title: 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.affiliation: Stanford University School of Medicine/Stanford Cancer Institute, 875 Blake Wilbur Drive, Room 2324, Stanford, CA, 94305-5821, USA. Jason.gotlib@stanford.edu.
authors.forename: Jason
authors.initials: J
authors.lastname: Gotlib
mesh_terms: D000906:Antibodies / Q000378:metabolism*; D004802:Eosinophilia / Q000378:metabolism*; D006801:Humans; D034721:Mastocytosis, Systemic / Q000188:drug therapy*; D009196:Myeloproliferative Disorders / Q000188:drug therapy*; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*
chemical_list: D000906:Antibodies; D047428:Protein Kinase Inhibitors
keywords: Idiopathic hypereosinophilic syndrome; Myeloproliferative disorders; Tyrosine kinase inhibitors