Rami S. Komrokji, MD
The first-in-class activin receptor antagonist sotatercept (ACE-011) stimulated erythropoiesis in nearly half of patients with myelodysplastic syndromes (MDS) and non-proliferative chronic myelomonocytic leukemia (CMML) following failure on erythropoiesis-stimulating agents (ESA), according to results from an ongoing phase II study presented at the 2015 International MDS Symposium.
“Erythroid hematological improvement was achieved in 40% of high transplant burdened patients and sustained increases in hemoglobin levels were seen in the majority of low transplant burdened patients,” lead author Rami S. Komrokji, MD, clinical director, Department of Malignant Hematology, H. Lee Moffitt Cancer Center, said when the data were presented.
In the ongoing open-label phase II study, 59 patients with IPSS low/intermediate-1-risk MDS or non-proliferative CMML were treated with subcutaneous sotatercept at 0.1, 0.3, 0.5, or 1.0 mg/kg once every 3 weeks. Patients were enrolled into the 0.1 and 0.3 mg/kg arms concurrently while the 0.5 and 1.0 mg/kg doses were enrolled sequentially, following the demonstration of tolerability. The study continues to enroll patients at a 2.0-mg/kg dose (NCT01736683).
All patients had anemia (hemoglobin level ≤9.0 g/dL) and had no response, loss of response, or a low chance of response to ESAs (defined as serum erythropoietin > 500 mIU/mL). Fifty (85%) were categorized as having a high-transfusion burden (HTB), defined as ≥4 red blood cell (RBC) units within an 8-week period. Those who received less than 4 RBC units were categorized as having a low transfusion burden (LTB; n = 8 [15%]).
The primary endpoint of the study was erythroid hematological improvement (HI-E). In the LTB group, this was defined as an increase in hemoglobin levels of ≥1.5 g/dL. For the HTB group, HI-E was defined as a ≥4 unit decline in RBC transfusions within an 8-week timeframe.
The median age of patients was 71 years, the majority was male (70%), and the median number of RBC units received in an 8-week period was 6 at baseline. Most patients were categorized as having IPSS intermediate-1 risk disease (66%).
At the data cutoff of February 4, 2015, 54 patients were evaluable for efficacy. For the full population, the HI-E rate was 44%. At the 1.0-mg/kg dose (n = 20), the HI-E rates were 40% and 63%, in the HTB and LTB groups, respectively.
Overall, 20% in the HTB group and 80% of patients in the LTB group achieved transfusion independence. In the LTB arm, the mean hemoglobin level increased from 1.7 to 3.6 g/dL. The median hemoglobin increase was 2.0 g/dL.
“In the HTB group, some of the responses were durable, lasting for 1 to 2 years, although the numbers are small,” Komrokji noted. “In the LTB group, the median duration of response was 367 days. Patient with a hemoglobin of greater than 11 grams were subject to dose delays, per protocol, which may have impacted assessment of duration of hemoglobin increase.”
The response rates were higher in a subset of patients defined by ring sideroblast (RS) status, suggesting a possible biomarker of response for sotatercept. In the 1-mg/kg arm, the HI-E rate was 56% in those who tested positive (>15% expression) compared with 20% in RS-negative patients.
“This is an ongoing analysis. Molecular analysis from the study is ongoing, and we will soon have data for that,” Komrokji said. “Efficacy results for the sotatercept 2 mg/kg group are not included, due to limited data. However, those patients were included in the safety analysis.”
In all patients enrolled at the analysis, 88% experienced an adverse event during the study, most of which were not related to the treatment, Komrokji explained. The most common adverse events were fatigue, headache, decreased appetite, and nausea. Grade 3/4 adverse events were reported in 31% of patients (5% were treatment-related). Four patients discontinued the trial, due to treatment-related adverse events.
“We also interestingly observed some platelet and neutrophil response,” Komrokji said. “Increase in the platelets was observed in patients with baseline platelets of less than 100 and increase of ANC [absolute neutrophil count] of more than 500 was observed in 5 out of 5 patients with baseline of less than 1000.”
Sotatercept consists of the extracellular domain of the activin receptor type IIA linked with the Fc protein from immunoglobulin G1. The treatment binds to activin A and other proteins in the transforming growth factor beta family causing increases in hemoglobin levels and erythrocytes.
Numerous phase II studies continue to explore sotatercept as a potential treatment for patients with hematologic malignancies. The drug is being examined in combination with lenalidomide and dexamethasone in patients with relapsed/refractory multiple myeloma (NCT01562405) and as a single-agent for anemic patients with myeloproliferative neoplasm-associated myelofibrosis (NCT01712308).