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

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/m² 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.