Despite inadequate data establishing effectiveness or the appropriate administration strategy, prophylactic high-dose methotrexate (HD-MTX) was frequently utilized for diffuse large B-cell lymphoma (DLBCL) patients at high risk of central nervous system (CNS) recurrence. A retrospective, multinational study of 1,384 patients receiving HD-MTX CNS prophylaxis either intercalated (i-HD-MTX) (n = 749) or at the conclusion (n = 635) of R-CHOP/R-CHOP-like treatment (EOT) was done. There were 78 CNS relapses (5.7% over three years), with no difference between i-HD-MTX and EOT: 5.7% versus 5.8%, P=.98; 3-year difference: 0.04% (2.0% to 3.1%). After correcting for baseline prognostic variables and doing a 6-month landmark analysis (n=1253), the conclusions were identical. 

The 3-year CNS recurrence rate in patients with a high CNS international prognostic score (n = 600) was 9.1%, with no difference between i-HD-MTX and EOT. In a multivariate analysis, the only independent risk variables for CNS recurrence were increasing age and renal/adrenal involvement. Concurrent intrathecal prophylaxis was not linked to a lower risk of CNS recurrence. R-CHOP delays of 7 days were considerably increased with i-HD-MTX compared to EOT, with 308 of 1,573 (19.6%) i-HD-MTX treatments resulting in a delay to subsequent R-CHOP (median 8 days). When the delivery date was later than day 10 of the R-CHOP cycle, the risk of delay increased in older individuals. 

In summary, researchers found no evidence that EOT delivery increased the risk of CNS relapse when compared to i-HD-MTX. The results in high-risk subgroups were constant. CNS recurrence rates in the HD-MTX-treated group were equivalent to those in comparable cohorts receiving rare CNS prophylaxis. If HD-MTX is still being considered for some high-risk patients, delivery might be postponed until R-CHOP is completed.