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

Program: Oral and Poster Abstracts
Type: Oral
Session: 621. Lymphomas: Translational – Molecular and Genetic: Molecular Profiling and Targets in Aggressive Lymphomas
Hematology Disease Topics & Pathways:
Research, Fundamental Science, Lymphomas, Non-Hodgkin lymphoma, B Cell lymphoma, Genomics, Diseases, Aggressive lymphoma, Lymphoid Malignancies, Biological Processes
Saturday, December 7, 2024: 2:30 PM

Jasper Chun Hei Wong1*, Fabian Frontzek, MD1*, Andrew Lytle, MD, PhD1, Brett Collinge1, Laura Hilton, PhD1, Susana Ben-Neriah1*, Graham W. Slack, MD1*, Pedro Farinha1, Alina S. Gerrie, MD, MPH1, Yang Li2*, Corinna Kosnopfel, PhD2*, James R. Cook, MD, PhD3, Itziar Salaverria4*, Elías Campo5, German Ott, MD6*, Andreas Rosenwald, MD7*, Catalina Amador, MD8*, Elaine S Jaffe, MD9, Timothy C. Greiner, MS, MD10*, Phillipp W. Raess, MD, PhD11*, Joo Y. Song, MD12, Giorgio Inghirami, MD13*, Dennis D. Weisenburger, MD14, Wing Chung Chan, MD12, Harald Holte, MD, PhD15, Klaus Beiske, MD, PhD16*, Kai Fu, MD, PhD17, Jan Delabie, MD, PhD18*, Stefania Pittaluga, MD, PhD9*, Andrew L. Feldman, MD19, Kerry J. Savage, MD, MSc1, Andrew J. Mungall, BSc, PhD20*, Christian Steidl, MD, PhD1, Georg Lenz2, Lisa M. Rimsza, MD21, Ryan Morin, PhD22 and David W. Scott, MBChB, PhD1

1Centre for Lymphoid Cancer, BC Cancer, Vancouver, BC, Canada
2Department of Medicine A, Hematology, Oncology and Pneumology, University Hospital Muenster, Muenster, Germany
3Department of Pathology and Laboratory Medicine, Cleveland Clinic, Cleveland, OH
4Institut D'Investigacions Biomèdiques August Pi I Sunyer, Barcelona, ESP
5Hematopathology Section, Pathology Department, Hospital Clínic de Barcelona, Barcelona, Spain
6Department of Clinical Pathology, Robert-Bosch-Krankenhaus, and Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany
7Comprehensive Cancer Center Mainfranken, University Hospital Würzburg, Würzburg, Germany
8Division of Hematopathology, University of Miami, Miami, FL
9National Cancer Institute, National Institute of Health, Bethesda, MD
10Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE
11Department of Pathology and Laboratory Medicine, Oregon Health & Science University, Portland, OR
12Department of Pathology, City of Hope National Medical Center, Duarte, CA
13Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY
14University of Nebraska Medical Center, Elkhorn, NE
15Department of Oncology, Oslo University Hospital, Oslo, NOR
16Oslo University Hospital, Oslo, Norway
17Department of Pathology & Laboratory Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY
18Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
19Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN
20Canada's Michael Smith Genome Sciences Centre, BC Cancer, Vancouver, Canada
21Department of Pathology and Laboratory Medicine, The University of Arizona, Tucson, AZ
22Simon Fraser University, Burnaby, BC, Canada

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 22% compared to 61%, 78%, and 54% of EBV+/MYC+, EBV+/MYC-, and EBV-/MYC- PBL patients, respectively (log-rank test p-adj. < 0.05).

Consistent with previous studies, we observed recurrent mutations affecting JAK-STAT (STAT3, SOCS1, SOCS3, DUSP2) in 41% of cases and RAS-RAF (NRAS, KRAS, BRAF) signaling in 38% of all PBLs. In contrast to ABC-DLBCL, very few mutations occurred in the NF-κB signalling pathway. Accordingly, PBL showed marked downregulation of genes involved in B-cell receptor and NF-κB signaling. Consistent with the lack of reliance on these pathways, functional analyses in PBL-1 showed resistance to treatment to ibrutinib as well as PI3K- and MALT1-inhibitors. Moreover, constitutive expression of the IκBα super-repressor did not affect viability of PBL-1 cells.

In situ single cell transcriptomic data analyses showed a sparse tumor microenvironment (TME) in PBL, with the primary non-malignant cell types being, on average, 10% macrophages, 7% NK/T cells, and 4% stromal cells of all represented cell types. EBV+/MYC+ tumors displayed a more abundant immune cell population with higher levels of macrophages (median 12%) and NK/T cells (median 9%), whereas EBV-/MYC- tumors were composed of the lowest levels of immune cells (median 4% macrophages and 1% NK/T cells). With respect to malignant cell phenotypes, we noted a novel population of SPP1-expressing cells that were enriched in EBV+/MYC+ tumors and a population of CD44-expressing cells that were enriched in EBV+/MYC- tumors.

Conclusion

Here we present novel subgroups of PBL with unique biology and clinical outcomes. We show that PBL does not rely on B-cell receptor signaling, instead relying on potentially targetable vulnerabilities in JAK-STAT, NOTCH, and RAS-RAF signaling according to EBV positivity and MYC rearrangement status. Lastly, we provide insight into the TME of PBL and demonstrate a novel population of SPP1 and CD44 expressing malignant cells in EBV+ tumors.

Disclosures: Gerrie: AstraZeneca, Beigene, Janssen, Lilly: Research Funding; AstraZeneca, Beigene, Janssen, Lily, Celgene: Honoraria. Inghirami: Daiichi Sankyo: Consultancy. Holte: Incyte: Consultancy; Pierre Fabre: Consultancy; SERB: Consultancy. Feldman: Zeno Pharmaceuticals: Patents & Royalties; Seattle Genetics: Research Funding. Savage: Bristol Myers Squibb: Consultancy, Research Funding; AbbVie: Consultancy; Seagen: Consultancy, Honoraria, Research Funding; Regeneron: Other: DSMC. Steidl: Bayer: Consultancy; EISAI: Consultancy; Seattle Genetics: Consultancy; Epizyme: Research Funding; Bristol Myers Squibb: Research Funding; AbbVie: Consultancy; Trillium Therapeutics Inc: Research Funding. Lenz: Novartis: Honoraria, Research Funding; Karyopharm: Honoraria; Genmab: Honoraria; Constellation: Honoraria; Lilly: Honoraria; Immagene: Honoraria; Incyte: Honoraria; Hexal/Sandoz: Honoraria; Genase: Honoraria; BeiGene: Honoraria; BMS: Honoraria; Amgen: Honoraria; AbbVie: Honoraria; ADC Therapeutics: Honoraria; Verastem: Research Funding; Roche: Honoraria, Research Funding; MSD: Honoraria; NanoString: Honoraria; PentixaPharm: Honoraria; Miltenyi Biotech: Honoraria; Pierre Fabre: Honoraria; Sobi: Honoraria, Speakers Bureau; Acerta: Research Funding; Roche, Gilead, BMS, Novartis, AstraZeneca, Abbvie, Incyte, Genmab, Constellation, ADC Therapeutics, Miltenyi, PentixaPharm, Sobi, Immagene, Genase, Hexal-Sandoz, Lilly, Beigene, MSD, Pierre Fabre: Consultancy; ELVESCA: Current equity holder in private company; Roche, Gilead, BMS, Novartis, AstraZeneca, Abbvie, Incyte, Genmab, Constellation, ADC Therapeutics, Miltenyi, PentixaPharm, Sobi, Immagene, Genase, Hexal-Sandoz, Lilly, Beigene, MSD, Pierre Fabre: Membership on an entity's Board of Directors or advisory committees; AbbVie, BeiGene, Sobi, Roche, Gilead, BMS: Other: Travel; MorphoSys: Honoraria, Research Funding; Gilead: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; AQUINOX: Research Funding; AstraZeneca: Honoraria, Research Funding; Bayer: Honoraria, Research Funding; AGIOS: Research Funding. Scott: Genmab: Consultancy, Honoraria; Veracyte: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; AstraZenenca: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Roche/Genentech: Research Funding; Nanostring: Patents & Royalties: use of gene expresssion to subtype aggressive lymphoma.

*signifies non-member of ASH