Περίληψη:
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
Συγγραφείς:
Saussele, S.
Richter, J.
Guilhot, J.
Gruber, F.X.
Hjorth-Hansen, H.
Almeida, A.
Janssen, J.J.W.M.
Mayer, J.
Koskenvesa, P.
Panayiotidis, P.
Olsson-Strömberg, U.
Martinez-Lopez, J.
Rousselot, P.
Vestergaard, H.
Ehrencrona, H.
Kairisto, V.
Machová Poláková, K.
Müller, M.C.
Mustjoki, S.
Berger, M.G.
Fabarius, A.
Hofmann, W.-K.
Hochhaus, A.
Pfirrmann, M.
Mahon, F.-X.
Ossenkoppele, G.
Pagoni, M.N.
Söderlund, S.
Escoffre-Barbe, M.
Etienne, G.
Dengler, J.
Huguet, F.
von Bubnoff, N.
Klamova, H.
Faber, E.
Guilhot, F.
Lotfi, K.
Rea, D.
Brümmendorf, T.H.
de Greef, G.E.
Stenke, L.
Nicolini, F.E.
Legros, L.
Burchert, A.
Voglova, J.
Charbonnier, A.
Gyan, E.
Kunzmann, V.
Westerweel, P.E.
EURO-SKI investigators
Λέξεις-κλειδιά:
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
