RARE DISEASE
Epstein-Barr virus-positive diffuse large B-cell lymphoma
Epstein-Barr virus-positive diffuse large B-cell lymphoma
Epstein-Barr virus-positive diffuse large B-cell lymphoma
Synonyms: EBV-positive DLBCL, Epstein-Barr virus-positive diffuse large B-cell lymphoma not otherwise specified, Epstein-Barr virus-positive diffuse large B-cell lymphoma, NOS
Synonyms: EBV-positive DLBCL, Epstein-Barr virus-positive diffuse large B-cell lymphoma not otherwise specified, Epstein-Barr virus-positive diffuse large B-cell lymphoma, NOS
Synonyms: EBV-positive DLBCL, Epstein-Barr virus-positive diffuse large B-cell lymphoma not otherwise specified, Epstein-Barr virus-positive diffuse large B-cell lymphoma, NOS
Drug discovery
2
drugs
With orphan designations
Overview
Epstein-Barr virus-positive diffuse large B-cell lymphoma (EBV+ DLBCL) is an aggressive B-cell malignancy linked to EBV latency, accounting for 5–15% of DLBCL cases. Previously termed "EBV+ DLBCL of the elderly," it was reclassified in 2016 (WHO) due to occurrences in younger adults. Patients often present with extranodal involvement, B symptoms, and high-risk IPI scores. Prognosis is generally poor but varies regionally, with worse outcomes in Asian populations [1][4][10].
Population
Primarily affects older adults (>50 years), but cases reported in younger immunocompetent patients [1][6][15].
Higher prevalence in Asia and Latin America (up to 15% of DLBCL) compared to Western countries (4-7%) [4][7][14].
Associated with immunosenescence or immunosuppression (e.g., post-transplant) [2][10].
Therapies
First-line: R-CHOP (± etoposide) with variable response rates [1][8][9].
Novel approaches: PD-1 inhibitors (e.g., pembrolizumab), CD30-targeted therapies (brentuximab vedotin), and adoptive T-cell therapies under investigation [12][14].
Reduced-intensity regimens considered for frail patients [3][18].
Categories: rare hematological diseases, rare neoplastic diseases, rare transplant-related disorders
Research Papers
162 drug discovery papers about Epstein-Barr virus-positive diffuse large B-cell lymphoma, with 1 first-in-class and 2 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
162 drug discovery papers about Epstein-Barr virus-positive diffuse large B-cell lymphoma, with 1 first-in-class and 2 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-07-28 | Clinical-Stage Nanatinostat Triggers Productive Epstein-Barr Virus Lytic Replication.
A phase 1b/2 study of the all-oral "kick-and-kill" combo nanatinostat + valganciclovir (nana-val) showed a ~40% overall response rate in patients with relapsed/refractory Epstein-Barr virus (EBV)-associated lymphomas. Despite the promising results in these difficult-to-treat cancers, there is little known about the effects of nanatinostat on EBV and cell death. In this work we demonstrate that nanatinostat, an HDAC1/3 inhibitor, robustly induces the full EBV lytic cycle in a panel of EBV-positive lymphoma and transformed cell lines (Burkitt, DLBCL, lymphoblastoid), spanning viral latency types and EBV genotypes. Nanatinostat drives lytic-gene transcription across all kinetic classes, viral genome replication, and virion release, and kills cells at nanomolar concentrations. Although valganciclovir does not increase cytotoxicity, its ability to block viral DNA synthesis and virion production justifies its inclusion to prevent viral dissemination. Importantly, the two main metabolites of nanatinostat lack histone-H3 acetylation activity and neither activate nor inhibit the EBV lytic phase, indicating that they are biologically inert with respect to EBV. These mechanistic insights clarify the clinical efficacy of nana-val and support further development of kick-and-kill strategies for EBV-driven malignancies.
2026-07-12 | Spatial Architecture of macrophages and T-cells Orchestrates Anti-Lymphoma Immunity and the Response to Immunochemotherapy in EBV+DLBCL
Epstein-Barr Virus (EBV)-positive Diffuse Large B-Cell Lymphoma (EBV+ DLBCL) is a rare and aggressive B-cell lymphoma characterized by heterogeneous pathological features and poor clinical outcomes. The cellular characteristics and spatial architecture of EBV+ DLBCL tumor microenvironment (TME) and its underlying mechanisms remain elusive. Twenty-one EBV+ DLBCL and 24 EBV-negative DLBCL (EBV- DLBCL) lymph node samples were analyzed using imaging mass cytometry (IMC) and the digital spatial profiler (DSP). Our findings revealed that EBV+ DLBCL exhibited a more suppressive TME with increased recruitment of CD163+ and IDO+ tumor-associated macrophages (TAMs) and more exhausted T cells compared to EBV- DLBCL. Consistently, spatial interaction analysis showed that T cells around TAMs displayed more exhausted phenotype. Additionally, more TAMs preemptively hijacked T cells before T-cell mediated attack in EBV+ DLBCL. Mechanistically, more TAMs recruited by EBV+ DLBCL resulted in upregulation of CCL5 through activation of JAK3/STAT3 pathway. Clinically, responders to immunochemotherapy exhibit higher levels of TAMs residing around tumor cells under T-cell attack compared to non-responders. Patients receiving immunomodulatory drugs (PD-1 inhibitors and lenalidomide) combined with immunochemotherapy seem to achieve better outcome. These insights enhance our understanding of the immune architecture in EBV+ DLBCL and identify new targets for immunotherapy, potentially improving patient outcomes.
2026-06-28 | Epstein‐Barr Virus MicroRNAs as Key Regulators of Lymphoma Pathogenesis: Immune Evasion Mechanisms and Therapeutic Opportunities
The ubiquitous human gamma-herpesvirus Epstein-Barr virus (EBV) infects over 90% of adults globally and was the first human virus identified with oncogenic potential. EBV enters a lifelong persistence in the host via a finely regulated life-cycle comprising primary infection, latency and lytic reactivation. Within infected B-cells and epithelial cells, EBV encodes a distinct repertoire of microRNAs (miRNAs), primarily from the BART (BamHI A rightward transcript) and BHRF1 (BamHI H rightward open reading frame) clusters, which play pivotal roles in modulating both viral and host gene expression. These viral miRNAs contribute to key oncogenic processes: by dampening apoptotic responses (e.g., via targeting PUMA, Bim, and PTEN), promoting proliferation of latently-infected B-cells, inhibiting host immune responses (e.g., via down-regulation of CXCL-11 by miR-BHRF1-3), and promoting epithelial-mesenchymal transition (EMT) and metastasis through modulation of E-cadherin and other adhesion molecules. In human lymphomas, such as Burkitt lymphoma, Hodgkin lymphoma, and EBV-positive diffuse large B-cell lymphoma, the interplay of latent viral gene expression, miRNA-mediated regulatory networks, and host microenvironmental factors underlies malignant transformation and disease progression. Emerging evidence also supports the utility of EBV-encoded miRNAs as diagnostic and prognostic biomarkers in EBV-associated cancers. Importantly, therapeutic strategies aimed at interrupting viral miRNA function, restoring host tumor-suppressor pathways, and re-sensitizing tumor cells to immune surveillance hold promise. This review synthesizes current mechanistic insights into EBV-encoded miRNAs in oncogenesis, elaborates on their roles in lymphoma pathogenesis, and evaluates the translational potential of miRNA-targeted therapies in EBV-associated malignancies.
2026-05-05 | Adult T-Cell Leukemia/Lymphoma and Epstein-Barr Virus-Positive DLBCL: A Rare Concomitant Association.
Adult T-cell leukemia/lymphoma (ATLL) is an aggressive lymphoma with a poor prognosis. The human T-lymphotropic virus 1 (HTLV-1) is associated with immunodeficiency and increased extranodal involvement in patients with diffuse large B-cell lymphoma (DLBCL). We report on a 47-year-old woman with spastic paraparesis and hepatitis B who was diagnosed with the acute form of ATLL. The clinical picture reveals peripheral generalized lymphadenopathy and splenomegaly. Findings on a hematologic exam indicated leukocytosis with lymphocytosis. A bone marrow biopsy/aspiration confirmed 50% T-cell lymphoid infiltration. Biochemistry results revealed hypercalcemia and a high lactate dehydrogenase value. Results of a CT scan indicated abdominal and thoracic adenopathy as well as moderate splenomegaly. A supraclavicular lymph node biopsy established a DLBCL diagnosis. The final diagnosis was composite lymphoma, DLBCL, and ATLL. The CHOP (cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate [Oncovin], and prednisone) regimen was chosen due to the patient's ECOG performance status. Multiple infectious complications were diagnosed during chemotherapy-induced secondary aplasia. A complete remission, confirmed via PET-CT imaging, was obtained. After 1 month, a skin tumor on the upper right thigh was discovered and biopsied, and the histopathological exam and immunochemistry findings indicated Epstein-Barr virus-DLBCL lymphoma. The association of 2 aggressive lymphomas in a single HTLV-1 carrier is a rare report, and the evolution was severe, complicated by opportunistic infections, and unfavorable.
2026-04-03 | Abstract 7218: Preliminary exploration of the synergistic mechanism between EBV LMP1 and MYD88 L265P mutation on the efficacy of PD-1 Inhibitors in ABC-DLBCL
Abstract Background: Activated B-cell-like diffuse large B-cell lymphoma (ABC-DLBCL) is aggressive with poor prognosis. Epstein-Barr virus (EBV) infection and the MYD88 L265P mutation are key molecular drivers in ABC-DLBCL, typically exhibiting mutual exclusivity, potentially due to functional overlap. PD-1 inhibitors show limited efficacy in unselected relapsed/refractory DLBCL patients. However, our retrospective analysis of relapsed/refractory non-GCB DLBCL patients suggested that rare "double-positive" (EBV-positive/MYD88 L265P mutant) patients had higher response rates to PD-1 inhibitors. Objective: This study investigated how EBV LMP1 modulates intracellular signaling in the context of MYD88 L265P mutation (causing constitutive JAK/STAT activation) and evaluated its synergistic effect with the PD-1 inhibitor tislelizumab. Methods: Clinical data from 54 relapsed/refractory non-GCB DLBCL patients treated with PD-1 antibodies were analyzed. Patients were stratified by EBER ISH (EBV) and MYD88 sequencing. The HBL-1 cell line (MYD88 L265P mutant, EBV-negative) was used. LMP1 was overexpressed via transfection. Groups: control, tislelizumab alone, LMP1 overexpression, LMP1+tislelizumab. qPCR measured mRNA levels of NF-κB p65, MMP9, c-Myc, TLR3, STAT3, JAK3, LMP1, PD-1, PD-L1. Western blot detected protein expression and phosphorylation of key molecules. Results: Among 21 patients with complete molecular data, both "double-positive" patients achieved an objective response (100%), compared to 22.2% in EBV-negative/MYD88 mutant (n=9) and 60.0% in EBV-positive/MYD88 wild-type (n=5) groups. HBL-1 cells showed high baseline p-JAK3 and p-STAT3. LMP1 overexpression suppressed p-JAK3 and p-STAT3. HBL-1 cells expressed tumor cell-intrinsic PD-1 mRNA. Tislelizumab alone inhibited p-JAK3/p-STAT3 phosphorylation. The combination of LMP1 overexpression and tislelizumab showed the strongest inhibition, indicating synergy. Conclusion: MYD88 L265P mutation may cause tumor cell addiction to STAT3 activation maintained by tumor cell-intrinsic PD-1 signaling. LMP1 co-existence adds inhibitory pressure, potentially enhancing this dependency. Tislelizumab blockade may yield a synthetic lethal effect. Combined EBV status and MYD88 profiling could predict PD-1 inhibitor sensitivity in DLBCL, requiring further validation. Citation Format: Chang Wang, Yingtao Lin, Jiesong Wang, . Preliminary exploration of the synergistic mechanism between EBV LMP1 and MYD88 L265P mutation on the efficacy of PD-1 Inhibitors in ABC-DLBCL [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 7218.
2026-07-28 | Clinical-Stage Nanatinostat Triggers Productive Epstein-Barr Virus Lytic Replication.
A phase 1b/2 study of the all-oral "kick-and-kill" combo nanatinostat + valganciclovir (nana-val) showed a ~40% overall response rate in patients with relapsed/refractory Epstein-Barr virus (EBV)-associated lymphomas. Despite the promising results in these difficult-to-treat cancers, there is little known about the effects of nanatinostat on EBV and cell death. In this work we demonstrate that nanatinostat, an HDAC1/3 inhibitor, robustly induces the full EBV lytic cycle in a panel of EBV-positive lymphoma and transformed cell lines (Burkitt, DLBCL, lymphoblastoid), spanning viral latency types and EBV genotypes. Nanatinostat drives lytic-gene transcription across all kinetic classes, viral genome replication, and virion release, and kills cells at nanomolar concentrations. Although valganciclovir does not increase cytotoxicity, its ability to block viral DNA synthesis and virion production justifies its inclusion to prevent viral dissemination. Importantly, the two main metabolites of nanatinostat lack histone-H3 acetylation activity and neither activate nor inhibit the EBV lytic phase, indicating that they are biologically inert with respect to EBV. These mechanistic insights clarify the clinical efficacy of nana-val and support further development of kick-and-kill strategies for EBV-driven malignancies.
2026-07-12 | Spatial Architecture of macrophages and T-cells Orchestrates Anti-Lymphoma Immunity and the Response to Immunochemotherapy in EBV+DLBCL
Epstein-Barr Virus (EBV)-positive Diffuse Large B-Cell Lymphoma (EBV+ DLBCL) is a rare and aggressive B-cell lymphoma characterized by heterogeneous pathological features and poor clinical outcomes. The cellular characteristics and spatial architecture of EBV+ DLBCL tumor microenvironment (TME) and its underlying mechanisms remain elusive. Twenty-one EBV+ DLBCL and 24 EBV-negative DLBCL (EBV- DLBCL) lymph node samples were analyzed using imaging mass cytometry (IMC) and the digital spatial profiler (DSP). Our findings revealed that EBV+ DLBCL exhibited a more suppressive TME with increased recruitment of CD163+ and IDO+ tumor-associated macrophages (TAMs) and more exhausted T cells compared to EBV- DLBCL. Consistently, spatial interaction analysis showed that T cells around TAMs displayed more exhausted phenotype. Additionally, more TAMs preemptively hijacked T cells before T-cell mediated attack in EBV+ DLBCL. Mechanistically, more TAMs recruited by EBV+ DLBCL resulted in upregulation of CCL5 through activation of JAK3/STAT3 pathway. Clinically, responders to immunochemotherapy exhibit higher levels of TAMs residing around tumor cells under T-cell attack compared to non-responders. Patients receiving immunomodulatory drugs (PD-1 inhibitors and lenalidomide) combined with immunochemotherapy seem to achieve better outcome. These insights enhance our understanding of the immune architecture in EBV+ DLBCL and identify new targets for immunotherapy, potentially improving patient outcomes.
2026-06-28 | Epstein‐Barr Virus MicroRNAs as Key Regulators of Lymphoma Pathogenesis: Immune Evasion Mechanisms and Therapeutic Opportunities
The ubiquitous human gamma-herpesvirus Epstein-Barr virus (EBV) infects over 90% of adults globally and was the first human virus identified with oncogenic potential. EBV enters a lifelong persistence in the host via a finely regulated life-cycle comprising primary infection, latency and lytic reactivation. Within infected B-cells and epithelial cells, EBV encodes a distinct repertoire of microRNAs (miRNAs), primarily from the BART (BamHI A rightward transcript) and BHRF1 (BamHI H rightward open reading frame) clusters, which play pivotal roles in modulating both viral and host gene expression. These viral miRNAs contribute to key oncogenic processes: by dampening apoptotic responses (e.g., via targeting PUMA, Bim, and PTEN), promoting proliferation of latently-infected B-cells, inhibiting host immune responses (e.g., via down-regulation of CXCL-11 by miR-BHRF1-3), and promoting epithelial-mesenchymal transition (EMT) and metastasis through modulation of E-cadherin and other adhesion molecules. In human lymphomas, such as Burkitt lymphoma, Hodgkin lymphoma, and EBV-positive diffuse large B-cell lymphoma, the interplay of latent viral gene expression, miRNA-mediated regulatory networks, and host microenvironmental factors underlies malignant transformation and disease progression. Emerging evidence also supports the utility of EBV-encoded miRNAs as diagnostic and prognostic biomarkers in EBV-associated cancers. Importantly, therapeutic strategies aimed at interrupting viral miRNA function, restoring host tumor-suppressor pathways, and re-sensitizing tumor cells to immune surveillance hold promise. This review synthesizes current mechanistic insights into EBV-encoded miRNAs in oncogenesis, elaborates on their roles in lymphoma pathogenesis, and evaluates the translational potential of miRNA-targeted therapies in EBV-associated malignancies.
2026-05-05 | Adult T-Cell Leukemia/Lymphoma and Epstein-Barr Virus-Positive DLBCL: A Rare Concomitant Association.
Adult T-cell leukemia/lymphoma (ATLL) is an aggressive lymphoma with a poor prognosis. The human T-lymphotropic virus 1 (HTLV-1) is associated with immunodeficiency and increased extranodal involvement in patients with diffuse large B-cell lymphoma (DLBCL). We report on a 47-year-old woman with spastic paraparesis and hepatitis B who was diagnosed with the acute form of ATLL. The clinical picture reveals peripheral generalized lymphadenopathy and splenomegaly. Findings on a hematologic exam indicated leukocytosis with lymphocytosis. A bone marrow biopsy/aspiration confirmed 50% T-cell lymphoid infiltration. Biochemistry results revealed hypercalcemia and a high lactate dehydrogenase value. Results of a CT scan indicated abdominal and thoracic adenopathy as well as moderate splenomegaly. A supraclavicular lymph node biopsy established a DLBCL diagnosis. The final diagnosis was composite lymphoma, DLBCL, and ATLL. The CHOP (cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate [Oncovin], and prednisone) regimen was chosen due to the patient's ECOG performance status. Multiple infectious complications were diagnosed during chemotherapy-induced secondary aplasia. A complete remission, confirmed via PET-CT imaging, was obtained. After 1 month, a skin tumor on the upper right thigh was discovered and biopsied, and the histopathological exam and immunochemistry findings indicated Epstein-Barr virus-DLBCL lymphoma. The association of 2 aggressive lymphomas in a single HTLV-1 carrier is a rare report, and the evolution was severe, complicated by opportunistic infections, and unfavorable.
2026-04-03 | Abstract 7218: Preliminary exploration of the synergistic mechanism between EBV LMP1 and MYD88 L265P mutation on the efficacy of PD-1 Inhibitors in ABC-DLBCL
Abstract Background: Activated B-cell-like diffuse large B-cell lymphoma (ABC-DLBCL) is aggressive with poor prognosis. Epstein-Barr virus (EBV) infection and the MYD88 L265P mutation are key molecular drivers in ABC-DLBCL, typically exhibiting mutual exclusivity, potentially due to functional overlap. PD-1 inhibitors show limited efficacy in unselected relapsed/refractory DLBCL patients. However, our retrospective analysis of relapsed/refractory non-GCB DLBCL patients suggested that rare "double-positive" (EBV-positive/MYD88 L265P mutant) patients had higher response rates to PD-1 inhibitors. Objective: This study investigated how EBV LMP1 modulates intracellular signaling in the context of MYD88 L265P mutation (causing constitutive JAK/STAT activation) and evaluated its synergistic effect with the PD-1 inhibitor tislelizumab. Methods: Clinical data from 54 relapsed/refractory non-GCB DLBCL patients treated with PD-1 antibodies were analyzed. Patients were stratified by EBER ISH (EBV) and MYD88 sequencing. The HBL-1 cell line (MYD88 L265P mutant, EBV-negative) was used. LMP1 was overexpressed via transfection. Groups: control, tislelizumab alone, LMP1 overexpression, LMP1+tislelizumab. qPCR measured mRNA levels of NF-κB p65, MMP9, c-Myc, TLR3, STAT3, JAK3, LMP1, PD-1, PD-L1. Western blot detected protein expression and phosphorylation of key molecules. Results: Among 21 patients with complete molecular data, both "double-positive" patients achieved an objective response (100%), compared to 22.2% in EBV-negative/MYD88 mutant (n=9) and 60.0% in EBV-positive/MYD88 wild-type (n=5) groups. HBL-1 cells showed high baseline p-JAK3 and p-STAT3. LMP1 overexpression suppressed p-JAK3 and p-STAT3. HBL-1 cells expressed tumor cell-intrinsic PD-1 mRNA. Tislelizumab alone inhibited p-JAK3/p-STAT3 phosphorylation. The combination of LMP1 overexpression and tislelizumab showed the strongest inhibition, indicating synergy. Conclusion: MYD88 L265P mutation may cause tumor cell addiction to STAT3 activation maintained by tumor cell-intrinsic PD-1 signaling. LMP1 co-existence adds inhibitory pressure, potentially enhancing this dependency. Tislelizumab blockade may yield a synthetic lethal effect. Combined EBV status and MYD88 profiling could predict PD-1 inhibitor sensitivity in DLBCL, requiring further validation. Citation Format: Chang Wang, Yingtao Lin, Jiesong Wang, . Preliminary exploration of the synergistic mechanism between EBV LMP1 and MYD88 L265P mutation on the efficacy of PD-1 Inhibitors in ABC-DLBCL [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 7218.
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Drug Discovery Landscape
2 orphan drug designations for Epstein-Barr virus-positive diffuse large B-cell lymphoma.
2 orphan drug designations for Epstein-Barr virus-positive diffuse large B-cell lymphoma.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
nanatinostat and valganciclovir | small molecules | FDA | 2021-11-24 | — | Viracta Subsidiary, Inc. |
autologous Epstein-Barr virus specific T-cells | cell therapies | FDA | 2015-03-09 | — | BCM Center for Cell and Gene Therapy |
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