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849 Polytypic B-Cells, B-Cell Lymphoproliferative Disorders/Lymphomas, and Neoplastic T-Cells Divergently Differentiate from TET2-/DNMT3A-Mutated Clonal Hematopoiesis in Patients with Follicular Helper T-Cell Lymphomas/Lymphoproliferative Disorders

Program: Oral and Poster Abstracts
Type: Oral
Session: 621. Lymphomas: Translational – Molecular and Genetic: Insights into Lymphoma: Unraveling the Molecular Complexity for Precision Diagnostics and Therapeutics
Hematology Disease Topics & Pathways:
Research, Translational Research, Lymphomas, B Cell lymphoma, genomics, T Cell lymphoma, Diseases, Lymphoid Malignancies, Biological Processes, molecular biology, pathogenesis
Monday, December 11, 2023: 3:15 PM

Natasha Lewis, MD1*, Kseniya Petrova-Drus, MD, PhD1,2*, Rohan Sardana, MD1*, Qi Gao, DCLS3*, Shenon Sethi, MBBS1*, Wenbin Xiao, MD, PhD1, Mikhail Roshal, MD, PhD3*, Jeeyeon Baik, BA, MPH1*, Himanshu Bhurtel, BS1*, Alison Moskowitz, MD4, Steven M. Horwitz, MD4 and Ahmet Dogan, MD, PhD1

1Department of Pathology and Laboratory Medicine, Hematopathology Service, Memorial Sloan Kettering Cancer Center, New York, NY
2Department of Pathology and Laboratory Medicine, Molecular Diagnostics Service, Memorial Sloan Kettering Cancer Center, New York, NY
3Memorial Sloan Kettering Cancer Center, New York
4Memorial Sloan Kettering Cancer Center, New York, NY


Patients with follicular helper T-cell lymphomas/lymphoproliferative disorders (TFH-LPDs) commonly develop B-cell lymphoproliferative disorders and lymphomas (B-LPDs), but the pathophysiology is incompletely understood. TFH-LPDs often arise from TET2-/DNMT3A-mutated clonal hematopoiesis (CH). Here we show TET2/DNMT3A mutations are commonly shared by polytypic B-cells (PBCs), B-LPDs, and TFH-LPDs, with the latter two often carrying additional unique mutations.


Pathology database search at Memorial Sloan Kettering identified patients with TFH-LPDs and PBCs or B-LPDs available for genotyping. If available, myeloid cells were also genotyped. PBCs lacked aberrancies by morphology and flow cytometry (FC) immunophenotyping (including polytypic light chain expression). TFH-LPDs and B-LPDs were defined using International Consensus Classification criteria. Genotyping assays included targeted next-generation sequencing (NGS) with (n=13) or without (n=8; cases 1, 4, 9, 10, 15, 16, 17, 22) a matched germline control and droplet digital PCR (n=4; cases 2, 3, 5, 6). Genotyping was performed on bulk samples or FC-sorted cells, including T-, B-, and myeloid as available. In bulk samples, mutations with allele frequencies (VAFs) >2x the percentage of neoplastic T- and myeloid cells combined in B-LPD samples and of neoplastic T- and total B-cells in bulk blood (PB)/bone marrow (BM) samples were considered present in B-LPD or myeloid compartments, respectively. A >2% VAF cutoff was utilized. EBV status was assessed using EBER in situ hybridization on tissues, serum EBV DNA by quantitative PCR, and/or evaluation of off target EBV reads by NGS. Statistical analyses utilized Mann-Whitney U tests.


In total, 25 patients (10 female, 15 male; median age 70 [range 38-82] years) with TFH-LPDs (19 TFH lymphoma, angioimmunoblastic type, 4 TFH lymphoma, NOS, 2 T-LPD with TFH phenotype [defined by morphologically and/or immunophenotypically atypical T-cells with both TFH-like phenotypes and genomic alterations that did not fulfill morphologic criteria for diagnosis of lymphoma]) were identified. The TFH-LPDs harbored TET2 (25/25, 100%), DNMT3A (12/25, 48%), RHOA p.G17 (15/25, 60%), and IDH2 p.R172 (9/25, 36%) mutations (Figure 1A).

PBCs from 11 patients were evaluated (7 EBV+, 3 EBV-, 1 EBV unknown; 5 from lymph node, 4 PB, 2 BM). PBCs from 7/11 (64%) shared identical TET2 (n=6; median VAF 0.11 [range 0.02 – 0.27]) and/or DNMT3A (n=3; median VAF 0.05 [range 0.03-0.49]) mutations with corresponding TFH-LPDs. PBCs in 1 patient harbored a unique mutation (TET2). Four of 8 (50%) patients in which myeloid cells were assessed harbored identical TET2 and/or DNMT3A mutations in the myeloid, PBC, and TFH-LPD compartments.

B-LPDs were evaluated from 14 patients (5 diffuse large B-cell lymphoma, 5 polymorphic B-LPD, 2 follicular lymphoma, 1 B-LPD, NOS, 1 plasma cell myeloma; 11 EBV+, 3 EBV-; 9 from tissue, 4 PB, 1 BM). Polymorphic B-LPDs showed atypical polymorphic morphology and an abnormal B-cell immunophenotype by FC and/or a clonal IgH gene rearrangement. The B-LPD, NOS showed an abnormal CD5-/CD10- immunophenotype with light chain restriction by FC without available tissue for morphologic evaluation. Nine of 14 (64%) B-LPDs shared identical mutations with corresponding TFH-LPDs (TET2 [n=9; median VAF 0.42 (range 0.10– 0.56)], DNMT3A [n=5; median VAF 0.27 (range 0.05-0.50)], TET3 [n=1; VAF 0.32]). Myeloid compartments in 9/12 (75%) patients shared identical TET2 and/or DNMT3A mutations with B- and/or T-LPDs. B-LPDs more commonly harbored additional mutations absent in corresponding TFH-LPDs than PBCs (12/14 [86%] vs 1/8 [13%] evaluated by NGS; p=0.001). Unique mutations in B-LPDs involved epigenetic/transcriptional regulation (n=14, e.g. TET2, KMT2D, SETD5), signaling pathways (n=22, e.g. DTX1, KRAS, EPHA5), and DNA damage response (n=3, e.g. ATM, CHEK2, BRCA2). Incidences of shared and unique mutations did not significantly differ among EBV+ and EBV- cases.


Both PBCs and B-LPDs in TFH-LPD patients are commonly EBV+ and share TET2/DNMT3A mutations with TFH-LPDs, consistent with common origin from CH. B-LPDs more often harbor additional unique mutations than PBCs. Thus, CH mutations and EBV activation in B-cells may predispose TFH-LPD patients to B-LPDs, which may develop with additional private genomic aberrations aiding transformation (Figure 1B).

Disclosures: Lewis: United States Drug Testing Laboratories: Consultancy, Membership on an entity's Board of Directors or advisory committees. Roshal: Physicians' Education Resource: Other: Provision of services; Celgene: Other: Provision of services; Auron Therapeutics: Other: Ownership/Equity interests; Provision of services; NGM: Other: Funding; Roche: Other: Funding; Beat AML: Other: Funding. Baik: Pauling.AI: Current Employment. Moskowitz: Merck: Honoraria, Research Funding; ADC Therapeutics: Research Funding; Bristol-Myers Squibb: Research Funding; Beigene: Research Funding; Incyte: Research Funding; Seattle Genetics: Honoraria, Research Funding. Horwitz: Takeda: Consultancy, Research Funding; Tubulis: Consultancy; Crispr Therapeutics: Research Funding; Millenium: Research Funding; Seattle Genetics: Research Funding; Verastem/SecuraBio: Research Funding; Trillium Therapeutics: Consultancy, Research Funding; Affimed: Research Funding; Celgene: Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Kyowa Hakko Kirin: Consultancy, Research Funding; ONO Pharmaceuticals: Consultancy; SecuraBio: Consultancy; Shoreline Biosciences, Inc.: Consultancy; ADC Therapeutics: Research Funding; Yingli Pharma Limited: Consultancy; Cimieo Therapeutics: Consultancy; Abcuro Inc.: Consultancy; Auxilius Pharma: Consultancy. Dogan: Incyte: Consultancy; Peer View: Honoraria; Loxo: Consultancy; EUSA Pharma: Consultancy; Physicians' Education Resource: Consultancy, Honoraria; Seattle Genetics: Consultancy; Takeda: Other: Research Funding; Roche: Other: Research Funding.

*signifies non-member of ASH