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Initial treatment of chronic myeloid leukemia in chronic phase

Authors
Robert S Negrin, MD
Charles A Schiffer, MD
Section Editor
Richard A Larson, MD
Deputy Editor
Alan G Rosmarin, MD

INTRODUCTION

Chronic myeloid leukemia (CML) is a myeloproliferative disorder associated with the Philadelphia chromosome t(9;22)(q34;q11) resulting in the BCR-ABL fusion gene. This genetic abnormality results in the formation of a unique gene product (BCR-ABL), which is a constitutively active tyrosine kinase. It is this deregulated tyrosine kinase that is implicated in the development of CML. (See "Molecular genetics of chronic myeloid leukemia".)

Inhibitors of this tyrosine kinase, most notably imatinib, dasatinib, and nilotinib, have been developed and used successfully to treat CML. Even with therapy, CML can progress from a relatively indolent disease (chronic stable phase) to a more aggressive disorder (accelerated phase), during which time disease control is more difficult to achieve. It can then culminate in an acute leukemia, termed "blast crisis," which is generally refractory to treatment.

The initial treatment of chronic phase CML will be discussed here. Treatment of chronic phase CML after the failure of initial therapy, treatment of accelerated phase and blast crisis, and specific details regarding the pharmacology of tyrosine kinase inhibitors are discussed separately. (See "Overview of the treatment of chronic myeloid leukemia" and "Treatment of chronic myeloid leukemia in chronic phase after failure of initial therapy" and "Treatment of chronic myeloid leukemia in accelerated phase" and "Treatment of chronic myeloid leukemia in blast crisis" and "Clinical use of tyrosine kinase inhibitors for chronic myeloid leukemia".)

INITIAL TREATMENT

Overview — The two main treatment options for patients with newly diagnosed CML in chronic phase are:

BCR-ABL tyrosine kinase inhibitors (TKIs), such as imatinib, dasatinib, and nilotinib.

                

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Literature review current through: Nov 2016. | This topic last updated: Mon Aug 15 00:00:00 GMT+00:00 2016.
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References
Top
  1. Cortes J, Kantarjian H. How I treat newly diagnosed chronic phase CML. Blood 2012; 120:1390.
  2. Baccarani M, Cortes J, Pane F, et al. Chronic myeloid leukemia: an update of concepts and management recommendations of European LeukemiaNet. J Clin Oncol 2009; 27:6041.
  3. Kantarjian H, Shah NP, Hochhaus A, et al. Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med 2010; 362:2260.
  4. Saglio G, Kim DW, Issaragrisil S, et al. Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia. N Engl J Med 2010; 362:2251.
  5. Gurion R, Gafter-Gvili A, Vidal L, et al. 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 2013; 98:95.
  6. 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.
  7. Cortes JE, Saglio G, Kantarjian HM, 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; 34:2333.
  8. Gambacorti-Passerini C, Antolini L, Mahon FX, et al. Multicenter independent assessment of outcomes in chronic myeloid leukemia patients treated with imatinib. J Natl Cancer Inst 2011; 103:553.
  9. Aichberger KJ, Herndlhofer S, Schernthaner GH, et al. Progressive peripheral arterial occlusive disease and other vascular events during nilotinib therapy in CML. Am J Hematol 2011; 86:533.
  10. Montani D, Bergot E, Günther S, et al. Pulmonary arterial hypertension in patients treated by dasatinib. Circulation 2012; 125:2128.
  11. Yeung DT, Osborn MP, White DL, 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 2015; 125:915.
  12. Experts in Chronic Myeloid Leukemia. The price of drugs for chronic myeloid leukemia (CML) is a reflection of the unsustainable prices of cancer drugs: from the perspective of a large group of CML experts. Blood 2013; 121:4439.
  13. Dusetzina SB, Winn AN, Abel GA, et al. Cost sharing and adherence to tyrosine kinase inhibitors for patients with chronic myeloid leukemia. J Clin Oncol 2014; 32:306.
  14. Marin D, Bazeos A, Mahon FX, 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; 28:2381.
  15. Druker BJ, Talpaz M, Resta DJ, et al. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med 2001; 344:1031.
  16. Braziel RM, Launder TM, Druker BJ, et al. Hematopathologic and cytogenetic findings in imatinib mesylate-treated chronic myelogenous leukemia patients: 14 months' experience. Blood 2002; 100:435.
  17. Hasserjian RP, Boecklin F, Parker S, et al. ST1571 (imatinib mesylate) reduces bone marrow cellularity and normalizes morphologic features irrespective of cytogenetic response. Am J Clin Pathol 2002; 117:360.
  18. Kantarjian H, Sawyers C, Hochhaus A, et al. Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia. N Engl J Med 2002; 346:645.
  19. Deininger MW, O'Brien SG, Ford JM, Druker BJ. Practical management of patients with chronic myeloid leukemia receiving imatinib. J Clin Oncol 2003; 21:1637.
  20. Rosti G, Martinelli G, Bassi S, et al. Molecular response to imatinib in late chronic-phase chronic myeloid leukemia. Blood 2004; 103:2284.
  21. Palandri F, Iacobucci I, Martinelli G, et al. Long-term outcome of complete cytogenetic responders after imatinib 400 mg in late chronic phase, philadelphia-positive chronic myeloid leukemia: the GIMEMA Working Party on CML. J Clin Oncol 2008; 26:106.
  22. Hochhaus A, Druker B, Sawyers C, et al. Favorable long-term follow-up results over 6 years for response, survival, and safety with imatinib mesylate therapy in chronic-phase chronic myeloid leukemia after failure of interferon-alpha treatment. Blood 2008; 111:1039.
  23. Hess G, Meyer RG, Schuch B, et al. Sustained remissions and low rate of BCR-ABL resistance mutations with imatinib treatment chronic myelogenous leukemia in patients treated in late chronic phase: a 5-year follow up. Am J Hematol 2008; 83:178.
  24. Kantarjian H, O'Brien S, Garcia-Manero G, et al. Very long-term follow-up results of imatinib mesylate therapy in chronic phase chronic myeloid leukemia after failure of interferon alpha therapy. Cancer 2012; 118:3116.
  25. Gugliotta G, Castagnetti F, Palandri F, et al. Frontline imatinib treatment of chronic myeloid leukemia: no impact of age on outcome, a survey by the GIMEMA CML Working Party. Blood 2011; 117:5591.
  26. O'Brien SG, Guilhot F, Larson RA, et al. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med 2003; 348:994.
  27. Kantarjian HM, Cortes JE, O'Brien S, et al. Imatinib mesylate therapy in newly diagnosed patients with Philadelphia chromosome-positive chronic myelogenous leukemia: high incidence of early complete and major cytogenetic responses. Blood 2003; 101:97.
  28. 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.
  29. Hahn EA, Glendenning GA, Sorensen MV, et al. Quality of life in patients with newly diagnosed chronic phase chronic myeloid leukemia on imatinib versus interferon alfa plus low-dose cytarabine: results from the IRIS Study. J Clin Oncol 2003; 21:2138.
  30. Druker BJ, Guilhot F, O'Brien SG, et al. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med 2006; 355:2408.
  31. Deininger M, O'Brien SG, Guilhot F, 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 (abstract 1126). Blood 2009; 114:126.
  32. Roy L, Guilhot J, Krahnke T, et al. Survival advantage from imatinib compared with the combination interferon-alpha plus cytarabine in chronic-phase chronic myelogenous leukemia: historical comparison between two phase 3 trials. Blood 2006; 108:1478.
  33. Kantarjian HM, Talpaz M, O'Brien S, et al. Survival benefit with imatinib mesylate versus interferon-alpha-based regimens in newly diagnosed chronic-phase chronic myelogenous leukemia. Blood 2006; 108:1835.
  34. de Lavallade H, Apperley JF, Khorashad JS, et al. Imatinib for newly diagnosed patients with chronic myeloid leukemia: incidence of sustained responses in an intention-to-treat analysis. J Clin Oncol 2008; 26:3358.
  35. Cortes J, Giles F, O'Brien S, et al. Result of high-dose imatinib mesylate in patients with Philadelphia chromosome-positive chronic myeloid leukemia after failure of interferon-alpha. Blood 2003; 102:83.
  36. Kantarjian H, Talpaz M, O'Brien S, et al. High-dose imatinib mesylate therapy in newly diagnosed Philadelphia chromosome-positive chronic phase chronic myeloid leukemia. Blood 2004; 103:2873.
  37. Hughes TP, Branford S, White DL, 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; 112:3965.
  38. Castagnetti F, Palandri F, Amabile M, 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 2009; 113:3428.
  39. Cortes JE, Kantarjian HM, Goldberg SL, et al. High-dose imatinib in newly diagnosed chronic-phase chronic myeloid leukemia: high rates of rapid cytogenetic and molecular responses. J Clin Oncol 2009; 27:4754.
  40. Cortes J, Quintás-Cardama A, Jones D, 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 alpha-2b and granulocyte-macrophage colony-stimulating factor. Cancer 2011; 117:572.
  41. Petzer AL, Wolf D, Fong D, et al. High-dose imatinib improves cytogenetic and molecular remissions in patients with pretreated Philadelphia-positive, BCR-ABL-positive chronic phase chronic myeloid leukemia: first results from the randomized CELSG phase III CML 11 "ISTAHIT" study. Haematologica 2010; 95:908.
  42. Baccarani M, Rosti G, Castagnetti F, 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 2009; 113:4497.
  43. Cortes JE, Baccarani M, Guilhot F, 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 2010; 28:424.
  44. Preudhomme C, Guilhot J, Nicolini FE, et al. Imatinib plus peginterferon alfa-2a in chronic myeloid leukemia. N Engl J Med 2010; 363:2511.
  45. Hehlmann R, Lauseker M, Jung-Munkwitz S, 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; 29:1634.
  46. Hehlmann R, Müller MC, Lauseker M, 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 2014; 32:415.
  47. Gardembas M, Rousselot P, Tulliez M, et al. Results of a prospective phase 2 study combining imatinib mesylate and cytarabine for the treatment of Philadelphia-positive patients with chronic myelogenous leukemia in chronic phase. Blood 2003; 102:4298.
  48. Deenik W, van der Holt B, Verhoef GE, et al. Dose-finding study of imatinib in combination with intravenous cytarabine: feasibility in newly diagnosed patients with chronic myeloid leukemia. Blood 2008; 111:2581.
  49. Deenik W, Janssen JJ, van der Holt B, et al. Efficacy of escalated imatinib combined with cytarabine in newly diagnosed patients with chronic myeloid leukemia. Haematologica 2010; 95:914.
  50. Simonsson B, Gedde-Dahl T, Markevärn B, et al. Combination of pegylated IFN-α2b with imatinib increases molecular response rates in patients with low- or intermediate-risk chronic myeloid leukemia. Blood 2011; 118:3228.
  51. Rosti G, Palandri F, Castagnetti F, et al. Nilotinib for the frontline treatment of Ph(+) chronic myeloid leukemia. Blood 2009; 114:4933.
  52. Cortes JE, Jones D, O'Brien S, et al. Nilotinib as front-line treatment for patients with chronic myeloid leukemia in early chronic phase. J Clin Oncol 2010; 28:392.
  53. Wang J, Shen ZX, Saglio G, et al. Phase 3 study of nilotinib vs imatinib in Chinese patients with newly diagnosed chronic myeloid leukemia in chronic phase: ENESTchina. Blood 2015; 125:2771.
  54. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm216181.htm. Accessed June 18, 2010.
  55. Kantarjian HM, Hochhaus A, Saglio G, et al. Nilotinib versus imatinib for the treatment of patients with newly diagnosed chronic phase, Philadelphia chromosome-positive, chronic myeloid leukaemia: 24-month minimum follow-up of the phase 3 randomised ENESTnd trial. Lancet Oncol 2011; 12:841.
  56. 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.
  57. Hochhaus A, Saglio G, Larson RA, et al. Nilotinib is associated with a reduced incidence of BCR-ABL mutations vs imatinib in patients with newly diagnosed chronic myeloid leukemia in chronic phase. Blood 2013; 121:3703.
  58. Larson RA, Hochhaus A, Saglio G, et al. Nilotinib vs imatinib in patients (pts) with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP): ENESTnd 4-year (y) update (abstract 7052). J Clin Oncol 2013.
  59. Hochhaus A, Saglio G, Hughes TP, 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; 30:1044.
  60. http://www.fda.gov/downloads/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/UCM217737.pdf (Accessed on August 20, 2010).
  61. Hazarika M, Jiang X, Liu Q, et al. Tasigna for chronic and accelerated phase Philadelphia chromosome--positive chronic myelogenous leukemia resistant to or intolerant of imatinib. Clin Cancer Res 2008; 14:5325.
  62. http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/021986s7s8lbl.pdf (Accessed on October 29, 2010).
  63. Kantarjian HM, Shah NP, Cortes JE, et al. Dasatinib or imatinib in newly diagnosed chronic-phase chronic myeloid leukemia: 2-year follow-up from a randomized phase 3 trial (DASISION). Blood 2012; 119:1123.
  64. Radich JP, Kopecky KJ, Appelbaum FR, et al. A randomized trial of dasatinib 100 mg versus imatinib 400 mg in newly diagnosed chronic-phase chronic myeloid leukemia. Blood 2012; 120:3898.
  65. Cortes JE, Jones D, O'Brien S, et al. Results of dasatinib therapy in patients with early chronic-phase chronic myeloid leukemia. J Clin Oncol 2010; 28:398.
  66. Cortes JE, Kim DW, Kantarjian HM, et al. Bosutinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia: results from the BELA trial. J Clin Oncol 2012; 30:3486.
  67. Brümmendorf TH, Cortes JE, de Souza CA, 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 2015; 168:69.
  68. Gratwohl A, Hermans J, Goldman JM, et al. Risk assessment for patients with chronic myeloid leukaemia before allogeneic blood or marrow transplantation. Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation. Lancet 1998; 352:1087.
  69. Saussele S, Lauseker M, Gratwohl A, et al. Allogeneic hematopoietic stem cell transplantation (allo SCT) for chronic myeloid leukemia in the imatinib era: evaluation of its impact within a subgroup of the randomized German CML Study IV. Blood 2010; 115:1880.
  70. Baccarani M, Deininger MW, Rosti G, et al. European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013. Blood 2013; 122:872.
  71. Michor F, Hughes TP, Iwasa Y, et al. Dynamics of chronic myeloid leukaemia. Nature 2005; 435:1267.
  72. Angstreich GR, Matsui W, Huff CA, et al. Effects of imatinib and interferon on primitive chronic myeloid leukaemia progenitors. Br J Haematol 2005; 130:373.
  73. Huff CA, Matsui W, Smith BD, Jones RJ. The paradox of response and survival in cancer therapeutics. Blood 2006; 107:431.
  74. Copland M, Hamilton A, Elrick LJ, et al. Dasatinib (BMS-354825) targets an earlier progenitor population than imatinib in primary CML but does not eliminate the quiescent fraction. Blood 2006; 107:4532.
  75. Graham SM, Jørgensen HG, Allan E, et al. Primitive, quiescent, Philadelphia-positive stem cells from patients with chronic myeloid leukemia are insensitive to STI571 in vitro. Blood 2002; 99:319.
  76. Bhatia R, Holtz M, Niu N, et al. Persistence of malignant hematopoietic progenitors in chronic myelogenous leukemia patients in complete cytogenetic remission following imatinib mesylate treatment. Blood 2003; 101:4701.
  77. Rousselot P, Huguet F, Rea D, et al. Imatinib mesylate discontinuation in patients with chronic myelogenous leukemia in complete molecular remission for more than 2 years. Blood 2007; 109:58.
  78. Rousselot P, Charbonnier A, Cony-Makhoul P, 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; 32:424.
  79. Mauro MJ, Druker BJ, Maziarz RT. Divergent clinical outcome in two CML patients who discontinued imatinib therapy after achieving a molecular remission. Leuk Res 2004; 28 Suppl 1:S71.
  80. Ghanima W, Kahrs J, Dahl TG 3rd, Tjonnfjord GE. Sustained cytogenetic response after discontinuation of imatinib mesylate in a patient with chronic myeloid leukaemia. Eur J Haematol 2004; 72:441.
  81. Higashi T, Tsukada J, Kato C, et al. Imatinib mesylate-sensitive blast crisis immediately after discontinuation of imatinib mesylate therapy in chronic myelogenous leukemia: report of two cases. Am J Hematol 2004; 76:275.
  82. Cortes J, O'Brien S, Kantarjian H. Discontinuation of imatinib therapy after achieving a molecular response. Blood 2004; 104:2204.
  83. Ali R, Ozkalemkaş F, Ozçelik T, et al. Pregnancy under treatment of imatinib and successful labor in a patient with chronic myelogenous leukemia (CML). Outcome of discontinuation of imatinib therapy after achieving a molecular remission. Leuk Res 2005; 29:971.
  84. Merante S, Orlandi E, Bernasconi P, et al. Outcome of four patients with chronic myeloid leukemia after imatinib mesylate discontinuation. Haematologica 2005; 90:979.
  85. Ault P, Kantarjian H, O'Brien S, et al. Pregnancy among patients with chronic myeloid leukemia treated with imatinib. J Clin Oncol 2006; 24:1204.
  86. Hess G, Bunjes D, Siegert W, et al. Sustained complete molecular remissions after treatment with imatinib-mesylate in patients with failure after allogeneic stem cell transplantation for chronic myelogenous leukemia: results of a prospective phase II open-label multicenter study. J Clin Oncol 2005; 23:7583.
  87. Mahon FX, Réa D, Guilhot J, 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; 11:1029.
  88. 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.
  89. Thielen N, van der Holt B, Cornelissen JJ, et al. Imatinib discontinuation in chronic phase myeloid leukaemia patients in sustained complete molecular response: a randomised trial of the Dutch-Belgian Cooperative Trial for Haemato-Oncology (HOVON). Eur J Cancer 2013; 49:3242.
  90. Russo D, Martinelli G, Malagola M, et al. Effects and outcome of a policy of intermittent imatinib treatment in elderly patients with chronic myeloid leukemia. Blood 2013; 121:5138.
  91. Mattison R, Larson RA. Discontinuing imatinib in chronic myeloid leukemia: don't try this at home. Leuk Lymphoma 2009; 50:868.
  92. Apperley JF. TWIST it but don't spin it. Blood 2013; 122:470.