TY - JOUR
TI - Discontinuation of tyrosine kinase inhibitor therapy in chronic myeloid leukaemia (EURO-SKI): a prespecified interim analysis of a prospective, multicentre, non-randomised, trial
AU - Saussele, S.
AU - Richter, J.
AU - Guilhot, J.
AU - Gruber, F.X.
AU - Hjorth-Hansen, H.
AU - Almeida, A.
AU - Janssen, J.J.W.M.
AU - Mayer, J.
AU - Koskenvesa, P.
AU - Panayiotidis, P.
AU - Olsson-Strömberg, U.
AU - Martinez-Lopez, J.
AU - Rousselot, P.
AU - Vestergaard, H.
AU - Ehrencrona, H.
AU - Kairisto, V.
AU - Machová Poláková, K.
AU - Müller, M.C.
AU - Mustjoki, S.
AU - Berger, M.G.
AU - Fabarius, A.
AU - Hofmann, W.-K.
AU - Hochhaus, A.
AU - Pfirrmann, M.
AU - Mahon, F.-X.
AU - Ossenkoppele, G.
AU - Pagoni, M.N.
AU - Söderlund, S.
AU - Escoffre-Barbe, M.
AU - Etienne, G.
AU - Dengler, J.
AU - Huguet, F.
AU - von Bubnoff, N.
AU - Klamova, H.
AU - Faber, E.
AU - Guilhot, F.
AU - Lotfi, K.
AU - Rea, D.
AU - Brümmendorf, T.H.
AU - de Greef, G.E.
AU - Stenke, L.
AU - Nicolini, F.E.
AU - Legros, L.
AU - Burchert, A.
AU - Voglova, J.
AU - Charbonnier, A.
AU - Gyan, E.
AU - Kunzmann, V.
AU - Westerweel, P.E.
AU - EURO-SKI investigators
JO - The lancet oncology
PY - 2018
VL - 19
TODO - 6
SP - 747-757
PB - The Lancet Publishing Group
SN - null
TODO - 10.1016/S1470-2045(18)30192-X
TODO - dasatinib;  imatinib;  nilotinib;  protein tyrosine kinase inhibitor;  antineoplastic agent;  BCR ABL protein;  BCR-ABL1 fusion protein, human;  protein kinase inhibitor;  tumor marker, abscess;  acute coronary syndrome;  adult;  aged;  alopecia;  angina pectoris;  arm pain;  arthralgia;  Article;  bile duct fistula;  blast cell crisis;  bone pain;  cancer growth;  cancer prognosis;  cancer survival;  cataract;  cerebrovascular accident;  chorioretinitis;  chronic myeloid leukemia;  cohort analysis;  common bile duct stone;  cornea ulcer;  cost control;  cost of illness;  coughing;  deep vein thrombosis;  depression;  diagnostic test accuracy study;  diplopia;  diverticulitis;  drug cost;  drug response;  drug withdrawal;  dyspnea;  enteropathy;  female;  follow up;  fragility fracture;  gluteal abscess;  heart arrhythmia;  heart failure;  heart infarction;  herpes zoster;  human;  hypertension;  hypothyroidism;  joint stiffness;  kidney cancer;  leg pain;  liver abscess;  low back pain;  lung cancer;  major clinical study;  male;  memory disorder;  mortality rate;  multicenter study;  musculoskeletal pain;  myalgia;  neck pain;  neuropathy;  open study;  pneumonia;  priority journal;  prospective study;  pyelonephritis;  recurrence free survival;  septicemia;  survival rate;  survival time;  throat disease;  throat edema;  thrombophlebitis;  transient ischemic attack;  treatment duration;  urine retention;  vertebral canal stenosis;  vestibular disorder;  withdrawal syndrome;  antagonists and inhibitors;  chronic myeloid leukemia;  clinical decision making;  clinical trial;  drug administration;  Europe;  genetics;  middle aged;  mortality;  pathology;  polymerase chain reaction;  predictive value;  risk assessment;  risk factor;  time factor, Adult;  Aged;  Antineoplastic Agents;  Biomarkers, Tumor;  Clinical Decision-Making;  Drug Administration Schedule;  Europe;  Female;  Fusion Proteins, bcr-abl;  Humans;  Leukemia, Myelogenous, Chronic, BCR-ABL Positive;  Male;  Middle Aged;  Polymerase Chain Reaction;  Predictive Value of Tests;  Progression-Free Survival;  Prospective Studies;  Protein Kinase Inhibitors;  Risk Assessment;  Risk Factors;  Time Factors
TODO - 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. © 2018 Elsevier Ltd
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