{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T03:15:04Z","timestamp":1790997304573,"version":"4.1.0"},"reference-count":36,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2022,8,12]],"date-time":"2022-08-12T00:00:00Z","timestamp":1660262400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"French Health Department","award":["PHRC-I 2008"],"award-info":[{"award-number":["PHRC-I 2008"]}]},{"name":"Centre Hospitalier de Versailles, Versailles, France","award":["PHRC-I 2008"],"award-info":[{"award-number":["PHRC-I 2008"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>The registered dose for imatinib is 400 mg\/d, despite high inter-patient variability in imatinib plasmatic exposure. Therapeutic drug monitoring (TDM) is routinely used to maximize a drug\u2019s efficacy or tolerance. We decided to conduct a prospective randomized trial (OPTIM-imatinib trial) to assess the value of TDM in patients with chronic phase chronic myelogenous treated with imatinib as first-line therapy (NCT02896842). Eligible patients started imatinib at 400 mg daily, followed by imatinib [C]min assessment. Patients considered underdosed ([C]min &lt; 1000 ng\/mL) were randomized in a dose-increase strategy aiming to reach the threshold of 1000 ng\/mL (TDM arm) versus standard imatinib management (control arm). Patients with [C]min levels \u2265 1000 ng\/mL were treated following current European Leukemia Net recommendations (observational arm). The primary endpoint was the rate of major molecular response (MMR, BCR::ABL1IS \u2264 0.1%) at 12 months. Out of 133 evaluable patients on imatinib 400 mg daily, 86 patients had a [C]min &lt; 1000 ng\/mL and were randomized. The TDM strategy resulted in a significant increase in [C]min values with a mean imatinib daily dose of 603 mg daily. Patients included in the TDM arm had a 12-month MMR rate of 67% (95% CI, 51\u201381) compared to 39% (95% CI, 24\u201355) for the control arm (p = 0.017). This early advantage persisted over the 3-year study period, in which we considered imatinib cessation as a censoring event. Imatinib TDM was feasible and significantly improved the 12-month MMR rate. This early advantage may be beneficial for patients without easy access to second-line TKIs.<\/jats:p>","DOI":"10.3390\/pharmaceutics14081676","type":"journal-article","created":{"date-parts":[[2022,8,15]],"date-time":"2022-08-15T03:33:20Z","timestamp":1660534400000},"page":"1676","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Imatinib Optimized Therapy Improves Major Molecular Response Rates in Patients with Chronic Myeloid Leukemia"],"prefix":"10.3390","volume":"14","author":[{"given":"Hyacinthe","family":"Johnson-Ansah","sequence":"first","affiliation":[{"name":"Department of Hematology, CHU C\u00f4te de Nacre, 14000 Caen, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin","family":"Maneglier","sequence":"additional","affiliation":[{"name":"Pharmacology Department, Centre Hospitalier de Versailles, 78150 Le Chesnay, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fran\u00e7oise","family":"Huguet","sequence":"additional","affiliation":[{"name":"Department of Hematology, CHU, Institut Universitaire du Cancer\u2014Oncopole, 31100 Toulouse, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laurence","family":"Legros","sequence":"additional","affiliation":[{"name":"Department of Hematology, H\u00f4pital Bic\u00eatre AP-HP, 94270 Bic\u00eatre, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martine","family":"Escoffre-Barbe","sequence":"additional","affiliation":[{"name":"Department of Hematology, Centre Hospitalier Pontchaillou, 35000 Rennes, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martine","family":"Gardembas","sequence":"additional","affiliation":[{"name":"Department of Hematology, CHU d\u2019Angers, 49100 Angers, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pascale","family":"Cony-Makhoul","sequence":"additional","affiliation":[{"name":"Department of Hematology, Centre Hospitalier Annecy Genevois, 74370 Pringy, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Val\u00e9rie","family":"Coiteux","sequence":"additional","affiliation":[{"name":"Department of Hematology, H\u00f4pital Huriez\u2014CHRU, 59000 Lille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laurent","family":"Sutton","sequence":"additional","affiliation":[{"name":"Department of Hematology, H\u00f4pital Victor Dupouy, 95107 Argenteuil, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wajed","family":"Abarah","sequence":"additional","affiliation":[{"name":"Department of Hematology, H\u00f4pital de Meaux, 77100 Meaux, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Camille","family":"Pouaty","sequence":"additional","affiliation":[{"name":"Department of Hematology, Centre Hospitalier de Dieppe, 76202 Dieppe, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Michel","family":"Pignon","sequence":"additional","affiliation":[{"name":"Department of Hematology, H\u00f4pital de Dunkerque, 59240 Dunkerque, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bachra","family":"Choufi","sequence":"additional","affiliation":[{"name":"Department of Hematology, H\u00f4pital de Boulogne, 62200 Boulogne, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sorin","family":"Visanica","sequence":"additional","affiliation":[{"name":"Department of Hematology, H\u00f4pital Notre Dame de Bon Secours, 57000 Metz, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"B\u00e9n\u00e9dicte","family":"Deau","sequence":"additional","affiliation":[{"name":"Department of Hematology, H\u00f4pital Cochin APHP, 75014 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laure","family":"Morisset","sequence":"additional","affiliation":[{"name":"Research Department, Centre Hospitalier de Versailles, 78150 Le Chesnay, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emilie","family":"Cayssials","sequence":"additional","affiliation":[{"name":"Inserm CIC 802, CHU de Poitiers, 86000 Poitiers, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mathieu","family":"Molimard","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Centre Hospitalier Pellegrin\u2014Tripode, 33000 Bordeaux, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"St\u00e9phane","family":"Bouchet","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Centre Hospitalier Pellegrin\u2014Tripode, 33000 Bordeaux, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fran\u00e7ois-Xavier","family":"Mahon","sequence":"additional","affiliation":[{"name":"Department of Hematology, Institut Bergoni\u00e9, 33076 Bordeaux, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Franck","family":"Nicolini","sequence":"additional","affiliation":[{"name":"Department of Hematology, Centre L\u00e9on B\u00e9rard, 69008 Lyon, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philippe","family":"Aegerter","sequence":"additional","affiliation":[{"name":"Unit\u00e9 de Recherche Clinique et D\u00e9partement de Sant\u00e9 Publique, GIRCI Ile de France, H\u00f4pital Ambroise Par\u00e9, 92100 Boulogne, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Michel","family":"Cayuela","sequence":"additional","affiliation":[{"name":"Hematology and Molecular Biology and EA3518, H\u00f4pital Saint-Louis, AP-HP, 75010 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc","family":"Delord","sequence":"additional","affiliation":[{"name":"Research Department, Centre Hospitalier de Versailles, 78150 Le Chesnay, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heriberto","family":"Bruzzoni-Giovanelli","sequence":"additional","affiliation":[{"name":"H\u00f4pital Saint-Louis, AP-HP\/INSERM, Universit\u00e9 Paris-Cit\u00e9 et CIC 1427, 75010 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philippe","family":"Rousselot","sequence":"additional","affiliation":[{"name":"Department of Hematology, Centre Hospitalier de Versailles, 78157 Le Chesnay, France"},{"name":"UMR1184, IDMIT Department, Commissariat \u00e0 L\u2019\u00e9nergie Atomique et aux Energies Alternatives, University of Versailles Saint-Quentin-en-Yvelines Paris-Saclay, 92265 Fontenay-Aux-Roses, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,8,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"302","DOI":"10.1053\/j.seminhematol.2010.07.001","article-title":"Chronic myeloid leukemia: A historical perspective","volume":"47","author":"Goldman","year":"2010","journal-title":"Semin. 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Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"917","DOI":"10.1056\/NEJMoa1609324","article-title":"Long-Term Outcomes of Imatinib Treatment for Chronic Myeloid Leukemia","volume":"376","author":"Hochhaus","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2260","DOI":"10.1056\/NEJMoa1002315","article-title":"Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia","volume":"362","author":"Kantarjian","year":"2010","journal-title":"N. Engl. J. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2251","DOI":"10.1056\/NEJMoa0912614","article-title":"Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia","volume":"362","author":"Saglio","year":"2010","journal-title":"N. Engl. J. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1200\/JCO.2017.74.7162","article-title":"Bosutinib Versus Imatinib for Newly Diagnosed Chronic Myeloid Leukemia: Results from the Randomized BFORE Trial","volume":"36","author":"Cortes","year":"2018","journal-title":"J. Clin. Oncol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1783","DOI":"10.1056\/NEJMoa1306494","article-title":"A phase 2 trial of ponatinib in Philadelphia chromosome-positive leukemias","volume":"369","author":"Cortes","year":"2013","journal-title":"N. Engl. J. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2333","DOI":"10.1200\/JCO.2015.64.8899","article-title":"Final 5-Year Study Results of DASISION: The Dasatinib Versus Imatinib Study in Treatment-Na\u00efve Chronic Myeloid Leukemia Patients Trial","volume":"34","author":"Cortes","year":"2016","journal-title":"J. Clin. Oncol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1044","DOI":"10.1038\/leu.2016.5","article-title":"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","volume":"30","author":"Hochhaus","year":"2016","journal-title":"Leukemia"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"6041","DOI":"10.1200\/JCO.2009.25.0779","article-title":"Chronic Myeloid Leukemia: An Update of Concepts and Management Recommendations of European LeukemiaNet","volume":"127","author":"Baccarani","year":"2009","journal-title":"J. Clin. Oncol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"872","DOI":"10.1182\/blood-2013-05-501569","article-title":"European LeukemiaNet recommendations for the management of chronic myeloid leukemia","volume":"122","author":"Baccarani","year":"2013","journal-title":"Blood"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"966","DOI":"10.1038\/s41375-020-0776-2","article-title":"European LeukemiaNet 2020 recommendations for treating chronic myeloid leukemia","volume":"34","author":"Hochhaus","year":"2020","journal-title":"Leukemia"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1385","DOI":"10.6004\/jnccn.2020.0047","article-title":"Chronic Myeloid Leukemia, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology","volume":"18","author":"Deininger","year":"2020","journal-title":"J. Natl. Compr. Cancer Netw."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1825","DOI":"10.1038\/s41375-022-01589-y","article-title":"Bosutinib versus imatinib for newly diagnosed chronic phase chronic myeloid leukemia: Final results from the BFORE trial","volume":"36","author":"Cortes","year":"2022","journal-title":"Leukemia"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"djw003","DOI":"10.1093\/jnci\/djw003","article-title":"Cost-effectiveness of Tyrosine Kinase Inhibitor Treatment Strategies for Chronic Myeloid Leukemia in Chronic Phase after Generic Entry of Imatinib in the United States","volume":"108","author":"Padula","year":"2016","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1038\/nrclinonc.2016.59","article-title":"Generic imatinib\u2014impact on frontline and salvage therapy for CML","volume":"13","author":"Gorkin","year":"2016","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"23","DOI":"10.4103\/0973-1482.191623","article-title":"Clinical efficacy and safety of high-dose imatinib for chronic myeloid leukemia patients: An updated meta-analysis","volume":"12","author":"Liu","year":"2016","journal-title":"J. Cancer Res. Ther."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"657","DOI":"10.1002\/ajh.22076","article-title":"High-dose imatinib for newly diagnosed chronic phase chronic myeloid leukemia patients\u2014Systematic review and meta-analysis","volume":"86","author":"Leader","year":"2011","journal-title":"Am. J. Hematol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"690","DOI":"10.1111\/fcp.12007","article-title":"Therapeutic drug monitoring of imatinib in chronic myeloid leukemia: Experience from 1216 patients at a centralized laboratory","volume":"27","author":"Bouchet","year":"2013","journal-title":"Fundam. Clin. Pharmacol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"4022","DOI":"10.1182\/blood-2007-10-116475","article-title":"Imatinib pharmacokinetics and its correlation with response and safety in chronic-phase chronic myeloid leukemia: A subanalysis of the IRIS study","volume":"111","author":"Larson","year":"2008","journal-title":"Blood"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"634","DOI":"10.1097\/01.ftd.0000175973.71140.91","article-title":"Quantification of imatinib in human plasma by high-performance liquid chromatography-tandem mass spectrometry","volume":"27","author":"Titier","year":"2005","journal-title":"Ther. Drug Monit."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"764","DOI":"10.1016\/j.leukres.2014.03.023","article-title":"Large-scale imatinib dose-concentration-effect study in CML patients under routine care conditions","volume":"38","author":"Gotta","year":"2014","journal-title":"Leuk. Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"S219","DOI":"10.1007\/s00277-015-2315-1","article-title":"Molecular monitoring of chronic myeloid leukemia: Principles and interlaboratory standardization","volume":"94","author":"Cross","year":"2015","journal-title":"Ann. Hematol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1038\/leu.2014.217","article-title":"A certified plasmid reference material for the standardization of BCR-ABL1 mRNA quantification by real-time quantitative PCR","volume":"29","author":"White","year":"2015","journal-title":"Leukemia"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2873","DOI":"10.1182\/blood-2003-11-3800","article-title":"High-dose imatinib mesylate therapy in newly diagnosed Philadelphia chromosome-positive chronic phase chronic myeloid leukemia","volume":"103","author":"Kantarjian","year":"2004","journal-title":"Blood"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"4754","DOI":"10.1200\/JCO.2008.20.3869","article-title":"High-dose imatinib in newly diagnosed chronic-phase chronic myeloid leukemia: High rates of rapid cytogenetic and molecular responses","volume":"27","author":"Cortes","year":"2009","journal-title":"J. Clin. Oncol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"424","DOI":"10.1200\/JCO.2009.25.3724","article-title":"Phase III, randomized, open-label study of daily imatinib mesylate 400 mg versus 800 mg in patients with newly diagnosed, previously untreated chronic myeloid leukemia in chronic phase using molecular end points: Tyrosine kinase inhibitor optimization and selectivity study","volume":"28","author":"Cortes","year":"2010","journal-title":"J. Clin. Oncol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"616","DOI":"10.1007\/s12185-014-1566-2","article-title":"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","volume":"99","author":"Baccarani","year":"2014","journal-title":"Int. J. Hematol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1634","DOI":"10.1200\/JCO.2010.32.0598","article-title":"Tolerability-adapted imatinib 800 mg\/d versus 400 mg\/d versus 400 mg\/d plus interferon-alfa in newly diagnosed chronic myeloid leukemia","volume":"29","author":"Hehlmann","year":"2011","journal-title":"J. Clin. Oncol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2398","DOI":"10.1038\/leu.2017.253","article-title":"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","volume":"31","author":"Hehlmann","year":"2017","journal-title":"Leukemia"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2511","DOI":"10.1056\/NEJMoa1004095","article-title":"Imatinib plus pegylated interferon-alpha2a in chronic myeloid leukemia","volume":"363","author":"Preudhomme","year":"2010","journal-title":"N. Engl. J. Med."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2332","DOI":"10.1038\/s41375-020-01117-w","article-title":"Long-term outcome of imatinib 400 mg compared to imatinib 600 mg or imatinib 400 mg daily in combination with cytarabine or pegylated interferon alpha 2a for chronic myeloid leukaemia: Results from the French SPIRIT phase III randomised trial","volume":"35","author":"Guilhot","year":"2021","journal-title":"Leukemia"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1111\/bjh.12618","article-title":"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","volume":"164","author":"Deininger","year":"2014","journal-title":"Br. J. Haematol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"e375","DOI":"10.1016\/S2352-3026(19)30094-8","article-title":"De-escalation of tyrosine kinase inhibitor therapy before complete treatment discontinuation in patients with chronic myeloid leukaemia (DESTINY): A non-randomised, phase 2 trial","volume":"6","author":"Clark","year":"2019","journal-title":"Lancet Haematol."}],"container-title":["Pharmaceutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4923\/14\/8\/1676\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:07:35Z","timestamp":1760141255000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4923\/14\/8\/1676"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,8,12]]},"references-count":36,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2022,8]]}},"alternative-id":["pharmaceutics14081676"],"URL":"https:\/\/doi.org\/10.3390\/pharmaceutics14081676","relation":{},"ISSN":["1999-4923"],"issn-type":[{"value":"1999-4923","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,8,12]]}}}