33.3% and 65.8%, respectively; p value not provided).

During the first 24 weeks of treatment, 58 patients in the luspatercept group (37.9%) achieved the primary endpoint of RBC transfusion independence for at least eight weeks, compared with 10 patients in the placebo group (13.2%; p<0.0001). The benefit with luspatercept was observed across all subgroup analyses, the authors reported, including according to average baseline transfusion requirement:

  • ≥6 units per 8 weeks: 9.1% vs. 3.0% (odds ratio [OR] = 3.2; 95% CI 0.37-27.7; p=0.27)
  • <6 units per 8 weeks: 59.8% vs. 20.9% (OR=5.61; 95% CI 2.4-13.1; p<0.001)

A larger proportion of patients in the luspatercept group also achieved the secondary endpoint of transfusion-independence for at least 12 weeks (28.1% vs. 7.9% at 24-week follow-up and 33.3% vs. 11.8% at 48-week follow-up; p<0.0003 for ). The median duration of response was 30.6 weeks (range = 20.6-40.6 weeks) in the luspatercept group, compared with 13.6 weeks (range = 9.1-54.9 weeks) in the placebo group (p value not reported).

Secondary endpoints such as erythroid response and mean change in Hb levels also significantly favored luspatercept (p<0.0001 for both), with luspatercept responders experiencing “a greater sustained rise in Hb concentration from baseline pre-transfusion levels, compared with nonresponders or placebo-treated patients,” he added.

“Overall, approximately 40 percent of luspatercept-treated patients remained transfusion-free at one year,” Dr. List reported.

The proportion of patients discontinuing treatment due to adverse events (AEs) was comparable in both arms (8.5% and 7.9%, respectively).

Treatment-emergent AEs that were reported more frequently in the luspatercept arm than the placebo arm included fatigue, diarrhea, asthenia, nausea, dizziness, and back pain.

“Of course, with anything that’s going to promote cell survival, we worry about leukemia, but there was no difference in the frequency of acute leukemia,” Dr. List added. Four luspatercept-treated patients (2%) and one placebo-treated patient (1.3%) progressed to acute myeloid leukemia during the study follow-up period.

The study’s findings are limited to patients with lower-risk MDS with ring sideroblasts, and the results may not be generalizable to patients with higher-risk MDS or those without ring sideroblasts. Dr. List noted that the phase III COMMAND trial is comparing luspatercept with placebo in patients with and without ring sideroblasts who are ESA-naïve; results from this study may provide more answers about luspatercept’s role in the larger MDS population.


In the randomized, double-blind, placebo-controlled BELIEVE trial, patients with beta thalassemia who received luspatercept had lower transfusion burdens, compared with those receiving placebo. The results, presented by lead author Maria Domenica Cappellini, MD, from the University of Milan in Italy, suggest that luspatercept is a potential new therapy for “this very demanding disease.”

Luspatercept holds the promise of alleviating the treatment burden for patients, she added. “These are young adult patients [being transfused] three units of blood every three weeks, so [the reduction in transfusion burden with luspatercept] has a substantial impact.”

In the BELIEVE trial, patients were eligible for inclusion if they had beta thalassemia or Hb E/beta thalassemia and were RBC transfusion-dependent, defined as requiring regular transfusions (6-20 RBC units) in the 24 weeks prior to randomization and having no transfusion-free period ≥35 days during that time.

Participants were then randomized 2:1 to receive either luspatercept at a starting dose level of 1 mg/kg, with titration up to 1.25 mg/kg, or placebo administered subcutaneously every three weeks for at least 48 weeks. In both treatment arms, patients continued to receive RBC transfusions and iron chelation therapy as needed. Crossover to the luspatercept arm was allowed after unblinding.

As of May 11, 2018 (data cutoff), 336 patients were treated: 224 in the luspatercept arm and 112 in the placebo arm. Participants’ median age was 30 years (range = 18-66 years), and 58 percent of patients were female. Most patients (58% of each arm) had undergone splenectomy prior to study randomization.

After , 48 of 224 patients (21.4%) in the luspatercept arm achieved the primary endpoint of RBC transfusion reduction (defined as a ≥33% reduction in RBC transfusion burden, with a reduction of ≥2 RBC units from baseline, during weeks 13-24). In the placebo group, just five of 112 patients (4.5%) experienced a clinically meaningful reduction in transfusion dependence (OR=5.79; p<0.001).

In addition, 158 of 224 luspatercept-treated patients (70.5%) achieved a ≥33-percent reduction in RBC transfusion requirements during any consecutive 12 weeks of treatment, while 33 of 112 placebo-treated patients (29.5%) achieved the same result (p<0.001).

The authors also observed statistically significant differences in favor of luspatercept for all other transfusion burden–related secondary endpoints, :

  • ≥33% reduction in transfusion burden at weeks 37-48: 19.6% (44 of 224 luspatercept-treated patients) vs. 3.6% (4 of 112 placebo-treated patients; p<0.001)
  • ≥50% reduction in transfusion burden at weeks 13-24: 7.6% (17/224) vs. 1.8% (2/112; p=0.03)
  • ≥50% reduction in transfusion burden at weeks 37-48: 10.3% (24/224) vs. 0.9% (1/112; p=0.002)

Among all patients, the median number of RBC units received in the 12 weeks prior to study treatment was six (range = 3-14), and the mean reduction in transfusion burden from baseline to weeks 13 to 24 was 1.35 units (p<0.001), the authors added.

“Luspatercept achieved a reduction in transfusion burden across any 12- or 24-week period – the most important observation, because each [patient’s disease] is different and may respond in a different time and outside of the fixed observation period,” Dr. Cappellini stressed.

AEs occurring with luspatercept were “generally mild to moderate and manageable, without requiring dose modifications or interruptions,” Dr. Cappellini reported. Common AEs included bone pain and thrombotic events, including stroke. No patient deaths were reported for those treated with luspatercept.

The findings of this placebo-controlled trial will need to be compared with available management strategies for beta thalassemia, including transfusions– as well as gene therapy options on the horizon. “In my point of view, to be really efficacious, gene therapy must be a cure,” Dr. Cappellini said. “We are not going to perform gene therapy for reducing transfusion burden – that’s not the scope of the treatment. There is still a ways to go to achieve that point.”

The authors of the MEDALIST and BELIEVE trials report financial relationships with Acceleron, the manufacturer of luspatercept. Celgene and Acceleron supported both trials.


  1. Fenaux P, Platzbecker U, Mufti GJ, et al. The MEDALIST trial: results of a phase 3, randomized, double-blind, placebo-controlled study of Luspatercept to treat anemia in patients with very low-, low-, or intermediate-risk myelodysplastic syndromes (MDS) with ring sideroblasts (RS) who require red blood cell (RBC) transfusions. Abstract #1. Presented at the 2018 ASH Annual Meeting, December 2, 2018; San Diego, CA.
  2. Cappellini MD, Viprakasit V, Taher A, et al. The BELIEVE trial: results of a phase 3, randomized, double-blind, placebo-controlled study of luspatercept in adult beta thalassemia patients who require regular red blood cell (RBC) transfusions. Abstract #163. Presented at the 2018 ASH Annual Meeting, December 1, 2018; San Diego, CA.