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Background: AcSé Pembrolizumab is a Phase 2, open-label, single-arm, multi-cohort, multicentric study investigating the efficacy and safety of pembrolizumab monotherapy in patients with advanced rare cancers (NCT03012620). Here, we report the first results of Pembrolizumab in the cohort of Primary Central Nervous System Lymphoma (PCNSL). Methods: Main inclusion criteria were: relapsed or refractory PCNSL after one or several lines of treatment including high dose Methotrexate based chemotherapy, pathologically confirmed diffuse large B cell lymphoma, age>18, HIV negative, concurrent steroid medication at a dose no greater than prednisone 20 mg/day or equivalent. Patients received pembrolizumab 200 mg IV as a 30-minute infusion on Day 1 of every 21-day cycles for a maximum of 2 years. The primary endpoint was the confirmed objective response rate according to IPCG at 84 day after the start of treatment. Secondary endpoints included best response (ORR), duration of response, progression-free survival (PFS), overall survival (OS), and safety. Analysis used all enrolled patients. Results: 50 patients suffering from PCNSL, including 9 primary vitreoretinal lymphoma (PVRL) were included from July, 2017 to October, 2019. Median age was 72 years (range: 43 to 83), Median PS (ECOG) was 1 (range 0-1). The median number of cycles was 4 (range 1-35). At 84 days from start of treatment, 6 patients responded (4 CR+2PR). Overall, 3 patients whose response was not assessed were considered as failures, and the rates of ORR (CR+PR), stable disease (SD), progressive disease (PD) were 26% (13/50, 8 CR + 5 PR), 10% (5/50), 58% (29/50), respectively. ORR was 29% (12/41) and 11% (1/9) in primary cerebral lymphoma and PVRL respectively. After a median follow-up of 6.7 months (range 0.2-27.4), median PFS was 2.6 months, with 6-month PFS of 29.8% and 6-month OS of 60.4%. In responders, median duration of response was estimated at 10 months (95%CI, 2.7 to 12.5). Grade III and IV toxicities related to the drug were observed in 4 patients (8%) and one patient (2%) respectively. No related toxic death was reported. Conclusion: Pembrolizumab shows moderate activity in relapsed/ refractory PCNSL with acceptable toxicity, supporting further studies evaluating its use in combination therapies. Disclosures Hoang-Xuan: BTG: Consultancy, Research Funding. Houot:Bristol-Myers Squibb: Honoraria; MSD: Honoraria; Gilead: Honoraria; Kite: Honoraria; Roche: Honoraria; Novartis: Honoraria; Janssen: Honoraria; Celgene: Honoraria. Schmitt:Celgene: Membership on an entity's Board of Directors or advisory committees; Roche, Janssen: Honoraria. Ahle:Roche: Honoraria; Novartis: Honoraria; Biogene: Honoraria; Abbvie: Honoraria; Sanofi: Honoraria. Bories:Abbvie: Consultancy; Celgen: Consultancy; Gilead: Consultancy; BMS: Honoraria; Novartis: Honoraria. Houillier:BTG: Consultancy.

Background The shared knowledge regarding management and outcome of PCNSL patients are usually based on results of clinical phase II studies that include limited series of selected patients, which imperfectly reflect the medical care in "real life". Methods The LOC network, certified by the national cancer institute (INCa), is a national network of expert centres for PCNSL. Since 2011, we are prospectively recording in the LOC database all newly diagnosed PCNSL patients from the 22 regional expert centres for PCNSL that cover the whole country. Data from PCNSL patients registered in the LOC database from January 2011 to March 18, 2016 were analyzed. Results Data from 971 patients were available in the LOC database at the time of analysis: sex ratio: 1.05, median age: 67 (18-92), median Karnofsky Performance Status: 60 (20-100), diffuse large B cell lymphoma: 97%, ocular involvement: 20%, cerebrospinal (CSF) involvement: 18%. Diagnosis procedure was biopsy (80%), tumor resection (9%), vitrectomy (8%), CSF cytology (3%). Treatment was initiated either by a neuro-oncology or a haematology team in 38% and 62%, respectively. Median delay between first symptoms and onset of treatment was 62 days. First line treatment was high-dose (HD) methotrexate (MTX) based chemotherapy (CT) (90%), other chemotherapy regimen (6%), or palliative care (4%). The use of Rituximab has gradually increased from 50 % of patients between 2011 and 2013, up to 87 % of patients in 2016. 16 % of patients were included in prospective trials. After first-line induction chemotherapy, responder patients < 60 years received a consolidation treatment in 75 % of cases consisting of either whole brain radiotherapy (WBRT) (49 %) or HD CT with autologous stem cell transplantation (HD CT-ASCT) (26 %). Low dose WBRT (23,4) is being used in younger CR patients since 2014. In responder patients > 60 years, WBRT was seldom given (9%) according to national guideline, and HD CT-ASCT was offered to 1% of patients. Response rates to first-line treatment among evaluable patients (n = 655) were: complete response: 59%; partial response: 10%; stable disease: 3%; progressive disease: 28%. Relapse occurred in 42 % patients < 60 y and in 62 % in older patients. At relapse, second line chemotherapy, HD CT-ASCT, WBRT and palliative care were offered in 50%, 18%, 12%, 20% of patients respectively. With a median follow-up of 20.4 months, median progression free survival (PFS) was 9.9 months for the whole population (< 60 years: 34.6 months; > 60 years: 7.9 months). Median overall survival (OS) and 5-year OS were 30 months and 41% respectively (< 60 years: not reached, 68%; > 60 years: 15 months, 30%). Conclusion The therapeutic practices in France reflect the current knowledge and controversies in PCNSL. Long-term survival has become frequent, especially among youngest patients who usually receive a consolidation treatment and to whom HD CT-ASCT can be offered at relapse. Relapse rate remains frequent and especially in elderly patients in whom consolidation treatment is omitted. Such an overview points out a couple of issues. Despite homogeneous treatments following national guidelines in accordance with the state of the art of medical care, standards of care are to be challenged, both for increasing the CR and decrease the relapse rates. The development of target and innovative therapies in PCNSL alone or in combinatorial regimen is needed. PFS and OS of patients according to age Figure 1. Figure 1. Figure 2. Figure 2. Disclosures Soussain: Roche: Research Funding; Celgene: Research Funding; Pharmacyclics: Research Funding. Ghesquieres:Mundipharma: Consultancy; Roche France: Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees. Choquet:Janssen: Consultancy; Celgene: Consultancy. Morschhauser:Servier: Consultancy, Honoraria; Janssen: Honoraria; Gilead Sciences: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Roche: Consultancy, Honoraria.

Unavailability of Carmustine and its dramatically increased cost by nearly 10 fold has led to its replacement by bendamustine (Be) and an increase use of Bendamustine-based (BeEAM) conditioning regimen before autologous stem cell transplantation for lymphoma. The aim of this study was to evaluate the safety of the BeEAM regimen in the real life use in several French centers. Median age of the 386 patients (233 male, 153 female) was 55 years (17-72). The majority of patients had aggressive B-cell (40%), follicular (17%), Hodgkin's (17%) and mantle cell lymphoma (15%). Two hundred and forty six patients (64%) were transplanted after 2nd line chemotherapy and the median number of prior lines of chemotherapy of 2 (1-9). Two hundred and sixty patients (67%) had received prior platinum chemotherapy and only 4% had a history of prior chronic renal failure (Table 1). The median creatinine level at conditioning initiation was 71(36-206) µmol/l. Be was administered at a median dose of 191 mg/m2/day (50-250) on day -7 and -6. Thirty two percent received 100-160 mg/m²/d and 58% of patients received more than 160 mg/m²/d. Median 24h-hydration volume was 3 l (1-6) which began within median time of 18 h (1-72) prior to conditioning initiation. The median duration time of Be perfusion was 60 min (30-143). Grade 1-4 acute renal failure (ARF) was reported in 107 cases (28%) (G ≥2; 34%) and appeared after a median time of 2 days (1-18) after conditioning start. Melphalan dosage was reduced, due to renal failure, in 10% of patients (Table 2). 84% of patients normalized their creatinine level within a median time of 10 days (1-77). The most frequent reported Grade 1-4 toxicities were mucositis (84%), gastroenteritis (53%), skin toxicity (34%), colitis (29%), liver toxicity (19%), pneumonitis (5%) and cardiac rhythm disorders (4%). Opportunistic infection was documented in 9.5% of patients, HHV6 reactivation in 6% of patients. Ten percent of patients needed intensive care management and toxic death was estimated at 5% (Table 3). Patients received a median of 3 (0-34) packed red blood cells and 4 (0-56) platelets units. The median time to neutrophils > 0.5 G/L and platelets > 20 G/L were 10 (0-50) and 12 (0-210) days. The median time of hospital stay was 23 (12-85) days. In comparison with the group of patient without renal failure, the group of patients with ARF had older age (58 vs 54), higher rate of pre-transplant chronic renal failure (10% vs 1%), higher rate of platinum treatment (77% vs 64%), higher day1 creatinine level (81 vs 69) and received higher median bendamustine (199 vs 182). Colitis (p=0.039), pneumonitis (p=0.008), cardia arrhythmia (p=160mg/m2 and age were independent prognostic factors for ARF. A three-point clinical predictor score for acute renal failure was identified and included creatinine level>65µmol/l, bendamustine dose >160mg/m² and age>57 years. ARF stratified by score, was 4% with score 0, 17% with score 1, 30% with score 2 and 45% with score 3. In conclusion, BeEAM induced 5% non-relapse mortality with high rate of renal toxicity. A simple, three-point scoring system can stratify patients by levels of risk for ARF. Rapid identification of higher risk patients may allow a reduction of the bendamustine dose to improve clinical outcomes. Prospective comparative studies are needed to confirm toxicity extents of this conditioning as compared with other type of high dose therapy. Disclosures Soussain: Pharmacyclics: Research Funding; Celgene: Research Funding; Roche: Research Funding. Malak:Novartis: Membership on an entity's Board of Directors or advisory committees.

Background The proliferation index (PI), defined by KI67 protein expression has been identified as a key prognostic factor (PF) in mantle cell lymphoma (MCL) (1, 2). A GOELAMS/LYSA study (n = 113 patients) identified a cut point of 26% for KI67 positivity as an independent predictor of overall survival together with LDH levels, B symptoms and ECOG-PS, in MCL (GOELAMS index : GI). (1) Recently, the European MCL network confirmed the independent prognostic power of KI67 protein expression levels to predict OS in MCL (n = 508) and proposed a new score "MIPIc" (KI67cut-off of 30%). (2) While these scores show prognostic impact in the immuno-chemotherapy setting, with or without ASCT and / or maintenance therapy, their predictive power in the setting of targeted therapy remains uncertain. Objective The aim of this study was to test the predictive power of the MIPIc and GI prognostic indices in a cohort of elderly MCL patients treated by a proteasome-inhibitor-based immunochermotherapy regimen within a prospective phase II trial of the LYSA group (LyMa SA 2010 ; Rituximab, Bendamustine, Velcade and Dexamethasone regimen : RiBVD). (3) Material and method The final analysis of the LyMA SA 2010, presented at ASH 2014 (3), showed overall clinical and molecular response rates of 86.5% and 85%. The 24 months estimated OS and PFS was respectively 80% and 70%. (3) In order to assess the prognostic power of KI67 expression levels for OS, all survival data were updated. KI67 staining was performed and reviewed centrally by one pathologist of the LYSA-P, according to the European guidelines. (4) The MIPIc and GI scores were calculated and their impact on survival analyzed (Logrank). In addition, all 6 variables comprising the MIPc and the GI indices were assessed separately by univariate analyzes for prognostic value (these were LDH, ECOG and KI67 that are common to the 2 indices, and Age and WBC for the MIPIc and B Symptoms for GI). Finally a Logrank permitted to define 3 groups of patients with a high statistically impact on survivals with the 3 common variables of MIPIc and GI. Results Among the 74 elderly MCL patients treated in first line by the RiBVD regimen, 59 are alive with a median follow up of 40 months. Estimated OS and PFS at 36 months are respectively 78.4% and 65%. The MIB1 was evaluated on 58 samples for which the MIPIc and GI could be calculated for 57 patients (no LDH value for one patient). MIPIc and GI were not able to define relevant prognostic subgroups for OS (p =0.55 and 0.11). Only the 3 common variables LDH (N vs >N), ECOG (O-1 vs >1) and MIB1 (with a cut-off at 46% corresponding to the fourth quartile of MIB1 expression levels) were individually predictive of OS by univariate analysis (respectively with p=0.0006, p=0.048 and p=0.0031). With these three variables the Logrank test separated three groups that were statistically discriminant for OS and PFS: one group with 0 risk factors n=24 patients, 42%), a second group with one risk factor (n=20 patients, 32%) and the last group with 2 or 3 risk factors (n=13 patients, 23%). Hence the 3 year OS of these 3 groups was respectively 96%, 75% and 30% (p In Conclusion The proteasome-inhibitor-based immunochemotherapy regimen, RiBVD, induces prolonged survival of "High risk" patients, as defined by this modified MIPIc score. More proliferative disease, defined by a KI67 superior to 46%, combined with a high LDH level and/or a high PS defines a high subgroup of patients under the RiBVD regimen (median PFS and OS of respectively 15 and 10 months). Ref: 1 Gressin R, Haematologica 2010. 2 Hoster E et al, J Clin Oncol 2016. 3 Gressin R et al, ASH Blood 2014. 4 Klapper W, H Hematop 2009. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures Cartron: Roche: Consultancy, Honoraria; Celgene: Honoraria; Gilead: Honoraria; Jansen: Honoraria. Dartigeas:Roche: Consultancy; Mundipharma: Other: travel grant. Dupuis:janssen: Honoraria; ABBVIE: Membership on an entity's Board of Directors or advisory committees. Karlin:takeda: Consultancy; Bristol: Consultancy; celgene: Consultancy, Honoraria; janssen-cilag: Consultancy, Honoraria; amgen: Consultancy, Honoraria.

Introduction Post-transplant lymphoproliferative disorders (PTLD) are a rare but severe complication occurring after organ transplantation as a result of immunosuppressive therapy (IST). Until recently, there was no consensus regarding best treatment practice. In 2006, a phase 2 trial using a monotherapy with rituximab showed an overall response rate of 44%, with a complete response (CR) rate of 28%. In 2012, the PTLD-1 international multicenter trial evaluating rituximab followed by CHOP chemotherapy proved an efficacy of 90% and an overall survival of 6.6 years in PTLD treatment. K-virogref is a French national expert network created in 2011 to structure and improve the management of viro-induced cancers, occurring in adult after transplantation, including PTLD. Within this network, an epidemiological observational study has been set up in September 2013. The aim of our study was to analyze the management of PTLD in France before the creation of the national database of K-virogref. Patients and methods We included solid organ or allogeneic stem cell recipients, aged 18 years and above, with a histologically proven PTLD, diagnosed between January 2010 and September 2013 in 19 French hematology departments. We collected from clinical charts data regarding transplant characteristics, PTLD presentation, first-line treatment and outcomes. Results The study population consisted of 94 patients, 67% were men and median age was 53 years (ranging 18 - 81 years). The majority of patients received kidney transplantation (54%), followed in almost equal proportion by heart (13%), liver (13%) and allogeneic stem cell transplantation (10%). Most of the time (80% of patients), PTLD occurred more than one year after organ transplantation with a median delay of 7.8 years. Histologically, mainly monomorphic PTLD were observed with 66% of diffuse large B cell lymphoma and PTLD was EBV associated in 54%. At the time of diagnosis, 80% were classified as stage IV according to Ann Arbor. The median follow-up time was 28.3 months (ranging 0.2 - 78 months). As far as treatment is concerned, modification of IST was performed in 68% of patients but response was rarely evaluable because a specific treatment was often started at the same time. Surprisingly, first line treatment consisted in rituximab alone or rituximab followed by CHOP chemotherapy in only 32% of the patients. Among these patients, the overall response rate was 81% with 55% of CR. Most patients (56%) received chemotherapy (n=11) or immunochemotherapy (n=46) without previous rituximab therapy. For these patients the overall response rate was 71% with a CR rate of 53%. At 1 and 3 years of follow-up, the relapse-free rates were 56% (95% confidence interval (CI) 46% - 68%) and 47% (95% CI 37% - 60%), respectively. Overall, 49% of patients died during follow-up of which 37% due to infectious complications and 32% due to PTLD progression. Conclusion This is one of the largest cohort study of PTLD in the literature, providing an overview of epidemiological features, treatments and outcomes of this rare disease. The lag between the management of PTLD and literature data emphasizes the usefulness of a national expert network such as K-virogref in order to generalize a less toxic and more powerful attitude. Disclosures Leblond: Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: 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, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria. Choquet:Celgene: Consultancy; Janssen: Consultancy.

Background: Many patient (pt) and disease factors have been shown to impact prognosis in multiple myeloma (MM). A recently described frailty scale categorized pts with MM into 3 groups: fit, intermediate, and frail based on age, comorbidities, and physical and cognitive functioning (Palumbo, Blood, 2015). These groups were predictive of risk of death. The pivotal phase 3 FIRST trial examined the impact of continuous therapy with lenalidomide plus low-dose dexamethasone until disease progression (Rd continuous) on outcomes in transplant-ineligible pts with newly diagnosed MM (NDMM; Benboubker, N Engl J Med, 2014). In this study, Rd continuous resulted in progression-free survival (PFS) and overall survival (OS) benefits compared with melphalan-prednisone-thalidomide (MPT). This analysis examined outcomes in pts by severity of frailty score in the FIRST trial, the largest clinical trial of transplant-ineligible NDMM to date. Methods: Pts with NDMM who were ineligible for transplant were randomized to treatment with Rd continuous, Rd for 18 cycles (Rd18; 72 weeks), or MPT for 12 cycles (72 weeks). Pts were categorized into 3 severity groups using a score based on age, Charlson Comorbidity Index score, and the Activities of Daily Living (measures of self-care) and Instrumental Activities of Daily Living (measures of usual activities) scales from the EQ-5D questionnaire at baseline, as previously described (Palumbo, Blood, 2015). This analysis examined PFS and OS outcomes by severity group in the overall pt population and between the Rd continuous and MPT arms, which were the primary comparators in this study, using an updated data cutoff of March 3, 2014. Results: This analysis included 1517 of 1623 pts from the intent-to-treat population; 106 pts were excluded because they did not have the required baseline data from the EQ-5D. The majority of pts enrolled in the FIRST trial were frail (54%) compared with fit (17%) or intermediate (30%). Similar breakdowns were observed across treatment arms (Figure 1). Frail pts were older and had higher Eastern Cooperative Oncology Group performance status scores, higher International Staging System (ISS) stage, higher lactate dehydrogenase levels, and worse renal function than fit or intermediate pts. In the overall pt population, better fitness was associated with significantly improved OS compared with worse fitness: fit vs intermediate (hazard ratio [HR] = 0.66; P = .004), fit vs frail (HR = 0.42; P < .0001), intermediate vs frail (HR = 0.62; P < .0001). Rd continuous treatment prolonged PFS compared with MPT for all pt severity groups (Figure 2). Rd continuous reduced the risk of progression or death vs MPT by 44%, 38%, and 21% in fit, intermediate, and frail groups, respectively. OS was also extended with Rd continuous vs MPT for all pt severity groups (Figure 2). Risk of death was reduced by 48%, 28%, and 20% in the fit, intermediate, and frail groups, respectively, with Rd continuous compared with MPT. Causes of death were primarily MM or complications of MM in fit (62% of deaths) and intermediate (57% of deaths) pts; while they were the cause of death in half of frail pts. Pts were further categorized within each fitness group by ISS stage: fit pts were classified by stage I vs II/III and intermediate and frail pts were classified by stage I/II vs III. Addition of ISS stage further improved prognostic classification within each severity group for both PFS and OS. Discussion: Results validated the feasibility of using the frailty scale for predicting risk of death in pts with NDMM and further demonstrated an association with PFS outcomes. The majority of pts fell into the frail category, which was associated with the poorest outcomes, indicating a need to further improve outcomes for a large proportion of pts with MM. Rd continuous resulted in PFS and OS benefits compared with MPT regardless of severity of frailty level, with the greatest benefits observed in fit pts. Poor outcomes of frail pts are likely further impacted by a higher proportion of deaths due to causes independent of MM compared with fit and intermediate pts, such as pre-existing comorbidities. These data support the use of Rd continuous as a standard frontline treatment option, even for frail pts with NDMM who are older and may have comorbidities or physical or cognitive impairments. Figure 1. Breakdown of Severity Group by Treatment Arm Figure 1. Breakdown of Severity Group by Treatment Arm Figure 2. PFS and OS by Pt Severity Group Figure 2. PFS and OS by Pt Severity Group Disclosures Facon: Celgene: Membership on an entity's Board of Directors or advisory committees; Jansen: Membership on an entity's Board of Directors or advisory committees; Millenium: Membership on an entity's Board of Directors or advisory committees; Onyx: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Hulin:Celgene Corporation: Honoraria; Bristol Myers Squibb: Honoraria; Amgen: Honoraria; Janssen: Honoraria. Dimopoulos:Janssen-Cilag: Honoraria; Genesis: Honoraria; Amgen: Honoraria; Genesis: Honoraria; Janssen: Honoraria; Onyx: Honoraria; Janssen-Cilag: Honoraria; Celgene: Honoraria; Novartis: Honoraria; Amgen: Honoraria; Novartis: Honoraria. Mohty:Celgene Corporation: Honoraria, Research Funding. Zamagni:Celgene Corporation: Honoraria, Speakers Bureau; Janssen Pharmaceuticals: Honoraria, Speakers Bureau; Amgen: Honoraria, Speakers Bureau. Renwick:Amgen: Other: Travel; Bayer: Speakers Bureau. Tempescul:Gilead: Other: Export Board Committee. Palumbo:Novartis, Sanofi Aventis: Honoraria; Celgene, Millennium Pharmaceuticals, Amgen, Bristol-Myers Squibb, Genmab, Janssen-Cilag, Onyx Pharmaceuticals: Consultancy, Honoraria. Sturniolo:Celgene Corporation: Employment. Ervin-Haynes:Celgene Corporation: Employment.

Background: Eight RCHOP/21 cycles followed by Rituximab maintenance is considered the standard of care for first line therapy in elderly MCL patients in Europe (1). However,complete clinical (CR) and molecular responses (MR) to therapy remain suboptimal(CR rate 30-35%, MR after 8 cycles 67 %). Regimen combining Rituximab and Bendamustine and more recently proteasome inhibitor Bortezomib (Velcade®) with CHOP regimen (VcR-CAP) demonstrated superior CR rates and PFS compared to R-CHOP. We have investigated the RiBVD regimen (Rituximab, Bendamustine,Velcade® and Dexamethasone) in a prospective phase II trial by the LYSA group. Aims of the study: The primary objective was to improve the median PFS by 6 months over the current 18 months PFS obtained with RCHOP when given without maintenance (ref Lenz, JCO 2005). The secondary objectives were to investigate the prognostic impact of molecular and FDG-PET responses on survival.. Methods and Material: All patients aged 65 or older with a diagnosis of MCL were treated by the RiBVD regimen if they fulfilled the following inclusion criteria: AAstage II-IV, PS < 3, no other neoplasm, no active HIV or HBV or HCV infections, no renal (creatinin clearance > 20ml/mn) or cardiac dysfunction, no diabetes. The RiBVD regimen was administered every 4 weeks with Rituximab 375 mg/m² IV on day(D)1, Bendamustine 90 mg/m² IV on D1, 2, Dexamethasone 40 mg IV on D2 and Bortezomib (Velcade®) 1.3 mg/m² subcutaneously on D1, 4, 8 and 11. Primary prophylaxis with valacyclovir was mandatory for Herpes virus reactivation, but there was no recommendation for bacterial prevention. Patients were scheduled to receive a total of 6 cycles, if they achieved at least PR at 4 cycles. The IWG criteria, with and without FDG-PET, were used to define responses after 4 and 6 cycles. FDG-PET response was evaluated in each center with the five-point scale visual method of Deauville. Molecular responses (MR) were evaluated centrally by RQ-PCR using patient specific IGH VDJ targets as previously described (2). Results: Seventy six patients were recruited in one year (from November 2011 to December 2012), 74 were evaluable [2 patients were excluded because HBV positivity (n=1) or misdiagnosis (n=1)]. Fifty four samples were centrally reviewed for diagnosis, 45 were classic form of MCL, 9 pleomorphic variant and one patient had a DLBCL. Clinical characteristics of the 74 patients were: Median age 73 yo (64-83), sex ratio M/F = 2 (49/25), AAstage II/III-IV = 4/70, PS 0-1/2 = 63/11, MIPIscore low/intermediate/high= 3/19/50 (2 undetermined). The median follow-up is 21 months. Thirteen patients died because of lymphoma progression (n=7), cardiac arrest (n=2) or in one case each,pneumonia, Progressive Multifocal LeukoEncephalopathy, pancreatic carcinoma or of unknown causes. After 4 cycles the ORR was 86% (n=64) and CR/CRu 57% (n=42). After 6 cycles, the CR/CRu raised to 74% (n=55) the PR rate was 9% (n=7), 2 patients had a stable disease, 4 progressed and 5 had died during the treatment. The complete MR rate after 6 months on blood samples or bone marrow was respectively 83% (43/50) and 74 % (32/43). At 24 months, the PFS was 69% and the OS 80%. The MIPI score (high vs low/int) and the blood MR after 6 cycles were the only two statistically prognostic factors for PFS and OS. Toxicities were essentially hematologic with grade 3 or 4 neutropenia and thrombocytopenia in 51% and 36% of the cases, respectively. The main grade 3 or 4 extra-hematologic toxicities were fatigue (19%), neuropathy (14%), cardiac (7%) or febrile neutropenia (5%). Conclusion: The RiBVD regimen can be safely administered as first line therapy to elderly patients with MCL. Toxicities are mild and manageable. With 74% of CR/CRu, a 2 year PFS of 69% and 86% of patients achieving an MRD negative status in the blood after 6 cycles, without maintenance therapy, the RiBVD regimen is identified as a highly effective, well tolerated, first line treatment for elderly MCL patients. Reference : 1 - Kluin Nelemans HC et al, NEJM 2012, 2 - Gimenez E et al, BJH 2012 Disclosures Gressin: mundipharma: Consultancy. Off Label Use: Bendamustine and Bortezomib did not have authorization to their use in first line for MCL in France. Karlin:Janssen: Honoraria; celgene: Consultancy, Honoraria; Sandoz: Consultancy. Le Gouill:Mundipharma: Honoraria; Roche: Honoraria; Janssen: Consultancy.

Abstract 4879 Background: In Waldenström's Macroglobulinemia (WM), response rates to rituximab (RTX) range from 30% to 75%. RTX is also known to generate a transient IgM flare in some patients. Our study aimed to characterize this phenomenon using the newly Hevylite® assay developed by The Binding Site that specifically quantifies IgM-kappa(K) and IgM-lambda(L). Methods: Between 2007 and 2009, 33 WM patients received a 6-course fludarabine-based regimen, 32 as first and 1 as second line. Partial response (PR), defined as a reduction ≥50% but Results: Of the 33 tested, at a variation threshold ≥20% relative to baseline IgM levels, 3 subgroups were defined: 15 or 45.5%, the no-flare patients, showed an increase or a decrease We also analyzed the data without defining a critical threshold in monoclonal IgM level variations. Patients were, then, separated in 2 subgroups: 17 flare patients and 16 anti-flare patients. Monoclonal K light chain was overrepresented in the 2 subgroups, with 13 K vs 4 L in flare patients and 13 K vs 3 L in anti-flare patients; no statistically significant difference was found between them regarding monoclonal K and L light chains (p=0.32). No association was seen with demographic and hematologic characteristics and RTX pharmacokinetics. Regarding FcgR IIIa-158 polymorphism, there was a statistically significant difference (p=0.03) as 12 patients were of the FF subtype and 5 of the VF one in the flare subgroup while 4 were of the FF subtype, 11 of the VF one and 1 of the VV one in the anti-flare subgroup. At response evaluation 3 months after the fourth injection of RTX, all patients were screened for SPE and 22 for IF. When we compared the 17 patients of the flare subgroup to the 16 ones of the anti-flare subgroup, no patient vs 1 reached complete remission defined as disappearance of BMP on SPE and negativity of IF, 1 vs 6 advanced to very good partial response defined as a decrease ≥90% in BMP on SPE and positivity of IF and the remaining 16 vs 9 improved their partial response by a mean additional reduction of 20% (range: 0–30%) vs 18.75% (range: 0–50%) in BMP, but there was no statistically significant difference in this regard (p=0.79). Conclusions: Using Hevylite® assay, monoclonal IgM up and down variations of at least 20% following RTX occurred in up to 54.5% of our patients and this raised to 100% when no threshold value was considered. Such assay provides a reliable and highly sensitive quantitative assessment, especially in patients whose monoclonal IgM was at low concentration. Patients of the flare subgroup were predominantly of the FF subtype of FcgR IIIa-158 polymorphism while patients of the anti-flare subgroup were predominantly of VF subtype, which was statistically significant. It is tempting to hypothesize a difference in RTX mechanism of action, with ADCC predominating in the anti-flare subgroup and CDC in the flare subgroup. It would be of interest to assess such an hypothesis on a larger cohort and to analyze its impact on response profile. Disclosures: Pietrantuono: The Binding Site: Employment.

Abstract 3066 Introduction: Advanced stage III/IV or relapsed/refractory follicular lymphoma (FL) can hardly be cured with conventional chemotherapy and patients, even after autologous stem cell transplantation (ASCT), experience innumerable relapse events occurring at decreasing progression-free intervals. Important progress was made since the introduction of RITUXIMAB as part of frontline chemoimmunotherapy or as maintenance after frontline treatment with or without ASCT. But, whatever the policy applied, no plateau is observed regarding overall survival (OS) and progression-free survival (PFS). Disease relapse, even in patients with documented complete remission (CR), is thought to be induced both by resistant minimal residual tumor cells and the lack of immunocompetent mechanisms to contain or eliminate them. Thus, it has been postulated that post-ASCT consolidative immunotherapy might eradicate minimal residual disease, based on antibody-dependent cell-mediated cytotoxicity (ADCC) mechanism, and have a favorable impact on relapse rate and even OS. This view has led to a considerable interest in immunotherapy as a promising therapeutic line to restore and enhance the impaired anti-tumor immune surveillance in the context of post-ASCT low tumor burden. Purpose: We conducted a phase II study to compare OS and PFS between patients with advanced or relapsed/refractory FL receiving consolidative immunotherapy combining recombinant interleukine-2 (rIL-2), recombinant interferon- α-2b (rINF- α-2b) and RITUXIMAB after ASCT, with the aim of controlling minimal residual disease, and other counterparts with FL receiving no further treatment after ASCT. Patients and Methods: From August, 1995, to October, 2009, 139 patients with FL were autografted in complete remission ≥1 or partial remission. Of these patients, 66 were considered eligible for immunotherapy. On adequate post-ASCT hematologic reconstitution, they received 4 weekly IV injections of RITUXIMAB administered on an outpatient fashion. This was followed by a home-based program of subcutaneous injections of rIL2 (6 million UI × 3 / week in 1st cycle; 9 million × 3 / week in 2d) and rINF- α-2b (1.5 million UI × 3 / week in 1st cycle; 3 million × 3 / week in 2d) administered over two 7-week cycles. These two cycles were separated by a two-week free interval. The other 73 patients did not receive any additional treatment after ASCT and served as controls. Results: The two groups were comparable regarding demographic characteristics, disease profile and treatment course, except that the control group had significantly less transformed FL (p =0.0156) and a higher mean treatment line number (p =0.018). Median OS and PFS were not reached in either the study group or the control group. OS, initially not different between the 2 groups (p =0.21), was found significantly higher in the study group after a cut-off follow-up time point of 86.6 months (p =0.017). A significantly higher PFS was also noted in favor of the study group over the control group (p =0.0131). With a median follow-up of 60 months (10 to 136) in the study group and of 82 months (0.7 to 174) in the control group, survival rate was 90.9% and 71.2%, respectively (p= 0.0034) and the overall relapse rate was 19.7% (13 patients) and 41.1% (30 patients), respectively (p= 0.0064). Adverse events were generally mild, consisting essentially of fever and chills with the rIL-2 and rINF- α-2b subcutaneous injections (rapidly controlled with PARACETAMOL), fatigue, grade 2 abnormal liver function tests in one third of patients and grade 2 or 3 cytopenias (anemia or neutropenia) in 40% of patients. Conclusion: These results confirm that post-ASCT immunotherapy with rIL2, rINF- α-2b and RITUXIMAB has a statistically significant impact on OS and PFS. In view of its tolerability, it appears to be quite feasible and safe and might be seen as a promising line of treatment designed for eradicating post-ASCT minimal residual disease and worth being tested within the frame of a randomized trial for validation as an essential step in the treatment algorithm of FL. Disclosures: No relevant conflicts of interest to declare.

Abstract 3558 Introduction: A minority of patients with diffuse large B cell lymphoma (DLBCL) can really be cured and the early or late relapse rate remains a subject of major concern. The occurrence of disease relapse, even in patients with documented complete remission (CR), is thought to be induced both by resistant minimal residual tumor cells and the lack of immunocompetent mechanisms to eradicate them. Thus, it has been postulated that post-autologous stem cell transplantation (ASCT) consolidative immunotherapy might eradicate minimal residual disease and, therefore, reduce relapse rate and even improve overall survival (OS). This view has led to a considerable interest in immunotherapy as a promising therapeutic line to restore and enhance the impaired anti-tumor immune surveillance in the setting of post-ASCT low tumor burden. Purpose: We conducted a phase II study to compare OS, relapse-free survival (RFS), death rate and overall relapse rate between patients with poor-risk DLBCL receiving consolidative immunotherapy combining recombinant interleukine-2 (rIL-2), recombinant interferon-α-2b (rINF-α-2b) and Rituximab after ASCT, with the aim of controlling minimal residual disease, and other patients with poor-risk DLBCL treated with ASCT alone. Patients and Methods: On 180 patients, 27 with DLBCL from Brest, autografted in complete remission (CR) ≥ 1 or partial remission (PR), were considered eligible for the study. They received, on adequate post-ASCT hematologic reconstitution, 4 weekly IV injections of Rituximab administered on an outpatient fashion. This was followed by a home-based program of subcutaneous injections of rIL2 (6 million UI × 3/week in 1st cycle; 9 million × 3/week in 2d) and rINF-α-2b (1.5 million UI × 3/week in 1st cycle; 3 million × 3/week in 2d) administered over two 7-week cycles. These two cycles were separated by a two-week free interval. One hundred and fifty three patients from Brest, Lille and Tours did not receive any additional treatment after ASCT and served as controls. Results: The two groups were comparable, except for age, which was older in the study group (p=0.018) and for pre-ASCT response pattern, which was better in the control group. There was no influence of recruitment center, sex, disease Ann Arbor stage, IPI score, RITUXIMAB administration before ASCT, graft source or ASCT conditioning regimen on the final results. Median OS and RFS were not reached in any group and are still under study. The median follow-up was 54.9 months in the study group and 48.8 months in the control group. In univariate analysis, the prevalence of death rate was 7.4% and 26.2% in the study group and the control group, respectively (OR = 0.23, 95%CI [0.05-0.99], p=0.03), and the overall relapse rate was 11.1% (3 patients) and 22.9% (35 patients), respectively (OR=0.42, 95%CI [0.12-1.48], p=0.17). In multivariate analysis, the risk of death was significantly decreased (OR 0.196; 95%CI [0.046-0.827] p=0.027) and there was a trend toward a decreased relapse rate (OR 0.348; 95%CI [0.104-1.168], p=0.088) in the study group compared to the control group. In addition, older age was independently associated with an increased risk of death (OR=1.053, 95%CI [1.02-1.09], p=0.002). Adverse events were generally mild, consisting essentially of fever and chills with the rIL-2 and rINF-α-2b subcutaneous injections responding well to PARACETAMOL, fatigue, grade 2 abnormal liver function tests in one third of patients, grade 3 neutropenia in 45% of patients and hypothyroidism in one patient. Conclusion: We found that post-ASCT immunotherapy with rIL2, rINF-α-2b and RITUXIMAB has a statistically significant favorable impact on death rate and a positive, although not statistically significant, effect relapse rate. In view of its toxicity profile, it appears to be quite feasible and safe and might be considered as a promising line of treatment designed for post-ASCT minimal residual disease and worth being evaluated within the frame of a prospective randomized trial. Disclosures: No relevant conflicts of interest to declare.

Abstract 4593 Introduction: The incidence of lymphoma is increasing in the western population. Autologous stem cell transplantation (ASCT) is the standard consolidation procedure in patients with lymphoma expressing bad features at the time of diagnosis or in patients relapsing after a first line of chemotherapy (or radiotherapy). It has already been proven that ASCT improves the overall survival and the disease free survival in younger patients. No data are available for the feasibility and the results of ABSCT in elderly patients (OMS defines elderly as age superior to 65 years). Purpose: We performed a retrospective study in our centre, comparing the feasibility and the results of ABSCT in elderly patients with lymphoma compare to patients younger than 65 years old. Patients and Methods: We identified 147 patients who underwent ASCT transplantation in Brest Transplantation Centre. Ninety-four patients were younger than 65 (mean51.44years) and 53 patients were older (mean 67.86 years). Results: Transplantation related mortality (TRM) (up to 100 days post ASCT) was similar for the two populations. There was no statistically significant difference between the two populations regarding the number of units of RBC and platelets transfused, the number of CD 34 reinjected and infectious complications. There was a statistically significant difference between the two populations regarding the duration of aplasia: 11.21 days in younger patients and 11.89 days in elderly population. There was no statistically significant difference between the two populations regarding the overall survival (OS) and the disease free survival (DFS). Conclusion: Our retrospective, monocentric, comparative study showed that ACST could be performed in selected elderly patients (over 65 years old) with no significant difference regarding TRM, DFS and OS but a little bit longer period of aplasia: 11.21 days for young patients and 11.89 in elderly (p-0.0005). Disclosures: No relevant conflicts of interest to declare.

Abstract 1946 Poster Board I-969 STATEMENT OF PURPOSE: Rituximab (RTX) is a chimeric antibody targeting CD20, a membranous B-cell specific protein, currently used in the treatment of B-cell malignancies and various autoimmune diseases. Despite its clear efficacy in non-Hodgkin's lymphoma, clinical and biological responses are highly variable between patients. Therefore, predictive factors are necessary to adapt therapy to each individual as early as possible. MATERIAL AND METHODS: We studied a set of biomarkers in a cohort of 39 patients with indolent non-Hodgkin's B-cell lymphoma (low grade follicular lymphoma or marginal zone lymphoma) and a low tumour burden, treated with single agent RTX as follows: 4 weekly 375 mg/m2 infusions, associated with short-course oral steroids. All patients benefited from FDG-PET analysis before treatment and 10 weeks later, allowing their classification into 3 early response groups: complete isotopic remission, partial response and no response. Dosage of rituximabemia, BAFF and Human Anti-Chimeric Antibodies (HACA) was performed with in-house ELISAs before each infusion and 2 months later. Polymorphisms of FcγRIIIa[158], FcγRIIa[131] and C1qA[276] genes were determined using allele-specific PCR or direct sequencing. Results were compared using Student's t-Test or two-tailed Fischer's exact test when appropriated. RESULTS: Referring to PET analysis, 18 patients were classified as complete isotopic remission, and 21 as partial or no response. Mean age was significantly lower in the first group (54 y+/-19 vs 66+/-13, p=0.022), as well as initial SUVmax (6.3+/-3.4 vs 10.8+/-6.8, p=0.024). Serum levels of RTX were highly variable between patients at each timepoint, but were not statistically different between the different response groups. Basal levels of BAFF were not statistically different between lymphoma patients and a control population, and did not vary after RTX-induced B cell depletion. No patient developed a HACA response during the study. Homozygous FcγRIIIa158V/V genotype was significantly associated with a complete response (p=0.037). Conversely, FcγRIIa[131] and C1qA[276] polymorphisms were not associated with the response. Genetic polymorphisms seemed to modify RTX pharmacokinetics, since homozygous FcγRIIa[131]H/H, FcγRIIIa[158]V/V and C1qA[276]G/G subjects displayed lower levels of RTX than others, without reaching statistical significance. CONCLUSIONS: Younger age, lower initial SUVmax and FcγRIIIa[158]V/V genotype are associated with a better early response to RTX in indolent lymphoma patients, as assessed by PET analysis. FcγR polymorphisms affect RTX kinetics probably through a modification of the efficacy of antibody dependant cell cytotoxicity. Determination of these factors could help in adapting individually therapeutic protocols. Disclosures: No relevant conflicts of interest to declare.

Abstract 4797 Hodgkin's disease (HD) is a commonly cured lymphoma. Unfortunately between 10 and 20% of patients are refractory or relapse after a first line of treatment. There is evidence that for these patients the best approach is salvage chemotherapy followed by high-dose chemotherapy (HDC) and autologous stem cell transplantation (ASCT). Existing salvage regimens of chemotherapy, mainly based on platines or aracytine, have a response rate between 60-85%. Usually is associated a toxicity resulting in delay of chemotherapy or dose reduction. It is very important to achieve complete remission before HDC/ABSCT. It has been proved that 18-FDG PET has a predictive value on Hodgkin's lymphoma. Into the pathophysiology of HD are implicated various cytokines like IL6, IL12, IL13, NFkB and angiogenic factors. Immunomodulatory drugs have an impact on microenvironment, altering cytokine secretion and the expression of adhesion molecules which can result in apoptosis of malignant B-cell. Lenalidomide, having both immunomodulatory and antiangiogenic activity, proved to be highly active into the treatment of myeloma and some forms of non-Hodgkin's lymphoma. Into a phase two studies, Lenalidomide administrated as a single agent, proves to be also active into the refractory or relapsed Hodgkin's lymphoma. During a period of one year, we identified eight patients with refractory ore relapsed HD. We have treated these patients with classical salvage chemotherapy regimen – ESAP- in which we associated Lenalidomide, administrated continuously during the whole period of treatment. We evaluate the response by 18-FDG PET, early, after two or three cycles of ESAP-Lenalidomide association. We obtained seven complete remissions and one very good partial remission (minimal residual disease in PET SCAN). The toxicity was essentially hematological, neutropenia and trombocytopenia. This small study proves that Lenalidomide, a new drug with both immunomodulatory and antiangiogenic effects, associated to a classical salvage regimen of chemotherapy is highly active on refractory or relapsing Hodgkin's lymphoma. Disclosures: No relevant conflicts of interest to declare.

Introduction Intensive treatments like autologous stem cells transplantations are final standard treatment in lymphoma and myeloma for young people (1,2). In the context of population’s ageing, those treatments should be eligible for older patients. One of the major causes which did not allowed these procedures in elderly patients is the reports of the impact of the age on the process of mobilisation of peripheral stem cell (3). We proceed a retrospective study to explore the feasibility of stem cells collection in patients older than 65 years, compared to younger people. Material and patients During the period of 1999–2006, we identified all the patients older than 65 years, with myeloma and lymphoma, who performed peripheral stem cells collection in Brest’s blood collection centre. We excluded patients for bone marrow collection. Patients were eligible if they achieved more than 2.106 CD34/kg. Then we compared the results obtained in older patients with the results obtained in younger people. Results We identified 100 patients older than 65 years between the 359 patients who underwent peripheral stem cell harvest in Brest’s harvest centre. We excluded 37 others patients for non-conformity. The elderly patients were significantly older (age 68.9 vs. 49.3 y, p0.05). The number of CD34/kg per patient was sufficient to realise more than one autologous transplantation in both groups of patients (5.3 vs. 6.67, p=0.004). Samples were sufficiently rich for CD34/kg (4.36 vs. 5.54, p=0.02). Patients were harvested in one (60), two (25) or more than 2 collections (15). Among the older patients, 71% achieved a sufficient collection of more than 2.106 CD34/kg in one sample only. Conclusion We identified one hundred patients older than 65 years, during a period of 8 years, who performed peripheral stem cells collection, with sufficient wealth (>2.106 CD34/kg). The majority of patients, 60%, need only one stem cells harvesting. The study confirmed that old patients could be harvested like young people, and eligible for stem cells autologous transplantation.