title: The clinical significance of ABCB1 overexpression in predicting outcome of CML patients undergoing first-line imatinib treatment.
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.
authors.affiliation: Cancer Theme, South Australian Health and Medical Research Institute (SAHMRI), Adelaide, SA, Australia.|Department of Medicine, University of Adelaide, Adelaide, SA, Australia.
authors.forename: L N
authors.initials: LN
authors.lastname: Eadie
authors.affiliation: Cancer Theme, South Australian Health and Medical Research Institute (SAHMRI), Adelaide, SA, Australia.
authors.forename: P
authors.initials: P
authors.lastname: Dang
authors.affiliation: Cancer Theme, South Australian Health and Medical Research Institute (SAHMRI), Adelaide, SA, Australia.
authors.forename: V A
authors.initials: VA
authors.lastname: Saunders
authors.affiliation: Cancer Theme, South Australian Health and Medical Research Institute (SAHMRI), Adelaide, SA, Australia.|Department of Medicine, University of Adelaide, Adelaide, SA, Australia.|Haematology Department, SA Pathology, Adelaide, SA, Australia.
authors.forename: D T
authors.initials: DT
authors.lastname: Yeung
authors.affiliation: Haematology Department, SA Pathology, Adelaide, SA, Australia.|Oncology Department, Women's and Children Hospital, Adelaide, SA, Australia.
authors.forename: M P
authors.initials: MP
authors.lastname: Osborn
authors.affiliation: Clinical Haematology, Austin Health, Heidelberg, VIC, Australia.
authors.forename: A P
authors.initials: AP
authors.lastname: Grigg
authors.affiliation: Cancer Theme, South Australian Health and Medical Research Institute (SAHMRI), Adelaide, SA, Australia.|Department of Medicine, University of Adelaide, Adelaide, SA, Australia.|Haematology Department, SA Pathology, Adelaide, SA, Australia.|Centre for Cancer Biology, Adelaide, SA, Australia.|Australasian Leukaemia and Lymphoma Group, Melbourne, VIC, Australia.
authors.forename: T P
authors.initials: TP
authors.lastname: Hughes
authors.affiliation: Cancer Theme, South Australian Health and Medical Research Institute (SAHMRI), Adelaide, SA, Australia.|Department of Medicine, University of Adelaide, Adelaide, SA, Australia.|Department of Paediatrics, University of Adelaide, Adelaide, SA, Australia.
authors.forename: D L
authors.initials: DL
authors.lastname: White
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000032:analysis / Q000235:genetics; D002478:Cells, Cultured; D019008:Drug Resistance, Neoplasm; D015870:Gene Expression; D006801:Humans; D000068877:Imatinib Mesylate / Q000494:pharmacology / Q000627:therapeutic use*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000175:diagnosis / Q000188:drug therapy*; D011237:Predictive Value of Tests; D011379:Prognosis; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; D000068877:Imatinib Mesylate