Outcome In Diffuse Large B-cell Lymphoma Patients Research Articles

Feasibility of Circulating Tumor DNA Detection in the Cerebrospinal Fluid of Patients With Central Nervous System Involvement in Large B-Cell Lymphoma.

We explored the utility of cerebrospinal fluid (CSF) circulating tumor DNA (ctDNA) sequencing as a noninvasive diagnostic tool for detecting central nervous system (CNS) involvement in patients with diffuse large B-cell lymphoma (DLBCL). Secondary CNS involvement in DLBCL, although rare (~5% of cases), presents diagnostic and prognostic challenges during systemic disease progression or relapse. Effective treatment is impeded by the blood-brain barrier. This was a prospective cohort study (Samsung Lymphoma Cohort Study III) involving 17 patients with confirmed CNS involvement. High-throughput sequencing was conducted using targeted gene panels designed to detect low-frequency variants and copy number alterations pertinent to lymphomas in ctDNA extracted from archived CSF samples. Despite challenges such as low DNA concentrations affecting library construction, the overall variant detection rate was 76%. Detected variants included those in genes commonly implicated in CNS lymphoma, such as MYD88. The study highlights the potential of CSF ctDNA sequencing to identify CNS involvement in DLBCL, providing a promising alternative to more invasive diagnostic methods such as brain biopsy, which are not always feasible. Further validation is necessary to establish the clinical utility of this method, which could significantly enhance the management and outcomes of DLBCL patients with suspected CNS involvement.

The impact of trial inclusion criteria on outcomes in DLBCL patients treated with R-CHOP in the first line: a Danish nationwide study

Up to 50% of diffuse large B-cell lymphoma (DLBCL) patients are ineligible for participation in clinical trials. Ineligible patients have inferior outcomes, but less is known about the impact of commonly used organ-function-based inclusion criteria on drug efficacy estimates. Data on DLBCL patients treated with CHOP+/-rituximab were retrieved from the Danish Lymphoma Registry. Trial inclusion criteria were extracted from four international DLBCL trials (REMoDL-B, GOYA, POLARIX, and HOVON-84). Differences in overall survival (OS) and 5-year restricted mean survival differences (5 y-RMSDs) between trial eligible and ineligible patients were computed. The effectiveness of adding rituximab to CHOP was quantified by the 5 y-RMSD between CHOP and R-CHOP-treated patients and the impact of individual trial criteria on estimated effectiveness was quantified by Shapley-values. In total, 4,083 R-CHOP-treated and 890 CHOP-treated DLBCL patients were included. Across the trials, 18.6-29.3% of the included R-CHOP-treated patients were deemed ineligible for trial based on organ function and performance status alone. Ineligible patients had significantly worse survival, with adjusted absolute differences in 5-year OS of 9-15%. The impact of individual criteria on the estimated effectiveness of adding rituximab to CHOP was small (Shapley-value range, −2.74-0.31). Using a smaller set of criteria derived from a data-driven approach, the number of eligible patients increased by 16-38% and the 5 y-RMSD increased by 0.7-3.1 months. In conclusion, OS among trial ineligible DLBCL patients is inferior as expected, but relaxing trial criteria would have increased the number of trial participants without making major changes in estimated efficacy for a hypothetical CHOP versus R-CHOP trial. This does not necessarily imply that trial findings based on selected patients are unreliable, as the estimated effectiveness of adding rituximab to CHOP was only slightly affected by omitting selected inclusion criteria.

Low NDRG2, regulated by the MYC/MIZ-1 complex and methylation, predicts poor outcomes in DLBCL patients.

Diffuse large B-cell lymphoma (DLBCL) represents the most common tumor in non-Hodgkin's lymphoma. N-Myc downstream-regulated gene 2 (NDRG2) is a tumor suppressor highly expressed in healthy tissues but downregulated in many cancers. Although cell proliferation-related metabolism rewiring has been well characterized, less is known about the mechanism of metabolic changes with DLBCL. Herein, we investigated the expressions of NDRG2, MYC and Myc-interacting zinc finger protein 1 (MIZ-1) in seven human lymphoma (mostly DLBCLs) cell lines. NDRG2 expression was inversely correlated with the expressions of MYC and MIZ-1. Further, we explored the regulatory mechanism and biological functions underlying the lymphomagenesis involving NDRG2, MYC and MIZ-1. MYC and MIZ-1 promoted DLBCL cell proliferation, while NDRG2 induced apoptosis in LY8 cells. Moreover, NDRG2 methylation was reversed by the 5-Aza-2'-deoxycytidine (5-Aza-CDR) treatment, triggering the downregulation of MYC and inhibiting DLBCL cell survival. MYC interacts with NDRG2 to regulate energy metabolism associated with mTOR. Remarkably, supporting the biological significance, the converse correlation between NDRG2 and MYC was observed in human DLBCL tumor tissues (R = -0.557). Bioinformatics analysis further validated the association among NDRG2, MYC, MIZ-1, mTOR, and related metabolism genes. Additionally, NDRG2 (P = 0.001) and MYC (P < 0.001) were identified as promising prognostic biomarkers in DLBCL patients through survival analysis. Together, our data demonstrate that the MYC/MIZ-1 complex interplays with NDRG2 to influence the proliferation and apoptosis of DLBCL cells and show the characterizations of NDRG2, MYC and MIZ-1 for metabolism features and prediction prognosis in DLBCL.

Comparison of the Prognostic Value of C-Reactive Protein to Albumin Ratio and Glasgow Prognostic Score in Patients with Diffuse Large B-Cell Lymphoma

To compare the prognostic value of two predictive models based on C-reactive protein (CRP) and albumin (ALB), namely the CRP to ALB ratio (CAR) and the Glasgow prognostic score (GPS), in newly diagnosed patients with diffuse large B-cell lymphoma (DLBCL). The data of newly diagnosed DLBCL patients admitted to our center from May 2014 to January 2022 were reviewed. A total of 111 patients who completed at least 4 cycles of R-CHOP or R-CHOP-like chemotherapy with detailed clinical, laboratory data and follow-up information were included. The receiver operating characteristic (ROC) curve was performed to evaluate the predictive value of pre-treatment CAR on disease progression and survival. Furthermore, the association between CAR and baseline clinical, laboratory characteristics of patients was evaluated, and progression-free survival (PFS) and overall survival (OS) were compared between different CAR and GPS subgroups. Finally, the univariate and multivariate COX propor-tional hazard regression models were used to analyze the factors affecting disease outcomes. ROC curve showed that the area under the curve (AUC) of CAR predicting PFS and OS in DLBCL patients was 0.687 (P =0.002) and 0.695 (P =0.005), respectively, with the optimal cut-off value of 0.11 for both predicting PFS and OS. Compared with the lower CAR (<0.11) group, the higher CAR (≥0.11) group had more clinical risk factors, including age >60 years (P =0.025), ECOG score ≥2 (P =0.004), Lugano stage III-IV (P < 0.001), non-germinal center B-cell-like (non-GCB) subtype (P =0.035), elevated lactate dehydrogenase (LDH) ( P < 0.001), extranodal involved site >1 (P =0.004) and IPI score >2 (P < 0.001). The interim response evaluation of patients showed that the overall response rate (ORR) and complete response rate (CRR) in the lower CAR group were both significantly better than those in the higher CAR group (ORR: 96.9% vs 80.0%, P =0.035; CRR: 63.6% vs 32.5%, P =0.008). With a median follow-up of 24 months, patients with lower CAR had significantly longer median PFS and OS than those with higher CAR (median PFS: not reached vs 67 months, P =0.0026; median OS: not reached vs 67 months, P =0.002), while there was no statistical difference in PFS (P =0.11) and OS (P =0.11) in patients with GPS of 0, 1, and 2. Multivariate Cox regression analysis indicated that only sex (male) and IPI score >2 were independent risk factors for both PFS and OS. CAR is significantly correlated with disease progression and survival in DLBCL patients; And compared with GPS, CAR has more advantages in predicting disease outcomes in DLBCL patients.

Identification of a prognostic signature based on five ferroptosis-related genes for diffuse large B-cell lymphoma.

Therapies for diffuse large B-cell lymphoma (DLBCL) are limited due to the diverse gene expression profiles and complicated immune microenvironments, making it an aggressive lymphoma. Beyond this, researches have shown that ferroptosis contributes to tumorigenesis, progression, and metastasis. We thus are interested to dissect the connection between ferroptosis and disease status of DLBCL. We aim at generating a valuable prognosis gene signature for predicting the status of patients of DLBCL, with focus on ferroptosis-related genes (FRGs). To examine the connection between ferroptosis-related genes (FRGs) and clinical outcomes in DLBCL patients based on public datasets. An expression profile dataset for DLBCL was downloaded from GSE32918 (https://www.ncbi.nlm.nih.gov/geo/ query/acc.cgi?acc=gse32918), and a ferroptosis-related gene cluster was obtained from the FerrDb database (http://www. zhounan.org/ferrdb/). A prognostic signature was developed from this gene cluster by applying a least absolute shrinkage and selection operator (LASSO) Cox regression analysis to GSE32918, followed by external validation. Its effectiveness as a biomarker and the prognostic value was determined by a receiver operator characteristic curve mono factor analysis. Finally, functional enrichment was evaluated by the package Cluster Profiler of R. Five ferroptosis-related genes (FRGs) (GOP1, GPX2, SLC7A5, ATF4, and CXCL2) associated with DLBCL were obtained by a multivariate analysis. The prognostic power of these five FRGs was verified by TCGA (https://xenabrowser.net/datapages/?dataset=TCGA.DLBC.sampleMap%2FHiSeqV2_PANCAN&host=https%3A%2F%2Ftcga.xenahubs.net&removeHub=https%3A%2F%2Fxena.treehouse.gi.ucsc.edu%3A44) and GEO (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=gse 32918) datasets, with ROC analyses. KEGG and GO analyses revealed that upregulated genes in the high-risk group based on the gene signature were enriched in receptor interactions and other cancer-related pathways, including pathways related to abnormal metabolism and cell differentiation. The newly developed signature involving GOP1, GPX2, SLC7A5, ATF4, and CXCL2 has the potential to serve as a prognostic biomarker. Furthermore, our results provide additional support for the contribution of ferroptosis to DLBCL.

Examining Racial Disparities in Diffuse Large B-Cell Lymphoma (DLBCL) Outcomes within the Veterans Health Administration (VHA)

INTRODUCTION: The incidence of DLBCL in the United Sates is projected to increase to 32, 443 new cases per year by 2025. With increasing incidence and prevalence, DLBCL prognosis has improved significantly in the past decade through the addition of novel therapies such as new monoclonal antibodies, chimeric antigen receptor T-cell (CAR-T) therapy, antibody-drug conjugates, and most recently bispecific T-cell engagers. Despite these improvements, racial and ethnic disparities continue to impact outcomes in DLBCL patients (Flowers 2012). The purpose of this study was to assess racial and ethnic differences in DLBCL patients and outcomes within the VHA, an equal access system where confounding factors such as disease biology and socioeconomic status are more controlled giving us an opportunity to examine racial disparities. The aim of this study is to present a final analysis the final analysis of racial and ethnic differences in DLBCL patients within the VHA over a time span of 11 years. METHODS: Trained abstractors performed a retrospective chart review of 6266 randomly selected DLBCL patients treated in the VHA nationwide between 1/1/2011 and 12/31/2021. Patients diagnosed with DLBCL were included. Patients were excluded if they had a diagnosis other than DLBCL, had incomplete records, or were diagnosed and treated outside the VHA. Data was collected on baseline patient demographics, disease characteristics, and treatment. Survival time was determined via electronic health record query on 1/4/2023. The study population was divided into non-Hispanic Black (NHB), non-Hispanic White (NHW), Hispanic (H), and other. Chi-squared tests were used to analyze the relationship between race and variables of interest. RESULTS: 3178 patients met inclusion criteria for analysis. Patients were predominantly male with a median age of 69 and presented primarily with advanced disease (Baseline Characteristics-Table 1). NHB were diagnosed at a younger median age (63 years) when compared to the NHW, H and other (69 years, P &amp;lt; 0.001). Patients in each subgroup presented with similar rates of stage I/II and III/IV disease with no statistically significant difference in stage at presentation amongst each racial subgroup (P=0.61). Of all the patients who received chemotherapy, the objective response (OR) rate was 79.2% with a complete response (CR) rate of 66.4%. The response rates were similar across the 4 subgroups with most patients achieving a CR after first-line therapy (P=0.74). There were no statistically significant differences in OR rates amongst subgroups (P = 0.95). Median overall survival (mOS) for the entire population was 69.6 months (95% CI = 65-75), with a mOS of 85.1 months (67-112), 85.9 months (60-112), 67.4 months (60-73), and 71.2 months (49-122) for NHB, H, NHW, and other patients respectively (Figure 1). There was no statistically significant difference in mOS amongst subgroups (P = 0.13). The 1-year, 3-year, and 5-year survival rates were also similar between subgroups (P=0.97, P= 0.39, P=0.32 respectively). CONCLUSION: This study represents one of the largest retrospective analyses of DLBCL in the VHA nationwide, highlighting that there is no statistically significant racial difference in DLBCL outcomes for patients treated within the VHA. Our study highlights the significance of equal access system and that disease biology and other social factors can be mitigated resulting in equal response to treatment and OS amongst all groups. Potential limitations of this study include using retrospective data on a predominantly white, male population that may not truly represent general DLBCL population data. The study period is mainly until 2021 with limited data on the accessibility of newer, novel treatments. With the development of newer, expensive treatments, especially Bispecific T Cell Engagers and CAR-T therapy, it is imperative to study utilizations of these novel treatments and study racial differences in this new treatment non-chemotherapy-based era.

Survival Trends in Diffuse Large B-Cell Lymphoma (DLBCL) in the CAR-T Cell Therapy Era Vs Pre-CAR-T Cell Therapy Era in the United States: A Population-Based Study

Background Chimeric Antigen Receptors (CARs) are novel engineered proteins that alter T-cell antigen specificity. CAR-T cell therapy is a novel form of immunotherapy that uses T-cells engineered with CARs to target tumor-associated antigens. The Food and Drug Administration (FDA) granted approval to the first CAR-T therapeutic agents in 2017. Axicabtagene ciloleucel (axicel) is one such therapy currently in use that was developed to target CD19 - a pan-B cell marker for the treatment of Diffuse Large B-Cell Lymphoma (DLBCL). 1 Previous population-based studies have shown improvements in Overall Survival (OS) after the introduction of rituximab (anti-CD20 monoclonal antibody) for the treatment of patients with DLBCL. 2 However, there is limited data on survival after the introduction of CAR-T cell therapy at the population level. With this study, we hypothesized that improvements in survival have been made in recent years with the introduction of CAR-T cell therapy for the treatment of DLBC and aim to demonstrate these outcomes. Methods We used the Surveillance, Epidemiology and End-Results (SEER-17) research program data to conduct a retrospective study of patients diagnosed with DLBCL between 2013-2020. This period was divided into two cohorts: pre-CAR-T approval (2013-2016) and post-CAR-T approval eras (2017-2020). Statistical analysis was performed using SPSS version 25. Patient characteristics were expressed as number (N) and percentages (%). Categorical variables were compared using the Chi-Square Test. The Kaplan Meier method was used to compare OS of both eras. OS was defined as the time from diagnosis to death. Cox proportional hazard regression was used to compare both cohorts and expressed as hazard ratios. A p-value ≤0.05 was considered statistically significant. Results All results are highlighted in Table 1. A total of 41219 DLBCL patients were identified between 2013 and 2020. Splitting by cohorts, 20139 DLBCL patients were identified in the pre-CAR-T cohort and 21080 DLBCL patients were identified in the post-CAR-T approval cohort. Patients in the post-CAR-T era demonstrated a higher proportion of patients ≥65 years (56.6% vs 53.7%) and distant stage disease (53.4% vs 52.1%) at the end of the time period.. The pre-CAR-T era demonstrated a higher proportion of people dead attributable to DLBCL (33% vs 23.5%). Figure 1 depicts OS for each group, with the post-CAR-T era (2017-2020) demonstrating a statistically significant higher OS (0.031). The post-CAR-T era cohort was associated with an improvement in overall survival (HR = 0.951, 95% CI: 0.913-0.990, p-value ≤0.014). Other independent prognostic variables found in our study were, ≥age 65 (HR = 2.351 95% CI: 2.251-2.455, p-value ≤0.001), male sex (HR = 1.260, 95% CI: 1.212-1.311, p-value ≤0.001), distant stage disease (HR = 1.653, 95% CI: 1.573-1.737, p-value ≤0.001), which indicated worse prognosis. Chemotherapy (HR = 0.331, 95% CI: 0.314-0.349, p-value ≤0.001) was found to be an independent prognostic factor for improvement of OS in DLBCL. Conclusion: To the best of our knowledge, our study is the first US population-based study to evaluate survival outcomes in DLBCL patients after the introduction of CAR-T cell therapy. The survival in patients in the CAR-T era improved compared with the pre-CAR-T era. A limitation of our study is that the SEER database does not contain data on the type of chemotherapy given to patients. Also, due to the relatively recent introduction of CAR-T cell therapy as a treatment modality further studies over longer time periods are required to better characterize its association with improvements in survival.

CCDC50, an essential driver involved in tumorigenesis, is a potential severity marker of diffuse large B cell lymphoma

Diffuse Large B Cell Lymphoma (DLBCL) is the most common form of blood cancer. Among the subtypes, the activated B-cell (ABC) subtype is typically more aggressive and associated with worse outcomes. However, the underlying mechanisms are not fully understood. In this study, we performed microarray analysis to identify potential ABC-DLBCL-associated genes. We employed Kaplan–Meier methods and cox univariate analysis to explore the prognostic value of the identified candidate gene Coiled-coil domain containing 50 (CCDC50). Additionally, we used DLBCL cell lines and mouse models to explore the functions and mechanisms of CCDC50. Finally, we isolated CCDC50-bearing exosomes from clinical patients to study the correlation between these exosomes and disease severity. Our results demonstrated that CCDC50 not only showed significantly positive correlations with ABC subtype, tumor stage and number of extranodal sites, but also suggested poor outcomes in DLBCL patients. We further found that CCDC50 promoted ABC-DLBCL proliferation in vitro and in vivo. Mechanistically, CCDC50 inhibited ubiquitination-mediated c-Myc degradation by stimulating the PI3K/AKT/GSK-3β pathway. Moreover, CCDC50 expression was positively correlated with c-Myc at protein levels in DLBCL patients. Additionally, in two clinical cohorts, the plasma CCDC50-positive exosomes differentiated DLBCL subtypes robustly (AUC > 0.80) and predicted disease severity effectively (p < 0.05). Our findings suggest that CCDC50 likely drives disease progression in ABC-DLBCL patients, and the CCDC50-bearing exosome holds great potential as a non-invasive biomarker for subtype diagnosis and prognosis prediction of DLBCL patients.

Prognostic value of geriatric nutritional risk index in patients with diffuse large B-cell lymphoma: a meta-analysis.

Geriatric nutritional risk index (GNRI) on the prognosis of patients with diffuse large B-cell lymphoma (DLBCL) remains unclear. The purpose of this meta-analysis was to discuss the value of the GNRI in evaluating long-term outcomes in DLBCL. We systematically and roundly retrieved PubMed, Cochrane Library, Embase, Scopus and Web of Science electronic databases from inception of the databases to March 20, 2023. At the same time, we calculated the pool hazard ratios (HRs) with their 95% confidence interval (CI) for overall survival and progression-free survival to assess the effect of GNRI on the prognosis of DLBCL patients. In our primary meta-analysis, 7 trials with a total of 2448 patients were enrolled. Results showed that lower level of GNRI was related to poorer overall survival (HR = 1.78, 95% CI 1.27, 2.50, p < 0.01) and worse progression-free survival (HR = 2.31, 95% CI 1.71, 3.13, p < 0.01) in DLBCL patients. The results of our meta-analysis indicate that a lower GNRI significantly associated with poorer prognosis for DLBCL. It is believed that GNRI was a promisingly predictive indicator of survival outcomes in DLBCL patients. However, large multicenter prospective studies are necessary to verify the results.

A unique expression pattern of LAG3 distinct from that of other immune checkpoints in diffuse large B-cell lymphoma.

Although some patients with diffuse large B-cell lymphoma (DLBCL) show a response to immunotherapy, there are still many who do not respond. This suggests that various immune checkpoints are complicatedly intertwined in the composition of the tumor microenvironment of DLBCL. To comprehensively understand the expression of various immune checkpoint genes in DLBCL, we performed NanoString assay in 98 patients to investigate 579 genes. In addition, we performed immunohistochemistry for LAG-3 and PD-L1 to compare the results with expression in NanoString assay. As a result of hierarchical clustering of NanoString assay, 98 DLBCLs were classified into three tumor immune microenvironment clusters. Most immune checkpoint genes showed the highest expression in cluster A and the lowest in cluster C. However, the expression of LAG3 was the highest in cluster C and the lowest in cluster A, showing an expression pattern opposite to that of other immune checkpoint genes. In Cluster A, the expression of genes related to T-cell activity such as CD8A and GZMB was increased. In Cluster C, the expression of genes related to major histocompatibility complex molecules was the highest. Immunohistochemical stains showed modest agreement with the NanoString results but did not help clustering. Our results show that the unique expression pattern of LAG3 in DLBCL contrasts with that of other immune checkpoints. We suggest that the combination of anti-PD-1/PD-L1 and anti-LAG-3 blockades in the immunotherapy of DLBCL patients can have a synergistic effect, improving the immunotherapy efficacy and outcome in DLBCL patients.

Survival outcomes of patients newly diagnosed with diffuse large B-cell lymphoma: real-world evidence from a German claims database.

Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma with increasing incidence. Although the burden of disease is high, only limited current real-world data on survival analysis, especially survival time, of German patients with DLBCL are available. This retrospective claims-based analysis was conducted to describe real-world survival evidence and treatment patterns of patients with DLBCL in Germany. Using a large claims database of the German statutory health insurance with 6.7 million enrollees, we identified patients between 2010 and 2019 who were newly diagnosed with DLBCL (index date) and had no other cancer co-morbidity. Overall survival (OS) from index date and from the end of each treatment line was plotted by means of the Kaplan-Meier estimator, both for the overall cohort and stratified by treatment regimen. Treatment lines were identified based on a predefined set of medications categorized by established DLBCL treatment recommendations. 2495 incident DLBCL patients were eligible for the study. After index date, 1991 patients started a first-line, 868 a second-line, and 354 a third-line therapy. In first line, 79.5% of patients received a Rituximab-based therapy. 5.0% of the of the 2495 patients received a stem cell transplantation. Overall, median OS after index was 96.0months. DLBCL-associated mortality is still high, especially in relapsed patients and in the elderly. Therefore, there is a high medical need for new effective treatments that can improve survival outcomes in DLBCL patients.

Altered serum lipid levels are associated with prognosis of diffuse large B cell lymphoma and influenced by utility of rituximab.

Diffuse large B cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma, and the prognosis of the disease varied. This research aims to investigate the impact of serum lipid level on the outcome of DLBCL patients and their interaction with rituximab (RTX). Data of newly diagnosed DLBCL in the third affiliated hospital of Soochow University were retrospectively collected. Baseline serum lipid levels, clinical data, and survival information were simultaneously recorded. Data of healthy controls were collected with age matching. Serum lipid levels significantly differed for the patients. All were transformed into categorical variables for the analysis of survival. During a median follow-up of 58 months, 32.8% patients died. Univariate analysis revealed all serum lipid indicators were associated with overall survival (OS); all except for total cholesterol (TC) and apolipoprotein B (apoB) showed significant impact on progression-free survival (PFS). Multivariable analysis confirmed the adverse effect of triglyceride (TG) on PFS (P = 0.013) and favorable impact of high-density lipoprotein (HDL) on OS (P = 0.003). For cases treated without RTX, apolipoprotein A (apoA) had independent favorable effect on both PFS (P = 0.004) and OS (P = 0.001). Comparably, for patients who received RTX, HDL showed remarkably predictive value of PFS (P = 0.011) and OS (P = 0.019). In conclusion, the abnormal serum lipids occurred throughout the course of DLBCL, and the associations of serum lipids and the prognosis of the disease were interfered by RTX. Trial registration: 2022()CL033; June 26, 2022, retrospectively registered.

Association Between the Neutrophil-to-Lymphocyte Ratio and Infection and Survival in Diffuse Large B Cell Lymphoma.

Infection is a common cause of morbidity and mortality in patients treated for diffuse large B-cell lymphoma (DLBCL). However, there is limited information on the impact and risk factors for infection among patients receiving rituximab, cyclophosphamide, vincristine, doxorubicin, and prednisolone (R-CHOP). A retrospective study evaluating patients with DLBCL receiving R-CHOP and R-COP between 2004 and 2021 was conducted at a medical center. Hospital patients' records for the five-item modified frailty index (mFI-5), sarcopenia, blood-based inflammatory markers, and clinical outcomes were statistically analyzed. Patients with frailty, sarcopenia, and high neutrophil-to-lymphocyte ratio (NLR) were associated with a higher risk of infections. The revised International Prognostic Index poor-risk group, high NLR, infections, and treatment modality were risk factors for shorter progression-free and overall survival. Pre-treatment high NLR was a predictor of infection and survival outcome in DLBCL patients.

Serum cell-free DNA concentration as a possible prognostic marker in newly diagnosed diffuse large B-cell lymphoma.

Cell-free DNA (cfDNA) is a fragment of DNA circulating in the blood, and its concentration is often elevated in cancer patients. To investigate the relationships between serum cfDNA concentration and clinical characteristics, including prognosis, we measured serum cfDNA concentration in 114 newly diagnosed lymphoma patients. The cfDNA concentrations in diffuse large B cell lymphoma (DLBCL) (62.5 ng/mL) and follicular lymphoma patients (51.6 ng/mL) were significantly elevated compared to healthy individuals (7.5 ng/mL, P < 0.001). In DLBCL, patients with elevated serum cfDNA (> 38.9 ng/mL) at diagnosis had significantly shorter time-to-progression compared to those without (P = 0.033). The addition of cfDNA concentration to the international prognostic index showed improved predictive power for time-to-progression. Moreover, cfDNA added significant prognostic value to other inflammatory markers such as B symptoms and sIL2R. There was a trend towards shorter progression-free survival and overall survival in patients with elevated cfDNA. Furthermore, B symptoms (P = 0.038), bulky masses (P = 0.031), non-GCB subtype (P = 0.012), and serum sIL-2R levels > 2,000 U/mL (P = 0.012) were associated with higher cfDNA levels. Our study showed that serum cfDNA concentration at diagnosis was associated with certain clinicopathological characteristics, and may be predictive of survival outcomes in DLBCL patients.

Pharmacologic screen identifies active combinations with BET inhibitors and LRRK2 as a novel putative target in lymphoma.

Inhibitors of the Bromo‐ and Extra‐Terminal domain (BET) family proteins have strong preclinical antitumor activity in multiple tumor models, including lymphomas. Limited single‐agent activity has been reported in the clinical setting. Here, we have performed a pharmacological screening to identify compounds that can increase the antitumor activity of BET inhibitors in lymphomas.The germinal center B‐cell like diffuse large B‐cell lymphoma (DLBCL) cell lines OCI‐LY‐19 and WSU‐DLCL2 were exposed to 348 compounds given as single agents at two different concentrations and in combination with the BET inhibitor birabresib. The combination partners included small molecules targeting important biologic pathways such as PI3K/AKT/MAPK signaling and apoptosis, approved anticancer agents, kinase inhibitors, epigenetic compounds. The screening identified a series of compounds leading to a stronger antiproliferative activity when given in combination than as single agents: the histone deacetylase (HDAC) inhibitors panobinostat and dacinostat, the mTOR (mechanistic target of rapamycin) inhibitor everolimus, the ABL/SRC (ABL proto‐oncogene/SRC proto oncogene) inhibitor dasatinib, the AKT1/2/3 inhibitor MK‐2206, the JAK2 inhibitor TG101209. The novel finding was the benefit given by the addition of the LRRK2 inhibitor LRRK2‐IN‐1, which was validated in vitro and in vivo. Genetic silencing demonstrated that LRRK2 sustains the proliferation of lymphoma cells, a finding paired with the association between high expression levels and inferior outcome in DLBCL patients.We identified combinations that can improve the response to BET inhibitors in lymphomas, and LRRK2 as a gene essential for lymphomas and as putative novel target for this type of tumors.

Metabolic Biomarkers Assessed with PET/CT Predict Sex-Specific Longitudinal Outcomes in Patients with Diffuse Large B-Cell Lymphoma.

Simple SummaryThere is a sex disparity in lymphoma where males have higher incidence and mortality compared to females. Sex differences in metabolism may be a significant factor underlying this phenomenon where visceral obesity, a known biomarker for poor outcomes in multiple pathophysiological states, is higher in males compared to females. Here, we report that visceral fat, although higher in males with diffuse large B-cell lymphoma (DLBCL), selectively predicted worse outcomes in females. Moreover, females that selectively gained visceral fat during chemotherapy did worse, and combining the change in visceral fat over the course of chemotherapy and tumor glucose uptake measured by FDG-PET at end of treatment identified a subgroup of females with extremely poor outcomes.In many cancers, including lymphoma, males have higher incidence and mortality than females. Emerging evidence demonstrates that one mechanism underlying this phenomenon is sex differences in metabolism, both with respect to tumor nutrient consumption and systemic alterations in metabolism, i.e., obesity. We wanted to determine if visceral fat and tumor glucose uptake with fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) could predict sex-dependent outcomes in patients with diffuse large B-cell lymphoma (DLBCL). We conducted a retrospective analysis of 160 patients (84 males; 76 females) with DLBCL who had imaging at initial staging and after completion of therapy. CT-based relative visceral fat area (rVFA), PET-based SUVmax normalized to lean body mass (SULmax), and end-of-treatment FDG-PET 5PS score were calculated. Increased rVFA at initial staging was an independent predictor of poor OS only in females. At the end of therapy, increase in visceral fat was a significant predictor of poor survival only in females. Combining the change in rVFA and 5PS scores identified a subgroup of females with visceral fat gain and high 5PS with exceptionally poor outcomes. These data suggest that visceral fat and tumor FDG uptake can predict outcomes in DLBCL patients in a sex-specific fashion.

Discovery of Pre-Treatment FDG PET/CT-Derived Radiomics-Based Models for Predicting Outcome in Diffuse Large B-Cell Lymphoma.

Simple SummaryDiffuse large B-cell lymphoma (DLBCL) is the most common type of lymphoma. Even with the improvements in the treatment of DLBCL, around a quarter of patients will experience recurrence. The aim of this single centre retrospective study was to predict which patients would have recurrence within 2 years of their treatment using machine learning techniques based on radiomics extracted from the staging PET/CT images. Our study demonstrated that in our dataset of 229 patients (training data = 183, test data = 46) that a combined radiomic and clinical based model performed better than a simple model based on metabolic tumour volume, and that it had a good predictive ability which was maintained when tested on an unseen test set.Background: Approximately 30% of patients with diffuse large B-cell lymphoma (DLBCL) will have recurrence. The aim of this study was to develop a radiomic based model derived from baseline PET/CT to predict 2-year event free survival (2-EFS). Methods: Patients with DLBCL treated with R-CHOP chemotherapy undergoing pre-treatment PET/CT between January 2008 and January 2018 were included. The dataset was split into training and internal unseen test sets (ratio 80:20). A logistic regression model using metabolic tumour volume (MTV) and six different machine learning classifiers created from clinical and radiomic features derived from the baseline PET/CT were trained and tuned using four-fold cross validation. The model with the highest mean validation receiver operator characteristic (ROC) curve area under the curve (AUC) was tested on the unseen test set. Results: 229 DLBCL patients met the inclusion criteria with 62 (27%) having 2-EFS events. The training cohort had 183 patients with 46 patients in the unseen test cohort. The model with the highest mean validation AUC combined clinical and radiomic features in a ridge regression model with a mean validation AUC of 0.75 ± 0.06 and a test AUC of 0.73. Conclusions: Radiomics based models demonstrate promise in predicting outcomes in DLBCL patients.

Prognostic impact of TP53 mutation in newly diagnosed diffuse large B-cell lymphoma patients treated in the FIL-DLCL04 trial.

The prognostic role of TP53 disruption has been established in diffuse large B-cell lymphoma (DLBCL). Aim of this analysis was to correlate TP53 mutations by Sanger sequencing, cell of origin (COO) profile by Lymph2Cx panel on the NanoString platform and MYC, BCL2 and BCL6 overexpression or re-arrangements by immunohistochemistry (IHC) and fluorescent in-situ hybridization (FISH), with outcome in DLBCL patients enrolled into the FIL-DLCL04 trial (NCT00499018). One hundred and twenty-five DLBCL patients with tumour block available were analyzed. TP53 was mutated in 11/125 (9%) cases; 60/125 patients received high-dose chemoimmunotherapy up-front, as for the randomization arm; COO was reported in 88 patients: 48 germinal centre B-cell like, 25 activated B-cell like and 17 unclassified; 26 patients were double expressors in IHC and 11 double hit in FISH. After a median follow-up of 72 months, five-year failure-free survival (FFS) for TP53 mutated versus wild-type was 24% and 72%, and five-year overall survival (OS) was 34% and 83%, respectively. Adjusted hazard ratio (HR) was 2·28 [95% confidence interval (CI) 0·89-5·86, p = 0·086] and 4·05 (95% CI 1·37-11·97, p = 0·011) for FFS and OS, respectively. In this series of young DLBCL patients, TP53 gene mutation identified a poor prognosis subgroup, regardless of treatment and other biological markers.

Long non-coding RNA HAGLROS promotes the development of diffuse large B-cell lymphoma via suppressing miR-100.

BackgroundLong non‐coding RNAs (lncRNAs), a vital component of functional regulators, are involved in various human cancers development, including diffuse large B‐cell lymphoma (DLBCL). In particular, lncRNA HAGLROS has been reported to be associated with several types of cancer in humans. Nevertheless, the role of HAGLROS in DLBCL has yet to be described.MethodsThe HAGLROS expression patterns and its relationship with clinicopathological features and survival were investigated in DLBCL patients. CCK‐8 and transwell assays were used to analyze the cell proliferation, migration, and invasion capacities. AGO2‐RIP, dual‐luciferase assay, RT‐qPCR, and rescue experiments were fulfilled to measure the physical interaction between HAGLROS and miR‐100. Xenograft assay was conducted to test tumor growth ability.ResultsHAGLROS was upregulated in DLBCL tissues and cells, and closely associated with advanced clinicopathological features. Upregulation of HAGLROS resulted in poor survival outcomes in DLBCL patients. In addition, HAGLROS knockdown inhibited the proliferation, migration, and invasion of DLBCL cells in vitro. Further experiments revealed that HAGLROS negatively regulated the expression of miR‐100 in DLBCL, and the expression of miR‐100 and HAGLROS showed an inverse correlation in DLBCL tissues. HAGLROS functioned as a competing endogenous RNA for miR‐100 in DLBCL cells, and miR‐100 overexpression abolished the oncogenic effects of HAGLROS upregulation on DLBCL progression. Besides, in‐vivo assays revealed that HAGLROS knockdown suppressed tumor growth in nude mice.ConclusionHAGLROS overexpression contributes to DLBCL development and poor prognosis via targeting miR‐100, which could be a potential prognostic biomarker and therapeutic target for DLBCL patients.

Impact of Cell-of-Origin on Outcome of Patients With Diffuse Large B-Cell Lymphoma Treated With Uniform R-CHOP Protocol: A Single-Center Retrospective Analysis From North India.

IntroductionThere is a scarcity of data from India on the impact of cell of origin (COO) on outcomes of diffuse large B-cell lymphoma (DLBCL). This study was conducted to evaluate the impact of COO on outcomes of DLBCL patients treated with uniform rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (RCHOP) protocol.Materials and MethodsThis retrospective analysis included patients who received uniform RCHOP chemoimmunotherapy during the study period (2014–2020) at the Department of Medical Oncology at All India Institute of Medical Sciences (AIIMS), New Delhi, India. The patients were classified as germinal center B-cell like (GCB) or activated B-cell (ABC) type using the Hans classification.ResultsFour hundred seventeen patients with median age of 48 years (range, 18–76) and a male-female ratio of 2:1 were included in the analysis. B symptoms and bulky disease were seen in 42.9% and 35.5%. Extranodal involvement was seen in 50.8% of cases. ECOG performance status (0-2) was present in 65%, and 51% presented with advanced disease. GCB subtype was seen in 43%, and 47% were ABC type. Low- and intermediate-risk international prognostic index (IPI) score was seen in 76% of cases. The overall response rate to RCHOP was 85.8%, including a complete response rate of 74.8%. After a median follow-up of 30 months, the 3-year event-free survival (EFS) and overall survival (OS) were 80% and 88%, respectively. The presence of B symptoms and poor ECOG performance status (3-4) was associated with inferior CR rate. Low albumin (p < 0.001), age >60 years (p = 0.001), bulky disease (p < 0.001), and extranodal involvement (p = 0.001) were associated with inferior EFS, whereas a high IPI risk score was associated with an inferior OS (p < 0.001). EFS and OS were not significantly different between the GCB and ABC subtypes. Grade III/IV anemia, neutropenia, and thrombocytopenia were seen in 7.6%, 13.6%, and 2.7% of patients, respectively. Febrile neutropenia was seen in 8.9% of patients, and there were four treatment-related deaths.ConclusionsCell of origin for DLBCL has no impact on CR, EFS, and OS if patients are appropriately treated with standard doses and frequency of RCHOP. RCHOP is well tolerated in our patients, and results are comparable with the Western data.