Work

The Efficacy and Toxicity of CNS Prophylaxis in Diffuse Large B‐Cell Lymphoma (CLSG‐CNS‐01): A Randomized, Multicenter, Prospective Phase 3 Trial

Year: 2026

Type: article

Study designs: Randomized Controlled Trial, Clinical Trial

Abstract: ABSTRACT 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/m 2 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.

Source: Hematological Oncology

DOI: 10.1002/hon.70193