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

Abstract

Background:This analysis was initiated to define the predictive value of the area under the curve of high-dose methotrexate (AUCHD-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 AUCHD-MTX from population PK analysis was tested on drug toxicity and clinical outcome using multivariate logistic regression analysis and Cox hazards modelling.Results:AUCHD-MTX, the IELSG score and treatment group were significant predictors for treatment response (complete or partial) in the adjusted model. The AUCHD-MTX did not predict toxicity, with the exception of liver toxicity and neutropaenia. A high AUCHD-MTX was associated with better event-free survival (EFS) (P=0.01) and overall survival (OAS) (P=0.02). Both the AUCHD-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 100 μmol l−1 h−1 increase in AUCHD-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.