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International audience; Poly-chemotherapy plus rituximab followed by autologous stem cell transplantation (auto-SCT) is standard care for untreated young patients with mantle cell lymphoma (MCL). Despite this intensive treatment, transplant patients remain highly susceptible to relapse over time. The French SFGM-TC performed a national survey on reduced-intensity conditioning allogeneic stem cell transplantation (RIC-allo-SCT) for fit relapsed/refractory patients who failed after auto-SCT (n=106). Median times of relapse after auto-SCT, and from auto-SCT to RIC-allo-SCT were 28 months and 3.6 years, respectively. Sixty per cent of patients received at least three lines of treatment before RIC-allo-SCT. Conditioning regimens for RIC-allo-SCT were heterogeneous. Twenty patients experienced grade III/IV aGvHD, extensive cGvHD was reported in 28 cases. Median follow-up after RIC-allo-SCT was 45 months. Median PFS after RIC-allo-SCT was 30.1 months and median overall survival was 62 months. Treatment-related mortality (TRM) at 1 year and 3 years were estimated at 28% and 32%, respectively. A total of 52 patients died; major causes of death were related to toxicity (n=34) and MCL (n=11). Patients in good response before RIC-allo-SCT experienced a better PFS and OS. Our work highlights the need for new RIC-allo-SCT MCL-tailored approaches to reduce TRM, and early and late relapse.

Optimal salvage treatment for multiple myeloma relapsing after allogeneic stem cell transplantation remains to be determined. Usually, such patients have been heavily pre-treated and present at relapse with a relatively refractory disease. Immunomodulatory properties of lenalidomide may be beneficial by facilitating a graft-versus-myeloma effect after allogeneic stem cell transplantation. However, the safety of such treatment is still under debate. We conducted a multicenter retrospective study and included 52 myeloma patients receiving lenalidomide alone or in combination with dexamethasone as salvage therapy after allogeneic stem cell transplantation. The first aim was to assess the efficacy and tolerance of this drug. The second aim was to evaluate its potential immunomodulatory effects evaluated on the occurrence of acute graft-versus-host disease under treatment. In this cohort, we show that lenalidomide can induce a high response rate of 83% (including 29% complete response). On lenalidomide therapy, 16 patients (31%) developed or exacerbated an acute graft-versus-host disease, which was the only factor significantly associated with an improved anti-myeloma response. Side effects were mostly reversible, whereas 2 deaths (4%) could be attributed to treatment toxicity and to graft-versus-host disease, respectively. With a median follow up of 16.3 months, the median overall and progression free survival were 30.5 and 18 months, respectively, independently of the occurrence of acute graft-versus-host disease under lenalidomide. Lenalidomide can induce high response rates in myeloma relapsing after allogeneic stem cell transplantation at least in part by triggering an allogeneic anti-myeloma response. Induced graft-versus-host disease has to be balanced against the potential benefit in terms of disease control. Further immunological studies would help us understand lenalidomide immunomodulatory activity in vivo.

Invariant natural killer T (iNKT) cells can experimentally dissociate GVL from graft-versus-host-disease (GVHD). Their role in human conventional allogeneic hematopoietic stem cell transplantation (HSCT) is unknown. Here, we analyzed the post-HSCT recovery of iNKT cells in 71 adult allografted patients. Results were compared with conventional T- and NK-cell recovery and correlated to the occurrence of GVHD, relapse, and survival. We observed that posttransplantation iNKT cells, likely of donor origin, recovered independently of T and NK cells in the first 90 days after HSCT and reached greater levels in recipient younger than 45 years (P = .003) and after a reduced-intensity conditioning regimen (P = .03). Low posttransplantation iNKT/T ratios (ie, < 10−3) were an independent factor associated with the occurrence of acute GVHD (aGVHD; P = .001). Inversely, reaching iNKT/T ratios > 10−3 before day 90 was associated with reduced nonrelapse mortality (P = .009) without increased risk of relapse and appeared as an independent predictive factor of an improved overall survival (P = .028). Furthermore, an iNKT/T ratio on day 15 > 0.58 × 10−3 was associated with a 94% risk reduction of aGVHD. These findings provide a proof of concept that early postallogeneic HSCT iNKT cell recovery can predict the occurrence of aGVHD and an improved overall survival.

Overview: Although advanced follicular lymphoma is considered incurable, patient outcomes have improved over the last decade with the use of anti-CD20 monoclonal antibodies. Multiple treatment options are available and their use depends on clinical presentation (i.e., Ann Arbor stage, tumor burden, symptoms) and patient condition and age. Radiation therapy for patients with limited stage disease remains useful, although its use in the era of anti-CD20 antibodies should be re-evaluated. Single-agent rituximab has been tested in multiple studies with patients with low tumor burden. Short treatment duration provides a response lasting 2 to 3 years, although the benefit of maintenance therapy with rituximab after induction therapy with rituximab remains unproven. When watchful waiting is not an option, a combination of rituximab with chemotherapy is the standard of care: alkylating agents with anthracycline or bendamustine appear to be the most widely used regimens, but alkylating agents alone may still be used in selected patients subgroups. The toxicity of regimens containing fludarabine appears to limit their indication as first-line treatment. In patients responding to one of these combinations, consolidation therapy with rituximab maintenance has been shown to prolong progression-free survival with acceptable toxicity. The benefit of radioimmunotherapy in first-line treatment is still uncertain. With patients surviving for many years, the therapeutic strategy of first-line management should weigh the quality and duration of response against the risk of long-term toxicities.

International audience; Several studies reported the benefits of switching from anticalcineurins to mTOR inhibitors to avoid cancer occurrence after organ transplantation. The purpose of our study was to determine in vivo biological markers to explain these benefits. Cellular changes related to cellular senescence and DNA damage were analyzed in peripheral blood lymphocytes. Thirty-five kidney transplanted patients receiving anticalcineurins were investigated: 17 patients were proposed to switch to rapamycin and 18 patients with similar age and transplantation duration, continued anticalcineurins. Rapamycin effects were studied one year after the switch. Thirteen healthy volunteers and 18 hemodialyzed patients were evaluated as control. Compared with the healthy group, hemodialyzed and transplanted patients exhibited a significant decrease in telomere length, an increase in p16(INK4A) mRNA expression and in lymphocytes with 53BP1 foci. A destabilization of the shelterin complexes was suggested by a significant TIN2 mRNA decrease in transplanted patients compared with controls and a significant increase in TRF1, TRF2 and POT1 expression in switch-proposed patients compared with the non-switched subgroup. Rapamycin treatment resulted in a significant decrease in DNA damage and a slight TIN2 increase. In vitro experiments strengthened in vivo results showing that rapamycin but not FK506 induced a significant DNA damage decrease and TIN2 expression increase compared with controls. The roles of rapamycin in the decrease in DNA damage in vivo and the rescue of shelterin gene expression are demonstrated for the first time. These data provide new insights into understanding of how rapamycin may overcome genomic injuries

Background: BIA-ALCL has recently been recognized as a distinct entity among T cell lymphomas. In the French Lymphopath network which has registered almost 60 000 lymphomas since 2010, 50 cases of BIA-ALCL were identified so far. Little is known about the causes, and prognostic factors of this disease. Methods: since 2016, a WebEx national multidisciplinary meeting has been implemented by the French Cancer Agency in order to better define therapeutic strategies for newly diagnosed cases after histologic confirmation. In the same time, BIA-ALCL registry was funded by LYSA in order to collect ambispectively patient clinical data including reasons for breast implantation (breast augmentation, reconstruction), implant manufacturer, treatments and outcome. Results: Thirty nine BIA-ALCL have been analyzed so far. Median age was 61 years (range 29-82) at diagnosis. In 20 out of 39 patients (pts) (51.3%) the first implant followed a mastectomy for breast cancer. Twelve pts were implanted twice (33%) and thirteen pts (36%) 3 times or more. The median delay between first implant and BIA-ALCL diagnosis was 11.9 years (range 4-37), and median delay from last implant to diagnosis was 3.6 years (range 0-26). The two clinical presentations i.e. seroma (n = 26 - 67%) and breast tumor mass with or without seroma (n = 9 - 23%) were most often correlated with the two distinct histological subtypes (in situ or infiltrative). The majority of pts (76.9%) were stage IE (n=30; 77%), and nine (23%) pts were stage IV. One hundred and thirty five implants have been used for these 39 patients. Considering available informations regarding the type of implants, almost all patients had at least one silicone-filled (n=35) and at least one textured implant (n=31). No patient had only smooth implant. Implant removal with total capsulectomy was performed in 33 patients and 13 underwent chemotherapy based mostly on CHOP or CHOP-like chemotherapy regimens (n=11; 85%). After 24 months of median follow-up, 33 pts are alive and free of evolutive disease. Two patients have not been evaluated. Four pts have died, either from lymphoma progression alone (n=2), or associated with concomitant breast cancer (n=2). All had an infiltrative histology, 3 were stage IV and one had a localized bulky disease. All but one received systemic chemotherapy and one received palliative care only due to concomitant breast cancer. One of these patients early relapsed after a first complete remission. Conclusions: In situ BIA-ALCLs have an indolent clinical course and remain in complete remission mainly after implant removal. Infiltrative BIA-ALCLs have a more aggressive clinical course. It is therefore critical to perform a rigorous staging using multi-imaging modality including TEP at baseline. Multiple implants could favor the occurrence of BIA-ALCL. New insights into the biology of BIA-ALCL might translate into more targeted and effective therapies in refractory or relapsed patients. The modalities of breast monitoring and reconstruction remain open questions for those patients. Disclosures Le Bras: Amgen: Consultancy. Bachy:Roche: Research Funding; Celgene: Consultancy; Amgen: Honoraria; Takeda: Research Funding; Janssen: Honoraria; Gilead Sciences: Honoraria; Sandoz: Consultancy. Fornecker:Servier: Honoraria; Takeda: Honoraria. Traverse-Glehen:Takeda: Research Funding; Astra Zeneca: Other: Travel. Tilly:Astra-Zeneca: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria; Celgene: Membership on an entity's Board of Directors or advisory committees. Xerri:Janssen: Other: Travel. Gaulard:Celgene: Research Funding; Roche: Honoraria; Takeda: Consultancy, Honoraria, Research Funding. Haioun:Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Gilead Sciences: Consultancy, Honoraria; Sciences: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria.

Introduction: AITL, one of the most common peripheral T-cell Lymphoma portends a poor prognosis. AITL is characterized by neoplastic T cells with a follicular helper immunophenotype, frequent mutations in epigenetic regulators TET2, IDH2, DNMT3A and in RHOA, and a prominent tumor microenvironment that could contribute to lymphomagenesis. Aiming to target this microenvironment and given the promising activity of lenalinomide (Len) in a relapsed setting (PMID: 23731832), we postulated that AITL patients (pts) might benefit from a treatment with Len combined with a classical CHOP regimen. This multicenter, open label, phase 2 trial (NCT01553786) investigates this treatment in previously untreated elderly pts. Patients and methods: Patients older than 59 years were treated with 8 cycles of Len + CHOP 21 (Len 25 mg/day (d), d1 to 14) and received intrathecal methotrexate prophylaxis. Thromboprophylaxis with low molecular weight heparin was mandatory. PET CTs at diagnosis and at the end of treatment were centrally reviewed. The primary objective was to evaluate the complete metabolic response rate according to the Lugano 2014 Classification. Secondary endpoints were safety, progression-free (PFS) and overall survival (OS). Mutations in TET2, IDH2, DNMT3A, RHOA, CD28, PLCG1, STAT3 and STAT5B were analyzed by deep sequencing (1000X) using DNA extracted from formalin-fixed paraffin-embedded tumor samples by PGM technology and were correlated to clinical parameters. Results: Between November 2011 and March 2017, 80 pts were enrolled, and 78 were evaluable. Central pathology review confirmed the diagnosis of AITL in 72 cases (92%). Median age was 69 (59-80), 52 % were female, 68% had a performance status of 0 to 1, 94% an Ann Arbor stage ≥III, 82% IPI≥3. Forty-five patients (58 %) completed the 8 planned cycles (mean number of cycles delivered, 5.9). Of the 624 planned treatment cycles, 458 (72 %) were completed. Treatment was stopped in 8 pts because of progressive disease, and in 15 because of adverse events. Toxicity was within the range expected of R-CHOP therapy with 70% grade 4 neutropenia and 31 % thrombocytopenia. Deep vein thrombosis occurred in 8 pts. Four secondary primary malignancies were reported. Five patients died from toxicity (4 from infection). Len dose reductions or interruptions were applied in 37 (5%) and 59 (9%) cycles, respectively, related to toxic effects. The median dose of Len per patient was 2275 mg (IQR 95-2825)-i.e. 81% of the planned dose of 2800 mg. Doxorubicin and cyclophosphamide were administrated at 98% and 97% of the planned dose. Complete metabolic response was observed in 34 patients (43.6%) (90%CI = [34.0%; 53.5%]), partial metabolic response in 3 (3.8%), no metabolic response in 2 (2.6%) and progressive metabolic disease in 16 (20.5%), the other being not evaluated because of progression (N=20) or death (N=3). With a median follow-up duration of 31.5 months (95%CI = [23.0; 43.7]) at the time of the cut-off, 2-year PFS is 42.3% (95%CI = [30.9%; 53.2%]) and 2-year OS is 60.1% (95%CI = [47.4%; 70.7%]). IPI was strongly associated with the survival (figure 1A). Mutational status was successfully determined in 64 pts with confirmed AITL diagnosis. TET2 mutations were detected in 49 cases (77%), with 28 (43%) pts bearing ≥2 TET2 mutations. RHOAG17V mutations in 34 pts (53%), DNMT3A mutations in 20 (31%) pts, including 6 with the DNMT3AR882X variant and IDH2 mutations in 14 (22%). CD28, PLCCG1 and STAT mutations were detected in less than 10% of pts (figure 1B). TET2 mutations correlated to age>65 years (p=0.006) and IPI 3-5 (p=0.007). Interestingly, DNMT3A mutations were associated with a decreased response rate (p=0.003), a shorter PFS (p=0.04) and a trend toward a shorter OS (0.08). It is noteworthy that none of the 6 pts with the DNMT3AR882X mutant had response, suggesting that the resistance to anthracycline reported in DNMT3AR882X mutated acute myeloid leukemia (PMID: 27841873) could also occur in DNMT3AR882X mutated AITL. No correlation between other detected mutations and outcome was observed (table 1C). Conclusion A combination of 25 mg of Len for 14 days with CHOP cycles gives acceptable toxicity in AITL elderly pts. However, response rate and outcome appear similar to previous studies. We also confirmed in a prospective study the frequency of mutations in epigenetic regulators and RHOA in AITL and clarified their prognostic impact. Figure Figure. Disclosures Bachy: Gilead Sciences: Honoraria; Sandoz: Consultancy; Janssen: Honoraria; Roche: Research Funding; Takeda: Research Funding; Amgen: Honoraria; Celgene: Consultancy. Cartron:Celgene: Consultancy, Honoraria; Sanofi: Honoraria; Gilead Sciences: Honoraria; Janssen: Honoraria; Roche: Consultancy, Honoraria. Casasnovas:Merck: Honoraria; Takeda: Honoraria; Roche: Honoraria; Gilead Sciences: Research Funding; Roche: Research Funding; Janssen: Consultancy; Gilead Sciences: Consultancy; MSD: Consultancy; merck: Consultancy; takeda: Consultancy; Roche: Consultancy; Janssen: Honoraria; Celgene: Honoraria; Gilead Sciences: Honoraria; MSD: Honoraria. Tilly:Celgene: Membership on an entity's Board of Directors or advisory committees; Roche: 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; Astra-Zeneca: Membership on an entity's Board of Directors or advisory committees. Gaulard:Celgene: Research Funding; Roche: Honoraria; Takeda: Consultancy, Honoraria, Research Funding. Haioun:Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Sciences: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Gilead Sciences: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria.

Introduction: Indolent non-Hodgkin lymphomas (iNHL), including follicular lymphoma (FL) and marginal zone lymphoma (MZL), are slow-growing lymphoid malignancies with high response rates to first-line treatment, but most patients (pts) will eventually relapse after initial response to treatment. For those with refractory disease (relapse ≤ 6 months after ending treatment), outcomes are worse. A number of treatment options based on chemo- and/or immunotherapy exist for pts with relapsed/refractory (R/R) iNHL, but currently there is no single standard treatment approach. There is a need to better understand the reported efficacy of available systemic treatments for R/R FL and MZL to guide treatment of iNHL. Methods: A SLR was carried out in accordance with PRISMA guidelines on September 1, 2017. Publications from MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), and clinicaltrials.gov databases, as well as proceedings from the European Hematology Association and American Society of Clinical Oncology conferences held from 2015 to 2017, the International Conference on Malignant Lymphomas from 2013, 2015, and 2017, and from the American Society of Hematology, and European Society for Medical Oncology conferences from 2014 to 2016, were included. Studies were limited to articles published in English, sample sizes ≥ 40, and studies evaluating systemic therapy for adults with any-stage R/R FL, MZL, or mixed histologies with ≥ 70% R/R FL/MZL pts. Controlled or uncontrolled clinical trials and observational studies were included. Studies varied with respect to prior treatment received and pt response to prior treatment at enrollment. Pts were classified as relapsed, refractory, refractory to rituximab (R-refractory including double-refractory pts), R/R but sensitive or naïve to rituximab, or as general R/R if the type of relapse and/or refractoriness was not specified. Efficacy measures included overall response rate, complete response rate, progression-free survival (PFS), and duration of response (DoR). Relevant interventions included bendamustine (B) (alone or with rituximab [BR] or obinutuzumab [O+B]), idelalisib (ID), ibrutinib (IB), copanlisib (C), lenalidomide (L) (alone or with rituximab [R2]), R + cyclophosphamide + doxorubicin + vincristine + prednisone (R-CHOP), R + cyclophosphamide + vincristine + prednisone (R-CVP), and R + chlorambucil (R-Chl). Results: Of 58 publications identified representing 36 studies involving 3,759 pts: 1 study reported on R2, 2 on L, 5 on B, 6 on BR, 3 on ID, 3 on IB, 2 on C, 1 on O+B, 1 on R-CHOP, and 12 on R alone. After excluding studies that did not meet criteria for similarity, 19 studies reporting outcomes in iNHL pts were included. Six studies each reported on general R/R pts or R-refractory pts, 4 studies reported on pts with relapsed disease, and 2 studies each reported on pts with refractory disease or R-naïve/sensitive refractory disease. PFS in the general R/R population (n = 1,668) ranged from 4.4 months (mo) in pts treated with L to 17.9 mo in pts treated with BR. Only 1 study reported DoR for pts in the general R/R population. In relapsed pts, PFS was only reported or reached in 1 study (22.9 mo) and DoR ranged from 21.0 to 41.9 mo for BR. In R-refractory pts, PFS ranged from 9.3 mo in B-treated pts to 29.2 mo in O+B-treated pts. DoR ranged from 9.2 to 22.6 mo. BR was investigated in the widest variety of disease subsets (4) with PFS ranging from 17.9 mo in the general R/R population to 34.2 mo in the R-naïve/sensitive R/R population (Table). Outcomes are likely to have been influenced by pt and disease characteristics (e.g., relapsed vs refractory, rituximab sensitive vs refractory, FL International Prognostic Index risk) and response criteria used (Cheson 1999, Cheson 2007, Laboratory of Experimental Oncology and Radiobiology [LEXOR], or unknown). Conclusions: In pts with R/R iNHL (FL and MZL), there is significant variation in reported response and survival outcomes following systemic therapy. Currently, there is no clear standard of care for R/R iNHL, as demonstrated by the use of 9 different therapies across 19 studies identified in this SLR. Limited information is available on treatment outcomes for pts with different disease status and further studies are needed to determine the most appropriate treatment approach for specific subgroups of pts with R/R iNHL. Disclosures Bachy: Roche: Honoraria; Beigene: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; Takeda: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees. Fox:Celgene: Consultancy, Other: travel support, Speakers Bureau; Roche: Consultancy, Other: travel support, Research Funding, Speakers Bureau; Gilead: Consultancy, Other: travel support, Research Funding, Speakers Bureau; Janssen: Consultancy, Other: travel support, Speakers Bureau; Abbvie: Consultancy, Other: travel support, Research Funding, Speakers Bureau; Sunesis: Consultancy. Howlett:Celgene: Employment, Equity Ownership. Snedecor:Celgene: Research Funding. Franek:Celgene Corp.: Consultancy. Zaidi:Celgene Corp.: Consultancy. Tabah:Celgene Corporation: Employment.

Introduction: standard treatment for relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) is high-dose chemotherapy followed by autologous stem-cell transplantation (ASCT) but this strategy is not appropriate for elderly DLBCL patients (pts) related to a high risk of toxicities. Multiple chemotherapy regimens had been developed for heavily pretreated elderly DLBCL patients such as R-bendamustine, R-gemcitabine-oxaliplatin (R-GEMOX) and pixantrone; the median progression free survival (PFS) of these regimens were 2, 4 and 3.5 months, respectively in prospective phase II studies for patients previously treated with R (Sehn 2017, Mounier 2013, Pettengel 2016). Adapted dose of ifosfamide and etoposide was firstly developed as sequential consolidation regimen after high-dose CHOP (ACVBP regimen) in first line therapy of young DLBCL patients (Tilly 2003). This regimen with a safe toxicity profile was then used in combination with R in Lyon University Hospital in elderly R/R DLBCL ineligible to intensive strategy. Methods: we retrospectively reviewed the efficacy and the safety profile of this regimen performed in two Lyon University Hospitals (Centre Hospitalier Lyon Sud and Leon Berard Cancer Center). Between June 2004 and March 2017, 75 pts with R/R DLBCL (63 de novo DLBCL, 12 transformed DLBCL) received R (375 mg/m2) in combination etoposide (300 mg/m2) and ifosfamide (1500 mg/m2) on day 1 (N=72, 96%) and on days 1-2 (N=3, 4%) at 2 (N=46, 61%) or 3-week (N=29, 39%) intervals. All medical records were reviewed for clinical and biological characteristics, modality of treatment and supportive care, toxicities, responses and outcome. Results: the median age was 79 years (range, 64-92) at the beginning of R-ifosfamide/VP16 treatment with 46% of the patients over 80 years. 13% of pts had a CIRS-G grade 3 or 4 >2 categories and 35% had a cumulative CIRS-G score more than 6. The performance status according to EORTC scale was 2-4 in 37% of the pts and 93% had III-IV Ann Arbor stages. Age-adjusted IPI were 0-1 in 20 pts (27%) and 2-3 in 55 pts (73%). All patients were previously treated in first-line therapy by R in combination with chemotherapy (CHOP, N=56, 75%, low-dose CHOP, N=14, 19%, other, N=5, 6%). The patients received a median number of 1 previous line (range, 1-8) and no patient was previously treated by ASCT. The median time between initial diagnosis and R-ifosfamide/VP16 was 20 months (range 4-187). The median time between the last treatment and R-ifosfamide/VP16 was 5 months (range 0-181). A refractory disease to first-line treatment was showed in 14 pts (19%). 31% of the patients had a refractory disease to the last regimen performed before R-ifosfamide/VP16. Patients received a median of 6 cycles (1-12). At the end of treatment, the overall response rate (ORR), defined by the rate of complete response (CR) and partial response (PR) was 37%, with 18% of CR. Evaluations were assessed for 29% of the pts by TEP scanner. For toxicity, among the 387 cycles, 10 patients developed febrile neutropenia (2.6%); 15 (20%) a grade 3-4 neutropenia; 7 (9%) a grade 3-4 thrombocytopenia; 5 patients needed platelet units and 16 patients received packed red blood cell units. No grade 3-4 non-hematological toxicity was observed and no toxic death occurred. With a median follow up of 31.3 months (range, 5.0-202.8), the median progression-free survival (PFS) was 4.3 months with a 1-year PFS rate of 26.0% (95%CI, 17.7-38.3) (Figure 1A). The median overall survival (OS) was 8.2 months with a 1-year OS rate of 40.8% (95%CI, 30.9-54.0) (Figure 1B). The median duration of response was 4 months (range 1-97). The median PFS was adversely affected by response (refractory versus CR/PR) to the last treatment (3.0 months versus 5.5 months, P=0.001) (Figure 1C). Conclusions: in this retrospective study, R-Ifosfamide/VP16 regimen provided effective results in R/R DLBCL transplant-ineligible pts with 37% of ORR and a median of PFS of 4.3 months with a safe toxicity profile. This regimen could also be considered as a platform for combinations with novel targeted agents in these categories of patients. Disclosures Karlin: Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Sarkozy:ROCHE: Consultancy. Bachy:Gilead Sciences: Honoraria; Takeda: Research Funding; Sandoz: Consultancy; Amgen: Honoraria; Roche: Research Funding; Celgene: Consultancy; Janssen: Honoraria. Salles:Abbvie: Honoraria; Epizyme: Honoraria; Amgen: Honoraria; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; Gilead: Honoraria, Other: Advisory Board; Acerta: Honoraria; Novartis: Consultancy, Honoraria; Servier: Honoraria; Servier: Honoraria, Other: Advisory Board; Takeda: Honoraria; BMS: Honoraria, Other: Advisory Board; Celgene: Honoraria, Other: Advisory Board, Research Funding; Janssen: Honoraria, Other: Advisory Board; Merck: Honoraria; Morphosys: Honoraria; Pfizer: Honoraria. Ghesquieres:Sanofi: Consultancy; Gilead: Consultancy; Celgene: Consultancy.

Purpose International Prognostic Index (IPS) is the most widely used risk stratification index for advanced stage Hodgkin's lymphoma (HL). The use of (18F)-fluorodeoxyglucose PET/CT at diagnosis allows a better characterization of extra-nodal involvement (ENI). We investigated if the type of ENI could affect the prognosis of stage IV HL patients diagnosed with PET/CT and if a specific prognostic index could be defined for these patients (pts). Patients and methods We retrospectively analyzed 220 stage IV HL patients treated from 2005 to 2015 in three LYSA centers. We considered the local investigator interpretation based on the nuclear medicine physician PET/CT report. Regarding ENI, six subgroups were identified: involvement of lung and/or pericard and/or pleural, liver, diffuse and/or focal bone involvement, digestive system, and other involvements; we also considered bone marrow involvement based on the results of bone marrow biopsy. The main outcome was event free survival (EFS) defined by relapse, progression, death from any cause and initiation of a new therapy. For prognostication, we first evaluated the six variables of IPS-6 (corresponding to IPS without "stage IV" item) in this population. ENI was tested adjusted on the retained IPS variables. Univariate and multivariate Cox models were used to assess their prognostic ability for EFS. Cross-validation (10-fold) was used to select the more robust variables avoiding optimism. The finally selected variables constituted a score that was tested on overall survival (OS). Results Among the 220 stage IV patients, 135 (61%) were male. Median age was 33 years (range, 16-86) and 72 pts (33%) were ≥45 years. 130 pts (59%) presented constitutional symptoms. Nodular sclerosis subtype was observed in 163 pts (74%), mixed cellularity subtype in 25 pts (11%) and 47/157 pts (30%) presented EBV-positive HL. For biological parameters of IPS, 158 pts (80%) had low albumin level 15G/L in 42pts (19%) and lymphocyte count Conclusions: For stage IV HL defined by PET/CT, we developed a simple prognostic score based on age (≥45y) and liver involvement that identify a subgroup of patients with a poor outcome. These findings need to be validated in independent cohorts. Based on these results, whether HL pathogenesis differs by ENI sites should be investigated. Disclosures Bachy: Celgene: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Beigene: Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria; Amgen: Honoraria. Karlin:Celgene: 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, Other: travel support; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support. Sarkozy:ROCHE: Consultancy. Traverse-Glehen:Takeda: Research Funding; Astra Zeneca: Other: Travel. Salles:F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; Servier: Honoraria, Other: Advisory Board; Novartis: Consultancy, Honoraria; BMS: Honoraria, Other: Advisory Board; Morphosys: Honoraria; Janssen: Honoraria, Other: Advisory Board; Abbvie: Honoraria; Pfizer: Honoraria; Amgen: Honoraria; Celgene: Honoraria, Other: Advisory Board, Research Funding; Epizyme: Honoraria; Gilead: Honoraria, Other: Advisory Board; Acerta: Honoraria; Merck: Honoraria; Servier: Honoraria; Takeda: Honoraria. Casasnovas:Takeda: Consultancy; Gilead: Consultancy, Research Funding; AbbVie: Consultancy; Roche: Consultancy, Research Funding; Bristol-Meyers Squibb: Consultancy; Merck: Consultancy. Ghesquieres:Celgene: Consultancy; Gilead: Consultancy; Sanofi: Consultancy.

Introduction Extranodal NK/T-cell lymphoma (ENKTL) is a rare disease; in Western countries it represents less than 1% of all Non-Hodgkin lymphoma. When localized, ENKTL is associated with a good prognosis. In contrast, patients (pts) with a disseminated disease still have a dismal outcome despite the use of asparaginase (ASPA) containing regimens that have significantly improved the prognosis of this lymphoma. Production of neutralizing anti-ASPA antibodies leading to inactivation of the enzyme can reduce its activity. Inactivation of ASPA activity is correlated with a worse prognosis in acute lymphoblastic leukemia (ALL). Monitoring of ASPA activity is therefore recommended in ALL pts with 100 IU/L as threshold value of serum enzymatic activity considered to be sufficient for complete depletion of l-asparagine in serum. However, ASPA monitoring is not routinely performed in pts with ENKTL, despite the frequent use of ASPA-containing regimens. The main objective of this study was to determine the proportion of pts with an insufficient ASPA activity corresponding to production of neutralizing anti-ASPA antibodies, risk of allergic reaction and inefficacy of the drug. Methods Adult pts with histologically confirmed ENKTL who received an ASPA-containing regimen between 2014 and 2018 and had a monitoring of ASPA activity were included. ASPA activity measurement was usually performed with a quantitive enzyme assay 48 hours after the last ASPA injection of each cycle for native forms of ASPA and 14 days after injection of the pegylated form. Activity below 100 UI/L was considered as insufficient. ASPA activity was correlated with pts outcome. The choice of initial form of ASPA and reasons to switch between two forms of ASPA were also analyzed. Results From 2014 to 2018, a total of 21 pts received an ASPA-containing regimen and were monitored for ASPA activity. Median age was 53 years with 14 men and 7 women. More than half of these pts had a stage IV disease (n=11/21), 6 were in stage I and 4 in stage II. Fifteen pts were in first line and 6 pts were in relapse. Pts have received either native e-coli L-asparaginase (Kidrolase®: KID) (n= 13 in the treatment-naïve group, n=2 in the relapsing group) or a pegylated form of e-coli- L-asparaginase (Oncaspar®: ONC) (n=2 in the treatment-naïve group, n=4 in the relapsing group). Most of the pts received ASPA (8 injections at each cycle for native forms and 1 injection for the pegylated form) associated with gemcitabine, methotrexate and dexamethasone, plus oxaliplatine for disseminated diseases. Six pts had optimal ASPA activity, 3/6 had localized disease: 2 had persistent RC and 1 relapsed, 3/6 had a disseminated disease: 2 progressed during treatment and 1 relapsed. Fifteen pts displayed low ASPA activity, 12/15 pts with a KID containing regimen after 1 cycle (n=10) or 3 cycles (n=2) and 3/6 pts with an ONC containing regimen after the first cycle (n=2) or the second (n=1). Among these 3 pts, 2 have been previously treated with KID that could induce an immunization against ONC. Ten pts received a second form of asparaginase: Erwinia asparaginase (Erwiniase®: ERW) in 9 pts and ONC in 1 pt. In 9/10 cases, this switch was justified by detection of low ASPA activity. Measurement of enzymatic activity in these 9 pts showed satisfactory levels in 2/5 pts treated with ERW and monitored for ASPA activity and in the pt receiving ONC, 4/6 pts with a localized form and 1/3 with a disseminated form are in persistent RC. Six pts with low ASPA activity including one case with a localized form and 5 cases with a disseminated disease, did not receive another form of ASPA, they all progressed or relapsed. Conclusion More than 2/3 of pts had sub-optimal ASPA activity after 1 to 3 cycles of ASPA containing regimens. This finding is probably due to the development of anti-ASPA inhibitory antibodies and may explain the poor outcome of pts with a disseminated disease despite the remarkable efficacy of ASPA in this disease. Although the series reported here is small and heterogeneous, our results still suggest a better outcome in pts with good ASPA activity or in case of switch between ASPA molecules in the context of low activity. ASPA activity monitoring should be recommended in pts with ENKTL, to avoid allergic reaction and ineffective treatment by switching ASPA molecules. Pegylated forms of ASPA, or encapsulated in red cells may, be less immunogenic, should be used in the first line setting instead of native forms. Table. Table. Disclosures Bachy: Celgene: Consultancy; Janssen: Honoraria; Gilead Sciences: Honoraria; Takeda: Research Funding; Sandoz: Consultancy; Amgen: Honoraria; Roche: Research Funding.

7554Background: BIA-ALCL is recognized as a distinct entity. In the French Lymphopath network with 59,356 lymphomas registered since 2010, 55 peripheral T-cell lymphomas (PTCL) out of 526 breast ly...

Diffuse large B-cell lymphoma (DLBCL) is the most frequent subtype of non-Hodgkin lymphoma in western countries. High prognostic heterogeneity is observed among patients with DLBCL with long-term survival ranging from 30% to more than 90% according to clinic-biological prognostics such as the International Prognostic Index (IPI) and its subsequent revised variants. Recent advances in the understanding of DLBCL biology as cell-of-origin (COO) determination has led to significant improvement of prognostic tools but also shed light on new potential targeted compounds for specific DLBCL subtypes. First DLBCL subset has been designed germinal center B-cell like DLBCL (GCB) because it expresses genes characteristic of germinal center B cells. Second DLBCL subset has been designed activated B-cell like DLBCL (ABC) because it expresses genes upregulated in response to in vitro activation. In this review, we will present state-of-the-art treatment of DLBCL in young and elderly patients, recent results in dose-dense regimen as well as potential interest for high-dose therapy followed by autologous stem cell transplant. A special emphasis will be given to new treatment developments according to COO in DLBCL. In particular, we will focus on new drugs that might alleviate the worse prognosis associated to DLBCL ABC subtype in the near future.

International audience; Background We determined the safety, pharmacokinetics, pharmacodynamics, and antitumour activity of abexinostat in B-cell lymphoma or chronic lymphocytic leukaemia. Patients and methods Thirty-five patients received oral abexinostat 30, 45, or 60 mg/m(2) bid in a 3 + 3 design in three 21-day schedules: 14 days on treatment in schedule 1 (D1-14); 10 days in schedule 2 (D1-5 and D8-12); and 12 days in schedule 3 (D1-4, D8-11, and D15-18). Safety, tumour response, plasma concentration, and histone H3 acetylation were measured. Results Two dose-limiting toxicities occurred in each schedule (one grade 3 febrile neutropenia; five grade 4 thrombocytopenia) at 60 mg/m(2) bid (maximal tolerated dose). The recommended dose was 45 mg/m(2) bid; schedule 1 was considered optimal. Non-haematological drug-related toxicities included grade 1 or 2 diarrhoea (43%), nausea (23%), and vomiting (11%); haematological toxicities included thrombocytopenia (31% grade 3, and 26% grade 4), which remained manageable and reversible on withdrawal. Of 29 evaluable patients, there were 2 complete and 6 partial responses; median duration of response was 14.6 months (range 3-16.5 months) (1 cycle is equivalent to 0.75 months). There was no evidence for nonlinear pharmacokinetics. There was a correlation between dose and histone acetylation. Conclusion Abexinostat has manageable toxicity and induced some durable complete and partial responses in B-cell lymphoma or chronic lymphocytic leukaemia. Our results suggest most favourable responses in patients with follicular lymphoma, though further research would be needed to confirm this finding.

The outcome of patients with follicular lymphoma (FL) has improved over the last two decades through the introduction of anti-CD20 monoclonal antibodies, usually used in combination with chemotherapy. However, patients with FL still experience multiple relapses, requiring several lines of treatment. Early toxicity of chemotherapy is a significant concern and as the life expectancy of patients with FL is increasing, late toxicities become an increasingly important concern. Progress made in understanding the biology of FL, especially dysregulation of intracellular pathways and immunological antitumor responses, recently allowed for the development of innovative chemo-free therapeutic approaches. In this report, different options such as new anti-CD20 antibodies, antibodies targeting other cell surface antigens, bi-specific antibodies, immunomodulation, idiotype vaccine and other targeted therapies are presented. The article also highlights how, although promising in early phase studies, the cost-effectiveness of new agents will have to be justified in Phase III trials. Furthermore, chemo-free regimen might not mean toxicity-free treatment and monitoring of early and late toxicities is required.

International audience; Nodular lymphocyte predominant Hodgkin lymphoma represents a distinct entity from classical Hodgkin lymphoma. We conducted a retrospective study to investigate the management of patients with nodular lymphocyte predominant Hodgkin lymphoma. Clinical characteristics, treatment and outcome of adult patients with nodular lymphocyte predominant Hodgkin lymphoma were collected in Lymphoma Study Association centers. Progression-free survival (PFS) and overall survival (OS) were analyzed, and the competing risks formulation of a Cox regression model was used to control the effect of risk factors on relapse or death as competing events. Among 314 evaluable patients, 82.5% had early stage nodular lymphocyte predominant Hodgkin lymphoma. Initial management consisted in watchful waiting (36.3%), radiotherapy (20.1%), rituximab (8.9%), chemotherapy or immuno-chemotherapy (21.7%), combined modality treatment (12.7%), or radiotherapy plus rituximab (0.3%). With a median follow-up of 55.8 months, the 10-year PFS and OS estimates were 44.2% and 94.9%, respectively. The 4-year PFS estimates were 79.6% after radiotherapy, 77.0% after rituximab alone, 78.8% after chemotherapy or immuno-chemotherapy, and 93.9% after combined modality treatment. For the whole population, early treatment with chemotherapy or radiotherapy, but not rituximab alone (Hazard ratio 0.695 [0.320-1.512], P=0.3593) significantly reduced the risk of progression compared to watchful waiting (HR 0.388 [0.234-0.643], P=0.0002). Early treatment appears more beneficial compared to watchful waiting in terms of progression-free survival, but has no impact on overall survival. Radiotherapy in selected early stage nodular lymphocyte predominant Hodgkin lymphoma, and combined modality treatment, chemotherapy or immuno-chemotherapy for other patients, are the main options to treat adult patients with a curative intent.

International audience; Detection of MUM1+ cells in follicular lymphoma (FL) tissues was previously found to be associated with poor prognosis in a single report, whereas the usefulness of Ki-67 immunostaining remains debated. Our goal was to establish whether these markers have predictive value for patients with FL. We analyzed MUM1 and Ki-67 expression using immunohistochemistry in biopsy samples from 434 patients from the PRIMA randomized trial. The MUM1 prognostic value was then validated in a cohort of 138 patients from the FL2000 randomized trial, using the optimal cutoff value obtained from the PRIMA cohort. The surface of positive staining was quantified using computerized image analysis. In the PRIMA cohort, both high levels of MUM1 positivity (cutoff value of 0.80%) and high levels of Ki-67 positivity (cutoff value of 10.25%) were significantly associated with a shorter progression-free survival (PFS) (P = .004 and P = .007 for MUM1 and Ki-67, respectively). In a multivariate Cox proportional hazards regression model, only MUM1 retained a statistical significance (hazards ratio 1.56; 95% confidence interval, 1.02-2.37; P = .038) after adjustment for the maintenance arm of treatment and the follicular lymphoma international prognostic index score. In the FL2000 cohort, high levels of MUM1 positivity were significantly associated to a shorter PFS (P = .004) and to a trend toward a shorter overall survival (P = .043). This remained significant using a multivariate Cox regression model after adjustment for the follicular lymphoma international prognostic index and the treatment arm for PFS (P = .016). These results show that MUM1 is a strong and robust predictive immunohistochemical marker in patients with FL.

International audience; Post-transplant lymphoproliferative disorder (PTLD) is an uncontrolled proliferation of transformed lymphocytes fostered by immunosuppression. In addition to chemotherapy, treatment of PTLD includes a reduction of maintenance immunosuppression. Patients with PTLD have an increased risk of graft loss, suggesting that reduced immunosuppression strategy needs to be optimized with regard to graft outcome. Here we retrospectively reviewed 101 cases involving PTLD to identify the risks associated with graft loss. During a median follow-up of 70 months, 39 patients died and 21 lost their graft. Multivariate analysis found that an eGFR under 30 ml/min per 1.73 m(2) at PTLD diagnosis, a biopsy-proven acute rejection episode following reduction of immunosuppression, and the absence of calcineurin inhibition in maintenance immunosuppression are independent risk factors for allograft loss. Neither the type of PTLD nor the chemotherapy regimen was predictive of allograft failure. Histological analysis of graft biopsies showed that maintaining calcineurin inhibition after the diagnosis of PTLD reduced the risk of developing de novo anti-HLA antibodies and humoral rejection. Remarkably, calcineurin inhibitor maintenance was neither associated with higher mortality nor with worse progression-free survival. Thus, maintaining calcineurin inhibition at a reduced dose after the diagnosis of PTLD seems safe and may improve renal graft outcome, possibly through better control of the recipient's humoral immune response.

INTRODUCTION: The benefits of ibrutinib (ibr) have been demonstrated by the phase 3 RESONATE and RESONATE-2 trials for patients (pts) with R/R and TN (≥ 65 years) CLL, respectively. In these studies, ibr showed significantly improved progression-free survival (PFS) and overall survival (OS) vs approved comparators (ofatumumab [ofa] in RESONATE and chlorambucil [clb] in RESONATE-2). However, a number of other treatment regimens are widely used in clinical practice for CLL based on individual patient and disease characteristics; it is currently unknown if ibr results in better survival outcomes when compared directly with each of these other treatments. AIM: In the absence of a head-to-head comparison, we investigated the relative efficacy of ibr vs physician's choice (PC) in pts with R/R or TN CLL by comparing pt-level data from RESONATE and RESONATE-2 with data from pts in a real-world setting (the Lyon-Sud database). This database holds electronic medical records for 390 pts with CLL from the academic Lyon-Sud Hospital in France; nearly all patients were diagnosed between 1990 and 2014. This is the first analysis of ibr vs PC in a real-world setting for pts with TN CLL. METHODS: Pt-level data from RESONATE (ibr, n = 195; ofa, n = 196) were compared with data on pts with CLL from Lyon-Sud who received 2nd(n = 107) or later-line treatment (3rd [n = 62], 4th [n = 43], and subsequent [n = 51] lines). Similarly, RESONATE-2 (ibr, n = 136; clb, n = 133) pt-level data were compared with those of pts aged ≥ 65 years who received 1st-line treatment (n = 131). In order to account for non-comparability due to lack of randomization, a multivariate Cox proportional hazards model was used to compare PFS and OS between treatments, including line of therapy, age, sex, disease stage (based on Binet/Rai), and deletion 17p or 11q mutations as covariates. For the definition of PFS, missing data for date of disease progression for pts in Lyon-Sud who initiated subsequent therapy were replaced by the conservative proxy of date of initiation of next treatment. Predicted PFS and OS curves for the Lyon-Sud cohort were derived from the multivariate model. RESULTS: For R/R pts in Lyon-Sud, across all treatment lines the most frequent regimens used were rituximab (R) + chemotherapy (n = 46), bendamustine + R (BR; n = 28), fludarabine + cyclophosphamide + R (FCR) (n = 27), clb + R (n = 19), R monotherapy (n = 21), and R-CHOP-based (n = 19); the remaining percentages comprised various other therapies, each used in < 5% of pts. Median age at treatment initiation for Lyon-Sud and RESONATE was 69 and 67 years, respectively; median number of prior therapies was 2 and 3, and median follow-up was 30.0 and 21.9 months. More lines of prior therapy, older age, male sex, advanced disease stage (Binet C/Rai III/IV), and presence of deletion 17p/11q were independent risk factors for worse PFS and OS outcome. After adjustment for differences in baseline characteristics, PFS and OS hazard ratios (HRs) for ibr vs PC were 0.18 (95% confidence interval [CI], 0.13-0.26) and 0.28 (0.17-0.46), respectively. Adjusted HRs for ibr vs the most frequent treatments ranged from 0.09 (R monotherapy) to 0.38 (FCR) for PFS and 0.21 (R monotherapy) to 0.33 (FCR) for OS; all were statistically significant. For TN pts in Lyon-Sud, the most frequent treatment regimens used were FCR (n = 40), clb + R (n = 21), clb monotherapy (n = 17), R-(mini)CHOP (n = 11), and BR (n = 11). Median age at treatment initiation was 73 years for both Lyon-Sud and RESONATE-2; median follow-up was 36.9 and 28.1 months, respectively. Older age, male sex, and advanced disease stage were independent risk factors for worse PFS and OS outcome. After adjustment for baseline differences, the PFS and OS HRs for ibr vs PC were 0.25 (0.14-0.47) and 0.41 (0.17-0.99). Predicted PFS and OS curves for both R/R and TN patients are presented in Figure 1. CONCLUSIONS: Investigation of survival outcomes suggests that ibr administered to pts in RESONATE and RESONATE-2 was more effective than PC used in a real-world cohort of French pts with R/R or TN CLL, suggesting a 4.8-fold improvement in PFS and a 3.4-fold improvement in OS in R/R pts and 4-fold and 2.4-fold improvements in TN pts, respectively. These results further support the growing evidence that ibr significantly improves both PFS and OS vs commonly used regimens in the R/R and TN settings, and could have important implications for improving treatment of CLL in clinical practice. Disclosures Salles: Janssen: Consultancy, Honoraria; Gilead: Honoraria, Research Funding; Mundipharma: Honoraria; Amgen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Roche/Genentech: Consultancy, Honoraria, Research Funding. Sarkozy:Sandoz: Research Funding; Janssen Research & Development: Honoraria; Gilead: Honoraria; Takeda: Research Funding. Ghesquieres:Mundipharma: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche France: Research Funding. Diels:Johnson & Johnson: Employment, Equity Ownership. Besson:Janssen: Employment. MacDougall:Janssen Research & Development: Research Funding; IMS Health: Employment. Hermans:Janssen Research & Development: Research Funding; IMS Health: Employment. Healy:Janssen Research & Development: Employment. Garside:Janssen Research & Development: Employment. Iraqi:Janssen Research & Development: Employment.

Anti-CD20-containing chemotherapy regimens have become the standard of care for patients with follicular lymphoma needing cytotoxic therapy. Four randomized trials demonstrated a clinical benefit for patients treated with rituximab. However, no long-term follow up (i.e. > 5 years) of these trials is yet available. Between May 2000 and May 2002, 358 newly diagnosed patients with high tumor burden follicular lymphoma were randomized to receive cyclophosphamide, adriamycin, etoposide and prednisolone plus interferon-α2a or a similar chemotherapy-based regimen plus rituximab, and outcome was up-dated. With a median follow up of 8.3 years, addition of rituximab remained significantly associated with prolonged event-free survival (primary end point) (P=0.0004) with a trend towards a benefit for overall survival (P=0.076). The Follicular Lymphoma International Prognostic Index score was strongly associated with outcome for both event-free and overall survival in univariate analysis and its prognostic value remained highly significant after adjusting for other significant covariates in multivariate models (P

Tumor-associated macrophages (TAMs) might be associated with worse outcome in classical Hodgkin lymphoma (cHL). Our aim was to determine whether TAMs correlated with refractoriness in cHL. In a cohort of 18 consecutive primary refractory or early relapsed cases and 41 randomly selected controls (responder patients), high TAM infiltration was significantly associated with refractoriness or early relapse (p = 0.004) and remained independently correlated with outcome in multivariate analysis (odds ratio 8.276, 95% confidence interval 1.214-56.408). This study provides evidence that the marker CD68 might accurately predict early outcome of de novo cHL and could be used in combination with c-kit and TiA1 staining.

Aims To describe 76 cases of splenic marginal zone lymphoma (SMZL), including correlations with clinical and other characteristics. Methods and results Patients were predominantly female, with a median age of 62 years. The main clinical presentation was splenomegaly, except for eight cases presenting with evolution of autoimmune disorders or spontaneous splenic rupture. White pulp infiltration was nodular, with a monophasic (42%) or biphasic (53%) pattern, and associated diffuse or nodular infiltration of the red pulp, except for four cases which had atrophic white pulp. Plasmacytic differentiation and the MYD88 L265P mutation were observed in 18% and 5% of the cases, respectively. Histological progression was considered in cases with a significant association of large cells with Ki67 > 30% and macronodular architecture (P = 0.001). Other significant correlations were found between del7q (44%) and del6q (17%) (P = 0.018), IGHV1-2*04 segment usage (35%) (P = 0.001) and unmutated IGHV (39%) (P = 0.019), and between CD5 expression (27%) and higher lymphocytosis (P = 0.002). Patients requiring intensive chemotherapy after splenectomy because of clinical and/or histological progression had significantly shorter overall survival (P = 0.012). Conclusions We report the histological spectrum of SMZL, and discuss the differential diagnosis and requirement for molecular and cytogenetic analysis in atypical cases.

High-dose therapy followed by autologous stem cell transplantation is widely accepted as salvage therapy for patients with relapsed aggressive lymphoma. In the pre-rituximab era, autologous stem cell transplantation had also been increasingly applied as a consolidation treatment for patients with indolent lymphoma in second or subsequent remission whereas controversies have emerged concerning its role in first line therapy from several randomized trials. Broad development and amazing efficacy of monoclonal antibody-based combination therapies for de novo or relapsing follicular lymphoma patients render previous conclusions outdated and underline the critical need for further phase III trials. This review focuses on available data from pre-rituximab and rituximab eras to help clarifying the precise role and timing of autologous stem cell transplantation among the current armamentarium for follicular lymphoma treatment.

International audience

In this issue of Blood, Horwitz et al present encouraging results of a phase 2 study assessing the efficacy of the antibody-drug conjugate (ADC) brentuximab vedotin (BV) in relapsed/refractory peripheral T-cell lymphoma (PTCL).

Prognostic factors able to predict lymphoma patient's outcome are necessary to inform the patient and to choose the appropriate treatment. Beside the essential documentation of the pathological lymphoma subtype, several factors (such as age, performance status, Ann Arbor disease stage, LDH level...) easy to assess are used and help to establish prognostic indexes for each lymphoma entity. Numerous biomarkers obtained on fresh or frozen tissue using molecular techniques are currently described and may help to optimize the clinical care of lymphoma patients tomorrow.

We analyzed 27 CML patients treated with imatinib (IM) who developed a BCR-ABLT315I mutation. These patients had poor prognostic features: High or intermediate Sokal index (82%), and lack of CCyR under IM (59%). At T315I discovery, patients were in advanced phase (59%), with clonal evolution (84%). Median time since diagnosis was 39 months, and progression occurred 13 months after IM initiation, regardless of disease phase. Overall survival since IM initiation was 42.5 months for chronic, and 17.5 months for advanced phases, and all patients progressed. This mutation seems related to or (partially?) responsible for progression and poor survival.

Background: Patients (pts) with classical Hodgkin Lymphoma (CHL) older than 60 years represent about 15% to 20% of CHL pts in population registries. Elderly CHL treated with standard protocols always have a poorer outcome as compared to younger pts. The aim of this retrospective study is to identify specific prognostic factors in a cohort of 165 CHL pts aged over 60 years. Methods: From two hospital registries in Lyon (France), we analyzed 165 CHL pts older than 60 years and treated between 1981 and 2012. None were HIV positive. The following clinical characteristics were recorded: age, gender, presence of B-symptoms, ECOG performance status (PS), Cumulative Illness Rating Scale (CIRS), Ann Arbor stage, bone marrow involvement, complete blood counts, lactate deshydrogenase(LDH), C-reactive protein (CRP), fibrinogen, serum albumin level and protein electrophoresis. International Prognostic Score (IPS) was collected for 116 pts (70%). A total of 136 pts (82%) were treated with an anthracycline based chemotherapy (CT) and 53 pts (32%) received radiation therapy. Clinical and biological characteristics at diagnosis were assessed by a Cox regression for univariate and multivariate analysis for progression free survival (PFS) and overall survival (OS). We then designed a prognostic score for PFS and OS based on significant variables from multivariate analysis at threshold p-value < 0.5 and compared the effectiveness of these scores to IPS by a receiver operating characteristic (ROC) analysis. Results: The median age at diagnosis was 69 years (range, 60-89). 60% were male, 65% presented with B-symptoms, 38% had a PS> 2 and 16% had at least one comorbidity scored 3 or 4 on CIRS. 56% had an Ann Arbor stage III-IV.65% of pts achieved a complete or a partial response, 16% were refractory or progressed within 6 months after the start of treatment and 19% died during treatment. Median follow up is 65 months (1.1-207.6). 47 pts (29%) have progressed or relapsed. Median duration of PFS is 39.6 months (95%CI: 23.9-73.3) with a 4-year PFS rate of 49% (95%CI: 40-56). 78 pts (47%) died, 22% within the first year after treatment initiation. Median duration of OS is 73.3 months (95%CI: 38.5-129.8) and the 4-year OS rate is 55% (95%CI: 47-63). The main causes of death were HL progression (39%), infection (17%), treatment toxicity (13%) and second cancer (10%). Pts treated with or without an anthracycline based CT did not have significantly different 4-year PFS (50% vs. 43%, P=0.55) or OS (57% vs. 47%, P=0.22). In univariate analysis, age, B-symptoms, PS, CIRS, albumin, hemoglobin, lymphocyte count, bone marrow involvement, Ann Arbor stage, protein, gammaglobulin, fibrinogen, LDH and CRP were associated with a shortened PFS. Factors associated with a shortened OS were: sex, age, PS , CIRS, albumin, hemoglobin, lymphocyte count, bone marrow involvement, Ann Arbor stage, protein, CRP, gammaglobulin and fibrinogen. In multivariate analysis, age>69 years (HR=3.97; 95%CI: 2.11-7.47, P5g/L (HR=2.29; 95%CI: 1.25-4.19, P=0.007) were independently associated with a shortened PFS. Pts with 0-1, 2 and 3-4 adverse factors had a median duration of PFS of 180, 37 and 4.6 months respectively (Figure, P=69 years (HR=3.66; 95%CI: 1.95-6.85, P 2 (HR=3.04; 95%CI: 1.69-5.45, P=0.0002) and gammaglobulin level Conclusion: This prognostic score identifies subgroups of elderly CHL pts at high risk of progression and early death, using simple biological and clinical parameters at diagnosis. Bone marrow involvement is one of the factors independently associated with PFS. This result supports bone marrow evaluation at diagnosis. This score better discriminates elderly CHL pts’ outcome compared to IPS. Our results should be confirmed in independent and prospective studies in combination with complete geriatric assessment. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Background. Peripheral T-cell lymphomas (PTCLs) originate from post-thymic T cells but compared to B-cell lymphomas the exact cell of origin is usually unknown except for angioimmunoblastic T-cell lymphoma arising from a follicular helper T-cell. Furthermore, no recurrent cytogenetic or molecular abnormalities are identified in PTCLs. Recently, recurrent impairment of the p53 pathway has been pointed out in PTCLs. However, p53 knockout (KO) mice are known to develop immature thymic T-cell lymphomas and solid tumors but surprisingly PTCLs have not been reported for more than 20 years in those mice. NKT cells are a T-cell subset responsive to glycolipids presented by CD1d, a major histocompatibility complex (MHC) class I-like antigen-presenting molecule, in contrast to conventional T cells, which recognize peptide antigens. Two types of NKT cells have been described so far: type I or invariant NKT cells (iNKT) that express a Valpha14-Jalpha18 (in mice) or Valpha24-Jalpha18 (in humans) constant chain and type II NKT cells that express a variable TCR but are CD1d-dependent as well. Most type II NKT cells are of alpha/beta phenotype but CD1d-restricted gamma/delta T cells have also been described in mice and humans. Methods. The development of PTCLs in p53 KO mice (B6.129S2-Trp53tm1Tyj/J) was studied. Identification of PTCLs was made by immunohistochemistry and flow cytometry analysis. Gene expression profile analysis (GeneChip Mouse Genome 430 2.0 array, Affymetrix) was performed to characterize lymphomas developed in the mouse model. Transfer experiments were done by intravenously retro-orbital injection into syngeneic, immunocompetent C57Bl/6J WT animals or immunocompromised CD3ε-/- mice. Therapeutic trials in mice were performed with the use of blocking anti-CD1d monoclonal antibodies (mAb) (clone HB323; BioXcell). Results. We found that p53 KO mice developed well-known and characterized thymic T-cell lymphomas and solid tumors as previously described. However, about 20% of p53 KO mice spontaneously developed a previously unrecognized entity of PTCLs originating from CD1d-restricted iNKT cells (ie type I NKT cells) referred to as NKTLs for NKT lymphomas thereafter. Both alpha-galactosylceramide-CD1d tetramer staining and unique Valpha14-Jalpha18 TCR rearrangement confirmed the iNKT nature of these lymphomas. Chronic injection of Streptococcus pneumoniae (Spn), reported to express glycolipid antigens activating NKT cells, significantly increased the incidence of these NKTLs compared to a control group of p53 KO mice injected with PBS (P=0.03). Gene expression profile analysis indicated a significant down-regulation of genes in the TCR signaling pathway of NKTLs (false discovery rate q-value=0.01 by gene set enrichment analysis) suggesting an underlying antigenic chronic stimulation as previously reported in chronically activated T cells (Figure 1). Moreover, NKTLs were characterized by upregulation of PD-1 and loss of NK1.1 expression compared to resting NKT cells (P We did not identify human PTCLs arising from type I iNKT cells by using alphaGalCer-CD1d tetramer staining. However, using sulfatide-loaded CD1d tetramers (ie another type of glycolipid-CD1d tetramer identifying type II NKT cells), we identified CD1d-restricted human PTCLs among gamma/delta hepatosplenic T-cell lymphomas (HSTLs) and PTCL-not otherwise specified (PTCL-NOS) expressing the Vd1 TCR but not the Vd2 TCR (Figure 3). Conclusion. This demonstrates for the first time the existence of human PTCLs arising from gamma/delta CD1d-restricted type II NKT cells. These results refine the classification of PTCLs in humans by identifying a new cell of origin and pave the way for the development of blocking anti-CD1d antibodies for therapeutic purposes. Figure 1. Figure 1. Figure 2. Figure 2. Figure 3. Figure 3. Disclosures No relevant conflicts of interest to declare.

Abstract 2401 Background. Compelling evidence suggests that chronic infections by various pathogens are linked to lymphoma development. The transformation process is supposed to be either direct (eg for EBV) or indirect. The association between Helicobacter pylori chronic infection and gastric marginal zone lymphoma (MZL) is the best characterized example for an indirect transformation. Several other pathogens such as hepatitis C virus, Campylobacter jejuni or Streptococcus Pneumoniae (Spn) are also suspected to promote B-cell lymphoma development through repeated stimulations of the BCR and/or inflammation. However, except for gastric MZL, animal models are lacking to study potential correlations between chronic infections and lymphoma development. Methods. To amplify and precipitate lymphomagenesis by precluding repair of DNA lesions potentially generated during chronic immune response, p53-deficient mice were used as a permissive model. Given the suspected role of carbohydrates from encapsulated bacteria such as Spn in promoting chronic lymphocytic leukemia, p53−/− (n=15) and p53+/− (n=53) mice were chronically injected with heat-killed Spn until disease development. P53-deficient mice chronically injected with PBS were used as control. Results. Unexpectedly, chronic injections of Spn promoted T-cell rather than B-cell lymphomagenesis in both p53−/− and p53+/− mice and shortened survival in p53+/− mice (P=.004). Whereas mostly thymic CD4+CD8+ double positive T-cell lymphomas have been described in p53-deficient mice, a vast majority of lymphomas observed following chronic Spn injections were of peripheral origin (TdT−) and exhibited an effector memory phenotype (CD44hiCD62LloCCR7−CD25−). Clonality and transferability of those peripheral T-cell lymphomas (PTCL) were established. Furthermore, lymphoma cells showed features of chronically stimulated T cells such as TCR, CD3 or CD4/CD8 co-receptor down-regulations along with PD-1 up-regulation. Several lines of evidence suggested a contribution of the TCR to the development of these PTCL: 1/all PTCL following Spn injections exhibited a Vß repertoire usage bias (Vß8 in 100%) consistent with a transformation process originating from a chronically-stimulated T cell by a pathogen-specific immunodominant peptide; 2/cyclosporin A, a strong TCR signaling inhibitor, decreased cell survival in vitro, and prolonged mice survival following transfer of lymphoma cells into recipient mice; 3/engraftment of CD8+ PTCL in MHC class I KO mice was significantly reduced compared to wild type mice (P The absence of B-cell lymphoma development in p53−/− mice and its very late onset in p53+/− mice (ie >450 days) compared to T-cell lymphoma prompted us to dissect the potential role of p53 in mature T-cell response in a context of chronic stimulation. WT and p53−/− negatively selected CD4+ and CD8+ T cells were repeatedly (ie every 7–10 days) stimulated in vitro using anti-CD3/anti-CD28-coated beads. In agreement with previous reports, no significant difference of cell viability was observed after the first or the second stimulation confirming the minor role of p53 in initial activation and proliferation as well as in activation-induced cell death. Nonetheless, a dramatic increase in cell viability was observed 48h after the third stimulation of p53−/− T cells, indicating a crucial function of p53 in deletion of chronically activated T cells. Conclusion. Chronic stimulations with heat-killed Spn unexpectedly increased peripheral T-cell lymphoma development in p53-deficient mice. Phenotypic characterization was consistent with a transformation process occurring in a pathogen-specific chronically-stimulated T cell. The incidence of p53 mutations is higher in T-cell than in B-cell mature malignancies in humans and the p53 pathway is functionally impaired in virtually all enteropathy-associated T-cell lymphomas, which are supposed to be a key model for an antigen-driven process. Therefore, aside from its known role in immature T-cell lymphoma development and in progression of B-cell malignancies, our work sheds light on a previously unsuspected physiopathological role of the p53 pathway in peripheral T-cell lymphomagenesis. Disclosures: No relevant conflicts of interest to declare.

Abstract 1794 Mantle cell lymphoma (MCL) is an aggressive B-cell malignancy that represents approximately 8% of lymphoma cases. Up-front treatment with intensive chemotherapy and autologous stem cell transplantation (ASCT) for younger patients has demonstrated improvement in prognosis and outcome but virtually all patients experience relapse. Thalidomide is an antiangiogenic and immunomodulatory drug whose mechanism of action is unclear. Promising results were reported but only on small series, with a limited median follow up. Thalidomide in France is currently not approved in this indication, but its use is allowed by French authorities (AFSSAPS) after reviewing unique patient medical chart, mainly indication (relapsed/refractory MCL) and absence of appropriate alternative treatment. There is no other inclusion or exclusion criteria based on past medical history or biological findings. Authorization has to be confirmed every 3 months, based on efficacy and safety data. Patient informed consent was required prior to inclusion. Overall, 58 patients (pts) with available data were included in this program between 06/2001 and 09/2009. There were 38 males and 20 females. At time of diagnosis, median age was 62.8 years (range 39.2–77.9); 89.5% of pts had PS £ 1; 89.7% presented with stage IV, including 78.9% with documented bone marrow involvement, 61.4% with leukemic phase and 28% with gastro-intestinal involvement. Before Thalidomide, pts received a median of 2 lines of chemotherapy (range 1–5), including ASCT for 39. All but 6 received prior Rituximab. Median time between diagnosis and start of Thalidomide was 41.8 months (range 3.5–196.8) and 2.1 months between last line of chemotherapy and Thalidomide (range 0–126.8). At time of inclusion, median age was 66.8 years (43.9-82.7); 86.2% of pts presented with stage IV and 18 (31%) with PS > 1. Thalidomide was administrated alone in 19 patients (32.7%), associated with Rituximab (n=19; 32.7%), Bortezomib (n=5; 8.6%), or both (n=9; 15.5%), or with others treatments (n=8; 13.8%). Initial dosage was 200 mg/d for 24 patients or less (100 or 50 mg/d) for 33 patients (unknown for 1 pt), according to physician decision. Grade 1–2 adverse events included fatigue, constipation and neuropathy as previously described with Thalidomide. Three pts experienced grade 3 neuropathy. There were 6 events related to thromboembolism (deep-vein thrombosis: n=5; stroke: n=1). Hematological toxicity consisted in 4 pts with grade 3 neutropenia, including 2 with febrile neutropenia. A patient experienced severe hepatitis but link with thalidomide was doubtful. Overall, 7.3% of pts experienced grade 3–4 adverse events. Finally, 13 pts discontinued Thalidomide because of toxicity, including 6 who received Rituximab and Bortezomib. The overall response rate (CR + PR) was 50%, with 12 pts (20.7%) who achieved a CR and 17 pts (29.3%) a PR, 17 pts (29.3%) had stable disease and 12 (20.7%) progressive disease. Median time to response was 3 months (range 1–8). Median follow-up was 41.3 months. For the entire cohort, 1-y TTF and OS rates were 29.3% (95% CI: 17.4–41.3) and 61.9% (95% CI: 49.0–74.8) respectively; 2-y TTF and OS rates were 10.9% (95% CI: 2.2–19.6) and 49.6% (95% CI: 36.0–63.2) respectively. In univariate analysis, factors predictive for better OS were male sex (p=0.037), stage < 4 (p=0.043), PS 0–1 (p 6 months (p=0.004) and addition of Rituximab (p=0.013). Addition of Bortezomib was not predictive for OS. LDH, leukocytes count at time of inclusion and Thalidomide dosage (200 mg/d) were only predictive for better TTF (respectively p=0.014; 0.008 and 0.041). In multivariate analysis, male sex (p=0.002), stage 6 months (p=0.010) showed prognostic relevance for OS. In conclusion, in this cohort of unselected patients, efficacy of Thalidomide compare favorably with currently approved drugs for relapsed MCL such as Bortezomib (ORR : 33%, median duration of response : 9.2 months) or Temsirolimus (ORR : 22%, median PFS : 4.8 months), with less toxicity. This efficacy is comparable with others Imids such as Lenalidomide with a trend to less toxicity and a better side effect profile, justifying its use with Rituximab for relapsed MCL as well as in a maintenance schedule. Disclosures: No relevant conflicts of interest to declare.

Abstract 346 Introduction: Invariant Natural Killer T (iNKT) cells express a highly restricted T cell receptor (TCR) repertoire composed of a single invariant Va14Ja18 chain in mice and a Va24Ja18 chain in humans. In contrast to their conventional counterpart, iNKT cells recognize CD1d-bound glycolipids rather than peptides. iNKT cells have elicited a lively interest in the last years because of their implication in several immune responses including experimental graft-versus-host-disease (GVHD). In this study, we addressed the question whether human iNKT cells could be associated with the outcome of allogeneic haematopoietic stem cell transplantation (HSCT). Materials and methods: Forty-seven patients allografted for diverse hematological malignancies in our institution entered prospectively the study. We sequentially analyzed the reconstitution of peripheral blood CD1d tetramer + iNKT, CD56+ NK, and CD4+, CD8+, CD4+CD25high T cells for 90 days after allogeneic HSCT by flow cytometry. Results were correlated to the clinical evolution of allogeneic HSCT. Results: We observed two groups of patients according to their iNKT/106 T cell ratios on days 30, 60 and 90 after HSCT. Patients with at least one point above the normal ratio of 1000 iNKT/106 T cells were considered in the iNKT high group (n=17), while those with a poor reconstitution, defined by all points below that threshold, were analyzed in the iNKT low group (n=30). iNKT reconstitution was the only significant difference in terms of immune reconstitution between the two groups since reconstitution of T CD4+, CD8+, or CD4+CD25high and NK cells was similar at all time points in both groups. Chimerism, analyzed by PCR amplification of short tandem repeat markers, showed that in all cases iNKT displayed a 100% donor origin. Pre-transplant characteristics of patients were similar between the two groups except for the conditioning regimen and the source of stem cells. Patients in the iNKT high group had more often received a reduced-intensity conditioning (80.5% versus 46.7%, p=0.004) and peripheral blood stem cells (88.5% versus 53.6%, p=0.015). Occurrence and severity of acute GVHD was significantly reduced in the iNKT high group (23.5 % grade I-II and 0% grade III-IV) compared to the iNKT low group (66.7 % grade I-II and 26.6% grade III-IV), (p Conclusion: Our data suggest that donor-derived iNKT cell reconstitution after allogeneic HSCT may represent a predictive factor of acute GVHD and a prognostic factor of transplant outcome. Disclosures: No relevant conflicts of interest to declare.

Abstract 1550 Poster Board I-573 Richter's syndrome represents the clinico-pathologic transformation of chronic lymphocytic leukemia to an aggressive lymphoma, most commonly diffuse large B cell lymphoma. Hodgkin lymphoma variant of Richter transformation are extremely rare. EBV infection has been identified in the lymphoma cells in a few patients with Richter's syndrome. However, the precise role of EBV remains to be established and a causative relation between EBV and Richter's syndrome has not been proven yet. Evidence supports EBV infection in the Hodgkin variant of Richter's transformation. Once the Richter's transformation has occurred, the prognosis is poor. The median survival time with conventional chemotherapy is less than 12 months. The purpose of this study is to assess the presenting characteristics, rates of response and outcomes of patients with a low grade lymphoma who developed Hodgkin lymphoma. In this study, we retrospectively collected a total of 34 patients from distinct haematology centres in France. Presenting features included a male preponderance (74%). The median age at diagnosis of low grade lymphoma was 61.6 years (range, 28-85), that of Hodgkin lymphoma was 66,4 years (range, 28-89). The median time from low grade lymphoma diagnosis to Hodgkin transformation was 3.25 years (range, 0-16), and included 1 patient who presented with concomitant low grade and Hodgkin lymphoma. The propensity of CLL to transform into Hodgkin lymphoma (45% in our study), is shared by other indolent B-cell lymphoproliferative disorder, namely follicular lymphoma (21%), marginal zone lymphoma (9%), and others. Most patients (79%) had been previously treated for low grade lymphoma, including oral chemotherapy (chlorambucil, fludarabine, and cyclophosphamide), intravenous chemotherapy (RCHOP, Gemox), immunotherapy (Rituximab), radiotherapy and splenectomy. 30% of patients had received > 1 prior therapy for treatment of low grade lymphoma. Most patients presented a nodular sclerosis subtype of Hodgkin lymphoma (65%). Epstein-Barr virus status was positive in 70% of patients. Patients presented with B symptoms were 56%. 87% patients had advanced Hodgkin disease, including 44% stage IV disease. First-line treatment for Hodgkin lymphoma consisted of chemotherapy, ABVD for 64% of patients, MOPP/ABV-25% and BEACOPP-10%; a small number of patients (1%) received other cytotoxic regimen, including rituximab (RCHOP). The overall response rate was 85% (complete response rate : 72%). The median overall survival duration was 23 months (range, 4-75). Concerning relapse, 52% of patients relapsed, half with Hodgkin lymphoma. None of localized Hodgkin lymphoma relapsed. In conclusion, patients with the Hodgkin variant of Richter's syndrome generally present with a more advanced stage of disease than do patients with de novo Hodgkin disease. The rates of response and survival in patients with this variant were inferior to those reported in patients with de novo Hodgkin lymphoma, but better than those with classic Richter's syndrome. In addition this study shows a strong association with EBV indicating that it may play an important role in the pathogenesis of Hodgkin transformation. Disclosures No relevant conflicts of interest to declare.

Purpose . Frontline treatment for newly diagnosed follicular lymphoma (FL) patients, ranging from watch and wait policy to high-dose therapy, still remains debated, even in the rituximab-based combination therapy era. Few studies have addressed the question whether complete remission (CR) translates into better survival compared to partial remission (PR). The aim of this study was to assess the potential correlation between response quality to first line treatment and overall survival in light of a long-term follow-up. Patients and methods. Data from 536 FL patients, 435 enrolled in the French and Belgian GELF86 trials and 101 additional patients treated with the same chemotherapy regimen (CHVP-IFN or CHVP regimen after the accrual stopping date with prospectively collected data), were analysed in the study. Data from the GELF86 trials have been previously reported: 193 patients had low tumor burden (LTB) (Brice et al., JCO, 1997) and 242 and the aforementioned 101 additional patients had high tumor burden (HTB) at diagnosis (Solal-Céligny et al., NEJM 1993). All patients with at least one criteria for HTB were treated as frontline therapy with an anthracycline based CHVP regimen: cyclophosphamide, doxorubicin, teniposide, and prednisone monthly for 6 months and then every 2 months for 1 more year. Patients were randomly assigned to the CHVP arm (n=153) or the CHVP-IFN arm (n=190) when they also received α-interferon three times weekly for 18 months. Patients with LTB FL were randomly assigned to one of the three arms: arm 1, no initial treatment (n=66); arm 2, prednimustine for 5 days per month for 18 months (n=64); or arm 3, IFN three times per week for 15 months (n=63). Results. Median follow-up was 14.3 years and median overall survival (OS) was 9.8 years for the whole cohort. As expected, the Follicular Lymphoma International Prognostic Index (FLIPI) was a strong prognostic factor as well as bone marrow involvement, erythrocyte sedimentation rate (ESR), and B symptoms in univariate analysis or the FLIPI, lymphocytes count, ESR and male sex in multivariate analysis, respectively. Furthermore, treated patients who achieved a CR (n=170, 40%) had a significant longer OS than those only reaching a PR (n=162, 38%) throughout treatment (10-year OS was 64% (95% CI, 57–71%) for CR patients and 46% (95% CI, 38–54%) for PR patients, logrank p=0.0002). In a subgroup analysis by tumour burden, CR remained highly predictive of a better outcome for HTB patients (logrank p=0.001) but not for LTB patients. No difference was observed between patients who went into early complete remission (≤ 6 months) versus late complete remission (> 6 months). Finally, when only HTB patients receiving CHVP-IFN were compared with those receiving the same treatment in the FL2000 trial (Salles et al., Blood, in press), Cox analysis adjusted for the FLIPI indicated a better outcome for FL2000 patients (HR=0.66, 95% CI 0.44–0.99, p=0.047). Conclusion. These data provide a long follow-up of these patients’ cohorts, and indicate strong evidence that better response to first line treatment translates into a favorable outcome for patients with newly diagnosed FL, especially for HTB patients.

Abstract 2649 Background. Conflicting results have been published to date concerning the impact of statin use on the prognosis of patients with non-Hodgkin lymphoma (NHL) treated with a rituximab-containing first-line regimen. By impairing protein prenylation and possibly lipid-raft formation, statins have been shown to exert an antitumoral activity both on solid and hematological malignancies in vitro as well as in animal models. However, in vitro experiments have demonstrated an unexpected impairment of anti-CD20 antibody binding due to changes in conformational epitopes of the molecule. As a result, statins were found to decrease anti-CD20 induced complement-dependent cytotoxicity and antibody-dependent cellular cytotoxicity. Several groups worldwide attempted to assess the outcome of patients on statins receiving rituximab for NHL. No detrimental effect was observed across studies for patients with diffuse large B-cell lymphoma treated upfront with R-CHOP or R-CHOP-like regimen but a surprising prolonged event-free survival (EFS) was observed for patients with follicular lymphoma (FL) in one study. However, several caveats of the study precluded definitive conclusions to be drawn such as treatment heterogeneity, the enrollment of patients who did not receive rituximab, the retrospective assessment of statin use through medical charts and the consideration of EFS as the primary endpoint without specific evaluation of overall survival (OS). The impact of statin use on the prognosis of patients with FL therefore requires further investigation. Patients and methods. The randomized, open-label PRIMA study enrolled 1217 patients with de novo FL from 223 centers in 25 countries. Patients achieving at least a partial response following frontline therapy with R-CHOP, R-CVP or R-FCM were randomized between 2-years rituximab maintenance (every 8 weeks) or observation. A significant improvement of progression-free survival (PFS) was observed in the rituximab maintenance arm (HR=0.55, 95% CI=0.44–0.68, p Results. As expected, the use of statins was associated to an older age at registration (P No difference in overall response rate to induction regimen as well as in the quality of the response (CR/Cru versus PR versus others) was noted (P=0.53). No further difference was found at the end of the maintenance period either for patients in the observation or in the rituximab treatment arm. Of note, no imbalance was detected concerning the rate of adverse events between the 2 groups of patients as a whole (grade 1–2 versus 3–4, P=0.18) or with regards to each particular toxicity. Finally, outcome in terms of EFS, PFS (see figure above), OS, TTNLT and TTNCT were similar regardless of the use of statins (P=0.76, P=0.43, P=0.21, P=0.83 and P=0.31 respectively). Importantly, further adjustment for potential confounding factors in multivariate Cox models such as age, FLIPI score or LDH (which were imbalanced between the 2 groups) did not reveal a potential beneficial effect. Conclusion. As for other subtypes of NHL, the use of statins in patients with FL in the rituximab era appeared safe and was not associated with an inferior outcome as suggested by in vitro experiments. Disclosures: No relevant conflicts of interest to declare.

Most CML patients are sensitive to Imatinib Mesylate (IM), however, a small fraction develop resistance, mostly through the onset of BCR-ABL mutations. More than 30 mutations have been described, mostly in advanced phase, and confer different levels of clinical resistance. In this setting, clinical trials with 2nd generation tyrosine kinase inhibitors (TKI) provide encouraging results, however neither in vitro nor clinical activity has been demonstrated when the most frequent BCR-ABL mutation, T315I, has been identified. In this retrospective study from 5 French centers, we analysed the features and clinical outcomes of 27 CML patients treated with IM and presenting either clinical, cytological, cytogenetic resistance or molecular progression, and harboring a BCR-ABLT315I mutation detected by direct sequencing (same method in the 5 different laboratories, quality control exchanges). The 27 patients were in chronic phase (CP) at diagnosis, with 17 M and 10 F with a median age at diagnosis of 52 (25–70). Sokal scores were high for 8 pts, intermediate for 6 pts, low for 3 pts and unknown for 8, 2 were in blast crisis (BC) at CML diagnosis. Transcripts were M-BCR for 22 patients and m-BCR for 2 patients and unknown for 3 pts. At diagnosis 4 pts had additional chromosomal abnormalities as a variant Ph1 chromosome, a -7, a -Y, and an additional t(3;7;12) to the Ph1. Progression has been defined as a 2-fold rise in BCR-ABL transcripts levels, loss of any previous response to IM, and a transition towards a more advanced phase of the disease. At T315I discovery, 11 pts were in CP, 4 in accelerated phase, and a majority in BC [7 in myeloid and 5 in lymphoid]. The median interval between diagnosis and IM was 20 Mo. (0–145.2). The median initial dose of IM was 464 mg/day. Most of the patients were poor responders to IM of which 12 pts that obtained no more than a CHR, 2 pts a PCyR, 7 pts a CcyR, 2 pts a MMR, 1 pt no response, and 3 unknown. Twenty-one pts harboured a T315I alone, 1 a T315I with a Y253H, 2 with a M351T, 1 with a E255K+E255V, 1 with a L324Q, and 1 with a F311L, with no impact on survival. The median time for progression from day 1 IM was short [13 Mo. (0–49.6)] regardless of the phase of the disease at T315I identification, and the median interval IM start-T315I identification was 20 Mo. (0–57.6). Median overall survival from D1 of IM was 17.5 Mo. for advanced phases and 42.5 Mo. for CP (p=0.08). All patients progressed with no difference for time to progression between phases (p>0.05). Figure Figure Neither additional mutations (p=0.91), nor additional chromosomal abnormalities (p=0.11), nor Dasatinib treatment (p=0.15) modified overall survival. In conclusion, the onset of BCR-ABLT315I mutations occurs preferentially in high-risk CML, seems more frequent in advanced phases, and is always responsible for progression and poor survival, underlying the need for alternative treatments, in patients lacking a histocompatible donor.

Peripheral T-cell lymphoma (PTCL) is an aggressive disease with poor outcome. First line therapies are usually unsatisfactory with frequent need for second-line therapies. Median progression free survival (PFS) and overall survival (OS) for relapse PTCL patients are very short with few available therapeutic options. Bendamustine has been shown to be effective in this setting. In order to assess the efficacy of bendamustine outside clinical trials, we conducted a national retrospective study of patients with the diagnosis of PTCL and who were treated with bendamustine. Between 2011 and 2013, about 200 patients with the diagnosis of PTCL have been treated in 27 centers with bendamustine. We present the results of 142 patients with complete clinical and biological data. The population median age was 64y (range 28-89) with male/female sex ratio of 1,4 (83/59). Histologies were: angio-immunoblastic (AILT=63), PTCL-NOS (n=44), anaplasic-large (ALCL=13), NK/TCL (n=3), mycosis fungoides (MF=7), subcutaneous panniculitis-like-TCL (n=2), hepato-splenic-TCL (n=1) and others (n=9). The majority of patients (96%, n=130) had stage-disseminated disease and 72% (n=102) of them had extranodal localisations. The median number of chemotherapy lines prior to bendamustine was 2 (range 0-8). Seven patients (5%) had received allogeneic stem cells transplantation (SCT) and 16 autologous SCT (11%) prior to bendamustine. The median duration of response (DoR) after the last prior to bendamustine chemotherapy was 4.3 months (range 1-70) and 50% of patients had refractory disease at bendamustine treatment. Seventy-four patients (52%) received less than 3 cycles, mostly because of disease progression. Overall, they received a median of 2 cycles (range 1-8) with a median dose of 90mg/m2 (range 50-150). The best overall response rate (ORR) was 32% (45/141) with complete response of 24% (CR=34). The median DoR was 3.3 months (1-39). For AITL patients, ORR was 52% (33/63) with CR of 41%, whereas it was 18% (8/44) with 11% of CR, in patients with PTCL-nos, respectively (p=0.01). Nine patients (6%) received allogeneic SCT in CR. Median PFS was 3 months (range 0.2-46.3) and median OS was 4.4 months (range 0.2-55.4). On multivariate analysis, chemotherapy refractory (p=0.001) patients' and extranodal disease localization (p=0.028) before bendamustine influenced adversely the ORR. With a median follow up 4.4 months, 72% of patients (102/142) died. The most frequent cause of death were: disease progression (92%) or toxicities (6%). Grade 3-4 thrombocytopenia, neutropenia and infections were reported in 22%, 17% and 23% of cases, respectively. Bendamustine as single agent must be considered as a therapeutic option for relapsed or refractory PTCL, particularly in patients with AITL. The safety profile was good. Combination of bendamustine with other drugs should be evaluated prospectively. Disclosures Off Label Use: Bendamustine, single molecule, alkylant agent with antimetabolite properties. Morschhauser:Genentech Inc./Roche: Other: Advisory boards. Cartron:Sanofi: Honoraria; GSK: Honoraria; Celgene: Honoraria; Gilead: Honoraria; Roche: Consultancy, Honoraria.