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Lookup NU author(s): Dr Feng Lin,
Professor Stephen O'Brien,
Dr Anne Lennard
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The deregulated tyrosine kinase activity of the BCR-ABL fusion gene is generally accepted as the primary cause of chronic myeloid leukemia (CML). We are currently using the new Abl tyrosine kinase inhibitor STI571 (imatinib mesylate, Glivec®) to treat CML patients in various phases of CML. Here we report the quantitative real time PCR (QRT-PCR) data for 31 patients (14 male, 17 female, median age 52.3 years [range 37.6-67.5]) with CML in chronic phase who achieved complete cytogenetic remission (CCR) after treatment with STI571. The median time to achieve CCR was 23 weeks (range - 12 to 64). CCR was defined as the absence of the Ph chromosome in at least 20 marrow metaphases. QRT-PCR assay could detect both b3a2 and b2a2 BCR-ABL transcripts in a single reaction. Triplicate QRT-PCR analyses were performed on blood specimens using ABL transcripts as the endogenous control. The ABL assay was performed in duplicate for each sample and the result reported as BCR-ABL/ABL percentage ratio. BCR-ABL transcripts were detected by QRT-PCR in all 31 patients with a median BCR-ABL/ABL ratio of 0.052% (range - negative to 0.7). In some cases the QRT-PCR data identified those patients who had achieved CCR before the cytogenetic data were available, thus providing further evidence of correlation between CCR status and BCR-ABL/ABL ratio values. A gradual reduction in BCR-ABL/ ABL ratio was observed among patients for whom serial samples were available. In one patient BCR-ABL transcripts were determined to be <1.0 with an ABL value of 4.1×104, which we report as undetectable, 23 weeks post STI571 treatment. In an additional 4 patients, the BCR-ABL/ABL ratio was <0.001% but these patients were still positive by nested RT-PCR. To date none of the patients revealed an increase in BCR-ABL/ABL ratio subsequent to a reduction. The fact that the BCR-ABL/ABL ratio was <2.0% in all CCR patients was consistent with our earlier observations in patients treated by IFN or allografting which showed that the Ph chromosome could not be detected in marrow metaphases when the BCR-ABL/ABL ratio was below 2.0%. Overall, our data confirm the value of QRT-PCR to monitor patient response to therapy. We should be able to define a threshold QRT-PCR level above which the finding of cytogenetic relapse is likely. In the absence of clear molecular prognostic indicators the MRD data may help to identify patients who are likely to do well on ST571 or develop resistance to it.
Author(s): Lin, F., Chase, A., O'Brien, S, Saunders, S., Lennard, A.L., McLean, R., Marin, D., Cross, N., Olavarria, E., Apperley, J, Goldman, J., Kaeda, J.
Publication type: Article
Publication status: Published
Print publication date: 01/01/2001
ISSN (print): 0006-4971
ISSN (electronic): 1528-0020