Biological and Prognostic Subgroups of Plasmablastic Lymphoma Defined By EBV Status and MYC Rearrangement- an L.L.M.P.P. Study

• Published in: Blood 2024-11, Vol.144 (Supplement 1), p.231-231
• Main Authors: Wong, Jasper Chun Hei, Frontzek, Fabian, Lytle, Andrew, Collinge, Brett, Hilton, Laura, Ben-Neriah, Susana, Slack, Graham W., Farinha, Pedro, Gerrie, Alina S., Li, Yang, Kosnopfel, Corinna, Cook, James R., Salaverria, Itziar, Campo, Elías, Ott, German, Rosenwald, Andreas, Amador, Catalina, Jaffe, Elaine S, Greiner, Timothy C., Raess, Phillipp W., Song, Joo Y., Inghirami, Giorgio, Weisenburger, Dennis D., Chan, Wing Chung, Holte, Harald, Beiske, Klaus, Fu, Kai, Delabie, Jan, Pittaluga, Stefania, Feldman, Andrew L., Savage, Kerry J., Mungall, Andrew J., Steidl, Christian, Lenz, Georg, Rimsza, Lisa M., Morin, Ryan, Scott, David W.
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2024-208880

Introduction Plasmablastic lymphoma (PBL) is a rare aggressive subtype of lymphoma. It is more common in HIV positive patients, and is often associated with Epstein-Barr virus (EBV) and MYC rearrangements. PBL is characterized by markers of plasmacytic differentiation including CD138 and MUM1/IRF4, and loss of B-cell markers such as CD20, which suggests a cell of origin similar to that of multiple myeloma (MM) or activated B-cell-like (ABC) diffuse large B-cell lymphoma (DLBCL). The standard of care for PBL is CHOP-based chemotherapy but this is frequently not curative. Other than EBV-negative status, which defines a high-risk group, no other biological features have been discovered that are associated with outcomes. Methods Here, we provide a comprehensive analysis of the genomic and transcriptomic landscape of PBL using a collection of 176 exomes and genomes (n=55 new, contributed by Lymphoma/Leukemia Molecular Profiling Project [LLMPP] sites and centrally reviewed by the LLMPP pathology panel [WHO 2016]; n=121 previously published [PMID: 33225311, 33951889, 34465776, 34714908]), 65 transcriptomes (n=44 new; n=21 published) and 37 in situ single cell transcriptomic profiles (CosMx Spatial Molecular Imager) from archival diagnostic tissue biopsies. Somatic mutations (SNVs/Indels) were identified using an ensemble of four variant callers (Strelka2, Lofreq, Mutect2, SAGE). Salmon and DESeq2 were used to identify differentially expressed genes. This multi-omics dataset was compared to other known B-cell malignancies including 92 MM, 238 Burkitt lymphomas (BL), and 208 DLBCLs. Cell segmentation of the CosMx data was performed using Baysor and downstream analyses were conducted using the Seurat workflow. For functional validation, cell viability assays (CellTiter-Glo Luminescent Assay) were conducted in the PBL cell line, PBL-1, and 4 control DLBCL cell lines. Results Within the cohort, 63% (106/169) of primary PBL cases were EBV-positive (EBV+) and 57% (82/144) harbored MYC rearrangements (MYC+). When stratifying patients by EBV and MYC rearrangement status, mutations in different genes were enriched in each group: STAT3 occurred in 55% (29/53) of EBV+/MYC+ PBLs; NOTCH1 in 19% (7/36) of EBV+/MYC-; MYC in 24% (6/25) and TP53 in 40% (10/25) of EBV-/MYC+ tumors; TET2 was mutated in 38% (9/24) and KRAS in 25% (6/24) of EBV-/MYC- PBLs. EBV-/MYC+ tumors represented a subgroup of patients with dismal outcomes. The 2-year overall survival (OS) of these patients was 2