Trough Plasma Imatinib Concentrations Are Associated with Both Cytogenetic and Molecular Responses to Standard-Dose Imatinib in Chronic Myeloid Leukemia.

BACKGROUND

Variable responses to imatinib, in the treatment of chronic myeloid leukemia (CML), are incompletely understood. Previous studies focused on cellular mechanisms of resistance to imatinib. Another hypothesis for variable response lies in pharmacokinetic variability that may reduce drug exposure in patients receiving imatinib.

METHODS

Using high-performance liquid chromatography-tandem mass spectrometry, we assessed trough plasma imatinib concentrations in CML patients who responded or not to standard-dose imatinib, after at least one year’s treatment. Complete cytogenetic response (CCR) was defined as 0 percent Philadelphia-chromosome-positive cells in bone marrow. Major molecular response (MMR) was defined as a 3 logarithm reduction of BCR-ABL transcripts, quantified from peripheral blood using real-time quantitative reverse-transcriptase polymerase chain reaction.

RESULTS

Sixty-eight patients were included. Mean trough plasma imatinib concentrations were significantly higher in the group with CCR (56 patients) than in the group without (P=0.02). Mean (±SD) trough plasma imatinib concentrations were significantly higher in the group with MMR (34 patients) than in the group without (1452.1±649.1 ng per milliliter vs. 869.3±427.5 ng per milliliter, P<0.001) whereas there was no difference in the imatinib daily dose. For trough plasma imatinib concentrations and their discrimination potential for MMR, the area under receiver-operating characteristic curve was 0.775, with best sensitivity (76.5 percent) and specificity (70.6 percent) at a plasma threshold of 1002 ng per milliliter.

CONCLUSIONS

Monitoring of plasma imatinib concentrations may become part of standard management of CML patients, or should at the very least be checked in the case of treatment failure or suboptimal response.