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Background Information

Mast cell disease and MPD

Systemic mastocytosis (SM) and the related entity SM plus associated hematological non-mast cell disease (SM-AHNMD) are rare myeloproliferative disorders in which acquired mutations in the KIT tyrosine kinase play a key role. The vast majority of cases are due to a single amino acid substitution (D816V) in the activating loop (exon 17), but rare cases with mutations in the juxtamembrane domain (exon 11) are also observed. The D816V mutant form of KIT is resistant to treatment with imatinib mesylate, while the exon 11 mutant forms are sensitive.

Testing for these mutations can serve two purposes:

  1. To confirm a suspected diagnosis.
  2. To assess the likelihood of a response to kinase inhibitor therapy.

AML

Mutations in KIT exon 8 or 17 are detected in 20-30% of AML patients with t(8;21) or inv(16)/t(16;16).6 The exon 8 mutations are associated with an increased rate of relapse, but may be sensitive to treatment with imatinib. The exon 17 mutations most commonly involved codon 816 (D816V or D816Y), which confer imatinib resistance.

References

  1. Tefferi A, Pardanani A. Systemic mastocytosis: current concepts and treatment advances.
    Curr Hematol Rep. 3:197-202, 2004.
  2. Pardanani A, Elliott M, Reeder T, Li CY, Baxter EJ, Cross NC, Tefferi A. Imatinib for systemic mast-cell disease. Lancet. 362(9383):535-6, 2003.
  3. Droogendijk HJ, Kluin-Nelemans HJ, van Doormaal JJ, Oranje AP, van de Loosdrecht AA, van Daele PL. Imatinib mesylate in the treatment of systemic mastocytosis: a phase II trial. Cancer 107:345-51, 2006.
  4. Heinrich MC, Corless CL, Demetri GD, Blanke CD, von Mehren M, Joensuu H, McGreevey LS, Chen C-J, Kiese B, Eisenberg B, Roberts PJ, Singer S, Fletcher CDM, Silberman S, Dimitrijevic S, Fletcher JA. Kinase mutations and imatinib mesylate response in patients with metastatic gastrointestinal stromal tumor. J Clin Onc 21:4342-4349, 2003.
  5. Debiec-Rychter M, Raf Sciot R, Le Cesne A, Schlemmer M, Hohenberger P, van Oosterom AT, Blay J-Y, Leyvraz S, Stul M, Casali PG, Zalcberg J, Verweij J, Van Glabbeke M, Hagemeijer A, Judson I. KIT mutations and dose selection for imatinib in patients with advanced gastrointestinal stromal tumours. Eur J Cancer 42:1093-103, 2006.
  6. Frohling S, Scholl C, Gilliland DG, Levine RL. Genetics of myeloid malignancies: pathogenetic and clinical implications. J Clin Oncol 23:6285-95, 2005.

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