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Tyrosine Kinase Inhibitors and Therapeutic Antibodies in Advanced Eosinophilic Disorders and Systemic Mastocytosis

  • Myeloproliferative Disorders (C Harrison, Section Editor)
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Abstract

World Health Organization-defined myeloproliferative neoplasms share a common pathobiologic theme of constitutive activation of tyrosine kinases (TKs). While myeloid/lymphoid neoplasms with eosinophilia and rearrangement of PDGFRA or PDGFRB exhibit exquisite responsiveness to imatinib, other eosinophilic disorders such as chronic eosinophilic leukemia—not otherwise specified (CEL-NOS) and idiopathic hypereosinophilic syndrome (HES) lack recurrent gene mutations or known druggable targets. In systemic mastocytosis (SM), KIT D816V is identified in ∼90 % of patients, but demonstrates imatinib resistance. Recently, the multikinase/KIT inhibitor midostaurin (PKC412) has demonstrated encouraging activity in patients with advanced SM, and selective KIT D816V inhibitors are entering clinical development. Pre-clinical rationale also exists for use of small molecule inhibitors of TK-linked pathways (e.g., BTK, JAK-STAT, PI3K/AKT, and FGFR1) that are implicated in normal or dysregulated signaling in eosinophils or mast cells. A complementary therapeutic approach is the use of naked antibody (e.g., mepolizumab and alemtuzumab) or antibody-based drug immunoconjugates (brentuximab vedotin) against targets expressed on the surface of eosinophils or mastocytes that can block proliferation and/or induce apoptosis of these cells. Ultimately, biologic and molecular characterization of eosinophilia and SM cases will help to optimize selection of TK inhibitors or therapeutic antibodies for individual patients.

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Conflict of Interest

Jason Gotlib declares the following conflicts of interest: Incyte, Inc.: receives funding to conduct a clinical trial of ruxolitinib in myelofibrosis; receives honoraria for serving on advisory boards; Pharmacyclics, Inc.: receives funding for administration of a clinical trial of ibrutinib in mastocytosis; Seattle Genetics: receives funding for conduct of a clinical trial with brentuximab vedotin in mastocytosis; Novartis, Inc.: receives funding to conduct clinical trials of midostaurin in mastocytosis and is Chair of study steering committee for the global trial of midostaurin in advanced mastocytosis.

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  1. Stanford University School of Medicine/Stanford Cancer Institute, 875 Blake Wilbur Drive, Room 2324, Stanford, CA, 94305-5821, USA

    Jason Gotlib

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  1. Jason Gotlib
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Correspondence to Jason Gotlib.

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This article is part of the Topical Collection on Myeloproliferative Disorders

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Gotlib, J. Tyrosine Kinase Inhibitors and Therapeutic Antibodies in Advanced Eosinophilic Disorders and Systemic Mastocytosis. Curr Hematol Malig Rep 10, 351–361 (2015). https://doi.org/10.1007/s11899-015-0280-3

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