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This is a nice historical accounting of this sometimes-challenging paradigm. No randomized, prospective trials exist to guide practice management.  The question in clinic is often, when to use prophylaxis and when not? The CNS-IPI is the best scoring system validated in the Rituximab era.  This did not account for double/triple hit genetics, ABC subtypes or sites of disease (gonads, >3 sites).  A high score or any of these groups are generally those that benefit the most from CNS-prophylaxis. The field has moved away from IT-MTX therapy to HD-IV-MTX since most secondary CNSL is parenchymal in nature. Most relapses occur at months 6-9 so sooner is probably better in terms of timing.