Imatinib Trough Plasma Concentration and Its Correlation with Clinical Response in Chronic Phase and Accelerated Phase of CML

Introduction: Imatinib mesylate trough plasma level is suggested to be one of the determinants of clinical efficacy in the treatment of patients with CML. Maintaining an imatinib trough level at or higher than 1000 ng/mL is suggested to be important for achieving optimal response.

Aim: Evaluation of clinical relevance of monitoring imatinib trough plasma level.

Material: Forty-seven imatinib treated CML patients (23 male/24 female, mean age 50±15.8 (SD) years) were included. Fifty one blood samples for pharmacokinetic analysis were taken. Patients treated with 400 mg of imatinib were in the first chronic phase. Patients treated with 600 mg of imatinib were in the first chronic phase resistant to imatinib 400 mg (loss of cytogenetic response) or accelerated phase at diagnosis. Mean imatinib treatment duration was 20 months (range 0.75–84 months). Blood samples were collected at 24 hours (most within ±3 hours) after the last dose of imatinib (steady state trough level).

Results: Mean trough imatinib plasma levels (Cmin) in patients treated with 400 mg and with 600 mg were 1102±574 (SD) ng/mL (females 1091ng/mL, males 1118 ng/mL) and 1337±577 (SD) ng/mL (females 1498 ng/mL, males 1287 ng/mL) respectively. In patients treated with 400 mg of imatinib optimal response was achieved in 82.8% (N=29) with Cmin=1153 ng/mL (range 370 –2524). Suboptimal response was achieved in 2.8% (N=1) of patients with Cmin=820 ng/mL. Resistance was showed in 14% (N=5) with Cmin=865 ng/mL (range 10–2436). In patients achieving CCyR and MMR Cmin was 731.4 ng/mL and 1305 ng/mL respectively. In patients treated with 600 mg of imatinib optimal response was achieved in 58.8% (N=10) with Cmin=1358 ng/mL (range 790–2133). Suboptimal response was achieved in 11.7% (N=2) of patients with Cmin=1347 ng/mL (range 1302–1392). Resistance was found in 17.6% (N=3) with Cmin=1007 ng/mL (range 250–2085). There was no correlation between Cmin and age, body mass or body surface area.

Discussion: Imatinib is the drug of choice for most patients with chronic and accelerated phase of CML. The mechanisms of resistance to imatinib are being investigated and the issue of non-compliance is considered. The data presented confirms the opinion that mean imatinib trough plasma level results should be analyzed together with other clinical data. In previous papers the importance of imatinib concentration monitoring in compliance evaluation was emphasized. The analysis presented suggests moreover considerable value of imatinib serum level monitoring in early diagnosis of resistance to treatment when analyzed together with fluctuations of the transcript level. High serum imatinib levels in resistant patients provide other than noncompliance mechanisms of resistance. Isolated cases when CMR is achieved and imatinib level is significantly below desirable value (581 and 383 ng/mL) remain remarkable. Imatinib serum level monitoring may appear particularly useful in monitoring of response in slow responders, when CCR and MMR is achieved beyond 12 months and 18 months of treatment respectively.

Conclusions: The data presented confirms the importance of monitoring imatinib trough plasma level as an adequate evaluation of treatment efficacy and allows taking optimal therapeutical decisions when considered together with cytogenetic and molecular assessments.