Emerging kinetics of BCR-ABL1 mutations and their effect on disease outcomes in chronic myeloid leukemia patients with imatinib failure.
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.
Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan. sly7012@adm.cgmh.org.tw
Lee-Yung
LY
Shih
Ming-Chung
MC
Kuo
Ching-Yuan
CY
Kuo
Tseng-Hsi
TH
Lin
Li-Yaun
LY
Bai
Tsai-Yun
TY
Chen
Ming-Chung
MC
Wang
Tung-Liang
TL
Lin
Yii-Jenq
YJ
Lan
Chih-Cheng
CC
Chen
Youngsen
Y
Yang
Pei-Ching
PC
Hsiao
Chang-Liang
CL
Lai
Chia-Hui
CH
Chang
Tung-Huei
TH
Lin
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001549:Benzamides; D005260:Female; D016044:Fusion Proteins, bcr-abl / Q000235:genetics*; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation; D010879:Piperazines / Q000627:therapeutic use*; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011743:Pyrimidines / Q000627:therapeutic use*; D017211:Treatment Failure
D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl