engleski

T315I mutation detection in patients resistant to imatinib mesylate therapy

Introduction: Chronic myeloid leukemia (CML) is a myeloproliferative disease characterized by the presence of BCR-ABL fusion gene and consequently bcr-abl fusion protein. Although the discovery of tyrosine kinase inhibitor (TKI), imatinib mesylate, improved the treatment of CML patients, a proportion of patients develop resistance to drug resulting in increased bcr-abl level. One of possible reasons for resistance are mutations in ABL kinase domain. Some mutations can be overcome by increasing the drug dose or by using the new generation of TKI. The only mutation resistant to currently available TKI is T315I. The aim of this study was to detect if the presence of T315I is the cause for increase or constantly high bcr-abl level. Materials and methods: Twenty-four CML patients with inadequate response to therapy were included in the study: 10 patients with suboptimal response, 8 patients with failure in response to therapy and 6 patients with > 1 log increase of bcr-abl level over time. ASO-PCR for T315I detection was performed according to Kang et al (Haematologica, 2006 ; 91:659). Positive control was DNA sample from a patient with confirmed T315I mutation. Results: T315I was detected in 4/24 patients (17%). All patients with mutation had high bcr-abl levels (12.7-38.1% ; 24.9-26.1% ; 12.5-30.4% according to International Scale and permanently positive qualitative PCR for the last patient). Mean bcr-abl level before the mutation request for all 4 patients was 23.1% and the patients did not respond to the increase of therapeutic dose. Conclusion: ASO-PCR enables, with sensitivity of 1/1000, detection T315I which is one of important prognostic factors for disease course as the treatment of choice for mutation carriers is bone marrow transplantation.

Chronic myeloid leukemia; T315I mutation

nije evidentirano