Susanne Saussele1, Johan Richter2, Joelle Guilhot3, Franz X Gruber4, Henrik Hjorth-Hansen5, Antonio Almeida6, Jeroen J W M Janssen7, Jiri Mayer8, Perttu Koskenvesa9, Panayiotis Panayiotidis10, Ulla Olsson-Strömberg11, Joaquin Martinez-Lopez12, Philippe Rousselot13, Hanne Vestergaard14, Hans Ehrencrona15, Veli Kairisto16, Katerina Machová Poláková17, Martin C Müller18, Satu Mustjoki19, Marc G Berger20, Alice Fabarius1, Wolf-Karsten Hofmann1, Andreas Hochhaus21, Markus Pfirrmann22, Francois-Xavier Mahon23. 1. Department of Haematology and Oncology, University Hospital Mannheim, Heidelberg University, Mannheim, Germany. 2. Department of Haematology, Oncology and Radiation Physics, Skåne University Hospital, Lund, Sweden. 3. Inserm Centre d'Investigation Clinique 1402, Centre Hospitalier Universitaire (CHU) de Poitiers, Poitiers, France. 4. Department of Haematology, University Hospital of North Norway, Tromsø, Norway. 5. Department of Haematology, St Olavs Hospital, Trondheim, Norway. 6. Instituto Portugues de Oncologia de Lisboa de Francisco Gentil, Lisbon, Portugal. 7. Department of Haematology, VU University Medical Center, Amsterdam, Netherlands. 8. Department of Internal Medicine, Haematology and Oncology, Masaryk University and University Hospital Brno, Brno, Czech Republic. 9. Haematology Research Unit Helsinki, University of Helsinki, Helsinki, Finland; Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland. 10. First Department of Internal Medicine, Laikon General Hospital, National and Kapodistrian University of Athens, Athens, Greece. 11. Department of Medical Science and Division of Haematology, University Hospital, Uppsala, Sweden. 12. Hospital Universitario 12 de Octubre, Centro Nacional de Investigaciones OncolÓgicas, Centro de Investigación Biomédica en Red de Cáncer, Universidad Complutense de Madrid, Madrid, Spain. 13. 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. 14. Department of Haematology, Odense University Hospital, Odense, Denmark. 15. Department of Clinical Genetics and Pathology, Laboratory Medicine, Office for Medical Services, Lund, Sweden; Division of Clinical Genetics, Lund University, Lund, Sweden. 16. Department of Clinical Chemistry and Department of Genetics, Turku University Central Hospital, Turku, Finland. 17. Institute of Haematology and Blood Transfusion, Prague, Czech Republic. 18. Institute for Hematology and Oncology, Mannheim, Germany. 19. Haematology Research Unit Helsinki, University of Helsinki, Helsinki, Finland; Department of Clinical Chemistry and Haematology, University of Helsinki, Helsinki, Finland; Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland. 20. 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. 21. Klinik für Innere Medizin II, Universitätsklinikum Jena, Jena, Germany. 22. Institut für Medizinische Informationsverarbeitung, Biometrie und Epidemiologie, Ludwig-Maximilians-Universität, Munich, Germany. 23. Bergonié Cancer Institute, Inserm Unit 916, University of Bordeaux, Bordeaux, France. Electronic address: francois-xavier.mahon@u-bordeaux.fr.
Abstract
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.
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.
Authors: Hein Than; Anthony D Pomicter; Dongqing Yan; Larry P Beaver; Anna M Eiring; William L Heaton; Anna Senina; Phillip M Clair; Sharon Shacham; Clinton C Mason; Thomas O' Hare; Michael W Deininger Journal: Leukemia Date: 2020-01-24 Impact factor: 11.528