Therapeutic Drug Monitoring of Imatinib in Paediatric Chronic Myeloid Leukaemia: Towards Practical Implementation and Interpretation of Measured Plasma Concentrations.
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BACKGROUND AND INTRODUCTION: Imatinib (IMA) revolutionised the treatment of chronic myeloid leukaemia (CML). Therapeutic drug monitoring (TDM) of IMA is recommended to improve treatment outcomes in adults, but guidance for reliable interpretation of plasma concentrations in children is limited. Using real-world paediatric data, we aimed to develop a practical algorithm with recommendations for an IMA TDM procedure in paediatric oncology. METHODS: Imatinib plasma concentrations and clinical data were collected from patients enrolled in the multicentre CML-PAED-II study and subsequent registry. We evaluated the method of exponential extrapolation for estimating interpretable IMA trough concentrations and used linear mixed effects models to assess plasma concentration predictors. Associations between IMA trough concentrations and molecular response were analysed, and a paediatric-specific target threshold was evaluated. Findings were integrated into an algorithm for clinical application of IMA TDM. RESULTS: In total, 269 IMA trough concentrations from 72 patients and BCR::ABL1/ABL1 transcript ratios from 50 patients were included. Using a correction tool, we obtained estimates of trough concentration by exponential extrapolation. Administered IMA dose was the main predictor of plasma concentrations. Higher trough concentrations tended to correlate with faster initial molecular response. The adult-derived target threshold of 1000 ng/mL proved applicable in paediatric practice. The developed algorithm outlines clinical decision points and consequences, which are key elements of existing intensified clinical pharmacological/pharmaceutical care programmes during oral antitumour therapy. CONCLUSION: The algorithm supports the use of TDM during paediatric IMA treatment, enabling early identification of exposure below the targeted concentration and variations in treatment efficacy to further improve treatment outcomes.