Advertisement

Annals of Hematology

, Volume 94, Supplement 2, pp 141–147 | Cite as

A review of the European LeukemiaNet recommendations for the management of CML

  • Michele Baccarani
  • Fausto Castagnetti
  • Gabriele Gugliotta
  • Gianantonio Rosti
Review Article

Abstract

Several guidelines and recommendations on the management of chronic myeloid leukemia (CML) have been prepared by several scientific societies. The European LeukemiaNet (ELN) appointed a panel of experts who submitted their recommendations to peer-reviewed scientific journals in 2006, 2009, and 2013. Here, we make a critical review of the last, 2013, ELN recommendations, concerning the use of the five available tyrosine kinase inhibitors (TKIs), the evaluation of cytogenetic and molecular response, and the strategy of treatment. Three TKIs (imatinib, nilotinib, dasatinib) are recommended first-line. Bosutinib and ponatinib are available second-line; ponatinib is particularly indicated in case of the T315I mutation. Achieving an optimal response, not only for survival but also for a deeper, stable, treatment-free remission, requires a BCR-ABL transcripts level ≤10 % at 3 months, ≤1 % at 6 months, ≤0.1 % at 1 year, and ≤0.01 % later on. Molecular monitoring must include mutational analysis in every case of failure. A successful treatment of accelerated and blastic phase requires TKIs, and in many cases also allogeneic stem cell transplantation.

Keywords

Chronic myeloid leukemia Tyrosine kinase inhibitors BCR-ABL1 Philadelphia chromosome 

Notes

Conflict of interest

The authors declare that they have no conflict of interest.

References

  1. 1.
    Hehlmann R, Hochhaus A, Baccarani M, on behalf of the European LeukemiaNet (2007) Chronic myeloid leukemia. Lancet 370:342–350CrossRefPubMedGoogle Scholar
  2. 2.
    Bjorkholm M, Ohm L, Eloranta S et al (2011) Success story of targeted therapy in chronic myeloid leukemia: a population-based study of patients diagnosed in Sweden from 1973 to. 2008. J Clin Oncol 29:2514–2520CrossRefPubMedCentralPubMedGoogle Scholar
  3. 3.
    Kantarjian H, O’Brien S, Jabbour E et al (2012) Improved survival in chronic myeloid leukemia since the introduction of imatinib therapy: a single-institution historical experience. Blood 119(9):1981–1987CrossRefPubMedCentralPubMedGoogle Scholar
  4. 4.
    Baccarani M, Saglio G, Goldman J et al (2006) Evolving concepts in the management of chronic myeloid leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet. Blood 108:1809–1820CrossRefPubMedGoogle Scholar
  5. 5.
    Baccarani M, Cortes J, Pane F et al (2009) Chronic myeloid leukemia: an update of concepts and management recommendations of European LeukemiaNet. J Clin Oncol 27:6041–6051CrossRefPubMedGoogle Scholar
  6. 6.
    Baccarani M, Deininger MW, Rosti G et al (2013) European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013. Blood 122(6):872–884CrossRefPubMedGoogle Scholar
  7. 7.
    O’Brien S, Abboud CN, Akhtari M et al (2014) Clinical practice guidelines in oncology. Chronic Myelogenous Leukemia, Version 3, National Comprehensive Cancer Network (NCCN). http://www.nccn.org
  8. 8.
    De Lavallade H, Apperley JF, Khorashad J et al (2008) Imatinib for newly diagnosed patients with chronic myeloid leukemia: incidence of sustained responses in an intention-to-treat analsys. J Clin Oncol 26:3358–3363CrossRefPubMedGoogle Scholar
  9. 9.
    Hughes T, Branford S, White DL et al (2008) 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 112:3965–3972CrossRefPubMedGoogle Scholar
  10. 10.
    Baccarani M, Rosti G, Castagnetti F et al (2009) A comparison of imatinib 400 mg and 800 mg daily in the first-line treatment of high risk, Philadelphia-positive, chronic myeloid leukemia. A European LeukemiaNet Study. Blood 113:4497–4504CrossRefPubMedGoogle Scholar
  11. 11.
    Cortes JE, Kantarjian HM, Goldberg SL et al (2009) High-dose imatinib in newly diagnosed chronic phase chronic myeloid leukemia: high rates of rapid cytogenetic and molecular responses. J Clin Oncol 27:4754–4759CrossRefPubMedGoogle Scholar
  12. 12.
    Cervantes F, Lopez-Garrido P, Montero MI et al (2010) Early intervention during imatinib therapy on patients with newly diagnosed chronic-phase chronic myeloid leukemia: a study of the Spanish PETHEMA group. Haematologica 95(8):1317–1324CrossRefPubMedCentralPubMedGoogle Scholar
  13. 13.
    Preudhomme C, Guilhot J, Nicolini FE et al (2010) Imatinib plus peginterferon alfa-2a in chronic myeloid leukemia. N Engl J Med 363:2511–2521CrossRefPubMedGoogle Scholar
  14. 14.
    Gugliotta G, Castagnetti F, Palandri F et al (2011) Frontline imatinib treatment of chronic myeloid leukemia: no impact of age on outcome, a survey by the GIMEMA CML working party. Blood 117(21):5591–5599CrossRefPubMedGoogle Scholar
  15. 15.
    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-α in newly diagnosed chronic myeloid leukemia. J Clin Oncol 29:1634–1642CrossRefPubMedGoogle Scholar
  16. 16.
    Simonsson B, Gedde-Dahl T, Markevarn B et al (2011) Combination of pegylated IFN-α2b with imatinib increases molecular response rates in patients with low- or intermediate-risk chronic myeloid leukemia. Blood 118(12):3228–3235CrossRefPubMedGoogle Scholar
  17. 17.
    Radich JP, Kopecky KJ, Appelbaum FR et al (2012) A randomized trial of dasatinib 100 mg versus imatinib 400 mg in newly diagnosed chronic-phase chronic myeloid leukemia. Blood 120(19):3898–3905CrossRefPubMedCentralPubMedGoogle Scholar
  18. 18.
    Hughes TP, Kaeda J, Branford S et al (2003) Frequency of major molecular response to imatinib or interferon alpa plus cytarabine in newly diagnosed chronic myeloid leukemia. N Engl J Med 349:1421–1432CrossRefGoogle Scholar
  19. 19.
    Druker BJ, Guilhot F, O’Brien SO et al (2006) Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med 355:2408–2417CrossRefPubMedGoogle Scholar
  20. 20.
    Hochhaus A, O’Brien SG, Guilhot F et al (2009) Six-year follow-up of patients receiving imatinib for the first-line treatment of chronic myeloid leukemia. Leukemia 23:1054–1061CrossRefPubMedGoogle Scholar
  21. 21.
    Cortes JE, Baccarani M, Guilhot F et al (2009) 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 endpoints: tyrosine kinase inhibitor optimization and selectivity study. J Clin Oncol 28:424–434CrossRefPubMedGoogle Scholar
  22. 22.
    Saglio G, Kim DW, Issaragrisil S et al (2010) Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia. N Engl J Med 362(24):2251–2259CrossRefPubMedGoogle Scholar
  23. 23.
    Kantarjian H, Shah NP, Hochhaus A et al (2010) Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med 362(24):2260–2270CrossRefPubMedGoogle Scholar
  24. 24.
    Kantarjian HM, Hochhaus A, Saglio G et al (2011) Nilotinib versus imatinib for the treatment of patients with newly diagnosed chronic phase, Philadlephia chromosome-positive, chronic myeloid leukemia: 24-month minimum follow-up of the phase 3 randomised ENESTnd trial. Lancet Oncol 12:841–851CrossRefPubMedGoogle Scholar
  25. 25.
    Larson RA, Hochhaus A, Hughes TP et al (2012) Nilotinib vs imatinib in patients with newly diagnosed Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase: ENESTnd 3-year follow-up. Leukemia 26(10):2197–2203CrossRefPubMedGoogle Scholar
  26. 26.
    Cortes JE, Kim DW, Kantarjian HM et al (2012) Bosutinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia: results from the BELA trial. J Clin Oncol 30(28):3486–3492CrossRefPubMedGoogle Scholar
  27. 27.
    Kantarjian HM, Shah NP, Cortes JE et al (2012) Dasatinib or imatinib in newly diagnosed chronic-phase chronic myeloid leukemia: 2-year follow-up from a randomized phase 3 trial (DASISION). Blood 119:1123CrossRefPubMedGoogle Scholar
  28. 28.
    Vardiman JW, Melo JV, Baccarani M and Thiele J (2008) Chronic myelogenous leukemia BCR-ABL1 positive in, Swerdlow SH, Campo E, Harris NL et al (eds), WHO classification of Tumors of Hematopoietic and Lymphoid Tissues, IARC, Lion 2, pp 32-37Google Scholar
  29. 29.
    Hehlmann R (2012) How I treat CML blast crisis. Blood 120(4):737–747CrossRefPubMedGoogle Scholar
  30. 30.
    Fabarius A, Leitner A, Hochhaus A et al (2011) Impact of additional cytogenetic aberrations at diagnosis on prognosis of CML: long-term observation of 1151 patients from the randomized CML Study IV. Blood 118:6760–6768CrossRefPubMedGoogle Scholar
  31. 31.
    Luatti S, Castagnetti F, Marzocchi G et al (2012) Additional chromosome abnormalities in Philadelphia-positive clone: adverse prognostic influene on frontline imatinib therapy: a GIMEMA Working Party on CML analysis. Blood 120(4):761–767CrossRefPubMedGoogle Scholar
  32. 32.
    Sokal JE, Cox EB, Baccarani M et al (1984) Prognostic discrimination in “good-risk” chronic granulocytic leukemia. Blood 63:789–799PubMedGoogle Scholar
  33. 33.
    Hasford J, Pfirmann M, Hehlmann R et al (1998) A new prognostic score for survival of patients with chronic myeloid leukemia treated with interferon alfa. J Natl Cancer Inst 90:850–858CrossRefPubMedGoogle Scholar
  34. 34.
    Hasford J, Baccarani M, Hoffmann V et al (2011) Predicting complete cytogenetic response and subsequent progression-free survival in 2060 patients with CML on imatinib treatment: the EUTOS score. Blood 118(3):686–692CrossRefPubMedGoogle Scholar
  35. 35.
    Hughes T, Deininger M, Hochhaus A et al (2006) Monitoring CML patients responding to treatment with tyrosine kinase inhibitors: review and recommendations for harmonizing current methodology for detecting BCR-ABL transcripts and kinase domain mutations and for expressing results. Blood 108:28–36CrossRefPubMedCentralPubMedGoogle Scholar
  36. 36.
    Müller MC, Cross NC, Erben P et al (2009) Harmonization of molecular monitoring of CML therapy in Europe. Leukemia 23(11):1957–196 5CrossRefPubMedGoogle Scholar
  37. 37.
    Cross NCP, White HE, Müller MC, Saglio G, Hochhaus A (2012) Standardized definitions of molecular response in chronic myeloid leukemia. Leukemia 26(10):2172–2175CrossRefPubMedGoogle Scholar
  38. 38.
    Branford S, Yeung DT, Parker WT, et al (2014) Prognosis for patients with CML and >10 % BCR-ABL1 after 3 months of imatinib depends on the rate of BC R-ABL1 decline. Blood., in pressGoogle Scholar
  39. 39.
    Hanfstein B, Shlyakhto V, Lauseker M, et al (2014) Velocity of early BCR-ABL transcript elimination as an optimal predictor of outcome in chronic myeloid leukemia patients in chronic phase on treatment with imatinib. Leukemia., in pressGoogle Scholar
  40. 40.
    Soverini S, Hochhaus A, Nicolini FE et al (2011) BCR-ABL kinase domain mutations analysis in chronic myeloid leukemia patients treated with tyrosine kinase inhibitors. Recommendations from an expert panel on behalf of European LeukemiaNet. Blood 118(5):1208–1215CrossRefPubMedGoogle Scholar
  41. 41.
    Parker WT, Ho M, Scott HS et al (2012) Poor response to second-line tyrosine kinase inhibitors in chronic myeloid leukemia patients with multiple low-level mutations, irrespective of their resisstance profile. Blood 119(10):2234–223CrossRefPubMedGoogle Scholar
  42. 42.
    Soverini S, De Benedittis C, Machova Polakova K et al (2013) Unraveling the complexity of tyrosine kinase inhibitor-resistant populations by ultra-deep sequencing of the BCR-ABL kinase domain. Blood 122(9):1634–1648CrossRefPubMedGoogle Scholar
  43. 43.
    Khorashad JS, Kelley TW, Szankasi P et al (2013) BCR-ABL1 compound mutations in tyrosine kinase inhibitor resistant CML: frequency and clonal relationship. Blood 121:489–498CrossRefPubMedCentralPubMedGoogle Scholar
  44. 44.
    Shah NP, Kim DW, Kantarjian H et al (2010) 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 95:232–240CrossRefPubMedCentralPubMedGoogle Scholar
  45. 45.
    Kantarjian HM, Giles FJ, Bhalla KN et al (2011) Nilotinib is effective in patients with chronic myeloid leukemia in chronic phase after imatinib resistance or intolerance: 24-month follow-up results. Blood 117(4):1141–1145CrossRefPubMedGoogle Scholar
  46. 46.
    Cortes JE, Kantarjian HM, Brummendorf TK et al (2011) Safety and efficacy of bosutinib (SKY-606) in chronic phase Philadelphia-chromosome positive chronic myeloid leukemia patients with resistance or intolerance to imatinib. Blood 118:4567–4576CrossRefPubMedGoogle Scholar
  47. 47.
    Giles FJ, le Coutre PD, Pinilla-Ibartz J et al (2013) 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 27:107–112CrossRefPubMedGoogle Scholar
  48. 48.
    Marin D, Ibrahim AR, Lucas C et al (2012) 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(3):232–238CrossRefPubMedGoogle Scholar
  49. 49.
    Hanfstein B, Muller MC, Hehlmann R et al (2012) Early molecular and cytogenetic response is predictive of long-term progression-free and overall survival in chronic myeloid leukemia. Leukemia 26:2096–2102CrossRefPubMedGoogle Scholar
  50. 50.
    Marin D, Hedgley C, Clark RE et al (2012) Predictive value of early molecular response in patients with chronic myeloid leukemia treated with first-line dasatinib. Blood 120(2):291–294CrossRefPubMedGoogle Scholar
  51. 51.
    Jain P, Kantarjian H, Nazha A et al (2013) Eraly responses predict better outcomes in patients with newly diagnoses chronic myeloid leukemia: results with four tyrosine kinase inhibitor modalities. Blood 121(24):4867–4874CrossRefPubMedCentralPubMedGoogle Scholar
  52. 52.
    Hughes TP, Saglio G, Kantarjian HM et al (2014) Early molecular response predicts outcomes in patients with chronic myeloid leukemia in chronic phase treated with frontline nilotinib or imatinib. Blood 123(9):1353–1360CrossRefPubMedGoogle Scholar
  53. 53.
    Jabbour E, Kantrajian HM, Saglio G et al (2014) Early response with dasatinid or imatinib in chronic myeloid leukemia: 3-year follow-up from a randomized phase 3 trial (DASISION). Blood 123(4):494–500CrossRefPubMedCentralPubMedGoogle Scholar
  54. 54.
    Cortes JE, Kantarjian H, Shah NP et al (2012) Ponatinib in refractory chromosome-positive leukemias. N Engl J Med 367:2075–2088CrossRefPubMedCentralPubMedGoogle Scholar
  55. 55.
    Cortes JE, Kim DW, Pinilla-Ibarz J et al (2013) A phase 2 trial of ponatinib in Philadelphia chromosome-positive leukemia. New Engl J Med 369:1783–1796CrossRefPubMedGoogle Scholar
  56. 56.
    Shami PJ, Deininger M (2012) Evolving treatment strategies for patients newly diagnosed with chronic myeloid leukemia: the role of second-generation BCR-ABL inhibitors as first-line therapy. Leukemia 26:214–224CrossRefPubMedGoogle Scholar
  57. 57.
    Huang X, Cortes J, Kantarjian H (2012) Estimation of the increasing prevalence and plateau prevalence of chronic myeloid leukemia in the era of tyrosine kinase inhibitor therapy. Cancer 118:3123–3127CrossRefPubMedCentralPubMedGoogle Scholar
  58. 58.
    Gurion R, Gafter-Gvili A, Vidal L et al (2013) Has the time for first-line treatment with second generation tyrosine kinase inhibitors in patients with chronic myelogenous leukemia already come? Systematic review and meta-analysis. Haematologica 98(1):95–102CrossRefPubMedCentralPubMedGoogle Scholar
  59. 59.
    Rousselot P, Huguet F, Rea D et al (2007) Imatinib mesylate discontinuation in patients with chronic myelogenous leukemia in complete molecular remission for more than 2 years. Blood 109:58–60CrossRefPubMedGoogle Scholar
  60. 60.
    Ross DM, Branford S, Seymour JF et al (2010) 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(10):1719–1724CrossRefPubMedGoogle Scholar
  61. 61.
    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 11:1029–1035CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Michele Baccarani
    • 1
  • Fausto Castagnetti
    • 1
    • 2
  • Gabriele Gugliotta
    • 1
    • 2
  • Gianantonio Rosti
    • 1
    • 2
    • 3
  1. 1.Department of Hematology and Oncology “L. and A. Seràgnoli”University of Bologna, S. Orsola-Malpighi University HospitalBolognaItaly
  2. 2.Department of Experimental, Diagnostic and Specialty MedicineUniversity of Bologna, S. Orsola-Malpighi University HospitalBolognaItaly
  3. 3.Institute of Hematology “L. and A. Seràgnoli”S.Orsola-Malpighi University HospitalBolognaItaly

Personalised recommendations