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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.
 Previous Article | Next Article 
Submitted April 18, 2005
Accepted June 9, 2005
Activity of the tyrosine kinase inhibitor PKC412 in a patient with mast cell leukemia with the D816V KIT mutation
Jason Gotlib*, Caroline Berube, 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 Arber, Michael C Heinrich, Len Neckers, Stephen J Galli, D G Gilliland, and Steven E Coutre
Department of Medicine, Division of Hematology, Stanford University School of Medicine, Stanford, CA, USA
Department of Medicine, Division of Hematology, Brigham and Women's Hospital, Boston, MA, USA
Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA
Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
Transgenomic, Inc., Gaithersburg, MD, USA
Department of Molecular Pathology, Armed Forces Institute of Pathology, Washington, DC, USA
Novartis Pharmaceuticals, Inc., East Hanover, NJ, USA
Oregon Health and Science University Cancer Institute, Portland VA Medical Center, Portland, OR, USA
Department of Medicine, Division of Hematology, Brigham and Women's Hospital, Boston, MA, USA; Howard Hughes Medical Institute, Harvard Medical School, Boston, MA, USA
* Corresponding author; email: jason.gotlib{at}stanford.edu.
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 utility 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 an IC50 of 30-40 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 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.
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