Novel Therapies in Myelofibrosis: Beyond JAK Inhibitors

To discuss the current treatment paradigm, review novel targets, and summarize completed and ongoing clinical trials that may lead to a paradigm shifts in the management of myelofibrosis (MF).

In addition to the recent approval and ongoing late-stage development of multiple novel JAK inhibitors, recent clinical studies demonstrate therapeutic potential of targeting multiple alternate proteins and pathways including BET, MDM2, telomerase, BCL2, LSD1, PI3K, SMAC, and PTX2 in patients with MF. MF is a myeloproliferative neoplasm characterized by clonal proliferation of myeloid cells and bone marrow fibrosis often causing cytopenias, extramedullary hematopoiesis resulting in hepatosplenomegaly, and increased pro-inflammatory cytokine production driving systemic symptoms. A significant proportion of morbidity and mortality is related to the propensity to transform to acute leukemia. Allogeneic hematopoietic stem cell transplantation is the only curative therapy; however, due to the high associated mortality, this treatment is not an option for the majority of patients with MF. Currently, there are three targeted Food and Drug Administration (FDA)-approved therapies for MF which include ruxolitinib, fedratinib, and pacritinib, all part of the JAK inhibitor class. Many patients are unable to tolerate, do not respond, or develop resistance to existing therapies, leaving a large unmet medical need. In this review, we discuss the current treatment paradigm and novel therapies in development for the treatment of MF. We review the scientific rationale of each targeted pathway. We summarize updated clinical data and ongoing trials that may lead to FDA approval of these agents.