title: Determining the rise in BCR-ABL RNA that optimally predicts a kinase domain mutation in patients with chronic myeloid leukemia on imatinib.
abstract: 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.
authors.affiliation: Department of Pathology, Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97201, USA. pressr@ohsu.edu
authors.forename: Richard D
authors.initials: RD
authors.lastname: Press
authors.forename: Stephanie G
authors.initials: SG
authors.lastname: Willis
authors.forename: Jennifer
authors.initials: J
authors.lastname: Laudadio
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Mauro
authors.forename: Michael W N
authors.initials: MW
authors.lastname: Deininger
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001549:Benzamides; D005260:Female; D016044:Fusion Proteins, bcr-abl / Q000032:analysis / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000175:diagnosis* / Q000188:drug therapy* / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000502:physiology; D010770:Phosphotransferases / Q000737:chemistry / Q000235:genetics; D010879:Piperazines / Q000627:therapeutic use*; D011379:Prognosis; D017434:Protein Structure, Tertiary / Q000235:genetics; D011743:Pyrimidines / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000032:analysis; D012189:Retrospective Studies; D015854:Up-Regulation / Q000235:genetics; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D012333:RNA, Messenger; D000068877:Imatinib Mesylate; D010770:Phosphotransferases; D016044:Fusion Proteins, bcr-abl