The JAK1 inhibitor ruxolitinib is the only therapy approved by the U.S. Food and Drug Administration for myelofibrosis (MF), but it often worsens anemia, which is common in myeloproliferative neoplasm (MPN)-associated MF. According to data presented at the 2017 ASH Annual Meeting, the fusion protein sotatercept improves anemia symptoms in patients with MPN-associated MF, both as a single agent and when used in combination with ruxolitinib.
“Sotatercept binds to ligands that belong to the [transforming growth factor-beta] superfamily,” lead author Prithviraj Bose, MD, of the Department of Leukemia at the University of Texas MD Anderson Cancer Center in Houston, explained to ASH Clinical News. “By sequestering [these proteins], sotatercept inhibits them from binding to the type 2 receptors and suppressing erythropoiesis.”
Dr. Bose presented updated results from a phase II trial of sotatercept, a first-in-class, activin receptor IIA ligand trap, in adult patients with primary, post-polycythemia vera (PPV), or post-essential thrombocythemia (PET) MF. Patients were included in the study if they had a hemoglobin (Hgb) <10 g/dL during the 12 weeks preceding study entry, had a Hgb <10 g/dL with sporadic red blood cell (RBC) transfusions, or were RBC transfusion–dependent (defined by the International Working Group for Myeloproliferative Neoplasms Research and Treatment 2013 criteria).
“The trial was initially conceived of as a single-arm trial, with patients receiving sotatercept alone, but, seeing the activity in those patients, we realized a greater unmet need in patients on ruxolitinib, which actually worsens anemia initially,” Dr. Bose noted. “Adding sotatercept would be a way of counteracting that anemia and allowing patients to stay on ruxolitinib and optimize the dose.”
Thirty-five people were treated at the time of data presentation: Twenty-four patients (median age = 66.5 years; range = 47-83 years) received sotatercept monotherapy at subcutaneous doses of 0.75 mg/kg (n=11) or 1 mg/kg (n=13) every three weeks, and 11 patients (median age = 67 years; range = 57-75 years) received sotatercept 0.75 mg/kg plus ruxolitinib. Patients in the combination cohort had received ruxolitinib at a stable dose for at least six months within at least two months prior to study entry.
In the sotatercept monotherapy cohort, 20 patients had primary MF, three had PET MF, and one had PPV MF, with the following detected mutations: JAK2V617F (n=16), MPLW515L (n=3), and CALR exon 9 indels (n=3). One patient had none of these mutations, and in another, the driver mutation status was unknown. In 19 patients, the median number of prior therapies was one (range = 1-5 therapies), while five were treatment-naïve.
In the combination cohort, six patients had PMF, two had PPV MF, and one had myelodysplastic syndromes/MPN, with the following detected mutations: JAK2V617F (n=7), MPLW515L (n=1), and CALR exon 9 indels (n=1). Patients received a median of two prior therapies (range = 1-4 therapies).
The median time from diagnosis was 1.2 years (range = 0.2-5.8 years) in the monotherapy group and 1.9 years (range = 0.4-11 years) in the combination cohort.
At the time of presentation, 28 patients were evaluable for response, 18 in the monotherapy group and 10 in the combination group. Dr. Bose noted that “Patients were required to be on study for at least 12 weeks, to exclude people who had an improvement in Hgb but not a sustained improvement, or who went off study for some other reason.”
Seven of the 18 evaluable patients in the monotherapy group (39%) responded to sotatercept, including four people who experienced improvement in Hgb levels and three people who became transfusion-independent. The median time to response was seven days (range not provided), and the median duration of response was 12 months (range not provided). Responses occurred at both dose levels, across driver mutation types, in both previously treated and treatment-naïve patients, and in both RBC transfusion-dependent and -independent patients.
One patient in each sotatercept dosing cohort reported grade 2 bilateral lower limb pain that was deemed possibly related to treatment. One patient reported hypertension, which was also deemed possibly related to sotatercept.
Twenty-two patients discontinued therapy after a median of five cycles (range = 1-23 cycles) because of lack of response (n=7), progressive MF (n=5), proceeding to a hematopoietic cell transplantation (HCT; n=3), withdrawal of consent (n=3), hypertension (n=1), transformation to acute myeloid leukemia (n=1), and unrelated medical complications (n=1). Five people who discontinued treatment responded to sotatercept, and two patients still in the study have received 35 cycles each.
Of the 10 evaluable patients receiving both ruxolitinib and sotatercept, three responded to treatment (30%), which occurred at seven, 14, and 140 days of treatment. Response durations ranged between three and 15 months, and all responses are ongoing. Five patients, including the three responders, continue on the study. “There are no toxicity concerns with using the two drugs together,” Dr. Bose said, as the six discontinuations were related to lack of response (n=3) and proceeding to HCT (n=3).
The study’s findings are limited by its small patient population, single-center design, and that only patient who tolerated therapy for a sustained period of time were considered evaluable for response. “The agents we have for anemia right now are not particularly effective and are not really the answer,” Dr. Bose said, adding that the preliminary results of this study are encouraging for sotatercept. “The numbers are small, but we are clearly seeing responses in both cohorts and sotatercept [represents] a promising way forward.”
Enrollment in the study is ongoing, he added, with a planned enrollment of 40 patients in the monotherapy arm and 20 in the combination cohort.
The authors report financial relationships with Incyte, the manufacturers of ruxolitinib.
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. Abstract #255. Presented at the 2017 American Society of Hematology Annual Meeting, December 9, 2017; Atlanta, GA.