179 | GENOMIC AND TRANSCRIPTIONAL SINGLE‐CELL HETEROGENEITY IN GERMINAL‐CENTER LYMPHOMAS: INSIGHTS INTO FOLLICULAR LYMPHOMA TRANSFORMATION

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Background: Follicular lymphoma (FL) represents the most common subtype of indolent non-Hodgkin's lymphoma.Extranodal involvement (ENI) indicates poor clinical outcome in patients received rituximab-based immunochemotherapy.Methods: Aiming to investigate the influence of oncogenic mutations and tumor microenvironment alterations on ENI in FL, the clinical features of 528 patients with newly diagnosed FL receiving rituximab-based therapy were analyzed, with DNA and RNA sequencing performed on 409 and 181 patients, respectively.Results: Multiple ENI was observed in 136 (26%) patients and significantly related to advanced Ann Arbor stage, descent hemoglobin, elevated lactate dehydrogenase, lymph nodes ≥ 5 sites, lymph nodes > 6 cm, and high risk of POD24.Increased KMT2D, CREBBP, CARD11, and STAT6 mutations, as well as downregulation of immune-associated pathways, were associated with multiple ENI.In the rituximab plus chemotherapy (R-chemo) cohort (n = 345), involvement of the bone marrow, lung, liver, bones, and kidney/adrenal gland were unfavorable predictors of progression-free survival (PFS), with involvement of the liver and kidney/adrenal glands as unfavorable predictors of overall survival (OS).However, in the rituximab plus lenalidomide immunotherapy (R2) cohort (n = 183), no ENI site showed significant difference in PFS and OS.Conclusions: Negative prognostic impact of multiple ENI upon immunochemotherapy could be overcome by immunotherapy in FL.Better understanding of the biological behavior of multiple ENI could provide potential clinical rationale for future mechanism-based therapy of FL.

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