In a study of high-risk, previously treated patients with diffuse large B-cell lymphoma (DLBCL), the use of prophylactic high-dose methotrexate (HD-MTX) was not associated with superior central nervous system (CNS) relapse or survival outcomes but was linked to greater toxicity. The study results were recently reported in the journal Blood Advances.

“In the absence of randomized controlled trials, the role of HD-MTX as CNS prophylaxis and its effect on survival outcomes in patients with DLBCL at high risk for CNS relapse are controversial,” the study investigators wrote in their report.

This retrospective analysis involved the presence or absence of prophylactic HD-MTX given to patients with DLBCL who had received prior rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in the first-line setting. High-risk patients were evaluated in this study, with risk referring to a high risk for CNS relapse. Safety and efficacy outcomes were assessed based on intention-to-treat (ITT) analysis.

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A total of 128 patients were in the HD-MTX group for ITT analysis, and 130 patients were in the non-HD-MTX group. The 2-year cumulative incidence of CNS relapse was similar between populations, with rates of 12.4% with HD-MTX and 13.9% without it (P =.96).

In survival analysis, the 2-year progression-free survival (PFS) rate was 62.4% with HD-MTX and 64.5% without it (P =.94). The 2-year overall survival (OS) rate was 71.7% with HD-MTX and 71.4% without it (P =.7). With propensity score-matching, rates of time-to-CNS-relapse, PFS, and OS were similar between populations.

Grade 3 or higher hematologic toxicity occurred at similar rates between groups. Grade 3 or higher oral mucositis was more common in the HD-MTX group (14.8%) than without HD-MTX (6.2%; P =.038). Alanine aminotransferase was also elevated more often in patients of the HD-MTX group (7.8%) than in those without HD-MTX (1.5%; P =.036).

“In conclusion, HD-MTX prophylaxis was not associated with reduced CNS relapse rates or improved survival outcomes, and it was accompanied by increased toxicities in DLBCL patients at high risk for CNS relapse,” the study investigators wrote in their report.


Jeong H, Cho H, Kim H, et al. Efficacy and safety of prophylactic high-dose MTX in high-risk DLBCL: a treatment intent–based analysis. Blood Adv. 2021;5(8):2142-2152. doi:10.1182/bloodadvances.2020003947