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Blood, 24 September 2009, Vol. 114, No. 13, pp. 2598-2605. Prepublished online as a Blood First Edition Paper on July 22, 2009; DOI 10.1182/blood-2008-08-173674. This Article Full Text Full Text (PDF) All Versions of this Article: blood-2008-08-173674v1 114/13/2598    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Google Scholar Articles by Press, R. D. Articles by Deininger, M. W. N. PubMed PubMed Citation Articles by Press, R. D. Articles by Deininger, M. W. N. Related Collections Free Research Articles Myeloid Neoplasia Clinical Trials and Observations Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  CLINICAL TRIALS AND OBSERVATIONS Determining the rise in BCR-ABL RNA that optimally predicts a kinase domain mutation in patients with chronic myeloid leukemia on imatinib Richard D. Press1, Stephanie G. Willis2, Jennifer Laudadio1, Michael J. Mauro2, and Michael W. N. Deininger2,3 1 Department of Pathology and 2 Center for Hematologic Malignancies, Knight Cancer Institute, Oregon Health & Science University, Portland; and 3 Department of Hematology, University of Leipzig, Leipzig, Germany In imatinib-treated chronic myeloid leukemia (CML), secondary drug resistance is often caused by mutations in the BCR-ABL kinase domain (KD). As alternative therapies are available for imatinib resistance, early identification of mutations may prevent disease progression. Because most patients are routinely monitored by BCR-ABL quantitative polymerase chain reaction (PCR), it is important to define the optimal increase in BCR-ABL that should trigger mutation testing. Expert panels have provisionally recommended a 10-fold BCR-ABL increase as the trigger for mutation screening, acknowledging the lack of consensus. To address this question, we monitored 150 CML patients by quantitative PCR and DNA sequencing. Thirty-five different mutations were identified in 53 patients, and, during 22.5 months (median) of follow-up after sequencing, mutations were significantly predictive of shorter progression-free survival. An unbiased receiver operating characteristic analysis identified a 2.6-fold increase in BCR-ABL RNA as the optimal cutoff for predicting a concomitant KD mutation, with a sensitivity of 77% (94% if including subsequent samples). The 2.6-fold threshold approximated the analytic precision limit of our PCR assay. In contrast, transcript rise cutoffs of 5-fold or greater had poor diagnostic sensitivity and no significant association with mutations. We conclude that the currently recommended 10-fold threshold to trigger mutation screening is insensitive and not universally applicable. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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