Diagnosis Of Diffuse Large B-cell Lymphoma Research Articles

Racial disparities in DLBCL: Analysis of SEER data from 2010-2019.

e18552 Background: Diffuse large B-cell lymphoma (DLBCL) is among the most common subtype of non-Hodgkin’s lymphoma accounting 31% of new cases. Introduction of immunotherapy and cell-based gene therapy has transformed the treatment landscape, yet there continue to be health disparities including differences in treatments received and health outcomes according to socioeconomic status. We aimed to quantify the association between race (white, black, American Indian/Alaska Native, Asian or Pacific Islander [API]) and cancer-specific survival among DLBCL patients. Methods: A retrospective observational study was conducted using the National Cancer Institute’s 2000-2019 Surveillance, Epidemiology, and End Results (SEER) Research Plus Data, 17 registries database. The SEER registry collects data on cancer incidence, patient and disease characteristics, and survival from approximately 35% of the US population. Patients were excluded if they had non-primary DLBCL or missing data. Survival analyses were used to evaluate cancer-specific mortality among 4 racial groups (white, black, American Indian/Alaska Native, API). Cox proportional hazards regression was used to assess the difference in cancer-specific mortality across race groups adjusting for age, sex, marital status, income, rurality, and Ann Arbor Stage. Results: The analytic sample included adult US patients diagnosed with DLBCL from 2010 to 2015 (N = 25,495). Of these 25,495 patients with DLBCL, the majority were White (82.8%), followed by API (9.3%), Black (7.4%), and American Indian/Alaska Native (0.5%). Age at diagnosis, sex, marital status, income differed across race groups. The crude cancer-specific mortality for blacks at year 2 was 29%, while 25% for whites, 24% for American Indians/Alaska Natives, and 29% for API. At year 6, the cancer-specific mortality was 36% for blacks, 33% for whites, 33% for American Indians/Alaska Natives, 35% for API. However, accounting for differences in patient characteristics (adjusting for age, sex, marital status, income, rurality, and Ann Arbor stage) resulted in an increased hazard risk (HR) of cancer-specific mortality for Black and Asian compared to whites (HR 1.28; 95% CI 1.18 to 1.40; and HR 1.19; 95% 1.11 to 1.29, respectively). The HR of cancer-specific mortality comparing American Indian/Alaska Natives to whites was 1.00; 95% CI .73 to 1.38, with the wide confidence intervals indicating that sample size is limited for this comparison. Conclusions: Despite advances in new treatment options, differences in cancer-specific mortality exists between different race groups among patients with DLBCL. The study highlights various sociodemographic features at diagnosis that could reflect disparities and lead to differences in cancer-specific mortality across race groups. It may be feasible to address some of the observed differences at DLBCL diagnosis and this may translate to better outcomes among patients with DLBCL.

Demographic factors impacting time to diagnosis of diffuse large B-cell lymphoma.

e18660 Background: Diffuse large B-cell lymphoma (DLBCL) is the most common form of non-Hodgkin’s lymphoma. Symptoms often include a palpable mass or fever; however, patients can be asymptomatic until the presentation of an oncological emergency, such as end organ complications or tumor lysis syndrome. Delayed diagnosis is related to spinal cord compression and an increased rate of complications from chemotherapy. We investigated factors impacting time until diagnosis. Methods: We performed a retrospective cohort study of DLBCL patients from the Montefiore Health System to determine how demographic factors impacted the time from initial symptom onset until diagnosis. Logistic regression models estimated the associations between race, socioeconomic status, and primary language spoken at home and increased time to diagnosis, stratified by insurance status. Odds ratios for increased time to diagnosis based on language were calculated, based on the number of participants with a time to diagnosis above the median value. Results: In a cohort of 1,076 patients that was 24.7% non-Hispanic White, 26.5% non-Hispanic Black, 7.25% Hispanic, and 41.5% “Other” as per information from Epic, the average time from symptom onset until DLBCL diagnosis was 115.76 days. Average time until diagnosis differed by race: Non-Hispanic White participants had the highest, while Hispanic participants had the lowest (188.4 vs 85.8, p = 0.03). Average age at diagnosis also differed by race: Non-Hispanic Black patients had the lowest age, whereas non-Hispanic White patients had the highest (57.3 vs. 67.4, p < 0.0001). Relative to patients with a preferred language of English, patients who had a preferred language that was Spanish (adjusted OR = 1.99, 95% CI = 0.97-4.06, p = 0.059), or “other” had an increased odds ratio of increased time to diagnosis (adjusted OR = 3.15, 95% CI = 1.01-9.75, p = 0.047). Conclusions: Non-English speaking patients experienced increased time to diagnosis, with non-Spanish speaking patients experiencing an even higher increase in time to diagnosis of DLBCL. Differences by racial or ethnic group supported the finding that primary Spanish speakers experience increased times until diagnosis – Hispanic participants had a lower average time to diagnosis than other racial or ethnic groups, suggesting that the effect of language alone may be greater than this analysis suggested when race and ethnicity is controlled for. Interventions targeted at increasing resources for non-English speaking patients in our diverse patient population, such as increasing the availability of interpretation services, patient literature on preventative screenings in non-English languages, and increasing the number of healthcare workers with competency in common foreign languages, may potentially reduce DLBCL morbidity.

17th International Conference on Malignant Lymphoma, Palazzo dei Congressi, Lugano, Switzerland, 13 - 17 June, 2023.

Introduction: Patients with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) typically have poor outcomes following standard treatment. Loncastuximab tesirine (loncastuximab tesirine-lpyl; Lonca), an antibody-drug conjugate (ADC) comprising a humanized anti-CD19 monoclonal antibody conjugated to a pyrrolobenzodiazepine (PBD) dimer toxin, received accelerated (US) and conditional (EU) approval in R/R DLBCL after ≥2 lines of systemic therapy, based on data from the phase 2 LOTIS-2 trial (Caimi PF et al. Lancet Oncol. 2021;22[6]:790). Rituximab (R), an anti-CD20 monoclonal antibody, is part of standard immunotherapy for DLBCL, both as frontline therapy and in subsequent treatments. Preclinical evidence suggests the addition of R to anti-CD19 ADC therapy may result in prolonged tumor control (Ryan MC et al. Blood. 2017;130[18]:2018). LOTIS-5 aims to evaluate Lonca-R vs standard immunotherapy of R + gemcitabine + oxaliplatin (R-GemOx) in R/R DLBCL. Methods: This is a phase 3, randomized, open-label, 2-part, 2-arm, multicenter study of Lonca-R in patients with R/R DLBCL (NCT04384484). The study consists of a safety run-in phase with Lonca-R (part 1) and a randomized phase evaluating efficacy and safety of Lonca-R vs R-GemOx (part 2). Approximately 350 patients will be enrolled across both parts: part 1 has completed; part 2 will enroll approximately 330 patients (randomized 1:1) to achieve 262 events for the primary end point analysis of progression-free survival by independent central review. Secondary end points include overall survival, overall response rate (2014 Lugano classification), complete response rate, duration of response, frequency and severity of adverse events, change from baseline in laboratory values, concentration and pharmacokinetic parameters of Lonca (conjugated and total antibody and unconjugated PBD), and changes in patient-reported outcomes from baseline. The dosing regimen for Lonca-R is Lonca 150 μg/kg + rituximab 375 mg/m2 every 3 weeks (Q3W) for 2 cycles, then Lonca 75 μg/kg + rituximab 375 mg/m2 Q3W for up to 6 cycles. The dose regimen of R-GemOx is rituximab 375 mg/m2, gemcitabine 1000 mg/m2, and oxaliplatin 100 mg/m2 every 2 weeks for up to 8 cycles. Key eligibility criteria include age ≥18 years, pathologic diagnosis of DLBCL (including patients with DLBCL transformed from indolent lymphoma) or high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements, ≥1 line of prior systemic therapy, previous stem cell transplant >30 days (autologous) or >60 days (allogenic) prior to start of study drug or stem cell transplant ineligibility, and measurable disease. The randomized part of LOTIS-5 began in January 2022 and has an estimated primary completion date of June 2025; enrollment continues, with a total of 45 active sites across the US, Canada, Spain, France, Belgium, Italy, Switzerland, Czech Republic, Poland, and China. The research was funded by: ADC Therapeutics SA; medical writing: CiTRUS Health Group Keywords: molecular targeted therapies, combination therapies, ongoing trials Conflicts of interests pertinent to the abstract C. Carlo-Stella Consultant or advisory role ADC Therapeutics, Celgene/Bristol Myers Squibb, Karyopharm, Novartis, Sanofi, Roche, Merck Sharp & Dohme, Scenic Biotech Honoraria: Merck Sharp & Dohme, Janssen Oncology, AstraZeneca, Celgene, Incyte, Gilead Sciences, Roche M. Chung Stock ownership: The Oncology Institute A. Stathis Honoraria: Eli Lilly, Bayer, Roche, Novartis, Janssen Oncology, AstraZeneca Research funding: ADC Therapeutics , Pfizer, Roche, Novartis, Bayer, Eli Lilly, MEI Pharma, Cellestia, Debiopharm Group, Merck/MSD, Abbvie, Amgen, AstraZeneca, Incyte, Loxo, Philogen Y. Wang Employment or leadership position: ADC Therapeutics Stock ownership: Johnson and Johnson (Family Member) L. Wang Employment or leadership position: ADC Therapeutics M. Hamadani Consultant or advisory role AbGenomics, ADC Therapeutics, Celgene, Incyte, Janssen R&D, Omeros, Pharmacyclics, TeneoBio, Verastem Research funding: Astellas Pharma, Spectrum Pharmaceuticals, Takeda Other remuneration: Speakers’ bureau for AstraZeneca, BeiGene, Sanofi Genzyme

CAR-T therapy access with Louisiana Medicaid: A single institution retrospective analysis.

e18580 Background: Chimeric antigen receptor (CAR)-T therapy has revolutionized the treatment of hematologic malignancies over the past few years. Axicabtagene-ciloleucel was initially approved by the food and drug administration in October 2017 for relapsed/refractory diffuse large B cell lymphoma (DLBCL) after 2 or more lines of systemic therapy. In April 2022, it was approved as second-line therapy for DLBCL that is refractory to first-line or relapses within 12 months of chemoimmunotherapy. Studies have reported complete responses in 50-60% and prolongation of overall survival by 12-18 months. However, CAR-T remains an expensive therapy that can cost up to 1 million USD. Accessibility to CAR-T is governed by various socioeconomic factors including insurance status. The state of Louisiana currently does not have any institution which offers CAR-T therapy. Our Medicaid population is further disadvantaged by the fact that their insurance does not cover out-of-state services. Hence, we conducted this institutional study to evaluate the accessibility to CAR-T and the factors associated with it. Methods: Our retrospective study included adult patients with a diagnosis of DLBCL treated at LSU Shreveport between January 2018 to December 2022. We excluded all other types of B-cell lymphomas, prisoners, and pregnant women. Our primary objective was to evaluate whether the lack of access to CAR-T due to insurance status affected mortality. Our secondary objective was to examine the various demographic factors associated. Analysis was conducted using SAS. Descriptive statistics, Chi-square tests were used to report the results. Results: Our study included a total of 84 patients with a mean age of 59 years. 58% were Caucasian and 38% were African American. 65% were male. 33% had Medicaid coverage and 31% had Medicare. 60% had advanced-stage DLBCL, and 40% had early-stage (Stages I and II). 6% had either double-hit or triple-hit lymphomas. 17% of patients were considered eligible for CAR-T at relapse as per clinician discretion. 33% of patients who were eligible could not get a referral for CAR-T due to factors like insurance status and costs associated with out-of-state living. This led to an increased mortality of 60% in that cohort vs 0% in those who got referrals (p-value of 0.02). Medicaid was the predominant insurance (67%) among those who were unable to get referrals for CAR-T, thus strengthening our hypothesis. Conclusions: Through our study, we aim to bring to light the disparity faced by Louisiana Medicaid patients wherein they don’t have access to a potentially curative therapy for DLBCL. While we do recognize the expenses associated with CAR-T, we wish to highlight that not all states have direct access to this therapy. Seeing how our patients must already uproot their lives temporarily to get CAR-T, their decision could be made easier if insurance can cover the cost at least on a case-to-case basis.

Diffuse Large B-Cell Lymphoma and Related Entities.

Diffuse large B-cell lymphoma (DLBCL) is the most common malignant B-cell neoplasm, with an incidence of 5.6 per 100 000 persons per year and a mean age of onset of approximately 65 years. It is an aggressive type of non-Hodgkin's lymphoma requiring urgent treatment with curative intent. Evidence-based guidelines have not been available to date. For this first international evidence-based DLBCL-specific guideline, various systematic literature searches were performed. 5 systematic reviews, 21 randomized controlled trials (RCTs), and 36 non-randomized studies were used to formulate 42 recommendations. 142 were formulated on the basis of expert consensus. All recommendations were approved in a structured consensus-finding process. For staging, combined positron emission tomography and computed tomography (PET/CT) should be performed (evidence: a prospective registry study). For all patients with a new diagnosis of DLBCL and without contraindications, R-CHOP based immunochemotherapy (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) should be initiated with curative intent (evidence: RCTs). The individual treatment strategy is tailored to the patient's age and risk constellation. Once immunochemotherapy has been completed, PET/CT should be performed again to check for remission. Patients with PET-positive residual disease that is amenable to radiotherapy should be treated with consolidating irradiation (evidence: retrospective cohort study). This clinical practice guideline on the diagnosis, treatment, and followup of patients with DLBCL and related entities provides a standardized clinical management approach, identifies areas where improvement would be desirable, and can serve as a basis for the development of further studies.

Integration of molecular testing for the personalized management of patients with diffuse large B-cell lymphoma and follicular lymphoma

Diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) are the most common forms of aggressive and indolent lymphoma, respectively. The majority of patients are cured by standard R-CHOP immunochemotherapy, but 30%-40% of DLBCL and 20% of FL patients relapse or are refractory (R/R). DLBCL and FL are phenotypically and genetically hereterogenous B-cell neoplasms. To date, the diagnosis of DLBCL and FL has been based on morphology, immunophenotyping and cytogenetics. However, next-generation sequencing (NGS) is widening our understanding of the genetic basis of the B-cell lymphomas. In this review we will discuss how integrating the NGS-based characterization of somatic gene mutations with diagnostic or prognostic value in DLBCL and FL could help refine B-cell lymphoma classification as part of a multidisciplinary pathology work-up. We will also discuss how molecular testing can identify candidates for clinical trials with targeted therapies and help predict therapeutic outcome to currently available treatments, including chimeric antigen receptor T-cell, as well as explore the application of circulating cell-free DNA, a non-invasive method for patient monitoring. We conclude that molecular analyses can drive improvements in patient outcomes due to an increased understanding of the different pathogenic pathways affected by each DLBCL subtype and indolent FL vs R/R FL.

Beta2-microglobulin is a valuable marker and identifies a poor-prognosis subgroup among intermediate-risk patients with diffuse large B cell lymphoma.

Prognosis of diffuse large B cell lymphoma (DLBCL) can be predicted by various factors. The most widely used tool for prediction is the international prognostic index (IPI). β2-microglobulin is a tumor marker commonly used in hematological malignancies. β2-microglobulin is well correlated with outcome of DLBCL. It has been used as an adjunctive tool in some scoring systems for prognostication of DLBCL. In this study, we collected data of patients with diagnosis of DLBCL between 2015 and 2019 in our institute. For each patient, IPI was calculated according to published literature. At diagnosis, serum levels of β2-microglobulin were measured in the clinical laboratory and the results were retrieved from medical records. A total of 516 patients (269 male and 247 female) were enrolled for retrospective analysis. The median age was 64 (range 22-96). The median follow-up period was 32.2months. The median level of β2-microglobulin was 2319μg/L (normal range < 2366μg/L in the clinical laboratory). Level of β2-microglobulin was significantly different between survivors and patients who succumbed to the disease. β2-microglobulin level was correlated with tumor stage, extranodal involvement, B symptoms and IPI, suggesting that it may be a good surrogate marker for disease severity and outcome prediction. We selected the intermediate-risk patients for further analysis. Patients with intermediate-risk IPI and high β2-microglobulin levels have overall survival comparable to patients with high-risk IPI, suggesting an important role of β2-microglobulin in subdivision of DLBCL patients. In conclusion, β2-microglobulin levels correlated with outcome of DLBCL. It may be used independently as a prognostic factor. Subdivision of patients with intermediate-risk IPI may identify a group of high-risk patients, which can be helpful in refining plans of treatment and follow-up.

Surface TREM2 on circulating M-MDSCs as a novel prognostic factor for adults with treatment-naïve diffuse large B-cell lymphoma

IntroductionCirculating monocytic myeloid-derived suppressive cells (M-MDSCs) are implicated as a poor prognostic factor and cause CAR T-cell failure in diffuse large B-cell lymphoma (DLBCL). Triggering receptors expressed on myeloid cells 2 (TREM2) are a transmembrane glycoprotein that polarize macrophages to anti-inflammation phenotype but have never been explored on M-MDSCs. This study aims to elucidate the expression and clinical impact of surface TREM2 on circulating M-MDSCs derived from DLBCL adults.MethodsThis prospective, observational study enrolled 100 adults with newly diagnosed and treatment-naïve DLBCL from May 2019 to October 2021. Human circulating M-MDSCs were obtained from freshly isolated peripheral blood, and each patient’s surface-TREM2 level on M-MDSCs was normalized via a healthy control at the same performance of flow-cytometry analysis. Murine MDSCs derived from bone marrow (BM-MDSCs) were adopted to assess the link between Trem2 and cytotoxic T lymphocytes.ResultsMore circulating M-MDSCs at diagnosis of DLBCL predicted worse progression-free (PFS) and overall survival (OS). Patients with higher IPI scores, bone marrow involvement, or lower absolute counts of CD4+ or CD8+ T cells in PB had significantly higher normalized TREM2 levels on M-MDSCs. Additionally, normalized TREM2 levels on M-MDSCs could be grouped into low (< 2%), medium (2–44%), or high (> 44%) levels, and a high normalized TREM2 level on M-MDSCs was proven as an independent prognostic factor for both PFS and OS via multivariate Cox regression analysis and associated with worst PFS and OS. Interestingly, normalized levels of surface TREM2 on M-MDSCs were negatively associated with absolute counts of PB CD8+ T cells and positively correlated with levels of intracellular arginase 1 (ARG1) within M-MDSCs. Wild-type BM-MDSCs had significantly higher mRNA levels of Arg1 and showed more prominent ability to suppress the proliferation of co-cultured CD8+ T cells than BM-MDSCs from Trem2 knockout mice, and the suppressive ability could be impaired by adding Arg1 inhibitors (CB1158) or supplementing L-arginine.ConclusionIn treatment-naïve DLBCL adults, a high surface-TREM2 level on circulating M-MDSCs is a poor prognostic factor for both PFS and OS and warrants further investigation for its potential as a novel target in immunotherapy.

Association of Preexisting Heart Failure With Outcomes in Older Patients With Diffuse Large B-Cell Lymphoma

Anthracycline-containing regimens are highly effective for diffuse large B-cell lymphoma (DLBCL); however, patients with preexisting heart failure (HF) may be less likely to receive anthracyclines and may be at higher risk of lymphoma mortality. To assess the prevalence of preexisting HF in older patients with DLBCL and its association with treatment patterns and outcomes. This longitudinal cohort study used data from the Surveillance, Epidemiology, and End Results (SEER)-Medicare registry from 1999 to 2016. The SEER registry is a system of population-based cancer registries, capturing more than 25% of the US population. Linkage to Medicare offers additional information from billing claims. This study included individuals 65 years and older with newly diagnosed DLBCL from 2000 to 2015 with Medicare Part A or B continuously in the year prior to lymphoma diagnosis. Data were analyzed from September 2020 to December 2022. Preexisting HF in the year prior to DLBCL diagnosis ascertained from billing codes required one of the following: (1) 1 primary inpatient discharge diagnosis, (2) 2 outpatient diagnoses, (3) 3 secondary inpatient discharge diagnoses, (4) 3 emergency department diagnoses, or (5) 2 secondary inpatient discharge diagnoses plus 1 outpatient diagnosis. The primary outcome was anthracycline-based treatment. The secondary outcomes were (1) cardioprotective medications and (2) cause-specific mortality. The associations between preexisting HF and cancer treatment were estimated using multivariable logistic regression. The associations between preexisting HF and cause-specific mortality were evaluated using cause-specific Cox proportional hazards models with adjustment for comorbidities and cancer treatment. Of 30 728 included patients with DLBCL, 15 474 (50.4%) were female, and the mean (SD) age was 77.8 (7.2) years. Preexisting HF at lymphoma diagnosis was present in 4266 patients (13.9%). Patients with preexisting HF were less likely to be treated with an anthracycline (odds ratio, 0.55; 95% CI, 0.49-0.61). Among patients with preexisting HF who received an anthracycline, dexrazoxane or liposomal doxorubicin were used in 78 of 1119 patients (7.0%). One-year lymphoma mortality was 41.8% (95% CI, 40.5-43.2) with preexisting HF and 29.6% (95% CI, 29.0%-30.1%) without preexisting HF. Preexisting HF was associated with higher lymphoma mortality in models adjusting for baseline and time-varying treatment factors (hazard ratio, 1.24; 95% CI, 1.18-1.31). In this study, preexisting HF in patients with newly diagnosed DLBCL was common and was associated with lower use of anthracyclines and lower use of any chemotherapy. Trials are needed for this high-risk population.

NTRK fusion protein expression is absent in a large cohort of diffuse large B-cell lymphoma.

Even though two NTRK-targeting drugs are available for the treatment of irresectable, metastatic, or progressive NTRK-positive solid tumors, less is known about the role of NTRK fusions in lymphoma. For this reason, we aimed to investigate if NTRK fusion proteins are expressed in diffuse large B-cell lymphoma (DLBCL) by systemic immunohistochemistry (IHC) screening and additional FISH analysis in a large cohort of DLBCL samples according to the ESMO Translational Research and Precision Medicine Working Group recommendations for the detection of NTRK fusions in daily practice and clinical research. A tissue microarray of 92 patients with the diagnosis of DLBCL at the University Hospital Hamburg between 2020 and 2022 was built. The clinical data were taken from patient records. Immunohistochemistry for Pan-NTRK fusion protein was performed and positive staining was defined as any viable staining. For FISH analysis only results with quality 2 and 3 were evaluated. NTRK immunostaining was absent in all analyzable cases. No break apart was detectable by FISH. Our negative result is consistent with the very sparse data existing on NTRK gene fusions in hematologic neoplasms. To date, only a few cases of hematological malignancies have been described in which NTRK-targeting drugs may provide a potential therapeutic agent. Even though NTRK fusion protein expression was not detectable in our sample cohort, performing systemic screenings for NTRK fusions are necessary to define further the role of NTRK fusions not only in DLBCL but in a multitude of lymphoma entities as long as the lack of reliable data exists.

The Diagnostic Accuracy of Bone Marrow Biopsy Versus PET/CT Scan in Identifying Bone Marrow Involvement in Diffuse Large B Cell Lymphoma Patients at a Cancer Hospital.

Background It is of great importance to assess bone marrow involvement (BMI) in diffuse large B cell lymphoma (DLBCL)for staging, prognostic, and therapeutic purposes.The gold standard method used for the identification of bone marrow involvement isbone marrow biopsy (BMB), but it has certain drawbacks. In recent years, positron emission tomography/computed tomography (PET/CT) has become ahighly effective method in the diagnosis and staging of lymphoma. Objective The objective of this study is to estimate the diagnostic accuracy of PET/CT in identifying bone marrow involvement in DLBCL patients in a cancer care hospital in Lahore, using BMB as a reference standard. Methods This descriptive cross-sectional study was conducted at the Department ofPathology of Shaukat KhanumMemorial Cancer Hospital and Research Centre (SKMCH&RC) from January 1, 2013, to December 31, 2018. A retrospective dataof 146 patients fulfilling the inclusion and exclusion criteria was retrieved from the hospital information system (HIS). The inclusion criteria includepatients aged 18-80 years, of either gender, and with a confirmed diagnosis of DLBCL on tissue biopsy. The exclusion criteria includepatients who had startedchemotherapy or radiotherapyfor DLBCL or were using granulocyte colony-stimulatingfactor (G-CSF) prior to their PET/CT scan. All patients underwent PET/CT and BMB, and the diagnostic accuracy of PET/CT was calculated, with BMB taken as the reference standard. Results The mean age of cases was 52.73 ± 16.27 years.There were 95 (65.1%) maleand 51 (34.9%) female cases, with a high male-to-female ratio. In the present study, 32.19% of cases had bone marrow involvement on BMB, and 34.2% of cases had bone marrow involvement on PET/CT. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and overall diagnostic accuracy ofPET/CT were found to be 93.61%, 93.93%, 88%, 96.88%, and 93.84%, respectively. Conclusion It is concluded that PET/CT scan has good sensitivity, specificity, positive predictive value, negative predictive value, and diagnostic accuracy. So, it is suggested to choose this non-invasive technique because the presence of a disease in extra-medullary space can also be detected and the evaluation of bone marrow in the whole body can be performed. PET/CT scan is an effective imaging modality in the detection of bone marrow involvement in DLBCL patients, and its relative advantages over bone marrow biopsy might conclude this to be a preferred technique.

Sequence analyses of relapsed or refractory diffuse large B-cell lymphomas unravel three genetic subgroups of patients and the GNA13 mutant as poor prognostic biomarker, results of LNH-EP1 study.

Advances in molecular profiling of newly diagnosed diffuse large B-cell lymphoma (DLBCL) have recently refine genetic subgroups. Genetic subgroups remain undetermined at the time of relapse or refractory (RR) disease. This study aims to decipher genetic subgroups and search for prognostic molecular biomarkers in patients with RR-DLBCL. From 2015 to 2021, targeted next-generation sequencing analyses of germline-matched tumor samples and fresh tissue from RR-DLBCL patients were performed. Unsupervised clustering of somatic mutations was performed and correlations with patient outcome were sought. A number of 120 patients with RR-DLBCL were included in LNH-EP1 study and a molecular tumor landscape was successfully analyzed in 87% of patients (104/120 tumor samples). The median age was 67.5 years (range 27.4-87.4), median number of previous treatments was 2 (range 1-9). The most frequently mutated genes were TP53 (n=53 mutations; 42% of samples), CREBBP (n=39; 32%), BCL2 (n=86; 31%), KMT2D (n=39; 28%) and PIM1 (n=54; 22%). Unsupervised clustering separated three genetic subgroups entitled BST (enriched in BCL2, SOCS1, and TNFRSF14 mutations); TKS (enriched in TP53, KMT2D, and STAT6 mutations); and PCM (enriched in PIM1, CD79B, and MYD88 mutations). Median overall survival (OS) was 11.0 (95% confidence interval [CI]: 8.1-12.6) months. OS was not significantly different between the three genetic subgroups. GNA13 mutant was significantly associated with an increased risk of death (hazard ratio: 6.6 [95% CI: 2.1-20.6]; p=.0011) and shorter OS (p=.0340). At the time of relapse or refractory disease, three genetic subgroups of DLBCL patients were delineated, which could help advance precision molecular medicine programs.

Meta-Analysis of MS-Based Proteomics Studies Indicates Interferon Regulatory Factor 4 and Nucleobindin1 as Potential Prognostic and Drug Resistance Biomarkers in Diffuse Large B Cell Lymphoma.

The prognosis of diffuse large B cell lymphoma (DLBCL) is inaccurately predicted using clinical features and immunohistochemistry (IHC) algorithms. Nomination of a panel of molecules as the target for therapy and predicting prognosis in DLBCL is challenging because of the divergences in the results of molecular studies. Mass spectrometry (MS)-based proteomics in the clinic represents an analytical tool with the potential to improve DLBCL diagnosis and prognosis. Previous proteomics studies using MS-based proteomics identified a wide range of proteins. To achieve a consensus, we reviewed MS-based proteomics studies and extracted the most consistently significantly dysregulated proteins. These proteins were then further explored by analyzing data from other omics fields. Among all significantly regulated proteins, interferon regulatory factor 4 (IRF4) was identified as a potential target by proteomics, genomics, and IHC. Moreover, annexinA5 (ANXA5) and nucleobindin1 (NUCB1) were two of the most up-regulated proteins identified in MS studies. Functional enrichment analysis identified the light zone reactions of the germinal center (LZ-GC) together with cytoskeleton locomotion functions as enriched based on consistent, significantly dysregulated proteins. In this study, we suggest IRF4 and NUCB1 proteins as potential biomarkers that deserve further investigation in the field of DLBCL sub-classification and prognosis.

FISH or not to FISH - Therapeutic Implications of sequential FISH studies in diagnosing B-cell “Double-Hit” and “Triple Hit” lymphomas

Why FISH… Patients with High Grade B Cell Lymphomas / Double Hit or Triple Hit or HGBL-DH/TH comprise around 10% of newly diagnosed Diffuse Large B Cell Lymphoma (DLBCL) and typically demonstrate poor response to standard initial therapy (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone; RCHOP). They are also shown to have limited survival when compared to those without HGBL-DH/TH. There has been a retrospective analysis on 394 patient samples and detected 19 cases of HGBL-DH (12%). After treatment with anthracycline-containing regimens, the HGBL-DH patients had a significantly shorter median OS of 8.2 months compared with 56.8 months in non- HGBL-DH patients [1, 2].

Primary colorectal diffuse large B-cell lymphoma: A report of eighteen cases in a tertiary care center

Primary colorectal diffuse large B-cell lymphoma (DLBCL) is very rare colon malignancy. It is important to know the main demographic and clinical characteristics of these patients. We conducted a retrospective analysis of 18 patients diagnosed with primary colorectal DLBCL during a 17-year period at the National Cancer Institute of Brazil (INCA) between 2000 and 2018. Demographic characteristics, tumor localization, HIV status, lactate dehydrogenase (LDH) levels, treatment modality and follow-up status were obtained from medical records. Survival was estimated from the date of diagnosis until death. There were 11 male and seven female patients in our cohort, the median age at diagnosis was 59.5 years and four patients were HIV positive. Tumor was mainly localized in the right colon. Patients were treated with chemotherapy (CT) and/or surgical resection. Eleven patients died during a median follow-up of 59 months and the median survival time was 10 months. Six or more cycles of CT (HR=0.19; CI 95% 0.054–0.660, p = 0.009), LDH levels below 350 U/L (HR=0.229; CI 95% 0.060–0.876, p = 0.031) and surgical resection (HR=0.23; CI 95% 0.065–0.828, p = 0.030) were associated with reduced risk of death in univariate analysis. Patient's age and DLBCL right colon localization should be considered at diagnosis to distinguish between DLBCL and other diseases for differential diagnosis. Six cycles of CT, LDH levels below 350 U/L and surgical resection were associated with better survival. Our results are consistent with previous publications and address the importance of correct colorectal DLBCL diagnosis and treatment.

Hepatic Involvement of Diffuse Large B-Cell Lymphoma Mimicking Antinuclear Antibody-Negative Autoimmune Hepatitis Diagnosed by Liver Biopsy

Non-Hodgkin's lymphoma (NHL) is the fifth most common hematologic disorder in the United States, and its prevalence has been rising in Western countries. Among the subtypes of NHL, diffuse large B-cell lymphoma (DLBCL) mostly involves the lymph nodes, stomach, and gastrointestinal tract, whereas hepatic involvement of DLBCL is rare. On serologic testing, elevated immunoglobulin G (IgG) levels can be observed in DLBCL; however, elevated IgG levels are mainly observed in autoimmune hepatitis. A targeted-lesion biopsy is required for the diagnosis of DLBCL. Based on a final diagnosis, the patient was treated with rituximab-based chemotherapy, including cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy (R-CHOP). Herein, we report a case of DLBCL mimicking antinuclear antibody-negative autoimmune hepatitis, which was finally diagnosed as DLBCL involving the liver, and was confirmed by liver biopsy.

Bioinformatics Analysis of miRNAs Targeting TRAF5 in DLBCL Involving in NF-κB Signaling Pathway and Affecting the Apoptosis and Signal Transduction.

Diffuse large B-cell lymphoma (DLBCL) is an aggressive B-cell lymphoma with high heterogeneity. There is an unmet need to investigate valid indicators for the diagnosis and therapy of DLBCL. GEO database was utilized to screen for differentially expressed genes (DEGs) and differential miRNAs in DLBCL tissues. The Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) were applied to analyse DEGs. Then multiple databases were searched for related miRNAs within DLBCL, TNF receptor-associated factor 5 (TRAF5) and NF-kappa B (NF-κB) signaling pathways. The KOBAS database was used to assist in the screening of miRNAs of interest and construct the regulatory network of miRNA-mRNA. Finally, the expression level and diagnostic performance of miRNAs were analyzed with GEO datasets, and DEGs were identified from the GEPIA database. DEGs were significantly concentrated in the NF-κB signaling pathway and cytokine-cytokine receptor interaction, and involved in the process of immune response and protein binding. MiR-15a-5p, miR-147a, miR-192-5p, miR-197-3p, miR-532-5p, and miR-650 were revealed to be targeting TRAF5 and participating in NF-κB signaling pathway and might impact the apoptosis and signal transduction of DLBCL. In the GEPIA database, TRAF5 was significantly overexpressed in DLBCL. The expression of miR-197-3p was upregulated within GEO datasets, while the rest of the miRNAs were downregulated in DLBCL. Subsets of miRNAs may participate in the NF-κB signaling pathway by co-targeting TRAF5 and could be prospective biomarkers exploring the pathogenesis of DLBCL.

49 GLOBAL LONGITUDINAL STRAIN TO EVALUATE THE SUCCESSFUL OF MEDICAL TREATMENT IN SECONDARY CARDIAC LYMPHOMA: A CASE REPORT

Abstract Background Cardiac lymphoma is often lately diagnosed and associated with a poor outcome because of delayed treatment. We report the case of a patient with diffuse large B-cell lymphoma (DLBCL) massively infiltrating the heart, who showed significant improvement in echocardiographic features after high-dose chemotherapy. Case summary A 39-year-old female was admitted to our hospital after a vasovagal syncope secondary to excisional biopsy of an inguinal lymph node. Symptoms and signs were consistent with heart failure. Brain natriuretic peptide was markedly elevated (472 pg/ml). Transthoracic echocardiography (TTE) revealed moderate hypertrophy of both ventricles, with preserved left ventricular ejection fraction, reduced function of the right ventricle and a monophasic diastolic pattern. Left Ventricular Global longitudinal strain (LV GLS) was significantly reduced (up to -5%). These findings led us to the strong suspicion of biventricular infiltrative heart disease. Positron emission tomography-computed tomography (PET-CT) scan showed metastases to the kidneys, mesenteric and skeletal systems. The results of histological analysis and immunohistochemical staining confirmed the diagnosis of stage IV-B DLBCL. Prompt and aggressive treatment was initiated, performing a multiparametric cardiac monitoring based on biomarkers and TTE prior to and after each cycle of chemotherapy. We early observed a significant reduction of myocardial infiltration with an impressive recovery of LV GLS up to -10% after the 1st cycle of chemotherapy. The echocardiographic abnormalities of the right chambers resulted totally restored. Complete regression of the cardiac lymphoma was obtained, with a recovery of LV GLS up to -11.2% at the end of protocol and -16.8% at the 1st month follow-up. The PET-CT scan confirmed the recovery of the heart. Discussion In this case, functional heart improvement due to total regression of cardiac lymphoma has been early detected by strain imaging. GLS could be an early indicator of therapy responsiveness and may be implemented in routinely evaluation of these patients with infiltrative cardiac diseases.

External Validation Shows That Baseline PET Radiomics Outperform the IPI Risk Score for Prediction of Outcome in DLBCL

Introduction Up to one-third of newly diagnosed diffuse large B-cell lymphoma (DLBCL) patients relapse or fail to achieve complete remission following first-line treatment. Adding PET radiomics features to currently used clinical predictors may improve the identification of poor prognosis patients. The objective of this study was to externally validate the radiomics model developed in the HOVON-84 trial (Eertink et al, EJNMMI 2021) using datasets from 6 other DLBCL research studies within the PETRA database. Methods 1195 newly diagnosed DLBCL patients with baseline 18F-FDG PET/CT scans with 2 years follow up in 7 studies in the PETRA database (https://petralymphoma.org) were included. 308 patients from the HOVON 84 were used as test set previously described. 887 patients from 6 studies in the PETRA database were used as external validation datasets. Primary outcome measures were 2-year progression free survival (PFS) and 2-year time to progression (TTP). Lesions were delineated using a fully automated preselection of 18F-FDG avid structures defined by a standardized Uptake Value (SUV) ≥ 4.0 and volume >3mL. Missed lesions were manually added and non-tumor regions were removed using the ACCURATE tool. Metabolic tumor volume (MTV), the maximum distance between the largest lesion and any other lesion (DmaxBulk) and the peak standardized uptake value (SUVpeak) were extracted for all patients. We tested the predictive value of the currently used international prognostic index (IPI) score and the radiomics model developed in the HOVON-84 trial, which included MTV, DmaxBulk, SUVpeak, WHO performance status and age. Model performance was assessed using the receiver-operator-characteristics area under the curve (AUC). To allow comparison of the continuous radiomics model with individual predicted probabilities per patient with the categorical IPI risk score, the high-risk group for the radiomics model was set as equal the size of the high-risk IPI group. Diagnostic performance was assessed using the positive predictive value (PPV). Differences between model performances of prediction models, expressed as AUC, were assessed with the two-sided DeLong test. Results Using 2-year PFS as outcome, the IPI model yielded an AUC of 0.62 using all 1195 patients (Table 1). Within the 6 external datasets, the AUC of the IPI model ranged from 0.51 for the SAKK study to 0.65 for the PETAL study. The radiomics model yielded an AUC of 0.71, which was significantly higher than the IPI model (p < 0.001). The AUC of the radiomics model ranged between 0.59 for the HOVON-130 study to 0.75 for the PETAL study. For all external datasets, the AUC of the radiomics model was higher than the AUC of the IPI model. Comparable results were found using 2-year TTP as outcome. The IPI model yielded an AUC of 0.62 and the radiomics model yielded an AUC of 0.71 when using all 1195 patients (p < 0.001). Again, the AUCs of the radiomics models were consistently higher than the AUCs of the IPI model for all individual studies. High-risk patients according to the IPI model had a 2-year PFS of 60.3% (95% confidence interval (CI): 54.4-67.0). High risk patients by the radiomics model had a 2-year PFS of 50.9% (95% CI: 44.8-57.7). The PPV increased from 35.5% for the IPI model to 49.1% for the radiomics model. For 2-year TTP as outcome, high-risk IPI patients had an overall survival rate of 66.4% (95%CI: 60.3-73.0). High-risk radiomics patients had a survival rate of 55.5% (95% CI: 49.1-62.6). The PPV increased from 33.7% to 44.6% for the radiomics model compared to the IPI model. Conclusion The radiomics model that was developed in the HOVON-84 dataset remained predictive of outcome in 6 independent first-line DLBCL studies, and had higher model performance than the currently used IPI risk score in all studies. Differences between IPI and radiomics model performance between individual studies are most likely caused by differences in patient characteristics between studies. Our radiomics model is able to select high-risk patients more accurately than the IPI model, with higher model performance and PPV. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Clinical Research in Africa: Collaborative Project between Senegal and France to Improve the Diagnosis and Therapeutic Management of Adult Lymphoma Patients

Background: Little is known about Non-Hodgkin Lymphoma (NHL) in Africa except for the high incidence of Burkitt lymphoma in children and the high association with HIV in Eastern Africa but not Western Africa. Difficulties including low access to health care, use of cytopuncture instead of nodal biopsy, cost of drugs and absence of supportive care lead to poor prognosis for NHL patients (pts) (overall response rate (ORR) <30%) (Diop et al., Bull Soc Patho Exo 2004). Meaningful lymphoma research cannot be conducted without accurate diagnosis (Naresh et al., Br J Hematol 2011). The Senegal Government has built a national anti-cancer program, focusing on prevention and improvement of diagnosis and treatment. A prospective single arm non-randomized phase 2 clinical trial was thus designed for adult pts with newly diagnosed diffuse large B-cell lymphoma (DLBCL) at Dakar (Senegal) University Hospital (DUH), in collaboration with Nancy (France) University Hospital (NUH). Methods: Histological results of suspected lymphoma in pts likely to be included in this trial are reported here. Only non-HIV adult patients were enrolled. A first histological study was performed in the pathology department of DUH. This included biopsies that were submitted to apposition before embedding. Hematoxylin and eosin staining was performed as well as immunohistochemistry (IHC). The panel used allowed to examine the expression of the following antigens: CD20, CD79a, CD3, CD5, CD23, cyclin D1, CD30, Bcl2, CD10 and Ki67. Biopsies were reviewed via an international telepathology platform using the i-Path software and retrospectively, in NUH Pathology department, by sending paraffin-embedded blocks on site. Findings: Between July 2018 and May 2022, 70 pts admitted with a clinical presentation suggestive of NHL were evaluated with a surgical biopsy, 31 of whom being confirmed with a diagnosis of DLBCL or equivalent as T-cell/histiocyte-rich large B cell LBCL, and thus eligible for the therapeutic trial. Median age of the 70 pts was 42 years old (18-70) and 32% were female. Other hematological diagnoses were Hodgkin lymphoma, small B-cell lymphoma, T-cell lymphoma, unclassed lymphoma and histiocytosis. There was no Burkitt lymphoma. Non-hematological diagnoses were achieved for 14 pts: lipoma, tuberculosis, reactive adenitis or metastasis of solid neoplasia. In nearly half of all cases, diagnosis was obtained without IHC, notably due to non-hematological diagnoses. In nearly half of all cases, the diagnosis was obtained without IHC. When IHC was used, CD20 and CD3 were mainly used to establish the diagnosis. The median time to obtain pathology results was 31 days. Thirty-one cases were diagnosed with the help of I-Path. Currently, 17 biopsies have been reviewed at NUH with diagnosis concordance in 71% of cases. The 5 inconsistent diagnoses were 2 NHL ultimately classified as adenocarcinoma, 1 reactive adenitis being in fact DLBCL and 2 T-cell/histiocyte-rich LBCL diagnosed as respectively DLBCL and small B-cell lymphoma. Interpretation: This is a large cohort of consecutive surgical biopsies performed in Senegal for lymphoma suspicion, showing the distribution of lymphoma in Western Africa and more interestingly, demonstrating that an accurate diagnosis is possible locally. The current hindrances in lymphoma diagnosis include basing treatment decisions on fine needle aspiration cytology in a large proportion of cases, poor quality histology or complete lack of IHC in cases where biopsies are performed, limited number of hematopathologists and lack of discussion between hematopathologists. In this study, systematic surgical biopsy, homogenous IHC staining procedures, electronic interaction between hematopathologists and retrospective review of biopsies have contributed to a huge improvement of the quality of diagnosis.