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Blood, 15 October 2005, Vol. 106, No. 8, pp. 2865-2870.
Prepublished online as a Blood First Edition Paper on June 21, 2005; DOI 10.1182/blood-2005-04-1568.
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NEOPLASIA
Brief report
Activity of the tyrosine kinase inhibitor PKC412 in a patient with mast cell leukemia with the D816V KIT mutation
Jason Gotlib,
Caroline Berubé,
Joseph D. Growney,
Ching-Cheng Chen,
Tracy I. George,
Christopher Williams,
Tomohiro Kajiguchi,
Jia Ruan,
Stan L. Lilleberg,
Jeffrey A. Durocher,
Jack H. Lichy,
Yanfeng Wang,
Pamela S. Cohen,
Daniel A. Arber,
Michael C. Heinrich,
Len Neckers,
Stephen J. Galli,
D. Gary Gilliland, and
Steven E. Coutré
From the Department of Medicine, Division of Hematology, Stanford University School of Medicine, Stanford, CA; the Department of Medicine, Division of Hematology, Brigham and Women's Hospital, Boston, MA; the Department of Pathology, Stanford University School of Medicine, Stanford, CA; the Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD; Transgenomic, Gaithersburg, MD; the Department of Molecular Pathology, Armed Forces Institute of Pathology, Washington, DC; Novartis Pharmaceuticals, East Hanover, NJ; Oregon Health and Science University Cancer Institute, Portland VA Medical Center, Portland, OR; Howard Hughes Medical Institute, Harvard Medical School, Boston, MA.
The 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. (Blood. 2005; 106:2865-2870)
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