Abstract: Abstract 415 Background and aim of the study Genomic gains and losses play a crucial role in the development and progression of DLBCL and are closely related to gene expression profiles (GEP), including the germinal center B-cell like (GCB) and activated B-cell like (ABC) cell of origin (COO) molecular signatures. To identify new oncogenes or tumor suppressor genes (TSG) involved in DLBCL pathogenesis and to determine their prognostic values, an integrated analysis of high-resolution gene expression and copy number profiling was performed. Patients and methods Two hundred and eight adult patients with de novo CD20+ DLBCL enrolled in the prospective multicentric randomized LNH-03 GELA trials (LNH03-1B, -2B, -3B, 39B, -5B, -6B, -7B) with available frozen tumour samples, centralized reviewing and adequate DNA/RNA quality were selected. 116 patients were treated by Rituximab(R)-CHOP/R-miniCHOP and 92 patients were treated by the high dose (R)-ACVBP regimen dedicated to patients younger than 60 years (y) in frontline. Tumour samples were simultaneously analysed by high resolution comparative genomic hybridization (CGH, Agilent, 144K) and gene expression arrays (Affymetrix, U133+2). Minimal common regions (MCR), as defined by segments that affect the same chromosomal region in different cases, were delineated. Gene expression and MCR data sets were merged using Gene expression and dosage integrator algorithm (GEDI, Lenz et al. PNAS 2008) to identify new potential driver genes. Results A total of 1363 recurrent (defined by a penetrance 〉 5%) MCRs within the DLBCL data set, ranging in size from 386 bp, affecting a single gene, to more than 24 Mb were identified by CGH. Of these MCRs, 756 (55%) showed a significant association with gene expression: 396 (59%) gains, 354 (52%) single-copy deletions, and 6 (67%) homozygous deletions. By this integrated approach, in addition to previously reported genes (CDKN2A/2B, PTEN, DLEU2, TNFAIP3, B2M, CD58, TNFRSF14, FOXP1, REL…), several genes targeted by gene copy abnormalities with a dosage effect and potential physiopathological impact were identified, including genes with TSG activity involved in cell cycle (HACE1, CDKN2C) immune response (CD68, CD177, CD70, TNFSF9, IRAK2), DNA integrity (XRCC2, BRCA1, NCOR1, NF1, FHIT) or oncogenic functions (CD79b, PTPRT, MALT1, AUTS2, MCL1, PTTG1…) with distinct distribution according to COO signature. The CDKN2A/2B tumor suppressor locus (9p21) was deleted homozygously in 27% of cases and hemizygously in 9% of cases. Biallelic loss was observed in 49% of ABC DLBCL and in 10% of GCB DLBCL. This deletion was strongly correlated to age and associated to a limited number of additional genetic abnormalities including trisomy 3, 18 and short gains/losses of Chr. 1, 2, 19 regions (FDR 〈 0.01), allowing to identify genes that may have synergistic effects with CDKN2A/2B inactivation. With a median follow-up of 42.9 months, only CDKN2A/2B biallelic deletion strongly correlates (FDR p.value 〈 0.01) to a poor outcome in the entire cohort (4y PFS = 44% [32–61] respectively vs. 74% [66–82] for patients in germline configuration; 4y OS = 53% [39–72] vs 83% [76–90] ). In a Cox proportional hazard prediction of the PFS, CDKN2A/2B deletion remains predictive (HR = 1.9 [1.1–3.2], p = 0.02) when combined with IPI (HR = 2.4 [1.4–4.1] , p = 0.001) and GCB status (HR = 1.3 [0.8–2.3], p = 0.31). This difference remains predictive in the subgroup of patients treated by R-CHOP (4y PFS = 43% [29–63] vs. 66% [55–78], p=0.02), in patients treated by R-ACVBP (4y PFS = 49% [28–84] vs. 83% [74–92], p=0.003), and in GCB (4y PFS = 50% [27–93] vs. 81% [73–90], p=0.02), or ABC/unclassified (5y PFS = 42% [28–61] vs. 67% [55–82] p = 0.009) molecular subtypes (Figure 1). Conclusion We report for the first time an integrated genetic analysis of a large cohort of DLBCL patients included in a prospective multicentric clinical trial program allowing identifying new potential driver genes with pathogenic impact. However CDKN2A/2B deletion constitutes the strongest and unique prognostic factor of chemoresistance to R-CHOP, regardless the COO signature, which is not overcome by a more intensified immunochemotherapy. Patients displaying this frequent genomic abnormality warrant new and dedicated therapeutic approaches. Disclosures: Salles: roche: Consultancy.

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.

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: Introduction: Rituximab-alkylator combinations are the standard therapies for patients (pts) with iNHL, however, refractory disease nearly uniformly develops. Once iNHL becomes double-refractory to both rituximab + alkylating agents, there are limited options to induce durable remissions. PI3K-delta signaling is critical for activation, proliferation and survival of B cells, and is hyperactive in many B-cell malignancies. Idelalisib, a selective oral inhibitor of PI3Kd, demonstrated considerable clinical activity in double-refractory iNHL (Gopal NEJM 2014). FDA granted accelerated approval for Idelalisib (Zydelig®) in patients who have received at least two prior systemic therapies with relapsed FL or SLL. Based on these encouraging initial results, we now describe long-term follow up, safety, and remission durations of this double-refractory iNHL population treated with idelalisib. Methods: Eligible iNHL pts included those with measurable disease refractory to both rituximab and an alkylating agent. Refractory was defined as lack of response to, or progression of lymphoma within 6 months of completion of index therapy, confirmed by imaging. Idelalisib 150 mg PO BID was administered continuously until disease progression or intolerance. Responses were evaluated by an independent review committee, using standard criteria (Cheson, 2007, and Owen 2013). The new data cutoff date for this analysis was June 2014, 20 months after the last patient enrolled. Results: Enrolled pts (N = 125) had a median age of 64 years and included follicular lymphoma (FL) n=72 (58%), small lymphocytic lymphoma (SLL) n=28 (22%), marginal zone lymphoma (MZL) n=15 (12%) and lymphoplasmacytic lymphoma (LPL)/Waldenstrom's macroglobulinemia (WM) n=10 (8%). The median number of prior therapies was 4 [range 2-12], including bendamustine/rituximab (BR) (n=60) and rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone (R-CHOP) (n=56) and autologous transplant (n=14). 81 pts (65%) had prior bendamustine, of which 61/81 (75%) were refractory. 112 pts (90%) were refractory to their last regimen, and 99 pts (79%) were refractory to ≥2 regimens. 38 pts (30%) had elevated LDH, and 33 pts (26%) had bulky disease 〉 7 cm. The median time to progression from last prior therapy was 3.9 months. With a median exposure of 11.1 months (range 0.7 to 35.4), the overall response rate (ORR) is 56% (95% CI = 46.8-64.9) with 70 responders, comprising 12 CRs (9.6%), 58 PRs (46.4%). The median time to response was 1.9 months (time of first evaluation) and time to CR was 4.5 months. There were 43 pts with stable disease (SD) (34.4%). 90% of pts experienced some decrease in tumor burden. ORR for iNHL subtypes is: FL (54%), SLL (61%), MZL (47%), and LPL/WM (70%). CR rate for iNHL subtypes is: FL (14%), SLL (4%), MZL (7%), and LPL/WM (0%). Among responders, median DOR is 13.9 (0.03-31.3) months. DOR for iNHL subtypes in months (Figure 1) is: FL 11.8, SLL 13.9, MZL 18.4, and LPL/WM (not yet reached). Median PFS for all pts is 11.0 months, in comparison to a median PFS of the last prior regimen of 3.9 months (p 〈 .0001). The median PFS for individual subtypes in months was: FL 11.0, SLL11.1, MZL 6.6, and LPL/WM 22.2. The median overall survival of all patients was 30.8 months. The adverse events include (total%/≥ grade 3%) diarrhea/colitis (50/18), fatigue (30/2), nausea (31/2), cough (32/0), pyrexia (30/2), dyspnea (18/5), rash (14/2), pneumonia (14/11), and pneumonitis (4/3). Based on central laboratory measurements, Grade ≥3 ALT/AST elevations occurred in 18 pts (14%). Drug was temporarily held in these pts, and 11/15 pts (73%) were re-treated without recurrence of ALT/AST elevation. Overall, 30 pts (24%) have discontinued therapy due to adverse events. Conclusions: The prolonged administration of idelalisib was well tolerated, had an acceptable safety profile, and was highly effective in inducing and maintaining remissions in double-refractory iNHL population with an ORR of 56%, PFS of 11 months, and DOR of 13.9 months. The response rate and long term duration of responses in the small number of subjects with LPL/WM is very promising, and will be evaluated in larger trials of this disease. The observed disease control compared to prior regimens suggests the potential for prolonged clinical benefit in this challenging patient population with unmet medical need. Figure 1: Duration of Response by Disease Group. Figure 1:. Duration of Response by Disease Group. Disclosures Gopal: Gilead Sciences: Research Funding. Off Label Use: Zydelig is a kinase inhibitor indicated for the treatment of patients with: 1) Relapsed chronic lymphocytic leukemia (CLL), in combination with rituximab, in patients for whom rituximab alone would be considered appropriate therapy due to other co-morbidities; 2) Relapsed follicular B-cell non-Hodgkin lymphoma (FL) in patients who have received at least two prior systemic therapies; and 3) Relapsed small lymphocytic lymphoma (SLL) in patients who have received at least two prior systemic therapies.. Kahl:Gilead Sciences: Research Funding. de Vos:Gilead Sciences: Research Funding. Wagner-Johnston:Gilead Sciences: Research Funding. Schuster:Gilead Sciences: Research Funding. Jurczak:Gilead Sciences: Research Funding. Flinn:Gilead Sciences: Research Funding. Flowers:Gilead Sciences: Research Funding. Martin:Gilead Sciences: Research Funding. Viardot:Gilead Sciences: Research Funding. Blum:Gilead Sciences: Research Funding. Goy:Gilead Sciences: Research Funding. Davies:Gilead Sciences: Research Funding. Zinzani:Gilead Sciences: Research Funding. Dreyling:Gilead Sciences: Research Funding. Holes:Gilead Sciences: Employment, Equity Ownership. Sorensen:Gilead Sciences: Employment, Equity Ownership. Godfrey:Gilead Sciences: Employment, Equity Ownership. Salles:Gilead Sciences: Research Funding.

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: Obinutuzumab (GA101), a type II, glycoengineered, humanized anti-CD20 monoclonal antibody, was superior to rituximab in human diffuse large B-cell lymphoma (DLBCL) and mantle-cell lymphoma (MCL) xenograft models. In phase I of our study, obinutuzumab (GA101) exhibited encouraging activity but no clear dose-response relationship, and few patients had aggressive histologies. The efficacy and safety of two doses of obinutuzumab (GA101) were explored in our randomized phase II trial in patients with heavily pretreated DBLCL and MCL. Patients and Methods Patients were randomly assigned to receive eight cycles of obinutuzumab (GA101) either as a flat dose of 400 mg for all infusions (days 1 and 8 of cycle 1; day 1 of cycles 2 to 8) or 1,600 mg on days 1 and 8 of cycle 1 and 800 mg on day 1 of cycles 2 to 8. Results Forty patients were enrolled: 21 patients in the 400/400-mg treatment arm (DLBCL, n = 10; MCL, n = 11) and 19 patients in the 1,600/800-mg arm (DLBCL, n = 15; MCL, n = 4). End-of-treatment response was 28% (32% and 24% in the 1,600/800-mg and 400/400-mg study arms, respectively). Best overall response rates were 37% in the 1,600/800-mg arm and 24% in the 400/400-mg study arm (DLBCL, eight [32%] of 25 patients; MCL, four [27%] of 15 patients). Five (20%) of 25 rituximab-refractory patients exhibited treatment response, including four of 12 in the 1,600/800-mg group. The most common adverse events were infusion-related reactions (IRRs), which were manageable. Three patients had grade 3/4 IRRs. Grade 3/4 neutropenia was seen in only one patient. Conclusion Obinutuzumab (GA101) 1,600/800 mg achieves early steady-state concentration and clinical activity with an acceptable safety profile in relapsed/refractory DLBCL and MCL, supporting further exploration.

Abstract: Introduction: The CD19 antigen is broadly and homogeneously expressed across different B-cell malignancies, including diffuse large B-cell lymphoma (DLBCL). MOR208 is an Fc-enhanced, humanized, monoclonal antibody that targets CD19, leading to natural killer (NK) cell-mediated antibody-dependent cytotoxicity, macrophage-mediated antibody-dependent phagocytosis and direct cytotoxicity. The immunomodulatory drug, lenalidomide (LEN), has both antiproliferative and antiangiogenic effects, and can stimulate the activity of immune effectors, such as NK cells. MOR208 and LEN have each shown single agent activity in patients with relapsed or refractory (R-R) DLBCL. In addition, MOR208 and LEN have shown synergy in in vitro and in vivo lymphoma models. We present results of an ongoing, multicenter phase II study designed to assess the safety and efficacy of MOR208 combined with LEN in patients with R-R DLBCL (NCT02399085). Methods:Patients 〉 18 years of age diagnosed with DLBCL, an Eastern Cooperative Oncology Group performance status 0-2, and adequate organ function, who had relapsed after or were refractory to at least one but not more than three prior systemic therapies, including at least one CD20-targeting regimen, and who were not candidates for high-dose chemotherapy (HDC) and autologous stem cell transplantation (ASCT), were eligible. Patients with primary refractory disease (defined as no response to or progression during or within 6 months after completion of frontline therapy for DLBCL) were excluded. Treatment comprises up to twelve 28-day cycles of MOR208, administered intravenously at a dose of 12 mg/kg weekly during cycles 1-3 (plus a loading dose on day 4 of cycle 1), and every second week during cycles 4-12. LEN was administered orally at a daily dose of 25 mg on days 1-21 of each cycle, for up to 12 cycles. Patients who were progression-free after 12 cycles received MOR208 every second week until progression. The primary endpoint is the objective response rate (ORR), centrally assessed, as per the International Working Group criteria 2007, incorporating PET-based imaging. Secondary endpoints include ORR as per investigator assessment, duration of response (DoR), progression-free survival (PFS) and overall survival (OS), safety, and analysis of outcomes by cell of origin and other biomarkers. Results: As of November 2017, 81 patients had been enrolled and recruitment is complete. We report here updated preliminary results with a data cutoff of 5 June 2018. Median age was 72 years (range 41-87); 40 (49%) patients had received ≥2 prior lines of therapy (median 2, range 1-4); 31 (38%) had rituximab refractory disease; 33 (41%) were refractory to the previous line of therapy, 43 (53%) had Ann Arbor stage ≥III disease; and 42 (52%) had an International Prognostic Index of 3-5 at study entry, indicating poor prognosis. The most common treatment-emergent adverse events (any grade/grade ≥3) were neutropenia in 39/35 (48%/43%) patients, thrombocytopenia in 26/14 (32%/17%), anemia in 25/7 (31%/9%), diarrhea in 24/1 (30%/1%), pyrexia in 18/1 (22%/1%) and asthenia in 16/2 (20%/2%) patients. Thirty-four (42%) patients required dose reduction with LEN, 58 (72%) patients overall could stay on a daily LEN dose of 20 mg or higher. Based on investigator assessments, complete and partial responses were observed in 27 (33%) and 20 (25%) patients, respectively, resulting in an ORR of 58%. A further 12 (15%) patients had stable disease. With a median follow-up of 12 months, the median PFS was 16.2 months (95% CI: 6.3-not reached [NR] ). Responses were durable with a median DoR not reached (95% CI: NR-NR) and 70% of responding patients were without progression at 12 months (Kaplan-Meier estimate). A significant proportion of patients (37/81; 46%) are still on study treatment, with 19 having been treated for over 12 months. Median OS has not been reached (95% CI: 18.6-NR); the 12-month OS rate was 73% (95% CI: 63-85). Conclusions: MOR208 in combination with LEN has shown highly encouraging activity in patients with R-R DLBCL who were ineligible for HDC and ASCT and who had a poor prognosis. These results indicate a significant improvement in outcome for these patients who have very limited treatment options. MOR208 plus LEN was well tolerated in this population, without evidence of additive toxicity. Treatment and follow-up are currently ongoing, as are cell of origin and other biomarker analyses. Disclosures Salles: Novartis: Consultancy, Honoraria; Epizyme: Honoraria; Gilead: Honoraria; Janssen: Honoraria; Merck: Honoraria; Morphosys: Honoraria; Pfizer: Honoraria; Servier: Honoraria; Takeda: Honoraria; Amgen: Honoraria; Acerta: Honoraria; AbbVie: Honoraria; Celgene: Honoraria, Research Funding; Roche: Honoraria, Research Funding. González-Barca:Roche: Speakers Bureau; Celtrion: Consultancy; Gilead: Consultancy; janssen: Consultancy, Speakers Bureau. Jurczak:Pharmacyclics: Research Funding; MorphoSys: Research Funding; Merck: Research Funding; Nordic Nanovector: Research Funding; Janssen: Research Funding; Epizyme: Research Funding; Celgene: Research Funding; Beigene: Research Funding; Bayer: Research Funding; Afimed: Research Funding; Sandoz-Novartis: Consultancy; Janssen: Consultancy; European Medicines Agency: Consultancy; AstraZeneca: Consultancy; Acerta: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; Servier: Research Funding; Roche: Research Funding; TG Therapeutics: Research Funding. Gaidano:Morphosys: Honoraria; AbbVie: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Kalakonda:Celgene: Research Funding. Dreyling:Bayer: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Acerta: Consultancy; Roche: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Mundipharma: Consultancy, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Sandoz: Consultancy. Zinzani:Janssen: Honoraria, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Speakers Bureau; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Honoraria, Speakers Bureau; SERVIER: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; PFIZER: Honoraria, Membership on an entity's Board of Directors or advisory committees; TG Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; TG Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celltrion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bayer: Membership on an entity's Board of Directors or advisory committees; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bayer: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; PFIZER: Honoraria, Membership on an entity's Board of Directors or advisory committees. Dirnberger-Hertweck:MorphoSys: Employment. Weirather:MorphoSys: Employment. Ambarkhane:MorphoSys: Employment. Maddocks:Pharmacyclics: Research Funding; Novartis: Research Funding; Pharmacyclics/Janssen: Honoraria; AstraZeneca: Honoraria; Teva: Honoraria; Merck: Research Funding; BMS: Research Funding.

Abstract: There are some evidences that blood transfusions, either red blood cell (RBC) or platelet, could impact survival of patients affected with various medical conditions. Mechanisms are largely unknown but immune dysfunction, storage duration, cytokines or iron releases could be involved. These concerns led to the publication of revised guidelines with a more restrictive approach for RBC and platelet transfusions in various conditions, mostly surgery and emergency. However, less was known for cancer patients receiving therapy with a curative attempt. 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 and an usual management of chemotherapy-induced anemia. In both arms, RBC and platelet transfusions were given according to physician decision without predefined threshold, but analysis of current practices showed that most patients were transfused with RBC for grade 3 or more anemia and with platelet for grade 4 thrombocytopenia. Results A total of 602 patients were included in the study and 599 have been analyzed for safety issues. Overall, 236 patients received at least one RBC transfusion (39%) with a higher incidence in the R-CHOP14 group (47% versus 31%, p=0.0001) and 60 patients (10%) received at least one platelet transfusion. Comparing with the whole study population, patients who were transfused presented with more aggressive baseline characteristics including percentage of patients with an aaIPI of 2 or 3 (72% versus 58%). Occurrence of RBC transfusion was associated with a worse outcome regarding progression-free (HR: 0.696, 95%CI: 0.547-0.885, p=0.0031) and overall survival (HR: 0.544, 95%CI: 0.414-0.714, p= 〈 0.0001). Moreover, the number of episode of red blood cell transfusion (0 vs. 1-2 vs. 〉 2) was also associated with PFS and OS. Occurrence of platelet transfusion was also associated with worse PFS (HR: 2.658, 95%CI: 1.922-3.677, p 〈 0.0001) and OS (HR: 3.257, 95%CI: 2.302-4.608, p 〈 0.0001), with an impact of the number of episode (0 vs. 1 vs. 〉 1). In a multivariate analysis including LDH level, ECOG performans status and β2-microglobulin level, RBC and platelet transfusions were both predictive for overall survival (HR: 1.575, 95%CI: 1.158-2.143, p=0.0038 and HR: 2.608, 95% CI: 1.736-3.917, p 〈 0.0001). Finally, no adverse event was associated with transfusion. Conclusion In elderly patients who received a first line immunochemotherapy for aggressive B-cell lymphoma, occurrence of transfusions as well as the number of blood products transfused appear to be significantly and independently associated with lower survival rates. These results suggest a direct effect of transfusion and will prompt us to explore possible mechanistic explanations in animal models and to validate this hypothesis in others cancer populations. Disclosures: No relevant conflicts of interest to declare.