Sotatercept for anemia of myelofibrosis: a phase II investigator-initiated study
Prithviraj Bose, Lucia Masárová, Naveen Pemmaraju, Sharon Bledsoe, Naval Daver, Elias Jabbour, Tapan M. Kadia, Zeev Estrov, Steven M. Kornblau, Michael Andreeff, Nitin Jain, Jörge E. Cortes, Gautam Borthakur, Yesid Alvarado, Mary Ann Richie, Mackenzie H. Dobbins, Selene Andrea McCrackin, Lingsha Zhou, Sherry Pierce, Xuemei Wang, Allison Pike, Guillermo Garcia‐Manero, Hagop M. Kantarjian, Srđan Verstovšek
Abstract
Sotatercept for anemia of myelofibrosis: a phase II investigator-initiated studyAnemia (hemoglobin <10 g/dL) is common in myelofibrosis (MF), present in about a third of patients at diagnosis and eventually developing in all patients.The Janus kinase 1/2 (JAK1/2) inhibitor ruxolitinib ameliorates splenomegaly and symptoms of MF and prolongs survival; 1 however, on-target anemia from JAK2 inhibition, especially pronounced in the first 12-24 weeks of therapy, is a significant problem.Anemia may be the most common cause of ruxolitinib discontinuation, 2 and frequently results in dose reduction.Spleen responses to ruxolitinib are dose-dependent and correlate with survival. 3,4Thus, counteracting ruxolitinib-induced anemia remains an important goal.Very recently, the JAK1/2 and activin receptor type 1 (ACVR1) inhibitor, momelotinib, was approved in the US for anemic patients with intermediate/high-risk myelofibrosis, based on the SIMPLIFY-1 and MOMENTUM trials. 5,6herapies currently used specifically for anemia of MF include corticosteroids, danazol, erythroid-stimulating agents (ESA) and immunomodulatory drugs, but responses are infrequent and often short-lived.Sotatercept (formerly ACE-011, Acceleron Pharma, Cambridge, MA, now Merck, Kenilworth, NJ), a novel fusion protein, is a first-in-class, activin receptor type IIA (ActRIIA) "ligand trap" that sequesters MF bone marrow-derived TGF-b superfamily ligands (such as Activin A and growth and differentiation factor 11) that inhibit terminal erythropoiesis via Smad signaling upon ActRIIA binding. 7,8Sotatercept demonstrated substantial efficacy in anemic patients with b-thalassemia and myelodysplastic syndromes (MDS). 9,10his was a phase II, open-label, single-institution, investigator-initiated trial (clinicaltrials gov.Identifier: NCT01712308).Adults (18 years) with primary MF (PMF) or post polycythemia vera/essential thrombocythemia myelofibrosis (post-PV/ET) MF were eligible if they were anemic (i.e., hemoglobin [Hg]b <10 g/dL sustained over 84 days preceding study entry without red blood cell [RBC] transfusions, or Hgb <10 g/dL with occasional transfusions but not RBC-transfusion dependant [TD] per International Working Group-Myeloproliferative Neoplasms Research and Treatment [IWG-MRT] criteria), or RBC-TD per IWG-MRT criteria. 11Sotatercept was administered subcutaneously every 3 weeks.All monotherapy patients after the first patient, who received 0.3 mg/kg, received 0.75 mg/kg or 1 mg/kg.Upon early demonstration of activity, a combination cohort was added: patients must have been on ruxolitinib for 6 months with a stable dose for the preceding 8 weeks.The sotatercept dose chosen for this cohort was 0.75 mg/kg, as most responses in the monotherapy cohort at the time had been observed at this dose.MF-directed therapies