Real-time quantitative PCR analysis can be used as a primary screen to identify patients with CML treated with imatinib who have BCR-ABL kinase domain mutations.
Mutations within the BCR-ABL kinase domain in imatinib-treated chronic myeloid leukemia (CML) are the main mechanism of acquired resistance. The early detection of mutations should provide clinical benefit by allowing early intervention. Quantitative polymerase chain reaction (RQ-PCR) results of BCR-ABL mRNA were correlated with mutation analysis in 214 patients treated with imatinib. We determined whether there was a difference in the incidence of mutations between the patients with a more than 2-fold rise in BCR-ABL and patients with stable or decreasing levels. Of the 56 patients with a more than 2-fold rise, 34 (61%) had detectable mutations (median rise, 3.0-fold; 25th-75th percentiles, 2.3-5.2). In 31 (91%) of these 34 patients, the mutation was present at the time of the rise and became detectable within 3 months in the remaining patients. Only 1 (0.6%) of 158 patients with stable or decreasing BCR-ABL levels had a detectable mutation, P less than .0001. Thus, a more than 2-fold rise identified 34 (97%) of 35 patients with a mutation. We conclude that a rise in BCR-ABL of more than 2-fold can be used as a primary indicator to test patients for BCR-ABL kinase domain mutations.
Branford
Susan
S
Division of Molecular Pathology, Institute of Medical and Veterinary Science, Adelaide, Australia. susan.branford@imvs.sa.gov.au
Rudzki
Zbigniew
Z
Parkinson
Ian
I
Grigg
Andrew
A
Taylor
Kerry
K
Seymour
John F
JF
Durrant
Simon
S
Browett
Peter
P
Schwarer
Anthony P
AP
Arthur
Chris
C
Catalano
John
J
Leahy
Michael F
MF
Filshie
Robin
R
Bradstock
Kenneth
K
Herrmann
Richard
R
Joske
David
D
Lynch
Kevin
K
Hughes
Tim
T
D001549:Benzamides; D004252:DNA Mutational Analysis / Q000379:methods; D016903:Drug Monitoring / Q000379:methods; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D016044:Fusion Proteins, bcr-abl / Q000097:blood* / Q000235:genetics*; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D010879:Piperazines / Q000627:therapeutic use*; D016133:Polymerase Chain Reaction / Q000379:methods*; D011237:Predictive Value of Tests; D017434:Protein Structure, Tertiary / Q000235:genetics; D011743:Pyrimidines / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000097:blood
D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D012333:RNA, Messenger; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl