Drugs

, Volume 61, Issue 12, pp 1765–1774 | Cite as

Imatinib

Adis New Drug Profile

Abstract

  • ▴ Imatinib inhibits the BCR-ABL tyrosine kinase created by the Philadelphia chromosome (Ph+) in chronic myeloid leukaemia (CML).

  • ▴ Complete haematological responses were achieved in 88% of patients and major cytogenetic responses were detected in 49% of patients with chronic phase CML treated with oral imatinib 400 mg/day in a multicentre noncomparative study of 532 patients.

  • ▴ Administration of oral imatinib 400 or 600 mg/day to 235 patients with accelerated phase CML in a multicentre noncomparative study resulted in haematological responses in 63% of patients and major cytogenetic responses in 21% of patients.

  • ▴ 26% of the 260 patients with blast crisis CML receiving imatinib 400 or 600 mg/day in a multicentre noncomparative trial sustained a haematological response and 13.5% of patients had a major cytogenetic response.

  • ▴ Imatinib 400 or 600 mg/day orally achieved a haematological response in 19 of 32 patients with Ph+ acute lymphoblastic leukaemia in a pilot study.

  • ▴ Clinical improvement was demonstrated in 89% of 36 patients with gastrointestinal stromal tumours unresponsive to standard chemotherapy duringtreatment with 400 or 600 mg/day oral imatinib in a noncomparative phase II trial.

  • ▴ Adverse events were frequent in clinical trials of imatinib but most events were mild or moderate in severity. Serious adverse events reported include severe fluid retention, cytopenias and hepatotoxicity.

References

  1. 1.
    Mauro M, Druker B. Chronic myelogenous leukemia. Curr Opin Oncol 2001 Jan; 13(1): 3–7PubMedCrossRefGoogle Scholar
  2. 2.
    Sawyers CL. Chronic myeloid leukemia. N Engl J Med 1999 Apr 29; 340: 1330–40PubMedCrossRefGoogle Scholar
  3. 3.
    Novartis Pharmaceuticals Corporation. Gleevec (imatinib mesylate) capsules prescribing information. East Hanover, (NJ): May 2001Google Scholar
  4. 4.
    Blanke CD, von Mehren M, Joensuu H, et al. Evaluation of the safety and efficacy of an oral molecularly-targeted therapy, STI571, in patients (Pts) with unresectable or metastatic gastrointestinal stromal tumors (GISTS) expressing C-KIT (CD117) [abstract no. 1]. J Clin Oncol 2001 May 12; 20 (Pt 1): 1aGoogle Scholar
  5. 5.
    Van Oosterom AT, Judson I, Verweij J, et al. STI571, an active drug in metastatic gastro intestinal stromal tumors (GIST), an EORTC Phase I study [abstract no. 2]. J Clin Oncol 2001 May 12; 20 (Pt 1): 1aGoogle Scholar
  6. 6.
    Joensuu H, Roberts PJ, Sarlomo-Rikala M, et al. Effect of the tyrosine kinase inhibitor STI571 in a patient with a metastatic gastrointestinal stromal tumor. N Engl J Med 2001 Apr 5; 344(14): 1052–6PubMedCrossRefGoogle Scholar
  7. 7.
    Schindler T, Bornmann W, Pellicena P, et al. Structural mechanism for STI-571 inhibition of Abelson tyrosine kinase. Science 2000 Sep 15; 289(5486): 1938–42PubMedCrossRefGoogle Scholar
  8. 8.
    Druker B, Tamura S, Buchdunger E, et al. Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells. Nature Medicine 1996 May; 2(5): 561–6PubMedCrossRefGoogle Scholar
  9. 9.
    Gambacorti-Passerini C, le Coutre P, Mologni L, et al. Inhibition of the ABL kinase activity blocks the proliferation of BCR/ABL+ leukemic cells and induces apoptosis. Blood Cells Mol Dis 1997 Oct 15; 23(19): 380–94PubMedCrossRefGoogle Scholar
  10. 10.
    Fang G, Kim CN, Perkins CL, et al. CGP57148B (STI-571) induces differentiation and apoptosis and sensitizes Bcr-Abl-positive human leukemia cells to apoptosis due to antileukemic drugs. Blood 2000 Sep 15; 96(6): 2246–53PubMedGoogle Scholar
  11. 11.
    Deininger MW, Goldman JM, Lydon N, et al. The tyrosine kinase inhibitor CGP57148B selectively inhibits the growth of BCR-ABL-positive cells. Blood 1997 Nov 1; 90(9): 3691–8PubMedGoogle Scholar
  12. 12.
    Marley S, Deininger M, Davidson R, et al. The tyrosine kinase inhibitor STI571, like interferon-cc, preferentially reduces the capacity for amplification of granulocyte-macrophage progenitors from patients with chronic myeloid leukemia. Exp Hematol 2000; 28(5): 551–7PubMedCrossRefGoogle Scholar
  13. 13.
    Okuda K, Weisberg E, Gilliland DG, et al. ARG tyrosine kinase activity is inhibited by ST 1571. Blood 2001 Apr 15; 97(8): 2440–8PubMedCrossRefGoogle Scholar
  14. 14.
    Beran M, Cao X, Estrov Z, et al. Selective inhibition of cell proliferation and BCR-ABL phosphorylation in acute lymphoblastic leukemia cells expressing Mr 190,000 BCR-ABL protein by a tyrosine kinase inhibitor (CGP-57148). Clin Cancer Res 1998 Jul; 4(7): 1661–72PubMedGoogle Scholar
  15. 15.
    Carroll M, Ohno-Jones S, Tamura S, et al. CGP 57148, a tyrosine kinase inhibitor, inhibits the growth of cells expressing BCR-ABL, TEL-ABL, and TEL-PDGFR fusion proteins. Blood 1997 Dec 15; 90(12): 4947–52PubMedGoogle Scholar
  16. 16.
    le Coutre P, Mologni L, Cleris L, et al. In vivo eradication of human BCR/ABL-positive leukemia cells with an ABL kinase inhibitor. J Natl Cancer Inst 1999 Jan 20; 91(2): 163–8PubMedCrossRefGoogle Scholar
  17. 17.
    Krystal GW, Honsawek S, Litz J, et al. The selective tyrosine kinase inhibitor STI571 inhibits small cell lung cancer growth. Clin Cancer Res 2000 Aug; 6(8): 3319–26PubMedGoogle Scholar
  18. 18.
    Wang WL, Healy ME, Sattler M, et al. Growth inhibition and modulation of kinase pathways of small cell lung cancer cell lines by the novel tyrosine kinase inhibitor STI 571. Oncogene 2000 Jul 20; 19(31): 3521–8PubMedCrossRefGoogle Scholar
  19. 19.
    Buchdunger E, Cioffi CL, Law N, et al. 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 2000 Oct; 295(1): 139–45PubMedGoogle Scholar
  20. 20.
    Heinrich MC, Griffith DJ, Druker BJ, et al. Inhibition of c-kit receptor tyrosine kinase activity by STI 571, a selective tyrosine kinase inhibitor. Blood 2000 Aug 1; 96(3): 925–32PubMedGoogle Scholar
  21. 21.
    Greco A, Roccato E, Miranda C, et al. Growth-inhibitory effect of STI571 on cells transformed by the COL1A1/PDGFB rearrangement. Int J Cancer 2001 May 1; 92(3): 354–60PubMedCrossRefGoogle Scholar
  22. 22.
    Buchdunger E, Zimmermann J, Mett H, et al. Inhibition of the Abl protein-tyrosine kinase in vitro and in vivo by a 2-phenylaminopyrimidine derivative. Cancer Res 1996 Jan 1; 56(1): 100–4PubMedGoogle Scholar
  23. 23.
    Tomasson M, Williams I, Hasserjian R, et al. TEL/PDGFβR induces hematologic malignancies in mice that respond to a specific tyrosine kinase inhibitor. Blood 1999 Mar 1; 93(5): 1707–14PubMedGoogle Scholar
  24. 24.
    Topaly J, Zeller WJ, Fruehauf S, et al. Synergistic activity of STI571 with chemotherapeutic drugs and irradiation [abstract]. Blood 2000 Nov 16; 96 (11 Pt 1): 736aGoogle Scholar
  25. 25.
    Thiesing JT, Ohno-Jones S, Kolibaba KS, et al. Efficacy of STI571, an Abl tyrosine kinase inhibitor, in conjunction with other antileukemic agents against Bcr-Abl-positive cells. Blood 2000 Nov 1; 96(9): 3195–9PubMedGoogle Scholar
  26. 26.
    Topaly J, Zeller WJ, Fruehauf S. Synergistic activity of the new ABL-specific tyrosine kinase inhibitor STI571 and chemotherapeutic drugs on BCR-ABL-positive chronic myelogenous leukemia cells. Leukemia 2001 Mar; 15(3): 342–7PubMedCrossRefGoogle Scholar
  27. 27.
    Kano Y, Akutsu M, Tsunoda S, et al. In vitro cytotoxic effects of a tyrosine kinase inhibitor STI571 in combination with commonly used antileukemic agents. Blood 2001 Apr 1; 97(7): 1999–2007PubMedCrossRefGoogle Scholar
  28. 28.
    Tabrizi R, Mahon F, Cony Makhoul P, et al. STI571 induced apoptosis in Philadelpia chromosome-positive chronic myeloid leukemia blasts is increased by daunorubicin. J Clin Oncol 2001 May 12; 20 (Pt 1): 82aGoogle Scholar
  29. 29.
    Gianni M, Kalaç Y, Ponzanelli I, et al. Tyrosine kinase inhibitor STI571 potentiates the pharmacologic activity of retinoic acid in acute promyelocytic leukemia cells: effects on the degradation of RARα and PML-RARα. Blood 2001 May 15; 97(10): 3234–43PubMedCrossRefGoogle Scholar
  30. 30.
    Shimizu A, O’Brien K, Sjoblom T, et al. The dermato-fibrosarcoma protuberans-associated collagen type Iα1/platelet-derived growth factor (PDGF) B-chain fusion gene generates a transforming protein that is processed to functional PDGF-BB. Cancer Res 1999 Aug 1; 59: 3719–23PubMedGoogle Scholar
  31. 31.
    Kilic T, Alberta J, Zdunek P, et al. Intracranial inhibition of platelet-derived growth factor-mediated glioblastoma cell growth by an orally active kinase inhibitor of the 2-phenylaminopyrimidine class. Cancer Res 2000 Sep 15; 60: 5143–50PubMedGoogle Scholar
  32. 32.
    Uehara H, Kim SJ, Karashima T, et al. Blockade of PDGF-R signaling by STI571 inhibits angiogenesis and growth of human protsate cancer cells in the bone of nude mice [abstract]. 92nd Annual Meeting of the American Association of Cancer Research; 2001 Mar; 42: 407Google Scholar
  33. 33.
    Jorgensen H, Elliott M, Allan E, et al. Alpha-1-acid glycoprotein as expressed in chronic myeloid leukemia does not mediate significant in vitro resistance to STI571 [abstract no.46]. 6th European Haematology Association Meeting; 2001 Jun 21–24; FrankfurtGoogle Scholar
  34. 34.
    Druker BJ, Talpaz M, Resta DJ, et al. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med 2001 Apr 5; 344(14): 1031–7PubMedCrossRefGoogle Scholar
  35. 35.
    Druker BJ, Sawyers CL, Kantarjian H, et al. 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 2001 Apr 5; 344(14): 1038–42PubMedCrossRefGoogle Scholar
  36. 36.
    Gorre M, Mohammed M, Ellwood K, et al. Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification. Science 2001 Aug 3; 293(5531): 876–80PubMedCrossRefGoogle Scholar
  37. 37.
    Gorre ME, Banks K, Hsu NC, et al. Relapse in Ph+ leukemia patients treated with an ABL-specific kinase inhibitor is associated with reactivation of BCR-ABL. Blood 2000 Nov 16; 96 (11 Pt l):470Google Scholar
  38. 38.
    Mohammed M, Shin S, Deng S, et al. BCR/ABL gene amplification: a possible mechanism of drug resistance in patients treated with an ABL-specific kinase inhibitor [abstract]. Blood 2000 Nov 16; 96 (11 Pt 1): 344Google Scholar
  39. 39.
    Kreil S, Lahaye T, Weisser A, et al. Molecular and chromosomal mechanisms of resistance in CML patents after STI571 (Glivec) monotherapy [abstract no. 47]. 6th European Haematology Association Meeting; 2001 Jun 21–24; FrankfurtGoogle Scholar
  40. 40.
    Mahon FX, Deininger MW, Schultheis B, et al. Selection and characterization of BCR-ABL positive cell lines with differential sensitivity to the tyrosine kinase inhibitor STI571: diverse mechanisms of resistance. Blood 2000 Aug 1; 96(3): 1070–9PubMedGoogle Scholar
  41. 41.
    Peng B, Hayes M, Druker B, et al. Clinical pharmacokinetics and pharmacodynamics of ST1571 in a phase I trial in chronic myelogenous leukemia (CML) patients [abstract]. Proceedings of the 91st Annual Meeting of the American Association for Cancer Research; 2000 Mar; 41: 544Google Scholar
  42. 42.
    Reckmann A, Fischer T, Peng B, et al. Effect of food on STI571 GLivec pharmacokinetics and bioavailability [abstract no. 1223]. J Clin Oncol 2001 May 12; 20(Pt 1): 307Google Scholar
  43. 43.
    Sawyers C, Hochhaus A, Feldman E, et al. A phase II study to determine the safety and anti-leukemic effects of ST1571 in patients with Philadelphia chromosome positive chronic myeloid leukemia in myeloid blast crisis [abstract]. Blood 2000 Nov 16; 96(11): 503Google Scholar
  44. 44.
    Ottmann OG, Sawyers C, Druker B, et al. A phase II study to determine the safety and anti-leukemic effects of STI571 in adult patients with Philadelphia chromosome positive acute leukemias. Blood 2000 Nov 16; 96 (11 Pt 1): 828Google Scholar
  45. 45.
    Talpaz M, Silver RT, Druker B, et al. A phase II study of STI 571 in adult patients with Philadelphia chromosome positive chronic myeloid leukemia in accelerated phase. Blood 2000 Nov 16; 96(11): 469Google Scholar
  46. 46.
    Kantarjian H, Sawyers C, Hochhaus A, et al. Phase II study of STI571, a tyrosine kinase inhibitor, in patients (pts) with resistant or refractory Philadelphia chromosome-positive chronic myeloid leukemia (Ph+CML) [abstract no. 2022]. Blood 2000 Nov 16; 96 (11 Pt 1): 470aGoogle Scholar
  47. 47.
    Hochhaus A, Sawyers C, Feldman E, et al. Glivec (imatinib mesylate, STI571) induces hematologic and cytogenetic responses in patients with chronic myeloid leukemia in myeloid blast crisis: results of a multicenter phase II study [abstract no. 049]. 6th European Haematology Association Meeting; 2001 Jun 21–24; FrankfurtGoogle Scholar
  48. 48.
    Goldman J, Talpaz M, Silver R, et al. Treatment of adult Philadelphia chromosome positive chronic myeloid leukaemia (CML) in accelerated phase with STI571: update of phase II results [abstract no. 737]. 6th European Haematology Association Meeting; 2001 Jun 21–24; FrankfurtGoogle Scholar
  49. 49.
    Hochhaus A, Kantarjian H, Sawyers C, et al. Glivec (imatinib mesylate, STI571) induces hematologic and cytogenetic responses in the majority of patients with chronic myeloid leukemia in late chronic phase: results of a phase II study [abstract no. 736]. 6th European Haematology Association Meeting; 2001 Jun 21–24; FrankfurtGoogle Scholar
  50. 50.
    Temple R. Letter to Novartis Pharmaceuticals Corporation referring to new drug application 21-335 for Gleevec [online]. Available from: URL: www.fda.gov/cder/approval/index.htm [Accessed 2001 2 July]

Copyright information

© Adis International Limited 2001

Authors and Affiliations

  1. 1.Adis International LimitedMairangi Bay, Auckland 10New Zealand

Personalised recommendations