Imatinib Mesylate

  • Cornelius F. WallerEmail author
Part of the Recent Results in Cancer Research book series (RECENTCANCER, volume 212)


Imatinib mesylate (Gleevec, Glivec [Novartis, Basel, Switzerland], formerly referred to as STI571 or CGP57148B) represents the paradigm of a new class of anticancer agents, so-called small molecules. They have a high selectivity against a specific molecular target known to be the cause for the establishment and maintenance of the malignant phenotype. Imatinib is a rationally designed oral signal transduction inhibitor that specifically targets several protein tyrosine kinases, Abl, Arg (Abl-related gene), the stem cell factor receptor (c-KIT), platelet-derived growth factor receptor (PDGF-R), and their oncogenic forms, most notably BCR-ABL. Imatinib has been shown to have remarkable clinical activity in patients with chronic myeloid leukemia (CML) and malignant gastrointestinal stroma tumors (GIST) leading to its approval for treatment of these diseases. Treatment with imatinib is generally well tolerated with a low incidence of severe side effects. The most common adverse events include mild to moderate edema, muscle cramps, diarrhea, nausea, skin rashes, and myelosuppression. Several mechanisms of resistance have been identified. Clonal evolution, amplification, or overexpression of BCR-ABL as well as mutations in the catalytic domain, P-loop, and other mutations have been demonstrated to play a role in primary and secondary resistance to imatinib, respectively. Understanding of the underlying mechanisms of resistance has led to the development of new second- and third-generation tyrosine kinase inhibitors (see chapters on dasatinib, nilotinib, bosutinib, and ponatinib).


CML Tyrosine kinase inhibitor Imatinib  


  1. Anafi M, Gazit A, Gilon C, Neriah YB, Levitzki A (1993a) Tyrphostin-induced differentiation of mouse erythroleukemia cells. FEBS Lett 330:260–264CrossRefPubMedGoogle Scholar
  2. Anafi M, Gazit A, Zehavi A, Ben-Neriah Y, Levitzki A (1993b) Tyrphostin-induced inhibition of p210bcr-abl tyrosine kinase activity induces K562 to differentiate. Blood 82:3524–3529PubMedGoogle Scholar
  3. Baccarani M, Russo D, Rosti G, Martinelli G (2003) Interferon-alfa for chronic myeloid leukemia. Semin Hematol 40:22–33CrossRefPubMedGoogle Scholar
  4. Baccarani M, Martinelli G, Rosti G, Trabacchi E, Testoni N, Bassi S, Amabile M, Soverini S, Castagnetti F, Cilloni D et al (2004) Imatinib and pegylated human recombinant interferon-alpha2b in early chronic-phase chronic myeloid leukemia. Blood 104:4245–4251CrossRefPubMedGoogle Scholar
  5. Baccarani M, Deininger MW, Rosti G, Hochhaus A, Soverini S, Apperley JF, Cervantes F, Clark RE, Cortes JE, Guilhot F et al (2013) European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013. Blood 122:872–884CrossRefPubMedPubMedCentralGoogle Scholar
  6. Barnhill RL, Xiao M, Graves D, Antoniades HN (1996) Expression of platelet-derived growth factor (PDGF)-A, PDGF-B and the PDGF-alpha receptor, but not the PDGF-beta receptor, in human malignant melanoma in vivo. Br J Dermatol 135:898–904CrossRefPubMedGoogle Scholar
  7. Blanke CD, Rankin C, Demetri GD, Ryan CW, von Mehren M, Benjamin RS, Raymond AK, Bramwell VH, Baker LH, Maki RG et al (2008) Phase III randomized, intergroup trial assessing imatinib mesylate at two dose levels in patients with unresectable or metastatic gastrointestinal stromal tumors expressing the kit receptor tyrosine kinase: S0033. J Clin Oncol 26:626–632CrossRefPubMedGoogle Scholar
  8. Branford S, Hughes T (2006) Detection of BCR-ABL mutations and resistance to imatinib mesylate. Methods Mol Med 125:93–106Google Scholar
  9. Buchdunger E, Zimmermann J, Mett H, Meyer T, Muller M, Regenass U, Lydon NB (1995) Selective inhibition of the platelet-derived growth factor signal transduction pathway by a protein-tyrosine kinase inhibitor of the 2-phenylaminopyrimidine class. Proc Natl Acad Sci U S A 92:2558–2562CrossRefPubMedPubMedCentralGoogle Scholar
  10. Buchdunger E, Zimmermann J, Mett H, Meyer T, Muller M, Druker BJ, Lydon NB (1996) Inhibition of the Abl protein-tyrosine kinase in vitro and in vivo by a 2-phenylaminopyrimidine derivative. Cancer Res 56:100–104PubMedGoogle Scholar
  11. Buchdunger E, Cioffi CL, Law N, Stover D, Ohno-Jones S, Druker BJ, Lydon NB (2000) Abl protein-tyrosine kinase inhibitor STI571 inhibits in vitro signal transduction mediated by c-kit and platelet-derived growth factor receptors. J Pharmacol Exp Ther 295:139–145PubMedGoogle Scholar
  12. Buchdunger E, Matter A, Druker BJ (2001) Bcr-Abl inhibition as a modality of CML therapeutics. Biochim Biophys Acta 1551:M11–M18PubMedGoogle Scholar
  13. Carlo-Stella C, Regazzi E, Sammarelli G, Colla S, Garau D, Gazit A, Savoldo B, Cilloni D, Tabilio A, Levitzki A, Rizzoli V (1999) Effects of the tyrosine kinase inhibitor AG957 and an Anti-Fas receptor antibody on CD34(+) chronic myelogenous leukemia progenitor cells. Blood 93:3973–3982PubMedGoogle Scholar
  14. Casali PG, Le Cesne A, Poveda Velasco A, et al (2015) Time to definitive failure to the first tyrosine kinase inhibitor in localized GI stromal tumors treated with imatinib as an adjuvant: A European Organisation for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group Intergroup randomized trial in collaboration with the Australasian Gastro-Intestinal Trials Group, UNICANCER, French Sarcoma Group, Italian Sarcoma Group, and Spanish Group for Research on Sarcomas. J Clin Oncol 33:4276–4283Google Scholar
  15. Cohen MH, Dagher R, Griebel DJ, Ibrahim A, Martin A, Scher NS, Sokol GH, Williams GA, Pazdur R (2002a) US Food and Drug Administration drug approval summaries: imatinib mesylate, mesna tablets, and zoledronic acid. Oncologist 7:393–400CrossRefPubMedGoogle Scholar
  16. Cohen MH, Williams G, Johnson JR, Duan J, Gobburu J, Rahman A, Benson K, Leighton J, Kim SK, Wood R et al (2002b) Approval summary for imatinib mesylate capsules in the treatment of chronic myelogenous leukemia. Clin Cancer Res 8:935–942PubMedGoogle Scholar
  17. Cohen MH, Johnson JR, Pazdur R (2005) U.S. Food and Drug Administration drug approval summary: conversion of imatinib mesylate (STI571; Gleevec) tablets from accelerated approval to full approval. Clin Cancer Res 11:12–19PubMedGoogle Scholar
  18. Cohen MH, Farrell A, Justice R, Pazdur R (2009) Approval summary: imatinib mesylate in the treatment of metastatic and/or unresectable malignant gastrointestinal stromal tumors. OncologistGoogle Scholar
  19. Corless CL, Ballman KV, Antonescu CR et al (2014) Pathologic and molecular features correlate with long-term outcome after adjuvant therapy of resected primary GI stromal tumor: the ACOSOG Z900 trial. J Clin Oncol 32:1563–1570CrossRefPubMedPubMedCentralGoogle Scholar
  20. Cortes J, Giles F, O’Brien S, Thomas D, Garcia-Manero G, Rios MB, Faderl S, Verstovsek S, Ferrajoli A, Freireich EJ et al (2003) Result of high-dose imatinib mesylate in patients with Philadelphia chromosome-positive chronic myeloid leukemia after failure of interferon-alpha. Blood 102:83–86CrossRefPubMedGoogle Scholar
  21. Dagher R, Cohen M, Williams G, Rothmann M, Gobburu J, Robbie G, Rahman A, Chen G, Staten A, Griebel D, Pazdur R (2002) Approval summary: imatinib mesylate in the treatment of metastatic and/or unresectable malignant gastrointestinal stromal tumors. Clin Cancer Res 8:3034–3038PubMedGoogle Scholar
  22. Daley GQ, Van Etten RA, Baltimore D (1990) Induction of chronic myelogenous leukemia in mice by the P210bcr/abl gene of the Philadelphia chromosome. Science 247:824–830CrossRefGoogle Scholar
  23. Deininger MW, Goldman JM (1998) Chronic myeloid leukemia. Curr Opin Hematol 5:302–308CrossRefPubMedGoogle Scholar
  24. Deininger MW, Goldman JM, Lydon N, Melo JV (1997) The tyrosine kinase inhibitor CGP57148B selectively inhibits the growth of BCR-ABL-positive cells. Blood 90:3691–3698PubMedGoogle Scholar
  25. Deininger MW, Goldman JM, Melo JV (2000) The molecular biology of chronic myeloid leukemia. Blood 96:3343–3356PubMedGoogle Scholar
  26. Deininger M, Buchdunger E, Druker BJ (2005) The development of imatinib as a therapeutic agent for chronic myeloid leukemia. Blood 105:2640–2653CrossRefPubMedGoogle Scholar
  27. Demetri GD (2002) Identification and treatment of chemoresistant inoperable or metastatic GIST: experience with the selective tyrosine kinase inhibitor imatinib mesylate (STI571). Eur J Cancer 38(Suppl 5):S52–S59CrossRefPubMedGoogle Scholar
  28. Demetri GD, von Mehren M, Blanke CD, Van den Abbeele AD, Eisenberg B, Roberts PJ, Heinrich MC, Tuveson DA, Singer S, Janicek M et al (2002) Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med 347:472–480CrossRefPubMedGoogle Scholar
  29. Druker BJ (2008) Translation of the Philadelphia chromosome into therapy for CML. Blood 112:4808–4817CrossRefPubMedGoogle Scholar
  30. Druker BJ, Lydon NB (2000) Lessons learned from the development of an abl tyrosine kinase inhibitor for chronic myelogenous leukemia. J Clin Invest 105:3–7CrossRefPubMedPubMedCentralGoogle Scholar
  31. Druker BJ, Tamura S, Buchdunger E, Ohno S, Segal GM, Fanning S, Zimmermann J, Lydon NB (1996) Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of BCR-ABL positive cells. Nat Med 2:561–566CrossRefPubMedPubMedCentralGoogle Scholar
  32. Druker BJ, Sawyers CL, Kantarjian H, Resta DJ, Reese SF, Ford JM, Capdeville R, Talpaz M (2001a) Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome. N Engl J Med 344:1038–1042CrossRefPubMedGoogle Scholar
  33. Druker BJ, Talpaz M, Resta DJ, Peng B, Buchdunger E, Ford JM, Lydon NB, Kantarjian H, Capdeville R, Ohno-Jones S, Sawyers CL (2001b) Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med 344:1031–1037CrossRefPubMedPubMedCentralGoogle Scholar
  34. Druker BJ, Guilhot F, O’Brien SG, Gathmann I, Kantarjian H, Gattermann N, Deininger MW, Silver RT, Goldman JM, Stone RM et al (2006) Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med 355:2408–2417CrossRefPubMedGoogle Scholar
  35. Etienne G, Guilhot J, Rea D, Rigal-Huguet F, Nicolini F, Charbonnier A, Guerci-Bresler A, Legros L, Varet B, Gardembas M, Dubruille V, Tulliez M, Noel MP, Ianotto JC, Villemagne B, Carré M, Guilhot F, Rousselot P, Mahon FX (2017) Long-term follow-up of the french stop imatinib (STIM1) study in patients with chronic myeloid leukemia. J Clin Oncol 35(3):298–305. Epub 2016 Oct 31CrossRefPubMedGoogle Scholar
  36. Gambacorti-Passerini C, Le Coutre P, Mologni L, Fanelli M, Bertazolli C, Marchesi E, Di Nicola M, Biondi A, Corneo GM, Belotti D et al (1997) Inhibition of the ABL kinase activity blocks the proliferation of BCR/ABL + leukemic cells and induces apoptosis. Blood Cells Mol Dis 23:380–394CrossRefPubMedGoogle Scholar
  37. Gardembas M, Rousselot P, Tulliez M, Vigier M, Buzyn A, Rigal-Huguet F, Legros L, Michallet M, Berthou C, Cheron N et al (2003) Results of a prospective phase 2 study combining imatinib mesylate and cytarabine for the treatment of Philadelphia-positive patients with chronic myelogenous leukemia in chronic phase. Blood 102:4298–4305CrossRefPubMedGoogle Scholar
  38. Gorre ME, Mohammed M, Ellwood K, Hsu N, Paquette R, Rao PN, Sawyers CL (2001) Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification. Science 293:876–880CrossRefPubMedPubMedCentralGoogle Scholar
  39. Gratwohl A, Hermans J, Goldman JM, Arcese W, Carreras E, Devergie A, Frassoni F, Gahrton G, Kolb HJ, Niederwieser D et al (1998) Risk assessment for patients with chronic myeloid leukaemia before allogeneic blood or marrow transplantation. Chronic leukemia working party of the European group for blood and marrow transplantation. Lancet 352:1087–1092CrossRefPubMedGoogle Scholar
  40. Greco A, Roccato E, Miranda C, Cleris L, Formelli F, Pierotti MA (2001) Growth-inhibitory effect of STI571 on cells transformed by the COL1A1/PDGFB rearrangement. Int J Cancer 92:354–360CrossRefPubMedGoogle Scholar
  41. Guilhot F (2004) Indications for imatinib mesylate therapy and clinical management. Oncologist 9:271–281CrossRefPubMedGoogle Scholar
  42. Hahn EA, Glendenning GA, Sorensen MV, Hudgens SA, Druker BJ, Guilhot F, Larson RA, O’Brien SG, Dobrez DG, Hensley ML, Cella D (2003) Quality of life in patients with newly diagnosed chronic phase chronic myeloid leukemia on imatinib versus interferon alfa plus low-dose cytarabine: results from the IRIS Study. J Clin Oncol 21:2138–2146CrossRefPubMedGoogle Scholar
  43. Hatfield A, Owen S, Pilot PR (2007) In reply to ‘Cardiotoxicity of the cancer therapeutic agent imatinib mesylate’. Nat Med 13, 13: author reply 15–16Google Scholar
  44. Hehlmann R, Berger U, Pfirrmann M, Heimpel H, Hochhaus A, Hasford J, Kolb HJ, Lahaye T, Maywald O, Reiter A et al (2007a) Drug treatment is superior to allografting as first-line therapy in chronic myeloid leukemia. Blood 109:4686–4692CrossRefPubMedGoogle Scholar
  45. Hehlmann R, Hochhaus A, Baccarani M (2007b) Chronic myeloid leukaemia. Lancet 370:342–350CrossRefPubMedGoogle Scholar
  46. Hehlmann R, Lauseker M, Jung-Munkwitz S, Leitner A, Muller MC, Pletsch N, Proetel U, Haferlach C, Schlegelberger B, Balleisen L et al (2011) Tolerability-adapted imatinib 800 mg/d versus 400 mg/d versus 400 mg/d plus interferon-alpha in newly diagnosed chronic myeloid leukemia. J Clin Oncol 29:1634–1642CrossRefPubMedGoogle Scholar
  47. Hehlmann R, Lauseker M, Saußele S, Pfirrmann M, Krause S, Kolb HJ, Neubauer A, Hossfeld DK, Nerl C, Gratwohl A, Baerlocher GM, Heim D, Brümmendorf TH, Fabarius A, Haferlach C, Schlegelberger B, Müller MC, Jeromin S, Proetel U, Kohlbrenner K, Voskanyan A, Rinaldetti S, Seifarth W, Spieß B, Balleisen L, Goebeler MC, Hänel M, Ho A, Dengler J, Falge C, Kanz L, Kremers S, Burchert A, Kneba M, Stegelmann F, Köhne CA, Lindemann HW, Waller CF, Pfreundschuh M, Spiekermann K, Berdel WE, Müller L, Edinger M, Mayer J, Beelen DW, Bentz M, Link H, Hertenstein B, Fuchs R, Wernli M, Schlegel F, Schlag R, de Wit M, Trümper L, Hebart H, Hahn M, Thomalla J, Scheid C, Schafhausen P, Verbeek W, Eckart MJ, Gassmann W, Pezzutto A, Schenk M, Brossart P, Geer T, Bildat S, Schäfer E, Hochhaus A, Hasford J (2017) Assessment of imatinib as first-line treatment of chronic myeloid leukemia: 10-year survival results of the randomized CML study IV and impact of non-CML determinants. Leukemia 31(11):2398–2406. Epub 2017 Aug 14CrossRefPubMedPubMedCentralGoogle Scholar
  48. Heinrich MC, Blanke CD, Druker BJ, Corless CL (2002a) Inhibition of KIT tyrosine kinase activity: a novel molecular approach to the treatment of KIT-positive malignancies. J Clin Oncol 20:1692–1703CrossRefPubMedGoogle Scholar
  49. Heinrich MC, Rubin BP, Longley BJ, Fletcher JA (2002b) Biology and genetic aspects of gastrointestinal stromal tumors: KIT activation and cytogenetic alterations. Hum Pathol 33:484–495CrossRefPubMedGoogle Scholar
  50. Heinrich MC, Corless CL, Demetri GD, Blanke CD, von Mehren M, Joensuu H, McGreevey LS, Chen CJ, Van den Abbeele AD, Druker BJ et al (2003a) Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor. J Clin Oncol 21:4342–4349CrossRefPubMedGoogle Scholar
  51. Heinrich MC, Corless CL, Duensing A, McGreevey L, Chen CJ, Joseph N, Singer S, Griffith DJ, Haley A, Town A et al (2003b) PDGFRA activating mutations in gastrointestinal stromal tumors. Science 299:708–710CrossRefGoogle Scholar
  52. Heinrich MC, Owzar K, Corless CL, Hollis D, Borden EC, Fletcher CD, Ryan CW, von Mehren M, Blanke CD, Rankin C et al (2008) Correlation of kinase genotype and clinical outcome in the North American Intergroup Phase III Trial of imatinib mesylate for treatment of advanced gastrointestinal stromal tumor: CALGB 150105 Study by Cancer and Leukemia Group B and Southwest Oncology Group. J Clin Oncol 26:5360–5367CrossRefPubMedPubMedCentralGoogle Scholar
  53. Heisterkamp N, Jenster G, ten Hoeve J, Zovich D, Pattengale PK, Groffen J (1990) Acute leukaemia in BCR/ABL transgenic mice. Nature 344:251–253CrossRefGoogle Scholar
  54. Hochhaus A, Druker B, Sawyers C, Guilhot F, Schiffer CA, Cortes J, Niederwieser DW, Gambacorti-Passerini C, Stone RM, Goldman J et al (2008) Favorable long-term follow-up results over 6 years for response, survival, and safety with imatinib mesylate therapy in chronic-phase chronic myeloid leukemia after failure of interferon-alpha treatment. Blood 111:1039–1043CrossRefPubMedGoogle Scholar
  55. Hochhaus A, La Rosee P, Muller MC, Ernst T, Cross NC (2011) Impact of BCR-ABL mutations on patients with chronic myeloid leukemia. Cell Cycle 10:250–260CrossRefPubMedGoogle Scholar
  56. Hochhaus A, Larson RA, Guilhot F, Radich JP, Branford S, Hughes TP, Baccarani M, Deininger MW, Cervantes F, Fujihara S, Ortmann CE, Menssen HD, Kantarjian H, O’Brien SG, Druker BJ, Investigators IRIS (2017) Long-term outcomes of imatinib treatment for chronic myeloid leukemia. N Engl J Med 376(10):917–927. Scholar
  57. Hoeper MM, Barst RJ, Bourge RC, Feldman J, Ghofrani HA, Galié N, Gómez-Sánchez MA, Grimminger F, Grünig E, Hassoun PM et al (2013) Imatinib mesylate as add-on therapy for pulmonary arterial hypertension results of the randomized IMPRES study. Circulation 127(10):1128–1138CrossRefPubMedGoogle Scholar
  58. Hughes TP, Kaeda J, Branford S, Rudzki Z, Hochhaus A, Hensley ML, Gathmann I, Bolton AE, van Hoomissen IC, Goldman JM, Radich JP (2003) Frequency of major molecular responses to imatinib or interferon alfa plus cytarabine in newly diagnosed chronic myeloid leukemia. N Engl J Med 349:1423–1432CrossRefPubMedGoogle Scholar
  59. Joensuu H, Eriksson M, Sundby Hall K, Hartmann JT, Pink D, Schutte J, Ramadori G, Hohenberger P, Duyster J, Al-Batran SE et al (2012) One versus three years of adjuvant imatinib for operable gastrointestinal stromal tumor: a randomized trial. JAMA 307:1265–1272CrossRefGoogle Scholar
  60. Jovanovic JV, Score J, Waghorn K, Cilloni D, Gottardi E, Metzgeroth G, Erben P, Popp H, Walz C, Hochhaus A et al (2007) Low-dose imatinib mesylate leads to rapid induction of major molecular responses and achievement of complete molecular remission in FIP1L1-PDGFRA-positive chronic eosinophilic leukemia. Blood 109:4635–4640CrossRefPubMedGoogle Scholar
  61. Kantarjian H, Sawyers C, Hochhaus A, Guilhot F, Schiffer C, Gambacorti-Passerini C, Niederwieser D, Resta D, Capdeville R, Zoellner U et al (2002a) Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia. N Engl J Med 346:645–652CrossRefPubMedPubMedCentralGoogle Scholar
  62. Kantarjian HM, O’Brien S, Cortes JE, Smith TL, Rios MB, Shan J, Yang Y, Giles FJ, Thomas DA, Faderl S et al (2002b) Treatment of philadelphia chromosome-positive, accelerated-phase chronic myelogenous leukemia with imatinib mesylate. Clin Cancer Res 8:2167–2176PubMedGoogle Scholar
  63. Kerkela R, Grazette L, Yacobi R, Iliescu C, Patten R, Beahm C, Walters B, Shevtsov S, Pesant S, Clubb FJ et al (2006) Cardiotoxicity of the cancer therapeutic agent imatinib mesylate. Nat Med 12:908–916CrossRefPubMedGoogle Scholar
  64. Konopka JB, Watanabe SM, Witte ON (1984) An alteration of the human c-abl protein in K562 leukemia cells unmasks associated tyrosine kinase activity. Cell 37:1035–1042CrossRefGoogle Scholar
  65. Larsen RA, Druker BJ, Guilhot F, O’Brien SG, Riviere GJ, Krahnke T, Gathmann I, Wang Y et al (2008) Imatinib pharmacokinetics and its correlation with response and safety in chronic phase chronic myeloid leukemia: a subanalysis of the IRIS study. Blood 111:4022–4028CrossRefGoogle Scholar
  66. Le Coutre P, Mologni L, Cleris L, Marchesi E, Buchdunger E, Giardini R, Formelli F, Gambacorti-Passerini C (1999) In vivo eradication of human BCR/ABL-positive leukemia cells with an ABL kinase inhibitor. J Natl Cancer Inst 92:163–168CrossRefGoogle Scholar
  67. Levitzky A, Gazit A (1995) Tyrosine kinase inhibition: an approach to drug development. Science 267:1782–1788CrossRefGoogle Scholar
  68. Lugo TG, Pendergast AM, Muller AJ, Witte ON (1990) Tyrosine kinase activity and transformation potency of BCR-ABL oncogene products. Science 247:1079–1082CrossRefGoogle Scholar
  69. Lux ML, Rubin BP, Biase TL, Chen CJ, Maclure T, Demetri GD, Xiao S, Singer S, Fletcher CD, Fletcher JA (2000) Kit extracellular and kinase domain mutations in gastrointestinal stromal tumors. Am J Pathol 156:791–795CrossRefPubMedPubMedCentralGoogle Scholar
  70. Lyseng-Williamson K, Jarvis B (2001) Imatinib. Drugs 61:1765–1774CrossRefPubMedGoogle Scholar
  71. Mahon FX, Rea D, Guilhot J, Guilhot F, Huguet F, Nicolini F, Legros L, Charbonnier A, Guerci A, Varet B et al (2010) Discontinuation of imatinib in patients with chronic myeloid leukaemia who have maintained complete molecular remission for at least 2 years: the prospective, multicentre Stop Imatinib (STIM) trial. Lancet Oncol 11:1029–1035CrossRefPubMedGoogle Scholar
  72. Mahon FX, Richter J, Guilhot J, Hjorth-Hansen H, Almeida A, Janssen JWM, Mayer J, Porkka K, Panayiotidis P, Stromberg U, Berger MG, Diamond J, Ehrencrona H, Kairisto V, Machova Polakova K, Mueller MC, Mustjoki S, Hochhaus A, Pfirrmann M, Saussele S (2016) Cessation of tyrosine kinase inhibitors treatment in chronic myeloid leukemia patients with deep molecular response: results of the Euro-Ski trial. Blood, 128, abstract 787Google Scholar
  73. Marangon E, Citterio M, Sala F, Barisone E, Lippi AA, Rizzari C, Biondi A, D’Incalci M, Zucchetti M (2009) Pharmacokinetic profile of imatinib mesylate and N-demethyl-imatinib (CGP74588) in children with newly diagnosed Ph + acute leukemias. Cancer Chemother Pharmacol 63:563–566CrossRefPubMedGoogle Scholar
  74. Mauro MJ, O’Dwyer M, Heinrich MC, Druker BJ (2002) STI571: a paradigm of new agents for cancer therapeutics. J Clin Oncol 20:325–334CrossRefPubMedGoogle Scholar
  75. Moinzadeh P, Hunzelmann N, Krieg T (2013) Pharmacology and rationale for imatinib in the treatment of scleroderma. J Exp Pharmacol 5:15–22CrossRefPubMedPubMedCentralGoogle Scholar
  76. Mueller BA (2009) Imatinib and its successors: how modern chemistry has changed drug development. Curr Pharm Design 15:120–133CrossRefGoogle Scholar
  77. NCCN Practice Guidelines in Oncology, v. 3 (2018).
  78. NCCN_Practice_Guidelines_in_Oncology, v. 1 (2018).
  79. Nowell PC, Hungerford DA (1960) A minute chromosome in human chronic granulocytic leukemia. Science 132:1497Google Scholar
  80. O’Brien SG, Guilhot F, Goldman J, Hochhaus A, Hughes T, Radich J, Rudoltz M, Filian J, Gathmann I, Druker B et al (2008) International randomized study of interferon versus STI571 (IRIS) 7-year follow-up: sustained survival, low rate of transformation and increased rate of major molecular response (MMR) in patients (pts) with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP) treated with imatinib (IM). Blood 112:76Google Scholar
  81. O’Brien S, Giles F, Talpaz M, Cortes J, Rios MB, Shan J, Thomas D, Andreeff M, Kornblau S, Faderl S et al (2003a) Results of triple therapy with interferon-alpha, cytarabine, and homoharringtonine, and the impact of adding imatinib to the treatment sequence in patients with Philadelphia chromosome-positive chronic myelogenous leukemia in early chronic phase. Cancer 98:888–893CrossRefPubMedGoogle Scholar
  82. O’Brien SG, Guilhot F, Larson RA, Gathmann I, Baccarani M, Cervantes F, Cornelissen JJ, Fischer T, Hochhaus A, Hughes T et al (2003b) Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med 348:994–1004CrossRefPubMedGoogle Scholar
  83. Ogawa A, Miyaji K, Matsubara H (2017) Efficacy and safety of long-term imatinib therapy for patients with pulmonary veno-occlusive disease and pulmonary capillary hemangiomatosis. Respir Med 131:215–219. Epub 2017 Sep 12CrossRefPubMedGoogle Scholar
  84. Okuda K, Weisberg E, Gilliland DG, Griffin JD (2001) ARG tyrosine kinase activity is inhibited by STI571. Blood 97:2440–2448CrossRefPubMedGoogle Scholar
  85. Ottmann OG, Druker BJ, Sawyers CL, Goldman JM, Reiffers J, Silver RT, Tura S, Fischer T, Deininger MW, Schiffer CA et al (2002) A phase 2 study of imatinib in patients with relapsed or refractory Philadelphia chromosome-positive acute lymphoid leukemias. Blood 100:1965–1971CrossRefPubMedGoogle Scholar
  86. Pardanani A, Tefferi A (2004) Imatinib targets other than BCR/ABL and their clinical relevance in myeloid disorders. Blood 104:1931–1939CrossRefPubMedGoogle Scholar
  87. Preudhomme C, Guilhot J, Nicolini FE, Guerci-Bresler A, Rigal-Huguet F, Maloisel F, Coiteux V, Gardembas M, Berthou C, Vekhoff A et al (2010) Imatinib plus peginterferon alfa-2a in chronic myeloid leukemia. N Engl J Med 363:2511–2521CrossRefPubMedGoogle Scholar
  88. Rea D, Nicolini FE, Tulliez M, Guilhot F, Guilhot J, Guerci-Bresler A, Gardembas M, Coiteux V, Guillerm G, Legros L, Etienne G, Pignon JM, Villemagne B, Escoffre-Barbe M, Ianotto JC, Charbonnier A, Johnson-Ansah H, Noel MP, Rousselot P, Mahon FX; France Intergroupe des Leucémies Myéloïdes Chroniques (2017) Discontinuation of dasatinib or nilotinib in chronic myeloid leukemia: interim analysis of the STOP 2G-TKI study. Blood. 16;129(7):846–854. Epub 2016 Dec 8
  89. Rea D, Mahon FX (2018) How I manage relapse of chronic myeloid leukaemia after stopping tyrosine kinase inhibitor therapy. Br J Haematol 180(1):24–32. Epub 2017 Oct 19CrossRefPubMedGoogle Scholar
  90. Rowley JD (1973) A new consistent abnormality in chronic myelogenous leukaemia identified by quinacrine fluorescence and Giemsa staining. Nature 243:290–293CrossRefGoogle Scholar
  91. Saußele S, Krauss MP, Hehlmann R, Lauseker M, Proetel U, Kalmanti L, Hanfstein B, Fabarius A, Kraemer D, Berdel WE, Bentz M, Staib P, de Wit M, Wernli M, Zettl F, Hebart HF, Hahn M, Heymanns J, Schmidt-Wolf I, Schmitz N, Eckart MJ, Gassmann W, Bartholom€aus A, Pezzutto A, Leibundgut EO, Heim D, Krause SW, Burchert A, Hofmann WK, Hasford J, Hochhaus A, Pfirrmann M, M€uller MC Schweizerische Arbeitsgemeinschaft fur Klinische Krebsforschung and the German CML Study Group (2015) Impact of comorbidities on overall survival in patients with chronic myeloid leukemia: results of the randomized CML study IV. Blood 126:42–49Google Scholar
  92. Saußele S, Richter J, Hochhaus A, Hochhaus A, Mahon FX (2016) The concept of treatment-free remission in chronic myeloid leukemia. Leukemia 30(8):1638–1647. Epub 2016 May 2CrossRefPubMedPubMedCentralGoogle Scholar
  93. Sawyers CL (1999) Chronic myeloid leukemia. N Engl J Med 340:1330–1340CrossRefGoogle Scholar
  94. Sawyers CL, Hochhaus A, Feldman E, Goldman JM, Miller CB, Ottmann OG, Schiffer CA, Talpaz M, Guilhot F, Deininger MW et al (2002) Imatinib induces hematologic and cytogenetic responses in patients with chronic myelogenous leukemia in myeloid blast crisis: results of a phase II study. Blood 99:3530–3539CrossRefPubMedPubMedCentralGoogle Scholar
  95. Schiffer CA (2007) BCR-ABL tyrosine kinase inhibitors in chronic myelogenous leukemia. N Engl J Med 357:258–265CrossRefPubMedGoogle Scholar
  96. Shah NP, Sawyers CL (2003) Mechanisms of resistance to STI571 in Philadelphia chromosome-associated leukemias. Oncogene 22:7389–7395CrossRefPubMedGoogle Scholar
  97. Shah NP, Kantarjian HM, Kim DW, Rea D, Dorlhiac-Llacer PE, Milone JH, Vela-Ojeda J, Silver RT, Khoury HJ, Charbonnier A et al (2008) Intermittent target inhibition with dasatinib 100 mg once daily preserves efficacy and improves tolerability in imatinib-resistant and intolerant chronic-phase chronic myeloid leukemia. J Clin Oncol 26:3204–3212CrossRefPubMedGoogle Scholar
  98. Talpaz M, Silver RT, Druker BJ, Goldman JM, Gambacorti-Passerini C, Guilhot F, Schiffer CA, Fischer T, Deininger MW, Lennard AL et al (2002) Imatinib induces durable hematologic and cytogenetic responses in patients with accelerated phase chronic myeloid leukemia: results of a phase 2 study. Blood 99:1928–1937CrossRefPubMedGoogle Scholar
  99. Verweij J, Casali PG, Zalcberg J, et al. (2004) Progression-free survival in gastrointestinal stromal tumours with high-dose imatinib: Randomised trial. Lancet 364:1127–1134Google Scholar
  100. von Bubnoff N, Peschel C, Duyster J (2003) Resistance of Philadelphia-chromosome positive leukemia towards the kinase inhibitor imatinib (STI571, Glivec): a targeted oncoprotein strikes back. Leukemia 17:829–838CrossRefGoogle Scholar
  101. von Mehren M, Joensuu H. (2018) Gastrointestinal Stromal Tumors. J Clin Oncol. 10; 36(2):136–143. Epub 2017 Dec 8
  102. van Oosterom AT, Judson I, Verweij J, et al. (2001) Safety and efficacy of imatinib (STI571) in metastatic gastrointestinal stromal tumours: A phase I study. Lancet 358:1421–1423Google Scholar
  103. Voncken JW, Kaartinen V, Pattengale PK, Germeraad WT, Groffen J, Heisterkamp N (1995) BCR/ABL P210 and P190 cause distinct leukemia in transgenic mice. Blood 86:4603–4611PubMedGoogle Scholar

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© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Haematology, Oncology and Stem Cell Transplantation, Faculty of MedicineUniversity Medical Centre Freiburg, University of FreiburgFreiburgGermany

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