Group Of non-Hodgkin Lymphomas Research Articles

Abstract 7001: Profiling the CpG methylation patterns of Epstein-Barr virus DNA in lymphoma patients from Ethiopia

Abstract Introduction: Epstein-Barr virus (EBV) is a tumor virus associated with various malignancies, driven by genetic mutations and epigenetic alterations, including DNA methylation. Abnormal CpG methylation holds promise as a diagnostic and therapeutic biomarker for EBV-associated tumors. However, the understanding of EBV's epigenetic mechanisms remain limited. Determining the methylation profile of EBV is crucial for gaining insights into the pathogenesis of EBV-associated tumors, developing diagnostic biomarkers, and exploring potential therapeutic strategies. Therefore, our study aimed to assess the CpG methylation profile of EBV DNA in lymphoma patients from Ethiopia. Methods: This study enrolled 115 lymphoma patients from Tikur Anbessa Specialized Hospital in Addis Ababa, Ethiopia. Plasma and formalin-fixed paraffin-embedded blocks were collected from the participants, and isolation of DNA was performed from these samples. The methylation analysis was performed using the methylation-iPLEX assay. iPLEX capture and extension primers were designed to amplify and target EBV CpGs from bisulfite-converted DNA sequences. Ethical approval was also obtained from respected institutions. Results: Among the 115 participants, 65.2% (n = 75) were male patients. The largest proportion (n = 35, 30.4%) fell within the 41-60 age group. Non-Hodgkin lymphoma (NHL) was diagnosed in 96 patients, while 19 had Hodgkin lymphoma (HL). In the NHL group, the majority (n = 27, 28.1%) were classified as diffuse large cell lymphoma, followed by follicular lymphoma (n = 24, 25%). Out of the different EBV genome methylation sites, we have identified 24 EBV genes to assess the methylation status of the EBV genome. Average methylation levels of these genes were ranged from 45% to 50%. Notably, the HL group exhibited significant heterogeneity in methylation levels, while the CpG methylation status of EBV genes in NHL subtypes demonstrated a consistent pattern. A significant proportion of our samples exhibited methylation loss in the lytic gene BZLF1 and at the origin of replication associated with lytic replication. Conclusions: This study presents the first data from East Africa, shedding light on the EBV DNA methylation status in a diverse group of lymphoma patients. Further investigations in different locations are necessary to elucidate the impact of EBV DNA methylation on tumor progression. Citation Format: Seifegebriel T. Feleke, Kidist Z. Shita, Abdulaziz A. Sherif, Fisihatsion T. Woldegebriel, Christoph Weigel, Elshafa H. Ahmed, Tamrat A. Zeleke, Robert A. Baiocchi. Profiling the CpG methylation patterns of Epstein-Barr virus DNA in lymphoma patients from Ethiopia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7001.

Expression of several deubiquitinase and tyrosine phosphatase genes involved in inflammatory response in lymphoma

Lymphoma represents a heterogeneous group of cancers affecting the lymphatic system, encompassing non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma (HL). The majority of NHL cases originate from B cells. HL is characterized by the presence of rare Hodgkin and Reed-Sternberg cells. Within the context of the inflammatory response, two SH2 domain-containing protein tyrosine phosphatases (SHPs), namely SHP-1 and SHP-2, serve as negative regulators. Deubiquitinating enzymes (DUBs) play a crucial role in inhibiting NF-κB activation in response to various stimuli. This study focuses on the DUBs OTUB1, OTUB2, and Cezanne. Blood samples were collected from 50 NHL patients, 26 HL patients, and 50 healthy individuals. Quantitative RT-PCR was employed to assess the mRNA expression of OTUB1, OTUB2, Cezanne, SHP-1,and SHP-2, while ELISA was used to determine IL-6 and CA125 concentrations. The results revealed that the mRNA level of OTUB1 was significantly downregulated in NHL patients but not in HL patients. Notably, Cezanne expression was downregulated in lymphoma patients, with significantly lower levels observed in HL compared to NHL patients. Furthermore, SHP-1 mRNA expression was significantly lower in the NHL group compared to the HL group or healthy individuals. Conversely, SHP-2 gene expression was upregulated in NHL patients but remained unchanged in HL patients. In conclusion, these findings highlight significant differences in the expressions of DUB and SHP genes and the inflammatory response in lymphoma patients. This study provides a foundation for further investigation into the roles of DUBs and tyrosine phosphatases in regulating the functional activation of lymphoma cells.

Epiregulin: A new prognostic molecule in non-Hodgkin lymphoma.

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

Severe sperm DNA fragmentation may persist for up to 3 years after cytotoxic therapy in patients affected by Hodgkin lymphoma and non-Hodgkin lymphoma.

Does sperm DNA recover from damage in all men after 2 years from the end of cytotoxic treatments? The current indication of 2 years waiting time for seeking natural pregnancy after cytotoxic treatment may not be adequate for all men, since severe sperm DNA damage is present in a proportion of subjects even after this timeframe. Data in the literature on sperm DNA fragmentation (SDF) in lymphoma patients after cytotoxic treatments are scarce. The largest longitudinal study evaluated paired pre- and post-therapy (up to 24 months) semen samples from 34 patients while one study performed a longer follow-up (36 months) in 10 patients. The median/mean SDF values >24 months after therapy did not show significant differences but the studies did not explore the proportion of patients with severe DNA damage and the analysis was done on frozen-thawed samples. In this study, 53 Hodgkin lymphoma (HL) and 25 non-Hodgkin lymphoma (NHL) post-pubertal patients were included over a recruitment period of 10 years (2012-2022). Among them, 18 subjects provided paired semen samples for SDF analysis at the three time points. SDF was evaluated in patients before (T0) and after 2 (T2) and 3 years (T3) from the end of, cytotoxic treatments (chemotherapy alone or in combination with radiotherapy). A cohort of 79 healthy, fertile, and normozoospermic men >18 years old served as controls (recruited between 2016 and 2019). SDF was evaluated on fresh semen samples (i.e. spermatozoa potentially involved in natural conception) from patients and controls using TUNEL (terminal deoxynucleotidyl transferase dUTP nick end labeling) assay coupled with flow cytometry. SDF median values were compared between groups: (i) HL and NHL patients versus controls at the three time points; (ii) HL versus NHL patients at baseline; and (iii) patients at T0 versus T2 and T3. Severe DNA damage (SDD) was defined for SDF levels above the 95th percentile of controls (50%) and the proportion of patients with SDD at all time points was established. At T0, patients displayed higher median SDF than controls, reaching statistical significance in the NHL group: 40.5% [IQR: 31.3-52.6%] versus 28% [IQR: 22-38%], P < 0.05. Comparing SDF pre-treatment to that post-treatment, HL patients exhibited similar median values at the three time points, whereas NHL showed significantly lower values at T3 compared to T0: 29.2% [IQR: 22-38%] versus 40.5% [IQR: 31.3-52.6%], P < 0.05. The proportion with SDD in the entire cohort at T2 was 11.6% and 13.3% among HL and NHL patients, respectively. At T3, only one in 16 NHL patients presented SDD. TUNEL assay requires at least 5 million spermatozoa to be performed; hence, severe oligozoospermic men were not included in the study. Although our cohort represents the largest one in the literature, the relatively small number of patients does not allow us to establish precisely the frequency of SDD at T2 which in our study reached 11-13% of patients. Our data provide further insights into the long-term effects of cytotoxic treatments on the sperm genome. The persistent severe DNA damage after 2 years post-treatment observed in some patients suggests that there is an interindividual variation in restoring DNA integrity. We propose the use of SDF as a biomarker to monitor the treatment-induced genotoxic effects on sperm DNA in order to better personalize pre-conceptional counseling on whether to use fresh or cryopreserved spermatozoa. This work was supported by grants from the Istituto Toscano Tumori (ITT), Fondazione Ente Cassa di Risparmio di Firenze, the European Commission-Reproductive Biology Early Research Training (REPROTRAIN). C.K., G.F., V.R., and A.R.-E. belong to COST Action CA20119 (ANDRONET) which is supported by the European Cooperation in Science and Technology (www.cost.eu). The authors declare no conflict of interest. N/A.

Occurrence and Outcomes of Acute Cerebrovascular Events in Patients with Non-Hodgkin Lymphoma

Background Stroke or Cerebrovascular Accident (CVA) is one of the leading causes of mortality in the world whether it be ischemic or hemorrhagic 1,2. There has been an association of increased incidence of stroke in patients with cancer due to multiple factors 3. Regarding hematologic malignancies, there have been studies to assess the risk of developing stroke in patients with Hodgkin lymphoma (HL), however the information on non-Hodgkin lymphoma (NHL) is limited and not well understood4. We conducted a retrospective case-control study to assess the incidence, risks, and complications and length of stay of patients with current or prior history of NHL who developed an ischemic stroke. Methods This case-control study identified 29,632 patients older than 18 years, with or without CVA and with or without active or history of Non-Hodgkin Lymphoma (NHL) who were admitted to diverse private hospitals between 2018-2022. The patients were divided into two groups, one with current or prior NHL (n=10,699) and a control group of patients (n=18,933) with similar characteristics. Patients with active hemorrhagic stroke, pregnancy, malignancies other than NHL, prior hemorrhagic or ischemic stroke, infective endocarditis, atrial fibrillation, and acute coronary syndrome on admission were excluded. We compared patient's characteristics and the risk of developing a stroke based on the presence or absence of NHL as well as the factors that increased hospital mortality. Length of stay was evaluated as a secondary outcome. Bivariate statistical analysis was used to calculate the odds ratios using RStudio 4.2.2 and JMP Pro 16.0 for all data analysis. Results Of the group with NHL 46.39 % (n=4958) were female, and 53.61% (n=5729) were male, 42% were current or former smokers (n=4497), 27.49% (n=2941) had diabetes, 44.68% (n=4780) had hypertension; 3.34% (357) of them passed away. Of the control group 57.51 % (n=10876) were female, and 42.49% (n=8036) were male, 35% were current or former smokers (n=6763), 16.43% (n=3111) had diabetes, 28.89% (n=5469) had hypertension; 0.47% (n=88) of them passed away. The mean length of stay of patients with stroke was 7.99 days in the NHL group, and 5.99 days in the control group. Regarding the admissions due to stroke, there were 214 patients in the group with NHL, and in the control group where there were 113. Patients with NHL are more likely to have a CVA compared to the control group (OR 2.39 p&amp;lt;0.0001 CI 1.47~3.85) Patients who have NHL are more likely to die (OR=6.08 p&amp;lt;0.001) CI 4.77~7.74) compared to patients without NHL from all causes. Conclusion Patients with Non-Hodgkin lymphoma have an increased risk of developing a stroke compared to patients with similar characteristics but without NHL (or other malignancies). It was also noted that patients had an increased length of stay. Other variables and characteristics of patients that were identified to be more likely to have a CVA and statistically significant for this sample are already well-known risk factors for CVA including diabetes, hypertension, and cardiovascular disease. However, this study aimed to isolate those variables to identify the risk for stroke in this unique population. Our study limitation is the broad spectrum of NHL and possible confounders between the different variants of NHL. More studies are needed to investigate this. References Navi B, Reiner A, Kamel H, et al. Risk of Arterial Thromboembolism in Patients with Cancer. J Am Coll Cardiol. 2017 Aug, 70 (8) 926-938.Turner, M., Murchie, P., Derby, S. et al. Is stroke incidence increased in survivors of adult cancers? A systematic review and meta-analysis. J Cancer Surviv 16, 1414-1448 (2022). https://doi.org/10.1007/s11764-021-01122-7Dardiotis E, Aloizou AM, Markoula S, et al. Cancer-associated stroke: Pathophysiology, detection, and management (Review). Int J Oncol. 2019;54(3):779-796. doi:10.3892/ijo.2019.4669Wei Y, Yang Q, Qin Q, et al. Profiling of the Risk Factors and Designing of a Model to Identify Ischemic Stroke in Patients with Non-Hodgkin Lymphoma: A Multicenter Retrospective Study. Eur Neurol. 2020;83(1):41-48. doi:10.1159/000506046

Effectiveness and safety of CD22 and CD19 dual-targeting chimeric antigen receptor T-cell therapy in patients with relapsed or refractory B-cell malignancies: A meta-analysis.

The efficacy of CD22 or CD19 chimeric antigen receptor T (CAR-T) cells in the management of acute lymphoblastic leukemia (ALL) and non-Hodgkin lymphoma (NHL) was observed. Because antigen loss and lack of CAR-T-cell persistence are the leading causes of progressive disease following single-antigen targeting, we evaluated CD22/CD19 dual-targeting CAR-T-cell therapy efficacy and safety in relapsed/refractory B-cell malignancies. The Web of Science, PubMed, Cochrane, and Embase databases were searched until July 2022. Patients confirmed with any relapsed/refractory B-cell hematological malignancies were included regardless of age, gender, or ethnicity, receiving CD22 and CD19-dual-targeting CAR-T-cell therapy. The studies conducted on patients with coexisting other cancer were excluded. We used random-effect models to explore the outcome, and heterogeneity was investigated by subgroup analysis. Fourteen studies (405 patients) were included. The pooled overall response (OR) and complete remission (CR) were 97% and 93%, respectively, for ALL patients. The 1-year proportions of overall survival (OS) and progression-free survival (PFS) were 70% and 49%, respectively. For NHL, OR occurred in 85% of patients, and 57% experienced CR. The results illustrated that the 1-year OS and 1-year PFS were 77% and 65%, respectively. The subgroup analysis showed that the dual-targeting modality achieved higher CR in the following cases: coadministration of CD22/CD19-CAR-T cells and third-generation CAR-T cells combined with ASCT and BEAM pretreatment. The ALL and NHL groups seemed similar in treatment-related toxicity: all grade cytokine release syndrome (CRS), severe CRS, and neurotoxicity occurred in 86%, 7%, and 12% of patients, respectively. Our meta-analysis demonstrated that the CD22/CD19 dual-targeting CAR-T-cell strategy has high efficiency with tolerable adverse effects in B-cell malignancies.

Abstract 6753: Non-HIV cryptococcal patients with hematological malignancies: A retrospective analysis of a ten-year study from a Peruvian oncologic center

Abstract Background Globally, cryptococcal infection has become a public health challenge. However, relatively little is known about cryptococcal infection in people with hematological disorders. Methods We developed a retrospective cohort study that includes hematological patients who had cryptococcosis infection seen in the Instituto Nacional de Enfermedades Neoplasicas between 2007 and 2017. Results During the 11-year study period, a total of 21 cases of cryptococcosis (incidence rate of 13,4 per 1000 hematological malignancies). The time of diagnosis of cryptococcosis since hematologic malignancy diagnosis was 42 (18-161) days. Non-Hodgkin lymphoma (NHL) was the most frequent malignancy (47.6%), followed by leukemias (23.8%), multiple myeloma in (19.1%), and HL (9.5%). Three cases of adult T-cell leukemia/lymphoma associated with HTLV-1 infection were identified in the NHL. Cryptococcemia was the most frequent diagnosis (85.7%) followed by pulmonary (52.4%) and CNS (38.1%) involvement. Regarding clinical presentation, f ever was the most common symptom in meningeal cryptococcosis (76.2%) and dyspnea in pulmonary cryptococcosis (61.9%). The use of immunosuppressant chemotherapy within a month before the diagnosis of cryptococcosis was the most common risk factor. The main characteristics between patients with cryptococcosis and type of neoplasms (NHL vs other hematological neoplasms) such as age at admission, site of presentation of cryptococcosis, and lymphocyte count at admission were different significantly between these groups. In the NHL group, there was less involvement of the lungs. Overall survival (OS) in 15 and 120 days were 70% (95%CI: 0.43-0.86) and 51% (95%CI: 0.26-0.72), respectively. OS for patients with NHL was 57% at 15 days (95% CI: 0.17-0.83) and 42% at 120 days (95%CI:0.09-0.73). OS for other hematological malignancies was 90% at 15 days (95%CI:0.47-0.98) and 60% at 120 days (95%CI: 0.25-0.82). Conclusions CNS cryptococcal infection was more frequent in patients with NHL. Citation Format: Kelly Meza, Luis E. Cuellar. Non-HIV cryptococcal patients with hematological malignancies: A retrospective analysis of a ten-year study from a Peruvian oncologic center. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6753.

The diagnostic landscape of diffuse large B cell lymphoma of the mandible: A case report

Lymphomas are a class of invasive haematopoietic malignancy constituting 2.2% of all humours of the head and neck. Two major set of lymphomas are Hodgkin’s lymphoma and non Hodgkin’s lymphoma (NHL) of which 90% are of the NHL group. The most frequently occuring NHL in the oral cavity is Diffuse Large B Cell Lymphoma (DLBCL) which involves waldeyer’s ring, base of the tongue, buccal mucosa and hard palate. This paper underscores a case report of DLBCL complications and the characteristic features which contributed to the diagnosis.

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.

Real-World Analysis of Cytopenias after Chimeric Antigen Receptor T-Cell Therapy: A Comparison of BCMA and CD19 Based Outcomes

Introduction: Chimeric Antigen Receptor (CAR) T-cell therapy is now approved as a second-line treatment for relapsed/refractory diffuse large B cell lymphoma (DLBCL), multiple myeloma (MM), and acute lymphoblastic leukemia. B-cell maturation antigen (BCMA) and CD19 CAR-T therapies are associated with substantial hematological toxicity, potentially causing complications in the post-CAR-T setting. It is unclear if cytopenia rates differ between CAR-T therapies. We evaluated differences in cytopenia, transfusion support, and associated outcomes in patients receiving CAR-T therapy for MM and non-Hodgkin's lymphoma (NHL) at our institution. Methods: We performed a retrospective analysis of patients diagnosed with MM and NHL from 2012-2022 who subsequently relapsed and received CAR-T-cell therapy at the Winship Cancer Institute at Emory University. Patients were excluded if they underwent apheresis but had not received infusion or had manufacturing failure. We compared rates of grade 3/4 cytopenias based on CIBMTR criteria and supportive care at day 0, 3mo, 6mo, and 1 year as well as date of hematological recovery. Day 0 was defined as onset of grade 3/4 cytopenia after CAR-T therapy. Hematological recovery was defined as sustained hemoglobin >8g/dL, platelets >50,000/µL, and ANC >1000/mm3 without need for support. Differences between groups were determined using Fisher's exact test and Kruskal-Wallis Test where appropriate. PFS and overall survival (OS) were estimated using the Kaplan-Meier method from CAR-T infusion to progression or death for those events and last contact for those censored. Statistical analysis was performed using SAS with significance at the 0.05 level. Results: Of 35 patients, 24 received BCMA and 11 received CD19 CAR-T therapy. Median age at CAR-T infusion for all patients was 58 years (36-78). Most patients were male (66.7%) and of white race (57.1%) [Table 1]. Overall, 4 patients (11.4%) had an initial ECOG ≥2. Twenty-one patients (87.5%) had penta-refractory MM disease with extramedullary involvement in 25%. All patients with NHL had stage 4 disease with bone marrow involvement in 33.3%. Eight patients had DLBCL (72.7%), 1 double hit lymphoma (18.2%), and 2 mantle cell lymphoma (9.1%). Six patients received tisa-cel, 2 axi-cel, 2 brexu-cel, and 1 liso-cel. The MM cohort underwent significantly more autologous transplantations as a prior line of therapy (p<0.001). Patients with NHL received CAR-T at a later median age (p=0.006). Median follow-up for the MM and NHL cohort was 2.38 years and 0.2 years respectively. There was no difference in time from last therapy to CAR-T infusion (p=0.171) nor days of hospitalization (p=0.681). Almost all patients (95.8%) achieved hematological recovery after infusion with similar recovery rates between groups (p=0.536). Median time to grade 3/4 anemia recovery was 6 days (1-90), neutropenia recovery at 15 days (1-336), and thrombocytopenia recovery at 28 days (14-277). Time to grade 3/4 anemia, neutropenia, and thrombocytopenia was 1 day (0-11), 2 days (0-11) and 2 days (0-15) respectively. Most patients required supportive care with growth factors (34.6%), packed red cells (57.7%), and platelets (23.1%) without significant group differences [Table 2]. One patient with MM received TPO. Prolonged grade 3/4 cytopenia rates were significant with 17.1% at 3mo, 22.9% at 6mo and 8.7% at 1 year. Both groups had similar rates of grade 3/4 cytopenia at day 0, 3mo, 6mo, and 1 year. The MM cohort had higher rates of infection (p<0.001). Rates of CRS (p=0.226) and neurotoxicity (p=0.063) were similar. Fourteen patients with MM (58.3%) and 3 patients with NHL (27.3%) progressed post-CAR-T. Median PFS overall was 1.7 years, 2 years (95%CI: 1, 3) in the MM group, and not reached (NR) (0.2, NA) in the NHL group. Median OS overall was NR, NR in MM (2.5, NA) and NR in NHL (0.3, NA). Grade 3/4 neutropenia and thrombocytopenia were not associated with survival at any time interval. Onset of grade 3/4 cytopenia were not associated with histopathological characteristics, inflammatory markers, or CRS/ICANS. Conclusions: This real-world study demonstrates comparable rates of upfront and prolonged cytopenia in patients receiving BCMA and CD19 CAR-T therapies. Over 20% of patients had prolonged, ongoing grade 3/4 cytopenias requiring supportive care at the 3-6mo mark. Further follow-up and larger prospective studies are needed to validate these findings. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Childhood lymphoma treatment impacts educational outcomes: a registry study from Sweden

PurposeThis study aimed to explore educational outcomes in individuals diagnosed with lymphoma in childhood concerning school grade year 9 and attendance in high school and post-compulsory education. Whether sex or age at diagnosis affected the assessed variables was also explored.MethodsData from 174 children born 1988–1996 and diagnosed with lymphoma before age 15 were matched with approximately five controls per patient. The mean time since diagnosis to receiving school year 9 grades was 4.88 years for Hodgkin lymphoma (HL) cases (mean age at diagnosis 10.62, 11.76, and 10.05 years for all, girls, and boys, respectively) and 7.79 years for non-Hodgkin lymphoma (NHL) cases (mean age at diagnosis 7.85, 7.87, and 7.84 years for all, girls, and boys, respectively).ResultsWe observed statistically significant differences between cases and controls in physical education, both for failing (p = 0.041) and the highest grade (p = 0.015). Compared with controls, HL cases were three times more likely to fail mathematics, and significantly fewer individuals in the whole lymphoma (p = 0.011) and NHL (p = 0.035) groups attended the third year of high school.ConclusionsEducational outcomes are impacted for children treated for lymphoma, especially in physical education. Since patients with HL are treated without central nervous system-directed therapy, other factors, such as absence from school, may affect school results. Physical late complications in lymphoma survivors warrant special attention.Implications for Cancer SurvivorsThe problems childhood lymphoma survivors face should be known by schools and parents, to enable their management. Children treated for lymphoma should be closely monitored and included in follow-up programs when needed, for example, to support physical activity.

Effect of 1st line treatment on aortic inflammation as assessed by 18 FDG PET/CT in patients with Hodgkin and non-Hodgkin lymphoma

Abstract Background Despite advances in the treatment of oncology patients, therapy-related side effects may lead to premature morbidity among cancer survivors. Inflammatory activation that has been linked to cardiovascular disease is particularly crucial for the pathogenesis of both Hodgkin (HL) and non-Hodgkin lymphoma (NHL). Objectives To assess the vascular effects of chemotherapy in patients with HL and NHL by 18-Fluorodeoxyglucose (FDG PET/CT) and to investigate possible interactions with systemic inflammation as assessed by circulating inflammatory markers. Methods Between July 2015 and July 2019, sixty-five consecutive patients (37 males, mean age 56±17.8 years) with histologically confirmed new diagnosis of either HL (n=33) or NHL (n=32), were prospectively studied. PET/CT imaging was performed at baseline, at an interim phase and after 1st line treatment. Aortic FDG uptake was assessed by measuring global aortic TBR. Serum interleukin-6 (IL6) and interleukin-1b (IL1b) were measured at each phase for all patients and served as circulating inflammatory markers. Results Patients with HL demonstrated significant reduction in aortic TBR after 1st line treatment (aortic TBRbaseline=1.98, aorticTBR3rdscan=1.75, p=0.001, F=8.335), which remained significant after adjustment for 10-year cardiovascular risk (Framingham risk score), dyslipidemia, hypertension and diabetes (p=0.002, F=7.664). In contrast, patients with NHL did not demonstrate a significant aortic inflammation response (aortic TBRbaseline = 2.13, aorticTBR3rd scan=2.015, p=0.596, F=0.527), Figure 1. Regarding inflammatory markers, after 1st line treatment IL6 levels were reduced significantly in both HL and NHL groups (IL6baseline HL=3.25, IL6 post 1st line treatment HL=0.448, p=0.00; IL6baseline NHL=0.475, IL6 post 1st line treatment NHL=0.144, p=0.001); IL1b levels did not change significantly in either group, Table 1. Conclusions We demonstrate for the first time that aortic inflammation as assessed by 18-FDG PET-CT is reduced in HL patients after 1st line treatment but not in NHL patients. These findings imply that different pathophysiological pathways and different therapies might affect the arterial bed in different ways in lymphoma patients. Further, a strong potential role of molecular imaging in cardio-oncology emerges, offering valuable information on disease prognosis and progression with a single examination. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): Hellenic Society of Hypertension

Texture analysis of conventional magnetic resonance imaging and diffusion-weighted imaging for distinguishing sinonasal non-Hodgkin's lymphoma from squamous cell carcinoma.

To evaluate the value of texture analysis (TA) of conventional magnetic resonance imaging (MRI) and diffusion-weighted imaging (DWI) in the differential diagnosis between sinonasal non-Hodgkin's lymphoma (NHL) and squamous cell carcinoma (SCC). Forty-two patients with sinonasal SCC and 30 patients with NHL were retrospectively enrolled. TAs were performed on T2-weighted image (T2WI), apparent diffusion coefficient (ADC) and contrast-enhanced T1-weighted image (T1WI). Texture parameters, including mean value, skewness, kurtosis, entropy and uniformity were obtained and compared between sinonasal SCC and NHL groups. Receiver-operating characteristic (ROC) curves and logistic regression analyses were used to evaluate the diagnostic value and identify the independent TA parameters. The mean value and entropy of ADC, and mean value of contrast-enhanced T1WI were significantly lower in the sinonasal NHL group than those in the SCC group (all P < 0.05). ROC analysis indicated that the entropy of ADC had the best diagnostic performance (AUC 0.832; Sensitivity 0.95; Specificity 0.67; Cutoff value 6.522). Logistic regression analysis showed that the entropy of ADC (P = 0.002, OR = 26.990) was the independent parameter for differentiating sinonasal NHL from SCC. TA parameters of conventional MRI and DWI, particularly the entropy value of ADC, might be useful in the differentiating diagnosis between sinonasal NHL and SCC.

Characteristics of Environmental Exposure-Associated Versus Unexposed High-Grade B-Cell Lymphomas in Veterans: A Single Center, Matched Case-Control Study

Introduction: Environmental exposures, such as Agent Orange and other chemicals, are associated with the development of non-Hodgkin lymphomas (NHL). Military personnel and civilians in theaters of conflict are especially at high risk. The mechanism is still not well understood. We have initiated studies to examine the association of dioxin exposure, changes in DNA methylation, and the development of high-grade B-cell NHL.Methods: Patients diagnosed with high grade B-cell NHL were identified from the VA Long Beach medical record system for database abstraction and tissue analysis. Subjects with sufficient clinical data including diagnosis, date of diagnosis, age of diagnosis, exposure to toxins, treatments, date of last follow up, date of death, cause of death were included in the study. Patients were matched by exposure vs no exposure and international prognostic index (IPI), as well as duration in military and tour of duty when possible. Formalin-fixed paraffin-embedded specimens from a subset of these patients (where sufficient tissue was available for analysis) with and without known exposures were analyzed for differences in DNA methylation by enzymatic methyl sequencing. Descriptive statistics were used to summarize patient characteristics. Two sample t- and chi-square tests were used to compare the exposed and unexposed lymphoma groups. Overall survival was calculated from time of diagnosis to death from any cause and plotted on a Kaplan-Meier curve and compared using the Log rank test. The Fisher's exact test was used to compare the causes of death between the two groups using SAS 9.Results: Fifty-two patients were included in the study. Patient characteristics were well-balanced between the two groups. The duration of active duty, interval from military enlistment to diagnosis of NHL, and first-line therapy (generally anthracycline-based) were similar. There was a trend toward higher proportion of patients with advanced (stage III or IV) disease and younger age of diagnosis in patients with exposure-associated NHL (p=0.07). The median duration of response to first-line therapy (DOR1) trended towards being shorter (median, 0.8 years; range 0.03-25 years) in patients with exposure related NHL compared to median DOR1 of 2.7 (range, 0.02-25 years) in those without exposure, p=0.056. Median overall survival was 11.5 years in the exposure group and 10 years in the unexposed group, p=0.31. A higher portion of patients in the exposed group died from NHL compared to unexposed group (38% vs 15%), p=0.057. Other competing causes of death, which were more likely in the unexposed group, included other cancers, cardiac disease, infection, end stage kidney disease, dementia and unknown. Six exposed and six unexposed samples were sequenced with over 10,000 statistically significant differentially methylated regions (DMRs) out of 40,605 DMRs tested. Details of differences in methylation of specific genes and their potential pathophysiological and therapeutic implications will be discussed in the presentation.Conclusions: Patients with exposure-related high-grade B cell NHL who were matched by IPI with unexposed lymphomas did not differ significantly in baseline characteristics including time from enlistment to diagnosis and overall survival. In the exposure-related NHL group, certain findings trended toward significance, including younger age at diagnosis, higher proportion diagnosed at an advanced stage, shorter DOR1, and higher proportion died of NHL. This single center cohort, however, was small and heterogeneous. We are therefore currently expanding this study to examine a larger, multi-center cohort to confirm and extend our clinical and translational findings. DisclosuresNo relevant conflicts of interest to declare.

Differential Diagnosis of Sinonasal Extramedullary Plasmacytoma, Non-Hodgkin’s Lymphoma, and Squamous Cell Carcinoma Using CT Scan and MRI

Background: The imaging features of sinonasal extramedullary plasmacytoma (EMP) are non-specific and similar to those of other lesions, such as sinonasal non-Hodgkin’s lymphoma (NHL) and squamous cell carcinoma (SCC). Objectives: To analyze the computed tomography (CT) and magnetic resonance (MR) images of patients with EMP, NHL, and SCC to identify the radiological characteristics differentiating sinonasal EMP from NHL and SCC. Patients and Methods: In this cross-sectional study, the CT and MR imaging features of 37 patients with sinonasal EMP, 46 patients with NHL, and 44 patients with SCC were analyzed. Sinonasal NHL was categorized into two distinct types, namely, natural killer/T-cell lymphoma (n = 32) and diffuse large B-cell lymphoma (n = 14). The tumor volume was determined by measuring the region of interest (ROI) in the picture archiving and communication system (PACS) program. Besides, homogeneity, apparent diffusion coefficient (ADC) in the ADC maps, degree of enhancement, adjacent bone destruction, and invasion to Waldeyer’s ring and cervical or retropharyngeal lymph nodes were evaluated. Results: Although the tumor volume was larger in the EMP group as compared to the NHL and SCC groups, the difference was not statistically significant. The NHL group showed the highest tumor homogeneity on both CT and MR images. EMP was more heterogenous than NHL, with moderate signal intensity on T1-weighted MR images. On the other hand, EMP and NHL showed significantly lower ADCs as compared to SCC. The majority of patients with sinonasal EMP, NHL, and SCC showed an avid enhancement. Also, destructive tumor growth involving the adjacent bone was more frequent in SCC than in EMP or NHL. However, there were no significant differences among sinonasal EMP, NHL, and SCC in terms of invasion to Waldeyer’s ring and cervical or retropharyngeal lymph node metastasis. Conclusion: Marked heterogeneity on T1-weighted images, low ADCs, and lack of adjacent bone destruction were the CT and MR imaging features that favored the diagnosis of EMP over NHL or SCC.

Full Uncapped Doses Of Chemotherapy In Non-Hodgkin's Lymphoma Patients With a High Body Surface Area Are Well Tolerated With No Increase In Toxicity, and a Trend Towards Improved Survival In Obese Patients

▪ IntroductionThe World Health Organisation estimated that in 2008 11% of the world adults population were obese, as defined by a body mass index (BMI) >30kg/m2. In this patient group, the appropriate dosing of chemotherapy has been contentious. Many clinicians prefer to cap the dose if the patients' body surface area (BSA), as calculated by the square root of height x weight divided by 3600, is above 2m2 due to concerns about the potential toxicity of high doses of chemotherapy. However, recent published data in patients receiving therapy for solid malignancies show no increase in toxicity amongst patients with high BSA receiving uncapped doses of chemotherapy. Furthermore, there is evidence that obese patients with aggressive non-Hodgkin's lymphoma (NHL) have better survival outcomes. The purpose of this study is to analyse whether patients with BSA of more than 2m2 who received uncapped doses of chemotherapy for NHL experienced higher rates of treatment-related toxicities and to assess whether this has any impact on clinical outcomes. MethodsA retrospective analysis of consecutive patients who received standard CHOP-like chemotherapy with or without rituximab for NHL between October 2006 and February 2013 was performed. Baseline characteristics were recorded. Treatment related adverse events (TRAEs) were categorised in accordance with Common Terminology Criteria for Adverse Events Version 4.0. Acute TRAEs were compared using a negative binomial regression model, and Fisher's exact test was used to compare delayed toxicities. Multivariable analysis was used to identify potential risk factors of treatment-related toxicity. Kaplan-Meier curves and log rank tests were used for survival analysis. ResultsIn total, 180 newly diagnosed NHL patients were included in the analysis with a median follow-up of 31.3 months (CI: 27.1 – 35.3 months). Fifty nine (32.8%) of these patients had a BSA of more than 2m2 and 50 (27.8%) were classified as obese. The group with a BSA of more than 2m2 was generally younger and had a lower International Prognostic Index (IPI) score. All patients received full uncapped doses of chemotherapy according to BSA calculated using actual body weight. The median number of acute TRAEs was 2 events per patient, with no clear relationship to BSA (Figure 1). In a covariate analysis, only IPI score was found to be significant. After adjusting for IPI score, there was a trend towards lower acute TRAEs in patients with a BSA of more than 2m2, although this was not statistically significant. There was no difference in the proportion of delayed toxicity between the two groups. The overall response rates were higher in the obese patients, 94.0% vs 86.2%, but that difference was not statistically significant (p = 0.1984). Obese patients had a trend towards better progression-free and overall survivals. This was seen in both the low and high grade B-cell NHL groups (Figure 2). [Display omitted] [Display omitted] ConclusionOur study demonstrates that NHL patients with high BSA receiving uncapped doses of chemotherapy do not experience more acute or delayed treatment-related toxicities. Similar to recently published data, the survival outcomes are comparable between the obese and non-obese patient groups. Our results do not support the common practice of capping chemotherapy doses at a BSA of 2 m2 and suggest that the historically inferior outcomes in obese patients with NHL could be due to relative under-dosing of chemotherapy in this group of patients. Disclosures:No relevant conflicts of interest to declare.

The Widow Maker: A National Inpatient Sample Study of Health Care Utilization Costs for Cardiovascular Complications Patients Diagnosed with Non-Hodgkin's Lymphoma from 2000-2014

Background:Combination chemotherapy has improved the prognosis of DLBCL but has the potential for cardiovascular toxicity that can contribute to long-term morbidity and mortality. There is limited literature assessing the health care utilization costs for cardiovascular outcomes in patients diagnosed with non Hodgkin Lymphoma (NHL). We conducted this study to evaluate trends in hospital cost, length of stay, complication rates, and in-hospital mortality in adult patients diagnosed with non-Hodgkin lymphomas admitted for cardiovascular complications.Methods:We conducted a population-based study from the Nationwide Inpatient Sample (NIS). All adult admissions with a diagnosis of NHL from 2000-2014 were identified using ICD-9 codes. A priori outcome measures were left heart failure, atrial or ventricular arrhythmias, malignant or accelerated hypertension, hypertensive encephalopathy, and aortic dissection. Total cost was adjusted for inflation using data from the U.S. Bureau of Labor Statistics. Logistic regression was used to compare rates of cardiovascular complications and mortality, cost, and length of stay between patients with NHL the general cardiovascular admissions (GCV), and between teaching and non-teaching hospitals.Results:Data were available for 9711761 hospitalized adults, of which 9711761 comprised the NHL group. The incidence of hospitalization for cardiovascular complications was 2.8 (OR = 2.78, 95% confidence interval [CI] 2.48+/-3.16) times higher in the NHL group than the general cardiovascular admissions (GCV) (58.7% versus 20.9%, P=0.005). Patients with Non Hodgkins lymphoma were 2.8 times more likely to be seen in the ED and admitted with cardiovascular complications than GCV patients (7,112,300 in the NHL group vs. 2,599,450 GCV group p< .005). Cardiovascular death was also twice as common in the NHL group (OR 2.2 95% confidence interval [CI] 1.9-3.6, 28.45% versus 19.54, P= 0.014). Risk factors for death included age ≥ 70 years (OR = 2.1, 95% confidence interval [CI] 1.4-3.0), male sex (OR=2.4, 95%CI 1.6-3.3) Caucasian race (OR=2.3, 95%CI 1.8-3.1), and admission at a teaching hospital (OR=1.67, 95%CI 1.2-2.4), average length of stay (4.8 days versus 2.3 days per 100 patients, p< 0.023) and total hospital cost ($960,554, 4206±45206 versus $479,167 ±19672, p = .002) were significantly higher in NHL patients than GCV patients. The leading cause of mortality was ventricular arrhythmias (88,350 death in the NHL group and 36,530 deaths in the GCV group). Rates for atrial arrhythmias, heart failure, acute myocardial infarction and accelerated hypertension were similar in both groups.Conclusions: There is a high rate of cardiovascular morbidity in NHL patients and survivors, which contributes hospitalization, cost, and increased morbidity and mortality. This large population based study identifies a need for cardiovascular screening and risk reduction strategies after treatment for NHL. DisclosuresNo relevant conflicts of interest to declare.

Texture Indices of 18F-FDG PET/CT for Differentiating Squamous Cell Carcinoma and Non-Hodgkin's Lymphoma of the Oropharynx.

We assessed the role of 18F-FDG PET/CT texture indices for the differentiation of squamous cell carcinoma (SCC) and non-Hodgkin's lymphoma (NHL) in the oropharynx. 18F-FDG PET/CT data for 27 patients with SCC and 25 patients with NHL in the oropharynx were investigated. The maximum standardized uptake value (SUVmax), metabolic tumor volume (MTV), total lesion glycolysis (TLG), and six texture indices (homogeneity, entropy, short-run emphasis, long-run emphasis, low gray-level zone emphasis [LGZE], and high graylevel zone emphasis [HGZE]) were derived from PET images. PET/CT parameters of the SCC patients were compared with those of the NHL patients. The diagnostic accuracy of the indices for differentiating SCC from NHL was calculated by a receiver operating characteristic curve analysis. 18F-FDG uptake in the oropharynx was observed in all of the patients. The SUVmax, MTV, and TLG did not differ significantly between the SCC and NHL groups, but two of the six texture indices (LGZE [p=0.004] and HGZE [p=0.03]) showed significant differences between the groups. LGZE was the best discriminative index for the differentiation of SCC and NHL (55.6% sensitivity, 88.0% specificity). The LGZE and HGZE texture indices derived from 18F-FDG PET/CT images may be useful in differentiating SCC and NHL in the oropharynx.

Second cancers and late toxicities after treatment of aggressive non-Hodgkin lymphoma with the ACVBP regimen: a GELA cohort study on 2837 patients

AbstractThe survival of patients with aggressive non-Hodgkin lymphoma (NHL) is increasing, but the incidence of secondary cancer and late toxicity is poorly defined for those treated with cyclophosphamide-hydroxydaunomycin/doxorubicin-Oncovin-prednisone (CHOP)–like chemotherapy. From February 1984 to January 1998, 2837 patients with aggressive NHL received the control-arm chemotherapy adriamycin-cyclophosphamide-vindesine-bleomycin-prednisone (ACVBP) in 3 consecutive Groupe d’Etude des Lymphomes de l’Adulte (GELA) studies. With a median follow-up time of 74 months, the 5-year overall and event-free survival rates were 60% and 52%. Two hundred two occurrences of nonneoplastic late toxicity were reported, resulting in a 5.35% cumulative probability of incidence at 7 years. Eighty-one second tumors developed, for which the 7-year cumulative incidence rate was 2.75%; 64 were solid tumors, and 17 were hematologic malignancies. In multivariate analysis, age was the only risk factor for the second development of cancer. Epidemiologic analysis allowed a comparison of this NHL group with the general population. Considering all tumors, no excess of second cancer was observed. In the male population, however, there was an excess of lung cancer (standardized incidence ratio [SIR], 2.45; P < .001) and myelodysplastic syndrome/acute myelocytic leukemia (MDS/AML) (SIR, 5.65; P = .006), and in the female population there was an excess of MDS/AML (SIR, 19.9; P < .001). With a long follow-up, the ACVBP regimen was highly effective for the treatment of aggressive NHL. Increases occurred in secondary MDS/AML and in lung cancer among men.

Performance of Positron Emission Tomography-Computed Tomography and Bone Marrow Biopsy in Detecting Bone Marrow Infiltration in Lymphoma Cases

Objective:Bone marrow infiltration (BMI) affects the stage diagnosis, and treatment of lymphoma. We aimed to evaluate the performance of bone marrow biopsy (BMB) and positron emission tomography-computed tomography (PET/CT) in detecting BMI in lymphoma patients.Materials and Methods:A total of 269 non-Hodgkin’s lymphoma (NHL) and 110 Hodgkin’s lymphoma (HL) patients were evaluated retrospectively. Sensitivity, negative predictive value (NPV), and accuracy were calculated for PET/CT and BMB in detecting BMI.Results:Sensitivity, NPV, and accuracy for PET/CT in detecting BMI in NHL cases were 65%, 78%, and 84.4%, respectively, while they were 55%, 73.4%, and 79.9% for BMB. PET/CT performance for diffuse large B-cell lymphoma and follicular lymphoma was better than that of BMB, whereas the performance of BMB was better for mantle-cell lymphoma, Burkitt’s lymphoma, and primary mediastinal B-cell lymphoma. Sensitivity, NPV, and accuracy for PET/CT in HL cases were 91.3%, 97.75%, and 98.18%, respectively, while they were 56.52%, 89.69%, and 90.91% for BMB. Due to BMB, 43 (15.9%) patients in the NHL group and 2 (1.8%) patients in the HL group were protected from downstaging.Conclusion:Although their results vary according to NHL subtypes, PET/CT and BMB are complementary methods in determining BMI. In HL, PET/CT is an important diagnostic tool for detecting BMI, and BMB is not necessary in a significant proportion of cases.