title: Coexisting with clonal evolution and BCR-ABL mutant in CML patients treated with second-generation tyrosine kinase inhibitors predict the discrepancy of in vitro drug sensitivity.
abstract: OBJECTIVE
  Second-generation tyrosine kinase inhibitors (second TKIs) such as nilotinib and dasatinib control the activity of most ABL kinase domain mutations observed in patients with imatinib resistance. Although in vitro data show that both agents can inhibit all mutations except T315I, some discrepancies have been observed in a small subset of mutation clones. Cytogenetic clonal evolution is the important resistance mechanism of chronic myeloid leukemia (CML). Accordingly, we observed the clinical significance of coexisting with clonal evolution and BCR-ABL mutant in CML patients treated with second TKIs.
  
  
  METHODS
  We monitored BCR-ABL transcript kinetics, interrelationship of clones expressing non-mutated and mutant transcripts and clonal aberrations within Philadelphia (Ph) positive and negative clones, respectively, in eight patients with CML receiving dasatinib or nilotinib for 3~41 months.
  
  
  RESULTS
  Clinical responses were correlated with in vitro sensitivity of the BCR-ABL mutants to the second TKIs in four patients. Four patients showed resistance to the second TKIs as compared to in vitro observations; three of them developed chromosomal abnormalities in the Ph chromosome positive or negative metaphases. Another patient lost the original mutation but acquired a more resistant new mutation and became resistant to the second TKI.
  
  
  CONCLUSIONS
  Cytogenetic clonal evolution is an independent poor prognostic factor in CML, which could explain the onset of mechanisms for second TKIs resistance to ABL kinase domain mutations. The results indicate that an additional evaluation of chromosomal abnormalities is warranted when BCR-ABL mutants are more resistant than indicated by in vitro data.
authors.affiliation: Department of Hematology-Oncology, Chonnam National University Hwasun Hospital, Hwasun, Korea.
authors.forename: Jae-Sook
authors.initials: JS
authors.lastname: Ahn
authors.forename: Yeo-Kyeoung
authors.initials: YK
authors.lastname: Kim
authors.forename: Se Ryeon
authors.initials: SR
authors.lastname: Lee
authors.forename: Li
authors.initials: L
authors.lastname: Yu
authors.forename: Deok-Hwan
authors.initials: DH
authors.lastname: Yang
authors.forename: Sang-Hee
authors.initials: SH
authors.lastname: Cho
authors.forename: Hyun Jeong
authors.initials: HJ
authors.lastname: Shim
authors.forename: Woo Kyun
authors.initials: WK
authors.lastname: Bae
authors.forename: Je-Jung
authors.initials: JJ
authors.lastname: Lee
authors.forename: Ik-Joo
authors.initials: IJ
authors.lastname: Chung
authors.forename: Myung Gun
authors.initials: MG
authors.lastname: Shin
authors.forename: Hyeoung-Joon
authors.initials: HJ
authors.lastname: Kim