Novel Therapies for Myelofibrosis

Abstract

Purpose of Review To provide a contemporary update of novel agents and targets under investigation in myelofibrosis in the JAK inhibitor era. Recent findings Myelofibrosis (MF) is a clonal stem cell disease characterized by marrow fibrosis and a heterogeneous disease phenotype with a variable degree of splenomegaly, cytopenias, and constitutional symptoms that significantly impact quality of life and survival. Overactive JAK/STAT signaling is a hallmark of MF. The only approved therapy for MF, JAK1/2 inhibitor ruxolitinib, can ameliorate splenomegaly, improve symptoms, and prolong survival in some patients. Therapeutic challenges remain, however. Myelosuppression limits the use of ruxolitinib in some patients, eventual drug resistance is common, and the underlying malignant clone persists despite therapy. A deeper understanding of the pathogenesis of MF has informed the development of additional agents. Summary Promising targets under investigation include JAK1 and JAK2, downstream intermediates in related signaling pathways, epigenetic modifiers, pro-inflammatory cytokines, and immune regulators.

Programmed Cell Death Deregulation in BCR-ABL1-Negative Myeloproliferative Neoplasms

“…As shown previously, deregulation of the JAK/STAT pathway is central to MPN development and is driven in most cases by activating mutations in JAK2, CALR, or MPL. Signaling through other pathways (RAS/RAF/MEK/ERK, PI3K/AKT/mTOR, and LNK) and alterations in other cellular processes such as DNA methylation (e.g., TET2 and DNMT3A mutations), histone modification (ASXL1 and EZH2 mutations), and RNA splicing (U2AF1, SF3B1, and SRSF2 mutations) further contribute to initiation, progression of myeloproliferation, and resistance to apoptosis [52,97].…”

“…PIM inhibitors have shown preclinical synergy with JAK inhibitors, as well as the ability to overcome JAK inhibitor resistance in MPN cell lines. PIM regulate JAK/ STAT signaling and are involved in oncogenesis through phosphorylation of cell cycle regulators, activation of antiapoptotic proteins, and enhancement of MYC expression [97]. A phase 1b study of RUX plus PIM inhibitor PIM447, or RUX plus CDK4/6 inhibitor ribociclib (LEE011), or the combination of all three is underway in several non-U.S. countries (NCT02370706).…”

“…Due to the preclinically proved synergic effects of PI3K/AKT/mTOR inhibitors and JAK inhibitors, several clinical studies were initiated: PI3K inhibitor TGR-1202 in combination with RUX (NCT02493530), PI3K inhibitor buparlisib with RUX (NCT01730248), PI3K inhibitor INCB050465 and RUX (NCT02718300), and selective PI3Kδ inhibitor TGR-1202 and RUX (NCT02493530). Preliminary results of buparlisib and RUX phase 1b study indicated that this drug association was well tolerated, and ≥ 50% reduction in splenomegaly was observed in 70% of JAK-inhibitor naive patients and 54% of patients who did not previously respond to JAK2 inhibitor monotherapy [97,127].…”

“…Therefore, MEK inhibitors were tested in different murine models, either alone or in combination with JAK inhibitors, showing a decrease in bone marrow fibrosis, inhibition of malignant cell growth, and HSC function recovery, associated with a prolonged survival. Moreover, a new trial that combines the MEK inhibitor selumetinib with the DNA hypomethylating agent azacitidine is soon expected [97].…”

Pacritinib and its Use in the Treatment of Patients with Myelofibrosis who have Thrombocytopenia

“…Itacitinib (INCB039110) is a selective JAK1 inhibitor that is currently in Phase II, it has been essentially tested in patients with intermediate-high-risk MF and platelet counts of ≥50,000/μl looking at efficacy and safety of three dose levels, so far providing evidence of clinically meaningful symptom relief, the modest SVR and limited myelosuppression [56]. Itacitinib is also being evaluated in parallel in an open-label multicenter Phase II study in combination with low-dose ruxolitinib or itacinitib alone in patients with MF is currently recruiting participants [57].…”