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

Although primary central nervous system lymphoma (PCNSL) is a rare disease, its incidence is rising with the aging population, and it will become even more important in the near future. Methotrexate at doses of roughly 3 g/m² (high-dose methotrexate; HDMTX) is the most active and widely used drug against PCNSL. 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 [1–4 ]. In 2004, Ferreri and colleagues found AUC-MTX >1100 μmol *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]. 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 >980 μmol*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. More recently, Blasco and colleagues showed that patients with PCNSL who were early non-responders to chemotherapy (n = 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 = 25) [1]. The mean AUC-MTX in the latter study was 1076 μmol*h/L per 3-week cycle, higher than that found in previous studies (731 μmol*h/L [2] and 931 μmol*h/L [3]). Although these patients had a fairly good drug exposure on average, some of them were non-responders, suggesting an unfavorable tumor biology in the latter. As a note of caution, MTX was given over 6–24 h infusion in the study by Blasco and colleagues, a regimen that is inferior to the 3 h MTX infusion because of suboptimal CNS penetration [5]. Accordingly, a 3 h MTX infusion has been recommended by the British Committee for Standards in Haematology [6]. While these previous studies did not find any significant impact of patient age or gender on the pharmacology of MTX, there are some indications that elderly patients may have a slower elimination and thus a higher AUC-MTX. In 50 elderly patients ≥57 years of age, AUC-MTX was higher in female patients as compared to male patients, and was remarkably high in the overall group of elderly patients (1512 μmol*h/L) (B. Casenda, personal communication). Even more interesting, OS was shorter in the elderly patients with above-average AUC-MTX compared to those with below-average AUC-MTX, suggesting that this high MTX exposure may be detrimental in the elderly patient.

In this issue of Leukemia and Lymphoma, Morris and colleagues performed a retrospective analysis of the relationship between AUC-MTX and clinical outcome in 39 patients with PCNSL, receiving upfront treatment with rituximab, HDMTX, procarbazine, vincristine, cytarabine, and low-dose radiotherapy [4]. These patients not only received intensive multimodal treatment, they also had a very good outcome, with a 2-year progression-free survival (PFS) of 81%. Because the median PFS was not reached, the results have to be interpreted with caution. Median AUC-MTX was similar to previous studies, but the authors did not find a difference in PFS in patients below the median MTX-AUC as compared to those above the median MTX-AUC, and there was no difference in response rate or OS. However, the hazard ratio (HR) for PFS for patients with above-average AUC-MTX was considerably lower than for patients with below-average AUC-MTX (HR = 0.63), although not statistically significant. Patients with an AUC-MTX >1100 μmol*h/L had a very favorable HR for PFS of 0.47, again not statistically significant. Because of the short follow-up in the study by Morris and colleagues, it would be important to have some update of the data with longer follow-up.

There are some methodological points that must be realized. Conventional TDM of MTX beginning at 24 or 48 h after MTX infusion makes intuitive sense, as intensification of leucovorin rescue may only be necessary with prolonged elimination of the drug. Due to the linear pharmacokinetics and the rapid distribution of MTX, data from TDM starting 24 h after drug infusion should be a good surrogate for the estimation of total drug exposure (AUC-MTX), at least in the case of stable renal function over time and the absence of third-space accumulation of the drug. Nevertheless, there are some concerns in the community concerning this issue. 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. On the other hand, population analysis has the advantage of being able to identify more or less the full MTX concentration–time curve, as all data contribute to the assessment of drug pharmacokinetics in a population model. The authors of the current article used a compartmental analysis that is not subject to parameter ‘shrinkage.’ Nevertheless, the authors describe a very large variability of AUC-MTX, and the reason for this large variability is most probably related to the mono-exponential 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. Therefore, it has become more difficult to define the impact of HDMTX as one treatment component on clinical outcome with the increasing complexity of the treatment of PCNSL. In fact, examples where research successfully showed that the pharmacokinetics of an anticancer drug had some relevant impact on clinical outcome were with single-agent 5-fluorouracil [8] and single-agent imatinib [9], respectively.

Although there are some indications for the clinical relevancy of AUC-MTX in patients with PCNSL, there remain some open issues. First, the potential bias from the lack of early pharmacokinetics data (<24 h post-infusion) for estimating individual AUC-MTX should be assessed. Second, it is important to look more specifically at the quantitative impact of patient age and gender on the elimination of MTX, as there is the potential for overdosing some elderly patients. Third, only by pooling much larger datasets will we be able to better understand the clinical relevancy of AUC-MTX for clinical outcome, and these efforts are currently under way. Finally, some guidance on what are clinically relevant endpoints for either exploratory or validating pharmacokinetics studies would be highly useful.

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