Linda Fletcher

Centre for Cancer Biology, Tarndarnya, South Australia, Australia

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Publications (5)21.82 Total impact

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    ABSTRACT: In CML patients, a BCR-ABL1 value >10% at 3 months of therapy is statistically associated with poorer outcome, yet many of these patients still achieve satisfactory outcomes. We investigated 528 first-line imatinib-treated patients to determine whether patients with the poorest outcome can be better discriminated at 3 months. All outcomes were significantly superior for the 410 patients with BCR-ABL1 ≤10% at 3 months, P<.001. However, the poorest outcomes among the 95 evaluable patients with BCR-ABL1 >10% at 3 months were identified by the rate of BCR-ABL1 decline from baseline; assessed by estimating the number of days over which BCR-ABL1 halved. Patients with BCR-ABL1 halving time less than 76 days (n=74) had significantly superior outcomes compared to patients whose BCR-ABL1 values did not halve by 76 days (n=21); 4 year overall survival 95% versus 58%, P=.0002; progression-free survival 92% versus 63%, P=.008; failure-free survival 59% versus 6%, P<.0001; and MMR 54% versus 5%, P=.008. By multivariate analysis, the halving time was an independent predictor of outcome in this poor risk group. Our study has highlighted that the rate of BCR-ABL1 decline may be a critical prognostic discriminator of the patients with very poor outcome among those >10% at 3 months. The Iris trial was registered at http://www.clinicaltrials.gov as NCT00006343. The Tops trial was registered at http://www.clinicaltrials.gov as NCT00124748. The TIDEL I trial was registered at www.ANZCTR.org.au as ACTRN12607000614493. The TIDEL II trial was registered at www.ANZCTR.org.au as ACTRN12607000325404.
    Blood 05/2014; · 9.06 Impact Factor
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    ABSTRACT: Achieving a major molecular response (MMR) is an important predictor of progression-free survival in chronic myeloid leukemia patients treated with imatinib. This requires accurate measurement of BCR-ABL1 transcripts normalized to a control gene, as well as defining a level (BCR-ABL1/control gene ratio) that will correlate with sustained clinical response. To make these measurements comparable between laboratories, an international scale (IS) is necessary. A BCR-ABL1/control gene ratio of 0.10% represents MMR in the IS. In collaboration with an international reference laboratory in Adelaide, S.A., Australia, we have established and validated a lab-specific conversion factor for expressing BCR-ABL1 transcript levels in the IS. In this report, we explain the process and steps involved in obtaining a valid lab-specific conversion factor for expressing BCR-ABL1 transcript levels in the IS.
    Acta Haematologica 01/2012; 127(3):135-42. · 0.89 Impact Factor
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    ABSTRACT: BACKGROUND: Real-time quantitative polymerase chain reaction (RQ-PCR) has been widely used for molecular monitoring for patients with chronic myeloid leukemia (CML). Currently, RQ-PCR is not based on the concept of international scale (IS) in Japan; mainly because none of the domestic laboratories have obtained their own conversion factor (CF) which makes it possible to convert locally scaled BCR-ABL (BCR-ABL (L)) value to the IS (BCR-ABL (IS)). To join the global trend of molecular assessment of BCR-ABL in CML patients, we have tried to obtain a CF in Japan. METHODS: Samples from 55 patients were exchanged between the Japanese laboratory and the reference laboratory in Adelaide, and BCR-ABL and internal control gene transcripts of the samples were measured using RQ-PCR. The patient bias conversion method was used to determine the CF for the IS using the Bland and Altman method. RESULTS: The local CF in the Japanese laboratory was determined to be 0.87. Based on this CF, 0.1% BCR-ABL (IS), defined as major molecular response, becomes equivalent to 731 copy/μg RNA BCR-ABL (L). CONCLUSION: This study is the first to introduce a laboratory-specific CF for harmonizing RQ-PCR methodology for detecting BCR-ABL transcripts to Japan, which may open new windows for molecular assessment of CML patients in Japan.
    International Journal of Clinical Oncology 10/2011; · 1.41 Impact Factor
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    ABSTRACT: Accurate and standardized methods for the quantitative measurement of BCR-ABL1 are a prerequisite for monitoring of treatment response in t(9;22)-positive leukemia. Here, we describe a novel multiplex assay system based on the proven TaqMan and Armored RNA technologies and optimized for sensitive detection of three BCR-ABL1 fusion transcripts and ABL1 in a single reaction. Analytical experiments confirmed the absence of significant competition between the simultaneous amplification reactions and established the sensitivity, linearity and precision of the assay. Comparative studies with 115 clinical specimens resulted in high qualitative and quantitative agreement with independent singleplex laboratory-developed tests routinely used in clinical testing. Direct comparison with a reference laboratory calibrated to the international scale (IS) demonstrated minimal analytical bias between methods and an overall accuracy and precision within the performance range required for quantitative measurement of BCR-ABL1 on the IS. We conclude that detection of e1a2, b2a2, b3a2 and ABL1 can be achieved in a multiplex assay format compatible with IS reporting. Further clinical validation of the assay could improve the operational efficiency of clinical laboratories, increase their adherence to current recommendations for b2a2/b3a2 reporting on the IS and provide for the first time an opportunity to standardize e1a2-monitoring results.
    Blood Cancer Journal 03/2011; 1(3):e13. · 1.40 Impact Factor
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    ABSTRACT: An international basis for comparison of BCR-ABL mRNA levels is required for the common interpretation of data derived from individual laboratories. This will aid clinical decisions for individual patients with chronic myeloid leukemia (CML) and assist interpretation of results from clinical studies. We aligned BCR-ABL values generated by 38 laboratories to an international scale (IS) where a major molecular response (MMR) is 0.1% or less. Alignment was achieved by application of laboratory-specific conversion factors calculated by comparisons performed with patient samples against a reference method. A validation procedure was completed for 19 methods. We determined performance characteristics (bias and precision) for consistent interpretation of MMR after IS conversion. When methods achieved an average BCR-ABL difference of plus or minus 1.2-fold from the reference method and 95% limits of agreement within plus or minus 5-fold, the MMR concordance was 91%. These criteria were met by 58% of methods. When not met, the MMR concordance was 74% or less. However, irrespective of precision, when the bias was plus or minus 1.2-fold as achieved by 89% of methods, there was good agreement between the overall MMR rates. This indicates that the IS can deliver accurate comparison of molecular response rates between clinical trials when measured by different laboratories.
    Blood 08/2008; 112(8):3330-8. · 9.06 Impact Factor