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Characteristics and mutation analysis of Ph-positive leukemia patients with T315I mutation receiving tyrosine kinase inhibitors
BACKGROUND: TKIs are the first-line treatment for patients with Ph-positive (Ph+) leukemia. However, drug resistance is frequently observed, mainly due to mutations within the breakpoint cluster region-Abelson leukemia virus (BCR-ABL) kinase domain. The T315I substitution confers complete resistance...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Dove Medical Press
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5626416/ https://www.ncbi.nlm.nih.gov/pubmed/29026321 http://dx.doi.org/10.2147/OTT.S142482 |
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author | Xu, Peipei Guo, Dan Shao, Xiaoyan Peng, Miaoxin Chen, Bing |
author_facet | Xu, Peipei Guo, Dan Shao, Xiaoyan Peng, Miaoxin Chen, Bing |
author_sort | Xu, Peipei |
collection | PubMed |
description | BACKGROUND: TKIs are the first-line treatment for patients with Ph-positive (Ph+) leukemia. However, drug resistance is frequently observed, mainly due to mutations within the breakpoint cluster region-Abelson leukemia virus (BCR-ABL) kinase domain. The T315I substitution confers complete resistance to TKIs. The aim of this study was to analyze the clinical characteristics of 17 patients with T315I mutation after TKI treatment and provide a basis for prognosis. PATIENTS AND METHODS: The clinical data of 17 TKI-resistant Ph+ leukemia patients who were found to have a ABL kinase domain mutation from September 2008 to January 2017 were collected. Karyotypes and BCR-ABL fusion gene were analyzed by R-banding and fluorescence in situ hybridization, respectively. Total RNA was extracted by TRIzol reagent, and the ABL kinase domain mutation was detected by direct sequencing. RESULTS: A total of 17 patients reached effective remission including major molecular response and complete cytogenetic response. However, all the patients subsequently developed a T315I mutation after treatment with TKIs. The rate of the BCR-ABL fusion gene in most of the patients who developed the T315I mutation was significantly higher than that before the mutation. At initial diagnosis, patients average platelet count was 149.7×10(9)/L, whereas the average platelet count was only 53.88×10(9)/L after the T315I mutation (P<0.01). The results also showed that the survival time of patients with a high proportion of blast cells or a high number of white blood cells was obviously shortened. CONCLUSION: Patients platelet count decreased when detected with the T315I mutation compared with the initial diagnosis. Combined use of different TKIs and complex chromosomal karyotypes may promote the development of the T315I mutation. When the ratio of blast cells was >50% and the number of white blood cells was >20×10(9)/L, poor survival prognosis was observed. |
format | Online Article Text |
id | pubmed-5626416 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Dove Medical Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-56264162017-10-12 Characteristics and mutation analysis of Ph-positive leukemia patients with T315I mutation receiving tyrosine kinase inhibitors Xu, Peipei Guo, Dan Shao, Xiaoyan Peng, Miaoxin Chen, Bing Onco Targets Ther Original Research BACKGROUND: TKIs are the first-line treatment for patients with Ph-positive (Ph+) leukemia. However, drug resistance is frequently observed, mainly due to mutations within the breakpoint cluster region-Abelson leukemia virus (BCR-ABL) kinase domain. The T315I substitution confers complete resistance to TKIs. The aim of this study was to analyze the clinical characteristics of 17 patients with T315I mutation after TKI treatment and provide a basis for prognosis. PATIENTS AND METHODS: The clinical data of 17 TKI-resistant Ph+ leukemia patients who were found to have a ABL kinase domain mutation from September 2008 to January 2017 were collected. Karyotypes and BCR-ABL fusion gene were analyzed by R-banding and fluorescence in situ hybridization, respectively. Total RNA was extracted by TRIzol reagent, and the ABL kinase domain mutation was detected by direct sequencing. RESULTS: A total of 17 patients reached effective remission including major molecular response and complete cytogenetic response. However, all the patients subsequently developed a T315I mutation after treatment with TKIs. The rate of the BCR-ABL fusion gene in most of the patients who developed the T315I mutation was significantly higher than that before the mutation. At initial diagnosis, patients average platelet count was 149.7×10(9)/L, whereas the average platelet count was only 53.88×10(9)/L after the T315I mutation (P<0.01). The results also showed that the survival time of patients with a high proportion of blast cells or a high number of white blood cells was obviously shortened. CONCLUSION: Patients platelet count decreased when detected with the T315I mutation compared with the initial diagnosis. Combined use of different TKIs and complex chromosomal karyotypes may promote the development of the T315I mutation. When the ratio of blast cells was >50% and the number of white blood cells was >20×10(9)/L, poor survival prognosis was observed. Dove Medical Press 2017-09-25 /pmc/articles/PMC5626416/ /pubmed/29026321 http://dx.doi.org/10.2147/OTT.S142482 Text en © 2017 Xu et al. This work is published and licensed by Dove Medical Press Limited The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. |
spellingShingle | Original Research Xu, Peipei Guo, Dan Shao, Xiaoyan Peng, Miaoxin Chen, Bing Characteristics and mutation analysis of Ph-positive leukemia patients with T315I mutation receiving tyrosine kinase inhibitors |
title | Characteristics and mutation analysis of Ph-positive leukemia patients with T315I mutation receiving tyrosine kinase inhibitors |
title_full | Characteristics and mutation analysis of Ph-positive leukemia patients with T315I mutation receiving tyrosine kinase inhibitors |
title_fullStr | Characteristics and mutation analysis of Ph-positive leukemia patients with T315I mutation receiving tyrosine kinase inhibitors |
title_full_unstemmed | Characteristics and mutation analysis of Ph-positive leukemia patients with T315I mutation receiving tyrosine kinase inhibitors |
title_short | Characteristics and mutation analysis of Ph-positive leukemia patients with T315I mutation receiving tyrosine kinase inhibitors |
title_sort | characteristics and mutation analysis of ph-positive leukemia patients with t315i mutation receiving tyrosine kinase inhibitors |
topic | Original Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5626416/ https://www.ncbi.nlm.nih.gov/pubmed/29026321 http://dx.doi.org/10.2147/OTT.S142482 |
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