title: Real-time quantitative PCR analysis can be used as a primary screen to identify patients with CML treated with imatinib who have BCR-ABL kinase domain mutations.
abstract: Mutations within the BCR-ABL kinase domain in imatinib-treated chronic myeloid leukemia (CML) are the main mechanism of acquired resistance. The early detection of mutations should provide clinical benefit by allowing early intervention. Quantitative polymerase chain reaction (RQ-PCR) results of BCR-ABL mRNA were correlated with mutation analysis in 214 patients treated with imatinib. We determined whether there was a difference in the incidence of mutations between the patients with a more than 2-fold rise in BCR-ABL and patients with stable or decreasing levels. Of the 56 patients with a more than 2-fold rise, 34 (61%) had detectable mutations (median rise, 3.0-fold; 25th-75th percentiles, 2.3-5.2). In 31 (91%) of these 34 patients, the mutation was present at the time of the rise and became detectable within 3 months in the remaining patients. Only 1 (0.6%) of 158 patients with stable or decreasing BCR-ABL levels had a detectable mutation, P less than .0001. Thus, a more than 2-fold rise identified 34 (97%) of 35 patients with a mutation. We conclude that a rise in BCR-ABL of more than 2-fold can be used as a primary indicator to test patients for BCR-ABL kinase domain mutations.
authors.affiliation: Division of Molecular Pathology, Institute of Medical and Veterinary Science, Adelaide, Australia. susan.branford@imvs.sa.gov.au
authors.forename: Susan
authors.initials: S
authors.lastname: Branford
authors.forename: Zbigniew
authors.initials: Z
authors.lastname: Rudzki
authors.forename: Ian
authors.initials: I
authors.lastname: Parkinson
authors.forename: Andrew
authors.initials: A
authors.lastname: Grigg
authors.forename: Kerry
authors.initials: K
authors.lastname: Taylor
authors.forename: John F
authors.initials: JF
authors.lastname: Seymour
authors.forename: Simon
authors.initials: S
authors.lastname: Durrant
authors.forename: Peter
authors.initials: P
authors.lastname: Browett
authors.forename: Anthony P
authors.initials: AP
authors.lastname: Schwarer
authors.forename: Chris
authors.initials: C
authors.lastname: Arthur
authors.forename: John
authors.initials: J
authors.lastname: Catalano
authors.forename: Michael F
authors.initials: MF
authors.lastname: Leahy
authors.forename: Robin
authors.initials: R
authors.lastname: Filshie
authors.forename: Kenneth
authors.initials: K
authors.lastname: Bradstock
authors.forename: Richard
authors.initials: R
authors.lastname: Herrmann
authors.forename: David
authors.initials: D
authors.lastname: Joske
authors.forename: Kevin
authors.initials: K
authors.lastname: Lynch
authors.forename: Tim
authors.initials: T
authors.lastname: Hughes
mesh_terms: D001549:Benzamides; D004252:DNA Mutational Analysis / Q000379:methods; D016903:Drug Monitoring / Q000379:methods; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D016044:Fusion Proteins, bcr-abl / Q000097:blood* / Q000235:genetics*; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D010879:Piperazines / Q000627:therapeutic use*; D016133:Polymerase Chain Reaction / Q000379:methods*; D011237:Predictive Value of Tests; D017434:Protein Structure, Tertiary / Q000235:genetics; D011743:Pyrimidines / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000097:blood
chemical_list: D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D012333:RNA, Messenger; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl