Sotatercept Boosts Hemoglobin in MPN-Associated Myelofibrosis

December 15, 2017
Wayne Kuznar

The investigational activin receptor IIA ligand trap sotatercept safely increases hemoglobin levels in patients with myeloproliferative neoplasm (MPN)-associated myelofibrosis, both when used alone and in combination with ruxolitinib (Jakafi).

Prithviraj Bose, MD

The investigational activin receptor IIA ligand trap sotatercept safely increases hemoglobin levels in patients with myeloproliferative neoplasm (MPN)-associated myelofibrosis, both when used alone and in combination with ruxolitinib (Jakafi).

A phase II investigator-initiated trial of sotatercept in this population showed responses in 10 of 28 evaluable patients, said Prithviraj Bose, MD, of updated findings presented at the 2017 ASH Annual Meeting.

Anemia is present in about one-third of patients with myelofibrosis at diagnosis and eventually develops in all patients. Only 20% to 30% of patients respond to current therapy, such as danazol and erythroid-stimulating agents.

The JAK1 inhibitor ruxolitinib is the only therapy approved by the FDA for the treatment of myelofibrosis. It initially causes a decline in hemoglobin levels before patients recover to a new and lower baseline. “Although anemia caused by ruxolitinib is not prognostically adverse, unlike disease-associated anemia, it is still a clinical problem because it prevents optimal dosing, or worse, result in its discontinuation prematurely,” said Bose, of the Department of Leukemia at The University of Texas MD Anderson Cancer Center in Houston. “This is important because spleen responses to ruxolitinib are dose-dependent; therefore, optimization of the dose is important, and they also correlate with survival.”

Sotatercept is a first-in-class activin receptor IIA ligand trap. It is a fusion protein consisting of the extracellular domain of the activin receptor IIA conjugated to the Fc fragment of human IgG1. “This fusion protein traps ligands of the TGF-ß superfamily and prevents them from binding to the activin receptor, thereby blocking the activation of the SMAD family of transcription factors and removing the inhibitory effect that these ligands have on the terminal stages of erythropoiesis,” he said.

Separately, sotatercept has also been shown to improve erythropoiesis in models of beta thalassemia, Diamond-Blackfan anemia, and hepcidin transgenic mice. Clinically, it has been shown effective in patients with anemia and lower-risk myelodysplastic syndromes.

In the phase II study, patients with primary or post-polycythemia vera (PV) or post-essential thrombocythemia (ET) myelofibrosis with hemoglobin levels persistently <10 g/dL, defined as ≥84 days preceding study entry, were enrolled into 1 of 2 cohorts. The monotherapy cohort was dosed with sotatercept subcutaneously every 3 weeks at either 0.75 mg/kg or 1 mg/kg. The combination cohort received 0.75 mg/kg in combination with ruxolitinib; patients in this cohort had been on ruxolitinib for ≥6 months with a stable dose of ruxolitinib for ≥2 months.

To be evaluable for response, patients had to have been on the study for ≥84 days. Response was defined as a hemoglobin response or a transfusion-independent response.

The overall response rate was a composite of the rate of transfusion independence, as defined by the International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) 2013 criteria, and the hemoglobin response, defined as a persistent (≥84 days) hemoglobin increase from baseline of ≥1.5 g/dL without red blood cell transfusions.

To date, 35 patients have been treated in the trial, 24 in the monotherapy cohort and 11 who were entered into the ruxolitinib combination cohort.

Of the 24 patients in the sotatercept monotherapy cohort, 20 had primary myelofibrosis. Ten were women and 14 were men, their median age was 66.5 years, and their median baseline hemoglobin level was 7.5 g/dL. AJAK2driver mutation was detected in 16 of the 24 patients. All 24 patients were intermediate-2 (n = 19) or high (n = 5) risk on the Dynamic International Prognostic Scoring System (DIPSS). Bone marrow fibrosis was grade ≥2 in all patients.

In the monotherapy cohort, 18 were evaluable for response. Seven of the 18 had a response, 4 of which were hemoglobin responses and 3 transfusion-independence responses. Responses occurred at both doses evaluated. Additionally, 2 patients not evaluable because of an insufficient time on the study had an increase from baseline in their hemoglobin level ≥1.5 g/dL. The median time to response was 7 days and the median duration of response was 12 months. Two patients who continue in the study have received 35 cycles each.

Twenty-two of the 24 in the monotherapy cohort have discontinued therapy: 1 due to possible toxicity (hypertension), 7 due to lack of response, 5 due to myelofibrosis progression in other aspects (ie, spleen symptoms), 3 went to allogeneic transplant, 3 withdrew consent, and 1 due to unrelated medical problems, 1 had transformation to acute myeloid leukemia, and 1 removed due to inability to comply with study requirements. Five of the 22 who discontinued were responders.

Of the 11 (7 men, 4 women) treated in the combination cohort, most had primary myelofibrosis. Their median age was 68 years, their median hemoglobin level at baseline was 7.2 g/dL, and most hadJAK2mutations. All were DIPSS intermediate-2 or high-risk and most had grade ≥2 bone marrow fibrosis. No patient had splenomegaly.

In the combination cohort, 10 of the 11 patients were evaluable, and there were 3 responses. “All of the responses were in anemic subjects; we did not actually see responses in transfusion-dependent subjects in this cohort,” said Bose. One patient who was not evaluable also had ≥1.5-g/dL in hemoglobin. In the 3 responders, responses began at 7, 14, and 140 days. Response durations are 3, 4, and 15 months, and all responses are ongoing. Five patients, including the 3 responders, continue on the study. The 6 discontinuations are due to lack of response (n = 3) and allogeneic transplant (n = 3).

Among all patients in the study, 3 had grade 3 hypertension and 2 had grade 2 hypertension and 2 reported bilateral lower limb pain. “The hypertension did not occur in the context of polycythemia, so this was not a high hemoglobin-related problem,” he said.

“In this investigator-initiated trial, we plan an enrollment of a total of 60 subjects,” said Bose. “There is a related drug called luspatercept (ACE-536) that is promising in anemic patients with low-risk myelodysplastic syndrome, and they have actually completed a pivotal trial in that population and now they’re going to start a multicenter phase II trial of luspatercept in myelofibrosis patients with anemia.”


Bose P, Daver N, Pemmaraju N, et al. Sotatercept (ACE-011) alone and in combination with ruxolitinib in patients (pts) with myeloproliferative neoplasm (MPN)-associated myelofibrosis (MF) and anemia. Presented at: 2017 ASH Annual Meeting; December 9-12, 2017. Abstract 255.