Pharmacology of high-dose methotrexate in patients with primary CNS lymphoma: A pharmacokinetic-pharmacodynamic analysis from the IELSG #20 trial.

Abstract

2566 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), and to identify clinical and therapeutic variables that could be manipulated to improve MTX efficacy in these patients. Methods: We included 55 patients with PCNSL and available PK-data from the IELSG #20 trial, randomized to HD-MTX (n=30) or HD-MTX and HD-AraC (n=25). Individual AUCHD-MTX from population pharmacokinetic analysis was tested on drug toxicity and clinical outcome using multivariate logistic regression analysis and Cox hazards modeling. Results: AUCHD-MTX, IELSG score, and treatment group were significant predictors for treatment response (complete or partial response) in the adjusted model. AUCHD-MTX did not predict toxicity, with the exception of liver toxicity and neutropenia. A high AUCHD-MTX was associated with better event-free survival (EFS) (p=.01) and overall survival (OAS) (p=0.02). AUCHD-MTX and IELSG score were significant predictors for EFS and OAS in the adjusted model, with a hazard ratio of 0.82 and 0.73 per 100μ mol·L/h increase in AUCHD-MTX, respectively. Conclusions: Individualized dosing of HD-MTX might have the potential to improve clinical outcome in patients with PCNSL, even when given concurrently with HD-AraC. In the future, this could be done by using first-cycle PK- modeling with determination of potential dose adaptations for later cycles using Bayesian analysis. No significant financial relationships to disclose.