Diagnosis Of Diffuse Large B-cell Lymphoma Research Articles

Use of Prephase Steroids in Older Patients Treated for Diffuse Large B-Cell Lymphoma

Background Treatment related morbidity and mortality (TRM) are significant contributors to overall morbidity and mortality for elderly patients with diffuse large B-cell lymphoma (DLBCL). Several studies have shown that TRM is greatest during the first two cycles of treatment. While attenuated doses of standard-of-care treatment regimens (such as R-mini-CHOP) are commonly used to reduce TRM, one additional strategy that has shown promise is the use of glucocorticoids prior to initiation of systemic chemoimmunotherapy (CIT). This approach, defined as prephase steroid use, has been evaluated in small studies, primarily single-center and retrospective in nature. However, older patients with comorbidities are both at greatest risk of TRM and less frequently included in clinical trials. Moreover, patient populations may differ across clinical settings. We conducted an analysis of prephase steroid use in a broader, real-world population treated across multiple centers. Methods We used longitudinal data from the US nationwide, Flatiron Health electronic health record-derived de-identified database. We included patients aged >60 with a diagnosis of DLBCL treated with CIT. This included high-grade B-cell lymphoma, but omitted diagnoses of Burkitt's or primary CNS lymphoma. We utilized a prespecified data analysis plan to determine whether outcomes differed by our exposure of interest, use of prephase steroids. The primary outcome measure was the combined endpoint of time to start of next treatment or death (real-world time to next treatment [rwTTNT]). The secondary outcome was real-world overall survival (rwOS). Outcomes were measured from frontline treatment start date. We also assessed rates of dose delays to evaluate whether prephase steroid use facilitates the maintenance of dose intensity. Prephase steroid use (the exposure) was defined as an order or administration for steroids occurring 5-21 days prior to the start of antineoplastic therapy (excluding steroids used as part of a standard treatment regimen). Patients were stratified by use of anthracycline-based CIT, with sensitivity analyses conducted limited to the anthracycline CIT group. To reduce confounding, we used propensity score-based inverse probability of treatment weighting (IPTW) for the primary analysis. Time to event endpoints were assessed using weighted Kaplan-Meier curves and log-rank tests. Odds of dose delays were assessed using weighted logistic regression. Results We included 3587 patients meeting our criteria, of whom 569 (15.9%) received prephase steroids prior to first-line CIT. A greater percentage of patients treated with anthracycline-based CIT received prephase steroids as compared to those treated with non-anthracyline CIT: 16.3% vs 12.4%, respectively (Table 1). In adjusted analysis using IPTW, there was no significant difference in the rwTTNT by prephase steroid use (p=0.807, Figure 1). Median rwTTNT was 41.2 months (95% CI, 34.6 to 52.4) vs 40.8 months (95% CI, 35.1 to 46.7) with and without prephase steroids, respectively. There was no difference in median rwOS by prephase steroid use: 65.7 months (95% CI, 52.4 to 84.8) vs 74.8 months (95% CI, 67.4 to 82.5) (p=0.707). No differences were seen in sensitivity analyses limiting to patients treated with anthracycline-based CIT. For dose delays, adjusted analysis showed a numerically lower odds of dose delay in patients administered prephase steroids in the total study population: 40.6% vs 50.7% (OR 0.796; p=0.0569). Discussion In this retrospective study of 3587 real-world, elderly patients with DLBCL, prephase steroid use within 21 days of induction CIT did not improve the rwTTNT or rwOS. There was a suggestion that use of prephase steroids may promote maintenance of dose intensity by reducing delays in CIT administration, though this finding did not reach statistical significance. The strengths of this analysis included use of a large, nationwide, real-world dataset and propensity score methods to control for confounding. Limitations include the retrospective nature of the study and potential for unmeasured confounding. In summary, in a real-world cohort of older patients with DLBCL, use of prephase steroids was not associated either with longer TTNT/death, or with longer OS. However, it may be associated with maintenance of CIT dose intensity. This finding is worth exploring in future studies.

Whole Exome Sequencing Analysis of Diffuse Large B-Cell Lymphoma That Progressed to Central Nervous System

Background: Recent sequencing analyses have identified distinct genetic subtypes of diffuse large B-cell lymphoma (DLBCL). The MCD subtype, characterized by MYD88 L265P and CD79B gene mutations, is frequently found in DLBCL that progresses to the central nervous system (CNS), known as secondary CNS lymphoma (sCNSL) (Ollila, Blood 2021). In addition, the MCD subtype is also frequently found in primary CNS lymphoma (PCNSL) (Radke, Nat commun 2022). Therefore, we hypothesized that specific genetic alterations that are present in the initial DLBCL tumors are associated with their progression to the CNS. We aimed to investigate i) the clinical impact of genetic subtypes of DLBCL and ii) genomic mutations that may be associated with sCNSL. To this end, genetic alterations in DLBCL samples at diagnosis that later developed into sCNSL were evaluated using whole-exome sequencing (WES). Methods: A total of 44 patients with DLBCL who developed sCNSL after receiving standard rituximab-containing chemotherapy between 2009 and 2020 were identified from five institutions. sCNSL was diagnosed on the basis of imaging and/or pathological findings. Genomic DNA (gDNA) was extracted from formalin-fixed, paraffin-embedded tumor samples obtained at the initial diagnosis of DLBCL. Finally, 26 of the 44 samples with sufficient gDNA were subjected to WES at BGI Genomic Co. Ltd. Single-nucleotide variants and short indels were detected using Mutect2 and filtered as described in Figure 1. Genetic subtypes were determined using the LymphGen algorithm (https://llmpp.nih.gov/lymphgen/index.php). The association between the clinicopathological features and genetic subtypes was also evaluated. In addition, recurrently mutated genes (>10% in our cohort) were identified and their alteration frequencies were compared with those in a representative general DLBCL cohort (N=574, available in the article by Schmitz, NEJM 2018) and PCNSL cohort (N=30, whole genome sequencing performed, available in the article by Radke, Nat Commun 2022) (Figure 1a). Results: The median age of the 26 patients was 69 years (range, 34-87). At the time of CNS progression, 54, 27, and 19% of the patients had parenchymal CNS disease, extraparenchymal CNS disease, and both, respectively. Immunohistological analysis showed that the non-germinal center B-cell-like (GCB) type, as defined using the Hans algorithm, and dual expression of MYC and BCL2 (DEL) were identified in 65% and 69% of patients, respectively. The median overall survival (OS) from CNS relapse was 16 months (95% confidence interval, 2-30). WES analysis showed that the median mean coverage depth of the 26 samples was 140 (range, 53-299). The median mapping rate was 94% (range, 80-99). As expected, the most frequently mutated genes in our cohort were MYD88 (50%), PIM1 (50%), BTG2 (31%), and CD79B (31%), corresponding to the MCD subtype. The LymphGen algorithm classified the 26 samples into MCD (n=12, 46%), EZB (n=5, 19%, including one with a composite feature of ST2), BN2 (n=1, 4%) and “not classified” (n=8, 31%) (Figure 1b). The CNS-IPI risk, DEL status, and CNS relapse sites did not differ among the genetic subgroups. In addition, univariate analysis showed that non-GCB status, DEL status, and genetic subtype at initial diagnosis did not influence OS. Next, we shortlisted 38 genes whose mutations were identified in three or more samples (>10%) of our cohort as well as in >10% of the PCNSL cohort (by Radke, Nat Commun 2022). We further selected genes that were less frequent (<3%) in the general DLBCL cohort and identified several genes, such as MUC16 and FAT4, that were more enriched in PCNSL and our sCNSL cases (Figure 1a). Metascape analysis (https://metascape.org/gp/index.html#/main/step1) revealed that the top three enriched processes associated with these genes were sensory organ development, cell adhesion via plasma membrane adhesion molecules, and morphogenesis of epithelium. Conclusion: Our study confirmed that MCD was a major genetic subtype of DLBCL that developed sCNSL. We identified recurrently mutated genes that were common in both sCSNL and PCNSL but not in the general DLBCL cohort; these genes may be associated with CNS progression. Validation of our results and investigation of the functions of these genes will help to understand the mechanisms of CNS relapse and develop more accurate markers to predict sCNSL. *Suzuki T and Yokomori R equally contributed to this study.

Risks and Outcomes of Tumor Lysis Syndrome in Patients Admitted with Diffuse Large B Cell Lymphoma; A Nationwide Analysis

Background: Tumor lysis syndrome (TLS) is a feared complication particularly among patients of diffuse large B cell lymphoma (DLBCL) with bulky lymphadenopathy. We conducted a national wide retrospective analysis to determine the impact of TLS on hospitalization among patients admitted for treatment of DLBCL. Methods: The data for this study was obtained from the National Inpatient Sample Database. Using the relevant International Classification of Diseases (1CD) 10 codes, hospitalizations with the primary diagnosis of DLBCL from 2015-19 were subclassified into cases with and without TLS. Univariate analysis was conducted using the chi-square and T-test to compare categorical and continuous variables, respectively between the two groups. Thereafter, propensity score matching (PSM) was performed to match the two groups for patient demographics, and comorbidities. Cochran-Mantel-Haenzel test was used for determining the odds ratio between the endpoints of interest. A p value of <0.05 was considered significant. The primary endpoint was the difference in all-cause mortality between the two matched cohorts. Other secondary endpoints included important hospitalization complications like acute kidney injury (AKI), cardiac arrhythmias (CA), renal failure requiring hemodialysis (HD), and respiratory failure requiring mechanical ventilation (MV). We also performed cost analysis to determine the difference in length of stay (LOS) and adjusted cost of stay between the two groups. Results: A total of 67910 weighted hospitalizations with a primary diagnosis of DLBCL were recorded from 2015-2019. Among these 3910 (5.8) hospitalizations had TLS.Cases with TLS were more likely to be male (61.5% vs57.1; p<0.01) and black (9.4% vs 8.7%, p<0.01). There was a higher proportion of patients with comorbid conditions in the TLS cohort compared to the no TLS cohort, notably history of coagulopathy (22% vs 10.6%), chronic kidney disease (21.9% vs 13.1%), congestive heart failure (15.6% vs 9.5%), diabetes (25.2% vs 23.4%), liver disease (10.4% vs 6.9%), and hypertension (57.0% vs 54.9%) (all p<0.01) (Table 1). After PSM adjusted for these baseline differences, 680 cases of TLS were matched with 680 cases without TLS. Hospitalizations with TLS had higher odds of all-cause mortality (Odds Ratio [OR] = 2.89, 95% confidence interval [CI]: 1.87-4.46; p<0.01). Patients with TLS also had higher odds of AKI (OR = 5.77, 95% CI: 4.53-7.35; p<0.01), HD (OR = 3.63, 95% CI: 1.79-7.40; p <0.01), and MV (OR = 3.79, 95% CI: 2.28-6.30; p<0.01). Though there was a trend towards higher odds of CA, the difference was not statistically significant. Patients with TLS also had a higher mean LOS (12.2 vs 10.8 days, p<0.01), and mean adjusted cost of hospitalization ($53933 vs $36958, p<0.01) (Table 2). Conclusions: Patients with DLBCL that develop TLS are at a higher risk of all-cause mortality and morbidity. Preventive strategies like generous hydration and early detection of TLS are pivotal to improve outcomes.

Prognostic indices in diffuse large B-cell lymphoma: a population-based comparison and validation study of multiple models

Currently, the International Prognostic Index (IPI) is the most used and reported model for prognostication in patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL). IPI-like variations have been proposed, but only a few have been validated in different populations (e.g., revised IPI (R-IPI), National Comprehensive Cancer Network IPI (NCCN-IPI)). We aimed to validate and compare different IPI-like variations to identify the model with the highest predictive accuracy for survival in newly diagnosed DLBCL patients. We included 5126 DLBCL patients treated with immunochemotherapy with available data required by 13 different prognostic models. All models could predict survival, but NCCN-IPI consistently provided high levels of accuracy. Moreover, we found similar 5-year overall survivals in the high-risk group (33.4%) compared to the original validation study of NCCN-IPI. Additionally, only one model incorporating albumin performed similarly well but did not outperform NCCN-IPI regarding discrimination (c-index 0.693). Poor fit, discrimination, and calibration were observed in models with only three risk groups and without age as a risk factor. In this extensive retrospective registry-based study comparing 13 prognostic models, we suggest that NCCN-IPI should be reported as the reference model along with IPI in newly diagnosed DLBCL patients until more accurate validated prognostic models for DLBCL become available.

The Prognostic Value of Prognostic Nutritional Index Combined with D-dimer in Patients with Diffuse Large B-Cell Lymphoma

To explore the effects of prognostic nutritional index (PNI) combined with D-dimer on the prognosis of patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL). The clinical data of 73 DLBCL patients at initial diagnosis were retrospectively evaluated, and the optimal cut-off point of PNI and D-dimer were determined by ROC curve. The overall survival (OS) rate and progression-free survival (PFS) rate in different subgroups were compared using Kaplan-Meier survival curves. Univariate and multivariate Cox regression analysis was performed to identify the factors associated with OS. Compared with the low PNI group (PNI<44.775), the high PNI group (PNI≥44.775) had better OS (P =0.022) and PFS (P =0.029), the 2-year OS rates of the two groups were 55.6% and 78.3% respectively (P =0.041). Compared with the high D-dimer group (D-dimer≥0.835), the low D-dimer group (D-dimer<0.835) had better OS (P <0.001) and PFS (P <0.001), the 2-year OS rates of the two groups were 51.4% and 86.8% respectively (P =0.001). Meanwhile, patients in the high PNI+ low D-dimer group had better OS (P =0.003) and PFS (P <0.001) than the other three groups, the 2-year OS rate was statistically different from the other three groups (P <0.05). The multivariate analysis revealed that NCCN-IPI (HR =2.083, 95%CI : 1.034-4.196, P =0.040), PNI (HR =0.267, 95%CI : 0.076-0.940, P =0.040) and PNI+D-dimer (HR =9.082, 95%CI : 1.329-62.079, P =0.024) were the independent risk factors affecting OS in patients with DLBCL. Subgroup analysis showed that PNI, D-dimer, and PNI combined with D-dimer could improve the prognostic stratification in low and low-intermediate risk DLBCL patients. High PNI, low D-dimer and combination of high PNI and low D-dimer at initial diagnosis suggest a better prognosis in DLBCL patients.

Clinicopathological analysis of diffuse large B-cell lymphoma using molecular biomarkers: a retrospective analysis from 7 Hungarian centers.

The clinical and genetic heterogeneity of diffuse large B-cell lymphoma (DLBCL) presents distinct challenges in predicting response to therapy and overall prognosis. The main objective of this study was to assess the application of the immunohistochemistry- and interphase fluorescence in situ hybridization (FISH)-based molecular markers in the diagnosis of DLBCL and its prognostic value in patients treated with rituximab-based immunochemotherapy. This is a multicenter, retrospective study, which analyzed data from 7 Hungarian hematology centers. Eligible patients were adults, had a histologically confirmed diagnosis of DLBCL, were treated with rituximab-based immunochemotherapy in the first line, and had available clinicopathological data including International Prognostic Index (IPI). On the specimens, immunohistochemistry and FISH methods were performed. Germinal center B-cell like (GCB) and non-GCB subtypes were classified by the Hans algorithm. Outcomes included overall survival (OS), event-free survival (EFS), and EFS at 2 years (EFS24). For survival analysis, we used Kaplan-Meier curves with the log-rank test and multivariate Cox regression. A total of 247 DLBCL cases were included. Cases were positive for MYC, BCL2, BCL6, and MUM1 expression in 52.1%, 66.2%, 72.6%, and 77.8%, respectively. BCL6 translocation, BCL2 gene copy number (GCN) gain, IGH::MYC translocation, MYC GCN gain, IGH::BCL2 translocation, and BCL6 GCN gain were detected in 21.4%, 14.1%, 7.3%, 1.8%, 7.3%, and 0.9%, respectively. At a median follow-up of 52 months, 140 patients (56.7%) had disease progression or relapse. The Kaplan-Meier estimate for EFS24 was 56.2% (CI: 50.4-62.8%). In univariate analysis, only IPI and BCL6 expression were significant predictors of both OS and EFS, whereas MUM1 predicted EFS only. In multivariate analysis, the IPI score was a significant independent negative, whereas MIB-1 and BCL6 protein expressions were significant independent positive predictors of both OS and EFS. In our study, we found that only IPI, BCL6 protein expression and MIB-1 protein expression are independent predictors of survival outcomes in DLBCL. We did not find any difference in survival by GCB vs. non-GCB subtypes. These findings may improve prognostication in DLBCL and can contribute to designing further research in the area.

A study on diagnosis and classification of gastrointestinal lymphoma based on histopathology and immunohistochemistry

Background: WHO 2019 classification makes important histopathology additions to gastrointestinal lymphoma. This study aimed to investigate the role of histopathology and immunohistochemistry in the diagnosis and classification of gastrointestinal lymphomas. Materials and method: We investigated 141 patients from three tertiary referral hospitals with primary malignant lymphoma of the gastrointestinal tract. The lesions were evaluated and analyzed by using histopathology to classify the prevalent histopathological patterns of gastrointestinal lymphoma according to the WHO 2019 classification based on histopathology and immunohistochemistry. Results: 90.8% of gastrointestinal lymphomas were lymphoid infiltrates on histopathology. The most common type was diffuse large B-cell lymphoma (DLBCL) in which activated -B cell (ABC) subtype accounted for 54%, and germinal-center B-cell (GCB) accounted for 46%. In the second place was mucosa-associated lymphoid tissue (MALT lymphoma) accounting for 24%, followed by follicular lymphoma at 10.6%. Histopathology can orient to the diagnosis of DLBCL and MALT with sensitivity at 31% and 29%, respectively. Conclusions: Orientation based on histopathology of those tumor classifications is challenging. However, the combination of histopathology and immunohistochemistry could help to classify the majority of gastrointestinal lymphoma types. Key words: Gastrointestinal lymphomas, DLBCL, MALT.

POSTER: ABCL-517 Phase III Trial of Subcutaneous Epcoritamab + R-CHOP Versus R-CHOP Alone in Patients With Newly Diagnosed Diffuse Large B-Cell Lymphoma (DLBCL): EPCORE DLBCL-2

POSTER: ABCL-517 Phase III Trial of Subcutaneous Epcoritamab + R-CHOP Versus R-CHOP Alone in Patients With Newly Diagnosed Diffuse Large B-Cell Lymphoma (DLBCL): EPCORE DLBCL-2

ABCL-517 Phase III Trial of Subcutaneous Epcoritamab + R-CHOP Versus R-CHOP Alone in Patients With Newly Diagnosed Diffuse Large B-Cell Lymphoma (DLBCL): EPCORE DLBCL-2

ABCL-517 Phase III Trial of Subcutaneous Epcoritamab + R-CHOP Versus R-CHOP Alone in Patients With Newly Diagnosed Diffuse Large B-Cell Lymphoma (DLBCL): EPCORE DLBCL-2

Factors determining whether diffuse large B-cell lymphoma samples are detected by flow cytometry.

Flow cytometry (FCM) is widely used in the diagnosis of mature B-cell neoplasms (MBN), and FCM data are usually consistent with morphological findings. However, diffuse large B-cell lymphoma (DLBCL), a common MBN, is sometimes not detected by FCM. This study aimed to explore factors that increase the likelihood of failure to detect DLBCL by FCM. Cases with a final diagnosis of DLBCL that were analysed by eight-colour FCM were retrospectively collated. Clinical, FCM, histopathological and genetic data were compared between cases detected and cases not detected by FCM. DLBCL cases from 135 different patients were analysed, of which 22 (16%) were not detected by FCM. In samples not detected by flow cytometry, lymphocytes were a lower percentage of total events (p = 0.02), and T cells were a higher percentage of total lymphocytes (p = 0.01). Cases with high MYC protein expression on immunohistochemistry were less likely to be missed by FCM (p = 0.011). Detection of DLBCL was not different between germinal centre B-cell (GCB) and non-GCB subtypes, not significantly affected by the presence of necrosis or fibrosis, and not significantly different between biopsy specimens compared to fine-needle aspirates, or between samples from nodal compared to extranodal tissue. The study identifies several factors which affect the likelihood of DLBCL being missed by FCM. Even with eight-colour analysis, FCM fails to detect numerous cases of DLBCL.

Expression and Prognostic Value of Cytokines in Patients with Newly Diagnosed Diffuse Large B-Cell Lymphoma

To investigate the expression and prognostic value of cytokines in patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL). Clinical data of 62 patients diagnosed with DLBCL in the First People's Hospital of Yunnan Province from June 2017 to November 2018 were collected. The differences in expression levels of 14 serum cytokines [interleukin (IL)-1β, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12p70, IL-17A, IL-17F, IL-22, interferon (IFN)-γ, tumor necrosis factor (TNF)-α, TNF-β] in patients with different survival outcomes, and the impact of the cytokines on 3-year progression-free survival (PFS) and 3-year overall survival (OS) of patients with DLBCL were analyzed retrospectively. Among the 14 cytokines, only the expression of IL-10 was significantly different in patients with different survival outcomes (P =0.007). According to the receiver operating characteristic (ROC) curve, the optimal cut-off value for IL-10 was 11.74 pg/ml. Serum IL-10 was positively correlated with infection markers procalcitonin (PCT) (r =0.321, P =0.029), C-reactive protein (CRP) (r =0.320, P =0.013) and tumor burden index lactate dehydrogenase (LDH) (r =0.439, P <0.001) in newly diagnosed DLBCL patients. The level of IL-10 in patients with pulmonary infection was significantly higher than that in patients without pulmonary infection (P =0.012). However, there was no statistically significant difference on the 3-year survival outcomes between patients with or without pulmonary infection. There was no significant difference in IL-10 level in patients with different Ann Arbor stages (P >0.05). Patients with high IL-10 level (IL-10>11.74 pg/ml) had significantly higher LDH level than those with low IL-10 level (IL-10≤11.74 pg/ml) (P <0.001). The 3-year PFS rate and 3-year OS rate of DLBCL patients with high IL-10 level were significantly lower than those of low IL-10 level group [(44.4±11.7)% vs (81.8±5.8)%, P <0.001; (61.6±11.5)% vs (93.2±3.8)%, P =0.001]. Serum IL-10 level in newly diagnosed DLBCL patients can reflect the inflammatory state of the body, which may be related to tumor load. Newly diagnosed DLBCL patients with serum IL-10>11.74 pg/ml have higher early mortality and worse prognosis.

Diagnostic and Prognostic Value of 18F-FDG PET/CT in Bone Marrow Infiltration of Newly Diagnosed Diffuse Large B-Cell Lymphoma

To explore the diagnostic value of 18F-FDG PET/CT in bone marrow infiltration (BMI) of newly diagnosed diffuse large B-cell lymphoma (DLBCL), compared with the results of bone marrow biopsy (BMB) and investigate whether the BMI diagnosed by 18F-FDG PET/CT and other factors have independent prognostic values. Ninety-four newly diagnosed DLBCL patients who underwent PET/CT in Clinical Medical College of Shanghai General Hospital of Nanjing Medical University were included. BMB was performed within 2 weeks before or after PET/CT, and standardized treatment was performed after PET/CT. The manifestations of bone marrow (BM) FDG uptake were recorded. The diagnostic criteria of BMI were BMB positive or focal BM FDG uptake confirmed by imaging follow-up. The relationship between clinical features and BM FDG uptake and the values of PET/CT and BMB in the diagnosis of BMI was analyzed. The progression-free survival (PFS) was analyzed by Kaplan-Meier survival curves, log-rank test was used to compare PFS rate, and Cox regression model was used to analyze the independent risk factors affecting PFS. Among 94 DLBCL patients, 34 patients showed focal BM uptake (fPET), 7 patients showed super BM uptake (sBMU), 11 patients showed diffuse homogenous uptake higher than liver (dPET), and the other 42 patients had normal BM uptake (nPET) (lower than liver). BMB positive was found in all sBMU patients, in 20.6%(7/34) of fPET patients, and in 27.3% (3/11) of dPET patients. All nPET patients had negative BMB results. dPET patients were associated with lower hemoglobin level and leukocyte count compared with nPET group (P < 0.001, P =0.026). Compared with fPET patients, sBMU patients were more likely to have B symptoms and elevated lactate dehydrogenase (LDH). A total of 44 patients were diagnosed BMI, including 17 cases with BMB+. The sensitivity and specificity of BMB in the diagnosis of BMI was 38.6% (17/44) and 100% (50/50), respectively. Using fPET and sBMU as criteria of PET BMI, the diagnostic sensitivity and specificity of PET/CT was 93.2% (41/44) and 100% (50/50), respectively. Kaplan-Meier analysis showed that there was no significant difference in 2-year PFS rate between nPET and dPET patients (P >0.05), while sBMU patients had lower 2-year PFS rate compared with fPET patients (P < 0.001). Multivariate analysis showed that higher Ann Arbor stage (HR=9.010, P =0.04) and sBMU (HR=3.964, P =0.002) were independent risk factors affecting PFS. Increased BM FDG uptake of DLBCL can be manifested as dPET, fPET and sBMU. fPET and sBMU can replace BMB to diagnose BMI. Although dPET cannot completely exclude the possibility of BMI, it does not affect the prognosis, so it can be diagnosed as PET BMI negative. sBMU is an independent prognostic risk factor.

MicroRNA sequencing for biomarker detection in the diagnosis, classification and prognosis of Diffuse Large B Cell Lymphoma

Despite being considered a single disease, Diffuse Large B Cell Lymphoma (DLBCL) presents with variable backgrounds, which results in heterogeneous outcomes among patients, with 40% of them still having primary refractory disease or relapse. Thus, novel biomarkers are needed. In addition, multiple factors regarding its pathogenesis remain unclear. In this context, recent investigations point to the relevance of microRNAs (miRNAs) in cancer. However, regarding DLBCL, there is inconsistency in the data reported. Therefore, in this work, the main goals were to determine a miRNA set with utility as biomarkers for DLBCL diagnosis, classification, prognosis and treatment response, as well as to decipher the mechanism of action of deregulated miRNAs in the origin of the disease. We analyzed miRNA expression in a cohort of 78 DLBCL patients and 17 controls using small RNA sequencing and performed a miRNA-mRNA interaction network analysis. This way, we were able to define new miRNA expression signatures for diagnosis, classification, treatment response and prognosis, and we identified plausible mechanisms of action by which deregulated miRNAs could be involved in DLBCL pathogenesis. In summary, our study remarks that miRNAs could play an important role in DLBCL.

Diagnostic Efficacy of 18F-FDG PET/CT in Detecting Bone Marrow Infiltration in Patients with Newly Diagnosed Diffuse Large B-Cell Lymphoma*

ObjectiveDiffuse large B-cell lymphoma (DLBCL) is often associated with bone marrow infiltration, and 2-deoxy-2-(18F) fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) has potential diagnostic significance for bone marrow infiltration in DLBCL. MethodsA total of 102 patients diagnosed with DLBCL between September 2019 and August 2022 were included. Bone marrow biopsy and 18F-FDG PET/CT examinations were performed at the time of initial diagnosis. Kappa tests were used to evaluate the agreement of 18F-FDG PET/CT with the gold standard, and the imaging features of DLBCL bone marrow infiltration on PET/CT were described. ResultsThe total detection rate of bone marrow infiltration was not significantly different between PET/CT and primary bone marrow biopsy (P = 0.302) or between the two bone marrow biopsies (P = 0.826). The sensitivity, specificity, and Youden index of PET/CT for the diagnosis of DLBCL bone marrow infiltration were 0.923 (95% CI, 0.759–0.979), 0.934 (95% CI, 0.855–0.972), and 0.857, respectively. Conclusion18F-FDG PET/CT has a comparable efficiency in the diagnosis of DLBCL bone marrow infiltration. PET/CT-guided bone marrow biopsy can reduce the misdiagnosis of DLBCL bone marrow infiltration.

T-cell redirecting therapies for B-cell non-Hodgkin lymphoma: recent progress and future directions.

Several key advances in the treatment of B-cell non-Hodgkin lymphoma (B-NHL) over the past two decades have strategically exploited B-cell lineage markers suitable for targeting by immunotherapies. First, the addition of the anti-CD20 monoclonal antibody (mAb) rituximab to a range of standard therapies conferred remarkable outcomes improvements in diverse settings, perhaps most prominently an overall survival advantage in newly diagnosed diffuse large B-cell lymphoma (DLBCL). Subsequently, multiple chimeric antigen receptor (CAR) T-cell therapies targeting CD19 have revolutionized the treatment of relapsed/refractory (rel/ref) DLBCL and are active in other B-NHL subtypes as well. Most recently, the longstanding aspiration to exploit patients' endogenous T-cells to combat lymphoma has been achieved via T-cell redirecting therapies such as bispecific antibodies (BsAbs) that incorporate dual targeting of a T-cell antigen such as CD3 plus a B-cell antigen such as CD19 or CD20 expressed by the tumor. These novel agents have demonstrated impressive activity as monotherapies in patients with heavily pre-treated, rel/ref B-NHL of a variety of subtypes. Now, myriad clinical trials are exploring combinations of T-cell redirectors with targeted therapies, antibody-drug conjugates, conventional chemotherapy, and even new immunotherapies. Here, we highlight key landmarks in the development of T-cell redirecting therapies for the treatment of B-NHL, emerging evidence and lessons from recent clinical trials, and exciting new directions in this arena.

Pancreatic Diffuse Large B-cell Lymphoma in the US Population.

Pancreatic lymphomas (PLs) represent <2% of all lymphomas and <0.5% of all pancreatic neoplasms. An accurate histologic diagnosis of PL is needed to predict prognosis and adequately treat the patient. This study aims to investigate the demographic, clinical, and pathological factors affecting the prognosis and survival of pancreatic diffuse large B-cell lymphoma (DLBCL). Demographic and clinical data from 493 cases of DLBCL of the pancreas were identified between 2000 and 2018 using the Surveillance, Epidemiology, and End Results (SEER) database. The most common age group was between the ages of 70 and 79 years (27.0%).While 44%of cases involved distant sites (a proxy for secondary pancreatic DLBCL), regional and localized involvement was seen in 33%, with the most common cause of death being a primary pancreatic DLBCL. Most patients (71%) received only chemotherapy (systemic therapy). The overall five-year observed survival was 46% (95% CI, 43.5-48.3). The one-year and five-year survival with chemotherapy only was 68% (95% CI, 65.3-70.3) and 48% (95% CI, 44.7-50.5), respectively. The one-year and five-year survival with surgery and chemotherapy was 96% (95% CI, 91.3-99.9) and 80% (95% CI, 71.4-89.2), respectively. Surgery with chemotherapy (HR: 0.397 (95% CI, 0.197-0.803), p = 0.010) were both positive predictors in survival prognosis. Multivariable analysis identified age >55 years (HR: 2.475 (95% CI, 1.770-3.461), p < 0.001), distant stage (HR: 6.894 (95% CI, 4.121-11.535), p < 0.001), and undergoing no surgery (HR: 2.610 (95% CI, 1.307-5.215), p = 0.007) as negative predictors for survival. PLs are rare malignant pancreatic neoplasms with DLBCL being the most common histological subtype. An accurate and timely diagnosis of pancreatic DLBCL is necessary to implement effective treatments and reduce mortality. Systemic therapy (chemotherapy) with or without surgical therapy improved survival. Increased age and regional and distant spread negatively impacted survival.

Phase 3 trial of subcutaneous epcoritamab + R-CHOP versus R-CHOP in patients (pts) with newly diagnosed diffuse large B-cell lymphoma (DLBCL): EPCORE DLBCL-2.

TPS7592 Background: In pts with newly diagnosed DLBCL, standard treatment with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) has a 5-year progression-free survival (PFS) rate of 67.0%, 58.4%, and 45.8% for International Prognostic Index (IPI) 2, 3, and 4–5, respectively (Ruppert et al, Blood 2020). Epcoritamab is a subcutaneously administered, bispecific antibody that binds CD3 on T cells and CD20 on B cells, inducing potent and selective T-cell–mediated killing of malignant CD20+ B cells (Hutchings et al, Lancet 2021). Epcoritamab monotherapy demonstrated deep and durable responses (overall response rate [ORR], 63%; complete response rate, 39%) and was generally well tolerated in pts with relapsed/refractory (R/R) aggressive, large B-cell lymphoma (LBCL) (Thieblemont et al, J Clin Oncol 2022). Results from an ongoing phase 1/2 study in high-risk pts with newly diagnosed DLBCL (EPCORE NHL-2 arm 1; NCT04663347) show that epcoritamab + R-CHOP has promising efficacy and a manageable safety profile in high-risk pts with IPI 3–5. Among efficacy-evaluable pts (n = 31), ORR was 100% and complete metabolic response (CMR) was 77%; cytokine release syndrome (CRS) events (n = 17/33; 52%) were mostly low-grade, had predictable timing, and did not lead to treatment discontinuation (Falchi et al, ASCO 2022, abstract 7523). These encouraging data support further evaluation of epcoritamab + R-CHOP for the treatment of newly diagnosed DLBCL. Methods: This phase 3, global, multicenter, open-label study (NCT05578976) evaluates the efficacy and safety of epcoritamab + R-CHOP in adults newly diagnosed with one of the following CD20+ DLBCL (de novo or transformed from follicular lymphoma [FL]): 1) DLBCL, not otherwise specified (NOS); 2) high-grade B-cell lymphoma with MYC and BCL-2 and/or BCL-6 rearrangement; 3) T-cell/histiocyte–rich LBCL; 4) Epstein-Barr virus–positive DLBCL, NOS; or 5) FL grade 3b. Other key eligibility criteria include IPI ≥2 (pts with IPI 2 not to exceed ~30% of total pts), ECOG PS 0–2, and ≥1 measurable disease site. Approximately 900 pts will be randomized 2:1 to either epcoritamab + R-CHOP (6 cycles, followed by 2 cycles of epcoritamab) or R-CHOP (6 cycles, followed by 2 cycles of rituximab). The primary efficacy endpoint is PFS in pts with IPI 3–5 (based on IRC assessment per Lugano criteria). The secondary efficacy endpoints are PFS in pts with IPI 2–5, event-free survival, CMR, overall survival, and minimal residual disease negativity. Safety endpoints include incidence and severity of treatment-emergent adverse events (AEs), serious AEs, and AEs of special interest (CRS, immune cell–associated neurotoxicity syndrome, and clinical tumor lysis syndrome. Enrollment began in January 2023 globally. Clinical trial information: NCT04663347 , NCT05578976 .

Mental health disorders and survival among older patients with diffuse large B-cell lymphoma in the USA: a population-based study

Mental health disorders can potentially decrease quality of life and survival in patients with cancer. Little is known about the survival implications of mental health disorders in patients with diffuse large B-cell lymphoma (DLBCL). We aimed to evaluate the effect of pre-existing depression, anxiety, or both on survival in a US cohort of older patients with DLBCL. Using the Surveillance, Epidemiology, and End Results-Medicare (SEER-Medicare) database, we identified patients aged 67 years or older, diagnosed with DLBCL in the USA between Jan 1, 2001, and Dec 31, 2013. We used billing claims to identify patients with pre-existing depression, anxiety, or both before their DLBCL diagnosis. We compared 5-year overall survival and lymphoma-specific survival between these patients and those without pre-existing depression, anxiety, or both using Cox proportional analyses, adjusting for sociodemographic and clinical characteristics, including DLBCL stage, extranodal disease, and B symptoms. Among 13 244 patients with DLBCL, 2094 (15·8%) had depression, anxiety, or both disorders; 6988 (52·8%) were female, and 12 468 (94·1%) were White. The median follow-up for the cohort was 2·0 years (IQR 0·4-6·9 years). 5-year overall survival was 27·0% (95% CI 25·1-28·9) for patients with these mental health disorders versus 37·4% (36·5-38·3) for those with no mental health disorder (hazard ratio [HR] 1·37, 95% CI 1·29-1·44). Although survival differences between mental health disorders were modest, those with depression alone had the worst survival compared with no mental health disorder (HR 1·37, 95% CI 1·28-1·47), followed by those with depression and anxiety (1·23, 1·08-1·41), and then anxiety alone (1·17, 1·06-1·29). Individuals with these pre-existing mental health disorders also had lower 5-year lymphoma-specific survival, with depression conferring the greatest effect (1·37, 1·26-1·49) followed by those with depression and anxiety (1·25, 1·07-1·47) and then anxiety alone (1·16, 1·03-1·31). Pre-existing depression, anxiety, or both disorders present within 24 months before DLBCL diagnosis, worsens prognosis for patients with DLBCL. Our data underscore the need for universal and systematic mental health screening for this population, as mental health disorders are manageable, and improvements in this prevalent comorbidity might affect lymphoma-specific survival and overall survival. American Society of Hematology, National Cancer Institute, Alan J Hirschfield Award.

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

Introduction: The optimal treatment for very elderly patients (pts) with newly diagnosed Diffuse Large B Cell Lymphoma (DLBCL) remains controversial. R-mini-CHOP is an established standard of care in elderly patients with DLBCL, with a 2 yr OS of 59% and PFS of 47% (Peyrade et al., Lancet Oncol 2011). We present our final data from this prospective Phase II study of ibrutinib, rituximab and mini-CHOP in pts ≥75 yrs with newly diagnosed DLBCL. Methods: Pts received six 21-day cycles of ibrutinib 560 mg daily and R-mini-CHOP (Rituximab 375 mg/m2, cyclophosphamide 400 mg/m2, doxorubicin 25 mg/m2, vincristine 1 mg on day 1 & prednisone 40 mg/m2 or 100 mg/d × 5) followed by an additional two 21 day cycles of rituximab + ibrutinib (or high dose methotrexate for CNS prophylaxis). Primary endpoints were deliverability and 2 year overall survival (OS). Sample size calculations were made using a one-sample two-sided approach to detect a 15% improvement on the fixed Peyrade reference OS (59%) and PFS (47%) rates. Results: Eighty pts were recruited from Nov 2015 to Nov 2018. One died prior to receiving treatment and is not included in the analysis. Median age was 82 yrs (75–95); 81% stage III/IV; 54% age adjusted IPI 2–3. With a median follow-up of 35.5 months (m) (0.2, 71.7) (data cut 6 September 2022), there was a non-significant trend towards improvement in 2-year OS of 68% (55.6%, 77.4%) compared to the reference Peyrade cohort of 59% (p = 0.11). Median OS was 72 m (95% CI 35 m to not reached (NR)). Median 2-year PFS of 60.0% (47.7%, 70.3%) was significantly improved compared to the reference cohort of 47% (p = 0.03), with a median PFS of 40 m (95% CI 20.41, NR). Overall response assessment assessed by investigators at the end of treatment was 76% (61/80 pts), with a complete response rate of 70% (56/80 pts). All 6 cycles of R-mini-CHOP were completed in 63/79 pts (80%) and 57/79 pts (71%) completed all 8 cycles of therapy. The median Average Relative Total Dose and Average Relative Dose Intensity for the entire regimen was 97% (IQR 82, 100; 88, 100). 34/79 pts (43%) have died, 17 due to progressive disease and 5 were treatment-related. 67% pts experienced an SAE. Most common AEs were infections and diarrhoea (majority grade 1–2). In the EORTC QLQ-C30 there was an improvement in functional and symptom scales and on the EQ-5D-5L survey, there was a significant improvement in the median health state classification score and median visual analogue scale thermometer score over time. Encore Abstract - previously submitted to EHA 2023 The research was funded by: Janssen-Cilag Pty Ltd. Keywords: Aggressive B-cell non-Hodgkin lymphoma, Combination Therapies Conflicts of interests pertinent to the abstract. E. Verner Research funding: Janssen-Cilag Pty Ltd. E. Hawkes Consultant or advisory role: Janssen-Cilag Pty Ltd. T. Cochrane Consultant or advisory role: Janssen Cilag Pty Ltd. C. Y. Cheah Consultant or advisory role: Janssen-Cilag Pty Ltd. Honoraria: Janssen-Cilag Pty Ltd. M. K. Gandhi Research funding: Janssen-Cilag Pty Ltd. B. E. Butcher Other remuneration: Janssen Cilag Pty Ltd. J. Trotman Research funding: Janssen-Cilag Pty Ltd.

Real-world outcomes with novel therapies in R/R DLBCL.

7552 Background: Outcomes have historically been poor for patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL). Despite an increase in approved R/R DLBCL treatment options, clinical outcomes of these therapies remain less certain. Novel treatments for R/R DLBCL patients include chimeric antigen receptor T-cell (CAR T) therapy, polatuzumab vedotin plus bendamustine and rituximab (pola-BR), tafasitamab plus lenalidomide (tafa-len), loncastuximab (lonca), and selinexor. The objective of this study was to examine real-world outcomes of these novel therapies. Methods: US patient data from the COTA electronic health records database (2010–2021) were used for this retrospective study. Patients had a diagnosis of DLBCL after 1/1/2010, with ≥1 prior line of systemic antineoplastic therapy (including an anti-CD20 antibody), and treatment with any of these novel therapies. Patients receiving variations of pola-BR or tafa-len regimens were included. Outcomes included overall response rate (ORR), complete response (CR) rate, median progression-free survival (mPFS), and median overall survival (mOS). Outcomes were also analyzed for those treated with any novel therapy following prior CAR T exposure. Results: A total of 175 R/R DLBCL patients were included (median age 63 y, 60.6% male, median of 2 prior therapies); 29.1% had an international prognostic index score ≥3, 61.7% had stage III/IV disease, and 65.7% had primary refractory disease. A total of 73, 69, and 27 patients were treated with CAR T, pola-BR, and tafa-len regimens, respectively. Only 6 patients were treated with lonca and no patients received selinexor. Among 169 patients treated in the 2L+ setting with tafa-len, pola-BR, and CAR T, the CR rate was 11.1%, 18.8%, and 52.1%, respectively (Table). A total of 112 patients were treated in the 3L+ setting with CR rate of 10.0%, 13.5%, and 41.8%, for tafa-len, pola-BR, and CAR T, respectively. Outcomes in the 18% of patients treated with any novel agent following CAR T exposure were ORR of 19.1%, CR of 4.8%, and mPFS and mOS of 1.4 mo and 2.3 mo, respectively. Conclusions: Outcomes of pola-BR and tafa-len regimens in the 2L+ and 3L+ R/R DLBCL setting remain suboptimal, with worse outcomes as patients advance through lines of therapy. Outcomes are particularly poor when these agents are used following CAR T therapy. [Table: see text]