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1535 Polyostotic DLBCL Is Characterized By a NF-Κb Pathway Affecting Molecular Profile and Superior Survival

Program: Oral and Poster Abstracts
Session: 621. Lymphomas: Translational—Molecular and Genetic: Poster I
Hematology Disease Topics & Pathways:
Research, Translational Research, Lymphomas, non-Hodgkin lymphoma, B Cell lymphoma, Diseases, Lymphoid Malignancies
Saturday, December 10, 2022, 5:30 PM-7:30 PM

Ruben A.L. De Groen, MSc1*, Fleur A De Groot1*, Lorraine M. De Haan2*, Tom van Wezel2*, Troy Noordenbos2*, Stefan Boehringer3*, Ronald Van Eijk2*, Richard Raghoo4*, Dina Ruano2*, Aniko Sijs-Szabo1*, Liane te Boome, MD5, Valeska Terpstra6*, Henriette Levenga7*, Aline Nicolae8*, Ward Posthuma, MD, PhD9, Isabelle Focke-Snieders9*, Lizan Hardi10*, Wietske den Hartog11*, Lara H. Böhmer, MD12*, Anke Van Den Berg, PhD13, Pim Mutseaers, MD14*, Marjolein W.M. Van Der Poel15, Myrurgia Abdul Hamid16*, F.J. Sherida H. Woei-a-Jin, MD MSc17*, Ann Janssens, MD, PhD18*, Thomas Tousseyn19*, Judith Bovée2*, Hendrik Veelken, MD, PhD1, Steven T Pals, MD, PhD20,21*, Arjan Diepstra, M.D., Ph.D.13, Marcel Nijland, MD, PhD22*, Marie José Kersten, MD, PhD21,23, Patty M. Jansen2*, Arjen Cleven2,24* and Joost S.P. Vermaat, MD, PhD1

1Department of Hematology, Leiden University Medical Center, Leiden, Netherlands
2Department of Pathology, Leiden University Medical Center, Leiden, Netherlands
3Leiden University Medical Center, Leiden, Netherlands
4Department of Radiology, LUMC, Leiden, Netherlands
5MCH, The Hague, NLD
6Pathology, Haaglanden MC, Den Haag, Netherlands
7Department of Hematology, Groene Hart Ziekenhuis, Gouda, Netherlands
8Groene Hart Hospital, Gouda, Netherlands
9Reinier de Graaf Hospital, Delft, Netherlands
10Department of Hematology, Alrijne Hospital, Leiderdorp, Netherlands
11Department of Pathology, Alrijne Hospital, Leiderdorp, Netherlands
12Department of Hematology, Haga Teaching Hospital, The Hague, Netherlands
13Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands
14Department of Hematology, Erasmus MC Cancer Center, Rotterdam, Netherlands
15Department of Hematology, Maastricht University Medical Center, Maastricht, Netherlands
16Maastricht University, Urmond, NLD
17Department of General Medical Oncology, University Hospitals Leuven, Leuven, Belgium
18Department of Hematology, Universitaire Ziekenhuizen Leuven, Leuven, Belgium
19Department of Pathology, UZ Leuven, Leuven, Belgium
20Department of Pathology, Academic Medical Center, Amsterdam, Netherlands
21Lymphoma and Myeloma Center Amsterdam-LYMMCARE, Amsterdam, Netherlands
22Department of Hematology, University Medical Center Groningen and University of Groningen, Groningen, Netherlands
23Department of Hematology, Cancer Center Amsterdam, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, Noord Holland, Netherlands
24Department of Pathology and Medical Biology, University of Groningen, Groningen, Netherlands


Polyostotic diffuse large B-cell lymphoma (DLBCL) is a rare extranodal disease with only multifocal bone localizations that has not extensively been studied. Other known bone DLBCL comprises primary bone (PB-)DLBCL with a single bone localization with(out) locoregional lymphadenopathy and disseminated-DLBCL with ≥1 bone lesion(s) and ≥1 (extra) nodal localization(s). Recently (PMID: 34478526, de Groen et al.), we demonstrated a germinal center B-cell (GCB)-subtype with a centrocyte-like phenotype and a unique corresponding molecular profile, reflecting favorable prognosis for PB-DLBCL compared to non-bone DLBCL with a GCB-subtype. Here, the molecular characteristics of polyostotic-DLBCL were assessed and compared to PB-DLBCL, disseminated-DLBCL, and nodal DLBCL-GCB, using an extensive targeted next-generation sequencing (tNGS) panel.


This retrospective multicenter study analyzed 14 polyostotic-DLBCL, 44 PB-DLBCL, 26 disseminated-DLBCL, and 36 nodal DLBCL-GCB cases (selection based on PET/CT-scan), including well-annotated histological and clinical data. Cases were diagnosed with immunohistochemistry following the revised WHO classification of 2016. Cell-of-origin (COO) was determined by Hans’ algorithm. Presence of MYC/BCL2/BCL6-rearrangements were identified through fluorescent in situ hybridization (FISH) and break-apart probes. High-grade B-cell lymphomas (double/triple hit) were excluded. As described (PMID: 34478526), tNGS was performed, using an extended panel consisting of 128 (LYMFv2, mostly used) or 52 (LYMFv1) B-cell lymphoma relevant genes.


Our cohort consisted of 120 patients (78 males, 65%) with a median age at diagnosis of 61 (range 13-91). Half of the polyostotic-DLBCL cases belonged to a GCB phenotype (8/14, 57%), while a GCB phenotype was more frequently identified in PB-DLBCL (31/44, 70%) and disseminated-DLBCL (18/26, 69%). Using tNGS with LYMFv2 and LYMFv1, respectively 57 and 36 cases were successfully analyzed, elucidating (in)activating pathogenic mutations in 124 different genes.

In polyostotic-DLBCL, frequent mutations in f.e. CARD11 and MYD88 demonstrated a unique mutational profile affecting the NF-κB pathway characteristic of ABC-genotypes (Figure 1, P=0.018), compared to PB-DLBCL, disseminated-DLBCL and nodal DLBCL-GCB. In contrast, an exclusive immunomodulatory profile with frequent mutations in B2M, IRF8 and TNFRSF14 was identified for PB-DLBCL (P=0.029). Focusing on GCB-associated epigenetic genes (CREBBP, EP300, EZH2, KMT2D, etc.), no significant difference was found between the mentioned DLBCL subgroups. Mutational profiles of disseminated-DLBCL revealed a broad spectrum of abnormalities (BCL2, CREBBP, TNFRSF14, and TP53), partially consistent with either an immunomodulatory or an epigenic genotype. Nodal DLBCL-GCB was specifically characterized by frequent aberrations in BCL2 and MYC and lacked an immunomodulatory or NF-κB activating genotype.

Given >1 extranodal localizations, polyostotic-DLBCL is classified as high-risk disease with Ann Arbor stage IV. Compared to disseminated-DLBCL with similar stage III/IV disease, polyostotic-DLBCL demonstrated a superior 3-year overall survival (Figure 2, log-rank, p<0.001, HR: 4.76, CI: 1.4-15.9).


Polyostotic-DLBCL showed a unique mutational profile with frequent NF-κB-activating mutations, in contrast to PB-DLBCL, disseminated-DLBCL and nodal DLBCL-GCB. Despite this ABC-associated profile of polyostotic-DLBCL and its high Ann Arbor stage, a favorable prognosis was identified especially compared to similar high Ann Abor stage disseminated-DLBCL. To study COO and tumor microenvironment in more detail to evaluate polyostotic-DLBCL as a separate biological disease entity, gene-expression profiling with the BLYM777 panel (PMID: 35454765) will be presented at the meeting.

Disclosures: Mutseaers: Astra Zeneca: Research Funding; Glaxo Smith Kline: Consultancy; BMS: Consultancy. Woei-a-Jin: Takeda: Research Funding; Kyowa Kirin: Research Funding. Janssens: Genmab: Current Employment; Abbvie: Consultancy, Other: Travel Grants, Speakers Bureau; Amgen: Consultancy, Other: travel grants, Speakers Bureau; Astra-Zeneca: Consultancy, Speakers Bureau; Beigene: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Sobi: Consultancy, Speakers Bureau; Sanofi Genzyme: Consultancy, Speakers Bureau; Roche: Consultancy; Celgene: Other: travel grants. Tousseyn: EUSA Pharma: Consultancy, Speakers Bureau. Bovée: Tracon pharmaceuticals: Research Funding. Diepstra: Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding. Nijland: Genmab: Consultancy; Takeda: Research Funding; Roche: Research Funding. Kersten: BMS/Celgene: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Kite, a Gilead Company: Honoraria, Research Funding; Mundipharma: Research Funding; Novartis: Honoraria; Takeda: Honoraria; Milteny Biotec: Honoraria; Adicet Bio: Honoraria.

*signifies non-member of ASH