title: Detection of BCR-ABL mutations in patients with CML treated with imatinib is virtually always accompanied by clinical resistance, and mutations in the ATP phosphate-binding loop (P-loop) are associated with a poor prognosis.
abstract: Imatinib-treated chronic myeloid leukemia (CML) patients with acquired resistance commonly have detectable BCR-ABL kinase domain mutations. It is unclear whether patients who remain sensitive to imatinib also have a significant incidence of mutations. We evaluated 144 patients treated with imatinib for BCR-ABL kinase domain mutations by direct sequencing of 40 accelerated phase (AP), 64 late chronic phase (> or = 12 months from diagnosis, late-CP), and 40 early-CP patients. Mutations were detected in 27 patients at 17 different residues, 13 (33%) of 40 in AP, 14 (22%) of 64 in late-CP, and 0 of 40 in early-CP. Acquired resistance was evident in 24 (89%) of 27 patients with mutations. Twelve (92%) of 13 patients with mutations in the adenosine triphosphate (ATP) binding loop (P-loop) died (median survival of 4.5 months after the mutation was detected). In contrast, only 3 (21%) of 14 patients with mutations outside the P-loop died (median follow-up of 11 months). As the detection of mutations was strongly associated with imatinib resistance, we analyzed features that predicted for their detection. Patients who commenced imatinib more than 4 years from diagnosis had a significantly higher incidence of mutations (18 [41%] of 44) compared with those treated within 4 years (9 [9%] of 100), P <.0001. Lack of a major cytogenetic response (MCR) was also associated with a higher likelihood of detecting a mutation; 19 (38%) of 50 patients without a MCR had mutations compared with 8 (8.5%) of 94 with an MCR, P <.0001. In conclusion, the detection of kinase domain mutations using a direct sequencing technique was almost always associated with imatinib resistance, and patients with mutations in the P-loop had a particularly poor prognosis.
authors.affiliation: Division of Molecular Pathology, Institute of Medical and Veterinary Science, South Australia 5000, 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: Sonya
authors.initials: S
authors.lastname: Walsh
authors.forename: Ian
authors.initials: I
authors.lastname: Parkinson
authors.forename: Andrew
authors.initials: A
authors.lastname: Grigg
authors.forename: Jeff
authors.initials: J
authors.lastname: Szer
authors.forename: Kerry
authors.initials: K
authors.lastname: Taylor
authors.forename: Richard
authors.initials: R
authors.lastname: Herrmann
authors.forename: John F
authors.initials: JF
authors.lastname: Seymour
authors.forename: Chris
authors.initials: C
authors.lastname: Arthur
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: D000255:Adenosine Triphosphate; D000328:Adult; D000368:Aged; D001549:Benzamides; D001665:Binding Sites / Q000235:genetics; D004252:DNA Mutational Analysis; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D016044:Fusion Proteins, bcr-abl / Q000235:genetics*; D016313:Genes, abl / Q000235:genetics; 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; D010879:Piperazines / Q000627:therapeutic use*; D011379:Prognosis; D017434:Protein Structure, Tertiary; D011743:Pyrimidines / Q000627:therapeutic use*; D016019:Survival Analysis
chemical_list: D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D000255:Adenosine Triphosphate; D016044:Fusion Proteins, bcr-abl