Radiotherapy in primary central nervous system lymphoma: Evolution of its role and current position in combined treatment strategies.

This study investigates the expansion of CAR T-cells and its association to treatment outcome. Patients with aggressive B-cell lymphomas treated with anti-CD19 CAR T-cell therapy axicabtagene ciloleucel (axi-cel) at Skåne and Sahlgrenska University Hospitals from 2019 to October 2024 were included. CAR T-cells in peripheral blood were measured by flow cytometry. Association between maximum levels of CAR T-cells and response, progression-free survival, overall survival, cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were investigated. Peak CAR T-cell levels were higher among patients with complete response (CR) at Day 30 (p = 0.013) and at 12 months (p = 0.036). CD8+ CAR T-cells were higher in patients with CR (median 135.7, IQR 52.8-433.9) compared to patients not obtaining CR (median 23.2, IQR 11.1-103.3) (p = 0.003). The ratio of CD4+:CD8+ CAR T-cells was lower in patients obtaining CR (p = 0.046). Patients with CAR T-cells above 52.4 CAR T-cells/μL showed superior progression-free survival (p < 0.001). Our study indicates that CAR T-cell levels after axi-cel correlate to durable response, progression-free survival, and that expansion of CD8+ CAR T-cells might be of specific importance for efficacy. Potentially, CAR T-cell levels may be used to enable early detection of patients with high risk of CAR T-cell treatment failure.

Angioimmunoblastic T-cell lymphoma (AITL) is an aggressive peripheral T-cell lymphoma with a poor prognosis. Lymphomatous serous effusion, defined as the presence of malignant lymphoma cells in the pleural, pericardial, or peritoneal fluid, is a rare but clinically important manifestation, particularly when a lymph node biopsy is difficult or delayed. We performed a narrative review of case reports and a small series of AITL cases with lymphomatous effusion, focusing on the clinical presentation, cytologic features, ancillary studies, and outcomes. Reported patients are typically older adults with advanced-stage disease; effusions are usually exudative, of low volume, and cytologically tumor-cell-poor but inflammation-rich; therefore, atypical T follicular helper (TFH)-type T cells are easily overlooked or misclassified. Immunocytochemistry (ICC) on cell block or cell-transfer preparations, flow cytometry, and EBER in situ hybridization improve the recognition of the AITL phenotype, whereas next-generation sequencing (NGS) can detect hallmark mutations such as RHOA G17V, TET2, DNMT3A, and IDH2 directly from effusion samples, enabling a less invasive diagnostic approach when tissue is not readily available. According to previous reports, lymphomatous effusion, which is frequently measured in months, is associated with a short survival. Based on these data and current World Health Organization (WHO) and National Comprehensive Cancer Network (NCCN) guidance, we propose a practical fluid-based diagnostic algorithm that integrates cytology, ancillary tools, and lymph node biopsy when feasible, and we highlight the need for standardized effusion-based workflows, multicenter registries, and the integration of liquid biopsies, multiomics, and artificial intelligence-assisted cytology to refine risk stratification and guide therapy in this distinct subgroup.

Plasmablastic lymphoma (PBL) is an aggressive B-cell non-Hodgkin lymphoma (NHL) commonly associated with immunosuppressed conditions, such as HIV infection. Historically, HIV-positive patients were not considered candidates for aggressive systemic therapies due to the risk of life-threatening opportunistic infections. However, with the advent of highly active antiretroviral therapy (HAART), the management of HIV-associated lymphomas has improved, allowing for more intensive treatments, including autologous stem cell transplantation (ASCT). This case series explores the safety and efficacy of ASCT in HIV-positive patients with PBL as consolidation at first complete response (CR1) following first-line chemotherapy.Patients who underwent ASCT for PBL at CR1 after first-line chemotherapy were selected from the Bone Marrow Transplant (BMT) registry from January 2015 to December 2024. Clinical details, transplant specific details and outcomes were collected from the case records.Three cases of HIV-positive patients diagnosed with PBL underwent ASCT as consolidation therapy were included in the case series. ASCT was done after achieving complete metabolic response (CMR) following induction chemotherapy. All patients received dose-adjusted EPOCH chemotherapy along with HAART. HAART was temporarily withheld during conditioning chemotherapy. Prophylactic medications were administered to prevent infections. Complications during the peri-transplant period included febrile neutropenia and mucositis, but no opportunistic infections were reported. CD4 counts dropped during the transplant period but stabilized post-transplant, with no significant long-term decline.ASCT is a safe and effective treatment option for HIV-positive patients with PBL who achieve CMR after induction chemotherapy. The procedure is well-tolerated, with manageable complications and favourable long-term outcomes. ASCT should be considered as a consolidation therapy for eligible HIV-positive patients with PBL, offering the potential for prolonged disease-free survival.

Cancer-related cognitive impairment (CRCI), a common side effect of cancer and its treatment, is characterised by difficulties in memory, attention and executive function. This qualitative sub-study was part of a single-site, parallel-group, pilot randomised controlled trial in which recruitment and retention exceeded our expectations. The aim was to explore participants' experience and motivation for sustained engagement with a web-based cognitive rehabilitation (eReCog) intervention amongst people with aggressive lymphoma who were self-reporting cognitive decline. We used an inductive qualitative approach, conducting semi-structured interviews with fourteen participants. Interviews were recorded, transcribed and a reflexive thematic approach was used to describe and interpret key themes and sub-themes in the data. Fourteen interviews were completed. We extracted four themes describing participants experience and motivation for sustained engagement with eReCog. These included information needs, experience of participation, support and ease of use. Participants were motivated to engage to gain knowledge and strategies to manage their CRCI symptoms; they enjoyed the experience and felt validated via the online community created. Finally, they valued the additional support they received and appreciated the convenience and flexibility of the web-based program. Our findings show that engagement with eReCog was driven by perceived cognitive improvements, psychosocial benefits and accessibility. Addressing both cognitive and psychosocial needs is warranted in web-based rehabilitation to foster continued participation engagement. Web-based cognitive rehabilitation interventions should enhance accessibility and earlier integration into the cancer trajectory to optimise long-term survivorship care in people with haematological cancers should be considered. Australian New Zealand Clinical Trials Registry ACTRN 12623000705684 on 30th June 2023.

Persistent and pathogen-specific infection risk during long-term survivorship after CD19 CAR-T: An Australian multi-centre cohort study.

Primary adrenal lymphoma (PAL) is a rare and aggressive extranodal lymphoma that may radiologically mimic primary adrenal carcinoma, often leading to diagnostic uncertainty and potentially unnecessary surgical intervention. Early tissue diagnosis is essential for accurate management. A 71-year-old man was evaluated for persistent left upper quadrant abdominal pain and progressive fatigue. Cross-sectional imaging revealed a large, heterogeneous mass originating from the left adrenal gland with radiologic features suggestive of local invasion. Based on the initial radiologic impression, primary adrenal carcinoma was suspected, and surgical intervention was planned accordingly. However, further review by an experienced radiologist raised suspicion of a lymphoproliferative disorder. A computed tomography-guided core needle biopsy was subsequently performed, and histopathological analysis confirmed the diagnosis of high-grade B-cell lymphoma with a Ki-67 proliferation index of approximately 80%. The patient received six cycles of well-tolerated R-CHOP chemotherapy (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone). Post-treatment imaging revealed complete resolution of the adrenal mass. At the 24-month follow-up, the patient remained in complete remission, with no evidence of disease recurrence. This case underscores the importance of multidisciplinary assessment and image-guided biopsy in the evaluation of adrenal masses. Avoiding unnecessary surgery through early tissue diagnosis enabled effective systemic treatment. In selected patients, R-CHOP chemotherapy may result in long-term disease control, even in elderly individuals with large unilateral adrenal tumors.

Tafasitamab plus lenalidomide and R-CHOP versus R-CHOP for first-line treatment of patients with high-risk diffuse large B-cell lymphoma (frontMIND): a global, phase 3, randomised, double-blind, placebo-controlled trial.

Extranodal NK/T-cell lymphoma (ENKTL) is a rare, aggressive lymphoma in which radioresistance remains a major cause of treatment failure in the relapsed/refractory (R/R) setting. We analysed XPO1 expression in ENKTL and assessed its role in radiosensitization using monoallelic XPO1-knockout models and KPT-330 in vitro and in xenografts. Mechanistic studies focused on the c-Myc-RAD51/CHEK1 axis, and clinical efficacy was evaluated in two R/R patients. Immunohistochemistry showed XPO1 overexpression in primary treatment-naïve ENKTL specimens relative to nasal polyp controls, and high XPO1 expression was associated with inferior overall survival. Monoallelic XPO1 knockout impaired homologous recombination (HR) repair, establishing a DNA repair defect exploitable as a radiosensitizing vulnerability. Pharmacologic inhibition of XPO1 with KPT-330 recapitulated these HR defects and synergised with radiotherapy. Mechanistically, KPT-330 disrupts the XPO1-c-Myc-RAD51/CHEK1 axis by blocking c-Myc nuclear export, reducing c-Myc abundance and promoter occupancy at the RAD51 and CHEK1 loci, thereby impairing HR. In two heavily pretreated R/R ENKTL patients, radiotherapy rechallenge plus low-dose KPT-330 achieved one partial response and one complete response with manageable toxicity. XPO1 inhibition impairs HR and enhances radiosensitivity by disrupting the c-Myc-RAD51/CHEK1 axis. These findings support prospective evaluation of KPT-330-based radiosensitization in R/R ENKTL.

Low triiodothyronine (T3) syndrome, also known as non-thyroidal illness syndrome (NTIS), was one of the common endocrinopathies in critical illness. The potential impacts of low T3 syndrome on survival, endocrine function, and nutritional status of patients with aggressive mature B-cell non-Hodgkin lymphoma (NHL) needed to be explored. We enrolled 225 patients. T3 levels were captured when starting chemotherapy, finishing chemotherapy, and at the first follow-up visit from 6 months after chemotherapy. Latest ultrasound results were recorded. Kaplan-Meier curves were used to compare overall survival (OS) or progression-free survival (PFS). We performed Cox's proportional hazards regression model to analyze prognostic factors of OS and PFS. Ultrasound abnormality and weight gain were tested with the χ2 test. The percentage of patients with low T3 syndrome decreased from 55.1% (124 out of 225) to 2.0% (4 out of 201), then further dropped down to 0 (0 out of 173). With a median follow-up of 32.9 months, low T3 syndrome was identified as a statistically significant factor affecting both OS (p = .047; hazard ratio [HR] = 8.18, 95% CI: 1.03-64.97) and PFS (p = .049; HR = 4.64, 95% CI: 1.01-21.31) in multivariate analysis. No significant effects of low T3 syndrome on abnormal thyroid ultrasound results and weight gain were found. In conclusion, low T3 syndrome has a high incidence in pediatric patients with aggressive mature B-cell NHL, and low T3 syndrome has a significant impact on long-term survival. It appears transient and could not contribute to impaired thyroid function.

Real-world patient-reported symptomatic adverse events and concordance with physician assessments after CAR T-cell therapy in patients with aggressive B-cell lymphomas: a prospective study.

Peripheral T-cell lymphomas are rare, generally aggressive lymphomas. Early stage disease represents a minority, and current treatment guidelines generally do not distinguish by stage or do so based on limited evidence. In order to understand practices and outcomes in this setting, we evaluated a multicenter cohort of patients with early stage nodal T-cell lymphomas (peripheral Tcell lymphoma, not otherwise specified [PTLC-NOS], nodal T-follicular helper cell lymphoma [TFHL], and anaplastic lymphoma kinase-negative anaplastic large cell lymphoma [ALK-negative ALCL]) from 2001 to 2022. We evaluated differences in outcomes by stage, histology, and treatment strategy, including consolidation after chemotherapy, which often includes radiation therapy (RT) and sometimes includes autologous stem cell transplant (ASCT). In total, we identified 132 patients. All patients received chemotherapy, 78 (59%) received chemotherapy plus RT, and 18 (14%) received ASCT. For the entire cohort, five-year progression-free (PFS) and overall survival (OS) was 56% and 68%. Outcomes were particularly encouraging in stage I disease, with five-year PFS and OS of 66% and 79%. Among patients with stage I disease responding to chemotherapy, patients treated with chemoradiation had especially favorable outcomes (five-year PFS: 70%, OS: 86%). Among patients with stage II disease responding to chemotherapy, outcomes were inferior to those with stage I disease and were similar regardless of treatment strategy. These findings show improved outcomes in early stage nodal T-cell lymphomas compared to historical data for allcomers. In addition, favorable outcomes in stage I disease treated with chemoradiation support such strategy as an excellent treatment option in this setting.

Development and Validation of a Risk Assessment Model for Hospital-Acquired Venous Thrombosis in Medical Inpatients with Cancer.

Epstein-Barr virus (EBV)-positive diffuse large B-cell lymphoma (EBV⁺DLBCL) is an aggressive lymphoma with poor outcomes and an incompletely understood pathogenesis, frequently attributed to immunosenescence. However, its occurrence across all age groups suggests alternative mechanisms. Here, we integrate functional profiling of peripheral antiviral T-cell immunity with high-dimensional spatial proteomics and mechanistic in vitro modelling to define the immunological landscape of EBV⁺DLBCL. We show that both EBV⁺ and EBV⁻DLBCL patients exhibit broad impairments in antiviral T-cell responses compared with healthy controls, affecting latent and lytic EBV antigens as well as non-EBV viral targets, with deficits most pronounced in EBV⁺ patients. Spatial proteomic analysis revealed that EBV⁺DLBCL harbours a profoundly immunosuppressive tumour microenvironment characterised by relative loss of intratumoural CD8⁺ T cells, expansion of PD-1⁺ regulatory and exhausted T-cell populations and dense aggregates of PD-L1⁺/IDO1⁺ macrophages. Compared with EBV⁺ classical Hodgkin lymphoma and infectious mononucleosis, EBV⁺DLBCL displayed the most marked macrophage-associated immunosuppressive signature and the lowest T-cell density. Suppressive myeloid niches were preferentially enriched around LMP1-expressing tumour cells, a feature not observed in the other EBV-associated conditions. Together, these findings indicate that EBV⁺DLBCL is driven by the convergence of systemic antiviral immune dysfunction and an LMP1-dependent suppressive tumour microenvironment.

Risk of lymphoma associated with biologics and immunosuppressants in inflammatory bowel disease patients: a nationwide nested case-control study.

Large B-cell lymphomas may exhibit morphology typical of a diffuse large B-cell lymphoma (DLBCL) or a Burkitt lymphoma. Rarely, they may exhibit either a blastoid morphology or features that are intermediate between a DLBCL and Burkitt lymphoma (the so-called intermediate/blastoid morphology); the term high-grade B-cell lymphoma (HGBL) is used to describe the latter. The presence of MYC and BCL2 rearrangements can be seen either in HGBL or in lymphomas with DLBCL morphology (so-called double-hit lymphoma) and rarely in plasmablastic lymphomas. Herein, we report a rare occurrence of a double-hit lymphoma with plasmablastic features in a patient with a history of follicular lymphoma (FL) aberrantly expressing keratin in the transformed component posing a diagnostic conundrum. Immunohistochemistry and molecular work-up in conjunction with clinical history were essential in arriving at the correct diagnosis and thus illustrating a diagnostic pitfall.

Peripheral T-cell lymphoma-not otherwise specified (PTCL-NOS) is a highly aggressive and heterogeneous lymphoma subtype with a poor prognosis. This study aims to develop a machine learning-based model to predict early death (within 3 months of diagnosis) in PTCL-NOS patients using data from the SEER database (2016-2021). A total of 1,156 patients were included and randomly divided into training (n = 809) and validation (n = 347) sets. Key predictive factors were identified through Boruta and LASSO algorithms, including chemotherapy, radiotherapy, age, B symptoms, primary tumor site, Summary Stage, and Ann Arbor Stage. Seven machine learning models were constructed and evaluated using AUROC, AUPRC, calibration curves, Brier scores, and decision curve analysis. XGBoost demonstrated the best predictive performance (AUROC = 0.842 in training and 0.774 in validation). This study provides a novel and interpretable predictive tool that can aid in early risk stratification and personalized treatment planning for PTCL-NOS patients, ultimately improving clinical outcomes.

Transdifferentiation from follicular lymphoma (FL) to histiocytic/dendritic cell sarcoma (HDS) is rare and requires molecular confirmation of shared clonal origin. Targetable mutations such as BRAF V600E may offer therapeutic opportunities in such aggressive neoplasms. We report an exceptional case of untreated localised FL transdifferentiated to an HDS after 18 years. Shared BCL2 rearrangement and mutation profile confirmed a clonal link, while the HDS acquired an additional BRAF V600E mutation. Treatment with BRAF/MEK inhibitors yielded a sustained 18-month clinical response. The disease later relapsed as high-grade B-cell lymphoma with MYC and BCL2 rearrangements (HGBCL-MYC/BCL2), still harbouring the BRAF mutation. Complete remission was achieved with Rituximab, Cyclophosphamide, Hydroxydaunorubicin, Oncovin and Prednisone, but the double-hit lymphoma relapsed 14 months later.This case illustrates sequential transformation from FL to BRAF-mutated HDS with excellent response to BRAF/MEK inhibition, followed by evolution into HGBCL-MYC/BCL2 responding transiently to immunochemotherapy, emphasising the value of repeated histological and molecular reassessment in FL evolution.

Burkitt lymphoma (BL) is an aggressive B-cell lymphoma predominantly affecting children in sub-Saharan Africa. It constitutes 50-70% of pediatric non-Hodgkin lymphomas in the region. In Tanzania, understanding the treatment outcomes and one-year survival rates at two major oncology centers can inform strategies to enhance survival. This retrospective cohort study analyzed children under 18 diagnosed with Burkitt lymphoma and treated at two tertiary care hospitals between January 2020 and December 2022. The study utilized Stata 18 to analyze data from medical records, focusing on demographic and clinical characteristics, Kaplan-Meier survival analysis, and Cox proportional hazards models to identify mortality predictors. The study analyzed 72 children with Burkitt lymphoma (mean age: 5.8 years), predominantly male (70.8%), with 52.8% from rural areas. Tumor sites were mainly mandibular (47.2%) and abdominal (41.7%). Treatment outcomes varied between hospitals: Kilimanjaro Christian Medical Centre had a higher complete remission rate (61.3%) compared to BMC (36.6%), while BMC experienced higher relapse (19.5%) and treatment abandonment rates (22.0%) than KCMC (6.5% and 3.2%, respectively). The one-year post-treatment survival rate was 75% overall, with a significantly longer mean survival time at KCMC (37.1 months) versus BMC (16.4 months). Key predictors of mortality included bone marrow involvement, adjusted hazard ratio (AHR) = 32.48 and CNS involvement (AHR = 34.00, 95% CI). The study reveals a 75% one-year survival rate for children with Burkitt lymphoma in Tanzania. However, this reflects short-term (one-year) survival and cannot be directly compared with the WHO Global Initiative for Childhood Cancer 2030 target, which refers to five-year overall survival. However, high treatment abandonment, relapse, and death rates, along with low complete remission rates, pose significant challenges. Key factors contributing to poor prognosis include CNS and bone marrow involvement. The study recommends comprehensive interventions, improved care access, and exploring alternative treatments like stem cell transplantation.

We evaluated the in vivo efficacy of polatuzumab vedotin (POLA), administered as a single agent or in combination with venetoclax (VEN), in relapsed/refractory (R/R) mantle cell lymphoma (MCL) and BCL2-positive diffuse large B-cell lymphoma (DLBCL). In addition, we investigated the mechanisms underlying acquired resistance to POLA in vivo. Experimental therapy was assessed using a panel of 8 cell line-derived xenografts (CDXs) and 16 patient-derived xenografts (PDXs) representing MCL and DLBCL. Bulk transcriptomic profiling was performed on 7 paired tumor samples obtained from POLA-resistant tumors (generated in mice following repeated POLA-based treatments) and their corresponding untreated controls. POLA demonstrated robust single-agent antitumor activity in vivo, including in PDX models derived from patients with ibrutinib-resistant MCL. In the majority of tested PDX models, the combination of POLA and VEN produced synergistic antitumor effects without evidence of measurable toxicity. CD79B expression levels did not correlate with POLA efficacy. Following POLA treatment failure, downregulation of CD79B was observed in only a minority of models, indicating the involvement of additional mechanisms of acquired resistance. Bulk transcriptomic analysis of 7 paired POLA-resistant versus untreated tumors identified a conserved gene expression signature across all models, comprising 523 downregulated and 284 upregulated genes. This signature likely reflects core pathways associated with POLA resistance and highlights potential novel therapeutic vulnerabilities. These findings strongly support further clinical investigation of POLA in combination with VEN as a BCL2- and MCL1-targeting therapeutic strategy in patients with R/R MCL and BCL2-positive R/R DLBCL.