Development Of non-Hodgkin Lymphoma Research Articles

Risk factors for Non-Hodgkin's lymphoma in autoimmune disease: a large database analysis.

Immune dysregulation in autoimmune diseases (ADs) is a risk factor for the development of Non-Hodgkin's lymphoma (NHL). However, the underlying mechanisms are not well understood. Hence, this retrospective study aims to describe the clinical and demographic factors that increase the risk of NHL development in patients with ADs. Our study utilised data from National Inpatient Sample (NIS) for the duration of 2016-2020 on all adult patients aged > 18 years who had NHL. We divided them into two cohorts: one with underlying ADs and one without underlying ADs. We then compared the adjusted odds ratios (aOR) of various risk factors. It was found that 0.9% of autoimmune cases had NHL, while 0.7% of non-autoimmune cases had NHL. Among those with autoimmune conditions, various factors influenced the presence of lymphoma, such as personal history of chemotherapy or radiation, family history of lymphoid malignancy, HIV infection, advanced age of 60-69 years, Asian and Pacific Islander ethnicity and viral hepatitis. The increased risk of NHL with autoimmune conditions is well established. Studies have also shown that these patients can overall have a poor prognosis from their NHL when compared to patients without autoimmune diseases. However, there is limited literature regarding the interplay of traditional NHL risk factors with underlying autoimmunity. Hence, our study sheds light on the lesser studied risk factors, such as patient characteristics and comorbidities.

Analysis of hepatitis B virus infection in 1424 patients with different pathological types of lymphoma (2018-2022): A real-world, retrospective study.

Recent studies have found a high prevalence of hepatitis B virus (HBV) infection in patients with non-Hodgkin's lymphoma (NHL), especially B-cell non-Hodgkin's lymphoma (B-NHL). However, most studies did not classify it and analyze the correlation between HBV and its various subtypes. The authors retrospectively analyzed 1424 patients with lymphoma. Differences in the prevalence of HBV infection in patients with different pathological types of lymphoma were analyzed. The clinical characteristics, progression-free survival (PFS), and overall survival (OS) of HBV-positive and negative B-NHL subtypes were compared according to HBV infection. The HBV infection rate in NHL patients was 7.65%, which was higher than that in HL patients (2.59%, p < 0.05). The HBV infection rate in the B-NHL was higher than that in the T-cell non-Hodgkin's lymphoma (T-NHL) (8.14% vs. 4.95%). The HBV infection rate in the aggressive B-NHL was similar to that of the indolent B-NHL (8.30% vs. 7.88%), and the highest HBV infection rates were found in diffuse large B-cell lymphoma and chronic lymphocytic leukemia/small lymphocytic lymphoma, but no significant differences in clinical characteristics, PFS, and OS were seen between HBV-positive and negative patients in the two subtypes. There was an association between HBV infection and the development of NHL and HBV infection may play a role in the pathogenesis of B-NHL, but not T-NHL.

B-Cell Activation Biomarkers in Salivary Glands Are Related to Lymphomagenesis in Primary Sjögren's Disease: A Pilot Monocentric Exploratory Study.

Primary Sjögren's disease is primarily driven by B-cell activation and is associated with a high risk of developing non-Hodgkin's lymphoma (NHL). Over the last few decades, microRNA-155 (miR-155) has arisen as a key regulator of B-cells. Nevertheless, its role in primary Sjögren's disease remains elusive. Thus, the purpose of this study was (i) to explore miR-155, B-cell activating factor (BAFF)-receptor (BAFF-R), and Interleukin 6 receptor (IL-6R) expression in the labial salivary glands (LSG) of patients with primary Sjögren's disease, aiming to identify potential B-cell activation biomarkers related to NHL development. Twenty-four patients with primary Sjögren's disease, and with available tissue blocks from a LSG biopsy performed at diagnosis, were enrolled. Among them, five patients developed B-cell NHL during follow-up (7.3 ± 3.1 years). A comparison group of 20 individuals with sicca disease was included. Clinical and laboratory parameters were recorded and the LSG biopsies were evaluated to assess local inflammation in terms of miR-155/BAFF-R and IL-6R expression. Stratifying the primary Sjögren's disease cohort according to lymphomagenesis, miR-155 was upregulated in primary Sjögren's disease patients who experienced NHL, more so than those who did not experience NHL. Moreover, miR-155 expression correlated with the focus score (FS), as well as BAFF-R and IL-6R expression, which were increased in primary Sjögren's disease patients and in turn related to neoplastic evolution. In conclusion, epigenetic modulation may play a crucial role in the aberrant activation of B-cells in primary Sjögren's disease, profoundly impacting the risk of NHL development.

Investigation of occupational risk factors for the development of non-Hodgkin's lymphoma in adults: A hospital-based case-control study.

Non-Hodgkin's Lymphoma (NHL) is a malignancy of the lymphoid lineage of the hematopoietic system has worldwide, especially in developed countries. Better diagnostic and recording techniques, longer life expectancy, and greater exposure to risk factors are hypotheses for this growing incidence curve. Occupational exposures to chemical, biological, and physical agents have also been associated with NHL development, but the results are still controversial. We have investigated the occupational and lifestyle case-control study design with 214 adult patients and 452 population controls. Socio-demographic, clinical, and occupational exposure data were obtained through individual interviews with a standardized questionnaire. Clinical, laboratory, and histopathological data were obtained through medical records. Risk of NHL (any subtype), B-cell lymphoma, DLBCL, Follicular lymphoma and T-cell lymphoma was elevated among the those who had ever been exposed to any solvents, hydrocarbon solvents, pesticides, meat and meat products, and sunlight and tended to increase by years of exposure. A significant upward trend with years of exposure was detected for any solvents and hydrocarbon solvents (NHL (any subtype) p-value for trend<0.001), B-cell lymphoma (p-value for trend<0.001), and T-cell lymphoma (p-value for trend<0.023), pesticides (NHL (any subtype), p for trend<0.001) and T-cell lymphoma (p for trend<0.002), meat and meat products (NHL (any subtype) (p for trend<0.001) and DLBCL (p for trend<0.001), and sunlight (B-cell lymphoma (p for trend<0.001). The results of this study agree line with other international studies, can be extrapolated to other countries that have the same socio-demographic and occupational characteristics as Brazil and support strategies for surveillance and control of work-related cancer.

Risk Factors for Non-Hodgkin's Lymphoma in Autoimmune Diseases: A Large Database Analysis

Introduction It has been well studied that immune dysregulation in autoimmune diseases is a risk factor for the development of Non-Hodgkin's lymphoma (NHL). However, the underlying mechanisms are not well understood. Although certain traditional risk factors like prolonged immunosuppression, infections, advanced age, family history, and history of organ transplantation are well described in NHL patients, there is limited literature regarding their interplay with autoimmune diseases. Hence, we conducted this retrospective study from the National inpatient sample database to describe the various clinical and demographic factors that increase the risk of NHL development in patients with autoimmune diseases. Methods Our study was conducted using the National Inpatient Sample, which is a large all-payer inpatient care database in the United States. We collected data from 2016-2020 on all adult patients aged &amp;gt; 18 years who had NHL. We divided them into two cohorts: one with underlying autoimmune diseases and one without underlying autoimmune conditions. We then compared the adjusted odds ratios (aOR) of various risk factors like age, race, gender, obesity, family history of lymphoproliferative diseases, personal history of chemotherapy or radiation, history of HIV, HTLV-1, Helicobacter pylori infection, Chlamydia infection, history of solid organ transplantation, and long-term steroid use among the two cohorts. Results Our data initially consisted of 148,755,036 patients ages ≥18 years, with 4,291,559 cases having autoimmune disorders like rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), Systemic sclerosis, sarcoidosis, sjogren's syndrome, and celiac disease. We found that 0.9% of autoimmune cases had NHL, while 0.7% of non-autoimmune cases had NHL (aOR 1.272, 95% CI 1.258-1.285, p&amp;lt;0.01). Among those with autoimmune conditions, various factors also influenced the presence of lymphoma, such as personal history of chemotherapy or radiation (aOR 5.778, 95% CI 5.595- 5.9675, p &amp;lt;0.001), family history of lymphoid malignancy (aOR 5.316, 95% CI 4.666-6.058, p&amp;lt;0.001), HIV infection (aOR 1.944, 95% CI 1.674-2.257,p&amp;lt;0.001), advanced age of 60-69 years (aOR 1.051, 95% CI 1.025-1.078, p&amp;lt;0.001) , Asian and Pacific Islander ethnicity (aOR 1.596, 95%CI 1.496-1.703, p&amp;lt;0.001) and viral hepatitis (aOR 1.620, 95% CI 1.480-1.774, p&amp;lt;0.001) (Table 1). Conclusion The increased risk of non-Hodgkin Lymphoma (NHL) with autoimmune conditions like rheumatoid arthritis and SLE is well established. Studies have also shown that these patients can overall have a poor prognosis from their NHL when compared to patients without autoimmune diseases. However, there is limited literature regarding the interplay of traditional NHL risk factors with underlying autoimmunity. Hence, our retrospective analysis sheds light on the lesser studied risk factors, such as patient characteristics and comorbidities. We found that older age, male sex, Asian and Pacific Islander race, family history of lymphoid malignancy, personal history of chemotherapy or radiation, and comorbidities like HIV, Viral Hepatitis, and HTLV-1 are some strong risk factors associated with the development of NHL in patients with autoimmune diseases. Infections like HIV and HTLV-1 played less of a role in the autoimmune cohort as opposed to the non-autoimmune cohort. Whereas personal histories of chemotherapy and radiation and family histories of lymphoid malignancies were demonstrated to be very strong risk factors in both settings. Hence, our study enables clinicians to identify the differences in the interplay of these risk factors and to perform stringent monitoring of patients when they do have these risk factors

Effectiveness and Safety of Orelabrutinib Combined with Rituximab As First-Line Treatment in Marginal Zone Lymphoma

Background: Marginal zone lymphoma (MZL) collectively is the third most common type of B-cell non-Hodgkin's lymphoma (NHL) worldwide, with an increased trend in incidence during the last two decades (Rossi D E et al., N Engl J Med. 2022). The lack of predominant first-line systemic therapy and toxicities associated with current rituximab-based therapies have inspired the exploration of more optimal treatment strategies (Becnel MR et al., Br J Haematol, 2019). Given the crucial role of bruton tyrosine kinase (BTK) in the B-cell receptor signaling pathway, BTK inhibitor has been proven to yield robust outcomes with improved tolerability in the development of NHL (Dhillon S et al., Drugs, 2021; Xu W et al., Blood, 2019; Song Y et al., Blood, 2019). Orelabrutinib is a novel BTK inhibitor with high selectivity and has been approved in China for relapsed/refractory MZL recently (Dhillon S et al., Drugs, 2021). Meanwhile, several clinical studies reported that orelabrutinib in combination with rituximab in NHL could preserve natural killer cell-mediated antibody-dependent cellular cytotoxicity induced by rituximab and enhance the clinical efficacy (Yu H et al., Mol Ther Oncolytics, 2021; Qu C et al., Blood, 2023). However, orelabrutinib plus rituximab as the first-line treatment for MZL remains largely understudied, thus, we conducted a retrospective study to evaluate its effectiveness and safety. Methods: Between July 27, 2021 and March 18, 2023, 10 patients with MZL who received orelabrutinib (150 mg, qd, po) with rituximab (375 mg/m 2, iv, day 1 of each 28-day cycle) as first-line therapy were included in this retrospective study. After 6 cycles of treatment, patients underwent orelabrutinib monotherapy (150 mg, qd, po) as maintenance for a year. Dynamic dose adjustment was performed according to the patient's clinical status. Effectiveness was assessed by positron emission tomography/computed tomography-based 2014 Lugano criteria. The primary endpoint was the overall response rate (ORR); secondary endpoints were progression-free survival (PFS), overall survival (OS), and safety. Results: Ten patients (6 males; median age 63.5 years, range 45-76) were included in this study, 4 with extranodal MZL of mucosa-associated lymphoid tissue (40.0%), 2 with nodal MZL (20.0%), 1 with splenic MZL (10.0%), and 3 with unknown subtype (30%). Among a total of 10 patients, 3 (30%) achieved complete response (CR) and 6 (60%) attained partial response (PR) as their best response for an ORR of 90% ( Figure 1). After a median follow-up of 13.0 months (range 7.8-24.7), the median PFS was not reached and a 6-month PFS rate was 100% ( Table 1). OS could not be assessed due to there were no deaths occurred. As of the cut-off date (May 6, 2023), 8 patients received orelabrutinib maintenance treatment and the median duration of maintenance treatment was 9.6 months (range 3.0-17.8). The ORR was 75% (6/8) during maintenance treatment, while 1 patient had stable disease (SD) and 1 developed progressive disease (PD). In addition, abnormal hematology due to disease gradually recovered with the therapy within 4 months. No serious adverse events were observed. The off-target related AEs such as atrial fibrillation, diarrhea, and major hemorrhage were not reported. Conclusion: This retrospective data suggests that orelabrutinib with rituximab has an encouraging anti-tumor activity in MZL, with a favorable safety profile. These results provide a potential first-line treatment strategy in MZL. Further verification in prospective clinical trials of clinical outcomes of orelabrutinib in first-line MZL is warranted in the future.

Expression and significance of jumonji domain-containing protein 2B and hypoxia inducible factor-1α in non-Hodgkin lymphoma tissues in children

To investigate the expression and significance of jumonji domain-containing protein 2B (JMJD2B) and hypoxia-inducible factor-1α (HIF-1α) in non-Hodgkin's lymphoma (NHL) tissues in children. Immunohistochemistry was used to detect the expression of JMJD2B and HIF-1α in lymph node tissue specimens from 46 children with NHL (observation group) and 24 children with reactive hyperplasia (control group). The relationship between JMJD2B and HIF-1α expression with clinicopathological characteristics and prognosis in children with NHL, as well as the correlation between JMJD2B and HIF-1α expression in NHL tissues, were analyzed. The positive expression rates of JMJD2B (87% vs 21%) and HIF-1α (83% vs 42%) in the observation group were higher than those in the control group (P<0.05). The expression of JMJD2B and HIF-1α was correlated with serum lactate dehydrogenase levels and the risk of international prognostic index in children with NHL (P<0.05). The expression of JMJD2B was positively correlated with the HIF-1α expression in children with NHL (rs=0.333, P=0.024). JMJD2B and HIF-1α are upregulated in children with NHL, and they may play a synergistic role in the development of pediatric NHL. JMJD2B can serve as a novel indicator for auxiliary diagnosis, evaluation of the severity, treatment guidance, and prognosis assessment in pediatric NHL.

PD-L1 Is Involved in the Development of Non-Hodgkin's Lymphoma by Mediating Circulating Lymphocyte Apoptosis.

Lymphocyte apoptosis plays a crucial role in tumor-induced immunosuppression. Programmed death ligand-1 (PD-L1) blocks lymphocyte activation via its receptor, PD-1. However, PD-L1/PD-1 expression and its role in enhancing immune suppression in non-Hodgkin lymphoma (NHL) have not been identified. The purpose of the study was to assess PD-L1/PD-1 expression in circulating lymphocytes in NHL and its role in immunosuppression. Twenty newly diagnosed NHL patients and twenty normal volunteers were enrolled in the study. PD-L1/PD-1 expression in circulating lymphocytes and the apoptosis of lymphocyte subsets were assessed using flow cytometry. The findings revealed that the PD-L1 expression in circulating CD3+, CD3+CD4+, CD3+CD8+, and CD20+ lymphocytes were dramatically upregulated in NHL patients (p < 0.001), whereas peripheral lymphocytes expressed low levels of PD-1. Compared with normal volunteers, a significant increase in lymphocyte apoptosis was revealed by annexin-V binding on T and B lymphocytes (p < 0.001). Peripheral lymphocytes expressing PD-L1 were four times more vulnerable to apoptosis than those expressing PD-1. Our findings imply that PD-L1 upregulation contributes to NHL development by promoting circulating lymphocyte apoptosis. This research adds to our understanding of the function of the PD-L1/PD-1 pathway in tumor evasion, establishing a novel therapeutic target in NHL. The results offer additional evidence for the immunomodulatory role of PD-L1 in circulating lymphocytes, providing a rationale for further investigations into immunological dysfunctions resulting from NHL. PD-L1+ lymphocytes could be employed as a biomarker to assess the effectiveness of immune systems and predict illness in patients with NHL.

Association of Obesity and Type 2 Diabetes with Non-Hodgkin Lymphoma: The Multiethnic Cohort.

Given the role of the immune system in non-Hodgkin lymphoma (NHL) etiology, obesity and type 2 diabetes (T2D) may impact NHL development. We examined the association of body mass index (BMI) and T2D with NHL in the multiethnic cohort (MEC). The MEC recruited >215,000 participants in Hawaii and Los Angeles from five racial/ethnic groups; NHL cases were identified through cancer registry linkages. T2D status, and BMI at age 21 and cohort entry were derived from repeated self-reports; for T2D, Medicare claims were also applied. HRs and 95% confidence intervals (CI) for BMI and T2D as predictors of NHL were determined using Cox regression adjusted for relevant covariates. Among 192,424 participants, 3,472 (1.8%) with NHL and 68,850 (36%) with T2D after 19.2±6.6 years follow-up, no significant association between T2D and NHL (HR, 1.04; 95% CI, 0.96-1.13) was observed. Stratification by BMI at cohort entry showed a significant association of T2D with NHL among individuals with normal weight only (HR, 1.18; 95% CI, 1.03-1.37). In a model with both BMI values plus T2D, only overweight (HR, 1.13; 95% CI, 1.01-1.26) and obesity (HR, 1.25; 95% CI, 0.99-1.59) at age 21 were associated with NHL incidence. Stratification by sex, race/ethnicity, and NHL subtype indicated no differences. Our findings suggest an association between T2D and NHL incidence in several subgroups but not in the total population and an elevated risk related to early-life BMI. Excess body weight in early life, rather than T2D, may be a predictor of NHL incidence.

Radiomic Features Associated with Lymphoma Development in the Parotid Glands of Patients with Primary Sjögren’s Syndrome

Non-Hodgkin Lymphoma (NHL) represents a severe complication and the main cause of morbidity in patients with primary Sjögren's syndrome (pSS). This study aimed to assess the role of textural analysis (TA) in revealing lymphoma-associated imaging parameters in the parotid gland (PG) parenchyma of patients with pSS. This retrospective study included a total of 36 patients (54.93 ± 13.34 years old; 91.6% females) diagnosed with pSS according to the American College of Rheumatology and the European League Against Rheumatism criteria (24 subjects with pSS and no lymphomatous proliferation; 12 subjects with pSS and NHL development in the PG, confirmed by the histopathological analysis). All subjects underwent MR scanning between January 2018 and October 2022. The coronal STIR PROPELLER sequence was employed to segment PG and perform TA using the MaZda5 software. A total of 65 PGs underwent segmentation and texture feature extraction (48 PGs were included in the pSS control group, and 17 PGs were included in the pSS NHL group). Following parameter reduction techniques, univariate analysis, multivariate regression, and receiver operating characteristics (ROC) analysis, the following TA parameters proved to be independently associated with NHL development in pSS: CH4S6_Sum_Variance and CV4S6_Inverse_Difference_Moment, with an area under ROC of 0.800 and 0.875, respectively. The radiomic model (resulting by combining the two previously independent TA features), presented 94.12% sensitivity and 85.42% specificity in differentiating between the two studied groups, reaching the highest area under ROC of 0.931 for the chosen cutoff value of 1.556. This study suggests the potential role of radiomics in revealing new imaging biomarkers that might serve as useful predictors for lymphoma development in patients with pSS. Further research on multicentric cohorts is warranted to confirm the obtained results and the added benefit of TA in risk stratification for patients with pSS.

Global Burden, Risk Factors, and Trends of Non-Hodgkin Lymphoma in 2020 and Projections to 2040: A Population-Based Study

Background: Non-Hodgkin lymphoma (NHL) is one of the major health problems worldwide, but the global burden and trends of NHL have not been extensively assessed. We aimed to describe the disease burden, risk factors, trends in incidence and mortality of NHL globally. Methods: We collected up-to-date incidence and mortality data of NHL from the GLOBOCAN 2020, focusing on geographic disparities worldwide. The incidence trends of NHL in 42 countries over 15 years were examined, while mortality trends of 39 countries were calculated by data extracted from cancer registries. Prevalence data from the World Health Organization database was used to estimate the attributable risk factors in the development of NHL. Future burden estimates for incidence and mortality in 2040 were calculated by applying population projections in 2020. We reported incidence and mortality by sex and age alongside corresponding age-standardized rates and the average annual percentage change. Results: In 2020, there were an estimated 545,000 new cases and 260,000 deaths of NHL globally. The age-standardized incidence rates (ASIR) varied drastically across world areas, at least 10-fold in both sexes, with the highest rates observed in Australia and New Zealand. A great burden of NHL was recognized in high-income countries as the highest incidence rates were in Australia and New Zealand (ASIR, 12.5), Northern America (ASIR, 12.0), and Northern Europe (ASIR, 11.4) (Figure 1). Conversely, countries with a low human development index (HDI), such as those in North Africa, encountered a larger mortality burden in NHL than in highly-developed countries. In terms of different continents or regions, higher mortality rates were seen in Melanesia (ASR, 4.0), North Africa (ASR, 3.7), and Micronesia (ASR, 3.6). Considering the global trends of incidence, it was found that most developed countries had a trend of steady growth, while some low HDI countries have relatively large fluctuations in the incidence. In subgroups of different genders, close to 20 populations exhibited higher ASIRs for women than men. Observed trends also differed across age groups. The incidence of NHL increased in 34 populations (AAPCs, 4.9 to 0.1) among individuals aged 60 years or older. Taking into account differences in NHL burden across countries, we also reported estimated burden of NHL by HDI category. Considering all 185 countries, the ASIRs of NHL rose with HDI levels (= 0.41, P < 0.001), whereas the ASMRs of NHL were not associated with the levels of HDI (= 0, P = 0.754). HIV was generally believed to be a possible contributing factor to the development of some types of NHL, we presented the linear relation between the magnitude of the NHL incidence, HIV prevalence, and the level of HDI which seemly constricted to very high HDI countries. Regarding associated lifestyle risk factors, higher incidence of NHL was linked to a higher prevalence of obesity (β = 0.399, P < 0.001), a decreased prevalence of diabetes (β = -0.468, P <0.001) and hypertension (β = -0.386, P <0.001) based on the multivariate linear regression. As a result, countries with higher incidence were more likely to have a higher prevalence of obesity. In terms of demographic change, NHL incident cases are projected to rise to approximately 778,000 by 2040. Conclusions: In this pooled analysis, we provided evidence for the growing incidence trends in NHL, particularly among women and elderly populations. Despite the stable or downward mortality trends observed in most countries, the marked increase in the older population is still a public health issue that requires more attention. Future efforts should be directed to cultivating health awareness and formulating effective and locally tailored cancer prevention strategies, especially in most developing countries. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Current Status of Racial and Ethnic Disparities for Follicular Lymphoma: A Surveillance, Epidemiology, and End Results (SEER) Database Analysis with Emphasis on Hispanics

Background Follicular lymphoma (FL) is the most common indolent non-Hodgkin lymphoma (NHL) in the Western hemisphere (Blood PMID: 26989204). In prior studies, better progression-free survival has been noted in Hispanics (HI), however, further characterization of this ethnic difference needs to be addressed. This result is consistent with previous research explaining the development of NHL as an heterogeneous process where unique outcomes for races have been noted. There is a need for further understanding of HI diagnosed with FL. METHODS: Data were analyzed on follicular FL patients in the United States (US) reported to the Surveillance, Epidemiology, and End Results (SEER) 18 database between 2000 and 2018. SEER 18 contains the most comprehensive population-based cancer information in the US, covering approximately 27% of the total US population, and up to 36% of HI alone. Racial groups analyzed included NH whites, HI whites, blacks, and Asians/PIs (Pacific Islanders). Patient characteristics, age-adjusted incidence rate, and survival rate were compared across ethnic groups, HI vs NH. Stratification by age, gender, and stage at diagnosis was considered. Kaplan-Meier and Cox regression analyses were used to compare overall survival (OS) between HI and NH. Multivariate analysis and propensity score matching were performed with adjustment for age, stage and B-symptoms. RESULTS Of 59250 FL patients, 11% were HI, and 89% NH. 48% of HI were male, compared to 50% of NH. The majority of HI (42%) were diagnosed in the age bracket of (40-60) vs majority of NH (50%) who were diagnosed in the age bracket of (60-80) (p<0.001). HI were diagnosed at a median younger age, 59 y.o vs 65 y.o, compared to NH (p<0.001). Regarding race, most of HI and NH were whites (96% vs 88%), followed by blacks (1% vs 5%). When examining stage, most of HI (22%) as well as NH (22%) were stage IV (p<0.001). In terms of radiation, 13% of HI received it, compared to 14% of NH (p<0.001). On survival analysis, the survival probability at 2, 5 and 10 years of HI vs NH were (87%vs 86%),(77% vs 74%), and (64% vs 86%), respectively. The median survival time was 17.1 years for HI, vs 13.2 years for NH; and there was OS difference favoring HI/NH with (p<0.001). On multivariate analysis, when adjusted for age, those patients who were older than 80 y.o and between 60 to 80 y.o, had worse OS compared to those younger than 60 y.o, with hazard ratio (HR) 9.4 (95% CI: 8.7 - 10 ) and HR 3 (95% CI: 2.8-3.2) respectively. Regarding stage, those who were at stage III and IV, had worse OS than those at early stage (I/II) with HR 1.3 (95% CI: 1.26 - 1.45) and HR 1.7 (95% CI: 1.6 - 1.8), respectively. CONCLUSION In this data analysis from the SEER 18 database, HI with FL lymphoma, had a statistically significant prolonged OS compared to NH. There were also, statistically significant differences in median survival at 2, 5, and 10 years among the HI cohorts. Unique characteristics from HI may explain why there is an increase in OS after a FL diagnosis in this data set. Biological differences in the background of HI with FL are needed to better understand improved outcomes on this cohort. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Association between Meat, Fish, and Fatty Acid Intake and Non-Hodgkin Lymphoma Incidence: The Japan Public Health Center–Based Prospective Study

BackgroundMeat, fish, and fatty acid intakes have been reported to be associated with non-Hodgkin lymphoma (NHL), although results have been inconclusive. We hypothesized that red meat and SFA intakes increase NHL risk, and fish and PUFA intakes decrease NHL risk. ObjectivesWe investigated the association between NHL incidence and meat, fish, and various fatty acid type intakes using the Japan Public Health Center–based Prospective Study. MethodsThe current cohort study included 93,366 participants aged 45–74 y who were eligible for analysis; they were followed up until December 2012. Participants answered an FFQ between 1995 and 1999. We analyzed the effects of meat, fish, total fatty acid, SFA, and PUFA intakes on NHL incidence using the Cox proportional hazard model. ResultsThe median age was 57 y (IQR: 51–63 y), and 46.5% of the participants were men. Participants were followed up for 1,345,001 person-years, and 230 patients with NHL were identified. Total fatty acid and SFA intakes were associated with an increased incidence of NHL, with an adjusted HR of 1.56 (95% CI: 1.04, 2.34 highest compared with lowest quartile; P-trend = 0.062), and 1.63 (95% CI: 1.11, 2.41; P-trend = 0.074), respectively. In subtype analysis, total fatty acid and SFA intakes were also associated with increased incidence of follicular lymphoma but were not significantly associated with diffuse large B-cell lymphoma. Conversely, total meat, processed meat, unprocessed meat, red meat, poultry, fish, MUFA, PUFA, n–3 (ω-3) PUFA, and n–6 (ω-6) PUFA intakes were not significantly associated with the incidence of NHL or its subtypes. ConclusionsTotal fatty acid and SFA intakes were associated with increased incidence of NHL in the Japanese adult population. Further large-scale studies are warranted to test whether fatty acid intakes affect the development of NHL.

Peripheral blood DNA methylation profiles predict future development of B-cell Non-Hodgkin Lymphoma

Lack of accurate methods for early lymphoma detection limits the ability to cure patients. Since patients with Non-Hodgkin lymphomas (NHL) who present with advanced disease have worse outcomes, accurate and sensitive methods for early detection are needed to improve patient care. We developed a DNA methylation-based prediction tool for NHL, based on blood samples collected prospectively from 278 apparently healthy patients who were followed for up to 16 years to monitor for NHL development. A predictive score was developed using machine learning methods in a robust training/validation framework. Our predictive score incorporates CpG DNA methylation at 135 genomic positions, with higher scores predicting higher risk. It was 85% and 78% accurate for identifying patients at risk of developing future NHL, in patients with high or low epigenetic mitotic clock respectively, in a validation cohort. It was also sensitive at detecting active NHL (96.3% accuracy) and healthy status (95.6% accuracy) in additional independent cohorts. Scores optimized for specific NHL subtypes showed significant but lower accuracy for predicting other subtypes. Our score incorporates hyper-methylation of Polycomb and HOX genes, which have roles in NHL development, as well as PAX5 - a master transcriptional regulator of B-cell fate. Subjects with higher risk scores showed higher regulatory T-cells, memory B-cells, but lower naïve T helper lymphocytes fractions in the blood. Future prospective studies will be required to confirm the utility of our signature for managing patients who are at high risk for developing future NHL.

P1274: EARLY DETECTION OF NON-HODGKIN LYMPHOMA IN PREDISPOSED PATIENT GROUPS THROUGH IMMUNOGENETIC SEQUENCING

Background: Since chronic lymphocytic leukemia development can be detected up to 16 years prior to diagnosis through immunogenetic sequencing, we aim to evaluate whether early detection through immunogenetic sequencing translates to other types of non-Hodgkin lymphoma (NHL). A particularly interesting group with potential clinical utility consists of patients with underlying conditions that confer an increased risk of lymphoma and leukemia. Generally, this group is characterized by dysregulation of the immune system, in the form of autoimmune diseases, primary immunodeficiencies, immunosuppressive treatment and several infectious diseases. Aims: To evaluate the capacity of immunogenetic sequencing for early detection of NHL and leukemia in patient groups at increased risk. Methods: We selected two patient groups with an increased risk of NHL and leukemia: solid organ transplant recipients and patients with auto-immune disease. For each group, we selected patients who had developed NHL and controls with the same underlying condition matched on sex, age and sampling window. Currently, we have included 16 cardiac and 10 renal transplant recipients and 10 primary Sjögren’s syndrome (SjS) patients (in total 18 cases and 18 controls). A total of 114 longitudinal pre-diagnostic samples were included in the study, taken a median of 1.2 years before diagnosis (IQR 3.5 years). Genomic DNA was isolated from the PBMC samples of the participants and the immunoglobulin heavy chain (IGH) was sequenced on the Illumina Miseq platform. All PBMC samples were taken after SjS diagnosis or solid organ transplantation and prior to NHL diagnosis. Results: In 7 out of 18 NHL patients we identified clonotypes in prediagnostic PBMC samples that were present at an abnormal frequency compared to the healthy background clonotypes. Notably, distribution of the IGH gene repertoire in controls was normal. Prevalence of IGH gene repertoire skewing was particularly pronounced among SjS patients (3 out of 5 patients) and cardiac transplant recipients (4 out of 8 patients) compared to renal transplant recipients (1 out of 5 patients). IGH gene repertoire skewing was restricted to samples taken within 5 months to two years before diagnosis for the majority of the cases. In solid organ transplant recipients with an abnormal clonotype, the degree of skewing of the IGH gene repertoire increased over time towards the moment of NHL diagnosis or remained stable at elevated levels. For the SjS patients, two out of the three abnormal clonotypes utilized the IGHV1-69/IGHJ4 or IGHV4-59/IGHJ5 rearrangements stereotypic for rheumatoid factors, which have previously been associated with MALT lymphoma development in SjS. Unbiased marker identification has yielded putative prediagnostic lymphoma markers for 7 out of 18 patients. Image:Summary/Conclusion: We conducted a pilot study investigating a novel method of early detection of NHL development in 36 patients at increased risk of hematological malignancy. In total, we observed an abnormal distribution of the IGH repertoire between 5 months to 2 years prior to NHL diagnosis in 7 out of 18 patients, compared to 0 out of 18 of the matched controls. While our results suggest potential merit for early detection of NHL development through immunogenetic sequencing, the current cohort size does not yet permit drawing definitive conclusions. Therefore, inclusion of additional patients will be a priority during the continuation of the study.

Rationale behind using valproic acid for Non-Hodgkin lymphoma: a biomolecular perspective.

Non-Hodgkin lymphoma (NHL) is a hematological malignancy with a high rate of relapse and refractory cases. It is believed to be caused by resistance to standard treatment modalities. Valproic acid (VPA), previously used as a broad-spectrum anticonvulsant drug, has been proposed for NHL owing to its action of epigenetic modification by inhibiting histone deacetylase. However, VPA studies on NHL are limited. This review describes the rationale behind the use of VPA for NHL treatment, particularly focusing on its molecular mechanism of action. This is a narrative review. The literature search strategy for indexed Scopus articles was performed randomly using PubMed and MEDLINE as the primary sources. No specific term was used. Several mechanisms are responsible for NHL development. VPA can modulate these mechanisms via epigenetic and nonepigenetic modifications. It may also have an impact on the proteins responsible for treatment resistance. The mechanisms of action of VPA in NHL are as follows: the induction of cell cycle arrest via the upregulation of cyclin-dependent protein kinase inhibitors; induction of Apo2 ligand or tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis; inactivation of B-cell lymphoma 6; inhibition of Janus kinase/signal transducer and activator of transcription, phosphoinositide 3-kinase/Akt, and nuclear factor kappa B signaling pathways; upregulation of tumor antigen as the primary target of immunotherapy; and strengthening of tumor immunosurveillance. Based on its biomolecular mechanism of action, VPA appears to be a promising initial treatment before initiating the standard treatment in patients with NHL to overcome resistance.

Ethnicity Matters When Comparing Overall Survival for Patients Diagnosed with Follicular Lymphoma

BackgroundFollicular lymphoma (FLy) is one of the most common subtypes of Non-Hodgkin Lymphomas (NHL) (Cancer EpidemiolPMC4323749). In prior studies, better progression-free survival has been noted in Hispanics (HI), however, further characterization of this ethnic minority needs to be addressed (Ann Lymphoma PMC5877479). This result is consistent with previous research explaining the development of NHL as an heterogeneous process where unique outcomes for races have been noted (Cancer PMID: 22434428). This is the first combined statewide population-based study of Texas (TX) and Florida (FL) evaluating ethnic differences for HI vs Non-Hispanics (NH) comparingdemographics, socioeconomic, clinical and survival patterns of patients diagnosed with FLy. The value of using these states relies on the fact that the percentage of HI in TX and FL are 39.7% and 26.4%, respectively (US Census 2020).Material and MethodsThis is a retrospective analysis of patients diagnosed with FLy recorded in the Texas Cancer Registry and the Florida Cancer Data System from 2006-2017. Inclusion criteria was histopathologic proven FLy. Patients were divided into HI and NH for comparison. Standard demographic, socioeconomic, clinical, and survival variables were reviewed. All statistical testing was determined using Fisher's Exact test, Pearson's Chi-square test, T-test or Wilcoxon test, as appropriate. Survival time was measured using the day of diagnosis to last date of follow up or death. Survival distribution were calculated based on Kaplan-Meier curves.ResultsFrom 2006-2017, 20,497 patients (HI n=3,176, NH n=17,321) were diagnosed with FLy (Table 1, Table 3). In TX, the median age at diagnosis for HI was 60 years (y) vs 64 y for NH [p-value <0.001]. In FL, it was 62 y and 67 y, respectively [p-value <0.001]. In both states, female sex predominated for HI and NH. In TX, the bracket of poverty index that prevailed for HI was 20-100% while for NH was 10-19.9% [p-value <0.001]. In FL, the largest number of HI and NH were in the 10-19.9% bracket [p-value <0.001]. In TX, both HI and NH were more likely be with government-sponsor insurance, however, up to 15% of HI did not have insurance vs 4% in NH [p-value <0.001]. This was also the case in FL, however their number of uninsurance corresponded to 6% and 2% respectively.In TX, the largest number of HI and NH patients were diagnosed at stage III-IV with 49% and 42% respectively [p-value <0.001]. In FL, for these stages it corresponded to 43% and 37% for HI and NH [p-value <0.001]. In TX, treatment at diagnosis showed a similar pattern for HI and NH, choosing mainly no treatment followed by multiple chemotherapy agents [p-value <0.001]. In FL, this trend was also seen. In both states and for HI and NH, most of the patients did not undergo transplant or radiation.In TX, the median overall survival for HI was 9.2 y vs 8.6 y for NH; the survival probability at 2, 5 and 10 y for HI corresponded to 0.835, 0.701 and 0.453, while for NH it was 0.850, 0.703 and 0.354, respectively; and the overall survival probability at 10 y had no statistically significant difference [p-value 0.44] (Table 2, Graph 1). In FL, the median overall survival for HI was not reached vs NH at 10.1 y; the survival probability for HI at 2, 5 and 10 y was 0.871, 0.777 and 0.601, while for NH it was 0.845, 0.709 and 0.506, respectively; and the overall survival probability at 10 y was statistically significant [p-value <0.0001] (Table 4, Graph 2).ConclusionsThis large two statewide population-based study identified statistical differences in oncological outcomes comparing HI and NH in patients diagnosed with FLy. HI diagnosed with FLy have higher survival at 10 y, and this difference was statistically significant in FL. Moreover, statistical significance was noted in demographic, sociodemographic and disease characteristics. Additional research should be carried out to identify the variables that drive this difference since advance stage, lack of insurance or treatment at diagnosis do not seem to be influencing it. There may be a combination of lifestyle factors (alcohol, cigarette, diet, other), occupational hazards, autoimmune diseases or protective mechanisms, infectious diseases exposures and unique epigenetic interactions that may explain why HI live longer when diagnosed with FLy. [Display omitted] DisclosuresDiaz Duque: Incyte: Consultancy; Morphosys: Speakers Bureau; Astra Zeneca: Research Funding; Hutchinson Pharmaceuticals: Research Funding; Epizyme: Consultancy; ADCT: Consultancy.

Non-Hodgkin lymphoma after pediatric kidney transplantation

Non-Hodgkin lymphoma (NHL) that develops after kidney transplantation belongs to post-transplant lymphoproliferative disorders (PTLD) occurring with an incidence of 2–3%. Most pediatric cases are related to primary infection with Epstein-Barr virus (EBV), able to transform and immortalize B cells and widely proliferate due to the lack of relevant control of cytotoxic T cells in patients receiving post-transplant immunosuppression. NHL may develop as a systemic disease or as a localized lesion. The clinical pattern is variable, from non-symptomatic to fulminating disease. Young age of transplant recipient, seronegative EBV status at transplantation, and EBV mismatch between donor and recipient (D+/R-) are regarded as risk factors. Immunosuppression impacts the development of both early and late NHLs. Specific surveillance protocols, including monitoring of EBV viral load, are used in patients at risk; however, detailed histopathology diagnosis and evaluation of malignancy staging is crucial for therapeutic decisions. Minimizing of immunosuppression is a primary management, followed by the use of rituximab in B-cell NHLs. Specific chemotherapeutic protocols, adjusted to lymphoma classification and staging, are used in advanced NHLs. Radiotherapy and/or surgical removal of malignant lesions is limited to the most severe cases. Outcome is variable, depending on risk factors and timing of diagnosis, however is positive in pediatric patients in terms of graft function and patient survival. Kidney re-transplantation is possible in survivors who lost the primary graft due to chronic rejection, however may be performed after at least 2–3 years of waiting time, careful verification of malignancy-free status, and gaining immunity against EBV.

Abstract 872: Pathogenesis underlying the bidirectional relationship between non-Hodgkin lymphomas and primary Sjögren's Syndrome

Abstract Introduction: Bidirectional relationship between non-Hodgkin lymphomas (NHLs) and Sjögren's syndrome (SS) has been recognized in large scale cohort studies. To investigate the underlying pathogenesis of this association, we identified highly expressed genes and altered pathways with RNA-sequencing (RNA-seq) data from SS and NHLs patients. Methods: Canonical pathway analysis was conducted by comparing RNA-seq data from whole-transcriptome expression profiling to identify underlying pathogenesis among NHL patients with Burkitt lymphoma (BL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL), or marginal zone lymphoma (MZL), and SS patients. Collected biopsies included lymphoma biopsies for NHLs, including BL (n = 59), DLBCL (n = 88), FL (n = 65), MCL (n = 43), and MZL (n = 23), sorted B cells from healthy donors (n=10), as well as parotid gland tissues for SS (n=17). Fold changes and z-scores were derived after normalized by the expression levels among controls. RNA-seq data with P values less than 0.05 or -log10(P) values larger than 1.3 were considered significantly expressed. Positive z-scores indicated up-regulation while negative z-scores indicated down-regulation. Results: There were 17 identified significantly expressed genes (P &amp;lt; 0.05 for all NHLs and SS), including well-known cancer-associated genes CXCL13, COL1A1, IGFBP7, COL3A1, CXCL9, CXCL12, CCL19, and CLU. Among them, CXCL13 was the most expressed gene involved in NHLs and SS. The fold changes of CXCL13 were 14.09, 465.57, 319.51, 369.70, 817.63, and 4.03 for BL, DLBCL, FL, MCL, MZL, and SS, respectively. Among all identified pathways underlying SS and NHL development, which were ordered based on the sum of z-scores, the endocannabinoid system-driven cancer inhibition pathways were the most significantly altered in both SS and NHLs, followed by interferon-involved antiviral responses, when compared to matched healthy controls. The z-scores of the cancer inhibition pathways were -0.14 for BL (-log10(P) = 4.54), -1.30 for DLBCL (-log10(P) = 3.00), -0.33 for FL (-log10(P) = 4.67), -0.87 for MCL (-log10(P) =3.77), -2.61 for MZL (-log10(P) = 4.31), and -1 for SS (-log10(P) = 1.44). Conclusion: The underlying pathogenesis for SS-associated NHL development involved 17 highly expressed genes, including CXCL13, and down-regulated cancer inhibition pathways. Citation Format: Kevin Sheng-Kai Ma, Cho-Han Chiang, Li-Tzu Wang. Pathogenesis underlying the bidirectional relationship between non-Hodgkin lymphomas and primary Sjögren's Syndrome [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 872.

A Review and Update with Perspective of Evidence that the Herbicide Glyphosate (Roundup) is a Cause of Non-Hodgkin Lymphoma

Glyphosate-based formulations (GBFs), such as Roundup, are the most heavily used herbicides in the world. In 2015, the International Agency for Research on Cancer (IARC) concluded that glyphosate and GBFs are probably carcinogenic to humans (group 2A), mainly for non-Hodgkin lymphoma (NHL). However, this finding has been controversial, and most pesticide regulatory agencies have not followed their lead. The purpose of this review was to examine the scientific literature linking exposure to glyphosate and GBFs to the development of NHL, with emphasis on new findings since publication of the IARC report. The epidemiologic studies provide ample evidence for an association between exposure to GBFs and an increased risk of NHL. Animal studies have shown that glyphosate is carcinogenic in rodents and causes NHL in mice. Mechanistic studies have demonstrated that glyphosate and GBFs are genotoxic to human lymphocytes, the normal cell of origin of NHL, both in vitro and in vivo. Genotoxic and other biological effects have also been shown in various animal and cell models with these agents even at low doses. A novel mechanism underlying the specificity of glyphosate for NHL, that is upregulation of the B-cell genome mutator enzyme activation-induced cytidine deaminase, has recently been demonstrated. These findings were evaluated holistically using the guidelines for evaluation of general causation set forth by Bradford Hill. This evaluation provides coherent and compelling evidence that glyphosate and GBFs are a cause of NHL in humans exposed to these agents. These findings should prompt new reviews by pesticide regulatory agencies around the world.