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

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.

• Authors: Jason Gotlib
• Journal: Current hematologic malignancy reports (Curr Hematol Malig Rep) Vol. 10 Issue 4 Pg. 351-61 (Dec 2015) ISSN: 1558-822X [Electronic] United States
• PMID: 26404639 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Review)

Chemical References

• Antibodies
• Protein Kinase Inhibitors

Topics

• Antibodies (metabolism)
• Eosinophilia (metabolism)
• Humans
• Mastocytosis, Systemic (drug therapy)
• Myeloproliferative Disorders (drug therapy)
• Protein Kinase Inhibitors (therapeutic use)