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Role of tyrosine-kinase inhibitors in myeloproliferative neoplasms: comparative lessons learned

Authors Pinilla-Ibarz J, Sweet K, Corrales-Yepez G, Komrokji R, Linder B

Received 15 December 2015

Accepted for publication 8 April 2016

Published 10 August 2016 Volume 2016:9 Pages 4937—4957

DOI https://doi.org/10.2147/OTT.S102504

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Colin Mak

Peer reviewer comments 3

Editor who approved publication: Dr Faris Farassati


Javier Pinilla-Ibarz, Kendra L Sweet, Gabriela M Corrales-Yepez, Rami S Komrokji

Department of Malignant Hematology, H Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA

Abstract: An important pathogenetic distinction in the classification of myeloproliferative neoplasms (MPNs) is the presence or absence of the BCR–ABL fusion gene, which encodes a unique oncogenic tyrosine kinase. The BCR–ABL fusion, caused by the formation of the Philadelphia chromosome (Ph) through translocation, constitutes the disease-initiating event in chronic myeloid leukemia. The development of successive BCR–ABL-targeted tyrosine-kinase inhibitors has led to greatly improved outcomes in patients with chronic myeloid leukemia, including high rates of complete hematologic, cytogenetic, and molecular responses. Such levels of treatment success have long been elusive for patients with Ph-negative MPNs, because of the difficulties in identifying specific driver proteins suitable as drug targets. However, in recent years an improved understanding of the complex pathobiology of classic Ph-negative MPNs, characterized by variable, overlapping multimutation profiles, has prompted the development of better and more broadly targeted (to pathway rather than protein) treatment options, particularly JAK inhibitors. In classic Ph-negative MPNs, overactivation of JAK-dependent signaling pathways is a central pathogenic mechanism, and mutually exclusive mutations in JAK2, MPL, and CALR linked to aberrant JAK activation are now recognized as key drivers of disease progression in myelofibrosis (MF). In clinical trials, the JAK1/JAK2 inhibitor ruxolitinib – the first therapy approved for MF worldwide – improved disease-related splenomegaly and symptoms independent of JAK2V617F mutational status, and prolonged survival compared with placebo or standard therapy in patients with advanced MF. In separate trials, ruxolitinib also provided comprehensive hematologic control in patients with another Ph-negative MPN – polycythemia vera. However, complete cytogenetic or molecular responses with JAK inhibitors alone are normally not observed, underscoring the need for novel combination therapies of JAK inhibitors and complementary agents that better address the complexity of the pathobiology of classic Ph-negative MPNs. Here, we discuss the role of tyrosine-kinase inhibitors in the current MPN-treatment landscape.

Keywords: chronic myeloid leukemia, myelofibrosis, tyrosine-kinase inhibitors, ruxolitinib, JAK inhibitor

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