Chronic myeloid leukemia. Genetic mechanisms of resistance to Imatinib

There is a subset of patients treated with Imatinib who either fail to achieve or lose hematological/ complete cytogenetic response (CCyR). Both BCR-ABL dependent and independent mechanisms of resistance have been described. We have performed an open label, multi-centric, non randomized, cross sectional study in order to investigate ABL kinase domain mutations, amplifications/overexpression of BCR-ABL transcripts in Imatinib resistant patients. A total of 96 patients (pts) were studied and 79 were evaluable. Twenty mutations were detected (25%), one patient (1.2%) had BCR-ABL amplifications with 4-6 signals in interphase nucleus and five patients (6.3%) had clonal evolution with double Ph chromosome. T3151 mutation was detected in one patient. Median time from CIVIL diagnosis and initiation of Imatinib therapy was 61(1.4-158) and 40 (1-66.5) months respectively. (p=0.08 and p=0.224). In a univariate model, advanced stage disease at time of Imatinib failure (p=0.007) was associated with development of mutations. P loop mutations were the most frequent. Point mutations of the AN kinase domain appear to be the more common mechanism of Imatinib resistance. Its early detection may induce changes in therapeutic strategy such as dose escalation, combination therapy or second generation tyrosine kinase inhibitors.