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Review
. 2015;11(20):2819-30.
doi: 10.2217/fon.15.200. Epub 2015 Sep 14.

A comprehensive review of pacritinib in myelofibrosis

Srdan Verstovsek  1 , Rami S Komrokji  2
Affiliations
Review

A comprehensive review of pacritinib in myelofibrosis

Srdan Verstovsek et al. Future Oncol. 2015.

Abstract

The first-in-class JAK1/JAK2 inhibitor ruxolitinib inhibits JAK/STAT signaling, inducing durable reductions in splenomegaly and constitutional symptoms in patients with myelofibrosis. However, the association of ruxolitinib therapy with myelosuppression indicates the continued need for optimal treatment choices in myelofibrosis. Pacritinib, a dual JAK2 and FLT3 inhibitor, improves disease-related symptoms and signs with manageable gastrointestinal toxicity in patients with myelofibrosis with splenomegaly and high-risk features, without causing overt myelosuppression, and therefore may provide an important treatment option for a range of patients with myelofibrosis. This article examines the role of JAK2 and FLT3 signaling in myelofibrosis and provides an overview of the clinical development of pacritinib as a new therapy for myelofibrosis.

Keywords: FLT3; JAK2; efficacy; myelofibrosis; pacritinib; safety; tyrosine kinase inhibitor.

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Figures

Figure 1
Figure 1. Clinical manifestations of myelofibrosis
Most patients with myelofibrosis typically present with symptoms of anemia or splenomegaly, or with constitutional symptoms. Evolution of the disease can result in marrow failure, abdominal symptoms from advancing splenomegaly, and constitutional symptoms such as weight loss, night sweats, and low-grade fever. Extramedullary hematopoiesis in sites other than the spleen and liver can occur in advanced stages of the disease. Reproduced with permission from the American Society of Hematology .
Figure 2
Figure 2. Aberrant JAK/STAT signaling in myeloproliferative neoplasms
Upon cytokine binding, JAK2 molecules are recruited to cytokine receptors and phosphorylated, with subsequent recruitment and phosphorylation of STAT proteins. Phosphorylated STAT proteins dimerize and translocate to the nucleus, where they are involved in the transcription and regulation of multiple genes involved in cell proliferation, differentiation, and apoptosis. The JAK2V617F mutation causes constitutive activation of this signaling pathway and activation of STAT5 molecules in MF, as well as activation of PI3K/AKT and RAS/MAPK signaling. JAK2 inhibitors abrogate the JAK/STAT pathway through inhibition of the kinase activity of JAK2V617F. Reproduced with permission from the American Association of Cancer Research.
Figure 3
Figure 3. Proposed mechanism of action of pacritinib inhibition in JAK2 and FLT3 signaling pathways
Pacritinib has inhibitory effects in both the (A) FLT3 and (B) JAK/STAT signaling pathways. ITD in FLT3 and mutations in the tyrosine kinase domain results in constitutive activation of FLT3 kinase and downstream signaling pathways, including RAS/MAPK and PI3K/AKT. In addition, FLT3-ITD induces activation of STAT5 signaling. Pacritinib inhibits FLT3, FLT3-ITD, and the FLT3 tyrosine kinase domain mutant FLT3D835Y. ITD: Internal tandem duplication. Reproduced with permission from Dove Medical Press Ltd.
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