Management of Chronic Myelogenous Leukemia Using Therapeutic Drug Monitoring of Imatinib: The French Experience of a Centralized Laboratory

Pharmacokinetic monitoring is widely used in different medical specialities, but it has been rarely applied in clinical oncology practice. The current gold standard treatment of chronic myelogenous leukemia (CML) is imatinib, a tyrosine kinase inhibitor. We have previously shown the necessity to obtain a trough plasma threshold of 1000 ng/mL for efficient treatment with imatinib. We routinely perform centralized quantification for patients in France and this has allowed the assessment of imatinib therapeutic monitoring and its use in a real-life setting. After 16 months of data collection, we had gathered 1607 samples for 1044 CML patients (mean age 55 years, F/M sex ratio 0.67) treated with imatinib 400 mg (median) range (100–800mg). We received only one sample for 739 patients and more than one sample for 305 patients. The mean trough plasma concentration of imatinib (Cmin) was 1043 ng/mL (median: 876 ng/mL) and 596 of the 1044 CML patients (57%) had a Cmin <1000ng/ml at first determination. Plasma concentration increased with dose, but there was a large inter-individual variability (64%) and intra-individual variability was twice as small. For plasma concentrations < 1000 ng/mL, mean dose was 420 mg and for those ≥ 1000 ng/mL, this was 510 mg. For the 189 patients having had at least 2 correct Cmin determination, 70% had initial Cmin< 1000 ng/mL (mean concentration of 1st determination: 583 ng/mL). Among the 62 patients who initially had a Cmin below 1000 ng/mL that subsequently rose above this threshold, 63% had their imatinib dose increased; the rest did not have a dose modification. For the latter, it is probable in view of low intra-individual variability that this was due to enhanced compliance. For the 32 patients with a first Cmin <1000 and no CCyR, none of those with Cmin remaining below 1000 ng/mL achieved CCyR, wheras 5 (28%) achieved CCyR when Cmin rose above 1000 ng/mL. In cases where there was suspicion of a drug–drug interaction, the most frequently combined drugs were proton pump inhibitors (such as omeprazole), diuretics, allopurinol and NSAIDs. The most recurrent adverse effects were digestive, hematological and muscular. Although the studied population had characteristics generally described for this pathology (age, sex ratio), there was probably selection bias at the beginning of study: we received first and foremost the patients having an insufficient response, and therefore low plasma concentration. Therapeutic drug monitoring of imatinib appears to be helpful for the management of CML patients and the resulting database allows a better understanding and use of this treatment.