Chronic phase chronic myeloid leukemia patients with low OCT-1 activity randomized to high-dose imatinib achieve better responses and have lower failure rates than those randomized to standard-dose imatinib.
BACKGROUND
The functional activity of the organic cation transporter 1 (OCT-1) protein (OCT-1 activity) is an excellent predictor of molecular response and progression-free survival in patients with newly diagnosed chronic phase chronic myeloid leukemia treated with imatinib as front-line therapy.


METHODS
In this study the predictive value of OCT-1 activity in patients treated with imatinib 400 mg/day or 800 mg/day was evaluated in relation to trough imatinib plasma levels assessed in 100 patients enrolled in the Tyrosine Kinase Inhibitor Optimization and Selectivity (TOPS) trial.


RESULTS
The rate of major molecular responses by 24 months in patients on imatinib 400 mg/day was significantly higher in those with high OCT-1 activity than in those with low OCT-1 activity (low OCT-1 activity, 57% of patients; high OCT-1 activity, 100%; P < 0.001); the corresponding difference in patients treated with imatinib 800 mg/day did not reach statistical significance (low OCT-1 activity, 68%; high OCT-1 activity, 95%; P = 0.073). In addition, the combination of low trough imatinib levels (< 1200 ng/mL) and low OCT-1 activity defined a group of patients who had the lowest rates of major molecular response (47%) by 24 months compared to all other patients (81%, P = 0.009). These patients were also at the highest risk of failed imatinib therapy when compared to all other patients (P<0.001).


CONCLUSIONS
High-dose imatinib leads to superior molecular responses in patients with low OCT-1 activity. In this group trough imatinib levels may define a group with inferior outcomes. Among patients with high OCT-1 activity, neither higher imatinib dose nor monitoring imatinib trough levels was found to be of significant clinical value. Hence OCT-1 activity determined prior to the start of therapy in newly diagnosed CML patients provides a valuable prognostic tool to determine the optimal up-front dose of imatinib in patients with newly diagnosed chronic phase chronic myeloid leukemia.
Department of Haematology, SA Pathology, RAH Campus, Adelaide, Australia. deborah.white@health.sa.gov.au
Deborah L
DL
White
Jerald
J
Radich
Simona
S
Soverini
Verity A
VA
Saunders
Amity K
AK
Frede
Phuong
P
Dang
Daniela
D
Cilloni
Peter
P
Lin
Lidia
L
Mongay
Richard
R
Woodman
Paul
P
Manley
Cassandra
C
Slader
Dong Wook
DW
Kim
Fabrizio
F
Pane
Giovanni
G
Martinelli
Giuseppe
G
Saglio
Timothy P
TP
Hughes
D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D001549:Benzamides; D001692:Biological Transport; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D054796:Drug Dosage Calculations; D005260:Female; D015870:Gene Expression; D006801:Humans; D000068877:Imatinib Mesylate; D015466:Leukemia, Myeloid, Chronic-Phase / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality; D008297:Male; D027702:Organic Cation Transporter 1 / Q000235:genetics* / Q000378:metabolism; D010879:Piperazines / Q000008:administration & dosage / Q000627:therapeutic use*; D011743:Pyrimidines / Q000008:administration & dosage / Q000627:therapeutic use*; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D001549:Benzamides; D014408:Biomarkers, Tumor; D027702:Organic Cation Transporter 1; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate