Sotatercept, an investigational activin receptor IIA ligand trap, when used alone or in combination with ruxolitinib (Jakafi), safely increases hemoglobin levels in patients with myeloproliferative neoplasm–associated myelofibrosis, according to data from a phase 2, investigator-initiated clinical trial.
Data presented at ASH 2017 showed that 10 of 28 patients had a hemoglobin response or a transfusion-independent response—7 of 18 evaluable patients in a cohort receiving sotatercept monotherapy, and 3 of 10 in a cohort receiving sotatercept plus ruxolitinib, said Prithviraj Bose, MD, Assistant Professor, Department of Leukemia, MD Anderson Cancer Center, Houston, TX.
Ruxolitinib is the only medication approved by the FDA for the treatment of myelofibrosis, but it causes an initial decline in hemoglobin levels before they recover to a new and lower baseline. This anemia can prevent optimal dosing of ruxolitinib or lead to its discontinuation.
“This is important, because spleen responses to ruxolitinib are dose-dependent; therefore, optimization of the dose is important, and they also correlate with survival,” said Dr Bose.
Patients with primary polycythemia vera, post–polycythemia vera, or post–essential thrombocythemia myelofibrosis, and hemoglobin levels persistently <10 g/dL were enrolled in the study presented by Dr Bose. A monotherapy cohort was given sotatercept subcutaneously every 3 weeks at 0.75 mg/kg or 1 mg/kg. A second cohort received 0.75 mg/kg of sotatercept in combination with ruxolitinib; patients in that cohort had been receiving ruxolitinib for ≥6 months.
To be evaluable for response, patients had to be in the study for ≥84 days. 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 2013 criteria, and the hemoglobin response, defined as a hemoglobin increase from a baseline of ≥1.5 g/dL consecutively over ≥84 days without red blood cell transfusions.
To date, 35 patients have received treatment—24 in the monotherapy cohort and 11 in the ruxolitinib combination cohort. Among all patients, 3 had grade 3 hypertension, 2 had grade 2 hypertension, and 2 reported bilateral lower-limb pain.
Monotherapy: 39% Response Rate
Of the 24 patients receiving sotatercept monotherapy, 20 had primary myelofibrosis. Their median baseline hemoglobin level was 7.5 g/dL. A JAK2 driver mutation was detected in 16 patients. All 24 patients were intermediate-2 or high-risk on the Dynamic International Prognostic Scoring System (DIPSS). Bone marrow fibrosis was grade 3 in 15 patients, and grade 2 in 9 patients.
Overall, 7 of 18 evaluable patients in the monotherapy cohort had a response, 4 of which were hemoglobin responses and 3 transfusion-independent responses. Responses occurred at both doses evaluated. Two patients who were not evaluable because of insufficient time in the study had an increase of ≥1.5 g/dL in their hemoglobin level. The median time to response was 7 days, and the median duration of response was 12 months. Two patients continuing in the study have received 35 cycles each.
A total of 22 patients in the monotherapy cohort have discontinued therapy—7 because of lack of response, 5 because of myelofibrosis progression, 1 because of possible hypertension, and 1 because of transformation to acute myeloid leukemia.
Combination Therapy: 27% Response Rate
Of the 11 patients in the combination cohort, most had primary myelofibrosis, and their median baseline hemoglobin level was 7.2 g/dL. Most had JAK2 mutations. All were DIPSS intermediate-2 or high-risk, and most had grade ≥2 bone marrow fibrosis. Of the 11 patients, 10 were evaluable, and 3 were responders.
“All of the responses [in the combination cohort] were in anemic subjects; we did not actually see responses in transfusion-dependent subjects in this cohort,” said Dr Bose.
There were 3 responders; responses began at 7, 14, and 140 days. Response durations are 3, 4, and 15 months, and the responses are ongoing. Five patients, including the 3 responders, continue in the study. Six patients discontinued—3 because of lack of response, and 3 because they had allogeneic transplants.
A multicenter, phase 2 clinical trial of a related drug, luspatercept, is planned in patients with myelofibrosis and anemia.