Methotrexate area under the curve is an important outcome predictor in patients with primary CNS lymphoma: A pharmacokinetic-pharmacodynamic analysis from the IELSG no. 20 trial

Background: This analysis was initiated to define the predictive value of the area under the curve of high-dose methotrexate (AUC_HD-MTX) in patients with primary central nervous system lymphoma (PCNSL).Patients and Methods:We included 55 patients with PCNSL and available pharmacokinetic (PK) data from the International Extranodal Lymphoma Study Group (IELSG) no. 20 trial, randomised to HD-MTX (n=30) or HD-MTX and high-dose cytarabine (HD-AraC) (n=25). Individual AUC_HD-MTX from population PK analysis was tested on drug toxicity and clinical outcome using multivariate logistic regression analysis and Cox hazards modelling.results: AUC HD-MTX, the IELSG score and treatment group were significant predictors for treatment response (complete or partial) in the adjusted model. The AUC_HD-MTX did not predict toxicity, with the exception of liver toxicity and neutropaenia. A high AUC _HD-MTX was associated with better event-free survival (EFS) (P=0.01) and overall survival (OAS) (P=0.02). Both the AUC_HD-MTX and the IELSG score were significant predictors of EFS and OAS in the adjusted model, with a hazard ratio of 0.82 and 0.73, respectively, per 100μ mol l^-1 h^-1 increase in AUC HD-MTX. Conclusions Individualised dosing of HD-MTX might have the potential to improve clinical outcome in patients with PCNSL, even when administered concurrently with HD-AraC. In the future, this could be carried out by using first-cycle PK modelling with determination of potential dose adaptations for later cycles using Bayesian analysis.