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15972446

Source:http://linkedlifedata.com/resource/pubmed/id/15972446

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pubmed-article:15972446pubmed:abstractTextThe majority of patients with systemic mast cell disease express the imatinib-resistant Asp816Val (D816V) mutation in the KIT receptor tyrosine kinase. Limited treatment options exist for aggressive systemic mastocytosis (ASM) and mast cell leukemia (MCL). We evaluated whether PKC412, a small-molecule inhibitor of KIT with a different chemical structure from imatinib, may have therapeutic use in advanced SM with the D816V KIT mutation. We treated a patient with MCL (with an associated myelodysplastic syndrome (MDS)/myeloproliferative disorder [MPD]) based on in vitro studies demonstrating that PKC412 could inhibit D816V KIT-transformed Ba/F3 cell growth with a 50% inhibitory concentration (IC50) of 30 nM to 40 nM. The patient exhibited a partial response with significant resolution of liver function abnormalities. In addition, PKC412 treatment resulted in a significant decline in the percentage of peripheral blood mast cells and serum histamine level and was associated with a decrease in KIT phosphorylation and D816V KIT mutation frequency. The patient died after 3 months of therapy due to progression of her MDS/MPD to acute myeloid leukemia (AML). This case indicates that KIT tyrosine kinase inhibition is a feasible approach in SM, but single-agent clinical efficacy may be limited by clonal evolution in the advanced leukemic phase of this disease.lld:pubmed
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pubmed-article:15972446pubmed:articleTitleActivity of the tyrosine kinase inhibitor PKC412 in a patient with mast cell leukemia with the D816V KIT mutation.lld:pubmed
pubmed-article:15972446pubmed:affiliationDepartment of Medicine, Division of Hematology, Stanford University, Stanford Cancer Center, 875 Blake Wilbur Dr, Rm 2327B, Stanford, CA 94305-5821, USA. jason.gotlib@stanford.edulld:pubmed
pubmed-article:15972446pubmed:publicationTypeJournal Articlelld:pubmed
pubmed-article:15972446pubmed:publicationTypeResearch Support, U.S. Gov't, P.H.S.lld:pubmed
pubmed-article:15972446pubmed:publicationTypeCase Reportslld:pubmed
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