High‐dose methotrexate plus rchop: efficacy and toxicity in the prevention of central nervous system relapse in patients with diffuse large b cell lymphoma

Introduction: Prophylactic high dose methotrexate (HD-MTX) is widely used for preventing central nervous system (CNS) relapse in patients with diffuse large b cell lymphoma (DLBCL), as intravenous HD-MTX achieves excellent blood-brain barrier penetration. Despite most of the published studies analyzing the efficacy of HD-MTX when combined with anthracycline based chemotherapy as frontline therapy advocate the administration of methotrexate midcycle (between days 10 and 15 after the RCHOP), the optimal dose and timing of methotrexate when combined with RCHOP remains unclear. Here, we aim to evaluate the efficacy, tolerability and toxicity of the combination HD-MTX-RCHOP. Methods: We report our experience of HD-MTX-RCHOP in patients with DLBCL and high risk of CNS relapse from 2017 to 2022. The regimen consisted in HD-MTX (dose ≥ 3 g/m2) administered as a 4-hour intravenous infusion on day 1 of the cycle followed by standard RCHOP on day 3, as 21-days cycles. Patients received HD-MTX as inpatient regimen. Nephrotoxicity was prevented with hyperhidration and urine alcalinization. Urinary pH was monitored every 3 hours and plasmatic MTX levels every 24 hours until clearance. Results: Nineteen patients receiving a total of 65 cycles of HD-MTX-RCHOP were included in the study. Patients received a median of 4 cycles (range 1-6) of HD-MTX-RCHOP as CNS prophylaxis. CNS-IPI score classified 9 patients (47.3%) as high risk of CNS relapse, 5 (26.3%) as intermediate risk and 5 (26.3%) as low-risk. These low-risk CNS-IPI patients received HD-MTX due to the involvement of high-risk sites. HD-MTX-RCHOP presented a favorable toxicity profile. Most common adverse event was oral mucositis (29.2% of cycles), with grade ≥ 3 mucositis in 7.69% of cycles. All reported hepatotoxicity was grade 1 (9.2% of cycles). MTX clearance was achieved at a median of 48 hours (range 24–69) after administration and only one case of nephrotoxicity was documented (1.5% of cycles) (table 1). Overall, only 13% of cycles were delayed by more than 7 days and 13 (68%) patients finished all programmed HD-MTX-RCHOP cycles without any delay. The most frequent cause of delay was neutropenic fever after RCHOP. With this treatment, 17 (89.47%) patients achieved complete response without relapse in the CNS in any of them. Overall, only one CNS relapse was observed, which occurred during treatment with HD-MTX-RCHOP (primary refractory DLBCL). Conclusion: Our data suggest that HD-MTX administration on day 1 of the RCHOP cycle is a feasible strategy, with a good safety profile that does not result in unacceptable delays in the administration of RCHOP. Although new prospective studies are needed to confirm these results. Keyword: aggressive B-cell non-Hodgkin lymphoma No conflicts of interests pertinent to the abstract.