Diffuse Large B-cell Lymphoma Group Research Articles

Open-Label Phase 2 Study Of The Bispecific T-Cell Engager (BiTE®) Blinatumomab In Patients With Relapsed/Refractory Diffuse Large B-Cell Lymphoma

IntroductionBlinatumomab, a bispecific T-cell engager (BiTE®) that redirects cytotoxic T cells to CD19+ B-lineage cells, has shown anticancer activity and acceptable toxicity in a phase 1 study in patients with relapsed/refractory non-Hodgkin lymphoma, including diffuse large B-cell lymphoma (DLBCL). Using a stepwise dose escalation treatment, the overall response rate (ORR) in patients with DLBCL was 55% (Goebeler et al. Hematol Oncol 2013;31[suppl 1]:197). This open-label phase 2 study has been initiated to investigate the efficacy and tolerability of blinatumomab in patients with relapsed/refractory DLBCL, comparing stepwise dose escalation with constant target dosing. MethodsIn this ongoing study, eligible patients must be ≥18 years of age, must have relapsed/refractory DLBCL and Eastern Cooperative Oncology Group performance status ≤2. Blinatumomab is administered by continuous intravenous infusion over 8 weeks. In part 1 of the study, two cohorts were evaluated using a double-step or flat dose escalation regimen, respectively, in order to achieve the target dose of 112 μg/d. Part 2 will investigate the selected treatment schedule from part 1. Data from part 1 (cohorts I and II) are presented herein. Patients in cohort I received stepwise blinatumomab dosing of 9, 28, and 112 μg/d during weeks 1, 2, and thereafter, respectively; patients in cohort II received blinatumomab at 112 μg/d throughout. After a 4-week treatment-free period, patients achieving an objective response were permitted to receive a 4-week consolidation cycle. All patients received prophylactic dexamethasone. The primary endpoint is ORR by Cheson (2007) revised response criteria for malignant lymphomas. ResultsTo date, 11 patients have been enrolled and treated in part 1 of the study: nine in cohort I and two in cohort II. The median age was 73 years (range, 55–85); 64% of patients were women. Six (55%) patients had received ≥3 lines of previous systemic antitumor therapy; study treatment was given as fourth-line (median) systemic treatment. Three patients had received autologous hematopoietic stem cell transplantation. At the time of this analysis, seven patients were evaluable for response (cohort I, n=6; cohort II, n=1). The ORR based on independent radiological assessment was 57% (cohort I: complete response, n=1; partial response, n=2; cohort II: partial response, n=1). Three patients had progressive disease (all in cohort I). Four patients were not evaluable for ORR per protocol definition: early treatment discontinuation after <1 week on target dose in absence of disease progression, n=3; transformed DLBCL, patient only pre-treated for follicular lymphoma (patient achieved a CR), n=1. The most common adverse events (AEs) regardless of causality were tremor (64%), diarrhea (46%), and fatigue (46%). Ten of 11 patients had at least one grade ≥3 AE regardless of causality, with two patients (both in cohort II) experiencing grade 4 AEs (one patient with neutropenia and leucopenia; one with respiratory insufficiency). There were no grade 5 AEs. Ten of 11 patients had central nervous system (CNS) AEs, mostly tremor (64%), speech disorder (36%), and disorientation (27%). Five patients (cohort I, n=3; cohort II, n=2) had grade 3 CNS AEs (there were no grade 4 or 5 CNS events). The overall benefit/risk assessment revealed the dose administered in cohort I (stepwise dosing: 9, 28, 112 μg/d) to be the recommended dose for part 2 of the protocol. ConclusionsIn this ongoing phase 2 study, blinatumomab was tolerable and showed antitumor activity in adult, heavily pretreated patients with relapsed/refractory DLBCL. Part 1 of the study established a recommended blinatumomab dose for this patient population. The study continues to enroll patients in part 2 (cohort III). Disclosures:Libicher:Amgen Inc.: Consultancy. Degenhard:Amgen Research (Munich) GmbH: Employment; Amgen Inc.: Equity Ownership. Stieglmaier:Amgen Research (Munich) GmbH: Employment; Amgen Inc.: Equity Ownership. Zhang:Amgen Inc.: Employment; Amgen Inc.: Equity Ownership. Nagorsen:Amgen Inc.: Employment; Amgen Inc.: Equity Ownership. Bargou:University of Würzburg: Consultancy; University of Würzburg: Honoraria; Amgen Inc.: patent, patent Other.

MicroRNA Profiling in Ocular Adnexal Lymphoma: A Role for MYC and NFKB1 Mediated Dysregulation of MicroRNA Expression in Aggressive Disease

Ocular adnexal lymphoma (i.e., lymphoma with involvement of the orbit, eyelids, conjunctiva, lacrimal gland, and lacrimal sac), although rare, is common among malignant tumors involving the ocular adnexal region. The main subtypes are low-grade extranodal marginal zone lymphoma (EMZL) and aggressive diffuse large B-cell lymphoma (DLBCL). In rare cases, low-grade EMZL are reported to transform to DLBCL. It is unclear, however, which genetic events distinguish low-grade disease from aggressive, potentially fatal disease. Using LNA-based arrays from Exiqon, we performed global microRNA (miRNA) expression profiling of 18 EMZLs and 25 DLBCLs involving ocular adnexal sites to investigate changes in the miRNA expression in low- versus high-grade disease. Findings were confirmed by real-time quantitative PCR (RTq-PCR). Our analysis revealed 43 miRNAs with altered expression profiles in DLBCL compared to EMZL. Seven of the miRNAs down-regulated in DLBCL relative to EMZL showed enrichment for a direct transcriptional repression by the oncoprotein MYC. We also report a possible loss-of-regulation of NFKB1 and its downstream miRNAs. In addition, our analysis identified a group of DLBCLs whose expression profiles resembled that of EMZL. Although transformation of EMZL to DLBCL in the ocular adnexal region is rare, we hypothesize that the intermediate group potentially may derive from transformation of EMZL that was not recognized by histology. We conclude that fundamental differences in miRNA expression exist between ocular adnexal EMZL and DLBCL, mainly due to differences in MYC and NF-ĸB regulatory pathways.

Diffuse large B‐cell lymphoma and mantle cell lymphoma of the ocular adnexal region, and lymphoma of the lacrimal gland: An investigation of clinical and histopathological features

Diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL) constitute two distinct subtypes of non-Hodgkin lymphoma (NHL) associated with considerable morbidity and mortality. Marked diversities with regard to molecular biology and clinical features are recognized in different subsets of the two lymphomas. Because these differences could be related to the location of the lymphoma, it is of interest to investigate the clinical and histopathological features of DLBCL and MCL involving the ocular adnexal region (i.e. the orbit, eyelids, conjunctiva, lacrimal gland and lacrimal sac). Similarly, the lacrimal gland is the only glandular structure within the orbit. Because the lacrimal gland represents an important part of the immunological system, it is of interest to investigate lymphomas involving this location with regard to clinical and histological characteristics. To characterize the clinical and histopathological features of Danish patients with DLBCL of the ocular adnexal region between 1980 and 2009 and of Danish ocular adnexal MCL patients from 1980 to 2005. Furthermore, the aim of this PhD was to review all specimens from patients with lymphoma of the lacrimal gland in Denmark between 1975 and 2009 to determine the distribution of lymphoma subtypes of the lacrimal gland and to describe the clinicopathological features of these patients. A total of 34 patients with DLBCL and 21 with MCL of the ocular adnexal region were identified. Twenty-seven patients had lacrimal gland lymphoma, including four DLBCLs and three MCLs from studies I and II. Elderly patients predominated in all three groups, with median ages of 78, 75 and 69 years in the DLBCL, the MCL and the lacrimal gland lymphoma groups, respectively. MCL patients had a preponderance of males, whereas females prevailed among lacrimal gland lymphoma patients. The orbit was the most common site of involvement in DLBCL and MCL. Most DLBCL patients had unilateral involvement, while MCL patients had a high frequency of bilateral involvement. Similarly, localized lymphoma was relatively frequently seen in DLBCL patients in contrast to the predominance of disseminated lymphoma in the MCL group. The majority of lacrimal gland lymphomas were low grade, and the distribution of subtypes was as follows: extranodal marginal zone lymphoma, 10 (37%); follicular lymphoma, 5 (19%); DLBCL, 4 (15%); MCL, 3 (11%); chronic lymphocytic leukaemia/small lymphatic lymphoma, 2 (7%); and unclassified B-cell lymphoma, 3 (11%). The overall survival rates at 3 and 5 years for the entire study group of DLBCL were 42% and 20%, whereas 58% and 22% of MCL patients were alive 3 and 5 years after the time of diagnosis. The 5-year overall survival rate of lacrimal gland lymphoma patients was 70%. Concordant bone marrow involvement and the International Prognostic Index score were predictive factors for the overall survival in the DLBCL group in Cox regression analysis. Rituximab-containing chemotherapy was associated with an improved survival rate in MCL patients. Diffuse large B-cell lymphoma and MCL involving the ocular adnexal region and lymphoma of the lacrimal gland are prevalent among elderly patients. The overall prognosis in DLBCL and MCL was poor, whereas the prognosis for lacrimal gland lymphoma patients was relatively good. Concordant bone marrow involvement and the International Prognostic Index score were independent predictive factors for mortality in the DLBCL group. Chemotherapy containing rituximab significantly improved survival in the MCL group.

Association of circulating regulatory T cell number with the incidence and prognosis of diffuse large B‐cell lymphoma

Regulatory T (Treg) cells are essential for maintaining immune tolerance. High Treg frequencies have been reported in peripheral blood and tissue samples of patients with solid tumors while their role in lymphomas, including diffuse large B-cell lymphoma (DLBCL) has not been clearly established. In this study, we analyzed the circulating Treg numbers in 27 patients with newly diagnosed DLBCL and 17 healthy individuals. Tregs were detected by flow cytometry based on CD4(+) CD25(high) FoxP3(+) phenotype. In addition, the expression of CD45RA, HLA-DR, CD62L, CD39, and CTLA4 was analyzed. The number of circulating Treg cells was lower in patients with DLBCL than in healthy controls: median 23 (range, 4-107)/μL vs. 41 (19-104)/μL (P = 0.04). In particular, the number of Tregs expressing CD45RA (naïve Tregs), HLA-DR (marker of activation), and CD62L (L-selectin) was decreased in the DLBCL group. Lower (below median) number of circulating Tregs was associated with reduced chance of achieving complete remission (29% vs. 69%, P = 0.05) and reduced probability of even-free survival (24% vs. 84% at 1 yr, P = 0.0004), independently on the International Prognostic Index. We conclude that low number of circulating Tregs may be associated with poor prognosis in patients with DLBCL. However, our observations require confirmation in larger patient population.

A retrospective analysis of primary gastric diffuse large B-cell lymphoma with or without concomitant mucosa-associated lymphoid tissue (MALT) lymphoma components

Primary gastric diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease entity that includes patients with (DLBCL/MALT) and without detectable mucosa-associated lymphoid tissue (MALT) lymphoma components (de novo DLBCL). We sought to evaluate the clinical characteristics and outcome of this disease in a large number of cases. Patients with primary gastric DLBCL (n=162) seen on 2001-2011 at the Tianjin Medical University Cancer Institute and Hospital and the First affiliated Hospital of Chinese PLA General Hospital were retrospectively reviewed. The distribution of sex, age, Lugano staging, and other main clinical characteristics was similar between the de novo DLBCL and DLBCL/MALT groups (p>0.05). However, the proportion of patients with a stage-modified international prognostic index (m-IPI) ≥ 2 was higher in the de novo DLBCL (34 %) than the DLBCL/MALT group (17 %) (p=0.026). In addition, the Helicobacter pylori infection rates were higher in the DLBCL/MALT (75 %) than the de novo DLBCL group (36 %) (p<0.001). Five-year progression-free survival (PFS) and overall survival (OS) estimates were similar for patients in the de novo DLBCL (p=0.705) and DLBCL/MALT groups (p=0.846). Surgical treatment did not offer survival benefits when compared with chemotherapy for 5-year PFS (p=0.607) and OS estimates (p=0.554). There were no significant differences in 5-year PFS and OS estimates for patients treated with rituximab-chemotherapy (p=0.261) or conventional chemotherapy (p=0.227). Non-GCB subtype and m-IPI ≥ 2 were independently associated with shorter OS, and advanced stages of lymphoma were independently associated with shorter PFS.

Standard R-CHOP Therapy in Follicular Lymphoma and Diffuse Large B-Cell Lymphoma

The introduction of rituximab (R) has measurably improved the outcome of patients with follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL). To evaluate the outcome of patients with FL and DLBCL under R plus CHOP therapy, we performed a retrospective analysis in Yokohama City University Hematology Group in Japan. Five hundred and twenty-six patients (158, FL ; 368, DLBCL) were scheduled to undergo primary therapy with 6 cycles of full-dose R-CHOP therapy with curative intent. The median observation periods in living patients with FL and DLBCL were 45 months and 43 months, respectively. The complete response, 5-year progression-free survival (PFS), and 5-year overall survival (OS) rates were 86%, 50%, and 92% in the FL group, and 89%, 72%, and 80% in the DLBCL group, respectively. Although PFS was significantly better in the DLBCL group than in the FL group, OS was significantly better in FL patients. We also found that the OS and PFS of grade 3 FL patients were not statistically different from those with grade 1-2. These findings indicate that all grades of FL should be categorized simply as "FL" with regard to R-CHOP therapy. Our results also demonstrate the incurability of FL (grade 1-3B), even with R-CHOP therapy.

Non-Hodgkin Lymphomas Presenting as Soft Tissue Masses: A Single Center Experience and Meta-Analysis of the Published Series

Lymphomas with involvement of soft tissues as a primary event are very rare. The published studies have a small sample size, most of them being reported as case reports. In this article we describe our experience with soft tissue non-Hodgkin lymphomas (NHL) diagnosed and treated in our institution over a 15-year period. Moreover, we systematically review the available data from the literature in the past 2 decades, considering all the published series and case reports available from 1990 to 2011 using a PubMed access. In the monocentric analysis, 16 consecutive patients treated at our Institution from 1996 to 2011 were considered. In the literature search, we selected 16 case reports (18 patients) and 5 case series (49 patients), including a total of 67 patients. Eighty-three patients were finally considered in the combined analysis. The most common histologic subtype was diffuse large B cell lymphoma (DLBCL) (>50% of cases in both groups). In both analyses we observed an inferior outcome for DLBCL compared with indolent B-cell NHL (5-year progression free survival: 34% vs. 64%, respectively, in the combined analysis; P = .01). Furthermore, the prognosis in the DLBCL group appears to be worse compared with the historical data of DLBCL patients treated with chemoimmunotherapy. Though indolent soft tissue B-cell NHLs appear to have a good outcome, soft tissue DLBCLs represent an anatomic-clinical entity with aggressive features, and dismal prognosis. Strategies of first-line therapy intensification could be considered. Studies aiming to a better biologic characterization of this peculiar entity are warranted.

A Retrospective Analysis of Gastric Diffuse Large B-Cell Lymphoma with or without MALT Component

Abstract 4856 Background:The aim of this study was to evaluate the clinical characteristics, prognostic factors and survival outcomes of patients with gastric diffuse large B-cell lymphoma (DLBCL). Patients and methods:162 patients with gastric DLBCL were evaluated retrospectively. Comparisons were made between patients of gastric DLBCL with component of mucosa-associated lymphoid tissue lymphoma (DLBCL/MALT) and patients of gastric DLBCL without detectable MALT component (de novo DLBCL). Results:Results according to the distribution of sex, age, stage, performance status, and other clinical characteristics were similar between de novo DLBCL group and DLBCL/MALT group (p>0.05). The ratio of patients with the germinal center B-cell-like (GCB) subtype to non-GCB subtype did not differ significantly between the two groups (1:1.1 versus 1:1.6, p=0.319). However, the proportion of patients with the stage-modified international prognostic index (m-IPI) ≥2 was higher in DLBCL/MALT groups (18%) than taht in de novo DLBCL groups (34%) (p=0.026). In addition, the H. pylori infection rate was 75% in DLBCL/MALT versus 38% in de novo DLBCL (p<0.001). Patients with de novo DLBCL have better 5-year PFS and OS estimates than those DLBCL/MALT patients (p=0.037 and 0.019 for the 5-year PFS and OS estimates, respectively). Surgical treatment did not offer survival benefit when compared with chemotherapy (p=0.405 and 0.065 for the 5-year PFS and OS estimates, respectively). Multivariate analysis revealed that non-GCB classification and m-IPI≥2 were independently associated with shorter OS and advanced stage was independently associated with shorter PFS. Conclusion:Gastric DLBCL is a heterogeneous disease that included de novo DLBCL and DLBCL/MALT lymphoma. Compared with the former, the latter has a higher H. pylori infection rate. And what’s more, the proportion of patients with m-IPI≥2 is higher in DLBCL/MALT groups. De novo DLBCL was associated with higher 5-year PFS and OS estimates. Non-surgical treatment should be a primary consideration for gastric DLBCL. Immunophenotype classification and m-IPI were the most reliable factors for OS, and advanced stage was for PFS. Disclosures:No relevant conflicts of interest to declare.

Expression of MYC but Not pSTAT3 Is an Adverse Prognostic Factor for Diffuse Large B Cell Lymphoma (DLBCL) Treated with Epratuzumab/R-CHOP

AbstractAbstract 1575We recently demonstrated in a phase II study that the anti-CD22 monoclonal antibody epratuzumab added to RCHOP improved DLBCL survival parameters. Despite these advances, 30–40% of DLBCL patients still relapse and die of disease. Recent advances have led to the identification of a variety of intracellular oncogenic pathways as potential targets for lymphoma therapy. Specifically, many studies have found that activation of the Signal transducer and activator of transcription 3 (STAT3) pathway promotes tumor cell survival in various types of cancers. STAT3 is a transcription factor and exerts its anti-apoptototic effect through several downstream targets such as MYC. MYC protein can be expressed in lymphoma cells with or without the presence of MYC translocation. The frequency of phosphorylated STAT3 (pSTAT3) and MYC expression and their prognostic relevance are unknown within diffuse large B-cell lymphoma (DLBCL), germinal center B-cell (GCB) and non-GCB subtypes. This study studied the tumor cell expression of pSTAT3 and MYC by IHC paired with serum cytokine levels in a DLBCL patient population uniformly treated on N0489.DLBCL tumor samples (n=38) were stained for detection of nuclear pSTAT3 expression. Using a threshold of ≥30% of tumor nuclei staining positive, 35 % (14/40) of tumors were pSTAT3+. An additional 17% (7/40) had between 10–30% pSTAT3+ cells. Non-malignant tonsil tissues (n=10) were positive for tSTAT3 in all cases but all but one case were pSTAT3 negative. Twenty-four of the same DLBCL tumors used for pSTAT3 expression were stained for MYC and 50% (12/24) were MYC positive (all nuclear) as defined by the criteria of ≥30% of cells staining positive. In cases (n=23) where both MYC and pSTAT3 IHC were performed, a positive pSTAT3 was more likely to have MYC expression whereas a positive MYC stain did not inform pSTAT3. By using a break apart probe for the MYC gene, MYC translocations in the major breakpoint regions were found in 10% (3/29) of cases. When MYC FISH was correlated with MYC IHC in the 24 DLBCL cases that had both techniques performed, all 3 MYC translocation cases were GCB by IHC, two were strongly positive for MYC by IHC, and 1 was negative. Among the 21 MYC FISH negative cases, 10 were MYC positive by IHC. These data suggest that MYC expression in lymphoma is not only controlled by genetic events such as translocations but also by other signaling pathways such as STAT3. pSTAT3 expression was correlated with an elevated serum LDH (p=0.0007). Neither MYC or pSTAT3 tumor expression correlated with other clinical or pathological features. Survival analysis revealed a trend toward shorter EFS for DLBCL patients whose tumors expressed MYC protein by IHC (p=0.2) or had a MYC translocation (p=0.09) by FISH; pSTAT3 expression status did not predict EFS (p=0.9). Within the GCB group 10 cases were MYC negative (10/17; 59%) and 7 cases were MYC positive (7/17; 41%). Among the non-GCB group 83% (5/6) were MYC positive. These data clearly suggest a trend of higher MYC positivity in the non-GCB DLBCL group (p=0.07). MYC positive cases had a clear trend of inferior EFS in both GCB (p=0.2) and in non-GCB (p=0.5) groups. The distribution of pSTAT3 (n=38) expression was also evaluated in the GCB (n=26) and non-GCB (n=12) DLBCL. In the GCB group 27% (7/26) were pSTAT3 positive compared to 58% (7/12) in the non-GCB group. Thus, there was a clear trend toward higher pSTAT3 positivity in non-GCB DLBCL tumors (p=0.06); however, pSTAT3 status did not correlate with EFS in either GCB or non-GCB DLBCL patients. In the present study we correlated pretreatment serum cytokines levels of these patients with pSTAT3 and MYC tumor cell expression. Out of the 30 cytokines tested, the only pre-treatment cytokines that were significantly correlated with pSTAT3 expression were IL-10 (p=0.05), G-CSF (p=0.03) and TNFa (p=0.04); none were correlated with MYC expression.Overall, our data provide evidence that over-expression of pSTAT3 and MYC is common in DLBCL. These biomarkers have potential as prognostic factors in the case of MYC and as a tool for selecting therapy for pSTAT3. MYC may be especially useful to further identify an adverse group of DLBCL patients within the otherwise favorable GCB tumor group. The availability of JAK/STAT and STAT-specific inhibitors provides the rationale to incorporate pSTAT3 staining in tumors from patients who are participating in these trials to learn if this biomarker can predict response Disclosures:No relevant conflicts of interest to declare.

MicroRNA Profiling in Low-Grade Ocular MALT and Diffuse Large B-Cell Lymphoma: A Role for MYC and NFKB1 Mediated Dysregulation of MicroRNA Expression in Aggressive Disease

AbstractAbstract 1600 Introduction:Although rare, ocular adnexal lymphomas (i.e. lymphoma of the orbit, eyelids, conjunctiva, lacrimal gland and lacrimal sac), are among the most common malignant tumors involving the ocular adnexal regions. The main subtypes are low-grade mucosa associated lymphoid tissue (MALT) lymphoma and aggressive diffuse large B cell lymphoma (DLBCL). In rare cases low-grade MALT lymphoma are reported to transform to DLBCL. It is unclear, however, which genetic events distinguish low-grade disease from aggressive, potentially fatal, disease. Material and methods:A total of 18 MALT lymphomas and 25 DLBCLs involving ocular adnexal sites were included in the study. All sections were analyzed immunohistochemically by two independent pathologists (ER, SH) using the following panel of antibodies: bcl-2, bcl-6, CD3, CD5, CD10, CD20, CD23, CD79α, cyclin D1, MUM-1 and Ki-67. Confirmed cases of DLBCL were categorized as either germinal centre B-cell-like (GCB) or non-GCB types according to the algorithm by Hans et al. Using LNA-based arrays from Exiqon, we performed global miRNA expression profiling of RNA extracted from formalin-fixed paraffin-embedded (FFPE) tissue. The most differentially expressed microRNAs were confirmed by RT-qPCR analyses. Microarray processing was performed using the R environment. Results:Of the18 MALT patients (pts.) 15 pts. (83%) presented with Stage I lymphoma and 3 pts. (17%) had Stage IV. The 5-year overall survival for the entire population was 77%.In the DLBCL group 13 pts. (52%) presented with Stage I lymphoma, 3 pts. (12%) Stage II lymphoma, 1 pt. (4%) Stage III and 8 pts. (32%) presented with Stage IV lymphoma. Nine of the DLBCLs were classified as GCB and 16 as non-GCB type. The 5-year overall survival for the entire group was only 13%.Our miR arrays and confirmatory qPCR analysis revealed 43 miRNAs with significantly altered expression profiles (41 down- and 2 upregulated) in DLBCL compared to MALT lymphoma. Seven of the miRNAs down-regulated in DLBCL relative to MALT lymphoma showed enrichment for a direct transcriptional repression by the oncoprotein MYC. Supervised hieracical clustering analysis identified tree clusters: Cluster 1: MALT (high expression), cluster 2: DLBCL (intermediate expression), cluster 3 DLBCL (low expression). Thus, apparently the DLBCLs in cluster 2 seem to resemble MALT more than DLBCLs in cluster 3. We also report loss of miRNAs involved in the regulation of NFKB1 and DNA methyltransferases in DLBCL vs MALT. Conclusion:We conclude that fundamental differences in miRNA expression exist between ocular adnexal MALT lymphoma and DLBCL. Among the possible consequences of altered miRNA expression are increased NF-kB signaling and DNA hypermethylation. However, in line with the recent observations in gastric MALT/DLBCL transformation1, we suggest the differences may at least in part be caused by MYC transcriptional regulation of miRNAs in aggressive cases. The fraction of DLBCL that is reported to arise from MALT is exceedingly low. However, in the current study we find a group of DLBCLs (cluster 2), whose level of MYC regulated miRNA expression is intermediate between MALT (cluster 1) and DLBCL (cluster 3). Thus it could be speculated whether cluster 2 DLBCLs have developed secondary to a preceding MALT lesion, which, however was not detected by histology. Disclosures:No relevant conflicts of interest to declare.

GSTP1andCYP1A1Gene Polymorphisms and Non-Hodgkin Lymphoma

Objective: To determine the association between genetic variants of GSTP1 and CYP1A1 enzymes and individual susceptibility to diffuse large B-cell lymphoma (DLBCL), as well as correlations with tobacco smoking. Methods: Fifty patients with DLBCL and 50 apparently healthy volunteers were genotyped for detection of GSTP1 and CYP1A1 polymorphisms by the restriction fragment length polymorphism (RFLP) technique. Results: For GSTP1 313 A→G polymorphism, statistically significant differences were observed between the DLBCL and control groups for the AA, AG, and GG genotypes, as well as the G allele. For CYP1A1 4889 A→G (M2) polymorphism, statistically significant differences were observed for the AA and AG genotypes and the G allele. The relationship of smoking status to susceptibility to DLBCL in the presence of these genetic polymorphisms revealed that smoking status had no effect. Conclusion: GSTP1 313 A→G polymorphism is associated with a decreased risk of lymphoma, whereas CYP1A1 4889 A→G (M2) polymorphism is associated with an increased risk of lymphoma regardless of smoking status. * NHL : non-Hodgkin lymphoma ECOG : Eastern Cooperative Oncology Group LDH : lactate dehydrogenase SNPs : single nucleotide polymorphisms GST : glutathione S-transferase NADPH : nicotinamide adenine dinucleotide phosphate NQO1 : quinone oxidoreductase 1 DLBCL : diffuse large B-cell lymphoma IPI : International Prognostic Index RFLP : restriction fragment length polymorphism EDTA : ethylenediaminetetraacetic acid PCR : polymerase chain reaction dNTP : deoxyribonucleotide triphosphate CI : confidence interval CSF : cerebrospinal fluid NATs : N-acetyltransferases B-CLL : B-cell chronic lymphocytic leukemia CYPs : cytochrome P450s SLL : small lymphotic lymphoma CLL : chronic lymphocytic leukemia

Clinical and molecular characterization of diffuse large B-cell lymphomas with 13q14.3 deletion

Deletions at 13q14.3 are common in chronic lymphocytic leukemia and are also present in diffuse large B-cell lymphomas (DLBCL) but never in immunodeficiency-related DLBCL. To characterize DLBCL with 13q14.3 deletions, we combined genome-wide DNA profiling, gene expression and clinical data in a large DLBCL series treated with rituximab, cyclophosphamide, doxorubicine, vincristine and prednisone repeated every 21 days (R-CHOP21). Affymetrix GeneChip Human Mapping 250K NspI and U133 plus 2.0 gene were used. MicroRNA (miRNA) expression was studied were by real-time PCR. Median follow-up of patients was 4.9 years. Deletions at 13q14.3, comprising DLEU2/MIR15A/MIR16, occurred in 22/166 (13%) cases. The deletion was wider, including also RB1, in 19/22 cases. Samples with del(13q14.3) had concomitant specific aberrations. No reduced MIR15A/MIR16 expression was observed, but 172 transcripts were significantly differential expressed. Among the deregulated genes, there were RB1 and FAS, both commonly deleted at genomic level. No differences in outcome were observed in patients treated with R-CHOP21. Cases with 13q14.3 deletions appear as group of DLBCL characterized by common genetic and biologic features. Deletions at 13q14.3 might contribute to DLBCL pathogenesis by two mechanisms: deregulating the cell cycle control mainly due RB1 loss and contributing to immune escape, due to FAS down-regulation.

Diffuse large B cell lymphoma: Variants, subgroups and subtypes/entities

Diffuse large B-cell lymphoma (DLBCL) is the most common type of lymphoma worldwide, and represents a clinically, pathologically and biologicaly very heterogeneous group of tumours. Recent studies have subdivided diffuse large B cell lymphomas into morphological variants, molecular and immunophenotypical subgroups and distinct entities. An immunophenotypical subdivision of DLBCL, into germinal centre-like (GCB) and non-germinal centre-like (non-GCB) subgroups, using a combination of antibodies to CD10, BCL6 and MUM1, does not correlate exactly with gene expression profile of GCB and activated peripheral B-cells (ABC). Some studies reported that combination of CD10, BCL6 and MUM1 expression could subdivide DLBCL patients into long- and short-time survivors. The WHO classification of 2008. recognizes a group of aggressive B-cell lymphomas that are not readily classified as either Burkitt lymphoma (BL) or DLBCL, and provisional category of B-cell neoplasms with features intermediate between DLBCL and classical Hodgkin lymphoma. Furthermore, the new classification recognizes the patient age, site-specific categories, and clinical factors in defining variants of DLBCL. The WHO classification of 2008. is the result of successful international collaboration among pathologists, biologists and clinicians, but heterogeneous group of DLBCL will be the subject of further investigation.

Comparison of Comorbidity Scores and the Impact of Comorbidities on Length of Stay and Survival in Patients with Non−Hodgkin’s Lymphoma Treated with Autologous Stem Cell Transplant

Abstract 2091Autologous stem cell transplant (ASCT) is the treatment of choice for relapsed aggressive histology Non-Hodgkin's lymphoma (NHL) and is part of first line therapy for mantle cell lymphoma (MCL). Although treatment related morbidity and mortality from ASCT is considerably less than for allogeneic transplant, it is not without risk and can be affected by comorbid conditions. Two comorbidity scores have been used for stem cell transplant patients to assess risk, the Charlson Comorbidity Index (CCI) (Biol Blood Marrow Transplant 2008;14:840-6) and the Hematopoietic Stem Cell Transplantation Comorbidity Index (HCT-CI) (Blood 2005;106:2912-19). The Cumulative Illness Rating- Geriatric Severity Index (CIRS-G SI) has also been used in patients with cancer (J Clin Oncol 1998;16:1582-7). This project compares these comorbidity scores and examines the effect of comorbid conditions on outcomes post transplant.A retrospective chart review was performed on 101 patients with NHL receiving ASCT from 2003 to 2010 at our institution. Patients were conditioned using BEAM chemotherapy (BCNU, etoposide, cytarabine, melphalan). Variables collected included age, gender, diagnosis, international prognostic index (IPI), comorbidity scores, length of stay (LOS) and overall survival. The length of stay was calculated as the extra LOS (ELOS) beyond day 14 to account for some patients who were able to be discharged early for proximity reasons. Correlations were calculated using the Pearson Correlation Coefficient. Linear and Cox regression were used in the analysis.The median age of the patient population was 57 years (range 26–68 years) and 38% were female. The majority of patients had diffuse large B cell lymphoma (DLBCL) 57%, other histological subtypes included MCL 10%, follicular lymphoma (FL) 10%, transformed FL 7% and others 16%. The median follow-up time was 17.2 months (0.5–96 months) for the entire group, and 28 months (0.5–83) for the DLBCL group. For the DLBCL group, the international prognostic index (IPI) at diagnosis was 0–1 in 67% and 2–5 in 33%. The IPI at relapse was 0–1 in 55% and 2–5 in 45%. The median number of reinfused stem cells was 4.9 × 106 CD34+/ kg (range 1.7–27).The median score on the CCI was 2 (range 2–5), 73% of patients had CCI score of 2 or less, 23% had score of 3 and 4% had a score 4 or greater. The median score on the CIRS-G SI was 3 (range 1.6 – 4). The median score on the HCT-CI was 0 (range 0–5), 66% had a score of 0, 27% had a score of 1 or 2, and 7% had a score of at least 3. The Pearson correlation between the CCI and HCT-CI was 0.8 (p<0.001), between HCT-CI and CIRS-G was 0.3 (p=0.001) and between CCI and CIRS-G was 0.2 (p=0.03).The median survival for the entire group and the for the DLBCL patients was not reached. Survival estimates were 75% for the entire group at 24 months, and 75% for the DLBCL group at 36 months. There was no statistically significant relationship between any of the comorbidity scores and overall survival using Cox regression for either the entire group or the DLBCL group. On univariate analysis, for the entire group of patients, CCI was significantly related to ELOS (p=0.011) but the other comorbidity scores were not. For the DLBCL group, univariate analysis showed that ELOS was associated with CCI (p=0.037) and trended towards significance with HCT-CI (p=0.098). We also performed a multivariable analysis on the entire group looking for predictive factors for ELOS using age, gender, albumin and CCI and found that CCI and gender were significant (p=0.001 for both). In the DLBCL group the same multivariable analysis was done with the addition of IPI at relapse and we found that CCI (p=0.007) and gender (p=0.014) were significant, IPI at relapse, age and albumin were not.In conclusion, the CCI and HCT-CI comorbidity scores are highly correlated for this group of ASCT patients. The CIRS-G SI did not correlate as well with the other comorbidity scores. In this group of patients we could not detect any influence of comorbidity score on survival, however there seems to be a statistically significant relationship between the CCI score and length of stay. The HCT-CI and CIRS-G SI did not affect LOS in this study. There also seems to be a relationship between gender and length of stay, as male patients had a shorter duration of hospitalization. The results of this study will need to be investigated further with a larger sample size. Disclosures:No relevant conflicts of interest to declare.

Standard R-CHOP Therapy in Follicular Lymphoma and Diffuse Large B-Cell Lymphoma

Abstract 1630 Background:In almost all cases, follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL) are CD20 positive. Since the introduction of rituximab (R), the outcome of the patients with FL or DLBCL has improved perceptively. Since 2001 and 2003, the Yokohama City University Hematology Group in Japan has uniformly treated FL and DLBCL patients, respectively, with 6 cycles of standard (21 days) R-CHOP therapy with curative intent, except in the case of stage 1 FL. Here, we report our experience. Patients and Methods: Five hundred and twenty-six untreated consecutive patients (158, FL; 368, DLBCL) between 2001 and 2009 were the subjects of this study. All the patients were scheduled to undergo primary therapy with 6 cycles of full-dose R-CHOP in our 7 hospitals. Patients who had partial remission (PR) after the 4 initial cycles were administered a total of 8 R-CHOP cycles. Patients who did not achieve PR after the 4 initial R-CHOP cycles or those with disease progression at any given time received salvage therapy, and that time point was designated as the point at which the disease had started progressing. Patients who required more than 20% dose reduction were excluded from the study. Those with special forms of DLBCL, such as intravascular lymphoma, primary mediastinal large B-cell lymphoma, and T-cell-rich B-cell lymphoma, were also excluded. Additional local irradiation was performed in patients with PR or complete remission (CR) if deemed necessary by the attending physician. No patients received maintenance therapy with R. DLBCL patients who achieved CR but were initially at risk of central nervous system (CNS) involvement received methotrexate (15 mg) and hydrocortisone (25 mg) 4 times intrrathecally for CNS prophylaxis. Central pathological reviews were not performed; only the individual institutional diagnoses were used. Results: In the cases of FL, the pathological grading was grade 1 for 65 patients, grade 2 for 61 patients, grade 3a for 20 patients, and grade 3b for 12 patients. There were 81 men and 77 women, and the median age at diagnosis was 57 years (range, 25–76). In accordance with the International Prognostic Index (IPI), 60 patients were at low risk (L); 60, at low-intermediate risk (LI); 26, at high-intermediate risk (HI); and 12, at high risk (H). According to the Follicular Lymphoma IPI, 43 patients were classified as L; 49, as being at intermediate risk; and 59, as H. For 7 patients, the risk was undetermined. Ten patients received additional local irradiation in PR/CR at the end of the R-CHOP therapy. None received CNS prophylaxis. Twelve deaths were observed among the FL patients, 10 of which were due to the lymphoma. In the DLBCL group, there were 209 men and 159 women, and the median age at diagnosis was 64 years (range, 18–80). According to the IPI, 158 patients were classified as L; 93, as LI; 57, as HI; and 60, as H. Thirty-seven patients received additional local irradiation in PR/CR at the end of the R-CHOP therapy. CNS prophylaxis was performed in 42 patients who had an initial CNS risk and achieved CR. In the observaton period, there were 58 deaths among the DLBCL patients, 50 of which were due to the lymphoma. The median observation period for the living patients with FL and DLBCL was 45 months and 43 months, respectively. For the FL group, the CR, 5-year progression-free survival (PFS), and 5-year overall survival (OS) rates were 86%, 50%, and 92%, respectively. Between patients with grade 1–2 FL, and grade 3 FL, the PFS (P = 0.16) and OS (P = 0.17) were not significantly different. This was found to also be true when the PFS (P = 0.19) and OS (P = 0.32) of grade 1–3a and grade 3b FL patients were compared. For the DLBCL group, the CR, 5year PFS, and 5-year OS rates were 89%, 72%, and 80%, respectively. The PFS rate was significantly higher in the DLBCL group compared to the FL group (Fig 1(A), P = 0.001), but the OS was significantly greater in the FL group (Fig 1(B), P = 0.006). Conclusion: Standard R-CHOP therapy is effective for patients with FL and DLBCL, with the 5-year OS rate exceeding 80% for both. However, in the FL group, the PFS did not show a plateau, suggesting the incurability of this lymphoma with R-CHOP therapy. The good OS indicated the effectiveness of salvage therapy for FL patients. Since the OS and PFS in patients with grade 3 FL were similar to those in patients with grade 1–2 FL, all grades of FL should probably be categorized simply as “FL” with regard to R-CHOP therapy. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Molecular Signature Distinguishes Between Primary Mediastinal B-Cell Lymphoma and Diffuse Large B-Cell Lymphoma with Primary Involvment of Mediastinal Lymph Nodes

Abstract 2654 Background.Primary mediastinal (thymic) B-cell lymphoma (PMBL) has been recognized as a subtype of diffuse large B-cell lymphoma (DLBCL). It has its distinctive clinical and morphological features but differs from other types of DLBCL due to peculiar immunophenotype and gene expression profile. PMBL have a distinct gene signature with several highly expressed genes including MAL, JAK2, PDL1, PDL2 and TRAF1. PMBL molecular signature was associated with a more favorable survival compared to DLBCL cases with a non-germinal and germinal-center profile, supporting a distinct natural history for PMBL [A. Rosenwald et al., 2003, G. Lenz et al., 2008]. Aim.The aim of our study was to determine whether the quantitative expression analysis of JAK2, MAL, PDL1, PDL2 and TRAF1 genes may distinguish PMBL cases from other variants of DLBCL with primary involved of mediastinal lymph nodes. Patients and methods.31 patients with DLBCL with primary involvement of mediastinal lymph nodes and 12 patients with DLBCL without involvement of mediastinal lymph nodes were enrolled in the study. The diagnosis was made by morphological and immunophenotypic analysis of lymph nodes biopsy samples. Six healthy donors of lymphocytes constituted control group. The expression of JAK2, MAL, PDL1, PDL2 and TRAF1 genes was analyzed with RQ-PCR TaqMan hydrolyzing probes. Results.Normal median value of JAK2, MAL, PDL1, PDL2 and TRAF1 gene expression have been established according the data obtained in the set of normal donors. The gene was considered to be overexpressed if its value was more than normal median value + 3SD. In 12 patients with DLBCL without involvement of mediastinal lymph nodes there was no overexpression of MAL, PDL1 and PDL2 genes. In this group only 1 of 12 (8%) pts has the overexpression of JAK2 and 2 out of 12 (16%) pts the overexpression of TRAF1. In patients with DLBCL with primary involvement of mediastinal lymph nodes JAK2 gene was overexpressed in the 18/31 cases (58%), MAL–in the 6/31 (19%), PDL1–in the 2/31 (6%), PDL2–in the 5/31 (16%) and TRAF1–in the 2/31 (6%). Based on the overexpression of more than 3 genes we have separated from DLBCL group (31 cases) a distinct group with primary mediastinal (thymic) B-cell lymphoma 18/31 (58%) patients. So, in PMBL we revealed significant overexpression of at least 3 genes in 18/18 pts whereas in DLBCL with primary involvement of mediastinal lymph nodes no cases have such expression. Summary.Our data suggest that the quantitative molecular analysis of JAK2, MAL, PDL1, PDL2 and TRAF gene expression enables to distinguish PMBL from DLBCL with primary involvement of mediastinal lymph nodes. Disclosures:No relevant conflicts of interest to declare.

Limited PET-CT May Be Adequate for Interim and End of Therapy Response Assessment in Patients with Early Stage Hodgkin and Aggressive Non-Hodgkin Lymphoma - A Retrospective Single Center Study

Abstract 1562 Background:PET-CT is of central importance in the staging of patients with Hodgkin (HL) and non-Hodgkin aggressive lymphoma and in the assessment of their response to therapy. Repeated imaging of patients is associated with cumulative exposure to substantial doses of radiation that have been linked to an increased life attributed risk of cancer. Reduction of the PET CT imaging region will decrease significantly the cumulative radiation dose. Objectives:This study aims to evaluate whether a limited PET-CT focused to the initially involved field of view (FOV) at diagnosis, above or below the diaphragm, is sufficient for effective follow up and decision making in patients with early stage curable lymphoma. Methods:We retrospectively reviewed all patients treated in our center for HD and non-Hodgkin aggressive lymphoma that were diagnosed with stage I or II disease according to the Ann-Arbor staging system during September 2006 to December 2010. Included were patients that had a PET-CT preformed as part of their initial staging and that were followed by interim PET-CT and/or a PET CT at the completion of therapy. Clinical and epidemiologic data were extracted from the patients' medical charts. All PET-CT were reviewed by a nuclear medicine specialist. We then analyzed whether limiting the PET-CT imaging to the initially involved FOV at diagnosis, above or below the diaphragm, would miss findings obtained by standard PET CT. Results:Out of 668 patients 44 were eligible for full analysis. Patient median age at diagnosis was 37.5 years (range 19–84) and 59% of patients were females. Twenty seven patients had HD and 17 had diffuse large B cell lymphoma (DLBCL). Two cases of primary mediastinal DLBCL were included in the DLBCL group. Forty two patients had stage II disease while 2 patients were diagnosed at stage I. Thirty five patients (79%) had their lymphoma located above the diaphragm while 9 patients (21%) had disease involvement below the diaphragm.One hundred twenty seven PET-CT examinations were analyzed. Of these, 44 were preformed at diagnosis. Of the 43 interim exams preformed 32 were compatible with complete response (CR) and 11 were compatible with partial response (PR). Of the 40 PET-CT preformed at the end of treatment 34 were compatible with CR, 4 were compatible with PR and 2 showed a stable or progressive disease. There was no single case in which disease progressed outside the initially involved FOV. Thus, elements of response to therapy were contained and available for analysis within the preliminary filed of involvement in all cases. Conclusion:Our findings suggest that limiting PET-CT analysis of the initially involved FOV, above or below the diaphragm, in patients with early stage curable lymphoma may be satisfactory for response assessment and the associated clinical decision making. The use of limited PET-CT will significantly reduce patient exposure to cumulative radiation. The time required to complete limited PET-CT is reduced by 50% and the cost by more than 15%. To our best of knowledge this is the first analysis demonstrating the potential utility of reduction of PET CT FOV in curable lymphoma in adults. Disclosures:No relevant conflicts of interest to declare.

Prevalence and Prognostic Molecular Profiles in Hepatitis B Virus Infected Patients with Diffuse Large B Cell Lymphoma: A Retrospective Study From Chinese Population

Abstract 5211 Introduction:Meta-analysis demonstrated that B cell lymphoma appears to be at high risk of infection by Hepatitis B Virus (HBV). Recently, cohort study showed HBV infection is associated with the increasing risk of B cell type lymphoma. Retrospective studies demonstrated high prevalence of HBV infection in Chinese lymphoma patients, with HBsAg-positive rates ranging from 23.5% to 30.5%. HBsAg-positive Diffuse Large B Cell Lymphoma (DLBCL) patients are associated with younger age and more advanced stage. However, the relation between HBV infection and poor prognosis in DLBCL remains uncertain. Molecular markers based on Immunohistochemical (IHC) expression were widely used as prognostic markers in DLBCL. Our study aimed to investigate the prevalence of HBVinfection in the different subtypes of lymphoma, and the molecular prognostic profiles in HBsAg-positive DLBCL. Patient and Methods:From Jan 2008 to Dec 2010, a total of 672 patients diagnosed as lymphoma were tested for HBsAg. Of these, 399 were male and 273 were female; 426 were B-NHL, 216 were T-NHL and 30 were HL. The expressions of BCL-2, BCL-6, CD10, MUM-1 were tested in patients diagnosed with DLBCL. Results:We found the overall HBsAg-positive rate was 15.9% (107/672) in total lymphoma patients. The positive rate of HBsAg was higher in B-NHL patients (20%,85/426) than T-NHL(9.7%,21/216) and HL (3.3%,1/30) (P<0.001).The lower prevalence were observed several subtypes of lymphoma including mantle cell lymphoma (0/20, 0%), Burkett’s lymphoma (0/13, 0%), HL (1/29, 3.3%) and PTCL (4/53, 7.5%).The rate of HBV infection was higher in DLBCL patients (20.9%, 68/326). Among prognostic molecular profiles in DLBCL, the positive expression rates of BCL-2, BCL-6, CD10 and MUM-1 were 65.4% (134/205), 51.3% (116/226), 17% (39/230) and 61.5% (139/226), respectively. The non-GCB subtype accounted of 68.7% of DLBCL. Between HBsAg negative and positive group of DLBCL, the positive expression rates of BCL-2 were 64.1% vs 69.2% (P=0.498), CD 10 were 16.6% v 18.2%(P=0.781), MUM-1 were 60.5% vs 64.8%(P=0.567). However, the BCL-6 positive rate was slight higher in HBsAg negative group compared with positive group (55% vs40%, P=0.053). Finally, non-GCB subtype rates were 67.7% vs 68.7% in HBsAg negative and positive group DLBCL. Conclusion:Our date demonstrated that the infection rate of HBV was higher in DLBCL, whereas lower in the subtypes of mantle cell lymphoma, burkitt's lymphoma and HL. Based on IHC analysis, non-GCB subtype accounted of two-third of DLBCL in our series. Patients with HBsAg-positive DLBCL had lower positive rate of BCL-6. However, the expression of Bcl-2, CD10, MUM-1 seems no significant difference between patients with HBsAg-positive and negative DLBCL. Disclosures:No relevant conflicts of interest to declare.

Baseline Quality of Life Assessed with the EORTC QLQ-C30 Predicts the Treatment Outcome of Patients with Diffuse Large B-Cell Lymphoma: Results of a Prospective Cohort Study

Abstract 1595 Background:The self-reported Quality of life (QoL) assessment has been widely used as an endpoint for clinical trials along with traditional endpoints of response and survival because the QoL can provide the health-related information, and it should be considered another parameter to estimate the efficacy of treatment. However, there is growing evidence that the QoL assessment can be used as a prognostic factor in cancer patients. Thus, the prognostic value of baseline QoL was reported in several different types of cancers independent of other clinical prognostic factors. Considering the performance status of patients is an important prognostic factor in lymphoma, the assessment of QoL at diagnosis might be an informative tool for predicting treatment outcome of lymphoma. However, few data exists regarding the prognostic relevance of baseline QoL in patients with lymphoma. Thus, we evaluated the prognostic impact of baseline QoL on the outcome of patients with diffuse large B-cell lymphoma (DLBCL), the most common subtype of non-Hodgkin lymphoma. Methods:The Samsung Medical Center Lymphoma Cohort Study (SMCLCS) is a prospective cohort study registering patients diagnosed with Hodgkin and non-Hodgkin lymphoma at the Samsung Medical Center (NCT00822731). All patients completed the version 3.0 of the European Organization for Research and Treatment of Cancer (EORTC) Core Questionnaire (QLQ-C30) after they provided written inform consents. Among patients registered in the SMCLCS, we analyzed the baseline QoL and clinical data of 263 patients consecutively diagnosed with DLBCL between September 2008 and February 2011. Primary CNS lymphoma was excluded, thus, all patients were treated with rituximab-CHOP. We made a prognostic model according to the scores of three items: (1) Global health status representing general health condition, (2) Functional scale representing physical function, (3) Symptom scales representing symptoms and signs. Each item was counted as one point if the score of each item was higher than 50. Thus, patients were classified as good (3 points), moderate (2 points) and poor QoL (score =0 or 1) groups. The QoL scores of patients with marginal zone B-cell lymphoma (MZL, n = 110) were used as a control. Results:The median score of Global health status was 50 (range 0–100) while the median scores of Functional and Symptom scales were 78.4 (24.1–100.0) and 79 (25.9–100.0), respectively in patients with DLBCL. These scores were significantly lower than a control group, MZL (P < 0.05). When patients were categorized into three groups, the good and moderate QoL groups accounted for 43.0% (n = 113) and 41.1% (n = 108) of patients, respectively. The proportion of poor QoL group of DLBCL was 16.0% (n = 42), and it was higher than that of MZL (2.7%). When the QoL at diagnosis was compared with other clinical factors, the poor QoL was significantly associated with poor ECOG performance status (≤ grade 2) whereas age older than 60 years was not significantly related with the poor QoL. The clinical factors representing high tumor burden such as elevated serum LDH, the number of extranodal involvement and Ann Arbor stage were significantly associated with the QoL model, thus, patients with high tumor burden showed poor QoL (P < 0.05). In consistent with this, patients with high or high-intermediate International Prognostic Index showed worse QoL scores than low or low-intermediate risk group. The frequency of treatment-related mortality was significantly higher in patients belonging to moderate and poor QoL groups than good QoL group (P < 0.05). As a result, more than 20% of the moderate or poor QoL group failed to complete the planned treatment schedule of rituximab-CHOP while only 10% of patients of the good QoL group could not finish the treatment. As a result, the overall survival of the good QoL group was significantly better than moderate and poor QoL groups (p < 0.05). This risk stratification based on the baseline QoL assessment was independently prognostic for overall survival in the multivariate analysis after controlling for International Prognostic Index. Conclusion:The baseline quality of life assessed with the EORTC QLQ-C30 is significantly associated with high tumor burden and worse overall survival of DLBCL. Thus, this prospective result suggests that the it may become a feasible prognostic factor in patients with DLBCL. Disclosures:No relevant conflicts of interest to declare.

Matched‐pair analysis comparing the outcomes of primary breast and nodal diffuse large B‐cell lymphoma in patients treated with rituximab plus chemotherapy

Primary breast diffuse large B-cell lymphoma (DLBCL) is an extremely rare presentation of non-Hodgkin's lymphoma that has been associated with poorer clinical outcomes compared with nodal DLBCL in the pre-rituximab era. The aim of this study was to investigate the impact of rituximab on clinical outcomes in patients with primary breast DLBCL. Data from 25 female patients with primary breast DLBCL receiving rituximab plus chemotherapy were matched to 75 female patients (1:3) with nodal DLBCL by following five established prognostic factors (age, Ann Arbor stage, Eastern Cooperative Oncology Group performance status, serum lactate dehydrogenase level and B symptoms). Overall survival (OS) was similar between primary breast and nodal DLBCL groups (3-year OS rate, 82.2% vs. 90.7%, respectively; p = 0.345). In the analysis of immunohistochemically defined prognostic subgroups, 19 of 20 available cases in the primary breast DLBCL group displayed a non-germinal center (GC) phenotype. Compared with patterns of recurrence, extranodal progression in the breast or central nervous system (CNS) was significantly higher in the primary breast DLBCL group than in the nodal DLBCL group (p < 0.001). Additionally, the stage-modified International Prognostic Index was the only independent prognostic factor for OS in this population. This suggests that clinical outcomes of primary breast DLBCL might no longer be inferior to those of nodal DLBCL in the rituximab era, which might be associated with the intrinsic biologic characteristics of the non-GC phenotype. However, despite including rituximab, extranodal progression in the breast or CNS was problematic. This study was registered at www.clinicaltrials.gov as no. NCT01266668.