Luspatercept Eyes Treatment of Anemia in Low-Risk MDS

Alexander M. Castellino, PhD

September 27, 2017

Myelodysplastic syndromes (MDS) — clonal stem-cell disorders — are characterized by anemia and a risk for transformation to leukemia. A mainstay of treatment in low-risk or intermediate-risk patients (defined by the International Prognostic Scoring System) is anemia management by the use of erythropoiesis-stimulating agents (ESAs).

But a new approach is under investigation. Luspatercept (under development by Acceleron Pharma and Celgene), a non-ESA agent, may emerge as an option to treat anemia in these patients if the promise of a phase 2 trial is borne out in future studies.

The phase 2 trial, known as PACE-MDS, was published online September 1 in Lancet Oncology. It showed  that luspatercept was associated with high rates of hematologic improvement and a high percentage of patients achieving red blood cell transfusion independence (RBC-TI).

"The efficacy and safety results in this phase 2 study support continued research into luspatercept for the treatment of refractory anemia, which often requires red blood cell transfusions in lower-risk MDS patients," said lead author, Uwe Platzbecker, MD, in a statement. "This novel investigational therapy has the potential to address a significant need in MDS patients who currently have very limited options for managing chronic anemia. We have already begun exploring luspatercept's activity across a range of MDS patient populations," he added.

Dr Platzbecker is professor of hematology and head of the MDS program at the University Hospital in Dresden, Germany.

Luspatercept is a chimeric protein composed of the extracellular domain of the activin receptor IIB stabilized by the Fc region of IgG. It acts as a ligand trap for members of the transforming growth factor-β superfamily involved in the late stages of erythropoiesis. Unlike ESAs, which stimulate early-stage erythrocyte precursor cells, luspatercept promotes late-stage erythrocyte precursor cell differentiation and maturation.

"[This study] has not only potentially opened new avenues for treatment of lower risk anaemic patients with myelodysplastic syndrome, but also has implications for the understanding the biology of myelodysplastic syndrome," writes Valeria Santini, MD, from the Department of Hematology, AOU Careggi University of Florence, Florence, Italy, in an accompanying commentary.

"ESAs are active in relieving anaemia, but their use in myelodysplastic syndrome has been empirical, and over the years the variables for evaluating responses have been challenging," she adds.


PACE-MDS was a phase 2, multicenter, dose-finding study, with long-term extension. Patients with International Prognostic Scoring System–defined low- or intermediate 1–risk MDS or nonproliferative chronic myelomonocytic leukemia were enrolled in the study.

Patients with low transfusion burden required fewer than four red blood cell units in the 8 weeks before treatment and baseline hemoglobin (Hb) level less than 10 g/dL; those with high transfusion burden required four or more red blood cell units.

Luspatercept was given subcutaneously once every 21 days at dose concentrations ranging from 0.125 mg/kg to 1.75 mg/kg. The study was done in two stages. In the base stage, patients received up to five doses over 12 weeks—from 0.125 mg/kg to 1.75 mg/kg. In the expansion phase, patients received luspatercept 1.0 mg/kg and dose titration to 1.75 mg/kg was allowed. Patients could be treated with luspatercept for a maximum of 5 years. The decision to enroll patients in the extension phase was based on recommendations from the safety review team.

The primary efficacy endpoint was modified hematologic improvement–erythroid (mHI-E) response. For patients with low transfusion burden, this was defined as Hb increase of at least 1.5 g/dL from baseline for at least 14 days in the absence of any transfusion. For those with high transfusion burden, mHI-E was defined as a reduction (vs pretreatment burden) in transfusion of four red blood cell units or more or a 50% or greater reduction in red blood cell units over 8 weeks.


Review of the efficacy data showed that doses between 0.125 and 0.5 mg/kg were subtherapeutic. Of 71 patients enrolled, 58 entered the study in the base phase; a total of 32 patients were enrolled in the extension phase. Of 71 patients, 51 received the higher dose concentrations (0.75 to 1.75 mg/kg) during the base and extension phases of the study.

"Our findings suggest that luspatercept 1.0 mg/kg body weight is the appropriate starting dose for further studies," the study authors noted.

Median follow-up was 3 months. Increases in mean Hb concentrations, which approached 2 g/dL, were sustained for at least 15 months in 13 patients with low transfusion burden receiving high doses of luspatercept. Of 51 patients who received therapeutic concentrations of luspatercept, 32 (63%) achieved mHI-E responses. Based on transfusion burden, 65% (11 of 17) patients with low transfusion burden showed mHI-E responses. Median duration of response was 8.3 months; mean time to response was 2.3 months. Of patients with high transfusion burden, 62% (21 of 34) showed mHI-E responses.

An RBC-TI response occurred in 38% of patients overall compared with 75% of patients with low transfusion burden and 29% of patients with high transfusion burden.

Prior use of ESA did not determine mHI-E response rates: 62% for patients with prior ESA use and 65% for patients without prior ESA use showed mHI-E responses.

The mHI-E response rate was highest (76%) in patients with low serum erythropoietin (<200 IU/L) concentration at baseline and lowest (43%) in patients with high serum erythropoietin (>500 IU/L) concentration at baseline.

"This shows that luspatercept is effective even in patients with higher erythropoietin concentrations, which are associated with poor ESA response," write the study investigators.

Of patients with ring sideroblasts who show refractory anemia, 69% showed mHI-E responses and 42% were reported to show an RBC-TI.

SF3B1 mutational status was strongly associated with responses. Higher mHI-E response rates were seen in 24 of 31 (77%) patients with SF3B1, the most common mutation seen in MDS.

"Luspatercept treatment was found to be particularly effective in patients who had 15% or higher ring sideroblasts, or an SF3B1 mutation, or both," the study authors noted.

The study had its limitations: single-arm, open-label design; small numbers of patients in certain subgroups; the extension study's inclusion of patients who responded in the base study.

Although few patients experienced low-grade adverse events, "in view of the relatively short follow up of clinical studies and the need for continuous treatment, the possibility of long-term adverse events remains," comments Dr Santini.

"Nevertheless, the activity and tolerability of this agent have prompted a[n] extremely rapid enrolment in the randomised study [NCT02631070] designed for patients with refractory anaemia with ring sideroblasts," Dr Santini notes. This is the MEDALIST study, an international phase 3 study that has been fully enrolled and will read out in mid-2018. The COMMANDS phase 3 study in first-line, lower-risk patients with MDS is planned to roll out in 2018.

A phase 2 study is also evaluating the efficacy of luspatercept in myelofibrosis. Given its mechanism of action, luspatercept is also being evaluated in medical scenarios outside oncology. For example, the BELIEVE study (NCT02604433) has enrolled patients with beta-thalassemia.

PACE-MDS was funded by Acceleron Pharma, which is developing luspatercept in partnership with Celgene Corporation. Several authors on the study, including Dr Platzbecker, have received honoraria and research support from Acceleron Pharma and Celgene. Dr Santini has reported receiving grants and personal fees from Celgene and personal fees from Janssen, Novartis, Otsuka, and AbbVie outside of this work.

Lancet Oncol. Published online September 1, 2017. Abstract, Comment  

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