The Pathogenesis, Diagnosis, And Treatment Of Systemic M

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Abstract

Mastocytosis is a disorder characterized by pathologic accumulation of mast cells in tissues, most commonly in skin and bone marrow. In order to assess whether skin involvement is predictive of bone marrow (systemic) disease, 67 patients were examined in a prospective study. Results revealed that an examination of the extent and density of skin lesions helps identify those with more extensive bone marrow disease with poorer prognostic features and require a more thorough evaluation. Skin lesions of mastocytosis (also termed urticaria pigmentosa), however, may decrease in intensity or regress in a small subset of patients. Another study reported 12 such patients who experienced regression of urticaria pigmentosa and analyzed the clinical correlates of this observation. It was found that old age and co-existence of another hematologic disorder were associated with apparent improvement of skin lesions in patients with mastocytosis. Activating mutations in the c-kit protooncogene codon 816 are found in most patients with systemic mastocytosis involving the bone marrow. Since c-kit encodes a transmembrane receptor tyrosine kinase, inhibition of this pathway by drugs such as imatinib (Gleevec) has been evaluated as a potential therapeutic strategy in mast cell disease. Using primary mast cells obtained from patient bone marrow aspirates, Gleevec has been shown to exert a potent cytotoxic activity on mast cells carrying c-kit with a wild-type codon 816. On the other hand, the drug was ineffective in killing mast cells carrying a codon 816 c-kit mutation. To complement these observations, a patient with a previously undescribed variant of mastocytosis was found to have a novel activating mutation in the transmembrane portion of c-kit, and showed a dramatic response to imatinib. Nevertheless, current treatment options for patients carrying codon 816 c-kit mutations are limited and clinical trials are needed to assess response to investigational therapies. In order to help interpretation of these future clinical trials, standardized response criteria were formulated in collaboration with other researchers in the field. Finally, pathologic mast cells may be encountered in other bone marrow disorders such as hypereosinophilic syndromes. Flow cytometric characterization of mast cells in patients with HES revealed mast cells to have unique surface phenotypes in a subset of patients with this disorder who have myeloproliferative features and respond to therapy with imatinib.