Chronic Myeloid Leukemia, Version 1.2019, NCCN Clinical Practice Guidelines in Oncology

Restricted access

Chronic myeloid leukemia (CML) is defined by the presence of Philadelphia chromosome (Ph), resulting from a reciprocal translocation between chromosomes 9 and 22 [t(9;22] that gives rise to a BCR-ABL1 fusion gene. CML occurs in 3 different phases (chronic, accelerated, and blast phase) and is usually diagnosed in the chronic phase. Tyrosine kinase inhibitor (TKI) therapy is a highly effective first-line treatment option for all patients with newly diagnosed chronic phase CML (CP-CML). The selection TKI therapy should be based on the risk score, toxicity profile of TKI, patient's age, ability to tolerate therapy, and the presence of comorbid conditions. This manuscript discusses the recommendations outlined in the NCCN Guidelines for the diagnosis and management of patients with CP-CML.

  • 1.

    Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin 2018;68:730.

  • 2.

    Faderl S, Talpaz M, Estrov Z. The biology of chronic myeloid leukemia. N Engl J Med 1999;341:164172.

  • 3.

    Verma D, Kantarjian HM, Jones D. Chronic myeloid leukemia (CML) with P190 BCR-ABL: analysis of characteristics, outcomes, and prognostic significance. Blood 2009;114:22322235.

    • Search Google Scholar
    • Export Citation
  • 4.

    Sawyers CL. Chronic myeloid leukemia. N Engl J Med 1999;340:13301340.

  • 5.

    Radich JP, Dai H, Mao M. Gene expression changes associated with progression and response in chronic myeloid leukemia. Proc Natl Acad Sci U S A 2006;103:27942799.

    • Search Google Scholar
    • Export Citation
  • 6.

    Jamieson CHM, Ailles LE, Dylla SJ. Granulocyte-macrophage progenitors as candidate leukemic stem cells in blast-crisis CML. N Engl J Med 2004;351:657667.

    • Search Google Scholar
    • Export Citation
  • 7.

    Mitelman F. The cytogenetic scenario of chronic myeloid leukemia. Leuk Lymphoma 1993;11 Suppl 1:1115.

  • 8.

    Cortes JE, Talpaz M, Giles F. Prognostic significance of cytogenetic clonal evolution in patients with chronic myelogenous leukemia on imatinib mesylate therapy. Blood 2003;101:37943800.

    • Search Google Scholar
    • Export Citation
  • 9.

    O'Dwyer ME, Mauro MJ, Blasdel C. Clonal evolution and lack of cytogenetic response are adverse prognostic factors for hematologic relapse of chronic phase CML patients treated with imatinib mesylate. Blood 2004;103:451455.

    • Search Google Scholar
    • Export Citation
  • 10.

    Wang W, Cortes JE, Lin P. Clinical and prognostic significance of 3q26.2 and other chromosome 3 abnormalities in CML in the era of tyrosine kinase inhibitors. Blood 2015;126:16991706.

    • Search Google Scholar
    • Export Citation
  • 11.

    Wang W, Tang G, Cortes JE. Chromosomal rearrangement involving 11q23 locus in chronic myelogenous leukemia: a rare phenomenon frequently associated with disease progression and poor prognosis. J Hematol Oncol 2015;8:32.

    • Search Google Scholar
    • Export Citation
  • 12.

    Wang W, Cortes JE, Tang G. Risk stratification of chromosomal abnormalities in chronic myelogenous leukemia in the era of tyrosine kinase inhibitor therapy. Blood 2016;127:27422750.

    • Search Google Scholar
    • Export Citation
  • 13.

    Verma D, Kantarjian H, Shan J. Survival outcomes for clonal evolution in chronic myeloid leukemia patients on second generation tyrosine kinase inhibitor therapy. Cancer 2010;116:26732681.

    • Search Google Scholar
    • Export Citation
  • 14.

    Fabarius A, Kalmanti L, Dietz CT. Impact of unbalanced minor route versus major route karyotypes at diagnosis on prognosis of CML. Ann Hematol 2015;94:20152024.

    • Search Google Scholar
    • Export Citation
  • 15.

    Fabarius A, Leitner A, Hochhaus A. Impact of additional cytogenetic aberrations at diagnosis on prognosis of CML: long-term observation of 1151 patients from the randomized CML Study IV. Blood 2011;118:67606768.

    • Search Google Scholar
    • Export Citation
  • 16.

    Alhuraiji A, Kantarjian H, Boddu P. 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;93:8490.

    • Search Google Scholar
    • Export Citation
  • 17.

    Bumm T, Muller C, Al-Ali H-K. Emergence of clonal cytogenetic abnormalities in Ph-cells in some CML patients in cytogenetic remission to imatinib but restoration of polyclonal hematopoiesis in the majority. Blood 2003;101:19411949.

    • Search Google Scholar
    • Export Citation
  • 18.

    Feldman E, Najfeld V, Schuster M. The emergence of Ph-, trisomy -8+ cells in patients with chronic myeloid leukemia treated with imatinib mesylate. Exp Hematol 2003;31:702707.

    • Search Google Scholar
    • Export Citation
  • 19.

    Medina J, Kantarjian H, Talpaz M. Chromosomal abnormalities in Philadelphia chromosome-negative metaphases appearing during imatinib mesylate therapy in patients with Philadelphia chromosome-positive chronic myelogenous leukemia in chronic phase. Cancer 2003;98:19051911.

    • Search Google Scholar
    • Export Citation
  • 20.

    Terre C, Eclache V, Rousselot P. Report of 34 patients with clonal chromosomal abnormalities in Philadelphia-negative cells during imatinib treatment of Philadelphia-positive chronic myeloid leukemia. Leukemia 2004;18:13401346.

    • Search Google Scholar
    • Export Citation
  • 21.

    Deininger MW, Cortes J, Paquette R. The prognosis for patients with chronic myeloid leukemia who have clonal cytogenetic abnormalities in Philadelphia chromosome-negative cells. Cancer 2007;110:15091519.

    • Search Google Scholar
    • Export Citation
  • 22.

    Jabbour E, Kantarjian HM, Abruzzo LV. Chromosomal abnormalities in Philadelphia chromosome negative metaphases appearing during imatinib mesylate therapy in patients with newly diagnosed chronic myeloid leukemia in chronic phase. Blood 2007;110:29912995.

    • Search Google Scholar
    • Export Citation
  • 23.

    Issa GC, Kantarjian HM, Gonzalez GN. Clonal chromosomal abnormalities appearing in Philadelphia chromosome–negative metaphases during CML treatment. Blood 2017;130:2084.

    • Search Google Scholar
    • Export Citation
  • 24.

    Karimata K, Masuko M, Ushiki T. Myelodysplastic syndrome with Ph negative monosomy 7 chromosome following transient bone marrow dysplasia during imatinib treatment for chronic myeloid leukemia. Intern Med 2011;50:481485.

    • Search Google Scholar
    • Export Citation
  • 25.

    Navarro JT, Feliu E, Grau J. Monosomy 7 with severe myelodysplasia developing during imatinib treatment of Philadelphia-positive chronic myeloid leukemia: two cases with a different outcome. Am J Hematol 2007;82:849851.

    • Search Google Scholar
    • Export Citation
  • 26.

    Douet-Guilbert N, Morel F, Le Charpentier T. Interphase FISH for follow-up of Philadelphia chromosome-positive chronic myeloid leukemia treatment. Anticancer Res 2004;24:25352539.

    • Search Google Scholar
    • Export Citation
  • 27.

    Seong DC, Kantarjian HM, Ro JY. Hypermetaphase fluorescence in situ hybridization for quantitative monitoring of Philadelphia chromosome-positive cells in patients with chronic myelogenous leukemia during treatment. Blood 1995;86:23432349.

    • Search Google Scholar
    • Export Citation
  • 28.

    Dewald GW, Wyatt WA, Juneau AL. Highly sensitive fluorescence in situ hybridization method to detect double BCR/ABL fusion and monitor response to therapy in chronic myeloid leukemia. Blood 1998;91:33573365.

    • Search Google Scholar
    • Export Citation
  • 29.

    Kantarjian HM, Talpaz M, Cortes J. Quantitative polymerase chain reaction monitoring of BCR-ABL during therapy with imatinib mesylate (STI571; gleevec) in chronic-phase chronic myelogenous leukemia. Clin Cancer Res 2003;9:160166.

    • Search Google Scholar
    • Export Citation
  • 30.

    Hughes T, Deininger M, Hochhaus A. 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;108:2837.

    • Search Google Scholar
    • Export Citation
  • 31.

    Biernaux C, Loos M, Sels A. Detection of major bcr-abl gene expression at a very low level in blood cells of some healthy individuals. Blood 1995;86:31183122.

    • Search Google Scholar
    • Export Citation
  • 32.

    Bose S, Deininger M, Gora-Tybor J. The presence of typical and atypical BCR-ABL fusion genes in leukocytes of normal individuals: biologic significance and implications for the assessment of minimal residual disease. Blood 1998;92:33623367.

    • Search Google Scholar
    • Export Citation
  • 33.

    Sokal J, Cox E, Baccarani M. Prognostic discrimination in “good-risk” chronic granulocytic leukemia. Blood 1984;63:789799.

  • 34.

    Hasford J, Pfirrmann M, Hehlmann R. 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;90:850858.

    • Search Google Scholar
    • Export Citation
  • 35.

    Hasford J, Baccarani M, Hoffmann V. Predicting complete cytogenetic response and subsequent progression-free survival in 2060 patients with CML on imatinib treatment: the EUTOS score. Blood 2011;118:686692.

    • Search Google Scholar
    • Export Citation
  • 36.

    Marin D, Ibrahim AR, Goldman JM. European Treatment and Outcome Study (EUTOS) score for chronic myeloid leukemia still requires more confirmation. J Clin Oncol 2011;29:39443945.

    • Search Google Scholar
    • Export Citation
  • 37.

    Jabbour E, Cortes J, Nazha A. EUTOS score is not predictive for survival and outcome in patients with early chronic phase chronic myeloid leukemia treated with tyrosine kinase inhibitors: a single institution experience. Blood 2012;119:45244526.

    • Search Google Scholar
    • Export Citation
  • 38.

    Yamamoto E, Fujisawa S, Hagihara M. European Treatment and Outcome Study score does not predict imatinib treatment response and outcome in chronic myeloid leukemia patients. Cancer Sci 2014;105:105109.

    • Search Google Scholar
    • Export Citation
  • 39.

    Hochhaus A, Larson RA, Guilhot F. Long-term outcomes of imatinib treatment for chronic myeloid leukemia. N Engl J Med 2017;376:917927.

  • 40.

    Cortes JE, Saglio G, Kantarjian HM. Final 5-year study results of DASISION: the dasatinib versus imatinib study in treatment-naive chronic myeloid leukemia patients trial. J Clin Oncol 2016;34:23332340.

    • Search Google Scholar
    • Export Citation
  • 41.

    Hochhaus A, Saglio G, Hughes TP. 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;30:10441054.

    • Search Google Scholar
    • Export Citation
  • 42.

    Cortes JE, Gambacorti-Passerini C, Deininger MW. Bosutinib versus imatinib for newly diagnosed chronic myeloid leukemia: results from the randomized BFORE trial. J Clin Oncol 2018;36:231237.

    • Search Google Scholar
    • Export Citation
  • 43.

    Baccarani M, Druker BJ, Branford S. 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;99:616624.

    • Search Google Scholar
    • Export Citation
  • 44.

    Deininger MW, Kopecky KJ, Radich JP. Imatinib 800 mg daily induces deeper molecular responses than imatinib 400 mg daily: results of SWOG S0325, an intergroup randomized PHASE II trial in newly diagnosed chronic phase chronic myeloid leukaemia. Br J Haematol 2014;164:223232.

    • Search Google Scholar
    • Export Citation
  • 45.

    Hehlmann R, Lauseker M, Saussele S. 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;31:23982406.

    • Search Google Scholar
    • Export Citation
  • 46.

    Preudhomme C, Guilhot J, Nicolini FE. Imatinib plus peginterferon alfa-2a in chronic myeloid leukemia. N Engl J Med 2010;363:25112521.

  • 47.

    Efficace F, Baccarani M, Breccia M. Chronic fatigue is the most important factor limiting health-related quality of life of chronic myeloid leukemia patients treated with imatinib. Leukemia 2013;27:15111519.

    • Search Google Scholar
    • Export Citation
  • 48.

    Berman E, Nicolaides M, Maki RG. Altered bone and mineral metabolism in patients receiving imatinib mesylate. N Engl J Med 2006;354:20062013.

    • Search Google Scholar
    • Export Citation
  • 49.

    Berman E, Girotra M, Cheng C. Effect of long term imatinib on bone in adults with chronic myelogenous leukemia and gastrointestinal stromal tumors. Leuk Res 2013;37:790794.

    • Search Google Scholar
    • Export Citation
  • 50.

    Tsao AS, Kantarjian H, Cortes J. Imatinib mesylate causes hypopigmentation in the skin. Cancer 2003;98:24832487.

  • 51.

    Aleem A. Hypopigmentation of the skin due to imatinib mesylate in patients with chronic myeloid leukemia. Hematol Oncol Stem Cell Ther 2009;2:358361.

    • Search Google Scholar
    • Export Citation
  • 52.

    Quintas-Cardama A, Han X, Kantarjian H, Cortes J. Tyrosine kinase inhibitor-induced platelet dysfunction in patients with chronic myeloid leukemia. Blood 2009;114:261263.

    • Search Google Scholar
    • Export Citation
  • 53.

    Porkka K, Khoury HJ, Paquette RL. Dasatinib 100 mg once daily minimizes the occurrence of pleural effusion in patients with chronic myeloid leukemia in chronic phase and efficacy is unaffected in patients who develop pleural effusion. Cancer 2010;116:377386.

    • Search Google Scholar
    • Export Citation
  • 54.

    Montani D, Bergot E, Gunther S. Pulmonary arterial hypertension in patients treated by dasatinib. Circulation 2012;125:21282137.

  • 55.

    Orlandi EM, Rocca B, Pazzano AS, Ghio S. Reversible pulmonary arterial hypertension likely related to long-term, low-dose dasatinib treatment for chronic myeloid leukaemia. Leuk Res 2012;36:e46.

    • Search Google Scholar
    • Export Citation
  • 56.

    Serpa M, Sanabani SS, Bendit I. Efficacy and tolerability after unusually low doses of dasatinib in chronic myeloid leukemia patients intolerant to standard-dose dasatinib therapy. Clin Med Insights Oncol 2010;4:155162.

    • Search Google Scholar
    • Export Citation
  • 57.

    Naqvi K, Jabbour E, Skinner J. Early results of lower dose dasatinib (50 mg daily) as frontline therapy for newly diagnosed chronic-phase chronic myeloid leukemia. Cancer 2018;124:27402747.

    • Search Google Scholar
    • Export Citation
  • 58.

    Bergeron A, Rea D, Levy V. Lung abnormalities after dasatinib treatment for chronic myeloid leukemia: a case series. Am J Respir Crit Care Med 2007;176:814818.

    • Search Google Scholar
    • Export Citation
  • 59.

    Aichberger KJ, Herndlhofer S, Schernthaner G-H. Progressive peripheral arterial occlusive disease and other vascular events during nilotinib therapy in CML. Am J Hematol 2011;86:533539.

    • Search Google Scholar
    • Export Citation
  • 60.

    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 2011;86:610611.

    • Search Google Scholar
    • Export Citation
  • 61.

    Giles FJ, Mauro MJ, Hong F. 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 2013;27:13101315.

    • Search Google Scholar
    • Export Citation
  • 62.

    Quintas-Cardama A, Kantarjian H, O'Brien S. Granulocyte-colony-stimulating factor (filgrastim) may overcome imatinib-induced neutropenia in patients with chronic-phase chronic myelogenous leukemia. Cancer 2004;100:25922597.

    • Search Google Scholar
    • Export Citation
  • 63.

    Quintas-Cardama A, De Souza Santos FP, Kantarjian H. Dynamics and management of cytopenias associated with dasatinib therapy in patients with chronic myeloid leukemia in chronic phase after imatinib failure. Cancer 2009;115:39353943.

    • Search Google Scholar
    • Export Citation
  • 64.

    Santos FP, Alvarado Y, Kantarjian H. Long-term prognostic impact of the use of erythropoietic-stimulating agents in patients with chronic myeloid leukemia in chronic phase treated with imatinib. Cancer 2011;117:982991.

    • Search Google Scholar
    • Export Citation
  • 65.

    Landstrom AP, Ketterling RP, Knudson RA, Tefferi A. Utility of peripheral blood dual color, double fusion fluorescent in situ hybridization for BCR/ABL fusion to assess cytogenetic remission status in chronic myeloid leukemia. Leuk Lymphoma 2006;47:20552061.

    • Search Google Scholar
    • Export Citation
  • 66.

    Muhlmann J, Thaler J, Hilbe W. Fluorescence in situ hybridization (FISH) on peripheral blood smears for monitoring Philadelphia chromosome-positive chronic myeloid leukemia (CML) during interferon treatment: a new strategy for remission assessment. Genes Chromosomes Cancer 1998;21:90100.

    • Search Google Scholar
    • Export Citation
  • 67.

    Testoni N, Marzocchi G, Luatti S. 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;114:49394943.

    • Search Google Scholar
    • Export Citation
  • 68.

    Lima L, Bernal-Mizrachi L, Saxe D. Peripheral blood monitoring of chronic myeloid leukemia during treatment with imatinib, second-line agents, and beyond. Cancer 2011;117:12451252.

    • Search Google Scholar
    • Export Citation
  • 69.

    Hughes T, Hochhaus A, Branford S. 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;116:37583765.

    • Search Google Scholar
    • Export Citation
  • 70.

    Akard LP, Cortes JE, Albitar M. Correlations between cytogenetic and molecular monitoring among patients with newly diagnosed chronic myeloid leukemia in chronic phase: post hoc analyses of the rationale and insight for Gleevec high-dose therapy study. Arch Pathol Lab Med 2014;138:11861192.

    • Search Google Scholar
    • Export Citation
  • 71.

    Branford S, Cross NCP, Hochhaus A. Rationale for the recommendations for harmonizing current methodology for detecting BCR-ABL transcripts in patients with chronic myeloid leukaemia. Leukemia 2006;20:19251930.

    • Search Google Scholar
    • Export Citation
  • 72.

    Cross NC. Standardisation of molecular monitoring for chronic myeloid leukaemia. Best Pract Res Clin Haematol 2009;22:355365.

  • 73.

    Branford S, Fletcher L, Cross NC. Desirable performance characteristics for BCR-ABL measurement on an international reporting scale to allow consistent interpretation of individual patient response and comparison of response rates between clinical trials. Blood 2008;112:33303338.

    • Search Google Scholar
    • Export Citation
  • 74.

    Guerin A, Chen L, Dea K. Association between regular molecular monitoring and tyrosine kinase inhibitor therapy adherence in chronic myelogenous leukemia in the chronic phase. Curr Med Res Opin 2014;30:13451352.

    • Search Google Scholar
    • Export Citation
  • 75.

    Hanfstein B, Muller MC, Hehlmann R. Early molecular and cytogenetic response is predictive for long-term progression-free and overall survival in chronic myeloid leukemia (CML). Leukemia 2012;26:20962102.

    • Search Google Scholar
    • Export Citation
  • 76.

    Marin D, Ibrahim AR, Lucas C. 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;30:232238.

    • Search Google Scholar
    • Export Citation
  • 77.

    Neelakantan P, Gerrard G, Lucas C. Combining BCR-ABL1 transcript levels at 3 and 6 months in chronic myeloid leukemia: implications for early intervention strategies. Blood 2013;121:27392742.

    • Search Google Scholar
    • Export Citation
  • 78.

    Nazha A, Kantarjian H, Jain P. Assessment at 6 months may be warranted for patients with chronic myeloid leukemia with no major cytogenetic response at 3 months. Haematologica 2013;98:16861688.

    • Search Google Scholar
    • Export Citation
  • 79.

    Branford S, Yeung DT, Parker WT. Prognosis for patients with CML and >10% BCR-ABL1 after 3 months of imatinib depends on the rate of BCR-ABL1 decline. Blood 2014;124:511518.

    • Search Google Scholar
    • Export Citation
  • 80.

    Branford S, Yeung DT, Ross DM. 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 [abstract]. Blood 2014;124:Abstract 816.

    • Search Google Scholar
    • Export Citation
  • 81.

    Hanfstein B, Shlyakhto V, Lauseker M. Velocity of early BCR-ABL transcript elimination as an optimized predictor of outcome in chronic myeloid leukemia (CML) patients in chronic phase on treatment with imatinib. Leukemia 2014;28:19881992.

    • Search Google Scholar
    • Export Citation
  • 82.

    Iriyama N, Fujisawa S, Yoshida C. Shorter halving time of BCR-ABL1 transcripts is a novel predictor for achievement of molecular responses in newly diagnosed chronic-phase chronic myeloid leukemia treated with dasatinib: results of the D-first study of Kanto CML study group. Am J Hematol 2015;90:282287.

    • Search Google Scholar
    • Export Citation
  • 83.

    Hochhaus A, O'Brien SG, Guilhot F. Six-year follow-up of patients receiving imatinib for the first-line treatment of chronic myeloid leukemia. Leukemia 2009;23:10541061.

    • Search Google Scholar
    • Export Citation
  • 84.

    Jabbour E, Kantarjian H, O'Brien S. 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;118:45414546.

    • Search Google Scholar
    • Export Citation
  • 85.

    Druker BJ, Guilhot F, O'Brien SG. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med 2006;355:24082417.

    • Search Google Scholar
    • Export Citation
  • 86.

    Press RD, Galderisi C, Yang R. 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;13:61366143.

    • Search Google Scholar
    • Export Citation
  • 87.

    de Lavallade H, Apperley JF, Khorashad JS. Imatinib for newly diagnosed patients with chronic myeloid leukemia: incidence of sustained responses in an intention-to-treat analysis. J Clin Oncol 2008;26:33583363.

    • Search Google Scholar
    • Export Citation
  • 88.

    Marin D, Milojkovic D, Olavarria E. European LeukemiaNet criteria for failure or suboptimal response reliably identify patients with CML in early chronic phase treated with imatinib whose eventual outcome is poor. Blood 2008;112:44374444.

    • Search Google Scholar
    • Export Citation
  • 89.

    Hehlmann R, Lauseker M, Jung-Munkwitz S. 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;29:16341642.

    • Search Google Scholar
    • Export Citation
  • 90.

    Jabbour E, Kantarjian HM, O'Brien S. Front-line therapy with second-generation tyrosine kinase inhibitors in patients with early chronic phase chronic myeloid leukemia: what is the optimal response? J Clin Oncol 2011;29:42604265.

    • Search Google Scholar
    • Export Citation
  • 91.

    Jabbour E, Kantarjian HM, Saglio G. Early response with dasatinib or imatinib in chronic myeloid leukemia: 3-year follow-up from a randomized phase 3 trial (DASISION). Blood 2014;123:494500.

    • Search Google Scholar
    • Export Citation
  • 92.

    Clark RE, Polydoros F, Apperley JF. De-escalation of tyrosine kinase inhibitor dose in patients with chronic myeloid leukaemia with stable major molecular response (DESTINY): an interim analysis of a non-randomised, phase 2 trial. Lancet Haematol 2017;4:e310e316.

    • Search Google Scholar
    • Export Citation
  • 93.

    Shah NP, Rousselot P, Schiffer C. Dasatinib in imatinib-resistant or -intolerant chronic-phase, chronic myeloid leukemia patients: 7-year follow-up of study CA180-034. Am J Hematol 2016;91:869874.

    • Search Google Scholar
    • Export Citation
  • 94.

    Giles FJ, le Coutre PD, Pinilla-Ibarz J. 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 2013;27:107112.

    • Search Google Scholar
    • Export Citation
  • 95.

    Cortes JE, Khoury HJ, Kantarjian HM. Long-term bosutinib for chronic phase chronic myeloid leukemia after failure of imatinib plus dasatinib and/or nilotinib. Am J Hematol 2016;91:12061214.

    • Search Google Scholar
    • Export Citation
  • 96.

    Cortes JE, Kim DW, Pinilla-Ibarz J. Ponatinib efficacy and safety in Philadelphia chromosome-positive leukemia: final 5-year results of the phase 2 PACE trial. Blood 2018.

    • Search Google Scholar
    • Export Citation
  • 97.

    Kantarjian HM, Talpaz M, O'Brien S. Dose escalation of imatinib mesylate can overcome resistance to standard-dose therapy in patients with chronic myelogenous leukemia. Blood 2003;101:473475.

    • Search Google Scholar
    • Export Citation
  • 98.

    Marin D, Goldman JM, Olavarria E, Apperley JF. Transient benefit only from increasing the imatinib dose in CML patients who do not achieve complete cytogenetic remissions on conventional doses. Blood 2003;102:27022704.

    • Search Google Scholar
    • Export Citation
  • 99.

    Jabbour E, Kantarjian HM, Jones D. Imatinib mesylate dose escalation is associated with durable responses in patients with chronic myeloid leukemia after cytogenetic failure on standard-dose imatinib therapy. Blood 2009;113:21542160.

    • Search Google Scholar
    • Export Citation
  • 100.

    Kantarjian HM, Larson RA, Guilhot F. Efficacy of imatinib dose escalation in patients with chronic myeloid leukemia in chronic phase. Cancer 2009;115:551560.

    • Search Google Scholar
    • Export Citation
  • 101.

    Yeung DT, Osborn MP, White DL. TIDEL-II: first-line use of imatinib in CML with early switch to nilotinib for failure to achieve time-dependent molecular targets. Blood 2015;125:915923.

    • Search Google Scholar
    • Export Citation
  • 102.

    Cortes JE, De Souza CA, Ayala M. Switching to nilotinib versus imatinib dose escalation in patients with chronic myeloid leukaemia in chronic phase with suboptimal response to imatinib (LASOR): a randomised, open-label trial. Lancet Haematol 2016;3:e581e591.

    • Search Google Scholar
    • Export Citation
  • 103.

    Cervantes F, López-Garrido P, Montero MI. Early intervention during imatinib therapy in patients with newly diagnosed chronic-phase chronic myeloid leukemia: a study of the Spanish PETHEMA group. Haematologica 2010;95:13171324.

    • Search Google Scholar
    • Export Citation
  • 104.

    Kantarjian H, Cortes J. Considerations in the management of patients with Philadelphia chromosome-positive chronic myeloid leukemia receiving tyrosine kinase inhibitor therapy. J Clin Oncol 2011;29:15121516.

    • Search Google Scholar
    • Export Citation
  • 105.

    Dorer DJ, Knickerbocker RK, Baccarani M. Impact of dose intensity of ponatinib on selected adverse events: Multivariate analyses from a pooled population of clinical trial patients. Leuk Res 2016;48:8491.

    • Search Google Scholar
    • Export Citation
  • 106.

    Cortes J, Lipton JH, Rea D. Phase 2 study of subcutaneous omacetaxine mepesuccinate after TKI failure in patients with chronic-phase CML with T315I mutation. Blood 2012;120:25732580.

    • Search Google Scholar
    • Export Citation
  • 107.

    Cortes J, Digumarti R, Parikh PM. Phase 2 study of subcutaneous omacetaxine mepesuccinate for chronic-phase chronic myeloid leukemia patients resistant to or intolerant of tyrosine kinase inhibitors. Am J Hematol 2013;88:350354.

    • Search Google Scholar
    • Export Citation
  • 108.

    Cortes JE, Nicolini FE, Wetzler M. Subcutaneous omacetaxine mepesuccinate in patients with chronic-phase chronic myeloid leukemia previously treated with 2 or more tyrosine kinase inhibitors including imatinib. Clin Lymphoma Myeloma Leuk 2013;13:584591.

    • Search Google Scholar
    • Export Citation
  • 109.

    Haouala A, Widmer N, Duchosal MA. Drug interactions with the tyrosine kinase inhibitors imatinib, dasatinib, and nilotinib. Blood 2011;117:e7587.

    • Search Google Scholar
    • Export Citation
  • 110.

    Noens L, van Lierde M-A, De Bock R. Prevalence, determinants, and outcomes of nonadherence to imatinib therapy in patients with chronic myeloid leukemia: the ADAGIO study. Blood 2009;113:54015411.

    • Search Google Scholar
    • Export Citation
  • 111.

    Marin D, Bazeos A, Mahon F-X. 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;28:23812388.

    • Search Google Scholar
    • Export Citation
  • 112.

    Ibrahim AR, Eliasson L, Apperley JF. Poor adherence is the main reason for loss of CCyR and imatinib failure for chronic myeloid leukemia patients on long-term therapy. Blood 2011;117:37333736.

    • Search Google Scholar
    • Export Citation
  • 113.

    Wu EQ, Guerin A, Yu AP. Retrospective real-world comparison of medical visits, costs, and adherence between nilotinib and dasatinib in chronic myeloid leukemia. Curr Med Res Opin 2010;26:28612869.

    • Search Google Scholar
    • Export Citation
  • 114.

    Yood MU, Oliveria SA, Cziraky M. Adherence to treatment with second-line therapies, dasatinib and nilotinib, in patients with chronic myeloid leukemia. Curr Med Res Opin 2012;28:213219.

    • Search Google Scholar
    • Export Citation
  • 115.

    Quintas-Cardama A, Cortes JE, Kantarjian H. Practical management of toxicities associated with tyrosine kinase inhibitors in chronic myeloid leukemia. Clin Lymphoma Myeloma 2008;8 Suppl 3:S8288.

    • Search Google Scholar
    • Export Citation
  • 116.

    Cornelison M, Jabbour EJ, Welch MA. Managing side effects of tyrosine kinase inhibitor therapy to optimize adherence in patients with chronic myeloid leukemia: the role of the midlevel practitioner. J Support Oncol 2012;10:1424.

    • Search Google Scholar
    • Export Citation
  • 117.

    Cortes JE, Lipton JH, Miller CB. Evaluating the impact of a switch to nilotinib on imatinib-related chronic low-grade adverse events in patients with CML-CP: the ENRICH study. Clin Lymphoma Myeloma Leuk 2016;16:286296.

    • Search Google Scholar
    • Export Citation
  • 118.

    Thomas J, Wang L, Clark RE, Pirmohamed M. Active transport of imatinib into and out of cells: implications for drug resistance. Blood 2004;104:37393745.

    • Search Google Scholar
    • Export Citation
  • 119.

    Mahon FX, Hayette S, Lagarde V. Evidence that resistance to nilotinib may be due to BCR-ABL, Pgp, or Src kinase overexpression. Cancer Res 2008;68:98099816.

    • Search Google Scholar
    • Export Citation
  • 120.

    Hegedus C, Ozvegy-Laczka C, Apati A. Interaction of nilotinib, dasatinib and bosutinib with ABCB1 and ABCG2: implications for altered anti-cancer effects and pharmacological properties. Br J Pharmacol 2009;158:11531164.

    • Search Google Scholar
    • Export Citation
  • 121.

    Picard S, Titier K, Etienne G. Trough imatinib plasma levels are associated with both cytogenetic and molecular responses to standard-dose imatinib in chronic myeloid leukemia. Blood 2007;109:34963499.

    • Search Google Scholar
    • Export Citation
  • 122.

    Larson RA, Druker BJ, Guilhot F. Imatinib pharmacokinetics and its correlation with response and safety in chronic-phase chronic myeloid leukemia: a subanalysis of the IRIS study. Blood 2008;111:40224028.

    • Search Google Scholar
    • Export Citation
  • 123.

    Bouchet S, Titier K, Moore N. Therapeutic drug monitoring of imatinib in chronic myeloid leukemia: experience from 1216 patients at a centralized laboratory. Fundam Clin Pharmacol 2013;27:690697.

    • Search Google Scholar
    • Export Citation
  • 124.

    White DL, Radich J, Soverini S. Chronic phase chronic myeloid leukemia patients with low OCT-1 activity randomised to high-dose imatinib achieve better responses, and lower failure rates, than those randomized to standard-dose. Haematologica 2012;97:907914.

    • Search Google Scholar
    • Export Citation
  • 125.

    Giannoudis A, Davies A, Lucas CM. Effective dasatinib uptake may occur without human organic cation transporter 1 (hOCT1): implications for the treatment of imatinib-resistant chronic myeloid leukemia. Blood 2008;112:33483354.

    • Search Google Scholar
    • Export Citation
  • 126.

    Hiwase DK, Saunders V, Hewett D. Dasatinib cellular uptake and efflux in chronic myeloid leukemia cells: therapeutic implications. Clin Cancer Res 2008;14:38813888.

    • Search Google Scholar
    • Export Citation
  • 127.

    Davies A, Jordanides NE, Giannoudis A. Nilotinib concentration in cell lines and primary CD34(+) chronic myeloid leukemia cells is not mediated by active uptake or efflux by major drug transporters. Leukemia 2009;23:19992006.

    • Search Google Scholar
    • Export Citation
  • 128.

    White DL, Saunders VA, Dang P. 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 2006;108:697704.

    • Search Google Scholar
    • Export Citation
  • 129.

    Branford S, Rudzki Z, Walsh S. 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;102:276283.

    • Search Google Scholar
    • Export Citation
  • 130.

    Soverini S, Martinelli G, Rosti G. 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;23:41004109.

    • Search Google Scholar
    • Export Citation
  • 131.

    Nicolini FE, Corm S, Le QH. Mutation status and clinical outcome of 89 imatinib mesylate-resistant chronic myelogenous leukemia patients: a retrospective analysis from the French intergroup of CML (Fi(phi)-LMC GROUP). Leukemia 2006;20:10611106.

    • Search Google Scholar
    • Export Citation
  • 132.

    Soverini S, Colarossi S, Gnani A. Contribution of ABL kinase domain mutations to imatinib resistance in different subsets of Philadelphia-positive patients: by the GIMEMA Working Party on Chronic Myeloid Leukemia. Clin Cancer Res 2006;12:73747379.

    • Search Google Scholar
    • Export Citation
  • 133.

    Khorashad JS, de Lavallade H, Apperley JF. 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;26:48064813.

    • Search Google Scholar
    • Export Citation
  • 134.

    Soverini S, Gnani A, Colarossi S. Philadelphia-positive patients who already harbor imatinib-resistant Bcr-Abl kinase domain mutations have a higher likelihood of developing additional mutations associated with resistance to second- or third-line tyrosine kinase inhibitors. Blood 2009;114:21682171.

    • Search Google Scholar
    • Export Citation
  • 135.

    Nicolini FE, Hayette S, Corm S. Clinical outcome of 27 imatinib mesylate-resistant chronic myelogenous leukemia patients harboring a T315I BCR-ABL mutation. Haematologica 2007;92:12381241.

    • Search Google Scholar
    • Export Citation
  • 136.

    Jabbour E, Kantarjian H, Jones D. Characteristics and outcomes of patients with chronic myeloid leukemia and T315I mutation following failure of imatinib mesylate therapy. Blood 2008;112:5355.

    • Search Google Scholar
    • Export Citation
  • 137.

    Soverini S, Colarossi S, Gnani A. Resistance to dasatinib in Philadelphia-positive leukemia patients and the presence or the selection of mutations at residues 315 and 317 in the BCR-ABL kinase domain. Haematologica 2007;92:401404.

    • Search Google Scholar
    • Export Citation
  • 138.

    Jabbour E, Kantarjian HM, Jones D. Characteristics and outcome of chronic myeloid leukemia patients with F317L BCR-ABL kinase domain mutation after therapy with tyrosine kinase inhibitors. Blood 2008;112:48394842.

    • Search Google Scholar
    • Export Citation
  • 139.

    Muller MC, Cortes JE, Kim D-W. Dasatinib treatment of chronic-phase chronic myeloid leukemia: analysis of responses according to preexisting BCR-ABL mutations. Blood 2009;114:49444953.

    • Search Google Scholar
    • Export Citation
  • 140.

    Hughes T, Saglio G, Branford S. Impact of baseline BCR-ABL mutations on response to nilotinib in patients with chronic myeloid leukemia in chronic phase. J Clin Oncol 2009;27:42044210.

    • Search Google Scholar
    • Export Citation
  • 141.

    Deininger MW, Hodgson JG, Shah NP. Compound mutations in BCR-ABL1 are not major drivers of primary or secondary resistance to ponatinib in CP-CML patients. Blood 2016;127:703712.

    • Search Google Scholar
    • Export Citation
  • 142.

    Soverini S, Branford S, Nicolini FE. Implications of BCR-ABL1 kinase domain-mediated resistance in chronic myeloid leukemia. Leuk Res 2014;38:1020.

    • Search Google Scholar
    • Export Citation
  • 143.

    Garg RJ, Kantarjian H, O'Brien S. The use of nilotinib or dasatinib after failure to 2 prior tyrosine kinase inhibitors: long-term follow-up. Blood 2009;114:43614368.

    • Search Google Scholar
    • Export Citation
  • 144.

    Branford S, Rudzki Z, Parkinson I. Real-time quantitative PCR analysis can be used as a primary screen to identify patients with CML treated with imatinib who have BCR-ABL kinase domain mutations. Blood 2004;104:29262932.

    • Search Google Scholar
    • Export Citation
  • 145.

    Wang L, Knight K, Lucas C, Clark R. The role of serial BCR-ABL transcript monitoring in predicting the emergence of BCR-ABL kinase mutations in imatinib-treated patients with chronic myeloid leukemia. Haematologica 2006;91:235239.

    • Search Google Scholar
    • Export Citation
  • 146.

    Kantarjian HM, Shan J, Jones D. Significance of increasing levels of minimal residual disease in patients with Philadelphia chromosome-positive chronic myelogenous leukemia in complete cytogenetic response. J Clin Oncol 2009;27:36593663.

    • Search Google Scholar
    • Export Citation
  • 147.

    Marin D, Khorashad JS, Foroni L. Does a rise in the BCR-ABL1 transcript level identify chronic phase CML patients responding to imatinib who have a high risk of cytogenetic relapse? Br J Haematol 2009;145:373375.

    • Search Google Scholar
    • Export Citation
  • 148.

    Press RD, Willis SG, Laudadio J. Determining the rise in BCR-ABL RNA that optimally predicts a kinase domain mutation in patients with chronic myeloid leukemia on imatinib. Blood 2009;114:25982605.

    • Search Google Scholar
    • Export Citation
  • 149.

    Mahon FX, Rea D, Guilhot J. 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 2010:10291035.

    • Search Google Scholar
    • Export Citation
  • 150.

    Etienne G, Guilhot J, Rea D. Long-term follow-up of the french stop imatinib (STIM1) study in patients with chronic myeloid leukemia. J Clin Oncol 2017;35:298305.

    • Search Google Scholar
    • Export Citation
  • 151.

    Ross DM, Branford S, Seymour JF. Safety and efficacy of imatinib cessation for CML patients with stable undetectable minimal residual disease: results from the TWISTER study. Blood 2013;122:515522.

    • Search Google Scholar
    • Export Citation
  • 152.

    Thielen N, van der Holt B, Cornelissen JJ. 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;49:32423246.

    • Search Google Scholar
    • Export Citation
  • 153.

    Rousselot P, Charbonnier A, Cony-Makhoul P. 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;32:424430.

    • Search Google Scholar
    • Export Citation
  • 154.

    Mori S, Vagge E, le Coutre P. Age and dPCR can predict relapse in CML patients who discontinued imatinib: the ISAV study. Am J Hematol 2015;90:910914.

    • Search Google Scholar
    • Export Citation
  • 155.

    Lee SE, Choi SY, Song HY. 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;101:717723.

    • Search Google Scholar
    • Export Citation
  • 156.

    Saussele S, Richter J, Guilhot J. 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;19:747757.

    • Search Google Scholar
    • Export Citation
  • 157.

    Rea D, Nicolini FE, Tulliez M. Discontinuation of dasatinib or nilotinib in chronic myeloid leukemia: interim analysis of the STOP 2G-TKI study. Blood 2017;129:846854.

    • Search Google Scholar
    • Export Citation
  • 158.

    Ross DM, Masszi T, Gomez Casares MT. Durable treatment-free remission in patients with chronic myeloid leukemia in chronic phase following frontline nilotinib: 96-week update of the ENESTfreedom study. J Cancer Res Clin Oncol 2018;144:945954.

    • Search Google Scholar
    • Export Citation
  • 159.

    Mahon FX, Boquimpani C, Kim DW. Treatment-free remission after second-line nilotinib treatment in patients with chronic myeloid leukemia in chronic phase: results from a single-group, pPhase 2, open-label study. Ann Intern Med 2018;168:461470.

    • Search Google Scholar
    • Export Citation
  • 160.

    Okada M, Imagawa J, Tanaka H. Final 3-year results of the dasatinib discontinuation trial in patients with chronic myeloid leukemia who received dasatinib as a second-line treatment. Clin Lymphoma Myeloma Leuk 2018;18:353360 e351.

    • Search Google Scholar
    • Export Citation
  • 161.

    Legros L, Nicolini FE, Etienne G. Second tyrosine kinase inhibitor discontinuation attempt in patients with chronic myeloid leukemia. Cancer 2017;123:44034410.

    • Search Google Scholar
    • Export Citation
  • 162.

    Ilander M, Olsson-Stromberg U, Schlums H. Increased proportion of mature NK cells is associated with successful imatinib discontinuation in chronic myeloid leukemia. Leukemia 2017;31:11081116.

    • Search Google Scholar
    • Export Citation
All Time Past Year Past 30 Days
Abstract Views 1 0 0
Full Text Views 10702 6436 321
PDF Downloads 5155 2840 160
EPUB Downloads 0 0 0