WASHINGTON, DC—An investigational drug can increase hemoglobin levels and eliminate transfusion dependence in patients with lower-risk myelodysplastic syndromes (MDS), results of a phase 2 trial suggest.
The drug, luspatercept, is a modified activin receptor type IIB fusion protein that acts as a ligand trap for members in the TGF-β superfamily involved in the late stages of erythropoiesis.
Luspatercept regulates late-stage erythrocyte precursor differentiation and maturation.
Uwe Platzbecker, MD, of the University Hospital in Dresden, Germany, presented results from an ongoing phase 2 study of luspatercept at the 13th International Symposium on Myelodysplastic Syndromes (abstract 53).
The trial is supported by Acceleron Pharma Inc. and Celgene Corporation, the companies developing luspatercept.
“We are excited by the results in lower-risk MDS patients, which confirm and extend our previous findings,” Dr Platzbecker said. “Luspatercept may be useful early in the treatment of lower-risk MDS patients, either as the initial treatment for anemia or in patients who do not respond or become refractory to treatment with erythropoiesis-stimulating agents.”
Patient and dosing details
The researchers enrolled 58 patients in this study. Twenty-seven have completed treatment as part of the dose-escalation cohort. These patients received luspatercept at 7 doses ranging from 0.125 mg/kg to 1.75 mg/kg.
Thirty-one patients are still receiving treatment in the expansion cohort. The starting dose in this cohort is 1.0 mg/kg, and patients are receiving individual dose titration up to 1.75 mg/kg. Seventeen patients from this cohort received at least 4 cycles of treatment or discontinued early and were included in the analysis presented at the meeting.
In all, Dr Platzbecker presented results in 44 patients. Their median age was 71 (range, 27-88), and 57% were male. The median time since diagnosis was 2.5 years (range, 0.2-13.6 years). Sixty-one percent of patients had received prior treatment with erythropoiesis-stimulating agents, and 21% had received lenalidomide.
Fifteen patients had a low transfusion burden (LTB), as they received less than 4 units of red blood cells (RBCs) over 8 weeks. For these patients, the median hemoglobin at baseline was 9.0 g/dL (range, 6.8-10.1), and the median number of RBCs transfused over 8 weeks was 2 (range, 2-2).
Twenty-nine patients had a high transfusion burden (HTB) and received 4 or more RBC units over 8 weeks. The median number of RBCs transfused in this group was 6 (range, 4-14).
Fifty percent of patients had low-risk MDS according to IPSS, 46% had intermediate-1-risk disease, and 4% had intermediate-2-risk MDS. Eighty-one percent of patients were positive for ring sideroblasts, and 58% had the SF3B1 splicing mutation.
Efficacy and safety
The study’s primary efficacy endpoint was an increase in hemoglobin and/or a reduction in transfusion use. For LTB patients, the endpoint was a hemoglobin increase of 1.5 g/dL or more for 2 weeks or longer. For HTB patients, it was decrease in transfusion of 4 or more RBC units or a 50% or greater reduction in transfusion over 8 weeks.
Among the 9 patients who received lower doses of luspatercept (0.125-0.5 mg/kg), 33% met the primary efficacy endpoint. And 63% of the 35 patients in the higher dose group (0.75-1.75 mg/kg) achieved the primary efficacy endpoint.
Twenty-two percent of patients in the lower dose group achieved the International Working Group (IWG) hematologic improvement-erythroid (HI-E) threshold of efficacy, as did 54% of patients in the higher dose group.
Fourteen percent of patients in the lower dose group achieved transfusion independence, as did 36% of patients in the higher dose group. In the higher dose group, this included 4 of 6 patients with LTB and 6 of 22 patients with HTB.
Among patients who were ring-sideroblast-positive and received higher doses of luspatercept, 39% achieved transfusion independence, and 63% achieved IWG HI-E.
The majority of adverse events (AEs) were mild to moderate (grade 1 or 2). AEs included nasopharyngitis (14%), diarrhea (14%), myalgia (11%), bone pain (9%), bronchitis (9%), headache (9%), and muscle spasms (9%).
There were 2 serious AEs—grade 3 muscle pain and grade 3 worsening of general condition—that were considered possibly related to treatment. One non-serious grade 3 AE of blast cell count increase was considered possibly treatment-related as well.
In closing, Dr Platzbecker said luspatercept was generally safe and well-tolerated, in addition to providing “robust hematologic improvement.” And these results support further study of the drug in patients with lower-risk MDS.
