信迪利单抗联合地西他滨基础上加用维布妥昔单抗治疗复发/难治性结外NK/T细胞淋巴瘤的增量疗效、耐受性及机制研究

Extranodal NK/T-cell lymphoma, nasal type, is a rare and highly aggressive disease with a grim prognosis. No therapeutic strategy is currently identified in relapsing patients. We report the results of a French prospective phase II trial of an L-asparaginase-containing regimen in 19 patients with relapsed or refractory disease treated in 13 centers. Eleven patients were in relapse and 8 patients were refractory to their first line of treatment. L-Asparaginase–based treatment yielded objective responses in 14 of the 18 evaluable patients after 3 cycles. Eleven patients entered complete remission (61%), and only 4 of them relapsed. The median overall survival time was 1 year, with a median response duration of 12 months. The main adverse events were hepatitis, cytopenia, and allergy. The absence of antiasparaginase antibodies and the disappearance of Epstein-Barr virus serum DNA were significantly associated with a better outcome. These data confirm the excellent activity of L-asparaginase–containing regimens in extranodal NK/T-cell lymphoma. L-Asparaginase–based treatment should thus be considered for salvage therapy, especially in patients with disseminated disease. First-line L-asparaginase combination therapy for extranodal NK/T-cell lymphoma warrants evaluation in prospective trials. This trial is registered at www.clinicaltrials.gov as #NCT00283985.

This study (ORIENT-4) aimed to assess the efficacy and safety of sintilimab, a humanized anti-PD-1 antibody, in patients with relapsed/refractory extranodal NK/T cell lymphoma (r/r ENKTL). ORIENT-4 is a multicenter, single-arm, phase 2 clinical trial (NCT03228836). Patients with r/r ENKTL who failed to at least one asparaginase-based regimen were enrolled to receive sintilimab 200 mg intravenously every 3 weeks for up to 24 months. The primary endpoint was the objective response rate (ORR) based on Lugano 2014 criteria. Twenty-eight patients with r/r ENKTL were enrolled from August 31, 2017 to February 7, 2018. Twenty-one patients (75.0%, 95% CI: 55.1–89.3%) achieved an objective response. With a median follow-up of 30.4 months, the median overall survival (OS) was not reached. The 24-month OS rate was 78.6% (95% CI, 58.4–89.8%). Most treatment-related adverse events (TRAEs) were grade 1–2 (71.4%), and the most common TRAE was decreased lymphocyte count (42.9%). Serious adverse events (SAEs) occurred in 7 (25.0%) patients, and no patient died of adverse events. Sintilimab is effective and well tolerated in patients with r/r ENKTL and could be a novel therapeutic approach for the control of ENKTL in patients.

This study aimed to assess the efficacy and safety of treatment with avelumab, an anti-programmed death ligand 1 (PD-L1) antibody, in patients with relapsed or refractory extranodal natural killer (NK)/T-cell lymphoma (ENKTL). In this phase II trial, 21 patients with relapsed or refractory ENKTL were treated with 10 mg/kg of avelumab on days 1 and 15 of a 28-day cycle (ClinicalTrials.gov Identifier: NCT03439501). The primary end point was the complete response (CR) rate based on the best response. Targeted sequencing and immunohistochemistry were performed using pretreatment tumor tissue, and blood samples were drawn pre- and post-treatment for measurement of cytokines and soluble programmed cell death protein 1 (PD1), PD-L1, and PD-L2. The CR rate was 24% (5/21) and the overall response rate was 38% (8/21). Although nonresponders showed early progression, five responders currently continue to receive treatment and have maintained their response. Most treatment-related adverse events were grade 1 or 2; no grade 4 adverse events were observed. Treatment responses did not correlate with mutation profiles, tumor mutation burden, serum levels of cytokines, or soluble PD1/PD-L1 and PD-L2. However, the response to avelumab was significantly associated with the expression of PD-L1 by tumor tissue (P = 0.001). Therefore, all patients achieving CR showed high PD-L1 expression, and their tumor subtyping based on PD-L1 expression correlated with treatment response. In conclusion, avelumab showed single-agent activity in a subset of patients with relapsed or refractory ENKTL. The assessment of PD-L1 expression on tumor cells might be helpful for identifying responders to avelumab.

… patients with refractory and relapsed extranodal NK/T-cell lympho… regimen, on refractory and relapsed extranodal NKTCL, … , 45 patients with refractory and relapsed extranodal NKTCL, …

Extranodal nasal NK/T cell lymphoma (NKTCL) is a rare, malignant neoplasm mainly affecting men in the fifth decade of life, that usually arises in the nose, paranasal sinuses, orbits or upper airway, and that can present with a nasal mass, nasal bleeding, nasal obstruction, palate perforation (i.e. midline perforation of the hard palate), and mid-facial and/or upper airway destructive lesions. In advanced disease stages, which are associated with a poor prognosis, NKTCL may disseminate to other organs. A few cases of NKTCL presenting primarily in the lymph nodes have also been described.

… Extranodal NK/T-cell lymphoma (ENKTL) is rare and has limited treatment options available for relapsed/refractory (R/R) disease. This multicenter single-arm phase II study evaluated …

… or progression is poor; however, data regarding clinical outcomes in relapsed and refractory ENKTL in the era of non-anthracycline-based regimens are scarce. In the absence of …

Extranodal natural killer/T-cell lymphoma (ENKTL) is an aggressive neoplasm with a poor outcome. Asparaginase-based regimens are recommended for patients with advanced-stage or relapsed/refractory ENKTL. We retrospectively investigated the efficacy and toxicity of combined gemcitabine, oxaliplatin, and pegaspargase (P-gemox) in these patients. A total of 35 patients with newly diagnosed stage III–IV, relapsed or refractory ENKTL were treated with 2 to 8 cycles of P-gemox: gemcitabine (1250 mg/m2) and oxaliplatin (85 mg/m2) injected intravenously and pegaspargase (2500 IU/m2) injected intramuscularly on day 1 and repeated every 2 weeks. Upon completion of treatment, the overall response rate was 80.0%, with a complete response in 51.4% of patients. The 1-, 2- and 3- year progression-free survival rates were 45.0%, 38.6% and 38.6%, and overall survival rates were 76.8%, 64.7% and 64.7%, respectively. Patients who attained a complete response showed better progression-free survival than those without a complete response (p = 0.01). The major adverse effects were hematologic toxicity and liver dysfunction. Grade 3/4 leucopenia and neutropenia occurred in 40.0% of patients. No treatment-related deaths occurred. These results indicate the P-gemox regimen is a safe and effective treatment for patients with newly diagnosed advanced-stage or relapsed/refractory ENKTL. We anticipate future prospective trials will confirm the efficacy.

… Currently, for patients with relapsed/refractory ENKL, l-… in the treatment of 17 relapsed/refractory ENKL patients. Clinical … produces favorable outcomes in relapsed/refractory ENKL, and …

Simple Summary Extranodal NK/T-cell lymphoma (ENKTL) is an aggressive blood cancer with poor survival rates, particularly for patients with advanced-stage and relapsed disease. Emerging research on the genetic and molecular causes of ENKTL have revealed new potential treatment strategies. In this review, we summarize how research on the biological causes of ENKTL has translated to new targets for the treatment of ENKTL, as well as the identification of new bi-omarkers which may predict prognosis and responses to specific anti-cancer therapies and enable a personalized medicine approach towards ENKTL therapy. Abstract Extranodal NK/T-cell lymphoma (ENKTL) is an aggressive extranodal non-Hodgkin lymphoma (NHL) with poor outcomes, particularly in advanced-stage and relapsed/refractory disease. Emerging research on molecular drivers of ENKTL lymphomagenesis by next-generation and whole genome sequencing has revealed diverse genomic mutations in multiple signaling pathways, with the identification of multiple putative targets for novel therapeutic agents. In this review, we summarize the biological underpinnings of newly-understood therapeutic targets in ENKTL with a focus on translational implications, including epigenetic and histone regulatory aberrations, activation of cell proliferation signaling pathways, suppression of apoptosis and tumor suppressor genes, changes in the tumor microenvironment, and EBV-mediated oncogenesis. In addition, we highlight prognostic and predictive biomarkers which may enable a personalized medicine approach toward ENKTL therapy.

Background Pembrolizumab, a monoclonal antibody against programmed death 1 receptor (PD-1) has been shown to be efficacious in relapsed/refractory (R/R) extranodal NK/T cell lymphoma (ENKTL), with an overall response rate (ORR) up to 100% in retrospective case series 1. In R/R mature T cell lymphoma, an overall response rate of 33% has been demonstrated in a phase II study 2. In this prospective phase II study, we aim to evaluate the efficacy of pembrolizumab in patients with R/R mature T- and NK-cell lymphomas. Methods Patients with R/R mature T- and NK-cell lymphomas who failed at least one line of prior therapies were recruited. Pembrolizumab was administered at 200mg intravenously every three weeks for up to two years (35 cycles) unless there was intolerable toxicity or disease progression. PET/CT was performed after at least three cycles of treatment for response evaluation. The primary endpoints were the efficacy and safety of pembrolizumab treatment. Secondary endpoints included progression-free survival (PFS) and overall survival (OS). Response assessment was made according to published criteria 3. Survival was analyzed using Kaplan-Meier method. Statistical calculations were performed with SPSS Statistics version 28. Results ENKTL cohort: Ten women and six men at a median age of 57 (range: 41-83 years) were included. Fourteen patients had been treated with L-asparaginase-containing regimens. Ten patients (62.5%) had relapsed disease while six patients (37.5%) had refractory disease. Other relevant features included staging (I, N=3, 18.8%; II, N=3, 18.8%; IV, N=10, 62.5%). Response assessments were performed in all patients, and their best responses were as below: complete response (CR), N=7, 44%; partial response (PR), N=1, 6%; indeterminate response (IR), N=2, 13%; stable or progressive disease (SD/PD), N=6, 38%. At a median follow-up of 24 months (range 1-51 months), the median PFS was 10 months and the OS was 25 months (Figure 1). Adverse events included immunotherapy-related adverse events (IRAE) in five patients (31%), including two endocrine (one grade 1 and one grade 2 toxicity), two hepatic (both grade 2) and one gastrointestinal (grade 2). Haematological toxicity was mild with one patient having grade 1 anaemia. Mature T-cell lymphomas cohort: Four men and four women at a median age of 60 (range: 22-80 years) were included. Underlying diseases were peripheral T cell lymphoma, not otherwise specified (PTCL-NOS) (N=4, 50%), angioimmunoblastic T-cell lymphoma/PTCL with T-follicular helper phenotype (AITL/PTCL-TFH) (N=2, 25%), hepatosplenic T-cell lymphoma (HSTCL) (N=1, 12.5%) and systemic Epstein-Barr Virus (EBV)-positive T cell lymphoma of childhood (N=1, 12.5%). All patients had advanced-stage diseases (stage 3, N=1, 12.5%; stage 4, N=7, 87.5%). The median line of the prior regimens was 2 (range: 1-3). Response assessment was performed in seven patients, and their best responses were as follows: CR, N=1, 14.2%; IR, N=2, 28.4%; SD/PD, N=4, 57.1%. At a median follow-up period of nine months, the progression-free survival was 4 months and overall survival was 7 months. The only patient with a durable response was the one with systemic EBV-positive T-cell lymphoma of childhood. Toxicity included IRAE in two patients (endocrine, N=1, grade 1; pulmonary, N=1, grade 4) and haematological toxicity in three patients (37.5%) (anaemia, N=1, grade 2; neutropenia, N=1, grade 1; thrombocytopenia, N=1, grade 1). Conclusion Pembrolizumab is a safe and efficacious therapy for R/R ENKTL with potentially durable remission. In R/R mature T-cell lymphomas, the benefit of pembrolizumab treatment was limited. With the durable response observed in EBV-positive T-cell lymphoma of childhood, the use of pembrolizumab in EBV-positive T-cell lymphoma warrants further investigation. Reference: 1. Kwong YL, Chan TSY, Tan D, et al. PD1 blockade with pembrolizumab is highly effective in relapsed or refractory NK/T-cell lymphoma failing l-asparaginase. Blood 2017; 129 (17): 2437-2442 2. Barta SK, Zain J, MacFarlane AW 4 th, et al. Phase II Study of the PD-1 Inhibitor Pembrolizumab for the Treatment of Relapsed or Refractory Mature T-cell Lymphoma. Clin Lymphoma Myeloma Leuk 2019; 19(6): 356-364.e3 3. Cheson BD, Ansell S, Schwartz L, et al. Refinement of the Lugano Classification lymphoma response criteria in the era of immunomodulatory therapy. Blood 2016 Nov 24;128(21):2489-2496

Extranodal NK/T-cell lymphoma (ENKTCL) is a highly aggressive mature NK/T-cell neoplasm marked by NK-cell phenotypic expression of CD3ε and CD56. While the disease is reported worldwide, there is a significant geographic variation with its highest incidence in East Asian countries possibly related to the frequent early childhood exposure of Epstein–Barr virus (EBV) and specific ethnic–genetical background, which contributes to the tumorigenesis. Historically, anthracycline-based chemotherapy such as CHOP (cyclophosphamide, adriamycin, vincristine, and prednisone) was used, but resulted in poor outcomes. This is due in part to intrinsic ENKTCL resistance to anthracycline caused by high expression levels of P-glycoprotein. The recent application of combined modality therapy with concurrent or sequential radiation therapy for early stage disease, along with non-anthracycline-based chemotherapy regimens consisting of drugs independent of P-glycoprotein have significantly improved clinical outcomes. Particularly, this neoplasm shows high sensitivity to l-asparaginase as NK-cells lack asparagine synthase activity. Even still, outcomes of patients with advanced stage disease or those with relapsed/recurrent disease are dismal with overall survival of generally a few months. Thus, novel therapies are needed for this population. Clinical activity of targeted antibodies along with antibody–drug conjugates, such as daratumumab (naked anti-CD38 antibody) and brentuximab vedotin (anti-CD30 antibody conjugated with auristatin E), have been reported. Further promising data have been shown with checkpoint inhibitors as high levels of programmed death-ligand 1 expression are observed in ENKTCL due to EBV-driven overexpression of the latent membrane proteins [latent membrane protein 1 (LMP1) and LMP2] with activation of the NF-κB/MAPK pathways. Initial case series with programmed death 1 inhibitors showed an overall response rate of 100% in seven relapsed patients including five with a complete response (CR). Furthermore, cellular immunotherapy with engineered cytotoxic T lymphocytes targeted against LMP1 and LMP2 have shown encouraging results with durable CRs as either maintenance therapy after initial induction chemotherapy or in the relapsed/refractory setting. In this paper, we review this exciting field of novel immunotherapy options against ENKTCL that hopefully will change the treatment paradigm in this deadly disease.

TO THE EDITOR: [Abstract] The treatment outcome of relapsed or refractory extranodal natural killer (NK)/T-cell lymphoma (ENKL) is poor. Brentuximab vedotin, an anti-CD30 antibody-drug conjugate, has recently been approved for the treatment of relapsed Hodgkin's lymphoma and anaplastic large-cell lymphoma (ALCL). We report on a case of a 63-year-old man who presented with multiple skin lesions, and was diagnosed with ENKL. Since the disease was refractory to most chemotherapy drugs, we performed an analysis of the skin biopsy to evaluate marker CD30. The patient's lymphoma cells demonstrated CD30-positivity, and treatment with single-agent brentuximab vedotin was commenced as of December 2013. Following 4 cycles of single-agent brentuximab vedotin treatment, all of the skin lesions had cleared, and a [18F]-fluorodeoxyglucose (FDG)-positron emission tomography (PET)/computed tomography (CT) scan demonstrated complete remission (CR) of the disease. This study suggests that single-agent brentuximab vedotin could be effective in the treatment of CD30-positive non-Hodgkin lymphomas other than ALCL. Extranodal natural killer (NK)/T-cell lymphoma (ENKL) is an aggressive, non-Hodgkin lymphoma for which a standard therapy has not yet been established. The treatment outcomes of advanced relapsed or refractory ENKL, with conventional chemotherapy, are extremely poor [1]. Brentuximab vedotin (Seattle Genetics Inc., Bothell, WA, USA) is an anti-CD30 antibody-drug conjugate that is covalently linked, via a protease-cleavable linker, to the microtubule-disrupting agent, monomethyl auristatin E. In a phase 1 clinical trial of 45 patients with relapsed or refractory CD30-positive lymphomas, treatment with single-agent brentuximab vedotin resulted in an overall response rate (ORR) of 67% [2]. In a phase 2 clinical trial for relapsed or refractory systemic anaplastic large-cell lymphoma (ALCL), single-agent brentuximab vedotin treatment resulted in an ORR of 86%, and a complete remission (CR) rate of 57% [3]. Based on these results, brentuximab vedotin was approved by the United States Food and Drug Administration, in August 2011, for the treatment of relapsed Hodgkin's lymphoma and ALCL. In a recent phase 2 clinical trial for relapsed T-cell lymphoma, treatment with single-agent brentuximab vedotin resulted in an ORR of 41% in relapsed T-cell lymphoma and 54% in angioimmunoblastic T-cell lymphoma patients, respectively [4]. Therefore, these studies demonstrate that single-agent brentuximab vedotin treatment in non-Hodgkin lymphoma patients with tumors expressing CD30 can induce objective responses. Here, we report on a case of a 63-year-old man with refractory CD30-positive ENKL in which CR was achieved with single-agent brentuximab vedotin treatment.

Extranodal NK/T-cell lymphoma, nasal type (ENKL), is a rare lymphoma subtype of peripheral T/NK-cell lymphoma that is very common in East Asia and Latin America. Two-thirds of patients have localized disease in the nasal cavity or adjacent sites. Large retrospective studies have revealed the clinicopathologic features of ENKL patients, identified risk factors for short survival time, and developed prognostic models. Next-generation sequencing studies have provided a comprehensive list of recurrent mutations in ENKL. Since the early 2000s, disease-specific therapeutic approaches have been developed, and the standard of care for ENKL has markedly changed. Non-anthracycline-containing chemotherapy with or without radiotherapy is the current standard approach for ENKL treatment. Emerging therapies, including the use of immune checkpoint inhibitors, are being investigated.

… Efficacy of L-asparaginase with methotrexate and dexamethasone (AspaMetDex regimen) in patients with refractory or relapsing extranodal NK/T-cell lymphoma, a phase 2 study. Blood…

Natural killer (NK) cell lymphomas are rare malignancies. They are classified as extranodal NK/T-cell lymphoma, nasal type, and aggressive NK cell leukemia. NK cell neoplasms are prevalent in Asian and South American populations, but are extremely rare in the West. They can be classified clinically into nasal, non-nasal, and aggressive lymphoma/leukemia subtypes. For nasal NK cell lymphomas, combined chemotherapy and radiotherapy are indicated for stage I/II disease. Chemotherapy is the main treatment for stage III/IV nasal NK cell lymphomas, as well as the non-nasal and aggressive subtypes. Regimens containing drugs not affected by the P-glycoprotein, particularly in combination with L-asparaginase, have resulted in much improvement in treatment outcome for high-risk, refractory or relapsed patients. Autologous or allogeneic hematopoietic stem cell transplantation should be considered for selected patients. Epstein-Barr virus DNA load as a surrogate marker for prognostication, and clinical stratification of patients should be incorporated in clinical management algorithms.

Natural killer (NK)/T-cell lymphomas arise mainly from NK-cells and occasionally T-cells, and are universally infected with Epstein Barr virus (EBV). They are uncommon lymphomas more prevalent in Asian and Central/South American populations. NK/T-cell lymphomas are clinically aggressive and predominantly extranodal. The most commonly involved sites are the nasal cavity, followed by non-nasal sites including the skin, gastrointestinal tract and testis. The diagnosis of extranodal NK/T-cell lymphoma is established with histological and immunohistochemical examination, together with the demonstration of EBV in the tumour cells. Staging by positron emission tomography computed tomography is essential to inform the optimal management. Plasma EBV DNA quantification should be performed as it serves as a marker for prognostication and treatment response. Survival outcomes of patients with early-stage disease are good following treatment with nonanthracycline based chemotherapy, together with sequential/concurrent radiotherapy. For advanced-stage disease, asparaginase-containing regimens are mostly used and allogeneic haematopoietic stem cell transplantation should be considered for those at high risk of relapse. Salvage chemotherapy is largely ineffective for relapsed/refractory disease, which has a grave prognosis. Novel therapeutic approaches including immune check-point blockade, EBV-specific cytotoxic T-cells, and monoclonal antibodies are being investigated to improve outcomes for those with high risk and relapsed/refractory disease.

We aimed to define the clinical features, outcome, and prognostic factors for extranodal NK/T‐cell lymphoma (ENKTL) patients in Taiwan.

Although classical Hodgkin lymphoma (cHL) is usually curable, 20–30% of the patients experience treatment failure and most of them are typically treated with salvage chemotherapy and autologous stem cell transplantation (autoSCT). However, 45–55% of that subset further relapse or progress despite intensive treatment. At the advanced stage of the disease course, recently developed immunotherapeutic approaches have provided very promising results with prolonged remissions or disease stabilization in many patients. Brentuximab vedotin (BV) has been approved for patients with relapsed/refractory cHL (rr-cHL) who have failed autoSCT, as a consolidation after autoSCT in high-risk patients, as well as for patients who are ineligible for autoSCT or multiagent chemotherapy who have failed ≥ two treatment lines. However, except of the consolidation setting, 90–95% of the patients will progress and require further treatment. In this clinical setting, immune checkpoint inhibitors (CPIs) have produced impressive results. Both nivolumab and pembrolizumab have been approved for rr-cHL after autoSCT and BV failure, while pembrolizumab has also been licensed for transplant ineligible patients after BV failure. Other CPIs, sintilimab and tislelizumab, have been successfully tested in China, albeit in less heavily pretreated populations. Recent data suggest that the efficacy of CPIs may be augmented by hypomethylating agents, such as decitabine. As a result of their success in heavily pretreated disease, BV and CPIs are moving to earlier lines of treatment. BV was recently licensed by the FDA for the first-line treatment of stage III/IV Hodgkin lymphoma (HL) in combination with AVD (only stage IV according to the European Medicines Agency (EMA)). CPIs are currently being evaluated in combination with AVD in phase II trials of first-line treatment. The impact of BV and CPIs was also investigated in the setting of second-line salvage therapy. Finally, combinations of targeted therapies are under evaluation. Based on these exciting results, it appears reasonable to predict that an improvement in survival and a potential increase in the cure rates of cHL will soon become evident.

The regulation of gene transcription by epigenetic modifications is closely related to many important life processes and is a hot research topic in the post-genomic era. Since the emergence of international epigenetic research in the 1990s, scientists have identified a variety of chromatin-modifying enzymes and recognition factors, and have systematically investigated their three-dimensional structures, substrate specificity, and mechanisms of enzyme activity regulation. Studies of the human tumor genome have revealed the close association of epigenetic factors with various malignancies, and we have focused more on mutations in epigenetically related regulatory enzymes and regulatory recognition factors in lymphomas. A number of studies have shown that epigenetic alterations are indeed widespread in the development and progression of lymphoma and understanding these mechanisms can help guide clinical efforts. In contrast to chemotherapy which induces cytotoxicity, epigenetic therapy has the potential to affect multiple cellular processes simultaneously, by reprogramming cells to achieve a therapeutic effect in lymphoma. Epigenetic monotherapy has shown promising results in previous clinical trials, and several epigenetic agents have been approved for use in the treatment of lymphoma. In addition, epigenetic therapies in combination with chemotherapy and/or immunotherapy have been used in various clinical trials. In this review, we present several important epigenetic modalities of regulation associated with lymphoma, summarize the corresponding epigenetic drugs in lymphoma, and look at the future of epigenetic therapies in lymphoma.

T cells play a vital role in the immune responses against tumors. Costimulatory or coinhibitory molecules regulate T cell activation. Immune checkpoint inhibitors, such as programmed cell death protein 1 (PD-1) and programmed death ligand 1 (PD-L1) have shown remarkable benefits in patients with various tumor, but few patients have displayed significant immune responses against tumors after PD-1/PD-L1 immunotherapy and many have been completely unresponsive. Thus, researchers must explore novel immune checkpoints that trigger durable antitumor responses and improve clinical outcomes. In this regard, other B7 family checkpoint molecules have been identified, namely PD-L2, B7-H2, B7-H3, B7-H4 and B7-H6. The aim of the present article was to address the expression, clinical significance and roles of B7 family molecules in lymphoma, as well as in T and NK cell-mediated tumor immunity. B7 family checkpoints may offer novel and immunotherapeutic strategies for patients with lymphoma.

Simple Summary Immune checkpoint inhibitors (ICI) are important options in the treatment of cancers. In hematological malignancies, classical Hodgkin lymphoma, primary mediastinal B-cell lymphoma, NK/T-cell lymphoma, immune-privileged site large B-cell lymphoma, and cutaneous T-cell lymphomas have been shown to be sensitive to ICI in variable proportions. The combination of ICI with conventional chemotherapy and other targeting molecules holds promise in further increasing efficacy and extending the disease spectrum in the management of hematological malignancies.

Epigenetic priming with DNMT inhibitors triggers a viral mimicry response that activates interferon signaling and remodels the tumor microenvironment, thereby potentiating anti−PD-1 therapy in NK/T-cell lymphoma.

Extranodal NK/T-cell lymphoma (ENKTCL) is the most common subtype of T/NK-cell lymphoma in Asia and Latin America, but very rare in North American and Europe. Patient survival has improved significantly over the past two decades. However, standard treatment has not yet been established, although dozens of prospective trials have been conducted. To help understand how the treatment of ENKTCL has evolved in the past and what trends lie ahead, we have comprehensively reviewed the treatment of this aggressive malignancy, with a particular focus on neglected or unanswered issues, such as the optimal staging method, the best partner of asparaginase (Asp), the individualized administration of Asp, the preferred sequence of CT and RT and so on. Overall, the 5-year overall survival (OS) of patients with Ann Arbor stage I/II disease increased from < 50% in the early 20th century to > 80% in recent years, and the median OS of patients with Ann Arbor stage III/IV disease increased from < 1 year to more than 3 years. The improvement in patient survival is largely attributable to advances in radiation technology and the introduction of Asp and anti-PD-1/PD-L1 immunotherapy into practice. Radiotherapy is essential for patients with early-stage disease, while Asp-based chemotherapy (CT) and PD-1/PD-L1 inhibitors significantly improved the prognosis of patients with advanced-stage disease. ENKTCL management is trending toward simpler regimens, less toxicity, and higher efficacy. Novel drugs, such as manufactured T cells, monoclonal antibodies, and small molecule inhibitors, are being intensively investigated. Based on the fact that ENKTCL is highly resistant to cytotoxic drugs except Asp, and aggressive CT leads to higher toxicity rather than better outcomes, we recommend it is unnecessary to expend additional resources to compare different combinations of Asp with cytotoxic agents. Instead, more efforts should be made to optimize the use of Asp and immunotherapy to maximize efficacy and minimize toxicity, explore ways to overcome resistance to Asp and immunotherapy, identify novel treatment targets, and define subpopulations who may benefit more from specific treatments.

The prognosis of patients with relapsed/refractory NK/T-cell lymphoma (NKTCL) is dismal. Immunotherapy has showed encouraging anti-tumor activity in patients with asparaginase-resistant NKTCL; however, only a portion of patients benefit and the median response duration is rather short. Treatment strategies have not been identified for immunotherapy-resistant NKTCL. We describe a patient with primary cutaneous NKTCL experienced disease progression after pegaspargase-based chemotherapy and PD-1 inhibitor (sintilimab)-based immunotherapy. Following a combined treatment of sintilimab and the HDAC inhibitor chidamide, the patient achieved a durable complete molecular response with mild toxicity. This case indicates that the combination of PD-1 inhibitor and HDAC inhibitor might be a treatment choice for immunotherapy-resistant NKTCL.

BACKGROUND Extranodal natural killer/T cell lymphoma, nasal type (ENKL) is a highly aggressive malignancy characterized by its association with Epstein-Barr virus (EBV) and extranodal involvement, which shows a poor clinical outcome. Although L-asparaginase-based chemotherapy has improved the response rates of relapsed/refractory (R/R) ENKL, relapse occurs in up to 50% of patients with disseminated disease. CASE SUMMARY Immune evasion has emerged as a critical pathway for survival in ENKL and may be effectuated via STAT3-driven upregulation of programmed cell death ligand 1 (PD-L1) or other molecular pathways. Anti-PD-1 is effective for R/R ENKL with EBV-driven upregulation of PD-L1 expression. Anti-PD-1 combined with decitabine showed positive preliminary results in a patient with R/R ENKL and resistance to anti-PD-1. CONCLUSION The treatment experience, in this case, demonstrated the potential ability of decitabine combined with PD-1 inhibitor to treat R/R ENKL, thus providing a new treatment strategy for this tumor.

Sintilimab (Tyvyt®) is a monoclonal antibody against programmed cell death protein 1 (PD-1). It could block the interaction between PD-1 and its ligands and help the anti-tumor effect of T-cells to recover. Sintilimab is developed by Innovent Biologics and Eli Lilly and Company and has been approved to treat relapsed or refractory classical Hodgkin lymphoma in patients who have undergone two or more lines of systemic chemotherapy by the National Medical Products Administration of China. Recently, sintilimab has been reported in plenty of literature and shows satisfying anti-tumor effect. Meanwhile, there are some reports showing its side effects. Overall, sintilimab has similar anti-tumor effects and a better safety profile compared to nivolumab and pembrolizumab in Hodgkin lymphoma, natural killer/T cell lymphoma and advanced non-small cell lung cancer. In this review, we aim to briefly describe the mechanisms, pharmacological characteristics, anti-tumor effects, predictive parameters of efficacy and side effects of sintilimab, providing valuable information of sintilimab for decision-making in the treatment of tumors in the future.

Cancer immunotherapies, especially immune checkpoint inhibitors (ICIs), have changed the landscape of treatment in various types of cancer ever since 2013, when cancer immunotherapy was rated as the breakthrough of the year by Science journal. Immune checkpoint proteins, such as PD-1, could facilitate tumor immune evasion by suppressing T-cell function via binding to PD-L1, which is often expressed on tumor cell surface. ICIs could release the immune break and remotivate T-cells to attack tumor cells. Due to the unique mechanism of action, ICIs have been shown to be effective in many malignancies, both solid tumors and hematologic cancers, such as melanoma, nonsmall cell lung cancer, gastric cancer, head and neck squamous cell cancer, Hodgkin lymphoma, extranodal NK/Tcell lymphoma, and so on. Moreover, there has been an avalanche of clinical trials underway in the whole pipeline of cancer treatment.

Histone deacetylase (HDAC) is one of the most characterized epigenetic modifiers, modulating chromatin structure and gene expression, which plays an important role in cell cycle, differentiation and apoptosis. Dysregulation of HDAC promotes cancer progression, thus inhibitors targeting HDACs have evidently shown therapeutic efficacy in multiple cancers. Tucidinostat (formerly known as chidamide), a novel subtype-selective HDAC inhibitor, inhibits Class I HDAC1, HDAC2, HDAC3, as well as Class IIb HDAC10. Tucidinostat is approved in relapsed or refractory (R/R) peripheral T-cell lymphoma (PTCL), advanced breast cancer and R/R adult T-cell leukemia-lymphoma (ATLL). Compared with other HDAC inhibitors, tucidinostat shows notable antitumor activity, remarkable synergistic effect with immunotherapy, and manageable toxicity. Here, we comprehensively summarize recent advances in tucidinostat as both monotherapy and a regimen of combination therapy in both hematological and solid malignancies in clinic. Further studies will endeavor to identify more combination strategies with tucidinostat and to identify specific clinical biomarkers to predict the therapeutic effect.

Simple Summary Natural killer/T-cell lymphoma is a rare but highly aggressive cancer that is closely linked to infection with the Epstein–Barr virus. Standard chemotherapy often has limited efficacy for this disease, and many patients relapse or experience severe side effects. In recent years, immunotherapy-based treatments have expanded treatment options for this disease. This review summarizes current and emerging immunotherapy-based treatment strategies with potential relevance for this disease and highlights how combining different therapeutic approaches may help improve and prolong treatment responses. These approaches include various forms of immunotherapy and strategies that combine immunotherapy with radiotherapy or other treatments that modify the tumor microenvironment. By integrating mechanistic insights with clinical evidence, this review outlines how immunotherapy is reshaping treatment options and suggests future directions toward more durable and personalized therapies for this challenging disease.

ABSTRACT Introduction Relapsed or refractory extranodal natural killer/T-cell lymphoma (R/R ENKTL) is a rare and aggressive subtype arising from natural killer or cytotoxic T-cells, predominantly affecting the nasal cavity and paranasal sinuses, lacking a standardized therapeutic approach. Sugemalimab, a fully human, full-length anti-PD-L1 immunoglobulin G4 (IgG4) monoclonal antibody (mAb), has been investigated in a Single-Arm, Multicenter, Phase II Study (GEMSTONE-201). The results demonstrated significant efficacy, favorable tolerability, and manageable adverse reactions of sugemalimab in R/R ENKTL. This study summarizes and compares the efficacy and safety profile of sugemalimab with several other PD-1/PD-L1 inhibitors in R/R ENKTL patients. Area covered We included a Phase II study (GEMSTONE-201) of sugemalimab in R/R ENKTL. Expert opinion The clinical trials have demonstrated superior efficacy of sugemalimab, evidenced by a complete response rate (CRR) of 35.9% and an overall response rate (ORR) of 44.9%. In comparison with other immune checkpoint inhibitors (ICIs), sugemalimab shows a notably higher CRR. Additionally, sugemalimab exhibits a manageable safety profile. Further evaluation of sugemalimab is required based on its efficacy and safety in real-world patient populations. Should sugemalimab be included in medical insurance in the future, it could potentially benefit a larger number of patients with R/R ENKTL.

Key Points • Tislelizumab monotherapy showed modest efficacy in R/R mature T- and NK-cell neoplasms with some long-lasting remissions.• Tislelizumab was well tolerated and demonstrated promising efficacy in R/R mycosis fungoides and Sézary syndrome.

Summary Extranodal NK/T-cell lymphoma (ENKTL) is an aggressive lymphoma associated with Epstein–Barr virus which does not respond to conventional anthracycline-based chemotherapy. Recent multi-omics studies have identified genetic and epigenetic alterations involved in the tumor pathogenesis and enabled the characterisation of distinct molecular subtypes with therapeutic and prognostic implications. Similarly, genomic and transcriptomic studies have shed new light on the tumor microenvironment (TME) and potential interactions with the EBV-infected malignant cells, as well as their potential influence on tumor development and progression. This review provides an update on the key genetic alterations and analysis of the recurrent mutations of ENKTL, the role of EBV, epigenetic modifications and emerging molecular classifications of both the tumor and the TME. We also explore the prognostic and therapeutic applications of these new insights, and how they are beginning to reshape the current understanding and future clinical management of this difficult-to-treat disease.

ABSTRACT Introduction: Brentuximab vedotin is an antibody-drug conjugate, which combines a CD30 monoclonal antibody with the microtubule-disrupting agent monomethylauristatin E. The utility of brentuximab vedotin has been explored in a number of diseases, with a recent focus on T-cell lymphoma, particularly systemic anaplastic large-cell lymphoma (sALCL) and cutaneous T-cell lymphoma (CTCL), as well as other peripheral T-cell lymphoma (PTCL) histologies. Areas covered: This review surveys current data on the efficacy of brentuximab vedotin in T-cell lymphoma, as well as embedding it in a therapeutic context by reviewing potential competitor agents in the clinic. Data are drawn from published literature, with a focus on clinical trial data rather than preclinical studies or case reports. Expert opinion: Brentuximab vedotin has a clear clinical benefit in CTCL and sALCL, and can achieve durable responses in a number of patients. Toxicities, particularly peripheral neuropathy, may limit treatment in some patients; however, the agent is generally well tolerated. In this context, brentuximab vedotin has been globally approved for use in sALCL and certain CTCL subtypes, however, further information is required to enhance our understanding of when and in whom to best employ this agent, as well as exploring rational combinations to augment responses.

Brentuximab vedotin (BV), a potent antibody-drug conjugate, targets the CD30 antigen. Owing to the remarkable efficacy shown in CD30-positive lymphomas, such as Hodgkin's lymphoma and systemic anaplastic large-cell lymphoma, BV was granted accelerated approval in 2011 by the US Food and Drug Administration. Thereafter, many large-scale trials in various situations have been performed, which led to extensions of the original indication. The aim of this review was to describe the latest updates on clinical trials of BV and the in-practice guidance for the use of BV.

Introduction Extranodal natural killer/T-cell lymphoma (ENKTL) is a unique lymphoma associated with Epstein-Barr virus infection. It is more common in Asia than in the Western. The prognosis is usually poor, especially in advanced disease, and no standard treatment exists. Brentuximab vedotin (BV) is a drug-conjugated monoclonal antibody which targets the cell-membrane protein CD30 linked to the potent anti-tubulin agent. Due to frequent expression of CD30 in ENKTL, we investigated the safety and efficacy of BV in combination with methotrexate, L-asparaginase, and dexamethasone (B-MAD) as frontline treatment in Thai patients with ENKTL. Methods The Thai Lymphoma Study Group conducted a prospective, multicenter phase I/II study and enrolled patients aged 18-60 years with newly diagnosed ENKTL between December 2018 and December 2021 from 9 hospitals in Thailand. Patients with localized ENKTL (stage I/II) received concurrent weekly cisplatin and involved-field radiation (IFRT) 40-50 Gy, followed by 3 cycles of B-MAD. Patients with advanced ENKTL (stage III/IV) received only B-MAD for 6 cycles. BV in combination with standard dose MAD chemotherapy was given every 21 days. The primary objective was to determine the safety and optimal dose of BV in B-MAD regimen using a 3+3 dose escalation design. The secondary objective was to evaluate the overall response rate (ORR) at the end of B-MAD treatment, safety, progression-free survival and overall survival. An analysis was performed at the data cutoff date of June 30, 2023. Results Thirty-four patients (pts.) were enrolled; 23 had localized and 11 had advanced diseases. The median age was 42 years (range, 18-59). Four pts. in the localized group did not receive B-MAD due to disease progression during concurrent cisplatin and IFRT (n=3) and consent withdrawal (n=1). Six pts. received B-MAD in phase I study (3 pts. at 1.2 mg/kg and 3 pts. at 1.8 mg/kg of BV). No dose-limiting toxicity was observed among six patients, therefore the recommended dose of BV in phase II study was 1.8 mg/kg. Of 30 evaluable pts., 20 (66.7%) achieved complete response (CR), 5 (16.7%) had partial response, and 5 (16.7%) progressed after treatment. The response rates (ORR/CR rate) in localized and advanced diseases were 89.5%/78.9% and 72.7%/45.5%, respectively. A total of 190 adverse events (AEs) were reported. The most common AEs were anemia 19/190 (10%), leukopenia 9/190 (4.7%), neutropenia 9/190 (4.7%), hypoalbuminemia 9/190 (4.7%), peripheral neuropathy 7/190 (3.7%), elevated ALT 7/190 (3.7%), and elevated serum creatinine level 5/190 (2.6%), respectively. Twenty-four events were classified as grade ≥ 3 including anemia (4/24), leukopenia (7/24), neutropenia (7/24), and elevated ALT (1/24), respectively. A total of 21 serious adverse events (SAEs) were reported. The causes of SAE were varied as follows: acute kidney injury 2/21, pneumonia 2/21, leukopenia 1/21, neutropenia 1/21, and thrombocytopenia 1/21. Most of the SAEs were suspected to be related to the treatment. Two cases of acute kidney injury related to methotrexate and one case of hypersensitivity reactions to L-asparaginase were reported as SAEs. They were manageable and completely resolved upon follow-up. There were no treatment-related deaths. At the data cutoff date, after the median follow up of 11.6 months, 25 pts. were alive, 7 experienced progressions, and 5 had died. Two pts. had progression in the central nervous system. Conclusion Treatment with standard-dose of BV in combination with MAD chemotherapy was well tolerated and showed encouraging efficacy in patients with newly diagnosed ENKTL. Evaluation of long-term survival data is ongoing. (ClinicalTrials.gov identifier: NCT03246750)

… NK/T cell lymphoma to brentuximab vedotin and bendamustine. a Angiocentricity in the lymphoma, with … d Positron emission tomography after three courses of brentuximab vedotin and …

Peripheral T-cell lymphoma (PTCL) is an extensive class of heterogeneous diseases with dismal outcomes. Brentuximab vedotin (BV) is an antibody–drug conjugate (ADC) comprising a CD30-directed antibody. This review aimed to evaluate the efficacy and safety of BV for treating PTCL. We searched the PubMed, Embase, Cochrane Library, and Web of Science databases for studies evaluating the efficacy of BV alone or in combination with other drugs for treating PTCL. The primary outcome measures included objective response rate (ORR), complete remission (CR), progression-free survival (PFS), and overall survival (OS). The secondary outcomes included 5-year OS, 5-year PFS, and adverse events. 22 studies involving 1137 patients were included. These studies reported the use patterns of BV, ORR, CR, PFS, OS, and adverse events. The pooled ORR and CR rates were 68% (95% CI: 59%–75%) and 43% (95% CI: 34%–53%). For survival outcomes, the longest median PFS was 8.3 months, and the longest median OS was 26.3 months. The most common adverse event was peripheral neuropathy and neutropenia. The analysis suggested that BV alone or in combination with other drugs improved the response and survival rates in PTCL patients and was associated with tolerable adverse effects.

Brentuximab vedotin (BV) and lenalidomide (Len) demonstrate independent activity in peripheral T cell lymphoma (PTCL) and cutaneous T cell lymphoma (CTCL). This study evaluated the efficacy and safety of this combination at reduced doses. This phase II trial enrolled 26 patients (table 1) with relapsed/refractory PTCL/CTCL. CD30 positivity was not required, and prior BV treatment was not exclusionary. Patients were treated with BV 1.2 mg/kg IV q3weeks and Len 20 mg PO daily. Len was reduced to 10 mg due to tolerability. The primary endpoint was overall response rate (ORR). Enrolled patients had a median age of 60 (37-90), 18 were male (69%), and had a median of 4.5 prior lines of therapy (1-9). Thirteen patients (50%) were diagnosed with mycosis fungoides, 8 with PTCL (31%), 3 with Sezary syndrome (12%), and 2 with CD30+ lymphoproliferative disorder (8%). The mean CD30 percent positivity was 7.5% (1-75%); CD30 was negative in 4 patients (18%). Five patients achieved complete response (2 CTCL, 3 PTCL), four achieved partial response (3 CTCL, 1 PTCL), and ten had stable disease (all CTCL). The ORR was 27.8% (5/18) for CTCL and 50% (4/8) for PTCL. Nineteen patients experienced grade 3 or higher adverse events, the most common of which were neutropenia (19.2%), lymphopenia, rash, fatigue, and abdominal pain (11.5% each) Patients came off treatment most commonly for progression (54%) and adverse events (23%). This combination demonstrated efficacy that was comparable to each agent when used as monotherapy. After reducing the Len dose to 10 mg, the combination had toxicity similar when compared to monotherapy at FDA approved dosing, although hematologic toxicity may be slightly higher. Including patients who were CD30 negative (4 patients, 18%) and having a relatively low median CD30 positivity at 7.5% may explain the lack of substantial improvement in efficacy over monotherapy with either agent. The trial was terminated early because of poor accrual.

Background: CD30-expressing peripheral T-cell lymphoma (PTCL) may have a particularly poor prognosis. Post-treatment recurrence rates in PTCL are alarmingly high, reaching 75%, with short median progression-free survival (PFS) and overall survival (OS). Consequently, numerous studies now focus on optimizing and enhancing anthracycline-based regimens, particularly through the significant ECHELON-2 trial. This trial compared brentuximab vedotin(BV) combined with CHP (A+CHP) against CHOP, showing a 5-year PFS of 51% and a 5-year OS of 70%. However, these results predominantly involved patients with ALCL. Other subtypes are limited. Therefore, novel first-line treatment strategies and post-remission consolidation/maintenance regimens for PTCL are urgently required. Chidamide is a novel histone deacetylase inhibitor. Pre-clinical mouse models have shown that BV and chidamide act synergistically, increasing the efficacy of treatment of xenograft tumors derived from HH lymphoma cells. However, there are few real-world reports on the efficacy and safety of the combination of BV and chidamide in treating patients with PTCL. Aims: This study aimed to evaluate the safety and efficacy of the combined use of BV and chidamide in the treatment of CD30-positive PTCL. Methods: Patients was received BV combined with chemotherapy (first line or the second or above-line regimen) for 4 cycles, then BV combined with adjust dose of chemotherapy for 2 cycles, followed by chidamide 20mg two times per week as maintenance treatment. 41 patients between February 2021 and July 2024 in our center with histologically confirmed PTCL (CD30 was positive) were enrolled, with a median follow-up of 23.2 months (range, 5-51 months). We evaluate the efficacy and safety of this strategy. Results: A total of 41 patients were enrolled. Of these, 23 were male（56.0%) and 18 were female（43.9%), with a median age of 58 (35-79) years. The clinical characteristics included ALCL 7 (17%), AITL 24 (58.5), PTCL（NOS）4 (9.8%), and NK/T 6 (14.6%). Thirty-seven patients (90.2%) had advanced-stage PTCL, 31 (75.6%) were classified as high risk, 90.2% had extra-nodal involvement, and 70.7% had EB virus infection. Thirty-three patients (80.5%) received BV combined with chidamide therapy as the first-line treatment, while 8 (19.5%) were classified as relapsed/refractory and received the treatment as second or above-line therapy. The first-line treatment group showed an ORR of 87.9% with a CRR of 75.8%. Patients receiving second or above-line treatment had an ORR of 37.5% and CRR of 12.5%. Three patients died from disease progression, one patient died from pneumonia resulting from COVID-19, and one patient died following myocardial infarction. Further analysis revealed that the two-year PFS and OS values of the first-line treatment group were significantly better (PFS 66.7% , OS 76.9%). No differences in ORR were observed between the different patient subtypes in the first-line therapy group（100% vs. 85.6% vs. 80.0% vs. 100%, p=0.373). One patient in the ATIL subgroup achieved PR during the first four cycles of BV-chemotherapy, changing to CR after combined treatment with chidamide. Of the five patients who were infected with EB virus infection, the viral load decreased to normal during the first three cycles, while in two patients with lymphoma progression and EB infection, the viral load remained high. No patients showed hemophagocytic syndrome. In terms of treatment-related side effects, the incidence of any adverse event was 28 (87.5%) , of whom 9 patients (21.9%) had grade III or above disease. In terms of these side effects, 15.9% of patients had neutropenia, 9.4% had anemia, 18.8% had thrombocytopenia, and 3.1% had pneumonia. Two patients required blood transfusions. Only 1 patient delayed treatment because of the side effects. Conclusion: In conclusion, Brentuximab vedotin combined with chemotherapy and chidamide as a maintenance treatment is both safe and effective for the treatment of PTCL. Similar results were found in different patient subtypes. Patients who received this treatment as first-line therapy had better ORR, CRR, and PFS. The adverse effects were relatively benign and controllable. Nevertheless, further follow-up is required to determine the long-term efficacy and safety of this treatment strategy.

Background: CD30 is frequently expressed in Epstein-Barr virus (EBV)-infected lymphoid cells and overexpressed in EBV-positive lymphomas. This open-labeled, multi-center, and investigator-initiated phase-II study evaluated the efficacy and safety of brentuximab vedotin in patients with relapsed or refractory EBV-positive and CD30-positive lymphomas (NCT02388490).&lt;br&gt;&lt;br&gt;Methods: Twenty-five patients with relapsed or refractory EBV-positive lymphomas having CD30-positivity (≥ 1% of tumor cells) were administered with 1.8 mg/kg brentuximab vedotin intravenously every 3 weeks up to 16 cycles until disease progression. The primary endpoint was objective response rate and toxicities, duration of response (DoR), progression-free survival (PFS), and overall survival (OS) were the secondary endpoints.&lt;br&gt;&lt;br&gt;Findings: Twenty-two patients (88%), median age of 65 years, were EBV-positive mature T/NK cell neoplasms (angioimmunoblastic T-cell lymphoma, n = 10; EBV-positive peripheral T-cell lymphoma, unspecified, n = 5; extranodal NK/T-cell lymphoma, nasal type, n = 4; and others, n = 3). Most patients (90%) had initial stage III/IV and 15 (60%) received ≥2 prior regimens. The objective response rate was 48% (90% CI, 31·0% to 64·3%; 12 of 25 patients), including five complete responses (20%) and seven partial responses (28%). Median DoR, PFS and OS were 10·1, 6·1, and 15·6 months, respectively. Common adverse events were peripheral neuropathy (48%), neutropenia (40%), thrombocytopenia (20%), and rashes (16%). Grade 3 and 4 adverse events were neutropenia (20%), thrombocytopenia (12%), and anemia (8%).&lt;br&gt;&lt;br&gt;Interpretation: Brentuximab vedotin is active and well tolerated in patients with relapsed or refractory EBV-positive and CD30-positive lymphomas.&lt;br&gt;&lt;br&gt;Trial Registration: (NCT02388490)&lt;br&gt;&lt;br&gt;Funding Statement: Takeda Pharmaceuticals Co. Ltd and Korea Health Industry Development Institute.&lt;br&gt;&lt;br&gt;Declaration of Interests: TMK received a research grant from AstraZeneca-KHIDI outside this work. DWK received travel and accommodation support for advisory board meeting attendance from Amgen and Daiichi-Sankyo outside this work. All other authors declare no competing interests. Seoul National University Hospital received grants from Alpha Biopharma, Amgen, Astrazeneca/Medimmune, Boehringer-Ingelheim, Daiichi-Sankyo, Hanmi, Janssen, Merus, Mirati Therapeutics, MSD, Novartis, ONO Pharmaceutical, Pfizer, Roche/Genentech, Takeda, TP Therapeutics, Xcovery and Yuhan.&lt;br&gt;&lt;br&gt;Ethics Approval Statement: The study was approved by the institutional review board at each participating site and written informed consent was obtained.

… Extranodal NK/T-cell lymphoma (NKTCL), nasal type, is generally associated with Epstein--Barr virus (EBV) infection, more commonly seen in Asian countries, and has extremely low …

The development of Brentuximab vedotin has opened a new era in the management of PTCL. The improved outcomes with BV-CHP versus CHOP in the ECHELON-2 trial are practice changing for common nodal CD30+ PTCLs. Questions regarding the optimal cut off of CD30 expression for BV-CHP therapy and the efficacy and safety of BV-CHP in less common subtypes of CD30+ PTCL subtypes await clarification.

ABSTRACT Introduction Peripheral T-Cell Lymphomas (PTCL) constitute a heterogeneous group of aggressive T – and natural killer (NK)-cell disorders and are associated with a poor prognosis. Frontline treatments often consist of anthracycline-based combination chemotherapy with the exception of NK-T cell lymphomas, where such combinations are ineffective due to the presence of P-glycoprotein which leads to multidrug resistance. Infectious and immune mediated side effects might be more pronounced in or unique to T-cell lymphomas due to the selection of agents which target multiple T-cell subtypes and also an immunocompromised state induced by the lymphomas themselves. Areas covered This review provides a comprehensive overview of safety considerations of treatment regimens used for peripheral T-cell lymphomas. We cover regimens used in both frontline and relapsed settings including combination chemotherapy, single agent chemotherapies and immunotherapies. Expert opinion Treatment of T-cell lymphomas often requires sequencing of several therapies due to lower efficacy of available treatment regimens in curing the disease compared to that seen in B-cell non-Hodgkin lymphomas. In addition, certain complications are more common in T-cell lymphomas due to their unique immunobiology. An understanding of these salient aspects is important for all providers who treat patients with this challenging disease group.

T cell non-Hodgkin lymphoma (T-NHL) is a rare and heterogeneous group of neoplasms of the lymphoid system. With the exception of a few relatively indolent entities, T-NHL is typically aggressive, treatment resistant, and associated with poor prognosis. Relatively few options with proven clinical benefit are available for patients with relapsed or refractory disease. Immunotherapy has emerged as a promising treatment for the management of patients with hematological malignancies. The identification of tumor antigens has provided a large number of potential targets. Therefore, several monoclonal antibodies (alemtuzumab, SGN-30, brentuximab vedotin, and mogamulizumab), directed against tumor antigens, have been investigated in different subtypes of T-NHL. In addition to targeting antigens involved in cancer cell physiology, antibodies can stimulate immune effector functions or counteract immunosuppressive mechanisms. Chimeric antigen receptor (CAR)-T cells directed against CD30 and immune checkpoint inhibitors are currently being investigated in clinical trials. In this review, we summarize the currently available clinical evidence for immunotherapy in T-NHL, focusing on the results of clinical trials using first generation monoclonal antibodies, new immunotherapeutic agents, immune checkpoint inhibitors, and CAR-T cell therapies.

Introduction Brentuximab vedotin (BV) showed high overall remission rates in refractory/relapsed classical Hodgkin’s lymphoma (HL) and systemic anaplastic large cell lymphoma (sALCL). Although the efficacy of BV has been reported in clinical trials, its efficacy as a frontline therapy in real world for patients with CD30 positive subtypes of non-Hodgkin’s lymphoma (NHL) such as peripheral T-cell lymphoma with T-follicular helper cell (TFH) phenotype (PTCL, TFH), anaplastic large-cell lymphoma (ALCL) and angioimmunoblastic T-cell lymphoma (AITL) in China has not been well documented. Methods Analysis of a real-world, observational, retrospective case series in patients suffering from AITL, sALCL and peripheral T-cell lymphoma with T-follicular helper phenotype (PTCL-TFH) and other types of PTCL treated with BV in frontline treatment was conducted. The patients were given treatment from May 2020 till June 28, 2021. All patients were pathologically diagnosed to have PTCL before treatment and expressed CD30. Patients received BV (1.8 mg/kg) combined with CEP (cyclophosphamide, epirubicin, prednisone acetate every 3 weeks). The primary endpoint was objective response rates (ORR), and secondary endpoints were duration of response and incidence of adverse events (AEs). Exploratory endpoints such as progression-free survival (PFS) are discussed even though after such a short period. Results Nineteen patients completed ≥ 1 cycles of BV-CEP treatment (16 cases completed ≥ 4 cycles, 3 cases only completed 1 cycle). Among them, the ORR reached 89.5% [CR 52.7%; partial response (PR) 36.8%]. In the ALCL group, CR reached 100% with the median duration of response of up to 8 months, while in the AITL group, the ORR was 75% and 2 patients had disease progression after treatment with BV + CEP. We also observed that BV-CEP may extend the PFS compared to traditional chemotherapy such as the CHOEP regimen (BV-CEP: not evaluable, CHOEP: 6.5 months), although the median follow-up was only 6.7 months. Adverse events (AEs), including incidence and severity of febrile neutropenia (26% patients in the BV-CEP group and 30% in the CHOEP group), were similar between groups. There was no incidence of AEs leading to treatment withdrawal or death under BV-CEP treatment. Conclusion BV is a promising treatment in patients with ALCL, AITL and PTCL-TFH in frontline treatment settings.

Natural killer/T-cell lymphoma (NKTL) is a sub-type of Epstein–Barr virus (EBV)-related non-Hodgkin lymphomas common in Asia and Latin America but rare elsewhere. Its pathogenesis is complex and incompletely understood. Lymphoma cells are transformed from NK- or T-cells, sometimes both. EBV-infection and subsequent genetic alterations in infected cells are central to NKTL development. Hemophagocytic syndrome is a common complication. Accurate staging is important to predict outcomes but there is controversy which system is best. More than two-thirds of NKTL lympohmas are localized at diagnosis, are frequently treated with radiation therapy only and have 5-year survival of about 70 percent. Persons with advanced NKTLs receive radiation therapy synchronously or metachronously with diverse multi-drug chemotherapy typically including l-asparginase with 5-year survival of about 40 percent. Some persons with widespread NKTL receive chemotherapy only. There are few data on safety and efficacy of high-dose therapy and a haematopoietic cell autotransplant. Immune therapies, histone deacetylase (HDAC)-inhibitors and other drugs are in early clinical trials. There are few randomized controlled clinical trials in NKTLs and no therapy strategy is clearly best; more effective therapy(ies) are needed. Some consensus recommendations are not convincingly evidence-based. Mechanisms of multi-drug resistance are considered. We discuss these issues including recent advances in our understanding of and therapy of NKTLs.

… Extranodal NK/T-cell lymphoma, nasal type, includes cases of natural killer cell and alphabeta, gammadelta, and alphabeta/gammadelta T-cell origin: a comprehensive …

Purpose The treatment outcome of brentuximab vedotin (BV) has not been related with CD30 expression in previous studies enrolling patients with a wide range of CD30 expression level. Thus, this study explored the efficacy of BV in high-CD30–expressing non-Hodgkin lymphoma (NHL) patients most likely to benefit. Materials and Methods This phase II study (Clinicaltrials.gov: NCT02280785) enrolled relapsed or refractory high-CD30–expressing NHL, with BV administered intravenously at 1.8 mg/kg every 3 weeks. The primary endpoint was > 40% disease control rate, consisting of complete response (CR), partial response (PR), or stable disease. We defined high CD30 expression as ≥ 30% tumor cells positive for CD30 by immunohistochemistry. Results High-CD30-expressing NHL patients (n=33) were enrolled except anaplastic large cell lymphoma. The disease control rate was 48.5% (16/33) including six CR and six PR; six patients (4CR, 2PR) maintained their response over 16 completed cycles. Response to BV and survival were not associated with CD30 expression levels. Over a median of 29.2 months of follow-up, the median progression-free and overall survival rates were 1.9 months and 6.1 months, respectively. The most common adverse events were fever (39%), neutropenia (30%), fatigue (24%), and peripheral sensory neuropathy (27%). In a post-hoc analysis for the association of multiple myeloma oncogene 1 (MUM1) on treatment outcome, MUM1-negative patients showed a higher response (55.6%, 5/9) than MUM1-positive patients (13.3%, 2/15). Conclusion BV performance as a single agent was acceptable in terms of disease control rates and toxicity profiles, especially MUM1-negative patients.

Introduction: Cutaneous T-cell lymphoma (CTCL) is an uncommon form of non-Hodgkin lymphoma. It is often untreatable, particularly at advanced stages or when it has proven refractory to repeated treatments. Recent research on CTCL has demonstrated promising results in treating the condition with brentuximab vedotin (BV) which is newly-developed antibody-drug conjugate that targets CD30-positive cells. The current study aims to evaluate the efficacy and safety of BV relative to standard therapy (ST) in the treatment of CTCL. Methods: The PubMed, Embase, and Cochrane Library were systematically searched to identify randomized controlled trials (RCTs) comparing BV versus ST in patients with CTCL. Key outcomes include overall response rate lasting for 4 or more months (ORR), complete response rate (CRR), mean progression-free survival (PFS), and overall survival rate (OS). The safety outcome measures included all-cause mortality and the incidence and remission of peripheral neuropathy (PN). Data were pooled using a random-effects model. Statistical heterogeneity was assessed using the I² statistic. A sensitivity analysis was performed for I² greater than 50% by excluding Barta et al., which was consistently identified as a source of heterogeneity due to differing effect estimates. Odds ratio (OR) and mean difference (MD) were reported for dichotomous and continuous outcomes, respectively. Results: We included four RCTs: Barta et al. (2024), Dummer et al. (2020), Kim et al. (2021), and Horwitz et al. (2021), which together comprised a total of 659 patients. ORR, CRR, and mean PFS were reported in 3 studies, and OS was reported in only 2 studies. The efficacy analysis revealed a higher ORR with BV compared to ST with high heterogeneity (I² = 78%). After sensitivity analysis, the pooled ORR analysis demonstrated a consistent direction of effect with no heterogeneity (OR 1.82; 95% CI 1.05–3.17; I² = 0%), although the p-value remained insignificant (p = 0.89). Similarly, we also observed longer mean PFS with BV but with very high heterogeneity (I²=98%). Sensitivity analysis again removed heterogeneity (MD 12.58 months; 95% CI 10.39–14.78, I² = 0%) but retained a non-significant p-value (p = 0.61). CRR also favored BV with high heterogeneity initially (I² = 72%) that resolved after excluding Barta et al. (OR 16.13; 95% CI 3.00–86.68, I² = 0%); though the p-value remained non-significant (p = 0.73). Lastly, a similar trend was observed with the three-year OS, with improved heterogeneity observed after the sensitivity analysis (OR 5.50; 95% CI 5.31–5.68, I² = 0%) but an insignificant p-value (p = 0.38). Upon assessing safety outcomes, we identified no statistically significant difference in all-cause mortality between BV and ST (OR 0.52; 95% CI 0.19–1.41, I² = 77%). BV was associated with a substantially higher risk of PN (OR 33.45; 95% CI 16.43–68.09; p = 0.84; I² = 0%), but among those who developed PN, resolution rates were similar (OR 1.00; 95% CI 0.18–5.57; p = 0.51; I² = 0%); however, this finding is severely limited by the small sample size of the control group (N=6). Conclusion: Although the CI excluded the null value, the p-value remained above the conventional threshold for significance, most likely due to the limited number of included studies and small sample size. Our findings suggest a potential treatment benefit; however, they should be interpreted cautiously. Thus, we suggest further large-scale trials to validate these efficacy outcomes and also identify predictors of PN and develop strategies to mitigate this adverse effect.

Abstract Background Since Food and Drug Administration approval of brentuximab vedotin in combination with cyclophosphamide, doxorubicin, and prednisone (A + CHP) as initial therapy for previously untreated CD30-expressing peripheral T-cell lymphoma (PTCL), there has been limited research on real-world patient characteristics, treatment patterns, and clinical outcomes. Methods We retrospectively analyzed claims of patients with PTCL treated with frontline A + CHP or CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) using the Symphony Health Solutions database. Adults with International Classification of Diseases-9/10 PTCL diagnosis codes who initiated A + CHP or CHOP between November 2018 and July 2021 were included. A 1:1 propensity score matching analysis was performed that adjusted for potential confounders between groups. Results A total of 1344 patients were included (A + CHP, n = 749; CHOP, n = 595). Before matching, 61% were men; median age at index was 62 (A + CHP) and 69 (CHOP) years. The most common A + CHP-treated PTCL subtypes were systemic anaplastic large cell lymphoma (sALCL; 51%), PTCL-not otherwise specified (NOS; 30%), and angioimmunoblastic T-cell lymphoma (AITL; 12%); the most common CHOP-treated subtypes were PTCL-NOS (51%) and AITL (19%). After matching, similar proportions of patients treated with A + CHP and CHOP received granulocyte colony-stimulating factor (89% vs. 86%, P = .3). Fewer patients treated with A + CHP received subsequent therapy than CHOP overall (20% vs. 30%, P < .001) and specifically with the sALCL subtype (15% vs. 28%, P = .025). Conclusions Characteristics and management of this real-world PTCL population who were older and had a higher comorbidity burden than that in the ECHELON-2 trial demonstrate the importance of retrospective studies when assessing the impact of new regimens on clinical practice.

Abstract Classical Hodgkin lymphoma (cHL) is a B-cell-derived lymphoid malignancy with the most favorable prognosis among various adult malignancies. However, once it becomes refractory disease to chemotherapy or relapses after high-dose chemotherapy (HDC) with autologous stem cell transplantation (ASCT), it is difficult to manage with conventional cytotoxic chemotherapy. The introduction of brentuximab vedotin (BV) has changed the treatment landscape of cHL in the past decade. Several studies demonstrated high efficacy of BV monotherapy in heavily treated patients with cHL relapsed or refractory after HDC/ASCT. Recent studies also reported high efficacy of concurrent or sequential combination of BV and chemotherapy in patients with transplant-eligible relapsed/refractory cHL at the second-line setting. In addition, a randomized phase III trial ECHELON-1 reported a positive result of BV in combination with AVD (doxorubicin, vinblastine, and dacarbazine) in patients with newly diagnosed advanced-stage cHL. In this review, we summarize available data of BV for cHL and discuss the current and future role of BV in the management of cHL.

vedotin to 4 weeks, as initial neuropa thy could not be excluded with certainty; otherwise, the patient did not experience any serious (> grade 2) complications like neutropaenia, sensorimotor neuropathy or infections under this treatment and presented with a good quality of life. However, 16 months after the start of brentuximab vedotin and 8 months after initiation of combination therapy, ECP was discontinued due to repetitive failure to achieve sufficient vascular access and further refusal by the patient. After discontinuation of this combined treatment, blood and skin manifestations were rapidly progres - sive and refractory to next-line treatment with bendamustine and the patient died 9 months after discontinuation of brentuximab vedotin/ECP treatment.

Combination of radiotherapy and asparaginase-based chemotherapy has drastically improved the survival outcomes for patients of early-stage extranodal NK/T-cell lymphoma (ENKTCL), with 5-year overall survival (OS) rate being 85%[1]. However, patients with advanced or relapsed/refractory ENKTCL fared poorly even in the era of asparaginase [2]. The advent of PD1 blockade provides a new prospect for the treatment of ENKTCL, as several small cohort studies have demonstrated impressive response rates and durable efficacy [3, 4]. A bunch of PD1 antibodies have been approved in treating Hodgkin lymphoma (HL), primary mediastinal large B-cell lymphoma, or ENKTCL, mainly due to high expression of PD-L1 or PD-L2 caused by either genetic alterations at chromosome 9p24. 1 (copy gain or amplification of the locus) or Epstein–Barr virus (EBV) infection [5]. Latent membrane protein 1 (LMP1), the oncogenic protein of EBV, could induce PD-L1 expression through activating NF-κB pathway in ENKTCL, and about 80% of patients with ENKTCL had PD-L1 expression in at least 5% of tumor cells [6]. Nevertheless, not all patients with positive expression of PD-L1 eventually benefit from PD1 blockade, and reliable efficacy predictive biomarkers are urgently needed to the implementation of precision medicine in ENKTCL.

… ), has been shown to target malignant lymphomas with CD30 expression. In particular, this … CD30 in ENKTL suggests anti‐CD30 antibody‐based therapy may be an effective treatment. …

At present, the treatment of lymphoma has entered the era of precision medicine, and CD30, as a transmembrane protein, has become an important marker to help the diagnosis and formulation of treatment plans for lymphomas. This protein is widely expressed in various types of lymphomas and can play a role through nuclear factor-κB (NF-κB), mitogen-activated protein kinase (MAPK), and other pathways, and ultimately lead to the up-regulation of CD30 expression to give tumor cells a survival advantage. Brentuximab vedotin (BV), as an antibody-drug conjugate (ADC) targeting CD30, is one of the first new drugs to significantly improve survival in patients with CD30+lymphomas. However, the biological function of CD30 has not been fully elucidated. Therefore, this review highlights the CD30-mediated tumor-promoting mechanisms and the molecular factors that regulate CD30 expression. We hope that a better understanding of CD30 biology will provide new insights into clinical treatment and improve the survival and quality of life of lymphoma patients.

OBJECTIVES Previous studies have been inconsistent concerning the association between the prognostic value of CD30 expression and extranodal natural killer/T-cell lymphoma (ENKTL). METHODS CD30 expression in 82 patients with newly diagnosed ENKTL (mean age, 50 years; 73.2% male) was assessed by immunohistochemistry on paraffin-embedded sections. The level of CD30 expression was categorized into negative (0%, no staining) and positive groups. RESULTS Sixty-seven cases exhibited positive CD30 expression, and the main between-group difference was the Chinese Southwest Oncology Group and Asia Lymphoma Study Group (CA) ENKTL stage and Eastern Cooperative Oncology Group (ECOG) performance status. The cutoff point for CD30 expression was 40% by restricted cubic splines analysis. The overall survival of patients with high expression (>40%) was statistically superior to negative (0%) and low-expression groups. A positive correlation was observed between CD30 and Epstein-Barr virus-encoded small RNA status (r = 0.305). Multivariable analysis suggested that positive CD30 expression (hazard ratio, 0.420 [95% CI, 0.193-0.914]; P = .029) and CA advanced stage (hazard ratio, 2.844 [95% CI, 1.371-5.896]; P = .005) were independent prognostic factors for ENKTL. CONCLUSIONS Positive CD30 expression was a favorable prognostic factor for ENKTL, and CD30 expression could restratify the survival of patients in clinical subgroups.

ABSTRACT Introduction CD30 is a transmembrane protein of the tumor necrosis factor receptor superfamily. It is expressed on a small subset of activated T and B lymphocytes, and various lymphoid neoplasms, including classical Hodgkin lymphoma and many non-Hodgkin lymphomas in both pediatric and adult populations. Areas covered This review delves into the significance of CD30 as a therapeutic target and a prognostic indicator for various lymphomas. It provides a comprehensive overview of anti-CD30 therapeutic interventions developed to date, offering insights into the future direction of lymphoma treatment research. Literature search was conducted from January 1987 to December 2024 using PubMed, Scopus, and Web of Science databases to identify relevant studies. Expert opinion CD30 has emerged as a critical marker of diagnosis, prognosis, and therapeutic strategies of lymphomas. The introduction of brentuximab vedotin (BV) (Adcetris), an antibody–drug conjugate targeting CD30, has significantly advanced the treatment landscape for multiple lymphoma types, demonstrating enhanced efficacy and manageable safety profiles in CD30+ lymphomas patients. However, drug resistance is observed in few patients. Concurrently, innovative therapeutic strategies targeting CD30, such as chimeric antigen receptor T-cells therapies and bispecific antibodies, are in development. This underscores a strong and ongoing research effort aimed at improving the management of patients with CD30+ lymphomas.

BackgroundExtranodal natural killer/T-cell lymphoma, nasal type (ENKTL), is an aggressive type of lymphoma whose standard treatment and validated prognostic model have not yet been defined.MethodsCD30 expression was detected using immunohistochemistry in 96 ENKTL patients, and the data were used to evaluate its relationship with clinical features, treatment response and prognosis.ResultsExpression of CD30 was detected in 31.2% of ENKTL patients, which was significantly correlated with B symptoms and elevated serum lactate dehydrogenase. The complete remission rate was not significantly different between CD30-positive and negative groups. After a median follow-up time of 31 months, 5-year overall survival (OS) and 5-year progression-free survival (PFS) rates in the CD30-positive group were both significantly lower than those in the CD30-negative group (34.1% vs. 64.4%, P = 0.002, for 5 year-OS; 26.0% vs. 66.7%, P < 0.001, for 5 year-PFS). In patients with an International Prognostic Index (IPI) or Korean Prognostic Index (KPI) score of 0–1, CD30 positivity was associated with shorter 5-year OS and PFS (IPI: P = 0.001 and 0.002, respectively; KPI: P = 0.018 and 0.023, respectively). In a multivariate Cox regression model, CD30 expression and stage were independent prognostic factors for OS (p = 0.004 and p = 0.012, respectively) and PFS (p = 0.001 and p = 0.022, respectively).ConclusionsOur results showed that expression of CD30 was not related to response to treatment but was an independent prognostic factor for both OS and PFS in ENKTL, nasal type, which suggests a role for CD30 in the pathogenesis of this disease and may support the incorporation of anti-CD30-targeted therapy into the treatment paradigm for ENKTL.

CD30 is a transmembrane protein from the tumour necrosis factor receptor superfamily. It is expressed on a small subset of activated T and B lymphocytes, and various lymphoid neoplasms. CD30 is a particularly interesting treatment target because its levels are high in tumours but low in healthy tissues. Several therapeutic strategies targeting CD30 have been developed, including monoclonal antibodies, conjugated antibodies (combination of brentuximab vedotin with chemotherapy or immunotherapy), bispecific antibodies and cell and gene therapies, such as anti‐CD30 CAR‐T cells in particular. We briefly review the biology of CD30 which makes it a good therapeutic target, and we describe all of the anti‐CD30 therapies that have emerged to date.

… of the target and … CD30 as a therapeutic target and the development and clinical activity of the ADC brentuximab vedotin in Hodgkin lymphoma (HL) and other B cell lymphomas…

… ) was recently introduced to treat CD30-positive lymphomas. Thus we investigated the … of CD30 expression in 72 patients with NKTCL. CD30-positive cases, defined as cases with CD30 …

Background The paradoxical reports about the prognostic value of the CD30 expression in extranodal NK/T-cell lymphoma (ENKTL) have restricted its further applications in clinical practice. To identify the common effects and the variation, we conducted this systematic review and meta-analysis. Methods PubMed, MEDLINE, Embase, and Web of Science were searched between January 1975 and 31 January 2017. The pooled hazard ratio was used to estimate the effect of the CD30 expression on overall survival. Bias was assessed by prespecified criteria referring to Reporting Recommendations for Tumor Marker Prognostic Studies and Newcastle-Ottawa Scale. Results Ten retrospective cohort studies with 310 patients are included. CD30 is associated with better overall survival significantly (HR 0.71, 95% CI 0.51 to 0.99, I2 = 0%). A greater effect is observed among studies including participants predominant in regional involvement (HR 0.31, 95%CI 0.13 to 0.76, I2 = 0%) compared with those in systemic involvement. Conclusions This study indicates that the CD30 expression is significantly associated with better prognosis in ENKTL, especially for patients with regional lymphoma involvement.

The tumor necrosis factor (TNF)‐receptor superfamily 8 receptor CD30 molecule is expressed in all tumor cells of Hodgkin lymphoma and anaplastic large cell lymphoma but is only weakly expressed in a small subset of large lymphoid cells in normal peripheral lymphoid tissues. This makes this molecule an important target for the diagnosis and treatment of CD30‐expressing lymphomas. We describe the road to the discovery of the CD30 molecule and the way CD30 has contributed to more precise diagnosis and classification of lymphomas. Moreover, we address how anti‐CD30 immunotherapy was developed and the impact of the anti‐CD30‐auristatin conjugate and anti‐CD30 CAR‐T cells in treating CD30‐expressing lymphomas.

… be important as we target CD30 for therapy, because microenvironmental targeting may affect … CD30 is strongly expressed in various lymphomas, particularly Hodgkin lymphoma and …

CONTEXT.— In the early 1980s, a monoclonal antibody termed Ki-1 was developed against a cell line derived from a patient with Hodgkin lymphoma. This antibody detected a limited number of benign activated lymphocytes in lymphoid tissue, whereas in Hodgkin lymphoma it appeared to be nearly specific for Reed-Sternberg cells and their mononuclear variants. Subsequent studies showed that Ki-1 expression defined a new type of lymphoma that was later designated anaplastic large cell lymphoma with or without anaplastic large cell kinase expression/translocation. In the past 30 years, numerous new lymphoma entities have been defined, many of which are variably positive for CD30. Many virally transformed lymphoproliferative disorders are also frequently positive for CD30. OBJECTIVE.— To illustrate the broad spectrum of CD30+ hematologic malignancies and to provide an update of CD30-targeted therapies. DATA SOURCES.— Personal experiences and published works in PubMed. CONCLUSIONS.— Because of its low expression in normal tissue, CD30 was studied as a therapeutic target for many years. However, the first functional humanized antibody against CD30 was developed only about 10 years ago. Brentuximab vedotin is a humanized anti-CD30 antibody linked to a cytotoxin, and was approved by the US Food and Drug Administration in 2012 for treating refractory Hodgkin lymphoma and anaplastic large cell lymphoma. Since then, the list of Food and Drug Administration-approved CD30-targeted hematologic malignancies has grown. Recently, the therapies using tumor antigen-specific chimeric antigen receptor T cells targeting CD30 have incited a great deal of enthusiasm and are studied in clinical trials.

… Brentuximab vedotin (BV) is an important targeted therapy which consists of toxin (… remission less than 12 months, or extranodal disease at the time of salvage therapy [61,62]. Patients …

ABSTRACT Introduction Recent studies have shown that CD30 expression can be an important feature of peripheral and cutaneous T-cell lymphomas (PTCLs and CTCLs) and CD30 testing has increased in importance with the emergence of CD30-directed therapy. Areas covered This article reviews the literature on CD30-related biology, prevalence, and therapy in patients with PTCL or CTCL. We searched the PubMed database from 1 January 2010 to 28 April 2020, using terms ‘CD30ʹ (‘peripheral T-cell lymphomas’ or ‘cutaneous T-cell lymphoma’) and ‘immunohistochemistry’ or ‘flow cytometry’ or ‘pathology,’ and synonyms including terms for T-cell lymphoma subtypes. Expert opinion CD30 is expressed at relatively high rates of prevalence across a broad range of PTCLs and CTCLs. CD30 expression may be critical to the development of a subset of PTCLs and also a biomarker for treatment choice in some subtypes. Large-scale randomized, controlled studies have shown that CD30-directed treatment with brentuximab vedotin is significantly more effective against CD30-expressing PTCL and CTCL than current standard-of-care regimens. However, accurate CD30 evaluation is limited by inconsistencies in detection methodology and expression cutoffs defining CD30-expressing disease. Greater understanding of CD30 testing and reporting will enable more patients with CD30-expressing PTCL and CTCL to be identified and treated appropriately.

… lymphoma, peripheral T-cell lymphoma, cutaneous T cell lymphoma, and even CD30-expressing B-cell lymphomas, … Prognostic implications of CD30 expression in extranodal natural …

CD30 is overexpressed in several lymphoma types, including classic Hodgkin lymphoma (cHL), some peripheral T-cell lymphomas (PTCL), and some cutaneous T-cell lymphomas. The antibody–drug conjugate brentuximab vedotin targets CD30-positive cells and has been evaluated for the treatment of various lymphoma entities. This narrative review summarizes 10 years of experience with brentuximab vedotin for the treatment of CD30-positive lymphomas, discusses novel therapies targeting CD30 in development, and highlights remaining controversies relating to CD30-targeted therapy across lymphoma types. The collective body of evidence for brentuximab vedotin demonstrates that exploitation of CD30 can provide sustained benefits across a range of different CD30-positive lymphomas, in both clinical trials and real-world settings. Preliminary experience with brentuximab vedotin in combination with immune checkpoint inhibitors for relapsed/refractory cHL is encouraging, but further exploration is required. The optimal use of brentuximab vedotin for first-line therapy of PTCL remains to be determined. Further research is required on brentuximab vedotin treatment in high-risk patient populations, and in rare lymphoma subtypes, for which no standard of care exists. Novel therapies targeting CD30 include chimeric antigen receptor therapies and bispecific antibody T-cell engagers, which may be expected to further improve outcomes for patients with CD30-positive lymphomas in the coming years.

… targeting the surface receptor CD30, which is overexpressed in HL and ALCL. Clinical studies are summarized and a comprehensive look into recent developments of antiCD30 mAb …

Simple Summary CD30 is overexpressed in many T-cell lymphomas. The antibody–drug conjugate brentuximab vedotin (BV) targets CD30-positive cells and is approved for the treatment of several lymphoma types. However, the development of resistance limits the long-term efficacy of BV. This review comprehensively summarizes the key clinical trials of BV as monotherapy and in combination with other therapies for T-cell lymphomas. Ongoing studies exploring BV combination therapies are listed, highlighting potential directions for its future application. To improve the understanding and efficacy of BV, we discuss the action mechanisms of BV in tumor cells and the tumor microenvironment. The mechanisms of resistance are also discussed to offer new insights into overcoming them, laying the groundwork for optimizing BV treatment strategies in the future.

… for CD30+ lymphomas. Unlike a systematic review, this narrative overview synthesizes recent advancements, emphasizing key therapeutic … to CD30+ cells, while targeted therapies may …

Extranodal natural killer/T‐cell lymphoma (NKTCL) is an aggressive type of lymphoma associated with Epstein–Barr virus (EBV) and characterized by heterogeneous tumor behaviors. To better understand the origins of the heterogeneity, this study utilizes single‐cell RNA sequencing (scRNA‐seq) analysis to profile the tumor microenvironment (TME) of NKTCL at the single‐cell level. Together with in vitro and in vivo models, the study identifies a subset of LMP1+ malignant NK cells contributing to the tumorigenesis and development of heterogeneous malignant cells in NKTCL. Furthermore, malignant NK cells interact with various immunocytes via chemokines and their receptors, secrete substantial DPP4 that impairs the chemotaxis of immunocytes and regulates their infiltration. They also exhibit an immunosuppressive effect on T cells, which is further boosted by LMP1. Moreover, high transcription of EBV‐encoded genes and low infiltration of tumor‐associated macrophages (TAMs) are favorable prognostic indicators for NKTCL in multiple patient cohorts. This study for the first time deciphers the heterogeneous composition of NKTCL TME at single‐cell resolution, highlighting the crucial role of malignant NK cells with EBV‐encoded LMP1 in reshaping the cellular landscape and fostering an immunosuppressive microenvironment. These findings provide insights into understanding the pathogenic mechanisms of NKTCL and developing novel therapeutic strategies against NKTCL.

T/NK-cell neoplasms represent rare and highly diverse cancers, distinguished by variability in their molecular architecture, local inflammatory milieu, and microenvironmental composition, which collectively underpin the diversity of clinical presentations and outcomes. The neoplastic tissue comprises malignant lymphoma/leukemic cells in concert with a spectrum of stromal elements and the acellular extracellular matrix (ECM), collectively constituting the lymphoma microenvironment (LME). These components engage in dynamic, reciprocal interactions, forming a self-regulating ecosystem capable of responding adaptively to both exogenous and endogenous stimuli. Historically, the LME was largely neglected in considerations of lymphomagenesis; however, emerging evidence highlights its pivotal role in driving core oncogenic processes, including sustained proliferative signaling, angiogenesis, immune evasion, and apoptotic resistance. Deciphering the intricate, multidirectional crosstalk among the cellular and acellular constituents of the T/NK-cell neoplastic microenvironment promises to deepen our understanding of disease biology and may inform the development of novel, mechanism-based therapeutic interventions.

Background Epstein–Barr virus (EBV)-positive nodal T/NK-cell lymphoma (EBV+ nTNKL) has recently been delineated in the WHO-HAEM5 classification as a distinct and exceptionally rare entity. Its biology and clinical trajectory remain obscure relative to Extranodal NK/T-cell lymphoma (ENKTL). Methods We applied spatial transcriptomics and multiplex immunofluorescence to representative ENKTL and EBV+ nTNKL specimens, integrating these data with a retrospective clinical cohort of 14 EBV+ nTNKL patients—constituting one of the largest series described to date. Results Spatial transcriptomics revealed fundamental differences between ENKTL and EBV+ nTNKL. ENKTL, of NK-cell origin, displayed higher malignant cell density, neutrophil enrichment, and an immune-desert phenotype, whereas EBV+ nTNKL, of T-cell origin, showed reduced tumor burden, B-cell enrichment, and an immune-active microenvironment with abundant cytotoxic T cells and PD-1/PD-L1 expression. Intercellular communication analyses further highlighted distinct signaling programs—TGF-β/BMP-driven tumor–neutrophil interactions in ENKTL versus CXCL/CCL–GPCR-mediated macrophage crosstalk in EBV+ nTNKL. In a retrospective cohort of 14 EBV+ nTNKL patients, the disease was frequently complicated by hemophagocytic lymphohistiocytosis and conferred significantly inferior survival, although selected patients achieved durable responses with immune checkpoint inhibitors or CAR-T therapy. Conclusion This study delineates the immunologic and molecular architectures of ENKTL and EBV+ nTNKL, providing rare insights into this understudied lymphoma. Despite limited sampling, these findings underscore the central role of EBV latency programs and tissue context in shaping tumor ecology and suggest avenues for subtype-tailored therapeutic strategies.

Purpose of review Epstein-Barr virus (EBV)-associated neoplasms derived from natural killer (NK) or T cells comprise a group of clinically and biologically heterogenous disorders affecting children and adults, which are overall rare but more prevalent in Asia and South America. This review focuses on neoplasms presenting in the adulthood, addressing recent genomic discoveries as well as therapeutic developments in these highly aggressive disorders. Recent findings Distinct molecular subtypes of extranodal NK/T-cell lymphomas (ENKTCLs) have been described, with differences in cell of origin, EBV pattern, genomic alterations, clinical characteristics, response to asparaginase-based therapies and to more recent approaches targeting molecular aberrations of the lymphoma. For the last two decades, progress in the clinical management of ENKTCL was based on L-asapraginase containing combinations and the incoroperation of radiotherapy. A subset of cases with PDL1-2 structural alterations may be more responsive to treatment with immune checkpoint inhibitors. Primary nodal EBV+ lymphomas derived from T or NK cells have distinctive features separating them from both peripheral T-cell lymphoma not otherwise specified and ENKTCL. Treatment algorithms correspond to those for advanced ENKTCL. Summary With better understanding of lymphomagenesis, genomic landscape and immunologic aspects of the diseases, future treatment options will include targeted therapies including immune checkpoint inhibitors and novel antibodies.

Rationale Natural killer/T-cell lymphoma (NKTCL) is an aggressive Epstein-Barr virus (EBV)-associated non-Hodgkin lymphoma with a poor prognosis. Recent genomic and transcriptomic studies of tumor tissues have advanced our understanding of NKTCL pathogenesis, but the systemic immune profile at initial diagnosis remains incompletely elucidated. Methods In this study, we characterized the immune landscape of peripheral blood mononuclear cells (PBMCs) from 20 newly diagnosed NKTCL patients and 12 healthy donors using single-cell RNA sequencing and confirmed our results through flow cytometry and PrimeFlow. Results We identified a distinct proliferative-NK/T (Proli-NK/T) cell subset in NKTCL, characterized by high expression of cell cycle-related genes but lacking a malignant phenotype. Additionally, we observed a reduction in total and classical memory B cells, accompanied by enrichment of apoptosis and cell differentiation signatures. NK cells showed increased expression of HLA class II and activation markers, along with enhanced predicted interactions with CD4+ T cells. The decrease of naive CD4+ T cells might imply their skewed differentiation into Th1 and Th17 cells, while expansion of granzyme K (GZMK+)-expressing CD8+ central memory T cells was associated with interferon-γ-driven responses. Patients with a high intracellular EBV load exhibited accumulation of highly cytotoxic CD56dim_PTPRCAP NK cells and GZMK+ GZMB+ CD8+ effector memory T cells, along with a marked depletion of memory B cells. This implies a correlation between intracellular EBV burden and peripheral immune dysregulation in NKTCL. Conclusions We have uncovered the dynamic changes in PBMCs of newly diagnosed NK/T cell lymphoma patients and identified specific characteristics in patients with high intracellular EBV levels. Our findings provide new insights into the immunopathogenesis of NKTCL, offering valuable information for immune-based stratification and the development of therapeutic strategies.

… with the immune checkpoint PD1 on effector T-cells to inhibit their function [24]. In EBV+ T-cell lymphomas, typically NK/T-cell lymphomas, … microenvironment beneficial to their survival. …

ABSTRACT Natural killer/T-cell lymphoma (NKTCL) is an incurable aggressive T-cell lymphoma closely correlated with Epstein‒Barr virus (EBV) infection. Chronic and consistent viral infection induces T-cell exhaustion. Herein, we describe T-cell dysfunction in NKTCL patients for the first time. Peripheral blood mononuclear cells (PBMCs) from age-matched healthy donors (HDs) and NKTCL patients were collected, and lymphocyte distributions, multiple surface inhibitory receptors (IRs), effector cytokine production and cell proliferation were determined by flow cytometry. PBMCs from HDs were cocultured with NKTCL cell lines to verify the clinical findings. IR expression was further assessed in NKTCL tumor biopsies using multiplex immunohistochemistry (mIHC). NKTCL patients have higher frequencies than HDs of inhibitory T regulatory cells (Tregs) and myeloid-derived suppressor cells (MDSCs). T-cell distribution also varies between NKTCL patients and HDs. T cells from NKTCL patients demonstrated higher expression levels of multiple IRs than HDs. Meanwhile, T-cell proliferation and interferon-γ production was significantly reduced in NKTCL patients. More importantly, the number of EBV-specific cytotoxic cells was lower in NTKCL patients, and these cells demonstrated upregulation of multiple IRs and secreted fewer effector cytokines. Interestingly, NKTCL cells caused normal PBMCs to acquire T-cell exhaustion phenotypes and induced generation of Tregs and MDSCs. In line with ex vivo finding, mIHC results showed that CD8+ T cells from NKTCL tumor biopsies expressed much higher level of IRs compared with reactive lymphoid hyperplasia individuals. The immune microenvironment of NKTCL patients exhibited T-cell dysfunction and accumulation of inhibitory cell components, which may contribute to impaired antitumor immunity.

Epstein-Barr virus (EBV) is a widely prevalent lymphotropic γ-herpesvirus, with approximately 95% of the population showing evidence of infection at some point during their lifetime. While most infections are asymptomatic or follow a self-limiting clinical course, in certain populations, EBV can lead to a range of lymphoproliferative disorders (LPDs), particularly subtypes originating from T cells and natural killer (NK) cells, which are often characterized by highly aggressive disease progression. This review aims to systematically discuss the molecular basis of EBV infection, covering its viral biological properties, regulation of the latent and lytic cycles, key viral protein functions (e.g., LMP1, LMP2A, EBNA1), miRNA regulatory mechanisms, and the activation of various host signaling pathways (such as NF-κB, PI3K-AKT, JAK-STAT) that contribute to the maintenance of latent infection, cell transformation, and immune evasion. Additionally, the review focuses on the pathogenic contributions of these mechanisms in EBV-related T/NK cell lymphoproliferative diseases. Research highlights include the in-depth analysis of virus-host genome interaction mechanisms, the identification of novel molecular biomarkers, and the development of targeted therapeutic strategies (e.g., PD-1/PD-L1 immune checkpoint inhibitors, EBV-specific T cell therapy). Through this comprehensive review, it is hoped that personalized medicine and artificial intelligence-assisted multimodal decision-making will be applied to the precise prevention and treatment of EBV-related diseases.

Primary Epstein-Barr virus (EBV)-positive nodal T/NK-cell lymphoma (PTCL-EBV) is a poorly understood disease which shows features resembling extranodal NK/T-cell lymphoma (ENKTL) and is currently not recognized as a distinct entity but categorized as a variant of primary T-cell lymphoma not otherwise specified (PTCL-NOS). Herein, we analyzed copy-number aberrations (n=77) with a focus on global measures of genomic instability and homologous recombination deficiency and performed gene expression (n=84) and EBV miRNA expression (n=24) profiling as well as targeted mutational analysis (n=16) to further characterize PTCL-EBV in relation to ENKTL and PTCL-NOS. Multivariate analysis revealed that patients with PTCL-EBV had a significantly worse outcome compared to patients with PTCL-NOS (P=0.002) but not to those with ENKTL. Remarkably, PTCL-EBV exhibited significantly lower genomic instability and homologous recombination deficiency scores compared to ENKTL and PTCL-NOS. Gene set enrichment analysis revealed that many immune-related pathways, interferon α/γ response, and IL6_JAK_STAT3 signaling were significantly upregulated in PTCLEBV and correlated with lower genomic instability scores. We also identified that NFKB-associated genes, BIRC3, NFKB1 (P50) and CD27, and their proteins are upregulated in PTCL-EBV. Most PTCL-EBV demonstrated a type 2 EBV latency pattern and, strikingly, exhibited downregulated expression of most EBV miRNA compared to ENKTL and their target genes were also enriched in immune-related pathways. PTCL-EBV also showed frequent mutations of TET2, PIK3CD and STAT3, and are characterized by microsatellite stability. Overall, poor outcome, low genomic instability, upregulation of immune pathways and downregulation of EBV miRNA are distinctive features of PTCL-EBV. Our data support the concept that PTCL-EBV could be considered as a distinct entity, provide novel insights into the pathogenesis of the disease and offer potential new therapeutic targets for this tumor.

While Epstein-Barr virus (EBV) was initially discovered and characterized as an oncogenic virus in B cell neoplasms, it also plays a complex and multifaceted role in T/NK cell lymphomas. In B cell lymphomas, EBV-encoded proteins have been shown to directly promote immortalization and proliferation through stimulation of the NF-κB pathway and increased expression of anti-apoptotic genes. In the context of mature T/NK lymphomas (MTNKL), with the possible exception on extranodal NK/T cell lymphoma (ENKTL), the virus likely plays a more diverse and nuanced role. EBV has been shown to shape the tumor microenvironment by promoting Th2-skewed T cell responses and by increasing the expression of the immune checkpoint ligand PD-L1. The type of cell infected, the amount of plasma EBV DNA, and the degree of viral lytic replication have all been proposed to have prognostic value in T/NK cell lymphomas. Latency patterns of EBV infection have been defined using EBV-infected B cell models and have not been definitively established in T/NK cell lymphomas. Identifying the expression profile of EBV lytic proteins could allow for individualized therapy with the use of antiviral medications. More work needs to be done to determine whether EBV-associated MTNKL have distinct biological and clinical features, which can be leveraged for risk stratification, disease monitoring, and therapeutic purposes.

In this study, we utilized next-generation sequencing data from 7 different studies of peripheral T-cell lymphoma (PTCL) patient samples to globally assess viral associations, provide insights into the contributions of EBV gene expression to the tumor phenotype, and assess the unique roles of EBV in modulating the immune cell tumor microenvironment. These studies revealed potential roles for EBV replication genes in some PTCL subtypes, the possible role of additional human tumor viruses in rare cases of PTCLs, and a role for EBV in providing a unique immune microenvironmental niche in one subtype of PTCLs. Together, these studies provide new insights into the understudied role of tumor viruses in PTCLs. ABSTRACT Certain peripheral T-cell lymphomas (PTCLs) have been associated with viral infection, particularly infection with Epstein-Barr virus (EBV). However, a comprehensive virome analysis across PTCLs has not previously been reported. Here we utilized published whole-transcriptome RNA sequencing (RNA-seq) data sets from seven different PTCL studies and new RNA-seq data from our laboratory to screen for virus association, to analyze viral gene expression, and to assess B- and T-cell receptor diversity paradigms across PTCL subtypes. In addition to identifying EBV in angioimmunoblastic T-cell lymphoma (AITL) and extranodal NK/T-cell lymphoma (ENKTL), two PTCL subtypes with well-established EBV associations, we also detected EBV in several cases of anaplastic large-cell lymphoma (ALCL), and we found evidence of infection by the oncogenic viruses Kaposi’s sarcoma-associated herpesvirus and human T-cell leukemia virus type 1 in isolated PTCL cases. In AITLs, EBV gene expression analysis showed expression of immediate early, early, and late lytic genes, suggesting either low-level lytic gene expression or productive infection in a subset of EBV-infected B-lymphocyte stromal cells. Deconvolution of immune cell subpopulations demonstrated a greater B-cell signal in AITLs than in other PTCL subtypes, consistent with a larger role for B-cell support in the pathogenesis of AITL. Reconstructed T-cell receptor (TCR) and B-cell receptor (BCR) repertoires demonstrated increased BCR diversity in AITLs, consistent with a possible EBV-driven polyclonal response. These findings indicate potential alternative roles for EBV in PTCLs, in addition to the canonical oncogenic mechanisms associated with EBV latent infection. Our findings also suggest the involvement of other viruses in PTCL pathogenesis and demonstrate immunological alterations associated with these cancers. IMPORTANCE In this study, we utilized next-generation sequencing data from 7 different studies of peripheral T-cell lymphoma (PTCL) patient samples to globally assess viral associations, provide insights into the contributions of EBV gene expression to the tumor phenotype, and assess the unique roles of EBV in modulating the immune cell tumor microenvironment. These studies revealed potential roles for EBV replication genes in some PTCL subtypes, the possible role of additional human tumor viruses in rare cases of PTCLs, and a role for EBV in providing a unique immune microenvironmental niche in one subtype of PTCLs. Together, these studies provide new insights into the understudied role of tumor viruses in PTCLs.

Natural killer (NK)/T-cell lymphomas are aggressive malignancies with a predilection for Asian and South American populations. Epstein–Barr virus (EBV) infection in lymphoma cells is universal. Predominantly extranodal, NK/T-cell lymphomas are divided clinically into nasal (involving the nose and upper aerodigestive tract), non-nasal (involving the skin, gastrointestinal tract, testes, and other organs), and aggressive leukaemia/lymphoma (involving the marrow and multiple organs) subtypes. Initial assessment should include imaging with positron emission tomography computed tomography (PET/CT), quantification of plasma EBV DNA as a surrogate marker of lymphoma load, and bone marrow examination with in situ hybridization for EBV-encoded small RNA. Prognostication can be based on presentation parameters (age, stage, lymph node involvement, clinical subtypes, and EBV DNA), which represent patient factors and lymphoma load; and dynamic parameters during treatment (serial plasma EBV DNA and interim/end-of-treatment PET/CT), which reflect response to therapy. Therapeutic goals are to achieve undetectable plasma EBV DNA and normal PET/CT (Deauville score ≤ 3). NK/T-cell lymphomas express the multidrug resistance phenotype, rendering anthracycline-containing regimens ineffective. Stage I/II nasal cases are treated with non-anthracycline asparaginase-based regimens plus sequential/concurrent radiotherapy. Stage III/IV nasal, and non-nasal and aggressive leukaemia/lymphoma cases are treated with asparaginase-containing regimens and consolidated by allogeneic haematopoietic stem cell transplantation (HSCT) in suitable patients. Autologous HSCT does not improve outcome. In relapsed/refractory cases, novel approaches comprise immune checkpoint blockade of PD1/PD-L1, EBV-specific cytotoxic T-cells, monoclonal antibodies, and histone deacetylase inhibitors. Future strategies may include inhibition of signalling pathways and driver mutations, and immunotherapy targeting the lymphoma and its microenvironment.

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Epstein Barr virus positive T/NK lymphoproliferative disorders (EBV-TNKLPD) comprise a spectrum of neoplasms ranging from cutaneous lymphoid proliferations to aggressive lymphomas. The spectrum includes extranodal NK/T-cell lymphoma (ENKTL), aggressive NK-cell leukemia, and a group of EBV-TNKLPDs affecting children which are poorly characterized in terms of their molecular biology. Gene and miRNA expression profiling has elucidated RNA abnormalities which impact on disease biology, classification, and treatment of EBV-TNKLPD. Pathways promoting proliferation, such as Janus associated kinase/ Signal Transducer and Activator of Transcription (JAK/STAT) and nuclear factor kB, are upregulated in ENKTL while upregulation of survivin and deregulation of p53 inhibit apoptosis in both ENKTL and chronic active EBV infection (CAEBV). Importantly, immune evasion via the programmed cell death-1 and its ligand, PD-1/PD-L1 checkpoint pathway, has been demonstrated to play an important role in ENKTL. Other pathogenic mechanisms involve EBV genes, microRNA deregulation, and a variety of other oncogenic signaling pathways. The identification of EBV-positive Peripheral T-cell lymphoma not otherwise specified (PTCL-NOS) as a tumor with a distinct molecular signature and clinical characteristics highlights the important contribution of the knowledge derived from gene and miRNA expression profiling in disease classification. Novel therapeutic targets identified through the study of RNA abnormalities provide hope for patients with EBV-TNKLPD, which often has a poor prognosis. Immune checkpoint inhibition and JAK inhibition in particular have shown promise and are being evaluated in clinical trials. In this review, we provide an overview of the key transcriptomic aberrancies in EBV-TNKLPD and discuss their translational potential.

Simple Summary Extranodal NK/T cell lymphoma (ENKTCL) is an aggressive lymphoma associated with Epstein-Barr virus (EBV) infection that occurs mainly in Asian and Latin American populations. In the last decade, the genetic landscape of ENKTCL has been characterized comprehensively using next-generation sequencing (NGS). This and similar high-throughput approaches revealed that these lymphomas are distinguished by frequent gene mutations leading to activation of the JAK-STAT pathway, and mutations in other genes such as BCOR, DDX3X and TP53. This review aims to provide a comprehensive overview about the role of EBV infection and a comparison of the EBV strains and LMP1 variants among different populations. Moreover, a brief summary of the ENKTCL genetic landscape is presented, highlighting the main therapeutically targetable pathways in ENKTCL oncogenesis: the JAK-STAT signaling pathway, the immune response evasion, MYC overexpression, as well as epigenetic alterations. Abstract Epstein-Barr virus (EBV) is a ubiquitous gamma herpes virus with tropism for B cells. EBV is linked to the pathogenesis of B cell, T cell and NK cell lymphoproliferations, with extranodal NK/T cell lymphoma, nasal type (ENKTCL) being the prototype of an EBV-driven lymphoma. ENKTCL is an aggressive neoplasm, particularly widespread in East Asia and the native population of Latin America, which suggests a strong genetic predisposition. The link between ENKTCL and different populations has been partially explored. EBV genome sequencing analysis recognized two types of strains and identified variants of the latent membrane protein 1 (LMP1), which revealed different oncogenic potential. In general, most ENKTCL patients carry EBV type A with LMP1 wild type, although the LMP1 variant with a 30 base pair deletion is also common, especially in the EBV type B, where it is necessary for oncogenic transformation. Contemporary high-throughput mutational analyses have discovered recurrent gene mutations leading to activation of the JAK-STAT pathway, and mutations in other genes such as BCOR, DDX3X and TP53. The genomic landscape in ENKTCL highlights mechanisms of lymphomagenesis, such as immune response evasion, secondary to alterations in signaling pathways or epigenetics that directly or indirectly interfere with oncogenes or tumor suppressor genes. This overview discusses the most important findings of EBV pathogenesis and genetics in ENKTCL.

Simple Summary Intravascular lymphoma is a neoplasm with tumor cells localized exclusively within blood vessel lumina. Most cases are of B-cell origin; only rare cases of NK or T-cell lineage. Unlike intravascular large B-cell lymphoma, which is a well-recognized entity in the WHO classification, intravascular NK/T-cell lymphoma is not considered a specific entity and there is still a debate about whether it is closer to aggressive NK leukemia or to extranodal NK/T-cell lymphoma. Our aim was to summarize the clinical, pathological, and molecular data on intravascular NK/T-cell lymphoma, which is a challenge both in terms of diagnosis and treatment. Recent molecular studies improved our understanding of the mechanism of lymphomagenesis, showing that multiple genetic events associated with EBV infection are required for the pathogenesis of this aggressive lymphoma. Promising therapeutic results may be offered by immune checkpoint inhibitors due to the high PD-L1 expression, which is possibly related to EBV infection. Abstract Intravascular lymphoma is a form of lymphoid malignancy characterized by neoplastic cells growing almost exclusively within the lumina of small- to medium-sized blood vessels. Most cases are of B-cell origin with rare cases of natural killer or T-cell lineage. Extranodal sites are affected, mainly the skin and central nervous system, although any organ may be involved. Intravascular NK/T-cell lymphoma deserves special attention because of its clinicopathologic features and the need for adequate immunophenotyping combined with clonality test for a proper diagnosis. Moreover, intravascular NK/T-cell lymphoma is strongly linked to Epstein–Barr virus (EBV), which is considered to play a role in tumorigenesis and to be responsible for the aggressive behavior of the disease. In this paper, we review the current knowledge on this rare lymphoma and, in particular, the most recent advances about its molecular landscape. The main distinguishing features with other EBV-related entities, such as extranodal NK/T-cell lymphoma, EBV-positive primary nodal T/NK-cell lymphoma, and aggressive NK-cell leukemia, are discussed to help pathologists obtain the correct diagnosis and consequently develop an adequate and prompt therapy response.

Simple Summary In most Epstein–Barr virus (EBV)-infected individuals, the virus establishes a lifelong latent infection with no specific clinical manifestation. However, EBV primary infection and secondary reactivation may cause various EBV-associated lymphoproliferative disorders (LPD), including hematologic malignancies. Among them, EBV-positive T/NK LPD are uncommon diseases defined by the proliferation of T- or NK-cells infected by EBV, more commonly encountered in Asians and Latin Americans. They encompass a spectrum of disorders ranging from indolent reactive lesions to malignant and aggressive diseases. Despite novel insights from high-throughput molecular studies, the pathogenesis of these disorders is not well understood, and EBV-positive T/NK LPD diagnoses remain challenging due to their rarity and considerable overlap. Indeed, this article discusses new insights into EBV-positive T/NK LPD and focuses on diagnosis challenges, describing the difficulties to clarify the borders between overlapping LPD subtypes. Abstract Epstein–Barr virus (EBV) is a ubiquitous virus detected in up to 95% of the general population. Most people are asymptomatic, while some may develop a wide range of EBV-associated lymphoproliferative disorders (LPD). Among them, EBV-positive T/NK LPD are uncommon diseases defined by the proliferation of T- or NK-cells infected by EBV. The 2017 World Health Organization (WHO) classification recognizes the following entities characterized by different outcomes: chronic active EBV infection of T- or NK-cell types (cutaneous and systemic forms), systemic EBV-positive T-cell lymphoma of childhood, EBV-positive aggressive NK-cell leukemia, extra nodal NK/T-cell lymphoma nasal type, and the new provisional entity known as primary EBV-positive nodal T/NK-cell lymphoma. In addition, EBV associated-hemophagocytic lymphohistiocytosis is part of EBV-positive T/NK LPD, but has not been included in the WHO classification due to its reactive nature. Despite novel insights from high-throughput molecular studies, EBV-positive NK/T-cell LPD diagnoses remain challenging, especially because of their rarity and overlap. Until now, an accurate EBV-positive NK/T LPD diagnosis has been based on its clinical presentation and course correlated with its histological features. This review aims to summarize clinical, pathological and molecular features of EBV-positive T/NK LPD subtypes and to provide an overview of new understandings regarding these rare disorders.

Cytotoxic peripheral T-cell lymphomas and EBV-positive T/NK-cell lymphoproliferative diseases were discussed at the 2022 European Association for Haematopathology/Society for Hematopathology lymphoma workshop held in Florence, Italy. This session focused on (i) primary nodal EBV-positive T and NK-cell lymphomas (primary nodal-EBV-TNKL), (ii) extranodal EBV-positive T/NK lymphoproliferative diseases (LPD) in children and adults, (iii) cytotoxic peripheral T-cell lymphomas, NOS (cPTCL-NOS), EBV-negative, and (iv) miscellaneous cases. Primary nodal-EBV-TNKL is a newly recognized entity which is rare, aggressive, and associated with underlying immune deficiency/immune dysregulation. All cases presented with lymphadenopathy but some demonstrated involvement of tonsil/Waldeyer’s ring and extranodal sites. The majority of tumors are of T-cell lineage, and the most frequent mutations involve the epigenetic modifier genes, such as TET2 and DNMT3A, and JAK-STAT genes. A spectrum of EBV-positive T/NK LPD involving extranodal sites were discussed and highlight the diagnostic challenge with primary nodal-EBV-TNKL when these extranodal EBV-positive T/NK LPD cases demonstrate predominant nodal disease either at presentation or during disease progression from chronic active EBV disease. The majority of cPTCL-NOS demonstrated the TBX21 phenotype. Some cases had a background of immunosuppression or immune dysregulation. Interestingly, an unexpected association of cPTCL-NOS, EBV-positive and negative, with TFH lymphomas/LPDs was observed in the workshop cases. Similar to a published literature, the genetic landscape of cPTCL-NOS from the workshop showed frequent mutations in epigenetic modifiers, including TET2 and DNMT3A, suggesting a role of clonal hematopoiesis in the disease pathogenesis.

Extranodal natural killer/T-cell lymphoma (NKTCL) is an aggressive malignancy that has been etiologically linked to Epstein-Barr virus (EBV) infection, with EBV gene transcripts identified in almost all cases. However, the humoral immune response to EBV in NKTCL patients has not been well characterized. We examined the antibody response to EBV in plasma samples from 51 NKTCL cases and 154 controls from Hong Kong and Taiwan who were part of the multi-center, hospital-based AsiaLymph case–control study. The EBV-directed serological response was characterized using a protein microarray that measured IgG and IgA antibodies against 202 protein sequences representing the entire EBV proteome. We analyzed 157 IgG antibodies and 127 IgA antibodies that fulfilled quality control requirements. Associations between EBV serology and NKTCL status were disproportionately observed for IgG rather than IgA antibodies. Nine anti-EBV IgG responses were significantly elevated in NKTCL cases compared with controls and had ORshighest vs. lowest tertile > 6.0 (Bonferroni-corrected P-values < 0.05). Among these nine elevated IgG responses in NKTCL patients, three IgG antibodies (all targeting EBNA3A) are novel and have not been observed for other EBV-associated tumors of B-cell or epithelial origin. IgG antibodies against EBNA1, which have consistently been elevated in other EBV-associated tumors, were not elevated in NKTCL cases. We characterize the antibody response against EBV for patients with NKTCL and identify IgG antibody responses against six distinct EBV proteins. Our findings suggest distinct serologic patterns of this NK/T-cell lymphoma compared with other EBV-associated tumors of B-cell or epithelial origin.