Prognostic Significance of MYC Rearrangement and Translocation Partner in Diffuse Large B-Cell Lymphoma: A Study by the Lunenburg Lymphoma Biomarker Consortium

PURPOSE MYC rearrangement ( MYC-R) occurs in approximately 10% of diffuse large B-cell lymphomas (DLBCLs) and has been associated with poor prognosis in many studies. The impact of MYC-R on prognosis may be influenced by the MYC partner gene (immunoglobulin [IG] or a non-IG gene). We evaluated a large cohort of patients through the Lunenburg Lymphoma Biomarker Consortium to validate the prognostic significance of MYC-R (single-, double-, and triple-hit status) in DLBCL within the context of the MYC partner gene. METHODS The study cohort included patients with histologically confirmed DLBCL morphology derived from large prospective trials and patient registries in Europe and North America who were uniformly treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone therapy or the like. Fluorescence in situ hybridization for the MYC, BCL2, BCL6, and IG heavy and light chain loci was used, and results were correlated with clinical outcomes. RESULTS A total of 5,117 patients were identified of whom 2,383 (47%) had biopsy material available to assess for MYC-R. MYC-R was present in 264 (11%) of 2,383 patients and was associated with a significantly shorter progression-free and overall survival, with a strong time-dependent effect within the first 24 months after diagnosis. The adverse prognostic impact of MYC-R was only evident in patients with a concurrent rearrangement of BCL2 and/or BCL6 and an IG partner (hazard ratio, 2.4; 95% CI, 1.6 to 3.6; P < .001). CONCLUSION The negative prognostic impact of MYC-R in DLBCL is largely observed in patients with MYC double hit/triple-hit disease in which MYC is translocated to an IG partner, and this effect is restricted to the first 2 years after diagnosis. Our results suggest that diagnostic strategies should be adopted to identify this high-risk cohort, and risk-adjusted therapeutic approaches should be refined further.

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Prognostic Significance of MYC Single, Double, Triple Hit and MYC-Translocation Partner Status in Diffuse Large B-Cell Lymphoma - a Study By the Lunenburg Lymphoma Biomarker Consortium (LLBC)

Blood ◽

10.1182/blood-2018-99-113368 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 344-344 ◽

Cited By ~ 11

Author(s):

Andreas Rosenwald ◽

Laurie H Sehn ◽

Delphine Maucort-Boulch

Keyword(s):

Clinical Trials ◽

B Cell ◽

Prognostic Significance ◽

B Cell Lymphoma ◽

Prognostic Impact ◽

B Cell Lymphomas ◽

Cox Models ◽

Partner Gene ◽

Post Therapy ◽

Large B Cell

Abstract Introduction MYC-rearrangement (MYC-R) occurs in approximately 10-15% of diffuse large B-cell lymphomas (DLBCL) and several studies suggest an inferior progression free (PFS) as well as overall survival (OS) compared to DLBCL without MYC-R. However, the prognostic significance of MYC single-hit (MYC-SH), MYC double/triple-hit (MYC and BCL2 and/or BCL6 translocation; MYC-DH/TH) in the context of the MYC translocation partner (MYC-IG versus MYC-non-IG) is less clear due to relatively small sample sizes in prior studies. The Lunenburg Lymphoma Biomarker Consortium (LLBC) set out to address these questions in a large number of DLBCL treated uniformly with rituximab (R)-CHOP- or R-CHOP-like chemotherapy. Methods Relevant clinical data (IPI factors, PFS, OS) from patients with aggressive B-cell lymphomas with confirmed DLBCL morphology derived from registry cohorts (Canada: British Columbia Cancer, UK: Leeds/HMRN, Barts, USA: Stanford) and prospective clinical trials (Germany: RICOVER, MegaCHOEP, France: LNH01-5B and LNH03-B, HOVON: HO 46 and 84) were pooled in the LLBC database (n=5118). Interphase FISH analysis (mostly on tissue microarrays) was used to determine the MYC-, BCL2- and BCL6-rearrangement status. All DLBCL with available tissue underwent break-apart testing for MYC (Vysis, LSI, Abbott). Identified MYC-R cases were subjected to FISH break-apart testing for the BCL2- and BCL6 loci as well as to MYC/IGH fusion testing and, if negative, to MYC/IGK and MYC/IGL testing to allow designation of the final MYC-R status (MYC-IG versus MYC-non-IG). Information on the cell of origin (COO) was generated using immunohistochemistry (Hans classifier) and/or gene expression based methods. Survival probabilities were estimated using the Kaplan Meier method and survival curves were compared with the log-rank test. The effects of variables of interest were estimated using univariate and multivariate Cox models stratified on the variable 'cohort' and 'trial'. Results 2380 DLBCL patients with full data on PFS, OS, IPI factors and MYC FISH results were available for analysis. 263 DLBCL cases (11%) had MYC-R which was associated with inferior PFS and OS compared to DLBCL patients without MYC-R (59% versus 72% OS at five years; log-rank <0.001; 56% versus 64% PFS at five years; log-rank <0.002). This effect was observed in both COO subgroups (GCB and non GCB). Out of 163 MYC-R patients with complete FISH data, 40 were MYC-SH with an IG partner (24.5%) and 17 (10.5%) with a non-IG partner. 53 patients had a MYC DH/TH constellation with an IG partner (32.5%) and 53 patients (32.5%) with a non-IG partner. The MYC-DH/TH group with an IG partner had the worst OS at 24 months: (50.9% compared to 76.4% for the remaining MYC-R DLBCL patients and to 82.4% for patients without MYC-R) (fig1). Similar results were obtained for PFS. In the MYC-DH group, there were no differences in OS and PFS between MYC/BCL2 and MYC/BCL6 'double hits'. Multivariate Cox models adjusting for the IPI and including a time-dependent effect showed, that the impact on outcomes was mainly seen in the first 24 months post therapy (hazard ratio (HR) of 2 [1.59-2.53] for MYC-R DLBCL patients compared to patients without MYC-R and a HR of 3.12 [2.09-4.64] for MYC-DH/TH tumors in which MYC is translocated to IG). In contrast, in MYC-R patients including MYC-SH and MYC-DH/TH without an IG partner, the HR was lower at 1.5 [1.01-2.24]. Conclusion This study by the LLBC in a very large cohort of DLBCL patients treated with R-CHOP or R-CHOP-like therapy confirms previous reports on the negative prognostic impact of an underlying MYC-translocation for both PFS and OS. This impact is predominantly observed in the first two years post therapy. Further, the large sample size extends previous observations that the partner gene of MYC (IG versus non-IG) also has prognostic impact. MYC-DH/TH DLBCL with an IG partner gene have the worst OS and PFS, while impact is moderate in other constellations (MYC-SH and MYC-DH/TH with a non-IG partner). Additionally, no differences between MYC/BCL2 and MYC/BCL6 'double hits' are seen in PFS and OS. Our results suggest that along with MYC testing in routine clinical practice, identification of the MYC partner gene (IG versus non-IG) is also warranted to identify further DLBCL subsets with poor outcomes which may have implications in the design and interpretation of future clinical trials. Figure 1. Figure 1. Disclosures Sehn: Merck: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria; Roche/Genentech: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Morphosys: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Lundbeck: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria.

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Conditional Survival of Patients with Diffuse Large B-Cell Lymphoma.

Blood ◽

10.1182/blood.v106.11.1911.1911 ◽

2005 ◽

Vol 106 (11) ◽

pp. 1911-1911

Author(s):

Michael B. Moller ◽

Niels T. Pedersen ◽

Bjarne E. Christensen

Keyword(s):

B Cell ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Risk Groups ◽

Prognostic Impact ◽

Conditional Survival ◽

Large B Cell Lymphoma ◽

The Individual ◽

The Impact ◽

Large B Cell

Abstract Purpose: Prognosis of lymphoma patients is usually estimated at the time of diagnosis, and the estimates are guided by the International Prognostic Index (IPI). However, survival rates calculated at the time of diagnosis may not be predictive of outcome for patients who have survived 1 or more years. For these patients conditional survival is more informative as only those patients who have already survived a period of time after treatment are considered. Conditional survival data have not been reported for lymphoma patients and the impact of the IPI on conditional survival is not known. Patients and Methods: Conditional survival was estimated for 1,209 patients with diffuse large B-cell lymphoma from the population-based LYFO-registry of the Danish Lymphoma Group. The patients were diagnosed between 1983 and 1998 with a median follow-up time of 7.8 years, and all patients were treated with curative intent. The Kaplan-Meier method was used to estimate conditional survival at 0–5 years after diagnosis. Results: The probability of surviving 5 years increased with each year survived for the first 3 years after diagnosis (from 43% to 70%) after which the increase was minimal (Figure 1). The median survival increased from 38 months for all patients to between 108 and 120 months conditioned on survival for at least 3 to 5 years. The distribution of patients in the IPI risk groups changed significantly over time. However this effect was only seen in the first 5 years. At diagnosis, 28% of the patients were allocated to the high-intermediate and high-risk groups, but only 11% of patients who survived 5 years were from these risk groups (P < .0001). Risk group allocation did not change the following 5 years (P = .7747). At the time of diagnosis overall survival differed greatly between the IPI risk groups (P < .0001; figure 2). However, 5 years after diagnosis the rates were similar (P = .0586). Furthermore, the prognostic impact of the individual clinical variables of the IPI (age, stage, performance score, LDH, and extranodal disease) was also significant at diagnosis, but 2 years after diagnosis only age had prognostic impact. Multivariate analysis (including the IPI and the individual IPI variables) of patients who survived ≥3 years identified only age as a prognostic factor (relative risk 4.1; P < .001). Conclusion: For patients with diffuse large B-cell lymphoma who have survived more than 1 year after diagnosis, the conditional survival probability provides more accurate prognostic information than the conventional survival rate estimated from the time of diagnosis. Furthermore, age is the most important factor for long-term survival, whereas the remaining IPI factors are not informative. Figure Figure Figure Figure

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Adverse Prognostic Impact of Neutrophil-to-Lymphocyte Ratio and Platelet-to-Lymphocyte Ratio in Patients with Diffuse Large B Cell Lymphoma

Blood ◽

10.1182/blood.v124.21.5410.5410 ◽

2014 ◽

Vol 124 (21) ◽

pp. 5410-5410

Author(s):

Sun-Young Kong ◽

Hyewon Lee ◽

Ji Yeon Sohn ◽

Hyeon-Seok Eom

Keyword(s):

B Cell ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Prognostic Impact ◽

Platelet To Lymphocyte Ratio ◽

Lymphocyte Ratio ◽

Large B Cell Lymphoma ◽

The Mean ◽

The Impact ◽

Large B Cell

Abstract Neutrophil-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) have been lightened as a prognostic factor in many types of solid tumor. However, there was a limited report for diffuse large B cell lymphoma (DLBCL). Thus, we investigated the impact of NLR and PLR on prognosis of patients with DLBCL. This study involved 234 DLBCL patients treated by rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) at National Cancer Center, Korea. The median patient age was 57 years, and 135 patients (58%) were men. Clinical characteristics as international prognostic index (IPI) including age, performance, LDH, stage and extra-nodal involvement, were evaluated. NLR and PLR at diagnosis were calculated by CBC data from automated hematologic analyzer XE2100 (Sysmex, Kobe, Japan) or differential count which was done by manually using stained peripheral blood slide when CBC data showed flags in auto-analyzer. Hazard ratios (HRs) were determined in terms of risk for overall survival using Cox proportional hazard regression analysis. The mean percentage of neutrophils and lymphocytes was 60 (range, 5-95) and 12 (2-79), and the number of platelets was 257 × 10^9/L (28-839). The mean and standard deviation of NLR and PLR was 3.62 (±4.77) and 14.7 (±20.16), respectively. IPI and stage were predictors for prognosis (p <0.01), and both NLR and PLR showed significant association with poor prognosis of HRs of 1.14 [95% confidence interval (CI), 1.10 to 1.20] and 1.02 [95%CI, 1.02-1.03]. Although both NLR and PLR represented association with IPI, there were still prognostic impacts as HR of 1.12 and 1.02 with IPI in multivariate analysis. These findings suggest that NRL and PLR may be significant prognostic indicators for patients with DLBCL treated by R-CHOP. Disclosures No relevant conflicts of interest to declare.

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

Frontiers in Oncology ◽

10.3389/fonc.2021.746577 ◽

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.

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

Blood ◽

10.1182/blood.v110.11.1565.1565 ◽

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

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

Journal of Clinical Oncology ◽

10.1200/jco.2009.26.3947 ◽

2010 ◽

Vol 28 (20) ◽

pp. 3360-3365 ◽

Cited By ~ 380

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.

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CD30 expression and its correlation with MYC and BCL2 in de novo diffuse large B-cell lymphoma

Journal of Clinical Pathology ◽

10.1136/jclinpath-2018-205039 ◽

2018 ◽

Vol 71 (9) ◽

pp. 795-801 ◽

Cited By ~ 2

Author(s):

Qi-Xing Gong ◽

Zhen Wang ◽

Chong Liu ◽

Xiao Li ◽

Ting-Xun Lu ◽

...

Keyword(s):

B Cell ◽

De Novo ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Clinicopathological Features ◽

Prognostic Impact ◽

Fluorescence In Situ Hybridisation ◽

Large B Cell Lymphoma ◽

The Impact ◽

Large B Cell

AimCD30+ diffuse large B-cell lymphoma (DLBCL) has emerged as a new immunophenotypic variant of de novo DLBCLs. However, the prevalence of CD30 positivity is variable according to different studies, and the prognostic significance of CD30 is also controversial. This study aimed to investigate the positive expression rate and prognostic impact of CD30 in de novo DLBCLs and try to find the correlated influences.MethodsA total of 241 patients with de novo DLBCL in east China from 2008 to 2015 were included to investigate the prevalence, clinicopathological features and outcomes of CD30+ de novo DLBCLs. Immunohistochemical evaluation for CD10, CD30, BCL2, BCL6, MUM1/IRF4, MYC and Ki67, and fluorescence in situ hybridisation for MYC and BCL2 gene alterations were performed.ResultsUsing a >0% threshold, CD30 expression was detected in approximately 10% patient with de novo DLBCL. These predominately presented with centroblastic or anaplastic morphological patterns, less frequently showing immunoblastic morphology or ‘starry sky’ pattern, mutually exclusive with MYC gene rearrangement, and negatively associated with BCL2 protein expression. CD30 expression was associated with a favourable prognosis of patients’ outcomes. However, the multivariate analysis revealed that it was not an independent prognostic factor in de novo DLBCLs. The impact of CD30 might be influenced by the international prognostic index and the expression of MYC and BCL2 proteins.ConclusionCD30+ DLBCL may be a subset of de novo DLBCLs with characteristic clinicopathological features, but the prognostic role of CD30 is limited.

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

Blood ◽

10.1182/blood.v124.21.5185.5185 ◽

2014 ◽

Vol 124 (21) ◽

pp. 5185-5185

Author(s):

Gisele Rodrigues Gouveia ◽

Suzete Cleusa Ferreira ◽

Sheila Siqueira ◽

Juliana Pereira

Keyword(s):

Gene Expression ◽

B Cell ◽

Cell Lymphoma ◽

International Prognostic Index ◽

B Cell Lymphoma ◽

Prognostic Impact ◽

Large B Cell Lymphoma ◽

Significant Difference ◽

The Impact ◽

Large B Cell

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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Prognostic Significance of BCL6 Translocation in Diffuse Large B-Cell Lymphoma Patients Treated with R-CHOP

Blood ◽

10.1182/blood.v112.11.3782.3782 ◽

2008 ◽

Vol 112 (11) ◽

pp. 3782-3782

Author(s):

Jesse Shustik ◽

Christian Steidl ◽

Laurie Sehn ◽

Randy D Gascoyne

Keyword(s):

Overall Survival ◽

B Cell ◽

Prognostic Value ◽

Cell Lymphoma ◽

Prognostic Significance ◽

B Cell Lymphoma ◽

Immunohistochemical Analysis ◽

Prognostic Impact ◽

Large B Cell Lymphoma ◽

Large B Cell

Abstract Translocation of the BCL6 oncogene is the most commonly-detected chromosomal abnormality in diffuse large B-cell lymphoma (DLBCL), but its prognostic significance remains uncertain. BCL6 translocation has been associated with variable outcomes in prior clinical series, and its clinical impact has not been reevaluated since the introduction of rituximab (R). The objective of this study was to determine the prognostic value of BCL6 translocation in DLBCL patients treated with both CHOP and R-CHOP immunochemotherapy. Methods We included 163 DLBCL patients treated with CHOP (n=72) or R-CHOP (n=73) at the British Columbia Cancer Agency between the years 1999–2002. Formalin-fixed paraffin-embedded diagnostic lymph node specimens were analyzed for BCL6 translocation on tissue microarray (TMA) by fluorescence in situ hybridization (FISH), using commercially available dual-color break-apart probes (Abbott Molecular, IL, USA). Immunohistochemical analysis was performed for BCL6, CD10, and MUM1 expression, and cases were categorized as germinal centre B-cell-like (GCB) or non-GCB using a standard algorithm (Hans, Blood 2004). Results BCL6 translocation status was evaluable in 145 cases, and was positive (BCL6+) in 26% (37/145). Median age (65 vs. 59 years, p=0.03) and overall IPI score (p=0.03) were higher in the BCL6+ than in the BCL6− subgroup. Presence of BCL6 translocation correlated with non-GCB phenotype by immunohistochemical analysis (p=0.03), and showed no significant association with BCL6 protein expression (p=0.32). Median follow-up duration was 4.8 years (range, 0.1–8.4). BCL6 translocation was associated with a trend toward decreased overall survival (OS) among patients treated with R-CHOP (5-year OS 46.7% vs. 68%, p=0.098), though not among CHOP-treated patients (5-year OS 36.4% vs.49.5%, p=0.393). Kaplan-Meier analysis limited to the BCL6+ subgroup showed no overall survival difference between patients treated with CHOP and R-CHOP (p=0.67). Conclusions BCL6 translocations are found in approximately 25% of patients with de novo DLBCL. Presence of BCL6 translocation appears to predict unfavorable outcome in DLBCL patients treated with R-CHOP. However, the adverse prognostic impact of BCL6 translocation is confounded by an association with high IPI score and with non-GCB phenotype. Prospective analysis within large clinical trials would help to determine the independent prognostic value of this marker in the rituximab era.

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LMO2 Protein Expression Predicts Survival in Patients with Diffuse Large B-Cell Lymphoma Treated with Immunochemotherapy (RCHOP): A Multicenter Validation Study

Blood ◽

10.1182/blood.v112.11.3769.3769 ◽

2008 ◽

Vol 112 (11) ◽

pp. 3769-3769

Author(s):

R. Advani ◽

N. Talreja ◽

R. Tibshirani ◽

S. Zhao ◽

A. Alizadeh ◽

...

Keyword(s):

Protein Expression ◽

B Cell ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Prognostic Impact ◽

Large B Cell Lymphoma ◽

The Impact ◽

Large B Cell ◽

Independent Cohort

Abstract Background: Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous entity which necessitates the characterization of prognostic markers to better define risk groups. Previously, we showed that the expression of LMO2 mRNA was a strong predictor of superior outcome in patients with DLBCL in a multivariate model of six genes (Lossos et al, NEJM 2004). Subsequently, using a novel monoclonal anti-LMO2 antibody, we showed that LMO2 protein expression predicted outcome in DLBCL patients treated with anthracyline-based chemotherapy with and without rituximab (Natkunam et al, JCO 2008). For validation of our prior findings we analyzed an independent cohort of DLBCL patients treated with RCHOP that had not been included in our previous study. Methods: 106 patients with de novo DLBCL treated with RCHOP and followed for clinical outcome were included. Immunohistochemistry (IHC) for LMO2 was performed on tissue microarrays containing cores of biopsies obtained at initial diagnosis. Specimens expressing LMO2 in more than 30% of neoplastic cells were defined as positive. LMO2 expression was correlated with the international prognostic index (IPI), overall survival (OS) and progression free survival (PFS). Results: The median age of the study population was 58.5 years (24–85). The distribution of patients according to the IPI was 47% low risk (0–1 factors), 24% low intermediate (2 factors), 14% high intermediate (3 factors) and 15% high risk disease (>=4 factors). 70 patients (66%) were LMO2 positive (compared to 55% in our original study). 18 patients (17%) have died and the median survival has not been reached. At a median follow-up of 32 months the 2 year OS for LMO2 positive versus negative cases was 91% (95% confidence interval [CI] 0.84, 0.98) versus 70.8% (95% CI 0.558, 0.875) respectively, p=0.04. No significant difference was observed in the 2 year PFS between LMO2 positive versus negative cases. A multivariate Cox regression analysis that included IPI scores and LMO2 expression as dependent variables for OS demonstrated a trend for LMO2 (p=0.07) and significance for the IPI (p=0.046) as independent predictors for OS. For PFS only the IPI remained statistically significant (p=0.03). Conclusions: This study validates the prognostic impact of LMO2 protein expression in the RCHOP treatment era in an independent cohort of DLBCL patients. Despite the higher proportion of LMO2 positive cases in the current cohort, a relatively short follow-up and few adverse events, LMO2 protein expression was associated with improved OS. Continued clinical follow-up of this cohort is ongoing to fully assess the impact on outcome. Assessment of LMO2 protein expression by routine IHC in biopsy samples of newly diagnosed DLBCL may help identify patients with different outcomes. Clinical trials will be necessary to assess the optimal therapy for patients based on LMO2 status.

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