Novel Concepts of Treatment for Patients with Myelofibrosis and Related Neoplasms

Abstract

Janus kinase (JAK) inhibition forms the cornerstone of the treatment of myelofibrosis (MF), and the JAK inhibitor ruxolitinib is often used as a second-line agent in patients with polycythemia vera (PV) who fail hydroxyurea (HU). In addition, ruxolitinib continues to be studied in patients with essential thrombocythemia (ET). The benefits of JAK inhibition in terms of splenomegaly and symptoms in patients with MF are undeniable, and ruxolitinib prolongs the survival of persons with higher risk MF. Despite this, however, "disease-modifying" effects of JAK inhibitors in MF, i.e., bone marrow fibrosis and mutant allele burden reduction, are limited. Similarly, in HU-resistant/intolerant PV, while ruxolitinib provides excellent control of the hematocrit, symptoms and splenomegaly, reduction in the rate of thromboembolic events has not been convincingly demonstrated. Furthermore, JAK inhibitors do not prevent disease evolution to MF or acute myeloid leukemia (AML). Frontline cytoreductive therapy for PV generally comprises HU and interferons, which have their own limitations. Numerous novel agents, representing diverse mechanisms of action, are in development for the treatment of these three classic myeloproliferative neoplasms (MPNs). JAK inhibitor-based combinations, all of which are currently under study for MF, have been covered elsewhere in this issue. In this article, we focus on agents that have been studied as monotherapy in patients with MF, generally after JAK inhibitor resistance/intolerance, as well as several novel compounds in development for PV/ET.

Keywords: CPI-0610; KRT-232; PRM-151; imetelstat; ropeginterferon alfa-2b.

Figure 1

Timeline of major milestones in MPN pathogenesis and therapy.

Figure 2

JAK2 transduces cytokine and growth factor signals from membrane-bound receptors through phosphorylation of the signal transducer and activator of transcription (STAT) family of transcription factors. Negative regulators of JAK2, such as LNK (lymphocyte adaptor protein), CBL (Casitas B-cell lymphoma) and SOCS (suppressor of cytokine signaling), lead to ubiquitinylation and proteasomal degradation of JAK2, whereas protein tyrosine phosphatases (PTPs) dephosphorylate cytokine receptors, JAKs, and STATs. The protein inhibitor of STATs (PIAS) prevents the binding of STATs to target DNA. JAK2 is a client of the chaperone protein heat shock protein 90 (HSP90), and HSP90 inhibitors and histone deacetylase 6 (HDAC6) inhibitors (through acetylation and disruption of HSP90 function) promote degradation of JAK2. JAK2 signals downstream of the PI3K/Akt/mTOR and Ras/Raf/MEK/ERK signaling cascades, which provides opportunities for combined inhibition of JAK2 and phosphatidylinositol-3-kinase (PI3K), mammalian target of rapamycin (mTOR) or mitogen activated protein kinase kinase 1/2 (MEK1/2). BH3 mimetics promote mitochondrial apoptosis, and synergism with ruxolitinib in MPN cells and animal models has been shown and validated in patients with myelofibrosis (MF). Synergism between ruxolitinib and the selective inhibitor of nuclear export (SINE) selinexor has also been demonstrated preclinically, and selinexor monotherapy is currently under study in a clinical trial in MF. Activated JAK2 promotes cell cycle progression, making combined inhibition of JAK2 and cyclin dependent kinases 4/6 (CDK4/6) a rational approach. Finally, nuclear JAK2 phosphorylates histone H3, activating transcription of many genes, including those encoding the proto-oncogene serine/threonine-protein (PIM) kinases, Bcl-xL, D-type cyclins, the cell cycle phosphatase CDC25A and SOCS (negative feedback). PIM kinase inhibitors are being studied, both alone and in combination with ruxolitinib. Epigenetic deregulation is frequent in MPNs, and combinations of ruxolitinib with epigenetic modifiers such as azacitidine and the bromodomain and extra-terminal (BET) protein inhibitor CPI-0610 have shown promise in patients with MF, as have single agents such as CPI-0610 or the lysine-specific demethylase 1 (LSD1) inhibitor, bomedemstat. Yet another epigenetic target is the arginine methyltransferase, PRMT5. Figure reproduced from Bose P, Verstovsek S. JAK2 inhibitors for myeloproliferative neoplasms: what is next? Blood. 2017, 130(2):115–125. © the American Society of Hematology.