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Macrophages are abundant immune cells in the microenvironment of diffuse large B-cell lymphoma (DLBCL). Macrophage estimation by immunohistochemistry shows varying prognostic significance across studies in DLBCL, and does not provide a comprehensive analysis of macrophage subtypes. Here, using digital spatial profiling with whole transcriptome analysis of CD68+ cells, we characterize macrophages in distinct spatial niches of reactive lymphoid tissues (RLTs) and DLBCL. We reveal transcriptomic differences between macrophages within RLTs (light zone /dark zone, germinal center/ interfollicular), and between disease states (RLTs/ DLBCL), which we then use to generate six spatially-derived macrophage signatures (MacroSigs). We proceed to interrogate these MacroSigs in macrophage and DLBCL single-cell RNA-sequencing datasets, and in gene-expression data from multiple DLBCL cohorts. We show that specific MacroSigs are associated with cell-of-origin subtypes and overall survival in DLBCL. This study provides a spatially-resolved whole-transcriptome atlas of macrophages in reactive and malignant lymphoid tissues, showing biological and clinical significance.

The B cell leukemia/lymphoma 2 (BCL-2) inhibitor venetoclax is effective in chronic lymphocytic leukemia (CLL); however, resistance may develop over time. Other lymphoid malignancies such as diffuse large B cell lymphoma (DLBCL) are frequently intrinsically resistant to venetoclax. Although genomic resistance mechanisms such as BCL2 mutations have been described, this probably only explains a subset of resistant cases. Using 2 complementary functional precision medicine techniques - BH3 profiling and high-throughput kinase activity mapping - we found that hyperphosphorylation of BCL-2 family proteins, including antiapoptotic myeloid leukemia 1 (MCL-1) and BCL-2 and proapoptotic BCL-2 agonist of cell death (BAD) and BCL-2 associated X, apoptosis regulator (BAX), underlies functional mechanisms of both intrinsic and acquired resistance to venetoclax in CLL and DLBCL. Additionally, we provide evidence that antiapoptotic BCL-2 family protein phosphorylation altered the apoptotic protein interactome, thereby changing the profile of functional dependence on these prosurvival proteins. Targeting BCL-2 family protein phosphorylation with phosphatase-activating drugs rewired these dependencies, thus restoring sensitivity to venetoclax in a panel of venetoclax-resistant lymphoid cell lines, a resistant mouse model, and in paired patient samples before venetoclax treatment and at the time of progression.

PURPOSE: Novel targeted and immunotherapies have improved outcomes in relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL), but toxicities limit widespread use. The selective Bruton tyrosine kinase (BTK) inhibitor acalabrutinib has activity in patients with R/R DLBCL but durable responses are uncommon. STAT3 inhibition has demonstrated clinical activity in DLBCL. PATIENTS AND METHODS: Final results of the phase I study of acalabrutinib plus STAT3 inhibitor (danvatirsen; AZD9150) in patients with R/R DLBCL are reported. Danvatirsen 200 mg intravenous infusion [Days 1, 3, 5 (Cycle 1); weekly infusions starting Day 8, Cycle 1] was administered in combination with oral acalabrutinib 100 mg twice daily until progressive disease (PD) or unacceptable toxicity. Primary endpoints were safety and tolerability. Secondary endpoints included efficacy, pharmacokinetics, and immunogenicity. RESULTS: Seventeen patients received combination treatment. One dose-limiting toxicity (Grade 3 liver transaminase) occurred in 1 patient. The most common reason for treatment discontinuation was PD (65%). In evaluable patients (n = 17), objective response rate was 24%; median duration of response was 1.9 months. All responders with available DLBCL cell-of-origin data were either activated B-cell or nongerminal center B-cell like subtype. Genetic subtype did not correlate with response. Baseline and longitudinal plasma cell-free DNA (cfDNA) concentrations were mostly higher in nonresponding patients. cfDNA changes were generally concordant with imaging. Pretreatment circulating B-cell levels were higher in responders versus nonresponders. CONCLUSIONS: Targeting both STAT3 and BTK in combination is safe and tolerable but efficacy is limited in R/R DLBCL. Results support evaluation of circulating tumor DNA as a biomarker for clinical response.

Introduction: Primary central nervous system lymphoma (PCNSL) is an extranodal lymphoid neoplasm that affects the brain, spinal cord, leptomeninges or the vitreous-retina space, without systemic involvement. It represents 3% of CNS tumors predominantly in the context of immunosuppression (HIV infection, post-transplant). The clinical presentation and radiological findings are highly variable, representing a diagnostic challenge especially in immunocompetent patients. Its prognosis is unfavorable despite the high response to initial treatment. Clinical case: 69-year-old man, hospitalized for upper motor neuron syndrome and intracranial hypertension. No abnormal laboratory studies were found and a contrast-enhanced tomography of the head revealed multiple contrastenhancing lesions with vasogenic edema. Extension studies in search of a primary tumor were negative. MRI demonstrated lesions with characteristics consistent with lymphoma. A PET/CT with 18-fluorodeoxyglucose was performed, which ruled out systemic involvement, and a brain biopsy confirmed PCNSL with histopathologic features of a diffuse large B cell lymphoma. The patient was sent to the hematooncology department at a third level hospital for chemotherapy, he completed two cycles of high-dose methotrexate plus rituximab without response and fatal outcome. Conclusions: PCNSL is an aggressive, low-incidence, extranodal lymphoma, which should be considered in immunocompetent patients over 60 years old with multiple brain lesions, in order to initiate treatment in a timely manner. [ABSTRACT FROM AUTHOR]

Background: Epiregulin is a molecule that plays a role in cell proliferation, tumor development, inflammation, and angiogenesis in malignant diseases. Aim: Our study aims to reveal, for the first time, the predictive value of this molecule in non-Hodgkin lymphoma (NHL) and its association with disease stage, cell type, and extranodal involvement. Methods: The study is an observational case–control trial involving 60 newly diagnosed NHL patients and 60 healthy individuals (control group) between 18 and 75 years old. Demographic characteristics of all volunteers, stages of patients' illnesses and lymphoma cell types, hemogram, biochemistry tests, beta 2-microglobulin, C-reactive protein (CRP), and epiregulin levels were measured and statistically evaluated. Results: Epiregulin levels were significantly higher in NHL patients compared to the control group (P < 0.0001). Similarly, a significant increase in epiregulin levels was observed in advanced NHL patients. Furthermore, the most common NHL subgroup within the NHL group, diffuse Large B Cell Lymphoma (DLBCL), and the subgroup with extranodal involvement also had significantly higher levels of epiregulin. A positive correlation was found between the epiregulin molecule and CRP, beta 2-microglobulin, and lactate dehydrogenase (LDH) levels in NHL patients. Conclusion: Our study suggests that serum epiregulin levels, discovered to increase in NHL patients for the first time, may be an independent predictive molecule in an advanced stage, extranodal involvement, and the DLBCL subtype of this disease. Epiregulin positively correlates with prognostic molecules such as beta 2-microglobulin, LDH, and CRP. Illuminating its potential role in NHL pathogenesis could make epiregulin a vital drug target for treatment. [ABSTRACT FROM AUTHOR]

Checkpoint inhibitor (CPI) therapy with anti-PD-1 antibodies has been associated with mixed outcomes in small cohorts of patients with relapsed aggressive B-cell lymphomas after CAR-T failure. To define CPI therapy efficacy more definitively in this population, we retrospectively evaluated clinical outcomes in a large cohort of 96 patients with aggressive B-cell lymphomas receiving CPI therapy after CAR-T failure across 15 US academic centers. Most patients (53%) had diffuse large B-cell lymphoma, were treated with axicabtagene ciloleucel (53%), relapsed early (≤180 days) after CAR-T (83%), and received pembrolizumab (49%) or nivolumab (43%). CPI therapy was associated with an overall response rate of 19% and a complete response rate of 10%. Median duration of response was 221 days. Median progression-free survival (PFS) and overall survival (OS) were 54 and 159 days, respectively. Outcomes to CPI therapy were significantly improved in patients with primary mediastinal B-cell lymphoma. PFS (128 vs 51 days) and OS (387 vs 131 days) were significantly longer in patients with late (>180 days) vs early (≤180 days) relapse after CAR-T. Grade ≥3 adverse events occurred in 19% of patients treated with CPI. Most patients (83%) died, commonly because of progressive disease. Only 5% had durable responses to CPI therapy. In the largest cohort of patients with aggressive B-cell lymphoma treated with CPI therapy after CAR-T relapse, our results reveal poor outcomes, particularly among those relapsing early after CAR-T. In conclusion, CPI therapy is not an effective salvage strategy for most patients after CAR-T, where alternative approaches are needed to improve post-CAR-T outcomes.

PURPOSE: Brexucabtagene autoleucel (brexu-cel) is an autologous CD19-directed chimeric antigen receptor (CAR) T-cell therapy approved for relapsed/refractory mantle cell lymphoma (MCL). This therapy was approved on the basis of the single-arm phase II ZUMA-2 trial, which showed best overall and complete response rates of 91% and 68%, respectively. We report clinical outcomes with brexu-cel in the standard-of-care setting for the approved indication. PATIENTS AND METHODS: Patients who underwent leukapheresis between August 1, 2020 and December 31, 2021, at 16 US institutions, with an intent to manufacture commercial brexu-cel for relapsed/refractory MCL, were included. Patient data were collected for analyses of responses, outcomes, and toxicities as per standard guidelines. RESULTS: Of 189 patients who underwent leukapheresis, 168 (89%) received brexu-cel infusion. Of leukapheresed patients, 79% would not have met ZUMA-2 eligibility criteria. Best overall and complete response rates were 90% and 82%, respectively. At a median follow-up of 14.3 months after infusion, the estimates for 6- and 12-month progression-free survival (PFS) were 69% (95% CI, 61 to 75) and 59% (95% CI, 51 to 66), respectively. The nonrelapse mortality was 9.1% at 1 year, primarily because of infections. Grade 3 or higher cytokine release syndrome and neurotoxicity occurred in 8% and 32%, respectively. In univariable analysis, high-risk simplified MCL international prognostic index, high Ki-67, TP53 aberration, complex karyotype, and blastoid/pleomorphic variant were associated with shorter PFS after brexu-cel infusion. Patients with recent bendamustine exposure (within 24 months before leukapheresis) had shorter PFS and overall survival after leukapheresis in intention-to-treat univariable analysis. CONCLUSION: In the standard-of-care setting, the efficacy and toxicity of brexu-cel were consistent with those reported in the ZUMA-2 trial. Tumor-intrinsic features of MCL, and possibly recent bendamustine exposure, may be associated with inferior efficacy outcomes.

Although prediagnostic circulating concentrations of the immune activation markers soluble CD27 (sCD27), sCD30 and chemokine ligand-13 (CXCL13) have been associated with non-Hodgkin lymphoma (NHL) risk, studies have been limited by sample size in associations with NHL subtypes. We pooled data from eight nested case-control studies to investigate subtype-specific relationships for these analytes. Using polytomous regression, we calculated odds ratios (ORs) with 95% confidence intervals (CIs) relating study-specific analyte tertiles to selected subtypes vs controls (n = 3310): chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL; n = 623), diffuse large B cell lymphoma (DLBCL; n = 621), follicular lymphoma (FL; n = 398), marginal zone lymphoma (MZL; n = 138), mantle cell lymphoma (MCL; n = 82) and T cell lymphoma (TCL; n = 92). We observed associations with DLBCL for elevated sCD27 [OR for third vs first tertile (ORT3 ) = 2.2, 95% CI = 1.6-3.1], sCD30 (ORT3  = 2.0, 95% CI = 1.6-2.5) and CXCL13 (ORT3  = 2.3, 95% CI = 1.8-3.0). We also observed associations with sCD27 for CLL/SLL (ORT3  = 3.3, 95% CI = 2.4-4.6), MZL (ORT3  = 7.7, 95% CI = 3.0-20.1) and TCL (ORT3  = 3.4, 95% CI = 1.5-7.7), and between sCD30 and FL (ORT3  = 2.7, 95% CI = 2.0-3.5). In analyses stratified by time from phlebotomy to case diagnosis, the sCD27-TCL and all three DLBCL associations were equivalent across both follow-up periods (

BackgroundTo examine the contribution of B-cell activation molecules to B-cell follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL), a prospective study was conducted using pre-diagnosis serial serum samples from the US Department of Defense Serum Repository.MethodsEach case (n = 142 FL, n = 211 DLBCL) was matched to two controls on age, gender, race, military branch, and blood collection dates. Immune activation molecules (IL1β, IL2, IL4, IL5, IL6, IL10, IL12, CXCL13, IL8, TNFα, IFNγ, GM-CSF, VEGF, sCD30, IgE) were quantified using ELISA or multiplex immunometric (Luminex) assay. Longitudinal data were analyzed using linear mixed modeling. As serial specimens were collected over several years before diagnosis, we evaluated the temporal dynamics of these markers.ResultsIncreased serum levels of sCD30, CXCL13, and to a lesser extent IL10, were associated with both FL and DLBCL in cases compared with controls, with a median follow-up of 5.5 years from the earliest specimen collection to diagnosis date. Significant increasing sCD30 and CXCL13 trajectories for FL and DLBCL subtypes were noted starting at the earliest time points and with IL10 levels increasing significantly at time points closer to diagnosis.ConclusionsThese results suggest that sCD30, CXCL13, and IL10 may contribute to the etiology of FL and DLBCL and are potential biomarkers for these non-Hodgkin lymphoma subtypes.ImpactThe increasing trajectories of the B-cell activation molecules, sCD30, CXCL13, and to a lesser extent IL10, may indicate early disease-induced effects or reflect the chronic stimulation of B-cells that promotes the development of FL and DLBCL subtypes.

Multicellular life requires altruistic cooperation between cells. The adaptive immune system is a notable exception, wherein germinal center B cells compete vigorously for limiting positive selection signals. Studying primary human lymphomas and developing new mouse models, we found that mutations affecting BTG1 disrupt a critical immune gatekeeper mechanism that strictly limits B cell fitness during antibody affinity maturation. This mechanism converted germinal center B cells into supercompetitors that rapidly outstrip their normal counterparts. This effect was conferred by a small shift in MYC protein induction kinetics but resulted in aggressive invasive lymphomas, which in humans are linked to dire clinical outcomes. Our findings reveal a delicate evolutionary trade-off between natural selection of B cells to provide immunity and potentially dangerous features that recall the more competitive nature of unicellular organisms.

Richter syndrome (RS) arising from chronic lymphocytic leukemia (CLL) exemplifies an aggressive malignancy that develops from an indolent neoplasm. To decipher the genetics underlying this transformation, we computationally deconvoluted admixtures of CLL and RS cells from 52 patients with RS, evaluating paired CLL-RS whole-exome sequencing data. We discovered RS-specific somatic driver mutations (including IRF2BP2, SRSF1, B2M, DNMT3A and CCND3), recurrent copy-number alterations beyond del(9p21)(CDKN2A/B), whole-genome duplication and chromothripsis, which were confirmed in 45 independent RS cases and in an external set of RS whole genomes. Through unsupervised clustering, clonally related RS was largely distinct from diffuse large B cell lymphoma. We distinguished pathways that were dysregulated in RS versus CLL, and detected clonal evolution of transformation at single-cell resolution, identifying intermediate cell states. Our study defines distinct molecular subtypes of RS and highlights cell-free DNA analysis as a potential tool for early diagnosis and monitoring.

Loss of function in the tumor suppressor gene TP53 is the most common alteration seen in human cancer. In mice, P53 deletion in all cells leads predominantly to the development of T-cell lymphomas, followed by B-cell lymphomas, sarcomas and teratomas. In order to dissect the role of P53 in the hematopoietic system, we generated and analyzed two different mouse models deficient for P53. A pan-hematopoietic P53 deletion mouse was created using Vav1-Cre based deletion; and a B-cell-specific deletion mouse was created using a CD19-Cre based deletion. The Vav1-P53CKO mice predominantly developed T-cell malignancies in younger mice, and myeloid malignancies in older mice. In T-cell malignancies, there was accelerated thymic cell maturation with overexpression of Notch1 and its downstream effectors. CD19-P53CKO mice developed marginal zone expansion in the spleen, followed by marginal zone lymphoma, some of which progressed to diffuse large B-cell lymphomas. Interestingly, marginal zone and diffuse large B-cell lymphomas had a unique gene expression signature characterized by activation of the PI3K pathway, compared with wild type marginal zone or follicular cells of the spleen. This study demonstrates lineage specific P53 deletion leading to distinct phenotypes secondary to unique gene expression programs set in motion.

Epstein-Barr virus (EBV; human herpesvirus 4; HHV-4) and Kaposi sarcoma-associated herpesvirus (KSHV; human herpesvirus 8; HHV-8) are human gammaherpesviruses that have oncogenic properties. EBV is a lymphocryptovirus, whereas HHV-8/KSHV is a rhadinovirus. As lymphotropic viruses, EBV and KSHV are associated with several lymphoproliferative diseases or plasmacytic/plasmablastic neoplasms. Interestingly, these viruses can also infect epithelial cells causing carcinomas and, in the case of KSHV, endothelial cells, causing sarcoma. EBV is associated with Burkitt lymphoma, classic Hodgkin lymphoma, nasopharyngeal carcinoma, plasmablastic lymphoma, lymphomatoid granulomatosis, leiomyosarcoma, and subsets of diffuse large B-cell lymphoma, post-transplant lymphoproliferative disorder, and gastric carcinoma. KSHV is implicated in Kaposi sarcoma, primary effusion lymphoma, multicentric Castleman disease, and KSHV-positive diffuse large B-cell lymphoma. Pathogenesis by these two herpesviruses is intrinsically linked to viral proteins expressed during the lytic and latent lifecycles. This comprehensive review intends to provide an overview of the EBV and KSHV viral cycles, viral proteins that contribute to oncogenesis, and the current understanding of the pathogenesis and clinicopathology of their related neoplastic entities.

Rare cases of human herpesvirus 8 (HHV8)-negative effusion-based large B-cell lymphoma (EB-LBCL) occur in body cavities without antecedent or concurrent solid mass formation. In contrast to HHV8 + primary effusion lymphoma (PEL), EB-LBCL has no known association with HIV or HHV8 infection. However, the small sample sizes of case reports and series worldwide, especially from non-Japanese regions, have precluded diagnostic uniformity. Therefore, we conducted a retrospective, multi-institutional study of 55 cases of EB-LBCL and performed a comprehensive review of an additional 147 cases from the literature to identify distinct clinicopathologic characteristics. In our study, EB-LBCL primarily affected elderly (median age 80 years), immunocompetent patients and manifested as lymphomatous effusion without a solid component. The lymphomatous effusions mostly occurred in the pleural cavity (40/55, 73%), followed by the pericardial cavity (17/55, 31%). EB-LBCL expressed CD20 (53/54, 98%) and PAX5 (23/23, 100%). Most cases (30/36, 83%) were of non-germinal center B-cell subtype per the Hans algorithm. HHV8 infection was absent (0/55, 0%), while Epstein-Barr virus was detected in 6% (3/47). Clinically, some patients were managed with drainage alone (15/34, 44%), while others received rituximab alone (4/34, 12%) or chemotherapy (15/34, 44%). Eventually, 56% (22/39) died with a median overall survival (OS) of 14.9 months. Our findings were similar to those from the literature; however, compared to the non-Japanese cases, the Japanese cases had a significantly higher incidence of pericardial involvement, a higher rate of chemotherapy administration, and longer median OS. Particularly, we have found that Japanese residence, presence of pericardial effusion, and absence of MYC rearrangement are all favorable prognostic factors. Our data suggest that EB-LBCL portends a worse prognosis than previously reported, although select patients may be managed conservatively. Overall, EB-LBCL has distinct clinicopathologic characteristics, necessitating the establishment of separate diagnostic criteria and consensus nomenclature.

Secondary central nervous system lymphoma (SCNSL) is associated with poor prognosis and new therapeutic approaches are needed. The pivotal trial that led to US Food and Drug Administration (FDA) approval of axicabtagene ciloleucel excluded patients with SCNSL and human immunodeficiency virus. In this multi-institutional retrospective study, 14 SCNSL patients treated with axicabtagene ciloleucel, 3 of whom had human immunodeficiency virus, experienced rates of severe neurotoxicity and complete response of 32% and 58%, respectively. This is similar to rates observed in the pivotal ZUMA-1 trial that led to the approval of axi-cel at median follow-up of 5.9 months. Chimeric antigen receptor T-cell therapy is potentially a life-saving therapy for SCNSL patients and should not be withheld.

BackgroundOdronextamab is a hinge-stabilised, fully human IgG4-based CD20 × CD3 bispecific antibody that binds CD3 on T cells and CD20 on B cells. We aimed to evaluate the safety and antitumour activity of odronextamab in patients with relapsed or refractory B-cell non-Hodgkin lymphoma.MethodsThis single-arm, multicentre, phase 1, dose-escalation and dose-expansion (ELM-1) trial was conducted at ten academic sites across the USA and Germany. Patients aged 18 years or older with CD20-positive relapsed or refractory B-cell malignancies who previously received CD20-directed antibody therapy and who had at least one measurable lesion, and an ECOG performance status of 0 or 1 were included. Patients received intravenous odronextamab, according to a step-up dosing schedule in cycle 1, followed by treatment once per week at target doses ranging from 0·1 mg to 320 mg during cycles 2-4 (each cycle was 21 days). After cycle 4, maintenance treatment occurred every 2 weeks until disease progression or unacceptable toxicity. The primary endpoint of safety was assessed by the incidence of adverse events and dose-limiting toxicities to determine the maximum tolerated dose or phase 2 dose of odronextamab, or both. Preliminary antitumour activity, as measured by objective response rate, was a secondary endpoint. This study is registered with ClinicalTrials.gov, NCT02290951.FindingsFrom Feb 4, 2015, to Sept 25, 2021, 145 heavily pretreated patients (median of 3 (IQR 2-5] previous therapies) were enrolled (94 to the dose-escalation and 51 to the dose-expansion part of the study). The median age of patients was 67·0 years (IQR 57·0-73·0); 101 (70%) were male and 44 (30%) were female; most participants were White (119 [82%]) and not Hispanic or Latino (132 [91%]). 42 (29%) patients received previous CAR T therapy and 119 (82%) were refractory to the last line of therapy. Median duration of follow-up was 4·2 months (IQR 1·5-11·5). During dose escalation, odronextamab was administered up to the maximum dose of 320 mg once per week and no dose-limiting toxicities were observed. The recommended dose for expansion in patients with follicular lymphoma grade 1-3a was 80 mg and was 160 mg for patients with diffuse large B-cell lymphoma. Cytokine release syndrome and neurological treatment-emergent adverse events were predominantly low grade and did not result in treatment discontinuation. The most common grade 3 or worse treatment-emergent adverse events were anaemia (36 [25%]), lymphopenia (28 [19%]), hypophosphataemia (27 [19%]), neutropenia (27 [19%]), and thrombocytopenia (20 [14%]). Serious treatment-emergent adverse events occurred in 89 (61%) of 145 patients; the most frequent were cytokine release syndrome (41 [28%]), pyrexia (11 [8%]), pneumonia (nine [6%]), and infusion-related reaction (six [4%]). Four deaths were considered related to treatment (gastric perforation in a patient with gastric involvement by lymphoma, lung infection, pneumonia, and tumour-lysis syndrome). Objective response rate was 51% (95% CI 42-59; 72 of 142). In patients with follicular lymphoma who received odronextamab doses of 5 mg or higher, the objective response rate was 91% (95% CI 75-98; 29 of 32) and the complete response rate was 72% (95% CI 53-86; 23 of 32). In patients with diffuse large B-cell lymphoma without previous CAR T-cell therapy who received doses of 80 mg or higher, the objective response rate was 53% (eight of 15) and all responses were complete responses. In patients with diffuse large B-cell lymphoma who had previous CAR T-cell therapy and received doses of 80 mg or higher, the objective response rate was 33% (ten of 30) and complete response rate was 27% (eight of 30).InterpretationOdronextamab monotherapy showed a manageable safety profile and encouraging preliminary activity, including durable responses in heavily pretreated patients with B-cell non-Hodgkin lymphoma, supporting further clinical investigation in phase 2 and 3 trials.FundingRegeneron Pharmaceuticals.

Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of lymphoma in dogs with a multicentric form. This study aimed to assemble 41 variants of the previously reported genes and to investigate these variants in canine DLBCL using the Agena MassARRAY platform. These variants were chosen based on the high prevalence observed in canine B- and T-cell lymphomas, their significance for target therapy, and compatibility for multiplex PCR amplification. Lymph node biopsy was performed from 60 dogs with B-cell lymphoma comprising 47 purebred and 13 crossbred dogs. All dogs presented single nucleotide polymorphisms (SNPs) at HYAL4 and SATB1 genes. The lesser mutual SNPs were observed at SEL1L, excluding a cocker spaniel, and c-Kit, with the exception of a pug and a French bulldog. Even though no statistical association was noted between each SNP and dog breed, purebreds were 3.88 times more likely to have a SNP at FLT3 rs852342480 (95%CI 0.50-45.03, p = 0.26), 3.64 times at TRAF3 F306X (95%CI 0.58-42.50, p = 0.43) and 2.66 times at TRAF3 E303EX (95%CI 0.56-13.12, p = 0.31). Also, DLBCL dogs (CHOP-based treatment) with c-Kit T425= had a poorer prognosis with shorter median overall survival times (OST) than dogs with the wild type. Dogs treated with COP chemotherapy and contained 3-5 variants at SEL1L were associated with decreased median OST. Therefore, this SNPs lymphoma panel provides valuable information that we can use to outline a prognosis and develop a treatment plan for the targeted therapy of each dog.

There are no studies comparing the prognosis for mature T-cell lymphoma (TCL) in people with HIV (PWH) to people without HIV (PWoH) and to AIDS-defining B-cell lymphomas (A-BCLs) in the modern antiretroviral therapy era. North American AIDS Cohort Collaboration on Research and Design and Comprehensive Oncology Measures for Peripheral T-cell Lymphoma Treatment are cohorts that enroll patients diagnosed with HIV and TCL, respectively. In our study, 52, 64, 101, 500, and 246 PWH with histologic confirmation of TCL, primary central nervous system lymphoma, Burkitt's lymphoma, diffuse large B-cell lymphoma (DLBCL), and Hodgkin's lymphoma (HL), respectively, and 450 TCLs without HIV were eligible for analysis. At the time of TCL diagnosis, anaplastic large-cell lymphoma (ALCL) was the most common TCL subtype within PWH. Although PWH with TCL diagnosed between 1996 and 2009 experienced a low 5-year survival probability at 0.23 (95% confidence interval [CI]: 0.13, 0.41), we observed a marked improvement in their survival when diagnosed between 2010 and 2016 (0.69; 95% CI: 0.48, 1; P = .04) in contrast to TCLs among PWoH (0.45; 95% CI: 0.41, 0.51; P = .53). Similarly, PWH with ALCLs diagnosed between 1996 and 2009 were associated with a conspicuously inferior 5-year survival probability (0.17; 95% CI: 0.07, 0.42) and consistently lagged behind A-BCL subtypes such as Burkitt's (0.43; 95% CI:0.33, 0.57; P = .09) and DLBCL (0.17; 95% CI: 0.06, 0.46; P = .11) and behind HL (0.57; 95% CI: 0.50, 0.65; P < .0001). Despite a small number, those diagnosed between 2010 and 2016 experienced a remarkable improvement in survival (0.67; 95% CI: 0.3, 1) in comparison with PWoH (0.76; 95% CI: 0.66, 0.87; P = .58). Thus, our analysis confirms improved overall survival for aggressive B- and T-cell malignancies among PWH in the last decade.

Diffuse large B cell lymphoma (DLBCL) is an aggressive but potentially curable malignancy; however, cure is highly dependent on the ability to deliver intensive, anthracycline-based chemoimmunotherapy. Nearly one third of cases of DLBCL occur in patients over age 75 years, and advanced age is an important adverse feature in prognostic models. Despite this incidence in older patients, there is no clear accepted standard of care due to under-representation of this group in large randomized clinical trials. Furthermore, insufficient assessments of baseline frailty and prediction of toxicity hamper clinical decision-making. Here, we present an ongoing randomized study of R-miniCHOP chemoimmunotherapy with or without oral azacitidine (CC-486, Onureg) for patients age 75 and older with newly diagnosed DLBCL and associated aggressive lymphomas. The incorporation of an oral hypomethylating agent is based on increased tumor methylation as a biologic feature of older patients with DLBCL and a desire to minimize the injection burden for this population. This is the first randomized study in this population conducted in North America by the National Clinical Trials Network (NCTN) and will enroll up to 422 patients including 40 patients in a safety run-in phase. This study incorporates an objective assessment of baseline frailty (the FIL Tool) and a serial comprehensive geriatric assessment (CGA). Key correlative tests will include circulating tumor DNA (ctDNA) assays at pre-specified timepoints to explore if ctDNA quantity and methylation patterns correlate with response. S1918 has the potential to impact future trial design and to change the standard of care for patients 75 years and older with aggressive lymphoma given its randomized design, prospective incorporation of geriatric assessments, and exploration of ctDNA correlatives. Trial registration: The trial is registered with ClinicalTrial.gov Identifier NCT04799275.

Allogeneic transplant (alloHCT) and chimeric antigen receptor modified (CAR)-T cell therapy are potentially cuarative options of diffuse large B-cell lymphoma (DLBCL) relapsing after an autologous (auto)HCT. Although the Center for International Blood and Marrow Transplant Research (CIBMTR) prognostic model can predict outcomes of alloHCT in DLBCL after autoHCT failure, corresponding models of CAR-T treatment in similar patient populations are not available. In this noncomparative registry analysis, we report outcomes of patients with DLBCL (≥18 years) undergoing a reduced intensity alloHCT or CAR-T therapy with axicabtagene ciloleucel during 2012 to 2019 after a prior auto-HCT failure and apply the CIBMTR prognostic model to CAR-T recipients. A total of 584 patients were included. The 1-year relapse, nonrelapse mortality, overall survival (OS), and progression-free survival for CAR-T treatment after autoHCT failure were 39.5%, 4.8%, 73.4%, and 55.7%, respectively. The corresponding rates in the alloHCT cohort were 26.2%, 20.0%, 65.6%, and 53.8%, respectively. The 1-year OS of alloHCT recipients classified as low-, intermediate- and high/very high-risk groups according to the CIBMTR prognostic score was 73.3%, 59.9%, and 46.3%, respectively (P = .002). The corresponding rates for low-, intermediate-, and high/very high-risk CAR-T patients were 88.4%, 76.4%, and 52.8%, respectively (P < .001). This registry analysis shows that both CAR-T and alloHCT can provide durable remissions in a subset of patients with DLBCL relapsing after a prior autoHCT. The simple CIBMTR prognostic score can be used to identify patients at high risk of treatment failure after either procedure. Evaluation of novel relapse mitigations strategies after cellular immunotherapies are warranted in these high-risk patients.

Primary diffuse large B-cell lymphoma presenting as an extranodal site in the pelvis is rare and can mimic a gynecological malignancy. Although management for diffuse large B-cell lymphoma is standardized and curative, prognosis depends on timely diagnosis and therapy. Diagnosis can be challenging as patients lack classical symptoms of fever, night sweats, weight loss, and lymphadenopathy associated with lymphoma. A multidisciplinary approach is recommended to diagnose and treat judiciously. In this article, we present cases of 2 females who presented with pelvic masses with initial suspicion of a gynecological malignancy but were ultimately diagnosed as diffuse large B-cell lymphoma of the pelvis and managed accordingly.

BackgroundLymphocytic neoplasms with frequent reactive lymphocytes are uncommonly reported in dogs, and can pose a diagnostic challenge. Different diagnostic modalities such as cytology, flow cytometry, histopathology, immunohistochemistry, and clonality testing, are sometimes required for a diagnosis. This report illustrates the value of using a multi-modal diagnostic approach to decipher a complex lymphocytic tumor, and introduces immune repertoire sequencing as a diagnostic adjunct.Case presentationA 10-month-old Great Dane was referred for marked ascites. Cytologic analysis of abdominal fluid and hepatic aspirates revealed a mixed lymphocyte population including numerous large lymphocytes, yielding a diagnosis of lymphoma. Flow cytometrically, abdominal fluid lymphocytes were highly positive for CD4, CD5, CD18, CD45, and MHC II, consistent with T cell lymphoma. Due to a rapidly deteriorating clinical condition, the dog was euthanized. Post mortem histologic evaluation showed effacement of the liver by aggregates of B cells surrounded by T cells, suggestive of hepatic T cell-rich large B cell lymphoma. Immune repertoire sequencing confirmed the presence of clonal B cells in the liver but not the abdominal fluid, whereas reactive T cells with shared, polyclonal immune repertoires were found in both locations.ConclusionsT cell-rich large B cell lymphoma is a rare neoplasm in dogs that may be challenging to diagnose and classify due to mixed lymphocyte populations. In this case, the results of histopathology, immunohistochemistry and immune repertoire sequencing were most consistent with a hepatic B cell neoplasm and reactive T cells exfoliating into the abdominal fluid. Immune repertoire sequencing was helpful in delineating neoplastic from reactive lymphocytes and characterizing repertoire overlap in both compartments. The potential pitfalls of equating atypical cytomorphology and monotypic marker expression in neoplasia are highlighted.

Objectives/hypothesisThis study utilizes a large population national database to comprehensively analyze prognosticators and overall survival (OS) outcomes of varying treatment modalities in a large cohort of sinonasal diffuse large B-cell lymphoma (SN-DLBCL) patients.Study designRetrospective database study.MethodsThe National Cancer Database was queried for all SN-DLBCL cases diagnosed from 2004 to 2015. Kaplan-Meier log-rank test determined differences in OS based on clinical covariates. Cox proportional-hazards analysis was used to determine clinical and sociodemographic covariates predictive of mortality.ResultsA total of 2,073 SN-DLBCL patients were included, consisting of 48% female with a mean age of 66.0 ± 16.2 years. Overall, 82% of patients were Caucasian, 74% had early-stage disease, and 49% had primary tumors in the paranasal sinuses. Early-stage patients were more likely to receive multi-agent chemoradiotherapy compared to multi-agent chemotherapy alone (P

Aims: Neurotoxicity (NT) is a common complication of chimeric antigen receptor (CAR) T-cell therapy. Data on early clinical identifiers for impending severe NT are lacking. Methods: The authors performed a retrospective study on 26 adult relapsed/refractory diffuse large B cell lymphoma patients treated with commercial CAR T-cell therapy (December 2017 - September 2018). Results: NT of any grade and severe NT occurred in 88 and 31% of patients, respectively. Dysgraphia (p

Chimeric antigen receptor (CAR)-T cell therapies have improved the outcome for many patients with relapsed or refractory aggressive B-cell lymphomas. In 2017, axicabtagene ciloleucel and soon after tisagenlecleucel became the first approved CAR-T cell products for patients with high-grade B-cell lymphomas or diffuse large B-cell lymphoma (DLBCL) who are relapsed or refractory to ≥ 2 prior lines of therapy; lisocabtagene maraleucel was approved in 2021. Safety and efficacy outcomes from the pivotal trials of each CAR-T cell therapy have been reported. Despite addressing a common unmet need in the large B-cell lymphoma population and utilizing similar CAR technologies, there are differences between CAR-T cell products in manufacturing, pivotal clinical trial designs, and data reporting. Early reports of commercial use of axicabtagene ciloleucel and tisagenlecleucel provide the first opportunities to validate the impact of patient characteristics on the efficacy and safety of these CAR-T cell therapies in the real world. Going forward, caring for patients after CAR-T cell therapy will require strategies to monitor patients for sustained responses and potential long-term side effects. In this review, product attributes, protocol designs, and clinical outcomes of the key clinical trials are presented. We discuss recent data on patient characteristics, efficacy, and safety of patients treated with axicabtagene ciloleucel or tisagenlecleucel in the real world. Finally, we discuss postinfusion management and preview upcoming clinical trials of CAR-T cell therapies.

Abstract Background Anal lymphomas are extremely rare. There are no relevant descriptions in professional books, and there are only a few case reports in the literature. Here, we report a new case and review the literature to summarize the clinical and pathological features of anal lymphoma. Methods We described a case of anal lymphoma confirmed by pathological diagnosis, then searched the PubMed database, and finally selected 12 reported cases to be included in the study. We described the clinical and pathological characteristics of the patients. Results Thirteen patients with anal lymphoma were confirmed. Seven men and six women with a median age of 50. There were four cases of HIV- and EBV-infected patients. The size of the tumor was 1–13 cm, all of which were diagnosed as B-cell lymphoma, and 61.5% were diffuse large B-cell lymphomas. Among the 13 patients, eight received chemotherapy or immunochemotherapy, two received radiotherapy, one received chemotherapy combined with radiotherapy, one received surgery, and one gave up treatment. Three patients died, and only 2 of 10 surviving patients had complete remission. Conclusion Anal lymphoma is extremely rare. Patients with persistent abscess complicated with HIV or EBV infection should undergo pathological biopsy to exclude anal lymphoma.

Primary mediastinal large B-cell lymphoma (PMBL) is an uncommon and aggressive subtype of non-Hodgkin large B-cell lymphoma that affects patients in the third and fourth decades of life. The objective of the present report is to describe the case of a male patient admitted to the emergency room with symptoms of dyspnea associated with signs of superior vena cava syndrome. The imaging exams revealed two masses in the mediastinum; the definitive diagnosis, established through an anatomopathological examination and immunohistochemistry, was of PMBL, and the patient was referred for chemotherapy.

BackgroundDiffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma and may occur with lymph node and/or extranodal involvement. However, DLBCL with intracardiac mass is exceedingly rare. In the reported literature, the intracardiac infiltration of DLBCL mostly involves the right ventricle. Lymphoma that invades the heart has an aggressive nature, with symptoms that are easily ignored initially and can lead to multiple complications in severe cases, resulting in a poor prognosis. Early screening and diagnosis may significantly improve the survival rate. Early diagnosis may significantly improve outcomes.Case summaryWe presented a 68-year-old woman with back pain. PET/CT suggested increased FDG metabolism in the left ventricle, right adrenal gland, right erector spinae intramuscularis, multiple bones and multiple lymph nodes. Contrast-enhanced ultrasound showed a left ventricular apical mass with ventricular septum thickening. Cardiac MRI suggested a 1.6*1.1*2.1 cm mass in the apical-central portion of the left ventricle. Biopsy of the right neck mass confirmed the pathologic diagnosis of diffuse large B-cell lymphoma. However, before the pathologic diagnosis was confirmed, the patient was paralyzed due to spinal cord compression caused by the progression of bone metastases. Subsequently, pathology confirmed the diagnosis of diffuse large B-cell lymphoma, and rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) was treated immediately as first-line therapy. In addition, glucocorticoids and mannitol dehydration were administered to relieve the symptoms of spinal cord compression. After 8 cycles of R-CHOP, the tumor at all sites had almost complete regression. The patient was able to walk normally and had no tumor-related symptoms.ConclusionsWe present a case of DLBCL with a very high tumor load that involved multiple organs, including the left ventricle, but exhibited no cardiac-related symptoms. The combination of various imaging modalities is valuable for the diagnosis of cardiac infiltration. The mass in the left ventricle almost completely regressed after R-CHOP treatment, and no recurrence has occurred in the 5 years of follow-up so far.

Background: Diffuse large B-cell lymphoma (DLBCL), the most common subtype of non-Hodgkin's lymphoma, often presents diagnostic challenges due to its diverse clinical presentation. We present a case of DLBCL that was initially misdiagnosed as a hematoma, highlighting the importance of considering malignancy when faced with unresponsive soft tissue swelling. Methods: A 76-year-old man presented to the emergency department with right periorbital swelling and ecchymosis following a traumatic injury. Despite ongoing anticoagulant therapy (warfarin) for atrial fibrillation, the symptoms persisted. A CT scan of the facial bones revealed a large, irregular, homogeneous mass. Initially, the clinical history and radiologic findings suggested an extraconal hematoma. As a result, an incision and drainage procedure was performed, and the old blood was evacuated. However, the patient's symptoms continued to worsen. A follow-up CT scan showed enlargement of the lesion, prompting a surgical excisional biopsy. Results: Pathologic examination of the excised mass revealed a diffuse infiltrate of lymphocytes surrounding the tissue, confirming the diagnosis of diffuse large B-cell lymphoma (DLBCL). The patient was subsequently referred to hematology for further management. Conclusions: Although rare, DLBCL is associated with a challenging prognosis. This case highlights the diagnostic complexities that can arise, particularly when factors such as prior injury and anticoagulant therapy confound the clinical picture. The initial misclassification of the condition as a hematoma led to a delay in diagnosis and the subsequent initiation of treatment. Therefore, it is imperative to remain vigilant and consider malignancy as a potential underlying cause of unresponsive soft tissue swelling. Timely recognition and accurate diagnosis are paramount to improving patient outcomes in DLBCL, an aggressive lymphoma with a diverse clinical presentation. [ABSTRACT FROM AUTHOR]

ZUMA-1 (NCT02348216) examined the safety and efficacy of axicabtagene ciloleucel (axi-cel), an autologous CD19-directed chimaeric antigen receptor (CAR)-T cell therapy, in refractory large B-cell lymphoma. To reduce treatment-related toxicity, several exploratory safety management cohorts were added to ZUMA-1. Specifically, cohort 6 investigated management of cytokine release syndrome (CRS) and neurologic events (NEs) with prophylactic corticosteroids and earlier corticosteroid and tocilizumab intervention. CRS and NE incidence and severity were primary end-points. Following leukapheresis, patients could receive optional bridging therapy per investigator discretion. All patients received conditioning chemotherapy (days -5 through -3), 2 × 106  CAR-T cells/kg (day 0) and once-daily oral dexamethasone [10 mg, day 0 (before axi-cel) through day 2]. Forty patients received axi-cel. CRS occurred in 80% of patients (all grade ≤2). Any grade and grade 3 or higher NEs occurred in 58% and 13% of patients respectively. Sixty-eight per cent of patients did not experience CRS or NEs within 72 h of axi-cel. With a median follow-up of 8·9 months, objective and complete response rates were 95% and 80% respectively. Overall, prophylactic corticosteroids and earlier corticosteroid and/or tocilizumab intervention resulted in no grade 3 or higher CRS, a low rate of grade 3 or higher NEs and high response rates in this study population.

Aims: Large B‐cell lymphoma with IRF4 rearrangement (LBCL‐IRF4) is a recently described entity included in the revised 4th edition of the WHO Classification of Haematolymphoid Tumours (2017). Here we highlight the difficulties in classification of those cases which arise in adult patients with unusual clinical features. Results: We present three cases with morphological and immunohistochemical features consistent with large B‐cell lymphoma arising in adult patients, which were found to have isolated IRF4 rearrangements on FISH analysis. Each patient presented with advanced‐stage disease and had a history of immunosuppression; clinical features that are not typical of LBCL‐IRF4 and which make the distinction from DLBCL, not otherwise specified (NOS) challenging. Conclusion: We propose that the clinical boundaries of LBCL‐IRF4 arising in adult patients need further delineation to allow distinction from true cases of DLBCL, NOS. [ABSTRACT FROM AUTHOR]

PurposeAxicabtagene ciloleucel (axi-cel) is an autologous CD19-directed chimeric antigen receptor (CAR) T-cell therapy approved for relapsed/refractory large B-cell lymphoma (LBCL) on the basis of the single-arm phase II ZUMA-1 trial, which showed best overall and complete response rates in infused patients of 83% and 58%, respectively. We report clinical outcomes with axi-cel in the standard-of-care (SOC) setting for the approved indication.Patients and methodsData were collected retrospectively from all patients with relapsed/refractory LBCL who underwent leukapheresis as of September 30, 2018, at 17 US institutions with the intent to receive SOC axi-cel. Toxicities were graded and managed according to each institution's guidelines. Responses were assessed as per Lugano 2014 classification.ResultsOf 298 patients who underwent leukapheresis, 275 (92%) received axi-cel therapy. Compared with the registrational ZUMA-1 trial, 129 patients (43%) in this SOC study would not have met ZUMA-1 eligibility criteria because of comorbidities at the time of leukapheresis. Among the axi-cel-treated patients, grade ≥ 3 cytokine release syndrome and neurotoxicity occurred in 7% and 31%, respectively. Nonrelapse mortality was 4.4%. Best overall and complete response rates in infused patients were 82% (95% CI, 77% to 86%) and 64% (95% CI, 58% to 69%), respectively. At a median follow-up of 12.9 months from the time of CAR T-cell infusion, median progression-free survival was 8.3 months (95% CI, 6.0 to15.1 months), and median overall survival was not reached. Patients with poor Eastern Cooperative Oncology Group performance status of 2-4 and elevated lactate dehydrogenase had shorter progression-free and overall survival on univariable and multivariable analysis.ConclusionThe safety and efficacy of axi-cel in the SOC setting in patients with relapsed/refractory LBCL was comparable to the registrational ZUMA-1 trial.

Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous entity of B-cell lymphoma. Cell-of-origin (COO) classification of DLBCL is required in routine practice by the World Health Organization classification for biological and therapeutic insights. Genetic subtypes uncovered recently are based on distinct genetic alterations in DLBCL, which are different from the COO subtypes defined by gene expression signatures of normal B cells retained in DLBCL. We hypothesize that classifiers incorporating both genome-wide gene-expression and pathogenetic variables can improve the therapeutic significance of DLBCL classification. To develop such refined classifiers, we performed targeted RNA sequencing (RNA-Seq) with a commercially available next-generation sequencing (NGS) platform in a large cohort of 418 DLBCLs. Genetic and transcriptional data obtained by RNA-Seq in a single run were explored by state-of-the-art artificial intelligence (AI) to develop a NGS-COO classifier for COO assignment and NGS survival models for clinical outcome prediction. The NGS-COO model built through applying AI in the training set was robust, showing high concordance with COO classification by either Affymetrix GeneChip microarray or the NanoString Lymph2Cx assay in 2 validation sets. Although the NGS-COO model was not trained for clinical outcome, the activated B-cell-like compared with the germinal-center B-cell-like subtype had significantly poorer survival. The NGS survival models stratified 30% high-risk patients in the validation set with poor survival as in the training set. These results demonstrate that targeted RNA-Seq coupled with AI deep learning techniques provides reproducible, efficient, and affordable assays for clinical application. The clinical grade assays and NGS models integrating both genetic and transcriptional factors developed in this study may eventually support precision medicine in DLBCL.

PURPOSE: Therapeutic advances for diffuse large B-cell lymphoma (DLBCL) have led to an increasing number of survivors. Both DLBCL and its treatments perturb the immune system, yet little is known about immune health during extended survivorship. METHODS: In this retrospective cohort study, we compared 21,690 survivors of DLBCL from the California Cancer Registry (CCR) to survivors of breast, prostate, head and neck, and melanoma cancers. We linked their CCR records to a statewide database documenting hospital, emergency room, and ambulatory surgery visits and investigated the incidence of autoimmune conditions, immune deficiencies, and infections 1-10 years after cancer diagnosis. RESULTS: We found elevated incidence rate ratios (IRRs) for many immune-related conditions in survivors of DLBCL compared with other cancer survivors, including significantly and consistently elevated IRRs for viral and fungal pneumonias (up to 10.8-fold), meningitis (up to 5.3-fold), as well as humoral deficiency (up to 17.6-fold) and autoimmune cytopenias (up to 12-fold). IRRs for most conditions remained high even in the late survivorship period (5-10 years after cancer diagnosis). The elevated risks could not be explained by exposure to chemotherapy, stem-cell transplantation, or rituximab, except for IRRs for humoral deficiency, which were consistently higher after the incorporation of rituximab into DLBCL treatments. CONCLUSION: To our knowledge, this is the largest cohort study with extended follow-up to demonstrate impaired immune health in survivors of DLBCL. The observed persistent, elevated risks for autoimmune diseases, immune deficiencies, and infectious conditions may reflect persistent immune dysregulation caused by lymphoma or treatment and may lead to excess morbidity and mortality during survivorship. Improved understanding of these risks could meaningfully improve long-term care of patients with DLBCL.

Background and objectiveDiffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma, with a median age of diagnosis of 66 years. Anthracycline-containing regimens are the most common treatments, but toxicity concerns can limit their use in patients older than 80 years. Understanding treatment patterns and associated survival in adults older than 80 years (vs adults aged 65-80 years) can help determine effective management strategies in this population. We sought to describe the impact of age on treatment regimens used and associated survival in older adults with DLBCL.MethodsData for 17,859 patients aged ≥65 years diagnosed with DLBCL from 2006 to 2017 were obtained from the California Cancer Registry. Detailed treatment information for each patient was extracted from treatment text fields. Multivariable logistic regression models examined characteristics associated with no treatment and multivariable Cox proportional hazards regression models examined the influence of treatment on overall survival and cancer specific survival.ResultsAcross both examined age groups (65-80 years and older than 80 years), the most common treatment was anthracycline-containing regimens followed by other drug combinations. For patients older than 80 years, fewer received anthracyclines (32.4%) and more received other drug combinations (17.6%) or had no treatment (13.1%) vs those aged 65-80 years (61.6% anthracyclines, 10.4% other combinations, 5% no treatment). Women were less likely to receive treatment, as were those who were older, had more comorbidities, received treatment at non-National Cancer Institute designated cancer centers, or were diagnosed more recently. For patients older than 80 years, anthracyclines and R-CVP conferred a survival advantage compared to other combinations.ConclusionIn this large, population-based group of older adults with DLBCL, patients older than 80 years were less likely to receive initial treatment and more likely to receive other drug combinations despite a survival advantage with more standard anthracycline and nonanthracycline regimen protocols.

BackgroundEvolution of indolent to aggressive lymphoma has been described in dogs but is difficult to distinguish from the de novo development of a second, clonally distinct lymphoma. Differentiation of these scenarios can be aided by next generation sequencing (NGS)-based assessment of clonality of lymphocyte antigen receptor genes.Case presentationAn 8-year-old male intact Mastiff presented with generalized lymphadenomegaly was diagnosed with nodal T zone lymphoma (TZL) based on cytology, histopathology, immunohistochemistry and flow cytometry. Thirteen months later, the dog re-presented with progressive lymphadenomegaly, and based on cytology and flow cytometry, a large B cell lymphoma (LBCL) was diagnosed. Sequencing-based clonality testing confirmed the de novo development of a LBCL and the persistence of a TZL.ConclusionsThe occurrence of two distinct lymphoid neoplasms should be considered if patient features and tumor cytomorphology or immunophenotype differ among sequential samples. Sequencing-based clonality testing may provide conclusive evidence of two concurrent and distinct clonal lymphocyte populations, termed most appropriately "composite lymphoma".

Diffuse large B-cell lymphoma (DLBCL) of the uterus and ovary is rare in clinic. The clinical and auxiliary examination usually have no special manifestations. The postoperative pathology and immunohistochemistry can confirm the diagnosis. The clinical data of one case of DLBCL in uterus and bilateral ovaries were retrospectively analyzed. The patient was a perimenopausal female who underwent abdominal hysterectomy, bilateral adnexectomy and greater omentectomy due to pelvic mass. The definite diagnosis of DLBCL was made by the pathology after surgery. The chemotherapy with rituximab, cyclophosphamide, vincristine, doxorubicin and prednisone was given for 6 cycles after surgery, and no recurrence was observed within 6 months after chemotherapy. [ABSTRACT FROM AUTHOR]

Although bortezomib and rituximab have synergistic activity in patients with lymphoma and both can attenuate graft-versus-host disease (GVHD), the drugs have not been used together in patients undergoing allogeneic stem cell transplantation (alloSCT). In this phase I/II trial, we assessed the safety and activity of bortezomib added to the rituximab (R) plus BEAM (carmustine, etoposide, cytarabine, melphalan) regimen in patients with relapsed lymphoma undergoing alloSCT. Primary GVHD prophylaxis consisted of tacrolimus and methotrexate. Bortezomib (1 to 1.3 mg/m2 per dose) was administered i.v. on days -13, -6, -1, and +2. We performed inverse probability weighting analysis to compare GVHD and survival results with an historical control group that received R-BEAM without bortezomib. Thirty-nine patients were assessable for toxic effects and response. The median age was 54 years. The most common diagnosis was diffuse large B cell lymphoma (41%). Twenty-two patients (56%) and 17 patients (44%) received their transplants from matched related and matched unrelated donors, respectively. The maximum tolerated bortezomib dose was 1 mg/m2. The weighted cumulative incidences of grades II to IV and III or IV acute GVHD were 50% and 34%, respectively; these incidences and survival rates were not significantly different from those of the control group. Median survival was not reached in patients age ≤ 50 years and with a long follow-up time of 60.7 months. The R-BEAM regimen has a survival benefit in lymphoma patients age ≤ 50 years undergoing alloSCT. The addition of bortezomib has no impact on survival or incidence of GVHD.

BACKGROUND: This population-based study considered the influence of rituximab on the survival of children (0-19 years), adolescents, and young adults (AYAs, 20-39 years) with diffuse large B-cell lymphoma (DLBCL), including patients with human immunodeficiency virus (HIV) infection. METHODS: Data on 642 children and AYAs diagnosed with DLBCL during 2001-2014 were obtained from the Greater Bay Area Cancer Registry in California. Facility-level reports provided treatment details. The Kaplan-Meier method estimated survival and Cox regression models examined the association between survival and rituximab use, adjusting for sociodemographic and clinical factors. RESULTS: Rituximab use increased from 2001-2007 to 2008-2014 among children (from 32% to 48%), AYAs (from 68% to 84%), and HIV patients (from 57% to 67%). Five-year survival was higher among children (91%) than AYAs (82%). On multivariable analysis, the hazard of death was 44% lower among rituximab recipients, and higher among uninsured patients, those with HIV, and those with advanced stage at diagnosis. HIV patients who received rituximab were 60% less likely to die than nonrecipients. CONCLUSIONS: Our study suggests a benefit of rituximab on the treatment of AYAs and HIV patients with DLBCL. The worse survival observed among HIV-positive and uninsured patients is of concern and calls for further investigation. Careful consideration should be given on whether to recommend rituximab more often on the front-line treatment of children and HIV-positive patients with DLBCL.

Primary central nervous system lymphoma (PCNSL) is a rare form of non-Hodgkin lymphoma that affects the brain parenchyma, spinal cord, eyes, and cerebrospinal fluid without evidence of systemic, non-CNS involvement. PCNSL is uncommon and only a few randomized trials have been completed in the first-line setting. Over the past decades, the prognosis of PCNSL has improved, mainly due to the introduction and widespread use of high-dose methotrexate, which is now the backbone of all first-line treatment polychemotherapy regimens. Despite this progress, durable remission is recorded in only 50% of patients, and therapy can be associated with significant late neurotoxicity. Here, we overview the epidemiology, clinical presentation, staging evaluation, prognosis, and current up-to-date treatment of immunocompetent PCNSL patients.

This study retrospectively compared long-term outcomes of nonmyeloablative/reduced intensity conditioning (NMC/RIC) allogeneic hematopoietic cell transplantation (allo-HCT) from a haploidentical family donor (haplo-HCT) using posttransplant cyclophosphamide (PTCy) with those of matched sibling donor (MSD) and matched unrelated donor (MUD) with or without T-cell depletion (TCD+/TCD-) in patients with relapsed diffuse large B-cell lymphoma (DLBCL). Adult patients with DLBCL who had undergone their first NMC/RIC allo-HCT between 2008 and 2015 were included. Recipients of haplo-HCT were limited to those receiving graft-versus-host disease (GVHD) prophylaxis with PTCy. GVHD prophylaxis in MSD was limited to calcineurin inhibitor (CNI)-based approaches without in vivo TCD, while MUD recipients received CNI-based prophylaxis with or without TCD. Outcome analyses for overall survival (OS) and progression-free survival (PFS), nonrelapse mortality (NRM), and disease relapse/progression were calculated. A total of 1438 patients (haplo, 132; MSD, 525; MUD TCD+, 403; and MUD TCD-, 378) were included. Patients with haplo donors were significantly older, had a better performance status and had more frequently received total body irradiation-based conditioning regimens and bone marrow grafts than MSD and MUD TCD+ or TCD-. 3-year OS, PFS, NRM and relapse/progression incidence after haplo-HCT was 46%, 38%, 22%, and 41%, respectively, and not significantly different from outcomes of matched donor transplants on multivariate analyses. Haplo-HCT was associated with a lower cumulative incidence of chronic GVHD compared with MSD, MUD TCD+/TCD-. NMC/RIC haplo-HCT with PTCy seems to be a valuable alternative for patients with DLBCL considered for allo-HCT but lacking a matched donor.

Diffuse large B cell lymphoma (DLBCL) is a rare malignant tumor of the ovary, the pathogenesis of which is still unclear, and the clinical manifestations and auxiliary examination are not specific, preoperative diagnosis is difficult, the diagnosis can only rely on the histopathological results and immunohistochemical results. It is very easy to be confused with other malignant tumors of the ovary and miss the best treatment time and delay the disease. We report a case of ovarian DLBCL in our hospital, in which the patient presented with the main complaint of abdominal distension and without other discomfort, and the atypical imaging examination. The patient was initially diagnosed as a pelvic mass after admission. The diagnosis was confirmed by exploratory laparotomy, and surgery and chemical treatment were given. Now we retrospectively analyze the clinical data of the patient and review the relevant literature to deepen the clinicians' understanding of this disease and effectively improve the clinical diagnosis and treatment. [ABSTRACT FROM AUTHOR]

Background: Diffuse large B-cell lymphoma (DLBCL), the most common subtype of non-Hodgkin’s lymphoma, often presents diagnostic challenges due to its diverse clinical presentation. We present a case of DLBCL that was initially misdiagnosed as a hematoma, highlighting the importance of considering malignancy when faced with unresponsive soft tissue swelling. Methods: A 76-year-old man presented to the emergency department with right periorbital swelling and ecchymosis following a traumatic injury. Despite ongoing anticoagulant therapy (warfarin) for atrial fibrillation, the symptoms persisted. A CT scan of the facial bones revealed a large, irregular, homogeneous mass. Initially, the clinical history and radiologic findings suggested an extraconal hematoma. As a result, an incision and drainage procedure was performed, and the old blood was evacuated. However, the patient’s symptoms continued to worsen. A follow-up CT scan showed enlargement of the lesion, prompting a surgical excisional biopsy. Results: Pathologic examination of the excised mass revealed a diffuse infiltrate of lymphocytes surrounding the tissue, confirming the diagnosis of diffuse large B-cell lymphoma (DLBCL). The patient was subsequently referred to hematology for further management. Conclusions: Although rare, DLBCL is associated with a challenging prognosis. This case highlights the diagnostic complexities that can arise, particularly when factors such as prior injury and anticoagulant therapy confound the clinical picture. The initial misclassification of the condition as a hematoma led to a delay in diagnosis and the subsequent initiation of treatment. Therefore, it is imperative to remain vigilant and consider malignancy as a potential underlying cause of unresponsive soft tissue swelling. Timely recognition and accurate diagnosis are paramount to improving patient outcomes in DLBCL, an aggressive lymphoma with a diverse clinical presentation.

The development of clinically functional chimeric antigen receptor (CAR) T cell therapy is the culmination of multiple advances over the last three decades. Axicabtagene ciloleucel (formerly KTE-C19) is an anti-CD19 CAR T cell therapy in development for patients with refractory diffuse large B cell lymphoma (DLBCL), including transformed follicular lymphoma (TFL) and primary mediastinal B cell lymphoma (PMBCL). Axicabtagene ciloleucel is manufactured from patients' own peripheral blood mononuclear cells (PBMC) during which T cells are engineered to express a CAR that redirects them to recognize CD19-expressing cells. Clinical trials have demonstrated the feasibility of manufacturing axicabtagene ciloleucel in a centralized facility for use in multicenter clinical trials and have demonstrated potent antitumor activity in patients with refractory DLBCL. Main acute toxicities are cytokine release syndrome and neurologic events. Axicabtagene ciloleucel holds promise for the treatment of patients with CD19-positive malignancies, including refractory DLBCL.

Purpose: We evaluated the effect on long-term survival of adding rituximab (R) to BEAM (carmustine, etoposide, cytarabine, and melphalan) conditioning with or without yttrium-90 ibritumomab tiuxetan (90YIT) in patients with relapsed diffuse large B-cell lymphoma (DLBCL) undergoing autologous stem cell transplant (ASCT).Experimental design: Patients were enrolled on three consecutive phase II clinical trials. Patients received two doses of rituximab (375 and 1,000 mg/m2) during mobilization of stem cells, followed by 1,000 mg/m2 on days +1 and +8 after ASCT with R-BEAM or 90YIT-R-BEAM (90YIT dose of 0.4 mCi/kg) conditioning.Results: One hundred thirteen patients were enrolled, with 73 receiving R-BEAM and 40 receiving 90YIT-R-BEAM. All patients had a prior exposure to rituximab. The median follow-up intervals for survivors were 11.8, 8.1, and 4.2 years in the three trials, respectively. The 5-year disease-free survival (DFS) rates were 62% for R-BEAM and 65% for 90YIT-R-BEAM (P = 0.82). The 5-year overall survival rates were 73% and 77%, respectively (P = 0.65). In patients with de novo DLBCL, survival outcomes of the germinal center/activated b-cell histologic subtypes were similar with 5-year OS rates (P = 0.52) and DFS rates (P = 0.64), irrespective of their time of relapse (1 year) after initial induction chemotherapy (P = 0.97).Conclusions: Administering ASCT with rituximab during stem cell collection and immediately after transplantation induces long-term disease remission and abolishes the negative prognostic impact of cell-of-origin in patients with relapsed DLBCL. The addition of 90YIT does not confer a further survival benefit. Clin Cancer Res; 24(10); 2304-11. ©2018 AACR.

Abstract Background Cancer cachexia is known to adversely affect the clinical course in patients with malignant lymphoma. The cachexia index (CXI) is a potential biomarker of cancer cachexia, and its implications for the prognosis and treatment outcome of lung cancer and aggressive lymphoma has been assessed in previous studies. Methods A total of 267 patients diagnosed with diffuse large B‐cell lymphoma who were treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R‐CHOP) immunochemotherapy were retrospectively reviewed. The CXI was calculated as the skeletal muscle index (SMI) × serum albumin/neutrophil–lymphocyte ratio (NLR). Although previous studies measured the SMI using the muscles of the L3 vertebral level, the present study used both the L3 vertebral muscles and the pectoralis muscles (PM) at the T4 vertebral level to measure the SMI. Depending on the type of muscles used, the CXI was termed the L3‐CXI or PM‐CXI. Using sex‐specific cutoff values for CXI, the patients were categorized as follows: (i) high‐CXI group (high L3‐CXI and high PM‐CXI), (ii) intermediate‐CXI group (high L3‐CXI and low PM‐CXI), and (iii) low‐CXI group (low L3‐CXI and low PM‐CXI). Results Complete responses to R‐CHOP were obtained in 145/173 (83.8%), 25/36 (69.4%), and 27/57 (47.4%) patients in the high‐CXI, intermediate‐CXI, and low‐CXI groups, respectively (P

BackgroundIn a phase 1 trial, axicabtagene ciloleucel (axi-cel), an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, showed efficacy in patients with refractory large B-cell lymphoma after the failure of conventional therapy.MethodsIn this multicenter, phase 2 trial, we enrolled 111 patients with diffuse large B-cell lymphoma, primary mediastinal B-cell lymphoma, or transformed follicular lymphoma who had refractory disease despite undergoing recommended prior therapy. Patients received a target dose of 2×106 anti-CD19 CAR T cells per kilogram of body weight after receiving a conditioning regimen of low-dose cyclophosphamide and fludarabine. The primary end point was the rate of objective response (calculated as the combined rates of complete response and partial response). Secondary end points included overall survival, safety, and biomarker assessments.ResultsAmong the 111 patients who were enrolled, axi-cel was successfully manufactured for 110 (99%) and administered to 101 (91%). The objective response rate was 82%, and the complete response rate was 54%.With a median follow-up of 15.4 months, 42% of the patients continued to have a response, with 40% continuing to have a complete response. The overall rate of survival at 18 months was 52%. The most common adverse events of grade 3 or higher during treatment were neutropenia (in 78% of the patients), anemia (in 43%), and thrombocytopenia (in 38%). Grade 3 or higher cytokine release syndrome and neurologic events occurred in 13% and 28% of the patients, respectively. Three of the patients died during treatment. Higher CAR T-cell levels in blood were associated with response.ConclusionsIn this multicenter study, patients with refractory large B-cell lymphoma who received CAR T-cell therapy with axi-cel had high levels of durable response, with a safety profile that included myelosuppression, the cytokine release syndrome, and neurologic events. (Funded by Kite Pharma and the Leukemia and Lymphoma Society Therapy Acceleration Program; ZUMA-1 ClinicalTrials.gov number, NCT02348216 .).