i-HD-MTX was associated with increased toxicity and R-CHOP delays compared to EOT delivery. Our data show a low rate of CNS relapse in both groups although we recognise potential for bias in a retrospective study. Concurrent IT therapy is a potentially confounding factor and the additional value of IT MTX during R-CHOP, when EOT HD-MTX is planned, remains unclear. Although we cannot conclude whether adopting an i-HD-MTX or EOT approach is superior, our data support delivering HD-MTX as early as possible during or following R-CHOP. Such decisions should be individualised, based on careful analysis of competing risks. Where i-HD-MTX is favoured, we recommend that it is scheduled before day 10 of the R-CHOP cycle.

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In this nationwide, population-based study, all studied subgroups of patients with DLBCL-except those aged 18-54 years-continue to experience considerable excess mortality after 5 years post-diagnosis in a modern era of chemoimmunotherapy. Late excess mortality in DLBCL could reflect the late sequelae of treatment or late relapses. Collectively, statistics on CRS beyond 24 months post-DLBCL-diagnosis provides information on excess mortality that would otherwise not be discernible when solely relying on EFS24 as an endpoint. Therefore, long-term surveillance after 5 years post-diagnosis can be considered in particular patient subsets.