scholarly journals An NCCN-IPI based immune-related gene prognostic model for diffuse large B-cell lymphoma

2021 ◽  
Author(s):  
Shidai Mu ◽  
Deyao Shi ◽  
Lisha Ai ◽  
Fengjuan Fan ◽  
Fei Peng ◽  
...  
Keyword(s):  
Gene Expression ◽  
B Cell ◽  
Prognostic Model ◽  
Cell Lymphoma ◽  
International Prognostic Index ◽  
Prognostic Significance ◽  
B Cell Lymphoma ◽  
Large B Cell Lymphoma ◽  
Risk Patients ◽  
Large B Cell

AbstractBackgroundAn enhanced International Prognostic Index (NCCN-IPI) was built to better discriminate diffuse large B-cell lymphoma (DLBCL) patients in the rituximab era. However, there is an urgent need to identify novel valuable biomarkers in the context of targeted therapies, such as immune checkpoint blockade (ICB) therapy.MethodsGene expression data and clinical information were obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets. 73 immune-related hub genes in DLBCL patients with different IPI levels were identified by weighted gene co-expression network analysis (WGCNA), and 4 genes were selected to construct an IPI-based immune-related prognostic model (IPI-IPM). Afterward, the genetic, somatic mutational and molecular profiles of IPI-IPM subgroups were analyzed, as well as the potential clinical response of ICB in different IPI-IPM subgroups.ResultsThe IPI-IPM was constructed base on the expression of LCN2, CD5L, NLRP11 and SERPINB2, where high-risk patients had shorter overall survival (OS) than low-risk patients, consistent with the results in the GEO cohorts. The comprehensive results showed that a high IPI-IPM risk score was correlated with immune-related signaling pathways, high KMT2D and CD79B mutation rates, high infiltration of CD8+ T cells and macrophages (M1, M2), as well as up-regulation of inhibitory immune checkpoints including PD-L1, LAG3 and BTLA, indicating more potential response to ICB therapy.ConclusionThe IPI-IPM has independent prognostic significance for DLBCL patients, which provides an immunological perspective to elucidate the mechanisms on tumor progression and drug resistance, also sheds a light on developing immunotherapy for DLBCL.

scholarly journals A new biologic prognostic model based on immunohistochemistry predicts survival in patients with diffuse large B-cell lymphoma

Blood ◽  
2012 ◽  
Vol 120 (11) ◽  
pp. 2290-2296 ◽  
Author(s):  
Anamarija M. Perry ◽  
Teresa M. Cardesa-Salzmann ◽  
Paul N. Meyer ◽  
Luis Colomo ◽  
Lynette M. Smith ◽  
...  
Keyword(s):  
Gene Expression ◽  
B Cell ◽  
Expression Profiling ◽  
Prognostic Model ◽  
Cell Lymphoma ◽  
International Prognostic Index ◽  
Prognostic Index ◽  
B Cell Lymphoma ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Abstract Biologic factors that predict the survival of patients with a diffuse large B-cell lymphoma, such as cell of origin and stromal signatures, have been discovered by gene expression profiling. We attempted to simulate these gene expression profiling findings and create a new biologic prognostic model based on immunohistochemistry. We studied 199 patients (125 in the training set, 74 in the validation set) with de novo diffuse large B-cell lymphoma treated with rituximab and CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) or CHOP-like therapies, and immunohistochemical stains were performed on paraffin-embedded tissue microarrays. In the model, 1 point was awarded for each adverse prognostic factor: nongerminal center B cell–like subtype, SPARC (secreted protein, acidic, and rich in cysteine) < 5%, and microvascular density quartile 4. The model using these 3 biologic markers was highly predictive of overall survival and event-free survival in multivariate analysis after adjusting for the International Prognostic Index in both the training and validation sets. This new model delineates 2 groups of patients, 1 with a low biologic score (0-1) and good survival and the other with a high score (2-3) and poor survival. This new biologic prognostic model could be used with the International Prognostic Index to stratify patients for novel or risk-adapted therapies.

Expression of a single gene, BCL-6, strongly predicts survival in patients with diffuse large B-cell lymphoma

Blood ◽  
2001 ◽  
Vol 98 (4) ◽  
pp. 945-951 ◽  
Author(s):  
Izidore S. Lossos ◽  
Carol D. Jones ◽  
Roger Warnke ◽  
Yasodha Natkunam ◽  
Herbert Kaizer ◽  
...  
Keyword(s):  
Gene Expression ◽  
B Cell ◽  
Mrna Expression ◽  
Cell Lymphoma ◽  
International Prognostic Index ◽  
Prognostic Significance ◽  
Prognostic Index ◽  
B Cell Lymphoma ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Diffuse large B-cell lymphoma (DLBCL) is characterized by a marked degree of morphologic and clinical heterogeneity. Establishment of parameters that can predict outcome could help to identify patients who may benefit from risk-adjusted therapies. BCL-6 is a proto-oncogene commonly implicated in DLBCL pathogenesis. A real-time reverse transcription–polymerase chain reaction assay was established for accurate and reproducible determination of BCL-6 mRNA expression. The method was applied to evaluate the prognostic significance ofBCL-6 expression in DLBCL. BCL-6 mRNA expression was assessed in tumor specimens obtained at the time of diagnosis from 22 patients with primary DLBCL. All patients were subsequently treated with anthracycline-based chemotherapy regimens. These patients could be divided into 2 DLBCL subgroups, one with high BCL-6 gene expression whose median overall survival (OS) time was 171 months and the other with low BCL-6 gene expression whose median OS was 24 months (P = .007). BCL-6 gene expression also predicted OS in an independent validation set of 39 patients with primary DLBCL (P = .01). BCL-6 protein expression, assessed by immunohistochemistry, also predicted longer OS in patients with DLBCL. BCL-6 gene expression was an independent survival predicting factor in multivariate analysis together with the elements of the International Prognostic Index (IPI) (P = .038). By contrast, the aggregate IPI score did not add further prognostic information to the patients' stratification byBCL-6 gene expression. High BCL-6 mRNA expression should be considered a new favorable prognostic factor in DLBCL and should be used in the stratification and the design of risk-adjusted therapies for patients with DLBCL.

Gene Expression Profile Associated with Survival in Patients with Diffuse Large B-Cell Lymphoma Treated by Chemotherapy and Rituximab.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 159-159
Author(s):  
Karen Leroy ◽  
Jean-Philippe Jais ◽  
Corinne Haioun ◽  
David Rickman ◽  
Aurelien de Reynies ◽  
...  
Keyword(s):  
Gene Expression ◽  
B Cell ◽  
Treatment Regimen ◽  
Clinical Characteristics ◽  
Cell Lymphoma ◽  
International Prognostic Index ◽  
Prognostic Significance ◽  
B Cell Lymphoma ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Abstract Molecular profiles have been shown to correlate with survival in patients with diffuse large B-cell lymphoma (DLBCL) receiving conventional chemotherapy. However, most patients now receive monoclonal anti-CD20 antibodies in addition to chemotherapy, which might erase the poor prognosis associated with some markers (Mounier et al, Blood2003;101:4279) and reveal new prognostic factors related to rituximab mechanisms of action. This prompted us to undertake a gene expression study on the samples of patients (pts) included in the GELA LNH98-5 study that compared CHOP and rituximab-CHOP (R-CHOP) regimen. We collected all available frozen tissue samples from patients included into the LNH98-5 trial and completed the series with patients treated with the same regimens in participating centers during the same period. All those patients were between 60 and 80 years old, had histologically reviewed DLBCL, Ann Arbor stage II to IV disease and an ECOG Performance Status ≤3. High quality RNA from 53 patient (43 from the study itself and 10 from the additional cohort) treated with CHOP (30 pts) or R-CHOP (23 pts) were analyzed with Affymetrix HU133A micro-arrays. The main clinical characteristics of this subset of patients were similar to that of the remaining group of 346 patients involved in the LNH98-5 study. Two parameters were strongly correlated with disease progression: a high International Prognostic Index (IPI = 4 or 5) (relative risk (RR) 3.9 when compared to pts with an IPI = 2 or 3, p=0.002) and treatment regimen (CHOP: RR 4.2 when compared to R-CHOP, p=0.001). In both treatment arms, patients with a germinal center (GC) DLBCL profile had a better outcome than patients with an activated B-cell (ABC) one (ABC versus GC, RR of progression 2.6, p=0.06) and several transcripts previously associated with prognosis, such as BCL6, showed a strong correlation with survival (BCL6 low versus BCL6 high, RR of progression 3.1, p=0.004), further corroborating the clinical relevance of this series of patients. We then used Cox models adjusted for IPI and treatment regimen to test the association with outcome of each Affymetrix microarray probeset 1) in the entire population, 2) or with a differential effect according to the treatment regimen.This strategy allowed us to identify several transcripts that were highly correlated with survival, either in both groups or specifically in the R-CHOP group. Interestingly, some of these transcripts are related to apoptosis regulation, immune cell infiltration or B-cell signal transduction. We are currently investigating the prognostic significance of this series of transcripts, using Quantitative RT-PCR, in an independent set of 43 DLBCL patients who presented the same clinical characteristics than the initial test group and received R-CHOP in GELA centers after the closure of the LNH98-5 trial.

scholarly journals International Prognostic Index-Based Immune Prognostic Model for Diffuse Large B-Cell Lymphoma

2021 ◽  
Vol 12 ◽  
Author(s):  
Shidai Mu ◽  
Deyao Shi ◽  
Lisha Ai ◽  
Fengjuan Fan ◽  
Fei Peng ◽  
...  
Keyword(s):  
Gene Expression ◽  
Prognostic Model ◽  
Cell Lymphoma ◽  
International Prognostic Index ◽  
Prognostic Index ◽  
B Cell Lymphoma ◽  
Immune Checkpoint Blockade ◽  
Large B Cell Lymphoma ◽  
Risk Patients ◽  
Large B Cell

BackgroundThe International Prognostic Index (IPI) is widely used to discriminate the prognosis of patients with diffuse large B-cell lymphoma (DLBCL). However, there is a significant need to identify novel valuable biomarkers in the context of targeted therapy, such as immune checkpoint blockade (ICB).MethodsGene expression data and clinical DLBCL information were obtained from The Cancer Genome Atlas and Gene Expression Omnibus datasets. A total of 371 immune-related genes in DLBCL patients associated with different IPI risk groups were identified by weighted gene co-expression network analysis, and eight genes were selected to construct an IPI-based immune prognostic model (IPI-IPM). Subsequently, we analyzed the somatic mutation and transcription profiles of the IPI-IPM subgroups as well as the potential clinical response to immune checkpoint blockade (ICB) in IPI-IPM subgroups.ResultsThe IPI-IPM was constructed based on the expression of CMBL, TLCD3B, SYNDIG1, ESM1, EPHA3, HUNK, PTX3, and IL12A, where high-risk patients had worse overall survival than low-risk patients, consistent with the results in the independent validation cohorts. The comprehensive results showed that high IPI-IPM risk scores were correlated with immune-related signaling pathways, high KMT2D and CD79B mutation rates, and upregulation of inhibitory immune checkpoints, including PD-L1, BTLA, and SIGLEC7, indicating a greater potential response to ICB therapy.ConclusionThe IPI-IPM has independent prognostic significance for DLBCL patients, which provides an immunological perspective to elucidate the mechanisms of tumor progression and sheds light on the development of immunotherapy for DLBCL.

scholarly journals Mutations in the DNA-binding codons of TP53, which are associated with decreased expression of TRAILreceptor-2, predict for poor survival in diffuse large B-cell lymphoma

Blood ◽  
2007 ◽  
Vol 110 (13) ◽  
pp. 4396-4405 ◽  
Author(s):  
Ken H. Young ◽  
Dennis D. Weisenburger ◽  
Bhavana J. Dave ◽  
Lynette Smith ◽  
Warren Sanger ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Binding ◽  
B Cell ◽  
Cell Lymphoma ◽  
International Prognostic Index ◽  
Prognostic Index ◽  
B Cell Lymphoma ◽  
Poor Survival ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Mutations of the TP53 tumor suppressor gene have been associated with poor survival in some series of diffuse large B-cell lymphoma (DLBCL) but not in other studies. The purpose of this study was to identify the frequency of TP53 alterations (mutations or deletions), characterize the gene expression of mutant/deleted cases, and determine the effects of mutations on survival. In a series of DLBCL that had previous gene expression profiling, we identified 24 mutations in 113 cases (21%). There was no difference in the frequency of mutations in the molecular subgroups of DLBCL. Twelve (50%) of the 24 cases had mutations localized to the DNA-binding codons in the core domain of TP53. The presence of any TP53 mutation correlated with poor overall survival (OS; P = .044), but DNA-binding mutations were the most significant predictor of poor OS (P < .001). Multivariate analysis confirmed that the International Prognostic Index, tumor size, and TP53 DNA-binding mutations were independent predictors of OS. Gene expression analysis showed that TRAILreceptor-2 (DR5) was the most differentially underexpressed gene in the TP53 mutated cases. Investigation is warranted into targeted therapy toward TRAIL receptor-2, to potentially bypass the adverse effect of mutated TP53 in DLBCL.

scholarly journals Clinical Features and Prognostic Significance of NOTCH1 Mutations in Diffuse Large B-Cell Lymphoma

2021 ◽  
Vol 11 ◽  
Author(s):  
Zhongqi Li ◽  
Fang Yu ◽  
Wenle Ye ◽  
Liping Mao ◽  
Jiansong Huang ◽  
...  
Keyword(s):  
B Cell ◽  
Clinical Features ◽  
Cell Lymphoma ◽  
International Prognostic Index ◽  
Prognostic Significance ◽  
Prognostic Index ◽  
B Cell Lymphoma ◽  
Prognostic Impact ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous group of large lymphoid B cell malignancy with distinct clinical and genetic features. Recently, NOTCH1 mutations were identified in DLBCL cases by Next-generation sequencing (NGS), but the clinical features and prognostic impact were not systematically studied. Here, NOTCH1 genes in 161 DLBCL samples were sequenced by NGS. The prognostic value of NOTCH1 mutations was assessed in the context of clinical and laboratory factors, such as international prognostic index (IPI), cell-of-origin classification, double expression of BCL2 and c-MYC. The combined data from three Western cohorts were used to validate these results. As a result, NOTCH1 mutations were found in 17(10.6%) patients, and three patients had a hotspot mutation of c.7541_7542delCT. The presence of NOTCH1 mutations was significantly associated with poor complete response and progression free survival(PFS), which was independent of established clinical and laboratory parameters. In addition, 30 (1.92%) of 1562 patients treated with R-CHOP regimen in those combined Western cohorts had NOTCH1 mutations. Meta-analysis of the Western cohorts confirmed that NOTCH1 mutations were also associated with poor PFS and OS. In conclusion, DLBCL patients with the NOTCH1 mutations have worse PFS and OS, and the NOTCH1 mutations can be used as an independent predictor for patients with DLBCL.

Prognostic significance of immunohistochemical biomarkers in diffuse large B-cell lymphoma: a study from the Lunenburg Lymphoma Biomarker Consortium

Blood ◽  
2011 ◽  
Vol 117 (26) ◽  
pp. 7070-7078 ◽  
Author(s):  
Gilles Salles ◽  
Daphne de Jong ◽  
Wanling Xie ◽  
Andreas Rosenwald ◽  
Mukesh Chhanabhai ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Lymphoma ◽  
International Prognostic Index ◽  
Prognostic Significance ◽  
Prognostic Index ◽  
B Cell Lymphoma ◽  
Cut Points ◽  
Large B Cell Lymphoma ◽  
Hla Dr ◽  
Large B Cell

The Lunenburg Lymphoma Biomarker Consortium (LLBC) evaluated the prognostic value of IHC biomarkers in a large series of patients with diffuse large B-cell lymphoma (DLBCL). Clinical data and tumor samples were retrieved from 12 studies from Europe and North America, with patients treated before or after the rituximab era. Using tissue microarrays from 1514 patients, IHC for BCL2, BCL6, CD5, CD10, MUM1, Ki67, and HLA-DR was performed and scored according to previously validated protocols. Optimal cut points predicting overall survival of patients treated in the rituximab era could only be determined for CD5 (P = .003) and Ki67 (P = .02), whereas such cut points for BCL2, BCL6, HLA-DR, and MUM1 could only be defined in patients not receiving rituximab. A prognostic model for patients treated in the rituximab era identified 4 risk groups using BCL2, Ki67, and International Prognostic Index (IPI) with improved discrimination of low-risk patients. Newly recognized correlations between specific biomarkers and IPI highlight the importance of carefully controlling for clinical and biologic factors in prognostic models. These data demonstrate that the IPI remains the best available index in patients with DLBCL treated with rituximab and chemotherapy.

Prognostic Impact of Tumor Infiltrating FOXP3 Positive Regulatory T Cells in Diffuse Large B-Cell Lymphoma at Diagnosis.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1565-1565
Author(s):  
Jae-Yong Kwak ◽  
Na-Ri Lee ◽  
Eun-Kee Song ◽  
Kyu Yun Jang ◽  
Ha Na Choi ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
B Cell ◽  
Cell Lymphoma ◽  
International Prognostic Index ◽  
Prognostic Significance ◽  
B Cell Lymphoma ◽  
Prognostic Impact ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Abstract Tumor infiltrating immune cells play an important role in host immune reactions against diffuse large B-cell lymphoma (DLBCL). In the present study, we have identified a subset of tumor infiltrating FOXP3-positive regulatory T cells (Tregs) in the initial DLBCL biopsy specimens and evaluated its prognostic significance. Ninety-six patients with DLBCL were retrospectively evaluated. Expression pattern of FOXP3 protein was examined using standard immunohistochemistry in paraffin-embedded tissue samples. The median overall survival (OS) was 28 months. Compared to the others, the patients with higher percentage of FOXP3-positive Tregs in the initial tumor biopsy, showed a significantly longer OS (p=0.003). When prognostic factors were evaluated in a multivariate model, the international prognostic index and the percentage of infiltrating FOXP3-positive Tregs in the initial biopsy were shown to be independent predictors of OS. In conclusion, the presence of increased percentage of FOXP3-positive Tregs in DLBCL predicts a better prognosis. Figure Figure

Prognostic Significance of Interim 18f-FDG PET/CT for the Treatment of Diffuse Large B-Cell Lymphoma In the Post-Rituximab Era.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1799-1799
Author(s):  
Deok-Hwan Yang ◽  
Jung-Joon Min ◽  
Ho-Chun Song ◽  
Yong Yeon Jeong ◽  
Woong-Ki Chung ◽  
...  
Keyword(s):  
B Cell ◽  
Fdg Pet ◽  
Cell Lymphoma ◽  
International Prognostic Index ◽  
Prognostic Significance ◽  
B Cell Lymphoma ◽  
Interim Pet ◽  
Large B Cell Lymphoma ◽  
Pet Ct ◽  
Large B Cell

Abstract Abstract 1799 18F-fluoro-2-dexoy-D-glucose-positron emission tomography (FDG-PET)/computerized tomography (CT) has been used for staging and monitoring responses to treatment in patients with diffuse large B cell lymphoma (DLBCL). The sequential interim PET/CT was prospectively investigated to determine whether it provided additional prognostic information and could be a positive predictable value within patients with the same international prognostic index (IPI) after the use of rituximab in DLBCL. Patients and methods: One hundred and sixty-one patients with newly diagnosed DLBCL were enrolled between August 2004 and December 2009 at a single institution. The assessment of the PET/CT was performed at the time of diagnosis and mid-treatment of R-CHOP chemotherapy. The clinical stage and response of the patients were assessed according to revised response criteria for aggressive lymphomas (Cheson, J Clin Oncol, 2007). The positivity of interim PET/CT was determined based on the semi-quantitative assessment of the maximal standardized uptake value (SUVmax cut-off value of 3.0). Results: Sixty-seven patients (41.6%) presented in advanced stage disease and 27 (16.8%) had bulky lesions. At diagnosis, 53 patients (32.9%) were classified as high/high-intermediate risk by the IPI and two patients could not check the interim response due to treatment-related mortality (TRM). Forty-three patients (26.7%) continued to have positive metabolic uptakes with a significantly high relapse rate (62.8%) compared to the patients with a negative interim PET/CT (12.1%) (P<0.01). After a median follow-up of 30.8 months, the positivity of interim PET/CT was found to be a prognostic factor for both OS and PFS, with a hazard ratio of 4.07 (2.62 – 6.32) and 5.46 (3.49 – 8.52), respectively. In the low-risk IPI group, the 3-year OS and PFS rate was significantly different in the patients with positive (53.3 and 52.5%) and negative (93.8 and 88.3%) interim PET/CT, respectively (P<0.01). These significant prognostic differences of interim PET/CT responses were consistent with the results of the patients with high-risk IPI group (P< 0.01). Conclusions: Interim PET/CT scanning had a significant predictive value for disease progression and survival of DLBCL in post-rituximab treatment; it might be the single most important determinant of clinical outcome in patients with the same IPI risk. Disclosures: No relevant conflicts of interest to declare.

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