Feasibility and safety of high‐dose methotrexate intercalated with r‐chop in diffuse large b‐cell lymphoma: a single‐center experience

Background: Central nervous system (CNS) relapse still represents an often-fatal event in diffuse large B cell lymphoma (DLBCL). Efforts to prevent it aimed to identify higher risk patients and to administer adequate prophylaxis. In this setting, unmet needs such as the type of prophylaxis (high-dose methotrexate, HD-MTX vs. triple intrathecal therapy) and its timing are still under debate. Hereby, we report our experience of DLBCL patients undergoing CNS prophylaxis with systemic HD-MTX intercalated with systemic chemotherapy. Methods: We retrospectively collected data of DLBCL patients receiving CNS prophylaxis with at least 1 cycle of HD-MTX from 2017 to 2022. The administration of HD-MTX was based on CNS-IPI and on lymphoma histology/clinical presentation in those cases who may not tolerate more intensified chemo-immunotherapy regimens. We performed a Kaplan-Meier analysis to estimate overall survival. Results: Twenty-one patients received HD-MTX. The mean age at diagnosis was 62 years (range 33–77), with 66% of patients over 60 years. The median Cumulative Illness Rating Scale (CIRS) was 8 (range 4–13). At presentation, 76% of patients had advance stage disease (III-IV) with more than 1 extranodal localization in 15 cases. Median IPI and CNS-IPI were 3 (range 0–5) and 3 (range 0–5), respectively. According to immunohistochemistry, a non-germinal center phenotype was shown in 24% and 52% patients had double-expressor profile. Patients received R-CHOP (71%) or R-COMP (29%) associated with variable HD-MTX dose, adjusted on age and comorbidities. At a mean delay of 2 days after R-CHOP, a median number of 3 HD-MTX cycles were administered at a mean dosage of 2 g/mq (range 1–3). Regarding safety, 19% of patients experienced acute renal injury (ARI), among them 2 in patients over 60 years and only one grade 3 ARI. We observed a complete response (CR) in 67% of patients, up to 79% if considering over 60 years. Particularly patients over 60 years were more likely to achieve CR (p = 0.052), even in those who delayed R-CHOP. At a mean follow-up of 24 months, 82% of patients over 60 years patients are alive (Figure 1). A substantial difference in overall survival was seen in patients reaching CR than others (100% vs. 33%) (p = 0.001). Six patients relapsed at a median time of 3 months, among them 4 died from lymphoma. Conclusions: Our report confirms the feasibility of HD-MTX in the treatment of DLBCL patients with high-risk features and high comorbidity burden. Patients over 60 years showed higher rate of complete remission without significant toxicity, independently on chemotherapy delay suggesting a good balance between response and toxicity with MRCHOP/COMP in this setting. Further studies with longer follow-up are needed to draw more definitive conclusions, especially in frail patients such as elderly. Keywords: aggressive B-cell non-Hodgkin lymphoma, chemotherapy No conflicts of interests pertinent to the abstract.