Comparison of Frequency and Sensitivity of BCR-ABL1 Kinase Domain Mutations in Asian and White Patients With Imatinib-resistant Chronic-Phase Chronic Myeloid Leukemia

Clin Lymphoma Myeloma Leuk. 2018 Oct;18(10):e391-e399. doi: 10.1016/j.clml.2018.06.031. Epub 2018 Jul 4.

Abstract

Introduction: BCR-ABL1 mutations require consideration during second-line tyrosine kinase inhibitor selection for patients with chronic myeloid leukemia (CML). The present retrospective analysis compared the frequency of BCR-ABL1 mutations in Asian and white patients in whom imatinib therapy had failed.

Patients and methods: A nonstudy cohort (76 Asian patients from community clinical practices) and 2 study cohorts (29 Asian and 352 white patients from dasatinib phase II and III clinical trials) were identified.

Results: In the nonstudy cohort, 80 mutations were identified; the most frequent was T315I (15%), followed by phosphate-binding loop mutations E255K (11%), G250E (10%), and Y253H (10%). Asian patients had a greater proportion of T315I and phosphate-binding loop mutations compared with the white patients. The nonstudy cohort was less likely to have multiple mutations compared with either study cohort. Single mutations highly resistant to dasatinib, nilotinib, and bosutinib were more frequent in the Asian than in the white cohorts.

Conclusion: These results suggest that mutational analysis findings will be invaluable for choosing an appropriate second-line tyrosine kinase inhibitor in Asia.

Keywords: Asian countries; BCR-ABL1 mutation; CML; Drug resistance; Imatinib.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Aniline Compounds / administration & dosage
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Asian People / genetics*
  • Biomarkers, Tumor
  • Clinical Trials, Phase II as Topic
  • Clinical Trials, Phase III as Topic
  • Cohort Studies
  • DNA Mutational Analysis
  • Dasatinib / administration & dosage
  • Drug Resistance, Neoplasm / genetics*
  • Female
  • Follow-Up Studies
  • Fusion Proteins, bcr-abl / genetics*
  • Gene Frequency
  • Humans
  • Imatinib Mesylate / administration & dosage
  • Leukemia, Myeloid, Chronic-Phase / drug therapy
  • Leukemia, Myeloid, Chronic-Phase / ethnology*
  • Leukemia, Myeloid, Chronic-Phase / genetics*
  • Male
  • Middle Aged
  • Mutation*
  • Nitriles / administration & dosage
  • Prognosis
  • Pyrimidines / administration & dosage
  • Quinolines / administration & dosage
  • Survival Rate
  • White People / genetics*
  • Young Adult

Substances

  • Aniline Compounds
  • Biomarkers, Tumor
  • Nitriles
  • Pyrimidines
  • Quinolines
  • bosutinib
  • Imatinib Mesylate
  • Fusion Proteins, bcr-abl
  • nilotinib
  • Dasatinib