Abstract: BACKGROUND: the combination of rituximab (RTX) and lenalidomide (LEN) has been shown to be synergistic in pre-clinical models and in patients (pts) with previously untreated and relapsed follicular lymphoma (FL). Furthermore, LEN demonstrated single agent efficacy in pts with mantle cell lymphoma (MCL) and diffuse large B cell lymphoma (DLBCL). We hypothesized that the combination of obinutuzumab (GA), a glycoengineered type II anti-CD20 antibody, with LEN (GALEN) might be even more efficient while retaining a similarly manageable safety profile. In 2012, we started a phase Ib/II study to assess the safety and efficacy of this combination (ClinicalTrials.gov: NCT01582776) in pts with relapsed/refractory lymphoma. Phase IB defined the recommended dose (RD) of LEN as being 20mg in combination with GA. Here, we report the results of the Phase II part assessing efficacy and safety of GALEN therapy during a 6 months induction followed, for responders, by a reduced LEN maintenance GALEN regimen (in a cohort of relapsed/refractory aggressive NHL (DLBCL or MCL) pts. METHODS: pts with a histologically confirmed DLBCL (de novo or transformed low-grade NHL) or MCL were eligible if they had a ECOG PS of ²2, a life expectancy 〉 3 months (mo) and had previously received ³1 prior therapy including at least one RTX-containing regimen. Induction treatment consisted of LEN 20 mg given orally once daily on days 1-21 of a 28-day cycle for the first cycle and on days 2-22 of a 28-day cycle from cycles 2 to 6. Intravenous infusions of GA were given at a flat dose of 1000mg on days 8, 15, and 22 of cycle 1 and at D1 of cycles 2 to 6 (total of 8 infusions). Responding pts then received 12 cycles of LEN at 10 mg daily on days 2-22 every 28 days for a total of 18 cycles and GA 1000mg every 8 weeks for 12 additional cycles until progression or unacceptable toxicity. All pts were required to take daily aspirin (100 mg) for deep vein thrombosis (DVT) prophylaxis during study period. Pts who were unable to tolerate aspirin and had a prior history of DVT or were at high risk for a DVT received low molecular weight heparin therapy or warfarin (coumadin) treatment. The primary study endpoint was overall response rate (ORR) by investigator assessment at the end of induction according to 1999 IWG criteria. Secondary endpoints included ORR and complete response (CR) according to IWG 2007, best ORR, duration of response, progression-free survival, overall survival (OS) and safety. RESULTS: ninety-one pts (DLBCL [n=77 including 18 transformed], MCL [n=13] , and other [n=1]) were enrolled between June 2014 and March 2015 at 22 LYSA centers in France and Belgium. At baseline, median age was 70 (range, 48-84) years with 64.7% men, ECOG PS of 1 (47.1%) or 2 (18.8%), 83.5% Ann Arbor stage III-IV and 66.3% with elevated LDH. Median number of prior systemic therapies was 2 (range, 1-9) including haematopoietic stem cell transplantation in 17pts (20%); 61% were refractory to a RTX-containing regimen and 53% refractory to last prior therapy. Three pts were withdrawn before receiving any treatment due to major protocol violation, concurrent illness or ulceration of the tumor in the stomach and 3 pts received one of both study drugs, leaving 85 pts assessable for efficacy. Cut-off date was March 25th 2016. With amedianfollow-up of 14.5 mo,39pts (45.8%) completed induction (32 DLBCL and 7 MCL) and 20 (23.5%) are still ongoing in maintenance (16 DLBCL, 4 MCL). At the time of the cut-off, 44pts (51.8%) had died mainly due to lymphoma (88.6%). Response at the end of induction, best ORR during induction and OS are summarized in the table. Table Analysis of other secondary endpoints and correlation with cell of origin is ongoing. The most common treatment emergent AEs during induction (all grades 〉 10%pts/ % grade 3/4) were neutropenia (51.1/31.8), infections (45.5/12.5), constipation (30.7/0.0), cough (21.6/1.1), diarrhea (17.0/3.4), nausea (17.0/0) anemia (15.9/10.2), thrombocytopenia (15.9/10.2), muscle spasms (13.6/0.0), fatigue (12.5/1.1) and dyspnea (11.4/4.5). Febrile neutropenia occurred in 4.5% pts. There was onlyone secondprimary malignancy (basal carcinoma). CONCLUSION: oral LEN plus GA infusion is effective in relapsed or refractory DLBCL and MCL pts with no unexpected toxicity. Longer follow-up and additional translational studies are needed to identify the subset of pts most benefiting of this regimen. Correlative studies will be presented at the meeting. Table Table. Disclosures Morschhauser: celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; servier: Consultancy, Honoraria; gilead: Consultancy, Honoraria; janssen: Honoraria. Cartron:Roche: Consultancy, Honoraria; Celgene: Honoraria; Gilead: Honoraria; Jansen: Honoraria. Salles:Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Gilead: Honoraria, Research Funding; Mundipharma: Honoraria; Novartis: Consultancy, Honoraria; Roche/Genentech: Consultancy, Honoraria, Research Funding. Maerevoet:ARGN-X: Membership on an entity's Board of Directors or advisory committees; roche: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Bonnet:ROCHE: Membership on an entity's Board of Directors or advisory committees; SERVIER: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; JANSSEN: Membership on an entity's Board of Directors or advisory committees.

Abstract: Abstract 57 Background The ACT trial (ACT-1, younger patients aged 18–60 yrs and ACT-2, elderly patients aged 〉 60 yrs) is the first international randomized phase III trial in newly diagnosed primary systemic peripheral T-cell lymphoma (PTCL). It tests, in both younger and elderly patients, the efficacy of the addition of alemtuzumab (ALZ) to 6 courses of bi-weekly CHOP followed, only in younger patients (ACT-1), by high-dose therapy with autologous stem cell rescue. A dose reduction amendment tapering the cumulative ALZ dose from 360 mg (30 mg on days 1 and 2 of CHOP courses 1–6) to 120 mg (30 mg on day 1 of CHOP courses 1–4), respectively, was introduced early on due to two cases of systemic fungal infection (Blood 2011,118;4110). To date, the trial has accrued a total of 186 patients (ACT-1 n=98; ACT-2 n=88). Aim Here, we present the results from the first interim efficacy and safety analysis of the ACT-1 trial based on the first 68 randomized patients. Results Of the 68 patients, 63 had a complete set of treatment data. The median follow-up was 15 months (range 0.5–42 months). Thirty-two patients belonged to the experimental arm (exp) and 31 to the standard arm (std). Of the 32 patients treated according to exp, 4 received the higher dose of ALZ and 28 the lower. Treatment arms were well balanced with regard to main prognostic features such as age (std: median 53 yrs, range 21–60 yrs; exp: median 50 yrs, range 22–64 yrs; p=0.705), IPI subgroups (std: low 10%, low-intermediate 51%, intermediate-high 29%, high 10%; exp: low 12%, low-intermediate 44%, intermediate-high 19%, high 25%; p=0.392), advanced clinical stage (std: stage III-IV 94%; exp: 97%; p=0.613), performance status ECOG 〉 1 (std: 23%; exp: 28%; p=0.613), elevated LDH (std: 68%; exp: 69%; p=0.932), presence of B-symptoms (std: 68%; exp: 75%; p=0.524), bulky disease (std: 13%; exp: 13%; p=1.0) and bone marrow involvement (std: 39%; exp: 31%; p=0.535). Histological subtypes were also similarly distributed among both treatment arms (std: PTCL-NOS 55%, AILT 23%, other 22%; exp: PTCL-NOS 56%, AILT 28%, other 16%). No cases of anaplastic large cell PTCL (regardless of ALK-protein status) were included. Neither of the treatment cohorts showed significant treatment delay. The median duration of chemotherapy (calculated for 5 bi-weekly cycles of an expected cumulative duration of 70 days) for non-ALZ vs. ALZ-treated patients was 73 vs. 81 days, respectively. No suspected unexpected serious adverse reactions (SUSARs) were reported. Grade 4 leucopenia was more frequent in ALZ-treated patients (std: 24%, exp: 69%; p=0,001), whereas grade 3–4 anemia and grade 3–4 thrombocytopenia were not significantly different between treatment arms (anemia, std: 19%, exp: 31%; p=0,278; thrombocytopenia, std: 20%, exp: 12%, p=0,682). Non-hematological toxicity unrelated to infectious complications was mild and had a similar frequency in both arms. The number of serious adverse events (SAEs) per patient was 0.86 for patients treated at post-amendment ALZ dose levels, representing a significant reduction compared to the pre-amendment value (3.25), and 0.46 for patients treated in the control arm (p=0.002). The frequency of bacterial and fungal infections (grade ≥3) was similar in both treatment arms. ALZ treated patients had more viral events (9/32; 28% vs. 3/31; 10%), mainly (6 out of 9) consisting of asymptomatic cytomegalovirus reactivations. The overall (non-arm specific) 1-year event-free survival (primary end-point), progression-free survival and overall survival were 55% (95% CI: 42%-67%), 54% (95% CI: 42%-67%) and 78% (95% CI: 67%-88%), respectively. Conclusion The safety profile of the current standard and experimental treatment schedules, as well as the interim outcome results, support a continuation of the trial. A final analysis will be performed in Q2 2015. Disclosures: Jantunen: Genzyme: Has participated in EU Leadership meeting organized by Genzyme as well as Medical Advisory Board meeting organized by Genzyme Other, Honoraria.

Abstract: [§ share last authorship] Background: In 2000-2010, the first large prospective trials in peripheral T-cell lymphoma (PTCL) showed outcomes burdened by high failure rates during induction. Concurrently, trials with the anti-CD52 monoclonal antibody alemtuzumab (ALZ) yielded promising responses in PTCL while demonstrating the feasibility of combining ALZ with CHOP. Hence, the Nordic Lymphoma Group initiated the randomized ACT-1 trial to test, in younger patients (pts) (18-65yrs), the addition of ALZ to CHOP + autologous stem cell transplant (ASCT). Primary endpoint was the 3 years event-free survival (EFS). Here, we present the final analysis of the ACT-1 trial (ClinicalTrials.gov: NCT00646854). Patients and Methods: Overall, 136 pts were randomized (43% of planned sample size due to slow accrual), five did not receive study treatment, and 131 were analyzed (ALZ-CHOP: 65; CHOP: 66). Due to lack of tumoral CD52 expression, anaplastic large cell lymphomas (ALCL) were not included in the ACT-1 trial. An amendment tapering ALZ dose from 360 mg (30 mg on days 1+2 of each CHOP course) to 120 mg (30 mg on day 1 of CHOP courses 1-4) was introduced early on due to systemic fungal infections in 2 pts. Of the 65 pts treated with ALZ-CHOP, 4 received the pre- and 61 (94%) the post-amendment dose. Monitoring for CMV- and EBV-DNA and antimicrobial prophylaxis were mandatory. Results: The median observation time for the Full Analysis Set was 66 months and the median age 51 yrs. The ALZ-CHOP and CHOP cohorts were well balanced with regard to classical prognostic factors and histological subtypes (PTCL-NOS 58% vs 54%, AILT 21% vs 25%, other 21% vs 21%). Feasibility: Neither CHOP nor ALZ-CHOP pts experienced substantial treatment delay. ALZ exposure did not affect stem cell harvest nor hematopoietic recovery. Grade 4 leucopenia was more frequent in ALZ-CHOP pts (73% vs 35%; p=0.001), whereas the occurrence of grade 3-4 anemia and thrombocytopenia did not differ significantly. After ALZ dose amendment, the frequency of bacterial and fungal infections of grade ≥3 was similar in both treatment arms. ALZ treated pts had more viral events (22/57=42% vs 4/23=17%), mainly due to asymptomatic CMV reactivations. The ratio of serious adverse events per ALZ-CHOP treated patient dropped markedly (from 3.25 to 0.86, comparable with 0.46 for CHOP) after dose amendment. Additional toxicity was mild and similar in both arms. Treatment related mortality was 4% (5% vs 3%). Efficacy: Complete remission (CR) was 52% in ALZ-CHOP vs 42% in CHOP. Primary refractory disease occurred for ALZ-CHOP and CHOP in 23% and 38% of pts, respectively. Overall, females had a significantly better outcome than males (p=0.004), also after adjustment for classical prognostic factors. Analyzing time-related endpoints without knowledge of CD52 expression, 3-years EFS, progression-free, and overall survival (PFS, OS) did not differ significantly between ALZ-CHOP and CHOP (EFS 35% vs 26%, PFS 37% vs 26%, OS 52% vs 50%). Fig.1A shows EFS by treatment arm, by gender, and by gender and treatment arm. Although not significantly different, EFS, PFS and OS values of ALZ-CHOP treated females in the ACT-1 trial were consistently higher than those of non-ALZ treated females or of males regardless of treatment group. RNA sequencing from evaluable pre-therapeutic tumor biopsies defined a signature of differentially expressed genes to be predictive of clinical outcome in ALZ-CHOP but not CHOP treated pts (n=33). Tumor microenvironment genes were prominent in determining response to ALZ. Tumors rich in B-cell milieu showed good responses, while the opposite was observed in tumors with signatures enriched with high endothelial cell genes (p 〈 0.001) (Fig.1B). The good risk signature was associated with a higher frequency of X-linked and the bad risk with a higher frequency of Y-linked transcripts (Fig.1B). Conclusion: In previously untreated younger non-anaplastic PTCL pts, the addition of ALZ to CHOP + ASCT was feasible. Overall, we did not find a significant outcome benefit. However, a gene expression signature predictive of ALZ response was identified and found predominantly in female patients. Carriers of this signature had an outcome benefit only if exposed to ALZ. A validation of this predictor of ALZ response is ongoing. Due to the limited sample size of the ACT-1 study cohort, both the negative and the positive findings of the trial should be interpreted with caution. Disclosures Leppä: Roche: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Research Funding; Bayer: Research Funding; Janssen: Consultancy, Research Funding; Celgene: Consultancy. Silva:Gilead Sciences: Research Funding; Abbvie, Gilead Sciences, Janssen, BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche, Janssen, Celgene: Other: Travel Support; Roche, Janssen: Other: Institution's payment for consultancy. Hagberg:Roche: Honoraria. Lugtenburg:takeda: Consultancy, Research Funding; servier: Consultancy, Research Funding; roche: Consultancy; BMS: Consultancy; Celgene: Consultancy; Sandoz: Consultancy; GenMab: Research Funding. Walewski:Roche, GSK/Novartis, Takeda, and Janssen-Cilag: Research Funding; Roche, Celgene, Takeda, Janssen-Cilag, and Servier: Honoraria; Roche, Celegene, Takeda, Janssen-Cilag, and Servier: Membership on an entity's Board of Directors or advisory committees. Hopfinger:Janssen: Honoraria; Gilead: Honoraria, Research Funding; GlaxoSmithKline: Honoraria; Celgene: Honoraria; Novartis: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Roche: Consultancy, Honoraria. Jantunen:Amgen: Honoraria; Genzyme/Sanofi: Honoraria; Takeda: Honoraria. Steidl:Seattle Genetics: Consultancy; Juno Therapeutics: Consultancy; Tioma: Research Funding; Bristol-Myers Squibb: Research Funding; Nanostring: Patents & Royalties: patent holding; Roche: Consultancy. Gascoyne:NanoString: Patents & Royalties: Named Inventor on a patent licensed to NanoString Technologies. Scott:Celgene: Consultancy, Honoraria; Janssen: Research Funding; Roche: Research Funding; NanoString: Patents & Royalties: Named Inventor on a patent licensed to NanoString Technologies, Research Funding.