Functional activity of the OCT-1 protein is predictive of long-term outcome in patients with chronic-phase chronic myeloid leukemia treated with imatinib.
OBJECTIVE
Organic cation transporter-1 (OCT-1) activity (OA), a measure of the OCT-1-mediated influx of imatinib into CML mononuclear cells (MNCs), is predictive of major molecular response (MMR) at 12 and 24 months in patients with untreated CML. We now report the impact of OA on loss of response, disease transformation, and survival after 5 years of imatinib.


METHODS
OA is defined as the difference in intracellular concentration of carbon-14-imatinib with and without OCT-1 inhibition. OA was measured in blood from 56 patients with untreated chronic-phase CML.


RESULTS
More patients who had high OA (ie, > median OA value) achieved MMR by 60 months compared with patients who had low OA (89% v 55%; P = .007). A low OA was associated with a significantly lower overall survival (87% v 96%; P = .028) and event-free survival (EFS; 48% v 74%; P = .03) as well as a higher kinase domain mutation rate (21% v 4%; P = .047). These differences were highly significant in patients who averaged less than 600 mg/d of imatinib in the first 12 months but were not significant in patients averaging >/= 600 mg/d. Patients with very low OA (ie, quartile 1) were the only group who developed leukemic transformation (21% in quartile 1 v 0% in all other quartiles; P = .002).


CONCLUSIONS
Measurement of OA pretherapy is a predictor for the long-term risk of resistance and transformation in patients with imatinib-treated CML. Early dose-intensity may reduce the negative prognostic impact of low OA. We propose that OA could be used to individualize dosage strategies for patients with CML to maximize molecular response and optimize long-term outcome.
White
Deborah L
DL
Haematology Department, Centre for Cancer Biology, SA Pathology (IMVS Campus), University of Adelaide, Frome Road, Adelaide, Australia. deb.white@imvs.sa.gov.au
Dang
Phuong
P
Engler
Jane
J
Frede
Amity
A
Zrim
Stephanie
S
Osborn
Michael
M
Saunders
Verity A
VA
Manley
Paul W
PW
Hughes
Timothy P
TP
D000368:Aged; D000704:Analysis of Variance; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects; D001549:Benzamides; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D005500:Follow-Up Studies; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects*; D006801:Humans; D000068877:Imatinib Mesylate; D053208:Kaplan-Meier Estimate; D015466:Leukemia, Myeloid, Chronic-Phase / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D027702:Organic Cation Transporter 1 / Q000235:genetics*; D010879:Piperazines / Q000008:administration & dosage* / Q000009:adverse effects; D011237:Predictive Value of Tests; D011336:Probability; D011743:Pyrimidines / Q000008:administration & dosage* / Q000009:adverse effects; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018570:Risk Assessment; D016019:Survival Analysis; D013997:Time Factors; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D001549:Benzamides; D027702:Organic Cation Transporter 1; D010879:Piperazines; D011743:Pyrimidines; D012333:RNA, Messenger; D000068877:Imatinib Mesylate