[1462] Loss of CD25 Expression in Advanced Systemic Mastocytosis Patients Treated with Midostaurin (PKC412)

Christian A Kunder, Daniel J Deangelo, Jason R Gotlib, Gary Gitana, Susan K Atwater, Tracy I George. Stanford University, Stanford, CA; Dana-Farber Cancer Institute, Boston, MA

Background: CD25 is aberrantly expressed in systemic mastocytosis. This may be related to the KIT-dependent constitutive phosphorylation of the transcription factor STAT5 in mastocytosis cells (1), as phosphorylated STAT5 mediates IL-2-directed CD25 upregulation in T cells (2). Midostaurin (PKC412) is an investigation drug that inhibits multiple receptor tyrosine kinases, including KIT, and is being studied for the treatment of advanced mast cell disease. The biologic effects of such therapy and its implications for disease monitoring are not well understood.
Design: Four cases of aggressive systemic mastocytosis with aspirates for flow cytometry and/or bone marrow core biopsies correlated with the timing of midostaurin therapy were examined in detail. Immunohistochemistry for CD117 and CD25 was performed on bone marrow core biopsies using standard methods, and CD117 and CD25 expression was also examined by flow cytometry.
Results: Three patients treated with midostaurin experienced large decreases in bone marrow mast cell CD25 expression shortly after starting therapy as measured by flow cytometry. Coexpression of CD25 by CD117+ cells in one case dropped from 79.8% to 3.4% over three months, remaining low at 2.2% at latest follow-up eleven months after starting treatment. In the second case it dropped from 91.2% to 7.9% over one month before trending back up to 30.8% at three months. In a third case, CD25 expression by bone marrow CD117+ cells decreased from 76.3% before treatment to 40% at two months and 15.8% at three months. This effect was also detectable by immunohistochemistry. Interestingly, midostaurin was discontinued in this case after 3.5 months of treatment, after which CD25/CD117 coexpression rebounded to 76.9% after 1.5 months. This reacquisition of aberrant CD25 expression was also detectable by immunohistochemistry. A fourth case showed a more muted effect, with CD25 coexpression dropping from 46.2% before therapy to around 35% on repeated measurements with five months of follow-up, with no detectable change by immunohistochemistry.
Conclusions: Rapid, durable, and reversible decreases in CD25 expression by neoplastic mast cells in advanced systemic mastocytosis were observed in response to treatment with the tyrosine kinase inhibitor midostaurin (PKC412). Further investigation will be required to determine the biologic significance of this finding in the context of abnormal KIT signaling in mastocytosis cells, as well as its potential utility in monitoring disease response to this new therapy.
Category: Hematopathology

Wednesday, March 21, 2012 9:30 AM

Poster Session V # 227, Wednesday Morning

 

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