The therapeutic landscape of chronic myeloid leukemia (CML) has profoundly changed over the past 7 years. Most patients with chronic phase (CP) now have a normal life expectancy. Another goal is achieving a stable deep molecular response (DMR) and discontinuing medication for treatment-free remission (TFR). The European LeukemiaNet convened an expert panel to critically evaluate and update the evidence to achieve these goals since its previous recommendations. First-line treatment is a tyrosine kinase inhibitor (TKI; imatinib brand or generic, dasatinib, nilotinib, and bosutinib are available first-line). Generic imatinib is the cost-effective initial treatment in CP. Various contraindications and side-effects of all TKIs should be considered. Patient risk status at diagnosis should be assessed with the new EUTOS long-term survival (ELTS)-score. Monitoring of response should be done by quantitative polymerase chain reaction whenever possible. A change of treatment is recommended when intolerance cannot be ameliorated or when molecular milestones are not reached. Greater than 10% BCR-ABL1 at 3 months indicates treatment failure when confirmed. Allogeneic transplantation continues to be a therapeutic option particularly for advanced phase CML. TKI treatment should be withheld during pregnancy. Treatment discontinuation may be considered in patients with durable DMR with the goal of achieving TFR.

3 Medizinische Klinik Medizinische Fakultät Mannheim Universität Heidelberg Mannheim Germany

Almazov National Research Centre St Petersburg Russian Federation

Amsterdam University Medical Center VUMC Amsterdam The Netherlands

Centre Hospitalier de Versailles University of Versailles Saint Quentin en Yvelines Versailles France

Centre Hospitalier Universitaire de Poitiers Poitiers France

Centre Léon Bérard Lyon France

Department Clinical Medicine and Surgery University Federico Secondo Naples Italy

Department of Hematology Oncology Policlinico S Orsola Malpighi University of Bologna Bologna Italy

Department of Internal Medicine Masaryk University Hospital Brno Czech Republic

Department of Molecular and Clinical Cancer Medicine University of Liverpool Liverpool UK

ELN Foundation Weinheim Germany

Fred Hutchinson Cancer Center Seattle WA USA

Georgia Cancer Center Augusta University Augusta GA USA

Hammersmith Hospital Imperial College London UK

Hôpital St Louis Paris France

Hospital Clinic IDIBAPS Barcelona Spain

Hospital de la Princesa Madrid Spain

Huntsman Cancer Center Salt Lake City Salt Lake City UT USA

Institut Bergonie Université de Bordeaux Bordeaux France

Karmanos Cancer Center Detroit MI USA

Klinik für Innere Medizin 2 Universitätsklinikum Jena Germany

MD Anderson Cancer Center Houston TX USA

National Research Center for Hematology Moscow Russian Federation

Norwegian University of Science and Technology Trondheim Norway

South Australian Health and Medical Research Institute Adelaide SA Australia

St Mary´s Hematology Hospital The Catholic University Seoul Korea

Universitätsklinikum Leipzig Germany

University of Chicago Chicago IL USA

University of Lund Lund Sweden

University of Toronto Toronto Canada

University of Turin Turin Italy

Weill Cornell Medical College New York NY USA

Zobrazit více v PubMed

Thielen N, Visser O, Ossenkoppele G, Janssen J. Chronic myeloid leukemia in the Netherlands: a population-based study on incidence, treatment, and survival in 3585 patients from 1989 to 2012. Eur J Haematol. 2016;97:145–54. doi: 10.1111/ejh.12695. PubMed DOI

Bower H, Bjorkholm M, Dickman PW, Hoglund M, Lambert PC, Andersson TM. Life expectancy of patients with chronic myeloid leukemia approaches the life expectancy of the general population. J Clin Oncol. 2016;34:2851–7. doi: 10.1200/JCO.2015.66.2866. PubMed DOI

Sasaki K, Strom SS, O’Brien S, Jabbour E, Ravandi F, Konopleva M, et al. Relative survival in patients with chronic-phase chronic myeloid leukaemia in the tyrosine-kinase inhibitor era: analysis of patient data from six prospective clinical trials. Lancet Haematol. 2015;2:e186–193. doi: 10.1016/S2352-3026(15)00048-4. PubMed DOI PMC

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. doi: 10.1038/leu.2017.253. PubMed DOI PMC

Welch HG, Kramer BS, Black WC. Epidemiologic signatures in cancer. N Engl J Med. 2019;381:1378–86. doi: 10.1056/NEJMsr1905447. PubMed DOI

Baccarani M, Saglio G, Goldman J, Hochhaus A, Simonsson B, Appelbaum F, et al. Evolving concepts in the management of chronic myeloid leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet. Blood. 2006;108:1809–20. doi: 10.1182/blood-2006-02-005686. PubMed DOI

Baccarani M, Cortes J, Pane F, Niederwieser D, Saglio G, Apperley J, et al. Chronic myeloid leukemia: an update of concepts and management recommendations of European LeukemiaNet. J Clin Oncol. 2009;27:6041–51. doi: 10.1200/JCO.2009.25.0779. PubMed DOI PMC

Baccarani M, Deininger MW, Rosti G, Hochhaus A, Soverini S, Apperley JF, et al. European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013. Blood. 2013;122:872–84. doi: 10.1182/blood-2013-05-501569. PubMed DOI PMC

Malhotra H, Radich J, Garcia-Gonzalez P. Meeting the needs of CML patients in resource-poor countries. Hematol Am Soc Hematol Educ Program. 2019;433–42. PubMed PMC

Rosti G, Castagnetti F, Gugliotta G, Baccarani M. Tyrosine kinase inhibitors in chronic myeloid leukaemia: which, when, for whom? Nat Rev Clin Oncol. 2017;14:141–54. doi: 10.1038/nrclinonc.2016.139. PubMed DOI

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 Canc Netw 2018;16:1108–35. PubMed

Khoury HJ, Williams LA, Atallah E, Hehlmann R. Chronic myeloid leukemia: what every practitioner needs to know in 2017. Am Soc Clin Oncol Educ Book. 2017;37:468–79. doi: 10.14694/EDBK_175712. PubMed DOI

Buesche G, Hehlmann R, Hecker H, Heimpel H, Heinze B, Schmeil A, et al. Marrow fibrosis, indicator of therapy failure in chronic myeloid leukemia - prospective long-term results from a randomized-controlled trial. Leukemia. 2003;17:2444–53. doi: 10.1038/sj.leu.2403172. PubMed DOI

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;21:2420–7. doi: 10.1038/sj.leu.2404917. PubMed DOI

Hidalgo-Lopez JE, Kanagal-Shamanna R, Quesada AE, Gong Z, Wang W, Hu S, et al. Bone marrow core biopsy in 508 consecutive patients with chronic myeloid leukemia: assessment of potential value. Cancer. 2018;124:3849–55. doi: 10.1002/cncr.31663. PubMed DOI

Fabarius A, Kalmanti L, Dietz CT, Lauseker M, Rinaldetti S, Haferlach C, et al. Impact of unbalanced minor route versus major route karyotypes at diagnosis on prognosis of CML. Ann Hematol. 2015;94:2015–24. doi: 10.1007/s00277-015-2494-9. PubMed DOI

Wang W, Cortes JE, Tang G, Khoury JD, Wang S, Bueso-Ramos CE, et al. Risk stratification of chromosomal abnormalities in chronic myelogenous leukemia in the era of tyrosine kinase inhibitor therapy. Blood. 2016;127:2742–50. doi: 10.1182/blood-2016-01-690230. PubMed DOI PMC

Hehlmann R, Voskanyan A, Lauseker M, Pfirrmann M, Kalmanti L, Rinaldetti S, et al. High-risk additional chromosomal abnormalities in CML herald death by blast crisis already at low blast levels. Blood. 2019;134:666. doi: 10.1182/blood-2019-127127. DOI

Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, et al. WHO classification of tumours of haematopoietic and lymphoid tissues. 4th ed. Lyon: International Agency for Research on Cancer; 2017.

Hoffmann VS, Baccarani M, Hasford J, Lindoerfer D, Burgstaller S, Sertic D, et al. The EUTOS population-based registry: incidence and clinical characteristics of 2904 CML patients in 20 European Countries. Leukemia. 2015;29:1336–43. doi: 10.1038/leu.2015.73. PubMed DOI

Sokal JE, Cox EB, Baccarani M, Tura S, Gomez GA, Robertson JE, et al. Prognostic discrimination in “good-risk” chronic granulocytic leukemia. Blood. 1984;63:789–99. doi: 10.1182/blood.V63.4.789.789. PubMed DOI

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;90:850–8. doi: 10.1093/jnci/90.11.850. PubMed DOI

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;118:686–92. doi: 10.1182/blood-2010-12-319038. PubMed DOI

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;30:48–56. doi: 10.1038/leu.2015.261. PubMed DOI

Geelen IGP, Sandin F, Thielen N, Janssen J, Hoogendoorn M, Visser O, et al. Validation of the EUTOS long-term survival score in a recent independent cohort of “real world” CML patients. Leukemia. 2018;32:2299–303. doi: 10.1038/s41375-018-0136-7. PubMed DOI

Castagnetti F, Gugliotta G, Breccia M, Stagno F, Specchia G, Levato L, et al. The use of EUTOS long-term survival score instead of Sokal score is strongly advised in elderly chronic myeloid leukemia patients. Blood. 2018;132:44. doi: 10.1182/blood-2018-99-117409. DOI

Hughes T, Deininger M, Hochhaus A, Branford S, Radich J, Kaeda J, et al. Monitoring CML patients responding to treatment with tyrosine kinase inhibitors: review and recommendations for harmonizing current methodology for detecting BCR-ABL transcripts and kinase domain mutations and for expressing results. Blood. 2006;108:28–37. doi: 10.1182/blood-2006-01-0092. PubMed DOI PMC

Branford S, Fletcher L, Cross NC, Müller MC, Hochhaus A, Kim DW, et al. 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;112:3330–8. doi: 10.1182/blood-2008-04-150680. PubMed DOI

Cross NC, White HE, Müller MC, Saglio G, Hochhaus A. Standardized definitions of molecular response in chronic myeloid leukemia. Leukemia. 2012;26:2172–5. doi: 10.1038/leu.2012.104. PubMed DOI

Lauseker M, Hanfstein B, Haferlach C, Schnittger S, Pfirrmann M, Fabarius A, et al. Equivalence of BCR-ABL transcript levels with complete cytogenetic remission in patients with chronic myeloid leukemia in chronic phase. J Cancer Res Clin Oncol. 2014;140:1965–9. doi: 10.1007/s00432-014-1746-8. PubMed DOI PMC

Cross NC, White HE, Colomer D, Ehrencrona H, Foroni L, Gottardi E, et al. Laboratory recommendations for scoring deep molecular responses following treatment for chronic myeloid leukemia. Leukemia. 2015;29:999–1003. doi: 10.1038/leu.2015.29. PubMed DOI PMC

Cross NC. Standardisation of molecular monitoring for chronic myeloid leukaemia. Best Pr Res Clin Haematol. 2009;22:355–65. doi: 10.1016/j.beha.2009.04.001. PubMed DOI

Guilhot J, Preudhomme C, Mahon FX, Guilhot F. Analyzing molecular response in chronic myeloid leukemia clinical trials: pitfalls and golden rules. Cancer. 2015;121:490–7. doi: 10.1002/cncr.29053. PubMed DOI

O’Brien SG, Guilhot F, Larson RA, Gathmann I, Baccarani M, Cervantes F, et al. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2003;348:994–1004. doi: 10.1056/NEJMoa022457. PubMed DOI

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;376:917–27. doi: 10.1056/NEJMoa1609324. PubMed DOI PMC

Hehlmann R, Müller MC, Lauseker M, Hanfstein B, Fabarius A, Schreiber A, 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;32:415–23. doi: 10.1200/JCO.2013.49.9020. PubMed DOI

Kalmanti L, Saussele S, Lauseker M, Müller MC, Dietz CT, Heinrich L, et al. Safety and efficacy of imatinib in CML over a period of 10 years: data from the randomized CML-study IV. Leukemia. 2015;29:1123–32. doi: 10.1038/leu.2015.36. PubMed DOI

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;363:2511–21. doi: 10.1056/NEJMoa1004095. PubMed DOI

Castagnetti F, Gugliotta G, Breccia M, Stagno F, Iurlo A, Albano F, et al. Long-term outcome of chronic myeloid leukemia patients treated frontline with imatinib. Leukemia. 2015;29:1823–31. doi: 10.1038/leu.2015.152. PubMed DOI

Cortes JE, Saglio G, Kantarjian HM, Baccarani M, Mayer J, Boque C, et al. Final 5-year study results of DASISION: the dasatinib versus imatinib study in treatment-naive chronic myeloid leukemia patients trial. J Clin Oncol. 2016;34:2333–40. doi: 10.1200/JCO.2015.64.8899. PubMed DOI PMC

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;30:1044–54. doi: 10.1038/leu.2016.5. PubMed DOI PMC

Wang J, Shen ZX, Saglio G, Jin J, Huang H, Hu Y, et al. Phase 3 study of nilotinib vs imatinib in Chinese patients with newly diagnosed chronic myeloid leukemia in chronic phase: ENESTchina. Blood. 2015;125:2771–8. doi: 10.1182/blood-2014-09-601674. PubMed DOI PMC

Cortes JE, Gambacorti-Passerini C, Deininger MW, Mauro MJ, Chuah C, Kim DW, et al. Bosutinib versus imatinib for newly diagnosed chronic myeloid leukemia: results from the randomized BFORE trial. J Clin Oncol. 2018;36:231–7. doi: 10.1200/JCO.2017.74.7162. PubMed DOI PMC

Cortes JE, Kim DW, Kantarjian HM, Brümmendorf TH, Dyagil I, Griskevicius L, et al. Bosutinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia: results from the BELA trial. J Clin Oncol. 2012;30:3486–92. doi: 10.1200/JCO.2011.38.7522. PubMed DOI PMC

Kwak JY, Kim SH, Oh SJ, Zang DY, Kim H, Kim JA, et al. Phase III Clinical Trial (RERISE study) Results of Efficacy and Safety of Radotinib Compared with Imatinib in Newly Diagnosed Chronic Phase Chronic Myeloid Leukemia. Clin Cancer Res. 2017;23:7180–8. doi: 10.1158/1078-0432.CCR-17-0957. PubMed DOI

Radich JP, Kopecky KJ, Appelbaum FR, Kamel-Reid S, Stock W, Malnassy G, et al. A randomized trial of dasatinib 100 mg versus imatinib 400 mg in newly diagnosed chronic-phase chronic myeloid leukemia. Blood. 2012;120:3898–905. doi: 10.1182/blood-2012-02-410688. PubMed DOI PMC

Hjorth-Hansen H, Stenke L, Soderlund S, Dreimane A, Ehrencrona H, Gedde-Dahl T, et al. Dasatinib induces fast and deep responses in newly diagnosed chronic myeloid leukaemia patients in chronic phase: clinical results from a randomised phase-2 study (NordCML006) Eur J Haematol. 2015;94:243–50. doi: 10.1111/ejh.12423. PubMed DOI PMC

O’Brien S, Cork L, Bandeira V, Bescoby R, Foroni L, Alaily L, et al. Spirit 2: final 5 year analysis of the UK national cancer research institute randomized study comparing imatinib with dasatinib in patients with newly diagnosed chronic phase CML. Blood. 2018;132:457. doi: 10.1182/blood-2018-99-110128. PubMed DOI

Steegmann JL, Baccarani M, Breccia M, Casado LF, Garcia-Gutierrez V, Hochhaus A, et al. European LeukemiaNet recommendations for the management and avoidance of adverse events of treatment in chronic myeloid leukaemia. Leukemia. 2016;30:1648–71. doi: 10.1038/leu.2016.104. PubMed DOI PMC

Michel C, Burchert A, Hochhaus A, Saussele S, Neubauer A, Lauseker M, et al. Imatinib dose reduction in major molecular response of chronic myeloid leukemia: results from the German Chronic Myeloid Leukemia-Study IV. Haematologica. 2019;104:955–62. doi: 10.3324/haematol.2018.206797. PubMed DOI PMC

Naqvi K, Jabbour E, Skinner J, Anderson K, Dellasala S, Yilmaz M, et al. Long-term follow-up of lower dose dasatinib (50 mg daily) as frontline therapy in newly diagnosed chronic-phase chronic myeloid leukemia. Cancer. 2020;126:67–75. doi: 10.1002/cncr.32504. PubMed DOI PMC

Hughes T, Saglio G, Larson R, Kantarjian H, Kim D-W, Issaragrisil S, et al. Long-term outcomes in patients with chronic myeloid leukemia in chronic phase receiving frontline nilotinib versus imatinib: ENESTnd 10-year analysis. Blood. 2019;134:2924. doi: 10.1182/blood-2019-128761. DOI

Gugliotta G, Castagnetti F, Breccia M, Levato L, Intermesoli T, D’Adda M, et al. Ten-year follow-up of patients with chronic myeloid leukemia treated with nilotinib in first-line: final results of the gimema CML 0307 trial. Blood. 2019;134:4145.. doi: 10.1182/blood-2019-126163. DOI

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;30:57–64. doi: 10.1038/leu.2015.270. PubMed DOI PMC

Gugliotta G, Castagnetti F, Breccia M, Iurlo A, D’Adda M, Stagno F, et al. Outcome of 472 chronic myeloid leukemia patients treated with frontline nilotinib: a GIMEMA CML WP analysis. Blood. 2018;132:458.. doi: 10.1182/blood-2018-99-119182. PubMed DOI

Do YR, Kwak J-Y, Kim J-A. Long-term data from a phase 3 study of radotinib versus imatinib in patients with newly diagnosed, chronic myeloid leukemia in the chronic phase (RERISE). Brit J Haematol. 2020. https://onlinelibrary.wiley.com/doi/full/10.1111/bjh.16381. PubMed DOI PMC

Talpaz M, Hehlmann R, Quintas-Cardama A, Mercer J, Cortes J. Re-emergence of interferon-alpha in the treatment of chronic myeloid leukemia. Leukemia. 2013;27:803–12. doi: 10.1038/leu.2012.313. PubMed DOI PMC

Hjorth-Hansen H, Stentoft J, Richter J, Koskenvesa P, Hoglund M, Dreimane A, et al. Safety and efficacy of the combination of pegylated interferon-alpha2b and dasatinib in newly diagnosed chronic-phase chronic myeloid leukemia patients. Leukemia. 2016;30:1853–60. doi: 10.1038/leu.2016.121. PubMed DOI

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:e37–46. doi: 10.1016/S2352-3026(14)00027-1. PubMed DOI

Simonsson B, Gedde-Dahl T, Markevarn B, Remes K, Stentoft J, Almqvist A, et al. Combination of pegylated IFN-alpha2b with imatinib increases molecular response rates in patients with low- or intermediate-risk chronic myeloid leukemia. Blood. 2011;118:3228–35. doi: 10.1182/blood-2011-02-336685. PubMed DOI

Malkan UY, Aksu S, Aktimur S, Atay H, Bektas O, Buyukasik Y, et al. Generic imatinib mesylate is as effective as original Glivec in the clinical management of CML. UHOD - Uluslararasi Hematol-Onkol Derg. 2015;25:215–21.

Islamagic E, Hasic A, Kurtovic S, Suljovic Hadzimesic E, Mehinovic L, Kozaric M, et al. The efficacy of generic imatinib as first- and second-line therapy: 3-year follow-up of patients with chronic myeloid leukemia. Clin Lymphoma Myeloma Leuk. 2017;17:238–40. doi: 10.1016/j.clml.2017.02.001. PubMed DOI

Eskazan AE, Sadri S, Keskin D, Ayer M, Kantarcioglu B, Demirel N, et al. Outcomes of chronic myeloid leukemia patients with early molecular response at 3 and 6 months: a comparative analysis of generic imatinib and glivec. Clin Lymphoma Myeloma Leuk. 2017;17:804–11. doi: 10.1016/j.clml.2017.07.255. PubMed DOI

Dusetzina SB, Winn AN, Abel GA, Huskamp HA, Keating NL. Cost sharing and adherence to tyrosine kinase inhibitors for patients with chronic myeloid leukemia. J Clin Oncol. 2014;32:306–11. doi: 10.1200/JCO.2013.52.9123. PubMed DOI

Winn AN, Keating NL, Dusetzina SB. Factors associated with tyrosine kinase inhibitor initiation and adherence among medicare beneficiaries with chronic myeloid leukemia. J Clin Oncol. 2016;34:4323–8. doi: 10.1200/JCO.2016.67.4184. PubMed DOI PMC

Padula WV, Larson RA, Dusetzina SB, Apperley JF, Hehlmann R, Baccarani M, et al. Cost-effectiveness of tyrosine kinase inhibitor treatment strategies for chronic myeloid leukemia in chronic phase after generic entry of imatinib in the United States. J Natl Cancer Inst. 2016;108. 10.1093/jnci/djw003. PubMed PMC

Shih YT, Cortes JE, Kantarjian HM. Treatment value of second-generation BCR-ABL1 tyrosine kinase inhibitors compared with imatinib to achieve treatment-free remission in patients with chronic myeloid leukaemia: a modelling study. Lancet Haematol. 2019;6:e398–e408. doi: 10.1016/S2352-3026(19)30087-0. PubMed DOI PMC

Yamamoto C, Nakashima H, Ikeda T, Kawaguchi SI, Toda Y, Ito S, et al. Analysis of the cost-effectiveness of treatment strategies for CML with incorporation of treatment discontinuation. Blood Adv. 2019;3:3266–77. doi: 10.1182/bloodadvances.2019000745. PubMed DOI PMC

Andrews CN, Lipton J. The true value of second-generation TKIs as first-line therapy in chronic myeloid leukaemia. Lancet Haematol. 2019;6:e385–e386. doi: 10.1016/S2352-3026(19)30112-7. PubMed DOI

Shah NP, Guilhot F, Cortes JE, Schiffer CA, le Coutre P, Brummendorf TH, et al. Long-term outcome with dasatinib after imatinib failure in chronic-phase chronic myeloid leukemia: follow-up of a phase 3 study. Blood. 2014;123:2317–24. doi: 10.1182/blood-2013-10-532341. PubMed DOI PMC

Giles FJ, le Coutre PD, Pinilla-Ibarz J, Larson RA, Gattermann N, Ottmann OG, et al. 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;27:107–12. doi: 10.1038/leu.2012.181. PubMed DOI

Smith B, Brümmendorf T, Roboz G, Gambacorti-Passerini C, Charbonnier A, Viquiera A, et al. Efficacy of bosutinib in imatinib-resistant vs dasatinib/nilotinib-resistant chronic phase chronic myeloid leukemia: results from the Phase 4 BYOND Study. Blood. 2019;134:1650.. doi: 10.1182/blood-2019-122230. DOI

Gambacorti-Passerini C, Aroldi A, Cordani N, Piazza R. Chronic myeloid leukemia: Second-line drugs of choice. Am J Hematol. 2016;91:67–75. doi: 10.1002/ajh.24247. PubMed DOI

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;369:1783–96. doi: 10.1056/NEJMoa1306494. PubMed DOI PMC

Cortes JE, Kim DW, Pinilla-Ibarz J, le Coutre PD, Paquette R, Chuah C, et al. Ponatinib efficacy and safety in Philadelphia chromosome-positive leukemia: final 5-year results of the phase 2 PACE trial. Blood. 2018;132:393–404. doi: 10.1182/blood-2016-09-739086. PubMed DOI PMC

Lipton JH, Chuah C, Guerci-Bresler A, Rosti G, Simpson D, Assouline S, et al. Ponatinib versus imatinib for newly diagnosed chronic myeloid leukaemia: an international, randomised, open-label, phase 3 trial. Lancet Oncol. 2016;17:612–21. doi: 10.1016/S1470-2045(16)00080-2. PubMed DOI

Andrews C, Lipton J. The role of ponatinib in chronic myeloid leukemia in the era of treatment free remission. Leuk Lymphoma. 2019;60:3099–101. doi: 10.1080/10428194.2019.1665667. PubMed DOI

Thanarajasingam G, Minasian LM, Baron F, Cavalli F, De Claro RA, Dueck AC, et al. Beyond maximum grade: modernising the assessment and reporting of adverse events in haematological malignancies. Lancet Haematol. 2018;5:e563–e598. doi: 10.1016/S2352-3026(18)30051-6. PubMed DOI PMC

Valent P, Hadzijusufovic E, Schernthaner GH, Wolf D, Rea D, le Coutre P. Vascular safety issues in CML patients treated with BCR/ABL1 kinase inhibitors. Blood. 2015;125:901–6. doi: 10.1182/blood-2014-09-594432. PubMed DOI

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;126:42–49. doi: 10.1182/blood-2015-01-617993. PubMed DOI PMC

Jain P, Kantarjian H, Boddu PC, Nogueras-Gonzalez GM, Verstovsek S, Garcia-Manero G, et al. Analysis of cardiovascular and arteriothrombotic adverse events in chronic-phase CML patients after frontline TKIs. Blood Adv. 2019;3:851–61. doi: 10.1182/bloodadvances.2018025874. PubMed DOI PMC

Dorer DJ, Knickerbocker RK, Baccarani M, Cortes JE, Hochhaus A, Talpaz M, et al. Impact of dose intensity of ponatinib on selected adverse events: Multivariate analyses from a pooled population of clinical trial patients. Leuk Res. 2016;48:84–91. doi: 10.1016/j.leukres.2016.07.007. PubMed DOI

Piepoli MF, Hoes AW, Agewall S, Albus C, Brotons C, Catapano AL, et al. 2016 European Guidelines on cardiovascular disease prevention in clinical practice: The Sixth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of 10 societies and by invited experts)Developed with the special contribution of the European Association for Cardiovascular Prevention & Rehabilitation (EACPR) Eur Heart J. 2016;37:2315–81. doi: 10.1093/eurheartj/ehw106. PubMed DOI PMC

Zamorano JL, Lancellotti P, Rodriguez Munoz D, Aboyans V, Asteggiano R, Galderisi M, et al. 2016 ESC Position Paper on cancer treatments and cardiovascular toxicity developed under the auspices of the ESC Committee for Practice Guidelines: The Task Force for cancer treatments and cardiovascular toxicity of the European Society of Cardiology (ESC) Eur Heart J. 2016;37:2768–801. doi: 10.1093/eurheartj/ehw211. PubMed DOI

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;104:93–101. doi: 10.3324/haematol.2018.188987. PubMed DOI PMC

Gong Z, Medeiros LJ, Cortes JE, Chen Z, Zheng L, Li Y, et al. Cytogenetics-based risk prediction of blastic transformation of chronic myeloid leukemia in the era of TKI therapy. Blood Adv. 2017;1:2541–52. doi: 10.1182/bloodadvances.2017011858. PubMed DOI PMC

Soverini S, Bavaro L, De Benedittis C, Martelli M, Iurlo A, Orofino N, et al. Prospective assessment of NGS-detectable mutations in CML patients with non-optimal response: the NEXT-in-CML study. Blood. 2019. 10.1182/blood.2019002969. PubMed

Kizilors A, Crisa E, Lea N, Passera R, Mian S, Anwar J, et al. Effect of low-level BCR-ABL1 kinase domain mutations identified by next-generation sequencing in patients with chronic myeloid leukaemia: a population-based study. Lancet Haematol. 2019;6:e276–e284. doi: 10.1016/S2352-3026(19)30027-4. PubMed DOI

Kok CH, Yeung DT, Lu L, Watkins DB, Leclercq TM, Dang P, et al. Gene expression signature that predicts early molecular response failure in chronic-phase CML patients on frontline imatinib. Blood Adv. 2019;3:1610–21. doi: 10.1182/bloodadvances.2019000195. PubMed DOI PMC

Grossmann V, Kohlmann A, Zenger M, Schindela S, Eder C, Weissmann S, et al. A deep-sequencing study of chronic myeloid leukemia patients in blast crisis (BC-CML) detects mutations in 76.9% of cases. Leukemia. 2011;25:557–60. doi: 10.1038/leu.2010.298. PubMed DOI

Branford S, Wang P, Yeung DT, Thomson D, Purins A, Wadham C, et al. Integrative genomic analysis reveals cancer-associated mutations at diagnosis of CML in patients with high-risk disease. Blood. 2018;132:948–61. doi: 10.1182/blood-2018-02-832253. PubMed DOI

Baccarani M, Castagnetti F, Gugliotta G, Rosti G, Soverini S, Albeer A, et al. The proportion of different BCR-ABL1 transcript types in chronic myeloid leukemia. an international overview. Leukemia. 2019;33:1173–83. doi: 10.1038/s41375-018-0341-4. PubMed DOI

Hehlmann R, Saussele S, Voskanyan A, Silver RT. Management of CML-blast crisis. Best Pr Res Clin Haematol. 2016;29:295–307. doi: 10.1016/j.beha.2016.10.005. PubMed DOI

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;127:2391–405. doi: 10.1182/blood-2016-03-643544. PubMed DOI

Spiers AS. Metamorphosis of chronic granulocytic leukaemia: diagnosis, classification, and management. Br J Haematol. 1979;41:1–7. doi: 10.1111/j.1365-2141.1979.tb03675.x. PubMed DOI

Soderlund S, Dahlen T, Sandin F, Olsson-Stromberg U, Creignou M, Dreimane A, et al. Advanced phase chronic myeloid leukaemia (CML) in the tyrosine kinase inhibitor era—a report from the Swedish CML register. Eur J Haematol. 2017;98:57–66. doi: 10.1111/ejh.12785. PubMed DOI

Jain P, Kantarjian HM, Ghorab A, Sasaki K, Jabbour EJ, Nogueras Gonzalez G, et al. Prognostic factors and survival outcomes in patients with chronic myeloid leukemia in blast phase in the tyrosine kinase inhibitor era: Cohort study of 477 patients. Cancer. 2017;123:4391–402. doi: 10.1002/cncr.30864. PubMed DOI PMC

Lubking A, Dreimane A, Sandin F, Isaksson C, Markevarn B, Brune M, et al. Allogeneic stem cell transplantation for chronic myeloid leukemia in the TKI era: population-based data from the Swedish CML registry. Bone Marrow Transpl. 2019;54:1764–74. doi: 10.1038/s41409-019-0513-5. PubMed DOI

Milojkovic D, Ibrahim A, Reid A, Foroni L, Apperley J, Marin D. Efficacy of combining dasatinib and FLAG-IDA for patients with chronic myeloid leukemia in blastic transformation. Haematologica. 2012;97:473–4. doi: 10.3324/haematol.2011.057513. PubMed DOI PMC

Copland M, Slade D, Byrne J. FLAG-IDA and ponatinib in patients with blast phase chronic myeloid leukaemia: results from the phase I/II UK trials acceleration programme matchpoint trial. Blood. 2019;134:497. doi: 10.1182/blood-2019-125591. DOI

Strati P, Kantarjian H, Thomas D, O’Brien S, Konoplev S, Jorgensen JL, et al. HCVAD plus imatinib or dasatinib in lymphoid blastic phase chronic myeloid leukemia. Cancer. 2014;120:373–80. doi: 10.1002/cncr.28433. PubMed DOI PMC

Gratwohl A, Pfirrmann M, Zander A, Kroger N, Beelen D, Novotny J, et al. Long-term outcome of patients with newly diagnosed chronic myeloid leukemia: a randomized comparison of stem cell transplantation with drug treatment. Leukemia. 2016;30:562–9. doi: 10.1038/leu.2015.281. PubMed DOI PMC

Efficace F, Cannella L. The value of quality of life assessment in chronic myeloid leukemia patients receiving tyrosine kinase inhibitors. Hematol Am Soc Hematol Educ Program. 2016;2016:170–9. doi: 10.1182/asheducation-2016.1.170. PubMed DOI PMC

Phillips KM, Pinilla-Ibarz J, Sotomayor E, Lee MR, Jim HS, Small BJ, et al. Quality of life outcomes in patients with chronic myeloid leukemia treated with tyrosine kinase inhibitors: a controlled comparison. Support Care Cancer. 2013;21:1097–103. doi: 10.1007/s00520-012-1630-5. PubMed DOI

Zulbaran-Rojas A, Lin HK, Shi Q, Williams LA, George B, Garcia-Manero G, et al. A prospective analysis of symptom burden for patients with chronic myeloid leukemia in chronic phase treated with frontline second- and third-generation tyrosine kinase inhibitors. Cancer Med. 2018;7:5457–69. doi: 10.1002/cam4.1808. PubMed DOI PMC

Kim DW, Saussele S, Williams LA, Mohamed H, Rong Y, Zyczynski T, et al. Outcomes of switching to dasatinib after imatinib-related low-grade adverse events in patients with chronic myeloid leukemia in chronic phase: the DASPERSE study. Ann Hematol. 2018;97:1357–67. doi: 10.1007/s00277-018-3295-8. PubMed DOI PMC

Sacha T, Gora-Tybor J, Wasak-Szulkowska E, Kyrcz-Krzemien S, Medras E, Becht R, et al. Quality of life and adherence to therapy in patients with chronic myeloid leukemia treated with nilotinib as a second-line therapy: a multicenter prospective observational study. Clin Lymphoma Myeloma Leuk. 2017;17:283–95. doi: 10.1016/j.clml.2017.01.001. PubMed DOI

Baccarani M, Efficace F, Rosti G. Moving towards patient-centered decision-making in chronic myeloid leukemia: assessment of quality of life and symptom burden. Haematologica. 2014;99:205–8. doi: 10.3324/haematol.2013.094045. PubMed DOI PMC

Kantarjian HM, Mamolo CM, Gambacorti-Passerini C, Cortes JE, Brummendorf TH, Su Y, et al. Long-term patient-reported outcomes from an open-label safety and efficacy study of bosutinib in Philadelphia chromosome-positive chronic myeloid leukemia patients resistant or intolerant to prior therapy. Cancer. 2018;124:587–95. doi: 10.1002/cncr.31082. PubMed DOI PMC

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;35:298–305. doi: 10.1200/JCO.2016.68.2914. PubMed DOI

Campiotti L, Suter MB, Guasti L, Piazza R, Gambacorti-Passerini C, Grandi AM, et al. Imatinib discontinuation in chronic myeloid leukaemia patients with undetectable BCR-ABL transcript level: a systematic review and a meta-analysis. Eur J Cancer. 2017;77:48–56. doi: 10.1016/j.ejca.2017.02.028. PubMed DOI

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;19:747–57. doi: 10.1016/S1470-2045(18)30192-X. PubMed DOI

Clark RE, Polydoros F, Apperley JF, Milojkovic D, Rothwell K, Pocock C, et al. Initial reduction of therapy prior to complete treatment discontinuation in chronic myeloid leukaemia: final results of the British DESTINY Study. Lancet Haematol. 2019;6:e375–e383. doi: 10.1016/S2352-3026(19)30094-8. PubMed DOI

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;32:424–30. doi: 10.1200/JCO.2012.48.5797. PubMed DOI

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;129:846–54. doi: 10.1182/blood-2016-09-742205. PubMed DOI

Hochhaus A, Masszi T, Giles FJ, Radich JP, Ross DM, Gomez Casares MT, et al. Treatment-free remission following frontline nilotinib in patients with chronic myeloid leukemia in chronic phase: results from the ENESTfreedom study. Leukemia. 2017;31:1525–31. doi: 10.1038/leu.2017.63. PubMed DOI PMC

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:e528–535. doi: 10.1016/S2352-3026(15)00196-9. PubMed DOI

Richter J, Soderlund S, Lubking A, Dreimane A, Lotfi K, Markevarn B, et al. Musculoskeletal pain in patients with chronic myeloid leukemia after discontinuation of imatinib: a tyrosine kinase inhibitor withdrawal syndrome? J Clin Oncol. 2014;32:2821–3. doi: 10.1200/JCO.2014.55.6910. PubMed DOI

Hughes TP, Ross DM. Moving treatment-free remission into mainstream clinical practice in CML. Blood. 2016;128:17–23. doi: 10.1182/blood-2016-01-694265. PubMed DOI

Saussele S, Richter J, Hochhaus A, Mahon FX. The concept of treatment-free remission in chronic myeloid leukemia. Leukemia. 2016;30:1638–47. doi: 10.1038/leu.2016.115. PubMed DOI PMC

Lichtin AE, Woolf SH, Silver RT, Hehlmann R. Chronic myeloid leukemia—ASH practice guideline and beyond. Hematol Am Soc Hematol Educ Prog. 1998:435–53.

Apperley J. Issues of imatinib and pregnancy outcome. J Natl Compr Canc Netw. 2009;7:1050–8. doi: 10.6004/jnccn.2009.0069. PubMed DOI

Carlier P, Markarian M, Bernard N, Lagarce L, Dautriche A, Bene J, et al. Erratum to: pregnancy outcome among partners of male patients receiving imatinib, dasatinib or nilotinib in chronic myeloid leukemia: reports collected by the French network pharmacovigilance centers. Arch Gynecol Obstet. 2017;295:1059. doi: 10.1007/s00404-017-4321-0. PubMed DOI

Cortes JE, Abruzzese E, Chelysheva E, Guha M, Wallis N, Apperley JF. The impact of dasatinib on pregnancy outcomes. Am J Hematol. 2015;90:1111–5. doi: 10.1002/ajh.24186. PubMed DOI PMC

Abruzzese E, de Fabritiis P, Trawinska MM, Niscola P, Apperley JF, Mauro MJ. Back to the future: treatment-free remission and pregnancy in chronic myeloid leukemia. Eur J Haematol. 2019;102:197–9. doi: 10.1111/ejh.13192. PubMed DOI

Abruzzese E, Scortechini AR, Gugliotta G, Pierri I, Musolino C, Iurlo A, et al. GIMEMA registry of conception/pregnancy in adult patients diagnosed with chronic myeloid leukemia (CML) treated with tyrosine kinase inhibitors (TKIs) Blood. 2014;124:1806. doi: 10.1182/blood.V124.21.1806.1806. DOI

Cortes JE, Gambacorti-Passerini C, Deininger MW, Abruzzese E, DeAnnuntis L, Brümmendorf TH. Pregnancy outcomes in patients treated with bosutinib. Blood. 2018;132:1729. doi: 10.1182/blood-2018-99-110547. PubMed DOI PMC

Nicolini FE, Alcazer V, Huguet F, Cony-Makhoul P, Heiblig M, Fort MP, et al. CML patients show sperm alterations at diagnosis that are not improved with imatinib treatment. Leuk Res. 2016;48:80–83. doi: 10.1016/j.leukres.2016.07.008. PubMed DOI

Lasica M, Willcox A, Burbury K, Ross DM, Branford S, Butler J, et al. The effect of tyrosine kinase inhibitor interruption and interferon use on pregnancy outcomes and long-term disease control in chronic myeloid leukemia. Leuk Lymphoma. 2019;60:1796–802. doi: 10.1080/10428194.2018.1551533. PubMed DOI

Chelysheva E, Turkina A. Risks and challenges of CML management during pregnancy: Looking for a balanced decision. Eur J Haematol. 2019;102:378–9. doi: 10.1111/ejh.13215. PubMed DOI

Chelysheva E, Aleshin S, Polushkina E, Shmakov R, Shokhin I, Chilov G, et al. Breastfeeding in patients with chronic myeloid leukaemia: case series with measurements of drug concentrations in maternal milk and literature review. Mediterr J Hematol Infect Dis. 2018;10:e2018027. doi: 10.4084/mjhid.2018.027. PubMed DOI PMC

Hughes TP, Lipton JH, Spector N, Cervantes F, Pasquini R, Clementino NC, et al. Deep molecular responses achieved in patients with CML-CP who are switched to nilotinib after long-term imatinib. Blood. 2014;124:729–36. doi: 10.1182/blood-2013-12-544015. PubMed DOI

Hughes TP, Leber B, Cervantes F, Spector N, Pasquini R, Clementino NCD, et al. Sustained deep molecular responses in patients switched to nilotinib due to persistent BCR-ABL1 on imatinib: final ENESTcmr randomized trial results. Leukemia. 2017;31:2529–31. doi: 10.1038/leu.2017.247. PubMed DOI PMC

Hughes TP, Mauro MJ, Cortes JE, Minami H, Rea D, DeAngelo DJ, et al. Asciminib in chronic myeloid leukemia after ABL kinase inhibitor failure. N Engl J Med. 2019;381:2315–26. doi: 10.1056/NEJMoa1902328. PubMed DOI PMC

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