European LeukemiaNet criteria for failure or suboptimal response reliably identify patients with CML in early chronic phase treated with imatinib whose eventual outcome is poor

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European LeukemiaNet criteria for failure or suboptimal response reliably identify patients with CML in early chronic phase treated with imatinib whose eventual outcome is poor
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  doi:10.1182/blood-2008-06-162388Prepublished online August 20, 2008; Klammer, Jaspal Kaeda, John M Goldman and Jane F ApperleyAlistair G Reid, Letizia Foroni, Katayoun Rezvani, Marco Bua, Francesco Dazzi, Jiri Pavlu, Matthias David Marin, Dragana Milojkovic, Eduardo Olavarria, Jamshid S Khorashad, Hugues de Lavallade,  whose eventual outcome is pooridentify patients with CML in early chronic phase treated with imatinib European LeukemiaNet criteria for failure or sub-optimal response reliably  (4217 articles)Neoplasia  (1730 articles)Free Research Articles  (3716 articles)Clinical Trials and Observations  Articles on similar topics can be found in the following Blood collections  http://bloodjournal.hematologylibrary.org/site/misc/rights.xhtml#repub_requests Information about reproducing this article in parts or in its entirety may be found online at:  http://bloodjournal.hematologylibrary.org/site/misc/rights.xhtml#reprints Information about ordering reprints may be found online at:  http://bloodjournal.hematologylibrary.org/site/subscriptions/index.xhtml Information about subscriptions and ASH membership may be found online at: digital object identifier (DOIs) and date of initial publication. theindexed by PubMed from initial publication. Citations to Advance online articles must include final publication). Advance online articles are citable and establish publication priority; they areappeared in the paper journal (edited, typeset versions may be posted when available prior to Advance online articles have been peer reviewed and accepted for publication but have not yet  Copyright 2011 by The American Society of Hematology; all rights reserved.20036.the American Society of Hematology, 2021 L St, NW, Suite 900, Washington DC Blood (print ISSN 0006-4971, online ISSN 1528-0020), is published weekly by  For personal use only.at Jinan University Library on June 5, 2013. bloodjournal.hematologylibrary.orgFrom   1 E UROPEAN L EUKEMIA N ET CRITERIA FOR FAILURE OR SUB - OPTIMAL RESPONSE RELIABLY IDENTIFY PATIENTS WITH CML  IN EARLY CHRONIC PHASE TREATED WITH IMATINIB WHOSE EVENTUAL OUTCOME IS POOR David Marin, Dragana Milojkovic, Eduardo Olavarria, Jamshid S. Khorashad, Hugues de Lavallade, Alistair G Reid, Letizia Foroni, Katayoun Rezvani, Marco Bua, Francesco Dazzi, Jiri Pavlu, Matthias Klammer, Jaspal Kaeda, John M. Goldman, and Jane F. Apperley Department of Haematology, Hammersmith Hospitals Trust, Imperial College London, London, UK Address correspondence to:  Dr David Marin, Department of Haematology, Imperial College London, Du Cane Road, London W12 0NN, United Kingdom. Tel: +44 20 8383 1627 e-mail: d.marin@imperial.ac.uk Blood First Edition Paper, prepublished online August 20, 2008; DOI 10.1182/blood-2008-06-162388   Copyright © 2008 American Society of Hematology  For personal use only.at Jinan University Library on June 5, 2013. bloodjournal.hematologylibrary.orgFrom   2 ABSTRACT The majority of patients with CML in chronic phase (CP) gain substantial benefit from imatinib but some fail to respond or lose their initial response. In 2006 the European LeukemiaNet published recommendations designed to help identify patients responding poorly to imatinib. Patients were evaluated at 3, 6, 12 and 18 months and some were classified as ‘failure’ or ‘suboptimal responders’. We analyzed outcomes for 224 patients with CML-CP treated in a single institution to validate these recommendations. Patients were followed for a median of 46.1 months. At each time-point patients classified as ‘failure’ showed significantly worse survival, progression-free survival (PFS) and cytogenetic response than other patients; for example based on the assessment at 12 months the 5-year survival was 87.1% vs 95.1%, (p=0.02), PFS 76.% vs 90%, (p=0.002), and complete cytogenetic response rate 26.7% vs 94.1% (p<0.0001). Similarly the criteria for ‘sub-optimal response’ at 6 and 12 months identified patients destined to fare badly, though criteria at 18 months were less useful. The predictive value of some other individual criteria varied. In general the LeukemiaNet criteria have useful predictive value, but a case could now be made for combining the categories ‘failure’ and ‘sub-optimal response’. For personal use only.at Jinan University Library on June 5, 2013. bloodjournal.hematologylibrary.orgFrom   3 INTRODUCTION For most of the twentieth century little important progress was made in the management of patients with Ph-positive (or BCR-ABL-positive) chronic myeloid leukemia (CML). The minority of patients who were treated by allogeneic stem cell transplantation could expect to be cured if they survived the procedure but for the majority interferon-alfa alone or in combination with cytarabine offered the prospect of prolonging survival by one to two years compared with earlier use of conventional cytotoxic drugs. 1,2  The introduction into clinical practice of imatinib mesylate in 1998 proved to be a remarkable contribution to the management of patients with CML in chronic phase (CP) and this drug at 400 mg daily has now become the recommended initial treatment for all adult patients throughout the world. The majority of patients can now expect to survive ten, twenty or more years. 3,4  It is even possible that some patients treated for a number of years can stop the imatinib and be regarded as cured of their leukemia. 5  With this background it is important to recognise that although the majority of patients fare extremely well when treated with imatinib as a single agent, a significant minority do not. 4  Given the current availability of both allogeneic stem cell transplantation and second generation tyrosine kinase inhibitors it is essential to identify at the earliest opportunity these patients so that alternative treatment strategies can be introduced. In 2006 Baccarani and colleagues on behalf of the European LeukemiaNet published a series of empirical recommendations designed to help clinicians identify CML-CP patients responding poorly to imatinib at standard dosage 2  (Table 1). The recommendations were based on assessing response to treatment at various time-points using specific hematologic, cytogenetic and molecular criteria. Based on these criteria, patients could be classified as ‘failure’ or ‘suboptimal response’. Additional features defined at diagnosis or during the course of the disease indicated the need for closer follow-up of individual patients and were classified as ‘warnings’. Though not based on detailed evaluation of large numbers of patients followed for many years, these recommendations did indeed prove very valuable in helping clinicians plan therapy for individual patients and have gained wide acceptance on both sides of the Atlantic and elsewhere. Here we show that the clinical outcome for 224 newly diagnosed CML-CP patients treated in a single institution do indeed conform very well with results that could be anticipated from application of the recommendations For personal use only.at Jinan University Library on June 5, 2013. bloodjournal.hematologylibrary.orgFrom   4 but we note certain discordances that may prove useful when the recommendations are revised. PATIENTS AND METHODS Patient characteristics and treatment Between June 2000 and May 2007 224 consecutive adult patients with BCR-ABL-positive CML in CP received imatinib as first line therapy. Imatinib was started within 6 months of diagnosis, but no patient had received any previous anti-leukemia treatment other than hydroxyurea. Seventeen of these patients were included in the IRIS study. The Hammersmith Hospital study protocol was reviewed by the research ethics committee and patients gave written informed consent in accordance with the Declaration of Helsinki to participate. The definitions of CP and complete hematologic responses (CHR) were those used for the European LeukemiaNet recommendations 2 . Patients received imatinib 400 mg daily by mouth as previously described. 4  Bone marrow morphology and cytogenetics were assessed at diagnosis and then every 3 months until patients achieved CCyR. Thereafter patients were monitored by real-time quantitative PCR (RQ-PCR, see below) and annual bone marrow examinations. CCyR was defined by the failure to detect any Philadelphia (Ph) chromosome-positive metaphases in two consecutive bone marrow examinations with a minimum of 30 metaphases examined and major cytogenetic response (MCyR) was defined by combining the number of complete and partial cytogenetic responses ( ≤  35% Ph-positive metaphases). Cytogenetic relapse (loss of CCyR) was defined by the detection of one or more Ph-positive marrow metaphases, also confirmed by a subsequent study, in a patient who had previously achieved CCyR. Bone marrow examination was triggered by a rise in BCR-ABL transcript numbers to a level consistent with cytogenetic relapse. 6  Disease progression was defined when the leukemia satisfied criteria for advanced phase (accelerated or blastic phases). 7  The median age was 46.1 (range 18-79); 94 (42%) patients were female. Sixty two (27.7%), 94 (41.9%) and 68 (30.4%) patients belonged to the low, intermediate and high Sokal risk groups respectively. The median interval from diagnosis to beginning imatinib was 1.7 months (range 0-6). The median follow-up from starting imatinib For personal use only.at Jinan University Library on June 5, 2013. bloodjournal.hematologylibrary.orgFrom
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