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Background: CC-122, a pleiotropic pathway modifier, modulates the cullin 4 ring E3 ligase complex, which results in recruitment and degradation of Aiolos and Ikaros. This substrate degradation results in cell autonomous anti-lymphoma and immunomodulatory effects on T- and NK-cell function (Gandhi, ASH 2012). The anti-CD20 monoclonal antibody, obinutuzumab, improves direct cell killing and antibody-dependent cell-mediated cytotoxicity (ADCC) activity compared to rituximab (Mössner, 2010; Niederfellner, 2011). The combination of obinutuzumab with CC-122 revealed synergistic effects in follicular lymphoma (FL) and additive effects in diffuse large B-cell lymphoma (DLBCL) in in vivo models when compared to either as single agents (Hsiling Chiu, ASH 2015). CC-122 monotherapy has shown encouraging activity against DLBCL and FL in a Phase I clinical trial (Rasco, ASH 2013). Obinutuzumab has demonstrated efficacy in patients with relapsed/refractory indolent non-Hodgkin lymphoma (iNHL) (Salles, 2013) and DLBCL (Morschhauser, 2013) and has been approved by the FDA and the European Medicinal Agency for patients with previously treated FL. The current study was designed to evaluate the safety and efficacy of escalating doses of CC-122 in combination with obinutuzumab in patients with relapsed/refractory DLBCL and iNHL (NCT02417285). Methods: Subjects with relapsed/refractory DLBCL and iNHL (FL and marginal zone lymphoma [MZL]) were enrolled in this phase 1b study of CC-122 given orally on 5 out of 7 days per week (5/7 days) for 28 day cycles. Subjects were enrolled in cohorts of escalating dose levels of CC-122 (1.0 mg [n=4], 2.0 mg [n = 4], 3.0 mg [n = 7], 4.0 mg [n = 6]), with a fixed dose of obinutuzumab. Obinutuzumab is administered as an intravenous (IV) infusion at a dose of 1000 mg on Days 2, 8, and 15 of Cycle 1 and on Day 1 of Cycles 2 through 8. The initial 4 dose levels evaluated active ingredient in capsule (AIC) CC-122 formulation. In Cohort 5 (3.0 mg, [n = 5]), subjects received CC-122 formulated capsules. Prophylaxis with granulocyte-colony stimulating factor (G-CSF) was not allowed during Cycle 1. As the study is ongoing, the CC-122 dose will be escalated until the maximum tolerated dose (MTD) is established on the CC-122 formulated capsule, using a modified 3+3 design. Subjects are evaluated for efficacy every 2 cycles(c) through c6 then every 3 cycles through c12, then every 6 cycles. Results: As of 1 June 2016, 26 subjects with relapsed/refractory DLBCL or iNHL were enrolled; all were evaluable for safety. The median age was 60 years and 84.6% were male. Thirteen subjects had DLBCL (50%), 13 (50%) had iNHL (12 FL [46.2%], 1 had MZL [3.8%]). All subjects were ECOG 0-1. One subject experienced a dose-limiting toxicity (DLT) of Grade 4 neutropenia (Cohort 3) and no dose was considered a non-tolerated dose (NTD). The most common (≥ 10%) study drug-related treatment emergent adverse events (TEAEs) were neutropenia (50%), thrombocytopenia (30.8%), diarrhea, chills, and increased ALT (11.5% each). Seventeen subjects (65.4%) experienced at least one NCI CTCAE grade 3-4 TEAE related to study treatment (most common [≥ 10%] were neutropenia [42.3%], thrombocytopenia [15.4%], and increased ALT [11.5%]). Seven subjects experienced at least one serious AE suspected to be related to study treatment by the investigator (infusion related reaction [3 subjects], febrile neutropenia, neutropenia, thrombocytopenia, and pneumonia, [1 subject each]). The overall response rate (ORR) for the 26 subjects enrolled, as of the efficacy cut off of 7 July 2016, was 53.8% (14/26); 8 of 12 (66.7%) FL, 5/13 (38.5%) DLBCL, and 1/1 MZL. Responses are ongoing in 12 of 14 of these subjects. ORR in the pooled higher dose cohorts of CC-122 (eg, a dose of 3 mg or higher, cohorts 3, 4, and 5) was 66.7% (12 of 18 subjects). Conclusion: The combination of CC-122 and obinutuzumab was well-tolerated in subjects with relapsed-refractory DLBCL and iNHL. AEs observed were consistent with the toxicity profile of CC-122 or obinutuzumab. Response rates observed were promising in this heavily pretreated population. Response rate appears higher in patients with FL however this warrants further investigation in a larger population. An NTD has not been reached and the MTD has not yet been established. Disclosures Michot: Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees. Vitolo:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Honoraria; Gilead: Honoraria; Takeda: Honoraria. Zinzani:Karyopharm: Membership on an entity's Board of Directors or advisory committees; Sandoz: Membership on an entity's Board of Directors or advisory committees; Millennium: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Infinity: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees; TG Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Kersten:Celgene: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding. Chiappella:Teva: Speakers Bureau; Janssen-Cilag: Speakers Bureau; Amgen: Speakers Bureau; Pfizer: Speakers Bureau; Roche: Speakers Bureau; Celgene: Speakers Bureau. Sarmiento:Celgene CITRE: Employment, Equity Ownership. Zuraek:Celgene Corporation: Employment, Equity Ownership. Pourdehnad:Celgene Corporation: Employment, Equity Ownership. Hege:Celgene Corporation: Employment, Equity Ownership. Nikolova:Celgene International: Employment, Equity Ownership. Ribrag:BMS: Membership on an entity's Board of Directors or advisory committees; ArgenX: Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees; Infinity: Membership on an entity's Board of Directors or advisory committees; Esai: Membership on an entity's Board of Directors or advisory committees; Pharmamar: Membership on an entity's Board of Directors or advisory committees; NanoString: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees.

Despite improvements in standard therapy with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone for patients with untreated, diffuse large B-cell lymphoma, up to 40% of these patients relapse. Lenalidomide alone or in combination with rituximab has been shown to be active in relapsed/refractory aggressive lymphomas. In this phase I study we determined the maximum tolerated dose of lenalidomide plus rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone in untreated, elderly (median age 68 years) patients with diffuse large B-cell lymphoma. Four lenalidomide doses (5, 10, 15, and 20 mg/day on days 1-14) allocated using the continual reassessment method were planned to be administered for 14 days in combination with each course of rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone for a total of six courses. Seven cohorts of patients (n=3 in each cohort) were treated (total n=21) at 10, 20, 15, 15, 15, 10, and 10 mg of lenalidomide. Dose-limiting toxicities occurred in seven patients during the first three courses of treatment. The third dose-level of lenalidomide (15 mg/day) was selected as the maximum tolerated dose, with an estimated probability of dose-limiting toxicities of 0.345 (95% credibility interval 0.164-0.553). Grade 3-4 hematologic adverse events were: neutropenia in 28% of the courses, thrombocytopenia in 9%, and anemia in 3%. Non-hematologic toxicities were moderate: grade 4 increase of creatinine phosphokinase (n=1), grade 3 cardiac (n=2), grade 3 neurological (n=3), and grade 3 gastrointestinal (n=1). In this phase I study, the overall response rate was 90%, with 81% achieving complete remission. This combination regimen appears safe in elderly patients with diffuse large B-cell lymphoma and its efficacy will be assessed in the ongoing phase II trial. This trial was registered at www.clinicaltrials.gov as NCT00907348.

To investigate the role of radiation therapy (RT) in patients affected with primary mediastinal B-cell lymphoma (PMBCL) with residual (18)fluorodeoxyglucose positron emission tomography ((18)FDG-PET)-positive disease after rituximab chemotherapy (R-CT).Thirty-seven patients treated with R-CT and RT, all with (18)FDG-PET scan at diagnosis and before RT, were included. All (18)FDG-PET scans were reviewed, and responses were classified according to the Deauville 5-point scoring system. Outcomes measures were overall survival (OS) and progression-free survival (PFS), estimated for the whole cohort and for subgroups according to (18)FDG-PET score after R-CT.The median follow-up time was 40.9 months. Three patients were assigned to Deauville score 1 (8.1%), 9 to score 2 (24.3%), 7 to score 3 (19%), 14 to score 4 (37.8%), and 4 to score 5 (10.8%). After RT, all patients with score 3-4 experienced a complete response (CR). Among patients with score 5, 1 was in CR (25%), 2 had persistent positivity (50%), and 1 showed progressive disease (25%). A total of 4 patients experienced progression or relapse: 1 of 33 (3%) with scores 1-4, and 3 of 4 (75%) with score 5. The 3-year OS and PFS of the whole cohort were 89.8% and 88.7%, respectively. OS was significantly different between scores 1-3 and scores 4-5 (100% vs 77% at 3 years, P.05). Patients with a score of 5 had a significantly worse outcome than did all other patients (OS at 2 years, 33.3% vs 100%).Approximately 50% of PMBCL patients show residual disease at (18)FDG-PET scan after R-CT. RT is able to convert to CR approximately 85% of these patients, but those with a Deauville score of 5 (10%) appear at high risk of progression and death, and they might be candidates for intensified programs.

We assessed the prognostic value of minimal residual disease (MRD) within the ML17638 phase 3 trial from the Fondazione Italiana Linfomi, investigating the role of rituximab maintenance in elderly follicular lymphoma (FL) patients after a brief first-line chemoimmunotherapy. MRD for the bcl-2/IgH translocation was determined on bone marrow cells in a centralized laboratory belonging to the Euro-MRD consortium, using qualitative and quantitative polymerase chain reactions (PCRs). Of 234 enrolled patients, 227 (97%) were screened at diagnosis. A molecular marker (MM) was found in 51%. Patients with an MM were monitored at 8 subsequent times. Of the 675 expected follow-up samples, 83% were analyzed. Conversion to PCR negativity predicted better progression-free survival (PFS) at all post-treatment times (eg, end of therapy: 3-year PFS, 72% vs 39%; P < .007). MRD was predictive in both maintenance (83% vs 60%; P < .007) and observation (71% vs 50%; P < .001) groups. PCR positivity at the end of induction was an independent adverse predictor (hazard ratio, 3.1; 95% confidence interval, 1.36-7.07). MRD is a powerful independent outcome predictor in FL patients who receive rituximab-intensive programs, suggesting a need to investigate its value for decision-making. This trial was registered at www.clinicaltrial.gov as #NCT01144364.

Central nervous system (CNS) involvement in mantle cell lymphoma (MCL) is uncommon, and the manifestations and natural history are not well described.We present the data on 57 patients with MCL who developed CNS involvement, from a database of 1396 consecutively treated patients at 14 institutions.The crude incidence of CNS involvement was 4.1%, with 0.9% having CNS involvement at diagnosis. Blastoid histology, B-symptoms, elevated lactate dehydrogenase, Eastern Cooperative Group performance status >= 2 and a high Mantle Cell Lymphoma International Prognostic Index score were enriched in the cohort with CNS involvement, and the presence of >= 1 of these features defined a high-risk subset (an actuarial risk of CNS involvement 15% at 5 years) in a single-institution subset. The median time to CNS relapse was 15.2 months, and the median survival from time of CNS diagnosis was 3.7 months. The white blood cell count at diagnosis In MCL, CNS involvement is uncommon, although some features may predict risk. Once manifest outlook is poor; however, some patients who receive intensive therapy survive longer than 12 months.

Purpose To evaluate the efficacy of rituximab maintenance in 60- to 75-year-old patients with advanced follicular lymphoma responding to brief first-line chemoimmunotherapy followed by rituximab consolidation. Patients and Methods A total of 234 treatment-naive 60- to 75-year-old patients began chemoimmunotherapy with four monthly courses of rituximab, fludarabine, mitoxantrone, and dexamethasone (R-FND) followed by four weekly cycles of rituximab consolidation. Of these, 210 patients completed the planned treatment, and 202 responders were randomly assigned to rituximab maintenance (arm A) for 8 months, once every 2 months for a total of four doses, or to observation (arm B). Results Median ages in arms A and B were 66 and 65 years, respectively. After induction and consolidation therapy, the overall response rate was 86%, with 69% complete remissions (CR). After a 42-month median follow-up from diagnosis, 3-year progression-free survival (PFS; the primary end point) and overall survival (OS) were 66% (95% CI, 59% to 72%) and 89% (95% CI, 85% to 93%), respectively. After randomization, 2-year PFS was 81% for rituximab maintenance versus 69% for observation, with a hazard ratio of 0.74 (95% CI, 0.45 to 1.21; P = .226), although this was not statistically significant. No differences between the two arms were detected for OS. Overall, the regimen was well-tolerated. The most frequent grade 3 to 4 toxicity was neutropenia (25% of treatment courses), with 13 infections. Two toxic deaths (0.8%) occurred during induction treatment. Conclusion A brief R-FND induction plus rituximab consolidation achieved excellent results with high CR and PFS rates, supporting the feasibility of this regimen in patients older than 60 years. A short rituximab maintenance did not achieve a statistically significant PFS improvement over observation.

7538Background: Gene expression profiling (GEP) represents a gold standard in identifying patients (pts) with activated B-cell–like (ABC) DLBCL, a subtype associated with inferior outcomes. Until r...

Background Recent studies show that the risk of VTE in NHL pts is similar to that observed in high risk solid tumors (i.e. pancreatic, ovarian cancer). VTE in NHL occurs in most cases within three months from diagnosis and can have substantial impact on treatment delivery and outcome as well as on quality of life. However few data are available on potential predictors. Aims To better clarify the epidemiology of early (within six months from treatment start) VTE in NHL we conducted a pooled data analysis of 12 clinical trials from FIL. Our analysis included basic demographic features, lymphoma-related characteristics as well the Khorana score (based on histology, BMI, platelets WBC and HB counts) which is extensively used in solid tumors to predict VTE risk. Patients and methods From Jan. 2010 to Dec. 2014, all pts with B-cell NHL enrolled in prospective clinical trials from FIL for frontline treatment were included. For 9 studies study period included the entire trial population was included. The analyses were conducted based on CRFs as well as pharmacovigilance reports. VTE definition and grading was stated according to standard criteria of toxicity (CTCAE V4.0). Cumulative incidence of VTE from the study enrollment was estimated using the method described by Gooley et al. accounting for death from any causes as a competing risk. The Fine & Gray survival model was used to identify predictors of VTE among NHL pts. Factors predicting the grade of VTE were investigated using an ordinal logistic regression model. This pooled data analysis was approved by local IRB. Results Overall, 1,717 patients belonging to 12 studies were evaluated. Eight were phase I/II or II (25% of pts) and 4 phase III (75% of pts). M/F ratio was 1.41, Median age was 57, (IQ range (IQR) 49-66). Histologies were: DLCL-B 34%, FL 41%, MCL 18%, other 6%. Median BMI was 25 (IQR 22-28). Median Hb, WBC and platelets counts were 13g/dl) (IQR 11.5-14.2), 7.1*10^9/l (IQR 5.6-10.3), 224*10^9/l (IQR 169-298), respectively. 1189 pts were evaluable Khorana score: 58% low risk, 30% intermediate risk, 12% were high risk. Human erythropoetin support was given to 9% of patients. All pts received Rituximab. Planned therapeutic programs included ASCT in 27% of pts, conventional chemotherapy in 67% a conventional chemotherapy plus lenalidomide in 6%. Overall 59 any grade VTE episodes occurred in 51 pts (2.9%), including 21 grade III-IV VTE (18 pts). None was fatal. Median time from study enrolment to VTE was 63 days (IQR: 35-110). Considering death as a competitive event the 6 months cumulative incidence of VTE was 2,2% in low risk Khorana score, 4.5% (95%IC: 2.3-6.7) in intermediate and 6.6% (95%IC: 2.4-10.8) in high risk (p = 0.012) (figure 1). Khorana score was predictive also for grade III-IV events as they were 0,7% (95% CI:0.1-1.4) in low risk and 2.0% (95% CI:0.8-3.3) in intermediate-high risk (p = 0.048). The results were similar also after excluding lenalidomide containing studies. The Fine and Gray multivariate analyses, adjusted for age and stage, showed that Khorana score (intermediate risk adjHR = 1.96; 95%IC: 0.84-4.56 and high risk adjHR = 3.81; 95%IC: 1.51-9.58) and DLCL-B histotype (adjHR = 2.58; 95% CI: 1.01-6.55) were independently associated to an increased risk of VTE. Moreover an ordinal logistical regression model indicated that the increase of one point in the Khorana score resulted in an increased risk of VTE (OR = 1.85; 95% CI: 1.23-2.79). Download : Download high-res image (130KB) Download : Download full-size image Fig. 1 . Conclusions Our results suggest that DLCL-B histotype and Khorana score are predictors of VTE in NHL. The latter might become a simple and effective tool to assess the risk of VTE in NHL. Prospective validation including also patients not eligible for clinical trials is needed.

Abstract 1615 Background: Diffuse large B cell lymphoma (DLBCL) is one of the most common types of non-Hodgkin's lymphoma. R-CHOP21 (C21) is considered the standard therapy but a large number of studies have tested R-CHOP14 (C14). Aims: The aim of our study was to evaluate retrospectively a cohort of patients (pts) treated with C21 or C14 and to compare the efficacy of the therapy. Methods: All pts with diagnosis of DLBCL or follicular grade IIIb lymphoma, treated with curative intent in 9 Italian Hematological Centers, were accrued. All patients treated with C14 used G-CSF as primary prophilaxis, and only elderly (over 70 years) patients treated with C21 used G-CSF as primary prophilaxis. Results: From january 2002 to june 2011, 950 pts were accrued, 643 pts were treated with C21 and 307 were treated with C14. The median age was 63 (range 19–89). The two cohorts of pts were balanced for all clinical characteristics a part for age (60 years) with more aged pts in C21 arm (p 0.001), bone marrow positivity and more than 3 lymph node stations involved that were higher in C14 arm (p: 0.05 and p: 0.001). After induction therapy 751 pts (79%) obtained a complete remission: 501/643 (78%) after C21 and 250/307 (81%) after C14. The remaining pts obtained partial response in 110 and 48 or no response in 32 and 9 respectively for C21 and C14. After a median period of observation of 38 months 104 pts relapsed (14%), 68 (65%) in the C21 arm and 36 (35%) in the C14 arm. After a median observation period of 3 years, considering the two therapies, C21 vs C14, no differences were reported in OS (Figure 1), PFS (Figure 2) and DFS: 80% vs 84%, 69% vs 71% and 54% vs 56% respectively. In univariate analysis OS was lower in older pts (azard ratio (ar): 2.57), IPI 2 (ar: 2.09), IPI 3 (ar: 4.36), IPI 4–5 (ar: 6.36), bulky disease (ar: 1.70), symptomatic disease (ar: 2.23). In multivariate analysis factors which mantained significantly worst prognosis were older age (ar: 1.35), IPI 2 (ar: 1.95), IPI 3 (ar: 3.76), IPI 4–5 (ar: 5.01) and bulky disease (ar: 1.43). As expected hematological grade III/IV toxicity was more frequent in pts treated with C14. No differences in extra-hematological toxicity were observed. Secondary malignancies were reported: 7 in C21 and 3 in C14. After 3 years of median observation 188 pts are dead: 137 (73%) in C21 and 51 (27%) in C14 (not statistically significant, p:0.08). The large majority of pts are dead for disease progression or relapse. Conclusions: In conclusion our results confirm that C14 do not improve the results of the standard C21 in the whole lymphoma population. Dose dense therapy did not affect OS or PFS also analysing sub group of pts. As expected a higher frequency of neutropenia was observed in C21 arm but did not translate in increasing infection rate. Further prospective randomized studies are needed to verify this preliminary observations. Disclosures: No relevant conflicts of interest to declare.

Role of interim-PET (I-PET) in diffuse large B-cell Lymphoma (DLBCL) is controversial. To determine predictive value of I-PET on progression-free survival (PFS), we enrolled 88 first-line DLBCL patients treated with 6-8 R-CHOP courses regardless of I-PET. PET/CT were performed at diagnosis, after 2 to 4 courses and at the end of therapy with central reviewing according to visual dichotomous criteria. Results are as follows: I-PET, 72% negative, 28% positive; final-PET (F-PET), 88% negative, 12% positive; clinical complete response 90%. Concordance between clinical response and F-PET negativity was 97% because of 2 false positive. With a median follow-up of 26.2 months, 2-year overall survival and PFS were 91% and 77%, respectively. Two-year PFS for I-PET and F-PET negative versus positive were as follows: I-PET 85% versus 72% (P = .0475); F-PET 83% versus 64% (P < .001). Because of a small number of events, 2 independent bivariate Cox models were tested for PFS. In model 1, F-PET contradicted I-PET (hazard ratio [HR] = 5.03, P = .015 vs 1.27, P = 691); in model 2, F-PET (HR = 4.54) and International propnostic Index score (HR = 5.36, P = .001) remained independent prognostic factors. In conclusion, positive I-PET is not predictive of a worse outcome in DLBCL; larger prospective studies and harmonization of I-PET reading criteria are needed.

We conducted a prospective study to compare epirubicin, cyclophosphamide, vinblastine, prednisone and rituximab (R-miniCEOP) with cyclophosphamide, doxorubicin, vincristine, prednisone and rituximab (R-CHOP) for the treatment of "fit" elderly patients with diffuse large B-cell lymphoma (DLBCL). Patients over the age of 65 with stage II-IV DLBCL were screened with a comprehensive geriatric assessment. Patients were randomized to receive six courses of R-miniCEOP (n = 114) or R-CHOP (n = 110). Overall, the rate of complete remission was 70% (p = 0.466). After a median follow-up of 42 months, 5-year event-free survival (EFS) rates were 46% and 48% for R-miniCEOP and R-CHOP, respectively (p = 0.538). Patients older than 72 years and with low-risk disease had a better outcome when treated with R-miniCEOP (p = 0.011). Overall R-CHOP and R-miniCEOP are similarly effective for elderly "fit" patients with DLBCL. The less intense R-miniCEOP may be an acceptable option for the treatment of relatively older patients with low-risk disease.

Introduction. Relapsed and primary refractory peripheral T-cell lymphomas (PTCL) show a dismal outcome, with a 5-year overall survival of only 30%. There is no standard salvage chemotherapy for these patients. Gemcitabine was proved to be an effective monotherapy, yelding 60-70% overall response rates in patients with advanced heavily pre-treated disease. Romidepsin, a histone deacetylase inhibitor recently approved by Food and Drug Administration, has demonstrate an overall response rate (ORR) of 30% and a complete response (CR) rate of 16%. We have recently designed a multicentric trial to investigate the role of the combination of gemcitabine plus romidepsin (GEMRO regimen) in relapsed or refractory PTCL, looking for a potential synergistic effect of the two drugs. Methods. Twenty relapsed/refractory PTCL patients were included in a multicentric, prospective phase II trial which contemplated an induction with romidepsin 12 mg/m2 intravenously (i.v.) on days 1, 8, 15, and gemcitabine, 800 mg/m2 i.v. on day 1 and 15, for 6 cycles, each cycle to be repeated every 28 days. After the induction phase, patient who obtained at least a partial remission (PR) proceeded onto romidepsin maintenance at the dose of 14 mg/m2 i.v. until disease progression. The primary endpoint was to evaluate the efficacy of GEMRO regimen after the induction phase, as assessed by complete response (CR) rate; safety assessment was regarded as a secondary objective. The trial was registered under EudraCT (2012-001404-38). Results. Twenty patients have been recruited for this study. At present time, all patients underwent the induction phase and are evaluable for response and toxicity. The median age of patients was 55 years (range, 24-77). According to histology, 10 patients had PTCL not otherwise specified, 9 had an angioimmunoblastic T-cell lymphoma, 1 had a kinase negative anaplastic large cell lymphoma. The median number of prior therapies was 2 (range, 1-4); 7/20 (35%) patients had failed a prior stem cell transplant. Nineteen out of 20 (95%) patients presented with advanced stage. At the end of induction phase, the ORR was 31% including 2 CRs and 3 PRs. One of the 2 CR patients discontinued the treatment after 4 cycles due to cardiac toxicity, however maintaining a continuous CR with a follow up of 2 years. The other CR patient is still on treatment in maintenance phase. Grade ≥3 adverse events were represented by thrombocytopenia (60%), neutropenia (50%), and anemia (20%). Conclusions. To date, data failed to show a superiority of the GEMRO combination regimen over single agent romidepsin as salvage therapy for refractory or relapsed PTCL patients. More mature data and an adequate follow-up will be required to better understand the role of this combination regimen. Disclosures Zinzani: Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; J&J: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Background. Bortezomib, an inhibitor of the proteasome, is effective in relapsed mantle cell lymphoma (MCL) and indolent lymphomas and it is synergistic with Rituximab to enhance apoptosis and NFkB depletion. On these basis, the FIL conducted a phase II multicenter study aimed to evaluate safety and efficacy of Bortezomib in association with Rituximab in relapsed/refractory non-follicular Lymphoma (Linfocytic, LL and Marginal Zone Lymphoma, MZL) and MCL, not eligible to high dose chemotherapy with stem cell transplantation. Patients and methods. The study was a prospective single arm phase II trial, designed on Simon two-stage Optimal Design. Primary end-point was to obtain an Overall Response Rate (ORR) > 40%. The aim of this analysis is to evaluate long term follow-up of Bortezomib and Rituximab combination. A central histological revision was planned in all the patients at the enrollment. Inclusion criteria were: 18-75 years, relapsed/refractory LL, MZL, MCL after 1-4 lines. Treatment schedule was: one course of 1.6 mg/sqm Bortezomib weekly in combination with standard 375 mg/sqm Rituximab on days 1, 8, 15, 22 followed by two courses of four weekly intravenous bolus of Bortezomib alone; patients with complete (CR), partial remission and stable disease at the intermediate evaluation were planned to be given three further courses with the same schedule. Results. From September 2006 to March 2008, 55 patients were enrolled and six were excluded at central histological revision. Clinical characteristics were: median age 68 (50-74); 16 (33%) LL, 8 (16%) MZL, 25 (51%) MCL; 42 (86%) stage III/IV; 33 (67%) bone marrow involvement. Median number of previous treatments was 2 (range 1-7); 34 (69%) were Rituximab pretreated; 21 (43%) had refractory disease. Thirty (61%) patients completed the treatment and 233 courses were delivered (median: 4.7 courses/patient); 19 (39%) patients did not because of no response in 13, adverse events in five, with only one toxic death due to interstitial pneumonia. ORR was 53% (CR 26.5%); no response was seen in 43% and 4% were not evaluable for response. ORRs by clinical subgroup were: LL 37%, MZL 50%, MCL 64%; Rituximab pretreated 62%, Rituximab naïve 33%; relapsed 64% and refractory 38%. With a median follow-up of 85 months, median Overall Survival (OS) was 61.5 months (95%CI: 35.0-81.5), with 5-years OS 51% (95% CI: 36-65) and median Progression Free Survival (PFS) was 8.9 months (95%CI: 5.3-18.3), with 5-years PFS 16% (95% CI: 7-28%). Five-years PFS by histology was: 12% (95% CI: 2-31) for LL, 17% (95% CI: 5-34) for MCL and 19% (95% CI: 11-53) for MZL. PFS rates were not different between Rituximab pretreated versus naïve nor international prognostic index 1-2 versus 3-4-5 nor refractory versus relapsed. By number of previous therapies, 5-years PFS for 1 previous therapy versus 2 versus 3 or more was: 24%, 14% and 13%, respectively, p=0.36. Conclusions. Weekly infusion of Bortezomib in combination with Rituximab is effective in relapsed/refractory indolent and MCL and represents a treatment option in this setting of patients. Disclosures No relevant conflicts of interest to declare.

Introduction: MYC and BCL2 overexpression and low BCL6 expression assessed by immunohistochemistry (IHC) have been reported as negative prognostic factors in DLBCL. We presented in a previous pilot study (Botto B, ASH 2014) a prognostic score based on overexpression of MYC, BCL2 and low expression of BLC6, assessed by IHC, in a retrospective cohort of 69 de-novo DLBCL, with an high proliferation index (MIB1 >70%), treated with R-CHOP between 2010 and 2013 (study cohort). Methods: The aim of the present study was to expand the analysis and validate this score in a larger retrospective cohort of DLBCL, regardless the proliferation index. Planned inclusion criteria were de-novo DLBCL diagnosis and combined modality treatment with Rituximab and CHOP treatment between January 2003 and December 2013 (validation cohort). Patients enrolled in the previous pilot study were considered as control group. Samples were investigated for MYC expression on Tissue Micro Arrays (TMA), while BCL2 and BCL6 expression were evaluated at diagnosis. Cases were considered positive for MYC, BCL2 or BCL6 expression by IHC if >40%, >40% or >25% of cells stained positive, respectively. FISH studies for MYC and BCL2 rearrangements are currently ongoing. PFS and OS were estimated with Kaplan-Meier method and compared between groups with the Cox model. Results: A total of 346 DLBCL were screened for this study; 203/346 had complete data for survival analysis; at the present time, 97/203 cases were fully investigated by histology and IHC. Clinical characteristics were: median age 65 years (IQR 55;73), 66 (69%) stage III-IV, 36 (38%) with LDH upper normal and 37 (39%) with IPI >2. These characteristics are superimposable to those of the pilot study, a part from a lower rate of IPI>2 (39% vs 67%). No differences in clinical presentation or in the outcome were seen between patients with or without histologic tissue for IHC. At the moment of the present analysis, MYC overexpression was detected in 33 (34%); BCL2 overexpression in 84 (87%) and BCL6 low expression in 32 (33%). Overall, 3y-PFS and OS were 68% and 77% respectively. Applying the prognostic model defined in our previous pilot study (adjusted for IPI and age) and based on different coefficient score (2 points for MYC or BCL2 positivity and 1 point for BCL6 negativity, pooled scores 0-1, 2 and >3) 5y-PFS rates were different across the 3 groups: 85% vs 67% vs 54% (HR 2.67 IC 0.85-8.40 p=0,094). Having found similar results in both cohorts, we integrated the two population (validation cohort and study cohort) in a total of 153 patients: 12 had score 0-1, 60 score 2 and 80 >3. 5y-PFS rates were significantly different across the 3 groups (Figure 1): 90% vs 62% vs 44% (HR 2.02 IC 95% 2.02-3.19, p=0.003). Indeed, 5-yrs-OS was significantly worse in high score group with 90% vs 76% vs 61% (HR 1.77 IC 95% 1.03-1.05, p=0,038) (Figure 2). Conclusion: Our data showed that a IHC prognostic score based on MYC, BCL2 and BCL6 expression, is a simple, reproducible and valid prognostic assessment that predicts outcome in a larger cohort of DLBCL, regardless of the proliferation index, forecasting significant different PFS and OS rates. Further extension of the study applying IHC and FISH analysis in the whole population of patients will be available at the time of ASH meeting and will be helpful to better refine the model. Figure 1. 5-yrs PFS in 153 patients (Validation cohort + Study cohort) Figure 1. 5-yrs PFS in 153 patients (Validation cohort + Study cohort) Figure 2. 5-yrs OS in 153 patients (Validation cohort + Study cohort) Figure 2. 5-yrs OS in 153 patients (Validation cohort + Study cohort) Disclosures No relevant conflicts of interest to declare.

Background. The prognostic role of cell of origin profile (COO) assessed by immunohistochemistry (IHC) is controversial in Rituximab era. FIL conducted a phase III randomized trial aimed at investigating the benefit of intensification with high dose therapy plus autotransplant compared to R-dose-dense therapy as first line in young DLBCL at poor risk (aa-IPI 2-3). Clinical results were reported (Vitolo, ASH 2012). The aim of BIO-DLCL04 was to correlate the biological markers with PFS. Patients and Methods. From 2005 to 2010, 412 untreated DLBCL at aa-IPI 2-3 were enrolled. Central histology revision was mandatory and 13 patients were excluded due to different histologies. Biological markers were analyzed on DLBCL NAS; COO analysis was performed by IHC and cases were classified in germinal center (GC) and non-GC according to Hans' algorithm; COO determined by gene expression profile using the NanoString® nCounter® Analysis System based on 20-gene assay (Lymph2Cx) using formalin fixed paraffin embedded tissue is ongoing; BCL2, BCL6 and MYC anomalies were tested by IHC; final analysis by fluorescent in situ hybridization (FISH) is ongoing. Cases were deemed positive if at least 30% of lymphoma cells were stained with each antibody (with the exception of at least 40% for MYC). Results. At the time of this analysis, 223 DLBCL NAS were analyzed: 131 non-GC and 92 GC; BCL2, BCL6 and MYC anomalies were tested in 196, 74 and 107 cases respectively. Clinical characteristics for non-GC vs GC were: median age 51 years for both, male 49% vs 45%, aa-IPI 3 15% vs 25%, bone marrow involvement (BM) 16% vs 24%. R-HDC was performed in 45% of non-GC patients and in 49% of GC. Complete response was recorded in 105 (80%) non-GC patients and in 62 (67%) GC. At a median follow-up of 49 months, the 3-year PFS for non-GC vs GC was 75% (95% CI: 67-82) vs 57% (95% CI: 46-67) with crude hazard ratio, HR 0.55 (0.35-0.87), p.01 and adjusted (for age, gender, aa-IPI, BM) aHR 0.56 (0.35-0.88), p.013. No significant differences by treatment were reported. Overexpression of MYC by IHC had a relevant prognostic impact, with aHR 1.84 (0.99-3.44), p.054. By IHC, 3-years PFS for double negative vs single BCL2 or MYC overexpression vs double positive, was 85% vs 68% vs 51% respectively, with an aHR for double expressors compared to double negative of 3.91 (1.13-13.53), p.031. At the time of the present report, FISH analysis was conducted in 88 cases: 43 were triple negative, 37 single hit and 8 double/triple hit. By FISH, 3-years PFS for triple negative vs single hit vs double/triple hit was 74% vs 84% vs 25% respectively, with an aHR for double/triple hit compared to triple negative of 5.73 (2.05 to 16.02), p.001. Conclusions. In conclusion, with the limit of the analysis performed by IHC based on Hans' algorithm, BIO-DLCL04 showed an unexpected better outcome for non-GC compared to GC, irrespective of treatment arm. The ongoing analysis conducted by Nanostring will be more informative. The overexpression of MYC was an unfavourable risk factor, mainly if associated with BCL2 overexpression, irrespective of type of treatment. Moreover, double/triple hit patients represent a subgroup with extremely poor prognosis. High dose therapy plus autotransplant was not able to reverse the inferior outcome of neither double expressors nor double hit patients and new strategies are deemed for these poor prognosis patients. Disclosures No relevant conflicts of interest to declare.

Background: Peripheral T-cell lymphomas (PTCL) have an aggressive clinical course with a poor 5-year overall survival with conventional therapy. Autologous stem cell transplantation (autoSCT) and allogeneic stem cell transplantation (alloSCT) can improve long-term disease control in first and second remission, respectively. Prognostic factors are not able to discriminate patients with chemorefractory disease. Preliminary evidence from gene expression profiling (GEP) and immunoistochemical study have suggested that the majority of PTCL-not otherwise specified (PTCL-NOS) can be subdivided in two different groups based on GATA3 and Tbet (transcription regulators of T-helper 2 and T-helper 1 lymphocytes) expression with a poorer prognosis in the former group. Because GEP studies are not feasible in routine clinical practice, we investigated whether expression changes of those proteins could be evaluated by immunohistochemistry (IHC) and used to predict prognosis. Material and Methods: We collected paraffin tissues from 63 consecutive patients (pts) with a diagnosis of PTCL [subtypes: PTCL-NOS (n=32), ALK-negative anaplastic large cell lymphomas (n=15, ALCL ALK-negative), angioimmunoblastic (n=16, AITL)] treated at different Italian Institutions. Sections were analyzed for Ki-67, GATA3, Tbet and CCR4 expression by IHC. Results were expressed as percentages of positive tumor cells. Histology was centrally reviewed. Median age was 58 years (range, 18-76 years); 20 of 63 (32%) pts were characterized by intermediate-high/high IPI; 47 of 63 (74%) pts were candidated to transplantation whereas 16 (25%) were not due to age ≥65 years (n=14) or limited stage/IPI 0 (n=2). Fifty-nine pts (93%) received anthracycline-based induction chemotherapy. Twenty of 47 (43%) pts underwent autoSCT in first (n=11) or subsequent remissions; 23 of 47 (49%) underwent alloSCT in first remission (n=3) or at relapse (n=20). The median follow-up of alive pts was 30 months (range, 8-250). Results: Expression of GATA3 was highly variable, but was significantly higher on average in PTCL-NOS [34% positive tumor cells (range, 1-99%)] than in other subtypes [11% (range,1-97%) in ALK-negative ALCL (p=0.027); 12% (range, 1-82) in AITL (p=0.0025)]; The mean value of Ki67 expression was higher in ALK-negative ALCL [87% (range, 70-95%)] as compared to other subtypes [46% (range,15-90%) in PTCL-NOS (p In PTCL-NOS (n=32), ROC curve analysis identified a cut-off of 27% for GATA3 with 16 pts showing a GATA3 expression higher than the cut-off value. While no significant difference in baseline clinical characteristics was observed among the two groups, pts with GATA3 ≥27% showed a significantly lower CR rate following induction [19% versus 62% (p=0.02)]. Cases with high GATA3 expression were significantly associated with a reduced 5-year PFS and OS as compared to those with low expression [PFS: 6% (95%CI:1%-24%) versus 49% (95%CI:22%-71%), (p=0,004); OS: 39% (95%CI:13%-65%) versus 72% (95%CI:35%-90%) (p=0,04) respectively]. In multivariate analysis including age, IPI score ≥2 and sex, high GATA3 expression retained a strong prognostic value in terms of PFS (p Conclusions: Our analysis identifies GATA3 ICH expression as a strong prognostic and predictive biomarker among PTCL-NOS. Pts with high GATA3 expression values were characterized by chemorefractory disease and poorer outcome even with transplantation strategies. Validation of this biomarker in a larger series of patients is ongoing. Disclosures No relevant conflicts of interest to declare.

Several drugs used for diffuse large B-cell lymphoma (DLBCL) treatment rely on DNA damage for tumor cell killing. We verified the prognostic impact of the host DNA repair genotype in 2 independent cohorts of DLBCL treated with R-CHOP21 (training cohort, 163 cases; validation cohort, 145 cases). Among 35 single nucleotide polymorphisms analyzed in the training series, MLH1 rs1799977 was the sole predicting overall survival. DLBCL carrying the MLH1 AG/GG genotype displayed an increased death risk (hazard ratio [HR] = 3.23; P < .001; q =0 .009) compared with patients carrying the AA genotype. Multivariate analysis adjusted for International Prognostic Index identified MLH1 AG/GG as an independent OS predictor (P < .001). The poor prognosis of MLH1 AG/GG was the result of an increased risk of failing both R-CHOP21 (HR = 2.02; P = .007) and platinum-based second-line (HR = 2.26; P = .044) treatment. Survival analysis in the validation series confirmed all outcomes predicted by MLH1 rs1799977. The effect on OS of MLH1, a component of the DNA mismatch repair system, is consistent with its role in regulating the genotoxic effects of doxorubicin and platinum compounds, which are a mainstay of DLBCL first- and second-line treatment.

P>To characterize diffuse large B-cell lymphoma (DLBCL) with chromosome 7 gains, we combined clinical data with genomic, RNA and miRNA profiling. Gains were associated with age > 60 years, female gender, a trend for higher complete response rate, lower death rate, and better overall survival in patients treated with R-CHOP. Lesions were inversely associated with bone marrow involvement and number of extra-nodal sites. Differentially expressed transcripts were enriched of genes belonging to specific pathways and miRNAs targets. MIR96, MIR182, MIR589, MIR25 were shown significantly up-regulated in 7q+ DLBCL by real-time PCR.

Purpose Primary testicular lymphoma (PTL) has poor prognosis with failures in contralateral testis, CNS, and extranodal sites. To prevent these events, we designed an international phase II trial (International Extranodal Lymphoma Study Group 10 [IELSG-10]) that addressed feasibility and activity of conventional chemoimmunotherapy associated with CNS prophylaxis and contralateral testis irradiation. The trial was conducted by the IELSG and the Italian Lymphoma Foundation. Patients and Methods Fifty-three patients (age 22 to 79 years) with untreated stage I or II PTL were treated with six to eight courses of rituximab added to cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) every 21 days (R-CHOP21); four doses of intrathecal methotrexate (IT-MTX) and radiotherapy (RT) to the contralateral testis (30 Gy) for all patients and to regional lymph nodes (30 to 36 Gy) for stage II disease. Results All patients received R-CHOP21, 50 received CNS prophylaxis, and 47 received testicular RT. With a median follow-up of 65 months, 5-year progression-free survival and overall survival rates were 74% (95% CI, 59% to 84%) and 85% (95% CI, 71% to 92%), respectively. Ten patients relapsed or progressed: two in lymph nodes, five in extranodal organs, and three in the CNS. The 5-year cumulative incidence of CNS relapse was 6% (95% CI, 0% to 12%). No contralateral testis relapses occurred. Ten patients died: lymphoma (n = 6), secondary leukemia (n = 2), heart failure (n = 1), and gastric cancer (n = 1). Grade 3 to 4 toxicities were neutropenia, 28%; infections, 4%; and neurologic, 13%. No deaths occurred as a result of toxicity. Conclusion This international prospective trial shows that combined treatment with R-CHOP21, IT-MTX, and testicular RT was associated with a good outcome in patients with PTL. RT avoided contralateral testis relapses, but CNS prophylaxis deserves further investigation.

Bone marrow ( BM) involvement in diffuse large B-cell lymphoma (DLBCL) can be morphologically discordant from the primary tumor. Concordant BM infiltration has been shown associated with a poorer outcome in patients treated with CHOP. In order to evaluate tumor-related factors leading to BM involvement in DLBCL, we performed an integrated analysis of i) genomic profiles obtained with a high-density genome wide SNP-based arrays ii) immunomorphological and iii) clinical data from 133 patients uniformly treated with R-CHOP. BM infiltration was found in 27 of 133 ( 20%) cases; and it was concordant in 18/27 (67%) cases. Concordant infiltration, but not discordant, influenced negatively OS, PFS and DFS and was associated with higher serum LDH, lower CR and higher PD rates. No association with cell of origin was found between BM+ and BM-DLBCL. As compared with BM- cases, BM+ DLBCL showed absence of 7q gain. Copyright (C) 2010 John Wiley & Sons, Ltd.

Abstract 2871 Introduction. The addition of Rituximab to standard CHOP chemotherapy has improved outcome of DLBCL; however, 30–40% of patients do not response or relapse after induction treatment. The use of Lenalidomide, as single-agent in relapsed or refractory aggressive NHL has been encouraging, with an overall response rate (ORR) of 19% for DLBCL. Preclinical evidence suggests that Lenalidomide may be synergistic with Rituximab. However the safety and efficacy of Lenalidomide combined with R-CHOP is not yet fully evaluated. Aims. On these basis, the IIL is running a prospective multicenter dose finding phase I-II pilot trial to evaluate efficacy and safety of Lenalidomide treatment plus R-CHOP21 (LR-CHOP21) for elderly patients with untreated DLBCL (registered at http://www.clinicaltrials.gov, NCT00907348). The primary endpoint for the phase I part of the study was: definition of Dose Limiting Toxicity (DLT) considered as the maximum dose inducing any grade ≥3 non-hematologic toxicity, or a >15 days delay of planned cycle date. The primary endpoint for the phase II part of the study was: complete response (CR) and ORR. Herein we report the results of phase I. Patients and Methods. Inclusion Criteria were: age 60–80; histologically proven CD20+ DLBCL; no prior chemotherapy and no prior malignancies in the last 3 years; Ann Arbor stage II, III, IV; International Prognostic Index (IPI) at low-intermediate, intermediate-high or high risk score. Treatment consisted of 6 courses of R-CHOP21 in association with Lenalidomide for days 1–14 at the established dose level (5, 10, 15, 20 mg), with Peg-Filgrastim support and prophylactic sc. low-molecular weight heparin. Phase I of the study was planned to define the Maximum Tolerated Dose (MTD) that is the dose that achieves a DLT in 33% or less patients evaluated after the first three courses of LR-CHOP21. The study was designed with the Continual Reassessment Method, a Bayesian “memory design” that begins with a subjective prediction of the dose-response relationship and uses, as dose allocation rule of the sequentially incoming patients, the re-estimated probability of toxicity based on the results obtained for the patients already observed. Four doses of Lenalidomide were tested: 5, 10, 15 and 20 mg. By decision of the steering committee of the study, a dose of 10 mg was administered to the first cohort of 3 patients; in the light of the observed toxicity the probability model assigned the next cohort to the dose with the higher probability to met the required MTD. At the end of each cohort, the dose level associated with an updated DLT probability closest to 33% was recommended to be administered to the next patient cohort. Results. In phase I, from May 2008 to February 2010, 21 patients were enrolled. Median age was 69 years (61-78), stage II/III/IV were 4/4/13 respectively, B symptoms in 11, PS 2 in 8, bone marrow involvement in 6, abnormal LDH in 8, intermediate-high or high IPI score in 15. Patient allocation by Lenalidomide dose was: none patients received 5 mg/day, nine patients received 10 mg/day, nine patients 15 mg/day and three patients 20 mg/day on days 1–14 of each LR-CHOP21 courses. The flow of the dose allocation and the observed DLTs are shown in figure 1. DLTs in the first three courses were recorded in seven patients (see figure 1 for details). These data, according to the continual reassessment method, determined Lenalidomide 15 mg as MTD in association to R-CHOP21. One-hundred-fifteen courses of LR-CHOP21 were performed in the whole series of 21 patients. Overall hematological toxicity was moderate: grade III or IV thrombocytopenia occurred in 10%, anemia in 4% and neutropenia in 28% of the courses. Extra-hematological toxicities were mild: only one patient with grade IV (increase of CPK), two patients with grade III cardiac, three with grade III neurological toxicities, and three patients with grade III infections (two pneumonias and one febrile neutropenia with diarrhea). At the end of six LR-CHOP21 courses, 15/21 patients achieved CR, 1/21 partial remission and 5/21 were not responsive. Conclusions. Lenalidomide 15 mg on days 1–14 in association with R-CHOP21 is the MTD for LR-CHOP. This schedule is safe and well tolerated in a population of elderly DLBCL patients. Preliminary efficacy results are promising. The ongoing phase II part of the LR-CHOP21 trial aims at evaluating the efficacy of 15 mg of Lenalidomide in association with R-CHOP21. Disclosure: Vitolo: Roche Italy: advisory committee; Celgene Italy: advisory committee; Janssen-Cilag: lecture-fee. Off Label Use: The use of Lenalidomide is off-label in untreated DLBCL.

Abstract 992 Several drugs utilized in diffuse large B cell lymphoma (DLBCL) rely on DNA damage for tumor killing. This study aimed at verifying whether single nucleotide polymorphisms (SNPs) of genes involved in DNA repair may contribute to prognostication of DLBCL treated with R-CHOP. The study utilized a training-validation design. The training cohort (n=163) was a mono-institutional, prospectively collected, consecutive series of DLBCL homogeneously treated with the same chemotherapeutic regimen both at diagnosis (R-CHOP21) and at relapse/progression (R-DHAP ± BEAM conditioned autologous stem cell transplant, ASCT). The validation cohort (n=156) was a multi-institutional retrospective series of DLBCL treated with R-CHOP at diagnosis. Candidate SNPs (n=35) were selected by an educated guess approach, and included SNPs belonging to genes involved in: i) mismatch repair (MLH1); ii) base excision repair (XRCC1, OGG1); iii) nucleotide excision repair (ERCC1, ERCC2, ERCC4, ERCC5, ERCC6, XPA, XPC); iv) double strand break repair (BRCA1, BRCA2, LIG4, XRCC2, XRCC3, XRCC4, XRCC6); and v) direct reversal (MGMT). Clinical endpoints were progression free survival (PFS) after R-CHOP, overall survival (OS) from diagnosis, and OS from salvage treatment. Univariate analysis controlled for multiple comparisons identified MLH1 rs1799977 as the sole SNP predicting DLBCL OS in the training series (AG/GG genotype: HR: 3.23; 4-year OS: 55.5% vs AA genotype: 4-year OS: 80.9%; p Disclosures: No relevant conflicts of interest to declare.

Background To evaluate the activity and safety of nonpegylated liposomal doxorubicin (Myocet™) when substituted for doxorubicin in the R-CHOP regimen (R-COMP). Patients and methods Seventy-five elderly patients with diffuse large B-cell lymphoma (DLBCL) were studied. Only patients with left ventricular ejection fraction (LVEF) ≥50% were allowed. R-COMP regimen was administered every 3 weeks for three cycles, followed by additional five cycles in case of complete response (CR) or partial response. Results From November 2002 to April 2005, 75 patients were registered, of which 72 were evaluated. Median age was 72 years (range 61–83); 56% of patients had high or high–intermediate International Prognostic Index score. Median LVEF at baseline was 61%. Thirty-eight patients had history of abnormal cardiovascular conditions. The overall response rate was 71%, with a CR rate of 57%. After a median follow-up of 33 months, the 3-year overall survival, failure-free survival, and progression-free survival rates were 72%, 39%, and 69%, respectively. Neutropenia (54%) was the most frequent grade 3–4 adverse event (AE); 21% of patients experienced cardiac AEs, graded as 3–4 in 4% of the cases. Conclusion R-COMP is an effective regimen for the treatment of DLBCL in elderly patients, with an acceptable tolerability profile.

Knowledge on the impact of pharmacogenetics in predicting outcome and toxicity in diffuse large B-cell lymphoma (DLBCL) is scant. We tested 106 consecutive DLBCL treated with R-CHOP21 for 19 single nucleotide polymorphisms (SNPs) from 15 genes potentially relevant to rituximab-CHOP (R-CHOP) pharmacogenetics. Associations of SNPs with event-free survival (EFS) and toxicity were controlled for multiple testing. Genotypic variants of nicotinamide adenine dinucleotide phosphate (NAD(P)H) oxidase p22phox (CYBA rs4673) and alpha1 class glutathione S-transferase (GSTA1 rs3957357) were independent predictors of EFS (CYBA rs4673 TT genotype: HR 2.06, P=0.038; GSTA1 rs3957357 CT/TT genotypes: HR 0.38, P=0.003), after adjusting for International Prognostic Index (IPI). CYBA rs4673 and GSTA1 rs3957357 also predicted outcome in DLBCL subgroups by IPI. Impact of SNPs on toxicity was evaluated in 658 R-CHOP21 courses utilizing generalized estimating equations. NCF4 rs1883112 was an independent predictor against hematologic (odds ratios (OR): 0.45; P=0.018), infectious (OR: 0.46; P=0.003) and cardiac toxicity (OR: 0.37; P=0.023). Overall, host SNPs affecting doxorubicin pharmacodynamics (CYBA rs4673) and alkylator detoxification (GSTA1 rs3957357) may predict outcome in R-CHOP21-treated DLBCL. Also, NCF4 rs1883112, a SNP of NAD(P)H oxidase p40phox, may have a function in protecting against hematologic and nonhematologic toxicity. These results highlight the need to improve characterization of the host genetic background for a better prognostication of DLBCL.

This study was designed to determine the usefulness of procalcitonin (PCT) as a predictive marker of infections in neutropenic patients following chemotherapeutic treatments. Over a 6-month period, 65 patients (34 affected by a solid tumor, 31 by a hematological disorder) were enrolled. Serum PCT concentrations were measured by an automated immunoassay on the leucocytes nadir and on the third day, when patients were checked for any sign of infection. Procalcitonin values were not affected by gender, age, therapeutic approach, use of G-CSF or performance status and did not differ between patients who subsequently developed a localized infection and those who did not. PCT concentrations resulted higher in patients affected by hematological disorders than in those affected by solid tumors (mean value 0.09 vs. 0.05 μg/L; p

Abstract 1706 Poster Board I-732 Introduction in order to maintain efficacy and reduce toxicity of the treatment in elderly follicular lymphoma (FL) patients, we designed a study with a short chemo-immunotherapy R-FND with Rituximab consolidation followed by randomization between R maintenance or observation. Material and methods: From January 2004 to December 2007, 242 patients (age 60-75) with untreated advanced stage FL were enrolled by 33 IIL centres. Treatment plan was: 4 courses of R-FND (standard doses of Rituximab, Fludarabine, Mitoxantrone, Dexamethasone) every 28 days followed by 4 weekly Rituximab infusions as consolidation; responding (CR+CRu+PR) patients were randomized between Rituximab maintenance, one dose every 2 months for a total of 4 doses or observation. Qualitative and quantitative PCR monitoring for IgH/Bcl-2 rearrangement on bone marrow (BM) was performed at diagnosis, after R-FND and R consolidation and during maintenance/observation. Results 234 patients were eligible for the study: median age was 66 yrs; advanced stage II 14%, stage III 21% and stage IV 65%; BM involvement and B symptoms were documented in 55% and 18% respectively. FLIPI score was: Low 11%, Intermediate 34%, High 55%. One and 2 or more comorbidities were present in 36% and 23% of the patients respectively. Qualitative PCR analysis for IgH/Bcl-2 was performed in 223 patients at diagnosis and 51% were positive. Two hundred and two (86%) patients completed the induction treatment and were randomized between maintenance or observation; 32 were not because of: stable/progressive disease (16), adverse events (10) or other causes (6). Overall response at the end of treatment was 86% with 69% CR and 18% PR; PCR negativity at the end of treatment was 75%. Rituximab consolidation was able to induce CR in 37/90 (41%) partial responders and to increase PCR negativity from 61% to 75%. With a median follow-up of 22 months, two-years OS and PFS were 92% (95% CI 87%-95%) and 75% (95% CI 68%-81%), respectively (see Figure). Two-years PFS rates according to FLIPI score were 85% for low/intermediate risk and 65% for high risk (p < 0.001); 2-years PFS rates were 57% and 79% respectively in patients with and without B symptoms (p < 0.001). The patients in more advanced decade (> 70 years) or those with 2 or more comorbidities did as well as younger ones or those with one or no comorbidities: 2-yr PFS rates for patients more or less seventy were 73% vs 76% (p = 0.39); for patients with ≥2 comorbidities or one or none were 84% vs 67% vs 76%, respectively (p = 0.82). A total of 1119 courses were delivered; the most frequent CTC grade 3-4 toxicity was neutropenia in 25% of the courses, with only 13 serious infections. One patients developed acute myelogenous leukaemia during treatment and died. Two toxic deaths during treatment (0.8%) occurred: 1 HBV reactivation and 1 Steven Johnson syndrome. So far 212 patients are alive; besides the above mentioned deaths, 15 patients died of lymphoma, 2 died of cardiac failure, 1 died of stroke and 1 died of drowning. So far too few events occurred to proper analyse the efficacy of the Rituximab maintenance. In the maintenance/observation phase the following severe (WHO grade 3-4) toxicities were recorded: 15 patients experienced neutropenia, seven cardiac events, four infections; no other relevant toxicities were recorded. The cumulative incidences of toxic events accounting for competing events at 18 months for maintenance arm (Arm A) versus observation arm (Arm B) were as follows: neutropenia 17% vs 1% (p Conclusions a short term chemo-immunotherapy R-FND + Rituximab consolidation is safe and effective with a good 2-yr PFS rate also in patients with high risk FLIPI score or in patients in more advanced decade or with comorbidities. Rituximab maintenance is safe with a more frequent neutropenia that was not associated with an increased risk of infections. Final results of the study will provide insights on the role of Rituximab maintenance after R-chemotherapy. Disclosures Vitolo: Roche: Lecture fees; Mundipharma: Lecture fees. Off Label Use: Study was supported by Roche: Rituximab maintenance in first line treatment is off-label. Boccomini:Roche: Lecture fees. Ladetto:Roche Italy: Research Funding; Amgen: Honoraria, Research Funding.

Abstract 3758 Poster Board III-694 Introduction The combination of Bortezomib (B) and Rituximab (R) has been shown in vitro synergistic apoptosis and enhanced NFkB depletion in Mantle Cell Lymphoma (MCL) and Marginal Zone Lymphoma (MZL) cells. Rituximab in combination with Bortezomib is well tolerated without overlapping toxicities. Our study was aimed to evaluate safety and efficacy of the association of Rituximab and Bortezomib in relapsed/refractory indolent non follicular and mantle cell lymphoma patients not eligible to high dose chemotherapy and ASCT. The study was designed according to Simon's two stage Optimal Design and the primary endpoint was the achievement of an Overall Response Rate (ORR) > 40%. Patients and methods From September 2006 to March 2008, 54 patients were enrolled into the study. Histology was centrally reviewed in all cases: 49 diagnosis fulfilled the inclusion criteria and were evaluable for the analysis. Clinical characteristics were as follows: 28 males and 21 females; median age 68 years (range 50-74); 16 lymphocytic/lymphoplasmacytic (LL), 8 MZL and 25 MCL; seven stage I-II disease, nine III and 33 IV; 33 were BM positive; according to IPI 36 patients were at low-intermediate risk and 18 at intermediate-high/high risk; 11 patients had 1 and 38 > 2 prior lines of chemotherapy; 15 were R-naïve patients and 34 R-pretreated, 21 patients had refractory disease ( 1 yr). The treatment plan was: one course of 4 weekly doses of Rituximab (375 mg/sqm) and Bortezomib (1.6 mg/sqm IV bolus) followed by 2 courses of 4 weekly IV bolus of B (1.6 mg/sqm) as single agent. Responding (CR+ PR) and stable disease patients were planned to be given three further courses with the same schedule. Results ORR was 26/49 (53%). Responses were as follows: 13 CR (26.5%) and 13 PR (26.5%). ORR by histology was: 6/16 (37.5%) in LL, 4/8 (50%) in MZL and 16/25 (64%) in MCL respectively. Pretreatment with Rituximab did not adversely affect the ORR: 21/34 (62%) in R-pretreated patients and 5/15 (33%) in R-naïve patients (p .06). ORR was higher in relapsed patients compared with refractory ones: 18/28 (64%) and 8/21 (38%) (p .06). With a median follow-up of one year, Overall Survival (OS) was 93% (95%CI: 79.7-97.9) and 1-year Progression free survival (PFS) was 45% (95%CI: 30-59) (Figure 1). A total of 233 courses were delivered with a median of 4.7 courses per patient. Twenty-eight patients completed the treatment plan and 21 were withdrawn from the study because of: 17 PD during treatment and 4 AE (1 concomitant gastric neoplasia, 1 neurotoxicity grade II, 1 pleural effusion and 1 toxic death due to interstitial pneumonia). Grade 3-4 CTC haematological toxicity was rare with neutropenia in 5% of the courses and thrombocytopenia in III in 5. Conclusions This study suggests that the combination of Rituximab and Bortezomib is feasible and effective in relapsed/refractory indolent non follicular lymphoma and MCL. This treatment combination is a good therapeutic option without chemotherapy mainly in MCL and MZL also in Rituximab pretreated patients. Our data suggest a promising PFS in this subset of heavily pretreated patients. The combination of Rituximab plus Bortezomib should be explored in further and larger studies. Disclosures: Vitolo: Roche: lecture fees. Off Label Use: Bortezomib was provided free by Jansen-Cilag who gave a research grant to support the study.

Abstract 3957 Poster Board III-893 BACKGROUND Despite recent therapeutic improvements, the clinical course of DLBCL still differs considerably among patients. Here, we present the final results of a study to identify distinct DLBCL subgroups in patients treated with R-CHOP. METHODS DNA from 166 frozen DLBCL samples (PMBL,HIV-related DLBCL, post-transplant DLBCL and Richter's Syndromes were excluded) was analyzed with Affymetrix Human Mapping 250K arrays. Affymetrix U133 PLUS 2.0 gene expression profiles (GEP) were available for 54 cases. An optimized non-negative matrix factorization (NMF) was used for unsupervised clustering. The impact of the recurrent lesions on OS, PFS and DFS was evaluated with the log-rank test followed by multiple test correction (MTC). RESULTS 20 lesions showed a statistical significant impact on OS. Only 8p23.1 loss maintained its significance after MTC and was associated with additional aberrations, such as 17p- and 15q-. Unsupervised clustering identified 5 clusters with distinct genetic profiles, clinical characteristics and outcome: 1 (61/166, 37%), 2 (22/166, 13%), 3 (5/166, 4%), 4 (29/166, 17%), 5 (7/166, 6%). Cluster 1 was characterized by a heterogeneous genomic profile, lacking the most recurrent lesions. When compared to cluster 2 and 4, there were more HCV infections (9/38, 24% vs 1/12, 8% and 0/20; p=0.014) and bone marrow involvement (16/57, 28% vs 1/19, 5% and 2/24, 8%; p=0.008). GEP and morphology data suggested that cluster 1 could represent DLBCL with a high content of infiltrating T-cells, partially explaining the low rate of aberrations. This cluster has characteristics similar to the “host response” cluster previously identified by Monti et al., 2005. The outcome was poor with a high relapse rate (13/49, 26%) and a 5-yr OS of 76%. Cluster 2 (1q+/3q+/6q-/17p-) had also a relatively poor OS 80%. Cluster 4 (7+/12+) had a good outcome with a 5-yr OS of 92%. Clusters 2 and 4 showed differences in the number of pts with a high IPI-score (9/16, 56% vs. 7/26, 27%; p=0.057) and in single IPI factors, CR-rate (17/22, 77% vs. 25/29, 86%) and relapse rate (5/17, 29% vs. 2/25, 8%; p= 0.068). Cluster 3 (6q-/9-/11q+) had a trend for a good outcome. Instead, cluster 5 (3q+/11q+/18q+/6q-/8p-/15q-/17p-) showed a poor outcome. Clusters 2 and 4 were similar to ABC and GCB, respectively. CONCLUSIONS ArrayCGH provides the capability to identify genetic features and clusters, associated with a different outcome in patients treated with R-CHOP. The 8p23.1 locus should be investigated further for a gene that may be important in the pathogenesis of DLBCL. Disclosures: No relevant conflicts of interest to declare.

Introduction : MYC, BCL2 and BCL6 overexpression, assessed by IHC, with the latter conferring a better prognosis, have been reported to be a prognostic factor in DLBCL, but data are not consistent and sometimes contradictory. The aim of the present study was to assess the prognostic impact of overexpression of MYC, BCL2, and BCL6 in a retrospective cohort of de-novo DLBCL, selected for an high proliferation index (MIB1 ≥70%), treated consecutively with R-CHOP regimen. Methods: Patients with de-novo DLBCL diagnosed between January 2010 and December 2013 were included into the study. Inclusion criteria were: high proliferation index MIB1 ≥ 70% and a full course of R-CHOP regimen. Paraffin-embedded tumor samples were collected and investigated using immunohistochemistry (IHC) for MYC, BCL2 and BCL6. Fluorescence in situ hybridization (FISH) is ongoing. MYC/BCL2+ or MYC/BCL6+ double expression cases were identified if they had rearrangements of MYC and BCL2 or BCL6. MYC immunochemistry was done on TMA sections using the antibody clone Y69. BCL2 and BCL6 staining had been evaluated previously at diagnosis. Tumor cells were defined positive for MYC and BCL2 or BCL6 protein expression by immunostaining if >40%, >40% and >25% of cells showed positive expression, respectively. Progression free survival curves (PFS) were estimated using the Kaplan-Meier method and compared between groups using the log-rank test and Cox models. Results : One hundred and sixty seven patients are evaluable for clinical characteristics and 69/167 had paraffin embedded tumor samples available for immunohistochemistry at the time of present analysis. Clinical characteristics of the 69 cases were: median age 66 years (IQR 57;73), 45 (65%) male, 47 (68%) stage III-IV, 35 (54%) with elevated LDH levels and 46 (67%) at International Prognostic Index (IPI) high intermediate or high risk. Overexpression of MYC was detected in 28 cases (41%), 50 (72%) and 38 (55%) showed BCL2 and BCL6 overexpression respectively. Nineteen (28%) cases showed MYC/BCL2+ and 17 (25%) MYC/BCL6+ double expression. With a median follow up of 26 months, the median 2-years PFS was 59%. Overexpression of MYC and BCL2 proteins and low expression of BCL6 were associated with an inferior 2-years PFS in univariate analysis: MYC- vs MYC+ 64% vs 55%; BCL2- vs BCL2+ 71% vs 56%; BCL6+ vs BCL6- 61% vs 54%. In a Cox multivariate regression model adjusted for IPI and age, MYC overexpression, BCL2 positivity and BCL6 negativity showed prognostic relevance as significant independent indicators with different risk (Hazard ratio 2.53 for MYC+, 2.08 for BCL2+ and 1.62 for BCL6-). Established that the three variable contributed with different risk in the multivariate analysis, an IHC sum additive score of 0-5 was calculated proportionally to the coefficient estimated (coefficient [Log hazard ratio] 0.92 for MYC+, 0.73 for BCL2+ and 0.48 for BCL6-), assigning an individual risk of 2 points for MYC or BCL2 positivity and 1 point for BCL6 negativity. Two years-PFS was significantly different between all separate groups (Hazard ratio for unit increase 1.57 95% CI 1.11-2.22, p=0.01). After pooling scores 0-1 (with or without BCL6), 2 (presence of MYC or BCL2 only), and 3-4-5 (MYC+/BCL6-, BCL2+/BCL6-, MYC+/BCL2+, MYC+/BCL2+/BCL6-) 2-yrs PFS rates were different across the three groups: 100% vs 64% vs 50% (log rank p= 0.04) (figure 1). Conclusion: Our data showed, with the limits of a small sample size, that MYC overexpression alone or with high expression of BCL2 and/or low expression of BCL6 correlates with a worse prognosis independently by IPI score in a cohort of DLBCL selected for high proliferation index and treated with R-CHOP. Assessment of MYC, BCL2 and BCL6 expression by IHC represents a rapid, inexpensive, and reproducible technique. These results need to be confirmed in our complete series of 167 patients (analysis ongoing) and validated prospectively in a larger cohort, using standardized staining and scoring methodologies. Thus, MYC and BCL2 represent relevant biomarkers that should be tested in future clinical trials using novel effective and targeted agents in order to improve the prognosis of DLBCL. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Backgrounds: Treatment of patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) not eligible to high dose therapy represents an unmet medical need. Histone deacetylases (DACs) regulate chromatin structure and function and are involved in crucial mechanisms of lymphoma cell growth. Panobinostat showed encouraging therapeutic activity in Hodgkin lymphoma, cutaneous T-cell lymphoma and other non-Hodgkin lymphomas, in studies conducted in lymphoma cell lines and in vivo in patients with advanced hematologic malignancies. Moreover, recent studies showed a potent activity of Panobinostat in DLBCL. Purpose: On this basis we performed a prospective, multicenter, phase II single arm study, to evaluate safety and efficacy of single agent Panobinostat as salvage therapy for R/R DLBCL adult patients and to evaluate a possible relationships between response and any biological features. Patients and Methods: Adult patients with R/R DLBCL who already performed high-dose chemotherapy followed by autologous stem cell transplantation (ASCT) or were not eligible for ASCT were included. The treatment plan included 6 induction courses with Panobinostat monotherapy followed by other 6 courses of consolidation; patients achieving complete response (CR), partial response (PR) or stable disease (SD), underwent maintenance for a maximum of 36 courses. In each 28-days course, Panobinostat was administered orally at the dosage of 40 mg/day three-times every week; dose adjustments for patients unable to tolerate the protocol-specified schedule were provided. The primary objective was to evaluate Panobinostat activity in terms of overall response (OR) according to the Cheson 1999 criteria; secondary objectives were: CR rate, time to response (TTR), progression-free survival (PFS), safety and feasibility of Panobinostat. We included evaluation of the impact of pharmacogenetics, immunohistochemical patterns and patient's specific gene expression and mutations as potential predictors of response to Panobinostat as explorative objectives. To this aim a pre-enrollment new tissue biopsy was mandatory. Results Thirty-five patients, 21 males (60%), were enrolled between June 2011 and March 2014. Clinical characteristics were: median age 73 (range 65-75), stage IV in 18 (55%), B-symptoms in 9 (28%), increased LDH in 24 (69%), high-intermediate or high International Prognostic Index (IPI) in 18 (51%). Patients received a median of 2 prior lines of therapy (range 1-4). At the end of induction phase, 7 responses (20%) were observed, including 4 CR (11%), while 28 patients (80%) discontinued treatment due to progressive disease (PD) in 21 (60%) or adverse events in 7 (20%). Median TTR in 9 responders was 2.6 months (range 1.8-12). With a median follow up of 6 months (range 1-34), the estimated 12 months PFS and OS were 27% and 30.5%, respectively. In univariate analysis, favourable IPI score and cutaneous involvement at enrollment showed a trend toward a higher ORR (p=0.007 and 0.061, respectively); pharmacogenetics, immunohistochemical and gene expression profile studies are still ongoing. No toxic deaths were reportewd; 18 patients died, 17 due to lymphoma progression and one for allogeneic transplant related complications, performed after PD. Grade 3-4 thrombocytopenia and neutropenia were the most common toxicities (in 29 (83%) and 12 (34%) patients, respectively), while grade 3-4 extra-hematological toxicity included diarrhoea in 4 (12%), infectious complications in 1 (3%) and supraventricular arrhythmia in 2 patients (6%). Conclusions The results of this study indicate that Panobinostat might be remarkably active in some patients with R/R DLBCL, showing durable CR. Feasibility was impaired by relevant hematological toxicity, mainly frequent and dose limiting grade 3-4 thrombocytopenia. Data that will be obtained from biological exploratory studies could hopefully be useful to better address the use of Panobinostat in peculiar subsets of patients. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures Off Label Use: Panobinostat in DLBCL.

Background: Diffuse large B-cell lymphoma (DLBCL) relapsed or refractory after chemoimmunotherapy have dismal prognosis; the standard salvage treatment is Rituximab plus high dose chemotherapy with autologous stem cell transplantation (R-HDC). However, no standardized treatment is available for patients not eligible for R-HDC because of age and/or comorbidity. The combination Rituximab plus Bendamustine (R-B) has shown to be non-inferior and with a favorable toxicity profile compared to R-CHOP in indolent B-cell lymphoma. The use of R-B in DLBCL is a matter of debate. Purpose: We designed an Italian multicenter retrospective study aimed to evaluate safety and efficacy of R-B as salvage treatment in patients with DLBCL relapsed or refractory after at least one complete course of Rituximab-chemotherapy, who were not eligible for R-HDC because of age and/or comorbidity or in patients with post-HDC recurrence. Patients and Methods: We retrospectively reported 43 unselected consecutive patients with relapsed or refractory DLCBL treated with R-B in 15 Italian haematological centers between October 2008 and January 2014. Schedule of R-B were: 6 courses of Bendamustine at 90 mg/mq or 70 mg/mq on days 1 and 2 of each 28-day cycle and Rituximab 375 mg/mq on day 1 of each cycle. They were analyzed for baseline characteristics (age, IPI, ECOG, comorbidity), outcome (ORR, PFS, OS) and toxicity (CTCAE). Results: The median age was 76 years (range 56-94). Eighty-three % of patients had advanced-stage disease (III-IV stage) and 67% had IPI score of ≥3. An extranodal involvement was present in 65% of cases (bone marrow, lung, stomach, skin, pleura, pericardium). More than half the patients (51%) presented with poor functional status with ECOG score of ≥2. Comorbidity assessment by CIRS-G revelead 30% of patients with ≥1 severely or very severely (level 3 or 4) affected organs and 27% of patients with moderate or severe (level ≥2) cardiopathy. The mean number of prior therapies was 1,7 (range 1-3). All patients were previously treated with Rituximab-chemotherapy and three patients had already received R-HDC. Twelve patients had a refractory disease and 31 experienced relapse after last treatment. Patients received a median of 5 cycles of planned 6 courses of R-B (range 2-6); 24 patients underwent Bendamustine at 90 mg/mq, 19 at 70 mg/mq. All patients received Rituximab 375 mg/mq. In 38% of patients treatment was stopped because of progression; in 4 patients (9%) progression occurred within the first 2 treatment cycles. The overall response rate was 47%, including 28% complete remission and 19% partial remission. One patient in partial remission after R-B achieved a complete remission after local radiotherapy. The median OS was 16 months (95% CI 10-20). The median PFS was 8 months (95% CI 6-11). The median follow up was 10 months (range 2-60). Nine patients are still alive and in complete remission at last follow up; 7 of these patients had a chemosensitive relapse before R-B (in 5 cases a first relapse) and only 2 had a refractory disease with progression after a previous lenalidomide treatment. Toxicity was moderate, mainly grade 1 and 2. Grade 3-4 adverse events were neutropenia in 14 patients (32%), thrombocytopenia in 5 patients (11%), anemia in one patient, infections in 3 patients (6%), skin rash in one patient, nausea in one patient, diarrhea in one patient. One patient died of septic shock after the third R-B cycle. One patient died of miocardial infarction related to underlying cardiac comorbidity. Conclusions: Bendamustine in combination with Rituximab showed promising efficacy results with a low toxicity profile in a poor prognosis population (advanced stage disease and extranodal involvement, high median age, poor functional status, comorbidities), not eligible for R-HDC. The optimal dosage and schedule of Bendamustine and/or combination with novel drugs should be further investigated, in order to improve the duration of response and reduce the rate of early progression. Disclosures Off Label Use: Bendamustine in diffuse large B-cell lymphoma. Marasca:Mundipharma: Honoraria.

Backgrounds Histone deacetylases (DACs) are involved in chromatin structure regulation and function. Treatment with DACs inhibitors leads to the activation or repression of genes regulating apoptosis, proliferation, differentiation, angiogenesis, immune responses. These agents resulted to be active for the treatment of T and B-cell lymphoma and other haematological malignancies. Previous in vitro studies underlined the possible pathophysiological role of DACs in diffuse large B-cell lymphoma (DLBCL). In FIL-PanAL10 we evaluate the therapeutic activity and safety of Panobinostat, a potent pan-DACs inhibitor, in patients with relapsed or refractory (R/R) DLBCL. Methods FIL-PanAL10 (NCT01523834) is a phase II, prospective multicenter trial of the Fondazione Italiana Linfomi (FIL). Enrolled patients are ≥ 18 years old with R/R DLBCL, following ≥ 1 line of chemo-immunotherapy (R-CHOP) including high dose therapy with autologous stem cell support (ASCT) in eligible patients. Patients with > 5 prior systemic lines of treatment, CNS involvement, HIV positivity, impaired cardiac function (according to the protocol) are excluded. Patients are scheduled to receive Panobinostat po 40 mg three-times every week as part of a 4-weeks treatment cycle up to disease progression, unacceptable toxicity, or patient’s refusal. The primary endpoint of the study is to explore the antitumor activity of Panobinostat in terms of overall response (ORR) according to the Cheson criteria 1999. Secondary objectives are the evaluation of complete response (CR), time to response (TTR), progression free survival (PFS), overall survival (OS) and safety. Exploratory objectives evaluate the predictive role of pharmacogenetics, immunohistochemical and specific gene expression in relation to the response to Panobinostat; for this aim a new lymph node or other pathologic tissue biopsy is requested before starting treatment. With the null (P0) and P1 hypothesis of overall response (ORR) corresponding to Results Between February 2011 and May 2013, 23 patients were enrolled on this study. Patients’ median age is 73 years (range 44-83 years); 7 (30%) patients received ≥ 3 previous lines of chemotherapy. Five patients responded to Panobinostat (ORR= 22%) including 3 CR (13%) and 2 (9%) partial response (PR): 1 patient had (4%) stable disease (SD). TTR was 2.5 months (range 2-3 months ). All 6 patients with ORR or SD are still in treatment with Panobinostat after 4, 5, 12, 12, 15, 24, months; 17 patients discontinued therapy because of progression (15) or side effects (2). After a median period of observation of 11 months from the beginning of treatment, 1-year PFS and OS are 22% and 28%, respectively. Most common observed grade 3-4 adverse events were hematological and included thrombocytopenia (88%) and neutropenia (34%); grade 3-4 diarrhoea was present in 3 (13%). The therapeutic schedule was modified from the three times week to three times every other week in 15 patients; a further dose reduction from 40 mg to 30 mg resulted to be necessary in 8 patients. The analysis of exploratory biologic objectives and of their relationship with outcome is still under investigation and will be ready for December 2013. Conclusions The preliminary results of this study indicates that Panobinostat is an active salvage therapy in nearly 20% of heavily pretreated R/R DLBCL patients; the relatively short TTR observed allows a prompt shift to other rescue treatments in non responders. The analysis of biologic biomarkers will hopefully better address Panobinostat therapy to a specific biologic subgroup. Disclosures: Zaja: Mundipharma: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Celgene: Consultancy; GSK: Consultancy, Honoraria; Amgen: Consultancy. Off Label Use: Panobinostat in DLBCL.

Introduction The role of bone marrow (BM) involvement as prognostic factor in untreated young patients with diffuse large B-cell lymphoma at poor prognosis is still a matter of debate. Recent data showed an adverse prognostic role of BM involvement in DLBCL including patients both at low and high IPI score (Sehn L et al, J Clin Oncol 2011). On this basis, FIL analyzed the impact of BM involvement in the prospective randomized phase III trial DLCL04 (Vitolo U et al, Blood, ASH annual Meeting 2012) that included only young patients at high-risk age-adjusted IPI (aa-IPI) score 2 or 3. Patients and Methods Inclusion criteria were: age 18-65; untreated DLBCL or follicular grade IIIb; aa-IPI score 2 or 3. Patients were stratified according to aa-IPI and randomized at diagnosis to receive: R-CHOP14 x 8 cycles; R-MegaCHOP14 (1200 mg/sqm Cyclophosphamide, 70 mg/sqm Doxorubicin, standard dose Vincristine and Prednisone) x 6; R-CHOP14 x 4 + R-HDC (Rituximab + High Dose Cytarabine + Mitoxantrone + Dexamethasone) followed by BEAM and ASCT; R-MegaCHOP14 x 4 + R-HDC + BEAM and ASCT. BM biopsy and aspirate were mandatory at diagnosis; at the end of treatment, BM assessment was mandatory only in case of positivity at baseline. BM involvement was defined as concordant if marrow was involved by large B-cell and discordant if involved by small B-cells. Flow cytometry, immunohistochemistry, and/or molecular studies were utilized to confirm a clonal B-cell population. Results From June 2005 to September 2010, 399 patients were randomized to receive: 199 R-HDC+ASCT and 200 R-dose-dense chemotherapy without ASCT. All patients were evaluable for analysis. BM involvement was reported in 84 patients (21%): 39 (20%) in the R-HDC+ASCT group and 45 (22%) in the R-dose-dense chemotherapy group. Pattern of involvement was: concordant in 63 patients, discordant in 14 and not specified in 7 patients. Patients with BM involvement (BM positive: 84) compared to those without BM involvement (BM negative: 315) were significantly older (median age 53 years vs 47 years, p1 43% vs 45%, bulky 25% vs 33%, extranodal sites > 1 26% vs 33%, LDH higher than normal value 93% vs 89%). With a median follow-up of 49 months, 3-year PFS for the whole series of 399 patients enrolled in the trial was: 67% (95% CI: 62-72). Three-year PFS was significantly worse in BM positive vs. BM negative: 46% (95% CI:35-56%) vs. 73% (95% CI:67-77%) p Conclusions Bone marrow involvement, namely concordant pattern, is a strong adverse predictor of outcome in young patients with untreated DLBCL at poor prognosis treated with R-chemotherapy regardless of intensification with HDC+ASCT. New treatment approaches are needed for these high-risk patients at poor prognosis. Disclosures: Vitolo: Roche: Speakers Bureau; Takeda: Speakers Bureau; Celgene: Speakers Bureau.

Introduction The standard treatment for elderly untreated diffuse large B-cell lymphoma (DLBCL) is RCHOP21, however up to 40% of patients experienced failures. Lenalidomide showed activity in heavily pretreated DLBCL and in vivo and in vitro data demonstrated a synergism with rituximab. In the phase I trial REAL07 (Chiappella et al, Haematol 2013), FIL demonstrated that the association of LRCHOP21 was feasible in elderly untreated DLBCL and identified 15 mg lenalidomide from day 1 to day 14 as the maximum tolerated dose in combination with RCHOP21. Patients and methods. The phase II trial REAL07 was designed based on Simon's two stage design to demonstrate an improvement of overall response rate (ORR) of 15% in LRCHOP21 compared to 70% of standard RCHOP21. Secondary endpoints were progression-free survival (PFS), overall survival (OS), event-free survival (EFS) and to correlate outcome with cell of origin (COO) profile. Response was evaluated according to 2007 Cheson criteria. Inclusion criteria were: age 60-80 FIT at the comprehensive geriatric assessment; untreated CD20+ DLBCL; Ann Arbor stage II/III/IV; international prognostic index (IPI) at low-intermediate/intermediate-high/high (LI/IH/H) risk. Treatment plan was: RCHOP21 plus 15 mg lenalidomide from day 1 to 14 for 6 courses. All cases were centrally reviewed by expert pathologist; COO profile analysis was conducted with immunohistochemistry according to Hans' algorithm and with gene expression profile (DASL assay). Results. From April 2010 to May 2011, 49 patients were enrolled. Clinical characteristics were: median age 69 years (range 61-80); stage III/IV 43 (88%), IPI IH/H 30 (61%). At the end of 6 LRCHOP21, ORR was 92%. Complete remissions (CR) were 42 (86%) and partial remission 3 (6%); 3 patients (6%) did not respond and one (2%) died for homicide. At a median follow-up of 28 months, 2-year OS was 92% (95% CI: 79-97), 2-year PFS was 80% (95% CI: 64-89) and 2-years EFS was 70% (95% CI: 55-81); 2-year PFS for IPI LI was 89% (95% CI: 62-97) and for IPI IH 76% (95% CI: 47-90) and for IPI H 72% (95% CI: 36-90). Hematological and extra-hematological toxicities were mild, with no grade IV extra-hematological events and no toxic deaths during treatment. Of the 294 planned courses of LRCHOP21, 277 (94%) were administered; median dose of lenalidomide delivered was 1185 mg (94% of the planned dose); at least 90% of the planned dose of each drug was administered in 91% of the RCHOP21 courses. Median interval time between RCHOP21 courses was 21 days (range 19-48). All 49 cases underwent central pathology review and diagnosis of DLBCL was confirmed. Regarding COO analysis, tissue block or stained slides were collected in 40/49 (82%), of which 32 were adequate for analysis. At the time of this abstract, COO analysis was reported according to immunohistochemistry data; DASL analysis is ongoing. Clinical characteristics between germinal center (GCB, 16 patients) and non-GCB (16 patients) were superimposable, excepted for a majority of H IPI risk in non-GCB group (p 0.067). ORR for GCB and non-GCB were 88% (CR 81%) and 88% (CR 88%), respectively. At a median follow-up of 28 months, 2-year PFS was 71% (95% CI: 40-88) in GCB-group and 2-years PFS was 81% (95% CI: 51-93) in non-GCB-group (Figure 1). Conclusions. In conclusion, LRCHOP21 is effective, also in poor risk patients, namely in non-GCB subgroup. These encouraging data warrant a future phase III randomized trial comparing LRCHOP21 vs. RCHOP21 in untreated non-GCB DLBCL. Disclosures: Off Label Use: lenalidomide in first line DLBCL is off lable. drug provided free by Celgene. Vitolo:Roche: Speakers Bureau; Celgene: Speakers Bureau; Takeda: Speakers Bureau.

Introduction The prognosis of young DLBCL patients at high risk treated with standard R-CHOP is still rather poor. With the aim to improve outcome of these patients the Italian (Vitolo U et al, Blood, ASH annual Meeting 2012) and German (Schmitz N et al, Lancet Oncology 2012:13,1250) cooperative study groups conducted two randomized phase III studies aimed to compare conventional chemotherapy with intensified chemotherapy with stem cell support both in combination with Rituximab (R). The standard reference arms were R-CHOP14 in the Italian and R-CHOEP14 in the German study. No randomized studies comparing R-CHOP14 and R-CHOEP14 exist. Therefore, FIL and DSHNHL did a joint analysis of the two randomized trials, with the aim to compare the two conventional arms R-CHOP14 and R-CHOEP14. Patients and Methods The primary endpoint of this joint analysis was to compare the progression free survival (PFS) of DLBCL patients treated with R-CHOP14 or R-CHOEP14 within the two prospective trials. Inclusion criteria were superimposable for the two studies as follows: age 18-60 years; untreated CD20+ DLBCL or follicular lymphoma grade IIIb; age-adjusted IPI (aa-IPI) score 2 or 3. FIL patients were treated with R-CHOP14 for 8 courses; DSHNHL patients were treated with R-CHOEP-14 for 8 courses. Involved-field radiotherapy (IF-RT) for patients with extranodal sites or with bulky disease was based on the investigator choice in the FIL trial and was mandatory in the DSHNHL study. Central nervous system prophylaxis was done in patients at risk for CNS recurrence. Response criteria used were the same in both studies (Cheson 1999). Results From June 2005 to September 2010 100 patients were enrolled in the FIL study and treated with R-CHOP14. From March 2003 to April 2009, 130 patients were enrolled in the DSHNHL study and treated with R-CHOEP14. All 230 patients were included in the present analysis. Clinical characteristics were: median age 49 (IQR 38; 55); stage III/IV 96%; LDH > normal 93%; ECOG PS >1 38%; aa-IPI score 2/3 74/26%; extranodal sites >1 41%, bulky disease 50% and bone marrow (BM) involvement 16%. All characteristics were well balanced between patients treated with R-CHOP14 or R-CHOEP14 with the exception of significantly more patients with elevated LDH and bulky disease in the R-CHOEP14 group (98% vs 87%; 59% vs 37%) and more patients with PS >1 in the R-CHOP14 group (45% vs 32%). IF-RT consolidation was less frequently used in the R-CHOP14 group (16% vs 74%). Median follow-up times were: 47 (R-CHOP14) and 42 (R-CHOEP14) months. Patients treated with R-CHOP14 had a 3-year PFS of 63% (95% CI:52-71%) compared to 74% of those treated with RCHOEP14 (95% CI:65-81%); p = .177 (Figure 1). In a Cox model for PFS including treatment arm, age, gender, aaIPI, extranodal sites, bulky disease and BM involvement the adjusted HR was 0.68 (95% CI: 0.42-1.2) in favor of RCHOEP14, but this difference was not significant (p = .128). The analysis of the role of consolidation IF-RT is ongoing. Conclusions This analysis comparing R-CHOP14 and R-CHOEP14 as standard arms in two prospective trials suggests that RCHOEP14+RT has high activity in young poor-risk DLBCL. To confirm these encouraging findings, a formal joint FIL/ DSHNHL randomized study comparing R-CHOEP+RT vs R-CHOP+RT +/- novel drugs is planned by the two cooperative groups. Disclosures: Vitolo: Roche: Speakers Bureau; Celgene: Speakers Bureau; Takeda: Speakers Bureau.

Introduction The role of interim-PET (i-PET), after two cycles of chemotherapy, in advanced stage Hodgkin's lymphoma is well defined; the same role in diffuse large B cell lymphoma (DLBCL) is still controversial. The Fondazione Italiana Linfomi planned a prospective randomized phase III trial, addressed to young poor prognosis DLBCL patients at the diagnosis, with a 2x2 factorial design aimed at investigating the possible benefit of intensification with R-HDC+ASCT after R-dose-dense chemotherapy delivered at two different level of dose (R-CHOP14/R-MegaCHOP14). During this study an ancillary study was designed to define the prognostic impact of i-PET on progression free survival (PFS) after two cycles of immunochemotherapy in all treatments arms. Patients and methods As described by Vitolo et al (oral communication, abs 688 ASH 2012), patients were stratified according to aa-IPI and randomized at diagnosis to receive: R-CHOP14 x 8 cycles; R-MegaCHOP14 (1200 mg/sqm Cyclophosphamide, 70 mg/sqm Doxorubicin, standard dose Vincristine and Prednisone) x 6; R-CHOP14 x 4 + R-HDC (Rituximab + High Dose Cytarabine + Mitoxantrone + Dexamethasone) followed by BEAM and ASCT; R-MegaCHOP14 x 4 + R-HDC + BEAM and ASCT. G-CSF support was mandatory. Seventeen centers agreed to participate in the study and enrolled patients. All evaluable patients had performed basal PET and i-PET. A visual dichotomous criteria, according to Deauville Criteria (First Consensus Conference, 2009), was used to define the i-PET result. The final response was identified according to 2007 Cheson response criteria. Results From June 2005 to September 2010, 399 patients were randomized in the overall DLCL04 study and 130 were enrolled for the ancillary PET study , 69 in the R-HDC+ASCT and 61 in R dose dense therapy respectively. The clinical characteristics, as in the overall DLCL04 study, were well balanced among the four arms of therapy excluding a selection bias in the group of patients studied with i-PET. The i-PET result was positive in 74 patients and negative in 56 patients, no differences were observed between negative and positive i-PET results according to clinical characteristics and group of treatment. In particular, in R-dose dense arm 27 were negative and 34 positive, in R-HDC+ASCT 29 were negative and 40 positive, according to immunochemotherapy scheme in R-CHOP14 29 were negative and 40 were positive, in MegaCHOP14 27 were negative and 34 were positive. With a median follow-up of 36 months, 3-year PFS and 3-year Overall Survival (OS) rates for the whole series were: 64% (95% CI:59-69) and 79% (95% CI:74-83) respectively. No differences in PFS was reported according to i-PET result. In particular 3-year PFS were 87%(95% CI:75-94) in i-PET negative patients and 76% (95% CI: 65-85) in i-PET positive patients respectively (p: 0.09 The 3-year PFS according to I- PET results in the different treatment arm were: in the R-HDT+ASCT group i-PET negative or i-PET positive patients had a 3-year PFS of 83% (95% CI:63-92) and 79% (95% CI:63-89) respectively; in the R-dose dense i-PET negative or i-PET positive patients had a 3-year PFS of 92% (95% CI:73-98) and 72% (95% CI:54-85) with a p value near the significance (0.07). According to OS, i-PET negative and i-PET positive patients had a 3-year OS of 89%(95% CI:76-95) and 83%(95% CI:72-90) respectively, p=0.219. Conclusions In our multicenter prospective study, addressed to young poor prognosis DLBCL patients at the diagnosis, i-PET, performed after two immunochemotherapy cycles and analyzed with a visual method, is not able to identify two different risk population. To confirm our data, we are planning in the near future a centralized revision of all evaluable PET. In conclusion, our feeling is that the i-PET after two cycles in poor prognosis DLBCL patients is too early to predict a chemorefractory disease and more parameters must be considered to define clinical response in these patients. Disclosures: No relevant conflicts of interest to declare.

Introduction Patients with relapsed or refractory aggressive non Hodgkin B-cell lymphomas (NHL) not eligible to high dose chemotherapy and transplantation had a dismal prognosis. Lenalidomide showed activity in this setting as single agent or in combination. On this basis, we conducted a single center retrospective study to investigate efficacy and safety of lenalidomide alone or in association with rituximab or steroids in patients with heavily pretreated aggressive B-cell NHL. Methods Primary end points of the study were response rate (RR), defined as complete response (CR), partial response (PR) and stable disease (SD), and duration of response (DOR); secondary end points were feasibility and safety. Inclusion criteria for the analysis were: patients with relapsed/refractory aggressive B-cell NHL, aged >18 years, treated with lenalidomide between August 2007 to June 2012. Treatment scheme were: standard dose of oral lenalidomide 25 mg/day for 21 days every 28 days as single agent; standard dose of lenalidomide with the same schedule in association to weekly dexamethasone (20 mg bolus); lenalidomide 20 mg/day for 21 days every 28 days in combination with rituximab (375 mg/sqm) every 28 days. Patients were treated until disease progression or unacceptable toxicities. Results A total of 53 patients were analyzed. Different histotypes of NHL were included in the study: 34 diffuse large B-cell lymphomas (DLBCL), 11 mantle cell, 5 follicular, 2 primitive mediastinal B-cell and one Burkitt lymphoma. At relapsed before lenalidomide treatment, the majority of the patients presented an advanced disease: 40 (75%) stage 3-4; intermediate high/high risk international prognostic index (IPI) 23 (43%). Bone marrow was involved in 20 (38%) patients and 20 (38%) cases presented a bulky disease. Prior treatment lines were as follows: 8 (15%) patients received lenalidomide at first relapse while 24 (45%) underwent more than 3 previous lines of therapy; 14 (26%) patients received high dose chemotherapy and autologous stems cell transplant, one (2%) patient was allogenic transplanted and 4 (8%) did both before lenalidomide. All patients analyzed received lenalidomide: 31 patients (58%) underwent lenalidomide as single agent, 11 (21%) received a combination scheme of lenalidomide plus rituximab and 11 cases (21%) were treated with lenalidomide plus steroids. Median time from diagnosis and the beginning of lenalidomide was 25,3 months (3,7- 145,9), while median time from last previous therapy and lenalidomide treatment was 3,2 months (0,4- 38). At the time of this analysis response assessment was done in 51 patients: Response rate was 35% (18 patients), with CR 8 (15%), PR 5 (10%), SD 5 (10%). All patients who obtained CR underwent more than 3 courses of therapy, while among 31 patients who did not respond to treatment, 21 failures occurred during the first three cycles. Concerning different schemes of therapy: in the arm treated with lenalidomide as single agent RR was 24%, among patients underwent lenalidomide plus rituximab was 55% and in the group receiving lenalidomide plus steroid 45%. Among 34 DLBCL patients, RR was 41% (n= 14: CR 5, PR 4, SD 5), while in 11 patients affected by mantle cell lymphoma RR was 27% (n= 3: CR2, PR 1). Median DOR for all 18 responding patients was 12 months (0,2-24). At a median follow-up of 20 months, 5 patients were in stable CR, 7 continued lenalidomide, 11 relapsed and 28 died. Patients received a total of 257 cycles of lenalidomide, of which 25 were earlier interrupted and 48 were reduced in dose or duration; 50% of patients had at least one interruption in the planned treatment, however globally 91% of the expected dose was given. One patient died due to heart failure during the treatment. Toxicity was globally mild: most common grade 3-4 adverse events were neutropenia (19%), anemia (17%) and thrombocytopenia (17%). Five patients had grade 3-4 infections and 3 patients had thromboembolic events (only one grade 3). Two cases of neuropathies, both grade ≤ 2 were observed. Conclusions Lenalidomide single agent or in association with rituximab or steroids is effective and safe in patients with relapsed or refractory aggressive B-cell NHL, showing a promising response rate also in patients with heavily pretreated disease and with a mild toxicity profile. Disclosures: Vitolo: Roche: Speakers Bureau; Celgene: Speakers Bureau; Takeda: Speakers Bureau.