Clinical Resistance to the Tyrosine Kinase Inhibitor Imatinib (STI571) and Detection of BCR-ABL Gene Mutations in Korean Patients with Chronic Myeloid Leukemia

Abstract

Background: Imatinib mesylate, the tyrosine kinase activity of the BCR-ABL fusion gene, induces a remarkable remission in chronic myeloid leukemia (CML) patients. However, resistance to imatinib has been observed in a significant proportion of subjects, with the point mutations of the BCR-ABL kinase domain clinically identified as a possible mechanism. The aim of this study was to investigate clinical resistance to imatinib in Korean CML patients, and search for the point mutation of the BCR-ABL gene. Methods: The clinical data and cytogenetic results of thirty two CML pat ients, who were treated with imatinib, between Jan. 2002 and Aug. 2003, were evaluated. Mutational analyses for the point mutations of the BCR-ABL kinase domain in clinically resistant patients were tested using RT-PCR and direct sequencing methods. Results: Complete hematological remission was obtained in all CML patients with a chronic phase and in 4 of 6 CML with accelerated or blast crisis. However, 4 patients (2 in the chronic phase and 2 with blast crisis) relapsed to blast crisis following continued treatment. A major cytogenetic response was observed in 67% of the chronic phase patients, but in 2, the Philadelphia chromosomes reemerged in a follow-up chromosome study. Mutational analyses showed point mutations in the 351st amino acid of the BCR-ABL kinase domain in 2 patients: M351T, which has previously been reported in many studies, and a novel substitution, M351L. Conclusion: The frequency of imatinib resistance in Koreans was similar to that found in well-controlled western studies. Point mutations of the BCR-ABL kinase domain were detected in two patients. Further studies, with more sensitive methods and a greater number of patients will help reveal other mechanisms of imatinib resistance and establish more effective treatment plans.