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KMID : 0366220050400020082
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Korean Journal of Hematology
2005 Volume.40 No. 2 p.82 ~ p.92
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Clinical Resistance to the Tyrosine Kinase Inhibitor Imatinib (STI571) and Detection of BCR-ABL Gene Mutations in Korean Patients with Chronic Myeloid Leukemia
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Sohn Yong-Hak
Chi Hyun-Sook
Park Chan-Jeoung
Lee Kyoo-Hyung
Seo Eul-Ju
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Abstract
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Background: Imatinib mesylate, targeting the tyrosine kinase activity of BCR-ABL fusion gene, induces the remarkable remission in chronic myeloid leukemia (CML) patients. But, the resistance to imatinib has been observed in a significant proportion. The point mutations of BCR-ABL kinase domain have been clinically identified as a possible mechanism. The aim of this study was to investigate the clinical resistance to imatinib in Korean CML patients and to search the point mutation of BCR-ABL gene.
Methods: We evaluated the clinical data and cytogenetic results in thirty two CML patients who were treated with imatinib from Jan 2002 to Aug 2003. Mutational analyses for the point mutations of BCR-ABL kinase domain in clinically resistant patients were tested using RT-PCR and direct sequencing method.
Results: Complete hematologic remission were obtained in all CML patients with chronic phase and 4 of 6 CML patients with accelerated or blast crisis. But 4 patients (2 in chronic phase and 2 in blast crisis) relapsed to blast crisis during continued treatment. Major cytogenetic response was observed in 67% of chronic phase patients, but in 2 patients, Philadelphia chromosomes reemerged in follow-up chromosome study. Mutational analyses showed the point mutations in 351th amino acid of BCR-ABL kinase domain in 2 patients: M351T, previously reported in many studies, and novel substitution, M351L.
Conclusion: The frequency of imatinib resistance in Korea is similar to that of well-controlled western studies. Point mutations of BCR-ABL kinase domain were detected in two patients. Studies with more sensitive method and more patients will be helpful to reveal other mechanisms of imatinib resistance and to establish more effective treatment plan.
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KEYWORD
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Chronic myelogenous leukemia, Imatinib resistance, BCR-ABL tyrosine kinase, Point mutation
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