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. DESIGN AND 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.

Long-term response to imatinib is not affected by the initial dose in patients with Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase: final update from the Tyrosine Kinase Inhibitor Optimization and Selectivity (TOPS) study.

The TOPS trial evaluated high- (800 mg/day; n = 319) versus standard-dose (400 mg/day; n = 157) imatinib in patients newly diagnosed with Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase. Patients had a minimum follow-up of 42 months or discontinued early. Major molecular response (MMR) rates were similar between arms at (51.6 vs 50.2 % for 400 and 800 mg/day, respectively; P = 0.77) and by (75.8 vs 79.0 %; P = 0.4807) 42 months. There were no differences in event-free survival (EFS), progression-free survival(PFS), or overall survival (OS) between arms. The estimated rates of PFS on treatment and OS at 42 months were significantly higher in patients with MMR at 6, 12, and 18 months compared with those without MMR.Adverse events were more frequent with high-dose imatinib. Patients with B1 treatment interruption (vs [1) and those able to maintain imatinib C600 mg/day (vs\600 mg/day) in the first year of treatment had faster and higher response rates, but no improvement in EFS or PFS. Adherence to prescribed dose without interruption may be more important than initiation of therapy with higher doses of imatinib. Achievement of MMR correlated with longterm clinical outcomes.