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Editorial Myeloproliferative Neoplasms
An Exciting New Era in the Treatment of
Naval Daver and Rita Assi
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas, US
M yeloproliferative neoplasms (MPNs), including primary myelofibrosis and myelofibrosis (MF) evolving from a pre-existing MPN
(post polycythemia vera- and post essential thrombocythemia-myelofibrosis) are clonal hematopoietic stem cell disorders with
heterogeneous symptoms, mutational profile, transformation risk and prognosis. Given the potentially chronic disease course, the
goal of therapy in MF is to alleviate associated signs and symptoms, including reduction in spleen size, weight gain, improved performance status,
and control of constitutional symptoms, leading to a prolonged survival and reduced transformation to leukemia.
Keywords Myeloproliferative neoplasms, interferon, Janus
kinase (JAK) inhibitors, targeted therapies
Disclosure: Rita Assi and Naval Daver has nothing to
declare in relation to this article. This article is a short
opinion piece and has not been submitted to external peer
reviewers, but was reviewed by the Editorial Board before
publication. Authorship: All named authors meet the International
Committee of Medical Journal Editors (ICMJE) criteria
for authorship of this manuscript. Rita Assi and Naval
Daver reviewed and collected the data, participated in
the discussion, wrote the manuscript, and approved the
current version of the manuscript.
Open Access: This article is published under the Creative
Commons Attribution Noncommercial License, which
permits any noncommercial use, distribution, adaptation,
and reproduction provided the original author(s) and source
are given appropriate credit.
Received: September 26, 2016
Published Online: November 2, 2016
Citation: Oncology & Hematology Review, 2016;12(2):71–4
Corresponding Author: Naval Daver, Department of
Leukemia, The University of Texas MD Anderson Cancer
Center, 1515 Holcombe Blvd, Unit 428, Houston, Texas, TX
77030, US. E: firstname.lastname@example.org
Support: This study was supported in part by the MD
Anderson Cancer Centre Support Grant (CCSG) CA016672.
Janus kinase/signal transducer and activator of
A major breakthrough in understanding the molecular drivers of myeloproliferative neoplasms
(MPNs) came in 2005, with the discovery of the Janus kinase 2 (JAK2) V617F driver mutation. 1
Mutated JAK activates a number of downstream pathways implicated in the proliferation and
survival of malignant cells, including the signal transducers and activators of transcription (STATs).
The pervasive activation of the JAK-STAT pathway in myelofibrosis (MF) lent credence to the
development JAK inhibitors. Two multicenter phase III clinical trials led to the approval of ruxolitinib,
a first-in-class JAK1/JAK2 inhibitor, initially in MF, 2,3 and more recently as second-line therapy in
hydroxyurea (HU)-resistant/intolerant polycythemia vera (PV). 4 In MF, ruxolitinib has been shown
to reduce spleen size, constitutional symptoms burden, induce hematologic (especially anemia)
improvements, reduce bone marrow fibrosis and JAK2 allele burden in a subset of patients, and
significantly improve five-year survival.
Janus kinase inhibitors
A number of novel JAK-inhibitors have entered clinical trials for patients with MF. 5 Pacritinib, an oral
dual JAK2 and FMS like tyrosine kinase 3 (FLT3) inhibitor has shown efficacy in reducing the spleen
size and symptom burden in patients with intermediate- and high-risk MF 6–8 with only marginal
worsening of anemia and thrombocytopenia, indicating that this agent could be administered in
patients with MF with low platelets at baseline, which is an area of unmet need. Unfortunately, the
pacritinib phase III study in MF was placed on hold by the US Food and Drug Administration (FDA)
effective February 2016, after an interim analysis showed increased mortality secondary to cardiac
events and intracranial bleeding.
Besides pacritinib, the clinical development of a number of other JAK2 inhibitors has been
prematurely halted due to drug-emergent toxicities. These included peripheral neuropathy
(seen with XL019), 9 Wernicke’s encephalopathy (with fedratinib), 10 and various toxicities recorded
with lestaurtinib. 11
Momelotinib remains the only other JAK inhibitor undergoing evaluation in a phase III trial for
patients with MF in the United States. In early phase trials, momelotinib showed significant clinical
improvements in anemia, splenomegaly, and constitutional symptoms. 12 The primary toxicity
associated with this agent was peripheral neuropathy. Momelotinib is currently being compared
to ruxolitinib in a phase III trial evaluating frontline therapy in patients with International Prognostic
Scoring System (IPSS) scores of intermediate-1 (Int-1) or -2 or high-risk MF who require therapy
(NCT01969838). Other selective JAK2 inhibitors currently under evaluation in phase I/II trials in MF
include NS018 and LY27A45445 (see Table 1).
TOU CH MED ICA L MEDIA