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Introduction: Reduced-intensity and non-myeloablative (RIC/NMA) conditioning regimens are frequently used in alloHCT for NHL, because they are associated with decreased non-relapse mortality (NRM) risk in comparison with myeloablative conditioning regimens and allow older patients and patients with comorbidities to receive alloHCT. However, the optimal RIC/NMA regimen in allo-HCT for NHL is not known. Using the CIBMTR database we compared the transplant outcomes between the commonly used RIC/NMA regimens in NHL. Methods: 1823 adult (≥18 years) NHL patients in CIBMTR registry undergoing alloHCT using matched related or unrelated donors, between 2008-2016 were included. Analysis was limited to patients receiving four commonly used RIC/NMA regimens: fludarabine/ i.v. busulfan (6.4mg/kg) (Flu/Bu), fludarabine/melphalan (140mg/m^2) (Flu/Mel 140), fludarabine/cyclophosphamide (Fly/Cy) and Flu/Cy with 2Gy Total Body Irradiation (Flu/Cy/TBI). Graft-versus-host disease (GVHD) prophylaxis was limited to calcineurin inhibitor-based regimens. Patients who received post transplantation cyclophosphamide for GVHD prophylaxis were excluded. The primary outcome was overall survival (OS). Secondary outcomes included cumulative incidence of NRM, relapse, progression-free survival (PFS) and cumulative incidence of acute and chronic GVHD. Probabilities of OS and PFS were calculated using the Kaplan-Meier estimator. Multivariable regression analysis was performed for GVHD, relapse/progression, NRM, PFS, and OS. Covariates with a p<0.01 were considered significant. Results: The study cohort was divided into 4 groups; Flu/Bu (n=458), Flu/Cy/TBI (n=89), Flu/Mel 140 (n=885) and Flu/Cy (n=391). The baseline characteristics are shown in Table 1. The 4 cohorts were comparable with respect to median patient age, gender, donor type, remission status at alloHCT, and use of prior auto HCT. There was no interaction between NHL histological subtype and type of conditioning regimen. Results of multivariate analysis are shown in Table 2. The Flu/Mel 140 regimen was associated with a higher NRM (HR 1.78, 95% CI 1.37-2.31; p<0.001) when compared to Flu/Bu. Although the risk of relapse with Flu/Mel 140 was lower when compared to Flu/Bu (HR 0.79, 95% CI 0.66-0.94); p=0.007), this did not result in an improvement in PFS. Moreover, the Flu/Mel 140 cohort had an inferior OS (HR 1.34, 95% CI 1.13-1.59; p<0.001) when compared to Flu/Bu. There was no significant difference in terms of OS, PFS, relapse and NRM between Flu/Bu, Flu/Cy and Flu/Cy/TBI. There was no difference in risk of grade 3-4 acute GVHD across the four cohorts and compared to Flu/Cy/TBI, Flu/Mel 140 had a higher risk of chronic GVHD (HR 1.38, 95% CI 1.15-1.65; p<0.001). Four year adjusted PFS was 38% for Flu/Bu, 51% for Flu/Cy/TBI, 39% for Flu/Mel 140 and 35% for Flu/Cy (p=0.07). Four year adjusted OS was 58% for Flu/Bu, 67% for Flu/Cy/TBI, 49% for Flu/Mel 140 and 63% for Flu/Cy (p<0.001). Disease relapse was the most common cause of death across all 4 cohorts. Conclusion: This is the largest analysis comparing the impact of various RIC/NMA conditioning regimens on the outcomes of NHL patients undergoing alloHCT. We report that the choice of RIC/NMA conditioning regimen significantly impacted OS. The most commonly used conditioning regimen, Flu/Mel 140 was associated with a higher NRM and an inferior OS. The Flu/Bu, Flu/Cy, and Flu/CY/TBI conditioning regimens appear to provide comparable OS. Disclosures Ghosh: Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Honoraria, Speakers Bureau; Gilead: Consultancy, Honoraria, Speakers Bureau; SGN: Consultancy, Honoraria, Research Funding, Speakers Bureau; TG Therapeutics: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Research Funding; Genentech: Research Funding; Forty Seven Inc: Research Funding; AstraZeneca: Honoraria, Speakers Bureau. Kharfan-Dabaja:Pharmacyclics: Consultancy; Daiichi Sankyo: Consultancy. Sureda:Amgen: Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria; Sanofi: Honoraria; Takeda: Consultancy, Honoraria, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support; Novartis: Honoraria; Roche: Honoraria. Hamadani:Merck: Research Funding; ADC Therapeutics: Consultancy, Research Funding; Celgene: Consultancy; Otsuka: Research Funding; Medimmune: Consultancy, Research Funding; Takeda: Research Funding; Pharmacyclics: Consultancy; Janssen: Consultancy; Sanofi Genzyme: Research Funding, Speakers Bureau.

Background Although rituximab‐based high‐dose therapy is frequently used in diffuse large B cell lymphoma (DLBCL) patients undergoing autologous hematopoietic cell transplantation (auto‐HCT), data supporting the benefits are not available. Herein, we report the impact of rituximab‐based conditioning on auto‐HCT outcomes in patients who have DLBCL. Methods Using the Center for International Blood and Marrow Transplant Research (CIBMTR) registry, 862 adult DLBCL patients undergoing auto‐HCT between 2003 and 2017 using BEAM (BCNU, etoposide, cytarabine, melphalan) conditioning regimen were included. All patients received frontline rituximab‐containing chemoimmunotherapy and had chemosensitive disease pre‐HCT. Early chemoimmunotherapy failure was defined as not achieving complete remission (CR) after frontline chemoimmunotherapy or relapse within 1 year of initial diagnosis. The primary outcome was overall survival (OS). Results The study cohort was divided into 2 groups: BEAM (n = 667) and R‐BEAM (n = 195). On multivariate analysis, no significant difference was seen in OS ( P = .83) or progression‐free survival (PFS) ( P = .61) across the 2 cohorts. No significant association between the use of rituximab and risk of relapse ( P = .15) or nonrelapse mortality ( P = .12) was observed. Variables independently associated with lower OS included older age at auto‐HCT ( P < .001), absence of CR at auto‐HCT ( P < .001) and early chemoimmunotherapy failure ( P < .001). Older age ( P < .0002) and non‐CR pre‐HCT ( P < .0001) were also associated with inferior PFS. There was no significant difference in early infectious complications between the 2 cohorts. Conclusion In this large registry analysis of DLBCL patients undergoing auto‐HCT, the addition of rituximab to the BEAM conditioning regimen had no impact on transplantation outcomes. Older age, absence of CR pre auto‐HCT, and early chemoimmunotherapy failure were associated with inferior survival.

PURPOSETo compare the outcomes of patients with Hodgkin or non-Hodgkin lymphoma undergoing nonmyeloablative haploidentical or unrelated cord blood (UCB) hematopoietic cell transplantation.PATIENTS AND METHODSWe retrospectively studied 740 patients with Hodgkin lymphoma (n = 283, 38%) and non-Hodgkin lymphoma (n = 457, 62%) age 18-75 years who received transplantations from 2009 to 2016. Data were reported to the Lymphoma Working Party of the European Society for Blood and Marrow Transplantation, Eurocord, or Center for International Blood and Marrow Transplant Research. Of the 526 patients who received haploidentical transplantation, 68% received bone marrow and 32% received peripheral blood. All patients received a uniform transplantation conditioning regimen (2 Gy of total-body irradiation, cyclophosphamide, and fludarabine) and graft-versus-host disease prophylaxis (calcineurin inhibitor and mycophenolate). In addition, patients who received a haploidentical transplantation received posttransplantation cyclophosphamide.RESULTSCompared with haploidentical bone marrow and peripheral-blood transplantations and adjusted for age, lymphoma subtype, and disease status, survival was lower after UCB transplantation (hazard ratio [HR], 1.55; P = .001; and HR, 1.59; P = .005, respectively). Similarly, progression-free survival was lower after UCB transplantations compared with haploidentical bone marrow and peripheral-blood transplantations (HR, 1.44; P = .002; and HR, 1.86; P < .0001), respectively. The 4-year overall and progression-free survival rates after UCB transplantation were 49% and 36%, respectively, compared with 58% and 46% after haploidentical bone marrow transplantation and 59% and 52% after peripheral-blood transplantation, respectively. Lower survival was attributed to higher transplantation-related mortality after UCB transplantation compared with haploidentical bone marrow and peripheral-blood transplantation (HR, 1.91; P = .0001; and HR, 2.27; P = .0002, respectively).CONCLUSIONWhen considering HLA-mismatched transplantation for Hodgkin or non-Hodgkin lymphoma, the data support haploidentical related donor transplantation over UCB transplantation.

(Text above this line is not copy/pasted in the abstract body) INTRODUCTION Allogeneic HCT using RIC regimens is the standard treatment for patients with relapsed/refractory cHL, however there is significant heterogeneity amongst the different regimens and a lack of data supporting a preferred RIC regimen. Using the CIBMTR database we evaluate the outcomes of the 3 most commonly used RIC regimens for cHL. METHODS In the CIBMTR registry, 492 adult patients underwent a first alloHCT using either a matched related or unrelated donor for cHL between 2008-2016, utilizing a RIC regimen with either fludarabine/ i.v. busulfan (6.4mg/kg) (Flu/Bu, n=102), fludarabine/melphalan 140mg/m^2 (Flu/Mel140, n=318) or fludarabine/cyclophosphamide (Flu/Cy, n=72). Graft-versus-host disease (GVHD) prophylaxis was calcineurin inhibitor (CNI) plus methotrexate, mycophenolate mofitil (MMF) or other agents, however post transplantation cyclophosphamide (post-CY) was excluded. The primary endpoint was overall survival (OS). Secondary endpoints included acute (a) and chronic (c) GVHD, non-relapse mortality (NRM), relapse/progression and progression-free survival (PFS). Probabilities of OS and PFS were calculated using the Kaplan-Meier estimator. Multivariable regression analysis was performed for GVHD, relapse/progression, NRM, PFS, and OS. Covariates with a p<0.01 were considered significant. RESULTS Baseline characteristics are shown in Table 1. The median patient age of the complete study cohort was only 33 years, with more than 80% receiving a prior autologous HCT. On multivariate analysis (Table 2), the 3 conditioning regimen cohorts were not statistically different in either risk of cGVHD nor risk of grade 3-4 aGVHD. No significant differences were seen in the NRM risk between the three regimens (p=0.54). Similarly, the risk of relapse (p=0.02) and PFS was comparable between regimens (p=0.14). Flu/Cy conditioning was associated with decreased risk of mortality in first 11months after alloHCT (OR 0.28, 95% CI 0.10-0.73, p=0.009, but beyond 11 months post alloHCT it was associated with a significantly higher risk of mortality, (OR 2.46, 95% CI 0.1.32-4.61, p=0.005; Figure 1) [11months post alloHCT cutoff chosen on the basis of the maximum likelihood value in the Cox model]. Four year adjusted PFS and OS were similar across the three regimens at 29% for Flu/Bu, 37% for Flu/Mel140 and 25% for Flu/Cy (p=0.07) for PFS and 62% for Flu/Bu, 59% for Flu/Mel140 and 55% for Flu/Cy (p=0.64) for OS, respectively. Relapse was the most common cause of death across all the regimens, followed by organ failure and GVHD. CONCLUSIONS The most commonly used RIC regimen in alloHCT for cHL is Flu/Mel140, which was compared to Flu/Bu and Flu/Cy, the next most frequently used regimens. The choice of conditioning regimen, in these young cHL patients (median age 33 years) did not confer any benefit in terms of the risk of relapse, decrease in NRM or improvement in PFS. There was no OS benefit between, Flu/Bu and Flu/Mel 140, but Flu/Cy was associated with a significantly higher risk of mortality in patients beyond 11 months from allo-HCT. Novel approaches are still needed to decrease post-HCT relapse risk and improve overall results. Figure 1 Disclosures Ghosh: Seattle Genetics: Consultancy, Speakers Bureau; Genentech: Research Funding; Gilead/Kite: Consultancy, Speakers Bureau; Pharmacyclics: Consultancy, Research Funding, Speakers Bureau; T G Therapeutics: Consultancy, Research Funding; Celgene: Consultancy, Research Funding, Speakers Bureau; Forty Seven Inc: Research Funding; Spectrum: Consultancy, Speakers Bureau; AbbVie: Consultancy, Speakers Bureau; Astra Zeneca: Speakers Bureau. Kharfan-Dabaja:Daiichi Sankyo: Consultancy; Pharmacyclics: Consultancy. Sureda:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support; Gilead: Honoraria; Novartis: Honoraria; Amgen: Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria; Roche: Honoraria; Sanofi: Honoraria; Takeda: Consultancy, Honoraria, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Hamadani:Merck: Research Funding; Janssen: Consultancy; Otsuka: Research Funding; Takeda: Research Funding; Medimmune: Consultancy, Research Funding; ADC Therapeutics: Consultancy, Research Funding; Celgene: Consultancy; Sanofi Genzyme: Research Funding, Speakers Bureau; Pharmacyclics: Consultancy.

Abstract Introduction: AITL is a distinct clinicopathologic entity among the mature T-cell and NK-cell lymphomas, accounting for approximately 1-2% of all non-Hodgkin lymphomas. Although autologous HCT (auto-HCT) provides high response rates, there is a high relapse risk associated with this procedure. Allo-HCT may result in a lower risk of relapse in part due to a graft-versus-lymphoma effect mediated by alloreactive donor cells. The role of allo-HCT in AITL with advanced disease (prior auto-HCT failure, or chemorefractory state) is not well described. Using the CIBMTR registry, we report here the outcomes of AITL patients undergoing an allo-HCT. Methods: We evaluated 249 adult (≥18years) patients with AITL who received a first allo-HCT during 2000-2016. Patients receiving mismatched unrelated donor, cord blood or haploidentical donor transplantation were excluded due to small numbers. The primary end-point was overall survival (OS). Secondary endpoints included cumulative incidence of acute graft-versus-host disease (GVHD), chronic GVHD, non-relapse mortality (NRM), relapse/progression (R/P) and progression-free survival (PFS). Results: Baseline patient characteristics are summarized in Table. The median patient age was 56 years (range=21-77 years). The graft source was mainly peripheral blood. Median follow-up of survivors was 49 months (range=4-170 months). The cumulative incidence of grade 2-4 and grade 3-4 acute GVHD at day 180 were 36% (95% CI=30-42)% and 12 (95% CI=8-17)%, respectively. The cumulative incidence of chronic GVHD at 2 years was 58% (95% CI=51-64)%. The 1-year NRM was 19% (95% CI=14-24)%, while the 4-year R/P, PFS, and OS were 21% (95% CI=16-27)%, 49% (95% CI=42-56)% and 56% (95% CI=49-63)%, respectively [Figure]. On multivariate analysis, chemoresistant status at allo-HCT was associated with a significantly higher risk for progression (RR=1.73 95% CI=1.08-2.77), while KPS <90% was associated with a significantly higher risk of mortality (RR=3.46 95% CI=1.75 - 6.87). Subgroup analysis looking at the effect of prior auto-HCT (no prior auto-HCT vs prior auto-HCT), the 4-year PFS (50% vs 47%, p=0.60) and OS (57% vs 54%, p=0.70) were not significantly different. Similarly, on comparing the disease status at allo-HCT (CR1 vs CR>1 vs PR vs refractory), there was no significant difference in the 4-year PFS (58% vs 45% vs 47% vs 38%, p=0.41) or OS (70% vs 54% vs 50% vs 52%, p=0.27). The 1-year NRM was 24%, while the 4-year R/P, PFS, and OS in patients with refractory AITL were 32%, 38%, and 52%, respectively. The most common cause of death was organ failure. Conclusion: In this largest series of mostly advanced AITL patients, allo-HCT was shown to provide durable disease control (4-year PFS=47%) with a clear plateau in relapse at 1-year post-transplantation. Allo-HCT provided durable disease control even in patients with a failed prior auto-HCT and those subjects with refractory disease at the time of allografting. Disclosures Kharfan-Dabaja: Alexion Pharmaceuticals: Speakers Bureau; Incyte Corp: Speakers Bureau; Seattle Genetics: Speakers Bureau. Smith:BMS: Consultancy; Portola: Honoraria. Sureda:Sanofi: Honoraria; Takeda: Consultancy, Honoraria, Speakers Bureau; Merck: Consultancy, Honoraria; Roche: Honoraria; BMS: Consultancy, Honoraria. Hamadani:Merck: Research Funding; Celgene Corporation: Consultancy; ADC Therapeutics: Research Funding; Sanofi Genzyme: Research Funding, Speakers Bureau; Ostuka: Research Funding; Janssen: Consultancy; MedImmune: Consultancy, Research Funding; Takeda: Research Funding; Cellerant: Consultancy.

Abstract Abstract 332 Background: The high response rates seen with the bortezomib, lenalidomide, and dexamethasone (VRD/RVD) regimen (Kumar S, et al. Blood 2012; Richardson PG, et al. Blood 2010) highlight the feasibility of combining a proteasome inhibitor with an immunomodulatory agent and a steroid in patients with previously untreated multiple myeloma (MM). MLN9708 is an investigational, oral, reversible proteasome inhibitor with promising anti-MM effects and favorable toxicity profile with low rates of peripheral neuropathy (PN). Here we report phase (Ph) 1 and preliminary Ph 2 results of the first study of MLN9708 in combination with lenalidomide and dexamethasone in patients with previously untreated MM (NCT01217957). Methods: Patients aged ≥18 yrs with measurable disease, ECOG performance status 0–2, and no grade ≥2 PN, received oral MLN9708 (days 1, 8, and 15) plus lenalidomide 25 mg (days 1–21) and dexamethasone 40 mg (days 1, 8, 15, 22) for up to twelve 28-day cycles, then maintenance therapy with MLN9708 (same schedule) every 28 days until progression. Patients could undergo stem cell collection after 3 cycles and discontinue for autologous stem cell transplant (ASCT) after 6 cycles. In Ph 1, dose escalation (1.68–3.95 mg/m2) proceeded using a standard 3+3 design, based on cycle 1 dose-limiting toxicities (DLTs). Ph 1 primary objectives were determination of safety, maximum tolerated dose (MTD), and recommended Ph 2 dose (RP2D); the Ph 2 primary objective was CR+VGPR rate. Secondary and exploratory objectives included characterization of MLN9708 pharmacokinetics (PK) and measurement of minimal residual disease using multiparameter flow cytometry. Responses were assessed by IMWG criteria. Adverse events (AEs) were graded by NCI-CTCAE v4.02. Results: From 22 November 2010 (Ph 1) and 14 October 2011 (Ph 2) to data cut-off (June 27, 2012), 65 patients (36 male) have been enrolled, 15 in Ph 1 and 50 in Ph 2. Median age was 66 yrs (range 34–86); 43% and 13% had ISS stage II and III. Patients have received a median of 5 cycles (range 1–15) – 6 cycles (range 1–15) in Ph 1 and 5 cycles (range 1–8) in Ph 2. 42 (65%) patients remain on treatment, 4 (27%) in Ph 1 and 38 (76%) in Ph 2. At 10 August 2012, 22 patients have discontinued: 16 to receive ASCT, 4 due to AEs (3 drug-related, 1 not drug-related GI bleed), 2 for other reasons (1 disease progression, 1 due to investigator decision). Of those who have undergone stem cell mobilization, a median yield of 9.1 × 106 CD34+ cells/L was reported. MLN9708 MTD was established as 2.97 mg/m2 and RP2D was selected as 2.23 mg/m2; RP2D converts to a 4.0 mg fixed dose based on population PK results. At 27 June, all-grade AEs related to any regimen drug and seen in ≥25% of patients were fatigue (32%), nausea (31%), and vomiting (25%). Grade 3 any-drug-related AEs were reported in 26 (40%) patients, including erythematous rash, nausea and vomiting (5% each). Grade 4 any-drug-related AEs were end-stage renal disease (related to progressing MM) and deep vein thrombosis in 1 patient each. One patient experienced grade 3 PN at the RP2D. At 10 August, 3 patients discontinued due to drug-related AEs – 1 in Ph 2 who stopped due to grade 1 resting tremor, grade 2 occasional memory loss (neurologic work-up was negative), and grade 2 peripheral sensory neuropathy, 1 patient in Ph 2 due to drug-related RSV pneumonia who subsequently died on study due to this AE, and 1 patient in Ph 1 with syncope (a DLT). Among all 65 patients (at 10 August), median patient follow-up was 3.88 months (Ph 1: 9.03 months, Ph 2: 3.68 months). The overall response rate (ORR; ≥PR, confirmed/unconfirmed) was 88% (100% in Ph 1 and 84% in Ph 2); this includes 40% ≥VGPR (53% in Ph 1 and 36% in Ph 2) and 18% CR (33% in Ph 1 and 14% in Ph 2). Median cycle number is limited, but 50 patients have received ≥4 cycles: ORR was 96%, with 44% ≥VGPR and 26% CR. Analyses by cytogenetic status will be presented at the meeting. At data cut-off, 50 of 52 responders remained in response, with responses durable for up to 13.2+ months. Median time to first response was 0.92 months (range 0.89–6.44). Conclusions: The combination of weekly oral MLN9708 plus lenalidomide and dexamethasone appears generally well tolerated, with one grade 3 PN at the RP2D. Preliminary data show antitumor activity at the RP2D in patients with previously untreated MM, and at data cut-off, 96% of patients had achieved ≥PR, including a ≥VGPR rate of 44% and a CR rate of 26%, with responses consistent with those reported with VRD/RVD. Disclosures: Kumar: Millennium Pharmaceuticals, Inc.: Research Funding; Novartis: Research Funding; Genzyme: Research Funding; Cephalon: Research Funding; Merck: Consultancy, Honoraria; Celgene: Consultancy, Research Funding. Off Label Use: A study of the investigational agent MLN9708 in combination with lenalidomide and dexamethasone for the treatment of patients with previously untreated multiple myeloma. Niesvizky:Celgene: Consultancy, Research Funding, Speakers Bureau; Millennium Pharmaceuticals, Inc.: Consultancy, Research Funding, Speakers Bureau; Onyx Pharmaceuticals: Consultancy, Research Funding, Speakers Bureau. Lonial:Onyx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Meyers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Millennium Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees. Stewart:Millennium Pharmaceuticals, Inc.: Consultancy, Research Funding. Hari:Celgene: Consultancy. Vescio:Millennium Pharmaceuticals, Inc.: Speakers Bureau. Berg:Millennium Pharmaceuticals, Inc.: Employment. Lin:Millennium Pharmaceuticals, Inc.: Employment. Di Bacco:Millennium Pharmaceuticals, Inc.: Employment. Gupta:Millennium Pharmaceuticals, Inc.: Employment. Hui:Millennium Pharmaceuticals, Inc.: Employment. Richardson:Millennium Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees; Janssen Pharmaceuticals and Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees.

Abstract Eukaryotic translation initiation factor 5A (eIF5A) has been implicated in the regulation of cell proliferation, apoptosis, and inflammation, and is the only known protein to be modified by hypusination. Hypusinated eIF5A, the predominant form of eIF5A in cancer cells, is involved in cell survival and activation of inflammatory pathways. In contrast, accumulation of the unhypusinated form of eIF5A is associated with apoptosis and mutants of eIF5A that cannot be hypusinated (e.g. eIF5AK50R) are pro-apoptotic. SNS01-T was designed to treat B-cell cancers and consists of two active components: a plasmid DNA expressing the pro-apoptotic eIF5AK50R under the control of a B cell-specific promoter, and an siRNA against an untranslated region of native eIF5A mRNA. When these two components are combined with linear polyethyleneimine (PEI), the nucleic acids are condensed into nanoparticles for protection from degradation in the blood and enhanced cellular delivery. The mode of action of SNS01-T is siRNA-mediated inhibition of hypusinated eIF5A and simultaneous over-expression of pro-apoptotic eIF5AK50R to induce cell death. In vitro cell studies and in vivo xenograft studies have demonstrated the efficacy of this approach. The safety and tolerability of intravenous administration of SNS01-T is being investigated in a first-in-human Phase1b/2a study in patients with relapsed or refractory multiple myeloma (MM), mantle cell lymphoma (MCL) or diffuse large B cell lymphoma (DLBCL). Eligible patients are being enrolled sequentially into four cohorts at increasing doses. Each patient receives an intravenous infusion of SNS01-T twice weekly for 6 consecutive weeks. Eligible patients must have been diagnosed with MM according to IMWG criteria, or with MCL or DLBCL with histologic confirmation. Patients also must have measurable disease, have relapsed or refractory disease after two or more prior treatment regimens, have a life expectancy of at least 3 months, and not be eligible to receive any other standard therapy known to extend life expectancy. The primary objective is to evaluate the safety and tolerability of multiple escalating doses of SNS01-T. Secondary objectives include analysis of pharmacokinetics, immunogenicity, pro-inflammatory cytokines, and therapeutic efficacy. The required 3 patients per cohort have completed the dosing schedule in cohorts 1 and 2 from a total of 10 patients enrolled (9 patients with MM and 1 with DLBCL). Of the ten patients enrolled, four completed the full treatment period, two did not complete dosing but were evaluable for safety, and four (three in cohort 1 and one in cohort 2) discontinued treatment after fewer than 8 doses and were not evaluable. There were no drug-related serious adverse events or dose limiting toxicities in either cohort 1 or 2. In cohort 1 (0.0125 mg/kg SNS01-T), two of three evaluable patients did not progress on treatment and were considered stable at week 3 and week 6, the end of the dosing regimen. The third patient progressed after receiving 10 of the 12 doses and was evaluable for safety. In cohort 2 (0.05 mg/kg), 3 patients (2 with MM and 1 with DLBCL) were evaluable for safety. Stabilization of serum monoclonal protein levels was observed in one MM patient of cohort 2. Two patients (1 with MM and 1 with DLBCL) progressed after receiving 8 of the 12 doses and were evaluable for safety. Results from ongoing pharmacokinetic studies, immunogenicity studies, and quantification of pro-inflammatory cytokines will be discussed. The planned dose levels for the third and fourth groups are 0.2 and 0.375 mg/kg, respectively. The results to date of this first-in-human clinical trial indicate that SNS01-T can be administered safely and the MTD has not yet been reached (Clinical Trials.gov Identifier: NCT01435720). Disclosures: Barranco: Senesco Technologies: Consultancy. Usmani:Celgene, Onyx, Millenium: Consultancy, Research Funding, Speakers Bureau. van Rhee:Jansen&Jansen: Research Funding. Thompson:Senesco Technologies: Consultancy, Equity Ownership, Membership on an entity’s Board of Directors or advisory committees, Research Funding. Taylor:Senesco Technologies: stock options Other. Dondero:Senesco Technologies: Employment. Browne:Senesco Technologies Inc.: Employment, Equity Ownership, Membership on an entity’s Board of Directors or advisory committees. Siegel:Celgene, Millenium, Onyx (same for all): Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau.

Abstract Background: Mantle cell lymphoma (MCL) remains challenging particularly in the relapsed/refractory setting, where patients often show chemoresistance. Novel molecular-based therapies have shown impressive and durable activity in that setting, although primary and acquired resistance remains problematic. A recent retrospective series of 114 patients who had failed ibrutinib (median of 4.7 month exposure) showed very short median overall survival of 2.9 months after ibrutinib cessation (Martin et al. Blood 2015). Here we report the results from the observationalMCL-004 study investigating outcomes of patients treated with lenalidomide (an IMiD® immunomodulatory agent) after failing ibrutinib; patients were either relapsed, progressed, refractory, or intolerant to ibrutinib. The objective here is to evaluate the clinical effectiveness of lenalidomide monotherapy or a lenalidomide-containing regimen in relapsed/refractory MCL after ibrutinib failure or intolerance. Methods: MCL-004 is a multicenter study in patients with MCL who relapsed/progressed after or were refractory/intolerant to ibrutinib, and were subsequently treated with lenalidomide. With patient informed consent, data were collected retrospectively from patients who, after their disease failed to respond to ibrutinib, received lenalidomide-based therapy from March 1, 2009 to June 9, 2015. The primary endpoint was investigator-assessed overall response rate (ORR) based on 2007 International Working Group criteria, with required patient monitoring and routine imaging. Results: Thirty patients were enrolled at 7 US sites and 1 EU site, including patients receiving lenalidomide monotherapy (n=8), lenalidomide + rituximab (n=8), and lenalidomide + other treatment (n=14). Lenalidomide + other treatment included combination with rituximab, carfilzomib, and dexamethasone (n=3); other combinations were given in ≤2 patients. Patients had a median age of 69 years (range, 50-84), and median time from last dose of ibrutinib to first dose of lenalidomide was 1.3 weeks (range, 0.1-21.7). All patients received ≥2 prior lines of therapy, and 83% received ≥3 prior therapies (median prior therapies, 3.5; range, 2-8). With prior ibrutinib, the best responses achieved were 10% complete response (CR), 43% partial response (PR), 3% stable disease, 40% relapse/progressive disease (PD), and 3% unknown. Primary reasons for ibrutinib discontinuation were 50% relapse/PD, 40% refractory, and 10% intolerance. Patients received a median of 2 cycles (range, 1-11) of lenalidomide-based treatment. Eight patients' disease responded (4 CR, 4 PR), resulting in an ORR of 27% (95% CI, 12%-46%). Five of 8 maintained their response at data cut-off (3 CR, 2 PR). ORR was similar for patients with relapse/PD vs. those refractory to ibrutinib (29% vs. 33%, respectively). Median duration of response (DOR) was 18 weeks (95% CI, 2.9-25+) for all patients. Median DOR was not reached in patients who previously relapsed/progressed with ibrutinib compared with a median of 11 weeks for those whose disease was refractory to ibrutinib. Most common treatment-emergent adverse events (TEAEs) were 33% fatigue; 27% nausea; and 23% each dyspnea, neutropenia, dizziness, or rash. In general, TEAEs were less common with lenalidomide monotherapy. The most frequently reported serious AEs were pneumonia, dyspnea, deep vein thrombosis, hypotension, and acute kidney injury (7% each). At data cutoff, 15 patients (50%) had died, mostly due to MCL and none due to second primary malignancy. Conclusions: Most patients received ≥3 prior lines of treatment, and median time from last dose of ibrutinib to first dose of lenalidomide was short. Lenalidomide-based treatment showed clinical activity in this difficult-to-treat patient population, including 27% ORR and 13% CR. No new safety signals for lenalidomide were identified. Overall, our results show that lenalidomide is active in a selected group of patients with relapsed/refractory MCL that previously failed ibrutinib. Disclosures Wang: BeiGene: Research Funding; Asana BioSciences: Research Funding; Acerta Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Research Funding; Celgene: Research Funding; Kite Pharma: Research Funding; Juno Therapeutics: Research Funding; Onyx: Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Martin:Acerta: Consultancy; Teva: Research Funding; Novartis: Consultancy; Janssen: Consultancy, Honoraria, Other: travel, accommodations, expenses; Celgene: Consultancy, Honoraria; Gilead: Consultancy, Other: travel, accommodations, expenses. Goy:Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Other: Writing support, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding; Johnson & Johnson: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; infinity: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding; Acerta: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Hamadani:Takeda: Research Funding. Ghosh:Gilead: Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; SGN: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Genentech: Research Funding; TG Therapeutics: Research Funding. Reeder:Millennium: Research Funding; BMS: Research Funding; Celgene: Research Funding; Novartis: Research Funding. Barnett:Celgene Corporation: Employment, Equity Ownership. Casadebaig Bravo:Celgene: Employment, Equity Ownership. Schuster:Pharmacyclics: Consultancy, Research Funding; Novartis: Research Funding; Gilead: Research Funding; Janssen Research & Development: Research Funding; Nordic Nanovector: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Research Funding; Genentech: Consultancy; Hoffman-LaRoche: Research Funding.

Abstract Background: Triplet regimens combining a proteasome inhibitor, an immunomodulatory drug, and a steroid have been shown to be active and well tolerated in previously untreated MM pts. Extended treatment represents an alternative paradigm to induction followed by ASCT in this setting; however, agents for continuous therapy need to be convenient and well tolerated. The investigational agent ixazomib is the first oral proteasome inhibitor to be studied clinically. Phase 1 studies have indicated single-agent activity in relapsed/refractory MM and shown ixazomib to be well tolerated with a manageable safety profile, including limited peripheral neuropathy (PN) (Richardson PG et al, Blood 2014; Kumar SK, et al, Blood 2014). Weekly ixazomib plus lenalidomide-dexamethasone has been investigated in a phase 1/2 study in previously untreated MM pts (NCT01217957); treatment comprised triplet induction therapy followed by single-agent ixazomib maintenance therapy. Results of induction therapy have been previously reported (Kumar SK, et al, ASH 2012). Here we report phase 2 efficacy and safety data in pts receiving ixazomib maintenance. Methods: In phase 2, pts aged ≥18 yrs with measurable disease and no grade ≥2 PN received oral ixazomib 4.0 mg on d 1, 8, 15, lenalidomide 25 mg on d 1–21, and dexamethasone 40 mg on d 1, 8, 15, 22, for up to twelve 28-d induction cycles, followed by maintenance ixazomib on d 1, 8, 15 every 28 d until progression at the dose last tolerated during induction. Transplant-eligible pts could discontinue from study for ASCT after 6 cycles. The primary objective was CR+VGPR rate. Responses were assessed by IMWG criteria. Adverse events (AEs) were graded by NCI-CTCAE v4.02. Results: Fifty pts were enrolled in phase 2; 29 discontinued during induction (cycles 1–12), primarily to undergo ASCT (n=14) or due to AEs (n=6) or pt withdrawal (n=4). Twenty-one pts received ixazomib maintenance therapy (cycle ≥13); 13 (62%) were male, and median age was 68 (range 34–77) years. At data cut-off (June 11, 2014), pts had received a median of 27 treatment cycles (range 15–32), including both induction and maintenance, with a median treatment duration of 26.6 mos (range 13.4–29.6). Mean ixazomib relative dose intensity was 95% and 89% in the induction and maintenance phases, respectively. The mean ixazomib dose administered during maintenance was 3.6 mg weekly. At data cut-off, 11 (52%) pts remained on ixazomib maintenance. Among 49 evaluable phase 2 pts, 44 (90%) achieved ≥PR, including 29 (59%) ≥VGPR. All 21 pts who received ixazomib maintenance had responded to induction therapy. Overall best confirmed/unconfirmed responses in the 21 pts included ≥CR in 11 (52%, of which 4 [19%] were stringent CRs [sCR]), ≥near-CR in 13 (62%), and ≥VGPR in 15 (71%), plus 6 (29%) PR. Responses were rapid and improved during treatment. Median time to first response (≥PR) was 0.99 mos (range 0.92–5.78) and to best response was 7.46 mos (range 1.02–24.74); 33% of pts improved their response during maintenance, including 2 VGPR to near-CR, 3 VGPR to CR, 1 VGPR to sCR, and 1 CR to sCR. At data cut-off, median duration of response was 26.5 mos (range 5.6–26.6+). Among 15 pts achieving ≥VGPR, 5 (33%) had progressed; median duration of ≥VGPR was 23.0 mos (range 3.7–26.1+). All pts were alive after follow-up of 24.6–30.3 mos, including a median follow-up from start of maintenance of 16.9 mos (range 12.9–18.9). Ixazomib maintenance was well tolerated; 15 (71%) pts had drug-related AEs, with only 2 (10%) pts with grade 3 drug-related AEs (hypokalemia, thrombocytopenia) and no grade 4 AEs. The most common (>1 pt) grade 1–2 drug-related AEs were diarrhea (n=8, 38%), nausea, pain in extremity (each n=3, 14%), anemia, and headache (each n=2, 10%). No PN was reported. Serious AEs were reported in 3 (14%) pts during maintenance, including grade 3 acute myocardial infarction, grade 3 pneumonia, and grade 3 orthostatic hypotension; all were considered not related to treatment. Only 1 pt required an ixazomib dose reduction due to an AE (neuralgia). Conclusions: These data indicate that single-agent ixazomib maintenance for up to 1.5 yrs was feasible and generally well tolerated, improved responses following ixazomib-lenalidomide-dexamethasone induction, and contributed to durable responses (median >2 yrs) in previously untreated MM pts not undergoing ASCT. The results support the ongoing phase 3 trial of ixazomib in the maintenance setting (NCT02181413). Disclosures Kumar: Celgene: Consultancy, Research Funding; Millennium: The Takeda Oncology Co.: Consultancy, Research Funding; Onyx Pharmaceuticals: Consultancy, Research Funding; Sanofi-Aventis: Consultancy, Research Funding; Array BioPharma: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Skyline Diagnostics: Membership on an entity's Board of Directors or advisory committees. Off Label Use: Investigational proteasome inhibitor ixazomib in combination with lenalidomide and dexamethasone and as maintenance therapy for patients with previously untreated multiple myeloma.. Niesvizky:Onyx Pharmaceuticals: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Millennium: The Takeda Oncology Company: Consultancy, Honoraria, Research Funding, Speakers Bureau. Lonial:Millennium: The Takeda Oncology Company: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Onyx Pharmaceuticals: Consultancy, Research Funding. Laubach:Novartis: Research Funding; Onyx Pharmaceuticals: Research Funding. Hamadani:Millennium: The Takeda Oncology Company: Research Funding. Stewart:Takeda Pharmaceuticals International Co.: Research Funding; Sanofi: Consultancy; Array BioPharma: Consultancy; Bristol Myers Squibb: Consultancy; Celgene: Consultancy; Novartis: Consultancy. Hari:Celgene: Consultancy, Honoraria, Research Funding; Onyx: Consultancy, Honoraria, Research Funding; Millennium: The Takeda Oncology Co.: Consultancy, Honoraria, Research Funding; Spectrum: Consultancy, Honoraria, Research Funding; Sanofi: Research Funding. Vescio:Celgene: Speakers Bureau; Millennium: The Takeda Oncology Co.: Speakers Bureau; Onyx Pharmaceuticals: Speakers Bureau. Kaufman:Millennium: The Takeda Oncology Co.: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Onyx: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Spectrum: Consultancy, Honoraria; Merck: Research Funding. Berg:Takeda Pharmaceuticals International Co.: Employment. Liao:Takeda Pharmaceuticals International Co.: Employment. Hui:Takeda Pharmaceuticals International Co.: Employment. Richardson:Millennium: The Takeda Oncology Co.: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees.

Abstract Abstract 2973 Eukaryotic translation initiation Factor 5A (eIF5A) has been implicated in the regulation of apoptosis and is the only known protein to be modified by hypusination. Hypusinated eIF5A is the predominant form of eIF5A in cancer cells. However, in its unhypusinated form, eIF5A is pro-apoptotic. SNS01-T, designed to treat B-cell cancers, consists of two active components: a plasmid DNA expressing eIF5AK50R (human eIF5A containing a lysine to arginine substitution at position 50) which remains pro-apoptotic because it cannot be hypusinated, and an siRNA against an untranslated region of native eIF5A mRNA. When these two components are combined with linear polyethyleneimine (PEI), the nucleic acids are condensed into nanoparticles for protection from degradation in the blood and enhanced delivery to tissues. The eIF5AK50R transgene is under the control of the B29 promoter and enhancer, which restricts expression to B cells. The mode of action of SNS01-T is to use an eIF5A-specific siRNA to deplete the pool of hypusinated eIF5A in myeloma cells while simultaneously adding pro-apoptotic eIF5AK50R. In vitro cell studies and in vivo xenograft studies have demonstrated the efficacy of this approach. Eligible patients are enrolled sequentially into four cohorts of increasingly higher doses. Each cohort will receive SNS01-T by intravenous infusion twice weekly for 6 consecutive weeks and then be observed every 4 weeks during a 24-week follow-up period. Eligible patients must have been diagnosed with multiple myeloma according to IMWG criteria, have measurable disease, have relapsed disease after two or more prior treatment regimens, have a life expectancy of at least 3 months, and not be eligible to receive any other standard therapy known to extend life expectancy. The primary objective is to evaluate the safety and tolerability of multiple ascending doses of SNS01-T. Secondary objectives include pharmacokinetics, immunogenicity studies, proinflammatory cytokine quantitation, and therapeutic efficacy. The required number of 3 patients completed the dosing schedule in Cohort 1 from a total of 6 patients enrolled. Two of three patients had not progressed on treatment, based on standard response criteria including the monoclonal protein, and were considered stable at week 3 and week 6 the end of the dosing regimen. Three patients were withdrawn from the study by their physicians due to disease progression before completing treatment. One of the responding patients has continued to have stable disease at week 10, a month after the end of treatment with SNS01-T. The first group of patients received 0.0125 mg/kg, approximately 1 mg per patient by intravenous infusion. The planned dose levels for the second, third and fourth groups are 0.05, 0.2 and 0.375 mg/kg, respectively. The results to date of this first in man clinical trial indicate that SNS01-T was safely administered without dose-limiting toxicities in the first group of multiple myeloma patients. The MTD has not yet been reached. (Clinical Trials.gov Identifier: NCT01435720.) Disclosures: Hamadani: Celgene Corp: Speakers Bureau; American Cancer Society 116837-IRG-09–061–01: Research Funding; ASBMT & Millennium New Investigator Award: Research Funding; Conquer Cancer Foundation of ASCO: Research Funding. Barranco:Senesco Technologies: Employment. Thompson:Senesco Technologies Inc.: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Taylor:Senesco Technologies Inc.: stock options Other. Dondero:Senesco Technologies Inc.: Employment.