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

Abstract

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.

Figure 1.

The proportion of patients achieving major molecular response (MMR) by 24 months based on (A) patients randomized to 400 mg/day and 800 mg/day, and (B) based on high and low OCTT-1 activity (OA). Kaplan Meier analysis demonstrate there that was no significant difference in the achievement of MMR between patients treated with imatinib 400 mg/day or 800 mg/day; however there was a significantly higher rate of MMR in patients with high OA than in those with low OA (P<0.001).

Figure 2.

The effect of randomized imatinib dose [400 mg (A) and 800 mg (B)] on the achievement of major molecular response (MMR) by 24 months in patients grouped into those with low and those with high OA. Kaplan-Meier analysis revealed a significant difference between low and high OA curves in patients randomized to 400 mg/day, but this difference was abrogated in patients treated with 800 mg/day. In addition, while the rate of response (time to achieve MMR) in patients with high OA was similar whether the patient was treated with 400 mg or 800 mg, in patients with low OA the rate of response was much faster in patients treated with 800 mg than in those treated with 400 mg.

Figure 3.

Box plot showing the median and range of trough imatinib plasma levels measured following 12 months of therapy in patients who did or did not achieve a major molecular response (MMR) within the group with low or high OCT-1 activity (OA). Focusing only on the low OA group reveals that the 12-month imatinib plasma level was significantly higher in patients achieving a MMR than in those who failed to achieve a MMR.

Figure 4.

Trough imatinib levels were divided into quartiles (Q) with Q1 being the lowest and Q4 the highest. Patients with Q1 imatinib trough levels had a lower rate of major molecular response (MMR) compared to all other groups (A). The poor response of patients in Q1 can be attributed to patients with low OCT-1 activity (OA) (B), but not to those with high OA (C).

Figure 5.

Assessment of imatinib failure (ELN criteria) in the setting of OCT-1 activity (OA) and trough imatinib levels in the overall cohort of patients (A), and in those with low (B) and high (C) OA. The impact of low trough imatinib levels (quartile 1) was significant in patients with low OA, but not in patients with high OA.