Large Cleaved and Immunoblastic Lymphoma May Represent Two Distinct Clinicopathologic Entities Within the Group of Diffuse Large B-Cell Lymphomas

2005 ◽  
Vol 23 (28) ◽  
pp. 7060-7068 ◽  
Author(s):  
Pascale De Paepe ◽  
Ruth Achten ◽  
Gregor Verhoef ◽  
Iwona Wlodarska ◽  
Michel Stul ◽  
...  
Keyword(s):  
B Cell ◽  
International Prognostic Index ◽  
Prognostic Significance ◽  
Prognostic Index ◽  
Disease Free Survival ◽  
B Cell Lymphomas ◽  
Not Otherwise Specified ◽  
Germinal Center B Cell ◽  
Cd10 Expression ◽  
Large B Cell

Purpose The reliability of immunohistochemistry for subdividing diffuse large B-cell lymphomas (DLBCL) into germinal center B-cell-like (GCB) and non-GCB prognostic subgroups is debated. In this study we evaluated the prognostic significance of such subgrouping on a series of 153 DLBCL patients. Furthermore, we investigated whether both subgroups could comprise clinicopathologic entities recognized by their morphology and characterized by a distinct phenotype, specific genetic abnormalities, and clinical characteristics. Patients and Methods All samples from patients were reviewed and morphologically subdivided into large cleaved, immunoblastic, and not otherwise specified DLBCL. GCB and non-GCB immunohistochemical profiles were established. The presence of chromosomal translocations involving BCL2, BCL6, and MYC and/or rearrangements of these genes was investigated. Results Subdividing DLBCL with either a GCB or non-GCB immunophenotypic profile was not of prognostic significance. Nevertheless, CD10 expression was a predictor of favorable outcome, whereas high bcl-2 expression and BCL6 rearrangement were adverse predictors of disease-free survival. Interestingly, large cleaved DLBCL was clearly associated with a GCB immunophenotypic profile, CD10 expression, BCL2 rearrangement, age younger than 60 years, and low to low/intermediate International Prognostic Index risk, but was not of prognostic significance. In contrast, immunoblastic morphology was associated with a non-GCB profile and was a significant predictor of unfavorable DFS. Conclusion Subdividing DLBCL into subgroups based on their immunohistochemical profile was not of prognostic significance. Nevertheless, it allowed the additional characterization of two lymphoma subgroups previously recognized in the Working Formulation. Both correspond to two distinct clinicopathologic entities within the DLBCL.

International prognostic index-based outcomes for diffuse large B-cell lymphomas

Cancer ◽  
2002 ◽  
Vol 94 (12) ◽  
pp. 3083-3088 ◽  
Author(s):  
Richard B. Wilder ◽  
Maria A. Rodriguez ◽  
L. Jeffrey Medeiros ◽  
Susan L. Tucker ◽  
Chul S. Ha ◽  
...  
Keyword(s):  
B Cell ◽  
International Prognostic Index ◽  
Prognostic Index ◽  
B Cell Lymphomas ◽  
Large B Cell

Diffuse Large B-Cell Lymphoma: Risk Stratification and Management of Relapsed Disease

Hematology ◽  
2005 ◽  
Vol 2005 (1) ◽  
pp. 252-259 ◽  
Author(s):  
John W. Sweetenham
Keyword(s):  
Gene Expression ◽  
Risk Stratification ◽  
B Cell ◽  
International Prognostic Index ◽  
Prognostic Significance ◽  
Prognostic Index ◽  
B Cell Lymphoma ◽  
Molecular Techniques ◽  
High Dose ◽  
Large B Cell

Abstract The clinical factors described by the International Prognostic Index (IPI) provide a model for risk stratification in diffuse large B-cell lymphomas (DLBCLs). However, there is variability in outcome within IPI risk groups, indicating the biological and clinical heterogeneity of these diseases. Studies of gene expression profiling (GEP) in DLBCL are uncovering biological heterogeneity with prognostic significance. Various gene expression signatures with predictive value independent of the IPI are now recognized. Immunophenotypic features of DLBCL have also been shown to have prognostic value. The use of fluorodeoxyglucose–positron emission tomography (FDG-PET) scanning may provide additional predictive information when used at diagnosis or soon after initiation of treatment. Future prognostic models in DLBCL are likely to incorporate functional imaging, immunophenotype and GEPs as well as clinical data in risk stratification and choice of treatment. Treatment of relapsed DLBCL remains a major problem. High-dose therapy (HDT) and stem cell transplantation (SCT) has been shown to produce superior overall survival (OS) compared with conventional dose salvage therapy in patients with relapsed, chemosensitive DLBCL. However, only 20% to 30% of patients are cured by this approach, and the effectiveness of HDT and SCT in patients treated with rituximab-based combinations as first-line therapy is unknown. Although new transplant techniques including non-myeloablative allogeneic SCT are being investigated, their role is unclear. New treatment strategies are needed for these patients. The use of molecular techniques such as GEP is identifying many potential new therapeutic targets in DLBCL including histone deacetylase, HLA-DR, bcl-2, bcl-6, mTOR and TRAIL.

Randomized Phase II Study of R-CHOP With or Without Bortezomib in Previously Untreated Patients With Non–Germinal Center B-Cell–Like Diffuse Large B-Cell Lymphoma

2017 ◽  
Vol 35 (31) ◽  
pp. 3538-3546 ◽  
Author(s):  
John P. Leonard ◽  
Kathryn S. Kolibaba ◽  
James A. Reeves ◽  
Anil Tulpule ◽  
Ian W. Flinn ◽  
...  
Keyword(s):  
B Cell ◽  
Germinal Center ◽  
Cell Lymphoma ◽  
International Prognostic Index ◽  
Prognostic Index ◽  
B Cell Lymphoma ◽  
Large B Cell Lymphoma ◽  
Germinal Center B Cell ◽  
The Impact ◽  
Large B Cell

Purpose To evaluate the impact of the addition of bortezomib to rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) on outcomes in previously untreated patients with non–germinal center B-cell–like (non-GCB) diffuse large B-cell lymphoma (DLBCL). Patients and Methods After real-time determination of non-GCB DLBCL using the Hans immunohistochemistry algorithm, 206 patients were randomly assigned (1:1; stratified by International Prognostic Index [IPI] score) to six 21-day cycles of standard R-CHOP alone or R-CHOP plus bortezomib 1.3 mg/m2 intravenously on days 1 and 4 (VR-CHOP). The primary end point, progression-free survival (PFS), was evaluated in 183 patients with centrally confirmed non-GCB DLBCL who received one or more doses of study drug (91 R-CHOP, 92 VR-CHOP). Results After a median follow-up of 34 months, with 25% (R-CHOP) and 18% (VR-CHOP) of patients having had PFS events, the hazard ratio (HR) for PFS was 0.73 (90% CI, 0.43 to 1.24) with VR-CHOP ( P = .611). Two-year PFS rates were 77.6% with R-CHOP and 82.0% with VR-CHOP; they were 65.1% versus 72.4% in patients with high-intermediate/high IPI (HR, 0.67; 90% CI, 0.34 to 1.29), and 90.0% versus 88.9% (HR, 0.85; 90% CI, 0.35 to 2.10) in patients with low/low-intermediate IPI. Overall response rate with R-CHOP and VR-CHOP was 98% and 96%, respectively. The overall survival HR was 0.75 (90% CI, 0.38 to 1.45); 2-year survival rates were 88.4% and 93.0%, respectively. In the safety population (100 R-CHOP and 101 VR-CHOP patients), grade ≥ 3 adverse events included neutropenia (53% v 49%), thrombocytopenia (13% v 29%), anemia (7% v 15%), leukopenia (26% v 25%), and neuropathy (1% v 5%). Conclusion Outcomes for newly diagnosed, prospectively enrolled patients with non-GCB DLBCL were more favorable than expected with R-CHOP and were not significantly improved by adding bortezomib.

Prognostic significance of metallothionein in B-cell lymphomas

Blood ◽  
2006 ◽  
Vol 108 (10) ◽  
pp. 3514-3519 ◽  
Author(s):  
Christian Bjørn Poulsen ◽  
Rehannah Borup ◽  
Niels Borregaard ◽  
Finn Cilius Nielsen ◽  
Michael Boe Møller ◽  
...  
Keyword(s):  
B Cell ◽  
International Prognostic Index ◽  
Prognostic Significance ◽  
Significant Risk ◽  
Prognostic Index ◽  
B Cell Lymphoma ◽  
Significant Risk Factor ◽  
Sustained Remission ◽  
B Cell Lymphomas ◽  
Lymphoma Cells

Abstract We have investigated metallothionein (MT) I and II mRNA and protein in B-cell lymphomas with particular reference to diffuse large B-cell lymphoma (DLBCL). The mRNA profiling was performed on Affymetrix arrays and showed up-regulated MT mRNA in 15 of 48 DLBCLs, including 12 of 23 activated B-cell (ABC) and 3 of 9 type-3 lesions. In contrast, MT mRNA was low to undetectable in 16 germinal center B-cell (GCB)-type DLBCLs. Only 1 of 15 patients with up-regulated MT mRNA achieved a sustained remission, suggesting that up-regulated MT mRNA constitutes a significant risk factor for treatment failure. This was confirmed in 2 independent series, which showed significantly shorter 5-year survival in DLBCL with high versus low MT-IIa levels. By immunohistology, MT was shown to be present in both macrophages and lymphoma cells. The proportion of MT-positive macrophages did not correlate with the survival. In contrast, in 115 DLBCLs, MT labeling of more than 20% lymphoma cells was associated with a significantly poorer 5-year survival, independent of the age, stage, or International Prognostic Index. Taken together, it is suggested that both increased MT mRNA and MT protein expression by more than 20% lymphoma cells constitute independent risk factors in DLBCL.

Dose-adjusted EPOCH chemotherapy for untreated large B-cell lymphomas: a pharmacodynamic approach with high efficacy

Blood ◽  
2002 ◽  
Vol 99 (8) ◽  
pp. 2685-2693 ◽  
Author(s):  
Wyndham H. Wilson ◽  
Michael L. Grossbard ◽  
Stefania Pittaluga ◽  
Diane Cole ◽  
Deborah Pearson ◽  
...  
Keyword(s):  
B Cell ◽  
International Prognostic Index ◽  
Oral Prednisone ◽  
Prognostic Index ◽  
Dose Intensity ◽  
Drug Clearance ◽  
B Cell Lymphomas ◽  
Prognostic Information ◽  
Drug Concentrations ◽  
Large B Cell

Abstract We hypothesized that incremental improvements in the cyclophosphamide-doxorubicin-vincristine-prednisone (CHOP) chemotherapy regimen through optimization of drug selection, schedule, and pharmacokinetics would improve outcome in patients with large B-cell lymphomas. A prospective multi-institutional study of administration of etoposide, vincristine, and doxorubicin for 96 hours with bolus doses of cyclophosphamide and oral prednisone (EPOCH therapy) was done in 50 patients with previously untreated large B-cell lymphomas. The doses of etoposide, doxorubicin, and cyclophosphamide were adjusted 20% each cycle to achieve a nadir absolute neutrophil count below 0.5 × 109/L. The median age of the patients was 46 years (range, 20-88 years); 24% were older than 60 years; and 44% were at high-intermediate or high risk according to International Prognostic Index (IPI) criteria. There was a complete response in 92% of patients, and at the median follow-up time of 62 months, the progression-free survival (PFS) and overall survival (OS) rates were 70% and 73%, respectively. Neither IPI risk factors nor the index itself was associated with response, PFS, or OS. Doses were escalated in 58% of cycles, and toxicity levels were tolerable. Significant inverse correlations were observed between dose intensity and age for all adjusted agents, and drug clearance of doxorubicin and free etoposide was also inversely correlated with age (r = −0.54 andP2 = .08 and r = −0.45 andP2 = .034, respectively). Free-etoposide clearance increased significantly during successive cycles (P2 = .015). Lymphomas with proliferation of at least 80% had somewhat lower progression and those expressing bcl-2 had significantly higher progression (P2 = .04). Expression of bcl-2 may discriminate the recently described activated B-like from germinal-center B-like large-cell lymphomas and provide important pathobiologic and prognostic information. Dose-adjusted EPOCH may produce more cell kill than CHOP-based regimens. Dynamic dose adjustment may overcome inadequate drug concentrations, particularly in younger patients, and compensate for increased drug clearance over time.

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.

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.

Rearrangement of MYC Is Associated With Poor Prognosis in Patients With Diffuse Large B-Cell Lymphoma Treated in the Era of Rituximab

2010 ◽  
Vol 28 (20) ◽  
pp. 3360-3365 ◽  
Author(s):  
Sharon Barrans ◽  
Simon Crouch ◽  
Alex Smith ◽  
Kathryn Turner ◽  
Roger Owen ◽  
...  
Keyword(s):  
Clinical Outcome ◽  
B Cell ◽  
Poor Prognosis ◽  
International Prognostic Index ◽  
Prognostic Significance ◽  
Prognostic Index ◽  
B Cell Lymphoma ◽  
Prognostic Impact ◽  
Large B Cell

Purpose Rearrangement of MYC occurs in a proportion of diffuse large B-cell lymphomas (DLBCL), where they may be associated with an adverse clinical outcome. The aim of this study was to determine the frequency of MYC translocations in DLBCL and their prognostic impact in the era of cyclophosphamide, doxorubicin, vincristine, and prednisone plus rituximab (CHOP-R) therapy. Patients and Methods Three hundred three patients with previously untreated DLBCL, with no evidence of underlying follicular lymphoma, were investigated using immunohistochemistry and interphase fluorescent in situ hybridization for MYC, BCL6, and t(14;18)/BCL2 rearrangements. All patients (median age, 71.1 years; range, 23 to 96 years) were treated when CHOP-R was standard therapy for DLBCL and observed for a maximum of 4 years. Overall survival (OS) at 3 years was 49% (95% CI, 42% to 56%). Results MYC rearrangements were demonstrated in 35 (14%) of 245 biopsies with data available. Of these, 26 (74%) also had a t(14;18), 10 (26%) were BCL6 and MYC rearranged, and seven had all three abnormalities. Only age, International Prognostic Index, and MYC rearrangement retained prognostic significance in the final model. OS was significantly worse for patients with rearrangement of MYC (survival probability at 2 years = 0.35 in v 0.61 in the nonrearranged group). Conclusion The presence of a MYC rearrangement is a strongly adverse prognostic factor in CHOP-R–treated patients and can be used in combination with patients' age and IPI to accurately predict clinical outcome. In DLBCL, rearrangement of MYC is rarely found as the sole genetic abnormality and the poor prognosis of these patients is likely to reflect a synergistic effect alongside deregulation of BCL6 or BCL2.

Prognostic significance of vascular endothelial growth factor (VEGF), VEGF receptors (VEGFR), and vascularity in diffuse large B-cell lymphoma treated with immunochemotherapy (R-CHOP)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 8581-8581
Author(s):  
D. Gratzinger ◽  
R. Advani ◽  
S. Zhao ◽  
N. Talreja ◽  
R. J. Tibshirani ◽  
...  
Keyword(s):  
B Cell ◽  
Cox Regression ◽  
De Novo ◽  
Cell Lymphoma ◽  
International Prognostic Index ◽  
Prognostic Significance ◽  
Prognostic Index ◽  
B Cell Lymphoma ◽  
Large B Cell Lymphoma ◽  
Large B Cell

8581 Background: Diffuse large B cell lymphoma (DLBCL) cells coexpress VEGF, VEGFR1 and VEGFR2. In patients (pts) treated with CHOP chemotherapy alone, VEGFR1 predicted improved overall survival (OS) while microvessel density (MVD) predicted poorer OS; VEGF and VEGFR2 were not predictive (Lab Invest. 2008;88:38). We now assess these factors in pts treated with R-CHOP. Methods: 162 pts with de novo DLBCL treated with R-CHOP and median followup of 44 months were evaluated retrospectively with immunohistochemistry on tissue microarrays. Scoring: VEGF, VEGFR1, VEGFR2, and phosphoVEGFR2 (pVEGFR2) in lymphoma cells (categorical variable) <5%, none; 5–30%, weak; >30%, strong. MVD (continuous variable): average CD34+ microvessels/4 hpf. Statistics: univariate Cox proportional hazards regression, and multivariate Cox regression for testing independence from the International Prognostic Index (IPI) for two endpoints, OS and progression-free survival (PFS). Pearson chi-square testing for independence of variables. Results: VEGF and MVD did not correlate with OS or PFS. Pts with higher VEGFR2 (53%) had poorer OS but not PFS independent of the IPI (z=3.15, p=0.0016; 2 yr OS 100%/84%/76%). Pts with any pVEGFR2 (13%) had worse PFS independent of IPI (z=1.98, p=0.048) and a trend toward poor OS (p=0.056). VEGFR1 did not correlate with OS or PFS in the group as a whole. Since VEGFR1 and VEGFR2 expression correlate strongly (Χ2=56, p =9.8E-12) opposing associations with outcome could be masked. On subset analysis the 39% of pts with weak VEGFR2 had better OS with higher VEGFR1 (z=-1.64, p=0.016; 2 yr OS 68%/85%/92%). Conclusions: In contrast to our prior observations in CHOP treated pts, in DLBCL treated with R-CHOP MVD was not prognostically significant. The association of VEGFR1 with better OS was previously seen with CHOP alone, whereas the correlation of VEGFR2 and phosphorylated VEGFR2 with poorer OS was only seen with R-CHOP. Independent confirmation will be important, especially because multiple comparisons were made with 5 predictors and 2 endpoints tested. It is possible that VEGFR1 and VEGFR2 oppose each other functionally; future studies are indicated to address the mechanism of this effect. No significant financial relationships to disclose.

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