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 (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 ¼ 30) or HD-MTX and high-dose cytarabine (HD-AraC) (n ¼ 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 ¼ 0.01) and overall survival (OAS) (P ¼ 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 100 mmol l À1 h À1 increase in AUC HD-MTX .

High-dose methotrexate in patients with primary central nervous system lymphoma: does drug exposure really matter?

“…More recently, Blasco and colleagues showed that patients with PCNSL who were early non-responders to chemotherapy (n ¼ 12) had a poorer progression-free survival and OS compared to patients who received three cycles of MBVP (HDMTX, methylprednisolone, etoposide, BCNU) combined with radiotherapy as planned (n ¼ 25) [1]. The mean AUC-MTX in the latter study was 1076 mmol*h/L per 3-week cycle, higher than that found in previous studies (731 mmol*h/L [2] and 931 mmol*h/ L [3]). Although these patients had a fairly good drug exposure on average, some of them were nonresponders, suggesting an unfavorable tumor biology in the latter.…”

“…Similar results were found in a subanalysis of the International Extranodal Lymphoma Study Group (IELSG) study no. 20 in 55 patients with PCNSL, showing AUC-MTX 4980 mmol*h/L (highest tertile) to be independently associated with an improved event-free survival and OS [3]. In these two studies, 40 out of 100 patients had single-agent MTX, 49 had combined HDMTX and high-dose cytarabine, and 11 patients had a combination of HDMTX, high-dose cytarabine, idarubicin, and thiotepa.…”

“…HDMTX is also the single anticancer drug in adult oncology whereby therapeutic drug monitoring (TDM) is routinely performed, primarily to guide leucovorin rescue. The availability of MTX plasma concentrations has triggered some research to understand the relationship between MTX drug intensity (area under the curve [AUC]-MTX) and clinical outcome [1][2][3][4]. In 2004, Ferreri and colleagues found AUC-MTX 41100 mmol *h/L to be independently associated with an improved overall survival (OS) in 45 patients with PCNSL receiving three different HDMTX-based combination regimens [2].…”

“…The method applied to derive individual AUC-MTX from sparse samples collected once daily can have a substantial impact on the outcome. Drug exposure as derived from population analysis [1,3] may be subject to bias as a result of parameter 'shrinkage toward the mean,' and this results in underestimation of the interindividual variability of AUC-MTX. In theory, however, this would result in an underestimation of the true correlation between AUC-MTX and clinical outcome.…”

“…Nevertheless, the authors describe a very large variability of AUC-MTX, and the reason for this large variability is most probably related to the monoexponential plasma concentration model used (compared to the two-compartment model as used in the IELSG no. 20 study [3]) that will underestimate the median AUC-MTX and overestimate the variability of AUC-MTX. Another point that adds some complexity is the fact that HDMTX is now frequently combined with high-dose cytarabine [7], rituximab [4], or sequentially with radiotherapy, especially in the case of residual tumor after chemo(immuno)therapy.…”