on behalf of the ANRS HC-13 Lympho-C Study Group Hepatitis C virus (HCV) infection increases the risk of B-cell non-Hodgkin lymphomas (B-NHL). Antiviral treatment (AT) can induce hematological responses in patients with marginal zone lymphomas (MZL). The ANRS HC-13 Lympho-C study aimed at a better understanding of the impact of AT on HCV associated B-NHL. This multicentric study enrolled 116 HCV-positive patients with B-NHL between 2006 and 2012. Cytological and histological samples were collected for centralized review. At lymphoma diagnosis, median age was 61 years and gender ratio M/F was 1. Cytohistological distribution was marginal zone lymphoma (MZL) n 5 45 (39%), diffuse large B-cell lymphoma (DLBCL) n 5 45 (39%), and other types n 5 26 (22%). MZL patients had more frequent detection of rheumatoid factor (68% vs. 35%; P 5 0.001) and more frequently mixed cryoglobulinemia (74% vs. 44%; P 5 0.021) than patients with DLBCL. Among patients receiving AT, a sustained virologic response was achieved in 23 of 38 (61%) patients with MZL and in 9 of 17 (53%) with DLBCL (P 5 0.42). Three-year overall survival (OS) and progression-free survival were 78% 95%CI and 64% , respectively, without difference between cytohistological groups. Outcome analysis showed a favorable association between OS and AT in all patients (P 5 0.05) and in the subgroup of MZL patients only (P 5 0.04). Our data support that AT improves the outcomes of HCV-associated NHLs. The impact of new AT regimen with protease inhibitor needs to be investigated in this setting. [clinicalTrials.gov Identification number NCT01545544]Am.

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1927 Poster Board I-950 Introduction: Hepatitis C virus (HCV) associated B-cell non-Hodgkin's lymphoma (B-NHL) is a rare entity that constitutes a model to study chronic immune stimulation related lymphomas. They are known to be preferentially Marginal Zone Lymphomas (MZL) and Diffuse Large B Cell Lymphoma (DLBCL) subtypes. Conflicting results are reported on the association between Follicular Lymphoma (FL) and HCV. In order to study the physiopathology of HCV-related B-NHL, we pursue a multicentric observational study in France. We present here the clinicopathological characteristics of the patients included. Patients and methods: Adult patients with a history of HCV associated B-NHL are included in the study. HCV infection is defined by a positive viral load at diagnosis of NHL. Patients with HIV infection are excluded from the study. Each patient is followed every 6 months during 5 years. At each follow-up, a blood sample is withdrawn allowing ancillary studies. Data collection concerns clinical presentation, treatment and evolution of NHL and HCV infection. Pathological and cytological materials are centralized in order to allow their review and a concerted analysis by a group of expert hematopathologists, haematologists and immunologists. Results: The data of the 54 consecutive patients included between november 2006 and april 2009 in 20 french centers are presented. Median age is 63 years (ranging from 39 to 87 years). There is a predominance of men: sex ratio (m/f) is 1.45 (32/22). Included women are older than men (p<0.01), median age being 71 among women and 60 years among men. HCV genotypic distribution does not differ from expected in a HCV infected population in France: 1: 51% (25/49), 2: 29% (14/49), 3: 8% (4/49), 4: 12% (6/49), 5 missing data. Transmission risk groups, known in 50% (27/54) of cases, are transfusion (18), drug abuse (5), endemic origin (2), and tattoo/acupuncture (2). Two patients are co-infected with HBV. Twenty-four patients out of 42 tested (57%) had positive cryoglobulinemia at diagnosis of NHL. This proportion did not differ with gender nor with genotype. Fifteen cases were included at diagnosis of B-NHL. The 39 other cases were included during follow-up of NHL. The median interval between NHL diagnosis and last follow-up is 15 months (range 0-13y). The histological subtype distribution is DLBCL 39% (21), MZL 35% (19), FL 13% (7), CLL 6% (3). Remarkably, there is a continuum between MZL and DLBCL, 6 cases with ongoing transformation. Four cases could not be classified due to small disease infiltration or lack of material. We confirm the link between cryoglobulinemia and MZL, 12+ out of 17 tested, 6+/12 in DLBCL versus 2+/5 in FL and 1+/2 in CLL. Nodal involvement is infrequent (5 out of 21 cases of DLBCL, 2/19 MZL, 4/7 FL). Extranodal involvements predominated in spleen (15 including 8 MZL), lung (6), digestive tract (4), liver (3), heart (1), skin (6) and bone marrow (4). The efficiency of antiviral treatment is confirmed in 5 cases with MZL, and remarkably, was followed by a good response in one case with FL. However, most patients in this observational study received treatment with Rituximab (R) either alone (5 cases with MZL), or combined with chemotherapy (including 15 cases with DLBCL and 4 with FL) or with antiviral treatment. This was associated with good clinical responses in most cases and low toxicity. Indeed, only 5 patients died during follow-up – two from disease progression - a 85 y man and a 40 y woman with liver DLBCL who was resistant to 3 lines of R-chemotherapy. The other patients died of sepsis (2), and cardiac ischemia (1). Conclusions: This study strengthens the heterogeneity of HCV-related lymphomas. The observation of cases with MZL and, remarkably, of one case with FL responding to antiviral treatment suggests that they are both linked to chronic immune stimulation. Therefore, the concept of antigen-driven lymphomagenesis seems more heterogeneous than initially anticipated: it could involve a T independent response in MZL, and a T dependent response in FL. The ongoing pathophysiological study will improve further understanding of the mechanisms by which antigen-driven lymphoproliferation arise. Disclosures: No relevant conflicts of interest to declare.

3116 Background: Hepatitis C virus (HCV) associated B-cell non-Hodgkin's lymphoma (B-NHL) is a rare entity that constitutes a model of chronic immune stimulation related lymphomas. They are preferentially Marginal Zone Lymphomas (MZL) and Diffuse Large B Cell Lymphoma (DLBCL) subtypes. In order to study the characteristics of HCV-related B-NHL, we pursue a prospective multicentric observational study in France. We present here the characteristics and evolution of the patients included in this study. Patients and methods: Adult patients with a history of HCV associated B-NHL were included in the study. HCV infection was defined by a positive viral load at diagnosis of NHL. Patients with HIV infection were excluded from the study. Each patient was followed every 6 months during 5 years. Data collection included clinical presentation, treatment and evolution of NHL and HCV infection. Pathological and cytological materials were centralized and reviewed by a group of expert hematopathologists, haematologists and immunologists. Results: The data of the 64 consecutive patients included between nov 2006 and march 2010 in 20 centers are presented. Median age is 62 years (ranging from 39 to 87 years). There is a predominance of men: sex ratio 1.37 (m37/f27). HCV genotypic distribution does not differ from expected in France: 1: 52% (30/56), 2: 25% (14), 3: 11% (6), 4: 12% (7), 7 missing data. Twenty-six cases were included at diagnosis of B-NHL, 33 during follow-up of NHL and 5 at relapse. The median interval between NHL diagnosis and last follow-up is 22 months (range 0–152). The histological subtype distribution is DLBCL 39% (22), MZL 37% (21), FL 16% (9), CLL 4% (2), mantle cell lymphoma 4% (2). Remarkably, there is a continuum between MZL and DLBCL, with 6 cases with ongoing transformation. Eight cases are not classified due to small disease infiltration or lack of material. Expert review led to reclassification in few cases from DLBCL to MZL and from FL to MZL. Among the 22 patients with DLBCL, 3 have no follow-up. The median follow-up of the remaining 19 patients is 21 months. Those patients were treated with polychemotherapy combined with rituximab (R) in all cases except one. Treatment was followed by long lasting complete remission (CR) in all cases except three: a 59 y woman relapsed after Richter syndrome following CLL, a 85 y man progressed on therapy and a 40 y woman with liver DLBCL was resistant to 3 lines of R-chemotherapy. These three patients died from disease progression. During follow-up, 9 patients were treated with antiviral treatment followed by virologic response in all cases but one. The 21 patients with MZL are 8 splenic MZL including one with transformed DLBCL, 7 nodal MZL, 3 extra-nodal, and 3 Waldenstrom macroglobulinemia; 15 out of 19 cases were associated with positive rheumatoid factor (RF) and/or cryoglobulinemia. Two patients had no follow-up. The median follow-up of the remaining 19 patients is 40 months. The efficacy of antiviral treatment alone on HCV-associated MZL was confirmed in 8 patients and had a RF. The other patients were treated with R-chemotherapy (4), R+antiviral (2), R (2), oral chemotherapy (1) or “watch and wait” (1). The patient with splenic high grade transformation was treated by splenectomy alone and is still in CR. During follow-up, one patient relapsed and is currently treated with R-chemotherapy, two patients died including one after progression to DLBCL. Among the 9 patients with FL, one had no follow-up, 6 long-lasting CR were obtained following R-chemotherapy, one following three lines of treatment. One other CR was obtained following R-antiviral therapy. Three other patients received antiviral therapy during follow-up with efficacy in one case. Among the two patients with mantle cell lymphoma, one had no follow-up, the other one is on long term CR 6 years following first line chemotherapy (R-CHOP/R-DHAP). Conclusions: This study strengthens the heterogeneity of HCV-related lymphomas and the need for systematic expert review. Overall, these patients have a favourable outcome. Cases with MZL frequently respond to antiviral treatment and one case with FL to R-antiviral. Combined therapy of R- antiviral seems a good option and should be evaluated for low grade lymphomas. Patients with DLBCL should receive R-CHOP therapy and should be referred in hepatology department for antiviral treatment after chemotherapy due to frequent virologic responses and follow up of liver functions. Disclosures: No relevant conflicts of interest to declare.

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Introduction HCV infection is associated with the development of B-cell non Hodgkin lymphomas (NHL), preferentially of marginal zone lymphomas (MZL) and diffuse large B-cell lymphomas (DLBCL) subtypes. Other subtypes of B-cell NHL are rare. HCV-related lymphomagenesis may constitute in some cases a model of lymphoma induced by chronic antigenic stimulation. Moreover, a direct role of an infection of B cells by HCV is also an alternative hypothesis. We performed a multicentric observational study of HCV-related B-cell NHL in France in order to study the real distribution of their histological subtypes and their correlation with in situ expression of HCV virus. Patients & Methods Adult patients with B-NHL and active HCV infection were included in an observational multicentric study with the exclusion of those who were co-infected with HIV. Data were collected from patients with either ongoing or past history of HCV infection. Cytological and histological samples were collected for centralized review and molecular analyses. A large panel of antibodies was performed on each sample for subtyping the B-cell NHL and HCV-NS3 antibody immunostaining was made each time we had enough material. Results Between 2006 and 2012, 133 consecutive patients were enrolled in 26 French hospitals, among them 17 patients were excluded from analysis. At lymphoma diagnosis the median age was 61 years and the gender M/F ratio was 1. Histological samples of 81/116 patients were reviewed by a panel of expert hematopathologists. The most frequent B-cell NHL subtype was DLBCL in 30/81 patients (37.5%) among them 14/30 (46.6%) were transformed from underlying low grade B-cell NHL. For 26/30 DLBCL we had enough material for performing Hans score: 18 (69%) were of non germinal center (GC) origin and 8 (31%) of GC origin. Interestingly, most de novo DLBCL were of non GC subtype (92%) whereas in transformed DLBCL 50% were of non GC subtype. MZL represent 22/81 cases (27%), 8/81 (9.9%) were follicular lymphomas and other small B-NHL subtypes represent the other cases. Patients with DLBCL displayed frequent extra-nodal involvement (digestive tract, liver) (60%) and those with MZL had the highest proportion (73%) of extranodal localisations (spleen, bone marrow, blood, eye) whereas follicular lymphomas were mainly developed in lymph nodes. Twenty-nine cases could be tested for HCV NS3 antibody, 26 exhibited evaluable staining: 12 B-NHL had in situ positive staining (most of them were DLBCL (67%) with a slight predominance of transformed DLBCL compared to de novo (62%) and 14 had negative staining (most of them were MZL or other small B-cell NHL (92%). Conclusion This study underlines the heterogeneity of HCV-related B-cell NHL with a majority of extra-nodal localizations of these lymphomas, a predominance of DLBCL and MZL and a high proportion of DLBCL developed on low grade B-NHL comparing to de novo DLBCL. We found a different GC/non GC repartition between de novo versus transformed DLBCL with a higher proportion of GC versus non GC in transformed DLBCL than in de novo DLBCL. In situ HCV virus expression was more frequently observed in DLBCL than in other subtypes of B-NHL which could indicate that the growth and development of lymphoma cells may be associated with the presence of HCV infection of B cells. Therefore, we postulate that the B cell transformation is linked with chronic antigenic stimulation in MZL and to direct infection in DLBCL. It might also explain that virological success seems to improve prognosis preferentially in MZL subtype in our series. Disclosures: Haioun: Roche: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding.

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