engleski

BCR-ABL KINASE DOMAIN MUTATIONS IN PRIMARY AND SECONDARY RESISTANT IMATINIB-TREATED CHRONIC MYELOID LEUKEMIA

Mutations of BCR-ABL tyrosine kinase domain are the major cause of resistance to imatinib in patients with chronic myeloid leukemia. However, it is not known whether KD mutant clones that are detectable prior to therapy are selected in the presence of imatinib, and whether they may predict for therapy outcome. We sought to investigate the occurrence and dynamics of 4 common KD mutations (T315I, F311L, E255K, E255V) in imatinib-treated patients lacking predicted therapy response (by ELN criteria). Eleven of 41 imatinib-treated CML patients showed primary resistance to imatinib with inadequate CgR and consistently high levels of BCR-ABL transcripts monitored by real-time PCR. Using ASO-PCR we investigated the prevalence and the evolution of the above mentioned mutations in pretherapeutic diagnostic samples and in follow-up samples collected throughout imatinib therapy. In 3 patients F311L mutation was detected in imatinib-naive pretherapeutic leukemic samples. Eight patients showed no mutations at the time of diagnosis. After 24 months of imatinib therapy identical mutation status was identified in 5/12 patients (41.6%). Two patients acquired additional mutation (E255K, E255V, one each) and had approximately 10 times higher BCR-ABL transcripts compared to patients with single KD mutation. T315I mutation was not detected. We conclude that: (1) increased proportion of mutated sequences during treatment detected by ASO-PCR suggests clonal evolution of mutated cells, (2) KD mutations are not restricted to the accelerated phase of the disease, and in some cases, mutations occur in chronic phase of the disease and prior to imatinib therapy.

CML; imatinib therapy; KD mutations; imatinib resistance; ASO-PCR

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