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: 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: 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: 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.

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: BACKGROUND: Obinutuzumab is a type II anti-CD20 monoclonal antibody that induces antibody-dependent cellular cytotoxicity, antibody-dependent cell-mediated phagocytosis, and direct cell death better than rituximab. Given promising results with lenalidomide and rituximab (R2), we assessed the safety and efficacy of lenalidomide combined with obinutuzumab (GALEN)in a large phase Ib/II study in separate patient populations (NCT01582776). In relapsed/refractory follicular B-cell lymphoma (FL), we found the GALEN regimen might be even more efficient than R2 while retaining a similarly manageable safety profile. Here, we report the results for the phase II part assessing efficacy and safety of GALEN in advanced untreated FL patients (pts) in need of systemic therapy. METHODS: Eligible pts had grade 1-3a FL and required systemic therapy per GELF criteria. Induction treatment consisted of lenalidomide (LEN) 20 mg on day (d) 1-21 of a 28-d cycle for the first cycle and on d2-22 of a 28-d cycle from cycles 2 to 6. Obinutuzumab (GA) 1000 mg was given IV on d8, 15, and 22 of cycle 1 and d1 of cycles 2 to 6. Responding pts then received maintenance with LEN at 10 mg on d2-22 every 28d for 12 cycles and GA 1000 mg every 8 wk for 12 cycles until progression or unacceptable toxicity. The primary study endpoint was complete response (CR)/CR unconfirmed (CRu) rate by investigator assessment at the end of induction according to 1999 IWG criteria. Secondary endpoints included overall response rate (ORR) and CR according to IWG 2007, progression-free survival (PFS), duration of response (DOR), overall survival (OS) and safety. RESULTS: 100 pts with WHO FL gr 1-2 (91%) and 3a (9%) according to local pathology reports were enrolled between October 2015 and February 2017. Median age was 60.5 years (range, 32-89), 43% had FLIPI score ≥3, 89% stage III/IV, and 31% bulky disease ( 〉 7 cm). All 100 pts were evaluable for safety and efficacy. At a median follow-up of 2.1 years, 96 pts (96%) completed induction, 41 completed maintenance, 36 were ongoing in maintenance, and 23 prematurely discontinued treatment due to disease progression (n=12, including 2 during induction), toxicity (n=6, including 2 during induction), concurrent illness (n=3), consent withdrawal (n=1), or other cause (n=1). At the end of induction, 61 pts had regression by more than 75% of sum of the product of the greatest diameters (SPD) of target lesions and 83/97 (85.6%) with PET assessment were PET negative (Juweid criteria) including 79/93 (84.9%) with a 5PS (Deauville scale) score of 1-3. Sixteen pts with SPD regression 〉 75% and 25 pts with negative PET were conservatively downgraded to PR due to missing bone marrow evaluation, leading to 47% CR/CRu rate and 59% CR rate at the end of induction per IWG1999 and 2007 criteria, respectively. Response rates at the end of induction, PFS, DOR and OS are summarized in the Table and Figure. Most common AEs ( 〉 10% of pts) during induction (% all gr/% gr 3/4) were neutropenia (43/42), asthenia (35/2), constipation (32/0), infusion-related reactions (23/3), diarrhea (21/2), rash (21/2), cough (18/0), nausea (13/0), pruritus (12/1), weight decrease (12/0), bronchitis (11/0), muscle spasms (11/1), and pyrexia (11/0). Febrile neutropenia occurred in 2% of pts. Eight second primary malignancies were reported in 8 pts, including 2 deemed unrelated since they were misdiagnosed at baseline. Three (3%) pts had died, 1 each due to lymphoma, toxicity of additional treatment, and intestinal adenocarcinoma. CONCLUSION: The immunomodulatory GALEN regimen is highly effective with no unexpected toxicity in advanced, untreated FL pts in need of systemic therapy and has the potential to challenge immunochemotherapy in this setting. Disclosures Morschhauser: BMS: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Gilead: 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; Epizyme: Consultancy; Janssen: Other: Scientific Lectures. Salles:Celgene: Honoraria, Research Funding; AbbVie: Honoraria; Acerta: Honoraria; Janssen: Honoraria; Gilead: Honoraria; Amgen: Honoraria; Epizyme: Honoraria; Merck: Honoraria; Morphosys: Honoraria; Takeda: Honoraria; Servier: Honoraria; Pfizer: Honoraria; Roche: Honoraria, Research Funding; Novartis: Consultancy, Honoraria. Feugier:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Cartron:Celgene: Consultancy, Honoraria; Janssen: Honoraria; Roche: Consultancy, Honoraria; Sanofi: Honoraria; Gilead Sciences: Honoraria. Maerevoet:abbvie: Membership on an entity's Board of Directors or advisory committees, Other: travel grant; roche: Other: travel grant; takeda: Membership on an entity's Board of Directors or advisory committees, Other: travel grant; Karyopharm: Membership on an entity's Board of Directors or advisory committees. Tilly:Roche: Membership on an entity's Board of Directors or advisory committees; Astra-Zeneca: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria. Haioun:Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Sciences: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Gilead Sciences: Consultancy, Honoraria; Roche: Consultancy, Honoraria. Houot:BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria; Janssen: Honoraria; Novartis: Honoraria.

Abstract: As previously reported (Colombat, Blood2001;97:101), rituximab (4 weekly doses of 375mg/m²) can lead to high response rates (RR) and prolonged remissions with minimal toxicity as 1st line therapy for low tumor burden FL. We report the final analysis of a trial evaluating long term efficacy and safety of rituximab in untreated low tumor burden FL (GELF criteria). 49 patients (pts) were included in the initial trial (median age 52 yrs), 2 refused consent for the extended F/Up period, and 1 pt died at M12. Molecular bcl2-JH rearrangement was assessed throughout the study. The median F/up was 83.8 mths. Overall best RR, complete/unconfirmed RR and partial RR at D78 were 74%, 50% and 24% respectively. Median PFS was 23.5 mths for the study population. Median duration of response (34 responders at D78, i.e 6 weeks after the last rituximab dose) was 28.6 mths, but response was still maintained without any further treatment in 11 pts after 5 years (24%) and in 7 pts after 7 years (15%). 31/46 pts were bcl2 positive in blood and/or marrow samples before rituximab: 11 (35%) became negative at D50, and 20 remained positive (65%). Median PFS was 37 mths for bcl2-negative pts at D50, and 12 mths for patients remaining positive (p=0.018 Log-rank). Of the 7 pts with sustained response after 7 years, 5 were bcl2 positive at D0, 2/5 became negative at D50, and 5/5 were still negative at M84. At year 7, 4/46 pts have died (1 from myelodysplasia, 3 from NHL), 35/42 have progressed, and 7 have never progressed without any other treatment than the initial rituximab therapy. Time to progression was significantly longer in the bcl2-negative population at D50 (p= 0.018, Log-rank). Duration of response was not correlated with bcl2 status at D50, but was associated with ‘Best response CR/Cru’ (p=0.007 Log-rank). Long-term tolerance was good, with only 13 SAE observed in 13 pts during the additional 4 years of F/Up (4 surgeries for non NHL-related pathologies, 1 node biopsy, 1 sleep apnea syndrome, 1 ischemic cardiopathy, 2 deaths from NHL, 1 depression, 1 pneumonia, 1 erysipela, 1 bronchitis). This long-term update confirms that a single 4-dose rituximab treatment yields durable benefits without the toxicity of chemotherapy for pts with low burden FL : Median PFS of 23.5 mths for the cohort, 28.6 mths for responders and 37 mths for pts turning bcl2-negative at D50, 15% of pts have maintained their response after 7 years, (2bis) the quality (CR/Cru) of the initial response was associated with a longer response duration high overall survival is observed with 4 deaths/46 pts (8.6%).