Clinical characteristics and molecular heterogeneity in Follicular lymphoma with extranodal involvement

Follicular lymphoma (FL) represents the most common subtype of indolent non-Hodgkin's lymphoma. Extranodal involvement (ENI) indicates a poor clinical outcome in patients who received rituximab-based immunochemotherapy. Recent studies indicate that genetic alterations and tumor microenvironment dysregulation drive extranodal dissemination and lymphoma progression. However, the molecular mechanisms underlying ENI in FL remain to be fully elucidated.

Aiming to investigate the influence of oncogenic mutations and tumor microenvironment alterations on ENI in FL, the clinical features of 501 patients with newly diagnosed FL receiving rituximab-based therapy were analyzed, with DNA and RNA sequencing performed on 403 and 175 patients, respectively.

Multiple ENI was observed in 120 (24%) patients and was significantly related to advanced Ann Arbor stage, decreased hemoglobin, elevated lactate dehydrogenase, elevated beta-2 microglobulin, lymph nodes ≥ 5 sites, lymph nodes > 6 cm, and high risk of progression of disease within 2 years (POD24). Increased KMT2D, CREBBP, CARD11, and STAT6 mutations, as well as downregulation of immune-associated pathways and alterations in lipid metabolism, were associated with multiple ENI. In the rituximab plus chemotherapy (R-chemo) cohort (n = 344), involvement of bone marrow, lung, liver, bones, and kidney/adrenal glands were unfavorable predictors of progression-free survival (PFS), with involvement of liver and kidney/adrenal glands as unfavorable predictors of overall survival (OS). However, in the rituximab plus lenalidomide immunotherapy (R2) cohort (n = 157), no ENI site showed a significant difference in PFS and OS.

Negative prognostic impact of multiple ENI upon R-chemo therapy could be overcome by R2 therapy in FL. Better understanding of the biological behavior of multiple ENI could provide a potential clinical rationale for future mechanism-based therapy of FL.