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.
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
Jason
J
Gotlib
Caroline
C
Berubé
Joseph D
JD
Growney
Ching-Cheng
CC
Chen
Tracy I
TI
George
Christopher
C
Williams
Tomohiro
T
Kajiguchi
Jia
J
Ruan
Stan L
SL
Lilleberg
Jeffrey A
JA
Durocher
Jack H
JH
Lichy
Yanfeng
Y
Wang
Pamela S
PS
Cohen
Daniel A
DA
Arber
Michael C
MC
Heinrich
Len
L
Neckers
Stephen J
SJ
Galli
D Gary
DG
Gilliland
Steven E
SE
Coutré
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