High-sensitivity detection of BCR-ABL kinase domain mutations in imatinib-naive patients: correlation with clonal cytogenetic evolution but not response to therapy.

Abstract

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 pretherapeutic specimens, consistent with selection of resistant clones in the presence of drug. However, the incidence of KD mutations in imatinibnaive patients, irrespective of response to therapy, is unknown. We studied mutation frequency in 66 patients with chronic myelogenous leukemia (CML), using cDNA sequencing and allele-specific oligonucleotide-polymerase chain reaction (ASO-PCR) assays for 8 common mutations. Thirteen patients were positive by ASO-PCR only, 1 by ASO-PCR and sequencing, and 1 by sequencing only (overall frequency, 22.7%). T315I was most frequent (12% of patients). Eleven of the 14 patients with positive ASO-PCR had follow-up samples available for sequencing. Wild-type sequence was detected in 6 of 11, 2 different mutations in 1 of 11, and identical mutations in 4 of 11 patients, 2 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 survival, 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.

• Authors: Stephanie G Willis, Thoralf Lange, Shadmehr Demehri, Sandra Otto, Lucy Crossman, Dietger Niederwieser, Eric P Stoffregen, Shannon McWeeney, Ines Kovacs, Byung Park, Brian J Druker, Michael W Deininger
• Journal: Blood (Blood) Vol. 106 Issue 6 Pg. 2128-37 (Sep 15 2005) ISSN: 0006-4971 [Print] United States
• PMID: 15914554 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Benzamides
• Piperazines
• Pyrimidines
• Imatinib Mesylate
• Protein-Tyrosine Kinases
• Fusion Proteins, bcr-abl

Topics

• Adult
• Aged
• Aged, 80 and over
• Benzamides
• Clone Cells
• DNA Mutational Analysis
• Drug Resistance, Neoplasm (genetics)
• Female
• Fusion Proteins, bcr-abl (genetics)
• Gene Frequency
• Humans
• Imatinib Mesylate
• Karyotyping
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive (drug therapy, genetics, mortality)
• Male
• Middle Aged
• Multivariate Analysis
• Mutation
• Piperazines
• Protein-Tyrosine Kinases (genetics)
• Pyrimidines
• Risk Factors
• Sensitivity and Specificity
• Treatment Outcome