RARE DISEASE
Primary mediastinal large B-cell lymphoma
Primary mediastinal large B-cell lymphoma
Primary mediastinal large B-cell lymphoma
Synonyms: Large cell lymphoma of the mediastinum, Med-DLBCL, Mediastinal diffuse large-cell lymphoma with sclerosis, Primary mediastinal clear cell lymphoma of B-cell type
Synonyms: Large cell lymphoma of the mediastinum, Med-DLBCL, Mediastinal diffuse large-cell lymphoma with sclerosis, Primary mediastinal clear cell lymphoma of B-cell type
Synonyms: Large cell lymphoma of the mediastinum, Med-DLBCL, Mediastinal diffuse large-cell lymphoma with sclerosis, Primary mediastinal clear cell lymphoma of B-cell type
Drug discovery
8
drugs
With orphan designations
Overview
Primary mediastinal large B-cell lymphoma (PMBCL) is a rare, aggressive non-Hodgkin lymphoma arising in the mediastinum, accounting for 2%-4% of NHL cases [1][7][15]. It primarily affects young adults (median age 35) with a female predominance (2:1 ratio) [2][3][12][20]. Clinical presentation often includes superior vena cava syndrome due to bulky tumors (>10 cm) compressing thoracic structures [7][9][15][20]. Diagnosis relies on histopathology showing CD20+/CD30± B-cells with fibrotic stroma [1][7][15]. First-line therapy achieves >80% 5-year survival using R-CHOP or R-EPOCH regimens, with PET-guided radiation consolidation [3][8][13][17].
Burden
23% develop chemotherapy-resistant relapse [12][17]; radiation-associated cardiovascular toxicity in 40% of long-term survivors [1][13]; 14% 5-year mortality despite improved therapies [12][15]
Emerging targeted therapies and response-adapted approaches aim to reduce late complications while maintaining efficacy [3][8][15][17].
Therapies
Categories: rare hematological diseases, rare neoplastic diseases, rare transplant-related disorders
Research Papers
466 drug discovery papers about Primary mediastinal large B-cell lymphoma, with 1 first-in-class and 9 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
466 drug discovery papers about Primary mediastinal large B-cell lymphoma, with 1 first-in-class and 9 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-06-26 | Dose-Adjusted EPOCH-R in Aggressive B-Cell Lymphomas: Efficacy, Molecular Prognostic Factors, and Real-World Outcomes from a Multicenter Turkish Cohort-A Turkish Oncology Group (TOG) Study.
Background and Objectives: Comprehensive real-world data on dose-adjusted EPOCH-R (DA-EPOCH-R) incorporating molecular prognostic stratification remain limited. We evaluated the long-term efficacy, safety, and prognostic determinants of DA-EPOCH-R in a multicenter Turkish cohort. Materials and Methods: This retrospective study included 140 patients with aggressive B-cell lymphoma (diffuse large B-cell lymphoma [DLBCL], n = 81; primary mediastinal B-cell lymphoma [PMBL], n = 39; other, n = 20) treated with DA-EPOCH-R at five academic centers (2015-2020). Molecular profiling included immunohistochemistry (MYC, BCL-2, BCL-6) and fluorescence in situ hybridization (FISH). Survival was estimated by Kaplan-Meier analysis with Cox regression for prognostic factors. Results: At a median follow-up of 50.1 months, 5-year overall survival (OS) and event-free survival (EFS) rates were 71.3% and 66.3%, respectively (complete response rate: 68.6%). Molecular subtypes included double-expressor (DEL; n = 39), triple-expressor (TEL; n = 21), double-hit (DHL; n = 17), and triple-hit lymphoma (THL; n = 11). Five-year OS by IPI risk group ranged from 88.6% (low) to 49.4% (high) (p = 0.005). DEL status did not confer inferior OS (p = 0.738), whereas DHL and THL had markedly poor outcomes (p < 0.001). In multivariate analysis, IPI ≥ 3 (HR 2.54; p = 0.007) and MYC FISH rearrangement (HR 3.62; p < 0.001) independently predicted inferior OS. Grade 3-4 neutropenia occurred in 57.1%, with no grade 3-4 cardiotoxicity. Conclusions: DA-EPOCH-R provides favorable long-term outcomes in aggressive B-cell lymphomas. DEL status did not confer a survival disadvantage, an association that is hypothesis-generating and requires confirmation, as the present design cannot establish a causal mechanism. FISH-defined DHL/THL remain associated with dismal outcomes, warranting novel therapeutic strategies.
2026-06-10 | Primary mediastinal large B cell lymphoma in pregnancy: a case report and review of the literature.
Primary mediastinal B-cell lymphoma (PMBCL) is a subtype of diffuse large B-cell lymphoma (DLBCL) that typically presents as a large mass originating in the mediastinum and infiltrating the surrounding organs, resulting in pleural and pericardial effusions. The occurrence of PMBCL during pregnancy presents a significant challenge to clinical management, necessitating a comprehensive consideration of the unique risks posed to both the pregnant woman and the foetus when selecting the optimal treatment. This report presents cases of PMBCL diagnosed during late pregnancy and reviews the pertinent literature, emphasising the necessity of prompt diagnosis and the implementation of tailored management strategies for different stages of pregnancy to enhance pregnancy outcomes. A 29-year-old woman with four documented pregnancies, yet no documented deliveries. At 15 weeks' gestation, the patient presented at the local hospital with a cough, which was diagnosed as an upper respiratory tract infection. She was treated with oral antibiotics; however, there was no significant improvement in her condition. During the 28th week of gestation, the patient's respiratory distress and dysphagia worsened, and she was unable to assume a recumbent position. The patient was admitted to our hospital with a computed tomography scan indicating the presence of a sizable mediastinal mass. Given the potential risks, benefits, and recent status, a decision was made to perform an emergency caesarean section. The procedure resulted in the successful delivery of the foetus, with Apgar scores of 6, 7, and 7 at 1, 5, and 10 minutes, respectively. A comprehensive examination of the neonate revealed no additional abnormalities and demonstrated normal developmental progress after a period of over four months. Following delivery, the diagnosis of PMBCL was confirmed by puncture biopsy of the mediastinal mass and PET-CT. The pregnant woman then received five doses of DA-EPOCH-R chemotherapy, resulting in a significant reduction of the mediastinal mass and remission of her symptoms. This case study illustrates the significant challenges associated with diagnosing and treating Primary mediastinal B-cell lymphoma during pregnancy. In this rare and complex case, the timing of termination of pregnancy and the choice of treatment regimen are of critical importance in order to improve maternal and infant outcomes.
2026-06-01 | Clinicopathological Features of Primary Mediastinal Large B-cell Lymphoma: A 5-Year Retrospective Study
Objective: To describe the clinicopathological features and treatment outcomes of primary mediastinal large B-cell lymphoma (PMBCL) at Siriraj Hospital, Thailand. Materials and Methods: This retrospective study included all patients diagnosed with PMBCL during 2020–2024. Clinical, pathological, treatment, and survival data were retrieved from medical records and pathology reports. Overall survival (OS) and progression-free survival (PFS) were estimated using the Kaplan–Meier method. Results: PMBCL accounted for 37 of 74 mediastinal lymphoma cases (50%). Median age was 29 years (IQR: 22–32), with female predominance (62.2%). Presentations included cough (79.4%), dyspnea (74.3%), and SVC syndrome (51.4%). Pleural or pericardial effusion was found in 75.0%. Bulky disease (>10 cm) and elevated LDH were 75.7% and 91.4%, respectively. Histologically, sclerotic pattern and HRS-like cells were observed in 41.7% and 31.4%, respectively. All cases were CD20-positive; CD23 and CD30 were expressed in 65.5% and 80.6%, respectively. A non-GCB phenotype was identified in 64.5% by the Hans algorithm. DA-EPOCH-R was the most common first-line regimen (63.9%). At a median follow-up of 25 months, the 24-month OS and PFS rates were 80.1% and 66.8%, respectively. Conclusion: This study provides the first characterization of PMBCL in a Thai cohort, showing frequent SVC syndrome and pleural or pericardial effusion at diagnosis. Given the overlapping features and complexity of differential diagnosis, comprehensive immunohistochemical workup was essential for accuracy. DA-EPOCH-R was the dominant first-line therapy, with 2-year outcomes comparable to the rituximab era. Prompt recognition, diagnostic expertise, and multidisciplinary management are critical for optimizing PMBCL outcomes.
2026-05-08 | Primary Mediastinal (Thymic) Large B-Cell Lymphoma in Children and Adolescents: Current Aspects of Pathogenesis, Diagnosis, Therapy, and Long-Term Treatment Complications
Первичная медиастинальная (тимическая) B-крупноклеточная лимфома (ПМBКЛ) у детей и подростков представляет собой редкий вариант лимфомы из зрелых В-клеток с локализацией опухоли в переднем средостении и высокой частотой жизнеугрожающих осложнений. В обзоре обобщены современные данные о клинико-морфологических особенностях, молекулярно-генетических механизмах патогенеза, диагностических подходах и стратегиях терапии ПМBКЛ в педиатрической популяции больных. Рассмотрены характерные морфологические и иммуногистохимические признаки, позволяющие дифференцировать ПМBКЛ от других лимфом с поражением органов средостения, а также ключевые генетические и эпигенетические нарушения, в том числе активация сигнальных путей JAK-STAT и PD-1/PD-L1. Представлены результаты применения различных подходов к терапии ПМВКЛ — от стандартных схем до программ, включающих высокодозную химиотерапию, таргетные и иммунотерапевтические препараты. Отдельное внимание уделено особенностям оценки ответа на лечение, а также проблеме поздних токсических эффектов, включая кардиотоксичность, вторичные злокачественные новообразования и нарушения функции эндокринной системы. Таким образом, основу современной диагностики ПМВКЛ составляет морфоиммуногистохимическое исследование, а распространенность опухолевого процесса оценивается с помощью позитронно-эмиссионной томографии, совмещенной с компьютерной томографией. Внедрение современных таргетных и иммунотерапевтических подходов в сочетании с сокращением токсичности лечения представляет собой перспективное направление, способное повысить выживаемость и качество жизни пациентов. Несмотря на прогресс в понимании биологии ПМBКЛ, требуется проведение многоцентровых исследований для оптимизации лечения и минимизации поздних осложнений у педиатрических больных.
2026-01-20 | Effective Use of Olanzapine for Chemotherapy-Induced Nausea and Vomiting in a Patient Receiving Dose-Adjusted Rituximab, Etoposide, Prednisone, Vincristine (Oncovin®), Cyclophosphamide, and Doxorubicin (R-EPOCH): A Case Report.
Dose-adjusted (DA) rituximab, etoposide, prednisone, vincristine (Oncovin®), cyclophosphamide, and doxorubicin (R-EPOCH) is a multiday chemotherapy regimen that includes anthracyclines and cyclophosphamide. Although olanzapine is used to prevent chemotherapy-induced nausea and vomiting (CINV), its efficacy in patients receiving DA-R-EPOCH has not yet been reported. We describe a case in which olanzapine was effective in preventing CINV during DA-R-EPOCH treatment. A 21-year-old woman was diagnosed with primary mediastinal large B-cell lymphoma. The patient had some CINV risk factors associated with a lower risk, such as no history of motion sickness or morning sickness (no history of pregnancy), as well as factors associated with a higher CINV risk, including a lack of habitual alcohol consumption and no history of smoking. The patient received prophylactic antiemetic therapy with olanzapine (5 mg after dinner for six days), palonosetron, and fosnetupitant during DA-R-EPOCH therapy. Prednisolone was administered at 60 mg/m2 for five days as part of the DA-R-EPOCH regimen; it also served as a corticosteroid with antiemetic activity. From days 1 to 10 of treatment, the food intake rate remained above 70%. Grade 1 nausea was observed on days 4 and 5, with no vomiting during the treatment period. Adverse events, such as constipation and somnolence, were also noted. A four-drug antiemetic regimen, including olanzapine, supported the feasibility of preventing CINV in this case involving DA-R-EPOCH therapy. However, adverse events potentially related to olanzapine were observed, suggesting the need for further investigation into its optimal dosage.
antibodies
2026-07-02 | PD-L2 is associated with lineage-related transcriptional programs distinct from PD-L1 in primary mediastinal large B-cell lymphoma.
Primary mediastinal large B-cell lymphoma (PMBCL) is characterized by recurrent 9p24.1 alterations driving constitutive overexpression of PD-1 ligands and high sensitivity to PD-1 blockade. While PD-L1 is widely used as a biomarker, the tumor-intrinsic functions of PD-1 ligands, and particularly PD-L2, remain poorly defined. Here, we investigated the distinct roles of PD-L1 and PD-L2 in PMBCL using CRISPR-Cas9-engineered isogenic models, immune co-culture assays, an immune-interactive in ovo chorioallantoic membrane (CAM) xenograft system, and integrative transcriptomic analyses of patient datasets. PD-L1 was most strongly associated with restraint of Th1-associated immune signaling and influenced responsiveness to PD-1 blockade, whereas PD-L2 was associated with preservation of lineage-associated transcriptional programs and distinct treatment-response patterns. Combined disruption of both ligands enhanced Th1 immune activation while altering B-cell transcriptional states. Consistent with these findings, transcriptomic analyses in PMBCL cohorts linked PDCD1LG2 expression to B-cell identity and signaling modules, whereas CD274 expression aligned with interferon-responsive immune programs. Together, these results support a model in which PD-L1 and PD-L2 associate with distinct immune and lineage-associated states in PMBCL and provide a framework for exploring biologically informed stratification strategies in this disease.
2026-06-04 | [Long-term remission in refractory diffuse large B-cell lymphoma with concurrent epcoritamab and radiotherapy].
Epcoritamab, a subcutaneous CD3×CD20 bispecific antibody, has shown high efficacy in relapsed or refractory large B-cell lymphoma (R/R LBCL). However, treatment options are limited for patients who fail to achieve durable remission after immune-based therapy. Here, we describe a case of refractory diffuse large B-cell lymphoma in an 87-year-old woman who achieved long-term remission through concurrent epcoritamab and radiotherapy. During the fifth cycle of third-line epcoritamab therapy, positron emission tomography/computed tomography revealed persistent fluorodeoxyglucose-avid lesions in the spleen and mediastinum. Volumetric modulated arc therapy of 36 Gy in 18 fractions was administered to both sites while continuing epcoritamab (administered during the sixth cycle for the splenic lesion and during the thirteenth and fourteenth cycles for the mediastinal lesion). The combined therapy resulted in complete metabolic response without significant adverse events, and the patient remains in remission beyond 27 treatment cycles. In this case, we obtained durable remission by adding radiotherapy for localized lymphoma refractory to epcoritamab. The absence of cross-resistance between radiotherapy and systemic chemotherapy supports the rationale for local irradiation as a complementary approach to bispecific antibody therapy. This combination may represent a feasible and well-tolerated option for elderly or heavily pretreated patients with localized refractory disease.
2026-06-04 | Immune checkpoint therapy in pediatric and adolescent lymphomas.
Immune checkpoint therapy (ICT) is designed to unleash the anti-tumor activity of Tlymphocytes. Cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) inhibition and programmed death 1 (PD-1) inhibition are the most commonly utilized ICTs in clinical cancer therapy, and they enhance anti-tumor immunity by interrupting the inhibitory signals CTLA-4 and programmed death ligand 1 (PD-L1) respectively. In pediatric Hodgkin lymphoma, ICT has demonstrated remarkable efficacy in both high-risk and relapsed disease, with investigation into the efficacy in low-risk disease ongoing. Pediatric mature B-cell lymphomas have variable expression of PD-L1 with very limited experience incorporating ICT. Primary mediastinal B-cell lymphoma (PMBCL), anaplastic large cell lymphoma (ALCL), aggressive natural killer-cell lymphoma (ANKL), and peripheral T-cell lymphoma, not otherwise specified (PTCL, NOS) all consistently express PD-L1, providing strong biologic rationale for the use of ICT in these diseases. In PMBCL, the Children's Oncology Group (COG) and the National Cancer Institute (NCI) National Clinical Trials Network (NCTN) recently completed a randomized phase III trial of nivolumab in combination with chemo-immunotherapy in children and adults with newly diagnosed PMBCL. Results of this trial are expected in 2027. In ALCL and ANKL, ongoing clinical trials are evaluating the efficacy of ICT. Given the transformational role of ICT for pediatric Hodgkin lymphoma, there is significant promise for the use of ICT in multiple subtypes of pediatric non-Hodgkin lymphoma with increased expression of PD-L1.
2026-04-21 | First-line Polatuzumab vedotin plus R-CHP in primary mediastinal B-cell lymphoma: A real-world study bridging the gap of the POLARIX trial
Objective primary mediastinal B-cell lymphoma (PMBCL) is a distinct, aggressive lymphoma predominantly affecting young adults. While dose-intensive regimens are often recommended, their associated long-term toxicities and the necessity of consolidative radiotherapy remain major concerns. Given that PMBCL was explicitly excluded from the landmark POLARIX trial, we sought to evaluate the real-world efficacy and safety of first-line Pola-R-CHP in this specific population. Methods this single-center study analyzed 16 consecutive patients with newly diagnosed PMBCL treated with six cycles of Pola-R-CHP between September 2023 and June 2025. Efficacy was assessed via PET/CT (Lugano 2014 criteria) and safety via NCI-CTCAE v5.0. Results the median age was 30 years, with a female predominance (62.5%). Bulky disease was present in 62.5% of patients, and 87.5% had low-risk aaIPI scores. All patients completed six cycles of Pola-R-CHP treatment, achieving an objective response rate of 100%. The end-of-treatment complete metabolic response rate was 93.8%, with profound response deepening observed between interim and final assessments. After a median follow-up of 16.4 months, no relapses or deaths occurred, with all patients remaining in sustained remission. The most common grade 3–4 adverse event was neutropenia (43.8%). Pola-related peripheral neuropathy was predominantly low-grade (56.3% grade 1–2). Conclusion our findings provide the first preliminary clinical evidence that Pola-R-CHP is a highly effective and well-tolerated frontline strategy for PMBCL in this real-world cohort, which warrants further validation in larger, multicenter studies.
2026-02-23 | Pre-treatment endocrine-nutritional signatures predict clinical benefit from PD-1/PD-L1 blockade in hematologic malignancies.
Hematologic malignancies pose significant global health burdens, with programmed cell death protein-1 (PD-1)/programmed cell death ligand 1 (PD-L1) inhibitors revolutionizing treatment in subtypes like classical Hodgkin lymphoma (cHL) and primary mediastinal large B-cell lymphoma (PMBCL), achieving high objective response rates (ORR). However, efficacy varies widely, with limited success in multiple myeloma (< 10% ORR) and leukemias, underscoring the need for better predictors beyond tumor-intrinsic biomarkers. This review highlights pre-treatment endocrine-nutritional signatures as key host factors influencing immunotherapy outcomes. Dysregulated hormones (cortisol, thyroid, sex steroids, insulin/insulin-like growth factor-1, adipokines) and nutritional status (vitamin D, zinc, protein-energy malnutrition, iron metabolism) modulate T-cell exhaustion, myeloid suppression, and tumor microenvironment dynamics, often leading to resistance. Evidence from cohorts shows hypercortisolism, hypothyroidism, insulin resistance, vitamin D deficiency, and hypoalbuminemia correlate with inferior ORR, progression-free survival, and overall survival, while thyroid immune-related adverse events and moderate obesity predict benefit. In hematologic contexts, marrow infiltration exacerbates these imbalances, explaining heterogeneous responses. Integrated signatures (e.g., Glasgow Prognostic Score, Prognostic Nutritional Index) offer superior prognostic value, enabling targeted interventions like vitamin D supplementation, metformin, or nutritional support to enhance immune checkpoint inhibitor efficacy. Mechanistic insights reveal convergence on mTOR/IFN-γ pathways and microbiome modulation. Translating these to clinical panels could personalize immunotherapy, addressing gaps in hematologic malignancies literature and improving outcomes in relapsed/refractory settings.
cell therapies
2026-07-30 | Allogeneic hematopoietic stem cell transplantation achieves complete response in refractory primary mediastinal large B-cell lymphoma after the failure of chemotherapy, CAR-T therapy, and PD-1 blockade.
Primary mediastinal large B-cell lymphoma (PMBCL) typically responds to chemotherapy, and immunotherapies such as chimeric antigen receptor T-cell (CAR-T) therapy and the programmed cell death protein 1 (PD-1) inhibitor pembrolizumab have shown promise in relapsed or refractory cases. However, the sequential use of multiple immunotherapies for PMBCL remains poorly characterized. Here, we report a case of a 19-year-old female with PMBCL involving the mediastinum and multiple extranodal sites. After a partial response to chemotherapy, she developed a central nervous system relapse that responded to high-dose methotrexate, and the number of regrowing mediastinal lesions was reduced by radiotherapy. Subsequently, new hepatic lesions that were refractory to both CAR-T therapy and pembrolizumab emerged. Following localized liver radiotherapy, allogeneic hematopoietic stem cell transplantation (allo-HSCT) was performed, resulting in complete response. Early post-transplant, she developed a hepatitis variant of acute graft-versus-host disease, which may have reflected a graft-versus-lymphoma (GVL) effect. Despite maintaining response, the patient died one year later form a disseminated infection with multitriazole-resistant Aspergillus fumigatus. This case highlights both the potential curative role and the substantial risks of allo-HSCT in PMBCL refractory to multiple immunotherapies. The pre-transplant use of pembrolizumab and localized radiotherapy may influence transplant outcomes and warrants further investigation.
2026-07-06 | Successful Postpartum CAR T-cell Salvage Therapy for Primary Mediastinal Large B-cell Lymphoma with Residual Disease after R-CHOP During Pregnancy.
Primary mediastinal large B-cell lymphoma (PMBCL) during pregnancy is rare and presents therapeutic challenges due to fetal safety concerns. We report the case of a 29-year-old woman diagnosed with PMBCL at 19 weeks of gestation who wished to continue her pregnancy despite her diagnosis. She received rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) chemotherapy with multidisciplinary management and delivered a healthy infant at term. Although the tumor partially responded, residual disease persisted after eight cycles of treatment. She subsequently underwent chimeric antigen receptor T-cell therapy and achieved a complete response. This case highlights the importance of individualized treatment decisions and multidisciplinary collaboration in managing PMBCL during pregnancy.
2026-01-03 | Safety and effectiveness of lisocabtagene maraleucel following PD-1 blockade in relapsed or refractory PMBCL.
Primary mediastinal B-cell lymphoma (PMBCL) is a distinct subtype of large B-cell lymphoma characterized by 9p24.1 copy-number alterations and PD-1-mediated immune evasion. This profile confers high sensitivity to PD-1 inhibitors such as pembrolizumab. CD19-directed chimeric antigen receptor (CAR) T-cell therapies have shown benefit in relapsed or refractory (R/R) PMBCL, but their optimal role remains undefined. We retrospectively analyzed 31 patients with R/R B-cell lymphoma treated with lisocabtagene maraleucel (liso-cel), including four with PMBCL who received pembrolizumab prior to CAR-T. All four achieved remission before infusion, and three maintained durable complete responses (≥ 30 months). Toxicities were comparable to those in patients not treated with pembrolizumab, although one pembrolizumab-treated patient experienced fatal neurotoxicity. Favorable hematologic recovery and preserved T-cell counts at leukapheresis suggest that preceding PD-1 blockade did not compromise CAR-T manufacturing and may have enhanced T-cell fitness. These findings suggest that sequential PD-1 blockade followed by liso-cel is clinically feasible and may improve outcomes by leveraging the immune vulnerability of PMBCL. While prior studies have focused on axicabtagene ciloleucel, this report provides the first real-world data supporting the feasibility and potential benefit of this approach with liso-cel. Prospective studies are needed to confirm efficacy, safety, and optimal sequencing.
2025-10-23 | CAR-T Cell Therapy in Primary Mediastinal B-cell Lymphoma
A specific type of CAR-T cell therapy, the CAR19 therapy has demonstrated notable efficacy for relapsed or refractory (R/R) hematologic cancers, including B-cell lymphomas. After the recent reclassification of the rare subtype Primary Mediastinal B-cell Lymphoma (PMBCL) from general Diffuse Large B-cell Lymphoma (DLBCL), questions have been raised about the application of immunotherapies in this cancer, including the most discussed CAR-T cell therapy. The CAR-T cell therapy, more specifically the CAR19, exerts anti-tumor effects in multiple mechanisms, including different cytotoxic pathways—apoptosis triggering via perforin–granzyme release and Fas/FasL-pathway—driven by calcium-dependent signaling MAPK, PI3K/Akt, and NF-κB. Multiple extant clinical trials have evaluated the response of PMBCL patients to CAR19, specifically the Axi-cel, Liso-cel, and Tisa-cel therapies, focusing the rates of complete response (CR), progression-free survival (PFS), and the overall survival (OS). Studies exclusive to PMBCL patients showed that bridging therapies and other first-line treatments did not influence CAR19 effectiveness, while post-relapse application of Pembrolizumab yielded durable CRs in some patients, and allo-HSCT was associated with high mortality. The CAR-SIE trial in Italy, comparing Axi-cel CAR19 in PMBCL cancer with other B-cell lymphomas, demonstrated a better result in PMBCL patients with higher ORR, CR, and PFS. This paper integrates the underlying mechanisms of CAR19 with clinical trials, aiming to demonstrate both the potential and the limitations of this therapy in PMBCL cancer.
2025-08-19 | Refractory/relapsed primary mediastinal large B-cell lymphoma: a changing paradigm for drug therapy
Primary mediastinal large B-cell lymphoma (PMBCL) is a fairly rare variant of large B-cell lymphomas (LBCL) and accounts for about 10% of them. Despite the relatively satisfactory results of induction immunochemotherapy for PMBCL, in 10—30% of cases refractoriness or relapse of the disease occurs. Reliable prognostic models for identifying patients at risk of failure of initial treatment in PMBCL have not yet been fully developed. Salvage therapy for refractory/relapsed (r/r) PMBCL is similar to that used for r/r diffuse large B-cell lymphoma and, provided the tumor is chemosensitive, involves high-dose consolidation with autologous hematopoietic stem cell transplantation. However, relapses of PMBCL often turn out to be chemo-refractory and the effective reserves of traditional salvage therapy are exhausted. With the understanding of the molecular genetic features of PMBCL, new therapeutic targets are being actively studied. In recent years, more and more evidence has accumulated, reliably demonstrating the high and long-term effectiveness of new therapeutic options, such as immune checkpoint inhibitors and CAR-T cell therapies, which are already beginning to be integrated into earlier stages of treatment. However, the rarity of PMBCL limits the possibility of conducting randomized prospective trials to study new treatment strategies, the results of which can guide therapy in the case of r/r disease. Therefore, r/r PMBCL still represents an unresolved clinical problem.
oligonucleotides
2022-07-28 | Toll-like receptor 9 agonists and combination therapies: strategies to modulate the tumour immune microenvironment for systemic anti-tumour immunity
Over the past decade, tremendous progress has taken place in tumour immunotherapy, relying on the fast development of combination therapy strategies that target multiple immunosuppressive signaling pathways in the immune system of cancer patients to achieve a high response rate in clinical practice. Toll-like receptor 9 (TLR9) agonists have been extensively investigated as therapeutics in monotherapy or combination therapies for the treatment of cancer, infectious diseases and allergies. TLR9 agonists monotherapy shows limited efficacy in cancer patients; whereas, in combination with other therapies including antigen vaccines, radiotherapies, chemotherapies and immunotherapies exhibit great potential. Synthetic unmethylated CpG oligodeoxynucleotide (ODN), a commonly used agonist for TLR9, stimulate various antigen-presenting cells in the tumour microenvironment, which can initiate innate and adaptive immune responses. Novel combination therapy approaches, which co-deliver immunostimulatory CpG-ODN with other therapeutics, have been tested in animal models and early human clinical trials to induce anti-tumour immune responses. In this review, we describe the basic understanding of TLR9 signaling pathway; the delivery methods in most studies; discuss the key challenges of each of the above mentioned TLR9 agonist-based combination immunotherapies and provide an overview of the ongoing clinical trial results from CpG-ODN based combination therapies in cancer patients.
other
2023-12-01 | Bendamustine impairs humoral but not cellular immunity to SARS-CoV-2 vaccination in rituximab-treated B-cell lymphoma–affected patients
Background Patients with B-cell lymphoma are a fragile category of subjects, particularly exposed to infections and characterized by an impaired vaccination response due to the disease itself and, even more, to the chemotherapy regimen. For this reason, extensive knowledge of the immune response status of these subjects is of fundamental importance to obtain possible indications for a tailored immunization strategy. Methods We enrolled two cohorts of patients with B-cell lymphoma under rituximab treatment or 3–24 months after treatment. In all patients, we evaluated both humoral and cellular immunological memory toward SARS-CoV-2, after standard vaccination and upon one booster dose. Results We observed no Spike-specific IgG production in patients (n = 25) under anti-CD20 treatment, whereas patients (n = 16) vaccinated after the completion of chemotherapy showed a higher humoral response. Evaluating SARS-CoV-2–specific T-cell response, we found that patients in both cohorts had developed robust cellular immunity after vaccination. Of the 21 patients (51%) that experienced a breakthrough SARS-CoV-2 infection, only six patients developed severe disease. Interestingly, these six patients had all been treated with rituximab plus bendamustine. Notably, we observed that Spike-specific IgG levels in patients treated with rituximab plus bendamustine were absent or lower compared with those in patients treated with rituximab plus other chemotherapy, whereas Spike-specific T-cell response was not different based on chemotherapy regiment. Discussion Our results show that, in patients with B-cell lymphoma under rituximab therapy, anti–SARS-CoV-2 mRNA vaccination induces a weak or absent humoral response but a consistent T-cell response. In addition, chemotherapy regimens with bendamustine further reduce patients’ ability to mount a Spike-specific humoral response even after a long time period from chemotherapy discontinuation. These results provide evidence that different chemotherapeutics display different immunosuppressive properties that could be taken in to account in the choice of the right drug regimen for the right patient. Moreover, they question whether immunocompromised patients, particularly those treated with bendamustine, need interventions to improve vaccine-induced immune response.
small molecules
2026-06-26 | Dose-Adjusted EPOCH-R in Aggressive B-Cell Lymphomas: Efficacy, Molecular Prognostic Factors, and Real-World Outcomes from a Multicenter Turkish Cohort-A Turkish Oncology Group (TOG) Study.
Background and Objectives: Comprehensive real-world data on dose-adjusted EPOCH-R (DA-EPOCH-R) incorporating molecular prognostic stratification remain limited. We evaluated the long-term efficacy, safety, and prognostic determinants of DA-EPOCH-R in a multicenter Turkish cohort. Materials and Methods: This retrospective study included 140 patients with aggressive B-cell lymphoma (diffuse large B-cell lymphoma [DLBCL], n = 81; primary mediastinal B-cell lymphoma [PMBL], n = 39; other, n = 20) treated with DA-EPOCH-R at five academic centers (2015-2020). Molecular profiling included immunohistochemistry (MYC, BCL-2, BCL-6) and fluorescence in situ hybridization (FISH). Survival was estimated by Kaplan-Meier analysis with Cox regression for prognostic factors. Results: At a median follow-up of 50.1 months, 5-year overall survival (OS) and event-free survival (EFS) rates were 71.3% and 66.3%, respectively (complete response rate: 68.6%). Molecular subtypes included double-expressor (DEL; n = 39), triple-expressor (TEL; n = 21), double-hit (DHL; n = 17), and triple-hit lymphoma (THL; n = 11). Five-year OS by IPI risk group ranged from 88.6% (low) to 49.4% (high) (p = 0.005). DEL status did not confer inferior OS (p = 0.738), whereas DHL and THL had markedly poor outcomes (p < 0.001). In multivariate analysis, IPI ≥ 3 (HR 2.54; p = 0.007) and MYC FISH rearrangement (HR 3.62; p < 0.001) independently predicted inferior OS. Grade 3-4 neutropenia occurred in 57.1%, with no grade 3-4 cardiotoxicity. Conclusions: DA-EPOCH-R provides favorable long-term outcomes in aggressive B-cell lymphomas. DEL status did not confer a survival disadvantage, an association that is hypothesis-generating and requires confirmation, as the present design cannot establish a causal mechanism. FISH-defined DHL/THL remain associated with dismal outcomes, warranting novel therapeutic strategies.
2026-06-10 | Primary mediastinal large B cell lymphoma in pregnancy: a case report and review of the literature.
Primary mediastinal B-cell lymphoma (PMBCL) is a subtype of diffuse large B-cell lymphoma (DLBCL) that typically presents as a large mass originating in the mediastinum and infiltrating the surrounding organs, resulting in pleural and pericardial effusions. The occurrence of PMBCL during pregnancy presents a significant challenge to clinical management, necessitating a comprehensive consideration of the unique risks posed to both the pregnant woman and the foetus when selecting the optimal treatment. This report presents cases of PMBCL diagnosed during late pregnancy and reviews the pertinent literature, emphasising the necessity of prompt diagnosis and the implementation of tailored management strategies for different stages of pregnancy to enhance pregnancy outcomes. A 29-year-old woman with four documented pregnancies, yet no documented deliveries. At 15 weeks' gestation, the patient presented at the local hospital with a cough, which was diagnosed as an upper respiratory tract infection. She was treated with oral antibiotics; however, there was no significant improvement in her condition. During the 28th week of gestation, the patient's respiratory distress and dysphagia worsened, and she was unable to assume a recumbent position. The patient was admitted to our hospital with a computed tomography scan indicating the presence of a sizable mediastinal mass. Given the potential risks, benefits, and recent status, a decision was made to perform an emergency caesarean section. The procedure resulted in the successful delivery of the foetus, with Apgar scores of 6, 7, and 7 at 1, 5, and 10 minutes, respectively. A comprehensive examination of the neonate revealed no additional abnormalities and demonstrated normal developmental progress after a period of over four months. Following delivery, the diagnosis of PMBCL was confirmed by puncture biopsy of the mediastinal mass and PET-CT. The pregnant woman then received five doses of DA-EPOCH-R chemotherapy, resulting in a significant reduction of the mediastinal mass and remission of her symptoms. This case study illustrates the significant challenges associated with diagnosing and treating Primary mediastinal B-cell lymphoma during pregnancy. In this rare and complex case, the timing of termination of pregnancy and the choice of treatment regimen are of critical importance in order to improve maternal and infant outcomes.
2026-06-01 | Clinicopathological Features of Primary Mediastinal Large B-cell Lymphoma: A 5-Year Retrospective Study
Objective: To describe the clinicopathological features and treatment outcomes of primary mediastinal large B-cell lymphoma (PMBCL) at Siriraj Hospital, Thailand. Materials and Methods: This retrospective study included all patients diagnosed with PMBCL during 2020–2024. Clinical, pathological, treatment, and survival data were retrieved from medical records and pathology reports. Overall survival (OS) and progression-free survival (PFS) were estimated using the Kaplan–Meier method. Results: PMBCL accounted for 37 of 74 mediastinal lymphoma cases (50%). Median age was 29 years (IQR: 22–32), with female predominance (62.2%). Presentations included cough (79.4%), dyspnea (74.3%), and SVC syndrome (51.4%). Pleural or pericardial effusion was found in 75.0%. Bulky disease (>10 cm) and elevated LDH were 75.7% and 91.4%, respectively. Histologically, sclerotic pattern and HRS-like cells were observed in 41.7% and 31.4%, respectively. All cases were CD20-positive; CD23 and CD30 were expressed in 65.5% and 80.6%, respectively. A non-GCB phenotype was identified in 64.5% by the Hans algorithm. DA-EPOCH-R was the most common first-line regimen (63.9%). At a median follow-up of 25 months, the 24-month OS and PFS rates were 80.1% and 66.8%, respectively. Conclusion: This study provides the first characterization of PMBCL in a Thai cohort, showing frequent SVC syndrome and pleural or pericardial effusion at diagnosis. Given the overlapping features and complexity of differential diagnosis, comprehensive immunohistochemical workup was essential for accuracy. DA-EPOCH-R was the dominant first-line therapy, with 2-year outcomes comparable to the rituximab era. Prompt recognition, diagnostic expertise, and multidisciplinary management are critical for optimizing PMBCL outcomes.
2026-05-08 | Primary Mediastinal (Thymic) Large B-Cell Lymphoma in Children and Adolescents: Current Aspects of Pathogenesis, Diagnosis, Therapy, and Long-Term Treatment Complications
Первичная медиастинальная (тимическая) B-крупноклеточная лимфома (ПМBКЛ) у детей и подростков представляет собой редкий вариант лимфомы из зрелых В-клеток с локализацией опухоли в переднем средостении и высокой частотой жизнеугрожающих осложнений. В обзоре обобщены современные данные о клинико-морфологических особенностях, молекулярно-генетических механизмах патогенеза, диагностических подходах и стратегиях терапии ПМBКЛ в педиатрической популяции больных. Рассмотрены характерные морфологические и иммуногистохимические признаки, позволяющие дифференцировать ПМBКЛ от других лимфом с поражением органов средостения, а также ключевые генетические и эпигенетические нарушения, в том числе активация сигнальных путей JAK-STAT и PD-1/PD-L1. Представлены результаты применения различных подходов к терапии ПМВКЛ — от стандартных схем до программ, включающих высокодозную химиотерапию, таргетные и иммунотерапевтические препараты. Отдельное внимание уделено особенностям оценки ответа на лечение, а также проблеме поздних токсических эффектов, включая кардиотоксичность, вторичные злокачественные новообразования и нарушения функции эндокринной системы. Таким образом, основу современной диагностики ПМВКЛ составляет морфоиммуногистохимическое исследование, а распространенность опухолевого процесса оценивается с помощью позитронно-эмиссионной томографии, совмещенной с компьютерной томографией. Внедрение современных таргетных и иммунотерапевтических подходов в сочетании с сокращением токсичности лечения представляет собой перспективное направление, способное повысить выживаемость и качество жизни пациентов. Несмотря на прогресс в понимании биологии ПМBКЛ, требуется проведение многоцентровых исследований для оптимизации лечения и минимизации поздних осложнений у педиатрических больных.
2026-01-20 | Effective Use of Olanzapine for Chemotherapy-Induced Nausea and Vomiting in a Patient Receiving Dose-Adjusted Rituximab, Etoposide, Prednisone, Vincristine (Oncovin®), Cyclophosphamide, and Doxorubicin (R-EPOCH): A Case Report.
Dose-adjusted (DA) rituximab, etoposide, prednisone, vincristine (Oncovin®), cyclophosphamide, and doxorubicin (R-EPOCH) is a multiday chemotherapy regimen that includes anthracyclines and cyclophosphamide. Although olanzapine is used to prevent chemotherapy-induced nausea and vomiting (CINV), its efficacy in patients receiving DA-R-EPOCH has not yet been reported. We describe a case in which olanzapine was effective in preventing CINV during DA-R-EPOCH treatment. A 21-year-old woman was diagnosed with primary mediastinal large B-cell lymphoma. The patient had some CINV risk factors associated with a lower risk, such as no history of motion sickness or morning sickness (no history of pregnancy), as well as factors associated with a higher CINV risk, including a lack of habitual alcohol consumption and no history of smoking. The patient received prophylactic antiemetic therapy with olanzapine (5 mg after dinner for six days), palonosetron, and fosnetupitant during DA-R-EPOCH therapy. Prednisolone was administered at 60 mg/m2 for five days as part of the DA-R-EPOCH regimen; it also served as a corticosteroid with antiemetic activity. From days 1 to 10 of treatment, the food intake rate remained above 70%. Grade 1 nausea was observed on days 4 and 5, with no vomiting during the treatment period. Adverse events, such as constipation and somnolence, were also noted. A four-drug antiemetic regimen, including olanzapine, supported the feasibility of preventing CINV in this case involving DA-R-EPOCH therapy. However, adverse events potentially related to olanzapine were observed, suggesting the need for further investigation into its optimal dosage.
antibodies
2026-07-02 | PD-L2 is associated with lineage-related transcriptional programs distinct from PD-L1 in primary mediastinal large B-cell lymphoma.
Primary mediastinal large B-cell lymphoma (PMBCL) is characterized by recurrent 9p24.1 alterations driving constitutive overexpression of PD-1 ligands and high sensitivity to PD-1 blockade. While PD-L1 is widely used as a biomarker, the tumor-intrinsic functions of PD-1 ligands, and particularly PD-L2, remain poorly defined. Here, we investigated the distinct roles of PD-L1 and PD-L2 in PMBCL using CRISPR-Cas9-engineered isogenic models, immune co-culture assays, an immune-interactive in ovo chorioallantoic membrane (CAM) xenograft system, and integrative transcriptomic analyses of patient datasets. PD-L1 was most strongly associated with restraint of Th1-associated immune signaling and influenced responsiveness to PD-1 blockade, whereas PD-L2 was associated with preservation of lineage-associated transcriptional programs and distinct treatment-response patterns. Combined disruption of both ligands enhanced Th1 immune activation while altering B-cell transcriptional states. Consistent with these findings, transcriptomic analyses in PMBCL cohorts linked PDCD1LG2 expression to B-cell identity and signaling modules, whereas CD274 expression aligned with interferon-responsive immune programs. Together, these results support a model in which PD-L1 and PD-L2 associate with distinct immune and lineage-associated states in PMBCL and provide a framework for exploring biologically informed stratification strategies in this disease.
2026-06-04 | [Long-term remission in refractory diffuse large B-cell lymphoma with concurrent epcoritamab and radiotherapy].
Epcoritamab, a subcutaneous CD3×CD20 bispecific antibody, has shown high efficacy in relapsed or refractory large B-cell lymphoma (R/R LBCL). However, treatment options are limited for patients who fail to achieve durable remission after immune-based therapy. Here, we describe a case of refractory diffuse large B-cell lymphoma in an 87-year-old woman who achieved long-term remission through concurrent epcoritamab and radiotherapy. During the fifth cycle of third-line epcoritamab therapy, positron emission tomography/computed tomography revealed persistent fluorodeoxyglucose-avid lesions in the spleen and mediastinum. Volumetric modulated arc therapy of 36 Gy in 18 fractions was administered to both sites while continuing epcoritamab (administered during the sixth cycle for the splenic lesion and during the thirteenth and fourteenth cycles for the mediastinal lesion). The combined therapy resulted in complete metabolic response without significant adverse events, and the patient remains in remission beyond 27 treatment cycles. In this case, we obtained durable remission by adding radiotherapy for localized lymphoma refractory to epcoritamab. The absence of cross-resistance between radiotherapy and systemic chemotherapy supports the rationale for local irradiation as a complementary approach to bispecific antibody therapy. This combination may represent a feasible and well-tolerated option for elderly or heavily pretreated patients with localized refractory disease.
2026-06-04 | Immune checkpoint therapy in pediatric and adolescent lymphomas.
Immune checkpoint therapy (ICT) is designed to unleash the anti-tumor activity of Tlymphocytes. Cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) inhibition and programmed death 1 (PD-1) inhibition are the most commonly utilized ICTs in clinical cancer therapy, and they enhance anti-tumor immunity by interrupting the inhibitory signals CTLA-4 and programmed death ligand 1 (PD-L1) respectively. In pediatric Hodgkin lymphoma, ICT has demonstrated remarkable efficacy in both high-risk and relapsed disease, with investigation into the efficacy in low-risk disease ongoing. Pediatric mature B-cell lymphomas have variable expression of PD-L1 with very limited experience incorporating ICT. Primary mediastinal B-cell lymphoma (PMBCL), anaplastic large cell lymphoma (ALCL), aggressive natural killer-cell lymphoma (ANKL), and peripheral T-cell lymphoma, not otherwise specified (PTCL, NOS) all consistently express PD-L1, providing strong biologic rationale for the use of ICT in these diseases. In PMBCL, the Children's Oncology Group (COG) and the National Cancer Institute (NCI) National Clinical Trials Network (NCTN) recently completed a randomized phase III trial of nivolumab in combination with chemo-immunotherapy in children and adults with newly diagnosed PMBCL. Results of this trial are expected in 2027. In ALCL and ANKL, ongoing clinical trials are evaluating the efficacy of ICT. Given the transformational role of ICT for pediatric Hodgkin lymphoma, there is significant promise for the use of ICT in multiple subtypes of pediatric non-Hodgkin lymphoma with increased expression of PD-L1.
2026-04-21 | First-line Polatuzumab vedotin plus R-CHP in primary mediastinal B-cell lymphoma: A real-world study bridging the gap of the POLARIX trial
Objective primary mediastinal B-cell lymphoma (PMBCL) is a distinct, aggressive lymphoma predominantly affecting young adults. While dose-intensive regimens are often recommended, their associated long-term toxicities and the necessity of consolidative radiotherapy remain major concerns. Given that PMBCL was explicitly excluded from the landmark POLARIX trial, we sought to evaluate the real-world efficacy and safety of first-line Pola-R-CHP in this specific population. Methods this single-center study analyzed 16 consecutive patients with newly diagnosed PMBCL treated with six cycles of Pola-R-CHP between September 2023 and June 2025. Efficacy was assessed via PET/CT (Lugano 2014 criteria) and safety via NCI-CTCAE v5.0. Results the median age was 30 years, with a female predominance (62.5%). Bulky disease was present in 62.5% of patients, and 87.5% had low-risk aaIPI scores. All patients completed six cycles of Pola-R-CHP treatment, achieving an objective response rate of 100%. The end-of-treatment complete metabolic response rate was 93.8%, with profound response deepening observed between interim and final assessments. After a median follow-up of 16.4 months, no relapses or deaths occurred, with all patients remaining in sustained remission. The most common grade 3–4 adverse event was neutropenia (43.8%). Pola-related peripheral neuropathy was predominantly low-grade (56.3% grade 1–2). Conclusion our findings provide the first preliminary clinical evidence that Pola-R-CHP is a highly effective and well-tolerated frontline strategy for PMBCL in this real-world cohort, which warrants further validation in larger, multicenter studies.
2026-02-23 | Pre-treatment endocrine-nutritional signatures predict clinical benefit from PD-1/PD-L1 blockade in hematologic malignancies.
Hematologic malignancies pose significant global health burdens, with programmed cell death protein-1 (PD-1)/programmed cell death ligand 1 (PD-L1) inhibitors revolutionizing treatment in subtypes like classical Hodgkin lymphoma (cHL) and primary mediastinal large B-cell lymphoma (PMBCL), achieving high objective response rates (ORR). However, efficacy varies widely, with limited success in multiple myeloma (< 10% ORR) and leukemias, underscoring the need for better predictors beyond tumor-intrinsic biomarkers. This review highlights pre-treatment endocrine-nutritional signatures as key host factors influencing immunotherapy outcomes. Dysregulated hormones (cortisol, thyroid, sex steroids, insulin/insulin-like growth factor-1, adipokines) and nutritional status (vitamin D, zinc, protein-energy malnutrition, iron metabolism) modulate T-cell exhaustion, myeloid suppression, and tumor microenvironment dynamics, often leading to resistance. Evidence from cohorts shows hypercortisolism, hypothyroidism, insulin resistance, vitamin D deficiency, and hypoalbuminemia correlate with inferior ORR, progression-free survival, and overall survival, while thyroid immune-related adverse events and moderate obesity predict benefit. In hematologic contexts, marrow infiltration exacerbates these imbalances, explaining heterogeneous responses. Integrated signatures (e.g., Glasgow Prognostic Score, Prognostic Nutritional Index) offer superior prognostic value, enabling targeted interventions like vitamin D supplementation, metformin, or nutritional support to enhance immune checkpoint inhibitor efficacy. Mechanistic insights reveal convergence on mTOR/IFN-γ pathways and microbiome modulation. Translating these to clinical panels could personalize immunotherapy, addressing gaps in hematologic malignancies literature and improving outcomes in relapsed/refractory settings.
cell therapies
2026-07-30 | Allogeneic hematopoietic stem cell transplantation achieves complete response in refractory primary mediastinal large B-cell lymphoma after the failure of chemotherapy, CAR-T therapy, and PD-1 blockade.
Primary mediastinal large B-cell lymphoma (PMBCL) typically responds to chemotherapy, and immunotherapies such as chimeric antigen receptor T-cell (CAR-T) therapy and the programmed cell death protein 1 (PD-1) inhibitor pembrolizumab have shown promise in relapsed or refractory cases. However, the sequential use of multiple immunotherapies for PMBCL remains poorly characterized. Here, we report a case of a 19-year-old female with PMBCL involving the mediastinum and multiple extranodal sites. After a partial response to chemotherapy, she developed a central nervous system relapse that responded to high-dose methotrexate, and the number of regrowing mediastinal lesions was reduced by radiotherapy. Subsequently, new hepatic lesions that were refractory to both CAR-T therapy and pembrolizumab emerged. Following localized liver radiotherapy, allogeneic hematopoietic stem cell transplantation (allo-HSCT) was performed, resulting in complete response. Early post-transplant, she developed a hepatitis variant of acute graft-versus-host disease, which may have reflected a graft-versus-lymphoma (GVL) effect. Despite maintaining response, the patient died one year later form a disseminated infection with multitriazole-resistant Aspergillus fumigatus. This case highlights both the potential curative role and the substantial risks of allo-HSCT in PMBCL refractory to multiple immunotherapies. The pre-transplant use of pembrolizumab and localized radiotherapy may influence transplant outcomes and warrants further investigation.
2026-07-06 | Successful Postpartum CAR T-cell Salvage Therapy for Primary Mediastinal Large B-cell Lymphoma with Residual Disease after R-CHOP During Pregnancy.
Primary mediastinal large B-cell lymphoma (PMBCL) during pregnancy is rare and presents therapeutic challenges due to fetal safety concerns. We report the case of a 29-year-old woman diagnosed with PMBCL at 19 weeks of gestation who wished to continue her pregnancy despite her diagnosis. She received rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) chemotherapy with multidisciplinary management and delivered a healthy infant at term. Although the tumor partially responded, residual disease persisted after eight cycles of treatment. She subsequently underwent chimeric antigen receptor T-cell therapy and achieved a complete response. This case highlights the importance of individualized treatment decisions and multidisciplinary collaboration in managing PMBCL during pregnancy.
2026-01-03 | Safety and effectiveness of lisocabtagene maraleucel following PD-1 blockade in relapsed or refractory PMBCL.
Primary mediastinal B-cell lymphoma (PMBCL) is a distinct subtype of large B-cell lymphoma characterized by 9p24.1 copy-number alterations and PD-1-mediated immune evasion. This profile confers high sensitivity to PD-1 inhibitors such as pembrolizumab. CD19-directed chimeric antigen receptor (CAR) T-cell therapies have shown benefit in relapsed or refractory (R/R) PMBCL, but their optimal role remains undefined. We retrospectively analyzed 31 patients with R/R B-cell lymphoma treated with lisocabtagene maraleucel (liso-cel), including four with PMBCL who received pembrolizumab prior to CAR-T. All four achieved remission before infusion, and three maintained durable complete responses (≥ 30 months). Toxicities were comparable to those in patients not treated with pembrolizumab, although one pembrolizumab-treated patient experienced fatal neurotoxicity. Favorable hematologic recovery and preserved T-cell counts at leukapheresis suggest that preceding PD-1 blockade did not compromise CAR-T manufacturing and may have enhanced T-cell fitness. These findings suggest that sequential PD-1 blockade followed by liso-cel is clinically feasible and may improve outcomes by leveraging the immune vulnerability of PMBCL. While prior studies have focused on axicabtagene ciloleucel, this report provides the first real-world data supporting the feasibility and potential benefit of this approach with liso-cel. Prospective studies are needed to confirm efficacy, safety, and optimal sequencing.
2025-10-23 | CAR-T Cell Therapy in Primary Mediastinal B-cell Lymphoma
A specific type of CAR-T cell therapy, the CAR19 therapy has demonstrated notable efficacy for relapsed or refractory (R/R) hematologic cancers, including B-cell lymphomas. After the recent reclassification of the rare subtype Primary Mediastinal B-cell Lymphoma (PMBCL) from general Diffuse Large B-cell Lymphoma (DLBCL), questions have been raised about the application of immunotherapies in this cancer, including the most discussed CAR-T cell therapy. The CAR-T cell therapy, more specifically the CAR19, exerts anti-tumor effects in multiple mechanisms, including different cytotoxic pathways—apoptosis triggering via perforin–granzyme release and Fas/FasL-pathway—driven by calcium-dependent signaling MAPK, PI3K/Akt, and NF-κB. Multiple extant clinical trials have evaluated the response of PMBCL patients to CAR19, specifically the Axi-cel, Liso-cel, and Tisa-cel therapies, focusing the rates of complete response (CR), progression-free survival (PFS), and the overall survival (OS). Studies exclusive to PMBCL patients showed that bridging therapies and other first-line treatments did not influence CAR19 effectiveness, while post-relapse application of Pembrolizumab yielded durable CRs in some patients, and allo-HSCT was associated with high mortality. The CAR-SIE trial in Italy, comparing Axi-cel CAR19 in PMBCL cancer with other B-cell lymphomas, demonstrated a better result in PMBCL patients with higher ORR, CR, and PFS. This paper integrates the underlying mechanisms of CAR19 with clinical trials, aiming to demonstrate both the potential and the limitations of this therapy in PMBCL cancer.
2025-08-19 | Refractory/relapsed primary mediastinal large B-cell lymphoma: a changing paradigm for drug therapy
Primary mediastinal large B-cell lymphoma (PMBCL) is a fairly rare variant of large B-cell lymphomas (LBCL) and accounts for about 10% of them. Despite the relatively satisfactory results of induction immunochemotherapy for PMBCL, in 10—30% of cases refractoriness or relapse of the disease occurs. Reliable prognostic models for identifying patients at risk of failure of initial treatment in PMBCL have not yet been fully developed. Salvage therapy for refractory/relapsed (r/r) PMBCL is similar to that used for r/r diffuse large B-cell lymphoma and, provided the tumor is chemosensitive, involves high-dose consolidation with autologous hematopoietic stem cell transplantation. However, relapses of PMBCL often turn out to be chemo-refractory and the effective reserves of traditional salvage therapy are exhausted. With the understanding of the molecular genetic features of PMBCL, new therapeutic targets are being actively studied. In recent years, more and more evidence has accumulated, reliably demonstrating the high and long-term effectiveness of new therapeutic options, such as immune checkpoint inhibitors and CAR-T cell therapies, which are already beginning to be integrated into earlier stages of treatment. However, the rarity of PMBCL limits the possibility of conducting randomized prospective trials to study new treatment strategies, the results of which can guide therapy in the case of r/r disease. Therefore, r/r PMBCL still represents an unresolved clinical problem.
oligonucleotides
2022-07-28 | Toll-like receptor 9 agonists and combination therapies: strategies to modulate the tumour immune microenvironment for systemic anti-tumour immunity
Over the past decade, tremendous progress has taken place in tumour immunotherapy, relying on the fast development of combination therapy strategies that target multiple immunosuppressive signaling pathways in the immune system of cancer patients to achieve a high response rate in clinical practice. Toll-like receptor 9 (TLR9) agonists have been extensively investigated as therapeutics in monotherapy or combination therapies for the treatment of cancer, infectious diseases and allergies. TLR9 agonists monotherapy shows limited efficacy in cancer patients; whereas, in combination with other therapies including antigen vaccines, radiotherapies, chemotherapies and immunotherapies exhibit great potential. Synthetic unmethylated CpG oligodeoxynucleotide (ODN), a commonly used agonist for TLR9, stimulate various antigen-presenting cells in the tumour microenvironment, which can initiate innate and adaptive immune responses. Novel combination therapy approaches, which co-deliver immunostimulatory CpG-ODN with other therapeutics, have been tested in animal models and early human clinical trials to induce anti-tumour immune responses. In this review, we describe the basic understanding of TLR9 signaling pathway; the delivery methods in most studies; discuss the key challenges of each of the above mentioned TLR9 agonist-based combination immunotherapies and provide an overview of the ongoing clinical trial results from CpG-ODN based combination therapies in cancer patients.
other
2023-12-01 | Bendamustine impairs humoral but not cellular immunity to SARS-CoV-2 vaccination in rituximab-treated B-cell lymphoma–affected patients
Background Patients with B-cell lymphoma are a fragile category of subjects, particularly exposed to infections and characterized by an impaired vaccination response due to the disease itself and, even more, to the chemotherapy regimen. For this reason, extensive knowledge of the immune response status of these subjects is of fundamental importance to obtain possible indications for a tailored immunization strategy. Methods We enrolled two cohorts of patients with B-cell lymphoma under rituximab treatment or 3–24 months after treatment. In all patients, we evaluated both humoral and cellular immunological memory toward SARS-CoV-2, after standard vaccination and upon one booster dose. Results We observed no Spike-specific IgG production in patients (n = 25) under anti-CD20 treatment, whereas patients (n = 16) vaccinated after the completion of chemotherapy showed a higher humoral response. Evaluating SARS-CoV-2–specific T-cell response, we found that patients in both cohorts had developed robust cellular immunity after vaccination. Of the 21 patients (51%) that experienced a breakthrough SARS-CoV-2 infection, only six patients developed severe disease. Interestingly, these six patients had all been treated with rituximab plus bendamustine. Notably, we observed that Spike-specific IgG levels in patients treated with rituximab plus bendamustine were absent or lower compared with those in patients treated with rituximab plus other chemotherapy, whereas Spike-specific T-cell response was not different based on chemotherapy regiment. Discussion Our results show that, in patients with B-cell lymphoma under rituximab therapy, anti–SARS-CoV-2 mRNA vaccination induces a weak or absent humoral response but a consistent T-cell response. In addition, chemotherapy regimens with bendamustine further reduce patients’ ability to mount a Spike-specific humoral response even after a long time period from chemotherapy discontinuation. These results provide evidence that different chemotherapeutics display different immunosuppressive properties that could be taken in to account in the choice of the right drug regimen for the right patient. Moreover, they question whether immunocompromised patients, particularly those treated with bendamustine, need interventions to improve vaccine-induced immune response.
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Drug Discovery Landscape
8 orphan drug designations for Primary mediastinal large B-cell lymphoma, including 4 approved therapies.
8 orphan drug designations for Primary mediastinal large B-cell lymphoma, including 4 approved therapies.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Surovatamig | antibodies | EMA | 2026-04-20 | — | AstraZeneca AB |
Methotrexate | — | EMA | 2025-08-22 | — | Helio Vision Germany GmbH |
nivolumab | antibodies | FDA | 2019-02-01 | — | Bristol-Myers Squibb Company |
Lisocabtagene maraleucel [Breyanzi] | cell therapies | EMA | 2018-11-20 | — | Bristol-Myers Squibb Pharma EEIG |
lisocabtagene maraleucel [Breyanzi] | cell therapies | FDA | 2018-07-12 | 2021-02-05 | Juno Therapeutics, Inc., a Bristol-Myers Squibb Company |
axicabtagene ciloleucel [Yescarta] | cell therapies | FDA | 2016-04-20 | 2017-10-18 | Kite Pharma, Inc. |
pembrolizumab [Keytruda] | antibodies | FDA | 2016-01-14 | 2018-06-13 | MSD International Business GmbH |
Autologous T cells transduced with retroviral vector encoding an anti-CD19 CD28/CD3-zeta chimeric antigen receptor [Yescarta] | cell therapies | EMA | 2015-10-09 | 2018-08-27 | Kite Pharma EU B.V. |
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