"Role of treatment in the appearance and selection of BCR-ABL1 kinase domain mutations" . "RIV/65269705:_____/12:#0001665" . . . "BACKGROUND AND OBJECTIVE: The availability of different tyrosine kinase inhibitors (TKIs) with distinct anti-leukemic potency enables optimization of current therapeutic regimens; however, some patients lose their therapy response and acquire TKI resistance. In this study, we describe a single-center experience of monitoring BCR-ABL1 kinase domain (KD) mutations and discuss the impact of treatment on mutation selection. METHODS: Chronic myelogenous leukemia (CML) patients treated with TKIs at the Department of Internal Medicine-Hematology and Oncology, Masaryk University and University Hospital Brno during 2003-2011 were included in this study. A total number of 100 patients who did not achieve an optimal therapy response or who lost their therapy response were screened for the presence of BCR-ABL1 KD mutations, using direct sequencing. RESULTS: Our data show that pretreatment with non-specific non-TKI drugs prior to TKI therapy does not preferentially select for initial BCR-ABL1 KD mutations, in contrast to first-line imatinib therapy, which shows a clear predominance of T315I or P-loop mutations compared with mutations located in other KD regions. In addition, the median time to detection of P-loop mutations was substantially shorter in patients treated with first-line imatinib than in those pretreated with non-TKI drugs. Furthermore, analysis of CML patients who had recurrent resistance to TKI therapy revealed possible therapy-driven selection of BCR-ABL1 KD mutations. Finally, we confirm the previously described poor prognosis of CML patients with mutations in the BCR-ABL1 KD, since 40.0% of our CML patients who harbored a BCR-ABL1 KD mutation died from CML while receiving TKI treatment. Moreover, among the patients who are still on treatment, 27.8% have already progressed. Our data also confirm the unique position of the T315I mutation with respect to its strong resistance to currently approved TKIs."@en . "8"^^ . . . "16" . "Role of treatment in the appearance and selection of BCR-ABL1 kinase domain mutations"@en . . "Molecular diagnosis & therapy" . "R\u00E1zga, Filip" . . "Mayer, Ji\u0159\u00ED" . . "V, Z(MSM0021622430)" . . . . . "Role of treatment in the appearance and selection of BCR-ABL1 kinase domain mutations"@en . "gene mutations"@en . "1177-1062" . "BACKGROUND AND OBJECTIVE: The availability of different tyrosine kinase inhibitors (TKIs) with distinct anti-leukemic potency enables optimization of current therapeutic regimens; however, some patients lose their therapy response and acquire TKI resistance. In this study, we describe a single-center experience of monitoring BCR-ABL1 kinase domain (KD) mutations and discuss the impact of treatment on mutation selection. METHODS: Chronic myelogenous leukemia (CML) patients treated with TKIs at the Department of Internal Medicine-Hematology and Oncology, Masaryk University and University Hospital Brno during 2003-2011 were included in this study. A total number of 100 patients who did not achieve an optimal therapy response or who lost their therapy response were screened for the presence of BCR-ABL1 KD mutations, using direct sequencing. RESULTS: Our data show that pretreatment with non-specific non-TKI drugs prior to TKI therapy does not preferentially select for initial BCR-ABL1 KD mutations, in contrast to first-line imatinib therapy, which shows a clear predominance of T315I or P-loop mutations compared with mutations located in other KD regions. In addition, the median time to detection of P-loop mutations was substantially shorter in patients treated with first-line imatinib than in those pretreated with non-TKI drugs. Furthermore, analysis of CML patients who had recurrent resistance to TKI therapy revealed possible therapy-driven selection of BCR-ABL1 KD mutations. Finally, we confirm the previously described poor prognosis of CML patients with mutations in the BCR-ABL1 KD, since 40.0% of our CML patients who harbored a BCR-ABL1 KD mutation died from CML while receiving TKI treatment. Moreover, among the patients who are still on treatment, 27.8% have already progressed. Our data also confirm the unique position of the T315I mutation with respect to its strong resistance to currently approved TKIs." . "NZ - Nov\u00FD Z\u00E9land" . "Jur\u010Dek, Tom\u00E1\u0161" . "\u017D\u00E1\u010Dkov\u00E1, Daniela" . . "To\u0161kov\u00E1, Martina" . "Dvo\u0159\u00E1kov\u00E1, Dana" . "RIV/65269705:_____/12:#0001665!RIV13-MZ0-65269705" . . . "Je\u017E\u00ED\u0161kov\u00E1, Ivana" . "Role of treatment in the appearance and selection of BCR-ABL1 kinase domain mutations" . . "R\u00E1\u010Dil, Zden\u011Bk" . . "9"^^ . . "4" . . . "166084" . "000308681100006" . . . . "8"^^ . "[24A01D31C760]" .