Mastocytosis pp 257-265 | Cite as

Tyrosine Kinase Inhibitors in Systemic Mastocytosis

  • Mohamad Jawhar
  • Jason Gotlib
  • Andreas ReiterEmail author


The strong association of systemic mastocytosis (SM) with mutations and constitutive activation of the receptor tyrosine kinase KIT in >90% of patients has led to great interest in investigating the clinical activity and safety of tyrosine kinase inhibitors (TKI) in these neoplasms. These agents were (a) either already approved for other hematologic neoplasms and demonstrated in vitro activity toward mutated forms of KIT, for example, imatinib, nilotinib or dasatinib; or (b) applied to patients with SM because of activity against KIT in vitro as part of a broader multikinase inhibitory profile, for example, midostaurin; or c) developed as specific KIT inhibitors, for example, avapritinib, ripretinib, or masitinib. Midostaurin and imatinib have been approved for specific indications by the regulatory health authorities, while avapritinib, ripretinib, and masitinib are still being investigated in clinical trials. Due to the low overall response rates, nilotinib and dasatinib are no longer actively pursued in SM.


Midostaurin Avapritinib Ripretinib Imatinib Masitinib Nilotinib Dasatinib 


  1. 1.
    Alvarez-Twose I, Matito A, Morgado JM, Sanchez-Munoz L, Jara-Acevedo M, Garcia-Montero A, et al. Imatinib in systemic mastocytosis: a phase IV clinical trial in patients lacking exon 17 KIT mutations and review of the literature. Oncotarget. 2017;8(40):68950–63.CrossRefGoogle Scholar
  2. 2.
    Metzgeroth G, Walz C, Score J, Siebert R, Schnittger S, Haferlach C, et al. Recurrent finding of the FIP1L1-PDGFRA fusion gene in eosinophilia-associated acute myeloid leukemia and lymphoblastic T-cell lymphoma. Leukemia. 2007;21(6):1183–8.CrossRefGoogle Scholar
  3. 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. 2006;107(2):345–51.CrossRefGoogle Scholar
  4. 4.
    Vega-Ruiz A, Cortes JE, Sever M, Manshouri T, Quintas-Cardama A, Luthra R, et al. Phase II study of imatinib mesylate as therapy for patients with systemic mastocytosis. Leuk Res. 2009;33(11):1481–4.CrossRefGoogle Scholar
  5. 5.
    Pagano L, Valentini CG, Caira M, Rondoni M, Van Lint MT, Candoni A, et al. Advanced mast cell disease: an Italian hematological multicenter experience. Int J Hematol. 2008;88(5):483–8.CrossRefGoogle Scholar
  6. 6.
    Pardanani A, Elliott M, Reeder T, Li CY, Baxter EJ, Cross NC, et al. Imatinib for systemic mast-cell disease. Lancet. 2003;362(9383):535–6.CrossRefGoogle Scholar
  7. 7.
    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(12):790–4.CrossRefGoogle Scholar
  8. 8.
    Iurlo A, Gianelli U, Beghini A, Spinelli O, Orofino N, Lazzaroni F, et al. Identification of kit(M541L) somatic mutation in chronic eosinophilic leukemia, not otherwise specified and its implication in low-dose imatinib response. Oncotarget. 2014;5(13):4665–70.CrossRefGoogle Scholar
  9. 9.
    Hoade Y, Metzgeroth G, Schwaab J, Reiter A, Cross NCP. Routine screening for KIT M541L is not warranted in the diagnostic work-up of patients with Hypereosinophilia. Acta Haematol. 2018;139(2):71–3.CrossRefGoogle Scholar
  10. 10.
    Jawhar M, Naumann N, Schwaab J, Baurmann H, Casper J, Dang TA, et al. Imatinib in myeloid/lymphoid neoplasms with eosinophilia and rearrangement of PDGFRB in chronic or blast phase. Ann Hematol. 2017;96(9):1463–70.CrossRefGoogle Scholar
  11. 11.
    Metzgeroth G, Schwaab J, Gosenca D, Fabarius A, Haferlach C, Hochhaus A, et al. Long-term follow-up of treatment with imatinib in eosinophilia-associated myeloid/lymphoid neoplasms with PDGFR rearrangements in blast phase. Leukemia. 2013;27(11):2254–6.CrossRefGoogle Scholar
  12. 12.
    Valent P, Akin C, Hartmann K, Nilsson G, Reiter A, Hermine O, et al. Advances in the classification and treatment of mastocytosis: current status and outlook toward the future. Cancer Res. 2017;77(6):1261–70.CrossRefGoogle Scholar
  13. 13.
    Valent P, Akin C, Hartmann K, George TI, Sotlar K, Peter B, et al. Midostaurin: a magic bullet that blocks mast cell expansion and activation. Ann Oncol. 2017;28(10):2367–76.CrossRefGoogle Scholar
  14. 14.
    Baird JH, Gotlib J. Clinical validation of KIT inhibition in advanced systemic mastocytosis. Curr Hematol Malig Rep. 2018;13(5):407–16.CrossRefGoogle Scholar
  15. 15.
    Gotlib J, Berube C, Growney JD, Chen CC, George TI, Williams C, et al. Activity of the tyrosine kinase inhibitor PKC412 in a patient with mast cell leukemia with the D816V KIT mutation. Blood. 2005;106(8):2865–70.CrossRefGoogle Scholar
  16. 16.
    DeAngelo DJ, George TI, Linder A, Langford C, Perkins C, Ma J, et al. Efficacy and safety of midostaurin in patients with advanced systemic mastocytosis: 10-year median follow-up of a phase II trial. Leukemia. 2018;32(2):470–8.CrossRefGoogle Scholar
  17. 17.
    Gotlib J, Kluin-Nelemans HC, George TI, Akin C, Sotlar K, Hermine O, et al. Efficacy and safety of midostaurin in advanced systemic mastocytosis. N Engl J Med. 2016;374(26):2530–41.CrossRefGoogle Scholar
  18. 18.
    Jawhar M, Schwaab J, Naumann N, Horny HP, Sotlar K, Haferlach T, et al. Response and progression on midostaurin in advanced systemic mastocytosis: KIT D816V and other molecular markers. Blood. 2017;130(2):137–45.CrossRefGoogle Scholar
  19. 19.
    Reiter A, Kluin-Nelemans HC, George T, Akin C, DeAngelo DJ, Hermine O, et al. Pooled survial analysis of midostaurin clinical study data (D2201 + A2213) in patients with advanced systemic mastocytosis (advSM) compared with historical controls. EHA. 2017; abstract S788.Google Scholar
  20. 20.
    Jawhar M, Schwaab J, Schnittger S, Meggendorfer M, Pfirrmann M, Sotlar K, et al. Additional mutations in SRSF2, ASXL1 and/or RUNX1 identify a high-risk group of patients with KIT D816V(+) advanced systemic mastocytosis. Leukemia. 2016;30(1):136–43.CrossRefGoogle Scholar
  21. 21.
    Jawhar M, Schwaab J, Schnittger S, Sotlar K, Horny HP, Metzgeroth G, et al. Molecular profiling of myeloid progenitor cells in multi-mutated advanced systemic mastocytosis identifies KIT D816V as a distinct and late event. Leukemia. 2015;29(5):1115–22.CrossRefGoogle Scholar
  22. 22.
    Schwaab J, Schnittger S, Sotlar K, Walz C, Fabarius A, Pfirrmann M, et al. Comprehensive mutational profiling in advanced systemic mastocytosis. Blood. 2013;122(14):2460–6.CrossRefGoogle Scholar
  23. 23.
    Damaj G, Joris M, Chandesris O, Hanssens K, Soucie E, Canioni D, et al. ASXL1 but not TET2 mutations adversely impact overall survival of patients suffering systemic mastocytosis with associated clonal hematologic non-mast-cell diseases. PLoS One. 2014;9(1):e85362.CrossRefGoogle Scholar
  24. 24.
    Jawhar M, Schwaab J, Meggendorfer M, Naumann N, Horny HP, Sotlar K, et al. The clinical and molecular diversity of mast cell leukemia with or without associated hematologic neoplasm. Haematologica. 2017;102(6):1035–43.CrossRefGoogle Scholar
  25. 25.
    Jawhar M, Dohner K, Kreil S, Schwaab J, Shoumariyeh K, Meggendorfer M, et al. KIT D816 mutated/CBF-negative acute myeloid leukemia: a poor-risk subtype associated with systemic mastocytosis. Leukemia. 2019;33(5):1124–34.CrossRefGoogle Scholar
  26. 26.
    Radia DH, Deininger MW, Gotlib J, Bose P, Drummond MW, Hexner EO et al. Avapritnib, a potent and selective inhibitor of KIT D816V, induces complete and durable responses in patients with advanced systemic mastocytosis (AdvSM). EHA. 2019; abstract S830.Google Scholar
  27. 27.
    Schneeweiss M, Peter B, Bibi S, Eisenwort G, Smiljkovic D, Blatt K, et al. The KIT and PDGFRA switch-control inhibitor DCC-2618 blocks growth and survival of multiple neoplastic cell types in advanced mastocytosis. Haematologica. 2018;103(5):799–809.CrossRefGoogle Scholar
  28. 28.
    Dubreuil P, Letard S, Ciufolini M, Gros L, Humbert M, Casteran N, et al. Masitinib (AB1010), a potent and selective tyrosine kinase inhibitor targeting KIT. PLoS One. 2009;4(9):e7258.CrossRefGoogle Scholar
  29. 29.
    Paul C, Sans B, Suarez F, Casassus P, Barete S, Lanternier F, et al. Masitinib for the treatment of systemic and cutaneous mastocytosis with handicap: a phase 2a study. Am J Hematol. 2010;85(12):921–5.CrossRefGoogle Scholar
  30. 30.
    Lortholary O, Chandesris MO, Bulai Livideanu C, Paul C, Guillet G, Jassem E, et al. Masitinib for treatment of severely symptomatic indolent systemic mastocytosis: a randomised, placebo-controlled, phase 3 study. Lancet. 2017;389(10069):612–20.CrossRefGoogle Scholar
  31. 31.
    Hochhaus A, Baccarani M, Giles FJ, le Coutre PD, Muller MC, Reiter A, et al. Nilotinib in patients with systemic mastocytosis: analysis of the phase 2, open-label, single-arm nilotinib registration study. J Cancer Res Clin Oncol. 2015;141(11):2047–60.CrossRefGoogle Scholar
  32. 32.
    Verstovsek S, Tefferi A, Cortes J, O'Brien S, Garcia-Manero G, Pardanani A, et al. Phase II study of dasatinib in Philadelphia chromosome-negative acute and chronic myeloid diseases, including systemic mastocytosis. Clin Cancer Res. 2008;14(12):3906–15.CrossRefGoogle Scholar
  33. 33.
    Verstovsek S, Mesa RA, Gotlib J, Levy RS, Gupta V, DiPersio JF, et al. Efficacy, safety, and survival with ruxolitinib in patients with myelofibrosis: results of a median 3-year follow-up of COMFORT-I. Haematologica. 2015;100(4):479–88.CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2020

Authors and Affiliations

  1. 1.Department of Hematology and OncologyUniversity Hospital MannheimMannheimGermany
  2. 2.Division of HematologyStanford Cancer InstituteStanfordUSA

Personalised recommendations