Early Management of CML

  • Naranie ShanmuganathanEmail author
  • Timothy P. Hughes
Chronic Myeloid Leukemias (G Saglio, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Chronic Myeloid Leukemias


Purpose of Review

The marked improvement in clinical outcomes for patients with chronic myeloid leukaemia (CML) can be solely attributed to the introduction of targeted therapies against the fusion oncoprotein, BCR-ABL1. However, patient responses, although generally positive, remain heterogenous. Careful drug selection, ensuring the optimal TKI, is chosen for each patient and involves a complex decision process which incorporates consideration of numerous factors.

Recent Findings

For some patients, with disease characteristics that indicate adverse intrinsic disease biology, more potent BCR-ABL1 inhibition is often appropriate, whereas other patients with major co-morbidities will benefit from a less aggressive approach to avoid life-shortening toxicities. For the vast majority of patients, the long-term goal of therapy will be the achievement of a deep molecular response and subsequent treatment-free remission and this consideration will play a large part in the drug selection process.


We explore early management of CML, from the first presentation through to frontline therapy selection.


TKI Deep molecular responses Drug toxicity Treatment-free remission 


Funding Information

N.S. received scholarship funding from the Royal Adelaide Hospital Research Foundation Dawes Scholarship. T.P.H. received support from the National Health and Medical Research Council of Australia (APP1135949) and has the financial support of Cancer Council SA’s Beat Cancer Project on behalf of its donors and the State Government of South Australia through the Department of Health.

Compliance with Ethical Standards

Conflict of Interest

N.S. received honoraria from Novartis and Bristol-Myers Squibb and travel and accommodation expenses from Novartis, Gilead, Amgen, and Janssen. T.P.H. holds a consultancy role in and has received research funding and honoraria from Novartis, Bristol-Myers Squibb, and Ariad.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.


Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Quintás-Cardama A, Cortes J. Molecular biology of bcr-abl1–positive chronic myeloid leukemia. Blood. 2009;113(8):1619–30. Scholar
  2. 2.
    Bower H, Björkholm M, Dickman PW, Höglund M, Lambert PC, Andersson TML. Life Expectancy of Patients With Chronic Myeloid Leukemia Approaches the Life Expectancy of the General Population. J Clin Oncol. 2016;34(24):2851–7. Scholar
  3. 3.
    •• Baccarani M, Deininger MW, Rosti G, Hochhaus A, Soverini S, Apperley JF. European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013. Blood. 2013;122. Current international guidelines regarding CML management.CrossRefGoogle Scholar
  4. 4.
    •• Radich JP, Deininger M, Abboud CN, Altman JK, Berman E, Bhatia R, et al. Chronic Myeloid Leukemia, Version 1.2019, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Cancer Netw. 2018;16(9):1108–35. Current international guidelines regarding CML management.CrossRefGoogle Scholar
  5. 5.
    •• Hochhaus A, Saussele S, Rosti G, Mahon FX, Janssen J, Hjorth-Hansen H, et al. Chronic myeloid leukaemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2017;28(suppl_4):iv41–51. Current international guidelines regarding CML management.CrossRefGoogle Scholar
  6. 6.
    Thompson PA, Kantarjian HM, Cortes JE. Diagnosis and Treatment of Chronic Myeloid Leukemia in 2015. Mayo Clin Proc. 2015;90(10):1440–54. Scholar
  7. 7.
    Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H et al., editors. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th edition ed. World Health Organization Classification of Tumours. France: International Agency for Research on Cancer; 2008.Google Scholar
  8. 8.
    Aqui N, O'Doherty U. Leukocytapheresis for the treatment of hyperleukocytosis secondary to acute leukemia. Hematology. 2014;2014(1):457–60. Scholar
  9. 9.
    Arber DA, Orazi A, Hasserjian R, Thiele J, Borowitz MJ, Le Beau MM, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016;127(20):2391–405. Scholar
  10. 10.
    Buesche G, Ganser A, Schlegelberger B, von Neuhoff N, Gadzicki D, Hecker H, et al. Marrow fibrosis and its relevance during imatinib treatment of chronic myeloid leukemia. Leukemia. 2007;21(12):2420–7 Scholar
  11. 11.
    Kantarjian HM, Bueso-Ramos CE, Talpaz M, O'Brien S, Giles F, Rios MB, et al. The degree of bone marrow fibrosis in chronic myelogenous leukemia is not a prognostic factor with imatinib mesylate therapy. Leuk Lymphoma. 2005;46(7):993–7. Scholar
  12. 12.
    Ohanian M, Kantarjian HM, Quintas-Cardama A, Jabbour E, Abruzzo L, Verstovsek S, et al. Tyrosine kinase inhibitors as initial therapy for patients with chronic myeloid leukemia in accelerated phase. Clin Lymphoma Myeloma Leuk. 2014;14(2):155–62.e1. Scholar
  13. 13.
    Pye SM, Cortes J, Ault P, Hatfield A, Kantarjian H, Pilot R, et al. The effects of imatinib on pregnancy outcome. Blood. 2008;111(12):5505–8. Scholar
  14. 14.
    Ault P, Kantarjian H, O'Brien S, Faderl S, Beran M, Rios MB, et al. Pregnancy among patients with chronic myeloid leukemia treated with imatinib. J Clin Oncol. 2006;24(7):1204–8. Scholar
  15. 15.
    Cortes JE, Abruzzese E, Chelysheva E, Guha M, Wallis N, Apperley JF. The impact of dasatinib on pregnancy outcomes. Am J Hematol. 2015;90(12):1111–5. Scholar
  16. 16.
    Berman E, Druker BJ, Burwick R. Chronic myelogenous leukemia: pregnancy in the era of stopping tyrosine kinase inhibitor therapy. J Clin Oncol. 2018;36(12):1250–6. Scholar
  17. 17.
    Yassin MA, Soliman AT, Elawa AS, El-Ayoubi HR, Desanctis V. Effects of Tyrosine Kinase Inhibitors On Spermatogenesis and Pituitary Gonadal Axis in Males with Chronic Myeloid Leukemia. Blood. 2012;120(Suppl 1):Abstract 1688.CrossRefGoogle Scholar
  18. 18.
    Hochhaus A, Larson RA, Guilhot F, Radich JP, Branford S, Hughes TP, et al. Long-Term Outcomes of Imatinib Treatment for Chronic Myeloid Leukemia. N Engl J Med. 2017;376(10):917–27. Scholar
  19. 19.
    • Hehlmann R, Lauseker M, Saußele S, Pfirrmann M, Krause S, Kolb HJ, et al. Assessment of imatinib as first-line treatment of chronic myeloid leukemia: 10-year survival results of the randomized CML study IV and impact of non-CML determinants. Leukemia. 2017;31:2398–406. The 10-year update on CML IV.CrossRefGoogle Scholar
  20. 20.
    • Hochhaus A, Saglio G, Hughes TP, Larson RA, Kim DW, Issaragrisil S, et al. Long-term benefits and risks of frontline nilotinib vs imatinib for chronic myeloid leukemia in chronic phase: 5-year update of the randomized ENESTnd trial. Leukemia. 2016;30(5):1044–54. The 5-year update on ENESTnd.CrossRefGoogle Scholar
  21. 21.
    • Cortes JE, Saglio G, Kantarjian HM, Baccarani M, Mayer J, Boqué C, et al. Final 5-year study results of DASISION: the dasatinib versus imatinib study in treatment-naïve chronic myeloid leukemia patients trial. J Clin Oncol. 2016. The 5-year update on DASISION.CrossRefGoogle Scholar
  22. 22.
    • Cortes JE, Gambacorti-Passerini C, Deininger MW, Mauro MJ, Chuah C, Kim D-W, et al. Bosutinib versus imatinib for newly diagnosed chronic myeloid leukemia: results from the randomized BFORE Trial. J Clin Oncol. 2017;36(3):231–7. The 5-year update on BFORE.CrossRefGoogle Scholar
  23. 23.
    Efficace F, Baccarani M, Breccia M, Alimena G, Rosti G, Cottone 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. 2011;118(17):4554–60. Scholar
  24. 24.
    O’Brien SG, Guilhot F, Larson RA, Gathmann I, Baccarani M, Cervantes F. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2003;348. Scholar
  25. 25.
    Hehlmann R, Lauseker M, Jung-Munkwitz S, Leitner A, Müller MC, Pletsch N, 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. 2011;29(12):1634–42. Scholar
  26. 26.
    Berman E, Nicolaides M, Maki RG, Fleisher M, Chanel S, Scheu K, et al. Altered bone and mineral metabolism in patients receiving imatinib mesylate. N Engl J Med. 2006;354(19):2006–13. Scholar
  27. 27.
    Yilmaz M, Lahoti A, O'Brien S, Nogueras-Gonzalez GM, Burger J, Ferrajoli A, et al. Estimated glomerular filtration rate changes in patients with chronic myeloid leukemia treated with tyrosine kinase inhibitors. Cancer. 2015;121(21):3894–904. Scholar
  28. 28.
    Sakurai M, Mori T, Karigane D, Kasahara H, Tozawa K, Matsuki E, et al. Long-Term Treatment with Imatinib Is Associated with Decreased Estimated Glomerular Filtration Rate and Hemoglobin Level in Patients with Chronic Myelogenous Leukemia. Blood. 2016;128(Suppl 1):Abstract 1888.CrossRefGoogle Scholar
  29. 29.
    Miranda MB, Lauseker M, Kraus MP, Proetel U, Hanfstein B, Fabarius A, et al. Secondary malignancies in chronic myeloid leukemia patients after imatinib-based treatment: long-term observation in CML Study IV. Leukemia. 2016;30:1255. Scholar
  30. 30.
    Gunnarsson N, Stenke L, Höglund M, Sandin F, Björkholm M, Dreimane A, et al. Second malignancies following treatment of chronic myeloid leukaemia in the tyrosine kinase inhibitor era. Br J Haematol. 2015;169(5):683–8. Scholar
  31. 31.
    Hughes TP, Branford S, White DL, Reynolds J, Koelmeyer R, Seymour JF, 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. 2008;112(10):3965–73. Scholar
  32. 32.
    • Baccarani M, Druker BJ, Branford S, Kim D-W, Pane F, Mongay L, et al. Long-term response to imatinib is not affected by the initial dose in patients with Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase: final update from the Tyrosine Kinase Inhibitor Optimization and Selectivity (TOPS) study. Int J Hematol. 2014;99(5):616–24. Addresses the question of optimal imatinib dosing.CrossRefGoogle Scholar
  33. 33.
    Kantarjian HM, Giles F, Gattermann N, Bhalla K, Alimena G, Palandri F, 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. 2007;110(10):3540–6. Scholar
  34. 34.
    Kantarjian H, Giles F, Wunderle L, Bhalla K, O'Brien S, Wassmann B, et al. Nilotinib in Imatinib-Resistant CML and Philadelphia Chromosome–Positive ALL. N Engl J Med. 2006;354(24):2542–51. Scholar
  35. 35.
    Cortes J, Kim DW, Raffoux E, Martinelli G, Ritchie E, Roy L, et al. Efficacy and safety of dasatinib in imatinib-resistant or -intolerant patients with chronic myeloid leukemia in blast phase. Leukemia. 2008;22(12):2176–83.CrossRefGoogle Scholar
  36. 36.
    Khoury HJ, Cortes JE, Kantarjian HM, Gambacorti-Passerini C, Baccarani M, Kim D-W, et al. Bosutinib is active in chronic phase chronic myeloid leukemia after imatinib and dasatinib and/or nilotinib therapy failure. Blood. 2012;119(15):3403–12. Scholar
  37. 37.
    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. Scholar
  38. 38.
    Quintas-Cardama A, Han X, Kantarjian H, Cortes J. Tyrosine kinase inhibitor-induced platelet dysfunction in patients with chronic myeloid leukemia. Blood. 2009;114. Scholar
  39. 39.
    Dahlen T, Edgren G, Lambe M, Hoglund M, Bjorkholm M, Sandin F, et al. Cardiovascular events associated with use of tyrosine kinase inhibitors in chronic myeloid leukemia: a population-based cohort study. Ann Intern Med. 2016;165(3):161–6. Scholar
  40. 40.
    Douxfils J, Haguet H, Mullier F, Chatelain C, Graux C, Dogne JM. Association between BCR-ABL tyrosine kinase inhibitors for chronic myeloid leukemia and cardiovascular events, major molecular response, and overall survival: a systematic review and meta-analysis. JAMA Oncology. 2016;2(5):625–32. Scholar
  41. 41.
    Rousselot P, Mollica L, Etienne G, Bouchet S, Guerci A, Nicolini FE, et al. Pharmacologic monitoring of dasatinib as first line therapy in newly diagnosed chronic phase chronic myelogenous leukemia (CP-CML) identifies patients at higher risk of pleural effusion: a sub-analysis of the OPTIM-Dasatinib Trial. Blood. 2012;120(21):Abstract 3770.CrossRefGoogle Scholar
  42. 42.
    Weatherald J, Chaumais M-C, Savale L, Jaïs X, Seferian A, Canuet M, et al. Long-term outcomes of dasatinib-induced pulmonary arterial hypertension: a population-based study. Eur Respir J. 2017;50(1):1700217. Scholar
  43. 43.
    Shah NP, Wallis N, Farber HW, Mauro MJ, Wolf RA, Mattei D, et al. Clinical features of pulmonary arterial hypertension in patients receiving dasatinib. Am J Hematol. 2015;90(11):1060–4. Scholar
  44. 44.
    The DIRECT study: individualised dasatinib dosing for elderly patients with chronic myelogenous leukaemia [database on the Internet]. ALLG. 2016. Accessed: 29/05/2019.Google Scholar
  45. 45.
    Cortes JE, Kim DW, Kantarjian HM, Brummendorf TH, Dyagil I, Griskevicius L. Bosutinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia: results from the BELA trial. J Clin Oncol. 2012;30. Scholar
  46. 46.
    Preudhomme C, Guilhot J, Nicolini FE, Guerci-Bresler A, Rigal-Huguet F, Maloisel F, et al. Imatinib plus peginterferon Alfa-2a in chronic myeloid leukemia. N Engl J Med. 2010;363(26):2511–21. Scholar
  47. 47.
    Yeung DT, Grigg AP, Shanmuganathan N, Cunningham I, Shortt J, Rowling P, et al. Combination of nilotinib and pegylated interferon Alfa-2b results in high molecular response rates in chronic phase CML: interim results of the ALLG CML 11 Pinnacle Study. Blood. 2018;132(Suppl 1):Abstract 459. Scholar
  48. 48.
    Hochhaus A, Saussele S, Baerlocher GM, Brümmendorf TH, Burchert A, La Rosée P, et al. Nilotinib vs nilotinib plus pegylated interferon-alpha2b induction and nilotinib or pegylated interferon-alpha2b maintenance therapy for newly diagnosed BCR-ABL+ chronic myeloid leukemia patients in chronic phase: interim analysis of the Tiger (CML V)-Study. Blood. 2018;132(Suppl 1):Abstract 460.CrossRefGoogle Scholar
  49. 49.
    Nicolini FE, Etienne G, Dubruille V, Roy L, Huguet F, Legros L, et al. Nilotinib and peginterferon alfa-2a for newly diagnosed chronic-phase chronic myeloid leukaemia (NiloPeg): a multicentre, non-randomised, open-label phase 2 study. Lancet Haematol. 2015;2(1):e37–46. Scholar
  50. 50.
    Hjorth-Hansen H, Stentoft J, Richter J, Koskenvesa P, Höglund M, Dreimane A, et al. Safety and efficacy of the combination of pegylated interferon-α2b and dasatinib in newly diagnosed chronic-phase chronic myeloid leukemia patients. Leukemia. 2016;30:1853. Scholar
  51. 51.
    Rea D, Nicolini FE, Tulliez M, Guilhot F, Guilhot J, Guerci-Bresler A, et al. Discontinuation of dasatinib or nilotinib in chronic myeloid leukemia: interim analysis of the STOP 2G-TKI study. Blood. 2017;129(7):846–54. Scholar
  52. 52.
    Mahon FX, Rea D, Guilhot J, Guilhot F, Huguet F, Nicolini F, 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. 2010;11(11):1029–35. Scholar
  53. 53.
    Saussele S, Richter J, Guilhot J, Gruber FX, Hjorth-Hansen H, Almeida A, et al. Discontinuation of tyrosine kinase inhibitor therapy in chronic myeloid leukaemia (EURO-SKI): a prespecified interim analysis of a prospective, multicentre, non-randomised, trial. Lancet Oncol. 2018;19(6):747–57. Scholar
  54. 54.
    Ross DM, Branford S, Seymour JF, Schwarer AP, Arthur C, Yeung DT, 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(4):515–22. Scholar
  55. 55.
    Lee S-E, Choi SY, Song H-Y, Kim S-H, Choi M-Y, Park JS, et al. Imatinib withdrawal syndrome and longer duration of imatinib have a close association with a lower molecular relapse after treatment discontinuation: the KID study. Haematologica. 2016;101(6):717–23. Scholar
  56. 56.
    Imagawa J, Tanaka H, Okada M, Nakamae H, Hino M, Murai K, et al. Discontinuation of dasatinib in patients with chronic myeloid leukaemia who have maintained deep molecular response for longer than 1 year (DADI trial): a multicentre phase 2 trial. Lancet Haematol. 2015;2(12):e528–35. Scholar
  57. 57.
    Etienne G, Guilhot J, Rea D, Rigal-Huguet F, Nicolini F, Charbonnier A, et al. Long-Term Follow-Up of the French Stop Imatinib (STIM1) Study in Patients With Chronic Myeloid Leukemia. J Clin Oncol. 2017;35(3):298–305. Scholar
  58. 58.
    Rousselot P, Charbonnier A, Cony-Makhoul P, Agape P, Nicolini FE, Varet B, et al. Loss of major molecular response as a trigger for restarting tyrosine kinase inhibitor therapy in patients with chronic-phase chronic myelogenous leukemia who have stopped imatinib after durable undetectable disease. J Clin Oncol. 2014;32(5):424–30. Scholar
  59. 59.
    Mahon F, Boquimpani C, Kim D, et al. Treatment-free remission after second-line nilotinib treatment in patients with chronic myeloid leukemia in chronic phase: results from a single-group, phase 2, open-label study. Ann Intern Med. 2018;168(7):461–70. Scholar
  60. 60.
    Kumagai T, Nakaseko C, Nishiwaki K, Yoshida C, Ohashi K, Takezako N, et al. Dasatinib cessation after deep molecular response exceeding 2 years and natural killer cell transition during dasatinib consolidation. Cancer Sci. 2018;109(1):182–92. Scholar
  61. 61.
    Saussele S, Krauss MP, Hehlmann R, Lauseker M, Proetel U, Kalmanti L, et al. Impact of comorbidities on overall survival in patients with chronic myeloid leukemia: results of the randomized CML study IV. Blood. 2015;126(1):42–9. Scholar
  62. 62.
    Chai-Adisaksopha C, Lam W, Hillis C. Major arterial events in patients with chronic myeloid leukemia treated with tyrosine kinase inhibitors: a meta-analysis. Leuk Lymphoma. 2016;57(6):1300–10. Scholar
  63. 63.
    Caocci G, Mulas O, Annunziata M, Luciano L, Bonifacio M, Orlandi EM, et al. Cardiovascular toxicity in patients with chronic myeloid leukemia treated with second-generation tyrosine kinase inhibitors in the real-life practice: identification of risk factors and the role of prophylaxis. Am J Hematol. 2018;93(7):E159–e61. Scholar
  64. 64.
    • Ross DM, Arthur C, Burbury K, Ko BS, Mills AK, Shortt J, et al. Chronic myeloid leukaemia and tyrosine kinase inhibitor therapy: assessment and management of cardiovascular risk factors. Intern Med J. 2018;48(Suppl 2):5–13. Review paper addressing cardiovascular health in CML patients.CrossRefGoogle Scholar
  65. 65.
    Breccia M, Molica M, Zacheo I, Serrao A, Alimena G. Application of systematic coronary risk evaluation chart to identify chronic myeloid leukemia patients at risk of cardiovascular diseases during nilotinib treatment. Ann Hematol. 2015;94(3):393–7. Scholar
  66. 66.
    Haouala A, Widmer N, Duchosal MA, Montemurro M, Buclin T, Decosterd LA. Drug interactions with the tyrosine kinase inhibitors imatinib, dasatinib, and nilotinib. Blood. 2011;117(8):e75–87. Scholar
  67. 67.
    Hughes TP, Laneuville P, Rousselot P, Snyder DS, Rea D, Shah NP, et al. Incidence, outcomes, and risk factors of pleural effusion in patients receiving dasatinib therapy for Philadelphia chromosome-positive leukemia. Haematologica. 2019;104(1):93–101. Scholar
  68. 68.
    Ozgur Yurttas N, Eskazan AE. Dasatinib-induced pulmonary arterial hypertension. Br J Clin Pharmacol. 2018;84(5):835–45. Scholar
  69. 69.
    Fox LC, Cummins KD, Costello B, Yeung D, Cleary R, Forsyth C, et al. The incidence and natural history of dasatinib complications in the treatment of chronic myeloid leukemia. Blood Adv. 2017;1(13):802–11. Scholar
  70. 70.
    Chang C-S, Tsai C-Y, Yan S-L. Hepatitis B reactivation in patients receiving targeted therapies. Hematology. 2017;22(10):592–8. Scholar
  71. 71.
    Sokal JE, Cox EB, Baccarani M, Tura S, Gomez GA, Robertson JE, et al. Prognostic discrimination in “good-risk” chronic granulocytic leukemia. Blood. 1984;63(4):789–99.CrossRefGoogle Scholar
  72. 72.
    Hasford J, Pfirrmann M, Hehlmann R, Allan NC, Baccarani M, Kluin-Nelemans JC, 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. 1998;90(11):850–9. Scholar
  73. 73.
    Hasford J, Baccarani M, Hoffmann V, Guilhot J, Saussele S, Rosti G, et al. Predicting complete cytogenetic response and subsequent progression-free survival in 2060 patients with CML on imatinib treatment: the EUTOS score. Blood. 2011;118(3):686–92. Scholar
  74. 74.
    Pfirrmann M, Baccarani M, Saussele S, Guilhot J, Cervantes F, Ossenkoppele G, et al. Prognosis of long-term survival considering disease-specific death in patients with chronic myeloid leukemia. Leukemia. 2016;30(1):48–56. Scholar
  75. 75.
    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. Scholar
  76. 76.
    Branford S, Yeung DT, Ross DM, Prime JA, Field CR, Altamura HK, et al. Early molecular response and female sex strongly predict stable undetectable BCR-ABL1, the criteria for imatinib discontinuation in patients with CML. Blood. 2013;121(19):3818–24. Scholar
  77. 77.
    Branford S, Yeung DT, Ross DM, Parker WT, Braley J, Seymour JF, et al. The Adverse Effect of High Sokal Risk for First Line Imatinib Treated Patients Is Overcome By a Rapid Rate of BCR-ABL Decline Measured As Early As 1 Month of Treatment. Blood. 2014;124(21):816.CrossRefGoogle Scholar
  78. 78.
    Hochhaus A, Rosti G, Cross NC, Steegmann JL, le Coutre P, Ossenkoppele G, et al. Frontline nilotinib in patients with chronic myeloid leukemia in chronic phase: results from the European ENEST1st study. Leukemia. 2016;30(1):57–64. Scholar
  79. 79.
    • Pfirrmann M, Baccarani M, Saussele S, Turkina A, Faber E, Steegmann JL et al., editors. The EUTOS long-term survival (ELTS) score is superior to the Sokal score for prognosis of survival probabilities of patients with chronic-phase chronic myeloid leukaemia. Oral presenation at the 23rd Annual Congress of the European Hematology Association; 2018; Stockholm, Sweden. Potential new scoring model developed in the TKI era.Google Scholar
  80. 80.
    Molica M, Canichella M, Alunni Fegatelli D, Colafigli G, Massaro F, Latagliata R, et al. The Eutos long-term survival score accurately predicts the risk of death in chronic myeloid leukaemia patients treated outside of clinical trials. Am J Hematol. 2017;92(12):E661–E4. Scholar
  81. 81.
    Fabarius A, Leitner A, Hochhaus A, Müller MC, Hanfstein B, Haferlach C, et al. Impact of ACA at diagnosis on prognosis of CML: long-term observation from 1151 patients of the randomized CML Study IV. Blood. 2011;118(26):6760–8. Scholar
  82. 82.
    Luatti S, Castagnetti F, Marzocchi G, Baldazzi C, Gugliotta G, Iacobucci I, et al. Additional chromosomal abnormalities in Philadelphia-positive clone: adverse prognostic influence on frontline imatinib therapy: a GIMEMA Working Party on CML analysis. Blood. 2012;120(4):761–7. Scholar
  83. 83.
    Krishna Chandran R, Geetha N, Sakthivel KM, Suresh Kumar R, Jagathnath Krishna KMN, Sreedharan H. Impact of additional chromosomal aberrations on the disease progression of chronic myelogenous leukemia. Front Oncol. 2019;9(88).
  84. 84.
    Alhuraiji A, Kantarjian H, Boddu P, Ravandi F, Borthakur G, DiNardo C, et al. Prognostic significance of additional chromosomal abnormalities at the time of diagnosis in patients with chronic myeloid leukemia treated with frontline tyrosine kinase inhibitors. Am J Hematol. 2018;93(1):84–90. Scholar
  85. 85.
    Jain P, Kantarjian H, Patel KP, Gonzalez GN, Luthra R, Shamanna RK, et al. Impact of BCR-ABL transcript type on outcome in patients with chronic-phase CML treated with tyrosine kinase inhibitors. Blood. 2016;127(10):1269–75. Scholar
  86. 86.
    Lucas CM, Harris RJ, Giannoudis A, Davies A, Knight K, Watmough SJ, et al. Chronic myeloid leukemia patients with the e13a2 BCR-ABL fusion transcript have inferior responses to imatinib compared to patients with the e14a2 transcript. Haematologica. 2009;94(10):1362–7. Scholar
  87. 87.
    Castagnetti F, Gugliotta G, Breccia M, Iurlo A, Levato L, Albano F, et al. The BCR-ABL1 transcript type influences response and outcome in Philadelphia chromosome-positive chronic myeloid leukemia patients treated frontline with imatinib. Am J Hematol. 2017;92(8):797–805. Scholar
  88. 88.
    Hanfstein B, Lauseker M, Hehlmann R, Saussele S, Erben P, Dietz C, et al. Distinct characteristics of e13a2 versus e14a2 BCR-ABL1 driven chronic myeloid leukemia under first-line therapy with imatinib. Haematologica. 2014;99(9):1441–7. Scholar
  89. 89.
    Claudiani S, Apperley JF, Gale RP, Clark R, Szydlo R, Deplano S, et al. E14a2 BCR-ABL1 transcript is associated with a higher rate of treatment-free remission in individuals with chronic myeloid leukemia after stopping tyrosine kinase inhibitor therapy. Haematologica. 2017;102(8):e297–e9. Scholar
  90. 90.
    Shanmuganathan N, Branford S, Yong ASM, Hiwase DK, Yeung DT, Ross DM, et al. The e13a2 BCR-ABL1 transcript is associated with higher rates of molecular recurrence after treatment-free remission attempts: retrospective analysis of the adelaide cohort. Blood. 2018;132(Suppl 1):Abstract 1731. Scholar
  91. 91.
    Marin D, Bazeos A, Mahon F-X, Eliasson L, Milojkovic D, Bua M, 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. 2010;28(14):2381–8. Scholar
  92. 92.
    Noens L, van Lierde MA, De Bock R, Verhoef G, Zachee P, Berneman Z, et al. Prevalence, determinants, and outcomes of nonadherence to imatinib therapy in patients with chronic myeloid leukemia: the ADAGIO study. Blood. 2009;113(22):5401–11. Scholar
  93. 93.
    Jabbour E, Saglio G, Radich J, Kantarjian H. Adherence to BCR-ABL inhibitors: issues for CML therapy. Clin Lymphoma Myeloma Leuk. 2012;12(4):223–9. Scholar
  94. 94.
    Usherwood T. Encouraging adherence to long-term medication. Aust Prescr. 2017;40:147–50.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Naranie Shanmuganathan
    • 1
    • 2
    • 3
    • 4
    • 5
    Email author
  • Timothy P. Hughes
    • 1
    • 2
    • 3
  1. 1.Precision Medicine ThemeSouth Australian Health and Medical Research InstituteAdelaideAustralia
  2. 2.School of MedicineUniversity of AdelaideAdelaideAustralia
  3. 3.Department of HaematologyRoyal Adelaide Hospital and SA PathologyAdelaideAustralia
  4. 4.Centre for Cancer BiologySA PathologyAdelaideAustralia
  5. 5.School of Health SciencesUniversity of South AustraliaAdelaideAustralia

Personalised recommendations