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.

Philadelphia-Negative MPN: A Molecular Journey, from Hematopoietic Stem Cell to Clinical Features

“…The first is a JAK2 inhibitor that showed a superior response in terms of reducing spleen volume and symptom burden compared to the best available therapy (in most cases, ruxolitinib) in patients with MF and thrombocytopenia [79]; the latter is a JAK1/2 inhibitor that showed a response in reducing transfusion burden, but less activity in reducing spleen size compared to the best available therapy (7% vs. 6%) in patients previously treated with ruxolitinib [80]. Another new drug under investigation is imetelstat, a telomerase inhibitor that showed promising results in terms of OS and symptoms burden in ruxolitinib-resistant MF in a phase 2 study [81,82].…”

Novel therapeutics for myelofibrosis

“…These requirements include management of anemia and thrombocytopenia, the prevention of the progression of MF to leukemia, prevention of suboptimal responses or resistance to ruxolitinib [ 29 ], and extension of the short overall survival (OS) [ 10 , 30 ]. Many researchers have focused on developing new monotherapies and rational combination treatments that exhibit complementary activity or act synergistically with ruxolitinib ( Table 1 ) [ 31 , 32 ]. Novel investigational agents may target biological pathways other than JAK/STAT, and/or enhance the efficacy of ruxolitinib.…”

Targeting Abnormal Hematopoietic Stem Cells in Chronic Myeloid Leukemia and Philadelphia Chromosome-Negative Classical Myeloproliferative Neoplasms

“…PIM kinase is a family of anti-apoptotic serine/threonine proto-oncogenes that are transcriptionally activated by JAK/STAT signalling [ 272 , 284 , 285 , 286 ]. In MPN, continuous activation of JAK/STAT pathway is observed, making PIM kinase a potential therapeutic target [ 272 , 286 ].…”

“…Efficacy is further demonstrated in a phase Ib clinical trial [ 301 ]. Although HDAC inhibitors exert multiple effects, poor tolerability remains a major issue [ 254 , 272 ] with the exception of treatment with givinostat in PV patients, which showed positive results in a few clinical trials [ 74 , 253 , 284 ] ( Table 3 ).…”