Next generation therapeutics for the treatment of myelofibrosis

Abstract

Myelofibrosis is a myeloproliferative neoplasm characterized by splenomegaly, constitu-tional symptoms, bone marrow fibrosis, and a propensity towards transformation to acute leuke-mia. JAK inhibitors are the only approved therapy for myelofibrosis and have been successful in reducing spleen and symptom burden. However, they do not significantly impact disease progression and many patients are ineligible due to coexisting cytopenias. Patients who are refractory to JAK inhibition also have a dismal survival. Therefore, non-JAK inhibitor-based therapies are being explored in pre-clinical and clinical settings. In this review, we discuss novel treatments in development for myelofibrosis with targets outside of the JAK-STAT pathway. We focus on the mecha-nism, preclinical rationale, and available clinical efficacy and safety information of relevant agents including those that target apoptosis (navitoclax, KRT-232, LCL-161, imetelstat), epigenetic modu-lation (CPI-0610, bomedemstat), the bone marrow microenvironment (PRM-151, AVID-200, alisertib), signal transduction pathways (parsaclisib), and miscellaneous agents (tagraxofusp. lus-patercept). We also provide commentary on the future of therapeutic development in myelofibrosis.