Activity of the tyrosine kinase inhibitor PKC412 in a patient with mast cell leukemia with the D816V KIT mutation - PubMed (original) (raw)

Case Reports

. 2005 Oct 15;106(8):2865-70.

doi: 10.1182/blood-2005-04-1568. Epub 2005 Jun 21.

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, Steven E Coutré

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Case Reports

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

Jason Gotlib et al. Blood. 2005.

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.

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Figures

Figure 1.

Figure 1.

Peripheral blood and bone marrow findings before and after treatment with PKC 412. (A-F) Before treatment. (G-I) After treatment. (A) Circulating mast cell (arrow, left) and dysplastic nucleated red blood cell (arrowhead, right) in peripheral blood. Wright-Giemsa, 1000 ×. (B) Hypercellular bone marrow with aggregates of pale-staining mast cells surrounding a dilated sinus (*). Hematoxylin and eosin, 40 ×. (C) Whorled nodule of mast cells with characteristic clear cytoplasm including spindled forms. Hematoxylin and eosin, 400 ×. (D) Increased mast cells show a nodular and interstitial pattern in the bone marrow occupying approximately 70% marrow cellularity. Mast cell tryptase, 40 ×. (E) The majority of mast cells are highlighted by CD25 antibody. CD25, 40 ×. (F) Few numbers of CD34-positive blasts (∼5%) detected on bone marrow biopsy. CD34, 400 ×. (G) The posttreatment bone marrow shows a similar mast cell burden as seen prior to treatment. Mast cell tryptase, 40 ×. (H) A slight decrease in CD25-positive mast cells (∼40% of marrow cellularity) is noted after therapy. CD25, 40 ×. (I) Increased numbers of CD34-positive blasts (10%-20%) in bone marrow biopsy indicating progression of this patient's AHNDMD, MDS/MPD. CD34, 400 ×.

Figure 2.

Figure 2.

Changes in the pharmacokinetics of PKC412 and patient mast cell disease-related parameters during PKC412 therapy. (A) Trough plasma concentration-time profiles of PKC412 and its major active metabolite CGP62221 and the sum of PKC412 and CGP62221 in the mast cell leukemia patient receiving PKC412 100 mg twice a day between day 1 and day 90, and 75 mg three times a day starting from day 90. (B) Serum histamine level and percent peripheral blood mast cells quantified by manual differential. (C) Normalized phospho-KIT/total KIT optical density ratio. The number of samples analyzed at each time point is shown in parentheses. (D) Semiquantitative DHPLC determination of the D816V KIT mutation frequency in the bone marrow and peripheral blood.

Figure 3.

Figure 3.

Ba/F3-KIT D816V is sensitive to PKC-412 but not to imatinib. Plotted is the percentage of 3H-thymidine incorporation in drug-treated wells relative to no drug controls. Cells were treated with imatinib (dashed lines, ○) or PKC412 (solid line, •) for 24 hours in the presence of 10 ng/mL IL-3 and the absence of recombinant human stem cell factor (SCF). Plotted is the percent 3H-thymidine incorporation in drug-treated wells relative to no drug controls. Data are the mean of triplicates (plot standard deviation). PKC412 IC50 30 nM-40 nM.

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