Search Results (606)

Epigenetic regulation is critical to B cell development, guiding gene expression via DNA methylation, histone modifications, chromatin remodeling, and noncoding RNAs. In mature B cell neoplasms, particularly diffuse large B cell lymphoma (DLBCL), follicular lymphoma (FL), and chronic lymphocytic leukemia (CLL), these mechanisms are frequently disrupted. Recurrent mutations in key epigenetic regulators such as EZH2, KMT2D, CREBBP, and TET2 lead to altered chromatin states, repression of tumor suppressor genes, and enhanced oncogenic signaling. Dysregulation of specific microRNAs (e.g., miR-155, miR-21) further contributes to pathogenesis and therapeutic resistance. In DLBCL, hypermethylation of SMAD1 and CREBBP mutations are associated with immune evasion and chemoresistance. In FL, EZH2 gain-of-function and KMT2D loss-of-function mutations alter germinal center B cell programming, while in CLL, DNA hypomethylation patterns reflect the cell of origin and correlate with clinical outcome. Targeted therapies such as the EZH2 inhibitor tazemetostat have demonstrated efficacy in EZH2-mutant FL, while HDAC and BET inhibitors show variable responses across B cell malignancies. The limitations of current epigenetic therapies reflect the complexity of targeting epigenetic dysregulation rather than therapeutic futility. These challenges nonetheless highlight the relevance of epigenetic alterations as biomarkers and therapeutic targets, with potential to improve the management of mature B cell neoplasms. Full article

Primary cutaneous lymphomas (PCLs), including cutaneous T-cell lymphomas (CTCL) and primary cutaneous B-cell lymphomas (PCBCL), are a diverse group of non-Hodgkin lymphomas that primarily affect the skin. Radiotherapy (RT) plays a pivotal role in the treatment of these lymphomas, particularly for localized disease, due to its ability to deliver precise, skin-directed treatment. Mycosis fungoides (MF) and Sézary syndrome (SS), the most common subtypes of CTCL, often require skin-directed therapies such as electron beam therapy and superficial brachytherapy to manage localized lesions. Electron beam therapy, including total skin electron beam therapy (TSEBT), has been utilized for decades, offering high response rates but with the risk of cumulative skin toxicity. Recently, low-dose radiotherapy (LDRT) has gained attention as an effective alternative that reduces toxicity while maintaining durable responses. Superficial brachytherapy is another modality that delivers radiation through custom molds, allowing for homogeneous dosing over complex anatomical areas like the face. Both teleradiotherapy and brachytherapy have demonstrated high complete response rates, with low recurrence rates observed when higher doses are used. In the context of primary cutaneous B-cell lymphomas, such as primary cutaneous marginal zone lymphoma (PCMZL) and primary cutaneous follicle center lymphoma (PCFCL), radiotherapy also offers excellent local control, particularly for indolent subtypes. However, more aggressive subtypes, such as diffuse large B-cell lymphoma, leg type (PCDLBCL-LT), may require systemic therapies in addition to radiation. Overall, teleradiotherapy and brachytherapy are essential components of the therapeutic arsenal for primary cutaneous lymphomas, offering effective disease control with manageable toxicity, while ongoing research focuses on optimizing treatment strategies and exploring novel combinations with systemic therapies. Full article

(1) Background: Bispecific antibodies (BsAbs) for the treatment of relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL) can be delivered in ambulatory healthcare settings; however, the safe and effective management of potential side effects, such as cytokine release syndrome (CRS), requires protocolized monitoring and management. (2) Methods: An Expert Working Group (EWG) of nine hematologists from across Canada, with experience in leading BsAb program implementation, combined a review of published literature, a comparison of national/provincial/regional guidance documents and protocols, and their professional experiences to produce an informed framework for BsAb program implementation in various healthcare settings. (3) Results: The EWG supports and recommends the progression of BsAb provision from predominantly inpatient hospital settings to community/ambulatory care settings closer to the patient’s home. A seven-step implementation process is outlined to support the safe and effective establishment of such programs, from establishing leadership, through customization of protocols, to education and execution. Strategies and considerations are offered to overcome potential barriers and empower healthcare professionals who are working to establish or improve BsAb programs across Canada. (4) Conclusions: For patients with R/R DLBCL, the safe and effective provision of BsAbs closer to home is both feasible and preferred. This guidance is intended to support the efficient and effective setup or enhancement of BsAb programs in lymphoma. Full article

CD20-negative aggressive B-cell lymphomas are a rare and heterogeneous group of lymphomas representing a diagnostic challenge for pathologists and a therapeutic issue for clinicians, because the outcome of these patients is poor with the current therapeutic approaches. CD20-negative aggressive lymphomas include plasmablastic lymphoma, primary effusion lymphoma, ALK-positive large B-cell lymphoma and HHV8-positive diffuse large B-cell lymphoma. Conditions of immunosuppression and viral infections, such as Epstein–Barr virus and Human Herpes virus 8, are associated with all of these lymphomas with the exclusion of ALK-positive large B-cell lymphoma, which occurs in immunocompetent hosts and is not associated with viral infections. Common features of these aggressive tumors are high-grade histology with immunoblastic or plasmablastic differentiation, the absence or weak expression of mature B-cell markers such as CD20 and the frequent expression of plasma cell-associated markers. The aim of this review is to highlight the diagnostic challenges associated with the group of CD20-negative aggressive B-cell lymphomas, emphasizing key morphologic and molecular features, which are critical in the diagnosis of the different entities belonging to this rare group of diseases. Full article

Objectives: Evaluation of the predictive potential of pre-CAR-T [¹⁸F]FDG PET/CT in Diffuse Large B-Cell Lymphoma (DLBCL) patients concerning Cytokine Release Syndrome (CRS) and Immune Effector Cell-associated Neurotoxicity Syndrome (ICANS). Methods: Eighteen DLBCL patients (mean age: 60 ± 12 years) who underwent pre-therapeutic [¹⁸F]FDG-PET/CT and CAR-T cell therapy were retrospectively included. Median follow-up time was ten months (IQR6-16) after CAR-T cell infusion. Age, sex, serum lactate dehydrogenase (LDH), interleukin-6 (IL-6), C-reactive protein (CRP), and modified Endothelial Activation and Stress Index (mEASIX) were obtained. Potential occurrence of CRS/ICANS and the SUV_max were evaluated. Pearson and Spearman correlations, group comparisons (Mann–Whitney U-test) and the odds ratio (OR) were calculated. P values below 0.05 were defined as statistically significant and 95%-confidence intervals (CI) were calculated. Results: Pre-therapeutic SUV_max correlated positively with LDH (r = 0.5; p = 0.02), with the grade of CRS (r = 0.5; p = 0.03) and with the grade of ICANS (r = 0.6; p = 0.01). Appearance of ICANS was significantly correlated with pre-therapeutic SUV_max (p = 0.03; U = 7.0; Z = −2.2). Using ROC analysis and Youden’s index, an SUV_max threshold of 17 (AUC: 0.865; p < 0.01) was defined. Patients exceeding a pre-therapeutic SUV_max of 17 had a significantly higher risk of CRS grade > 1 (OR = 22; CI 2, 314; p = 0.03) and ICANS grade > 1 (OR = 18; CI 1, 271; p = 0.04). Conclusions: Pre-therapeutic SUV_max may be a useful marker for identifying DLBCL patients at risk for CRS and ICANS. Full article

We aimed to establish non-invasive diagnostic models comparable to pathology testing and explore reliable digital imaging biomarkers to classify diffuse large B-cell lymphoma (DLBCL) and invasive ductal carcinoma (IDC). Our study enrolled 386 breast nodules from 279 patients with DLBCL and IDC, which were pathologically confirmed and underwent ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG) positron emission tomography/computed tomography (PET/CT) examination. Patients from two centers were separated into internal and external cohorts. Notably, we introduced 2.5D deep learning and machine learning to extract features, develop models, and discover biomarkers. Performances were assessed using the area under curve (AUC) and confusion matrix. Additionally, the Shapley additive explanation (SHAP) and local interpretable model-agnostic explanations (LIME) techniques were employed to interpret the model. On the internal cohort, the optimal model PT_TDC_SVM achieved an accuracy of 0.980 (95% confidence interval (CI): 0.957–0.991) and an AUC of 0.992 (95% CI: 0.946–0.998), surpassing the other models. On the external cohort, the accuracy was 0.975 (95% CI: 0.913–0.993) and the AUC was 0.996 (95% CI: 0.972–0.999). The optimal imaging biomarker PET_LBP-2D_gldm_DependenceEntropy demonstrated an average accuracy of 0.923/0.937 on internal/external testing. Our study presented an innovative automated model for DLBCL and IDC, identifying reliable digital imaging biomarkers with significant potential. Full article

B-cell lymphomas, including Burkitt lymphoma (BL), diffuse large B-cell lymphoma (DLBCL), and follicular lymphoma (FL), evade CD4+ T-cell immunity through novel HLA class II-associated immunosuppressive mechanisms. Despite expressing surface HLA-DR, these tumors fail to activate antigen-specific CD4+ T cells, independent of co-stimulation or PD-L1 checkpoint inhibition. We identified lymphoma-secreted factors that broadly disrupt HLA class II-mediated antigen presentation in both malignant B cells and dendritic cells (DCs), silencing T-cell responses. This inhibition is allele-independent (affecting DR1, DR4, DR7) but spares HLA class I-mediated CD8+ T-cell recognition, indicating a targeted immune evasion strategy. Biochemical and mass spectrometry (MALDI-MS) analyses revealed unique low-molecular-weight peptides (693–790 Da) in BL cells, absent in normal B cells, which may mediate this suppression. Functional fractionation confirmed bioactive inhibitory fractions in lymphoma lysates, further implicating tumor-intrinsic molecules in immune escape. These findings highlight a previously unrecognized axis of B-cell lymphoma immune evasion, where secreted factors disable HLA class II function across antigen-presenting cells. Therapeutically, neutralizing these immunosuppressive molecules could restore CD4+ T-cell surveillance and enhance immunotherapies in B-cell malignancies. This work underscores the importance of HLA class II dysfunction in lymphoma progression and identifies candidate targets for reversing immune suppression. Full article

T-cell-engaging antibodies are a promising new type of treatment for patients with refractory or relapsed (R/R) diffuse large B-cell lymphoma, which has changed the prognosis and evolution of these patients in clinical trials. Bispecific antibodies (BsAbs) bind to two different targets (B and T lymphocytes) at the same time and in this way mimic the action of CAR (chimeric antigen receptor) T-cells. They are the T-cell-engaging antibodies most used in practice and are a solution for patients who do not respond to second- or later-line therapies, including chemoimmunotherapy, followed by salvage chemotherapy and hematopoietic stem cell transplantation. They are a therapeutic option for patients who are ineligible for CAR T-cell therapy and are also active in those with prior exposure to CAR T-cell treatment. A remarkable advantage of BsAbs is their rapid availability, even if the disease progresses rapidly, unlike CAR T-cell treatment, and they avoid the practical and financial challenges raised by autologous CAR T-cell therapies. CAR-T has been proven to have better efficacy compared to BsAbs, but cytokine release syndrome and neurotoxicity have appeared significantly more frequently in patients treated with CAR T-cells. The possibility of combining BsAbs with chemotherapy and their administration for relapses or as a frontline therapy is being studied to increase their efficacy. BsAbs are a life-saving therapy for many patients with diffuse large B-cell malignant non-Hodgkin’s lymphoma (NHL) who have a poor prognosis with classical therapies, but are not without adverse effects and require careful monitoring. Full article

Background/Objectives: Diffuse Large B-Cell Lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma and demands precise segmentation and classification of nuclei for effective diagnosis and disease severity assessment. This study aims to evaluate the performance of HoVerNet, a deep learning model, for nuclei segmentation and classification in CMYC-stained whole slide images and to assess its integration into a user-friendly diagnostic tool. Methods: A dataset of 122 CMYC-stained whole slide images (WSIs) was used. Pre-processing steps, including stain normalization and patch extraction, were applied to improve input consistency. HoVerNet, a multi-branch neural network, was used for both nuclei segmentation and classification, particularly focusing on its ability to manage overlapping nuclei and complex morphological variations. Model performance was validated using metrics such as accuracy, precision, recall, and F1 score. Additionally, a graphic user interface (GUI) was developed to incorporate automated segmentation, cell counting, and severity assessment functionalities. Results: HoVerNet achieved a validation accuracy of 82.5%, with a precision of 85.3%, recall of 82.6%, and an F1 score of 83.9%. The model showed powerful performance in differentiating overlapping and morphologically complex nuclei. The developed GUI enabled real-time visualization and diagnostic support, enhancing the efficiency and usability of DLBCL histopathological analysis. Conclusions: HoVerNet, combined with an integrated GUI, presents a promising approach for streamlining DLBCL diagnostics through accurate segmentation and real-time visualization. Future work will focus on incorporating Vision Transformers and additional staining protocols to improve generalizability and clinical utility. Full article

Background and aim: Advanced Therapy Medicinal Products (ATMPs) are innovative drugs based on genes, tissues, or cells that target rare and severe diseases. ATMPs have shown promising clinical outcomes but are associated with high costs, raising questions about cost-effectiveness. Hence, this systematic review aims to analyze the cost-effectiveness and cost-utility profiles of the European Medicines Agency-authorized ATMPs for treating rare diseases. Methods: A systematic review was conducted following PRISMA guidelines. Studies were identified by searching PubMed, Embase, Web of Science, and ProQuest scientific databases. Economic evaluations reporting incremental cost-effectiveness/utility ratios (ICERs/ICURs) for ATMPs were included. Costs were standardized to 2023 Euros, and a cost-effectiveness plane was constructed to evaluate the results against willingness-to-pay (WTP) thresholds of EUR 50,000, EUR 100,000, and EUR 150,000 per QALY, as part of a sensitivity analysis. Results: A total of 61 studies met the inclusion criteria. ATMPs for rare blood diseases, such as tisagenlecleucel and axicabtagene ciloleucel, were found to be cost-effective in a majority of studies, with incremental QALYs ranging from 1.5 to 10 per patient over lifetime horizon. Tisagenlecleucel demonstrated a positive cost-effectiveness profile in the treatment of acute lymphoblastic leukemia (58%), while axicabtagene ciloleucel showed a positive profile in the treatment of diffuse large B-cell lymphoma (85%). Onasemnogene abeparvovec for spinal muscular atrophy (SMA) showed uncertain cost-effectiveness results, and voretigene neparvovec for retinal diseases was not cost-effective in 40% of studies, with incremental QALYs around 1.3 and high costs exceeding the WTP threshold set. Conclusions: ATMPs in treating rare diseases show promising economic potential, but cost-effectiveness varies across indications. Policymakers must balance innovation with system sustainability, using refined models and the long-term impact on patient outcomes. Full article

FMC63-CAR T cell therapy targeting CD19 protein on malignant B-cells is effective in patients with relapsed or refractory diffuse large B-cell lymphoma (r/r DLBCL), with complete response rates of 43–54%. Common germline variants of the immune-checkpoint regulator CTLA-4 may elicit different responses to CAR-T cell therapy. The CTLA4 gene single-nucleotide polymorphism rs231775 coding threonine or alanine at amino acid position 17 of the CTLA-4 protein was prevalent in 55% of the studied DLBCL patients. In a retrospective comparative analysis of clinical outcome, there were significant differences in CTLA4 A17hom vs. T17Ahet and T17hom carriers with four-year progression-free survival at 77%, 59%, and 30% (p = 0.019), four-year overall survival was 79%, 41%, and 33% (p = 0.049), the relapse rates were 20%, 37%, and 56% (p = 0.025), and the death rates 20%, 54%, and 52% (p = 0.049). Conclusions: CTLA4 rs231775 polymorphism may impact the treatment outcome in FMC63-anti-CD19 CAR-T cell therapy, with an association of the CTLA4 minor allele A17 to favorable treatment outcome. Full article

Background and Objectives: Metabolic tumor volume (MTV) and inflammation-based indices have recently gained attention as potential prognostic markers of diffuse large B-cell lymphoma (DLBCL). We aimed to evaluate the prognostic significance of metabolic and systemic inflammatory parameters in predicting treatment response, relapse, and overall survival (OS) in patients with DLBCL. Materials and Methods: This retrospective cohort study included 70 patients with DLBCL. Clinical characteristics, laboratory values, and metabolic parameters, including maximum standardized uptake value (SUVmax^liver and SUVmax), heterogeneity indices HI1 and HI2, and MTV were analyzed. Survival outcomes were assessed using Kaplan–Meier and log-rank tests. Receiver operating characteristic analyses helped evaluate the diagnostic performance of the selected biomarkers in predicting relapse and mortality. Univariate and multivariate logistic regression analyses were conducted to identify the independent predictors. Results: The mean OS and mean relapse-free survival (RFS) were 71.6 ± 7.4 and 38.7 ± 2.9 months, respectively. SUVmax^liver ≤ 22 and HI2 > 62.3 were associated with a significantly shorter OS. High lactate dehydrogenase (LDH) levels and HI2 > 87.9 were significantly associated with a reduced RFS. LDH, SUVmax^liver, and HI2 had a significant predictive value for relapse. SUVmax^liver and HI2 levels were also predictive of mortality; SUVmax^liver ≤ 22 and HI2 > 62.3 independently predicted mortality, while HI2 > 87.9 independently predicted relapse. MTV was not significantly associated with survival. Conclusions: Metabolic tumor burden and inflammation-based markers, particularly SUVmax^liver and HI2, are significant prognostic indicators of DLBCL and may enhance risk stratification and aid in identifying patients with an increased risk of relapse or mortality, potentially guiding personalized therapy. Full article

Relapsed/refractory diffuse large B-cell lymphoma and other non-Hodgkin lymphomas represent significant clinical challenges, particularly in patients who have exhausted standard immunochemotherapy and cellular therapies. Bispecific antibodies and antibody–drug conjugates have emerged as promising treatments, offering targeted and more effective treatment options compared to current standards. Bispecific antibodies, including epcoritamab and glofitamab, third-line therapies for diffuse large B-cell lymphoma, are recombinant immunoglobulins engineered to recognize two distinct antigens or epitopes simultaneously. This capability enhances therapeutic precision by bridging immune effector cells and tumor cells and modulating multiple signaling pathways involved in the pathogenesis of non-Hodgkin lymphoma. In the context of new therapies, antibody–drug conjugates, such as loncastuximab tesirine, are therapies composed of monoclonal antibodies linked to cytotoxic agents, in which the antibody selectively binds to tumor-associated antigens, delivering the cytotoxic payload directly to cancer cells while minimizing off-target effects. They combine the specificity of antibodies with the potency of chemotherapy, offering enhanced efficacy and safety in hematological malignancies. Ongoing clinical trials are investigating other molecules like odronextamab and the use of bispecific antibodies in combination regimens and earlier lines of therapy. The aim of this review is to explore actual therapies in relapsed/refractory diffuse large B-cell lymphoma, focusing on bispecific antibodies and antibody–drug conjugates. Full article

Background and Clinical Significance: Hematologic malignancies, including diffuse large B-cell lymphoma (DLBCL), have been associated with the development of Guillain–Barré syndrome (GBS). Specifically, treatment with the immunomodulator rituximab, which is used in the backbone of DLBCL treatment, has increasingly been used in this patient population. Case Presentation: We present the case of a man in his 60s with DLBCL who presented to the hospital with the progressive weakness of the bilateral upper and lower extremities within 6 weeks of the completion of treatment including rituximab. The temporal relationship between the completion of rituximab and subsequent polyradiculoneuropathy, as well as a favorable response to intravenous immunoglobulin (IVIG), affirmed the diagnosis of treatment-induced GBS. Conclusions: The increased use of rituximab as part of a standard treatment regimen for hematologic malignancies demonstrates the need for an awareness of a possible association between rituximab and the subsequent paradoxical development of GBS, which will allow for expeditious evaluation for better patient outcomes. Full article