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Abstract

The widespread introduction of tyrosine kinase inhibitor (TKI) therapy has radically changed the treatment strategy and goals of treatment of chronic myeloid leukemia (CML). In the past, allogeneic transplantation offered the only alternative for “curative” therapy, and the use of this modality was limited by patient age and donor availability. In a mere decade of use, TKI therapy has pushed transplantation to a salvage therapy, and most chronic-phase patients can expect prolonged response, with a small risk of progression to advanced-phase disease. Indeed, we now can speak of a “functional cure” and can now even consider discontinuing therapy for those patients without molecular evidence of disease. Given the multiple tyrosine kinase inhibitors now available to clinicians, as well as sensitive and relatively noninvasive methods to monitor disease response, we are now at the enviable phase of being able to optimize response based on the individual treatment goals of the patient and physician.

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References

  1. Druker BJ, Guilhot F, O’Brien SG, Gathmann I, Kantarjian H, Gattermann N, et al. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med. 2006;355(23):2408–17.

    Article  CAS  PubMed  Google Scholar 

  2. Deininger M, O’Brien SG, Guilhot F, Goldman JM, Hochhaus A, Hughes TP, et al. International randomized study of interferon vs STI571 (IRIS) 8-year follow up: sustained survival and low risk for progression or events in patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP) treated with imatinib. Blood. 2009;114:462. ASH Abstract 1126.

    Google Scholar 

  3. Kantarjian H, Shah NP, Hochhaus A, Cortes J, Shah S, Ayala M, et al. Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2010;362(24):2260–70.

    Article  CAS  PubMed  Google Scholar 

  4. Radich JP, Kopecky KJ, Appelbaum FR, Kamel-Reid S, Stock W, Malnassy G, et al. A randomized trial of dasatinib 100 mg versus imatinib 400 mg in newly diagnosed chronic-phase chronic myeloid leukemia. Blood. 2012;120(19):3898–905.

    Google Scholar 

  5. Saglio G, Kim DW, Issaragrisil S, le Coutre P, Etienne G, Lobo C, et al. Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia. N Engl J Med. 2010;362(24):2251–9.

    Article  CAS  PubMed  Google Scholar 

  6. Hochhaus A, O’Brien SG, Guilhot F, Druker BJ, Branford S, Foroni L, et al. Six-year follow-up of patients receiving imatinib for the first-line treatment of chronic myeloid leukemia. Leukemia. 2009;23(6):1054–61.

    Article  CAS  PubMed  Google Scholar 

  7. Branford S, Rudzki Z, Walsh S, Parkinson I, Grigg A, Szer J, et al. Detection of BCR-ABL mutations in patients with CML treated with imatinib is virtually always accompanied by clinical resistance, and mutations in the ATP phosphate-binding loop (P-loop) are associated with a poor prognosis. Blood. 2003;102(1):276–83.

    Article  CAS  PubMed  Google Scholar 

  8. Khorashad JS, de Lavallade H, Apperley JF, Milojkovic D, Reid AG, Bua M, et al. Finding of kinase domain mutations in patients with chronic phase chronic myeloid leukemia responding to imatinib may identify those at high risk of disease progression. J Clin Oncol. 2008;26(29):4806–13.

    Article  CAS  PubMed  Google Scholar 

  9. Soverini S, Martinelli G, Rosti G, Bassi S, Amabile M, Poerio A, et al. ABL mutations in late chronic phase chronic myeloid leukemia patients with up-front cytogenetic resistance to imatinib are associated with a greater likelihood of progression to blast crisis and shorter survival: a study by the GIMEMA Working Party on Chronic Myeloid Leukemia. J Clin Oncol. 2005;23(18):4100–9.

    Article  CAS  PubMed  Google Scholar 

  10. Hughes T, Saglio G, Branford S, Soverini S, Kim DW, Muller MC, et al. Impact of baseline BCR-ABL mutations on response to nilotinib in patients with chronic myeloid leukemia in chronic phase. J Clin Oncol. 2009;27(25):4204–10.

    Article  CAS  PubMed  Google Scholar 

  11. Muller MC, Cortes JE, Kim DW, Druker BJ, Erben P, Pasquini R, et al. Dasatinib treatment of chronic-phase chronic myeloid leukemia: analysis of responses according to preexisting BCR-ABL mutations. Blood. 2009;114(24):4944–53.

    Article  PubMed  Google Scholar 

  12. Cortes JE, Kim DW, Pinilla-Ibarz J, le Coutre P, Paquette R, Chuah C, et al. A phase 2 trial of ponatinib in Philadelphia chromosome-positive leukemias. N Engl J Med. 2013;369(19):1783–96.

    Article  CAS  PubMed  Google Scholar 

  13. Cortes JE, Kantarjian HM, Brummendorf TH, Kim DW, Turkina AG, Shen ZX, 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. 2011;118(17):4567–76.

    Article  CAS  PubMed  Google Scholar 

  14. Oehler VG, Gooley T, Snyder DS, Johnston L, Lin A, Cummings CC, et al. The effects of imatinib mesylate treatment before allogeneic transplantation for chronic myeloid leukemia. Blood. 2007;109(4):1782–9.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  15. Radich JP, Gooley T, Bensinger W, Chauncey T, Clift R, Flowers M, et al. HLA-matched related hematopoietic cell transplantation for chronic-phase CML using a targeted busulfan and cyclophosphamide preparative regimen. Blood. 2003;102(1):31–5.

    Article  CAS  PubMed  Google Scholar 

  16. Cortes J, Rousselot P, Kim DW, Ritchie E, Hamerschlak N, Coutre S, et al. Dasatinib induces complete hematologic and cytogenetic responses in patients with imatinib-resistant or -intolerant chronic myeloid leukemia in blast crisis. Blood. 2007;109(8):3207–13.

    Article  CAS  PubMed  Google Scholar 

  17. Guilhot F, Apperley J, Kim DW, Bullorsky EO, Baccarani M, Roboz GJ, et al. Dasatinib induces significant hematologic and cytogenetic responses in patients with imatinib-resistant or -intolerant chronic myeloid leukemia in accelerated phase. Blood. 2007;109(10):4143–50.

    Article  CAS  PubMed  Google Scholar 

  18. O’Brien S, Radich JP, Abboud CN, et al. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) chronic myelogenous leukemia version 1.2015. © 2015 National Comprehensive Cancer Network, Inc. Available at NCCN.org. Accessed 11 Apr 2015.

    Google Scholar 

  19. Baccarani M, Deininger MW, Rosti G, et al. European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013. Blood. 2013;122:872–84.

    Article  CAS  PubMed  Google Scholar 

  20. O’Brien SG, Deininger MW. Imatinib in patients with newly diagnosed chronic-phase chronic myeloid leukemia. Semin Hematol. 2003;40(2 Suppl 2):26–30.

    Article  PubMed  Google Scholar 

  21. Testoni N, Marzocchi G, Luatti S, et al. Chronic myeloid leukemia: a prospective comparison of interphase fluorescence in situ hybridization and chromosome banding analysis for the definition of complete cytogenetic response: a study of the GIMEMA CML WP. Blood. 2009;114:4939–43.

    Article  CAS  PubMed  Google Scholar 

  22. Jabbour E, Kantarjian H, O’Brien S, et al. The achievement of an early complete cytogenetic response is a major determinant for outcome in patients with early chronic phase chronic myeloid leukemia treated with tyrosine kinase inhibitors. Blood. 2011;118:4541–6.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  23. Hardling M, Wei Y, Palmqvist L, et al. Serial monitoring of BCR-ABL transcripts in chronic myelogenous leukemia (CML) treated with imatinib mesylate. Med Oncol. 2004;21:349–58.

    Article  CAS  PubMed  Google Scholar 

  24. Bao F, Munker R, Lowery C, et al. Comparison of FISH and quantitative RT-PCR for the diagnosis and follow-up of BCR-ABL-positive leukemias. Mol Diagn Ther. 2007;11:239–45.

    Article  CAS  PubMed  Google Scholar 

  25. Hughes TP, Kaeda J, Branford S, et al. Frequency of major molecular responses to imatinib or interferon alfa plus cytarabine in newly diagnosed chronic myeloid leukemia. N Engl J Med. 2003;349:1423–32.

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  27. Larson RA, Hochhaus A, Hughes TP, et al. Nilotinib vs imatinib in patients with newly diagnosed Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase: ENESTnd 3-year follow-up. Leukemia. 2012;26:2197–203.

    Article  CAS  PubMed  Google Scholar 

  28. Hughes T, Deininger M, Hochhaus A, et al. 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. 2006;108:28–37.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  29. Cortes J, Quintas-Cardama A, Jabbour E, et al. The clinical significance of achieving different levels of cytogenetic response in patients with chronic phase chronic myeloid leukemia after failure to front-line therapy: is complete cytogenetic response the only desirable endpoint? Clin Lymphoma Myeloma Leuk. 2011;11(5):421–6.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  30. Kantarjian HM, Talpaz M, O’Brien S, Smith TL, Giles FJ, Faderl S, et al. Imatinib mesylate for Philadelphia chromosome-positive, chronic-phase myeloid leukemia after failure of interferon-alpha: follow-up results. Clin Cancer Res. 2002;8(7):2177–87.

    CAS  PubMed  Google Scholar 

  31. Marin D, Marktel S, Bua M, Szydlo RM, Franceschino A, Nathan I, et al. Prognostic factors for patients with chronic myeloid leukaemia in chronic phase treated with imatinib mesylate after failure of interferon alfa. Leukemia. 2003;17(8):1448–53.

    Article  CAS  PubMed  Google Scholar 

  32. Guilhot F, Larson RA, O’Brien SG, et al. Time to Complete Cytogenetic Response (CCyR) does not affect long-term outcomes for patients on imatinib therapy. Blood. 2007;110:abstract 27.

    Google Scholar 

  33. Tam CS, Kantarjian H, Garcia-Manero G, et al. Failure to achieve a major cytogenetic response by 12 months defines inadequate response in patients receiving nilotinb or dasatinib as second or subsequent line therapy for CML. Blood. 2008;112(3):516–8.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  34. Paschka P, Muller MC, Merx K, et al. Molecular monitoring of response to imatinib (Glivec) in CML patients pretreated with interferon alpha. Low levels of residual disease are associated with continuous remission. Leukemia. 2003;17:1687–94.

    Article  CAS  PubMed  Google Scholar 

  35. Hughes TP, Hochhaus A, Branford S, et al. Long-term prognostic significance of early molecular response to imatinib in newly diagnosed chronic myeloid leukemia: an analysis from the International Randomized Study of Interferon and STI571 (IRIS). Blood. 2010;116:3758–65.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  36. Kantarjian H, O’Brien S, Shan J, et al. Cytogenetic and molecular responses and outcome in chronic myelogenous leukemia: need for new response definitions? Cancer. 2008;112:837–45.

    Article  PubMed  Google Scholar 

  37. Press RD, Galderisi C, Yang R, et al. A half-log increase in BCR-ABL RNA predicts a higher risk of relapse in patients with chronic myeloid leukemia with an imatinib-induced complete cytogenetic response. Clin Cancer Res. 2007;13:6136–43.

    Article  CAS  PubMed  Google Scholar 

  38. Hamilton A, Helgason GV, Schemionek M, et al. Chronic myeloid leukemia stem cells are not dependent on Bcr-Abl kinase activity for their survival. Blood. 2012;119:1501–10.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  39. Mahon FX, Rea D, Guilhot J. Intergroupe Francais des Leucemies Myeloides Chroniques. Discontinuation of imatinib in patients with chronic myeloid leukemia who have maintained complete molecular remission for at least 2 years: the prospective, multicenter Stop Imatinib (STIM) trial. Lancet Oncol. 2010;11:1029–35.

    Article  CAS  PubMed  Google Scholar 

  40. Ross DM, Branford S, Seymour JF, et al. Safety and efficacy of imatinib cessation for CML patients with stable undetectable minimal residual disease: results from the TWISTER study. Blood. 2013;122:515–22.

    Article  CAS  PubMed  Google Scholar 

  41. Marin D, Ibrahim AR, Lucas C, 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. 2012;30:232–8.

    Article  CAS  PubMed  Google Scholar 

  42. Jain P, Kantarjian H, Nazha A, et al. Early responses predict better outcomes in patients with newly diagnosed chronic myeloid leukemia: results with four tyrosine kinase inhibitor modalities. Blood. 2013;121:4867–74.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  43. Branford S, Yeung DT, Parker WT, et al. Prognosis for patients with CML and >10% BCR-ABL1 after 3 months of imatinib depends on the rate of BCR-ABL1 decline. Blood. 2014;124:511–8.

    Article  CAS  PubMed  Google Scholar 

  44. Bartley PA, Latham S, Budgen B, et al. A DNA real-time quantitative PCR method suitable for routine monitoring of low levels of minimal residual disease in chronic myeloid leukemia. J Mol Diagn. 2015;17:185–92.

    Article  CAS  PubMed  Google Scholar 

  45. Goh H-G, Lin M, Fukushima F, et al. Sensitive quantitation of minimal residual disease in chronic myeloid leukemia using nanofluidic digital polymerase chain reaction assay. Leuk Lymphoma. 2011;52:896–904.

    Article  CAS  PubMed  Google Scholar 

  46. Huggett FJ, Cowen S, Foy CA. Considerations for digital PCR as an accurate molecular diagnostic tool. Clin Chem. 2015;61:1–10.

    Article  Google Scholar 

  47. Jennings LJ, George D, Czech J, Yu M, Joseph L. Detection and quantification of BCR-ABL1 fusion transcripts by droplet digital PCR. J Mol Diagn. 2014;16(2):174–9.

    Article  CAS  PubMed  Google Scholar 

  48. Soverini S, De Benedittis C, Polakova KM, et al. Unraveling the complexity of tyrosine kinase inhibitor-resistant populations by ultra-deep sequencing of the BCR-ABL kinase domain. Blood. 2013;122:1634–48.

    Article  CAS  PubMed  Google Scholar 

  49. Schmitt MW, Kennedy SR, Salk JJ, Fox EJ, Hiatt JB, Loeb LA. Detection of ultra-rare mutations by next-generation sequencing. Proc Natl Acad Sci U S A. 2012;109:14508–13.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

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Correspondence to Jerald Radich MD .

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Radich, J., Egan, D. (2016). Goals of CML Treatment in the Tyrosine Kinase Inhibitor Era. In: Kizaki, M. (eds) Molecular Pathogenesis and Treatment of Chronic Myelogenous Leukemia. Springer, Tokyo. https://doi.org/10.1007/978-4-431-55714-2_4

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  • DOI: https://doi.org/10.1007/978-4-431-55714-2_4

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