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Statements

Subject Item
n2:RIV%2F65269705%3A_____%2F12%3A%230001665%21RIV13-MZ0-65269705
rdf:type
n5:Vysledek skos:Concept
dcterms:description
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. 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.
dcterms:title
Role of treatment in the appearance and selection of BCR-ABL1 kinase domain mutations Role of treatment in the appearance and selection of BCR-ABL1 kinase domain mutations
skos:prefLabel
Role of treatment in the appearance and selection of BCR-ABL1 kinase domain mutations Role of treatment in the appearance and selection of BCR-ABL1 kinase domain mutations
skos:notation
RIV/65269705:_____/12:#0001665!RIV13-MZ0-65269705
n5:predkladatel
n6:ico%3A65269705
n4:aktivita
n16:V n16:Z
n4:aktivity
V, Z(MSM0021622430)
n4:cisloPeriodika
4
n4:dodaniDat
n12:2013
n4:domaciTvurceVysledku
n9:5378605 n9:4585623 n9:1344153 n9:4376285 n9:3004880 n9:3715434 n9:4500970 n9:1344552
n4:druhVysledku
n13:J
n4:duvernostUdaju
n15:S
n4:entitaPredkladatele
n8:predkladatel
n4:idSjednocenehoVysledku
166084
n4:idVysledku
RIV/65269705:_____/12:#0001665
n4:jazykVysledku
n18:eng
n4:klicovaSlova
gene mutations
n4:klicoveSlovo
n10:gene%20mutations
n4:kodStatuVydavatele
NZ - Nový Zéland
n4:kontrolniKodProRIV
[24A01D31C760]
n4:nazevZdroje
Molecular diagnosis & therapy
n4:obor
n11:FD
n4:pocetDomacichTvurcuVysledku
8
n4:pocetTvurcuVysledku
8
n4:rokUplatneniVysledku
n12:2012
n4:svazekPeriodika
16
n4:tvurceVysledku
Rázga, Filip Mayer, Jiří Jurček, Tomáš Žáčková, Daniela Tošková, Martina Dvořáková, Dana Ježíšková, Ivana Ráčil, Zdeněk
n4:wos
000308681100006
n4:zamer
n17:MSM0021622430
s:issn
1177-1062
s:numberOfPages
9