Influence of methotrexate exposure on outcome in patients treated with MBVP chemotherapy for primary central nervous system lymphoma

Abstract

What is already known about this subject: Although treated using the same high-dose methotrexate (HD-MTX)-based multiagent chemotherapy, patients with primary central nervous system lymphoma (PCNSL) have significant differences in outcome. However, little information has been published about factors influencing outcome in PCNSL. As it is known that the pharmacokinetics of MTX vary considerably between subjects leading to different exposure in patients receiving the same dose, it is important to evaluate its role in response to chemotherapy.

What this study adds: This study is the first to evaluate the exposure-response relationship in patients treated with MBVP chemotherapy. We found that patients who were early non-responders to MBVP chemotherapy had poor survival, whatever the salvage regimen. Tumour response at early evaluation was not associated with MTX pharmacokinetics and increasing the dose would probably not improve results.

Aims: Although the standard treatment for primary central nervous system lymphoma (PCNSL) consists of three cycles of MBVP (methotrexate, BCNU, VP16, methylprednisolone) and radiotherapy, early failure of treatment may require modification of the treatment. However, our understanding of the outcome in such patients and of the factors involved in early failure of treatment is poor. In addition to known prognostic factors, we evaluated the influence of methotrexate (MTX) exposure on the response to MBVP chemotherapy in patients treated for PCNSL after the first two cycles.

Methods: We retrospectively analyzed all patients with PCNSL treated with the MBVP regimen over the previous 10 years. Clinical, personal data and known prognostic factors were studied. The parameters of MTX exposure were estimated using a population pharmacokinetic approach with NONMEM. Objective response (OR), overall survival (OS) and failure-free survival (FFS) were evaluated in all patients.

Results: Thirty-seven patients were studied. We observed lower FFS and OS (0.49 years) in patients who were not able to receive the planned treatment (group 1, n=12) than in those who received three cycles (8.04 years) (group 2, n=25). Known prognostic factors were comparable in both groups, but mean dose of MTX and mean AUC tended to be lower in patients who failed prematurely or showed no response after two cycles.

Conclusions: We found that patients who were early non-responders to MBVP chemotherapy had poor survival, without major influence of MTX exposure. It is thus probably unlikely that increasing the dose of MTX would improve outcome.

Figure 1

Kaplan–Meier curves representing overall survival of all patients. Black curves correspond to group 1, red curves correspond to group 2 and empty circles represent censored data

Figure 2

Distribution plot (A) of the Normalized Prediction Distribution Error (NPDE) and scatter plot of the NPDE vs. time (B) after 1000 Monte Carlo simulations