Alan List, MD
Treatment with luspatercept significantly reduced the need for frequent red blood cell (RBC) transfusions in nearly 53% of patients with anemia associated with low- to intermediate-risk myelodysplastic syndrome (MDS), according to results from the phase III Medalist trial presented at the 2018 ASH Annual Meeting.
Moreover, the novel agent was generally well tolerated among patients who required regular RBC transfusions and demonstrated abnormal iron overload in RBC precursors (ring sideroblasts) before participating in the trial, study investigator Alan F. List, MD, said during a press conference.
In the randomized trial, 37.9% of patients treated with luspatercept experienced RBC transfusion independence (RBC-TI) for ≥8 weeks, which was the primary endpoint of the study, compared with 13.2% in the placebo arm (odds ratio [OR], 5.1; P
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 ≥12 weeks compared with 7.9% of the placebo group (OR, 5.1; P
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.
“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,” said List, who also is a senior member in the Department of Malignant Hematology and the Experimental Therapeutics Program at Moffitt.
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.
Medalist Trial Details
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 ≥15% or ≥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 ≥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 ≥8 weeks between week 1 and week 24 served as the primary endpoint. Secondary endpoints included RBC-TI for ≥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 ≥4 RBC units over 8 weeks or a mean hemoglobin increase of ≥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 ≥6 RBC units/8 weeks, 27.9% who had ≥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.