High sensitivity detection of BCR-ABL kinase domain mutations in imatinib-naive patients: correlation with clonal cytogenetic ev | CMLHope.Com

Posted by rob on May 27, 2005 under Uncategorized | Be the First to Comment

Mutations in the kinase domain (KD) of BCR-ABL are the leading cause of acquired imatinib resistance. In some cases, identical mutations were detected at relapse and in pre-therapeutic specimens, consistent with selection of resistant clones in the presence of drug. However, the incidence of KD mutations in imatinib-naive patients, irrespective of response to therapy, is unknown. We studied mutation frequency in 66 CML patients, using cDNA sequencing and allele specific oligonucleotide (ASO) – PCR assays for 8 common mutations. Thirteen patients were positive by ASO-PCR only, 1 by ASO-PCR and sequencing in 1 patient and 1 by sequencing only (overall frequency 22.7%). T315I was most frequent (12% of patients). Eleven of the 14 ASO-PCR-positive patients had follow-up samples available for sequencing. Wild type sequence was detected in 6/11, two different mutations in 1/11 and identical mutations in 4/11 patients, two of whom had achieved major cytogenetic response. In multivariate analysis mutation detection was associated with clonal cytogenetic evolution, exposure to 6-Thioguanine and a low platelet count, but not with response to imatinib, event-free and overall survival. KD mutants present at low levels do not invariably lead to relapse and additional factors are required to induce a fully drug resistant phenotype.

High sensitivity detection of BCR-ABL kinase domain mutations in imatinib-naive patients: correlation with clonal cytogenetic ev | CMLHope.Com