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1546 Nodular Lymphocyte Predominant Hodgkin Lymphoma with Splenic Involvement Is Characterized By Inflamed Tumor Microenvironment, High Expression of Checkpoint Molecule Gene-Signature and Adverse Outcome

Program: Oral and Poster Abstracts
Session: 622. Lymphomas: Translational–Non-Genetic: Poster I
Hematology Disease Topics & Pathways:
adult, Hodgkin lymphoma, Research, Translational Research, Lymphomas, genomics, immune mechanism, Diseases, immunology, Lymphoid Malignancies, Biological Processes, Technology and Procedures, molecular biology, Human, Study Population, profiling, Pathology
Saturday, December 10, 2022, 5:30 PM-7:30 PM

Ilja Kalashnikov, MD1*, Marja-Liisa Karjalainen-Lindsberg, MD, PhD2*, Panu Kovanen, MD, PhD2*, Johannes Dunkel2*, Annika Pasanen, MD, PhD1*, Rachel Kositsky, BS3*, Sarah L. Ondrejka, DO4*, Eric D. Hsi, MD4,5, Andrew G Evans, MD, PhD6, Mette Ø Pedersen, MD PhD7*, Peter H. Norgaard, MD, PhD7, Anne Ortved Gang, MD PhD7*, Magdalena Czader, MD, PhD8, Jiehao Zhou, MD8*, Mina L Xu, MD9*, Nathan Paulson10*, Ridas Juskevicius, MD11*, Yasodha Natkunam, MD, PhD12,13, Abner Louissaint Jr., MD, PhD14, Haley Martin14*, Elizabeth Thacker15*, Cassandra Love3, Shari Tian3*, Choon Kiat Ong, PhD16, Chee Leong Cheng, FRCPA, FRCPath, MBBS16*, Chad M. McCall, MD, PhD3*, Jean L. Koff, MD, MSc17, Sheren F. Younes, MD, PhD13*, Mary Ann Arildsen, MD, PHD11*, Jennifer R Chapman-Fredricks, MD18*, Catalina Amador, MD18*, Yuri Fedoriw, MD19*, Carla Casulo, MD6, Amy Chadburn, MD20, Payal Sojitra, MD21*, Amir Behdad, MD22*, Eric Tse, MBBS, PhD, FRCP, FRCPath23, Kikkeri N Naresh, MD, MBBS24, C. Cameron Yin, MD, PhD25, Rashmi S. Goswami, MD, PhD26*, Sandeep Dave3* and Sirpa Leppa, MD, PhD1

1University of Helsinki and Helsinki University Hospital, Helsinki, Finland
2Helsinki University Hospital, Helsinki, Finland
3Duke University Medical Center, Durham, NC
4Cleveland Clinic, Cleveland, OH
5Wake Forest Baptist Medical Center, Winston Salem, NC
6University of Rochester Medical Center, Rochester, NY
7Copenhagen University Hospital, Herlev, Denmark
8Indiana University, Indianapolis, IN
9Yale University School of Medicine and Yale Cancer Center, New Haven, CT
10Yale University School of Medicine, New Haven, CT
11Vanderbilt University Medical Center, Nashville, TN
12Stanford University Medical Center, Stanford, CA
13Stanford University School of Medicine, Stanford, CA
14Massachusetts General Hospital, Boston, MA
15Data Drive Biosciences, Durham, NC
16National Cancer Centre Singapore, Singapore, Singapore
17Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA
18University of Miami Miller School of Medicine, Miami, FL
19Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC
20Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY
21Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ
22Northwestern University Feinberg School of Medicine, Chicago, IL
23Queen Mary Hospital, University of Hong Kong, Pokfulam, Hong Kong
24Fred Hutchinson Cancer Center, Seattle, WA
25The University of Texas MD Anderson Cancer Center, Houston, TX
26Sunnybrook Health Sciences Centre, Toronto, ON, Canada

Background: Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a rare B-cell malignancy characterized by infrequent neoplastic cells embedded in an immunologically active tumor microenvironment (TME). Histologically, NLPHL can be divided into classical (Fan A-B) and variant (Fan C-F) growth patterns. Clinical course is generally indolent, and the majority of patients present with limited stage disease. However, advanced stage with splenic involvement and variant histology are known to be associated with more aggressive disease. The molecular features underlying this association remain unknown. To gain further insights into disease biology, we recruited NLPHL cases as part of the Atlas of Blood Cancer Genomes (ABCG) initiative, a consortium consisting of 26 institutions.

Design: We collected comprehensive clinicopathological data including splenic involvement from 135 NLPHL patients, with centralized review performed by a panel of dedicated hematopathologists to ensure accurate diagnosis per 2016 WHO criteria. We performed RNA sequencing on formalin-fixed paraffin-embedded (FFPE) diagnostic tumor lymph nodes (n=100) and enumerated tumor-infiltrating immune cell compositions using FARDEEP with signature matrix LM22 from CIBERSORT. In addition, we performed gene set enrichment analysis to compare molecular pathways between the patients with and without splenic involvement. The Kaplan-Meier method was used to calculate overall survival (OS) and progression free survival (PFS) probabilities, and the log-rank test was used for comparisons between groups. Continuous variables were compared using the Wilcoxon rank-sum test.

Results: The median age at diagnosis was 42 years (range 5-80 years). Most patients were males (n=96; 71%) and had limited stage disease (n=96, 74%). Splenic involvement was present in 17 patients (13%). Histologic growth pattern was available for 97 cases, 41 (42%) with variant and 56 (58%) with classical histology. Variant histology was enriched in the patients with splenic involvement. Thirty-five (28%) relapses and 5 (3.9%) transformations occurred during a median follow-up of 80 months (range 0.36-604 months). Ten-year OS and PFS rates for the whole cohort were 86% (95% CI, 78-95%) and 59% (95% CI, 50-71%), respectively. Patients with splenic involvement at diagnosis tended to have inferior outcome at 10 years compared with those without splenic involvement (PFS 40% vs 62%, P=0.129; OS 79% vs 88%, P=0.0553).

According to in silico immunophenotyping, NLPHLs with splenic involvement were characterized by a lower proportion of naïve B cells and increased proportions of CD8+ T cells and M1-macrophages compared to the NLPHLs without splenic involvement (P<0.001 for all comparisons). Moreover, splenic involvement was associated with higher expression of checkpoint protein-encoding genes, including PDCD1 (PD-1), CD274 (PD-L1), CTLA4, LAG3, HAVCR2 (TIM-3) and TIGIT (Figure 1; P<0.001). Finally, we found a strong association between splenic involvement and gene expression profile related to inflammatory response (P<0.001), response to interferon gamma (P<0.001) and complement pathways (P<0.001).

Conclusion: Our study represents the largest comprehensive clinical and transcriptomic analyses of NLPHL to date. The results demonstrate that NLPHLs with splenic involvement are characterized by inflamed TME with high expression of checkpoint molecule gene-signature and are associated with inferior outcomes.

Figure 1. Unsupervised clustering for expression of checkpoint genes stratified by spleen involvement. Samples are ordered by the sum of normalized checkpoint gene expression values (checkpoint score)

Disclosures: Hsi: Virtuoso: Research Funding; Novartis: Consultancy; Eli Lilly: Research Funding; Abbvie: Research Funding; Cytomx: Consultancy; Astellas: Consultancy; Abcon: Consultancy; Abcon: Current holder of stock options in a privately-held company. Czader: Beckman Coulter: Membership on an entity's Board of Directors or advisory committees. Xu: Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Pure Marrow: Consultancy; Blueprint Medicines: Consultancy; Seattle Genetics: Consultancy. Louissaint: Lymphoma Research Foundation: Research Funding. Thacker: Data Driven Bioscience: Current Employment. Love: Data Driven Biosciences: Consultancy, Current holder of stock options in a privately-held company. Ong: SymBio Pharmaceuticals Limited: Research Funding. Koff: Atara BioTherapeutics: Research Funding; Gamida Cell: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Morphosys: Membership on an entity's Board of Directors or advisory committees; Oncternal Therapeutics: Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees; Viracta Therapeutics: Research Funding. Casulo: Bristol Myers Squibb: Research Funding; Verastem: Research Funding; Genentech: Research Funding; Secura Bio: Research Funding; Gilead: Research Funding. Chadburn: NorthShore University HealthSystem (Eavanston IL: Honoraria; U Chicago: Honoraria; Lieca Biosystems: Consultancy; Leica Biosystems: Membership on an entity's Board of Directors or advisory committees; USCAP: Honoraria. Behdad: Leica: Honoraria; Leica: Membership on an entity's Board of Directors or advisory committees; Thermofisher scientific: Honoraria; Foundation Medicine/Roche China: Honoraria; advisory committee: Membership on an entity's Board of Directors or advisory committees; Lilly: Honoraria. Tse: MSD: Research Funding. Leppa: Incyte: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Research Funding; Gilead Sciences: Consultancy, Honoraria; BMS: Consultancy, Research Funding; Bayer: Research Funding; Orion Pharma: Consultancy; Pfizer: Consultancy; Beigene: Consultancy; Genmab: Research Funding; Nordic Nanovector: Research Funding.

*signifies non-member of ASH