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
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.
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