Cell Lymphoma Research Articles

EBV-Positive Diffuse Large B Cell Lymphoma associated with ITK-mutated Primary Immunodeficiency

EBV-Positive Diffuse Large B Cell Lymphoma associated with ITK-mutated Primary Immunodeficiency

MicroRNA Expression in Exosome Extracellular Vesicles as Targets for Personalized Medicine in Diffuse Large B Cell Lymphoma Patients with HIV Infection.

Extracellular Vesicles (EVs), more specifically exosomes (xEVs), have been associated with Diffuse Large B-cell Lymphoma (DLBCL). These xEVs contain a variety of biomolecules, such as proteins and nucleic acids (e.g., microRNA, LncRNA, and DNA). The expressions of these vesicles in the setting of Human Immunodeficiency Virus (HIV) have been linked to disease progression. Studies have explored the use of EVs in more practical clinical settings. Several studies have found that biomolecules within xEVs can serve to detect disease progression. The biomolecule content within xEVs is useful in prognostication and has even been associated with mechanisms of resistance for some DLBCL treatment modalities. This review article explores the role of xEV biomolecule content in DLBCL progression in the context of HIV infection and its applied use in practical disease management.

Causal effect estimation in survival analysis with high dimensional confounders.

With the ever advancing of modern technologies, it has become increasingly common that the number of collected confounders exceeds the number of subjects in a data set. However, matching based methods for estimating causal treatment effect in their original forms are not capable of handling high-dimensional confounders, and their various modified versions lack statistical support and valid inference tools. In this article, we propose a new approach for estimating causal treatment effect, defined as the difference of the restricted mean survival time (RMST) under different treatments in high-dimensional setting for survival data. We combine the factor model and the sufficient dimension reduction techniques to construct propensity score and prognostic score. Based on these scores, we develop a kernel based doubly robust estimator of the RMST difference. We demonstrate its link to matching and establish the consistency and asymptotic normality of the estimator. We illustrate our method by analyzing a dataset from a study aimed at comparing the effects of two alternative treatments on the RMST of patients with diffuse large B cell lymphoma.

Epidemiology and tumor microenvironment of ocular surface and orbital tumors on growth and malignant transformation.

The ocular surface and orbit constitute unique microenvironments in the human body. Current advances in molecular research have deepened our understanding of tumor development in these regions. Tumors exhibit greater heterogeneity compared to normal tissues, as revealed by pathological and histological examinations. The tumor microenvironment (TME) plays a crucial role in the proliferation and progression of cancer cells. Factors from the external environment or the body's own inflammation and microcirculation interact within the TME, maintaining a delicate balance. Disruption of this balance, through uncontrolled signal pathway activation, can transform normal or benign tissues into malignant ones. In recent years, various systemic immunotherapies have been developed for cancer treatment. This study reviews the epidemiology of ocular surface and orbital tumors include squamous cell carcinoma, basal cell carcinoma, sebaceous carcinoma and lymphoma in conjunction with their occurrence, growth, and underlying mechanisms. We propose that by examining clinical histopathological images, we can identify specific and shared microscopic features of tumors. By collecting, classifying, and analyzing data from these clinical histopathological images, we can pinpoint independent diagnostic factors characteristic of tumors. We hope this study provides a basis for future exploration of the mechanisms underlying different ocular diseases.

EZB-type diffuse large B-cell lymphoma cell lines have superior migration capabilities compared to MCD-type.

Diffuse large B-cell lymphoma (DLBCL) represents the most prevalent aggressive B-cell lymphoma. The group is heterogeneous and the outcome is variable. A variety of approaches have been employed with the objective of improving the stratification of DLBCL patients according to their prognosis, based on the cell of origin. Recently, distinct genetic subtypes of DLBCL have been identified. Given the importance of cell migration in immune cells, the objective of this study was to ascertain whether different genetic subtypes of DLBCL exhibit disparate migration abilities. MCD- and EZB-type DLBCL cell lines were subjected to testing to ascertain their basal velocity in straight microchannels and their ability to overcome tight constrictions of 2 μm. The EZB-type cell lines showed superior basal migration velocity and constriction passage time, and a similar trend was observed in live cell imaging of native human DLBCL tissue. In addition, MCD-type DLBCL exhibited significantly elevated levels of nuclear lamin A/C, which is responsible for the stiffness of the nuclear envelope and could thus explain the disparate migration behaviours observed among these subtypes. Our study suggests that different genetic subtypes of DLBCL may not only influence the outcome after therapy but also the motility of the tumour cells.

The Tumor Microenvironment as a Therapeutic Target in Cutaneous T Cell Lymphoma.

Cutaneous T cell lymphomas (CTCLs) are a heterogeneous group of non-Hodgkin lymphomas, with mycosis fungoides and Sézary syndrome being the two common subtypes. Despite the substantial improvement in early-stage diagnosis and treatments, some patients still progress to the advanced stage with an elusive underpinning mechanism. While this unsubstantiated disease mechanism coupled with diverse clinical outcomes poses challenges in disease management, emerging evidence has implicated the tumor microenvironment in the disease process, thus revealing a promising therapeutic potential of targeting the tumor microenvironment. Notably, malignant T cells can shape their microenvironment to dampen antitumor immunity, leading to Th2-dominated responses that promote tumor progression. This is largely orchestrated by alterations in cytokines expression patterns, genetic dysregulations, inhibitory effects of immune checkpoint molecules, and immunosuppressive cells. Herein, the recent insights into the determining factors in the CTCL tumor microenvironment that support their progression have been highlighted. Also, recent advances in strategies to target the CTCL tumor micromovement with the rationale of improving treatment efficacy have been discussed.

Nasal Extranodal NK/T Cell Lymphoma with Orbital Involvement: A Rare Entity of Common Presentations.

Nasal Extranodal NK/T Cell Lymphoma is an aggressive tumour affecting the nasal and midline structures, causing surrounding tissue destruction as the result of its progression. The initial presentations are similar to symptoms of benign nasal polyps, such as nasal obstruction, hyposmia and nasal discharge. As the disease progresses, the involvement of the palate, paranasal sinuses, orbit and skin become alarming symptoms. We report a case of a young male with Nasal ENKTL who presented with symptoms similar to acute on chronic rhinosinusitis with orbital complications. The challenges of diagnosing and getting to the correct management pathway are discussed.

Quantitative modeling of signaling in aggressive B cell lymphoma unveils conserved core network.

B cell receptor (BCR) signaling is required for the survival and maturation of B cells and is deregulated in B cell lymphomas. While proximal BCR signaling is well studied, little is known about the crosstalk of downstream effector pathways, and a comprehensive quantitative network analysis of BCR signaling is missing. Here, we semi-quantitatively modelled BCR signaling in Burkitt lymphoma (BL) cells using systematically perturbed phosphorylation data of BL-2 and BL-41 cells. The models unveiled feedback and crosstalk structures in the BCR signaling network, including a negative crosstalk from p38 to MEK/ERK. The relevance of the crosstalk was verified for BCR and CD40 signaling in different BL cells and confirmed by global phosphoproteomics on ERK itself and known ERK target sites. Compared to the starting network, the trained network for BL-2 cells was better transferable to BL-41 cells. Moreover, the BL-2 network was also suited to model BCR signaling in Diffuse large B cell lymphoma cells lines with aberrant BCR signaling (HBL-1, OCI-LY3), indicating that BCR aberration does not cause a major downstream rewiring.

Silencing GNAS enhances HDAC3i efficacy in CREBBP wild type B cell lymphoma.

The genetic era has opened the opportunity of using personalized therapeutic approaches, in part based on targeting genes with somatic mutations. For example, lymphomas harboring the highly recurrent CREBBP mutation show dependency on HDAC3, thus selective inhibition of HDAC3 reversed the epigenetic effects of CREBBP mutation, halted lymphoma growth, and induced MHC class II expression, enabling the T-cells to recognize and kill lymphoma cells. However, CREBBP wild type (WT) cells are less sensitive to this approach. In this issue of Leukemia, He et al. have executed a genome-wide CRISPR screening that identified GNAS as a target to maximize the therapeutic activity of HDAC3 inhibition in CREBBP WT lymphoma.

S2734 Regression of Concurrent Colonic and Gastric Low Grade B Cell Lymphoma After Eradication of Helicobacter pylori

S2734 Regression of Concurrent Colonic and Gastric Low Grade B Cell Lymphoma After Eradication of Helicobacter pylori

The Impact of Social Determinants of Health on Peripheral T Cell Lymphoma Outcomes: Treatment Center-Type Emerges as a Powerful Prognostic Indicator

BackgroundPrognostic models in peripheral T cell lymphoma (PTCL) have identified biological factors including age, performance status, LDH, and bone marrow involvement as prognostic for survival. The association of nonbiological factors, termed social determinants of health (SDH), on PTCL outcomes remains unexplored. MethodsTo evaluate the impact of actionable SDH on PTCL mortality across race groups, we conducted a retrospective cohort study that included all White, Hispanic, Asian/Pacific Islander (PI) and Black adult patients with PTCL (AITL, ALCL, NKTCL and PTCL, NOS), diagnosed from 2000 to 2020, in California. We utilized Chi2 and Wilcoxon rank-sum tests for descriptive metrics and Kaplan-Meier statistics for mortality estimation. Regression models included patient- (age, sex, race, stage, Charlson Comorbidity Index, histology, treatment type, treatment at an academic center, payer), and neighborhood-level factors (socioeconomic (SES) quintile, proportion without a high school diploma, and rural/urban). Risk factors significant in univariate regression at a P-value < .10 were incorporated into the multivariable model. FindingsOur analysis included 6158 patients: 51.8% White, 25.8% Hispanic, 14.7% Asians/PI, and 7.6% Black. Hispanics exhibited the longest median survival (33 months) followed by Whites, Blacks, and Asian/PI (25, 20, and 14 months, respectively; P = .011). Risk factors independently associated with inferior lymphoma-specific survival (LSS) included Asian/PI compared with NH White race (HR, 1.23; 95% CI, 1.10-1.34; P = .0002), AITL and ALCL compared with PTCL, NOS histology (AITL HR, 1.14; 95% CI, 1.02-1.25; P = .011; ALCL HR, 1.15; 95% CI, 1.04-1.26; P = .004), academic compared to nonacademic facility-type (HR 0.71; 95% CI, 0.64-0.77; P < .01), Medicare compared with uninsured status (HR 1.48, 95% CI, 1.25-1.73; P < .01), and the lowest 3 education quartiles compared to the highest education quartile (Q2 HR 1.13; 95% CI, 1.01-1.25; P = .021; Q3 HR 1.14; 95% CI, 1.02-1.26; P = .018; Q4 HR 1.22; 95% CI, 1.08-1.36; P < .001). In the least resourced patients, histology, treatment, treatment facility-type, payer and education were independently prognostic for LSS. Treatment at an academic institution was associated with a striking improvement in LSS (academic institution: yes = 101 months, no = 17 months; P < .01). InterpretationThese data identify treatment facility-type, payer and education, as an independent actionable SDH for PTCL mortality. Treatment center-type had the strongest prognostic association with LSS in our PTCL cohort, conferring a risk reduction of PTCL mortality by nearly 30%. Interventions targeted at improving access to academic centers may improve outcomes for all PTCL patients.

Integrative single-cell multi-omics of CD19-CARpos and CARneg Tcells suggest drivers of immunotherapy response in B cell neoplasias.

The impact of phenotypic, clonal, and functional heterogeneity of chimeric antigen receptor (CAR)-T cells on clinical outcome remains understudied. Here, we integrate clonal kinetics with transcriptomic heterogeneity resolved by single-cell omics to interrogate cellular dynamics of non-transduced (CARneg) and transduced (CARpos) Tcells, in the infusion product (IP) and at the CAR-T cell expansion peak in five B cell acute lymphoblastic leukemia (B-ALL) patients treated with CD19CAR-T cells (varni-cel). We identify significant differences in cellular dynamics in response to therapy. CARpos Tcells at IP of complete response patients exhibit a significantly higher CD4:CD8 ratio, validated in a larger cohort B-ALL patients (n= 47). Conversely, at the expansion peak, there is a clonal expansion of CD8+ effector memory and cytotoxic Tcells. Cytotoxic CARpos γδ-T cells expansion correlates with treatment efficacy validated in a cohort of B-ALL (n= 18) and diffuse large B cell lymphoma (DLBCL) patients (n= 58). Our data provide insights into the complexity of Tcell responses following CAR-T cell therapy and suggest drivers of immunotherapy response.

A-296 Efficacy and safety of pembrolizumab and radiotherapy in relapsed/refractory cutaneous T cell lymphoma: results of the PORT trial

A-296 Efficacy and safety of pembrolizumab and radiotherapy in relapsed/refractory cutaneous T cell lymphoma: results of the PORT trial

A-161 CTPS1 is a novel therapeutic target in cutaneous T cell lymphoma

A-161 CTPS1 is a novel therapeutic target in cutaneous T cell lymphoma

A-164 B cells are associated with aggressive Cases of Cutaneous T cell Lymphoma and a distinct spatio-temporal composition of the tumor microenviroenment

A-164 B cells are associated with aggressive Cases of Cutaneous T cell Lymphoma and a distinct spatio-temporal composition of the tumor microenviroenment

Serum concentrations of per- and polyfluorinated substances and risk of B-cell non-Hodgkin lymphoma

Per- and polyfluoroalkyl substances (PFAS) are persistent organic pollutants that are detectable in the serum of most U.S. adults. Some studies of highly-exposed individuals have suggested positive associations between PFAS and B-cell non-Hodgkin lymphoma (B-NHL). To investigate whether associations exist at lower exposure levels, we conducted a nested case-control study investigating serum PFAS concentrations and B-NHL within the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. We measured pre-diagnostic serum concentrations of five PFAS among 706 cases (age at diagnosis = 55–93 years, median 73 years) and 706 controls individually matched on age at blood draw, sex, self-reported race and ethnicity, study center, and year of blood collection (the median follow-up years = 10). We estimated odds ratios (ORs) and 95 % confidence intervals (CIs) for PFAS concentrations in relation to B-NHL, both overall and for selected histologic subtypes [diffuse large B cell lymphoma (DLBCL), follicular lymphoma (FL), and marginal zone lymphoma (MZL)] using conditional logistic regression. We found no evidence of a positive association with B-NHL for any of the five PFAS. In analyses of histologic subtypes, perfluorohexane sulfonate (PFHxS) was significantly associated with DLBCL in a model adjusting for all other PFAS (OR for highest vs. lowest quintile = 2.19, 95 % CI = 1.21, 3.95; Ptrend = 0.02), but not in a model without mutual adjustment (OR = 1.37, 95 % CI = 0.82, 2.29; Ptrend = 0.26). We also observed an inverse association between perfluorononanoate and DLBCL (mutually-adjusted OR = 0.83, 95 % CI = 0.69, 0.99 per doubling in concentration), although the association was null among participants with blood drawn prior to 1997 (OR<1997 = 1.00, 95 % CI = 0.82, 1.21; OR≥1997 = 0.65, 95 % CI = 0.53, 0.79; Pinteraction = 0.0003). In conclusion, our findings from a prospective cohort study with PFAS serum concentrations comparable to that of the general population do not support an association with increased risk of B-NHL overall. The suggestive evidence of a positive association between PFHxS and DLBCL warrants further investigation.

Addition of Nivolumab Tailored by Expansion of CAR-T Cells in Patients with Stable/Progressive Large B Cell Lymphoma at Lymphodepletion—A Phase 2, Prospective Interventional Study

Addition of Nivolumab Tailored by Expansion of CAR-T Cells in Patients with Stable/Progressive Large B Cell Lymphoma at Lymphodepletion—A Phase 2, Prospective Interventional Study

S5000 Gastric Nodules as a Rare Presentation of Diffuse Large B Cell Lymphoma

S5000 Gastric Nodules as a Rare Presentation of Diffuse Large B Cell Lymphoma

Dimeric natural product panepocyclinol A inhibits STAT3 via di-covalent modification

Homo- or heterodimeric compounds that affect dimeric protein function through interaction between monomeric moieties and protein subunits can serve as valuable sources of potent and selective drug candidates. Here, we screened an in-house dimeric natural product collection, and panepocyclinol A (PecA) emerged as a selective and potent STAT3 inhibitor with profound anti-tumor efficacy. Through cross-linking C712/C718 residues in separate STAT3 monomers with two distinct Michael receptors, PecA inhibits STAT3 DNA binding affinity and transcription activity. Molecular dynamics simulation reveals the key conformation changes of STAT3 dimers upon the di-covalent binding with PecA that abolishes its DNA interactions. Furthermore, PecA exhibits high efficacy against anaplastic large T cell lymphoma in vitro and in vivo, especially those with constitutively activated STAT3 or STAT3Y640F. In summary, our study describes a distinct and effective di-covalent modification for the dimeric compound PecA to disrupt STAT3 function.

Upfront Management of Blastoid Variant Mantle Cell Lymphoma: Making the Case for 2nd/3rd-Generation Bruton Tyrosine Kinase Inhibitor-Based Therapies.

Blastoid variant-mantle cell lymphoma (BV-MCL) represents an aggressive subset of patients with no established standard of care treatment approach. We performed a retrospective analysis of the clinical characteristics and outcomes of 17 de novo BV-MCL patients treated at our institution between May 2009 and September 2023. In addition, we reviewed the literature supporting 2nd/3rd generation Bruton's Tyrosine-kinase (BTKi)-based therapies for upfront management. The complete response rate to frontline and salvage therapy was 66.7% and 25%, respectively. Two-year overall survival (OS) was low at 62.5% (95% CI, 34.7%-81.1%). Variables associated with higher OS included receipt of consolidative HSCT (p = 0.017), TP53-wild type (p = 0.031), intermediate- versus high-risk Mantle Cell Lymphoma Prognostic Index score (p = 0.026), and achieving complete response with induction therapy (p = 0.027). Treatment outcomes with chemo-immunotherapy in BV-MCL patients are poor, especially among TP53-mutated patients. Recent findings describing positive outcomes with novel BTKi-based therapies are encouraging and should be considered in this high-risk population.