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Targeted therapy in KITD816V-positive mastocytosis: waiting for proof-of-principle

Mastocytosis results from clonal proliferation of mast cells. The World Health Organization (WHO) classification system for hematologic malignancies recognizes several categories of mastocytosis including: (i) cutaneous mastocytosis (limited to the skin, and variants include urticaria pigmentosa, cutaneous mastocytoma, diffuse cutaneous mastocytosis, and telangiectasia macularis eruptiva perstans), (ii) extracutaneous mastocytoma (unifocal non-destructive mast cell tumor with low-grade cellular atypia), (iii) mast cell sarcoma (destructive unifocal mast cell tumor with poorly differentiated mast cells), and (iv) systemic mastocytosis (SM) [1]. SM always involves the bone marrow, and is the predominant form of mastocytosis in adults. The WHO system subclassifies SM into four subcategories: indolent SM (ISM; no evidence of extracutaneous organ dysfunction), aggressive SM (ASM; presence of extracutaneous organ dysfunction), SM associated with another clonal hematological non-mast cell lineage disease (SM-AHNMD), and mast cell leukemia (MCL) [1]. MCL is rare, whereas the percentage of patients with ISM, ASM, and SM-AHNMD, among 342 consecutive adult cases seen at the Mayo Clinic, was 46%, 12%, and 40%, respectively [2]. Life-expectancy in ISM is not significantly different from that of the control population [2], but quality of life might be affected by symptomatic/ cosmetically unacceptable skin disease or mast cell mediator release symptoms (MCMRS) such as frequent syncopal episodes and gastrointestinal disturbances. ASM is characterized by organ impairment as a result of mast cell infiltration (e.g. cytopenias, hepatosplenomegaly with liver function test abnormalities, bone fractures from severe osteopenia or lytic bone lesions, cachexia from malabsorption) [2]. Clinical manifestations in SM-AHNMD are often influenced by the non-mast cell lineage component of the disease, and include cytosis or cytopenia and hepatosplenomegaly. Current therapy in SM includes observation alone, local therapy for cutaneous disease, use of anti-MCMRS drugs (e.g. antihistamines), and cytoreductive therapy. In regard to the latter, in a recent retrospective study, 120 Mayo Clinic patients with SM were treated with cladribine, interferon-a (IFN-a), with or without prednisone, hydroxyurea, or imatinib mesylate (IM) [3]. The corresponding response rates were 46%, 41%, 21%, and 20%. Cladribine response was less likely in the presence of leukocytosis, monocytosis, or circulating immature myeloid cells. The presence of anemia or elevated erythrocyte sedimentation rate was associated with inferior response to IFN-a. KIT is a type III receptor tyrosine kinase (RTK) and the transmembrane receptor for stem cell factor. Neoplastic mast cells often harbor mutant KIT. Wild-type or non-D816V mutant KIT is usually sensitive to inhibition with IM [4–6] or several other kinase inhibitors, including dasatinib (a dual ABL and SRC kinase inhibitor) [7], nilotinib (a potent ABL kinase inhibitor) [8,9], INNO-406 (a dual ABL and Lyn-kinase inhibitor) [4], MLN518 (a quinazoline-based type III RTK inhibitor) [10], PD180170 (a multikinase inhibitor of ABL, SRC, and KIT) [10], PKC412 (a multikinase inhibitor of protein kinase C, vascular endothelial growth factor receptor, platelet-derived growth factor receptor, and FLT3) [11], and EXEL-0862 (a multikinase inhibitor of fibroblast growth factor receptor, vascular endothelial growth factor receptor, platelet-derived growth factor receptor, and FLT3) [12]. However, the kinase domain KIT mutation found in virtually all