Emerging kinetics of BCR-ABL1 mutations and their effect on disease outcomes in chronic myeloid leukemia patients with imatinib failure

Lee Yung Shih, Ming Chung Kuo, Ching Yuan Kuo, Tseng Hsi Lin, Li Yaun Bai, Tsai Yun Chen, Ming Chung Wang, Tung Liang Lin, Yii Jenq Lan, Chih Cheng Chen, Youngsen Yang, Pei Ching Hsiao, Chang Liang Lai, Chia Hui Chang, Tung Huei Lin

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Abstract

Some chronic myeloid leukemia (CML) patients treated with tyrosine kinase inhibitor (TKI) do not respond or relapse. BCR-ABL1 mutations are the principal cause of TKI resistance, but the kinetics of emerging mutations in CML patients treated with imatinib remain to be determined. To investigate the emergence dynamics of mutations and their effects on outcomes, we conducted a systematically longitudinal study of BCR-ABL1 mutation dynamics during TKI therapy. Seminested polymerase chain reaction followed by denaturing high-performance liquid chromatography with sequence confirmation were used to detect BCR-ABL1 mutations in 202 CML patients with imatinib resistance at different CML phases. We detected 68 mutations in 58 imatinib-failure patients. Mutations were present in 27.6% of patients who failed front-line imatinib therapy and in 68.1% with advanced disease. Mutations were not detected in patients before commencing imatinib treatment. Pyrosequencing was then used to quantitatively monitor the mutant levels sequentially and also traced back for their earlier appearance. The mutants differed in rapidity of emergence which appeared to arise in different time frame as well as in speed of rising mutant levels. In the 78 front-line imatinib-failure patients, mutation positive patients had significantly higher risk of disease progression or relapse and inferior progression-free survival compared to those without mutations (p=0.006). Our study demonstrates kinetics of different BCR-ABL1 mutant emergence and an association between BCR-ABL1 mutations and disease progression.

Original languageEnglish
Pages (from-to)43-49
Number of pages7
JournalLeukemia Research
Volume37
Issue number1
DOIs
Publication statusPublished - 2013 Jan 1

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Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Mutation
Protein-Tyrosine Kinases
Disease Progression
Imatinib Mesylate
Leukemia, Myeloid, Chronic Phase
Recurrence
Disease-Free Survival
Longitudinal Studies
Therapeutics
High Pressure Liquid Chromatography
Polymerase Chain Reaction

All Science Journal Classification (ASJC) codes

  • Hematology
  • Oncology
  • Cancer Research

Cite this

Shih, Lee Yung ; Kuo, Ming Chung ; Kuo, Ching Yuan ; Lin, Tseng Hsi ; Bai, Li Yaun ; Chen, Tsai Yun ; Wang, Ming Chung ; Lin, Tung Liang ; Lan, Yii Jenq ; Chen, Chih Cheng ; Yang, Youngsen ; Hsiao, Pei Ching ; Lai, Chang Liang ; Chang, Chia Hui ; Lin, Tung Huei. / Emerging kinetics of BCR-ABL1 mutations and their effect on disease outcomes in chronic myeloid leukemia patients with imatinib failure. In: Leukemia Research. 2013 ; Vol. 37, No. 1. pp. 43-49.
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abstract = "Some chronic myeloid leukemia (CML) patients treated with tyrosine kinase inhibitor (TKI) do not respond or relapse. BCR-ABL1 mutations are the principal cause of TKI resistance, but the kinetics of emerging mutations in CML patients treated with imatinib remain to be determined. To investigate the emergence dynamics of mutations and their effects on outcomes, we conducted a systematically longitudinal study of BCR-ABL1 mutation dynamics during TKI therapy. Seminested polymerase chain reaction followed by denaturing high-performance liquid chromatography with sequence confirmation were used to detect BCR-ABL1 mutations in 202 CML patients with imatinib resistance at different CML phases. We detected 68 mutations in 58 imatinib-failure patients. Mutations were present in 27.6{\%} of patients who failed front-line imatinib therapy and in 68.1{\%} with advanced disease. Mutations were not detected in patients before commencing imatinib treatment. Pyrosequencing was then used to quantitatively monitor the mutant levels sequentially and also traced back for their earlier appearance. The mutants differed in rapidity of emergence which appeared to arise in different time frame as well as in speed of rising mutant levels. In the 78 front-line imatinib-failure patients, mutation positive patients had significantly higher risk of disease progression or relapse and inferior progression-free survival compared to those without mutations (p=0.006). Our study demonstrates kinetics of different BCR-ABL1 mutant emergence and an association between BCR-ABL1 mutations and disease progression.",
author = "Shih, {Lee Yung} and Kuo, {Ming Chung} and Kuo, {Ching Yuan} and Lin, {Tseng Hsi} and Bai, {Li Yaun} and Chen, {Tsai Yun} and Wang, {Ming Chung} and Lin, {Tung Liang} and Lan, {Yii Jenq} and Chen, {Chih Cheng} and Youngsen Yang and Hsiao, {Pei Ching} and Lai, {Chang Liang} and Chang, {Chia Hui} and Lin, {Tung Huei}",
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Shih, LY, Kuo, MC, Kuo, CY, Lin, TH, Bai, LY, Chen, TY, Wang, MC, Lin, TL, Lan, YJ, Chen, CC, Yang, Y, Hsiao, PC, Lai, CL, Chang, CH & Lin, TH 2013, 'Emerging kinetics of BCR-ABL1 mutations and their effect on disease outcomes in chronic myeloid leukemia patients with imatinib failure', Leukemia Research, vol. 37, no. 1, pp. 43-49. https://doi.org/10.1016/j.leukres.2012.09.012

Emerging kinetics of BCR-ABL1 mutations and their effect on disease outcomes in chronic myeloid leukemia patients with imatinib failure. / Shih, Lee Yung; Kuo, Ming Chung; Kuo, Ching Yuan; Lin, Tseng Hsi; Bai, Li Yaun; Chen, Tsai Yun; Wang, Ming Chung; Lin, Tung Liang; Lan, Yii Jenq; Chen, Chih Cheng; Yang, Youngsen; Hsiao, Pei Ching; Lai, Chang Liang; Chang, Chia Hui; Lin, Tung Huei.

In: Leukemia Research, Vol. 37, No. 1, 01.01.2013, p. 43-49.

Research output: Contribution to journalArticle

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T1 - Emerging kinetics of BCR-ABL1 mutations and their effect on disease outcomes in chronic myeloid leukemia patients with imatinib failure

AU - Shih, Lee Yung

AU - Kuo, Ming Chung

AU - Kuo, Ching Yuan

AU - Lin, Tseng Hsi

AU - Bai, Li Yaun

AU - Chen, Tsai Yun

AU - Wang, Ming Chung

AU - Lin, Tung Liang

AU - Lan, Yii Jenq

AU - Chen, Chih Cheng

AU - Yang, Youngsen

AU - Hsiao, Pei Ching

AU - Lai, Chang Liang

AU - Chang, Chia Hui

AU - Lin, Tung Huei

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