Activity of the tyrosine kinase inhibitor PKC412 in a patient with mast cell leukemia with the D816V KIT mutation. uri icon

Overview

abstract

  • 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.

publication date

  • June 21, 2005

Research

keywords

  • Aspartic Acid
  • Leukemia, Mast-Cell
  • Protein Kinase Inhibitors
  • Protein-Tyrosine Kinases
  • Proto-Oncogene Proteins c-kit
  • Staurosporine

Identity

PubMed Central ID

  • PMC1895309

Scopus Document Identifier

  • 27144506215

Digital Object Identifier (DOI)

  • 10.1182/blood-2005-04-1568

PubMed ID

  • 15972446

Additional Document Info

volume

  • 106

issue

  • 8