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Ferrata Storti Foundation
Chronic Myeloid Leukemia
BCR-ABL1 genomic DNA PCR response kinetics during first-line imatinib treatment of chronic myeloid leukemia
Ilaria S. Pagani,1,2 Phuong Dang,1 Ivar O. Kommers,3 Jarrad M. Goyne,1 Mario Nicola,4 Verity A. Saunders,1 Jodi Braley,4 Deborah L. White,1,2,5,6,7 David T. Yeung,1,2,8,9 Susan Branford,2,4,6,10 Timothy P. Hughes,1,2,8,9,10
and David M. Ross1,2,8,9,10,11
Haematologica 2018 Volume 103(12):2026-2032
1Cancer Theme, South Australian Health & Medical Research Institute, Adelaide,
2
Australia; School of Medicine, Faculty of Health Sciences, University of Adelaide,
Australia; 3VU University Medical Center, Amsterdam, the Netherlands; 4Genetic and Molecular Pathology, SA Pathology, Adelaide, Australia; 5School of Biological Sciences, Faculty of Sciences, University of Adelaide, Australia; 6School of Paediatrics, Faculty of Health Sciences, University of Adelaide, Australia; 7Health Sciences UniSA, Adelaide, Australia; 8Australasian Leukaemia and Lymphoma Group, Melbourne, Australia; 9Department of Haematology, Royal Adelaide Hospital and SA Pathology, Australia; 10Centre for Cancer Biology, School of Pharmacy and Medical Science, University of South Australia, Adelaide, Australia and 11Flinders University and Medical Centre, Adelaide, Australia
ABSTRACT
Accurate quantification of minimal residual disease (MRD) during treatment of chronic myeloid leukemia (CML) guides clinical deci- sions. The conventional MRD method, RQ-PCR for BCR-ABL1 mRNA, reflects a composite of the number of circulating leukemic cells and the BCR-ABL1 transcripts per cell. BCR-ABL1 genomic DNA only reflects leukemic cell number. We used both methods in parallel to deter- mine the relative contribution of the leukemic cell number to molecular response. BCR-ABL1 DNA PCR and RQ-PCR were monitored up to 24 months in 516 paired samples from 59 newly-diagnosed patients treated with first-line imatinib in the TIDEL-II study. In the first three months of treatment, BCR-ABL1 mRNA values declined more rapidly than DNA. By six months, the two measures aligned closely. The expression of BCR-ABL1 mRNA was normalized to cell number to generate an expres- sion ratio. The expression of e13a2 BCR-ABL1 was lower than that of e14a2 transcripts at multiple time points during treatment. BCR-ABL1 DNA was quantifiable in 48% of samples with undetectable BCR-ABL1 mRNA, resulting in MRD being quantifiable for an additional 5-18 months (median 12 months). These parallel studies show for the first time that the rapid decline in BCR-ABL1 mRNA over the first three months of treatment is due to a reduction in both cell number and tran- script level per cell, whereas beyond three months, falling levels of BCR-ABL1 mRNA are proportional to the depletion of leukemic cells.
Introduction
Real-time reverse transcriptase quantitative PCR (RQ-PCR) for BCR-ABL1 mRNA is widely used for the routine monitoring of chronic myeloid leukemia (CML) patients receiving tyrosine kinase inhibitor (TKI) therapy. The achievement of molecularly-defined therapeutic targets during TKI treatment is associated with superior progression-free and overall survival.1 The BCR-ABL1 mRNA level is a composite measurement that reflects both the proportion of leukemic cells in the sample, and the expression of BCR-ABL1 relative to its control gene. Pre-analytical factors, such as the rate of degradation of the target mRNA, and methodological factors, such as the efficiency of reverse transcription or the choice of control gene, may have a significant influence on the final result of RQ-PCR.2,3 Substantial effort has been invested to minimize variation due to such factors through the develop- ment of an International Scale (IS) for BCR-ABL1.4
Correspondence:
David.Ross@sa.gov.au
Received: January 29, 2018. Accepted: July 4, 2018. Pre-published: July 5, 2018.
doi:10.3324/haematol.2018.189787
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/103/12/2026
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