Subtype Of non-Hodgkin Lymphoma Research Articles

Novel approaches for HTLV-1 therapy: innovative applications of CRISPR-Cas9.

The human T-cell lymphotropic virus type 1 (HTLV-1) is a single-stranded positive-sense RNA virus that belongs to the Retroviridae family, genus Deltaretro, and infects approximately five to 10 million people worldwide. Although a significant number of individuals living with HTLV-1 remain asymptomatic throughout their lives, some develop one or more severe clinical conditions, such as HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), a progressive and debilitating disease, and/or a subtype of non-Hodgkin's lymphoma with a more threatening course known as adult T-cell leukemia/lymphoma (ATLL). Moreover, current therapeutic options are limited and focus primarily on treating symptoms and controlling viral latency. CRISPR-Cas9 gene editing is proposed as a promising tool to address the intricate links associated with HTLV-1. By targeting or silencing key genes during initial infection and dysregulating immune signaling pathways, CRISPR-Cas9 offers potential intervention opportunities. In this review, we address the therapeutic potential of CRISPR-Cas9 gene editing, as well as examine the primary mechanisms involved in editing potential target genes and discuss the existing evidence in the current scientific literature.

Epidemiological and histopathological aspects of lymphomas at Zinder National Hospital, Niger

Introduction: Lymphoma is a malignant lymphocytic hemopathy characterized by diffuse lymph node or extranodal infiltration. It occurs at all ages and poses a problem for us in terms of positive diagnosis and management. The objective of this study is to determine the epidemiological and histological aspects of lymphomas at the National Hospital Zinder. Methodology: This was a retrospective cross-sectional study of patient records collected for histopathological examination between November 2019 and December 2023. Included were patients of any age and of both sexes with their histopathological findings available. Results: Lymphomas accounted for 3.47% of all malignancies. The 40 to 60 age group was the most affected with 40.90% (n=9) of cases. The mean age was 45±20.05. The sex ratio was 1.75. Lymph node localization accounted for 68.18% (n=15) of cases. Histological examination confirmed the type of non-Hodgkin lymphoma in 77.27% (n=17) of cases. Phenotype B lymphoma predominates in 86.36% of cases (n=19). Our study showed that indolent lymphoma was the most common histological subtype of non-Hodgkin lymphoma in 31.82% (n=7) of cases. Hodgkin's lymphocytic depleted lymphoma was found in 13.63% (n=3) of cases. Conclusion: The analysis of these results allowed us to appreciate the extent of lymphomas and their multiple implications in our society by highlighting a high frequency of non-Hodgkin's lymphomas in the region.

Diffuse Large B Cell Lymphoma: Immunohistochemical Classification According to Hans Algorithm and Association With Outcome in A Moroccan Institution.

The most prevalent subtype of non-Hodgkin lymphoma is diffuse large B-cell lymphoma (DLBCL). Germinal center B-cell (GCB) and non-germinal center B-cell (non GCB) are the two main biologically different molecular subtypes identified utilizing an immunohistochemistry-based approach. Our objective in this study is to analyze the impact of immunohistochemical subtypes of DLBCL (GCB or non GCB) on demographic and clinicopathological parameters, response to chemotherapy and survival outcomes. This is a retrospective study including 106 cases of DLBCL collected in the department of pathology, Hassan II university hospital, Fez (Morocco), over a period of 12 years (January 2010-September 2022). The subtypes of DLBCLs were defined according to Hans algorithm, using immunohistochemistry by three biomarkers (CD10, BCL6, MUM1). Independent t tests and analyses of variance were used for the comparison of mean values. We employed the SPSS 26.0 program to achieve this. A statistically significant value was set at P < .05. Seventy-five patients (71%) were non-GCB subtype, while thirty-one patients (29%) had the GCB immunosubtype. We have found a significant (P < .05) correlations between DLBCL immunosubtypes and treatment responses on one hand and survival in the other hand. In the GCB subtype, the response rate and survival were significantly improved. A significant association was found between Ki 67 expression and survival on univariate analysis. On multivariate analysis, we note a correlation between Ki 67 expression, DLBCL immunohistochemical subtypes and survival outcome. Non GCB subtype is associated with poor response to treatment and inferior survival outcome compared to GCB subtype in Moroccan context, especially when combined with high expression of Ki 67 marker.

Polatuzumab vedotin combined with bendamustine and rituximab for relapsed/refractory diffuse large B-cell lymphoma: A systematic review protocol.

Diffuse large B-cell lymphoma (DLBCL) is an aggressive non-Hodgkin lymphoma subtype with a significant relapse rate and poor prognosis in relapsed/refractory (R/R) patients. Polatuzumab vedotin in combination with bendamustine and rituximab (Pola-BR) has demonstrated promising efficacy and safety as salvage therapy for R/R DLBCL. This systematic review protocol aims to comprehensively evaluate the efficacy of Pola-BR for the treatment of R/R DLBCL by synthesizing data from relevant randomized controlled trials. This protocol details the eligibility criteria, search strategy, study selection, data extraction, and analysis methods for the systematic review. Randomized controlled trials comparing Pola-BR with other interventions for R/R DLBCL will be included. The primary endpoint is overall survival, with secondary endpoints being progression-free survival and incidence of adverse events. A comprehensive search will be conducted across databases such as Medline/PubMed, Cochrane Library, Web of Science, Scopus, EMBASE, ProQuest, EU Clinical Trials Register, WHO International Clinical Trials Registry Platform (ICTRP), and ClinicalTrials.gov from the January 2000 to April 2024. To assess the potential risk of bias, the Cochrane Risk of Bias 1 tool will be used. Data synthesis will utilize fixed-effect or random-effects models, and subgroup and meta-regression analyses will examine heterogeneity. Additionally, publication bias and sensitivity analyses will be performed, and the GRADE approach will be applied to assess the certainty of the evidence. This systematic review and meta-analysis protocol provides a rigorous framework for evaluating the efficacy of Pola-BR in the treatment of R/R DLBCL. The results will inform clinical decision-making and guideline development, addressing the unmet need for effective and tolerable treatments for this challenging patient population. Potential limitations and biases will be acknowledged, and future research directions will be discussed.

Accessibility to Rituximab and its impact on treatment outcomes in major Non-Hodgkin Lymphoma subtypes: Insights from a resource-limited setting

Accessibility to Rituximab and its impact on treatment outcomes in major Non-Hodgkin Lymphoma subtypes: Insights from a resource-limited setting

Aligning outcomes: DLBCL prognosis at a 4th Level University Hospital in Bogotá is comparable to high-income nations, identification of additional prognostic markers for overall survival and relapse.

Diffuse large B-cell lymphoma (DLBCL), a prevalent non-Hodgkin lymphoma subtype, displays diverse clinical outcomes with persistently high mortality and relapse rates, despite treatment advancements. Notably, the Hispanic demographic lacks consideration in existing prognostic indices for DLBCL. A retrospective cohort study encompassing 112 DLBCL patients diagnosed between 2010 and 2020 was conducted at our institution. Patient data, including overall survival (OS), treatment response, and relapse, were analysed. With a median age of 65 years and a predominant male population (60.7%), both the International Prognostic Index (IPI) and revised IPI correlated with OS. In multivariate analysis, patients with ki-67 ≥ 60% exhibited higher mortality risk (Hazard Ratio: 2.35, 95% confidence intervals (CI) 1.05-5.27, p = 0.039), even when controlled by IPI category and B2-microglobulin levels. The absence of B symptoms served as a protective factor for relapse (p < 0.01, OR: 0.147, 95% CI 0.058-0.376) when controlling for ki-67, CD5, and IPI. Our cohort demonstrated a 5-year OS rate comparable to high-income countries, highlighting the need for tailored prognostic models for Hispanic DLBCL patients. This study identifies easily accessible parameters aligning with regional resource constraints, providing insights into additional prognostic factors for DLBCL in the Hispanic population.

In silico study of polyphenols as potential inhibitors of MALT1 protein in non-Hodgkin lymphoma.

Non-Hodgkin lymphoma (NHL) is one of the most common cancer types. Deregulated signaling pathways can trigger certain NHL subtypes, including Diffuse Large B-cell lymphoma. NF-ĸB signaling pathway, which is responsible for the proliferation, growth, and survival of cells, has an essential role in lymphoma development. Although different signals control NF-ĸB activation in various lymphoid malignancies, the characteristic one is the CARD11-BCL10-MALT1 (CBM) complex. The CBM complex is responsible for the initiation of adaptive immune response. Our study is focused on the molecular docking of ten polyphenols as potential CARD11-BCL10-MALT1 complex inhibitors, essentially through MALT1 inhibition. Molecular docking was performed by Auto Dock Tools and AutoDock Vina tool, while SwissADME was used for drug-likeness and absorption, distribution, metabolism, excretion, and toxicity (ADMET) analysis of the ligands. Out of 66 ligands that were used in this study, we selected and visualized five. Selection criteria were based on the binding energy score and position of the ligands on the used protein. 2D and 3D visualizations showed interactions of ligands with the protein. Five ligands are considered potential inhibitors of MALT1, thus affecting NF-ĸB signaling pathway. However, additional in vivo and in vitro studies are required to confirm their mechanism of inhibition.

Epstein-Barr virus-associated lymphomas decoded.

Epstein-Barr virus (EBV)-associated lymphomas cover a range of histological B- and T-cell non-Hodgkin and Hodgkin lymphoma subtypes. The role of EBV on B-cell malignant pathogenesis and its impact on the tumour microenvironment are intriguing but incompletely understood. Both the International Consensus Classification (ICC) and 5th Edition of the World Health Organization (WHO-HAEM5) proposals give prominence to the distinct clinical, prognostic, genetic and tumour microenvironmental features of EBV in lymphoproliferative disorders. There have been major advances in our biological understanding, in how to harness features of EBV and its host immune response for targeted therapy, and in using EBV as a method to monitor disease response. In this article, we showcase the latest developments and how they may be integrated to stimulate new and innovative approaches for further lines of investigation and therapy.

Incidental Bystander or Essential Culprit: A Systematic Review of Bacterial Significance in the Pathogenesis of Breast Implant-Associated Anaplastic Large Cell Lymphoma.

Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is a distinct subtype of T-cell non-Hodgkin lymphoma that arises in the context of prolonged exposure to textured breast implants. The intent of this manuscript is to explore whether the bacterial presence in biofilms on these implants is a mere incidental finding or plays a pivotal role in the pathogenesis of BIA-ALCL. Our goal is to delineate the extent of bacterial involvement, offering insights into potential underlying mechanisms, and establishing future research priorities aimed at resolving the remaining uncertainties surrounding this complex association. A comprehensive systematic review of several databases was performed. The search strategy was designed and conducted by an experienced librarian using controlled vocabulary with keywords. The electronic search identified 442 publications. After evaluation, six studies from 2015 to 2021 were included, encompassing 201 female patients aged 23 to 75. The diagnosis span post-implantation ranged from 53 to 135.6 months. Studies consistently found bacteria near breast implants in both BIA-ALCL cases and controls, with varied microbial findings. Both BIA-ALCL cases and controls exhibited the presence of specific bacteria, including Pseudomonas aeruginosa, Klebsiella oxytoca, Staphylococcus aureus, and Ralstonia spp., without any statistically significant differences between groups. The use of antiseptic and antimicrobial agents during implant insertion did not demonstrate any impact on reducing or altering the risk of developing BIA-ALCL. Our systematic review reveals that the current evidence is inadequate to link bacterial etiology as a central factor in the development of BIA-ALCL. The limitations in the existing data prevent a complete dismissal of the role of biofilms in its pathogenesis. The observed gap in knowledge underscores the need for more focused and comprehensive research, which should be structured in a multi-faceted approach. Initially, this involves the utilization of sophisticated genomic and proteomic methods. Following this, it is crucial to delve into the study of immunological reactions specifically induced by biofilms. Finally, this research should incorporate extended observational studies, meticulously tracking the evolution of biofilm development and its correlation with the emergence of BIA-ALCL. In light of the inconclusive nature of current findings, further investigation is not only justified but urgently needed to clarify these unresolved issues.

Characteristics and outcomes of children, adolescents and young adults with relapsed/refractory non-hodgkin lymphoma undergoing autologous stem cell transplant

BackgroundThere is paucity of data regarding outcomes of children, adolescents and young adults (CAYA) patients with non-Hodgkin lymphoma (NHL) undergoing autologous stem cell transplantation (ASCT).MethodsPatients aged 0–39 years undergoing first ASCT for NHL at MD Anderson Cancer Center between 2000 and 2020 were analyzed.ResultsTwo hundred twenty-one patients were included in the analysis, 129 (58%) were male and the median age was 32 (range 6–39) years. The most common histological subtypes were diffuse large B cell lymphoma (DLBCL) (44%), T-NHL (19%) and primary mediastinal B-Cell lymphoma (PMBCL) (19%). Younger patients (age ≤ 25) had lower incidence of DLBCL and higher incidence of PMBCL and T-NHL compared to older patients (age > 25) (P = 0.02). None of the younger patients had double hit (DH)/double expressor (DE) DLBCL, compared to 14 patients in the older age group (18%, P = 0.07). Considering the three main aggressive NHL subtypes (DLBCL, PMBCL and T-NHL), younger patients had numerically better 15-year post-transplant progression free survival (PFS) (67% vs. 54%) and overall survival (OS) (71% vs. 62%) compared to older patients, yet these differences did not reach statistical significance (P = 0.19 and P = 0.24, respectively). In multivariate analysis, not achieving a CR prior to ASCT was independently predictive of worse PFS [partial remission (PR) (HR, 3.9); stable disease (SD) (HR, 18.0), P = 0.03] and of worse OS [PR (HR, 4.2), SD (HR, 6.5) and progressive disease (HR, 4.7), P < 0.0001]. DH/DE status was an independent adverse predictor of PFS in multivariate analysis (HR 5.8, p = 0.03).Ten patients (4.5%) (all aged > 25 years) developed second primary malignancies (SPM), at a median of 34.4 (range, 1.0–196.6) months after ASCT, and SPM was the cause of death in five (50%) of them.ConclusionsCAYA NHL patients aged ≤ 25 years who received ASCT presented a distinct NHL histology as compared to older CAYA patients, and none in this younger age group had DH/DE DLBCL. We observed a trend towards improved PFS and OS in younger patients. Disease status at ASCT was predictive of both PFS and OS. DH/DE status was an adverse predictor of PFS.

Spatial Multiomics Profiling of Angioimmunoblastic T-Cell Lymphoma

Introduction: Angioimmunoblastic T-cell lymphoma (AITL) is a subtype of non-Hodgkin lymphoma (NHL) characterized primarily by a T follicular helper cell (TFH) phenotype. AITL presents with a highly complex tumor microenvironment with the tumor cells on a scaffold of highly arborized CD21+ follicular dendritic cells found in proximity to high endothelial venules (HEVs). The organized structure of the lymph node with distinct B cell and T cell zones is disrupted in the lymph node samples from patients with AITL. Lymphoid follicles in most AITL cases tend to be depleted, not hyperplastic as in other lymphomas. AITL tumor cells express CD10, BCL6, PD1, CXCL13, C-X-C motif chemokine receptor 5 (CXCR5), ICOS, and signaling lymphocytic activation molecule-associated protein (SAP) with diagnosis based on the expression of at least 2 of these markers. Our study uses novel spatial omics technology (Deterministic Barcoding in Tissue (DBiT-seq) and multiplexed immunofluorescence staining (CODEX)) to fully characterize the transcriptional and proteomic landscape of AITL. Methods: In this study, initial FFPE biopsy specimens from 22 patients with AITL were collected from archives. 10 µm thick tissue sections on poly-L-lysine coated slides were prepared for the performance of multiplexed immunofluorescence imaging (CODEX) for 12 immune-related markers: Podoplanin, CD20, CD4, CD8, CD68, CD45RO, CD3e, GranzymeB, PD1, Ki67, CD21 and CD34 using the PhenoCycler-Fusion system. We also validated anti-EBV Latent Membrane Protein 1 antibody. Cell segmentation was performed using a Stardist-based model in QuPath and downstream analysis done using the Seurat package. On an adjacent tissue section, we used Spatial CITE-seq to co-map the whole transcriptome and ~160 proteins. Results: From the multiplexed immunofluorescence staining, we observed CD21+ Follicular dendritic cells in close proximity to HEVs as expected from the spatial architecture of AITL. We also found 11 spatially distinct clusters differentially expressing the marker proteins. We observed a lower number of CD8+ cytotoxic T cells relative to CD4+ Helper T cells. We also identified cellular neighborhoods and their composition found a population of FDCs that directly interact with the tumor cells. From spatial CITE-seq, we average of ~670 genes were found in each spot. We also found the expression of CXCL13, TET2, DNMT3A and PDCP1 which are markers associated with AITL. There was a strong correlation between the transcript signals detected in Spatial CITE-seq and the protein expression from CODEX. Conclusions: Our study revealed the spatial organization of the tumor microenvironment of AITL. We envision that combining multiplexed immunofluorescence and Spatial CITE-seq will further our understanding of the AITL tumor environment and could lead to the discovery of novel clinical targets.

Infectious Complications in Patients with Relapsed or Refractory (R/R) Non-Hodgkin's Lymphoma (NHL) Treated with the Anti-CD20xCD3 Bispecific Antibody (BsAb) Mosunetuzumab

Introduction:NHL treatment with anti-CD20 antibodies is associated with an increased risk of infections. Mosunetuzumab (mosun) is a novel anti-CD20xCD3 BsAb that has been examined in clinical trials for different NHL subtypes and was recently approved for treating R/R follicular lymphoma. While the open-label clinical trial of mosun reported that 17% of the patients experienced infectious complications, a detailed analysis of the incidence and types of infections in patients receiving this treatment has not been reported. Methods: This is a single-center, IRB-approved, retrospective analysis of patients with R/R NHL receiving mosun, either on a study protocol (NCT02500407) at the recommended phase 2 dose or as commercial use. Patients who completed at least 1 treatment cycle and had at least 30 days of follow-up were included in this analysis. Patient demographics, information on the lymphoma, and infection variables were collected by chart review. All infection-specific variables were collected from the start of mosun therapy until the initiation of the next line of therapy or the last follow-up, whichever came first. The data cut-off was on 7/22/23. Infectious events were graded according to common terminology criteria for adverse events (CTCAE) version 5.0. Baseline characteristics were analyzed for infection risk by performing a Cox regression analysis. Results: Between October 2016 and July 2023, 48 patients were treated with mosun at our center, and 44 met the study inclusion criteria. Four patients had only received one dose or did not have sufficient follow at the time of the analysis. Baseline characteristics are summarized in Table 1. After a median follow-up of 6.8 months (range 0.7-59.7), we recorded 37 infection episodes in 16/44 patients (36.4%). Amongst these, the frequencies of viral, bacterial, and fungal infections were 54.1% (20/37), 43.2% (16/37), and 2.7% (1/37), respectively. The most common infection types were upper respiratory tract infections 42.1% (20/37), skin and soft tissue infections16.2% (6/37), including 3 shingles episodes), genitourinary infections 10.8% (4/37), and lower respiratory tract infections 10.8% (4/37). Of all the infections, 9/37 (24.3%) were Grade 3 or higher; of these, 2/37 (5.4%) were Grade 5 (1 biliary sepsis, 1 COVID pneumonia). The cumulative incidence of infection was 25% over the follow-up period (figure 1). The median time to the first infection was 144 days (range 29-1821). Among the patients who experienced infections, the infection rate was 1.54 every 100 days at risk within the first three months. The infection rate was 1.69 every 100 days at risk between three and six months and 0.37 every 100 days at risk beyond six months for patients with infection. We evaluated the type of lymphoma (i.e., aggressive vs. indolent), patients' age, number of prior therapies before BsAb administration, prior CAR-T therapy, prior autologous SCT, baseline hypogammaglobulinemia, and baseline cytopenia's as risk factors of infection with a univariate Cox regression analysis. We found that none of these characteristics were associated with the risk of infection with statistical significance. However, in a multivariate Cox regression analysis, patients who received CAR-T therapy before starting a BsAb were at a slightly higher risk of developing an infection (OR = 6.13; 95% CI: 0.90, 41.74, p = 0.063). Conclusion: Infection risk in patients with R/R NHL treated with mosun either on protocol or for commercial use appears to be higher than in the clinical trial experience reported in the literature. Viral infections were especially common, including respiratory infections and shingles episodes. Our findings highlight the need for careful monitoring and implementation of preventive strategies to decrease the infection burden in these vulnerable patients.

A Phase I Study Evaluating the Safety, Tolerability, Pharmacokinetics, and Preliminary Antitumor Activity of Dual CK1ε/PI3Kδ Inhibitor HZ-H08905 in Adult Patients with Relapsed and/or Refractory Hematologic Malignancies

Background: HZ-H08905 is a first-class and potent CK1ε/PI3Kδ dual inhibitor, which was previously reported (Abstract 5502, ASH 2022). Phase I study is ongoing in China, and here we present preliminary results of HZ-H08905 monotherapy in hematologic malignancies. Methods: HZ-H08905-101 is an ongoing Phase 1, first-in-human, open-label, multicenter, multiple-dose escalation and expansion study in China (CTR20213233). Primary objectives: safety/tolerability, maximum tolerated dose (MTD), and recommended phase 2 dose (RP2D) of HZ-H08905 monotherapy; secondary objectives: pharmacokinetic properties and preliminary anti-tumor activity of HZ-H08905 in patients with relapsed/refractory (R/R) non-Hodgkin lymphoma (NHL), including B-cell lymphoma (BCM) and T-cell lymphoma (TCL). HZ-H08905 was administered orally once daily in 28-day cycles until disease progression or unacceptable toxicity. The dose escalation part was initiated with a dose titration in the initial cohort (50mg once daily), followed by a 3 + 3 design (100mg, 300 or 450 mg once daily). Dose-limiting toxicity (DLT) for each cohort was evaluated in the first 28-day cycle. Dose expansion was conducted in selected doses and cohorts. Safety was assessed per CTCAE 5.0 and efficacy was measured according to IWWM-7 for WM, or IWCLL 2018 for CLL/SLL, or Lugano 2014 criteria for other NHL. Results: At the data cutoff date of 25 May 2023, 38 pts were analyzed, including 26 R/R TCL [12 AITL, 10 PTCL-NOS, 2 ALK negative ALCL, 1 NKTCL 1 EATCL] and 12 R/R BCM [5 DLBCL, 3 FL, 2 WM, 1 CLL, 1 MCL]. 1 pt received 50mg/d, 9 pts received 100mg/d, 14 pts received 200mg/d, 13 pts received 300mg/d and 1pts received 450mg/d. No DLT occurred and MTD was not reached. Pts were with a median age of 61 years (range: 38-78), median ECOG 1 (range: 0-2) and a median of 2 prior systemic therapies (range: 1-5). 35 of 38 pts (92%) experienced a treatment related adverse event (TRAE). TRAEs of ≥Grade 3 (≥5%) were neutropenia (26.3%), pneumonia (7.9%), leukopenia (5.3%), elevated aspartate aminotransferase (5.3%), elevated alanine aminotransferase (5.3%) and herpes zoster (5.3%). 10 pts (26.3%) had dose interruption, 3pts (7.9%) had dose reduction, and 1 pt (2.6%) discontinued from the study due to TRAEs. Of 35 pts available for tumor assessment (26 TCL; 12 BCM), the overall response rate (ORR) was 60% (95%CI: 42.11, 76.13), including 17% (6 pts) complete response (CR), 40% (14 pts) partial response (PR), 3% (1 pt) minor response (MR) and 20% (7 pts) stable disease (SD), contributing to an 80% (95%CI: 63.06, 91.56) disease control rate (DCR). The median time to response (mTTR) was 1.9 months (95%CI: 1.87, 2.10). The median duration of response (mDOR) and median progression free survival (mPFS) had not been reached, with 21 pts (55%) are still on HZ-H08905 treatment. HZ-H08905 exhibited excellent antitumor efficacy in several NHL subtypes, including CLL, DLBCL, FL, MCL, PTCL and WM, with ORR ranged from 50%~100% and DCR ranged from 76%~100%. Conclusions: These results demonstrated that HZ-H08905 monotherapy was well tolerated and showed promising efficacy in patients with R/R NHL. A Phase 2 R/R PTCL registration study in China is currently planned.

Impact of Deployment on Survival in Military Personnel with Non-Hodgkin Lymphoma

Introduction: It is estimated that approximately 3.5 million active duty service members (ADSM) have deployed to Afghanistan and Iraq from 2001-2022. There has been concern about potential exposure to carcinogenic or environmental hazards during overseas deployment. A recent study found ADSM with no prior deployments had an increased risk of cancer mortality compared to those who had served in Operation Iraqi Freedom/Operation Enduring Freedom. Moreover, Nordic personnel with military deployments were also found to have a lower risk of cancer related death when compared to the general population. While there may be a link between potential environmental exposures, there is a lack of data on non-Hodgkin lymphoma (NHL) survival in servicemembers who have previously deployed. Additionally, there are no studies comparing risk of aggressive B-cell lymphoma in these patient populations. Methods: Documented cases of NHL in the DoD's Tumor Registry (Oncolog) from 2001-2022 were obtained. This information was compared to the Defense Manpower Data Center's deployment data and the two datasets were merged. ADSMs and retirees were included; dependents were excluded. A multivariable logistic regression analysis was done to assess the impact of prior deployment on cancer survival in NHL, accounting for age, race, cancer stage, ethnicity, and gender. Results: There were 2,295 servicemembers and retirees diagnosed with NHL from 2001-2022. About 20% had previously deployed (n=467). Median age at diagnosis in those who had deployed was 35 years compared to 54 years for non-deployed (p&amp;lt;0.001). Race, ethnicity, and gender were similar between both arms. Multivariable logistic regression analysis demonstrated prior deployment was associated with better survival after accounting for age, race, stage, ethnicity, and gender (OR 0.63, 95% CI 0.40-0.97, p=0.037). In addition to deployment status, other variables that influenced survival were age (OR 1.04, 95% CI 1.03-1.54, p&amp;lt;0.001), stage (OR 2.92 for stage IV vs. stage I, 95% CI 2.06-4.15, p&amp;lt;0.001), and race (OR 1.97 for black vs. white race, 95% CI 1.37-2.83, p&amp;lt;0.001). To assess whether NHL subtype played a role in these findings, a post-hoc analysis was performed on patients with B-cell NHLs, revealing that ADSM with prior deployment were equally likely to have indolent and aggressive subtypes of B-cell NHL as ADSM who had never deployed. Among personnel with prior deployment, 29.6% and 70.4% had indolent and aggressive B-cell NHLs respectively, compared to 32.9% and 67.1% amongst those who never deployed (p=0.25). Conclusions: Military personnel with NHL who had previously deployed lived longer than those with no prior deployment, even after adjusting for age differences between the two cohorts. These findings are not attributable to B-cell NHL subtype (i.e. deployed personnel did not have more indolent NHLs than non-deployed personnel). These results highlight the healthy deployer effect, in which ADSM who are deployable are required to meet minimum fitness standards, undergo a physical health assessment, and do not have disqualifying comorbidities. This study did not evaluate whether an overseas deployment is associated with an increased risk of NHL, but it does appear to provide evidence that potential deployment-related exposures do not appear to alter the biology or subtype of B-cell NHLs. Disclaimer: The contents of this publication are the sole responsibility of the author(s) and do not necessarily reflect the views, opinions or policies of the Department of Defense (DoD) or the Departments of the Army, Navy, or Air Force. Mention of trade names, commercial products, or organizations does not imply endorsement by the U.S. Government.

Baseline Immunoglobulin G and Immune Function in Lymphoma: A Retrospective Analysis

Introduction: Non-Hodgkin's lymphoma (NHL) encompasses a diverse group of lymphoma subtypes with a wide range in disease course. Previous studies show that hypogammaglobulinemia in treatment-naïve patients is associated with poorer survival in high grade B-cell non-Hodgkin's lymphomas, though data is lacking on how this applies across all B-cell lymphoid malignancies. We conducted a retrospective study of immunoglobulin levels and clinical outcomes including survival, hospitalization, and infection rates in patients diagnosed with B-cell non-Hodgkin lymphomas of all grades at our institution. Methods: Patient data was collected from January 2010 to June 2022. Two-hundred twenty-three adults (aged &amp;gt; 18 years) with available pre-treatment IgG levels were selected, with hypogammaglobulinemia defined as IgG&amp;lt; 500 mg/mL. For this analysis, DLBCL (n=90), Primary CNS (n=5), and Burkitt's lymphoma (n=1) was classified as high-grade, while CLL (n=52), mantle cell (n=20), marginal zone (n=25), follicular (n=21), and lymphoplasmacytic lymphomas (n=5) as low-grade. Baseline clinical, staging, and laboratory information was collected including hospital admissions, date of death, and number of infections. Preliminary results for overall survival, 3-year survival and 5-year survival were also analyzed. Multivariate logistic models were used to predict outcomes dichotomized for baseline IGG and high/low grade cancers. Kaplan-Meier estimates and Cox model were performed to analyze the overall survival data. Results: The incidence of pre-treatment hypogammaglobulinemia was 47% in the high-grade B-cell lymphoma cohort and 57% the low-grade B-cell lymphoma cohort (p=.9371). Across all NHL subtypes, individuals with baseline IgG&amp;lt; 500 showed an increased rate of hospitalization (4.453, CI: 1.955-10.54, p= 0.0005) and higher mortality (3.325, CI:1.258, 8.491, p= 0.013), yet no association in number of infections when compared with those with IgG&amp;gt;500. There was no statistical difference in patients' hospitalization rate when they were treated with IVIG only, rituximab only, or a combination (p=.141792). Additionally, there was no statistically significant correlation with COVID infections when evaluating grade of lymphoma (p=.8527) or IgG level (p=.6535). There was no statistically significant difference in individuals who were alive after three years and five years in those with baseline IgG&amp;lt;500. Discussion: Our study is the first to analyze incidence of hypogammaglobulinemia at time of diagnosis of NHL as a potential biomarker of interest for future outcomes including hospitalization and infection. These findings demonstrate an association between hypogammaglobulinemia when comparing the rate of hospitalization and mortality across the spectrum of B-cell NHL. This effect was further amplified in patients with aggressive B-cell lymphoma. Given the common use of monoclonal antibodies to treat B cell lymphomas of all subtypes and the known risk of hypogammaglobulinemia from these treatments and the common finding of hypogammaglobulinemia at diagnosis of B cell NHL, pretreatment screening of IgG levels may be important to identify patients at risk for infection, hospitalization and death. Further clinical equipoise exists requiring a randomized clinical trial to indicate the use as a prognostic factor for infection, hospitalization, and mortality.

A Phase 4, Observational Study Evaluating the Efficacy and Safety of the Bruton Tyrosine Kinase Inhibitor (BTKi) Zanubrutinib in Patients with Waldenström Macroglobulinemia (WM)

Background and Significance:Zanubrutinib, a next-generation, selective BTKi, is approved for treatment of WM based on data from the phase 3 ASPEN study (NCT03053440), in which zanubrutinib showed a favorable benefit-risk profile vs ibrutinib, a first-generation BTKi, in patients with symptomatic WM (Tam CS, et al. Blood. 2020;136:2038-2050). In ASPEN, zanubrutinib showed consistent efficacy across patient subgroups, including prior treatment status (treatment naive or relapsed/refractory) and MYD88 mutational status (shown to affect prognosis and response to treatment). This registry study will contribute to a more inclusive evidence base for zanubrutinib treatment in populations underrepresented in previous clinical studies, specifically patients who are treatment naive, have non-L265 MYD88 mutations, orare from racial and ethnic minority groups. Study Design and Methods:This is a hybrid (retrospective and prospective), multicenter (US only), noninterventional registry study (NCT05640102) in adult patients (aged ≥18 years) with a histologically confirmed diagnosis of WM who are either receiving or planning to initiate zanubrutinib treatment (Figure). Patients with measurable disease (immunoglobulin M level &amp;gt;0.5 g/dL) at zanubrutinib initiation are eligible. Patients with disease transformation prior to zanubrutinib initiation, other non-Hodgkin lymphoma subtypes, or other malignancies (active or in the past ≤1 year) are excluded. Patients will be assigned to 1 of 2 cohorts based on MYD88 status determined using bone marrow specimens. Cohort 1 will include patients with MYD88L265P mutations who are treatment naive (arm A) or have relapsed/refractory disease (arm B). Arm A will enroll mostly patients from racial and ethnic minority groups (Black/African American, Asian, Indigenous/Native American, Native Hawaiian/Other Pacific Islander, and Hispanic/Latino), and arm B will only enroll patients from racial and ethnic minority groups. Cohort 2 will include patients with non-L265P MYD88 mutations or MYD88 wild type who are treatment naive or have relapsed/refractory disease in a single arm (arm C). The dose and duration of zanubrutinib treatment is at the discretion of the prescribing physician. Data collection will occur at screening, every 3 cycles during year 1 of zanubrutinib treatment, and every 6 cycles thereafter (28-day cycles). The primary endpoint is the major response rate (MRR) per investigator using Sixth International Workshop on Waldenström Macroglobulinemia response criteria (Owen RG, et al. Br J Haematol. 2013;160:171-176). Secondary endpoints are very good partial response or better (VGPR+) rate, overall response rate (ORR), duration of response (DOR), and treatment-emergent adverse events. Efficacy and safety analyses will be conducted descriptively for each study arm. MRR, VGPR+ rate, and ORR will be presented with 95% CIs, and median DOR will be estimated with the Kaplan-Meier method. The study is currently open for enrollment.

Pembrolizumab with Rituximab in Relapsed/Refractory Follicular Lymphoma and Diffuse Large B Cell Lymphoma

Background: The tumor microenvironment (TME) plays a role in follicular lymphoma (FL) pathogenesis and survival. PD-1/PDL-1 inhibitors have been effective in non-Hodgkin lymphoma subtypes, such as primary mediastinal B-cell lymphoma, and pembrolizumab + rituximab (P-R) produced a complete response (CR) in 50% of patients with rituximab-sensitive, relapsed/refractory (R/R) FL (Nastoupil ASH 2017, Blood Adv 2022). In 2018, we conducted a phase 2 study to assess the efficacy and safety of P-R in R/R FL and diffuse large B cell lymphoma (DLBCL) including rituximab-resistant patients. Methods: This phase 2, single-center, open-label, non-randomized trial aimed to determine the objective response rate (ORR) of P-R in R/R FL (Arm A) and R/R DLBCL (Arm B). A 3 rd arm with P + Obinutuzumab (O) for R/R FL was added later (Arm C). Eligible patients had R/R disease; for FL, patients must have received prior anti-CD20 therapy and have an indication for treatment; for DLBCL, patients must have relapsed after or be ineligible for autologous stem cell transplantation. Arm A sought to include &amp;gt; 9 patients with rituximab-refractory disease. Weekly R 375 mg/m2 x 4 and 4 doses of P (200 mg in q21 day cycles) were given as induction; responders could receive extended P monotherapy for up to 2 years. In Arm C, patients received weekly O x 4; those with at least SD and clinical benefit could receive P for up to 2 years and 6 more doses of O given every 3 months. CT was used for on-treatment tumor assessments after cycles 4 and 8, then every 12 weeks. A 2-stage design required response at cycle 4 among at least 3 of the first 7 patients in Arm A, and among 3 of the first 9 patients in Arm B, to permit accrual to 20 (Arm A) and 17 patients (Arm B). In Arm C, at least 6 responses in the first 12 patients would be needed to proceed to total accrual of 25 patients. Additional stopping rules were included for excess deaths (&amp;gt;10%) and serious adverse events (SAEs) (&amp;gt;50%). Results: Between 4/2018 and 11/2021, 18 patients were treated on study (Table 1). All were previously treated with rituximab, with 9 refractory to their last rituximab-containing regimen. Median age was 56, 78, and 45 and median prior lines of therapy was 4, 3, and 2 in Arms A, B, and C respectively. In Arm A, 2/7 patients had rituximab-refractory disease, and int- or high-risk FLIPI. All patients in Arm B were refractory to their most recent line of therapy, and 75% had IPI &amp;gt; 3. In Arm A, ORR was 29% (1 CR, 1 PR). In Arm B, no patients responded (6 PD, 1 SD, 1 unevaluable). In Arm C, 3 were accrued and achieved SD as best response. Figure 1 shows outcomes of all accrued patients. Treatment-related adverse events (AE) occurred in 83% of patients, with 9 grade 3/4 AEs occurring in 5 (28%) patients (1 acute kidney injury, 2 diarrhea, 1 hypokalemia, 1 arthralgia, 1 infusion reaction, 1 back pain, 1 generalized muscle weakness, 1 heart failure). There were 5 possible grade 3/4 immune-related AEs, including 2 suspected colitis treated with steroids. With a median follow up of 4.2 years, there were 8 deaths, 6 from progressive lymphoma, 1 from AML likely related to prior therapy, and 1 from a combination of progressive lymphoma and therapy-related AML. Arms A and B closed due to futility, having failed to exceed minimum efficacy for further accrual. Arm C was closed after demonstration of no responses and discussion with the study sponsor following accrual of 3 patients. Conclusion: P-R has modest, expected toxicity but low efficacy in R/R FL and DLBCL patients previously treated with R. Our data align with CHECKMATE-140 in FL (4% ORR, Armand Blood 2021) and data from post-transplant DLBCL (10% ORR post-ASCT, Ansell JCO 2019). Despite similarities in age and FLIPI distribution with data from Nastoupil et al, we failed to confirm those efficacy findings, a finding partly attributable to inclusion of rituximab-resistant patients. Our data suggest limited utility of combined anti-CD20 and anti-PD-1 therapy in R/R FL and DLBCL, and support exploration of alternative strategies to target the TME in these diseases.

Lymphoma-Derived IL-10 Is a Key Immunomodulatory Factor at the Tumor Microenvironment of Activated B-Cell Diffuse Large B-Cell Lymphoma and Influences In Vivo Responses to Immunotherapy

Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of aggressive non-Hodgkin's lymphoma with ~40% of patients experiencing refractory or relapsed disease to R-CHOP immunochemotherapy. These higher risk patients often exhibit gene expression profiles that resemble a late germinal center-derived activated B-cell (ABC) phenotype, where diverse specific mutations in genes along BCR and TLR signaling pathways converge into constitutive activation of the NF-κB pathway. Identification of factors that contribute to the survival of malignant ABC-DLBCL cells is crucial for designing specific interventions. In this setting, previous in vitro studies in DLBCL cell lines have evidenced that IL-10 is a direct target of NF-κB signaling that sustains lymphoma cell survival by an auto-stimulatory loop via STAT3 signaling. However, the action of IL-10 could be more complex within the lymphoma microenvironment, as IL-10 can have both stimulatory and inhibitory effects depending on the cellular source of IL-10, the timing of its secretion, and the type of immune cells that receives signals via IL-10 receptor (IL-10R). To explore in vivo the relevance of lymphoma-derived IL-10, we have generated a novel quintuple transgenic mouse model that we call pBIC10, after crossing our previous ABC-DLBCL-like pBIC mice carrying constitutive NF-κB signaling (Pascual et al., Blood 2019) to mice with a floxed Il10 gene for conditional knock-out of IL-10 specifically in malignant ABC-DLBCL cells. As expected, increased intracellular IL-10 signaling was detected in primary murine DLBCL cells from pBIC mice but not in IL-10 deficient pBIC10 mice, which promoted lymphoma cell survival ex vivo as revealed by perturbation studies of the IL-10/JAK1/STAT3 autocrine loop with blocking monoclonal antibodies or selected inhibitors. However, in vivo genetic deletion of lymphoma-derived IL-10 did not offer improved overall survival but, on the contrary, notably accelerated DLBCL progression in pBIC10 mice (Figure 1A, left). A comprehensive integration of multiparametric flow cytometry and transcriptomic analyses using bulk and single-cell RNA-seq of lymphoma cells and the tumor microenvironment coupled with BCR- and TCR-seq, identified lymphoma-derived IL-10 as a key immunomodulator of the DLBCL microenvironment, including unexpected protective paracrine functions in the progression of DLBCL. By comparing IL-10-proficient (pBIC) and -deficient (pBIC10) murine DLBCL models, we observed a multifaceted role of IL-10 produced by DLBCL cells, enabling immune-effector processes (facilitating immune chemotaxis, antigen presentation, and IFNγ responses) that yielded higher percentages of long-lived stem-like CD8 +TCF-1 +PD-1 lo/int T cells and dendritic cells, while restraining PD-1/LAG3-driven T-cell exhaustion and reducing immunosuppression by CD4 +CD25 +FOXP3 + regulatory T (Treg) cells. Thus, depletion of lymphoma-derived IL-10 decreased T-cell cytotoxicity and increased Treg-driven immunosuppression, which collectively accelerated lymphoma development. Consequently, T-cell targeted immune-checkpoint therapy (with anti-PD-1 antibodies) was effective only in IL-10-proficient DLBCL but not in IL-10-deficient pBIC10 mice (Figure 1A, right). Further comparative studies between pBIC and pBIC10 mice showed that tumor vascularization and expression of B-cell calcium channels, which have been previously associated with sensitivity to rituximab, were counteracted by lymphoma-derived IL-10. Accordingly, anti-CD20-based targeting of lymphoma cells (with rituximab surrogate antibodies) showed best in vivo responses in IL-10-deficient DLBCL mice with respect to pBIC mice (Figure 1A, right). Consistent with this preclinical data, analyses of transcriptional IL-10-associated hallmarks to stratify DLBCL patients (Schmitz et al., NEJM 2018) identified better clinical responses to R-CHOP in patients with pBIC10-like DLBCL phenotype (Figure 1B). Collectively, our study provides new functional and mechanistic insights into the role of lymphoma-derived IL-10 in the pathogenesis of DLBCL and the restraint of an immunosuppressed tumor microenvironment, which holds predictive potential as a biomarker for immunotherapy responses in DLBCL.

Sgr-1505 Is a Potent MALT1 Protease Inhibitor with a Potential Best-in-Class Profile

Background: MALT1 (Mucosa-associated lymphoid tissue lymphoma translocation protein 1) is a component of the MALT1-BCL10-CARD11 complex downstream from the Bruton Tyrosine Kinase (BTK) on the B-cell receptor signaling pathway. MALT1 is a key mediator of nuclear factor kappa B (NF-κB) signaling, which is the main driver of a subset of B-cell lymphomas. MALT1 is considered a potential therapeutic target for several subtypes of non-Hodgkin B-cell lymphomas and chronic lymphocytic leukemia (CLL), including tumors with acquired BTK inhibitor (BTKi) resistance. Constitutive activation of the NF-κB is a molecular hallmark of activated B cell-like diffuse large B cell lymphoma (ABC-DLBCL), and MALT1 may have utility as a treatment option for ABC-DLBCL. Previously, we described the discovery of novel MALT1 inhibitors with anti-proliferative effects in non-Hodgkin B-cell lymphoma cells and the strong anti-tumor activity of our MALT1 inhibitors across multiple tumor models as well as combination potential with agents including standard-of-care (ref 1, 2). SGR-1505 is an oral potent small molecule allosteric inhibitor of MALT1 that inhibits MALT1 enzymatic activity and demonstrates anti-proliferative activity in ABC-DLBCL cell lines, both BTKi-sensitive (OCI-LY10) and BTKi-resistant (OCI-LY3). When administered as a single agent and in combination with the approved Bruton's tyrosine kinase (BTK) inhibitor, ibrutinib, SGR-1505 demonstrated tumorostatic and regressive antitumor activity in ABC-DLBCL cell line-derived xenograft and patient-derived xenograft models. These data suggest that SGR-1505-mediated MALT1 inhibition has therapeutic potential for patients with selected B-cell lymphomas. Here we further characterized SGR-1505, in a series of in vitro and ex vivo assays, as well as RNA-seq analysis to examine changes in gene expression from in vivo tumor samples. We also compared SGR-1505 with a competitor Phase I candidate, JNJ-67856633 (JNJ-6633) (ref 3, 4). Results: SGR1505 potency and downstream effects were evaluated in a series of biochemical and cell based assays. SGR-1505 showed excellent potency in the biochemical assay and strong anti-proliferative effects on ABC-DLBCL cells. SGR-1505 was more potent than JNJ-6633 in all assays tested (Table 1). These results are also consistent with the result from a human primary T-cell based assay, where SGR-1505 showed at least ten-fold better potency than JNJ-6633. RNA-seq analysis was conducted to examine changes in gene expression from in vivo tumor samples. Greater modulation of BIOCARTA NF-kB pathway genes was seen with SGR-1505 compared to JNJ-6633, as measured by mean absolute change in gene expression. At 6 hr and later timepoints, we also observed a trend of increases in genes related to cell cycle pathways, such as cell cycle, DNA damage, and apoptosis. SGR-1505 is being evaluated in the SGR-1505-102 phase 1 study, which is an ongoing first-in-human, single center, dose escalation study to evaluate the safety, tolerability, PK and PD of SGR-1505 tablets in healthy participants (ACTRN12623000358640p). Preliminary data showed changes in target engagement markers at concentrations predicted by the in vitro and ex vivo assays, consistent with MALT1 protease inhibition. Conclusions: SGR-1505, a MALT1 protease small molecule inhibitor, consistently demonstrated better potency in in vitro and ex vivo assays when compared to the clinical-stage JNJ-6633 compound and greater effects on NF-kB pathway gene expression in in vivo tumor samples based on RNA-seq analysis. Changes in biological pathways mediated by MALT1 were also observed at relevant doses in the ongoing SGR-1505 healthy volunteer study. Currently, a phase 1 clinical trial in patients with mature B cell neoplasms is also ongoing (NCT05544019). The data presented suggests SGR-1505 has a potential best-in-class profile and supports advancing the ongoing clinical development of SGR-1505.

Gp350-Targeted CAR-T Therapy in EBV-Positive NK/T-Cell Lymphoma: Pre-Clinical Development of gp350CAR-T

Introduction: Epstein-Barr virus (EBV) positive NK/T cell lymphoma is a subtype of non-Hodgkin's lymphoma strongly associated with EBV infection. EBV infection has been reported in 85-100% of cases. It has been suggested to be central in pathogenesis. The incidence of EBV+ NK/T cell lymphoma is increasing worldwide, particularly in Asia and Latin America, and it has a poor prognosis with few effective treatment options. Therefore, novel approaches for treating EBV-associated NK/T cell lymphoma are urgently needed. Developing chimeric antigen receptor (CAR)-T cells therapy targeting EBV specific protein in the context of this EBV-positive aggressive lymphoma will provide a novel therapeutic strategy for patients with limited treatment options. Targeting EBV lytic protein for control EBV in vivo replication and tumorigenesis have been explored lately. The gp350 protein is a major glycoprotein on the surface of EBV during its lytic phase, after fusion between virus and host cell membrane, gp350 is left on the host cell surface. The distinct surface distribution pattern of gp350 in both freshly infected host cells and the lytic phase host cells renders it an attractive target for immunotherapy. Method and Result: We developed EBV specific CAR-T cells targeting gp350. We utilized single-chain variable fragments (scFvs) derived from four novel, gp350-binding, neutralizing monoclonal antibodies (mAbs) (12C10, 7D11, 6A12, 7A8) to generate the CAR constructs. We demonstrated that these scFvs, when fused to a second-generation CAR backbone consisting of 4-1BB and CD3ζ signal domains, are efficiently expressed on the surface of transduced T cells. These gp350 CAR-T cells exhibit specific activation and cytotoxic effects in vitro. Of note, the clone 6A12 scFv of CAR displayed the most potent cytotoxicity effects in gp350 positive cancer coculture toxicity assays. To optimize the CAR structure further, we designed various linker and transmembrane domains based on the clone 6A12 scFv, including CD8 linker, IgG4 hinge, IgG1 Fc linker, and CD28 linker and transmembrane domains. Our cytotoxicity assay screening indicated that the CD8 linker and transmembrane domain resulted in the most advanced cytotoxicity and target specificity (Figure A, B). To assess gp350 CAR-T efficacy in vivo, we established a T-cell leukaemia animal model in NOD immune-deficient mice through intravenous injection of Jurkat-gp350-luc cells. On post xenograft day 7, the Jurkat-gp350-luc xenografted mice were separated into three groups and each group with 5 mice (except PBS group with 2 mice). CAR-T and T cell were infused by tail vein injection with mock T 2x10^6/mouse, 6A12CAR-T 2x10^6/mouse and PBS control. The tumor growth in mice was monitored by in vivo luminescence with IVIS imaging system. Upon engraftment, Jurkat-gp350-luc cells established disseminated leukaemia expanding preferentially in the spine, femur, head, and pelvis, with few cells in peripheral blood. Mice receiving control mock T cells or without T cell PBS control developed rapid disease progression and were euthanized by day 35 after Jurkat-gp350-luc engraftment. In contrast, mice receiving gp350 CART cells were significantly protected from rapid progression (Figure C, D). Conclusion: In pre-clinical development, we designed, constructed, and screened gp350 CAR-T cells to demonstrate its efficacy in vitro and in vivo against and kill gp350 positive leukaemia cells and prevent formation and development leukaemia in xenograft mice model.