OS06.8.A PROSPECTIVE STUDY ON THE IMPACT OF THE GUT MICROBIOME COMPOSITION TO PATIENT’S RESPONSE TO STANDARD TREATMENT IN PCNSL

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Abstract BACKGROUND Gut microbiota has gained attention as a potential modulator of occurrence, progression, and response to cancer therapy, with host immune regulation as one potential mechanism. Primary central nervous system lymphoma (PCNSL) is a rare and distinct entity within diffuse large B-cell lymphoma whose treatment relies on a high-dose methotrexate (HD-MTX) regimen with or without consolidation. However, whether there is a specific microbiota composition association with treatment response and clinical outcomes remains incompletely understood. MATERIAL AND METHODS To identify the relationship between gut microbiome composition and response standard treatment in patients with PCNSL, we conducted a prospective study of PCNSL patients, included in the clinical trial NCT02313389 and the ancillary study NCT04253496 from 2020 to 2023 (patients aged more than 60 years, HD-MTX based induction and randomized HD-MTX-based maintenance versus follow-up without consolidation). Stool and cerebrospinal fluid (CSF) samples (n=49) were collected before (n=35) or after (n=14) therapy initiation to perform metagenomic and flow cytometry analyses. Clinical data, including treatment response, progression-free survival (PFS), and overall survival (OS), were collected and correlated with microbiome composition and immune cell content in CSF. RESULTS Analysis of paired samples (before versus after HD-MTX), revealed slight changes in microbial composition, especially the loss of a bacteria belonging to the Verrucomicrobiota Phylum. Unsupervised clustering on microbial data revealed two microbial communities associated with significantly distinct PFS (33.65 vs 7.60 months, p=0.001) and OS (36.75 vs 23.95 months, p=0.005) in PCNSL patients. Linear discriminant analysis Effect Size and differential abundance analysis between these communities revealed a specific organism belonging to the Bacteroidota Phylum whose enrichment is associated with improved OS and PFS at both univariate and multivariate models. Further stratifying patients according to this bacteria content showed an association with CD8 T cell infiltration to the CSF, suggesting a link between host immune cell regulation and gut microbiome composition. CONCLUSION Our findings suggest that gut microbiome communities may influence responses to standard treatment and clinical outcomes in PCNSL patients. Moreover, the identification of this particular microorganism could potentially provide a basis for patient stratification and guide personalized therapeutic strategies. We are currently working in a validation cohort to reinforce our findings and to elucidate the mechanisms underlying the interaction between the gut microbiome, the host immune regulation, and the treatment response.

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