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      Bosutinib for pretreated patients with chronic phase chronic myeloid leukemia: primary results of the phase 4 BYOND study

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          Abstract

          Bosutinib is approved for newly diagnosed Philadelphia chromosome-positive (Ph+) chronic phase (CP) chronic myeloid leukemia (CML) and for Ph+ CP, accelerated (AP), or blast (BP) phase CML after prior treatment with tyrosine kinase inhibitors (TKIs). In the ongoing phase 4 BYOND study (NCT02228382), 163 CML patients resistant/intolerant to prior TKIs ( n = 156 Ph+ CP CML, n = 4 Ph+ AP CML, n = 3 Ph-negative/ BCR-ABL1+ CML) received bosutinib 500 mg once daily (starting dose). As of ≥1 year after last enrolled patient (median treatment duration 23.7 months), 56.4% of Ph+ CP CML patients remained on bosutinib. Primary endpoint of cumulative confirmed major cytogenetic response (MCyR) rate by 1 year was 75.8% in Ph+ CP CML patients after one or two prior TKIs and 62.2% after three prior TKIs. Cumulative complete cytogenetic response (CCyR) and major molecular response (MMR) rates by 1 year were 80.6% and 70.5%, respectively, in Ph+ CP CML patients overall. No patient progressed to AP/BP on treatment. Across all patients, the most common treatment-emergent adverse events were diarrhea (87.7%), nausea (39.9%), and vomiting (32.5%). The majority of patients had confirmed MCyR by 1 year and MMR by 1 year, further supporting bosutinib use for Ph+ CP CML patients resistant/intolerant to prior TKIs.

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          European LeukemiaNet 2020 recommendations for treating chronic myeloid leukemia

          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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            Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia.

            Treatment with dasatinib, a highly potent BCR-ABL kinase inhibitor, has resulted in high rates of complete cytogenetic response and progression-free survival among patients with chronic myeloid leukemia (CML) in the chronic phase, after failure of imatinib treatment. We assessed the efficacy and safety of dasatinib, as compared with imatinib, for the first-line treatment of chronic-phase CML. In a multinational study, 519 patients with newly diagnosed chronic-phase CML were randomly assigned to receive dasatinib at a dose of 100 mg once daily (259 patients) or imatinib at a dose of 400 mg once daily (260 patients). The primary end point was complete cytogenetic response by 12 months, confirmed on two consecutive assessments at least 28 days apart. Secondary end points, including major molecular response, were tested at a significance level of 0.0001 to adjust for multiple comparisons. After a minimum follow-up of 12 months, the rate of confirmed complete cytogenetic response was higher with dasatinib than with imatinib (77% vs. 66%, P=0.007), as was the rate of complete cytogenetic response observed on at least one assessment (83% vs. 72%, P=0.001). The rate of major molecular response was higher with dasatinib than with imatinib (46% vs. 28%, P<0.0001), and responses were achieved in a shorter time with dasatinib (P<0.0001). Progression to the accelerated or blastic phase of CML occurred in 5 patients who were receiving dasatinib (1.9%) and in 9 patients who were receiving imatinib (3.5%). The safety profiles of the two treatments were similar. Dasatinib, administered once daily, as compared with imatinib, administered once daily, induced significantly higher and faster rates of complete cytogenetic response and major molecular response. Since achieving complete cytogenetic response within 12 months has been associated with better long-term, progression-free survival, dasatinib may improve the long-term outcomes among patients with newly diagnosed chronic-phase CML. (ClinicalTrials.gov number, NCT00481247.) 2010 Massachusetts Medical Society
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              Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia.

              Nilotinib has been shown to be a more potent inhibitor of BCR-ABL than imatinib. We evaluated the efficacy and safety of nilotinib, as compared with imatinib, in patients with newly diagnosed Philadelphia chromosome-positive chronic myeloid leukemia (CML) in the chronic phase. In this phase 3, randomized, open-label, multicenter study, we assigned 846 patients with chronic-phase Philadelphia chromosome-positive CML in a 1:1:1 ratio to receive nilotinib (at a dose of either 300 mg or 400 mg twice daily) or imatinib (at a dose of 400 mg once daily). The primary end point was the rate of major molecular response at 12 months. At 12 months, the rates of major molecular response for nilotinib (44% for the 300-mg dose and 43% for the 400-mg dose) were nearly twice that for imatinib (22%) (P<0.001 for both comparisons). The rates of complete cytogenetic response by 12 months were significantly higher for nilotinib (80% for the 300-mg dose and 78% for the 400-mg dose) than for imatinib (65%) (P<0.001 for both comparisons). Patients receiving either the 300-mg dose or the 400-mg dose of nilotinib twice daily had a significant improvement in the time to progression to the accelerated phase or blast crisis, as compared with those receiving imatinib (P=0.01 and P=0.004, respectively). No patient with progression to the accelerated phase or blast crisis had a major molecular response. Gastrointestinal and fluid-retention events were more frequent among patients receiving imatinib, whereas dermatologic events and headache were more frequent in those receiving nilotinib. Discontinuations due to aminotransferase and bilirubin elevations were low in all three study groups. Nilotinib at a dose of either 300 mg or 400 mg twice daily was superior to imatinib in patients with newly diagnosed chronic-phase Philadelphia chromosome-positive CML. (ClinicalTrials.gov number, NCT00471497.) 2010 Massachusetts Medical Society
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                Author and article information

                Contributors
                andreas.hochhaus@med.uni-jena.de
                Journal
                Leukemia
                Leukemia
                Leukemia
                Nature Publishing Group UK (London )
                0887-6924
                1476-5551
                22 June 2020
                22 June 2020
                2020
                : 34
                : 8
                : 2125-2137
                Affiliations
                [1 ]ISNI 0000 0000 8517 6224, GRID grid.275559.9, Klinik für Innere Medizin II, , Universitätsklinikum Jena, ; Jena, Germany
                [2 ]ISNI 0000 0001 2174 1754, GRID grid.7563.7, University of Milano-Bicocca, ; Monza, Italy
                [3 ]ISNI 0000 0001 2355 7002, GRID grid.4367.6, Washington University School of Medicine, ; St. Louis, MO USA
                [4 ]Haukeland University Hospital, Helse Bergen, and University of Bergen, Bergen, Norway
                [5 ]ISNI 0000 0000 8653 1507, GRID grid.412301.5, Universitätsklinikum RWTH Aachen, ; Aachen, Germany
                [6 ]ISNI 0000 0000 8741 3625, GRID grid.280502.d, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, ; Baltimore, MD USA
                [7 ]ISNI 0000 0000 9854 2756, GRID grid.411106.3, CIBER Enfermedades Raras, , Miguel Servet University Hospital, ; Zaragoza, Spain
                [8 ]ISNI 0000 0001 2351 3333, GRID grid.412354.5, University of Uppsala and Department of Hematology, University Hospital, ; Uppsala, Sweden
                [9 ]Universitätsmedizin Mannheim, Heidelberg University, Mannheim, Germany
                [10 ]Pfizer International Operation-Oncology, Paris, France
                [11 ]GRID grid.424551.3, Pfizer SLU, ; Madrid, Spain
                [12 ]ISNI 0000 0000 8800 7493, GRID grid.410513.2, Pfizer Inc, ; Cambridge, MA USA
                [13 ]ISNI 0000 0000 8800 7493, GRID grid.410513.2, Pfizer Inc, ; New York, NY USA
                [14 ]University Hospital, University of Bologna, Bologna, Italy
                [15 ]ISNI 0000 0004 1936 8606, GRID grid.26790.3a, University of Miami, Sylvester Comprehensive Cancer Center, ; Miami, FL USA
                [16 ]Developmental Therapeutics Consortium, Chicago, IL USA
                [17 ]ISNI 0000 0004 1760 4441, GRID grid.416628.f, Ospedale S. Eugenio, ; Rome, Italy
                [18 ]Indiana Blood and Marrow Transplantation-Clinic, Indianapolis, IN USA
                [19 ]SOD Ematologia, Firenze, Italy
                [20 ]ISNI 0000 0000 9635 9413, GRID grid.410458.c, Hospital Clinic IDIBAPS, ; Barcelona, Spain
                [21 ]Centre Regional De Lutte Contre Le Cancer, Marseille, France
                [22 ]Policlinico Vittorio Emanuele, Catania, Italy
                [23 ]ISNI 0000 0004 0639 0505, GRID grid.476460.7, Institut Bergonie, ; Bordeaux, France
                [24 ]ISNI 0000 0000 9248 5770, GRID grid.411347.4, Hospital Universitario Ramon y Cajal, ; Madrid, Spain
                [25 ]ISNI 0000 0004 1765 1301, GRID grid.410527.5, CHU Brabois, ; Vandoeuvre-les-Nancy, France
                [26 ]St Olav Hospital, Trondheim, Norway
                [27 ]ISNI 0000 0001 2322 4179, GRID grid.410528.a, CHU Nice-Hopital Archet, ; Nice, France
                [28 ]ISNI 0000 0001 2156 6853, GRID grid.42505.36, University of Southern California, Norris Comprehensive Cancer Center, ; Los Angeles, CA USA
                [29 ]ISNI 0000 0001 2218 4662, GRID grid.6363.0, Charité – Universitätsmedizin Berlin, ; Berlin, Germany
                [30 ]GRID grid.488466.0, Hospital Universitario Quiron de Madrid, Pozuelo de Alarcon, ; Madrid, Spain
                [31 ]ISNI 0000 0004 0431 6950, GRID grid.430269.a, Seattle Cancer Care Alliance, ; Seattle, WA USA
                [32 ]ISNI 0000 0001 0675 8654, GRID grid.411083.f, Vall dʼHebron University Hospital, ; Barcelona, Spain
                [33 ]Ordensklinikum Linz Gmbh Barmherzige Schwestern, Linz, Austria
                [34 ]GRID grid.416200.1, Ospedale Niguarda Ca Granda, ; Milano, Italy
                [35 ]San Luigi Gonzaga SCDU, Orbassano, Italy
                [36 ]GRID grid.488470.7, Institut Universitaire du Cancer Toulouse, ; Toulouse, France
                [37 ]Weill Cornell Medical College - New York-Presbyterian Hospital, New York, NY USA
                [38 ]Centre Hospitalier de Versailles, Hopital Andre Mignot, Le Chesnay, France
                [39 ]GRID grid.411258.b, Hospital Clinico Universitario de Salamanca, ; Salamanca, Spain
                [40 ]ISNI 0000 0001 0360 9602, GRID grid.84393.35, Hospital Universitari i Politecnic La Fe, ; Valencia, Spain
                [41 ]ISNI 0000 0001 2180 3484, GRID grid.13648.38, Universitätsklinikum Hamburg-Eppendorf, ; Hamburg, Germany
                [42 ]ISNI 0000 0000 8852 305X, GRID grid.411097.a, Universitätsklinikum Köln, ; Köln, Germany
                [43 ]ISNI 0000 0000 8853 2677, GRID grid.5361.1, Medizinische Universität Innsbruck, ; Innsbruck, Austria
                [44 ]Policlinico Consorziale di Bari, Bari, Italy
                [45 ]ISNI 0000 0004 1767 647X, GRID grid.411251.2, Hospital Universitario de La Princesa, ; Madrid, Spain
                [46 ]Hematologiskt Centrum, Stockholm, Stockholm, Sweden
                Article
                915
                10.1038/s41375-020-0915-9
                7387243
                32572189
                3d61e2f6-46d3-4930-97d3-cb272c68f369
                © 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
                : 25 May 2020
                : 1 June 2020
                : 4 June 2020
                Funding
                Funded by: FundRef https://doi.org/10.13039/100004319, Pfizer (Pfizer Inc.);
                Categories
                Article
                Custom metadata
                © Springer Nature Limited 2020

                Oncology & Radiotherapy
                drug development,chronic myeloid leukaemia
                Oncology & Radiotherapy
                drug development, chronic myeloid leukaemia

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