Mutation detection and dynamics of BCR-ABL mutated clones in chronic myeloid leukemia patients on second generation tyrosine kinase inhibitors previously treated with imatinib

BENGIO RAQUEL; FERRI CRISTIAN; MOIRAGHI BEATRIZ; CARNAVI A; DRAGOSKY M; CRUSET S; PALMER S; SHANLEY C; VENTRIGLI V; RISSI M; MUROLO P; DIAZ VELEZ N; ROMINA M; FREITAS JBIANCHINI M; LARRIPA I

Estoril

Congreso; ESH: 17th Annual John Goldman Conference on Chronic Myeloid Leukemia: Biology and Therapy; 2015

European School of Hematology

Point mutations in the BCR-ABL oncogene arising as the major mechanism of resistance are associated with disease progression and shorter survival.Second line Tyrosine Kinase Inhibitors (TKIs) s are used to overcome resistance to IM; however, mutations have also been detected in a varying proportion of cases treated with nilotinib or dasatinib.The aim of our study was to detect and analyze the dynamics of the mutations over a period of 12 months follow up in patients (pts) on second line TKIs.Twenty nine resistant pts were enrolled into the study using the European Leukemia Net criteria of failure. Twenty four evaluable pts with a median age of 52 years old were systematically analyzed at 3 time-points: at study entry, at 6 and 12 months follow up. Three cases were in accelerated phase and 21 in chronic phase of disease. The detection was performed by both, Direct Sequencing (DS) and a more sensitive High Resolution Melting (HRM) analysis. An ARMS-PCR was used for quantification and dynamics assessment of the mutated clones in serial blood samples.HRM allowed mutation detection which overtook DS in only 1 patient.BCR-ABL1 mutations were detected at study entry and at sixth months in 16/24 pts (67%). At 12 months the mutations findings were:Undetectable in six patients; decrease in the size of mutant clones in five; two pts with compound mutations (two and three, respectively) had no significant quantitative variations through evolution. Three cases showed no changes in mutant clones.Seventeen mutations were identified at study entry: T315I in 4/14 (28, 6%), F317I in 2/14 (14, 2%), V299L in 2/14 (14, 2%), G250E in 2/14 (14, 2%) and F359V, L248M, E355K, E355G, Y253H, E255V, E244V in one case (7%). At six month, two more mutations were detected (Q252H and L364I), suggesting a clone selection by the second line therapy. The median time from diagnosis to study entry was 7.8 years, without significant differences between pts with or without mutations, while Sokal score (9.66±6.7 vs 1.33±0.2) was at the limit of significance.A decreased of the mutant clones was observed in 11/16 cases (69%), attributable to therapeutic interventions or another reasons under evaluation.Conclusion: the high frequency of pts with mutations is consistent with the characteristics of patient?s inclusion on 2nd or third relapse. It is remarkable that the assessment of the dynamics of mutations correlate with therapeutic changes.