Characteristics and mutation analysis of Ph-positive leukemia patients with T315I mutation receiving tyrosine kinase inhibitors
Authors Xu PP, Guo D, Shao XY, Peng MX, Chen B
Received 24 May 2017
Accepted for publication 16 August 2017
Published 25 September 2017 Volume 2017:10 Pages 4731—4738
Checked for plagiarism Yes
Review by Single-blind
Peer reviewers approved by Dr Akshita Wason
Peer reviewer comments 2
Editor who approved publication: Dr Carlos Vigil Gonzales
Peipei Xu,1 Dan Guo,2 Xiaoyan Shao,1 Miaoxin Peng,1 Bing Chen2
1Department of Hematology, Drum Tower Hospital, School of Medicine, Nanjing University, 2Department of Hematology, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, People’s Republic of China
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 149.7×109/L, whereas the average platelet count was only 53.88×109/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 >20×109/L, poor survival prognosis was observed.
Keywords: acute lymphoblastic leukemia, chronic myeloid leukemia, BCR-ABL positive, T315I mutation
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