Novel therapeutics in myeloproliferative neoplasms

Abstract

Hyperactive signaling of the Janus-Associated Kinase/Signal Transducers and Activators of Transcription (JAK/STAT) pathway is central to the pathogenesis of Philadelphia-chromosome-negative myeloproliferative neoplasms (MPN), i.e., polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF) which are characterized by inherent biological and clinical heterogeneity. Patients with MPNs suffer from substantial symptom burden and curtailed longevity due to thrombohemorrhagic complications or progression to myelofibrosis or acute myeloid leukemia. Therefore, the management strategies focus on thrombosis risk mitigation in PV/ET, alleviation of symptom burden and improvement in cytopenias and red blood cell transfusion requirements, and disease course alteration in PMF. The United States Food and Drug Administration's (USFDA) approval of two JAK inhibitors (ruxolitinib, fedratinib) has transformed the therapeutic landscape of MPNs in assuaging the need for frequent therapeutic phlebotomy (PV) and reduction in spleen and symptom burden (PV and PMF). Despite improving biological understanding of these complex clonal hematopoietic stem/progenitor cell neoplasms, none of the currently available therapies appear to modify the proclivity of the disease per se, thereby remaining an urgent unmet clinical need and an ongoing area of intense clinical investigation. This review will highlight the evolving targeted therapeutic agents that are in early- and late-stage MPN clinical development.

Keywords: CALR; CALR vaccine; ET; Fedratinib; Imetelstat; JAK-STAT; MF; PV; Pacritinib; Ruxolitinib.

Fig. 1

Agents in clinical development in MF. i—inhibitor; JAK—Janus-associated Kinase; PIM—Proviral Integration Site for Moloney Murine Leukemia Virus; PI3K—Phosphatidylinositol 3-Kinase; TGF—tumor growth factor; Hsp—heat-shock protein; AURKA—Aurora Kinase A;GSK—glycogen synthase kinase; NCT—nuclear-cytoplasmic transport; MAB—monoclonal antibody; NEDD—neddylation; BH—B-cell lymphoma homology; MDM—murine double minute; SMAC—second mitochondria-derived activator of caspases; TRAIL—tumor necrosis factor-related apoptosis inducing ligand; DNMT—DNA methyl transferase; IDH—isocitrate dehydrogenase; BET—bromodomain and extra-terminal motif; LSD1—lysine-specific demethylase 1

Fig. 2

Positioning of JAK inhibitors in the treatment schema of myelofibrosis. ESA—erythropoiesis-stimulating agent; EMA—erythroid maturation agent; IMiD—immunomodulatory imide drugs; BET—Bromodomain and Extraterminal domain Protein; PI3K—Phosphatidylinositol 3-Kinase; MDM—murine double minute; IDH—isocitrate dehydrogenase