Three‐Hour Infusion of Methotrexate at 3 g/m 2 With or Without Intrathecal Chemotherapy Significantly Reduces CNS Relapses and Improves Survival in Patients With Large B‐Cell Lymphomas at Increased CNS Risk

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ABSTRACT Concerns about the efficacy of high‐dose methotrexate (HD‐MTX) in preventing CNS recurrence in large B‐cell lymphomas (LBCL) are based on studies with interpretation biases and incomplete information about HD‐MTX dosing schedule and CNS events. We evaluated a pharmacokinetic‐informed, CNS‐directed HD‐MTX protocol (3 g/m 2 over 3 h, preceded by a bolus) in 336 LBCL patients achieving CMR after RCHOP or derivatives. HD‐MTX use was based on institutional risk scores. In this study, CNS risk was reassessed using updated criteria: CNS‐IPI ≥ 4, ≥ 3 extranodal sites, or involvement of testis, kidney, adrenal gland, uterus, or breast. According to these criteria, risk was low in 228 (68%) patients and high in 108 (32%); HD‐MTX was given to 20 (9%) and 49 (45%), respectively. HD‐MTX was well tolerated: 96% completed therapy. After a median follow‐up of 77 months, 13 (4%) patients experienced CNS relapse, always as isolated events. Among high‐risk patients, CNS relapse occurred in 19% (11/59) without HD‐MTX versus 0% (0/49) with HD‐MTX ( p = 0.0009); significant reductions were seen in patients with high‐risk organ involvement (32% to 0%, p = 0.002) or ≥ 3 extranodal sites (18% to 0%, p = 0.04). HD‐MTX was independently associated with improved PFS and OS in high‐risk patients, likely due to reduced CNS relapses (0% vs. 19%; p = 0.0009), whereas rates of unrelated deaths (8% vs. 15%; p = 0.26) and systemic relapses (18% vs. 22%; p = 0.81) were similar. In conclusion, HD‐MTX, administered via a pharmacokinetic‐informed, CNS‐directed schedule, with or without intrathecal chemotherapy, significantly reduces CNS relapses and improves outcomes in high‐risk LBCL patients in CMR. Trial Registration: ClinicalTrials.gov Identifier: NCT07181785.

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