The Efficacy and Toxicity of CNS Prophylaxis in Diffuse Large B-Cell Lymphoma (CLSG-CNS-01): A Randomized,...

The randomized, multicenter, prospective Phase 3 trial (NCT02777736) evaluated central nervous system (CNS) prophylaxis using either intravenous (i.v.) or intrathecal (i.t.) methotrexate (MTX) in diffuse large B-cell lymphoma (DLBCL). Treatment consisted of six cycles of R-CHOP + 2xR or DA-EPOCH-R + 2xR. Patients with intermediate or high-risk CNS International Prognostic Index (CNS-IPI) were randomized to receive CNS prophylaxis with either 2 doses of MTX 3 g/m² i.v. (arm A) or 6 doses of MTX 12 mg i.t. (arm B). Patients with low-risk CNS-IPI did not receive MTX prophylaxis (arm C). The primary objective was to compare the cumulative incidence of CNS relapse between arms A and B. Secondary objectives included evaluation of overall response rate (ORR), complete remission rate (CRR), progression-free survival (PFS), overall survival (OS), and treatment-related safety across all arms. Between 7/2015 and 5/2024, a total of 100 patients were enrolled: 30 in arm A, 31 in arm B, and 39 in arm C. ORR did not differ among arms (p = 0.20). During a median follow-up of 54.9 months, CNS relapses were observed in three patients who had received MTX prophylaxis-one in arm A and two in arm B. The 5-year cumulative incidence of CNS relapse was 0% in arm A and 8.7% in arm B (p = 0.72). However, due to the small sample size, the primary endpoint results are inconclusive. Median PFS was comparable between arms A and B (HR 0.66, p = 0.20). MTX i.v. was associated with a significantly higher grade ≥ 3 neutropenia (p = 0.0003) and infection (p = 0.0063). The higher infection rate contributed to a worse 5-year OS in arm A versus B (47.2% vs. 72.4%, HR 0.46, p = 0.04). Conclusion: our trial faced limitations due to a low number of randomized participants, making the interpretation of results challenging. A larger, international randomized trial is necessary to determine the benefit of CNS prophylaxis.