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: 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%).

Abstract: Abstract 1632 R-CHOP is the standard front-line treatment for most patients (pts) with B-cell lymphoma. Single-agent studies of lenalidomide in relapsed/refractory lymphoma have demonstrated a significant activity in both indolent and aggressive lymphomas. We conducted a phase I study to determine the recommended dose of lenalinomide when given in combination with R-CHOP-21 for patients with previously untreated CD20+ B-cell lymphoma. Pts received oral lenalidomide on days 1–14 with R-CHOP (rituximab 375 mg/m2, cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, vincristine 1.4 mg/m2, all on day 1, prednisone 100 mg/m2 days 1–5) given every 3 weeks for 6 cycles. Lenalidomide dose was increased from 5 mg to 25 mg (5 mg per dose level), using a 3+3 escalation design. Pegfilgrastim was administered on day 4 and oral aspirin prophylaxis (100 mg) was given daily during the treatment. Maximum tolerated dose was determined by the number of dose limiting toxicities (DLT) during the first 2 cycles. DLT was defined as grade 3 or more nonhematological toxicity, grade 3 hematological toxicity lasting more than 7 days, or grade 4 hematological toxicity lasting more than 3 days. Twenty-seven pts were enrolled in the study from January 2009 to June 2010. Eighteen pts had follicular lymphoma, 4 pts diffuse large B-cell lymphoma, 3 pts mantle cell lymphoma and 2 pts indolent B-cell lymphoma. Twenty-five pts had a disseminated disease. Two hematological DLTs were observed in 6 pts of the 20mg cohort allowing escalating the dose to 25mg. At this dose, 2 DLTs occurred (1 hepatic, 1 hematological) in 6 pts, during the first two cycles. Therefore, 25mg was considered as the recommended dose and that cohort was expanded to a total of 12 patients. Hematological toxicity was the most frequent adverse event with 59% grade 3–4 neutropenia (7 % of patients with grade 3 or 4 febrile neutropenia) and 30% grade 3–4 thrombocytopenia. Grade 1–2 peripheral neurotoxicity was observed in 48% of the pts and was not related to a particular lenalidomide dose level. No grade 3–4 neurotoxicity occurred. One patient had pulmonary embolism of moderate severity and one patient has a deep vein thrombosis. lenalidomide was stopped in five pts due to toxicity according to protocol defined criteria. Six pts experienced delay in the administration of R2-CHOP. No death occurred on study. Complete remission (CR + CRu) was observed in 20 pts and 6 pts had PR. One patient with follicular lymphoma had rapid progression after the fifth cycle of R2-CHOP. The combination of 25mg of lenalidomide during 14 days with 21-day R-CHOP cycles has an acceptable safety profile in patients with B-cell lymphoma. A phase 2 study of the combination in patients with high burden follicular lymphoma is now ongoing. Disclosures: Tilly: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Off Label Use: lenalidomide for lymphoma. Morschhauser:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche/Genetech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Salles:Celgene: Consultancy, Speakers Bureau. Haioun:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Coiffier:Celgene: Honoraria.

Abstract: This study reports the final analysis of the outcome of relapsed/progressive patients who participated in the FL2000 trial. The FL2000 prospective trial evaluated the combination of rituximab with chemotherapy plus interferon as a first line treatment of follicular lymphoma (FL) patients (pts). Untreated high tumor burden pts (n=359) were randomly assigned to receive either 12 × CHVP (cyclophosphamide, adriamycin, etoposide and prednisolone) plus interferon-α2a over 18 months (Arm A) or 6 × CHVP combined with 6 × rituximab and interferon for the same time period (Arm B). The final analysis (Salles et al. ASH 2007) confirmed the superiority of Arm B. Second line treatment was left at the discretion of the investigators. PATIENTS CHARACTERISTICS: All of the 175 relapsed/refractory FL2000 pts were considered for the purpose of this analysis. Patients had a confirmed FL. Sixty-three pts experienced progression while on therapy (26 during induction phase and 37 during consolidation phase), while 112 progressed after completion of their first line treatment (follow-up period). At time of first progression, median age was 60 (range, 25– 75) y. 105 patients were initially randomized in Arm A and 70 in Arm B. Median time from diagnosis to progression for pts who experienced relapse/progression after completion of the first line treatment was 2.75 y. In all, 154 pts received salvage therapy at first relapse/progression: a cytarabine-based regimen in 24% of cases, an alkylating agent-based regimen in 23%, an anthracycline-based regimen in 22% and a fludarabine-based regimen in 16.5%. Fifty-three pts did not receive anti-CD20 (with or without chemotherapy) at that time, including 24 ps initially randomized in arm A. Finally, 42 pts could proceed to auto-SCT at first relapse. RESULTS: After salvage therapy, 80 pts reached CR/CRu and 23 reached PR (missing data, 20%). The median follow-up (calculated from time of first progression) is 30.8 m. The 3- and 5-year progression-free survival (PFS) estimates were 50% and 26%, respectively. The 3- and 5-year overall survival (OS) estimates were 72% and 52%, respectively. When taking into account the initial randomization, no differences in OS and PFS were observed between arm A and B. In univariate analysis, 5 parameters significantly influenced PFS and OS: younger age (p=0.035 and p=0.004; respectively), relapse/progression occurring during the follow-up period (p=0.001 and p=0.0004; respectively), low FLIPI score at diagnosis (p=0.015 and p=0.004; respectively), and actual performance of auto-SCT (p=0.0015 and p=0.001; respectively). Of note, an anti-CD20- containing therapy improved the PFS (p=0.005). In multivariate analysis, 3 parameters remained significant for PFS: period of relapse/progression (p=0.0001); an anti-CD20 containing therapy (p=0.03) and auto-SCT (p=0.002). 2 parameters remained significant for OS: period of relapse/progression (p=0.0001) and auto-SCT (p=0.0001). The 3-year OS for patients younger than 70 years who received ASCT was 92% compared to 59% for other patients (p=0.0001) CONCLUSION: These results suggest that Rituximab should be included in the salvage regimen for relapsed FL, even for those patients who previously received Rituximab. Furthermore, such pts may benefit from auto-SCT both in terms of PFS and OS. Therefore, a Rituximab-based chemotherapy regimen followed by auto-SCT is likely to be the standard of care for eligible relapsed/refractory FL patients.

Abstract: Background. The FL2000 study evaluated the combination of the anti-CD20 monoclonal antibody rituximab with chemotherapy plus interferon in the first line treatment of follicular lymphoma patients. Methods. Untreated follicular lymphoma patients (n=359) presenting with a high tumor burden were randomly assigned to receive either 12 courses of the chemotherapy regimen CHVP (cyclophosphamide, adriamycin, etoposide and prednisolone) plus interferon-α2a (CHVP+I arm) over 18 months or 6 courses of the same chemotherapy regimen combined with 6 infusions of 375 mg/m2 of rituximab and interferon for the same time period (R-CHVP+I arm). The primary endpoint of the study was event free survival and all results are shown as intent to treat. Results. Six months after treatment initiation, 156 out of 183 (85%) and 164 out of 175 (94%) patients had a response to therapy in the CHVP+I and R-CHVP+I study arm, respectively (P=.009). At the end of the 18 months treatment period, 59% and 75% of the patients were respectively in CR or CRu in the CHVP+I and R-CHVP+I arm (P 〈 .05). After a median follow-up of five years, event-free survival (EFS) estimates were respectively 37% [95% C.I. 29 – 44] and 53% [95% C.I. 45 – 60] in the CHVP+I and R-CHVP+I arm (P=.0004). Response duration in CR/CRu or PR patients at the end of the 18 months treatment was also improved in the R-CHVP+I arm (P=.012). 5-year overall survival (OS) estimates were not statistically different in the CHVP+I (79%) [95% C.I. 72 – 84]) and R-CHVP+I (84% [95% C.I. 78 – 84] ) arms. The Follicular Lymphoma International Prognostic Index (FLIPI) score allowed separation of the whole study population into 3 different risk categories with significantly different outcome for each group both for 5 year EFS and OS (P 〈 .0001, respectively each). In a multivariate regression analysis, event free survival was significantly influenced by both the FLIPI score (HR=2.08; 95% C.I. [1.6 – 2.8]) and the treatment arm (HR=0.59; 95% C.I. [0.44 – 0.78] ). In an exploratory analysis considering the 187 patients with a low/intermediate ( 〈 3) FLIPI score, the outcome according to each treatment arm was not statistically different while the benefit of the rituximab combination was highly significant in term of EFS (P=.0002) and OS (P=.025) in the 162 patients with a high (≥3) FLIPI score. Conclusions. These results extend our previous interim analyses and confirm that with a five year follow-up, the combination of rituximab with CHVP+I provides superior disease control in follicular lymphoma patients despite a shorter duration of chemotherapy. However, this combination appears to benefit essentially to high risk patients for whom overall survival is also significantly improved.

Abstract: Background. Although Hodgkin lymphoma is a highly curable malignancy, about 15% and 30% of patients with respectively localized or disseminated disease do not respond or relapse after initial treatment. Several scoring systems using conventional biological and clinical parameters have been developed for limited and advanced stages in order to adapt the therapeutic strategy. However, the identification of patients with adverse outcome needs to be improved. Cytokines have an important role in the pathogenesis of Hodgkin lymphoma. Several studies have shown that plasma cytokine dosage at diagnosis has prognostic relevance. Various cytokine genes variants are known to influence cytokine productions and have been associated with lymphoma outcomes. We then evaluated the influence of cytokine gene polymorphisms on response to treatment and outcome in patients with Hodgkin lymphoma. Methods. Between 1998 and 2002, we prospectively investigated the prognostic role of plasma cytokines and soluble receptors in Hodgkin lymphoma patients (Casasnovas et al. JCO 2007). A sample was collected at diagnosis specifically to investigate single nucleotide polymorphisms (SNPs) in cytokine genes. Ten SNPs that could be functionally important in seven genes (IL10, TNF-alpha, IL6, IL1B, IL1RN, INF-gamma, CCL17) were studied. DNA was extracted from venous blood samples. All genotyping experiments were performed in duplicate using Taqman technology (ABI Prism 7000, Applied Biosystems): IL10 rs1800890 (−3584 & gt;A), 448 pts; IL10 rs1800896 (−1116A & gt;G), 459 pts; IL10 rs1800871 (−853C & gt;T), 446 pts; IL10 rs1800872 (−626C & gt;A), 447 pts; TNFalpha rs1800629 (−487G & gt;A), 464 pts; IL6 rs1800795 (−236G & gt;C), 201 pts; IL1B rs16944 (−1060T & gt;C), 198 pts; ILRNrs419598 (Ex5–35T & gt;C), 199 pts; INF-gamma rs2430561 (+874A & gt;T), 200 pts; CCL17rs223828 (−431T & gt;C), 198 pts. We estimated the prognostic value of each individual SNP and the IL10 haplotype for response to treatment, relapse and overall survival (OS). Results. The median age of the 464 patients studied was 32 years (range, 15–93); 263 (57%) were male. At diagnosis, 335 patients (72%) were in Ann Arbor stage I–II and 206 (44%) presented with B symptoms. Histology was nodular sclerosis in 384 patients (84%). Treatment consisted of 4 to 6 courses of anthracycline-based chemotherapy (CT) followed by involved-field radiotherapy for stages I–II and 8 courses of anthracycline-based CT for stages III–IV. Complete response (CR) and uncertain CR (uCR) were observed in 417 patients (90%), partial response in 15 (3%) and stable and progressive disease in 32 (7%). Relapse occurred in 71 patients (15%) and 35 patients (8%) died, 24 of whom (5%) of Hodgkin lymphoma. After a median follow-up of 3.6 years months, the 4-year progression free survival (PFS) and OS were 83.4% and 93.6%, respectively. Regarding treatment response, only the IL10-1082AA genotype was associated with a better CR + uCR than other IL10 genotypes (95% vs. 88% p=0.02). Neither individual SNPs or IL10 haplotype influenced OS and PFS. Conclusions. In this large series of Hodgkin lymphoma patients with particularly favorable outcome, the IL10-1082AA genotype was associated with better response to initial treatment. These data indicate that some genes associated with non-Hodgkin lymphoma outcome do not predict Hodgkin lymphoma outcome and that other target need to be analyzed to decipher the putative role of host’s immunogenetic background in this disease.

Abstract: Abstract 3655 Obinutuzumab (GA101) is a type II glycoengineered, humanized anti-CD20 monoclonal antibody that has increased antibody-dependent cellular cytotoxicity and direct cell death activity but lower complement-dependent cytotoxicity compared with type I anti-CD20 antibodies such as rituximab and ofatumumab. GA101 is in clinical development for the treatment of lymphoma and chronic lymphocytic leukemia. The Phase I/II study BO20999 has evaluated the efficacy and safety of GA101 monotherapy in patients with relapsed/refractory aggressive non-Hodgkin's lymphoma (aNHL). Here, we report updated Phase II results including progression-free survival (PFS) and best overall response (BOR). Patients (n = 40) were randomized to receive GA101 (D1, D8 and D22, then 3-weekly for total of 9 infusions) at either a high dose (1,600 mg on D1 and D8, then 800 mg thereafter; 1,600/800 mg cohort; n = 19), or a flat low dose of 400 mg (400/400 mg cohort; n = 21). Baseline patient characteristics were similar for both cohorts (Table 1). The median observation time for all patients was 9.5 months (0.3–26.1 months). BOR rates are given in Table 2, with 8/25 diffuse large B-cell lymphoma (DLBCL) patients (32%) and 4/15 mantle cell lymphoma (MCL) patients (27%) responding to GA101. Among the patients with rituximab-refractory disease, a response was observed in 1/13 patients (7.7%) and 4/12 patients (33.3%) treated in the 400/400 mg and 1,600/800 mg cohorts, respectively. Of these, 4 patients (1,600/800 mg cohort) had a response duration 〉 6 months, with 2 patients having an ongoing response (response duration: 9.8, 16.5+, 19.5 and 20.0+ months). Median PFS for patients with DLBCL (Figure 1) was 1.9 months (range: 0.3–15.7 months) for the 400/400 mg cohort and 2.7 months (range: 0.2–22.3) months) for the 1,600/800 mg cohort (hazard ratio: 0.70; 95% CI: 0.30–1.66). For the DLBCL subgroup, response duration was 3.1, 3.1+, 5.8, 16.5+ and 19.5 months for the 5 responders in the 1,600/800 mg cohort, compared with 6.3, 8.6 and 9.8 months for the 3 responders in the 400/400 mg cohort. Individual response data indicated that 2 MCL patients had an ongoing response for ≥ 20 months (20.0 and 20.4 months). GA101 was well tolerated in both cohorts. Infusion-related reactions (IRRs; all grades) were the most common adverse event (AE), occurring in 81% of patients in the 400/400 mg cohort and 68% of patients in the 1600/800 mg cohort. Grade 3/4 AEs occurring in 〉 5% of patients across both cohorts included IRRs (10%), tumor lysis syndrome (10%), cardiac failure (not treatment-related; 10%), anemia (14%) and thrombocytopenia (14%) in the 400/400 mg cohort and IRRs (5%) and anemia (5%) in the 1,600/800 mg cohort.Table 1.Baseline patient characteristicsCharacteristic400/400 mg (n = 21)1,600/800 mg (n = 19)All (n = 40)Median age, years (range)70 (43–80)72 (22–85)71 (22–85)Histology, nDLBCL101525MCL11415Median number of prior treatments, n (range)4 (1–17)3 (1–6)3 (1–17)Previous rituximab, n211940Rituximab refractory*, n131225Prior stem cell transplant, n268DLBCL, diffuse large B-cell lymphoma; MCL, mantle cell lymphoma.*Rituximab refractory defined as patients who had a response of 〈 6 months or who failed to respond to a rituximab-containing regimen (rituximab monotherapy or in combination with chemotherapy) at any point during their treatment history.Table 2.Best overall response according to diagnosis and cohortDLBCLMCLResponse, n (%)400/400 mg (n = 10)1,600/800 mg (n = 15)400/400 mg (n = 11)1,600/800 mg (n = 4)Complete response (CR)0 (0.0)3 (20.0)2 (18.2)0 (0.0)CR unconfirmed1 (10.0)0 (0.0)0 (0.0)0 (0.0)Partial response2 (20.0)2 (13.3)0 (0.0)2 (50.0)Stable disease1 (10.0)1 (6.7)3 (27.3)0 (0.0)Progressive disease5 (50.0)9 (60.0)6 (54.5)2 (50.0)No response assessment1 (10.0)0 (0.0)0 (0.0)0 (0.0)DLBCL, diffuse large B-cell lymphoma; MCL, mantle cell lymphoma.Figure 1.Progression-free survival for patients with diffuse large B-cell lymphomaFigure 1. Progression-free survival for patients with diffuse large B-cell lymphoma In conclusion, GA101 shows encouraging single-agent efficacy in these heavily pretreated patients with relapsed/refractory aNHL (DLBCL or MCL). A Phase III trial of rituximab plus CHOP vs GA101 plus CHOP in first-line DLBCL has recently started. Disclosures: Morschhauser: Roche: Honoraria; Celgene: Consultancy, Honoraria. Cartron:Roche: Consultancy, Honoraria; GSK: Honoraria; LFB: Honoraria. Milpied:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees. Wenger:Roche: Employment. Wassner-Fritsch:Roche: Employment. Asikanius:Roche: Employment. Salles:Roche: Consultancy, Honoraria.

Abstract: Single-agent studies of lenalidomide in relapsed/refractory follicular lymphoma (FL) have demonstrated significant activity. Recent studies reported that the combination of lenalidomide and rituximab yields high response rates in patients with FL. Three recent phase 1 studies have shown that lenalidomide administered on 10 to 14 days of 21-day cycle of R-CHOP could be safe in the initial treatment of aggressive or indolent B-cell lymphomas. Two of these studies determined 25 mg of lenalidomide as the recommended daily dose. This multicenter, open label, phase 2 trial (NCT01393756) investigated the combination of lenalidomide with R-CHOP in patients (pts) with high burden FL. Methods Pts with previously untreated FL grade 1, 2 or 3a and a high tumor burden according to GELF criteria were eligible. Pts received an induction therapy with 6 cycles of R2-CHOP given every 3 weeks (25 mg oral lenalidomide on days 1-14) followed by two additional rituximab infusions. Pegfilgrastim was administered on day 4 and oral aspirin prophylaxis (100 mg) was given daily during the cycles. Lenalidomide dose was adapted to toxicities. Pts responding to induction therapy received rituximab maintenance every 8 weeks for 2 years. The primary endpoint was the complete remission (CR/CRu) rate, according to IWRC 99, at the end of induction treatment. Secondary endpoints were safety, progression free survival, duration of response and overall survival. Results Eighty pts were enrolled from 16 LYSA centres between December 2010 and January 2012. Median age was 57 y (range 29-71); 50% were male; 92% Ann Arbor stage III-IV; 28% B symptoms, 69% ECOG performance status = 0; 25% mass 〉 10cm; 53% bone marrow involved; 40% LDH elevated; 63% FLIPI 3-5. Sixty-eight pts (85%) received the complete induction regimen. Median interval between R2-CHOP cycles remained 21 days during treatment. Thirty-three pts (41%) experienced at least one dose reduction of lenalidomide. The complete remission (CR/CRu) rate was 74% (CI 95%: 63%-83%) and ORR was 94% (CI95%: 86%-98%).Current median follow-up is 13 months. So far, 9 pts (11%) experienced a progression/relapse. Hematologic toxicity was in the range of that observed with R-CHOP regimen with 65% grade 4 neutropenia; 12.5% grade 4 thrombocytopenia; 7.5% febrile neutropenia and no toxic death. Grade 1-2 sensory neuropathy was observed in 28 pts (36%), one pt had a grade 3 neuropathy. Twenty-nine pts (36%; grade 1-2: 27; grade 3: 2) had reversible skin toxicity, usually during the course of the first cycle. Five episodes of thrombosis occurred during treatment or follow-up, 3 were related to venous access devices and only one required discontinuation of lenalidomide. Three cases of neoplasm were observed during follow-up. Conclusion The combination of 25mg of lenalidomide for 14 days with 21-day R-CHOP cycles is well tolerated and yields a high rate of complete remission in patients with high tumor burden follicular lymphoma. Disclosures: Tilly: Roche: Honoraria; Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity’s Board of Directors or advisory committees; Pfizer: Honoraria; Janssen: Honoraria; Amgen: Research Funding. Off Label Use: Use of lenalidomide to enhance R-CHOP efficacy in follicular lymphoma. Morschhauser:Celgene: advisory boards Other, Honoraria, Research Funding, Speakers Bureau. Casasnovas:ROCHE: Consultancy, Honoraria, Research Funding. Molina:Merck: Honoraria. Salles:roche: Consultancy, Honoraria, Research Funding; Celgene: Honoraria. Haioun:Roche: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity’s Board of Directors or advisory committees.

Abstract: Rituximab alone may be given as initial treatment for FL either as a single treatment or as an induction treatment followed by a maintenance. In 2002, we have reported the response rates and progression-free survival (PFS) of 49 patients (pts) treated with 4 weekly 375 mg/m² doses of rituximab (Blood2002; 97: 101–6). All patients had FL and a low-tumor burden according to the GELF criteria. These pts have been followed during at least 5 years. According to the Follicular Lymphoma International Prognostic Index (Blood, in press). 22 pts were in the low-risk group (45%), 20 (41%) in the intermediate risk group and 7 (14%) in the poor risk group. Best response rate was 80% with 49% CR/CRu and 31% PR, and response was maintained in 34% without further treatment after at least 5 years. Median F/Up was 60 months. The median PFS was 18 months. Among these 49 pts, only 3 pts died (2 from NHL, 1 from lung carcinoma). Among the 32 pts who were bcl-2 positive in the blood and/or the bone marrow before treatment with rituximab, 10 (33%) became negative and 20 (67%) remained positive at d50. 6 (60%) relapsed among the former and 15 (75%) among the latter. Median PFS was 37 months for pts who became bcl-2 negative and 14 months for those who remained positive (p[log-rank test] = 0.10). Among the 4 patients who had information on molecular biology who did not relapse after a 5-year F/Up, 3 were bcl-2 negative and 1 was bcl-2 positive. The long F/Up of these pts (i) confirms the median PFS of 18 months for all pts and the median relapse-free survival of 27 months for best responders (ii) shows that some patients (i.e. 28% of all pts and 34 % of responders) may have a relapse-free survival longer than 5 years after a single first line treatment with rituximab in monotherapy ; (iii) shows an excellent overall survival (only 3 death (6%) during the study) in these FL pts. These results confirm the relevance of on-going trials comparing a maintenance treatment with rituximab and treatment at the time of relapse.