Therapeutic drug monitoring in CML patients on imatinib

To the editor:

Imatinib dosing in patients with chronic myeloid leukemia (CML) is flat, as pharmacokinetic (PK) studies showed that plasma trough concentrations are correlated with dose, whereas body weight or body surface area are of minor importance.^1,2  However, there is considerable interindividual variability. In a recent study, Picard et al³  reported that the median imatinib plasma concentration at steady-state is higher in patients with a major molecular response (MMR) than in patients without MMR, suggesting that therapeutic drug monitoring may be useful for optimizing therapy.

We have measured imatinib plasma concentrations in selected patients in specific clinical situations (Table 1). In patients nos. 1 to 3, unusually severe toxicity raised the question of higher than expected imatinib plasma concentrations. All 3 patients were treated with a starting dose of 300 mg imatinib twice a day because of high Sokal risk or an initial delay in commencing therapy. Dominant side effects were grade 3 myalgia in patient no. 1, transfusion-dependent erythropoietin-refractory anemia (associated with bone marrow hypoplasia) in patient no. 2, and diffuse pulmonary infiltrates in patient no. 3. Plasma trough concentrations on the initial dose of imatinib (patient nos. 1 and 2) or on 400 mg imatinib daily after transient escalation to 400 mg twice a day were considerably higher than expected from the phase 1 data (Table 1).⁴  After dose reduction, myalgia improved in patient no. 1 and patient no. 2 became transfusion independent. Repeat PK studies showed plasma concentrations that were similar to or slightly above the concentrations observed in the phase 1 study, providing reassurance that after dose reduction drug concentrations were still in a therapeutic range. In patient no. 3, imatinib was permanently discontinued, as the risk of further aggravating her side effects was felt to be unacceptable.

In 2 patients, PK studies were done because of concerns about inadequate imatinib plasma concentrations. Patient no. 4, a 9-year-old girl, achieved a complete cytogenetic response but not MMR after 11 months on 300 mg of imatinib. Dose escalation to 400 mg/day failed to improve on the molecular response, which raised the issue of inadequate drug concentrations. However, the plasma imatinib concentration was higher than expected at 2341 ng/mL.¹  Based on this, the dose was not escalated because of concerns about side effects. Patient no. 5 failed to attain a complete hematologic response (CHR) on 400 mg imatinib daily. Replacement of carbamazepine with valproic acid for suspected drug interaction and dose escalation to 600 mg/day led to CHR but without any cytogenetic response. Sequencing of BCR-ABL did not reveal a kinase domain mutation. Given multiple comedications, low plasma imatinib concentrations were suspected due to drug-drug interactions. However, PK testing revealed an adequate plasma imatinib concentration of 1342 ng/mL. These patients illustrate that monitoring plasma imatinib concentrations is useful for guiding therapeutic decisions when excessive or inadequate drug concentrations are suspected clinically. Even if the results do not lead to dose adjustment, they provide important reassurance for patients and physicians. Once testing is more widely available, drug monitoring may become an integral part of clinical management of patients on imatinib.