184 | GENOMIC PROFILING OF EXTRANODAL DISEASE IN PATIENTS WITH DIFFUSE LARGE B‐CELL LYMPHOMA: A COMBINED ANALYSIS OF POLARIX AND GOYA

Introduction: DLBCL is characterized by genomic heterogeneity and EN dissemination impacts prognosis. Genomic analyses of pts with EN disease from POLARIX were previously presented (Lue et al. 2024). We performed a retrospective study of additional genomic analysis in pts with previously untreated DLBCL and EN disease from two Phase III studies. Methods: POLARIX (NCT03274492; Tilly et al. 2022) and GOYA (NCT01287741; Vitolo et al. 2017) have been previously described. For comparison with POLARIX, pts from GOYA were limited to those with an IPI score ≥ 2. EN disease was confirmed by presence of radiographic lesions or pathological reports. Mutation analysis and gene expression profiling (RNAseq) were performed centrally. Differential expression and gene set enrichment analysis (GSEA) were compared in pts with and without EN disease. Pts with multiple EN sites were counted once per site within analysis of each separate site. Results: EN disease was confirmed in 1222/1837 pts (67%; POLARIX, n = 558/779, 72%; GOYA, n = 664/1058, 63%). Among pts with EN disease, the most common EN sites were gastrointestinal (GI, 36.1%), thorax (25.7%) and bone marrow (BM, 24.5%). In pts with ≥ 2 distinct EN sites (n = 502), co-occurrence of GI and thorax involvement was common (POLARIX, 18.9%; GOYA, 24.6%). Mutational data (n = 583; POLARIX, n = 365; GOYA, n = 218) showed similar mutation spectrums within specific EN sites between studies. High frequencies of PIM1 and MYD88 mutations (MCD) were associated with urinary, endocrine/reproductive and head/neck presentations. EZB characterizing mutations were enriched in thorax and bone. TP53 mutations were seen in various EN sites. Pts with multiple EN sites showed enrichment in mutations for MCD, EZB and A53 subtypes. For RNAseq data (n = 656; POLARIX, n = 419; GOYA, n = 237), GSEA demonstrated a common downregulation of adaptive and innate immune responses, and an increase in proliferation-associated pathways (Figure). Upregulation of metabolic pathways was present in pts with thorax, endocrine/reproductive, GI, and urinary system disease. Downregulation of pathways characteristic of myeloid, natural killer and stromal cells in the lymphoma microenvironment was notable in pts with endocrine/reproductive, GI, head/neck and BM disease, suggestive of an ‘immune cold’ microenvironment. Notch-mediated pathways were downregulated in pts with endocrine/reproductive, GI, and urinary disease. Conclusions: This analysis represents the largest collection of pts with DLBCL and EN disease paired with detailed genomic analysis. Mutation analysis revealed differential enrichment of genetic subtypes associated with specific sites of EN involvement. RNAseq analysis suggested dysregulation of immune surveillance and proliferation were common, with unique pathway aberrations associated with specific EN sites, including impact on tumor microenvironment. These data can be leveraged to help develop novel and tailored therapeutics for difficult-to-treat populations. Research funding declaration: The POLARIX study was sponsored by F. Hoffmann La-Roche Ltd. Third-party editorial assistance, under the direction of the authors, was provided by Rachel Bell, PhD, of Ashfield MedComms, an Inizio company, and was funded by F. Hoffmann La-Roche Ltd. Keywords: genomics, epigenomics, and other -omics; aggressive B-cell non-Hodgkin lymphoma; diagnostic and prognostic biomarkers Potential sources of conflict of interest: J. K. Lue Consultant or advisory role: BMS, AbbVie, Genmab, ADC Therapeutics, Merck, Genentech Other remuneration: Research funding: Kymera Therapeutics F. Morschhauser Consultant or advisory role: BMS, AbbVie, Roche, Miltenyi, Janssen, Modex Therapeutics Honoraria: Takeda, Kite/Gilead, AstraZeneca Other remuneration: Research funding: Roche, BMS, Kite/Gilead H. Tilly Consultant or advisory role: Roche Educational grants: Janssen Other remuneration: Roche, AstraZeneca, BMS, Incyte, BeiGene, Daiichi Sankyo, Lilly, Novartis, Pharmacyclics, ADC Therapeutics, Epizyme (all via institution) G. Lenz Consultant or advisory role: Roche, Novartis, BMS, Abbvie, Sobi, Flindr, AstraZeneca, Gilead, Incyte, Genmab, ADC Therapeutics, PentixaPharm, Hexal-Sandoz, Lilly, MSD, Exscientia, Beigene, Pierre Fabre Honoraria: Roche, Novartis, BMS, AbbVie, Sobi, Flindr, AstraZeneca, Gilead, Incyte, Genmab, ADC Therapeutics, PentixaPharm, Hexal-Sandoz, Lilly, MSD, Exscientia, BeiGene, Pierre Fabre Educational grants: BeiGene, AbbVie, Sobi, Roche, Gilead Other remuneration: Research funding: AstraZeneca, AbbVie, Sobi; Speaker's bureau: Sobi, Roche, AbbVie, BMS, Gilead, Incyte, Lilly, BeiGene F. Jardin Honoraria: Roche, Gilead, Novartis, BMS, Johnson & Johnson Educational grants: AbbVie, Roche A. F. Herrera Consultant or advisory role: Bristol Myers Squibb, Genentech, Merck, Seagen, AstraZeneca, ADC Therapeutics, Takeda, Genmab, Pfizer, AbbVie, Allogene Therapeutics Other remuneration: Research funding: Bristol Myers Squibb, Genentech, Merck, Seagen, AstraZeneca J. P. Sharman Consultant or advisory role: AbbVie, AstraZeneca, BeiGene, Genentech, Genmab, Lilly, Janssen Honoraria: AbbVie, AstraZeneca, BeiGene, Genentech, Genmab, Lilly, Janssen C. R. Flowers Consultant or advisory role: AbbVie, Bayer, BeiGene, Celgene, Denovo Biopharma, Foresight Diagnostics, Genentech/Roche, Genmab, Gilead, Karyopharm, N-Power Medicine, Pharmacyclics/Janssen, Seagen, Spectrum Stock ownership: Foresight Diagnostics, N-Power Medicine Other remuneration: Research funding: 4D, AbbVie, Acerta, Adaptimmune, Allogene, Amgen, Bayer, BostonGene, Celgene, Cellectis EMD, Gilead, Genentech/Roche, Guardant, Iovance, Janssen Pharmaceutical, Kite, MorphoSys, Nektar, Novartis, Pfizer, Pharmacyclics, Sanofi, Takeda, TG Therapeutics, Xencor, Ziopharm, Burroughs Wellcome Fund, Eastern Cooperative Oncology Group, National Cancer Institute, V Foundation, Cancer Prevention and Research Institute of Texas (RR190079): CPRIT Scholar in Cancer Research J. W. Friedberg Other remuneration: Research funding: Enterome M. Trněný Consultant or advisory role: Takeda, Bristol Myers Squibb, Incyte, AbbVie, Amgen, Roche, Gilead Sciences, Janssen, MorphoSys, Novartis, Genmab, SOBI, Autolus, Caribou Biosciences Honoraria: Janssen, Gilead Sciences, Takeda, Bristol Myers Squibb, Amgen, AbbVie, Roche, MorphoSys, Novartis, SOBI, Swixx Educational grants: Gilead Sciences, Takeda, Roche, Janssen, AbbVie, SOBI C. Herbaux Consultant or advisory role: Roche, Janssen, AbbVie, Gilead/Kite, Incyte, Novartis Honoraria: Roche, Janssen, AbbVie, Gilead/Kite, Incyte, Novartis Educational grants: Roche, Janssen, AbbVie, Gilead/Kite, Incyte, Novartis Other remuneration: Research funding: AbbVie, Takeda M. Yan Employment or leadership position: Hoffmann-La Roche Stock ownership: Hoffmann-La Roche Other remuneration: Patents, royalties, other intellectual property: Hoffmann-La Roche S. Chohan Employment or leadership position: Hoffmann-La Roche M. Sugidono Employment or leadership position: Genentech, Inc. Stock ownership: Genentech/Roche L. Wang Employment or leadership position: Roche, Genentech Y. Jiang Employment or leadership position: Roche/Genentech Stock ownership: Roche Educational grants: Roche Other remuneration: Patents, royalties, other intellectual property: Roche C. L. Batlevi Employment or leadership position: Roche/Genentech Consultant or advisory role: BMS, Seattle Genetics, Kite, Karyopharm, TG Therapeutics, ADC Therapeutics, AbbVie, Genentech, Treeline Bioscience Stock ownership: Roche Honoraria: Dava Oncology, TouchIME, Medscape Other remuneration: Research funding: Epizyme, Autolus, Roche, Vincerx W. Leung Employment or leadership position: Roche/Genentech Stock ownership: Roche Educational grants: Roche/Genentech W. Harris Employment or leadership position: Genentech, Inc. Stock ownership: Roche Other remuneration: Patents, royalties, other intellectual property: Genentech, Inc. G. Salles Consultant or advisory role: AbbVie, ATB Therapeutics, BeiGene, Bristol Myers Squibb, Debiopharm, Genentech/Roche, Genmab, Innate Pharma, Incyte, Ipsen, Janssen, Kite/Gilead, Loxo/Lilly, Merck, Modex, Molecular Partners, Nordic Nanovector, Novartis, Nurix, Orna Therapeutics, Treeline Stock ownership: Owkin Honoraria: Genentech/Roche, Incyte, Merck Other remuneration: Speaker's bureau: Genentech/Roche, Incyte, Merck; Research funding from AbbVie, Genentech, Genmab, Janssen, Ipsen L. H. Sehn Consultant or advisory role: AbbVie, Amgen, AstraZeneca, BeiGene, Bristol Myers Squibb, Kite, Gilead, Incyte, Janssen, Merck, Seagen, Genentech/Roche Honoraria: AbbVie, Amgen, AstraZeneca, BeiGene, Bristol Myers Squibb, Kite, Gilead, Incyte, Janssen, Merck, Seagen, Genentech/Roche Other remuneration: Research funding: Genentech/Roche, Teva

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