Abstract 72: A case of immune therapy-refractory composite lymphoma: The complex interplay between two distinct tumors within a single spatial microenvironment

Abstract Immune checkpoint (IC) therapy with anti-PD1 agents is typically used in treatment-refractory classic Hodgkin lymphoma (CHL). However, we present a rare case of composite classic Follicular lymphoma (cFL) and CHL whereby frontline use of anti-PD1 therapy (Nivolumab) in combination with standard AVD (Doxorubicin, Vinblastine, Dacarbazine) was clinically justified. We performed the Visium spatial transcriptomics assay to gain insight into the unique tumor cell characteristics and immune cell composition of the tumor microenvironment both pre- and post-IC therapy. Our case is a of a 44-year-old female who presented with fever, night sweats, and cervical lymphadenopathy. The patient underwent frontline IC combination therapy with single-agent Nivolumab and standard AVD. She showed nearly complete treatment response after 6 cycles. However, three months post-therapy, she developed new symptoms of fatigue, fever, and inguinal lymphadenopathy. Excisional biopsy of the inguinal lymph node showed recurrence of the cFL with no evidence of the previous CHL. The clinicopathologic findings suggest a primary treatment response of the CHL to IC combination therapy, but refractory response of the cFL. To understand the complex immune cell composition of this rare lymphoma, we performed the 10X Genomics Visium CytAssist assay on a representative tumor area from the formalin-fixed paraffin-embedded tissue block of the initial diagnostic biopsy. The data were analyzed using a bioinformatics workflow for cell deconvolution to identify cellular composition, ligand-receptor interaction analysis to study cell-cell communication, and spatial gene expression analysis to understand the disease context. Pathologic diagnosis of the lymph node excision showed a composite lymphoma comprised of cFL and CHL. Cytogenetic fluorescence in situ hybridization (FISH) study for BCL2 rearrangement was negative. Our analysis revealed distinct transcriptomic profiles associated with cFL and CHL regions within the lymph node excision. We identified unique immune cell infiltration patterns with pronounced CD4(+) T-cell memory signatures in both cFL and CHL regions. We observed transitional zones between the two lymphomas characterized by a mixed expression profile with increased stromal and stem cell markers. Furthermore, we uncovered T-cell immunoregulatory and trafficking signals localized to the CHL and transitional zones, potentially influencing the surrounding tumor microenvironment. In conclusion, this study provides an unprecedented investigation into a rare case of composite lymphoma treated with frontline IC combination therapy through molecular and spatial profiling. Further analysis using the Visium assay is pending on the subsequent post-therapy tissue biopsy which may undoubtedly reveal underlying unique biologic relationships. Citation Format: Ashley K. Volaric, James Gerson, Karamatullah Danyal, Rangsinee Nusapan, Seth Frietze. A case of immune therapy-refractory composite lymphoma: The complex interplay between two distinct tumors within a single spatial microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 72.