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.
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.
Ahn
Jae-Sook
JS
Department of Hematology-Oncology, Chonnam National University Hwasun Hospital, Hwasun, Korea.
Kim
Yeo-Kyeoung
YK
Lee
Se Ryeon
SR
Yu
Li
L
Yang
Deok-Hwan
DH
Cho
Sang-Hee
SH
Shim
Hyun Jeong
HJ
Bae
Woo Kyun
WK
Lee
Je-Jung
JJ
Chung
Ik-Joo
IJ
Shin
Myung Gun
MG
Kim
Hyeoung-Joon
HJ