Is there a role for JAK inhibitors in BCR-ABL1-negative myeloproliferative neoplasms other than myelofibrosis?

Abstract

Current data suggest that constitutively active JAK-STAT signaling plays a central role in the pathogenesis of BCR-ABL1-negative myeloproliferative neoplasms (MPNs), regardless of the specific underlying molecular abnormality. This observation provides strong rationale for use of JAK inhibitors for MPN treatment, and these drugs were first tested in myelofibrosis (MF) patients. Ruxolitinib, a JAK-1/2 inhibitor, is effective at controlling splenomegaly and constitutional symptoms, but has limited benefit in reversing bone marrow fibrosis or inducing complete or partial remissions. Ruxolitinib is currently in Phase 3 testing for treatment of hydroxyurea resistant/intolerant polycythemia vera (PV). Preliminary data reveals response rates of 60% for hematocrit control and 38% for spleen volume reduction per protocol-defined criteria, in addition to improving disease-related symptoms. These endpoints however have limited value as surrogates for long-term clinically relevant outcomes such as freedom-from-cardiovascular/thrombohemorrhagic events or time-to-hematological transformation, and the early crossover design of the aforementioned trial introduces limitations in terms of analysis of these latter endpoints. In contrast, other recent trials in PV have demonstrated the feasibility of using long-term clinically relevant outcomes as a primary endpoint. We also discuss the role of JAK inhibitors for treatment of CSF3RT618I-mutated chronic neutrophilic leukemia and hematologic malignancies with rearranged JAK2 gene.

Keywords::

• polycythemia vera
• essential thrombocythemia
• chronic neutrophilic leukemia
• tyrosine kinase inhibitor
• JAK2V617F
• JAK2

Authorship contributions: This manuscript was conceived and written by AP and AT without the involvement of medical writers or other form of editorial support. Both approved the final version of the manuscript.

Conflict of interest: AP and AT have served as Principal Investigator for several clinical trials for treatment of myeloproliferative neoplasms with JAK inhibitors and other investigational drugs. Sponsor funding in these instances was limited to clinical trial support. AP has received research funding from Blueprint Medicines and Stemline Therapeutics.