Patients with myelofibrosis (MF) can experience a decline in hemoglobin levels when they are given the JAK inhibitor ruxolitinib (RUX) as first-line therapy; these levels eventually stabilize at lower-than-normal baseline range. This anemia—depending on degree and duration—can result in termination of RUX therapy in some patients, while historically various drugs aiming to treat MF-induced anemia have been largely ineffective.
Sotatercept (ACE-011) is a first-in-class, activin receptor type IIA ligand trap fusion protein approved for treating pulmonary hypertension. Sotatercept may improve anemia by regulating transforming growth factor beta (TGFβ) signaling and reducing production of red blood cells. This effect is currently under investigation in patients with MF. In this phase 2, open-label trial, sotatercept was administered subcutaneously every 3 weeks in patients with MF-mediated anemia. All patients considered for evaluation (n = 55) received sotatercept either as a monotherapy (n = 16; 0.75 mg/kg and n = 18; 1 mg/kg) or sotatercept (n = 21; 0.75 mg/kg) with a stable dose of RUX. Seventeen transfusion-dependent (TD) and 17 non-TD patients received sotatercept alone for a median of 11 cycles (range, 3-73). Patients must have been treated with RUX for ≥6 months and at a stable RUX dose for the 8 weeks prior to initiation of treatment with sotatercept.
Both TD and non-TD evaluable patients (27 and 19, respectively) achieved an anemia response rate with sotatercept alone (30%) and when used with a stable dose of RUX (32%). Although some non–response-evaluable patients in both cohorts achieved increases in hemoglobin (≥1.5 g/dL) from baseline, none were sustained for 12 weeks because of early termination from the trial. In addition, some responding patients with hemoglobin levels >11.5 g/dL required multiple breaks from and modifications to therapy, which was resumed once hemoglobin levels were <11.5 g/dL.
Seven (21%) patients treated with sotatercept alone were on-study for <84 days and not evaluable for response. Eight of 27 (30%) evaluable patients responded to sotatercept treatment at both the 0.75-mg/kg dose (n = 6) and the 1-mg/kg dose (n = 2). Of these, 5 showed anemia responses and 3 patients in the TD cohort achieved transfusion independence. Median time to anemia response was 19 days (range, 1-22 days) and median duration of response was 23.3 months (range, 3.9-68.4 months). Patients discontinued treatment for various reasons, primarily due to lack or loss of response (n = 14), progressive MF (n = 6), and interim stem-cell transplant (n = 4).
The cohort receiving combination sotatercept plus RUX was comprised of 15 non-TD patients and 6 TD patients. Median RUX dose at initiation of the study was 10 mg (range, 5-25) twice daily with a median number of cycles of 25 (range, 2-49). Two (10%) patients were on-study for <84 days and therefore not response-evaluable (1 having undergone a stem-cell transplant and 1 due to loss of insurance). Six of 19 (32%; all non-TD) evaluable patients in the combination cohort responded with median time to anemia response at 14 days (range, 6-147 days) and median duration of response, 18.2 months (range, 3.7-56.8 months). Discontinuation of treatment primarily resulted from lack or loss of anemia response to treatment (n = 8). The most common adverse treatment-related event reported in both the TD and non-TD cohorts was pain (n = 22), 15 occurrences of which were grade 1, 5 were grade 2, and 3 were grade 3.
Current study data indicate sotatercept was well-tolerated in both transfusion-dependent and ‑independent patients with MF-associated anemia. Taken together, the study provides support for the use of sotatercept in the MF treatment landscape, which should be further investigated.
Source: Bose P, Masarova L, Pemmaraju N, et al. Final results of a phase 2 study of sotatercept (ACE-011) for anemia of MPN-associated myelofibrosis. American Society of Hematology Annual Meeting and Exposition; December 11-14, 2021. Abstract 144.
