Novel and combination therapies for polycythemia vera and essential thrombocythemia: the dawn of a new era

Abstract

Introduction: Essential thrombocythemia (ET) and polycythemia vera (PV) belong to the BCR-ABL1-negative myeloproliferative neoplasms and are characterized by the clonal proliferation of hematopoietic stem and progenitor cells. The contribution of aberrant immune regulation within the bone marrow microenvironment to ET and PV pathogenesis as well as the underlying molecular landscape is becoming increasingly understood.

Areas covered: Authors searched PubMed and conference abstracts in August 2020 for preclinical and clinical studies to provide an overview of the immune pathobiology in ET and PV and the rationale for several novel agents. A discussion of recent clinical trials on interferon and ruxolitinib in ET and PV patients is provided followed by an outline of the future challenges in the field particularly for novel therapeutics and an increasingly individualized, molecularly driven approach to treatment selection. Several novel agents are currently being actively evaluated and are reviewed herein as well.

Expert opinion: While hydroxyurea remains the first-line treatment for cytoreduction in most high-risk ET and PV patients, the disease-modifying potential of IFN is promising and could make it a preferred option for selected patients. Advances in molecular testing will enable a more individualized approach to prognostication and treatment selection.

Keywords: Essential thrombocythemia; imetelstat; immunology; interferon; novel therapies; polycythemia vera; ruxolitinib.

Figure 1:. Mechanisms of action of novel therapies in ET and PV

JAK kinases are associated with and mediate signaling via EPO and MPL receptors. Mutated JAK2 and CALR activate cell proliferation via the JAK-STAT and RAS-RAF-MAPK pathways leading to proliferation of hematopoietic cells. JAK-STAT pathway activation can be inhibited by the JAK1/2 inhibitor ruxolitinib at the level of the EPO and MPL receptor. IFNs have been associated with a variety of mechanisms of action which are not fully elucidated to date. IFN has been associated with immunomodulatory effects, stimulation of HSC differentiation and apoptosis. Epigenetic processes such as DNA methylation and histone (de)acetylation can be targeted by HDAC inhibitors (e.g. vorinostat and givinostat), the LSD1 inhibitor IMG-7289, and hypomethylating agents. Navitoclax inhibits anti-apoptotic signaling via BCL-2 and has been successfully tested in myelofibrosis patients but not ET or PV.