Background: Methotrexate (MTX) is often administered either through intrathecal (IT) or intravenous (IV) routes along with R-CHOP chemotherapy in the management of diffuse large B-cell lymphoma (DLBCL). In this study, we compare the clinical outcomes and toxicity profiles of IT and IV routes of MTX administration.

Methods: Utilizing data from the TriNetX global federated health research network, a retrospective cohort study was performed on adult patients with DLBCL treated with standard R-CHOP regimen. Two cohorts were created and matched: IT MTX (n=121) and IV MTX (n=121). Propensity score matching balanced clinical characteristics and demographics. Outcomes assessed were CNS relapse, death, acute kidney injury (AKI), hepatotoxicity, and pancytopenia during a follow-up period of up to 10 years.

Results: Risk of CNS relapse was comparable in both cohorts (8.3% each; Risk Ratio=1.00, p=1.00). Overall survival probability at the end of the follow-up period, favored IT MTX (97.86%) over IV MTX (88.92%, Log-Rank p=0.045). The mortality risk was significantly reduced in the IT MTX cohort (26.4% vs. 40.5%; Risk Ratio=0.653, p=0.021), with better survival probabilities (63.71% vs. 49.47%, Log-Rank p=0.033). IT MTX patients also had significantly reduced rates of AKI (16.5% vs. 31.4%; Risk Ratio=0.526, p=0.007), hepatotoxicity (0% vs. 8.3%; p=0.001), and pancytopenia (22.3% vs. 48.8%; Risk Ratio=0.458, p<0.001).

Conclusion: Intrathecal methotrexate in patients with DLBCL receiving R-CHOP is linked to better overall survival and a dramatically lower risk of systemic toxicities, such as AKI, hepatotoxicity, and pancytopenia, when compared with intravenous use. Additional prospective research is needed to validate these results.

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2025
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