Skip to main content
SpringerLink
Log in

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

  • Chapter
  • First Online:
Small Molecules in Hematology

Part of the book series: Recent Results in Cancer Research ((RECENTCANCER,volume 212))

Abstract

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.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
eBook
USD 16.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 99.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 129.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Similar content being viewed by others

References

  • 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):5353–5358

    PubMed  CAS  Google Scholar 

  • 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):4991–4997

    Article  CAS  PubMed  Google Scholar 

  • 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):1009–1016

    Article  CAS  PubMed  Google Scholar 

  • 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):1063–1068

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chu TF, Rupnick MA, Kerkela R et al (2007) Cardiotoxicity associated with tyrosine kinase inhibitor sunitinib. Lancet (9604);370:2011–2019

    Google Scholar 

  • 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:c6764

    Article  PubMed  Google Scholar 

  • Cohen SS, Skovbo S, Vestergaard H et al (2014) Epidemiology of systemic mastocytosis in Denmark. Br J Haematol 166(4):521–528

    Article  PubMed  Google Scholar 

  • 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):273–282

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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):3674–3681

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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):479–482

    Article  CAS  PubMed  Google Scholar 

  • 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):1255–1263

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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):1223–1234

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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):139–150

    Article  CAS  PubMed  Google Scholar 

  • Fabbro D, Ruetz S, Bodis S et al (2000) PKC412-a protein kinase inhibitor with a broad therapeutic potential. Anticancer Drug Des 15(1):17–28

    PubMed  CAS  Google Scholar 

  • 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):1005–1014

    Article  CAS  PubMed  Google Scholar 

  • 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):2366–2372

    Article  CAS  PubMed  Google Scholar 

  • 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):3645–3652

    Article  CAS  PubMed  Google Scholar 

  • Gilliland DG, Griffin JD (2002) The roles of FLT3 in hematopoiesis and leukemia. Blood 100(5):1532–1542

    Article  CAS  Google Scholar 

  • Georgin-Lavialle S, Lhermitte L, Dubreuil P, Chandesris MO, Hermine O, Damaj G (2013) Mast cell leukemia. Blood 121(8):1285–1295

    Article  CAS  PubMed  Google Scholar 

  • 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):2865–2870

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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):2530–2541

    Article  CAS  PubMed  Google Scholar 

  • Griffith J, Black J, Faerman C et al (2004) The structural basis for autoinhibition of FLT3 by the juxtamembrane domain. Mol Cell 13(2):169–178

    Article  CAS  PubMed  Google Scholar 

  • Gu TL, Nardone J, Wang Y, et al (2011) Survey of activated FLT3 signaling in leukemia. PLoS One 6:e19169

    Google Scholar 

  • 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):643–648

    Article  CAS  PubMed  Google Scholar 

  • 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):249–257

    Article  CAS  PubMed  Google Scholar 

  • 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):624–631

    Article  CAS  PubMed  Google Scholar 

  • 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):540–555

    Article  CAS  PubMed  Google Scholar 

  • 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 54–63

    Google Scholar 

  • Hernán MA, Robins JM (2017) Per-protocol analyses of pragmatic trials. N Engl J Med 377(14):1391–1398

    Article  PubMed  Google Scholar 

  • 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):1225–1230

    PubMed  CAS  Google Scholar 

  • Karaman MW, Herrgard S, Treiber DK et al (2008) A quantitative analysis of kinase inhibitor selectivity. Nat Biotechnol 26(1):127–132

    Article  CAS  PubMed  Google Scholar 

  • Kayser S, Schlenk RF (2017) Targeting the FLT3 mutation in acute myeloid leukemia. Eur Oncol Haematol 13(2). Epub ahead of print

    Google Scholar 

  • Kayser S, Levis MJ (2017) Advances in targeted therapy for acute myeloid leukaemia. Br J Haematol. 2017 Nov 28. https://doi.org/10.1111/bjh.15032. [Epub ahead of print] Review

  • Kluin-Nelemans HC, Oldhoff JM, Van Doormaal JJ et al (2003) Cladribine therapy for systemic mastocytosis. Blood 102(13):4270–4276

    Article  CAS  PubMed  Google Scholar 

  • 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):180–188

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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 2017

    Google Scholar 

  • 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):1145–1150

    Article  CAS  PubMed  Google Scholar 

  • 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):3477–3483

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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):673

    Google Scholar 

  • Lim KH, Tefferi A, Lasho TL et al (2009a) Systemic mastocytosis in 342 consecutive adults: survival studies and prognostic factors. Blood 113(23):5727–5736

    Article  CAS  PubMed  Google Scholar 

  • 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):790–794

    Article  CAS  PubMed  Google Scholar 

  • Liu Y, Ramirez J, Ratain MJ (2011) Inhibition of paracetamol glucuronidation by tyrosine kinase inhibitors. Br J Clin Pharmacol 71(6):917–920

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Meshinchi S, Appelbaum FR (2009) Structural and functional alterations of FLT3 in acute myeloid leukemia. Clin Cancer Res 15(13):4263–4269

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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):316–323

    Article  CAS  PubMed  Google Scholar 

  • 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):1993–2003

    Article  PubMed  PubMed Central  Google Scholar 

  • 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 9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pardanani A, Hoffbrand AV, Butterfield JH, Tefferi A (2004) Treatment of systemic mast cell disease with 2-chlorodeoxyadenosine. Leuk Res 28(2):127–131

    Article  CAS  PubMed  Google Scholar 

  • 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):1485–1492

    Article  CAS  PubMed  Google Scholar 

  • Quintas-Cardama A, Aribi A, Cortes J et al (2006) Novel approaches in the treatment of systemic mastocytosis. Cancer 107(7):1429–1439

    Article  CAS  PubMed  Google Scholar 

  • 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):1641–1650

    PubMed  CAS  Google Scholar 

  • 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):3286–3293

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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 

  • Siebenhaar F, Von Tschirnhaus E, Hartmann K et al (2016) Development and validation of the mastocytosis quality of life questionnaire: MCQoL. Allergy 71(6):869–877

    Article  CAS  PubMed  Google Scholar 

  • 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):54–60

    Article  CAS  PubMed  Google Scholar 

  • 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):2061–2068

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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):454–464

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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 2017

    Google Scholar 

  • Tefferi A, Li C-Y, Butterfield JH, Hoagland HC (2001) Treatment of systemic mastcell disease with cladribine. N Engl J Med 344(4):307–309

    Article  CAS  PubMed  Google Scholar 

  • 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):751–764

    Article  CAS  PubMed  Google Scholar 

  • 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):104–110

    Google Scholar 

  • 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):1261–1270

    Google Scholar 

  • 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):1585–1593

    Article  PubMed  Google Scholar 

  • 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):433–443

    Article  CAS  PubMed  Google Scholar 

  • 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):732–738

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. NCT-Trial Center, German Cancer Research Center, Heidelberg, Germany

    Richard F. Schlenk

  2. Department of Internal Medicine V, University Hospital of Heidelberg, Heidelberg, Germany

    Sabine Kayser

  3. Clinical Cooperation Unit Molecular Hematology/Oncology, German Cancer Research Center (DKFZ), University of Heidelberg, Heidelberg, Germany

    Sabine Kayser

Authors
  1. Richard F. Schlenk
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sabine Kayser
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Richard F. Schlenk .

Editor information

Editors and Affiliations

  1. MOLIT Institute, Cancer Center Heilbronn-Franken, SLK-Clinics, Heilbronn, Baden-Württemberg, Germany

    Uwe M. Martens

Rights and permissions

Reprints and permissions

Copyright information

© 2018 Springer International Publishing AG, part of Springer Nature

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Schlenk, R.F., Kayser, S. (2018). Midostaurin: A Multiple Tyrosine Kinases Inhibitor in Acute Myeloid Leukemia and Systemic Mastocytosis. In: Martens, U. (eds) Small Molecules in Hematology. Recent Results in Cancer Research, vol 212. Springer, Cham. https://doi.org/10.1007/978-3-319-91439-8_10

Download citation

  • DOI: https://doi.org/10.1007/978-3-319-91439-8_10

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-319-91438-1

  • Online ISBN: 978-3-319-91439-8

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation