Pathogenesis, Diagnosis, Classification, and Management of Systemic Mastocytosis

  • Animesh Pardanani
  • Ayalew TefferiEmail author
Part of the Contemporary Hematology book series (CH)


Mast cell disease (MCD) or mastocytosis is a heterogenous disorder ­characterized by the abnormal growth and accumulation of morphologically and immunophenotypically abnormal mast cells in one or more organs. The clinical presentation of mastocytosis is diverse, and many patients do not fit the classical description – namely, a variably long history of urticaria pigmentosa (UP), followed by the insidious onset of flushing, cramping abdominal pain, diarrhea, and bone pain [1–3]. Other disease manifestations include osteopenia, hepatosplenomegaly, and abnormalities of blood and bone marrow (BM). Unlike pediatric cases, most adults with UP-like skin lesions have systemic disease (i.e., systemic mastocytosis [SM]) at presentation, a condition generally confirmed by means of a BM biopsy [4]. Diagnosis requires BM examination including immunohistochemical stains for mast cell tryptase or CD117 (KIT receptor). More sensitive techniques to detect clonal mast cells include immunophenotyping for CD25 or mutation screening for the KIT D816V mutation.


Mast cell Myeloproliferative neoplasm KIT mutations 


  1. 1.
    Lim KH, Tefferi A, Lasho TL, et al. Systemic mastocytosis in 342 consecutive adults: survival studies and prognostic factors. Blood. 2009;113:5727–5736.PubMedCrossRefGoogle Scholar
  2. 2.
    Patnaik MM, Rindos M, Kouides PA, Tefferi A, Pardanani A. Systemic mastocytosis: a concise clinical and laboratory review. Arch Pathol Lab Med. 2007;131:784–791.PubMedGoogle Scholar
  3. 3.
    Travis WD, Li CY, Bergstralh EJ, Yam LT, Swee RG. Systemic mast cell disease. Analysis of 58 cases and literature review. Medicine (Baltimore). 1988;67:345–368.Google Scholar
  4. 4.
    Czarnetzki BM, Kolde G, Schoemann A, Urbanitz S, Urbanitz D. Bone ­marrow findings in adult patients with urticaria pigmentosa. J Am Acad Dermatol. 1988;18:45–51.PubMedCrossRefGoogle Scholar
  5. 5.
    Valent P, Spanblochl E, Sperr WR, et al. Induction of differentiation of human mast cells from bone marrow and peripheral blood mononuclear cells by recombinant human stem cell factor/kit-ligand in long-term culture. Blood. 1992;80:2237–2245.PubMedGoogle Scholar
  6. 6.
    Scheijen B, Griffin JD. Tyrosine kinase oncogenes in normal hematopoiesis and hematological disease. Oncogene. 2002;21:3314–3333.PubMedCrossRefGoogle Scholar
  7. 7.
    Garcia-Montero AC, Jara-Acevedo M, Teodosio C, et al. KIT mutation in mast cells and other bone marrow hematopoietic cell lineages in systemic mast cell disorders: a prospective study of the Spanish Network on Mastocytosis (REMA) in a series of 113 patients. Blood. 2006;108:2366–2372.PubMedCrossRefGoogle Scholar
  8. 8.
    Hashimoto K, Tsujimura T, Moriyama Y, et al. Transforming and differentiation-inducing potential of constitutively activated c-kit mutant genes in the IC-2 murine interleukin-3-dependent mast cell line. Am J Pathol. 1996;148:189–200.PubMedGoogle Scholar
  9. 9.
    Piao X, Bernstein A. A point mutation in the catalytic domain of c-kit induces growth factor independence, tumorigenicity, and differentiation of mast cells. Blood. 1996;87:3117–3123.PubMedGoogle Scholar
  10. 10.
    Kitayama H, Kanakura Y, Furitsu T, et al. Constitutively activating mutations of c-kit receptor tyrosine kinase confer factor-independent growth and tumorigenicity of factor-dependent hematopoietic cell lines. Blood. 1995;85:790–798.PubMedGoogle Scholar
  11. 11.
    Kitayama H, Tsujimura T, Matsumura I, et al. Neoplastic transformation of normal hematopoietic cells by constitutively activating mutations of c-kit receptor tyrosine kinase. Blood. 1996;88:995–1004.PubMedGoogle Scholar
  12. 12.
    Ferrao PT, Gonda TJ, Ashman LK. Constitutively active mutant D816VKit induces megakayocyte and mast cell differentiation of early haemopoietic cells from murine foetal liver. Leuk Res. 2003;27:547–555.PubMedCrossRefGoogle Scholar
  13. 13.
    Mayerhofer M, Aichberger KJ, Florian S, et al. c-kit D816V provides a strong signal for myelomastocytic differentiation and cluster formation in murine Ba/F3 Cells. Blood. 2004;104:141a.Google Scholar
  14. 14.
    Zappulla JP, Dubreuil P, Desbois S, et al. Mastocytosis in mice expressing human Kit receptor with the activating Asp816Val mutation. J Exp Med. 2005;202:1635–1641.PubMedCrossRefGoogle Scholar
  15. 15.
    Furitsu T, Tsujimura T, Tono T, et al. Identification of mutations in the coding sequence of the proto-oncogene c-kit in a human mast cell leukemia cell line causing ligand-independent activation of c-kit product. J Clin Invest. 1993;92:1736–1744.PubMedCrossRefGoogle Scholar
  16. 16.
    Nagata H, Worobec AS, Oh CK, et al. Identification of a point mutation in the catalytic domain of the protooncogene c-kit in peripheral blood mononuclear cells of patients who have mastocytosis with an associated hematologic disorder. Proc Natl Acad Sci U S A. 1995;92:10560–10564.PubMedCrossRefGoogle Scholar
  17. 17.
    Longley BJ, Jr, Metcalfe DD, Tharp M, et al. Activating and dominant inactivating c-KIT catalytic domain mutations in distinct clinical forms of human mastocytosis. Proc Natl Acad Sci U S A. 1999;96:1609–1614.PubMedCrossRefGoogle Scholar
  18. 18.
    Pullarkat VA, Pullarkat ST, Calverley DC, Brynes RK. Mast cell disease associated with acute myeloid leukemia: detection of a new c-kit mutation Asp816His. Am J Hematol. 2000;65:307–309.PubMedCrossRefGoogle Scholar
  19. 19.
    Pignon JM, Giraudier S, Duquesnoy P, et al. A new c-kit mutation in a case of aggressive mast cell disease. Br J Haematol. 1997;96:374–376.PubMedCrossRefGoogle Scholar
  20. 20.
    Hartmann K, Wardelmann E, Ma Y, et al. Novel germline mutation of KIT associated with familial gastrointestinal stromal tumors and mastocytosis. Gastroenterology. 2005;129:1042–1046.PubMedCrossRefGoogle Scholar
  21. 21.
    Tang X, Boxer M, Drummond A, Ogston P, Hodgins M, Burden AD. A germline mutation in KIT in familial diffuse cutaneous mastocytosis. J Med Genet. 2004;41:e88.PubMedCrossRefGoogle Scholar
  22. 22.
    Akin C, Fumo G, Yavuz AS, Lipsky PE, Neckers L, Metcalfe DD. A novel form of mastocytosis associated with a transmembrane c-kit mutation and response to imatinib. Blood. 2004;103:3222–3225.PubMedCrossRefGoogle Scholar
  23. 23.
    Beghini A, Tibiletti MG, Roversi G, et al. Germline mutation in the juxtamembrane domain of the kit gene in a family with gastrointestinal stromal tumors and urticaria pigmentosa. Cancer. 2001;92:657–662.PubMedCrossRefGoogle Scholar
  24. 24.
    Zhang LY, Smith ML, Schultheis B, et al. A novel K509I mutation of KIT ­identified in familial mastocytosis-in vitro and in vivo responsiveness to imatinib therapy. Leuk Res. 2006;30:373–378.PubMedCrossRefGoogle Scholar
  25. 25.
    Akin C. Molecular diagnosis of mast cell disorders: a paper from the 2005 William Beaumont Hospital Symposium on Molecular Pathology. J Mol Diagn. 2006;8:412–419.PubMedCrossRefGoogle Scholar
  26. 26.
    Delhommeau F, Dupont S, Della Valle V, et al. Mutation in TET2 in myeloid cancers. N Engl J Med. 2009;360:2289–2301.PubMedCrossRefGoogle Scholar
  27. 27.
    Tefferi A, Pardanani A, Lim KH, et al. TET2 mutations and their clinical correlates in polycythemia vera, essential thrombocythemia and myelofibrosis. Leukemia. 2009;23:905–911.PubMedCrossRefGoogle Scholar
  28. 28.
    Tefferi A, Levine RL, Lim KH, et al. Frequent TET2 mutations in systemic mastocytosis: clinical, KITD816V and FIP1L1-PDGFRA correlates. Leukemia. 2009;23:900–904.PubMedCrossRefGoogle Scholar
  29. 29.
    Tefferi A, Lim KH, Abdel-Wahab O, et al. Detection of mutant TET2 in myeloid malignancies other than myeloproliferative neoplasms: CMML, MDS, MDS/MPN and AML. Leukemia. 2009;23:1343–1345.PubMedCrossRefGoogle Scholar
  30. 30.
    Langemeijer SM, Kuiper RP, Berends M, et al. Acquired mutations in TET2 are common in myelodysplastic syndromes. Nat Genet. 2009;41:838–842.PubMedCrossRefGoogle Scholar
  31. 31.
    Cools J, DeAngelo DJ, Gotlib J, et al. A tyrosine kinase created by fusion of the PDGFRA and FIP1L1 genes as a therapeutic target of imatinib in idiopathic hypereosinophilic syndrome. N Engl J Med. 2003;348:1201–1214.PubMedCrossRefGoogle Scholar
  32. 32.
    Klion AD, Noel P, Akin C, et al. Elevated serum tryptase levels identify a subset of patients with a myeloproliferative variant of idiopathic hypereosinophilic syndrome associated with tissue fibrosis, poor prognosis, and imatinib responsiveness. Blood. 2003;101:4660–4666.PubMedCrossRefGoogle Scholar
  33. 33.
    Klion AD, Robyn J, Akin C, et al. Molecular remission and reversal of myelofibrosis in response to imatinib mesylate treatment in patients with the myeloproliferative variant of hypereosinophilic syndrome. Blood. 2004;103:473–478.PubMedCrossRefGoogle Scholar
  34. 34.
    Pardanani A, Brockman SR, Paternoster SF, et al. FIP1L1-PDGFRA fusion: prevalence and clinicopathologic correlates in 89 consecutive patients with moderate to severe eosinophilia. Blood. 2004;104:3038–3045.PubMedCrossRefGoogle Scholar
  35. 35.
    Pardanani A, Ketterling RP, Brockman SR, et al. CHIC2 deletion, a surrogate for FIP1L1-PDGFRA fusion, occurs in systemic mastocytosis associated with eosinophilia and predicts response to imatinib mesylate therapy. Blood. 2003;102:3093–3096.PubMedCrossRefGoogle Scholar
  36. 36.
    Pardanani A, Ketterling RP, Li CY, et al. FIP1L1-PDGFRA in eosinophilic disorders: prevalence in routine clinical practice, long-term experience with imatinib therapy, and a critical review of the literature. Leuk Res. 2006;30:965–970.PubMedCrossRefGoogle Scholar
  37. 37.
    Robyn J, Lemery S, McCoy JP, et al. Multilineage involvement of the fusion gene in patients with FIP1L1/PDGFRA-positive hypereosinophilic syndrome. Br J Haematol. 2006;132:286–292.PubMedCrossRefGoogle Scholar
  38. 38.
    Horny HP, Metcalfe DD, Bennett JM, et al. Mastocytosis. In: Swerdlow SH, Campo E, Harris NL, et al., eds. WHO Classification of Tumors of Hematopoietic and Lymphoid Tissues (ed 4th). Lyon: International Agency for Research and Cancer (IARC); 2008:54–63.Google Scholar
  39. 39.
    Horny HP, Sotlar K, Sperr WR, Valent P. Systemic mastocytosis with associated clonal haematological non-mast cell lineage diseases: a histopathological challenge. J Clin Pathol. 2004;57:604–608.PubMedCrossRefGoogle Scholar
  40. 40.
    Horny HP, Sillaber C, Menke D, et al. Diagnostic value of immunostaining for tryptase in patients with mastocytosis. Am J Surg Pathol. 1998;22:1132–1140.PubMedCrossRefGoogle Scholar
  41. 41.
    Horny HP, Valent P. Histopathological and immunohistochemical aspects of mastocytosis. Int Arch Allergy Immunol. 2002;127:115–117.PubMedCrossRefGoogle Scholar
  42. 42.
    Sotlar K, Horny HP, Simonitsch I, et al. CD25 indicates the neoplastic phenotype of mast cells: a novel immunohistochemical marker for the diagnosis of systemic mastocytosis (SM) in routinely processed bone marrow biopsy specimens. Am J Surg Pathol. 2004;28:1319–1325.PubMedCrossRefGoogle Scholar
  43. 43.
    Jordan JH, Walchshofer S, Jurecka W, et al. Immunohistochemical properties of bone marrow mast cells in systemic mastocytosis: evidence for expression of CD2, CD117/Kit, and bcl-x(L). Hum Pathol. 2001;32:545–552.PubMedCrossRefGoogle Scholar
  44. 44.
    Valent P, Horny HP, Escribano L, et al. Diagnostic criteria and classification of mastocytosis: a consensus proposal. Leuk Res. 2001;25:603–625.PubMedCrossRefGoogle Scholar
  45. 45.
    Escribano L, Garcia Montero AC, Nunez R, Orfao A. Flow cytometric analysis of normal and neoplastic mast cells: role in diagnosis and follow-up of mast cell disease. Immunol Allergy Clin North Am. 2006;26:535–547.PubMedCrossRefGoogle Scholar
  46. 46.
    Pardanani A, Kimlinger T, Reeder T, Li CY, Tefferi A. Bone marrow mast cell immunophenotyping in adults with mast cell disease: a prospective study of 33 patients. Leuk Res. 2004;28:777–783.PubMedCrossRefGoogle Scholar
  47. 47.
    Walz C, Metzgeroth G, Haferlach C, et al. Characterization of three new imatinib-responsive fusion genes in chronic myeloproliferative disorders generated by disruption of the platelet-derived growth factor receptor beta gene. Haematologica. 2007;92:163–169.PubMedCrossRefGoogle Scholar
  48. 48.
    Schwartz LB. Clinical utility of tryptase levels in systemic mastocytosis and associated hematologic disorders. Leuk Res. 2001;25:553–562.PubMedCrossRefGoogle Scholar
  49. 49.
    Schwartz LB, Metcalfe DD, Miller JS, Earl H, Sullivan T. Tryptase levels as an indicator of mast-cell activation in systemic anaphylaxis and mastocytosis. N Engl J Med. 1987;316:1622–1626.PubMedCrossRefGoogle Scholar
  50. 50.
    Keyzer JJ, de Monchy JG, van Doormaal JJ, van Voorst Vader PC. Improved diagnosis of mastocytosis by measurement of urinary histamine metabolites. N Engl J Med. 1983;309:1603–1605.PubMedCrossRefGoogle Scholar
  51. 51.
    WHO subvariants of indolent mastocytosis: clinical details and prognostic evaluation in 159 consecutive adults. Blood. 2010 Jan 7;115(1):150–151.Google Scholar
  52. 52.
    Sotlar K, Fridrich C, Mall A, et al. Detection of c-kit point mutation Asp-816 > Val in microdissected pooled single mast cells and leukemic cells in a patient with systemic mastocytosis and concomitant chronic myelomonocytic leukemia. Leuk Res. 2002;26:979–984.PubMedCrossRefGoogle Scholar
  53. 53.
    Yavuz AS, Lipsky PE, Yavuz S, Metcalfe DD, Akin C. Evidence for the involvement of a hematopoietic progenitor cell in systemic mastocytosis from single-cell analysis of mutations in the c-kit gene. Blood. 2002;100:661–665.PubMedCrossRefGoogle Scholar
  54. 54.
    Sotlar K, Escribano L, Landt O, et al. One-step detection of c-kit point mutations using peptide nucleic acid-mediated polymerase chain reaction clamping and hybridization probes. Am J Pathol. 2003;162:737–746.PubMedCrossRefGoogle Scholar
  55. 55.
    Tefferi A, Vardiman JW. Classification and diagnosis of myeloproliferative neoplasms: the 2008 World Health Organization criteria and point-of-care diagnostic algorithms. Leukemia. 2008;22:14–22.PubMedCrossRefGoogle Scholar
  56. 56.
    Vardiman JW, Thiele J, Arber DA, et al. The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes. Blood. 2009;114:937–951.PubMedCrossRefGoogle Scholar
  57. 57.
    Pardanani A, Lim KH, Lasho TL, et al. Prognostically relevant breakdown of 123 patients with systemic mastocytosis associated with other myeloid malignancies. Blood. 2009;114:3769–3772.PubMedCrossRefGoogle Scholar
  58. 58.
    Travis WD, Li CY, Yam LT, Bergstralh EJ, Swee RG. Significance of systemic mast cell disease with associated hematologic disorders. Cancer. 1988;62:965–972.PubMedCrossRefGoogle Scholar
  59. 59.
    Dunphy CH. Evaluation of mast cells in myeloproliferative disorders and myelodysplastic syndromes. Arch Pathol Lab Med. 2005;129:219–222.PubMedGoogle Scholar
  60. 60.
    Akin C, Kirshenbaum AS, Semere T, Worobec AS, Scott LM, Metcalfe DD. Analysis of the surface expression of c-kit and occurrence of the c-kit Asp816Val activating mutation in T cells, B cells, and myelomonocytic cells in patients with mastocytosis. Exp Hematol. 2000;28:140–147.PubMedCrossRefGoogle Scholar
  61. 61.
    Kim Y, Weiss LM, Chen YY, Pullarkat V. Distinct clonal origins of systemic ­­mastocytosis and associated B-cell lymphoma. Leuk Res. 2007;31:1749–1754.PubMedCrossRefGoogle Scholar
  62. 62.
    Pardanani A, Tefferi A. Proposal for a revised classification of systemic mastocytosis. Blood. 2010;115:2720–2721.PubMedCrossRefGoogle Scholar
  63. 63.
    Horny HP, Parwaresch MR, Lennert K. Bone marrow findings in systemic mastocytosis. Hum Pathol. 1985;16:808–814.PubMedCrossRefGoogle Scholar
  64. 64.
    Tefferi A, Pardanani A. Clinical, genetic, and therapeutic insights into systemic mast cell disease. Curr Opin Hematol. 2004;11:58–64.PubMedCrossRefGoogle Scholar
  65. 65.
    Casassus P, Caillat-Vigneron N, Martin A, et al. Treatment of adult systemic mastocytosis with interferon-alpha: results of a multicentre phase II trial on 20 patients. Br J Haematol. 2002;119:1090–1097.PubMedCrossRefGoogle Scholar
  66. 66.
    Kluin-Nelemans HC, Jansen JH, Breukelman H, et al. Response to interferon alfa-2b in a patient with systemic mastocytosis. N Engl J Med. 1992;326:619–623.PubMedCrossRefGoogle Scholar
  67. 67.
    Butterfield JH. Response of severe systemic mastocytosis to interferon alpha. Br J Dermatol. 1998;138:489–495.PubMedCrossRefGoogle Scholar
  68. 68.
    Hauswirth AW, Simonitsch-Klupp I, Uffmann M, et al. Response to therapy with interferon alpha-2b and prednisolone in aggressive systemic mastocytosis: report of five cases and review of the literature. Leuk Res. 2004;28:249–257.PubMedCrossRefGoogle Scholar
  69. 69.
    Kluin-Nelemans HC, Oldhoff JM, Van Doormaal JJ, et al. Cladribine therapy for systemic mastocytosis. Blood. 2003;102:4270–4276.PubMedCrossRefGoogle Scholar
  70. 70.
    Tefferi A, Li CY, Butterfield JH, Hoagland HC. Treatment of systemic mast-cell disease with cladribine. N Engl J Med. 2001;344:307–309.PubMedCrossRefGoogle Scholar
  71. 71.
    Pardanani A, Hoffbrand AV, Butterfield JH, Tefferi A. Treatment of systemic mast cell disease with 2-chlorodeoxyadenosine. Leuk Res. 2004;28:127–131.PubMedCrossRefGoogle Scholar
  72. 72.
    Pardanani A, Elliott M, Reeder T, et al. Imatinib for systemic mast-cell disease. Lancet. 2003;362:535–536.PubMedCrossRefGoogle Scholar
  73. 73.
    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. 2006;107:345–351.PubMedCrossRefGoogle Scholar
  74. 74.
    Vega-Ruiz A, Cortes JE, Sever M, et al. Phase II study of imatinib mesylate as therapy for patients with systemic mastocytosis. Leuk Res. 2009;33:1481–1484.PubMedCrossRefGoogle Scholar
  75. 75.
    Lim KH, Pardanani A, Butterfield JH, Li CY, Tefferi A. Cytoreductive therapy in 108 adults with systemic mastocytosis: Outcome analysis and response prediction during treatment with interferon-alpha, hydroxyurea, imatinib mesylate or 2-chlorodeoxyadenosine. Am J Hematol. 2009;84:790–794.PubMedCrossRefGoogle Scholar
  76. 76.
    Tanaka A, Konno M, Muto S, et al. A novel NF-kappaB inhibitor, IMD-0354, suppresses neoplastic proliferation of human mast cells with constitutively activated c-kit receptors. Blood. 2005;105:2324–2331.PubMedCrossRefGoogle Scholar
  77. 77.
    Gabillot-Carre M, Lepelletier Y, Humbert M, et al. Rapamycin inhibits growth and survival of D816V-mutated c-kit mast cells. Blood. 2006;108:1065–1072.PubMedCrossRefGoogle Scholar
  78. 78.
    Pan J, Quintas-Cardama A, Kantarjian HM, et al. EXEL-0862, a novel tyrosine kinase inhibitor, induces apoptosis in vitro and ex vivo in human mast cells expressing the KIT D816V mutation. Blood. 2007;109:315–322.PubMedCrossRefGoogle Scholar
  79. 79.
    Pan J, Quintas-Cardama A, Manshouri T, Cortes J, Kantarjian H, Verstovsek S. Sensitivity of human cells bearing oncogenic mutant kit isoforms to the novel tyrosine kinase inhibitor INNO-406. Cancer Sci. 2007;98:1223–1225.PubMedCrossRefGoogle Scholar
  80. 80.
    Dubreuil P, Letard S, Ciufolini M, et al. Masitinib (AB1010), a potent and selective tyrosine kinase inhibitor targeting KIT. PLoS One. 2009;4:e7258.PubMedCrossRefGoogle Scholar
  81. 81.
    Zermati Y, De Sepulveda P, Feger F, et al. Effect of tyrosine kinase inhibitor STI571 on the kinase activity of wild-type and various mutated c-kit receptors found in mast cell neoplasms. Oncogene. 2003;22:660–664.PubMedCrossRefGoogle Scholar
  82. 82.
    Akin C, Brockow K, D’Ambrosio C, et al. Effects of tyrosine kinase inhibitor STI571 on human mast cells bearing wild-type or mutated c-kit. Exp Hematol. 2003;31:686–692.PubMedCrossRefGoogle Scholar
  83. 83.
    Nakagomi N, Hirota S. Juxtamembrane-type c-kit gene mutation found in aggressive­ systemic mastocytosis induces imatinib-resistant constitutive KIT activation. Lab Invest. 2007;87:365–371.PubMedGoogle Scholar
  84. 84.
    Verstovsek S, Akin C, Manshouri T, et al. Effects of AMN107, a novel aminopyrimidine tyrosine kinase inhibitor, on human mast cells bearing wild-type or mutated codon 816 c-kit. Leuk Res. 2006;30:1365–1370.PubMedCrossRefGoogle Scholar
  85. 85.
    von Bubnoff N, Gorantla SH, Kancha RK, Lordick F, Peschel C, Duyster J. The systemic mastocytosis-specific activating cKit mutation D816V can be inhibited by the tyrosine kinase inhibitor AMN107. Leukemia. 2005;19:1670–1671.PubMedCrossRefGoogle Scholar
  86. 86.
    Schittenhelm MM, Shiraga S, Schroeder A, et al. Dasatinib (BMS-354825), a dual SRC/ABL kinase inhibitor, inhibits the kinase activity of wild-type, juxtamembrane, and activation loop mutant KIT isoforms associated with human malignancies. Cancer Res. 2006;66:473–481.PubMedCrossRefGoogle Scholar
  87. 87.
    Shah NP, Lee FY, Luo R, Jiang Y, Donker M, Akin C. Dasatinib (BMS-354825) inhibits KITD816V, an imatinib-resistant activating mutation that triggers neoplastic growth in most patients with systemic mastocytosis. Blood. 2006;108:286–291.PubMedCrossRefGoogle Scholar
  88. 88.
    Gleixner KV, Mayerhofer M, Sonneck K, et al. Synergistic growth-inhibitory effects of two tyrosine kinase inhibitors, dasatinib and PKC412, on neoplastic mast cells expressing the D816V-mutated oncogenic variant of KIT. Haematologica. 2007;92:1451–1459.PubMedCrossRefGoogle Scholar
  89. 89.
    Aichberger KJ, Sperr WR, Gleixner KV, Kretschmer A, Valent P. Treatment responses to cladribine and dasatinib in rapidly progressing aggressive mastocytosis. Eur J Clin Invest. 2008;38:869–873.PubMedCrossRefGoogle Scholar
  90. 90.
    Ustun C, Corless CL, Savage N, et al. Chemotherapy and dasatinib induce long-term hematologic and molecular remission in systemic mastocytosis with acute myeloid leukemia with KIT D816V. Leuk Res. 2009;33:735–741.PubMedCrossRefGoogle Scholar
  91. 91.
    Verstovsek S, Tefferi A, Cortes J, et al. Phase II study of dasatinib in Philadelphia chromosome-negative acute and chronic myeloid diseases, including systemic mastocytosis. Clin Cancer Res. 2008;14:3906–3915.PubMedCrossRefGoogle Scholar
  92. 92.
    Purtill D, Cooney J, Sinniah R, et al. Dasatinib therapy for systemic mastocytosis: four cases. Eur J Haematol. 2008;80:456–458.PubMedCrossRefGoogle Scholar
  93. 93.
    Growney JD, Clark JJ, Adelsperger J, et al. Activation mutations of human c-KIT resistant to imatinib mesylate are sensitive to the tyrosine kinase inhibitor PKC412. Blood. 2005;106:721–724.PubMedCrossRefGoogle Scholar
  94. 94.
    Gleixner KV, Mayerhofer M, Aichberger KJ, et al. PKC412 inhibits in vitro growth of neoplastic human mast cells expressing the D816V-mutated variant of KIT: comparison with AMN107, imatinib, and cladribine (2CdA) and evaluation of cooperative drug effects. Blood. 2006;107:752–759.PubMedCrossRefGoogle Scholar
  95. 95.
    Gotlib J, Berube C, Growney JD, et al. Activity of the tyrosine kinase inhibitor PKC412 in a patient with mast cell leukemia with the D816V KIT mutation. Blood. 2005;106:2865–2870.PubMedCrossRefGoogle Scholar
  96. 96.
    Gotlib J, George TI, Corless C, et al. The KIT tyrosine kinase inhibitor midostaurine (PKC412) exhibits a high response rate in aggressive systemic mastocytosis (ASM): interim results of a Phase II trial. ASH Annual Meeting Abstracts. 2007;110:3536.Google Scholar

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© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.Division of HematologyMayo ClinicRochesterUSA

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