Functional Activity of the OCT-1 Protein Is Predictive of Long-Term Outcome in Patients With Chronic-Phase Chronic Myeloid Leukemia Treated With Imatinib J Clin Oncol. 2010 Apr 26;

2010 Apr 26; Epub ahead of print, DL White, P Dang, J Engler, A Frede, S Zrim, M Osborn, VA Saunders, PW Manley, TP Hughes

Supplementary editorial provided by OncologySTAT

TAKE-HOME MESSAGE
Pretherapy OCT-1 protein activity predicts the long-term risk of resistance to imatinib and transformation to blast phase in patients with chronic myeloid leukemia and can help determine optimal dosing.

STUDY IN CONTEXT
Attempts to prevent resistance to imatinib in patients with chronic-phase chronic myeloid leukemia (CP-CML) have focused on using higher first-line imatinib doses. Yet studies of 600 or 800 mg/day vs 400 mg/day have had conflicting results. Higher dosing may increase the response rate in some patients, but toxicity may lead to treatment interruptions, and thus poorer results, in others. Methods of identifying predisposition to imatinib resistance in patients with CP-CML are needed, as well as determination of optimal dosing.

The major active influx pump for imatinib is the human organic cation transporter-1 (OCT-1), the functional activity of which is measured by the OCT-1 activity (OA) assay. In the phase II TIDEL I trial, high OA was associated with achievement of a major molecular response (MMR) by 24 months in CP-CML patients able to tolerate imatinib 600 mg/day (85% vs 45% of patients with low OA). The TIDEL I investigators now report 5-year follow-up data, evaluating pretreatment OA levels as an indicator of loss of response to imatinib and as a predictor of survival and disease progression.

TIDEL I enrolled patients with newly diagnosed CP-CML. The starting dose of imatinib (600 mg/day) was increased to 800 mg/day in nonresponders. Although nearly half of the patients in the TIDEL I trial (23 of 56 patients) received less than the average daily dose of 600 mg/day during the first year of imatinib therapy, outcomes did not differ significantly between the patients who did and did not maintain this dosing level.

Follow-up at 60 months showed that a larger percentage of patients with high OA than those with low OA had achieved MMR (89% vs 55% ; P = .007). In multifactor analysis, OA was the only significant predictor of response. Achievement of a complete molecular response (CMR) at 60 months was also significantly associated with high OA: 59% vs 31% of patients with low OA (P = .038).

At 60 months, event-free survival (EFS) was 74% for patients with high OA, compared with 48% for those with low OA (P = .03). In multifactor analysis, OA was the only significant predictor of EFS. Overall, 68% of the events occurred in the patients with low OA. Three patients underwent transformation to blast crisis, all of whom had low OA. Overall survival (OS) was also significantly better in the high vs the low OA group (96% vs 87%; P = .031).

Imatinib dose was also analyzed together with OA. Among patients who received less than the average daily dose of imatinib 600 mg, high OA patients had significantly better MMR, EFS, and transformation-free survival (TFS) than did low OA patients. However, for patients who did receive 600 mg as the average daily dose, outcomes were similar between those with low and high OA. This indicates that higher dosing can partially overcome the effect of a low OA.

The 3 patients who had transformed to blast crisis all had received less than the 600 mg average daily dose during the first year of treatment. Further analysis showed a significant effect of dose on TFS. These data suggest that in patients with low OA, use of early intensified dosing of imatinib may be essential for long-term response.

This is the first study to show that a bioassay performed on blood mononuclear cells prior to imatinib treatment strongly predicts long-term outcome. The findings regarding EFS and TFS show that OA also identifies patients who are at highest risk of imatinib resistance and transformation to blast crisis.

When stratified into OA quartiles, patients in the lowest quartile (<4.0 ng/200,000 cells) had poor molecular response, early transformation, and poor OS, particularly when the imatinib average daily dose was less than 600 mg. This suggests that imatinib 400 mg/day is an inadequate dose for patients in the lowest OA quartile. For the majority of patients with high OA, however, the standard 400 mg/day dose represents optimal therapy. A prospective trial in which imatinib dosing is individualized based on pretherapy OA is warranted.

ABSTRACT

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