Novel therapeutics and targets in myelofibrosis

Abstract

Myelofibrosis is a myeloproliferative neoplasm characterized by clonal proliferation of myeloid cells, bone marrow fibrosis and cytopenias, extramedullary hematopoiesis and hepatosplenomegaly, increased pro-inflammatory cytokine production, and systemic symptoms. Patients with MF also have a propensity toward leukemic transformation. Allogeneic hematopoietic stem cell transplantation (aHCT) is the only curative therapy for patients with MF; however, transplant-related morbidity and mortality precludes this option for the majority of patients. In the last decade, two targeted therapies have been approved for the treatment of MF, both JAK2 inhibitors, ruxolitinib and fedratinib. Despite the clinical efficacy of these two compounds in terms of splenomegaly and symptom burden reduction, there remain many areas of unmet need in the treatment of myelofibrosis. In this review, we discuss the limitations of currently approved treatment options and novel therapeutic targets with drug candidates in late-stage (phase II or III) clinical development for the treatment of MF. We delve into the mechanism of action and scientific rational of each candidate agent as well as the available clinical data, and ongoing trials that could lead to the approval of some of these novel therapies.

Keywords:

• Myelofibrosis
• novel therapies
• novel targets
• clinical trials
• targeted therapy

Author contributions

J.W., C.H., and J.M. contributed equally to writing, editing, and reviewing this paper without the assistance of a medical writer or contribution from a third party entity.

Disclosure statement

J.W. reports no conflicts of interest. J.M. receives clinical research funding paid to the institution from Incyte, Novartis, Roche, Merck, Kartos, CTI Bio, PharmaEssentia, Geron, Promedior, Forbius, Celgene/BMS, and consulting fees from Incyte, Celgene/BMS, Roche, Novartis, Sierra Oncology, CTI Bio, PharmaEssentia, Constellation, Kartos, and Karyopharm. C.H. reports grants and personal fees from Novartis, grants and personal fees from BMS, personal fees from Sierra Oncology, personal fees from CTI pharmaceuticals, personal fees from Jannsen, personal fees from Geron, grants and personal fees from AOP, personal fees from Galecto, grants, personal fees and other from Constellation.