Outcome In Diffuse Large B-cell Lymphoma Research Articles

Predicting diffuse large B-cell lymphoma outcomes with lesion-to-liver maximum standardized uptake value for interim-treatment and end-of-treatment positron emission tomography-computed tomography.

18F-fluorodeoxyglucose (18F-FDG) positron emission tomography-computed tomography (PET-CT) has been used in response evaluation systems for malignant lymphomas and is an important tool for determining efficacy and prognosis. The Deauville 5-point scale (D-5PS) is an 18F-FDG PET-CT image-interpretation protocol for patients with lymphoma. Nevertheless, a number of limitations in visual image interpretation, such as interobserver disagreement and the increase of false-positive results, suggests that new parameters are needed. In this study, we aimed to evaluate the prognostic values of interim-treatment (I-) and end-of-treatment (EOT) PET-CT by comparing D-5PS to the semiquantitative lesion-to-liver maximum standardized uptake value ratio (RLL). A total of 90 patients with diffuse large B-cell lymphoma (DLBCL) (45 I-PET and 45 EOT-PET) were analyzed, and the RLL was calculated. Patients were additionally evaluated using the D-5PS system. We determined the optimal cutoff value of RLL using receiver operating characteristic (ROC) analysis. Kaplan-Meier survival analysis was used to compare the outcome predictions, while multivariate Cox regression analysis was used to identify the predictive factors. Among the patients examined, 41 (20 I-PET and 21 EOT-PET) experienced progression, and 49 (25 I-PET, 24 EOT-PET) did not. The optimal cutoff values of the RLL for predicting disease progression were 1.37 for I-PET (sensitivity 75%, specificity 88%) and 2.03 for EOT-PET (sensitivity 45.5%, specificity 100%), while the cutoffs of the D-5PS were scores 4 for I-PET (sensitivity 80%, specificity 72%) and 5 for EOT-PET (sensitivity 40.9%, specificity 100%). The prognostic efficacy was higher for the RLL at interim than for the D-5PS [area under the curve (AUC) =0.848 vs. 0.741]. The EOT prognostic efficacy of both evaluation methods was essentially equivalent (AUC =0.785 vs. 0.725). Univariate and multivariate analyses showed that RLL and D-5PS were independent factors affecting DLBCL outcomes for both interim and EOT assessment. RLL and D-5PS have independent predictive values for the interim and EOT evaluation of outcomes in patients with DLBCL. The RLL has better interim predictive ability than does D-5PS and can optimize D-5PS interpretation, thus improving interim outcome prediction.

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.

An artificial intelligence method using FDG PET to predict treatment outcome in diffuse large B cell lymphoma patients

Convolutional neural networks (CNNs) may improve response prediction in diffuse large B-cell lymphoma (DLBCL). The aim of this study was to investigate the feasibility of a CNN using maximum intensity projection (MIP) images from 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) baseline scans to predict the probability of time-to-progression (TTP) within 2 years and compare it with the International Prognostic Index (IPI), i.e. a clinically used score. 296 DLBCL 18F-FDG PET/CT baseline scans collected from a prospective clinical trial (HOVON-84) were analysed. Cross-validation was performed using coronal and sagittal MIPs. An external dataset (340 DLBCL patients) was used to validate the model. Association between the probabilities, metabolic tumour volume and Dmaxbulk was assessed. Probabilities for PET scans with synthetically removed tumors were also assessed. The CNN provided a 2-year TTP prediction with an area under the curve (AUC) of 0.74, outperforming the IPI-based model (AUC = 0.68). Furthermore, high probabilities (> 0.6) of the original MIPs were considerably decreased after removing the tumours (< 0.4, generally). These findings suggest that MIP-based CNNs are able to predict treatment outcome in DLBCL.

Role of body composition and metabolic parameters extracted from baseline 18F-FDG PET/CT in patients with diffuse large B-cell lymphoma.

This study aimed to clarify the clinical and prognostic role of body composition and metabolic parameters extracted from baseline 18F-FDG PET/CT in patients with diffuse large B-cell lymphoma (DLBCL). We retrospectively collected the clinicopathological and 18F-FDG PET/CT parameters of 181 DLBCL patients. The indexes of skeletal muscle, subcutaneous adipose tissue, and visceral adipose tissue were calculated using the area measured at the 3rd lumbar level normalized for height. Additionally, the metabolic activity of corresponding muscle and adipose tissue, and maximum standardized uptake value (SUVmax), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) of all lesions were measured. Survival endpoints included progression-free survival (PFS) and overall survival (OS). We identified 75 (41.4%) patients with low skeletal muscle index (sarcopenia), presenting risk factors including male, high β2-microglobulin, low BMI, high visceral adipose tissue index, low SUVmax of skeletal muscle, and high SUVmax of visceral adipose tissue. Male, low BMI, low visceral adipose tissue index, and high SUVmax of subcutaneous adipose tissue were risk factors for low subcutaneous adipose tissue index diagnosed in 105 (58.0%) patients. In total, 132 (79.2%) patients represented low visceral adipose tissue index, associated with younger age, B symptoms, and low BMI. Eastern Cooperative Oncology Group (ECOG) status, sarcopenia, and visceral adipose tissue index were found independently predictive of PFS and OS, while β2-microglobulin was independently predictive of OS. In conclusion, body composition indexes were correlated with both clinical characteristics and 18F-FDG PET/CT metabolic parameters, significantly impacting survival, such that sarcopenia and high visceral adipose tissue index were powerful predictors of poor DLBCL outcomes.

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

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

Identification of a novel model based on ferroptosis-related genes for predicting the prognosis of diffuse large B-cell lymphomas

ABSTRACTBackgroundDiffuse large B-cell lymphomas (DLBCLs) are phenotypically and genetically heterogeneous. We aimed to build a ferroptosis-related gene (FRG) prognostic signature to predict the outcome of DLBCLs.MethodsOur study retrospectively investigated the mRNA expression level and clinical data of 604 DLBCL patients from three GEO public datasets. We performed Cox regression analysis to extract the FRGs with prognostic values. ConsensusClusterPlus was used to categorize the DLBCL samples according to gene expression. The least absolute shrinkage and selection operator (LASSO) method and univariate Cox regression were implemented to construct the FRG prognostic signature. The association between the FRG model and clinical characteristics was also investigated.ResultsWe identified 19 FRGs with potential prognostic values and classified the patients into clusters 1 and 2. Cluster 1 showed a shorter overall survival (OS) time than cluster 2. The two clusters had different patterns of infiltrating immune cells. LASSO was used to generate a six-gene risk signature (GCLC, LPCAT3, NFE2L2, ABCC1, SLC1A5, and GOT1), based on which a risk score formula and prognostic model were constructed for predicting the OS of DLBCL patients. Kaplan–Meier survival analysis proved that poorer OS was exhibited in the higher-risk patients stratified by the prognostic model in both the training and test cohorts. In addition, both the decision curve and the calibration plots showed that the nomogram had good agreement between the predicted results and actual observations.ConclusionsWe developed and validated a novel FRG-based prognostic model which could help to predict the outcomes of DLBCL patient.

A novel prognostic index for diffuse large B-cell lymphoma combined baseline metabolic tumour volume with clinical and pathological risk factors.

This study aimed to develop a novel prognostic index integrating baseline metabolic tumour volume (MTV) along with clinical and pathological parameters for diffuse large B-cell lymphoma (DLBCL). This prospective trial enrolled 289 patients with newly diagnosed DLBCL. The predictive value of novel prognostic index was compared with Ann Arbor staging and National Comprehensive Cancer Network International Prognostic Index (NCCN-IPI). We used the concordance index (C-index) and a calibration curve to determine its predictive capacity. Multivariate analysis revealed high MTV (>191 cm 3 ), Ann Arbor stage (III-IV) and MYC/BCL2 double expression lymphoma (DEL) to be independently associated with inferior progression-free survival (PFS) and overall survival (OS). Ann Arbor stage and DEL could be stratified by MTV. Our index, combining MTV with Ann Arbor stage and DEL status, identified four prognostic groups: group 1 (no risk factors,), group 2 (one risk factor), group 3 (two risk factors), and group 4 (three risk factors). The 2-year PFS rates were 85.5, 73.9, 53.6, and 13.9%; 2-year OS rates were 94.6, 87.0, 67.5, and 24.2%, respectively. The C-index values of the novel index were 0.697 and 0.753 for PFS and OS prediction, which was superior to Ann Arbor stage and NCCN-IPI. The novel index including tumour burden and clinicopathological features may help predict outcome of DLBCL (clinicaltrials.gov identifier: NCT02928861).

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.

Abstract 5557: Patterns of oncogene co-expression at single cell resolution influence survival in diffuse large B-cell lymphoma

Abstract Background: Cancers often overexpress multiple clinically relevant oncogenes. However, it is not known if multiple oncogenes within a cancer combineuniquely in specific cellular sub-populations to influence clinical outcome.We studied this phenomenon using the prognostically relevantoncogenes MYC, BCL2 and BCL6 in Diffuse Large B-Cell Lymphoma(DLBCL). Methods: Quantitative multispectral imaging simultaneously measured oncogene co-expression at single-cell resolution in reactive lymphoid tissue (n=12)and four independent cohorts (n=409) of DLBCL. Mathematically derived co-expression phenotypes were evaluated in DLBCLs with immunohistochemistry (n=316) and nine DLBCL cohorts with gene expression data (n=3974). Bulk and single-cell RNA sequencing was performed on patient-derived B-cells with induced co-expression of MYC,BCL2 and BCL6. Results: Unlike in non-malignant lymphoid tissue where the co-expression of MYC, BCL2 and BCL6 in a B-cell is limited, DLBCLs show multiple permutations of oncogenic co-expression in malignant B-cells. The percentage of cells with a unique combination MYC+BCL2+BCL6-(M+2+6-) consistently predicts survival in contrast to that of other combinations (including M+2+6+). An estimated percentage of M+2+6-cells can be derived from any quantitative measurement of the component individual oncogenes, and correlates with survival in immunohistochemistry and gene expression datasets. Comparative transcriptomic analysis of DLBCLs and transformed patient-derived B-cells identifies cyclin D2 (CCND2) as a potential BCL6-repressedregulator of proliferation in the M+2+6- population. Conclusions: Unique patterns of oncogene co-expression at single-cell resolution affect clinical outcomes in DLBCL. Similar analyses evaluating oncogenic combinations at the cellular level may impact diagnostics and target discovery in other cancers. Citation Format: Michal M. Hoppe, Patrick Jaynes, Shuangyi Fan, Yanfen Peng, Shruti Sridhar, Phuong Mai Hoang, Xin Liu, Sanjay de Mel, Limei Poon, Esther Chan, Joanne Lee, Choon Kiat Ong, Tiffany Tang, Soon Thye Lim, Chandramouli Nagarajan, Nicholas F. Grigoropoulos, Soo-Yong Tan, Susan Swee-Shan Hue, Sheng-Tsung Chang, Shih-Sung Chuang, Shaoying Li, Joseph D. Khoury, Hyungwon Choi, Pedro Farinha, Anja Mottok, David W. Scott, Carl Harris, Alessia Bottos, Gayatri Kumar, Kasthuri Kannan, Laura J. Gay, Hendrik F. Runge, Ilias Moutsopoulos, Irina Mohorianu, Daniel J. Hodson, Yen-Chee Lin, Wee-Joo Chng, Siok-Bian Ng, Claudio Tripodo, Anand D. Jeyasekharan. Patterns of oncogene co-expression at single cell resolution influence survival in diffuse large B-cell lymphoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5557.

Gene expression profiling and FDG-PET radiomics uncover radiometabolic signatures associated with outcome in DLBCL.

Emerging evidence indicates that chemoresistance is closely related to altered metabolism in cancer. Here, we hypothesized that distinct metabolic gene expression profiling (GEP) signatures might be correlated with outcome and with specific fluorodeoxyglucose positron emission tomography (FDG-PET) radiomic profiles in diffuse large B-cell lymphoma (DLBCL). We retrospectively analyzed a discovery cohort of 48 consecutive patients with DLBCL treated at our center with standard first-line chemoimmunotherapy by performing targeted GEP (T-GEP)- and FDG-PET radiomic analyses on the same target lesions at baseline. T-GEP-based metabolic profiling identified a 6-gene signature independently associated with outcomes in univariate and multivariate analyses. This signature included genes regulating mitochondrial oxidative metabolism (SCL25A1, PDK4, PDPR) that were upregulated and was inversely associated with genes involved in hypoxia and glycolysis (MAP2K1, HIF1A, GBE1) that were downregulated. These data were validated in 2 large publicly available cohorts. By integrating FDG-PET radiomics and T-GEP, we identified a radiometabolic signature (RadSig) including 4 radiomic features (histo kurtosis, histo energy, shape sphericity, and neighboring gray level dependence matrix contrast), significantly associated with the metabolic GEP-based signature (r= 0.43, P= .0027) and with progression-free survival (P= .028). These results were confirmed using different target lesions, an alternative segmentation method, and were validated in an independent cohort of 64 patients. RadSig retained independent prognostic value in relation to the International Prognostic Index score and metabolic tumor volume (MTV). Integration of RadSig and MTV further refined prognostic stratification. This study provides the proof of principle for the use of FDG-PET radiomics as a tool for noninvasive assessment of cancer metabolism and prognostic stratification in DLBCL.

Lenalidomide maintenance fails to overcome the unfavourable prognosis of low NK-cell counts in rituximab-chemotherapy responsive elderly DLBCL patients: A LYSA group study.

Low baseline NK-cell counts (NKCCs) in patients with diffuse large B-cell lymphoma (DLBCL) are associated with a poor prognosis. The REMARC phase III trial (NCT01122472) showed that lenalidomide maintenance prolonged PFS in rituximab-chemotherapy responders. We conducted a REMARC ancillary study analysing the impact of lenalidomide maintenance on the prognostic value of low NKCCs. Blood samples from 335 elderly French patients enrolled in the REMARC trial were analysed by flow cytometry to obtain NKCCs at diagnosis (n = 220), at randomization (n = 186) and/or six months after randomization (n = 184). Baseline NKCCs < 100 cells/μl were associated with shorter PFS and OS (HRs=[2.2 (1.4, 3.3), p < 0.001] and [2.8 (1.7, 4.5), p < 0.001], respectively), independently of aaIPI. In a competing risk analysis, low NKCCs at baseline were associated with a higher risk of relapse/progression (p=0.0025), but not of death without progression (p=0.33). Lenalidomide did not affect the prognosis value of low baseline NKCCs (p =0.6349). Similar results were obtained for low NKCCs at randomization. Our results demonstrate that low NKCCs at baseline and post rituximab-chemotherapy are robust prognostic factors in DLBCL and reveal that lenalidomide has no impact on this parameter. Other therapeutic strategies aiming at improving NK-cell function could improve outcomes in DLBCL.

Characteristics and Outcomes of Alberta Lymphoma Patients with a History of Immunosuppressive therapy for Autoimmune Conditions.

Other iatrogenic immunosuppression associated lymphoproliferative disorders (Oii-LPD) is rare subset of lymphoma. There are limited published data on the clinical characteristics and outcomes of this patient population. The primary objective of this study was to describe the clinical characteristics and outcomes of Alberta patients diagnosed with lymphoma following immunosuppressive therapy for autoimmune conditions. Secondary objectives included describing the incidence of Oii-LPD, proportions of subtypes of lymphoma diagnosed and the nature of immunosuppressants used. The outcomes of patients with iatrogenic immunodeficiency-associated diffuse large B cell lymphoma (DLBCL) were compared against a matched control group of patients with de novo DLBCL. The study is a descriptive retrospective cohort study with a matched historical control comparison for patients with DLBCL. Alberta lymphoma patients, diagnosed from January 2011 to December 2019, with a history of iatrogenic immunosuppression were identified and described. The incidence of Oii-LPD was 1% of total Alberta lymphoma cases. Majority of this cohort were diagnosed with DLBCL (54.9%) and the most common immunosuppressive agents were methotrexate (62%), hydroxychloroquine (42%), and TNF inhibitors (31%). Survival was not different between Oii-LPD DLBCL and de novo DLBCL with 5-year survival rates of 64.1% and 67%, respectively (HR 1.11 [95% CI, 0.64-1.94]). Oii-LPD are rare with the most frequent subtype being DLBCL occurring in the setting of methotrexate use. In this population-based analysis, the outcomes of iatrogenic immunodeficiency-associated DLBCL were not significantly different from those of de novo DLBCL patients.

MRD Status By Clonoseq ® Is a Poor Predictor of Long-Term Outcomes after Bispecific LV20.19 CAR T-Cell Therapy for Relapsed, Refractory B-Cell NHL

INTRODUCTION: The clonoSEQ® Assay (Adaptive Biotechnologies Corporation, Seattle, USA) uses next-generation sequencing (NGS) based testing to identify disease-specific immunoglobulin sequences and detect evidence of minimal residual disease (MRD). MRD assessments have been shown to predict progression-free survival and overall survival in non-Hodgkin's lymphoma (NHL) patients. We report MRD results via the commercially available clonoSEQ® assay and its association with durability of response in patients treated with bispecific LV20.19 CAR in our phase 1/2 trial (NCT04186520). METHODS: We conducted a phase 1/2 single-center prospective trial (NCT04186520) to evaluate the efficacy and safety of LV20.19 CAR T-cells in patients with NHL at 2.5x106 cells/kg dose. LV20.19 CAR T-cells were manufactured onsite at varying lengths of manufacturing (8 vs 12 days) in the CliniMACS Prodigy device with IL7+15 for cell expansion, with the goal of fresh infusion. The commercial clonoSEQ® assay (by Adaptive Biotechnologies) was used to identify and track tumor clonotypes in responding patients at first assessment performed between Day 28-60. We evaluated associations between MRD status and long-term response post LV20.19 CAR-T cell therapy. Descriptive statistics were utilized for baseline characteristics. Survival analyses were calculated utilizing the Kaplan-Meier method and differences between groups were evaluated via the log-rank test. RESULTS: Among the 32 patients enrolled in the trial, there were 26 responders on Day 28. Of these responders, 23 patients had clonoSEQ® B-cell MRD assay done between Day 28-60 post CAR infusion (Table 1). MRD was performed in 11 patients with Diffuse Large B-cell Lymphoma (DLBCL), 3 patients with Follicular lymphoma (FL), and 9 patients with Mantle Cell Lymphoma (MCL). The median age was 64 years (45-74) and the median lines of prior therapy were 4 (2-11). Of the 23 patients with early MRD status available, the day 28 objective response rate (ORR) was 100% (complete response=57%, n=13 and partial response=43%, n=10). Eighteen patients (78%) were MRD negative at first assessment between days 28-60 and 5 (22%) were MRD positive. Of the 5 patients who were MRD positive, 3 became MRD negative at day 90, 1 patient was non-evaluable due to a non-relapse mortality event, and the remaining patient remains positive but with decreasing MRD status at Day 90. None of the patients with MRD positivity at day 28 have relapsed to date. Among patients who achieved early MRD negativity (n=18), 7 (39%) have relapsed, and all were patients with either DLBCL or FL. No MRD-negative MCL patient has relapsed to date. The duration of response in MRD-negative patients was significantly improved in MCL patients compared to DLBCL/FL patients (Figure 1), p=0.02. Among the 7 MRD negative patients who relapsed, only 1 patient was detected to have disease relapse by MRD positivity, 2 were detected simultaneously on MRD testing and imaging, while 3 were detected by physical exam or imaging findings and did not have MRD testing. Interestingly, 1 patient had a central nervous system relapse while being MRD negative. CONCLUSION: Relapse after CAR T-cell therapy remains a significant clinical challenge. New predictors are indicated to determine which responding patients after CAR-T cell therapy are more likely to relapse. Utilizing the commercially available Adaptive clonoSEQ® assay, early MRD assessment was not predictive of long-term clinical outcomes in DLBCL and FL. MRD positive patients maintained durable remission and converted to MRD negativity, while early MRD negative patients continued to relapse. In contrast, MRD negativity post-CAR-T therapy did appear to predict durable clinical remission in MCL patients. Newer assays, including cell-free technologies, may be more informative for non-MCL histologies. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Disparities in Outcomes of Diffuse Large B Cell Lymphoma in Adolescent and Young Adults: A SEER Database Analysis

Background Diffuse large B-cell lymphoma (DLBCL) is the second most common lymphoid malignancy in the adolescent and young adults (AYA) age group defined as young people between 15 to 39 years of age (Blum et al, BJH, 2018) and AYA patients with DLBCL have better 5-year(yr) relative survival than adult patients with DLBCL. While outcomes of DLBCL in the United States have improved significantly over the years, significant racial disparities remain. Black patients with DLBCL present at younger age, more advanced stage, and have inferior survival (Shenoy et al, Cancer, 2011). We sought to determine whether similar racial disparities exist in AYA-DLBCL and analyze the specific factors associated with survival disparities in this population. Methods The surveillance, epidemiology and end-result (SEER) registry 2019 research plus database was utilized to assess the survival outcomes and predictors of survival in AYA population diagnosed with DLBCL non-specified (NOS). Log-rank cox proportional hazards regression was used to analyze factors associated with the survival. Both univariate and multivariate analysis were performed. All analysis were adjusted to confounding factors. Wilcoxon rank sum test, Pearson chi square test were used to compare baseline characteristics. RStudio 2022.02.3+492 was used and a two-sided p-value <0.05 was considered significant. Results A total of 9312 AYA-DLBCL patients were identified in the SEER database between 2000-2019. Baseline characteristics were as follows- gender: male 60%, female 40%; age distribution: 15yr-19yr 8%, 20-24yr 13%, 25-29yr 18%, 30-34yr 25%, 35-39yr 35%; race distribution: white 73%, black 15%, Asian/Pacific Islander 10%, American Indian/Alaskan native 0.6%, unknown 1.1%; disease stage: I 1.2%, II 2.1%, III 2.9%, IV 3.7, unknown 90.2%. In the entire cohort, 89% patients received systemic therapy, 26.8% received RT and 11% received no therapy. Compared to other races, black patients were more likely to be men (63% vs 59%, p=0.02) and belong to low-income families (p<0.001). While a higher percentage of black patients presented with advanced stage (III/IV) disease (54% vs 44.8%), this finding was not statistically significant (p=0.14) due to lack of staging data in a majority of the cohort (90%). Notably, black patients were less likely to receive chemotherapy than other races (83% vs 88%, p<0.001). (See table 1 for baseline characteristics) The 5-year overall survival (OS) was 78.5% in the entire cohort. Black patients had an inferior 5-year OS compared to other races (66.6% vs 80.7%, p< 0.001) (Figure 1). Older age (p<0.0001), male gender (p<0.0001), lower household income (p<0.0001) and omitting systemic chemotherapy (p<0.0001) were also associated with inferior 5-year OS. Black patients were more likely to die from DLBCL compared to other races (HR 1.94, SE 0.51, 95% CI 1.75-2.14, P<0.001). On multivariate analysis, the difference in survival between black patients and other races remained significant even after adjusting for age, gender, stage of disease, household family income and receipt of chemotherapy. Impact of year of diagnosis on outcomes and racial disparities is currently being analyzed and will be reported at the meeting. Conclusion Black AYA-DLBCL patients had higher mortality and inferior 5-year overall survival compared to other races. The outcome disparities in black patients persisted even after adjusting for age, gender, stage, household family income, and receipt of chemotherapy. Further studies should examine differences in disease biology and other socioeconomic factors such as access to transportation, health insurance, level of healthcare education and others that may underlie the observed racial differences in presentation and outcome. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Risk Stratification of Diffuse Large B-Cell Lymphoma Based on Cell Surface Markers Using Flow Cytometry

Background: Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of malignant lymphoma. Approximately 80% of patients with DLBCL can achieve remission with chemotherapy. However, the prognosis of relapsed and refractory patients is poor. The International Prognostic Index (IPI) is the most widely used prognostic score for non-Hodgkin lymphoma, but it cannot accurately identify a high-risk population for DLBCL. Although gene expression profiles and genomic classifications are other useful tools for predicting outcomes, they are rarely performed in clinical practice. Some antigens, such as CD5 and CD43, have been reported to negatively predict the outcome of DLBCL, while expression of CD10 may have a better prognosis. Most previous studies have been based on immunohistochemistry, in which discordant judgment may occur. Using multicolor flow cytometry, the expression of antigens on lymphoma cells can undoubtedly be documented and surface markers and their combinations may be able to predict prognosis. The present study aimed to develop a new predictive model based on cell surface markers expressed on DLBCL cells. Methods: Baseline cell surface markers data of the newly diagnosed DLBCL patients enrolled in the present study were analyzed by flow cytometry. The expressions of CD5, CD10, CD19, CD20, CD21, CD22, CD23, CD25, CD38, CD40, CD43, CD44, CD200, and HLA-DR, which are routinely analyzed at our hospital, were obtained for all patients. As the primary endpoint was to determine the 2-year progression-free survival rate (PFS), we applied a decision tree methodology to define which of the abovementioned markers were significant clinical predictors of PFS and established a new cell surface marker-based prognostic score. Based on this analysis, we stratified the patients into good, intermediate, and poor prognosis groups. Survival outcomes for the three groups were estimated using the Kaplan-Meier method and the hazard ratio (HR) and 95% confidence interval (CI) from multivariate Cox regression, considering IPI as a covariate. In addition, the sensitivity and specificity of the new score combined with the IPI score was compared to that of the IPI score alone using the area under the curve (AUC) of receiver operating characteristic (ROC) curves. Results: A total of 139 patients with DLBCL were included. The median age at diagnosis was 71 years (range 33-97), and 53% of the patients were male. Regarding IPI scores, 28 patients were in the low-risk group, 28 in the low-intermediate-risk group, 37 in the high-intermediate-risk group, and 46 in the high-risk group. The decision tree method indicated CD5, CD10, CD21, CD43, and HLA-DR as significant predictive variables for 2-year PFS (Figure 1A). The good (51 patients), intermediate (33 patients), and poor (55 patients) prognosis groups identified based on the new score showed a 2-year PFS of 84.5% (95%CI: 70.2-92.3%), 56.3% (95%CI: 37.6-71.4%), and 40.4% (95%CI: 27.0-53.4%), respectively (Figure 1B). The adjusted HR for 2-year PFS was 3.17 (95%CI: 1.27-7.87, P = 0.013) in the intermediate prognosis group and 4.51 (95%CI: 1.97-10.3, P < 0.001) in the poor prognosis group, when compared to the good prognosis group. The ROC analysis showed that adding the new score to the IPI score significantly improved the predictive accuracy of the 2-year PFS from an AUC of 0.688 to 0.767 (P = 0.020). Conclusion: The new cell surface marker-based risk score for DLBCL patients established here is more useful for predicting the 2-year PFS than the IPI score alone. Further external validation is required to increase the prognostic accuracy of this new score. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Degree of stemness predicts micro-environmental response and clinical outcomes of diffuse large B-cell lymphoma and identifies a potential targeted therapy.

Some cells within a diffuse large B-cell lymphoma (DLBCL) have the genotype of a stem cell, the proportion of which is termed degree of stemness. We interrogated correlations between the degree of stemness with immune and stromal cell scores and clinical outcomes in persons with DLBCL. We evaluated gene expression data on 1,398 subjects from Gene Expression Omnibus to calculate the degree of stemness. Subjects were classified into low- and high-stemness cohorts based on restricted cubic spline plots. Weighted gene co-expression network analysis (WGCNA) was used to screen for stemness-related genes. Immune and stromal scores correlated with the degree of stemness (both P < 0.001). A high degree of stemness correlated with a shorter progression-free survival (PFS; Hazard Ratio [HR; 95% Confidence Interval [CI] =1.90 (1.37, 2.64; P < 0.001) and a shorter survival (HR = 2.29 (1.53, 3.44; P < 0.001). CDC7 expression correlated with the degree of stemness, and CDC7-inhibitors significantly increased apoptosis (P < 0.01), the proportion of cells in G1 phase (P < 0.01), and inhibited lymphoma growth in a mice xenograft model (P = 0.04). Our data indicate correlations between the degree of stemness, immune and stromal scores, PFS, and survival. These data will improve the prediction of therapy outcomes in DLBCL and suggest potential new therapies.

Extra copy number of BCL2 is correlated with increased BCL-2 protein expression and poor survival in diffuse large B-cell lymphoma treated with chemoimmunotherapy

The clinical significance of extra copy (EC) genotypes of BCL2, MYC, and BCL6 have not been fully elucidated. We evaluated the EC and translocation statuses of BCL2, MYC, and BCL6 in 190 diffuse large B-cell lymphoma (DLBCL) cases using fluorescence in situ hybridization. EC genotype was sub-classified according to copy number-gained tumor cell ratio (EC1, >20% but ≤50%; EC2, >50%). Only the BCL2-EC groups, not MYC-EC or BCL6-EC groups, displayed significantly increased immunoreactivity of the corresponding protein. Moreover, the BCL2-EC2 group was significantly associated with poor overall survival (OS) and progression-free survival (PFS) in a 147 R-CHOP-treated patient subset, which was also statistically significant as per the multivariate survival analysis for PFS. No significant differences in the survival of MYC, BCL6, concurrent BCL2/MYC, BCL6/MYC, BCL2/BCL6, or triple EC groups were observed. BCL2-EC may contribute to increased BCL-2 protein expression and serve as a predictor of treatment outcomes in DLBCL.

P1180: ARE EXTRANODAL LIMITED-STAGE DIFFUSE LARGE B-CELL LYMPHOMA MORE AGRESSIVE THAN NODAL FORMS?

Background: Limited-stage diffuse large B-cell lymphoma (DLBCL) is associated with favourable outcomes with overall survival of 70-80% at 10 years. Stage-modified IPI (sm-IPI) predicts the risk of relapse and death based on clinical factors that do not include extranodal (EN) involvement, although in some studies it has been associated with worse outcomes. Aims: To analyse the characteristics and outcomes of limited-stage DLBCL in a single center series and evaluate the prognostic impact of EN involvement. Methods: We conducted a retrospective analysis of consecutive patients with newly diagnosed stage I-II DLBCL treated with curative intent at a single centre from 2015 to 2019. Primary central nervous system (CNS) lymphoma, primary testicular lymphoma, primary mediastinal B-cell lymphoma and transformed lymphoma were excluded. Response to therapy was assessed according to Lugano criteria. Overall (OS) and progression free survival (PFS) were calculated by Kaplan-Meier method and comparisons done by the log rank test. Cumulative incidence of relapse was calculated using competing risk models and Gray test for group comparisons. Cox regression was used to identify prognostic factors for PFS. Results: Of 152 patients identified, 53 (35%) had EN disease and 99 (65%) were nodal (N). The most common EN sites were stomach (30%), sinus/nasal cavity (13%), skin and soft tissue (9%) and breast (9%). Seventy-two (47%) had low risk sm-IPI (45 N; 27 EN). Clinical characteristics were similar between both groups, except for stage (stage I in 50.9% of EN vs 32.3% of N cases) and bulky disease (EN 15.1% vs N 37.4%). All patients received R-CHOP (median 6 cycles; range 1-8). Eight patients, all with EN involvement (3 sinus/nasal cavity, 2 breast, 2 bone and 1 orbit), received CNS prophylaxis. Seventeen out of 152 patients received additional radiotherapy (RT), 71% of whom had nodal involvement; 16/17 were irradiated due to bulky disease and/or treatment with abbreviated immunochemotherapy. Globally, 89% patients had a complete response (CR) to treatment: 85% in the N and 96% in the EN group (p=0.212). Nine patients relapsed at a median of 18 (7-52) months after obtaining CR (6 from the N and 3 from the EN group). The 4-year cumulative incidence of relapse was similar: 11.2% (95%CI 9.0-13.9%) in EN and 6.7% (95%CI 5.9-7.5%) in N group (p=0.778). No gastric lymphomas relapsed. The most common sites of relapse were lymph nodes (3), soft tissue (3) and CNS (2). Nineteen (14 N; 5 EN) patients died at a median of 12 (0-47) months after starting treatment, mostly (52.6%) due to lymphoma progression. With a median follow-up of 43 months, 4-year OS and PFS were 87% and 82%, respectively. No significant survival differences were observed in patients with N or EN presentation with a 4-year PFS of 81.8% and 81.3% (p=0.428), respectively. On multivariable analysis adjusting for RT, sm-IPI and bulky disease, EN involvement was not associated with a decreased PFS compared with N involvement (HR 0.77; 95%CI 0.31-1.90; p=0.570). Image:Summary/Conclusion: Our study corroborates the very favourable outcomes of localized DLBCL. We could not find differences in PFS according to N and EN presentations when controlling for other prognostic factors. These results do not support different treatment strategies for EN disease; however, due to limited sample size the role of RT and the prognostic impact of specific locations cannot be fully ascertained.

Impact of equal access by race and ethnicity on patients in the Veterans Health Administration (VHA) treated for diffuse large B-cell lymphoma (DLBCL).

6526 Background: Racial and ethnic disparities in access to care and outcomes are well-established and are critical issues across several malignancies, including DLBCL. Previous studies from national registry datasets have shown racial disparities in DLBCL disease characteristics, treatment and outcomes. The VHA is an equal access system providing a unique environment to investigate cancer disparities across the disease continuum. Methods: This is a retrospective chart review of 4033 randomly selected patients with an ICD code for lymphoma treated within the VHA between 01/01/2011 and 12/31/2017. Data abstractors collected baseline patient and disease characteristics and treatment responses for those with an initial diagnosis of DLBCL in that time frame. Survival time was determined via electronic health record query on 11/30/2021. Chi-square tests were used to analyze relationship between race and variables of interest. Cox proportional hazards model was used to estimate hazard ratios (HR) for race and controlling factors. Results: 2141 DLBCL patients met our inclusion criteria. 97% were male. Majority were Non-Hispanic Whites (NHW 75%) followed by Non-Hispanic Blacks (NHB 12.5%), Hispanics (H 5.7%) and others (O 6.8%). NHB were diagnosed at younger median age (63 years) when compared to the NHW, H and O (68 years). There was no statistically significant difference in stage at diagnosis, IPI score, cell of origin (COO) and hit status amongst racial subgroups. Outcomes analysis (Table) revealed similar treatment and response rates, median OS, 1- and 2- year survival across all racial subgroups. However, after adjusting for age, IPI, COO, and exposure to agent orange, and including up to 10-years of survival data, H had 36% lower risk of death (HR=0.64, 95% CI 0.44-0.93) than NHW, while NHB and O had similar outcomes to NHW. Conclusions: This large retrospective study is a continuation of our group’s work (Williams et al, 2020) that doubles the cohort size and confirms that when standard of care therapy is given with equal access to care, short-term treatment and survival outcomes are same for all races. Further studies are needed to analyze risk factors associated with differences in long term outcomes.[Table: see text]

Ki67 Immunohistochemical Expression Level ≥70%, Bulky Presentation ≥7.5 cm, Meningeal Lymphomatosis, and Interim PET ΔSUVmax After 4 Treatment Cycles

Currently, prognostic models in diffuse large B-cell lymphoma (DLBCL) fail to closely reflect patients' biological, clinical, and survival heterogeneity. We, therefore, assessed the impact of clinical, biological, immunohistochemical (IHC), baseline (0), and interim (after 2 and 4 treatment cycles) PET (PET0, PET2, and PET4) data not yet included in any scoring system on DLBCL outcome. The analysis was conducted on 89 previously untreated adult patients of the Finistere Observatory Cohort (O.Ly.Fin) with documented DLBCL, recruited between January 2010 and December 2017, with progression-free survival (PFS) and overall survival (OS) as primary and secondary endpoints, respectively. Seventy-eight patients were treated with rituximab, cyclophosphamide, hydroxyadriamycin, vincristine, and prednisone (R-CHOP), while 11 received R-dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, and hydroxyadriamycin (EPOCH). Patients were followed up until June 20, 2020. On multivariate analysis, Ki67 ≥ 70% on IHC (K), bulky presentation ≥7.5 cm (B), meningeal lymphomatosis (M), and PET0-PET4 ΔSUVmax <71% (P4) were identified as strong independent predictors of PFS, and all variables but bulky disease also strongly and independently predicted OS. Using these 4 parameters, we designed a scoring model named KBMP4 stratifying patients into low- (0 parameter), intermediate- (1 or 2), and high-risk (≥3) subgroups by the Kaplan-Meier analysis. At a median follow-up of 43 months, PFS and OS were both 100% in the low-risk subgroup, 71.4 and 90.5%, respectively, in the intermediate-risk subgroup, and 0 and 55.5%, respectively, in the high-risk subgroup. Use of the KBMP4 model in clinical practice may improve accuracy in prognostic prediction and treatment decisions in de novo DLBCL patients.