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Tyrosine kinase inhibitors in chronic myeloid leukaemia: which, when, for whom?

Nature Reviews Clinical Oncology volume 14, pages 141–154 (2017)Cite this article

Subjects

Key Points

  • Several tyrosine kinase inhibitors (TKIs) are currently available for patients with chronic myeloid leukaemia (CML) at different stages of the disease

  • Different end points, such as survival, treatment-free remission or response milestones, can guide the selection of the most appropriate TKI; other factors (for example, age, prognostic category or safety) should also be considered

  • Imatinib is the 'gold standard' therapy for the treatment of CML and is already available as a generic drug in many countries, but a considerable proportion of patients develop resistance or intolerance to this drug

  • Nilotinib, dasatinib, bosutinib and ponatinib are TKIs with a higher inhibitory action than imatinib, but also associated with different safety profiles

Abstract

The therapeutic armamentarium for chronic myeloid leukaemia (CML) comprises mainly tyrosine kinase inhibitors (TKIs), with several agents available for frontline treatment, or for the treatment of disease resistance or intolerance to the first-choice or second-choice drug. The availability of different drugs is a major achievement, but means that choices must be made — which can be difficult and questionable at times. The most important end point considered in decision-making regarding treatment for any cancer is overall survival, but additional factors (such as age, prognostic category, safety, or the possibility of achieving treatment-free remission) should be considered when selecting an agent for frontline treatment. Regardless of the TKI selected for first-line treatment, guidelines that define the importance of reaching specific response indicators and procedures for vigilant follow-up monitoring are established to ensure timely implementation of second-line TKIs. Herein, we discuss the benefits and risks of the different TKIs available for the treatment of patients with CML, and how to decide when to employ these agents at different treatment settings.

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References

  1. Druker, B. J. et al. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N. Engl. J. Med. 355, 2408–2417 (2006).

    Article  CAS  PubMed  Google Scholar 

  2. Hochhaus, A. et al. Long-term benefits and risks of frontline nilotinib versus imatinib for chronic myeloid leukemia in chronic phase: 5-year update of the randomized ENESTnd trial. Leukemia 30, 1044–1054 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Jabbour, E. et al. Early response with dasatinib or imatinib in chronic myeloid leukemia: 3-year follow-up from a randomized phase 3 trial (DASISION). Blood 123, 494–500 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Druker, B. J. & Lydon, N. B. Lessons learned from the development of an abl tyrosine kinase inhibitor for chronic myelogenous leukemia. J. Clin. Invest. 105, 3–7 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. O'Brien, S. G. et al. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N. Engl. J. Med. 348, 994–1004 (2003).

    Article  CAS  PubMed  Google Scholar 

  6. Hochhaus, A. et al. Six-year follow-up of patients receiving imatinib for the first-line treatment of chronic myeloid leukemia. Leukemia 23, 1054–1061 (2009).

    Article  CAS  PubMed  Google Scholar 

  7. O'Hare, T. et al. In vitro activity of Bcr-Abl inhibitors AMN107 and BMS-354825 against clinically relevant imatinib-resistant Abl kinase domain mutants. Cancer Res. 65, 4500–4505 (2005).

    Article  CAS  PubMed  Google Scholar 

  8. Tokarski, J. S. et al. The structure of dasatinib (BMS-354825) bound to activated ABL kinase domain elucidates its inhibitory activity against imatinib-resistant ABL mutants. Cancer Res. 66, 5790–5797 (2006).

    Article  CAS  PubMed  Google Scholar 

  9. Shah, N. P. et al. Overriding imatinib resistance with a novel ABL kinase inhibitor. Science 305, 399–401 (2004).

    Article  CAS  PubMed  Google Scholar 

  10. Baccarani, M. et al. European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013. Blood 122, 872–884 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Baccarani, M. et al. Comparison of imatinib 400 mg and 800 mg daily in the front-line treatment of high-risk, Philadelphia-positive chronic myeloid leukemia: a European LeukemiaNet Study. Blood 113, 4497–4504 (2009).

    Article  CAS  PubMed  Google Scholar 

  12. Hehlmann, R. et al. Deep molecular response is reached by the majority of patients treated with imatinib, predicts survival, and is achieved more quickly by optimized high-dose imatinib: results from the randomized CML-study IV. J. Clin. Oncol. 32, 415–423 (2014).

    Article  PubMed  CAS  Google Scholar 

  13. Kantarjian, H. M., Cortes, J., La Rosee, P. & Hochhaus, A. Optimizing therapy for patients with chronic myelogenous leukemia in chronic phase. Cancer 116, 1419–1430 (2010).

    Article  CAS  PubMed  Google Scholar 

  14. Cervantes, F. et al. Early intervention during imatinib therapy in patients with newly diagnosed chronic-phase chronic myeloid leukemia: a study of the Spanish PETHEMA group. Haematologica 95, 1317–1324 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Faber, E. et al. Treatment of consecutive patients with chronic myeloid leukaemia in the cooperating centres from the Czech Republic and the whole of Slovakia after 2000 — a report from the population-based CAMELIA Registry. Eur. J. Haematol. 87, 157–168 (2011).

    Article  PubMed  Google Scholar 

  16. de Lavallade, H. et al. Imatinib for newly diagnosed patients with chronic myeloid leukemia: incidence of sustained responses in an intention-to-treat analysis. J. Clin. Oncol. 26, 3358–3363 (2008).

    Article  PubMed  Google Scholar 

  17. Preudhomme, C. et al. Imatinib plus peginterferon alfa-2a in chronic myeloid leukemia. N. Engl. J. Med. 363, 2511–2521 (2010).

    Article  CAS  PubMed  Google Scholar 

  18. Castagnetti, F. et al. Long-term outcome of chronic myeloid leukemia patients treated frontline with imatinib. Leukemia 29, 1823–1831 (2015).

    Article  CAS  PubMed  Google Scholar 

  19. White, D. et al. Measurement of in vivo BCR-ABL kinase inhibition to monitor imatinib-induced target blockade and predict response in chronic myeloid leukemia. J. Clin. Oncol. 25, 4445–4451 (2007).

    Article  CAS  PubMed  Google Scholar 

  20. White, D. et al. In vitro sensitivity to imatinib-induced inhibition of ABL kinase activity is predictive of molecular response in patients with de novo CML. Blood 106, 2520–2526 (2005).

    Article  CAS  PubMed  Google Scholar 

  21. Larson, R. A. et al. Imatinib pharmacokinetics and its correlation with response and safety in chronic-phase chronic myeloid leukemia: a subanalysis of the IRIS study. Blood 111, 4022–4028 (2008).

    Article  CAS  PubMed  Google Scholar 

  22. Picard, S. et al. Trough imatinib plasma levels are associated with both cytogenetic and molecular responses to standard-dose imatinib in chronic myeloid leukemia. Blood 109, 3496–3499 (2007).

    Article  CAS  PubMed  Google Scholar 

  23. Sohn, S. K. et al. Trough plasma imatinib levels are correlated with optimal cytogenetic responses at 6 months after treatment with standard dose of imatinib in newly diagnosed chronic myeloid leukemia. Leuk. Lymphoma 52, 1024–1029 (2011).

    Article  CAS  PubMed  Google Scholar 

  24. Thomas, J., Wang, L., Clark, R. E. & Pirmohamed, M. Active transport of imatinib into and out of cells: implications for drug resistance. Blood 104, 3739–3745 (2004).

    Article  CAS  PubMed  Google Scholar 

  25. White, D. L. et al. OCT-1-mediated influx is a key determinant of the intracellular uptake of imatinib but not nilotinib (AMN107): reduced OCT-1 activity is the cause of low in vitro sensitivity to imatinib. Blood 108, 697–704 (2006).

    Article  CAS  PubMed  Google Scholar 

  26. White, D. L. et al. Chronic phase chronic myeloid leukemia patients with low OCT-1 activity randomized to high-dose imatinib achieve better responses and have lower failure rates than those randomized to standard-dose imatinib. Haematologica 97, 907–914 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. White, D. L. et al. Most CML patients who have a suboptimal response to imatinib have low OCT-1 activity: higher doses of imatinib may overcome the negative impact of low OCT-1 activity. Blood 110, 4064–4072 (2007).

    Article  CAS  PubMed  Google Scholar 

  28. Branford, S., Melo, J. V. & Hughes, T. P. Selecting optimal second-line tyrosine kinase inhibitor therapy for chronic myeloid leukemia patients after imatinib failure: does the BCR-ABL mutation status really matter? Blood 114, 5426–5435 (2009).

    Article  CAS  PubMed  Google Scholar 

  29. Hochhaus, A. et al. Nilotinib is associated with a reduced incidence of BCR-ABL mutations versus imatinib in patients with newly diagnosed chronic myeloid leukemia in chronic phase. Blood 121, 3703–3708 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Muller, M. C. et al. Dasatinib treatment of chronic-phase chronic myeloid leukemia: analysis of responses according to preexisting BCR-ABL mutations. Blood 114, 4944–4953 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Khoury, H. J. et al. Bosutinib is active in chronic phase chronic myeloid leukemia after imatinib and dasatinib and/or nilotinib therapy failure. Blood 119, 3403–3412 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Cortes, J. E. et al. A phase 2 trial of ponatinib in Philadelphia chromosome-positive leukemias. N. Engl. J. Med. 369, 1783–1796 (2013).

    Article  CAS  PubMed  Google Scholar 

  33. Soverini, S., de Benedittis, C., Mancini, M. & Martinelli, G. Mutations in the BCR-ABL1 kinase domain and elsewhere in chronic myeloid leukemia. Clin. Lymphoma Myeloma Leuk. 15 (Suppl.), S120–S128 (2015).

    Article  PubMed  Google Scholar 

  34. Cortes, J. E. et al. Bosutinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia: results from the BELA trial. J. Clin. Oncol. 30, 3486–3492 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Saglio, G. et al. Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia. N. Engl. J. Med. 362, 2251–2259 (2010).

    Article  CAS  PubMed  Google Scholar 

  36. Kantarjian, H. et al. Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia. N. Engl. J. Med. 362, 2260–2270 (2010).

    Article  CAS  PubMed  Google Scholar 

  37. Cortes, J. E. et al. Phase III, randomized, open-label study of daily imatinib mesylate 400 mg versus 800 mg in patients with newly diagnosed, previously untreated chronic myeloid leukemia in chronic phase using molecular end points: tyrosine kinase inhibitor optimization and selectivity study. J. Clin. Oncol. 28, 424–430 (2010).

    Article  CAS  PubMed  Google Scholar 

  38. Hehlmann, R. et al. Tolerability-adapted imatinib 800 mg/d versus 400 mg/d versus 400 mg/d plus interferon-α in newly diagnosed chronic myeloid leukemia. J. Clin. Oncol. 29, 1634–1642 (2011).

    Article  CAS  PubMed  Google Scholar 

  39. Hughes, T. et al. Impact of baseline BCR-ABL mutations on response to nilotinib in patients with chronic myeloid leukemia in chronic phase. J. Clin. Oncol. 27, 4204–4210 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Cortes, J. E. et al. Nilotinib as front-line treatment for patients with chronic myeloid leukemia in early chronic phase. J. Clin. Oncol. 28, 392–397 (2010).

    Article  CAS  PubMed  Google Scholar 

  41. Rosti, G. et al. Nilotinib for the frontline treatment of Ph(+) chronic myeloid leukemia. Blood 114, 4933–4938 (2009).

    Article  CAS  PubMed  Google Scholar 

  42. Wang, J. et al. Phase 3 study of nilotinib versus imatinib in Chinese patients with newly diagnosed chronic myeloid leukemia in chronic phase: ENESTchina. Blood 125, 2771–2778 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Aichberger, K. J. et al. Progressive peripheral arterial occlusive disease and other vascular events during nilotinib therapy in CML. Am. J. Hematol. 86, 533–539 (2011).

    Article  CAS  PubMed  Google Scholar 

  44. Tefferi, A. & Letendre, L. Nilotinib treatment-associated peripheral artery disease and sudden death: yet another reason to stick to imatinib as front-line therapy for chronic myelogenous leukemia. Am. J. Hematol. 86, 610–611 (2011).

    Article  PubMed  Google Scholar 

  45. Le Coutre, P. et al. Severe peripheral arterial disease during nilotinib therapy. J. Natl. Cancer Inst. 103, 1347–1348 (2011).

    Article  CAS  PubMed  Google Scholar 

  46. Gugliotta, G. et al. Long-term outcome of a phase 2 trial with nilotinib 400 mg twice daily in first-line treatment of chronic myeloid leukemia. Haematologica 100, 1146–1150 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Valent, P. et al. Vascular safety issues in CML patients treated with BCR/ABL1 kinase inhibitors. Blood 125, 901–906 (2015).

    Article  CAS  PubMed  Google Scholar 

  48. Castagnetti, F. et al. Nilotinib 300 mg twice daily: an academic single-arm study of newly diagnosed chronic phase chronic myeloid leukemia patients. Haematologica http://dx.doi.org/10.3324/haematol.2016.144949.

  49. Rea, D. et al. Incidence of hyperglycemia by 3 years in patients (Pts) with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP) treated with nilotinib (NIL) or imatinib (IM) in ENESTnd. Blood 120, 1686–1686 (2012).

    Google Scholar 

  50. Giles, F. J. et al. Rates of peripheral arterial occlusive disease in patients with chronic myeloid leukemia in the chronic phase treated with imatinib, nilotinib, or non-tyrosine kinase therapy: a retrospective cohort analysis. Leukemia 27, 1310–1315 (2013).

    Article  CAS  PubMed  Google Scholar 

  51. Dahlén, T. et al. Increased risk of cardiovascular events associated with TKI treatment in chronic phase chronic myeloid leukemia. Data from Swedish population-based registries. Blood 124, 3134–3134 (2014).

    Google Scholar 

  52. Rea, D. et al. Usefulness of the 2012 European CVD risk assessment model to identify patients at high risk of cardiovascular events during nilotinib therapy in chronic myeloid leukemia. Leukemia 29, 1206–1209 (2015).

    Article  CAS  PubMed  Google Scholar 

  53. Pene-Dumitrescu, T. & Smithgall, T. E. Expression of a Src family kinase in chronic myelogenous leukemia cells induces resistance to imatinib in a kinase-dependent manner. J. Biol. Chem. 285, 21446–21457 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Cortes, J. et al. Final study results of the phase 3 dasatinib versus imatinib in newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP) trial (DASISION, CA180-056). Blood 124, 152 (2014).

    Google Scholar 

  55. Hughes, T.P. et al. BCR-ABL1 mutation development during first-line treatment with dasatinib or imatinib for chronic myeloid leukemia in chronic phase. Leukemia 29, 1832–1838 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Brixey, A. G. & Light, R. W. Pleural effusions due to dasatinib. Curr. Opin. Pulm. Med. 16, 351–356 (2010).

    Article  PubMed  Google Scholar 

  57. Rosti, G., Castagnetti, F., Gugliotta, G., Palandri, F. & Baccarani, M. Second-generation BCR-ABL inhibitors for frontline treatment of chronic myeloid leukemia in chronic phase. Crit. Rev. Oncol. Hematol. 82, 159–170 (2012).

    Article  PubMed  Google Scholar 

  58. Shah, N. P. et al. 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, 3204–3212 (2008).

    Article  CAS  PubMed  Google Scholar 

  59. Montani, D. et al. Pulmonary arterial hypertension in patients treated by dasatinib. Circulation 125, 2128–2137 (2012).

    Article  CAS  PubMed  Google Scholar 

  60. Steegmann, J. L. et al. European LeukemiaNet recommendations for the management and avoidance of adverse events of treatment in chronic myeloid leukaemia. Leukemia 30, 1648–1671 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Kerkela, R. et al. Cardiotoxicity of the cancer therapeutic agent imatinib mesylate. Nat. Med. 12, 908–916 (2006).

    Article  PubMed  CAS  Google Scholar 

  62. Rosti, G., Martinelli, G. & Baccarani, M. In reply to 'Cardiotoxicity of the cancer therapeutic agent imatinib mesylate'. Nat. Med. 13, 15; author reply 15–16 (2007).

    Article  CAS  PubMed  Google Scholar 

  63. Efficace, F., Cardoni, A., Cottone, F., Vignetti, M. & Mandelli, F. Tyrosine-kinase inhibitors and patient-reported outcomes in chronic myeloid leukemia: a systematic review. Leuk. Res. 37, 206–213 (2013).

    Article  CAS  PubMed  Google Scholar 

  64. Efficace, F. et al. Health-related quality of life in chronic myeloid leukemia patients receiving long-term therapy with imatinib compared with the general population. Blood 118, 4554–4560 (2011).

    Article  CAS  PubMed  Google Scholar 

  65. Hochhaus, A. Educational session: managing chronic myeloid leukemia as a chronic disease. Hematology Am. Soc. Hematol. Educ. Program 2011, 128–135 (2011).

    Article  PubMed  Google Scholar 

  66. Williams, L. A. et al. Measuring the symptom burden associated with the treatment of chronic myeloid leukemia. Blood 122, 641–647 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Efficace, F. et al. International development of an EORTC questionnaire for assessing health-related quality of life in chronic myeloid leukemia patients: the EORTC QLQ-CML24. Qual. Life Res. 23, 825–836 (2014).

    Article  PubMed  Google Scholar 

  68. Noens, L. et al. Prevalence, determinants, and outcomes of nonadherence to imatinib therapy in patients with chronic myeloid leukemia: the ADAGIO study. Blood 113, 5401–5411 (2009).

    Article  CAS  PubMed  Google Scholar 

  69. Marin, D. et al. Adherence is the critical factor for achieving molecular responses in patients with chronic myeloid leukemia who achieve complete cytogenetic responses on imatinib. J. Clin. Oncol. 28, 2381–2388 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Noens, L. et al. Measurement of adherence to BCR-ABL inhibitor therapy in chronic myeloid leukemia: current situation and future challenges. Haematologica 99, 437–447 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Falchi, L. et al. Significance of deeper molecular responses in patients with chronic myeloid leukemia in early chronic phase treated with tyrosine kinase inhibitors. Am. J. Hematol. 88, 1024–1029 (2013).

    Article  CAS  PubMed  Google Scholar 

  72. Saussele, S., Richter, J., Hochhaus, A., & Mahon, F. X. The concept of treatment-free remission in chronic myeloid leukemia. Leukemia 30, 1638–1647 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Hughes, T. P. & Ross, D. M. Moving treatment-free remission into mainstream clinical practice in CML. Blood 128, 17–23 (2016).

    Article  CAS  PubMed  Google Scholar 

  74. Mahon, F. X. et al. 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, 1029–1035 (2010).

    Article  CAS  PubMed  Google Scholar 

  75. Ross, D. M. et al. Patients with chronic myeloid leukemia who maintain a complete molecular response after stopping imatinib treatment have evidence of persistent leukemia by DNA PCR. Leukemia 24, 1719–1724 (2010).

    Article  CAS  PubMed  Google Scholar 

  76. Etienne, G. et al. Long-Term Follow-up of the French 1 Stop Imatinib Study (STIM1) in chronic myeloid leukemia patients. Blood 126, 345–345 (2015).

    Google Scholar 

  77. Mahon, F.-X. et al. Interim analysis of a pan European stop tyrosine kinase inhibitor trial in chronic myeloid leukemia: the EURO-SKI study. Blood 124, 151–151 (2014).

    Article  Google Scholar 

  78. Branford, S. et al. Early molecular response and female sex strongly predict stable undetectable BCR-ABL1, the criteria for imatinib discontinuation in patients with CML. Blood 121, 3818–3824 (2013).

    Article  CAS  PubMed  Google Scholar 

  79. O'Brien, S. et al. Chronic myelogenous leukemia, version 1.2015. J. Natl. Compr. Canc. Netw. 12, 1590–1610 (2014).

    Article  CAS  PubMed  Google Scholar 

  80. Brummendorf, T. H. et al. Bosutinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukaemia: results from the 24-month follow-up of the BELA trial. Br. J. Haematol. 168, 69–81 (2015).

    Article  PubMed  CAS  Google Scholar 

  81. Marin, D. et al. Assessment of BCR-ABL1 transcript levels at 3 months is the only requirement for predicting outcome for patients with chronic myeloid leukemia treated with tyrosine kinase inhibitors. J. Clin. Oncol. 30, 232–238 (2012).

    Article  CAS  PubMed  Google Scholar 

  82. Jain, P. et al. Early responses predict better outcomes in patients with newly diagnosed chronic myeloid leukemia: results with four tyrosine kinase inhibitor modalities. Blood 121, 4867–4874 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Hughes, T. P. et al. Early molecular response predicts outcomes in patients with chronic myeloid leukemia in chronic phase treated with frontline nilotinib or imatinib. Blood 123, 1353–1360 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Castagnetti, F. et al. Clinical significance of early molecular response in chronic myeloid leukemia patients treated frontline with imatinib mesylate. Haematologica 98 (Suppl. 1), 59 (2013).

    Google Scholar 

  85. Gugliotta, G. et al. Early cytogenetic and molecular responses and long-term outcome in early chronic phase chronic myeloid leukemia patients treated with nilotinib. Haematologica 98 (Suppl. 1), 58 (2013).

    Google Scholar 

  86. Lipton, J. H. et al. Ponatinib versus imatinib for newly diagnosed chronic myeloid leukaemia: an international, randomised, open-label, phase 3 trial. Lancet Oncol. 17, 612–621 (2016).

    Article  CAS  PubMed  Google Scholar 

  87. Yeung, D. T. et al. TIDEL-II: first-line use of imatinib in CML with early switch to nilotinib for failure to achieve time-dependent molecular targets. Blood 125, 915–923 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Sokal, J. E. et al. Prognostic discrimination in “good-risk” chronic granulocytic leukemia. Blood 63, 789–799 (1984).

    CAS  PubMed  Google Scholar 

  89. Hasford, J. et al. A new prognostic score for survival of patients with chronic myeloid leukemia treated with interferon alfa. Writing committee for the collaborative CML prognostic factors project group. J. Natl. Cancer Inst. 90, 850–858 (1998).

    Article  CAS  PubMed  Google Scholar 

  90. Hasford, J. et al. Predicting complete cytogenetic response and subsequent progression-free survival in 2060 patients with CML on imatinib treatment: the EUTOS score. Blood 118, 686–692 (2011).

    Article  CAS  PubMed  Google Scholar 

  91. Baccarani, M. et al. Evolving concepts in the management of chronic myeloid leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet. Blood 108, 1809–1820 (2006).

    Article  CAS  PubMed  Google Scholar 

  92. Kantarjian, H. et al. Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia. N. Engl. J. Med. 346, 645–652 (2002).

    Article  CAS  PubMed  Google Scholar 

  93. Kantarjian, H. M. et al. Imatinib mesylate for Philadelphia chromosome-positive, chronic-phase myeloid leukemia after failure of interferon-α: follow-up results. Clin. Cancer Res. 8, 2177–2187 (2002).

    CAS  PubMed  Google Scholar 

  94. Cervantes, F. et al. Imatinib mesylate therapy of chronic phase chronic myeloid leukemia resistant or intolerant to interferon: results and prognostic factors for response and progression-free survival in 150 patients. Haematologica 88, 1117–1122 (2003).

    CAS  PubMed  Google Scholar 

  95. Kantarjian, H. M. et al. Long-term survival benefit and improved complete cytogenetic and molecular response rates with imatinib mesylate in Philadelphia chromosome-positive chronic-phase chronic myeloid leukemia after failure of interferon-α. Blood 104, 1979–1988 (2004).

    Article  CAS  PubMed  Google Scholar 

  96. Rosti, G. et al. Molecular response to imatinib in late chronic-phase chronic myeloid leukemia. Blood 103, 2284–2290 (2004).

    Article  CAS  PubMed  Google Scholar 

  97. Lahaye, T. et al. Response and resistance in 300 patients with BCR-ABL-positive leukemias treated with imatinib in a single center: a 4.5-year follow-up. Cancer 103, 1659–1669 (2005).

    Article  PubMed  Google Scholar 

  98. Guilhot, F. et al. High rates of durable response are achieved with imatinib after treatment with interferon α plus cytarabine: results from the International Randomized Study of Interferon and STI571 (IRIS) trial. Haematologica 94, 1669–1675 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Druker, B. J. et al. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N. Engl. J. Med. 344, 1031–1037 (2001).

    Article  CAS  PubMed  Google Scholar 

  100. Cortes, J. et al. Immune modulation of minimal residual disease in early chronic phase chronic myelogenous leukemia: a randomized trial of frontline high-dose imatinib mesylate with or without pegylated interferon α-2b and granulocyte-macrophage colony-stimulating factor. Cancer 117, 572–580 (2011).

    Article  CAS  PubMed  Google Scholar 

  101. Jabbour, E. et al. Imatinib mesylate dose escalation is associated with durable responses in patients with chronic myeloid leukemia after cytogenetic failure on standard-dose imatinib therapy. Blood 113, 2154–2160 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Hughes, T. P. et al. Impact of early dose intensity on cytogenetic and molecular responses in chronic- phase CML patients receiving 600 mg/day of imatinib as initial therapy. Blood 112, 3965–3973 (2008).

    Article  CAS  PubMed  Google Scholar 

  103. Castagnetti, F. et al. Results of high-dose imatinib mesylate in intermediate Sokal risk chronic myeloid leukemia patients in early chronic phase: a phase 2 trial of the GIMEMA CML Working Party. Blood 113, 3428–3434 (2009).

    Article  CAS  PubMed  Google Scholar 

  104. Cortes, J. E. et al. High-dose imatinib in newly diagnosed chronic-phase chronic myeloid leukemia: high rates of rapid cytogenetic and molecular responses. J. Clin. Oncol. 27, 4754–4759 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Petzer, A. L. et al. High-dose imatinib induction followed by standard-dose maintenance in pre-treated chronic phase chronic myeloid leukemia patients — final analysis of a randomized, multicenter, phase III trial. Haematologica 97, 1562–1569 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Hochhaus, A. et al. Dasatinib induces durable cytogenetic responses in patients with chronic myelogenous leukemia in chronic phase with resistance or intolerance to imatinib. Leukemia 22, 1200–1206 (2008).

    Article  CAS  PubMed  Google Scholar 

  107. Hochhaus, A. et al. Dasatinib induces notable hematologic and cytogenetic responses in chronic-phase chronic myeloid leukemia after failure of imatinib therapy. Blood 109, 2303–2309 (2007).

    Article  CAS  PubMed  Google Scholar 

  108. Kantarjian, H. et al. Dasatinib or high-dose imatinib for chronic-phase chronic myeloid leukemia resistant to imatinib at a dose of 400 to 600 milligrams daily: two-year follow-up of a randomized phase 2 study (START-R). Cancer 115, 4136–4147 (2009).

    Article  CAS  PubMed  Google Scholar 

  109. Shah, N. P. et al. Long-term outcome with dasatinib after imatinib failure in chronic-phase chronic myeloid leukemia: follow-up of a phase 3 study. Blood 123, 2317–2324 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Shah, N. P. et al. Potent, transient inhibition of BCR-ABL with dasatinib 100 mg daily achieves rapid and durable cytogenetic responses and high transformation-free survival rates in chronic phase chronic myeloid leukemia patients with resistance, suboptimal response or intolerance to imatinib. Haematologica 95, 232–240 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Kantarjian, H. M. et al. Nilotinib (formerly AMN107), a highly selective BCR-ABL tyrosine kinase inhibitor, is effective in patients with Philadelphia chromosome-positive chronic myelogenous leukemia in chronic phase following imatinib resistance and intolerance. Blood 110, 3540–3546 (2007).

    Article  CAS  PubMed  Google Scholar 

  112. Kantarjian, H. M. et al. Nilotinib is effective in patients with chronic myeloid leukemia in chronic phase after imatinib resistance or intolerance: 24-month follow-up results. Blood 117, 1141–1145 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Giles, F. J. et al. Nilotinib in imatinib-resistant or imatinib-intolerant patients with chronic myeloid leukemia in chronic phase: 48-month follow-up results of a phase II study. Leukemia 27, 107–112 (2013).

    Article  CAS  PubMed  Google Scholar 

  114. Hughes, T. P. et al. Deep molecular responses achieved in patients with CML-CP who are switched to nilotinib after long-term imatinib. Blood 124, 729–736 2014).

    Article  CAS  PubMed  Google Scholar 

  115. Cortes, J. E. et al. Safety and efficacy of bosutinib (SKI-606) in chronic phase Philadelphia chromosome-positive chronic myeloid leukemia patients with resistance or intolerance to imatinib. Blood 118, 4567–4576 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Gambacorti-Passerini, C. et al. Bosutinib efficacy and safety in chronic phase chronic myeloid leukemia after imatinib resistance or intolerance: minimum 24-month follow-up. Am. J. Hematol. 89, 732–742 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Kantarjian, H. M. et al. Bosutinib safety and management of toxicity in leukemia patients with resistance or intolerance to imatinib and other tyrosine kinase inhibitors. Blood 123, 1309–1318 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Cortes, J. et al. Ponatinib efficacy and safety in heavily pretreated leukemia patients: 3-year results of the PACE trial [abstract 234]. Haematologica 100 (Suppl. 1), 64 (2015).

    Google Scholar 

  119. Cortes, J. E. et al. Long-term follow-up of ponatinib efficacy and safety in the phase 2 PACE trial. Blood 124, 3135–3135 (2014).

    Google Scholar 

  120. Pritchard, J. R. et al. High-resolution analysis of the relationship between dose and molecular response in CP-CML patients treated with ponatinib or imatinib. Blood 124, 3153–3153 (2014).

    Google Scholar 

  121. Dorer, D. J. et al. Impact of dose intensity of ponatinib on selected adverse events: Multivariate analyses from a pooled population of clinical trial patients. Leuk. Res. 48, 84–91 (2016).

    Article  CAS  PubMed  Google Scholar 

  122. Lipton, J. H. et al. Comparative efficacy of tyrosine kinase inhibitor treatments in the third-line setting, for chronic-phase chronic myelogenous leukemia after failure of second-generation tyrosine kinase inhibitors. Leuk. Res. 39, 58–64 (2015).

    Article  CAS  PubMed  Google Scholar 

  123. Russo Rossi, A. et al. Outcome of 82 chronic myeloid leukemia patients treated with nilotinib or dasatinib after failure of two prior tyrosine kinase inhibitors. Haematologica 98, 399–403 (2013).

    Article  PubMed  CAS  Google Scholar 

  124. Soverini, S. et al. BCR-ABL kinase domain mutation analysis in chronic myeloid leukemia patients treated with tyrosine kinase inhibitors: recommendations from an expert panel on behalf of European LeukemiaNet. Blood 118, 1208–1215 (2011).

    Article  CAS  PubMed  Google Scholar 

  125. Hehlmann, R. How I treat CML blast crisis. Blood 120, 737–747 (2012).

    Article  CAS  PubMed  Google Scholar 

  126. Saussele, S. & Silver, R. T. Management of chronic myeloid leukemia in blast crisis. Ann. Hematol. 94 (Suppl. 2), S159–S165 (2015).

    Article  PubMed  CAS  Google Scholar 

  127. Innes, A. J., Milojkovic, D. & Apperley, J. F. Allogeneic transplantation for CML in the TKI era: striking the right balance. Nat. Rev. Clin. Oncol. 13, 79–91 (2016).

    Article  CAS  PubMed  Google Scholar 

  128. Cross, N. C. et al. Laboratory recommendations for scoring deep molecular responses following treatment for chronic myeloid leukemia. Leukemia 29, 999–1003 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Hanfstein, B. et al. Early molecular and cytogenetic response is predictive for long-term progression-free and overall survival in chronic myeloid leukemia (CML). Leukemia 26, 2096–2102 (2012).

    Article  CAS  PubMed  Google Scholar 

  130. Baccarani, M. et al. Chronic myeloid leukemia: an update of concepts and management recommendations of European LeukemiaNet. J. Clin. Oncol. 27, 6041–6051 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors acknowledge the financial support from BolognAIL, European LeukemiaNet, GIMEMA and Onlus. The authors acknowledge the valuable administration assistance of Miriam Fogli and Michela Apolinari.

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  1. Department of Experimental, Institute of Haematology and Medical Oncology Lorenzo ed Ariosto Seràgnoli, Diagnostic and Specialty Medicine, Bologna University School of Medicine, S.Orsola-Malpighi University Hospital, Via Massarenti 9, Bologna, 40138, Italy

    Gianantonio Rosti, Fausto Castagnetti, Gabriele Gugliotta & Michele Baccarani

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  1. Gianantonio Rosti
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Contributions

G.R. and M.B. wrote the first version of the manuscript, which was revised by F.C. and G.G. All authors revised and edited subsequent versions before submission.

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Correspondence to Gianantonio Rosti.

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Competing interests

G.R. has acted as a consultant for and received honoraria from ARIAD Pharmaceuticals, Bristol-Myers Squibb, Novartis, Pfizer and Roche, and served on the speakers' bureaus of Bristol Myers-Squibb and Novartis. F.C. has acted as a consultant for and received honoraria from ARIAD Pharmaceuticals, Bristol-Myers Squibb, Novartis and Pfizer. G.G. has acted as a consultant and received honoraria from Bristol-Myers Squibb and Novartis. M.B. has received honoraria from ARIAD Pharmaceuticals, Bristol-Myers Squibb, Novartis and Pfizer, and served on the speakers' bureaus of Bristol Myers-Squibb and Novartis.

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Rosti, G., Castagnetti, F., Gugliotta, G. et al. Tyrosine kinase inhibitors in chronic myeloid leukaemia: which, when, for whom?. Nat Rev Clin Oncol 14, 141–154 (2017). https://doi.org/10.1038/nrclinonc.2016.139

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