The landscape of BCR-ABL mutations in patients with Philadelphia chromosome-positive leukaemias in the era of second-generation tyrosine kinase inhibitors

Sheng Hsuan Chien, Hsueng Mei Liu, Po Ming Chen, Po Shen Ko, Jeong Shi Lin, Ying Ju Chen, Li Hsuan Lee, Liang Tsai Hsiao, Tzeon Jye Chiou, Jyh Pyng Gau, Muh Hwa Yang, Chun Yu Liu

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)

Abstract

BCR-ABL mutations are associated with resistance to tyrosine kinase inhibitors (TKIs) in Philadelphia chromosome-positive leukaemia. The emergence of these mutations in the era of second-generation TKIs, such as dasatinib and nilotinib, remains an evolving field. We conducted a retrospective study to quantitatively characterize the BCR-ABL transcript and mutation status during treatment with first-generation and second-generation TKI therapies. BCR-ABL mutations were detected by direct sequencing for patients with Philadelphia chromosome-positive leukaemia receiving TKI therapies. The efficacy of TKI therapy was quantitatively assessed by calculating the log reduction of BCR-ABL transcripts, which was measured using real-time quantitative polymerase chain reaction. Fisher's exact test was performed to analyse the associations of log reduction <3 and mutation status. We found 35 patients harbouring 55 mutations of 43 different types, of which 30% occurred in patients receiving imatinib, 27% in nilotinib, and 43% in dasatinib. We found a novel germline mutation, N336 N (AAC➔AAT), and two novel frameshift mutations, Asn358Thr fs*14 and Gly251Ala fs*16. T315I was the most common missense mutation, followed by V299L and F317L. Intron 8 35-bp insertion was the most frequent frameshift mutation. Both missense and multiple BCR-ABL mutations were significantly associated with worse molecular response compared with the molecular response of patients without mutation. Missense mutations, rather than frameshift, were associated with less log reduction, while the T315I, F317L, and T315A mutations were significantly correlated with poor log reduction. Collectively, amino acid substitutions at T315I, F317L, and T315A accounted for the majority of missense mutations and the loss of major molecular response. Mutation analysis is essential for patients receiving TKI therapy who exhibit an unfavourable response. The present study provided a landscape of BCR-ABL mutations in the era of second-generation TKIs.

Original languageEnglish
Pages (from-to)390-398
Number of pages9
JournalHematological Oncology
Volume38
Issue number3
DOIs
Publication statusPublished - Aug 1 2020
Externally publishedYes

Keywords

  • BCR-ABL
  • chronic myeloid leukaemia
  • log reduction
  • mutation
  • tyrosine kinase inhibitor

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

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