BACKGROUND: Tyrosine kinase inhibitors (TKIs) have improved the survival of patients with chronic myeloid leukaemia. Many patients have deep molecular responses, a prerequisite for TKI therapy discontinuation. We aimed to define precise conditions for stopping treatment. METHODS: In this prospective, non-randomised trial, we enrolled patients with chronic myeloid leukaemia at 61 European centres in 11 countries. Eligible patients had chronic-phase chronic myeloid leukaemia, had received any TKI for at least 3 years (without treatment failure according to European LeukemiaNet [ELN] recommendations), and had a confirmed deep molecular response for at least 1 year. The primary endpoint was molecular relapse-free survival, defined by loss of major molecular response (MMR; >0·1% BCR-ABL1 on the International Scale) and assessed in all patients with at least one molecular result. Secondary endpoints were a prognostic analysis of factors affecting maintenance of MMR at 6 months in learning and validation samples and the cost impact of stopping TKI therapy. We considered loss of haematological response, progress to accelerated-phase chronic myeloid leukaemia, or blast crisis as serious adverse events. This study presents the results of the prespecified interim analysis, which was done after the 6-month molecular relapse-free survival status was known for 200 patients. The study is ongoing and is registered with ClinicalTrials.gov, number NCT01596114. FINDINGS: Between May 30, 2012, and Dec 3, 2014, we assessed 868 patients with chronic myeloid leukaemia for eligibility, of whom 758 were enrolled. Median follow-up of the 755 patients evaluable for molecular response was 27 months (IQR 21-34). Molecular relapse-free survival for these patients was 61% (95% CI 57-64) at 6 months and 50% (46-54) at 24 months. Of these 755 patients, 371 (49%) lost MMR after TKI discontinuation, four (1%) died while in MMR for reasons unrelated to chronic myeloid leukaemia (myocardial infarction, lung cancer, renal cancer, and heart failure), and 13 (2%) restarted TKI therapy while in MMR. A further six (1%) patients died in chronic-phase chronic myeloid leukaemia after loss of MMR and re-initiation of TKI therapy for reasons unrelated to chronic myeloid leukaemia, and two (<1%) patients lost MMR despite restarting TKI therapy. In the prognostic analysis in 405 patients who received imatinib as first-line treatment (learning sample), longer treatment duration (odds ratio [OR] per year 1·14 [95% CI 1·05-1·23]; p=0·0010) and longer deep molecular response durations (1·13 [1·04-1·23]; p=0·0032) were associated with increasing probability of MMR maintenance at 6 months. The OR for deep molecular response duration was replicated in the validation sample consisting of 171 patients treated with any TKI as first-line treatment, although the association was not significant (1·13 [0·98-1·29]; p=0·08). TKI discontinuation was associated with substantial cost savings (an estimated €22 million). No serious adverse events were reported. INTERPRETATION: Patients with chronic myeloid leukaemia who have achieved deep molecular responses have good molecular relapse-free survival. Such patients should be considered for TKI discontinuation, particularly those who have been in deep molecular response for a long time. Stopping treatment could spare patients from treatment-induced side-effects and reduce health expenditure. FUNDING: ELN Foundation and France National Cancer Institute.

1st Department of Internal Medicine Laikon General Hospital National and Kapodistrian University of Athens Athens Greece

Bergonié Cancer Institute Inserm Unit 916 University of Bordeaux Bordeaux France

Department of Clinical Chemistry and Department of Genetics Turku University Central Hospital Turku Finland

Department of Clinical Chemistry and Haematology University of Helsinki Helsinki Finland

Department of Clinical Genetics and Pathology Laboratory Medicine Office for Medical Services Lund Sweden

Department of Haematology and Oncology Centre Hospitalier de Versailles Inserm Unité Mixte de Recherche 1173 Université Versailles Saint Quentin en Yvelines Université Paris Saclay Le Chesnay France

Department of Haematology and Oncology University Hospital Mannheim Heidelberg University Mannheim Germany

Department of Haematology Odense University Hospital Odense Denmark

Department of Haematology Oncology and Radiation Physics Skåne University Hospital Lund Sweden

Department of Haematology St Olavs Hospital Trondheim Norway

Department of Haematology University Hospital of North Norway Tromsø Norway

Department of Haematology VU University Medical Center Amsterdam Netherlands

Department of Internal Medicine Haematology and Oncology Masaryk University and University Hospital Brno Brno Czech Republic

Department of Medical Science and Division of Haematology University Hospital Uppsala Sweden

Division of Clinical Genetics Lund University Lund Sweden

Haematology Research Unit Helsinki University of Helsinki Helsinki Finland

Helsinki University Hospital Comprehensive Cancer Center Helsinki Finland

Hématologie Biologique and Equipe d'Accueil 7453 Hemopaties Chroniques Heterogeneite Intra clonale Microenvironnement et Resistance Therapeutique CHU Estaing and Université Clermont Auvergne Clermont Ferrand France

Hospital Universitario 12 de Octubre Centro Nacional de Investigaciones OncolÓgicas Centro de Investigación Biomédica en Red de Cáncer Universidad Complutense de Madrid Madrid Spain

Inserm Centre d'Investigation Clinique 1402 Centre Hospitalier Universitaire de Poitiers Poitiers France

Institut für Medizinische Informationsverarbeitung Biometrie und Epidemiologie Ludwig Maximilians Universität Munich Germany

Institute for Hematology and Oncology Mannheim Germany

Institute of Haematology and Blood Transfusion Prague Czech Republic

Instituto Portugues de Oncologia de Lisboa de Francisco Gentil Lisbon Portugal

Klinik für Innere Medizin 2 Universitätsklinikum Jena Jena Germany

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