Diffuse Large B-cell Lymphoma Research Articles

TGFBI regulates the TGF-β pathway to affect the malignant progression and cisplatin sensitivity in diffuse large B-cell lymphoma.

Despite the association between aberrant TGFBI expression and tumors development found in various cancer types, the role of TGFBI in diffuse large B-cell lymphoma (DLBCL) progression is not clear. This study attempted to reveal how TGFBI impacts malignant progression and cisplatin sensitivity in DLBCL. Bioinformatics and qRT-PCR were used to analyze expression of TGFBI. To investigate the effect of TGFBI on malignant progression and cisplatin sensitivity in DLBCL cells, cell viability and IC50 values were assessed by CCK-8. Cell proliferation ability was detected by colony formation assay. Cell apoptosis rate was detected by flow cytometry. The degree of DNA damage in cells from different treatment groups was detected by comet assay. Protein expression of TGF-β pathway-related proteins like TGF-β1, Smad2, and p-Smad2 was detected by western blot. Bioinformatics and molecular experiments results revealed substantial upregulation of TGFBI in DCBCL. Cell experiment results indicated that high TGFBI expression expedited DCBCL progression and reduced cisplatin sensitivity. Further rescue experiments revealed that SB525334, a TGF-β pathway inhibitor, could weaken the acceleration of DCBCL progression and restore reduced cisplatin sensitivity both induced by high TGFBI expression. TGFBI could promote malignant progression and inhibit the cisplatin sensitivity of DLBCL cells by regulating the TGF-β pathway. In brief, TGFBI has the potential to be a target in DLBCL treatment.

Audit of B-cell Cancer Genes.

Comprehensive genetic analysis of tumors with exome or whole genome sequencing has enabled the identification of the genes that are recurrently mutated in cancer. This has stimulated a series of exciting advances over the past 15 years, guiding us to new molecular biomarkers and therapeutic targets among the common mature B-cell neoplasms. In particular, diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL) and Burkitt lymphoma (BL) have each been the subject of considerable attention in this field. Currently, more than 850 genes have been reported as targets of protein-coding mutations in at least one of these entities. To reduce this to a manageable size, we describe a systematic approach to prioritize and categorize these genes, based on the quality and type of supporting data. For each entity, we provide a list of candidate driver genes categorized into Tier 1 (high-confidence genes), Tier 2 (candidate driver genes), or Tier 3 (lowest-confidence genes). Collectively, this reduces the number of high-confidence genes for these three lymphomas to a mere 144. This further affirms the substantial overlap between the genes relevant in DLBCL and each of FL and BL. These highly curated and annotated gene lists will continue to be maintained as a resource to the community. These results emphasize the extent of the knowledge gap regarding the role of each of these genes in lymphomagenesis. We offer our perspective on how to accelerate the experimental confirmation of drivers using a variety of model systems, using these lists as a guide for prioritizing genes.

Design, Synthesis, and Biological Evaluation of Thieno[3,2-d]pyrimidine Derivatives as the First Bifunctional PI3Kδ Isoform Selective/Bromodomain and Extra-Terminal Inhibitors.

The concomitant inhibition of PI3Kδ and bromodomain and extra-terminal (BET) that exerts a synergistic effect on the B-cell receptor signaling pathway provides a new strategy for the treatment of aggressive diffuse large B-cell lymphoma (DLBCL). Herein, a merged pharmacophore strategy was utilized to discover a series of thieno[3,2-d]pyrimidine derivatives as the first-in-class bifunctional PI3Kδ-BET inhibitors. Through optimization, a highly potent compound (10b) was identified to possess excellent and balanced activities against PI3Kδ [inhibitory concentration (IC50) = 112 ± 8 nM] and BRD4-BD1 (IC50 = 19 ± 1 nM) and exhibited strong antiproliferative activities in DLBCL cells. Notably, this compound demonstrated good PI3Kδ selectivity over other kinases with minimal cytotoxicity in normal cells. Moreover, 10b has a good oral pharmacokinetic profile in mice and achieves outstanding antitumor activity in the SU-DHL-6 xenograft model. Taken together, these results indicate that targeting PI3Kδ and BET with a bifunctional inhibitor is a promising strategy to treat DLBCL.

Central nervous system involvement in Waldenström macroglobulinemia: a comparative population-based study of Bing-Neel syndrome and histological transformation.

Central nervous system (CNS) involvement in Waldenström macroglobulinemia (WM) is a rare complication that can manifest as Bing-Neel syndrome (BNS) or as histological transformation (HT) to diffuse large B-cell lymphoma (DLBCL). We report data from a single-center cohort of 469 patients consecutively diagnosed with WM between 2000 and 2022. BNS was identified in 1.5% (n = 7) and HT with CNS involvement (CNS-HT) in 1.7% (n = 8) of patients. The cumulative incidence of BNS and CNS-HT at 15 years was 2.6% and 2.7%, respectively, with CNS-HT more likely to develop in closer proximity to the initial WM diagnosis. One patient with CNS-HT exhibited a preceding phase of BNS before transformation. In general, patients with BNS and CNS-HT presented with diverse neurological symptoms and clinical features. Parenchymal lesions were uniformly found in all patients with CNS-HT, while neuroimaging findings were less consistent in patients with BNS. Involvement of multiple extramedullary sites was observed in approximately half of the patients with both BNS and CNS-HT. Patients with CNS-HT had poor outcomes, with a median overall survival of 10 months following the onset of CNS involvement, whereas BNS was associated with a more favorable prognosis, particularly in patients treated with ibrutinib. This study is the first to present a comparative analysis of BNS and CNS-HT in WM, providing novel insights into their incidence, clinical features, and outcomes.

Diffuse Large B-Cell Lymphoma With the "Leopard Man" Appearance on 18F-FDG PET/CT.

Subcutaneous nodules and masses as the primary manifestation of diffuse large B-cell lymphoma are exceedingly rare. We present 18F-FDG PET/CT findings of multiple hypermetabolic nodules and masses distributed throughout the body, creating a characteristic "leopard man" appearance on the MIP image, in a 65-year-old man. An excisional biopsy of the right thigh mass confirmed the diagnosis of diffuse large B-cell lymphoma.

Knockout IL4I1 affects macrophages to improve poor efficacy of CD19 CAR-T combined with PD-1 inhibitor in relapsed/refractory diffuse large B-cell lymphoma

Chimeric antigen receptor (CAR) T-cell therapy plays a critical role in the treatment of B-cell hematologic malignancies. The combination of PD-1 inhibitors and CAR-T has shown encouraging results in treating patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL). However, there are still cases where treatment is ineffective. This study aimed to investigate the role of IL4I1 in the poor efficacy of CD19 CAR-T combined with PD-1 inhibitors in R/R DLBCL and to explore potential mechanisms. Transcriptomic and metabolomic correlation analyses were performed on tumor tissue from DLBCL patients. We employed an in vitro co-culture system consisting of Pfeiffer cells, CD19 CAR-T and macrophages to investigate the underlying mechanisms. It was found that IL4I1 levels were significantly increased in the tumor tissues of R/R DLBCL patients compared to responders. Correlation analysis revealed a positive association between IL4I1 and tryptophan (Trp)-kynurenic acid (Kyn) related metabolites. In the in vitro co-culture model, the presence of IL4I1 inhibited the cytotoxicity of CAR-T cells. Depletion of IL4I1 disrupted the IDO-AHR-Kyn signaling pathway, thereby enhancing the effectiveness of PD-1 inhibitors in combination with CD19 CAR-T for DLBCL treatment. CAR-T-mediated cytotoxicity was significantly inhibited when IL4I1 was present in the in vitro co-culture model. These findings suggest that IL4I1 may be a contributing factor to poor prognosis in R/R DLBCL patients. IL4I1 expression enhances immunosuppression via the IDO-AHR-Kyn pathway, inhibiting the effectiveness of PD-1 inhibitors combined with CD19 CAR-T. Therefore, suppression of IL4I1 may represent a potential target for combination therapy in DLBCL.

Therapeutic approach to patients with early stage diffuse large B cell lymphoma: retrospective, multicenter, real-life study of the ‘RTL’ (regional Tuscan lymphoma network)

Treatment strategies for early stage diffuse large B-cell lymphoma (ES-DLBCL) include R-CHOP, with a similar schedule to that used in advanced stage, or a reduced number of cycles followed by radiation therapy (RT). We retrospectively analyzed 179 ES-DLBCL patients, managed according to the clinical practice. Treatment regimens include chemoimmunotherapy 4–6 cycles +/- RT as consolidation. First-line therapy was R-CHOP/CHOP-like in 88.8% of cases. RT as consolidation was administered to 29.9% of cases. Complete response rate was 87.2%, median PFS and OS were not reached. IPI 2–3 and first-line regimen with 3–4 cycles of R-CHOP without RT were the 2 prognostic variables for OS in multivariate analysis. After a median follow-up of 48 months, 31 patients died (17.3%). We suggest that both R-CHOP 6 cycles and 3–4 cycles followed by RT as consolidation seem to be valid first-line regimens, while an abbreviated strategy without RT could be associated to inferior outcome.

Is first-line treatment with polatuzumab vedotin–rituximab–cyclophosphamide, doxorubicin and prednisone (pola-R-CHP) for previously untreated diffuse large B-cell lymphoma cost-effective in China? A cost-effectiveness analysis using a Markov model

ObjectiveTo evaluate the cost-effectiveness of polatuzumab vedotin–rituximab–cyclophosphamide, doxorubicin and prednisone (pola-R-CHP) in CD20-positive patients with previously untreated diffuse large B-cell lymphoma (DLBCL) in China.DesignA Markov model was constructed to analyse...

Retrospective Analysis of R-COMP Therapy in Patients with Diffuse Large B-Cell Lymphoma (DLBCL): Assessing the Impact of Sample Selection Bias.

Background: Retrospective studies are often criticized for their susceptibility to case selection bias compared to prospective studies, which include all patients consecutively and are thus less prone to such limitations. However, the larger sample sizes typical of retrospective studies can sometimes offset this drawback. On behalf of the Fondazione Italiana Linfomi (FIL), a substantial retrospective study involving 946 patients was conducted to examine the use of non-pegylated liposomal anthracycline (Myocet). This was followed by a prospective study, the Prospective Elderly Project, which enrolled 308 patients treated with the same liposomal anthracycline regimen. Methods: The objective of this analysis was to determine whether the patient cohort from the retrospective study significantly differed from the cohort in the prospective study. Statistical hypothesis testing was applied to assess whether the samples from both studies originated from the same underlying population. The Anderson-Darling test, a non-parametric statistical method, was utilized to evaluate and compare the overall survival distributions between the two patient cohorts. Results: The statistical tests produced conflicting results, suggesting a potential selection bias in the retrospective study or the possibility that the two groups were from the same population. These discrepancies may have arisen due to the choice of statistical methods or the quality of the data analyzed. Conclusions: This study highlights the challenges of comparing retrospective and prospective cohorts and underscores the importance of selecting appropriate statistical methodologies. The findings provide valuable insights and lay the groundwork for developing innovative approaches to improve such comparisons in future research.

Molecular clustering on ctDNA improves the prognostic stratification of DLBCL patients compared to ctDNA levels.

Circulating tumor DNA (ctDNA) levels can help predict outcomes in diffuse large B-cell lymphoma (DLBCL), but its integration with DLBCL molecular clusters remains unexplored. Using the LymphGen tool in 77 DLBCL with both ctDNA and tissue biopsy, a 95.8% concordance rate in molecular cluster assignment was observed, showing the reproducibility of molecular clustering on ctDNA. A multicenter, prospective cohort of 166 newly diagnosed DLBCL was analyzed for ctDNA levels and molecular clusters using CAPP-seq. Patients with ctDNA levels < 2.5 log10hGE/mL had a 4-year progression-free survival (PFS) and overall survival (OS) of 71.7% and 85.7%, respectively, compared to 50.3% and 61.0% for those with higher ctDNA levels (p=0.0018 and p=0.0017). Recursive partitioning showed that patients with ctDNA levels > 2.5 log10hGE/mL were further stratified by clusters ST2/BN2. In this group, ST2/BN2 patients associated with a favorable outcome with a 4-year PFS and OS of 87.5% and 100%, respectively, compared to 38.0% and 47.1% for other clusters (p=0.003 and p=0.001). Combining ctDNA levels and ST2/BN2 clusters improved outcome prediction. Low-risk patients (N=51), characterized by ctDNA levels < 2.5 log10hGE and/or BN2/ST2 cluster, had a 4-year PFS and OS of 75.3% and 87.8%. High-risk patients (N=115), with ctDNA levels > 2.5 log10hGE and no BN2/ST2 cluster, had a 4-year PFS and OS of 38.0% and 47.1%. Adding cluster assignment to ctDNA levels improved the model's C statistics (0.63 vs. 0.59 for PFS and 0.68 vs. 0.63 for OS). Liquid biopsy thus provides a multi-layered approach for outcome prediction in DLBCL.

Definitions and use of tumour bulk in phase 3 lymphoma trials: a comprehensive literature review.

Tumour 'bulk' has historically been considered an important prognostic marker and clinical tool to guide treatment in patients with lymphoma. However, its use and definitions in trial designs varies significantly and it is unclear how this has influenced the relevance of bulk in contemporary practice. This comprehensive literature review evaluated the definitions, applications and prognostic impact of bulk in phase 3 randomised trials in four major lymphoma subtypes. Overall, 87 studies were identified across follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), peripheral T-cell lymphoma (PTCL) and Hodgkin lymphoma (HL) with a wide range of bulk thresholds employed (5cm, 6cm, 7cm, 7.5cm, 10cm and >1/3 mediastinal mass ratio (MMR)). The most common threshold was: FL; 7cm (58%), DLBCL; 7.5cm and 10cm (44% each), PTCL; 7.5cm (66%) and HL; 1/3 MMR (91%). Bulk threshold was used by trials to determine eligibility (66%), stratification (24%), as a prognostic risk factor (37%) and decision tool for risk-adapted treatment e.g. radiotherapy (29%), however bulk definitions used for these varied both between, and within, lymphoma subtypes, and even within single trials in 25%. Thirty-two studies incorporated bulk in prognostic analyses with only five showing significance for differential survival outcomes. Our analysis demonstrates high inconsistency in thresholds defining tumour bulk and use of bulk in phase 3 lymphoma trials across eligibility, stratification, therapeutic risk-adaptation plus prognostication. This highlights an urgent need for international consensus on definitions of bulk within trials to improve its prognostic and predictive value and refine its application in clinical practice.

Epcoritamab-Induced fatal pleural effusion in diffuse large B-Cell lymphoma: a case report and literature review.

Epcoritamab, a bispecific T-cell engager (BiTE) antibody targeting CD3 and CD20, has shown significant efficacy in treating refractory diffuse large B-cell lymphoma (DLBCL). However, its use can lead to severe side effects, such as tumor flare. Here, we report the case of an 84-year-old male with relapsed DLBCL who developed fatal unilateral pleural effusion following Epcoritamab treatment. Initially, the patient showed a favorable response, but later developed significant pleural effusion with elevated interleukin-6 (IL-6) levels, indicating a severe inflammatory response. This suggests that Epcoritamab directly affected the pleural lesions and caused a local cytokine release syndrome (L-CRS). Despite aggressive management, including Tocilizumab and Dexamethasone, the patient's condition worsened, leading to his death. This case underscores the importance of regular lab tests and imaging follow-ups to monitor and manage severe inflammatory reactions based on tumor location. Comprehensive monitoring protocols are needed to mitigate risks associated with novel immunotherapies. To our knowledge, this is the first reported case of fatal unilateral pleural effusion in a patient with relapsed DLBCL following Epcoritamab treatment.

Targeting refractory diffuse large B cell lymphoma by CAR-WEE1 T-cells: In vitro evaluation.

Refractory Diffuse Large B-cell Lymphoma (DLBCL) presents a major therapeutic challenge due to its resistance to standard treatments. Engineered T-cells, especially Chimeric Antigen Receptor (CAR) T-cells, have shown promise in overcoming drug resistance. This study investigates the effectiveness of WEE1-engineered T-cells in targeting and eliminating refractory DLBCL in vitro. CAR T-cells were created by transducing a 5th-generation CAR construct designed to recognize WEE1, a surface antigen commonly found on refractory DLBCL cells. The cytotoxic effect of engineered T-cells was tested against Rituximab-resistant DLBCL cells (RR-NU-DUL-1). Apoptosis and cell cycle were evaluated using flow cytometry. Quantitative Real-time PCR (RT-PCR) was used to measure the expression of WEE1, BCL2, and CDK2. The results showed a significant increase in target cell lysis, apoptosis, and necrosis, a significant reduction in the percentage of cells in the G2M phase of the cell cycle, as well as a decrease in gene expression level, indicating strong anti-tumor activity. These findings suggest that CAR T-cell therapy holds great promise for treating refractory DLBCL, offering a potential path for clinical application. This in vitro evaluation highlights the potential of WEE1-engineered T-cells as a targeted treatment strategy for refractory DLBCL, emphasizing their clinical applicability and ability to overcome resistance mechanisms in this aggressive lymphoma subtype.

Bruton’s tyrosine kinase inhibitor zanubrutinib-based regimens in relapsed/refractory primary diffuse large B-cell lymphoma of the central nervous system

Patients with relapsed/refractory primary central nervous system lymphoma (R/R PCNSL) usually have a poor prognosis and limited treatment options. We respectively reviewed 38 patients with R/R PCNSL treated with zanubrutinib-based regimens in our center. The overall response rate, complete response rate and disease control rate were 76.3%, 47.4% and 92.1%, respectively. The median progression-free survival (PFS) was 31.0 months, the median overall survival (OS) was not reached. Unitivariate analysis by Cox’s proportional hazards model revealed that overall response (vs. no response, HR = 0.18, 95%CI:0.07,0.48, p = 0.001), long duration of zanubrutinib (≥6months vs 2-5 months, HR = 0.20, 95%CI:0.06,0.63, p = 0.006) were independent factors for prolonged PFS. The log-rank analysis indicated a prolongation of PFS among patients exhibiting a higher Tumor mutational burden (TMB, ≥14.75muts/Mb) following zanubrutinib-based treatment (p = 0.016). Our data showed promising efficacy with tolerable safety of zanubrutinib-based therapies in patients with R/R PCNSL. Long duration of zanubrutinib may be associated with prolonged PFS.

CRISPR/Cas9-Enhanced CAR-T Cell Therapy for Hematological Malignancies

CRISPR/Cas9 technology has brought revolution to the field of gene editing, offering precise and efficient tools for genetic modifications. One of its most promising applications lies in improving CAR-T cell therapy for treating hematological malignancies. Among approaches to treating blood cancers, CAR-T therapy, which programs T cells to recognize and eliminate cancer cells, has shown some success for B-cell malignancies such as diffuse large B-cell lymphoma (DLBCL) and B-cell acute lymphoblastic leukemia (ALL). However, challenges such as immune evasion, cytokine release syndrome (CRS), neurotoxicity, and limited CAR-T persistence remain significant barriers. CRISPR/Cas9 can optimize CAR-T therapy by precisely inserting CAR genes into specific loci, knocking out inhibitory genes like PD-1 to enhance persistence, and enabling multi-targeting strategies to overcome tumor immune escape. Clinical trials demonstrate the feasibility and potential of CRISPR-edited CAR-T cells, showing improved safety, durability, and efficacy. This study explores the synergistic application of CRISPR/Cas9 in CAR-T therapy, addressing its current limitations and providing a pathway to safer and more effective treatments for hematological malignancies

Resveratrol as a BCL6 natural inhibitor suppresses germinal center derived Non-Hodgkin lymphoma cells growth.

Non-Hodgkin lymphomas (NHL), including diffuse large B-cell lymphoma (DLBCL), Burkitt lymphoma (BL), and follicular lymphoma (FL), predominantly arise from B cells undergoing germinal center (GC) reactions. The transcriptional repressor B-cell lymphoma 6 (BCL6) is indispensable for GC formation and contributes to lymphomagenesis via its BTB domain-mediated suppression of target genes. Dysregulation of BCL6 underpins the pathogenesis of GC-derived NHL. While pharmacological targeting the BCL6-BTB domain has shown therapeutic promise, natural product-based inhibitors remain underexplored. In this study, resveratrol, a polyphenolic compound derived from grapes, was identified as a potent BCL6 inhibitor through a comprehensive screen of traditional Chinese medicine monomers using Homogeneous Time-Resolved Fluorescence (HTRF) assay. As a BCL6 natural inhibitor, resveratrol effectively disrupted the BCL6/SMRT interaction, reactivated suppressed gene expression, and inhibited the proliferation of GC-derived NHL cells. It also exhibited synergistic efficacy when combined with EZH2 and PRMT5 inhibitors. In vivo, resveratrol suppressed GC formation, reduced follicular helper T-cell frequencies, impaired class-switch recombination, and disrupted immunoglobulin affinity maturation. Furthermore, it markedly inhibited the progression of GC-derived NHL in animal models. Our findings demonstrate that resveratrol functions as a natural BCL6 inhibitor with significant therapeutic potential for the treatment of GC-derived NHL.

Advances in the Classification of Aggressive B-cell Lymphomas.

Aggressive B-cell lymphomas are a biologically and clinically very heterogeneous group of tumors that may be related to different stages of B-cell differentiation development. This review aims to summarize recent advances in the understanding of these tumors with a focus on the practical approach to the diagnosis of these entities. We analyze the defining characteristics of the different subtypes of aggressive B-cell lymphomas, including nodal and extranodal diffuse large B-cell lymphoma, virus-associated lymphomas, terminally differentiated B-cell lymphomas, high-grade B-cell lymphomas, and Burkitt lymphoma. This review particularly explores the integration of morphologic, immunophenotypic, and genetic data that refine diagnostic accuracy and prognostic stratification, underscoring the necessity for a standardized approach in clinical practice. By synthesizing current knowledge, this review aims to enhance the understanding of aggressive B-cell lymphomas within the context of the evolving classification system, paving the way for future research and clinical advancements.

Routine magnetic resonance central nervous system imaging may be avoided in high-risk systemic diffuse large B-cell lymphoma with negative cerebrospinal fluid analyses

Routine magnetic resonance central nervous system imaging may be avoided in high-risk systemic diffuse large B-cell lymphoma with negative cerebrospinal fluid analyses

Diffuse Large B-Cell Lymphoma/High Grade B-Cell Lymphoma with MYC and BCL6 Rearrangements: a study of 60 Cases.

Classification of cases of diffuse large B-cell lymphoma (DLBCL)/high-grade B-cell lymphoma (HGBL) with MYC and BCL6 rearrangements, also known as BCL6 double hit lymphoma (DHL), is controversial. We assessed 60 cases of BCL6-DHL and compared this cohort to 224 cases of DHL with MYC and BCL2 rearrangements (BCL2-DHL) and 217 cases of DLBCL not otherwise specified. Compared with the DLBCL cohort, BCL6-DHL patients had more aggressive clinical features such as frequent extranodal involvement, high-stage disease, high IPI score and elevated serum lactate dehydrogenase level (p <0.01 for all). Compared with the BCL2-DHL cohort, BCL6-DHL patients had similarly aggressive clinical features but a lower frequency of germinal center B-cell (GCB) immunophenotype and MYC and BCL2 double expression. Patients with BCL6-DHL showed an overall survival (OS) intermediate between patients with DLBCL and BCL2-DHL. Following induction with R-CHOP chemotherapy, BCL6-DHL patients demonstrated a poor OS similar to BCL2-DHL patients and worse than that of DLBCL patients (p = 0.024). However, among patients who received R-EPOCH, there was no significant difference in OS among the three groups (p = 0.146). Gene expression profiling showed that 60% of BCL6-DHL cases had a double hit (DH)-like signature compared with 10% of DLBCL-GCB and 93% of BCL2-DHL. The DH-like signature in BCL6-DHL cases was associated with a GCB immunophenotype. Based on these data, we suggest that BCL6-DHL cases are clinically more aggressive than DLBCL and patients may benefit from a more aggressive therapy than R-CHOP. The data also suggest that BCL6-DHL as currently defined, is heterogeneous and that neoplasms with a GCB immunophenotype are more likely to have DH-like signature and behave more aggressively. Lastly, we suggest that BCL6-DHL cases deserve to be recognized separately in a lymphoma classification to facilitate further understanding of these neoplasms and for optimal patient management.

Epcoritamab plus GemOx in transplant-ineligible relapsed/refractory DLBCL: results from the EPCORE NHL-2 trial.

Patients with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) have poor outcomes. Gemcitabine + oxaliplatin (GemOx) with rituximab, a standard salvage therapy, yields complete response (CR) rates of approximately 30% and median overall survival (OS) of 10-13 months. Patients with refractory disease fare worse, with a CR rate of 7% for subsequent therapies and median OS of 6 months. Epcoritamab, a CD3xCD20 bispecific antibody approved for the treatment of R/R DLBCL after ≥2 therapy lines, has shown promising safety and efficacy in various combinations. We report results from the phase 1b/2 EPCORE® NHL-2 trial evaluating epcoritamab + GemOx in patients with R/R DLBCL who were ineligible for or had failed autologous stem cell transplant (ASCT). Patients received 48-mg subcutaneous epcoritamab after 2 step-up doses until progression or unacceptable toxicity; GemOx was given Q2W for 8 doses. The primary endpoint was overall response rate (ORR). As of December 15, 2023, 103 patients were enrolled (median follow‑up, 13.2 months). Patients had a median age of 72 years and challenging-to-treat disease: ≥2 prior therapy lines, 62%; prior CAR T, 28%; primary refractory disease, 52%; refractory to last therapy, 70%. ORR/CR rates were 85%/61%. Median duration of CR and OS were 23.6 and 21.6 months. Common treatment‑emergent adverse events were cytopenias and cytokine release syndrome (CRS). CRS events had predictable timing, were primarily low grade (52% overall, 1% grade 3), and resolved without leading to discontinuation. Epcoritamab + GemOx yielded deep, durable responses and favorable long-term outcomes in ASCT‑ineligible R/R DLBCL. NCT04663347.