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      European LeukemiaNet 2020 recommendations for treating chronic myeloid leukemia

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          Abstract

          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.

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          European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013.

          Advances in chronic myeloid leukemia treatment, particularly regarding tyrosine kinase inhibitors, mandate regular updating of concepts and management. A European LeukemiaNet expert panel reviewed prior and new studies to update recommendations made in 2009. We recommend as initial treatment imatinib, nilotinib, or dasatinib. Response is assessed with standardized real quantitative polymerase chain reaction and/or cytogenetics at 3, 6, and 12 months. BCR-ABL1 transcript levels ≤10% at 3 months, 10% at 6 months and >1% from 12 months onward define failure, mandating a change in treatment. Similarly, partial cytogenetic response (PCyR) at 3 months and complete cytogenetic response (CCyR) from 6 months onward define optimal response, whereas no CyR (Philadelphia chromosome-positive [Ph+] >95%) at 3 months, less than PCyR at 6 months, and less than CCyR from 12 months onward define failure. Between optimal and failure, there is an intermediate warning zone requiring more frequent monitoring. Similar definitions are provided for response to second-line therapy. Specific recommendations are made for patients in the accelerated and blastic phases, and for allogeneic stem cell transplantation. Optimal responders should continue therapy indefinitely, with careful surveillance, or they can be enrolled in controlled studies of treatment discontinuation once a deeper molecular response is achieved.
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            Final 5-Year Study Results of DASISION: The Dasatinib Versus Imatinib Study in Treatment-Naïve Chronic Myeloid Leukemia Patients Trial.

            We report the 5-year analysis from the phase III Dasatinib Versus Imatinib Study in Treatment-Naïve Chronic Myeloid Leukemia Patients (DASISION) trial, evaluating long-term efficacy and safety outcomes of patients with chronic myeloid leukemia (CML) in chronic phase (CP) treated with dasatinib or imatinib.
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              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

              In the phase 3 Evaluating Nilotinib Efficacy and Safety in Clinical Trials–Newly Diagnosed Patients (ENESTnd) study, nilotinib resulted in earlier and higher response rates and a lower risk of progression to accelerated phase/blast crisis (AP/BC) than imatinib in patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP). Here, patients' long-term outcomes in ENESTnd are evaluated after a minimum follow-up of 5 years. By 5 years, more than half of all patients in each nilotinib arm (300 mg twice daily, 54% 400 mg twice daily, 52%) achieved a molecular response 4.5 (MR4.5; BCR-ABL⩽0.0032% on the International Scale) compared with 31% of patients in the imatinib arm. A benefit of nilotinib was observed across all Sokal risk groups. Overall, safety results remained consistent with those from previous reports. Numerically more cardiovascular events (CVEs) occurred in patients receiving nilotinib vs imatinib, and elevations in blood cholesterol and glucose levels were also more frequent with nilotinib. In contrast to the high mortality rate associated with CML progression, few deaths in any arm were associated with CVEs, infections or pulmonary diseases. These long-term results support the positive benefit-risk profile of frontline nilotinib 300 mg twice daily in patients with CML-CP.
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                Author and article information

                Contributors
                andreas.hochhaus@med.uni-jena.de
                hehlmann.eln@gmail.com
                Journal
                Leukemia
                Leukemia
                Leukemia
                Nature Publishing Group UK (London )
                0887-6924
                1476-5551
                3 March 2020
                3 March 2020
                2020
                : 34
                : 4
                : 966-984
                Affiliations
                [1 ]ISNI 0000 0000 8517 6224, GRID grid.275559.9, Klinik für Innere Medizin II, , Universitätsklinikum, ; Jena, Germany
                [2 ]ISNI 0000 0004 1757 1758, GRID grid.6292.f, Department of Hematology/Oncology, Policlinico S. Orsola-Malpighi, , University of Bologna, ; Bologna, Italy
                [3 ]ISNI 000000041936877X, GRID grid.5386.8, Weill Cornell Medical College, ; New York, NY USA
                [4 ]ISNI 0000 0001 1456 7807, GRID grid.254444.7, Karmanos Cancer Center, ; Detroit, MI USA
                [5 ]ISNI 0000 0001 2113 8111, GRID grid.7445.2, Hammersmith Hospital, Imperial College, ; London, UK
                [6 ]ISNI 0000 0000 9635 9413, GRID grid.410458.c, Hospital Clinic IDIBAPS, ; Barcelona, Spain
                [7 ]ISNI 0000 0004 1936 8470, GRID grid.10025.36, Department of Molecular & Clinical Cancer Medicine, , University of Liverpool, ; Liverpool, UK
                [8 ]ISNI 0000 0001 2284 9329, GRID grid.410427.4, Georgia Cancer Center, , Augusta University, ; Augusta, GA USA
                [9 ]Huntsman Cancer Center Salt Lake City, Salt Lake City, UT USA
                [10 ]ISNI 0000 0000 9336 4276, GRID grid.411162.1, Centre Hospitalier Universitaire de Poitiers, ; Poitiers, France
                [11 ]ISNI 0000 0001 1516 2393, GRID grid.5947.f, Norwegian University of Science and Technology, ; Trondheim, Norway
                [12 ]GRID grid.430453.5, South Australian Health and Medical Research Institute, ; Adelaide, SA Australia
                [13 ]ISNI 0000 0004 0435 165X, GRID grid.16872.3a, Amsterdam University Medical Center, VUMC, ; Amsterdam, The Netherlands
                [14 ]ISNI 0000 0001 2291 4776, GRID grid.240145.6, MD Anderson Cancer Center, ; Houston, TX USA
                [15 ]ISNI 0000 0004 0470 4224, GRID grid.411947.e, St. Mary´s Hematology Hospital, , The Catholic University, ; Seoul, Korea
                [16 ]ISNI 0000 0004 1936 7822, GRID grid.170205.1, University of Chicago, ; Chicago, IL USA
                [17 ]ISNI 0000 0001 2157 2938, GRID grid.17063.33, University of Toronto, ; Toronto, Canada
                [18 ]ISNI 0000 0001 2106 639X, GRID grid.412041.2, Institut Bergonie, , Université de Bordeaux, ; Bordeaux, France
                [19 ]ISNI 0000 0004 0609 2751, GRID grid.412554.3, Department of Internal Medicine, , Masaryk University Hospital, ; Brno, Czech Republic
                [20 ]ISNI 0000 0001 0200 3174, GRID grid.418116.b, Centre Léon Bérard, ; Lyon, France
                [21 ]ISNI 0000 0000 8517 9062, GRID grid.411339.d, Universitätsklinikum, ; Leipzig, Germany
                [22 ]Department Clinical Medicine and Surgery, University Federico Secondo, Naples, Italy
                [23 ]ISNI 0000 0001 2180 1622, GRID grid.270240.3, Fred Hutchinson Cancer Center, ; Seattle, WA USA
                [24 ]ISNI 0000 0001 2300 6614, GRID grid.413328.f, Hôpital St. Louis, ; Paris, France
                [25 ]ISNI 0000 0001 0930 2361, GRID grid.4514.4, University of Lund, ; Lund, Sweden
                [26 ]ISNI 0000 0001 2323 0229, GRID grid.12832.3a, Centre Hospitalier de Versailles, , University of Versailles Saint-Quentin-en-Yvelines, ; Versailles, France
                [27 ]ISNI 0000 0001 2336 6580, GRID grid.7605.4, University of Turin, ; Turin, Italy
                [28 ]ISNI 0000 0001 2190 4373, GRID grid.7700.0, III. Medizinische Klinik, Medizinische Fakultät Mannheim, , Universität Heidelberg, ; Mannheim, Germany
                [29 ]ISNI 0000 0004 1767 647X, GRID grid.411251.2, Hospital de la Princesa, ; Madrid, Spain
                [30 ]GRID grid.466123.4, National Research Center for Hematology, ; Moscow, Russian Federation
                [31 ]Almazov National Research Centre, St. Petersburg, Russian Federation
                [32 ]ELN Foundation, Weinheim, Germany
                Article
                776
                10.1038/s41375-020-0776-2
                7214240
                32127639
                55223b53-3f3f-42d7-a533-2d17c1b9ad62
                © The Author(s) 2020

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 10 February 2020
                : 11 February 2020
                : 13 February 2020
                Categories
                Review Article
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                © Springer Nature Limited 2020

                Oncology & Radiotherapy
                chronic myeloid leukaemia,targeted therapies
                Oncology & Radiotherapy
                chronic myeloid leukaemia, targeted therapies

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