Discontinuation of tyrosine kinase inhibitor therapy in chronic myeloid leukaemia (EURO-SKI): a prespecified interim analysis of a prospective, multicentre, non-randomised, trial
Language English Country Great Britain, England Media print-electronic
Document type Clinical Trial, Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't
PubMed
29735299
DOI
10.1016/s1470-2045(18)30192-x
PII: S1470-2045(18)30192-X
Knihovny.cz E-resources
- MeSH
- Fusion Proteins, bcr-abl antagonists & inhibitors genetics MeSH
- Time Factors MeSH
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive drug therapy genetics mortality pathology MeSH
- Progression-Free Survival MeSH
- Adult MeSH
- Risk Assessment MeSH
- Protein Kinase Inhibitors administration & dosage adverse effects MeSH
- Clinical Decision-Making MeSH
- Middle Aged MeSH
- Humans MeSH
- Biomarkers, Tumor antagonists & inhibitors genetics MeSH
- Polymerase Chain Reaction MeSH
- Predictive Value of Tests MeSH
- Prospective Studies MeSH
- Antineoplastic Agents administration & dosage adverse effects MeSH
- Risk Factors MeSH
- Drug Administration Schedule MeSH
- Aged MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Clinical Trial MeSH
- Multicenter Study MeSH
- Research Support, Non-U.S. Gov't MeSH
- Geographicals
- Europe MeSH
- Names of Substances
- Fusion Proteins, bcr-abl MeSH
- BCR-ABL1 fusion protein, human MeSH Browser
- Protein Kinase Inhibitors MeSH
- Biomarkers, Tumor MeSH
- Antineoplastic Agents MeSH
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.
Bergonié Cancer Institute Inserm Unit 916 University of Bordeaux Bordeaux France
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 Medical Science and Division of Haematology University Hospital Uppsala Sweden
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
References provided by Crossref.org
European LeukemiaNet 2020 recommendations for treating chronic myeloid leukemia
ClinicalTrials.gov
NCT01596114
