Prognostic Impact of Germinal Center–Associated Proteins and Chromosomal Breakpoints in Poor-Risk Diffuse Large B-Cell Lymphoma

2006 ◽  
Vol 24 (25) ◽  
pp. 4135-4142 ◽  
Author(s):  
Gustaaf W. van Imhoff ◽  
Evert-Jan G. Boerma ◽  
Bronno van der Holt ◽  
Ed Schuuring ◽  
Leo F. Verdonck ◽  
...  
Keyword(s):  
B Cell ◽  
Expression Profile ◽  
Germinal Center ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
High Dose ◽  
Prognostic Impact ◽  
Poor Risk ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Purpose Outcome of diffuse large B-cell lymphoma (DLBCL) with a germinal center B-cell (GCB) expression profile is superior to that of non-GCB DLBCL. This conclusion is mainly derived from patients with mixed international prognostic index (IPI) risk profiles treated with CHOP-like therapy (cyclophosphamide, doxorubicin, vincristine, and prednisone). We wondered whether the prognostic impact of the expression profile would hold out in a homogeneous cohort of poor-risk DLBCL patients treated with high-dose sequential therapy (HDT) and autologous stem-cell transplantation (ASCT) as first-line therapy. Patients and Methods DLBCL from 66 newly diagnosed poor-risk patients, treated in two sequential prospective Dutch Hemato-Oncology Association (HOVON) trials, were studied retrospectively for expression of CD10, bcl6, MUM1/IRF4, bcl2, Ki67, and CD21+ follicular dendritic cells (FDC) by immunohistochemistry, and for the breakpoints of BCL2, BCL6, and MYC by fluorescent in situ hybridization (FISH). Lymphomas with any follicular component were excluded. Results A GCB immunophenotype profile was found in 58% and non-GCB immunophenotype profile in 42% of the tumors. Clinical characteristics of both groups were similar. Complete response (CR) rate was higher in patients with CD10+ tumors (58% v 30%; P = .03). A GCB immunophenotype profile, its constituting markers CD10 more than 30% and MUM1 less than 70%, and bcl2 less than 10% were each associated with a better overall survival (OS). FDC networks, equally present in GCB and non-GCB tumors, had superior CR (73% v 31%; P = .01), but disease-free survival rates were lower and there was no difference in OS rates. None of the breakpoints had a prognostic impact on outcome. Conclusion Also in patients with poor-risk DLBCL treated with HDT and ASCT, the GCB immunophenotype and bcl2 expression retained a major impact on survival.

The Germinal Center/Activated B-Cell Subclassification Has a Prognostic Impact for Response to Salvage Therapy in Relapsed/Refractory Diffuse Large B-Cell Lymphoma: A Bio-CORAL Study

2011 ◽  
Vol 29 (31) ◽  
pp. 4079-4087 ◽  
Author(s):  
Catherine Thieblemont ◽  
Josette Briere ◽  
Nicolas Mounier ◽  
Hans-Ullrich Voelker ◽  
Wendy Cuccuini ◽  
...  
Keyword(s):  
B Cell ◽  
Germinal Center ◽  
Cell Lymphoma ◽  
Univariate Analysis ◽  
International Prognostic Index ◽  
B Cell Lymphoma ◽  
High Dose ◽  
Prognostic Impact ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Purpose To evaluate the prognostic value of the cell of origin (COO) in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBLC), prospectively treated by rituximab, dexamethasone, high-dose cytarabine, and cisplatin (R-DHAP) versus rituximab, ifosfamide, carboplatin, and etoposide and followed by intensive therapy plus autologous stem-cell transplantation on the Collaborative Trial in Relapsed Aggressive Lymphoma (CORAL) trial. Patients and Methods Among the 396 patients included on the trial, histologic material was available for a total of 249 patients at diagnosis (n = 189 patients) and/or at relapse (n = 147 patients), which included 87 matched pairs. The patient data were analyzed by immunochemistry for CD10, BCL6, MUM1, FOXP1, and BCL2 expression and by fluorescent in situ hybridization for BCL2, BCL6 and c-MYC breakpoints. The correlation with survival data was performed by using the log-rank test and the Cox model. Results Characteristics of immunophenotype and chromosomal abnormalities were statistically highly concordant in the matched biopsies. In univariate analysis, the presence of c-MYC gene rearrangement was the only parameter to be significantly correlated with a worse progression-free survival (PFS; P = .02) and a worse overall survival (P = .04). When treatment interaction was tested, the germinal center B (GCB) –like DLBCL that was based on the algorithm by Hans was significantly associated with a better PFS in the R-DHAP arm. In multivariate analysis, independent prognostic relevance was found for the GCB/non-GCB the Hans phenotype interaction treatment (P = .04), prior rituximab exposure (P = .0052), secondary age-adjusted International Prognostic Index (P = .039), and FoxP1 expression (P = .047). Confirmation was obtained by gene expression profiling in a subset of 39 patients. Conclusion COO remains a major and independent factor in relapsed/refractory DLBCL, with a better response to R-DHAP in GCB-like DLBCL. This needs confirmation by a prospective study.

Rituximab compared to observation after high-dose consolidative first-line chemotherapy (HDC) with autologous stem cell transplantation in poor-risk diffuse large B-cell lymphoma: Updated results of the LNH98-B3 GELA study

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 8012-8012 ◽  
Author(s):  
C. Haioun ◽  
N. Mounier ◽  
J. F. Emile ◽  
S. Bologna ◽  
B. Coiffier ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Induction Treatment ◽  
High Dose ◽  
Induction Phase ◽  
Rituximab Maintenance ◽  
Poor Risk ◽  
Large B Cell Lymphoma ◽  
Large B Cell

8012 Background: Rituximab has been evaluated as a single agent and also in combination with chemotherapy in aggressive and indolent lymphomas with evidence of efficacy. More recently, rituximab maintenance therapy has been successfully used to keep responding patients in remission. We have shown that consolidative HDC improves outcome of poor risk responder-patients (pts) with aggressive lymphoma. Methods: The aim of the present study was to evaluate the potential benefit, as randomly compared to observation, rituximab - 375 mg/m2/week for 4 weeks - 2 months after HDC, in decreasing the relapse rate (second randomization: R2). A secondary objective was to improve the response rate before HDC using the intensified ACE chemotherapy regimen (doxorubicin 75mg/m2 d1, cyclophosphamide 1g/m2 d1-d2, etoposide 150mg/m2 d1-d3) as compared to the standard ACVBP induction regimen (R1). Four cycles were delivered every 15 days. In responding pts, HDC (mitoxantrone 45 mg/m2, cyclophosphamide 1500 mg/m2 × 4d, etoposide 250 mg/m2 × 4d and carmustine 300 mg/m2) was started between d80 and d90. Results: From 10/99 to 05/03 (closing date), 476 pts younger than 60 years with diffuse large B-cell lymphoma and aa-IPI 2 or 3 (aa-IPI 3: 29%). were enrolled. 237 pts were assigned to ACE and 239 to ACVBP. Complete response (CR+CRu) rates to induction treatment did not significantly differ between the 2 regimens (65% and 63%, respectively). Death rate during induction phase was 4% in both arms. Among the 331 pts who received HDC, 269 were randomized (R2) to receive either rituximab (n=139) or observation (n=130). 545 infusions of rituximab were administered with no clinically relevant infectious toxicity except two severe VZV infections. With a median follow-up of 4 years after R2, a trend toward a better 4y-EFS was observed in the rituximab group (80% vs 71%, p=0.098). In addition, a two-sided log-rank test stratified by aa-IPI, induction treatment and response after HDC was performed and confirmed the results of the unstratified analysis. Conclusions: We conclude that early and brief rituximab maintenance is feasible after HDC and may prolong remission status. [Table: see text]

MicroRNA Expression Profiling of Diffuse Large B-Cell Lymphoma Reveals Differences between Germinal Center-Like and Activated B Cell-Like Subtypes.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3002-3002
Author(s):  
Charles H. Lawrie ◽  
Shamit Soneji ◽  
Christopher D. Cooper ◽  
Chris Hatton
Keyword(s):  
Gene Expression ◽  
B Cell ◽  
Cell Lines ◽  
Expression Profile ◽  
Germinal Center ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Large B Cell Lymphoma ◽  
Large B Cell ◽  
Clinical Cases

Abstract MicroRNAs (miRNA) are a recently discovered class of short non-coding RNA molecules that negatively regulate gene expression. They have been shown to play a critical role in many biological functions. In humans about 320 miRNAs have been identified, some of which are expressed in a cell-specific and developmental stage-specific manner. Recently it has been shown that the expression profile of miRNAs can be used to subtype clinical cases (and cell lines) according to diagnosis with a greater degree of accuracy than traditional gene expression analysis. The identity of miRNAs associated with different lymphoma types however remains poorly defined. Previous expression studies have revealed the presence of at least two subtypes of diffuse large B-cell lymphoma (DLBCL) representing the postulated cell of origin; those that are germinal center B cell derived (GCB-type) and those that are activated B-cell derived (ABC-type). The latter subtype has been linked with poor prognostic outcome. It is not known whether these subtypes are also defined at the miRNA level. Therefore we examined the miRNA expression profile of DLBCL cell lines of defined subtypes as well as sub-populations of B-lymphocytes by microarray analysis. Consistent with recent publications, we found that mir-19a, 19b and 17-5p (part of mir-17-92 cluster) were up-regulated in cell lines but not in normal lymphocyte populations. Furthermore, cluster analysis showed that GCB-type cell lines (SUD-HL4, SUD-HL6 & SUD-HL10) have a distinct miRNA profile from ABC-type cell lines (OCI-Ly3 & OCI-Ly10). Most notably, high levels of expression of mir-155, mir-181b and mir-325 were found in ABC-type cell lines whilst high levels of mir-181a were found in GCB-type cell lines. We looked at expression of mir-155, 181a, 143, 145, 378 and 16 in these cell lines as well as clinical cases of DLBCL by RNase-protection assay. Consistent with the microarray data, we found that mir-155 was expressed in ABC-type cell lines but not GCB-type cell lines whilst the converse was true for mir-181a. Clinical cases showed similar patterns of expression but have still to be sub-typed according to immunohistochemical markers. Although still preliminary, our data suggests that miRNA profiling may be a useful tool in predicting the subtype of DLBCL cases and hence clinical outcome.

Prognostic impact of immunohistochemically defined germinal center phenotype in diffuse large B-cell lymphoma patients treated with immunochemotherapy

Blood ◽  
2007 ◽  
Vol 109 (11) ◽  
pp. 4930-4935 ◽  
Author(s):  
Heidi Nyman ◽  
Magdalena Adde ◽  
Marja-Liisa Karjalainen-Lindsberg ◽  
Minna Taskinen ◽  
Mattias Berglund ◽  
...  
Keyword(s):  
High Risk ◽  
B Cell ◽  
Germinal Center ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Risk Groups ◽  
Control Group ◽  
Prognostic Impact ◽  
Large B Cell Lymphoma ◽  
Large B Cell

AbstractGerminal center (GC) and non-GC phenotypes are predictors of outcome in diffuse large B-cell lymphoma (DLBCL) and can be used to stratify chemotherapy-treated patients into low- and high-risk groups. To determine how combination of rituximab with chemotherapy influences GC-associated clinical outcome, GC and non-GC phenotypes were identified immunohistochemically from samples of 90 de novo DLBCL patients treated with rituximab in combination with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone)–like regimen (immunochemotherapy). One hundred and four patients previously treated with chemotherapy served as a control group. Consistent with previous studies, chemotherapy-treated patients with immunohistochemically defined GC phenotype displayed a significantly better overall (OS) and failure-free survival (FFS) than the non-GC group (OS, 70% vs 47%, P = .012; FFS, 59% vs 30%, P = .001). In contrast, immunohistochemically defined GC phenotype did not predict outcome in immunochemotherapy-treated patients (OS, 77% vs 76%, P = ns; FFS, 68% vs 63%, P = ns). In comparison, International Prognostic Index (IPI) could separate the high-risk patients from low- and intermediate-risk groups (OS, 84% vs 63%, P = .030; FFS, 79% vs 52%, P = .028). We conclude that rituximab in combination with chemotherapy seems to eliminate the prognostic value of immunohistochemically defined GC- and non-GC phenotypes in DLBCL.

scholarly journals In situ transcriptional profile of a germinal center plasmablastic burst hints at an unfavorable Diffuse Large B-cell Lymphoma subset.

2021 ◽  
Author(s):  
Vincenzo L'Imperio ◽  
Gaia Morello ◽  
Valeria Cancila ◽  
Giorgio Bertolazzi ◽  
Saveria Mazzara ◽  
...  
Keyword(s):  
B Cell ◽  
Germinal Center ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Functional Differentiation ◽  
Cytokine Signaling ◽  
Prognostic Impact ◽  
Large B Cell Lymphoma ◽  
Large B Cell

The germinal center (GC) reaction results in the selection of B-cells acquiring effector Ig secreting ability by progressing towards plasmablastic differentiation. This transition is associated with exclusion from the GC microenvironment. The aberrant expansion of plasmablastic elements within the GC fringes configures an atypical condition, the biological characteristics of which have not been defined yet. We investigated the in situ immunophenotypical and transcriptional characteristics of a non-clonal germinotropic expansion of plasmablastic elements (GEx) occurring in the tonsil of a young patient. Compared to neighboring GC and peri-follicular regions, the GEx showed a distinctive signature featuring key regulators of plasmacytic differentiation, cytokine signaling, and cell metabolism. The GEx signature was tested in the setting of diffuse large B-cell lymphoma (DLBCL) as a prototypical model of lymphomagenesis encompassing transformation at different stages of GC and post-GC functional differentiation. The signature outlined DLBCL clusters with different overall survival, highlighting the negative prognostic impact of the overexpression of hallmark genes of this peculiar condition.

Applicability of Different Immunohistochemistry Algorithms to Assess Gene Expression Profile In Patients with Diffuse Large B-Cell Lymphoma

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4134-4134
Author(s):  
Gonzalo Gutierrez-Garcia ◽  
Teresa Cardesa ◽  
Luis Colomo ◽  
Fina Climent ◽  
Santiago Mercadal ◽  
...  
Keyword(s):  
Gene Expression ◽  
B Cell ◽  
Gene Expression Profile ◽  
Expression Profile ◽  
Conflicts Of Interest ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Prognostic Impact ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Abstract Abstract 4134 Gene expression profile (GEP) allows to distinguish two groups with different origin in patients with diffuse large B-cell lymphoma (DLBCL): germinal-center (GC) and activated (ABC), with the latter having a significantly poorer outcome. However, GEP is a technique not available in current clinical practice. For this reason, attempts to reproduce GEP data by immunophenotyping algorithms have been made. The aim of this study was to apply the most popular algorithms in a series of patients with DLBCL homogeneously treated with immunochemotherapy, in order to assess the correlation with GEP data and their usefulness to predict response and outcome of the patients. One hundred fifty seven patients (80M/77F; median age 65 years) diagnosed with DLBCL in 5 institutions of the Grup per l'Estudi dels Limfomes de Catalunya I Balears (GELCAB) during a 5-year period, treated with Rituximab-containing regimens (in most cases, R-CHOP), in whom histological material to construct a tissue microarrays (TMA) was available, constituted the subjects of the present study. Four algorithms were applied: Colomo (Blood 2003, 101:78) using CD10, bcl-6 and MUM1/IRF4; Hans (Blood 2004, 103:275) using CD10, bcl-6 and MUM1/IRF4; Muris (J Pathol 2006, 208:714) using CD10 and MUM1/IRF4, and Choi (Clin Cancer Res 2009, 15:5494), using CD10, bcl-6, GCET1, FOXP1 and MUM1/IRF4. The thresholds used were those previously described. GEP studies were performed in 62 patients in whom fresh frozen material was available. Main clinical and evolutive data were recorded and analyzed. The proportion of positive cases for the different single antigens was as follows: CD10 26%, bcl-6 64%, GCET1 46%, FOXP1 78% and MUM1/IRF4 28%. The distribution of cases (GC vs. non-GC) according to the algorithms is detailed in the table. In 88 of 110 patients (80%) with all the antigens available, the patients were allocated in the same group (either GC or non-GC). When the immunochemistry was compared with GEP data, the sensitivity in the GC group was 59%, 52%, 70% and 40% for Colomo, Hans, Muris and Choi algorithms, respectively. The sensitivity in the non-GC group was 81%, 85%, 62% and 84%, respectively. On the other hand, the positive predictive value (PPV) in the GC group was 81%, 83%, 72% and 77%, respectively. In non-GC subset the PPV for the different algorithms was 59%, 55%, 72% and 52%, respectively. We observed a higher percentage of misclassified cases in the GC-phenotype subset than in the non-GC subgroup. None of the immunohistochemical algorithms showed a significant superiority as surrogate of GEP information among the others. The ability of GEP groups as well as of groups defined by the algorithms to predict complete response (CR) rate, progression-free survival (PFS) and overall survival (OS) of the patients is showed in the table. Thus, whereas the GEP groups showed significant prognostic value for CR rate, PFS and OS, none of the immunohistochemical algorithms were able to predict the outcome. In conclusion, in a homogeneous series of DLBCL patients treated with immunochemotherapy, the different immunohistochemical algorithms were not able to mimic the GEP information. The prognostic impact of the groups defined by immunohistochemistry (GC vs. non-GC) was particularly low. N (%) CR rate N (%) 5-year PFS (%) 5-year OS (%) Colomo algorithm GC 53 (44) 39 (74) 48 54 Non-GC 68 (56) 53 (78) 55 62 Hans algorithm GC 61 (41) 47 (77) 54 60 Non-GC 88 (59) 67 (76) 52 59 Muris algorithm GC 87 (57) 63 (72) 48 57 Non-GC 65 (43) 51 (78) 56 63 Choi algorithm GC 45 (33) 32 (71) 48 54 Non-GC 90 (67) 70 (78) 52 61 Gene expression profile 30 (58) 25 (83) 76* 80** GC Activated 22 (42) 17 (77) 31* 45** * p=0.005, ** p=0.03. Disclosures: No relevant conflicts of interest to declare.

Prognostic impact of immunohistochemically defined germinal center B-cell and nongerminal center B-cell subtypes of diffuse large B-cell lymphoma in rituximab era.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e18517-e18517
Author(s):  
Yabing Cao ◽  
Ying Huang ◽  
Sheng Ye ◽  
Tongyu Lin
Keyword(s):  
B Cell ◽  
Germinal Center ◽  
Survival Data ◽  
Prognostic Value ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Prognostic Impact ◽  
Large B Cell Lymphoma ◽  
Germinal Center B Cell ◽  
Large B Cell

e18517 Background: Diffuse large B-cell lymphoma (DLBCL) can be molecularly subtyped as either germinal center B-cell (GCB) or non-GCB. The role of rituximab(R) in these two groups remains unclear. Methods: We studied 204 patients with de novo DLBCL (107 treated with CHOP; 97 treated with R-CHOP); patients being stratified into GCB and non-GCB on the basis of BCL-6, CD10 and MUM1 protein expression. The relationships between clinical characteristics, survival data and immunophenotype were studied. Results: The median follow-up was 51months for CHOP group and 56 months for R-CHOP group. The 5-year overall survival (OS) in the CHOP and R-CHOP group was 50.4% and 66.6% (p=0.031), respectively. GCB patients had a better 5-year OS than non-GCB patients whether treated with CHOP (65.0% vs. 40.9%; p=0.011). In contrast, there’s no difference in the 5-year OS for the GCB and non-GCB with R-CHOP (76.5% vs. 61.3%; p=0.141). In non-GCB subtype, additional rituximab improved survival than CHOP (61.3% vs. 40.9%; p=0.0303). Conclusions: These results indicated that addition of rituximab to standard chemotherapy eliminate the prognostic value of immunohistochemically defined GCB and non-GCB phenotypes in DLBCL by improving the prognostic value of non-GCB subtype of DLBCL

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