title: Most CML patients who have a suboptimal response to imatinib have low OCT-1 activity: higher doses of imatinib may overcome the negative impact of low OCT-1 activity.
abstract: Interpatient variability in intracellular uptake and retention (IUR) of imatinib may be due to variable function of the OCT-1 influx pump. OCT-1 activity was measured in pretherapy blood from chronic myeloid leukemia (CML) patients by calculating the difference in IUR of [(14)C]-imatinib with and without OCT-1 inhibition. Of patients with higher than median (high) OCT-1 activity, 85% achieved major molecular response (MMR) by 24 months, versus 45% with no more than a median (low) OCT-1 activity. Assessing patients receiving 600 mg imatinib per day and those averaging fewer than 600 mg over 12 months of therapy revealed patients with high OCT-1 activity achieved excellent molecular response regardless of dose, whereas response of patients with low OCT-1 activity was highly dose dependent. Of patients with low OCT-1 activity who received fewer than 600 mg, 45% failed to achieve a 2-log reduction by 12 months, and 82% failed to achieve a MMR by 18 months, compared with 8% and 17% in the cohort with high OCT-1 activity and dose less than 600 mg/day (P = .017 and P = .022). OCT-1 activity is an important determinant of molecular response to imatinib, with predictive value closely linked to dose. This pretherapy assay identifies patients at greatest risk of suboptimal response where dose intensity is critical, and those likely to respond equally well to standard dose imatinib.
authors.affiliation: Division of Haematology, Institute of Medical and Veterinary Science, Adelaide, Australia. deb.white@imvs.sa.gov.au
authors.forename: Deborah L
authors.initials: DL
authors.lastname: White
authors.forename: Verity A
authors.initials: VA
authors.lastname: Saunders
authors.forename: Phuong
authors.initials: P
authors.lastname: Dang
authors.forename: Jane
authors.initials: J
authors.lastname: Engler
authors.forename: Amity
authors.initials: A
authors.lastname: Venables
authors.forename: Stephanie
authors.initials: S
authors.lastname: Zrim
authors.forename: Andrew
authors.initials: A
authors.lastname: Zannettino
authors.forename: Kevin
authors.initials: K
authors.lastname: Lynch
authors.forename: Paul W
authors.initials: PW
authors.lastname: Manley
authors.forename: Timothy
authors.initials: T
authors.lastname: Hughes
mesh_terms: D000328:Adult; D001549:Benzamides; D015331:Cohort Studies; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000097:blood* / Q000188:drug therapy*; D008297:Male; D027702:Organic Cation Transporter 1 / Q000378:metabolism*; D010879:Piperazines / Q000493:pharmacokinetics*; D047428:Protein Kinase Inhibitors / Q000493:pharmacokinetics*; D011743:Pyrimidines / Q000493:pharmacokinetics*; D012074:Remission Induction; D012307:Risk Factors; D013997:Time Factors
chemical_list: D001549:Benzamides; D027702:Organic Cation Transporter 1; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000068877:Imatinib Mesylate