Luspatercept, a first-in-class erythroid maturation agent, significantly reduced the need for blood transfusions in more than 50% of patients with myelodysplastic syndromes (MDS) who were anemic, required regular red blood cell (RBC) transfusions, and/or had abnormal iron overload.
In the phase 3 MEDALIST clinical trial, 38% of patients randomized to the luspatercept arm were able to avoid RBC transfusions for at least 8 weeks, according to data presented at ASH 2018. Responses to luspatercept were durable—approximately 40% of patients remained transfusion-free after 1 year.
“Luspatercept is a potential new therapy, and we think it could be very effective in patients with lower-risk MDS and ring sideroblasts who are RBC transfusion–dependent,” said lead investigator Alan F. List, MD, President and Chief Executive Officer, Moffitt Cancer Center, Tampa, FL.
“For patients with lower-risk MDS, anemia is the most common symptomatic cytopenia that we deal with,” Dr List said. “For most of these patients over time, the disease becomes transfusion-dependent. With that comes the attendant complications of iron loading.”
Erythropoiesis-stimulating agents (ESAs) are a first-line treatment for anemia associated with lower-risk MDS, but few treatment options exist for those who are refractory to or ineligible for ESAs.
Luspatercept, which regulates late-stage RBC maturation, was evaluated in 229 patients with MDS-associated anemia and ring sideroblasts who require RBC transfusions. To be enrolled in the study, patients had to have a very low-, low-, or intermediate-risk MDS and ≥15% ring sideroblasts in the bone marrow or ≥5% ring sideroblasts and an SF3B1 mutation. All patients had either failed to respond to, were intolerant of, or were ineligible for ESA therapy and required RBC transfusions at least every 2 months.
Patients were randomized in a double-blind fashion to luspatercept (N = 153) or to placebo (N = 76), both administered via injection every 3 weeks for at least 6 months. Patients were followed for at least 3 years for progression of acute myeloid leukemia (AML), and their subsequent MDS treatment.
Patients received a median of 5 RBC units over 8 weeks during the 16 weeks before treatment. At baseline, 60.3% of patients had serum erythropoietin levels <200 IU/L, 25.3% had levels of 200 to 500 IU/L, and 14.0% had levels >500 IU/L. Most patients (95.2%) had previously received ESAs.
Overall, 37.9% of patients receiving luspatercept and 13.2% of those receiving placebo achieved RBC transfusion–independence (P <.0001) for at least 8 weeks, which was the study’s primary end point. In the luspatercept arm, 28.1% of patients had at least 12 weeks without a transfusion versus 8% in the placebo arm.
Overall, 53% of patients in the luspatercept arm had a significant reduction in the number of transfusions required or an increase in hemoglobin levels even without a transfusion compared with 11.8% of patients in the placebo arm.
“That’s a major reduction, and with that we also saw a decrease in ferritin over time with treatment, which we did not see in the placebo arm; ferritin levels just continued to increase,” Dr List said. “So it was impactful for decreasing iron loading and also potentially for quality of life.”
The median overall duration of transfusion independence was 31 weeks in the luspatercept arm versus 10 weeks in the placebo arm.
“The important thing is that it’s maintained in 40% of the patients for a year or longer,” he added.
“This was a very clean drug and very safe drug. There were no differences in treatment-emergent adverse events and absolutely no differences in severe adverse events or the frequency of progression of AML,” Dr List concluded.
The most common reported adverse effects with luspatercept treatment included fatigue and muscle pain.