Need for RBC Transfusion Reduced With Novel Agent for Low-Risk MDS-Related Anemia


The need for frequent red blood cell transfusions was reduced with luspatercept in nearly 53% of patients with anemia associated with low- to intermediate-risk myelodysplastic syndrome.

Alan List, MD

The need for frequent red blood cell (RBC) transfusions was reduced with luspatercept in nearly 53% of patients with anemia that was associated with low- to intermediate-risk myelodysplastic syndrome (MDS). This novel agent was well tolerated in patients who required regular RBC transfusions and demonstrated abnormal iron overload in RBC precursors (ring sideroblasts) before participating in the trial, said phase III Medalist study investigator Alan F. List, MD, during a press conference at the 2018 ASH Annual Meeting.

In the randomized trial, 37.9% of patients treated with luspatercept experienced RBC transfusion independence (RBC-TI) for &ge;8 weeks, which was the primary endpoint of the study, compared with 13.2% in the placebo arm (odds ratio [OR], 5.1;P<.0001).

Additionally, luspatercept improved outcomes for 2 key secondary endpoints. Overall, 52.9% of patients treated with luspatercept achieved a modified hematologic improvement-erythroid (mHI-E) response compared with 11.8% of those given placebo (P<.0001). In addition, 28.1% of the luspatercept arm achieved RBC-TI for &ge;12 weeks compared with 7.9% of the placebo group (OR, 5.1;P= .0002).1

Luspatercept is a first-in-class erythroid maturation agent that is believed to regulate late-stage RBC maturation. Lower-risk MDS-associated anemia may be associated with ineffective erythropoiesis, which leads to anemia, and further, RBC transfusion dependence, explained List, who is president and chief executive officer of Moffitt Cancer Center in Tampa, Florida.

&ldquo;For patients with lower-risk MDS anemia, it is the most common symptomatic cytopenia that we deal with, and for most of these patients over time, the disease becomes transfusion dependent. And with that, comes complications of iron loading,&rdquo; said List, who also is a senior member in the Department of Malignant Hematology and the Experimental Therapeutics Program at Moffitt.

Medalist Trial Details

Erythropoiesis-stimulating agents (ESAs) are first-line therapy for anemia associated with lower-risk MDS; however, few treatment options exist for patients who are refractory to, unresponsive to, or ineligible for these agents, List added. This results in an unmet clinical need for safe and effective treatment options to reduce the RBC transfusion burden in these patients, he said.The Medalist trial evaluated the efficacy and safety of luspatercept compared with placebo in patients aged 18 years or older who had anemia due to MDS defined as very low-, low-, or Intermediate-risk according to the Revised International Prognostic Scoring System. Eligible participants also had ring sideroblasts &ge;15% or &ge;5% with an SF3B1 mutation, required 2 or more RBC transfusions every 2 months, bone marrow blasts <5%, and were refractory to, intolerant of, or ineligible for ESAs. The study was conducted between March 2016 to June 2017 across 65 sites in the United States, Canada, Turkey, and Europe.

As of the May 8 cutoff date, 229 patients with a median age of 71 years (range, 26-95) were randomized 2:1 to receive either luspatercept subcutaneously at a starting dose level of 1 mg/kg every 3 weeks, with titration up to 1.75 mg/kg, if needed (n = 153) or placebo subcutaneously every 3 weeks (n = 76) for &ge;24 weeks.

Investigators assessed for MDS disease after 24 weeks and every 6 months thereafter until discontinued treatment or disease progression. Patients were followed for at least 3 years after their last dose for acute myeloid leukemia (AML) progression, and subsequent MDS treatment and survival.

RBC-TI for &ge;8 weeks between week 1 and week 24 served as the primary endpoint. Secondary endpoints included RBC-TI for &ge;12 weeks between week 1 and 24, and between week 1 and 48. Achievement of mHI-E response for any consecutive 56-day period also was assessed using International Working Group 2006 criteria, which defines mHI-E as a reduction in transfusion burden of &ge;4 RBC units over 8 weeks or a mean hemoglobin increase of &ge;1.5 g/dL over 8 weeks in the absence of transfusions.

Patients were a median 41.8 months (range 3-421) from diagnosis, and the majority were male (62.9%). They received a median 5 RBC units (range 1-20) transfused over 8 weeks during the 16 weeks prior to treatment, including 43.2% who had &ge;6 RBC units/8 weeks, 27.9% who had &ge;4 to <6 RBC units/8 weeks, and 28.8% who had <4 RBC units/8 weeks.

At baseline, 138 (60.3%) participants had serum erythropoietin levels <200 IU/L, 58 (25.3%)with levels 200 to 500 IU/L, and 32 (14%) with levels >500 IU/L. In total, 218 patients (95.2%) previously received ESAs. Additionally, 206 (90.0%) tested positive for an SF3B1 mutation.

The safety profile of luspatercept appeared consistent with that reported for the drug in the dose-finding phase II PACE-MDS study2: 3 treatment-related grade 3 adverse events occurred in 1 patient each (myalgia, increased blast cell count, and general physical health deterioration).

Celgene and Acceleron Pharma, the companies jointly developing the drug, intend to submit regulatory applications to the FDA in the first half of 2019. In addition, the companies are investigating the agent in ESA-na&iuml;ve patients with low- to intermediate-risk MDS in the phase III COMMANDS study (NCT03682536).3

&ldquo;Luspatercept is a potential new therapy, we think, to be very effective in the treatment for patients with lower-risk MDS associated anemia ring sideroblasts who require red blood cell transfusions,&rdquo; concluded List.

David P. Steensma, MD, who moderated the press conference, agreed that, pending future research findings, luspatercept could be a useful agent in a treatment landscape that has not seen much progress in recent years.

&ldquo;It will be helpful to have this new addition to our MDS treatment arm,&rdquo; said Steensma, an associate professor of medicine and an attending physician at Dana-Farber Cancer Institute/Harvard Cancer Center in Boston, Massachusetts. &ldquo;It&rsquo;s been 12 years since we&rsquo;ve had an FDA-approved drug in MDS; there&rsquo;s been 7 in AML in the last year and a half. So, it&rsquo;s our turn.&rdquo;


  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) transfusion. Presented at: 2018 ASH Annual Meeting; Dec. 1-4, 2018; San Diego. Abstract 1.
  2. Platzbecker U, Germing U, G&ouml;tze KS, 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 [erratum in Lancet Oncol. 2017;18(10):e562].Lancet Oncol.2017;18(10):1338-1347. doi: 10.1016/S1470-2045(17)30615-0.
  3. Celgene and Acceleron announce luspatercept achieved primary and key secondary endpoints in phase III &lsquo;MEDALIST&rsquo; study in patients with low-to-intermediate risk myelodysplastic syndromes [news release]. Summit, NJ and Cambridge, MA: Celgene Corporation and Acceleron Pharma Inc; June 28, 2018. Accessed November 30, 2018.
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