Safety and feasibility of high dose methotrexate addition to R-CHOP chemotherapy for prophylaxis and treatment of secondary cns involvement by large B-cell lymphoma in a community-based hospital setting

Abstract Introduction: High dose methotrexate (HDMTX) is commonly used in large B-cell lymphoma (LBCL) patients with CNS involvement (SCNSL) and in those at elevated risk of CNS relapse due to its ability to penetrate the blood brain barrier. HDMTX is administered in a hospital setting with continuous intravenous fluids, urine alkalinization, drug level monitoring, and leucovorin rescue. Despite these precautions, it can cause significant toxicities including acute kidney injury, myelosuppression, and mucositis. Therefore, when used for CNS prophylaxis (PPX) it is typically given at the end of treatment to avoid delays in R-CHOP administration. Yet, CNS relapses tend to occur at a median of 6 to 8 months from DLBCL diagnosis (Siegal et al., Blood Rev2012; Klanova et al., Blood 2019), suggesting earlier administration of HDMTX may be beneficial. Secondary CNS lymphoma (SCNSL) is an aggressive presentation of LBCL with historically poor outcomes. Intensive regimens such as MATRix RICE have demonstrated efficacy in this population, with ORR of 65% and 1-year PFS of 58% (Ferreri et al., Lancet Haematol 2021). However, these regimens are associated with substantial toxicity and logistical challenges, particularly outside of academic centers. In our institution, we incorporate HDMTX to R-CHOP early in the treatment algorithm for patients with evidence of CNS involvement or at high-risk of CNS relapse. Here we report our experience with MR-CHOP administration in a community-based hospital setting. Methods: This retrospective single-center study included 36 patients treated with MR-CHOP at our center between January 1st, 2020 and Dec 31st, 2024. Patients were divided in two groups (SCNSL, n= 14 and CNS PPX, n= 22). Patients in both groups received MR-CHOP as follows: Rituximab 375 mg/m2 on Day 0, HDMTX 3 to 3.5 g/m2 infused over 4 hours on Day 1, and CHOP on Day 3. The sequence of administration was modified to accommodate for hospitalization logistics or alkalinization needs while maintaining the goal to administer HDMTX and R-CHOP within a 3-day period. For SCNSL patients, responses in CNS were assessed using International PCNSL Collaborative Group's criteria (Abrey et al., JCO 2005). Progression-free survival (PFS) and overall survival (OS) were estimated using log-rank testing with the Kaplan Meier curves. Results: The median age was 70 years (range, 19 to 84). Twenty (55%) pts were female; 30 (83%) pts were Hispanic; ECOG ≤2 in 31 (86%) pts; histology was DLBCL NOS in 11 (30.5%) and transformed LBCL in 9 (25%) pts. Cell of origin by Han's algorithm was non-GCB in 14 (38%) pts; double expressor status by immunohistochemistry was reported in 8 (22%) pts. The SCNSL group received up to 6 cycles of HDMTX and the CNS PPX group received 2 or 3 cycles depending on the treating physicians' discretion. For transplant eligible patients with SCNSL who achieved an objective response to MR-CHOP an autologous SCT was recommended as consolidation. HDMTX was administered from cycle 1 for both treatment and prophylaxis. Among the 14 patients with SCNSL the best CR and ORR rates in CNS were 57.1% and 71.4%, respectively. All the patients with an objective response in the CNS achieved a CR by PET as best systemic response. Median follow up in the SCNSL group was 20 months (range, 11 – 41) with 1-year PFS and OS estimates of 60.6% (95% CI, 33.5%-87.7%) and 71.6% (95% CI, 44.2%-99%), respectively. The main indications for CNS PPX included epidural disease, high CNS-IPI score, and involvement of high-risk EN sites (testicular, renal/adrenal, breast). One (4.5%) of 22 pts experienced a CNS relapse. At a median follow up of 22 months (range, 10-40) the 1-year PFS was 73.1% (95% CI, 52.7%-93.4%) and the 1-year OS was 90% (95% CI, 76.9%-100%) in the CNS prophylaxis group. Nephrotoxicity defined as an increase in serum creatinine ≥1.5 from baseline within 4 days after HDMTX occurred in 6 (16.6%) pts. HDMTX was dose reduced or omitted for at least 1 cycle in 10 (27.7%) patients. HDMTX was discontinued due to progression or toxicity in 9 (25%) pts. Conclusion: Addition of HDMTX to R-CHOP for prophylaxis and treatment of SCNSL is feasible and safe in a community-based hospital setting. Clinical outcomes in our SCNSL cohort are similar to real-world reports from academic centers. Administering HDMTX prophylaxis concurrently with R-CHOP early in the course of treatment may minimize the risk of CNS relapse in high-risk LBCL patients.