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Title: The clinical significance of ABCB1 overexpression in predicting outcome of CML patients undergoing first-line imatinib treatment
Austin Authors: Eadie, LN;Dang, P;Saunders, VA;Yeung, David T;Osborn, Michael P;Grigg, Andrew P ;Hughes, Timothy P;White, Deborah L
Affiliation: Cancer Theme, South Australian Health and Medical Research Institute (SAHMRI), Adelaide, South Australia, Australia
Department of Medicine, University of Adelaide, Adelaide, South Australia, Australia
Haematology Department, SA Pathology, Adelaide, South Australia, Australia
Oncology Department, Women's and Children Hospital, Adelaide, South Australia, Australia
Clinical Haematology, Austin Health, Heidelberg, Victoria, Australia
Centre for Cancer Biology, Adelaide, South Australia, Australia
Australasian Leukaemia and Lymphoma Group, Melbourne, Victoria, Australia
Department of Paediatrics, University of Adelaide, Adelaide, South Australia, Australia
Issue Date: 15-Jul-2016 2016-07-15
Publication information: Leukemia 2016; online first: 15 July
Abstract: Tyrosine kinase inhibitor (TKI) therapy results in excellent responses in the majority of patients with chronic myeloid leukaemia. First-line imatinib treatment, with selective switching to nilotinib when patients fail to meet specific molecular targets or for imatinib intolerance, results in excellent overall molecular responses and survival. However, this strategy is less effective in cases of primary imatinib resistance; moreover, 25% of patients develop secondary resistance such that 20-35% of patients initially treated with imatinib will eventually experience treatment failure. Early identification of these patients is of high clinical relevance. Since the drug efflux transporter ABCB1 has previously been implicated in TKI resistance, we determined if early increases in ABCB1 mRNA expression (fold change from diagnosis to day 22 of imatinib therapy) predict for patient response. Indeed, patients exhibiting a high fold rise (⩾2.2, n=79) were significantly less likely to achieve early molecular response (BCR-ABL1IS ⩽10% at 3 months; P=0.001), major molecular response (P<0.0001) and MR4.5 (P<0.0001). Additionally, patients demonstrated increased levels of ABCB1 mRNA before the development of mutations and/or progression to blast crisis. Patients with high fold rise in ABCB1 mRNA were also less likely to achieve major molecular response when switched to nilotinib therapy (49% vs 82% of patients with low fold rise). We conclude that early evaluation of the fold change in ABCB1 mRNA expression may identify patients likely to be resistant to first- and second-generation TKIs and who may be candidates for alternative therapy.
DOI: 10.1038/leu.2016.179
PubMed URL:
Type: Journal Article
Appears in Collections:Journal articles

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