Search Results (174)

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

Classical Hodgkin lymphoma (cHL) is a biologically and clinically unique malignancy characterized by rare Hodgkin and Reed–Sternberg (HRS) cells surrounded by a dense and diverse inflammatory infiltrate. These malignant cells actively reshape the tumor microenvironment (TME) through metabolic reprogramming and immune evasion strategies. This review synthesizes current knowledge on how metabolic alterations contribute to tumor survival, immune dysfunction, and therapeutic resistance in cHL. We discuss novel therapeutic approaches aimed at disrupting these processes and examine the potential of combining metabolic interventions with immune-based strategies—such as immune checkpoint inhibitors (CPIs), epigenetic modulators, bispecific antibodies, and CAR-T/CAR-NK cell therapies—which may help overcome resistance and enhance anti-tumor responses. Several agents are currently under investigation for their ability to modulate immune cell metabolism and restore effective immune surveillance. Altogether, targeting metabolic vulnerabilities within both tumor and immune compartments offers a promising, multifaceted strategy to improve clinical outcomes in patients with relapsed or refractory cHL. Full article

Background/Objectives: Hodgkin’s lymphoma (HL) affects 2–4 individuals per 100,000 annually. Standard treatment includes radiotherapy and ABVD chemotherapy, achieving a 95% survival rate. However, HL survivors face an elevated risk of treatment-related morbidity, particularly the development of secondary malignancies. Previous studies have demonstrated that ABVD treatment induces a high frequency of chromosomal aberrations (CAs) in lymphocytes from HL patients, with higher frequencies one year after treatment than during treatment. This study aimed to determine whether HL treatment also induces unclassified chromosomal/nuclear aberrations (UnCAs) in the lymphocytes of HL patients, and whether these alterations may serve as complementary indicators of genomic instability. Methods: Peripheral blood lymphocytes from HL patients were collected at three time points: before treatment (BT), during treatment (DT), and one year after treatment (1yAT) with ABVD chemotherapy and radiotherapy. A minimum of 3000 nuclei were analyzed per patient to identify and quantify UnCAs. These results were compared to UnCA frequencies in healthy individuals. Results: The percentage of cells presenting UnCAs per 3000 nuclei was 23.92% BT, 18.58% DT, and 30.62% 1yAT. All values were significantly higher (p < 0.016) than the 8.16% observed in healthy controls. The increase was primarily driven by free chromatin and micronuclei clusters. UnCA frequency was lower during treatment than one year after, likely due to the elimination of highly damaged cells through apoptosis or lack of proliferative capacity. Over time, however, persistent genomic damage appears to accumulate in surviving cells, becoming more evident post-treatment. A parallel trend was observed between the frequencies of UnCAs free chromatin, micronucleus and micronuclei clusters, and classical CAs, showing a similar pattern of genomic damage induced by therapy. Conclusions: The post-treatment increase in UnCAs indicates ongoing genomic instability, possibly driven by the selective survival of hematopoietic stem cells with higher genomic fitness. Given their persistence and association with therapy-induced damage, free chromatin and micronuclei clusters may serve as early biomarkers for secondary cancer risk in HL survivors. Full article

Follicular lymphoma (FL) is one of the most common types of non-Hodgkin’s lymphomas. The tumor is characterized by a wide range of clinical manifestations, ranging from indolent forms to early transformation and progression with a poor prognosis. The search for clinically significant genetic changes is essential for personalized risk assessment and treatment selection. The CREBBP gene is frequently mutated in this type of lymphoma, with changes occurring at the level of the earliest tumor precursor cells. However, the prognostic and diagnostic significance of the CREBBP gene mutation status in FL has not been fully established. In this study, we analyzed sequencing data of exons 22–30 of the CREBBP gene in 86 samples from patients with different grades of FL (1–3B), including those in the 3A–3B subgroup without the t(14;18) translocation. We also investigated the prognostic significance of CREBBP gene mutations in relation to the treatment options, namely high-dose chemotherapy with autologous hematopoietic stem cell transplantation (HDCT/auto-HSCT) and conventional chemotherapy programs (CCT). It was found that FL patients with a single missense mutation in the KAT domain of the CREBBP gene experienced an extremely low number of early adverse events related to lymphoma and had better long-term survival rates, regardless of treatment option. In contrast, when comparing patients with FL without a missense mutation in the KAT domain or those with multiple mutations in the CREBBP gene, overall and progression free survival were worse, and early progression and histological transformation were more common. Compared to standard therapy, patients who underwent HDCT/auto-HSCT in the FL 1–3B (14;18)-positive group without a single missense mutation in the KAT domain had better survival rates and lower rates of transformation and early progression. In addition, among patients with FL 3A–3B (14;18)-negative, we found that there were no cases of a missense mutation in the KAT domain of the CREBBP gene. This suggests that a single missense mutation in the CREBBP gene may be a feature that discriminates 14;18-positive FL with a favorable prognosis from a high-risk disease. FL 3A–3B (14;18)-negative may represent a distinct variant with different biology and underlying mechanisms of development compared to classical FL. Full article

Intravascular lymphoma (IVL) is a rare, aggressive subtype of non-Hodgkin lymphoma (NHL) characterized by the selective proliferation of neoplastic lymphoid cells within small and medium-sized blood vessels, most frequently of B-cell origin (IVLBCL). Its protean clinical presentation, lack of pathognomonic findings, and absence of tumor masses or lymphadenopathies often lead to diagnostic delays and poor outcomes. IVLBCL can manifest in classic, hemophagocytic syndrome-associated (HPS), or cutaneous variants, with extremely variable organ involvement including the central nervous system (CNS), skin, lungs, and endocrine system. Diagnosis requires histopathologic identification of neoplastic intravascular lymphoid cells via targeted or random tissue biopsies. Tumor cells are highly atypical and display a non-GCB B-cell phenotype, often expressing CD20, MUM1, BCL2, and MYC; molecularly, they frequently harbor mutations in MYD88 and CD79B, defining a molecular profile shared with ABC-type DLBCL of immune-privileged sites. Therapeutic approaches are based on rituximab-containing chemotherapy regimens (R-CHOP), often supplemented with CNS-directed therapy due to the disease’s marked neurotropism. Emerging strategies include autologous stem cell transplantation (ASCT) and novel immunotherapeutic approaches, potentially exploiting the frequent expression of PD-L1 by tumor cells. A distinct but related entity, intravascular NK/T-cell lymphoma (IVNKTCL), is an exceedingly rare EBV-associated lymphoma, showing unique own histologic, immunophenotypic, and molecular features and an even poorer outcome. This review provides a comprehensive overview of the current understandings about clinicopathological, molecular, and therapeutic landscape of IVL, emphasizing the need for increased clinical awareness, standardized diagnostic protocols, and individualized treatment strategies for this aggressive yet intriguing malignancy. Full article

Immune checkpoints such as PD-1/PD-L1, CTLA-4, LAG-3, TIM-3, and TIGIT play critical roles in regulating anti-tumor immunity and are exploited by hematological malignancies to evade immune surveillance. While classic Hodgkin lymphoma (HL) demonstrates notable responsiveness to immune checkpoint inhibitors (ICIs), which is attributed to genetic alterations like chromosome 9p24.1 amplification, the responsiveness of non-Hodgkin lymphoma (NHL), acute myeloid leukemia (AML), and multiple myeloma (MM) remain inconsistent and generally modest. In NHL, the heterogeneous immune microenvironment, particularly variations in tumor-infiltrating lymphocytes and PD-L1 expression, drives differential ICI outcomes. AML shows limited responsiveness to monotherapy, but the combination of monotherapy with hypomethylating agents yield encouraging results, particularly in selected patient subsets. Conversely, MM trials have largely failed, potentially due to genetic polymorphisms influencing checkpoint signaling pathways and the inherently immunosuppressive bone marrow microenvironment. Both intrinsic tumor factors (low tumor mutational burden, impaired antigen presentation, IFN-γ pathway alterations) and extrinsic factors (immunosuppressive cells and alternative checkpoint upregulation) contribute significantly to primary and acquired resistance mechanisms. Future strategies to overcome resistance emphasize combination therapies, such as dual checkpoint blockade, epigenetic modulation, and reprogramming the tumor microenvironment, as well as biomarker-driven patient selection, aiming for precision-based, tailored immunotherapy across hematological malignancies. Full article

Programmed death-ligand 1 (PD-L1) on tumor cells, including Hodgkin and Reed–Sternberg (HRS) cells in classical Hodgkin’s lymphoma (cHL), suppresses immune responses in the tumor immune microenvironment (TME). We analyzed PD-L1 expression in macrophages and HRS cells of 98 cHL cases and correlated the findings with clinicopathological features, overall survival (OS), and progression-free survival (PFS). Epstein–Barr virus (EBV) was detected by in situ hybridization for EBV-encoded RNA. Ten high-power fields were evaluated to count the total number of macrophages and PD-L1+ macrophages, and to calculate PD-L1 histoscore (H-score) in HRS cells. EBV-positive cHL was found in 22.5% of patients. The median H-score was 80 (range 0–300). Bulky disease was associated with a lower number of PD-L1+ macrophages, and extranodal disease with a higher number (p = 0.05). EBV-positive cHL showed a higher PD-L1 H-score in HRS cells and a greater number of PD-L1⁺ macrophages (p = 0.005); both of these features, along with the proportion of PD-L1⁺ macrophages, were associated with shorter PFS and OS (p < 0.001). High PD-L1 expression in HRS and macrophages may be linked to worse clinical outcomes. Full article

Background: Delays in treatments are frequent in real-world lymphoma management. This study evaluates the impact of diagnosis-to-treatment intervals (DTIs) and first inter-cycle delay (IcD) on outcomes in patients with Hodgkin lymphoma (HL) receiving ABVD chemotherapy. Methods: We retrospectively analyzed 137 patients with classical HL treated with ABVD at a single institution between 2015 and 2022. Results: The median age was 34 years (range: 18–73), and 62% were male. The median DTI was 14 days, with 24.1% of patients experiencing a delay of >7 days between the first and second chemotherapy cycles. The most frequent reason for delay was neutropenia, observed in 69% of delayed cases. Neither DTI nor IcD was significantly associated with PFS or OS. Multivariate analysis identified elevated beta-2 microglobulin as an independent predictor of both inferior PFS and OS. Conclusions: This is the first study to evaluate both DTI and first IcD as independent prognostic factors in HL. Modest delays in treatment initiation or early cycle administration did not negatively affect survival. Timely but flexible scheduling of ABVD may be appropriate in HL. Prospective studies are warranted in the era of novel therapeutic agents. Full article

Background/Objectives: Classic Hodgkin lymphoma (cHL) is a predominantly curable B-cell malignancy. However, primary refractory and relapsed (R/R) cHL remain therapeutic challenges, especially in regions with high tuberculosis (TB) prevalence, where clinical and radiologic features overlap and can obscure the correct diagnosis. This article, presenting a case of R/R cHL mimicking disseminated TB, reviews the evolving paradigm in R/R cHL management. Methods: A 30-year-old Middle Eastern male with advanced nodular sclerosis cHL initially achieved a complete remission (CR) with escalated BEACOPP chemotherapy. Shortly afterward, he developed respiratory symptoms and diffuse miliary pulmonary nodules, highly suggestive of disseminated TB. Despite extensive negative TB workup, including QuantiFERON-TB Gold testing, sputum acid-fast bacilli (AFB) staining, and PCR, his imaging raised concern for recurrent cHL. Due to the small size and diffuse distribution of nodules, biopsy was unfeasible, prompting empiric salvage therapy with DEHAP-Carbo, brentuximab vedotin (BV), and nivolumab. Results: The rapid and robust metabolic response on PET/CT supported lymphoma relapse rather than TB. Following four cycles of this combined regimen, he proceeded to autologous stem cell transplantation and achieved a second CR. Conclusions: This case highlights the diagnostic difficulties in differentiating cHL relapse from TB in endemic regions, emphasizes the critical role of PET/CT in guiding therapy when histopathological confirmation is impractical, and illustrates the impact of novel immunotherapies in improving outcomes. By underscoring the importance of early diagnostic suspicion and multimodal assessment, this article also reviews the evolving paradigm in R/R cHL management, where personalized approaches and targeted agents increasingly complement or replace traditional chemotherapy regimens. Full article

Classic Hodgkin lymphoma (cHL) in patients with immune deficiency/dysregulation represents a critical unmet need in hematology, demanding the appropriate revision of classification and therapeutic paradigms. Epstein–Barr virus (EBV) is a pivotal driver of lymphomagenesis in this high-risk subset, where viral oncoproteins (e.g., LMP1/2A) exploit immune vulnerabilities to activate NF-κB, rewire tumor microenvironments (TME), and evade immune surveillance. EBV-positive cHL, prevalent in immunosuppressed populations, exhibits distinct molecular hallmarks, including reduced somatic mutations, unique HLA associations, and profound PD-L1-mediated immune suppression, that diverge from EBV-negative cases reliant on genetic aberrations. Despite advances in combined antiretroviral therapy, HIV co-infection exacerbates pathogenesis, M2 macrophage dominance, and T-cell exhaustion, while links to other viruses remain ambiguous. Current therapies fail to adequately target these viral and immune complexities, leaving patients with poorer outcomes. This review synthesizes insights into EBV’s etiological role, immune contexture disparities, and the genetic–environmental interplay shaping cHL heterogeneity. The WHO classification highlights the need to reclassify EBV-associated cHL as a distinct subset, integrating viral status and immune biomarkers into diagnostic frameworks. Urgent priorities include global epidemiological studies to clarify causal mechanisms, development of virus-targeted therapies (e.g., EBV-specific T-cell strategies, PD-1/CTLA-4 blockade), and personalized regimens for immune-dysregulated cohorts. Full article

Background: Classical Hodgkin lymphoma (cHL) is a treatable malignancy; however, relapsed or refractory (R/R) cases pose significant challenges. PD-1 inhibitors have shown efficacy, but the role of hematopoietic stem cell transplantation (HSCT) following PD-1 blockade remains uncertain. This study aims to evaluate the impact of HSCT after PD-1 blockade on progression-free survival (PFS) and overall survival (OS) in patients with R/R cHL. Methods: We conducted a multicenter, retrospective study involving 42 patients with R/R cHL who received PD-1 inhibitors between 2016 and 2021. Patients were categorized into two groups: those who underwent HSCT after PD-1 therapy (n = 19) and those who continued PD-1 inhibitors without HSCT (n = 23). Results: Among the 42 patients, 27 achieved complete remission (CR) and 15 achieved partial remission (PR) following PD-1 blockade. In the HSCT group, 92% of patients remained progression-free at 3 years, compared to 65% in the non-HSCT group (p = 0.021). OS rates were similar between groups (100% vs. 96%, p = ns). Notably, 80% of PR patients in the HSCT group converted to CR. Relapse rates were significantly lower in the HSCT group (5%) compared to the non-HSCT group (43%, p = 0.005). Conclusions: HSCT following PD-1 blockade enhances PFS in patients with R/R cHL, particularly among those with PR, without offering a significant OS benefit. Further research is warranted to optimize treatment strategies for this patient population strategies. Full article

Background/Objectives: Brentuximab vedotin (BV) has been shown to be effective in the treatment of classical Hodgkin’s lymphoma (cHL), systemic anaplastic large cell lymphoma (sALCL), and CD30-positive cutaneous T-cell lymphoma (CTCL). This study aimed to evaluate the effectiveness and safety of BV retreatment in patients with relapsed/refractory cHL, sALCL, and CD30-positive CTCL. Methods: This multicenter, non-interventional, retrospective medical chart review study analyzed medical records from 43 patients retreated with BV in Spain. Patients were included if they had relapsed or refractory cHL, sALCL, or CD30-positive CTCL and were previously treated with BV. Demographic characteristics, disease stage, response to treatment, survival outcomes, and adverse events were analyzed. Results: The study population included 16 patients with cHL, 13 with sALCL, and 14 with CTCL. The majority were male (58.1%) with a mean age of 46.2 years and baseline ECOG scores of 0–1. Among cHL and sALCL patients, disease stage, according to the Ann Arbor classification, ranged from I to IVB, while in CTCL, EORTC clinical stages ranged from IA to IVB. The overall response rate to BV retreatment was 76.7%, with the highest response observed in sALCL (92.3%). Complete remission was achieved in 60.5% of patients. Median progression-free survival was 25.4 months, and overall survival reached 50 months. Treatment failure occurred in 37.2% of patients. BV was generally well tolerated, with peripheral neuropathy being the most frequently reported adverse event. Conclusions: The BELIEVE study is the largest study to date demonstrating that retreatment with BV is an effective and well-tolerated option for patients with relapsed or refractory CD30-positive malignancies. Full article

Background: Hodgkin lymphoma (HL) is a B-cell-derived malignancy and one of the most frequent types of lymphoma. The tumour cells typically exhibit multiple genomic alterations together with aberrantly activated signalling pathways, driven by paracrine and/or autocrine modes. SPP1 (alias osteopontin) is a cytokine acting as a signalling activator and has been connected with relapse in HL patients. To understand its pathogenic role, here, we investigated the mechanisms and function of deregulated SPP1 in HL. Methods: We screened public patient datasets and cell lines for aberrant SPP1 expression. HL cell lines were stimulated with SPP1 and subjected to siRNA-mediated knockdown. Gene and protein activities were analyzed by RQ-PCR, ELISA, Western blot, and immuno-cytology. Results: SPP1 expression was detected in 8.3% of classic HL patients and in HL cell line SUP-HD1, chosen to serve as an experimental model. The gene encoding SPP1 is located at chromosomal position 4q22 and is genomically amplified in SUP-HD1. Transcription factor binding site analysis revealed TALE and HOX factors as potential regulators. Consistent with this finding, we showed that aberrantly expressed PBX1 and HOXB9 mediate the transcriptional activation of SPP1. RNA-seq data and knockdown experiments indicated that SPP1 signals via integrin ITGB1 in SUP-HD1. Accordingly, SPP1 activated NFkB in addition to MAPK/ERK which in turn mediated the nuclear import of ETS2, activating oncogenic JUNB expression. Conclusions: SPP1 is aberrantly activated in HL cell line SUP-HD1 via genomic copy number gain and by homeodomain transcription factors PBX1 and HOXB9. SPP1-activated NFkB and MAPK merit further investigation as potential therapeutic targets in affected HL patients. Full article

Thrombosis is a critical complication in lymphomas, driven by chronic inflammation. To observe this systemic mechanism, we evaluated inflammatory cytokines, neutrophil and monocyte activation, and platelet function in diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and Hodgkin lymphoma (HL), with and without thrombosis using ELISA and flow cytometry according to laboratory and clinical data. Interleukin-1β was elevated across lymphomas and inversely correlated with the Khorana score for venous thromboembolism, while increased tumor necrosis factor-alpha (TNF-α) was inversely associated with the International Prognostic Index (IPI) in thrombosis-associated lymphomas. Neutrophil activation was increased in DLBCL, while elevated neutrophil extracellular traps (NETs) biomarkers were inversely consistent with thrombosis and the ThroLy score. NETs were elevated in HL. Classical monocytes were increased in all lymphoma subtypes, with intermediate and tissue factor (TF)-carrying monocytes elevated in DLBCL and HL. Platelet activation was pronounced, with platelet–monocyte aggregates and platelet-associated TF elevated in DLBCL and FL but not HL. P-selectin was increased in lymphomas with thrombosis, aligned with Khorana and ThroLy scores, and reflected clinical stage while inversely correlating with IPI in non-thrombotic lymphomas. These findings highlight distinct thromboinflammatory mechanisms across lymphoma subtypes, providing insights into biomarkers for thrombosis risk and therapeutic targets in lymphoma management. Full article