Abstract: Background. R-CHOP is the standard first-line treatment for elderly patients with diffuse large B-cell lymphoma (DLBCL). However 30% of patients will relapse and 70% of relapsed patients will die within 2 years of diagnosis. The REMARC study (clinicalTrials.gov NCT01122472) is an international, multicenter, double-blind, randomized, placebo controlled, phase III trial that assessed the benefit of lenalidomide (LEN) maintenance after response to R-CHOP in patients aged 60 to 80 years with untreated DLBCL, FL3b or transformed lymphoma. Patients achieving CR or PR at the end of 6 or 8 cycles of R-CHOP21 or R-CHOP14 were stratified by CR/PR status and country and randomized 1:1 to receive 2 years of LEN maintenance (25 mg/day for 21 of every 28 days) or placebo (PBO). The primary endpoint of the study was progression-free survival (PFS). Secondary endpoints were safety, PR to CR conversion rate, and overall survival (OS). Diagnosis was retrospectively centrally reviewed. In patients with adequate samples, GCB/nonGCB profile was assessed by the Hans algorithm and GCB/ABC/unclassified profile was assessed using NanoString gene expression profiling technology. Methods. From 05/2009 to 05/2014, 784 patients were enrolled either before R-CHOP (n= 437) or after completion of 6 or 8 cycles of R-CHOP (n= 347). At the end of R-CHOP therapy, 650 patients were randomized to maintenance, either in CR (n= 495) or in PR (n= 152). Central review found that 3 patients were randomized in SD or PD, all in LEN arm. At time of diagnosis, median age was 68 y (range 58-80), 43.5% were older than 70 y, and 56% were male. aaIPI was low in 38.5% and high in 57.5% of patients (missing data 4%). COO analyses are ongoing for both Hans algorithm and NanoString technology. Results. With a median follow-up of 40 months, median PFS (according to independent centralized radiology review) was not reached in the LEN group versus 68 months in the PBO group (hazard ratio favoring the LEN group, 0.708 (95% CI 0.537-0.932; p=0.0135))(See Figure). In the LEN group, 18 patients (21%) converted from PR to CR during maintenance compared to 13 patients (14%) in the PBO group. Immature overall survival data did not show any benefit for LEN arm, a lack of difference not attributable to an excess of lymphoma relapse, secondary cancer or safety problems in LEN arm. Deaths generally occurred off study drug (median time from last dose of study drug to death was 277 days (range 20, 1291) in LEN arm and 334 (41, 1594) in control arm. During maintenance, the most common observed grade 3 or 4 AEs were neutropenia (56% vs. 22%), rash (5% vs. 1%), infections (8% vs. 6%), and thrombocytopenia (2.5% vs. 0.6%) in LEN and PBO arms, respectively. Dose adjustments were necessary in 72% of the LEN patients and 42% of PBO patients. 59% of patients stopped LEN and 40% stopped PBO for toxicity (p 〈 0.001). Median number of cycles was 15 in LEN and 25 in PBO (p 〈 0.001). Secondary primary malignancies occurred in 33 patients receiving LEN and in 42 patients on PBO. Conclusion. This analysis of the REMARC study shows that 2 years of LEN maintenance in patients responding to R-CHOP significantly improved PFS (primary endpoint) without an early significant impact on OS. The COO analysis is currently ongoing. This is the first report finding that using an immunomodulatory agent as maintenance therapy prolongs PFS for patients with DLBCL after first line treatment with R-CHOP. Figure 1. Progression-free survival of elderly patients with diffuse large B-cell lymphoma in response to R-CHOP treated in maintenance with either lenalidomide or placebo Figure 1 Figure 1. Disclosures Thieblemont: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Research Funding; Bayer healthcare: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees. Gomez da Silva:Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; ROche: Consultancy, Membership on an entity's Board of Directors or advisory committees; takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol Meyer Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees. Morschhauser:Celgene: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Gilead Sciences: Consultancy, Honoraria; Janssen: Honoraria; Servier: Consultancy, Honoraria. Haioun:Sandoz: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees. Cabecadas:celgene: Consultancy, Honoraria. Salles:Gilead: Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Mundipharma: Honoraria; Roche/Genentech: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Coiffier:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Mundipharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Astra-Zeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celltrion: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

Abstract: Abstract 3676 Background: Diffuse Large B-cell Lymphoma (DLBCL) is a heterogeneous disease based on biological analyses of tumor cells, with for instance the determination of two molecular subgroups, one with a profile close to germinal center B-cells and the second to activated B-cells. Data from the biology of tumor microenvironment could also be helpful to define different prognostic subgroups of DLBCL. The role of the biology of the patient with DLBCL, i.e. the host-related factors is little explored. Epidemiological studies showed that some inherited genetic variation in immune genes could increase the risk of lymphoma development and some retrospective studies indicated that patient's outcome could be predicted by some germ line polymorphisms (SNPs) in cytokine genes. The aim of this study is to determine the prognostic impact of 13 SNPs in 7 immune genes, IL10 (4 SNPs), Tumor Necrosis factor α (TNFA), lymphotoxin α (LTA), BAFF (3 SNPs), IL1A, IL8RB, IL4R (2 SNPs) in a cohort of newly diagnosed DLBCL patients included in the GELA LNH2003 prospective trials all treated by rituximab combined with chemotherapy. Patients and Methods: 1564 patients from France, Switzerland and Belgium were included in the 5 prospective multicentric trials of the LNH2003 program of the GELA designed for DLBCL patients who were stratified in different subgroups based on age and International Prognostic Index (IPI) score. A sample of peripheral blood lymphocytes was collected before treatment from 760 patients who signed a specific consent form for this genetic study. After pathologic review and exclusion of patients not receiving rituximab (48 patients), 554 DLBCL patients were available for this study. SNPs were genotyped using a TaqMan® based assay. Results: The median age of the 554 patients was 61 years (range, 18–93 years), 57% of them were male and 50% of patients presented at diagnosis a 2–3 age-adjusted IPI score. Chemotherapy regimen consisted in a combination of rituximab with CHOP-21 (110 patients, 20%), CHOP-14 (181 patients, 33%), low dose CHOP for patients older than 80 years (60 patients, 11%), or ACVBP regimen (203 patients, 36%). At the end of treatment, complete response (CR) or unconfirmed CR was observed in 75% of patients. After a median follow-up of 38 months, the 3-year progression free survival (PFS) and overall survival (OS) was 70.2% and 75.7%, respectively. All the polymorphism distributions of the SNPs analyzed were consistent with Hardy-Weinberg equilibrium. The main initial clinical characteristics of patients were not different according to the 13 studied SNPs, except for IL4R (rs2107356), CC carriers presented less frequently B symptoms than CT and TT carriers (28% vs. 41% and 61%, P = .01). No correlation was observed between the quality of the response at the end of the treatment and each genotype of the 13 studied SNPs. The 3-year PFS and OS were overall not influenced by the genotyping of the 13 SNPs. However, a trend for a better 3-year PFS for LTA +252GG carriers compared to LTA +252AG and AA carriers was observed (79.7% vs. 64.6% and 72.7%, P = .04). Conclusions: To our knowledge, this is the largest prospective multicentric study that investigates the role of immune SNPs on treatment response and outcome in a large cohort of newly diagnosed patients with DLBCL receiving rituximab. No correlation between SNPs and treatment response was observed. Analyses of the impact on outcome of each individual SNP showed only a trend for a prognostic role on PFS of LTA A252G SNP, which is already described as a functional SNP. The results will be further precise by the correlation of IL10, BAFF and TNFA /LTA full haplotypes with response and outcome. Disclosures: No relevant conflicts of interest to declare.

Abstract: Anemia is a common feature at diagnosis of patients with lymphoid malignancies and has been previously described as an important prognostic factor (Moullet et al. Ann Oncol 1998). Recent guidelines recommend evaluating iron parameters as part of the initial assessment of cancer associated anemia in order to propose iron therapy for patients with functional or absolute iron deficiency. However, incidence of iron parameters abnormalities and impact on prognosis is largely unknown. Methods The phase III randomized LNH 03-6B protocol included elderly patients from 60 to 80-year with untreated diffuse large B-cell lymphoma and an age-adjusted International Prognostic Index (aaIPI) of 1 or more. Patients were randomized between 8 cycles of R-CHOP given every 2 or 3 weeks (Delarue et al. Lancet Oncol 2013) and between a prophylactic treatment with Darbepoetin alfa in order to maintain hemoglobin level between 13 and 14 g/dL versus an usual management of chemotherapy-induced anemia including ESAs and transfusions. Iron parameters including serum iron, transferrin and ferritin levels and transferrin saturation (TSAT) were measured at screening and at the end of study treatment. Iron deficiency was defined by TSAT below 20% and was considered either as true or functional if ferritin level was below or above normal or value, respectively. Results At diagnosis, median serum iron level was 9 µmol/L (n=358 patients, range: 0.14-62.6), median transferrin level was 2.1 g/L (n=262 patients, range: 0.3-29), median ferritin level was 325 ng/mL (n=321 patients, range: 6-6071) and median TSAT was 17% (n=258 patients, range: 2-57). Among patients with available TSAT data, 163/258 (63%) presented a coefficient lower than 20%. When comparing with the whole study population, patients with TSAT ≤ 20% had similar baseline characteristics including aaIPI. In univariate analysis, there is no difference of PFS (HR: 1.078, 95%CI: 0.734-1.584, p=0.7006) and OS (HR: 0.963, 95%CI: 0.622-1.491, p=0.8664) according to TSAT. By contrast, in univariate and multivariate analysis, patients with ferritin level lower than normal and patients with ferritin level higher than normal presented, compared with patients with normal ferritin level, worse PFS (respectively, HR: 4,973, 95%CI: 1.673-14.780, p=0.039; HR: 1,654, 95%CI: 1.094-2.499, p =0,017) and OS (respectively HR: 6.204, 95%CI: 1.713-22.475, p=0.0055; HR: 1.8, 95%CI: 1.108-2.923, p =0.0175). Conclusion Elderly patients with untreated aggressive lymphoma and iron deficiency as measured by TSAT showed similar characteristics compared to the whole population. TSAT level did not impact prognosis in contrast to ferritin level, whose variations could be independent of iron metabolism. The high frequency of iron deficiency at diagnosis raise the question of the use of IV iron as a frontline treatment of chemotherapy-associated anemia. A prospective, placebo-controlled, phase III trial is planned within our group, whose primary objective will be to demonstrate efficacy of ferric carboxymaltose alone compared to placebo as measured by the diminution of percentage of patients requiring red blood cell transfusion and/or ESA administration. Disclosures: No relevant conflicts of interest to declare.

Abstract: Abstract 90 Background: rituximab had dramatically improved the prognosis of patients with Diffuse Large B-cell Lymphoma (DLBCL) in combination with chemotherapy. Many biological and clinical studies suggested considerable inter-individual variability in term of anti-CD20 monoclonal antibody (mAb) activity with tumor and host-related influencing factors. Among host-related factors, the presence of functional polymorphisms in FcG receptors genes as FCGR3A-158V/F influences the affinity for IgG1 and consequently the antibody dependant cellular cytotoxicity (ADCC) with therapeutic mAbs such as rituximab. The clinical consequence reported to date consists in a better response rate to rituximab monotherapy for FCGR3A-158V homozygous patients treated for follicular lymphoma compared FCGR3A-158F carriers. In DLBCL and in the context of combination with chemotherapy, the role of FCGR3A and FCGR2A SNPs on treatment response and patient's outcome is not clear with few prospective studies. The aim of this study is to determine the impact of FCGR3A and FCGR2A SNPs on response and outcome of newly diagnosed DLBCL patients included in the prospective trials of the GELA (LNH2003 program). Patients and Methods: 1564 patients from France, Switzerland and Belgium were included in the 5 prospective multicentric trials of the LNH2003 program of the GELA designed for DLBCL patients who were stratified in different subgroups based on age and International Prognostic Index (IPI) score. A sample of peripheral blood lymphocytes was collected before treatment from 760 patients who signed a specific consent form for this genetic study. After pathologic review and exclusion of patients not receiving rituximab (48 patients), 554 DLBCL patients were available for this study. SNPs were genotyped using a TaqMan® based assay. Results: The median age of the 554 patients was 61 years (range, 18–93 years), 57% of them were male and 50% of patients presented at diagnosis a 2–3 age-adjusted IPI score. Chemotherapy regimen consisted in a combination of rituximab with CHOP-21 (110 patients, 20%), CHOP-14 (181 patients, 33%), low dose CHOP for patients older than 80 years (60 patients, 11%), or ACVBP regimen (203 patients, 36%). At the end of treatment, complete response (CR) or unconfirmed CR was observed in 75% of patients. After a median follow-up of 38 months, the 3-year progression free survival (PFS) and overall survival (OS) was 70.2% and 75.7%, respectively. The distribution of the VV, VF and FF FCGR3A alleles was 14.8%, 46.4%, 38.8%, and 27.8%, 48.6%, 23.6% for HH, HR and RR FCGR2A alleles, respectively, and were therefore consistent with Hardy-Weinberg equilibrium. Initial clinical characteristics of patients (age, sex, Performance Status, stage, B-symptoms, number of extra-nodal sites, LDH level, IPI) were not different according to the two FCGR SNPs. CR/CRu after induction therapy was observed in 61%, 66%, 61% for VV, VF and FF carriers (P = .46) and 60%, 64%, 64% for HH, HR and RR carriers (P =.70), respectively. No difference of response after consolidation treatment was observed between each genotype of FCGR3A and FCGR2A SNPs. The 3-year PFS was 65.3%, 71.4%, 70.5% for FCGR3A VV, VF and FF carriers (P = .43) and 69.2%, 67.6%, 76.6% for FCGR2A HH, HR, RR carriers (P =.09), respectively. The 3-year OS was also not different between the three genotypes of each FCGR SNPs. Conclusions: To our knowledge, this is the largest prospective multicentric study that investigates the role of FCGR2A and FCGR3A SNPs on treatment response and outcome in a large series representing the whole spectrum of DLBCL patients. Based on these results, modification of rituximab schedule according to the FCGR3A and FCGR2A genotypes does not appear worth investigating. Others host-related factors influencing the efficiency of immunotherapy need to be investigate. Disclosures: No relevant conflicts of interest to declare.