S229: prophylactic efficacy of intrathecal versus intravenous methotrexate for cns relapse in high-risk diffuse large b cell lymphoma: a phase iii randomized, controlled study

Background: The outcome of patients with central nervous system (CNS) relapse in diffuse large B cell lymphoma (DLBCL) is poor, with a median survival of only 2 to 7 months. Intrathecal methotrexate (ITMTX) has traditionally been used, although its efficacy for CNS prophylaxis is contradictory. High-dose intravenous methotrexate (IVMTX) has been suggested as an alternative approach. Aims: The aim of this randomized study was to compare the efficacy of ITMTX and IVMTX for prophylaxis of CNS relapse in a subgroup of patients with DLBCL at high risk for CNS relapse. Methods: This prospective, open-label, multi-center, randomized, phase III trial was conducted at 14 centers in Korea (CISL1703, NCT03123718). The main eligibility criteria included newly diagnosed DLBCL, age ≥18 and <80 years, Eastern Cooperative Oncology Group Performance Status ≤2, and at least one of the following factors: (1) International Prognostic Index (IPI) score ≥ 4 or age-adjusted IPI score ≥2 plus high serum lactate dehydrogenase plus ≥1 extra-nodal site involvement or (2) high risk extra-nodal site (epidural space, testicle, breast, bone marrow, adrenal gland and kidney) involvement. All patients underwent cerebrospinal fluid study to confirm the absence of CNS involvement at diagnosis, and receipt of a single dose of ITMTX (15mg) before registration. A total of 151 patients were stratified by age and randomly assigned to ITMTX or IVMTX for further CNS prophylaxis with a standard RCHOP21 treatment of 6 cycles. ITMTX (15mg, fixed dose) was administered on RCHOP day 3 throughout the second to fourth cycles of RCHOP in the ITMTX arm, and IVMTX (3 mg/m2 in ≤70 years: 2 mg/m2 in >70 years) was administered on day 14 of the second and sixth cycles of RCHOP in the IVMTX arm. The primary endpoint was the cumulative incidence of CNS relapse at 2 years from the end of treatment. The data cut-off date was 31 December 2022. Results: A total of 142 patients were included for this analysis (ITMTX, n=73; IVMTX, n=69). The reasons for the exclusion of 9 patients were CNS involvement at diagnosis confirmed (n=2), withdrawal of consent before CNS prophylaxis (n=6), and investigator decision (n=1). The median age in both arms was 63 years (range, 23-79), and baseline demographics were similar between the two groups. Most patients completed six cycles of RCHOP: 89% ITMTX and 91% IV MTX. All planned MTX doses were completed in 70 of 73 patients (95.8%) in the ITMTX arm and 60 of 69 patients (87.0%) in the IVMTX arm. Reasons for discontinuation of CNS prophylaxis were CNS relapse (n=2) and death from pneumonia (n=1) in the ITMTX arm, and systemic progression during RCHOP treatment (n=4), RCHOP-related adverse event (n=1), IVMTX-related toxicity (n=1), and patient refusal (n=1) in the IVMTX arm. The safety profile of both regimens were manageable. After a median follow-up duration of 23.6 months (range, 1.0-45.6), there was no significant difference in the 2-year cumulative incidence of CNS relapse between the ITMTX arm (5.5%, 95% confidence interval 0.6-19.1) and the IVMTX arm (4.9%, 0.2-23.9; p=0.749). The median time from randomization to CNS relapse was 4.4 months (range 1.0-11.9) in ITMTX arm and 12.0 months (range 8.5-18.9) in IVMTX arm. The 2-year progression-free survival was also similar between the two groups (70.4% in ITMTX versus 66.4% in IVMTX, p=0.571). Summary/Conclusion: This is the first phase 3 study to address the prophylactic efficacy of ITMTX versus IVMTX in DLBCL. According to the result of this study, we found no significant difference between ITMTX and IVMTX for CNS relapse prophylaxis in newly diagnosed DLBCL patients at high risk for CNS relapse. Keywords: Diffuse large cell lymphoma, Prophylaxis, CNS, Methotrexate