Linked Life Data

12623848

Source:http://linkedlifedata.com/resource/pubmed/id/12623848

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
1
pubmed:dateCreated
2003-6-19
pubmed:abstractText
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.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
AIM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jul
pubmed:issn
0006-4971
pubmed:author
pubmed:issnType
Print
pubmed:day
1
pubmed:volume
102
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
276-83
pubmed:dateRevised
2007-11-15
pubmed:meshHeading
pubmed-meshheading:12623848-Adenosine Triphosphate, pubmed-meshheading:12623848-Adult, pubmed-meshheading:12623848-Aged, pubmed-meshheading:12623848-Binding Sites, pubmed-meshheading:12623848-DNA Mutational Analysis, pubmed-meshheading:12623848-Disease Progression, pubmed-meshheading:12623848-Drug Resistance, Neoplasm, pubmed-meshheading:12623848-Female, pubmed-meshheading:12623848-Fusion Proteins, bcr-abl, pubmed-meshheading:12623848-Genes, abl, pubmed-meshheading:12623848-Humans, pubmed-meshheading:12623848-Leukemia, Myelogenous, Chronic, BCR-ABL Positive, pubmed-meshheading:12623848-Male, pubmed-meshheading:12623848-Middle Aged, pubmed-meshheading:12623848-Mutation, pubmed-meshheading:12623848-Piperazines, pubmed-meshheading:12623848-Prognosis, pubmed-meshheading:12623848-Protein Structure, Tertiary, pubmed-meshheading:12623848-Pyrimidines, pubmed-meshheading:12623848-Survival Analysis
pubmed:year
2003
pubmed:articleTitle
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.
pubmed:affiliation
Division of Molecular Pathology, Institute of Medical and Veterinary Science, South Australia 5000, Australia. susan.branford@imvs.sa.gov.au
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't