Citations

Introduction: Patients with intracranial hemorrhage (including intracerebral hemorrhage, subarachnoid hemorrhage, and traumatic hemorrhage) are commonly admitted to the intensive care unit (ICU). Although indications for oral antiplatelet agents are increasing, the impact of preadmission use on outcomes in patients with intracranial hemorrhage admitted to the ICU is unknown. We sought to evaluate the association between preadmission oral antiplatelet use, in-hospital mortality, resource utilization, and costs among ICU patients with intracranial hemorrhage. Methods: We retrospectively analyzed a prospectively collected registry (2011-2016) and included consecutive adult patients from 2 hospitals admitted to ICU with intracranial hemorrhage. Patients were categorized on the basis of preadmission oral antiplatelet use. We excluded patients with preadmission anticoagulant use. The primary outcome was in-hospital mortality and was analyzed using a multivariable logistic regression model. Contributors to total hospital cost were analyzed using a generalized linear model with log link and gamma distribution. Results: Of 720 included patients with intracranial hemorrhage, 107 (14.9%) had been using an oral antiplatelet agent at the time of ICU admission. Oral antiplatelet use was not associated with in-hospital mortality (adjusted odds ratio: 1.31 [95% confidence interval [CI]: 0.93-2.22]). Evaluation of total costs also revealed no association with oral antiplatelet use (adjusted ratio of means [aROM]: 0.92 [95% CI: 0.82-1.02, P = .10]). Total cost among patients with intracranial hemorrhage was driven by illness severity (aROM: 1.96 [95% CI: 1.94-1.98], P < .001), increasing ICU length of stay (aROM: 1.05 [95% CI: 1.05-1.06], P < .001), and use of invasive mechanical ventilation (aROM: 1.76 [95% CI: 1.68-1.86], P < .001). Conclusions: Among ICU patients admitted with intracranial hemorrhage, preadmission oral antiplatelet use was not associated with increased in-hospital mortality or hospital costs. These findings have important prognostic implications for clinicians who care for patients with intracranial hemorrhage.

Abstract Background: Despite advances in chemotherapy, relapsed/refractory (R/R) Hodgkin lymphoma (HL) remains a significant clinical challenge and an unmet medical need. HL has a unique biology in which a small number of malignant Hodgkin Reed-Sternberg (HRS) cells propagate an immunosuppressive microenvironment. We hypothesized that using immune checkpoint inhibitor therapy to activate the immune cells in the tumor microenvironment, and concurrently targeting HRS cells with the CD30 antibody-drug conjugate brentuximab vedotin (BV), could overcome tumor cell resistance. E4412 is a Phase 1 ECOG-ACRIN sponsored study of the combination of BV and ipilimumab (IPI) and nivolumab (Nivo) in patients with R/R HL. Here we present the preliminary safety and response data on the patients treated with BV + Nivo (Arms D and E). Methods: Patients with confirmed R/R HL were treated with Nivo 3mg/kg and BV 1.2mg/kg (Arm D: Dose Level 1) or 1.8mg/kg (Arm E: Dose Level 2) in dose escalation with a 3+3 design and an expansion cohort (Arm F) of 9 patients. BV and Nivo are given every 21 days for 16 cycles; Nivo may be continued for an additional year (total 2 years of Nivo therapy). Dose limiting toxicity (DLT) was defined for purposes of dose escalation within the first cycle of therapy. Patients are followed for toxicity up to 30 days beyond their last treatment. Results: As of 7/20/2016 10 patients (1 ineligible) have been treated with BV + Nivo. We report the data on the dose escalation population: 3 patients: Arm D, 7 patients: Arm E. Data will be updated to include the full BV + Nivo dose escalation and dose expansion cohorts (Arms D, E & F) (N = 19) by the time of the Annual Meeting. Median age was 46; (range: 25-53). Six patients were male. Patients were heavily pretreated with a median of 3 prior therapies. Six patients had prior SCT (5 autologous, 1 allogeneic); 2patients had prior treatment with BV. Safety: Ten of 10 patients are evaluable for safety. Overall safety profiles show that the regimen of BV + Nivo was extremely well tolerated. One patient out of 7 in dose level 2 experienced a DLT (pneumonitis grade 3 with grade 3 dyspnea and hypoxia, and typhilits grade 3), this patient had received a prior SCT, and made a full recovery from his toxicities. Per protocol he discontinued further therapy. No other DLTs were noted for the remaining 9 patients. Common and relevant toxicities considered at least possibly related to drug during any cycle of treatment are shown in Table 1. There were no Grade 4 treatment related adverse events (AEs). The only additional grade 3 AEs noted were one each grade 3 rash and puritis. The most common grade 1-2 treatment related adverse events were: transaminitis (9), peripheral sensory neuropathy (6), and rash (3). Other AEs of interest included: diarrhea (3), blurry vision (2), and myalgias (2). One grade 1-2 infusion reaction was noted, this patient was able to receive subsequent therapy with pre-medication. Response: Eight of 10 patients are evaluable for response. One patient is not yet evaluable. For the 8 evaluable patients the overall response rate (ORR) for the combination of BV + Nivo was 100%, with a CR rate of 62.5% (5/8), with 95% CI of 0.25-0.91. One patient was ineligible for laboratory studies that were out of range at screening, however this patient continues on therapy, and also had a response. One of 5 CRs occurred at in dose level 1 (BV 1.2 mg/kg). Both patients who had been treated with prior BV achieved CRs. The progression free survival (PFS) to date is 100% with a median follow-up of 0.3 years. Conclusion: In this first reported study of the combination of the checkpoint inhibitor Nivo and the ADC BV therapy was well tolerated with one DLT, and primarily grade 1 and 2 toxicities. In a heavily pretreated patient population, 20% of whom had had prior BV and 60% of whom were s/p ASCT, the ORR of 100% and CR rate of 62.5% suggests a deepening of response compared to either therapy alone. Optimization of this combination strategy is planned with ongoing accrual to cohorts receiving BV + Nivo, and BV + Ipi + Nivo. Data will be updated to include the full BV + Nivo cohort (N = 19) by the time of the Annual Meeting. Disclosures Diefenbach: Seattle Genetics: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Research Funding; Merck: Research Funding; Genentech: Research Funding; Incyte: Research Funding; LAM Therapeutics: Research Funding; Molecular Templates: Research Funding; Oncomed: Research Funding; This study was coordinated by the ECOG-ACRIN Cancer Research Group (Robert L. Comis, MD and Mitchell D. Schnall, MD, PhD, Group Co-Chairs) and supported by the National Cancer Institute of the National Institutes of Health under the following award number: Research Funding. Hong:This study was coordinated by the ECOG-ACRIN Cancer Research Group (Robert L. Comis, MD and Mitchell D. Schnall, MD, PhD, Group Co-Chairs) and supported by the National Cancer Institute of the National Institutes of Health under the following award number: Research Funding. Cohen:Seattle Genetics: Consultancy, Honoraria, Research Funding; BMS: Research Funding. Advani:Stanford University: Employment; Juno: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Spectrum: Consultancy, Honoraria; Sutro: Consultancy, Honoraria; Genentech: Consultancy, Honoraria, Research Funding; Kura: Research Funding; Merck: Research Funding; Celgene: Research Funding; Janssen: Research Funding; Seattle Genetics: Research Funding; Regeneron: Research Funding; Agensys: Research Funding; Pharmacyclics: Research Funding; Infinity: Research Funding; Millennium: Research Funding; FortySeven: Consultancy, Honoraria; Kyowa Hakko Kirin: Consultancy, Honoraria. Kahl:This study was coordinated by the ECOG-ACRIN Cancer Research Group (Robert L. Comis, MD and Mitchell D. Schnall, MD, PhD, Group Co-Chairs) and supported by the National Cancer Institute of the National Institutes of Health under the following award number: Research Funding. Ansell:BMS, Seattle Genetics, Merck, Celldex and Affimed: Research Funding.

Background: Standard first-line treatment for patients diagnosed with diffuse large B-cell lymphoma (DLBCL) is the R-CHOP regimen. Despite numerous efforts to improve on this regimen, in all comers and specifically in those with activated B-cell (ABC)-type DLBCL, results from large randomized studies have failed to show a significant clinical advantage above this standard. Recently, 2 large clinical trials in previously untreated DLBCL evaluated the combination of lenalidomide/R-CHOP (R2-CHOP) vs standard R-CHOP and demonstrated discordant results. We analyzed data from these trials to identify differences that may have impacted the disparate trial outcomes while identifying patient characteristics associated with benefit from the addition of lenalidomide across the trials. Methods: The 2 trials included in this evaluation are ROBUST, an international, randomized, double-blinded, placebo-controlled, phase III study of R2-CHOP vs placebo/R-CHOP, and the Intergroup ECOG-ACRIN 1412 (E1412) trial, a US-only, randomized, open-label, phase II study of R2-CHOP vs R-CHOP. Additional key study design differences included dosing, and subtype timing and inclusion (both studies used gene expression profiling [GEP] by NanoString). R-CHOP dosing differed only for prednisone, which was a flat 100 mg dose, d1-5 in ROBUST and 100 mg/m2, d1-5 in E1412. The lenalidomide dose and schedule varied between studies: 15 mg/d, d1-14/21 for ROBUST (210 mg/cycle) and 25 mg/d, d1-10/21 (250 mg/cycle) for E1412. ROBUST enrolled only patients prospectively identified with the ABC subtype, whereas E1412 enrolled all otherwise eligible patients and retrospectively evaluated for ABC-type with prespecified ABC-type accrual and power parameters. Both studies enrolled patients with IPI status ≥ 2, ECOG PS 0-2, and Ann Arbor stage II-IV (E1412 stage II with mass > 10 cm). The primary endpoint in both was progression-free survival (PFS; central review for ROBUST and investigator-assessed for E1412). Secondary endpoints included event-free survival (EFS; key for ROBUST), overall and complete response rates, overall survival (OS), and safety. Results: ROBUST enrolled 570 ABC patients and E1412 enrolled 280 GCB, ABC, and unclassified DLBCL patients. Patient profiles in both studies (ROBUST [ABC]/E1412 [all COO]) were similar in terms of median ages (65 y/66 y), male sex (58%/61%), and ECOG PS 1-2 (55%/63%). Patients in E1412 were more high risk: IPI 2 (42% ROBUST/34% E1412), IPI ≥ 3 (58%/66%), and Ann Arbor stage III/IV disease (87%/97%). Importantly, there was a notable difference in the time from patient diagnosis to treatment: median 31 days for ROBUST and 21 days (22% > 31 d) for E1412. Only 6% of patients in ROBUST were treated within 2 weeks of diagnosis vs 30% in E1412. At a median follow-up of ~2.5 y for both studies, E1412 met its primary endpoint of improvement in PFS with 34% reduction in the risk of PD/death (2-y PFS: 76% vs 70%) for all patients, but did not reach statistical significance in ABC-DLBCL patients for 2-y PFS (71% vs 61%) or 2-y OS (88% vs 76%). ROBUST showed no significant improvement in the primary PFS endpoint (2-y PFS: 67% vs 64%) or 2-y OS (79% vs 80%) in ABC patients. Subgroup analyses of PFS comparing R2-CHOP vs R-CHOP control within each study suggested that certain baseline factors favor the R2-CHOP arm, including: female sex, high IPI score (≥ 3), non-bulky disease (< 7 cm), and high Ann Arbor stage IV disease. Conclusion: While the ROBUST study design integrated state-of-the-art, real-time GEP to prospectively identify ABC-DLBCL patients with rapid lab turnaround time, cases of logistical delays in tissue submission for central analysis and staging procedures may have resulted in accrual of patients with lower-risk DLBCL and prolonged time from diagnosis to treatment. In contrast, E1412 retrospectively stratified patients by COO through GEP and was able to accrue higher-risk patients irrespective of COO within a shorter time from diagnosis to treatment, which among other differences (eg, smaller population size, study phase), could contribute to the improvement over R-CHOP control. Our comparative findings have significant implications for the design of future biomarker-driven trials and provide momentum for studies of novel combinations with R-CHOP in DLBCL. Further investigation into other factors, including dose intensity and their correlation with outcomes, will be presented. Disclosures Nowakowski: Celgene: Consultancy, Research Funding; NanoString: Research Funding; MorphoSys: Consultancy, Research Funding; Genentech, Inc.: Research Funding; F. Hoffmann-La Roche Ltd: Research Funding; Selvita: Membership on an entity's Board of Directors or advisory committees; Curis: Research Funding; Bayer: Consultancy, Research Funding. Chiappella:Servier: Other: advisory board, Speakers Bureau; Roche: Speakers Bureau; Teva: Speakers Bureau; Celgene: Other: advisory board, Speakers Bureau; Janssen: Other: advisory board, Speakers Bureau. Hong:Dana Farber Cancer Institute: Employment; Merck: Consultancy. Scott:Roche/Genentech: Research Funding; Celgene: Consultancy; Janssen: Consultancy, Research Funding; NanoString: Patents & Royalties: Named inventor on a patent licensed to NanoSting [Institution], Research Funding. Amengual:Appia Pharmaceuticals: Research Funding; Epizyme: Speakers Bureau. Leonard:BeiGene: Consultancy; Miltenyi: Consultancy; Sandoz: Consultancy; Gilead: Consultancy; Celgene: Consultancy; ADC Therapeutics: Consultancy; MorphoSys: Consultancy; ADC Therapeutics: Consultancy; Epizyme, Inc: Consultancy; Miltenyi: Consultancy; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy; Karyopharm Therapeutics: Consultancy; Akcea Therapeutics: Consultancy; Merck: Consultancy; Nordic Nanovector: Consultancy; Akcea Therapeutics: Consultancy; Bayer Corporation: Consultancy; Sandoz: Consultancy; MorphoSys: Consultancy; Gilead: Consultancy; BeiGene: Consultancy; AstraZeneca: Consultancy; Nordic Nanovector: Consultancy; Sutro Biopharma: Consultancy; Merck: Consultancy. Friedberg:Bayer: Honoraria, Other: Data & Safety Monitoring Committee; Acerta: Other: Data & Safety Monitoring Committee. Kostakoglu:F. Hoffman-La Roche: Consultancy; Genentech: Consultancy. Jurczak:Morphosys: Research Funding; Bayer: Research Funding; Roche: Research Funding; Incyte: Research Funding; Gilead: Research Funding; Celgene Corporation: Research Funding; Sandoz: Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk: Research Funding; Servier: Research Funding; Takeda: Research Funding; TG Therapeutics: Research Funding; Celtrion: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Loxo: Membership on an entity's Board of Directors or advisory committees, Research Funding. Yamamoto:Bristol-Myers Squibb: Consultancy, Honoraria; Bayer: Research Funding; Celgene Corporation: Consultancy, Honoraria, Research Funding; Mundipharma: Consultancy, Honoraria, Research Funding; Astra-Zeneca: Consultancy, Research Funding; Eisai: Consultancy, Honoraria, Research Funding; Meiji Seika Pharma: Consultancy, Honoraria; ARIAD: Research Funding; MSD: Consultancy, Honoraria; Gilead Sciences: Research Funding; Ono: Consultancy, Honoraria, Research Funding; SymBio: Research Funding; HUYA/IQVIA Services Japan: Consultancy, Honoraria; AbbVie: Consultancy, Research Funding; Chugai: Consultancy, Honoraria, Research Funding; Pfizer: Honoraria; Sumitomo Dainippon: Honoraria; Incyte: Research Funding; Janssen: Honoraria; Kyowa Kirin: Honoraria; Novartis: Honoraria, Research Funding; Otsuka: Honoraria; Sanofi: Honoraria; Solasia Pharma: Research Funding; Takeda: Consultancy, Honoraria, Research Funding. Czuczman:Celgene Corporation: Employment, Equity Ownership. Russo:Celgene Corporation: Employment, Equity Ownership. Hudak:Celgene Corporation: Employment, Equity Ownership; Novartis: Employment, Equity Ownership. Zhang:Celgene Corporation: Employment, Equity Ownership. Wade:Celgene: Employment, Equity Ownership. Kahl:ADC Therapeutics: Consultancy, Research Funding; BeiGene: Consultancy; TG Therapeutics: Consultancy; Seattle Genetics: Consultancy. Vitolo:Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; F. Hoffmann-La Roche: Speakers Bureau; Juno Therapeutics: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kite: 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; Janssen: 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. OffLabel Disclosure: Yes, these trials discuss off-label clinical trial investigation of lenalidomide plus R-CHOP in patients with newly diagnosed diffuse large B-cell lymphoma.

Introduction: Waldenström macroglobulinemia (WM) is characterized by circulating monoclonal IgM and bone marrow infiltration with lymphoplasmacytic lymphoma (LPL) cells. Presently, there is limited data to guide prognosis or treatment options of WM based on the proportion of lymphocytes or plasma cells in the LPL population on the pathology. In this study, we aim to look at differing clinical features and outcomes of patients with WM based on the plasma cell (PC) percentage in the diagnostic bone marrow biopsy. Methods Patients with WM seen at Mayo Clinic, Rochester, MN between January 2001 and December 2017, with a bone marrow biopsy and a corresponding serum free light chain (FLC) examination at diagnosis of WM were included. The percentage of lymphocytes and PCs in the marrow biopsy was determined based on morphology ± immunohistochemistry. On immunohistochemistry, CD138 and/or MUM-1 positivity was used to quantify PCs, whereas CD20 and/or PAX5 were used to quantify lymphocytes. Patients with ≥10% PC component in the lymphoplasmacytic (LPL) cells on bone marrow biopsy were considered to have WM with excess plasma cells (WMEPC), while those with &lt;10% PCs were considered to have lymphocytic WM (LWM). Continuous variables were compared using Wilcoxon test and categorical variables were compared using Chi square test or Fisher's exact test. Time-to-next therapy (TTNT) was defined as the period from initiation of first line therapy to start of second line therapy or death due to any cause before second line therapy. Time-to-event analyses were conducted using Kaplan Meier method. Results: Of 228 evaluable patients, 147 (64%) had ≥ 10% PCs in the initial marrow biopsy. The median follow-up was 3.4 years (95% CI: 2.3-4.3 years) for LWM and 4.3 years (95% CI: 3.4-4.8 years) for WMEPC (p=0.33). The baseline characteristics of WMEPC versus LWM are depicted in Table 1. Patients with WMEPC had lower bone marrow involvement by LPL (30%) compared to LWM (60%; p&lt;0.001) at diagnosis, but the rate of symptomatic hyperviscosity was higher in WMEPC during the disease course (Table 1). The TTNT was shorter for WMEPC [2.6 years (95% CI: 1.8-4.5 years)] compared to LWM [4.5 years (95% CI 3.2-8.2)], although it did not reach statistical significance (p=0.09, Figure 1). There was a trend towards shorter OS for WMEPC [Not reached (95% CI 7.2- NR)] compared to LWM [10.7 years (95% CI 7.3 -12.1 years); p=0.28], Figure 2. Of the 228 patients, 79% (n=182) had data available for systemic therapy. The rate of PR or better with frontline therapy was higher in rates in LWM compared to WMEPC (61 % vs 42% p=0.02, Table 1). Among WMEPC cohort, patients receiving either a proteasome inhibitor (PI)-based or an immunomodulatory (IMiD)-based combination as frontline therapy (n=16) had higher rates of partial response or better (68%) compared to non-PI/non-IMiD based therapy (n=114), p=0.04. Conclusion: WM with excess plasma cells at diagnosis is associated with a trend towards shorter TTNT and OS compared to WM with &lt;10% plasma cells in the lymphoplasmacytic population at diagnosis. Our preliminary data shows higher rates of partial response or better with the use of PI/IMiD based therapy, but the small cohort size limits the strength of this finding which needs to be validated externally. Disclosures Ansell: Bristol-Myers Squibb: Research Funding; Trillium: Research Funding; Bristol-Myers Squibb: Research Funding; Bristol-Myers Squibb: Research Funding; LAM Therapeutics: Research Funding; Mayo Clinic Rochester: Employment; Regeneron: Research Funding; Trillium: Research Funding; Bristol-Myers Squibb: Research Funding; Affimed: Research Funding; Seattle Genetics: Research Funding; Regeneron: Research Funding; Bristol-Myers Squibb: Research Funding; Affimed: Research Funding; LAM Therapeutics: Research Funding; Trillium: Research Funding; Mayo Clinic Rochester: Employment; Seattle Genetics: Research Funding; Mayo Clinic Rochester: Employment; Bristol-Myers Squibb: Research Funding; Seattle Genetics: Research Funding; Mayo Clinic Rochester: Employment; Trillium: Research Funding; LAM Therapeutics: Research Funding; Affimed: Research Funding; Affimed: Research Funding; Bristol-Myers Squibb: Research Funding; Regeneron: Research Funding; Mayo Clinic Rochester: Employment; Trillium: Research Funding; Bristol-Myers Squibb: Research Funding; Seattle Genetics: Research Funding; Regeneron: Research Funding; LAM Therapeutics: Research Funding; LAM Therapeutics: Research Funding; Regeneron: Research Funding; Mayo Clinic Rochester: Employment; Affimed: Research Funding; Mayo Clinic Rochester: Employment; Trillium: Research Funding; Regeneron: Research Funding; Regeneron: Research Funding; Seattle Genetics: Research Funding; Affimed: Research Funding; Seattle Genetics: Research Funding; Mayo Clinic Rochester: Employment; Trillium: Research Funding; Trillium: Research Funding; Bristol-Myers Squibb: Research Funding; Trillium: Research Funding; LAM Therapeutics: Research Funding; LAM Therapeutics: Research Funding; Regeneron: Research Funding; Regeneron: Research Funding; Affimed: Research Funding; Seattle Genetics: Research Funding; LAM Therapeutics: Research Funding; Seattle Genetics: Research Funding; Seattle Genetics: Research Funding; Affimed: Research Funding; Mayo Clinic Rochester: Employment; LAM Therapeutics: Research Funding; Affimed: Research Funding. Gertz:Spectrum: Honoraria, Research Funding; Janssen: Honoraria; Celgene: Honoraria; Prothena: Honoraria; Alnylam: Honoraria; Ionis: Honoraria. Dingli:alexion: Consultancy; Janssen: Consultancy; Millenium: Consultancy; Rigel: Consultancy; Karyopharm: Research Funding. Nowakowski:Selvita: Membership on an entity's Board of Directors or advisory committees; NanoString: Research Funding; MorphoSys: Consultancy, Research Funding; Genentech, Inc.: Research Funding; F. Hoffmann-La Roche Ltd: Research Funding; Curis: Research Funding; Bayer: Consultancy, Research Funding; Celgene: Consultancy, Research Funding. Dispenzieri:Alnylam: Research Funding; Celgene: Research Funding; Takeda: Research Funding; Pfizer: Research Funding; Janssen: Consultancy; Intellia: Consultancy; Akcea: Consultancy. Lacy:Celgene: Research Funding. Kumar:Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Takeda: Research Funding. Kapoor:Janssen: Research Funding; Cellectar: Consultancy; Glaxo Smith Kline: Research Funding; Amgen: Research Funding; Takeda: Honoraria, Research Funding; Sanofi: Consultancy, Research Funding; Celgene: Honoraria.

Background: Venetoclax (Ven) is a highly selective, potent, oral BCL-2 inhibitor that induces apoptosis in multiple myeloma (MM) cells and has shown synergistic activity with the proteasome inhibitor (PI) bortezomib (B) and dexamethasone (d). Ven ± d had encouraging clinical efficacy in both t(11;14) MM and in pts irrespective of genetic background when administered with B, with a tolerable safety profile in Phase 1 studies. Here, we provide updated efficacy and safety of Ven vs placebo (Pbo) + Bd in pts with relapsed/refractory (RR) MM, including subgroup analyses, in the BELLINI study. Methods: BELLINI (NCT02755597) was a Phase 3, randomized, double-blind, multicenter study of Ven or Pbo + Bd in pts with RRMM who received 1 - 3 prior therapies and were either sensitive or naïve to PIs. Pts were randomized 2:1 to receive Ven 800 mg/day or Pbo + Bd. Cycles 1-8 were 21-day with B 1.3 mg/m2 on Days 1, 4, 8, 11 + d 20 mg on Days 1, 2, 4, 5, 8, 9, 11, 12. Cycles 9+ were 35-day with B 1.3 mg/m2 on Days 1, 8, 15, 22 + d 20 mg Day 1, 2, 8, 9, 15, 16, 22, 23. The primary endpoint was progression-free survival (PFS) by independent review committee (IRC). Results: A total of 291 pts were randomized, 194 to the Ven arm and 97 to the Pbo arm. Median age was 66 (range, 36 - 87); 53% had ISS II/III disease; 54% received 2 or 3 prior lines of therapy; 59% had prior stem cell transplant; 70% had prior PI, 68% had prior immunomodulatory drug, 41% had both. Among pts with evaluable results, 18% had high-risk cytogenetics, 13% had MM positive for t(11;14), and 79% had high levels of BCL-2 protein by immunohistochemistry (IHC). In the primary endpoint analysis per IRC, the median PFS was 22.4 months (m) in Ven vs 11.5 m in Pbo (HR=0.630, p=0.01), with a median follow-up of 18.7 m (as of 26 Nov 2018). As of updated analysis based on a data cut-off of 18 March 2019, the median PFS (per investigator [INV]) was 22.9 m in Ven vs 11.4 m in Pbo (HR=0.587, p=0.001; Table 1), with a median follow-up of 22.7 m. Per INV, higher overall response (ORR, 84% vs 70%, p=0.009) and very good partial or better response (≥VGPR, 61% vs 40%, p<0.001; Table 2) rates were observed in Ven vs Pbo. Minimal residual disease negativity rate (by next-generation sequencing) was also higher in the Ven arm vs Pbo (MRD- [10-5], 13% vs 1%). Median duration of response was 23.4 m for Ven and 12.8 m for Pbo. In the overall population, median overall survival (OS) was not reached in either arm but continued to favor Pbo (HR 1.474, 95% CI=0.870-2.498). A total of 70 deaths have been reported, 51 (26%) in the Ven arm and 19 (20%) in the Pbo arm. In the safety population (N=289), the most common treatment-emergent adverse events (TEAEs; Ven/Pbo) were diarrhea (59%/48%), nausea (37%/22%), constipation (35%/31%), and fatigue (31%/32%). The most common Grade 3/4 TEAEs were neutropenia (18%/8%), pneumonia (17%/12%), anemia (16%/15%), thrombocytopenia (15%/30%), and diarrhea (15%/12%); 23%/12% discontinued Ven due to a TEAE. The rates of serious AEs (51%/51%) and serious infections (30%/28%) were comparable between arms. There were 69 deaths in the safety population: in the Ven arm, 14 were treatment-emergent (TE; treatment start to 30 days after discontinuation) and 36 were non-TE (>30 days after treatment discontinuation); in the Pbo arm, 1 was TE and 18 were non-TE. In the t(11;14) subgroup, median PFS has not been reached for pts receiving Ven, but was 9.3 m for Pbo (HR=0.095; per INV). In the t(11;14)-negative (neg) subgroup, median PFS was 22.4 m and 10.7 m for Ven and Pbo, respectively (HR=0.627; per INV). Median OS has not been reached in either arm for the t(11;14) and t(11;14)-neg subgroups, although the HR favored Ven in t(11;14) pts, and Pbo in t(11;14)-neg pts. Analyses indicate that low BCL-2 expression by IHC and high-risk cytogenetics (defined as t(4;14, t(14;16), or del(17p)) were associated with decreased PFS and OS in the Ven arm (Table 1). In the high-risk cytogenetics pts, median PFS was 11.4 m in both arms (HR=0.99), and median OS has not been reached in either arm but favors Pbo (HR=10.6). In the subgroup with low BCL-2 expression by IHC, median PFS was 11.7 m and 17.0 m for Ven and Pbo, respectively (HR=1.42), and median OS was 21.3 m in the Ven arm and not reached in Pbo (HR=4.58). Conclusions: Updated analysis of BELLINI continue to reflect a favorable benefit-risk profile in t(11;14) pts, with meaningful clinical responses and improvement in PFS, as well as a positive trend in OS in this subgroup when treated with Ven + Bd. Disclosures Moreau: Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria. Harrison:Janssen Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Consultancy, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: investigator on studies, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Cavo:sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel accommodations, Speakers Bureau; celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel accommodations, Speakers Bureau; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; bms: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; novartis: Honoraria. De La Rubia:Janssen: Consultancy; Takeda: Consultancy; Celgene Corporation: Consultancy; AMGEN: Consultancy; AbbVie: Consultancy. Popat:Celgene Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel, accommodations, expenses; Janssen: Honoraria, Other: travel support to meetings; Takeda: Honoraria, Other: travel, accommodations, expenses; GSK: Consultancy, Honoraria; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees. Gasparetto:Celgene: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed ; BMS: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed ; Janssen: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed . Hungria:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Salwender:Amgen: Honoraria, Other: Travel or accommodations; Takeda: Honoraria, Other: Travel or accommodations; Bristol-Myers Squibb: Honoraria, Other: Travel or accommodations; Sanofi: Honoraria, Other: Travel or accommodations; Celgene: Honoraria, Other: Travel or accommodations; AbbVie: Honoraria; Janssen Cilag: Honoraria, Other: Travel or accommodations. Suzuki:Ono: Research Funding; BMS: Honoraria, Research Funding; Takeda: Honoraria; Janssen: Honoraria; Celgene: Honoraria. Gay:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: 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; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees. Mikala:Takeda: Honoraria; Roche: Honoraria; Novartis: Honoraria; Janssen: Honoraria; Celgene: Honoraria, Research Funding; Amgen: Honoraria; AbbVie: Honoraria, Research Funding. Punnoose:Genentech, Inc.: Employment; Roche: Other: Stock/stock options. Hong:Genentech Inc.: Employment, Equity Ownership; Roche: Equity Ownership. Sood:AbbVie: Employment, Other: Stock/stock options. Jalaluddin:AbbVie: Employment, Other: Stock/stock options. Ross:AbbVie: Employment, Other: Stock/stock options. Ward:AbbVie: Employment, Other: Stock/stock options. Maciag:AbbVie: Employment, Other: Stock/stock options. Kumar:Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Takeda: Research Funding. OffLabel Disclosure: Venetoclax is a BCL-2 inhibitor that is FDA-approved in some indications. This presentation will focus on venetoclax for treatment of multiple myeloma, which is not an approved indication.

Abstract Pathogenic sequence variants (PSV) in BRCA1 or BRCA2 (BRCA1/2) are associated with increased risk and severity of prostate cancer. We evaluated whether PSVs in BRCA1/2 were associated with risk of overall prostate cancer or high grade (Gleason 8+) prostate cancer using an international sample of 65 BRCA1 and 171 BRCA2 male PSV carriers with prostate cancer, and 3,388 BRCA1 and 2,880 BRCA2 male PSV carriers without prostate cancer. PSVs in the 3′ region of BRCA2 (c.7914+) were significantly associated with elevated risk of prostate cancer compared with reference bin c.1001-c.7913 [HR = 1.78; 95% confidence interval (CI), 1.25–2.52; P = 0.001], as well as elevated risk of Gleason 8+ prostate cancer (HR = 3.11; 95% CI, 1.63–5.95; P = 0.001). c.756-c.1000 was also associated with elevated prostate cancer risk (HR = 2.83; 95% CI, 1.71–4.68; P = 0.00004) and elevated risk of Gleason 8+ prostate cancer (HR = 4.95; 95% CI, 2.12–11.54; P = 0.0002). No genotype–phenotype associations were detected for PSVs in BRCA1. These results demonstrate that specific BRCA2 PSVs may be associated with elevated risk of developing aggressive prostate cancer. Significance: Aggressive prostate cancer risk in BRCA2 mutation carriers may vary according to the specific BRCA2 mutation inherited by the at-risk individual.

Carrying premature termination codons in 1 allele of the ABCA7 gene is associated with an increased risk for Alzheimer’s disease (AD). While the primary function of ABCA7 is to regulate the transport of phospholipids and cholesterol, ABCA7 is also involved in maintaining homeostasis of the immune system. Since inflammatory pathways causatively or consequently participate in AD pathogenesis, we studied the effects of Abca7 haplodeficiency in mice on brain immune responses under acute and chronic conditions. When acute inflammation was induced through peripheral lipopolysaccharide injection in control or heterozygous Abca7 knockout mice, partial ABCA7 deficiency diminished proinflammatory responses by impairing CD14 expression in the brain. On breeding to App NL-G-F knockin mice, we observed increased amyloid-β (Aβ) accumulation and abnormal endosomal morphology in microglia. Taken together, our results demonstrate that ABCA7 loss of function may contribute to AD pathogenesis by altering proper microglial responses to acute inflammatory challenges and during the development of amyloid pathology, providing insight into disease mechanisms and possible treatment strategies.

Objective: The ε4 allele of the APOE gene ( APOE4 ) is the strongest genetic risk factor for Alzheimer disease when compared with the common ε3 allele. Although there has been significant progress in understanding how apoE4 (apolipoprotein E4) drives amyloid pathology, its effects on amyloid-independent pathways, in particular cerebrovascular integrity and function, are less clear. Approach and Results: Here, we show that brain pericytes, the mural cells of the capillary walls, differentially modulate endothelial cell phenotype in an apoE isoform-dependent manner. Extracellular matrix protein induction, tube-like structure formation, and barrier formation were lower with endothelial cells cocultured with pericytes isolated from apoE4-targeted replacement (TR) mice compared with those from apoE3-TR mice. Importantly, aged apoE4-targeted replacement mice had decreased extracellular matrix protein expression and increased plasma protein leakages compared with apoE3-TR mice. Conclusions: ApoE4 impairs pericyte-mediated basement membrane formation, potentially contributing to the cerebrovascular effects of apoE4.

Abstract Background CDI is an important cause of morbidity and mortality in SOT and HCT patients (pts). In retrospective single-center analyses, severe disease and relapse were common. We undertook a multicenter prospective observational study to evaluate outcomes of CDI among both SOT and HCT patients. Methods Adults with a first episode of CDI, defined as 3 liquid stools/24 h with the detection of C. difficile toxin in stool, within the first 2 years of SOT or HCT were recruited from 12 centers internationally in the INSIGHT network. At enrollment, demographics, comorbidities, medication histories and outcomes were collected prospectively over 90 days to assess clinical cure, recurrences and complications and to define baseline risk factors for clinical cure and recurrent CDI. Results 132 patients (81 SOT, 51 HCT (32 allogeneic)) were enrolled: median age 56 years, 62.1% were males, 97% were hospitalized. 80.3% were diagnosed by DNA assay. CDI occurred a median of 20 days post transplant (IQR: 6–133). 108 patients were on PPIs. 98.5% were on antibiotics before CDI. 1st line treatment regimen was oral vancomycin in 66 patients (40 SOT, 26 HCT), metronidazole in 48 patients (27 SOT, 21 HCT), both drugs in 14 (10 SOT, 4 HCT), fidaxomicin (3) and linezolid (1). Rejection within 60 days before CDI was uncommon (6.2% SOT) as was GVHD (27.5%). 110 patients (83%, 95% CI: 46–89)) (65 SOT, 45 HCT) had clinical cure; 18% (95% CI: 11–27) had recurrent CDI, 2 were admitted to the ICU due to CDI, 11 (8.3%) died (2 HCT related to CDI). Among baselines variables, only first-line regimen was associated with a higher rate of clinical cure (P = 0.003), most notably for SOT. Factors that did not have a statistically significant negative impact on clinical cure included sex, age > 60, race, country, transplant type, steroids, diabetes, CMV viremia/disease, WBC > 15,000, creatinine > 1.5 mg/dL, or specific antibiotic given prior to CDI. Higher recurrence rates were associated with metronidazole-only regimen (OR: 4.6, 95% CI: 1.6–12.8; P = 0.004) and a history of CMV after transplant (OR: 5.2, 95% CI: 1.7–15.7; P = 0.003). Conclusion Despite their immunosuppressed state, recurrence, ICU admission and mortality occurred in a minority of SOT and HCT with CDI. Initial use of metronidazole and CMV viremia/disease were associated with higher recurrence rates. Disclosures All authors: No reported disclosures.