Data from the pivotal phase III MEDALIST trial (NCT02631070) shows that treatment with luspatercept (ACE-536), an investigational drug for the treatment of patients with myelodysplastic syndromes, resulted in statistically significant increased red blood cell transfusion independence compared to placebo. Based on the these results Celgene and Acceleron Pharma, the developers of the drug, are planning regulatory submissions in the United States and Europe in the first half of 2019.[1][2]

Myelodysplastic Syndromes or MDS, also referred to as bone marrow failure disorders, are a group of diverse bone marrow disorders in which the bone marrow does not produce healthy blood cells, including red blood cells, white blood cells, and/or platelets.

While it is primarily a disease of the elderly the disease can also affect younger people.

MDS is associated with an erythroid maturation defect. This is characterized by ineffective erythropoiesis leading to anemia, which is considered to be one of the most prevalent cytopenias in patients who have myelodysplastic syndromes.

Ranging in severity from mild (asymptomatic) to severe, anemia can result in patients being treated regularly with red blood cell (RBC) transfusions. In turn, this can lead to further complications from iron overload. In lower-risk MDS, treatment of anemia remains an unmet medical need.

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Although erythropoietin (EPO) stimulates proliferation of early-stage erythrocyte precursors and is widely used for the treatment of chronic anemia, this approach is not possible in several types of EPO-resistant anemia, characterized by defects in late-stage erythropoiesis, which is EPO independent.

Erythroid Maturation Agent
Luspatercept is a first-in-class erythroid maturation agent (EMA), a novel fusion protein which binds to transforming growth factor beta (TGFβ) superfamily ligands to reduce aberrant Smad2/3 signaling and enhance late-stage erythropoiesis and is believed to regulate late-stage red blood cell maturation.[3][4]

The phase III clinical trials continue to evaluate the safety and efficacy of luspatercept in patients with MDS (the MEDALIST trial) and in patients with beta-thalassemia (the BELIEVE trial). The COMMANDS phase III trial in first-line, lower-risk, MDS patients, the BEYOND phase II trial in non-transfusion-dependent beta-thalassemia, and a phase II trial in myelofibrosis are ongoing.

Trial design
The MEDALIST trial is a phase III, randomized, double blind, placebo-controlled, multi-center study evaluating the safety and efficacy of luspatercept in anemic patients who are categorized as International Prognostic Scoring System-Revised (IPSS-R) with very low-, low-, or intermediate-risk non-del(5q) myelodysplastic syndromes. All patients participating in the trial were RBC transfusion dependent and were either refractory or intolerant to prior erythropoiesis-stimulating agent (ESA) therapy, or were ESA na?ve with endogenous serum erythropoietin 200 U/L, and had no prior treatment with disease modifying agents.[2]

The median age of the patients enrolled in the trial was 71 years in the luspatercept treatment group and 72 years in the placebo group. Median transfusion burden in both treatment arms was 5 RBC units/8 weeks. 229 patients were randomized to receive either luspatercept 1.0 mg/kg (153 patients) or placebo (76 patients) via subcutaneous injection once every 21 days. The study was conducted at 65 sites in 11 countries.[2]

Photo 1.0: Alan List, MD, President and CEO of the Moffitt Cancer Center speaks during the annual meeting of the American Society of Hematology about new and novel agents for the treatment of blood diseases and disorders Photo by © ASH/Scott Morgan 2018

In the phase III MEDALIST trial researchers evaluated the efficacy and safety of luspatercept to treat patients with ring sideroblast (RS+) myelodysplastic syndromes (MDS)-associated anemia who require red blood cell transfusions and who had failed, were intolerant to, or ineligible for erythropoietin therapy.

Results of the trial were presented by Alan F. List, MD, President and CEO of Moffitt Cancer Center, during the Plenary Scientific Session at the 60th annual meeting of the American Society of Hematology (ASH).

“Severe anemia resulting in red blood cell transfusion dependence is a significant challenge for patients with low- and intermediate-risk MDS. Those who become resistant or refractory to currently available treatments have limited alternatives,” List said.

“The findings from MEDALIST trial are very exciting as they support the hypothesis that targeting red blood cell precursor maturation could help to address patients anemia and allow them to achieve transfusion independence,” he added.

Primary endpoint
The MEDALIST trial met the primary endpoint of red blood cell transfusion independence (RBC-TI) for 8 or more weeks during the first 24 weeks of the study. Treatment with luspatercept resulted in a statistically significantly greater proportion of patients achieving RBC-TI 8 weeks compared to placebo. The study also found in secondary endpoints that treatment with luspatercept resulted in a statistically significant higher percentage of patients achieving RBC-TI of 12 or more weeks in the first 24 or 48 weeks of the study, as well as hematologic improvement-erythroid (HI-E) of 8 or more weeks.

RBC-TI ?8 weeks (weeks 1-24)37.9 % (58/153)13.2 % (10/76)< 0.0001
RBC-TI ?12 weeks (weeks 1-24)28.1 % (43/153)7.9 % (6/76)0.0002
RBC-TI ?12 weeks (weeks 1-48)33.3 % (51/153)11.8 % (9/76)0.0003
HI-E ? 8 weeks (IWG 2006, weeks 1-24)52.9 % (81/153)11.8 % (9/76)< 0.0001


Adverse events
Treatment-emergent adverse events (TEAEs) of Grade 3 or 4 were reported in 42.5% (65/153) of patients receiving luspatercept and 44.7% (34/76) of patients receiving placebo. Progression to acute myeloid leukemia (AML) occurred in four patients, three patients (2.0%) receiving luspatercept and one patient (1.3%) receiving placebo. Five patients receiving luspatercept (3.3%) and four patients receiving placebo (5.3%) experienced one or more TEAE that resulted in death.

Most common TEAEs of any Grade in Greater than 10% of Patients in Either Arm

Luspatercept | N=153Placebo |N=76
Fatigue26.8 %13.2 %
Diarrhea22.2 %9.2 %
Asthenia20.3 %11.8 %
Nausea20.3 %7.9 %
Dizziness19.6 %5.3 %
Back pain19.0 %6.6 %


“The MEDALIST results demonstrate the potential clinical benefit of luspatercept in achieving red blood cell transfusion independence in patients with low-to-intermediate risk RS+ MDS, an area in need of new treatments,” said Alise Reicin, MD, President, Global Clinical Development for Celgene.

“Based on these results, we are encouraged that this first-in-class erythroid maturation agent may help these patients address the underlying cause of their disease-related chronic anemia,” Reicin added.

“It’s truly an honor to showcase the results from the MEDALIST trial as the first presentation of the ASH Plenary Session,” said Habib Dable, President and Chief Executive Officer of Acceleron.

“The results from the MEDALIST trial increase our confidence in the potential of luspatercept to provide a meaningful treatment option for patients suffering from lower-risk RS+ MDS worldwide. We’re excited to continue our clinical development program in MDS, beta-thalassemia, and myelofibrosis, while also exploring additional applications for luspatercept in a range of diseases associated with anemia,” Dable concluded.

[1] Fenaux P, Platzbecker U, Mufti GJ, Garcia-Manero G, Buckstein R, Santini V, D?ez-Campelo M, 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 | General Sessions | Plenary Scientific Session | Hematology Disease Topics & Pathways: Biological, Diseases, MDS, Myeloid Malignancies. Presented during the 60th annual meeting of the American Society of Hematology (ASH), December 2, 2018.[Abstract]
[2] A Study of Luspatercept (ACE-536) to Treat Anemia Due to Very Low, Low, or Intermediate Risk Myelodysplastic Syndromes (MEDALIST) – NCT02631070
[3] Suragani RN, Cadena SM, Cawley SM, Sako D, Mitchell D, Li R, Davies MV, et al. Transforming growth factor-? superfamily ligand trap ACE-536 corrects anemia by promoting late-stage erythropoiesis. Nat Med. 2014 Apr;20(4):408-14. doi: 10.1038/nm.3512. Epub 2014 Mar 23.[Pubmed]
[4] Platzbecker U, Germing U, G?tze KS, Kiewe P, Mayer K, Chromik J, Radsak M, et al. Luspatercept for the treatment of anaemia in patients with lower-risk myelodysplastic syndromes (PACE-MDS): a multicentre, open-label phase 2 dose-finding study with long-term extension study. Lancet Oncol. 2017 Oct;18(10):1338-1347. doi: 10.1016/S1470-2045(17)30615-0. Epub 2017 Sep 1.[Pubmed]

Last Editorial Review: December 2, 2018

Featured Image: Attendees during general views at the American Society of Hematology 60th Annual Meeting at the San Diego Center, Sunday December 2, 2018. Courtesy: 2018 ? American Society of Hematology/Scott Morgan 2018. Used with permission.?Photo 1.0: Alan F. List, MD, President and CEO of Moffitt Cancer Center,? speaks during the Plenary Scientific Session of the 60th annual meeting of the American Society of Hematology in San Diego, CA, on Saturday December 1, 2018. Courtesy: 2018 ? American Society of Hematology/Scott Morgan 2018. Used with permission.

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