OCT1 gene Expression Is an Independent Prognostic Factor in Diffuse Large B Cell Lymphoma

Abstract Background: Transcription factors associated with the POU domain modulate the expression of several genes of B lymphoid differentiation, including the IgH. The study of these factors allowed to better understand the pathogenesis of lymphomas and to establish the lineage and the differentiation stage of the malignant cell. The silencing of OCT1 in tumor cell lines reduced its malignant transformation, but its ectopic expression enhanced the tumorigenesis ability. However, few studies has been evaluated the role of the OCT1 gene expression in lymphoma. In this study we assessed the impact of the OCT1 gene expression in the survival of patients with Diffuse Large B Cell Lymphoma (DLBCL). Methods: From January 2006 to January 2011 were evaluated 77 patients with DLBCL treated with R-CHOP at Clinical Hospital and Cancer Institute of Sao Paulo University. The RNA was extracted from the paraffin block at lymphoma diagnosis and gene expression analysis was performed by relative quantification method by Real-Time PCR (qRT-PCR). After the data normalization using two different reference genes, the median expression of OCT1 was obtained. The overall survival (OS) and progression-free survival (PFS) were estimated by the Kaplan-Meier method. The relative risks were obtained by Cox regression bivariate intervals with 95% of confidence. The significance level of 5% was accepted and the IBM SPSS Statistics software version 20.0 was used. Results: Patients showing OCT1 expression < the median presented higher OS (p = 0.010) and PFS (p = 0.016) than patients with OCT1 expression ≥ median with a hazard rate (HR) for OS and PFS of 2.45 and 1.14, respectively. In multivariate analysis the PFS was also higher in patients with OCT1 expression < the median (p = 0.035). The stratification by the international prognostic index (IPI) and age showed that the expression of OCT1 < median showed a statistically significant difference in the OS (p = 0.048) in IPI intermediate-high (HI) and high (HR) patients (p = 0.048), with a HR of 2.32 in HI plus HR group. The PFS (p = 0.025) and OS (p = 0.025) were lower in patients ≥ 60 years and OCT1 expression ≥ the median. Conclusion: Our data suggest that the expression of OCT1 showed a predictive prognostic impact in DLBCL independently of IPI. Patients with lower expression of OCT1 presented a better OS and PFS. Figure 1 SG curve for the OCT1 gene expression. Figure 1. SG curve for the OCT1 gene expression. Figure 2 SLP curve for the OCT1 gene expression. Figure 2. SLP curve for the OCT1 gene expression. Figure 3 SG curve for to expression of OCT1 gene for subgroup IPI intermediate-high and high. Figure 3. SG curve for to expression of OCT1 gene for subgroup IPI intermediate-high and high. Disclosures No relevant conflicts of interest to declare.

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LAG3: a novel immune checkpoint expressed by multiple lymphocyte subsets in diffuse large B-cell lymphoma

Blood Advances ◽

10.1182/bloodadvances.2019001390 ◽

2020 ◽

Vol 4 (7) ◽

pp. 1367-1377 ◽

Cited By ~ 8

Author(s):

Colm Keane ◽

Soi C. Law ◽

Clare Gould ◽

Simone Birch ◽

Muhammed B. Sabdia ◽

...

Keyword(s):

Gene Expression ◽

T Cells ◽

B Cells ◽

B Cell ◽

Cell Lymphoma ◽

International Prognostic Index ◽

B Cell Lymphoma ◽

Large B Cell Lymphoma ◽

The Impact ◽

Large B Cell

Abstract Blockade of the PD-1 axis has modest efficacy in diffuse large B-cell lymphoma (DLBCL), but data regarding LAG3 are sparse. The impact of LAG3 digital gene expression was tested in 309 patients with DLBCL treated with standard chemoimmunotherapy. Cellular distribution of LAG3 protein was determined by immunohistochemistry and flow cytometry. In tumor-infiltrating lymphocytes (TILs), LAG3 expression was highest on CD4+ regulatory T cells (Tregs) and was also highly expressed on CD8+ T cells compared with CD4+ non-Tregs (both P = .008). LAG3high TILs were enriched in PD-1 and TIM-3. LAG3 was also expressed on a proportion of malignant B cells, and these patients had significantly higher LAG3 messenger RNA in their biopsies (P = .03). LAG3high gene expression was associated with inferior survival in discovery/validation cohorts, independent of cell of origin and the international prognostic index. Patients who were PD-L1high were fivefold more likely to be LAG3high (P < .0001). Patients who were LAG3high/PD-L1high had an inferior progression-free survival (P = .011) and overall survival (P = .005) compared with patients who were LAG3low/PD-L1high. Digital spatial protein analysis confirms LAG3 expression on T cells and, surprisingly, tumor-associated macrophages (TAMs) at higher levels than found on CD20+ B cells in the tumor microenvironment. LAG3 is frequently expressed on CD4+ Tregs and CD8+ TILs, typically with other immune checkpoints, and is also present in a proportion of malignant B cells in DLBCL and in areas enriched for TAMs. LAG3high expression is associated with poor outcome independent of conventional prognosticators.

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

10.1101/2021.03.03.433839 ◽

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.

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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

Journal of Clinical Oncology ◽

10.1200/jco.2017.73.2784 ◽

2017 ◽

Vol 35 (31) ◽

pp. 3538-3546 ◽

Cited By ~ 77

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.

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No Benefit from Rituximab Containing Regimens in Patients with Primary Extranodal Diffuse Large B-Cell Lymphoma

Blood ◽

10.1182/blood.v112.11.3615.3615 ◽

2008 ◽

Vol 112 (11) ◽

pp. 3615-3615

Author(s):

Gonzalo Gutiérrez-García ◽

Luis Colomo ◽

Neus Villamor ◽

Leonor Arenillas ◽

Antonio Martínez ◽

...

Keyword(s):

B Cell ◽

Cell Lymphoma ◽

International Prognostic Index ◽

Primary Cns Lymphoma ◽

Prognostic Index ◽

B Cell Lymphoma ◽

Cns Lymphoma ◽

Large B Cell Lymphoma ◽

The Impact ◽

Large B Cell

Abstract Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous category of lymphoid tumors that comprises different clinical forms not fully recognized in the WHO classification. In this regard, extranodal (EN) DLBCLs have particular clinicobiological features and outcome, sometimes related to the specific site where the lymphoma arises. Nowadays, rituximab plus chemotherapy (CT) is the gold-standard in the treatment of DLBCL. However, the superiority of rituximab-CT (R-CT) over CT alone has not been addressed for all the clinical subsets of the disease and, in fact, the clinical role of the new therapies might be different for primary nodal or EN DLBCLs. The aim of this study was to assess the impact of rituximab in patients suffering from nodal or EN DLBCL. Two-hundred and thirty non-immunocompromised patients (112M/118F; median age, 61 years) diagnosed with CD20+DLBCL in a single institution between 1997 and 2006 (five years before and after establishing R-CT as the standard treatment in DLBCL) and treated with adriamycin-containing regimens were the subject of the present study. The series included 148 primary nodal and 82 EN DLBCL. Patients with primary CNS lymphoma were excluded and lymphomas arising at Waldeyer ring were considered as nodal DLBCL. The main EN sites were GI (n=26), bone (n=13), soft tissue (n=13), lung/pleura (n=9), liver (n=9), and other (n=12). Main clinico-biological and evolutive variables were analyzed. One hundred nineteen patients received only CT and 111 R-CT. Eighty-seven cases with available information were assigned to germinal center B-cell-like (GCB) (41%) or non-GCB (59%) groups according to the Hans method (Blood2004;103:275–82) based on CD10, BCL6 and MUM1 expression. Main initial features, including the primary nodal or EN origin, international prognostic index (IPI), and GCB/non-GCB categories were similar for CT and R-CT groups. No correlation was observed between the GCB/non-GCB groups and the primary site of the tumor, although nodal lymphomas more frequently expressed MUM1 than EN (69% vs. 31%, respectively; p=0.01). CR rate and 5-year overall survival (OS) according to the treatment arm (CT vs. R-CT) is detailed for the whole series and for the nodal and EN groups in the table and OS curves depicted in the figure. In the whole series, variables predicting poor OS in the multivariate analysis were high-risk IPI (RR 2.5; p<0.001), primary nodal involvement (RR 1.6; p=0.04) and no R-CT treatment (RR 1.9; p=0.002). In the nodal group, IPI and no R-CT maintained the prognostic value, whereas in the primary EN only IPI predicted OS. Moreover, no difference in OS was observed according to the nodal or EN origin in those patients receiving R-CT. Biological subtypes GCB vs. non-GCB did not add predictive information neither in the whole series nor in the nodal or EN groups. In conclusion, patients with primary EN DLBCL seem to have little benefit from the use of R-CT. Nevertheless, this intriguing observation should be confirmed in further prospective studies. Complete response CR (%) 5-years OS (%) CT R-CT CT R-CT *p<0.002 R-CT vs. CT All cases (n=230) 59 79* 46 70* Primary nodal (n=148) 54 78* 34 71* Primary extranodal (n=82) 68 78 70 69 Figure Figure

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Clinical Significance of Immunohistochemical Markers of Diffuse Large B-Cell Lymphoma In the Rituximab Era.

Blood ◽

10.1182/blood.v116.21.1800.1800 ◽

2010 ◽

Vol 116 (21) ◽

pp. 1800-1800

Author(s):

Miyuki Hayama ◽

Masataka Okamoto ◽

Yuki Hagiwara ◽

Ken Tanae ◽

Mika Kohri ◽

...

Keyword(s):

Prognostic Factors ◽

B Cell ◽

Combination Chemotherapy ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Prognostic Impact ◽

Survival Ratio ◽

Large B Cell Lymphoma ◽

Significant Difference ◽

Large B Cell

Abstract Abstract 1800 Rituximab combination chemotherapy has significantly improved the treatment outcome of diffuse large B-cell lymphoma (DLBCL). Therefore, the prognostic factors of DLBCL in the rituximab era are different from previously reported prognostic factors. Biological prognostic markers have been analyzed to help understand the biologic basis of treatment outcome. Hans, et al. reported that patients with non-germinal center B-cell like (GCB)-type DLBCL had a significantly poorer prognosis than those with GCB-type DLBCL in the pre-rituximab era. In patients who received rituximab combination chemotherapy, there is a report that did not find a difference in survival ratio between those with GCB DLBCL or non-GCB DLBCL. On the other hand, there was a report that found a difference in survival ratio between patients with GCB DLBCL and those with non-GCB DLBCL. In the present study, we compared the prognostic factors of DLBCL between patients who received CHOP-like chemotherapy and those who received rituximab combined with CHOP-like therapy. The subjects were 204 DLBCL patients who underwent rituximab + CHOP-like therapy and in whom markers could be analyzed. We evaluated CD5, CD10, BCL2, BCL6, and MUM1 expression by immunohistochemistry. One hundred forty-six DLBCL patients who underwent CHOP-like therapy were assumed as historical controls. The median age was 52 years in both groups. In the R-CHOP-like and CHOP-like groups, patients with stage III or IV disease comprised 75% and 67%, respectively, patients with performance status3a2 comprised 28% and 20%, respectively, and patients with serum LDH >normal comprised 60% and 77%, respectively. There were no significant differences in clinical characteristics between the CHOP-like group and R-CHOP-like group. BCL2 was positive in 85(63%) of the 134 patients who received the R-CHOP-like regimen and in 66 (46%) of the 142 patients who received the CHOP-like regimen. When the 202 patients who received the R-CHOP-like regimen were divided into the GCB group and the non-GCB group, the GCB group consisted of 92 patients (46%) and the non-GCB group consisted of 110 patients. The relationships between immunohistological markers and outcome among the patients with DLBCL who received CHOP-like therapy were studied. CD5, CD10, and BCL6 had no prognostic impact on 5-year overall survival (OS) and progression-free survival (PFS) rates. When the patients were divided into the GCB DLBCL and non-GCB DLBCL groups, the 5-year OS of the GCB group was 78% and that of the non-GCB group was 57% (p<0.05). The 5-year PFS of the GCB group was 73% and that of the non-GCB group was 52% (p<0.05). The 5-year OS rate of the BCL2-positive and -negative groups was 61% and 74%, respectively (p<0.05). The 5-year PFS rate of the BCL2-positive and -negative groups was 55% and 70%, respectively (p<0.05). Thus, among patients who received the CHOP-like regimen, the BCL2-positive group showed significantly poorer prognosis than the BCL2-negative group. Next, the effect of rituximab with chemotherapy was examined. CD5, CD10, BCL2, BCL6, and MUM-1 had no prognostic impact on 5-year OS and PFS rates. When the patients were divided into the GCB DLBCL (n=92) and non-GCB DLBCL (n=110) groups, the 5-year OS of the GCB group was 74% and that of the non-GCB group was 75%, showing no significant difference. The 5-year PFS of the GCB group was 71% and the 5-year PFS of the non-GCB group was 69%, showing no significant difference. In the rituximab era, BCL2, MUM1 and non-GCB were not prognostic factors. As to reports on patients with DLBCL who received rituximab combination chemotherapy, there was a report in which the cases were separated into the GCB-type DLBCL and non-GCB-type DLBCL groups and compared. Fu, et al. reported that the survival of patients with GCB-type DLBCL was still superior to that of patients with non-GCB-type DLBCL in the rituximab era. However, other reports did not find a difference in survival ratio between those with GCB-type DLBCL or non-GCB-type DLBCL. In conclusion, the finding of improved OS and PFS with the addition of rituximab indicates that new biomarkers should be studied. Disclosures: No relevant conflicts of interest to declare.

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Comparison Between CD20-Negative and CD20-Positive Diffuse Large B Cell Lymphoma; Characteristics and Clinical Outcome

Blood ◽

10.1182/blood.v116.21.4891.4891 ◽

2010 ◽

Vol 116 (21) ◽

pp. 4891-4891

Author(s):

Jungmin Jo ◽

Changhoon Yoo ◽

Yongchel Ahn ◽

Seong Joon Park ◽

Shin Kim ◽

...

Keyword(s):

Clinical Outcome ◽

B Cell ◽

Conflicts Of Interest ◽

Cell Lymphoma ◽

Risk Group ◽

International Prognostic Index ◽

B Cell Lymphoma ◽

Large B Cell Lymphoma ◽

Significant Difference ◽

Large B Cell

Abstract Abstract 4891 Background CD20 is a non-glycosylated phosphoprotein expressed on the surface of all mature B-cells. CD20 is expressed on all stages of B cell development except the first and last. However, complete lack of CD20 expression occurred in a few cases without previous rituximab (R-) treatment. The immunohistochemostry (IHC) studies which we used were not perfect for confirmation of expression. However, we intended to investigate characteristics and clinical outcome of CD20-negative diffuse large B-cell lymphoma (DLBCL), not detected with usual method, and to compare with CD20-positive. Methods The records of Non-Hodgkin's Lymphoma patient registry were reviewed in Asan Medical Center. Between September 2003 and February 2009, a total of 407 patients were diagnosed DLBCL and 16 patients (3.9%) out of 407 confirmed CD20-negative DLBCL by IHC. The rest of patients (n=391) were CD20-positive and unconfirmed cases were excluded. Retrospective analysis of complete response (CR), disease-free survival (DFS), and overall survival (OS) was performed. Results The median age was 60.5 years old (range 31–81) in CD20-negative patients. Ten patients were males. The Ann Arbor stage was I in 3 patients, II in 3 patients, and III or IV in 10. Six patients were low risk group, 7 patients in intermediate, and 3 in high risk group according to international prognostic index (IPI). Most of patients (62.5%) received cyclophosphamide, doxorubicin, vincristin, and prednisone (CHOP) chemotherapy in CD20-negative and 295 patients (75.4%) with R-CHOP in CD20-positive DLBCL. The Baseline characteristics was not different in both groups except Hans classifier (p=0.02). With a median follow-up time of 32.3 months (range 0.5–83.4), the CR rate was 73.5%, the 3-year OS was 69.5%, and 3-year DFS 74.2% in all patients. CD20-positive and CD20 negative groups had a CR rate of 73.7%, 68.8% (p=0.146), respectively, a 3-year OS of 70.7%, 40.0% (p=0.003), a 3-year DFS of 75.4%, 44.6% (p< 0.001), respectively. The 3-year OS and DFS also had significant difference with adjusted IPI (p<0.001, respectively). Conclusions CD20-negaive DLBLC was not infrequently with usual IHC method (around 4%). The survival outcome was poor compared with CD20-positive DLBLC because of high relapse rate. It was caused without rituximab treatment in CD20-negative. Development of novel target agents like rituximab should be explored to improve outcome and maintain the CR status of CD20-negative DLBCL. Disclosures: No relevant conflicts of interest to declare.

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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 ◽

10.1182/blood-2007-02-072082 ◽

2007 ◽

Vol 110 (13) ◽

pp. 4396-4405 ◽

Cited By ~ 64

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.

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Impact of Concordant and Discordant Bone Marrow Involvement on Outcome in Diffuse Large B-Cell Lymphoma Treated With R-CHOP

Journal of Clinical Oncology ◽

10.1200/jco.2010.33.3419 ◽

2011 ◽

Vol 29 (11) ◽

pp. 1452-1457 ◽

Cited By ~ 132

Author(s):

Laurie H. Sehn ◽

David W. Scott ◽

Mukesh Chhanabhai ◽

Brian Berry ◽

Anna Ruskova ◽

...

Keyword(s):

Bone Marrow ◽

B Cell ◽

Cell Lymphoma ◽

Bone Marrow Involvement ◽

International Prognostic Index ◽

B Cell Lymphoma ◽

Prognostic Impact ◽

Bone Marrow Biopsies ◽

Large B Cell Lymphoma ◽

Large B Cell

Purpose In diffuse large B-cell lymphoma (DLBCL), prior studies suggest that concordant bone marrow involvement with DLBCL portends a poorer prognosis, whereas discordant bone marrow involvement with small B-cell lymphoma does not. We examined the significance of bone marrow involvement in patients treated in the current era of therapy including rituximab. Patients and Methods We performed a retrospective analysis of the prognostic impact of bone marrow involvement in an unselected population of patients with newly diagnosed DLBCL treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone in British Columbia and Auckland, New Zealand, with complete clinical information and evaluable staging bone marrow biopsies. Results In total, 795 patients were identified. Six hundred seventy (84.3%) of 795 had a negative bone marrow, 67 patients (8.4%) had concordant and 58 (7.3%) had discordant involvement. Median follow-up was 41 months (range, 1 to 115). Progression-free survival (PFS) was inferior in those with concordant (P < .001) and discordant (P = .019) involvement while overall survival (OS) was inferior in those with concordant involvement (P < .001) only. In a multivariate analysis controlling for the International Prognostic Index (IPI) score, concordant involvement remained an independent predictor of PFS (P < .001) and OS (P = .007). Discordant involvement was associated with older age, elevated lactate dehydrogenase, advanced stage, and increased number of extranodal sites and was not a negative prognostic factor independent of the IPI score. Conclusion The negative prognostic impact of discordant involvement is adequately represented by the IPI score, while the risk with concordant involvement is greater than that encompassed by this predictor. The results emphasize the need for accurate staging assessment of bone marrow involvement in DLBCL.

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Frequency of MYC Overexpression and MYC-BCL2 Double Expression (DEL) in Localized Diffuse Large B-Cell Lymphoma (DLBCL) at a Large Academic Cancer Center

Blood ◽

10.1182/blood-2018-99-111902 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4223-4223

Author(s):

Stephanie Ryanne Corder ◽

Ankit Agarwal ◽

Jonathan Galeotti ◽

Xianming Tan ◽

Natalie S Grover ◽

...

Keyword(s):

Risk Factors ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Stage I ◽

Prognostic Impact ◽

Advanced Stage ◽

Large B Cell Lymphoma ◽

Significant Difference ◽

The Impact ◽

Large B Cell

Abstract Background: Genetic and functional drivers of diffuse large B-cell lymphoma (DLBCL) have increasingly been used to prognosticate and occasionally even guide treatment for patients with advanced stage DLBCL. In advanced disease, the non-germinal center (non-GC) phenotype, double hit lymphomas (DHLs), and double expression lymphomas (DELs) have poorer outcomes. However, the incidence and impact of these factors on patient outcomes in the limited stage setting is not as well described. In particular, the prevalence of MYC and BCL2 overexpression has not been previously described in the literature for early stage DLBCL. The purpose of our analysis was to determine the incidence of these high-risk factors and analyze if these have an impact on outcomes in patients with stage I-II DLBCL. Methods: We performed a single site retrospective study of patients newly diagnosed with stage I-II DLBCL as defined by the Ann-Arbor staging system. All patients were treated at our institution, between 2011 and 2017. Patients with stage III-IV disease, concomitant follicular lymphoma, primary mediastinal lymphoma, or CNS lymphomas were excluded. The stage-modified IPI was used to categorize patients into different risk categories. Cell of origin (COO) was determined by the Hans criteria. Double expression was defined as overexpression of both MYC (positive ≥50%) and BCL2 (positive ≥70%). Molecular rearrangements of MYC with either BCL2 or BCL6 were used to define DHLs. MYC overexpression, BCL2 overexpression, double (MYC and BCL2) expression, MYC rearrangement, and Ki67 were quantified. Whenever possible, original patient histologic tissue samples were examined if information was not available in the original pathology report. The study examined the impact of these clinical and pathologic factors on progression-free survival (PFS). The impact of prognostic factors was analyzed with the Wilcoxon rank-sum for continuous variables and chi-square tests for categorical variables. Results: A total of 35 patients were identified with stage I-II DLBCL. The median age was 60 years old (range 25-86). Twelve patients (34%) were female. Patient characteristics are summarized in Table 1. Fifteen patients (43%) were treated with chemotherapy alone, while 20 patients (57%) were treated with a combination of chemotherapy and radiation. There were 8 patients (23%) with MYC overexpression and 27 patients (77%) with BCL2 overexpression. Six patients (17%) had double expression. Of the 6 patients who were double expressers, 2 (33.3%) progressed after frontline therapy, while 4 of 25 non-double expressers progressed (16%), although this was not a statistically significant difference. The COO was the non-GC type in 16 patients (45.7%) by Hans criteria. There was 1 patient with MYC rearrangement, and this patient had progression at distant sites. We did not identify any DHLs. There was 1 patient with CNS relapse, but this patient did not have double expression or MYC rearrangement. There was no significant difference in PFS associated with any of our identified clinical and pathological factors. Conclusion: In this retrospective review, we identified the proportion of patients who have high risk genetic and pathologic risk factors. The prognostic impact of the COO in localized DLBCL has been described, and our data support the previously published studies showing no difference in localized DLBCL (Savage et al., Blood 2016 and Johnson et al., JCO 2012). The prognostic impact of DELs has been well described in advanced stage DLBCL; however, the prognostic impact of DELs in localized DLBCL is not well described. To our knowledge, this is the first study reporting the frequency of MYC and BCL2 overexpression in localized DLBCL. While it is difficult to compare rates across trials, the rate of patients with double expression at 17% is lower than the rate of approximately 30% described for advanced stage DLBCL (Johnson et al., JCO 2012 and Hu et al., Blood 2013). Additionally, there was not a significant difference in the risk of progression for DEL versus non-DEL, but this was limited by the small sample size. Disclosures Grover: Seattle Genetics: Consultancy. Dittus:Seattle Genetics: Consultancy.

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Low Absolute Lymphocyte Counts in the Peripheral Blood Predict Inferior Survival and Improve the International Prognostic Index in Testicular Diffuse Large B-Cell Lymphoma

Cancers ◽

10.3390/cancers12071967 ◽

2020 ◽

Vol 12 (7) ◽

pp. 1967

Author(s):

Pauli Vähämurto ◽

Marjukka Pollari ◽

Michael R. Clausen ◽

Francesco d’Amore ◽

Sirpa Leppä ◽

...

Keyword(s):

B Cell ◽

Cell Lymphoma ◽

International Prognostic Index ◽

Prognostic Index ◽

B Cell Lymphoma ◽

Prognostic Impact ◽

Large B Cell Lymphoma ◽

Increased Risk ◽

Absolute Lymphocyte Counts ◽

Large B Cell

Low absolute lymphocyte counts (ALC) and high absolute monocyte counts (AMC) are associated with poor survival in patients with diffuse large B-cell lymphoma (DLBCL). We studied the prognostic impact of the ALC and AMC in patients with testicular DLBCL (T-DLBCL). T-DLBCL patients were searched using Southern Finland University Hospital databases and the Danish lymphoma registry. The progression free survival (PFS) and overall survival (OS) were assessed using Kaplan-Meier and Cox proportional hazards methods. We identified 178 T-DLBCL patients, of whom 78 (44%) had a low ALC at diagnosis. The ALC did not correlate with survival in the whole cohort. However, among the patients treated with rituximab (R) containing regimen, a pre-therapeutic low ALC was associated with an increased risk of progression (HR 1.976, 95% CI 1.267–3.086, p = 0.003). Conversely, intravenous (iv) CNS directed chemotherapy translated to favorable outcome. In multivariate analyses, the advantage of an iv CNS directed chemotherapy was sustained (PFS, HR 0.364, 95% CI 0.175–0.757, p = 0.007). The benefit of R and intravenous CNS directed chemotherapy was observed only in non-lymphopenic patients. The AMC did not correlate with survival. A low ALC is an adverse prognostic factor in patients with T-DLBCL. Alternative treatment options for lymphopenic patients are needed.

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