Oncologie

, Volume 14, Issue 10–11, pp 583–588 | Cite as

Inhibiteur de tyrosine-kinase de 1re génération: place des associations

Mise au Point / Update
First Online:
Received:
Accepted:
  • 90 Downloads

Résumé

La leucémie myéloïde chronique (LMC) est l’hémopathie maligne qui a démontré demanière évidente l’implication du système immunitaire dans le phénomène de réaction du greffon contre la leucémie (GVL). Les interférons (IFN) ont démontré ensuite leur intérêt avant l’ère des inhibiteurs de tyrosine-kinase (ITK). Le traitement actuel de la phase chronique de la LMC, l’imatinib à la dose de 400mg, ne permet pas l’éradication des cellules souches leucémiques. La plupart des patients en rémission moléculaire gardent des cellules souches leucémiques sources de rechutes moléculaires si le traitement est interrompu. Des travaux récents ont souligné l’intérêt de l’IFN pour aider à l’éradication des cellules souches quiescentes. Les inhibiteurs de deuxième génération comme le dasatinib, le nilotinib ou le bosutinib n’éliminent pas non plus les cellules souches, ce qui amène à la conclusion qu’il y a une persistance de cellules souches leucémiques et que cela est un phénomène général au cours des thérapeutiques par les ITK. Certains mécanismes responsables des résistances incluent une forte activité de Bcr-Abl et une forte activité phospho-CRKL, une expression faible de OCT-1 et des taux élevés des protéines ABCB1 et ABCG2. Cependant, deux groupes scientifiques ont récemment démontré l’intérêt de l’IFN alpha en tant que molécule pouvant stimuler le turn-over et la prolifération des cellules souches hématopoïétiques in vivo. Cette nouvelle approche de la compréhension du mécanisme d’action des IFN alpha sur les cellules souches hématopoïétiques permet de suggérer l’intérêt d’une thérapeutique combinant les ITK avec les IFN alpha.

Mots clés

Leucémie myéloïde chronique Inhibiteurs de tyrosine-kinase Cellules souches leucémiques Interféron 

First-generation tyrosine-kinase inhibitors: the role of combination therapy

Abstract

Chronic myeloid leukemia (CML) is a malignant disorder in which the immune system has been described as important for the graft versus leukemia effect after stem cell transplantation. With imatinib at a dose of 400 mg, the current treatment of chronic phase CML does not eradicate the leukemic stem cells. Most of the patients in molecular response remain with leukemic stem cells responsible for relapse if the treatment is discontinued. Recent studies have suggested that interferon may be useful in order to eradicate the quiescent stem cells. The second-generation inhibitors like dasatinib, nilotinib or bosutinib do not eliminate either the stem cells; this leads to the conclusion that either there is a persistence of leukemic stem cells or there is a general phenomenon with TKI. The mechanisms of resistance include high activities of Bcr-Abl and CrkLPhospho, a weak expression ofOCT-1 and high levels of proteins ABCB1 and ABCG2. However, two scientific groups have recently demonstrated the value of interferon alpha as a molecule that may stimulate the turnover and proliferation of hematopoietic stem cells in vivo. This new approach to understanding the mechanism of action of interferon alpha on hematopoietic stem cells supports the use of combination therapy of TKI plus interferon.

Keywords

Chronicmyeloid leukemia Tyrosine-kinase inhibitors Leukemic stem cells Interferon 
This is a preview of subscription content, log in to check access.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

Références

  1. 1.
    Baccarani M, Martinelli G, Rosti G, et al. (2004) Imatinib an pegylated human recombinant interferon-α2b in early chronic-phase chronic myeloid leukemia. Blood 104: 4245–4251PubMedCrossRefGoogle Scholar
  2. 2.
    Bhattacharya, S, Zheng H, Tzimas C, et al. (2011) Bcr-Abl signals to desensitize chronic myeloid leukemia cells to IFNalpha via accelerating the degradation of its receptor. Blood 118(15): 4179–4187PubMedCrossRefGoogle Scholar
  3. 3.
    Byrd N, Becker S, Maye P, et al. (2002) Hedgehog is required for murine yolk sac angiogenesis. Development 129(2): 361–372PubMedGoogle Scholar
  4. 4.
    Chronic Myeloid Leukemia Trialists’ Collaborative Group (1997) Interferon alpha versus chemotherapy for Chronic Myeloid Leukemia: a meta analysis of seven randomized trials. J Natl Cancer Inst 89: 1616–1620CrossRefGoogle Scholar
  5. 5.
    Copland M, Hamilton A, Elrick LJ, et al. (2006) Dasatinib (BMS-354825) targets an earlier progenitorpopulation than imatinib in primary CML but does not eliminatethe quiescent fraction. Blood 107: 4532–4539PubMedCrossRefGoogle Scholar
  6. 6.
    Dierks C, Beigi R, Guo GR, et al. (2008) Expansion of Bcr-Abl-positive leukemic stem cells is dependent on Hedgehog pathway activation. Cancer Cell 14(3): 238–249PubMedCrossRefGoogle Scholar
  7. 7.
    Essers MA, Offner S, Blanco-Bose WE, et al. (2009) IFNalpha activates dormant haematopoietic stem cells in vivo. Nature 458: 904–908PubMedCrossRefGoogle Scholar
  8. 8.
    Gardembas M, Rousselot P, Tulliez M, et al. (2003) Results of a phase II study combining imatinib mesylate and cytarabine for the treatment of Philadelphiapositive chronic myelogenous leukaemia patients in chronic phase. Blood 102: 4298–4305PubMedCrossRefGoogle Scholar
  9. 9.
    Graham SM, Jorgensen HG, Allan E, et al. (2002) Primitive, quiescent, Philadelphiapositive stemcells from patients with chronic myeloid leukaemia are insensitiveto STI571 in vitro. Blood 99: 319–325PubMedCrossRefGoogle Scholar
  10. 10.
    Guilhot F, Chastang C, Michallet M, et al. (1997) Interferon alfa-2b combined with cytarabine versus interferon alone in chronic myelogenous leukemia. N Engl J Med 337: 223–229PubMedCrossRefGoogle Scholar
  11. 11.
    Guilhot F, Druker B, Larson RA, et al. (2009) High rates of durable response are achieved with Imatinib after treatment with interferon alpha plus cytarabine: results from the International Randomized Study of Interferon and STI571 (IRIS) trial. Haematologica 94: 1669–1675PubMedCrossRefGoogle Scholar
  12. 12.
    Guilhot F, Roy L, Saulnier PJ, Guilhot J (2009) Interferon in chronic myeloid leukaemia: past and future. Best Pract Res Clin Haematol 22: 315–329PubMedCrossRefGoogle Scholar
  13. 13.
    Guilhot F, Roy L, Tomowiak C (2012) Current treatment strategies in chronic myeloid leukemia. Curr Opin Hematol 19(2): 102–109PubMedCrossRefGoogle Scholar
  14. 14.
    Hehlmann R, Lauseker M, Jung-Munkwitz S, et al. (2011) Tolerability-adapted imatinib 800 mg/d versus 400 mg/d versus 400 mg/d plus interferon-a in newly diagnosed chronic myeloid leukemia. J Clin Oncol 29: 1634–1642PubMedCrossRefGoogle Scholar
  15. 15.
    Holyoake T, Jiang X, Eaves C, Eaves A (1999) Isolation of a highly quiescent subpopulation of primitive leukemic cells in chronic myeloid leukaemia. Blood 94: 2056–2064PubMedGoogle Scholar
  16. 16.
    Johnson-Ansah H, Guilhot J, Rousselot P, et al. (2011) Pegylated interferon a2a (PegIFN) at the dose of 45 μg per week in combination with imatinib 400 mg is the recommended initial dose for patients (pts) with chronic phase chronic myeloid leukemia (CML-CP): results from the French SPIRIT Trial of the French CML Group (FI LMC). ASH Annual Meeting Abstracts 118(21): 456Google Scholar
  17. 17.
    Kolb HJ, Schattenberg A, Goldman JM, et al. (1995) Graft-versus-leukaemia effect of donor lymphocyte transfusions in marrow grafted patients. Blood 86: 2041–2050PubMedGoogle Scholar
  18. 18.
    Mahon FX, Rea D, Guilhot J, 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: 1029–1035PubMedCrossRefGoogle Scholar
  19. 19.
    O’Brien S, Vallance SE, Craddock C, et al. (2001) Pegintron® and STI571 combination evaluation study (PISCES) in chronic phase Chronic Myeloid Leukemia. Blood 98: 3512aGoogle Scholar
  20. 20.
    Palandri F, Iacobucci I, Castagnetti F, et al. (2008) Front line treatment of Philadelphia positive chronic myeloid leukemia with imatinib and interferon-α: 5 years outcome. Haematologica 93: 770–774PubMedCrossRefGoogle Scholar
  21. 21.
    Preudhomme C, Guilhot J, Nicolini FE, et al. (2010) Imatinib plus peginterferon alfa-2a in chronic myeloid leukemia. N Engl J Med 363: 2511–2521PubMedCrossRefGoogle Scholar
  22. 22.
    Sato T, Onai N, Yoshihara H, et al. (2009) Interferon regulatory factor-2 protects quiescent hematopoietic stem cells from type I interferon-dependent exhaustion. Nat Med 15: 696–700PubMedCrossRefGoogle Scholar
  23. 23.
    Simonsson B, Gedde-Dahl T, Markevärn B, et al. (2011) Combination of pegylated IFN-alpha2b with imatinib increases molecular response rates in patients with low-or intermediate-risk chronic myeloid leukemia. Blood 118(12): 3228–3235PubMedCrossRefGoogle Scholar
  24. 24.
    Topaly J, Zeller WJ, Fruehauf S (2001) Synergistic activity of the new ABLspecific tyrosine kinase inhibitor imatinib mesylate and chemotherapeutic drugs on Bcr-Abl positive chronic myelogenous leukemia cells. Leukemia 15: 342–347PubMedCrossRefGoogle Scholar
  25. 25.
    Tyler Thiesing J, Ohno-Jones S, Kolibaba KS, Druker BJ (2000) Efficacy of imatinib mesylate, an Abl tyrosine kinase inhibitor, in conjunction with other antileukemic agents against Bcr-Abl-positive cells. Blood 96(9): 3195–3199Google Scholar

Copyright information

© Springer-Verlag France 2012

Authors and Affiliations

  1. 1.CIC Inserm 0802CHU de PoitiersPoitiersFrance

Personalised recommendations