-Author name in bold denotes the presenting author
-Asterisk * with author name denotes a Non-ASH member
Clinically Relevant Abstract denotes an abstract that is clinically relevant.

PhD Trainee denotes that this is a recommended PHD Trainee Session.

Ticketed Session denotes that this is a ticketed session.

176 Unraveling the Transcriptional Landscape of Nodular Lymphocyte-Predominant Hodgkin Lymphoma and T-Cell/Histiocyte Rich Large B-Cell Lymphoma: Impact of Tumor Microenvironment and Checkpoint Gene Expression

Program: Oral and Poster Abstracts
Type: Oral
Session: 622. Lymphomas: Translational – Non-Genetic: Illuminating the Tumor Microenvironment and Immune Landscape in Lymphoma
Hematology Disease Topics & Pathways:
Research, Hodgkin lymphoma, adult, Translational Research, Lymphomas, Clinical Research, Diseases, real-world evidence, Lymphoid Malignancies, young adult , Biological Processes, molecular biology, Technology and Procedures, profiling, Study Population, Human
Saturday, December 9, 2023: 2:15 PM

Ilja Kalashnikov, MD1*, Veronica Russell2*, Panu Kovanen, MD, PhD3*, Johannes Dunkel, MD, PhD3*, Marja-Liisa Karjalainen-Lindsberg, MD, PhD3*, Annika Pasanen, MD, PhD4*, Rachel Kositsky, PhD5*, Sarah L. Ondrejka, DO6, Tanu Goyal, MD7*, Eric D. Hsi, MD8, Mette Ølgod Pedersen, MD9*, Anne Ortved Gang, MD10*, Magdalena Czader, MD, PhD11*, Jiehao Zhou12*, Mina Xu, MD13*, Nathan Paulson13*, Jean L. Koff, MD, MSc14, Andrew G Evans, MD, PhD15*, Yasodha Natkunam, MD, PhD16, Ridas Juskevicius, MD17, Abner Louissaint, MD, PhD18*, Elizabeth Thacker19*, Tushar Dave2*, Cassandra L. Love2, Chad M McCall, MD, PhD20*, Choon Kiat Ong, PhD, BSc21*, Michael Churnetski, BS22*, Haley Martin23*, Jennifer R. Chapman-Fredricks, MD24*, Javeed Iqbal, PhD, MSc25*, Amy Chadburn, MD26, Payal Sojitra27*, Amir Behdad, MD28*, William Choi, MBBS, MRCP29, Jie Xu, MD PhD30*, Emily F. Ferguson Mason, MD, PhD17*, Kikkeri N Naresh31, Yuri D. Fedoriw, MD32*, Dina Sameh Soliman, MD, MBBS, MSc33, Sandeep Dave, M.D.34* and Sirpa Leppä, Professor1,4

1University of Helsinki, Helsinki, Finland
2Duke University, Durham, NC
3Department of Pathology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
4Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland
5AstraZeneca, Waltham, MA
6Department of Laboratory Medicine, Cleveland Clinic, Cleveland, OH
7Cleveland Clinic, Cleveland, OH
8Department of Pathology, Wake Forest Baptist Medical Center, Winston Salem, NC
9Herlev hospital, Herlev, DNK
10Copenhagen University Hospital, Herlev, Denmark
11Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN
12Indiana University, Indianapolis, IN
13Yale University, New Haven, CT
14Winship Cancer Institute, Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA
15Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY
16Stanford Univ. Med. Ctr., Stanford, CA
17Vanderbilt University Medical Center, Nashville, TN
18Massachusetts General Hospital, Boston, MA
19Data Driven Bioscience, Durham, NC
20Carolinas Pathology Group, Charlotte, NC
21National Cancer Centre Singapore, Singapore, Singapore, SGP
22Emory University, Atlanta, GA
23Department of Pathology, Massachusetts General Hospital, Boston, MA
24University of Miami Miller School of Medicine, Miami, FL
25Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE
26Department of Pathology and Laboratory Medicine, Weill Cornell Medicine/New York Presbyterian Hospital, New York, NY
27Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ
28Regents of The University of Michigan, Ann Arbor, MI
29Tuen Mun Hospital, Happy Valley, NA, HKG
30Department of Hematopathology, The University of Texas M.D. Anderson Cancer Center, Houston, TX
31Fred Hutchinson Cancer Center, Seattle, WA
32University of North Carolina, Chapel Hill, NC
33HMC-Qatar, Doha, QAT
34Duke University Medical Center, Durham, NC

Introduction: Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a rare B-cell malignancy with a paucity of malignant cells embedded in a diverse tumor microenvironment (TME). The histological composition of the TME is known to influence outcomes, with nodular B-cell rich TME (classical histology, Fan patterns A&B) associated with indolent clinical course, while T-cell infiltration or diffuse growth (variant histology, Fan patterns C-F) may resemble aggressive T/cell-histiocyte rich large B-cell lymphoma (THRLBCL) to which NLPHL can transform. Molecular features of NLPHL and THRLBCL remain to be discovered. To gain further insights into the biology of these lymphomas, we recruited NLPHL and THRLBCL cases as part of the Atlas of Blood Cancer Genomes (ABCG) initiative, a consortium consisting of 26 institutions.

Design: We collected comprehensive clinicopathological, treatment and outcome data from 154 NLPHL and 21 THRLBCL patients, with centralized pathology review performed by a panel of dedicated hematopathologists. Fan patterns of the NLPHL samples were documented in all samples where possible. RNA sequencing was performed on formalin-fixed paraffin-embedded (FFPE) diagnostic tumor samples (n=129 NLPHL; n=17 THRLBCL). Tumor-infiltrating immune cell compositions were enumerated using FARDEEP with signature matrix LM22 from CIBERSORT.

Results: Median age at diagnosis for the patients with THRLBCL and NLPHL was 54 years (interquartile ratio [IQR] 43-65) and 40 years (IQR 24-53), respectively. The majority of patients with NLPHL had limited stage (74%), whereas the patients with THRLBCL predominantly had advanced stage at diagnosis (95%). In both diseases, most patients were males (NLPHL, 69%; THRLBCL, 76%). Spleen involvement was present in 11 NLPHL patients (8%) and histological growth pattern was documented in 112 patients (73%). Out of those, 47 (42%) presented with variant histology and 65 with classical histology. Variant histology was enriched in NLPHL patients with splenic involvement.

During a median follow-up of 6.4 years (IQR 3.8-10.1), 12 NLPHL patients and 9 THRLBCL patients died. Patients with THRLBCL had worse 10-year overall survival (OS, 31% vs 89%; p<0.001) and progression-free survival (PFS, 30% vs 66%; p=0.002) compared to patients with NLPHL. Moreover, NLPHLs with variant histology had inferior 10-year OS compared to NLPHLs with classical histology (81% vs 91%; P=0.03; Figure 1).

According to in silico immunophenotyping, THRLBCL cases had the highest median proportions of M1-macrophages (11.0%) and CD8+ T-cells (17.0%), followed by NLPHLs with variant histology (M1-macrophages, 6.5%; CD8+ T-cells, 14.5%), with the lowest proportion observed in NLPHLs with classical histology (M1-macrophages, 5.2%; CD8+ T-cells, 10.9%). In contrast, the median proportions of naïve B cells followed an opposite trend across subtypes (NLPHL classical histology, 15.5%; NLPHL variant histology, 11.0%; THRLBCL, 2.0%), whereas the median proportion of CD4+ T-cells was similar across both lymphomas (NLPHL classical histology, 33.9%; NLPHL variant histology, 33.9%; THRLBCL, 32.4%).

Despite differences in the overall transcriptomic landscape, gene expression patterns posited THRLBCL and NLPHL as comprising a biological continuum. THRLBCL shared more similarities with NLPHL with variant histology, while NLPHLs with classical histology exhibited upregulation of genes related to cell growth and proliferation through the MYC pathway (P<0.001). Finally, we identified a strong association between THRLBCL and upregulation of checkpoint genes (P<0.001) and gene expression related to inflammatory response (P<0.001) (Figure 2). Furthermore, NLPHLs with a high checkpoint score (above the 75th percentile) were associated with spleen involvement (P<0.001) and worse outcome (5-year PFS 61% vs 87%; P=0.02).

Conclusion: Our study provides the largest comprehensive clinical and transcriptomic analyses of NLPHL and THRLBCL to-date. The findings suggest that the inferior outcomes observed in THRLBCL and in a subset of NLPHL are attributable to a higher degree of inflammation in the TME, increased expression of checkpoint genes, and a high proportion of macrophages.

Disclosures: Kositsky: Haleon: Current equity holder in publicly-traded company; Merck: Current equity holder in publicly-traded company; GSK: Current equity holder in publicly-traded company; Abbvie: Current equity holder in publicly-traded company; AstraZeneca: Current Employment. Hsi: Novartis: Consultancy. Koff: Viracta Therapeutics: Research Funding; BeiGene: Consultancy. Thacker: Data Driven Bioscience: Current Employment, Current equity holder in private company. Love: Data Driven Bioscience: Consultancy, Current equity holder in private company. McCall: Bristol Myers Squibb: Speakers Bureau. Chadburn: Boehringer Ingelheim Pharmaceuticals, Inc.: Consultancy; Leica Biosystems: Consultancy; Medical College of Wisconsin: Honoraria. Dave: Data Driven Bioscience: Current equity holder in private company. Leppä: Genmab: Consultancy; Celgene/BMS: Research Funding; Orion: Consultancy; Novartis: Honoraria, Research Funding; Nordic Nanovector: Research Funding; Bayer AG: Research Funding; Roche: Consultancy, Research Funding; Sobi: Consultancy; Gilead: Consultancy, Honoraria; Hutchmed: Research Funding; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Beigene: Consultancy; Abbvie: Consultancy.

*signifies non-member of ASH