Activity of the tyrosine kinase inhibitor PKC412 in a patient with mast cell leukemia with the D816V KIT mutation.
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.
Gotlib
Jason
J
Department of Medicine, Division of Hematology, Stanford University, Stanford Cancer Center, 875 Blake Wilbur Dr, Rm 2327B, Stanford, CA 94305-5821, USA. jason.gotlib@stanford.edu
Berubé
Caroline
C
Growney
Joseph D
JD
Chen
Ching-Cheng
CC
George
Tracy I
TI
Williams
Christopher
C
Kajiguchi
Tomohiro
T
Ruan
Jia
J
Lilleberg
Stan L
SL
Durocher
Jeffrey A
JA
Lichy
Jack H
JH
Wang
Yanfeng
Y
Cohen
Pamela S
PS
Arber
Daniel A
DA
Heinrich
Michael C
MC
Neckers
Len
L
Galli
Stephen J
SJ
Gilliland
D Gary
DG
Coutré
Steven E
SE
D001224:Aspartic Acid / Q000235:genetics*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D016130:Immunophenotyping; D007946:Leukemia, Mast-Cell / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics*; D019311:Staurosporine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use
D047428:Protein Kinase Inhibitors; D001224:Aspartic Acid; D011505:Protein-Tyrosine Kinases; D019009:Proto-Oncogene Proteins c-kit; D019311:Staurosporine; C059539:midostaurin