Analysis of Bcr-Abl kinase domain mutations in Korean chronic myeloid leukaemia patients: poor clinical outcome of P-loop and T315I mutation is disease phase dependent.
Despite durable responses to imatinib in chronic myeloid leukaemia (CML), mutations in Bcr-Abl kinase domain (KD) are known to induce imatinib resistance and cause poor clinical outcome. We characterized Bcr-Abl KD mutations in 137 Korean CML patients with imatinib resistance (n = 111) or intolerance (n = 26) using allele specific oligonucleotide polymerase chain reaction (PCR) and direct sequencing. Seventy (51%) patients harboured 81 mutations of 20 different types with increasing prevalence in advanced phase. Nine (13%) patients had multiple mutations. No mutation was found in intolerant patients. T315I was the most common mutation and P-loop was the hottest spot in Bcr-Abl KD. Patients harbouring P-loop mutation, T315I, or multiple mutations showed poor overall survival and progression free survival compared with patients harbouring other mutations. Survival analysis according to disease phase of mutation being detected and type of mutations provided correlation between P-loop or T315I mutation and poor overall survival in blast crisis, but not in accelerated phase (AP) or chronic phase (CP), indicating poor clinical outcome of particular mutations depends on disease phase. CML patients with imatinib resistance showed high rate (63%) of mutations in Bcr-Abl KD and therefore CML patients who do not respond to imatinib should be the candidates for mutation screening as molecular monitoring.
Kim
Soo-Hyun
SH
Molecular Genetics Research Institute, The Catholic University of Korea, Seoul, Korea.
Kim
Dongho
D
Kim
Dong-Wook
DW
Goh
Hyun-Gyung
HG
Jang
Se-Eun
SE
Lee
Jeong
J
Kim
Wan-Seok
WS
Kweon
Il-Young
IY
Park
Sa-Hee
SH
D000293:Adolescent; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology; D001549:Benzamides; D004252:DNA Mutational Analysis; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm; D005260:Female; D016044:Fusion Proteins, bcr-abl / Q000235:genetics*; D006801:Humans; D000068877:Imatinib Mesylate; D007723:Korea / Q000453:epidemiology; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics; D008297:Male; D008875:Middle Aged; D010879:Piperazines / Q000494:pharmacology*; D011379:Prognosis; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D011743:Pyrimidines / Q000494:pharmacology*; D015996:Survival Rate; D016896:Treatment Outcome; D055815:Young Adult
D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl