Luspatercept Leads to Increased Hemoglobin Levels, Transfusion Independence in MDS Patients

Treatment with luspatercept, an investigational fusion protein for the treatment of anemias with ineffective red blood cell (RBC) production, was associated with increased hemoglobin counts and greater rates of transfusion-independence in patients with lower-risk myelodysplastic syndromes (MDS), according to preliminary data from the phase II PACE-MDS extension study.

“MDS patients have increase Smad2/3 signaling in the bone marrow, leading to ineffective erythropoiesis,” lead author Aristoteles Giagounidis, MD, PhD, head of the Department of Oncology, Hematology, and Palliative Care at Marien Hospital in Düsseldorf, Germany, explained in his presentation during the 2015 ASH Annual Meeting in Orlando, Florida.

“Luspatercept inhibits Smad2/3 signaling and promotes late-stage erythroid differentiation, thereby correcting the ineffective erythropoiesis.” Luspatercept contains a modified activin receptor B, fused to a human IgG Fc domain. The activin receptor is responsible for blockade of TGF-beta superfamily ligands, which in turn inhibits Smad2/3 signaling.

Dr. Giagounidis reported results from the 24-month extension of the phase II, multi-center, open-label PACE-MDS study, which evaluated the longer-term effects of luspatercept on anemia in 32 patients with lower-risk MDS (IPSS classification of low/int-1). In the PACE-MDS base study, patients were eligible for inclusion if they were ≥18 years old, had anemia with high or low transfusion burden and hemoglobin <10.0 g/dL, and were non-responsive or refractory to erythropoiesis-stimulating agents (ESA).

Luspatercept was administered via subcutaneous injection once every three weeks in sequential cohorts at dose levels ranging from 0.125 to 1.75 mg/kg for up to five doses. Patients were followed for three months. Patients who completed the three-month base study were then eligible for enrollment in the expansion cohort; the starting dose level was 1.0 mg/kg, and individual patient dose adjustment was allowed, with patients continuing to receive luspatercept every three weeks for up to 24 months.

Of these 32 patients, 13 patients had a low transfusion burden (LTB; patients requiring <4 RBC units per 8 weeks), and 19 had a high transfusion burden (HTB; patients requiring ≥4 RBC units per 8 weeks).

Most patients (59%) had been treated previously with ESA therapy, and 19 percent had been treated with lenalidomide. Patients had received continuous luspatercept treatment for a median of eight cycles (range = 5-12). Twenty-nine patients (91%) were ring sideroblast positive (≥15% of erythroid cells in bone marrow samples were ring sideroblasts).

Nine of the 13 LTB patients (69%) achieved an erythroid response, defined as a hemoglobin increase ≥1.5 g/dL for eight or more weeks. At the data cut-off date, the mean increase in hemoglobin reached levels between 2.0 and 2.5 g/dL and was maintained for nine months. Numbers were similar in the HTB group: 13 of 19 (68%) patients achieved an erythroid response, defined as a reduction of ≥4 RBC units transfused over eight weeks. Notably, eight of these patients (42%) achieved transfusion independence for eight or more weeks.

Five of the seven patients considered ineligible for ESAs achieved an erythroid response, Dr. Giagounidis added, with two patients achieving transfusion independence.

Luspatercept has been generally well tolerated in the extension study, the authors noted, with no grade 3 or higher related adverse events reported. The most common adverse events included bone pain, headache, hypotonia, myalgia, and nausea.

“These results for longer-term luspatercept treatment in lower-risk MDS patients are very exciting,” Dr. Giagounidis said. “There is substantial unmet medical need for patients who do not respond or become refractory to treatment with ESAs or who are considered ineligible to receive them.”

Given the “encouraging activity” of luspatercept in these patients, he added, the drug is now being studied in the phase III MEDALIST study of patients with very low- to intermediate-risk MDS.


Giagounidis A, Platzbecker U, Germing U, et al. Luspatercept treatment leads to long-term increases in hemoglobin and reductions in transfusion burden in patients with low or intermediate-1 risk myelodysplastic syndromes (MDS): preliminary results from the phase 2 PACE-MDS extension study. Abstract #92. Presented at the 2015 ASH Annual Meeting, December 5, 2015; Orlando, Florida.