Abstract
Simple SummaryMyelofibrosis (MF) is an advanced form of a group of rare, related bone marrow cancers termed myeloproliferative neoplasms (MPNs). Some patients develop myelofibrosis from the outset, while in others, it occurs as a complication of the more indolent MPNs, polycythemia vera (PV) or essential thrombocythemia (ET). Patients with PV or ET who require drug treatment are typically treated with the chemotherapy drug hydroxyurea, while in MF, the targeted therapies termed Janus kinase (JAK) inhibitors form the mainstay of treatment. However, these and other drugs (e.g., interferons) have important limitations. No drug has been shown to reliably prevent the progression of PV or ET to MF or transformation of MPNs to acute myeloid leukemia. In PV, it is not conclusively known if JAK inhibitors reduce the risk of blood clots, and in MF, these drugs do not improve low blood counts. New approaches to treating MF and related MPNs are, therefore, necessary.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.
Highlights
Given the universal activation of the Janus kinase (JAK) signal transducer and activator of transcription (STAT) signaling observed in the classic, Philadelphia chromosome (Ph)-negative myeloproliferative neoplasms (MPNs) [1], the central role that JAK inhibitors play in these diseases is not surprising [2,3]
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 polycythemia vera (PV)/essential thrombocythemia (ET)
The widespread use of JAK inhibitors has brought the need for effective treatment of anemia further into focus, and the development of the activin receptor ligand traps has been exciting in this regard [100]
Summary
Given the universal activation of the Janus kinase (JAK) signal transducer and activator of transcription (STAT) signaling observed in the classic, Philadelphia chromosome (Ph)-negative myeloproliferative neoplasms (MPNs) [1], the central role that JAK inhibitors play in these diseases is not surprising [2,3]. Ruxolitinib has not been shown to statistically significantly reduce the risk of thromboembolic events, a major goal of therapy, in patients with PV [25], it does provide sustained control of the hematocrit, leukocyte and platelet counts, splenomegaly and symptoms [26]. 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. Another epigenetic target is the arginine methyltransferase, PRMT5.
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