Midostaurin: A Multiple Tyrosine Kinases Inhibitor in Acute Myeloid Leukemia and Systemic Mastocytosis

  • Richard F. SchlenkEmail author
  • Sabine Kayser
Part of the Recent Results in Cancer Research book series (RECENTCANCER, volume 212)


Midostaurin (PKC412, Rydapt®) is an oral multiple tyrosine kinase inhibitor. Main targets are the kinase domain receptor, vascular endothelial-, platelet derived-, and fibroblast growth factor receptor, stem cell factor receptor c-KIT, as well as mutated and wild-type FLT3 kinases. Midostaurin was approved by the Food and Drug Administration (FDA) and the European Medical Agency (EMA) for acute myeloid leukemia with activating FLT3 mutations in combination with intensive induction and consolidation therapy as well as aggressive systemic mastocytosis (ASM), systemic mastocytosis with associated hematological neoplasm (SM-AHN) or mast cell leukemia (MCL). Several clinical trials are active or are planned to further investigate the role of midostaurin in myeloid malignancies and mastocytosis.


Multikinase inhibitor  AML with activating FLT3 mutations Systemic mastocytosis 


  1. Andrejauskas-Buchdunger E, Regenass U (1992) Differential inhibition of the epidermal growth factor-, platelet-derived growth factor-, and protein kinase C-mediated signal transduction pathways by the staurosporine derivative CGP 41251. Cancer Res 52(19):5353–5358PubMedGoogle Scholar
  2. Bali P, George P, Cohen P et al (2004) Superior activity of the combination of histone deacetylase inhibitor LAQ824 and the FLT-3 kinase inhibitor PKC412 against human acute myelogenous leukemia cells with mutant FLT-3. Clin Cancer Res 10(15):4991–4997CrossRefPubMedGoogle Scholar
  3. Barete S, Lortholary O, Damaj G et al (2015) Long-term efficacy and safety of cladribine (2-CdA) in adult patients with mastocytosis. Blood 126(8):1009–1016CrossRefPubMedGoogle Scholar
  4. Budworth J, Davies R, Malkhandi J, Gant TW, Ferry DR, Gescher A (1996) Comparison of staurosporine and four analogues: their effects on growth, rhodamine 123 retention and binding to P-glycoprotein in multidrug-resistant MCF-7/Adr cells. Br J Cancer 73(9):1063–1068CrossRefPubMedPubMedCentralGoogle Scholar
  5. Chu TF, Rupnick MA, Kerkela R et al (2007) Cardiotoxicity associated with tyrosine kinase inhibitor sunitinib. Lancet (9604);370:2011–2019Google Scholar
  6. Claridge LC, Eksteen B, Smith A et al (2010) Acute liver failure after administration of paracetamol at the maximum recommended daily dose in adults. BMJ 341:c6764CrossRefPubMedGoogle Scholar
  7. Cohen SS, Skovbo S, Vestergaard H et al (2014) Epidemiology of systemic mastocytosis in Denmark. Br J Haematol 166(4):521–528CrossRefPubMedGoogle Scholar
  8. Craig DG, Bates CM, Davidson JS et al (2011) Overdose pattern and outcome in paracetamol- induced acute severe hepatotoxicity. Br J Clin Pharmacol 71(2):273–282CrossRefPubMedPubMedCentralGoogle Scholar
  9. DeAngelo DJ, Stone RM, Heaney ML et al (2006) Phase 1 clinical results with tandutinib (MLN518), a novel FLT3 antagonist, in patients with acute myelogenous leukemia or high- risk myelodysplastic syndrome: safety, pharmacokinetics, and pharmacodynamics. Blood 108(12):3674–3681CrossRefPubMedPubMedCentralGoogle Scholar
  10. Delaporte E, Piérard E, Wolthers BG et al (1995) Interferon-alpha in combination with corticosteroids improves systemic mast cell disease. Br J Dermatol 132(3):479–482CrossRefPubMedGoogle Scholar
  11. Del Corral A, Dutreix C, Huntsman-Labed A et al (2012) Midostaurin does not prolong cardiac repolarization defined in a thorough electrocardiogram trial in healthy volunteers. Cancer Chemother Pharmacol 69(5):1255–1263CrossRefPubMedPubMedCentralGoogle Scholar
  12. Dutreix C, Munarini F, Lorenzo S, Roesel J, Wang Y (2013) Investigation into CYP3A4-mediated drug-drug interactions on midostaurin in healthy volunteers. Cancer Chemother Pharmacol 72(6):1223–1234CrossRefPubMedPubMedCentralGoogle Scholar
  13. Eder JP Jr, Garcia-Carbonero R, Clark JW et al (2004) A phase I trial of daily oral 4’- N -benzoyl- staurosporine in combination with protracted continuous infusion 5-fluorouracil in patients with advanced solid malignancies. Invest New Drugs 22(2):139–150CrossRefPubMedGoogle Scholar
  14. Fabbro D, Ruetz S, Bodis S et al (2000) PKC412-a protein kinase inhibitor with a broad therapeutic potential. Anticancer Drug Des 15(1):17–28PubMedGoogle Scholar
  15. Furukawa Y, Vu HA, Akutsu M et al (2007) Divergent cytotoxic effects of PKC412 in combination with conventional antileukemic agents in FLT3 mutation-positive versus -negative leukemia cell lines. Leukemia 21(5):1005–1014CrossRefPubMedGoogle Scholar
  16. Garcia-Montero AC, Jara-Acevedo M, Teodosio C et al (2006) 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 108(7):2366–2372CrossRefPubMedGoogle Scholar
  17. George P, Bali P, Cohen P et al (2004) Cotreatment with 17-allylaminodemethoxygeldanamycin and FLT-3 kinase inhibitor PKC412 is highly effective against human acute myelogenous leukemia cells with mutant FLT-3. Cancer Res 64(10):3645–3652CrossRefPubMedGoogle Scholar
  18. Gilliland DG, Griffin JD (2002) The roles of FLT3 in hematopoiesis and leukemia. Blood 100(5):1532–1542CrossRefGoogle Scholar
  19. Georgin-Lavialle S, Lhermitte L, Dubreuil P, Chandesris MO, Hermine O, Damaj G (2013) Mast cell leukemia. Blood 121(8):1285–1295CrossRefPubMedGoogle Scholar
  20. Gotlib J, Berubé C, Growney JD et al (2005) Activity of the tyrosine kinase inhibitor PKC412 in a patient with mast cell leukemia with the D816V KIT mutation. Blood 106(8):2865–2870CrossRefPubMedPubMedCentralGoogle Scholar
  21. Gotlib J, Kluin-Nelemans HC, George TI et al (2016) Efficacy and safety of midostaurin in advanced systemic mastocytosis. N Engl J Med 374(26):2530–2541CrossRefPubMedGoogle Scholar
  22. Griffith J, Black J, Faerman C et al (2004) The structural basis for autoinhibition of FLT3 by the juxtamembrane domain. Mol Cell 13(2):169–178CrossRefPubMedGoogle Scholar
  23. Gu TL, Nardone J, Wang Y, et al (2011) Survey of activated FLT3 signaling in leukemia. PLoS One 6:e19169Google Scholar
  24. Hannum C, Culpepper J, Campbell D et al (1994) Ligand for FLT3/FLK2 receptor tyrosine kinase regulates growth of haematopoietic stem cells and is encoded by variant RNAs. Nature 368(6472):643–648CrossRefPubMedGoogle Scholar
  25. Hauswirth AW, Simonitsch-Klupp I, Uffmann M et al (2004) Response to therapy with interferon alpha-2b and prednisolone in aggressive systemic mastocytosis: report of five cases and review of the literature. Leuk Res 28(3):249–257CrossRefPubMedGoogle Scholar
  26. Hayakawa F, Towatari M, Kiyoi H et al (2000) Tandem-duplicated Flt3 constitutively activates STAT5 and MAP kinase and introduces autonomous cell growth in IL-3-dependent cell lines. Oncogene 19(5):624–631CrossRefPubMedGoogle Scholar
  27. He H, Tran P, Tedesco V et al (2017) Midostaurin, a novel protein kinase inhibitor for the treatment of acute myelogenous leukemia: insights from human absorption, metabolism, and excretion studies of a BDDCS II drug. Drug Metab Dispos 45(5):540–555CrossRefPubMedGoogle Scholar
  28. Horny MP, Metcalfe DD, Bennett JM (2008) Mastocytosis. In: Swerdlow SH, Campo E (eds) WHO classification of tumors of hematopoietic and lymphoid tissues. International Agency for Research and Cancer, Lyon, France, pp 54–63Google Scholar
  29. Hernán MA, Robins JM (2017) Per-protocol analyses of pragmatic trials. N Engl J Med 377(14):1391–1398CrossRefPubMedGoogle Scholar
  30. Ikegami Y, Yano S, Nakao K et al (1995) Antitumor activity of the new selective protein kinase C inhibitor 4’-N-benzoyl staurosporine on murine and human tumor models. Arzneimittelforschung 45(11):1225–1230PubMedGoogle Scholar
  31. Karaman MW, Herrgard S, Treiber DK et al (2008) A quantitative analysis of kinase inhibitor selectivity. Nat Biotechnol 26(1):127–132CrossRefPubMedGoogle Scholar
  32. Kayser S, Schlenk RF (2017) Targeting the FLT3 mutation in acute myeloid leukemia. Eur Oncol Haematol 13(2). Epub ahead of printGoogle Scholar
  33. Kayser S, Levis MJ (2017) Advances in targeted therapy for acute myeloid leukaemia. Br J Haematol. 2017 Nov 28. [Epub ahead of print] Review
  34. Kluin-Nelemans HC, Oldhoff JM, Van Doormaal JJ et al (2003) Cladribine therapy for systemic mastocytosis. Blood 102(13):4270–4276CrossRefPubMedGoogle Scholar
  35. Kristensen T, Vestergaard H, Møller MB (2011) Improved detection of the KIT D816V mutation in patients with systemic mastocytosis using a quantitative and highly sensitive real-time qPCR assay. J Mol Diagn 13(2):180–188CrossRefPubMedPubMedCentralGoogle Scholar
  36. Larson RA et al (2017) An analysis of maintenance therapy and post-midostaurin outcomes in the international prospective randomized, placebo-controlled, double-blind trial (CALGB 10603/RATIFY [Alliance]) for newly diagnosed acute myeloid leukemia (AML) patients with FLT3 mutations blood 2017:ASH 2017Google Scholar
  37. Levis M, Pham R, Smith BD et al (2004) In vitro studies of a FLT3 inhibitor combined with chemotherapy: sequence of administration is important to achieve synergistic cytotoxic effects. Blood 104(4):1145–1150CrossRefPubMedGoogle Scholar
  38. Levis M, Brown P, Smith BD, Stine A, Pham R, Stone R et al (2006) Plasma inhibitory activity (PIA): a pharmacodynamic assay reveals insights into the basis for cytotoxic response to FLT3 inhibitors. Blood 108(10):3477–3483CrossRefPubMedPubMedCentralGoogle Scholar
  39. Levis MJ, Perl AE, Dombret H et al (2012) Final results of a phase 2 open-label, monotherapy efficacy and safety study of quizartinib (AC220) in patients with FLT3-ITD positive or negative relapsed/refractory acute myeloid leukemia after second-line chemotherapy or hematopoietic stem cell transplantation. Blood 120(12):673Google Scholar
  40. Lim KH, Tefferi A, Lasho TL et al (2009a) Systemic mastocytosis in 342 consecutive adults: survival studies and prognostic factors. Blood 113(23):5727–5736CrossRefPubMedGoogle Scholar
  41. Lim KH, Pardanani A, Butterfield JH, Li CY, Tefferi A (2009b) 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 84(12):790–794CrossRefPubMedGoogle Scholar
  42. Liu Y, Ramirez J, Ratain MJ (2011) Inhibition of paracetamol glucuronidation by tyrosine kinase inhibitors. Br J Clin Pharmacol 71(6):917–920CrossRefPubMedPubMedCentralGoogle Scholar
  43. Meshinchi S, Appelbaum FR (2009) Structural and functional alterations of FLT3 in acute myeloid leukemia. Clin Cancer Res 15(13):4263–4269CrossRefPubMedPubMedCentralGoogle Scholar
  44. Monnerat C, Henriksson R, Le Chevalier T et al (2004) Phase I study of PKC412 (N-benzoyl- staurosporine), a novel oral protein kinase C inhibitor, combined with gemcitabine and cisplatin in patients with non-small-cell lung cancer. Ann Oncol 15(2):316–323CrossRefPubMedGoogle Scholar
  45. Nagel G, Weber D, Fromm E et al (2017) German-Austrian AML Study Group (AMLSG). Epidemiological, genetic, and clinical characterization by age of newly diagnosed acute myeloid leukemia based on an academic population-based registry study (AMLSG BiO). Ann Hematol 96(12):1993–2003CrossRefPubMedPubMedCentralGoogle Scholar
  46. Papaemmanuil E, Gerstung M, Bullinger L et al (2016) Genomic classification and prognosis in acute myeloid leukemia. N Engl J Med 374(23):2209–2221 2016 Jun 9CrossRefPubMedPubMedCentralGoogle Scholar
  47. Pardanani A, Hoffbrand AV, Butterfield JH, Tefferi A (2004) Treatment of systemic mast cell disease with 2-chlorodeoxyadenosine. Leuk Res 28(2):127–131CrossRefPubMedGoogle Scholar
  48. Propper DJ, McDonald AC, Man A, Thavasu P, Balkwill F, Braybrooke JP et al (2001) Phase I and pharmacokinetic study of PKC412, an inhibitor of protein kinase C. J Clin Oncol 19(5):1485–1492CrossRefPubMedGoogle Scholar
  49. Quintas-Cardama A, Aribi A, Cortes J et al (2006) Novel approaches in the treatment of systemic mastocytosis. Cancer 107(7):1429–1439CrossRefPubMedGoogle Scholar
  50. Rosnet O, Marchetto S, deLapeyriere O et al (1991) Murine Flt3, a gene encoding a novel tyrosine kinase receptor of the PDGFR/CSF1R family. Oncogene 6(9):1641–1650PubMedGoogle Scholar
  51. Sato T, Yang X, Knapper S et al (2011) FLT3 ligand impedes the efficacy of FLT3 inhibitors in vitro and in vivo. Blood 117(12):3286–3293CrossRefPubMedPubMedCentralGoogle Scholar
  52. Schlenk RF, Fiedler W, Salih H et al (2016) Impact of age and midostaurin-dose on response and outcome in acute myeloid leukemia with FLT3-ITD: interim-analyses of the AMLSG 16-10 Trial (NCT01477606). Blood 128(22):449 (abstract)Google Scholar
  53. Siebenhaar F, Von Tschirnhaus E, Hartmann K et al (2016) Development and validation of the mastocytosis quality of life questionnaire: MCQoL. Allergy 71(6):869–877CrossRefPubMedGoogle Scholar
  54. Stone RM, DeAngelo DJ, Klimek V et al (2005) Patients with acute myeloid leukemia and an activating mutation in FLT3 respond to a small-molecule FLT3 tyrosine kinase inhibitor, PKC412. Blood 105(1):54–60CrossRefPubMedGoogle Scholar
  55. Stone RM, Fischer T, Paquette R et al (2012) Phase IB study of the FLT3 kinase inhibitor midostaurin with chemotherapy in younger newly diagnosed adult patients with acute myeloid leukemia. Leukemia 26(9):2061–2068CrossRefPubMedPubMedCentralGoogle Scholar
  56. Stone RM, Mandrekar SJ, Sanford BL et al (2017a) Midostaurin plus chemotherapy for acute myeloid leukemia with FLT3 mutation. N Engl J Med 377(5):454–464CrossRefPubMedPubMedCentralGoogle Scholar
  57. Stone RM et al (2017b) The addition of midostaurin to standard chemotherapy decreases cumulative incidence of relapse (CIR) in the international prospective randomized, placebo-controlled, double-blind trial (CALGB 10603/RATIFY [Alliance]) for newly diagnosed acute myeloid leukemia (AML) patients with FLT3 mutations. Blood 2017:ASH 2017Google Scholar
  58. Tefferi A, Li C-Y, Butterfield JH, Hoagland HC (2001) Treatment of systemic mastcell disease with cladribine. N Engl J Med 344(4):307–309CrossRefPubMedGoogle Scholar
  59. Tolcher AW, Appleman LJ, Shapiro GI et al (2011) A phase I open-label study evaluating the cardiovascular safety of sorafenib in patients with advanced cancer. Cancer Chemother Pharmacol 67(4):751–764CrossRefPubMedGoogle Scholar
  60. Utz I, Hofer S, Regenass U et al (1994) The protein kinase C inhibitor CGP 41251, a staurosporine derivative with antitumor activity, reverses multidrug resistance. Int J Cancer 57(1):104–110Google Scholar
  61. Valent P, Akin C, Hartmann K, Nilsson G, Reiter A, Hermine O et al (2017) Advances in the classification and treatment of mastocytosis: current status and outlook toward the future. Cancer Res 77(6):1261–1270Google Scholar
  62. Van Anrooij B, Kluin-Nelemans JC, Safy M et al (2016) Patient-reported disease-specific quality-of-life and symptom severity in systemic mastocytosis. Allergy 71(11):1585–1593CrossRefPubMedGoogle Scholar
  63. Weisberg E, Boulton C, Kelly LM et al (2002) Inhibition of mutant FLT3 receptors in leukemia cells by the small molecule tyrosine kinase inhibitor PKC412. Cancer Cell 1(15):433–443CrossRefPubMedGoogle Scholar
  64. Zaugg K, Rocha S, Resch H et al (2001) Differential p53-dependent mechanism of radiosensitization in vitro and in vivo by the protein kinase C-specific inhibitor PKC412. Cancer Res 61(2):732–738PubMedGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.NCT-Trial Center, German Cancer Research CenterHeidelbergGermany
  2. 2.Department of Internal Medicine VUniversity Hospital of HeidelbergHeidelbergGermany
  3. 3.Clinical Cooperation Unit Molecular Hematology/Oncology, German Cancer Research Center (DKFZ)University of HeidelbergHeidelbergGermany

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