Citations

Abstract Despite its efficacy, chimeric antigen receptor T-cell therapy (CART) is limited by the development of cytokine release syndrome (CRS) and neurotoxicity (NT). While CRS is related to extreme elevation of cytokines and massive T cell expansion, the exact mechanisms for NT have not yet been elucidated. Preliminary studies suggest that NT might be mediated by myeloid cells that cross the blood brain barrier. This is supported by correlative analysis from CART19 pivotal trials where CD14+ cell numbers were increased in the cerebrospinal fluid of patients that developed severe NT (Locke et al, ASH 2017). Therefore, we aimed to investigate the role of GM-CSF neutralization in preventing CRS and NT after CART cell therapy via monocyte control. First, we investigated the effect of GM-CSF blockade on CART cell effector functions. Here, we used the human GM-CSF neutralizing antibody (lenzilumab, Humanigen, Burlingame, California) that has been shown to be safe in phase II clinical trials. Lenzilumab (10 ug/kg) neutralizes GM-CSF when CART19 cells are stimulated with the CD19+ Luciferase+ acute lymphoblastic leukemia (ALL) cell line NALM6, but does not impair CART cell function in vitro. We have found that malignancy associated macrophages reduce CART proliferation. GM-CSF neutralization with lenzilumab results in enhanced CART cell antigen specific proliferation in the presence of monocytes. To confirm this in vivo, NOD-SCID-g-/- mice were engrafted with high disease burdens of NALM6 and treated with low doses of CART19 or control T cells (to induce tumor relapse), in combination with lenzilumab or isotype control antibody. The combination of CART19 and lenzilumab resulted in significant anti-tumor activity and overall survival benefit compared to control T cells (Fig 1A), similar to mice treated with CART19 combined with isotype control antibody, indicating that GM-CSF neutralization does not impair CART cell activity in vivo. This anti-tumor activity was validated in an ALL patient derived xenograft model. Next, we explored the impact of GM-CSF neutralization on CART cell related toxicities in a novel patient derived xenograft model. Here, NOD-SCID-g-/- mice were engrafted with leukemic blasts (1-3x106 cells) derived from patients with high risk ALL. Mice were then treated with high doses of CART19 cells (2-5x106 intravenously). Five days after CART19 treatment, mice began to develop progressive motor weakness, hunched bodies, and weight loss that correlated with massive elevation of circulating human cytokine levels. Magnetic Resonance Imaging (MRI) of the brain during this syndrome showed diffuse enhancement and edema, associated with central nervous system (CNS) infiltration of CART cells and murine activated myeloid cells. This is similar to what has been reported in CART19 clinical trials in patients with severe NT. The combination of CART19, lenzilumab (to neutralize human GM-CSF) and murine GM-CSF blocking antibody (to neutralize mouse GM-CSF) resulted in prevention of weight loss (Fig 1B), decrease in critical myeloid cytokines (Fig 1C-D), reduction of cerebral edema (Fig 1E), enhanced leukemic disease control in the brain (Fig 1F), and reduction in brain macrophages (Fig 1G). Finally, we hypothesized that disrupting GM-CSF through CRISPR/Cas9 gene editing during the process of CART cell manufacturing would result in functional CART cells with reduced secretion of GM-CSF. We designed guide RNA targeting exon 3 of the GM-CSF gene and generated GM-CSFk/o CART19 cells. Our preliminary data suggest that these CARTs produce significantly less GM-CSF upon activation but continue to exhibit similar production of other cytokines and exhibit normal effector functions in vitro (Fig 1H). Using the NALM6 high tumor burden relapse xenograft model as described above, GM-CSFk/o CART19 cells resulted in slightly enhanced disease control compared to CART19 cells (Fig 1I). Thus, modulating myeloid cell behavior through GM-CSF blockade can help control CART mediated toxicities and may reduce their immunosuppressive features to improve leukemic control. These studies illuminate a novel approach to abrogate NT and CRS through GM-CSF neutralization that also potentially enhances CART cell functions. Based on these results, we have designed a phase II clinical trial using lenzilumab as a modality to prevent CART related toxicities in patients with diffuse large B cell lymphoma. Disclosures Ahmed: Humanigen: Employment. Sahmoud:Humanigen: Employment. Durrant:Humanigen: Employment. Russell:Vyriad: Equity Ownership. Kay:Morpho-sys: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Tolero Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees; Agios Pharm: Membership on an entity's Board of Directors or advisory committees; Cytomx Therapeutics: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Infinity Pharm: Membership on an entity's Board of Directors or advisory committees; Acerta: Research Funding. Kenderian:Novartis: Patents & Royalties; Tolero Pharmaceuticals: Research Funding; Humanigen: Research Funding.

Abstract Despite the remarkable outcomes and recent FDA approval of CD19 directed chimeric antigen receptor T (CART19) cell therapy in B cell malignancies, the durable responses in diffuse large B cell lymphoma are less than 40% and CART activity in chronic lymphocytic leukemia (CLL) is further limited. This is thought to be related to loss of CART persistence, poor trafficking to lymph nodes and inhibition by the leukemic microenvironment. Therefore, strategies to enhance CART cell function to overcome these limitations are needed. Recent studies have shown that abnormal expression of the receptor tyrosine kinase (RTK) AXL is associated with poor prognosis in human cancers. AXL signaling is associated with tumor proliferation, survival, metastasis, and drug resistance. Inhibition of AXL RTK with TP-0903, a high affinity AXL inhibitor has been found to induce robust apoptosis of CLL B cells. Based on the significant modulation of T cell functions observed with BTK inhibitor, we examined the role of AXL RTK inhibition with TP-0903 on T cell function in CLL and other B cell malignancies. First, we investigated the effect of AXL inhibition on T cell phenotype in normal donors. When naïve T cells were stimulated with PMA/Ionomycin and cultured with low dose TP0903, cytokine production was favorably altered through the promotion of Th1 and reduction of Th2 cytokines. This was associated with a significant reduction of inhibitory receptors (Fig 1a). Western blot of T cell lysates suggests low dose TP-0903 results in inhibition of LCK. When effector T cells and regulatory T cells (Treg) were treated with TP-0903 for 3 days, there was a preferential reduction of Treg (Fig 1b). Next, we investigated the influence of TP-0903 on CART19 cell phenotype and functions. Here, we used 41BB costimulated, lentiviral-transduced CART cells. Similar to our findings on naïve T cells, TP-0903 treatment led to polarization of CART cells into a Th1 phenotype when T cells were stimulated with the CD19+ mantle cell lymphoma (MCL) cell line JeKo or with leukemic B cells isolated from CLL patients (Fig 1c). TP-0903 treatment also significantly downregulated inhibitory receptors on activated CART cells, including a reduction of canonical cytokines known to be associated with the development of cytokine release syndrome (CRS) (Fig 1c). The combination of CART19 cells and TP-0903 yielded a synergistic antitumor activity against JeKo in vitro, at low E:T ratios (Fig 1d). Western blot of T cell lysates revealed phosphorylation of LCK was remarkably reduced in the presence of TP-0903, suggesting a mechanism for the observed Th1 polarization. We compared the transcriptome of activated CART cells treated with TP-0903 and more than 100 genes were differentially expressed compared to non-treated cells. Among these genes, immune synapse related genes such as cell junction and cell migration related genes were significantly increased in activated CART cells treated with TP-0903. To investigate the effect of AXL RTK inhibition of CART cells with TP-0903 in vivo, we established MCL xenografts through the injection of 1.0x106 of JeKo into NSG mice. A week after the injection of JeKo, mice were treated with either vehicle alone, TP-0903 (20mg/kg/day) alone, 0.5x106 of CART19 alone, or TP-0903 (20mg/kg/day)+0.5x106 of CART19. Three weeks after the treatment, mice were rechallenged with 1.0x106 of JeKo. Mice treated with CART19 and TP-0903 rejected the JeKo tumor challenge while mice previously treated with CART19 alone redeveloped JeKo, suggesting that AXL inhibition enhanced CART cell persistence (Fig 1e). Finally, we validated our preclinical findings in a correlative analyses of Phase I clinical trial of TP-0903 for patients with solid tumors (NCT02729298). Blood T cells from 3 patients were isolated and analyzed before and a week after treatment with TP-0903. Similar to our findings, there was a significant reduction in Tregs, reduction of inhibitory receptors and polarization to a Th1 phenotype. These findings will be further investigated in a planned Phase I clinical trial of TP-0903 in relapsed/refractory CLL (NCT03572634). In summary, we demonstrated for the first time that AXL inhibitior is capable of polarizing T cells into a Th1 phenotype, downregulates inhibitory receptors, reduces CRS associated cytokines and synergizes with CART cells in B cell malignancies. These findings encourage further study of TP-0903 as an enhancer of T cell immunotherapies. Disclosures Mouritsen: Tolero Pharmaceuticals: Employment. Foulks:Tolero Pharmaceuticals: Employment. Warner:Tolero Pharmaceuticals: Employment. Parikh:Janssen: Research Funding; Abbvie: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; MorphoSys: Research Funding; Pharmacyclics: Honoraria, Research Funding; Gilead: Honoraria. Ding:Merck: Research Funding. Kay:Gilead: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Infinity Pharm: Membership on an entity's Board of Directors or advisory committees; Tolero Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta: Research Funding; Agios Pharm: Membership on an entity's Board of Directors or advisory committees; Cytomx Therapeutics: Membership on an entity's Board of Directors or advisory committees; Morpho-sys: Membership on an entity's Board of Directors or advisory committees. Kenderian:Tolero Pharmaceuticals: Research Funding; Humanigen: Research Funding; Novartis: Patents & Royalties.

Abstract Introduction: Unprecedented clinical outcomes were reported after CD19 chimeric antigen receptor T cell (CART19) therapy and led to their FDA approval in diffuse large B cell lymphoma and in acute lymphoblastic leukemia. However, the complete response rate in chronic lymphocytic leukemia (CLL) after CART19 therapy is much lower, at approximately 20-30%, and the mechanism(s) for this relative lack of success is unclear. The dominant known mechanism(s) that prevent successful CART cell therapy in CLL have been limited to CART expansion and poor persistence. However, potential mechanisms are not limited to the CLL T-cell. Several immune defects have been identified in CLL that result from the complex bi-directional interaction between B-CLL cells and their microenvironment. In CLL the leukemic microenvironment is rich with extracellular vesicles (EVs) secreted by B-CLL cells. There is growing evidence that these vesicles play an important role in intracellular communication by the delivery of growth factors, genetic material and microenvironmentally relevant molecules. Therefore, we aimed to investigate the role and interactions of EVs in the diminished or absent CART response seen in some CLL patients. Methods: EVs were isolated from peripheral blood of 16 patients with untreated CLL at different Rai stages (8 patients had early and 8 had advanced stage disease) and risk profile by FISH (8 patients had low risk and 8 patients had high risk disease, based on the presence of 17p deletion). Cytometry was used to determine size, number of particles per µl, Annexin V and CD19 expression. These variables were correlated to the Rai stage and risk category of the disease. To investigate the impact of EVs on CART cell functions, CART19 cells were stimulated with either CLL EVs alone or in combination with the CD19 positive cell line JeKo1. After coincubation different effector functions were analysed. Results: Two patterns of EVs in CLL patients were identified; a single versus two distinct EV size populations (small [EVssmall]; 50-240nm, median=110nm) and large [EVslarge]; 180-560nm, median = 360nm Fig 1.A). In 25% of patients, EVs were CD19 positive (EVCD19+). CD19 positivity was detected only in patients with the EVslarge (Fig 1.B). The EVs concentration, CD19 expression (EVsCD19+ vs EVsCD19-), or the size (EVssmall vs EVslarge) did not correlate with disease stage (early vs advanced Rai stage) or risk profile of CLL (low vs high risk) although some variation could be seen (Fig 1.C). To investigate our hypothesis that EVs could modulate CART19 function, CART19 cell effector functions were examined in the presence of EVsCD19+, EVsCD19-, EVssmall, or EVslarge. EVs, 1.5x10e5 particles, alone were insufficient to stimulate CART19 cells. However when CART19 cells were stimulated with the CD19 positive cell line JeKo1, their effector functions were reduced only in the presence of EVsCD19+, 50,000 particles, 2.5 x 10e3/ µl, but not EVsCD19- at the same concentration. This included a significant reduction in CART specific killing (Fig 1.D) and a reduction in cytokine production. The impairment of CART cell functions was independent of the size of EVs, i.e. there was no impairment of CART functions with large or small size EVCD19- in co-culture. Summary: We identify CD19 positive large size EVs from patients with CLL and demonstrate that these EVs play a role in the leukemic microenvironment by reducing CART cell activity. Studies are ongoing to define the mechanism(s). Disclosures Parikh: Janssen: Research Funding; AstraZeneca: Honoraria, Research Funding; Pharmacyclics: Honoraria, Research Funding; Gilead: Honoraria; MorphoSys: Research Funding; Abbvie: Honoraria, Research Funding. Kay:Cytomx Therapeutics: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta: Research Funding; Infinity Pharm: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Agios Pharm: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Morpho-sys: Membership on an entity's Board of Directors or advisory committees; Tolero Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees. Kenderian:Tolero Pharmaceuticals: Research Funding; Humanigen: Research Funding; Novartis: Patents & Royalties.

Abstract Introduction: Diabetes mellitus is often cited as a VTE risk factor. However, persons with diabetes are frequently hospitalized for medical illness or undergo surgery, both major VTE risk factors. Thus, the association of VTE with diabetes independent of surgery or hospitalization is uncertain. Methods: Using longitudinal, population-based Rochester Epidemiology Project resources, we identified all Olmsted County, MN residents who met objective criteria for incident VTE over the 25-year period, 1976–2000 (n=1922), and one to two controls per case, matched on age, gender, Olmsted County residency, and length of medical history (n=2115). For cases and controls, we reviewed their complete medical history in the community for baseline characteristics previously identified as independent VTE risk factors, including clinically-diagnosed diabetes mellitus. We tested diabetes as a potential VTE risk factor both alone and after adjusting for other baseline characteristics, and in the subset of cases with idiopathic VTE, using conditional logistic regression. Results: Among all cases and controls, 231 (12%) and 199 (9.4%) had diabetes, respectively. Univariately, diabetes was associated with overall VTE (odds ratio [OR]=1.32; 95% CI: 1.07, 1.62; p=0.009). However, after controlling for body mass index (OR=1.04, p<0.001), hospitalization with major surgery (OR=25.2, p<0.001) or hospitalization for medical illness (OR=7.3, p<0.001), active cancer (OR=8.3, p<0.001) and varicose veins (OR=1.3, p=0.003), diabetes was no longer associated with VTE (OR=1.09; 95% CI: 0.85, 1.41; p=0.49). Among 458 idiopathic VTE cases and 518 matched controls, 43 (9.4%) and 46 (8.9%) had diabetes, respectively. Diabetes was not associated with idiopathic VTE (OR=1.07, 95% CI: 0.69, 1.67; p=0.76). Conclusions: Diabetes mellitus is not an independent risk factor for overall or idiopathic incident VTE.

Abstract Abstract 1241 Background: Hospitalization (with or without surgery) is a major risk factor for incident venous thromboembolism (VTE); however, the contribution of interim hospitalization to risk of recurrent VTE is unknown. Objective: To estimate risk of recurrent VTE related to interim hospitalization by conducting a population-based longitudinal review of provider-linked detailed medical records. Methods: We performed a nested case-cohort study. The cohort consisted of all Olmsted County residents with incident VTE 1988–2000 and ≥1 day follow-up. Cases were cohort members with recurrent VTE. Subjects were followed for all interim hospitalizations and warfarin use from incident VTE until earliest of emigration, death, recurrent VTE, or 12/31/2005. Data were analyzed using Cox proportional hazards and time dependent covariates to test for the effects of interim hospitalization and prophylaxis on VTE recurrence, adjusting for gender and age at incident VTE. Analyses were limited to subjects who survived free of death and recurrent VTE for ≥ 6 months. Results: Of 1262 incident VTE events (cohort), there were 309 VTE recurrences (cases). We randomly sampled 272 subjects from the cohort and 163 cases. Of the random samples, 210 incident events and 83 cases survived ≥ 6 months free of death and recurrent VTE and form our analysis population. The rate of secondary (interim) prophylaxis was approximately 50% for both incident events and cases, and was not predictive of recurrence (p=0.73). Male gender and interim hospitalization were associated with increased VTE recurrence even after adjusting for age at incident VTE and use of secondary warfarin prophylaxis. The hazard of recurrent VTE was nearly 10-fold higher for subjects with interim hospitalization versus those with none (HR: 9.6; 95% CI: 6.6, 13.8); men had a 1.5-fold increased recurrence rate compared with women (HR: 1.5; 95% CI: 1.1, 2.1). Conclusions: Our results, for the first time, show the importance of interim hospitalization as a predictor of VTE recurrence. Disclosures: No relevant conflicts of interest to declare.

Abstract Rearrangements involving TCF3 (E2A) at 19p13.3 are a common cytogenetic abnormality in B-lymphoblastic leukemia/lymphoma (B-LL) across all age groups accounting for at least 5% of B-LL. The most common translocation partner, PBX1 at 1q23, is associated with an unbalanced der(19) or a balanced t(1;19) in 80% vs. 20% patients, respectively, and results in a PBX1/TCF3 fusion transcriptional activator. Several other rearrangement partners have been described, and as such TCF3 is approaching the dubious status of a "promiscuous" gene partner. Clinically, our laboratory uses a dual-color, dual fusion PBX1/TCF3 FISH probe to characterize the most common gene fusion; however, this FISH strategy also allows for the identification of atypical disruptions of the TCF3 gene region, and may suggest a gene partner based on abnormal metaphases/metaphase-FISH. Interrogation of our pediatric leukemia database (ages 0-30) identified 219 patients with abnormal TCF3 FISH results. We selected 23 samples for mate-pair evaluation to test the methodology, characterize novel rearrangements and identify new TCF3 fusion partners. In total, 19 patient samples were successfully sequenced by Mate-Pair, including 13 samples with variants of the 1;19 translocation. Of the samples with TCF3/PBX1 fusion, 3 patients demonstrated novel insertional translocation events characterized by mate-pair. A total of 6 samples with undefined/unknown TCF3 partner genes were evaluated. The mate-pair results identified 5 samples with a t(12;19)(p13.31;p13.3), resulting in TCF3/ZNF384 fusion. Interestingly, two of the ZNF384 rearrangements were observed in the unbalanced form, suggesting a similar mechanism related to the der(19)t(1;19) regularly observed in the common PBX1-TCF3 rearrangement. From a karyotype perspective, since these rearrangements result in only a small portion of chromosome 12p translocated onto distal 19p, this rearrangement would "cryptic" by conventional karyotyping. One patient sample demonstrated a new TCF3 gene fusion partner (TEF), associated with a t(19;22)(p13.3;q13.2). Overall, our results demonstrate the utility of mate-pair evaluation as an adjunct methodology in the identification of novel TCF3 rearrangements in B-LL. We have successfully expanded the application of mate-pair to characterize other novel/cryptic abnormalities in various hematologic and oncologic neoplasms encountered in our laboratory. Disclosures No relevant conflicts of interest to declare.

Abstract Background: Non-Hodgkin lymphoma (NHL) is a relatively uncommon cancer with annual incidence of ~70,000 cases but with over 50 distinct subtypes. The goal of this study was to determine the extent to which the number of NHL patients treated annually in a facility (facility volume) affects overall survival (OS). This study used the National Cancer Data Base (NCDB), a nationwide oncology database covering 70% of the US cancer population, to address this question. Methods: We used the NCDB to identify patients with NHL diagnosed from 1998 to 2006. Year 2006 was used as a cut-off in order to allow a minimum of five years of follow-up for all patients. Only patients treated at facilities with continuous annual reporting to NCDB were included. We classified treatment facilities by quartiles based on facility volume (mean patients/year): Quartile 1 (Q1: 2-13), Quartile 2 (Q2: 14-20), Quartile 3 (Q3: 21-32) and Quartile 4 (Q4: ≥33). We used Pearson correlation methods to examine collinearity, unadjusted Kaplan-Meier methods to estimate OS rates, log rank test to compare survival distributions, and multivariable Cox proportional hazards model to examine the associations between hospital volume and OS adjusting for other covariates of interest. We also included random effects for hospital to more fully adjust for clustering of outcomes within hospitals. To examine non-linear effects of hospital volume, we utilized smoothing splines. Results: There were 278,985 NHL patients cared for at 1,151 facilities. The distribution of patients according to facility volume was Q1 (10.7%), Q2 (13.5%), Q3 (23.3%) and Q4 (52.5%) and according to facility type was academic (31.2%), comprehensive community (55.9%), community (10.6%) and other (2.3%) centers. The unadjusted median OS by facility volume was: Q1: 61.8 months, Q2: 65.9 months, Q3: 71.4 months and Q4: 83.6 months. After multivariable analysis adjusting for demographic (sex, age, race, ethnicity), socioeconomic (income, insurance type), geographic (area of residence), disease-specific (NHL subtype, stage) and facility-specific (type and location) factors, we show that facility volume remains an independent predictor of all-cause mortality. Compared to patients treated at Q4 facilities, patients treated at lower quartile facilities had a worse OS (Q3HR: 1.05 [95% CI, 1.04-1.06]; Q2HR: 1.08 [1.07-1.10]; Q1HR: 1.14 [1.11-1.17]). We adjusted for hospital as a random effect, performed sensitivity analyses removing primary payor and facility type (due to collinearity with age and facility volume, respectively), and adjusted for Charlson-Deyo co-morbidity score (available only for patients diagnosed after 2003) in secondary models and found similar results. Using smoothing splines, we found a significant non-linear effect of hospital volume on OS (P &lt;0.001). This is depicted in the Figure wherein the hazard ratio of 1.0 corresponded to the average predicted hazard, which occurred at a hospital volume of 59 patients per year. Conclusions: Patients who were treated for NHL at higher volume facilities had longer OS than those who were treated at facilities with a lower volume. This is the first study in the US using a national sample to show that a volume-outcome relationship exists in the medical management of cancer. Figure 1. Figure 1. Disclosures No relevant conflicts of interest to declare.

Abstract Abstract 476 Background: The burden of VTE among nursing home (NH) residents is known to be high. Yet very little data exist to help determine which NH residents to target for VTE prophylaxis. The need to characterize VTE risk in this population is especially great because the advanced age and high comorbidity that typify NH residents contribute to increased likelihood of adverse consequences from VTE prophylaxis. To compound the problem, results of our prior univariate analyses of certain factors known to contribute substantially to VTE risk in the general population (e.g., major surgery, medical hospitalization, trauma) suggest that impact of these factors on VTE may be less substantial among NH residents. Objective: To use the longitudinal population-based resources of the Rochester Epidemiology Project (REP) to investigate the contribution of multiple clinical characteristics to risk of VTE among NH residents. Methods: We took advantage of the previous identification of all Olmsted County, MN residents who met research criteria for incident VTE 1988 through 2005 (N=2,332). We then determined which individuals were resident of a local NH at time of VTE symptom onset, regardless of location of symptom onset (i.e., individuals whose VTE occurred in-hospital having been admitted from a NH were considered NH residents). For each such NH VTE case (N=269), we identified 2 same sex Olmsted County residents of similar age and duration of medical history who were also resident of a local NH at the time of the case's VTE event (i.e., index date) (N=538). We reviewed the detailed provider-linked medical records of NH VTE cases and NH non-VTE controls for 3 months before index for information on multiple characteristics identified or hypothesized as contributing to VTE risk in studies of the general population and other at-risk subgroups by our group and others (e.g., patient demographics, body mass index, major surgery, hospitalization for acute medical illness, outpatient surgical procedures, trauma/fracture, leg paresis, active cancer, superficial vein thrombosis, varicose veins, infections, diabetes mellitus, coronary artery disease, congestive heart failure, and multiple medications, including anticoagulants, statins, beta-blockers, ACE inhibitors and angiotensin II receptor antagonists). We tested and estimated the odds ratio associated with each factor using step-wise conditional logistic regression. Variables for which <10 cases or <10 controls exhibited the characteristic were excluded from analysis. Results: The first five variables to enter the model were urinary tract infection, active cancer, superficial vein thrombosis, pneumonia, and leg paresis. The respective odds ratios (95% confidence intervals) with all five in the model were 1.7 (1.2, 2.4); 2.1 (1.3, 3.5); 2.1 (1.3, 3.4); 1.9 (1.3, 2.8); 2.3 (1.3, 4.2); each p value was <0.01. Variables associated with high VTE risk in the general population (i.e., surgery, hospitalization for medical illness, trauma/fracture) were not included in the top five risk factors for NH residents. Conclusions: Infection is a potent VTE risk factor among NH residents. Our study results will help inform development of practice guidelines in the NH and stimulate future research on putative VTE mechanisms. REP data afford limited information on cognitive and physical disability, immobility, and need for NH care. Additional investigations are needed that combine information from clinical and NH assessments. Disclosures: No relevant conflicts of interest to declare.

Abstract Abstract 5118 Background: Increased factor VIII:C (FVIII:C) and hypofibrinolysis are VTE risk factors, and beta-blockers and angiotensin converting enzyme (ACE) inhibitors reduce FVIII:C and enhance fibrinolysis, respectively. Objective: To test the hypotheses that beta-blockers and ACE inhibitors reduce VTE risk. Methods: Using longitudinal, population-based Rochester Epidemiology Project resources, we identified all Olmsted County, MN residents with objectively-diagnosed incident VTE over the 13-year period, 1988–2000 (n=1306), and one to two Olmsted County residents per case matched on age, event year and duration of prior medical history (n=1500). For cases and controls, we reviewed their complete medical history in the community for previously-identified VTE risk factors (e.g., hospitalization with or without surgery, nursing home confinement, trauma/fracture, leg paresis, active cancer, superficial vein thrombosis and varicose veins), as well as body mass index (BMI), coronary artery disease (CAD), congestive heart failure (CHF), and the use of statins, beta-blockers, ACE inhibitors and angiotensin II receptor antagonist drugs. Using conditional logistic regression, we tested beta-blockers and ACE inhibitors/angiotensin II receptor antagonists for an association with VTE, both individually and after adjusting for age, BMI, previously-identified VTE risk factors, CAD, CHF and the use of statins. Results: Among cases and controls respectively, 191 and 173 received beta-blockers, and 171 and 154 received ACE inhibitors/angiotensin II receptor antagonists. Univariately, both beta-blockers (unadjusted OR=1.31; p=0.02) and ACE inhibitors/angiotensin II receptor antagonists (unadjusted OR=1.32; p=0.02) were modestly associated with increased VTE risk. However, after controlling for age, BMI, previously-identified VTE risk factors, CAD, CHF and the use of statins, beta-blockers (OR=1.06; 95% CI: 0.74, 1.51; p=0.75) and ACE inhibitors/angiotensin II receptor antagonists (OR=0.94; 95% CI: 0.65, 1.37; p=0.75) were no longer associated with VTE. Conclusions: Beta-blockers and ACE inhibitors/angiotensin II receptor antagonists do not appear to be protective against VTE. Disclosures: No relevant conflicts of interest to declare.

Abstract Abstract 2984 Poster Board II-960 In previous studies of venous thromboembolism (VTE) among all residents of Olmsted County, MN, the odds of VTE associated with surgery, medical hospitalization, or active cancer were extremely high (Univariate odds ratio [OR] =14.6; 4.6, and 8.4 respectively). We also showed that nursing home (NH) residency was an independent risk factor for VTE (OR =5.6). From a clinical practice perspective, it is important to identify which NH residents are at risk of VTE. While it might be assumed that, similar to estimates for the population generally, surgery, medical hospitalization, and cancer are associated with increased risk of VTE within the NH population, the answer remains unclear. We took advantage of the previous identification of all Olmsted County, MN residents who met research criteria for incident VTE 1998-2005 (N=1168). We then determined which individuals were resident of a local NH at time of symptom onset, regardless of location of symptom onset (i.e., for purposes of this study, individuals whose VTE occurred in-hospital having been admitted from a NH were considered NH residents). For each such NH VTE case (N=96), we identified 2 same sex Olmsted County residents of similar age and duration-of-medical-history who were resident of a local NH at the time of the case's VTE event (i.e., index date) (N=192). The detailed provider-linked medical records of NH VTE cases and NH non-VTE controls were reviewed for 3 months before index for surgery or medical hospitalization and for 6 months surrounding index for active cancer. Using conditional logistic regression, we tested and estimated the odds ratio associated with each of these potential risk factors. The proportions of NH VTE cases and NH non-VTE controls with surgery (33%, 28%), medical hospitalization (44%, 46%), and active cancer (12%, 9%) were similar. Univariate odds ratios (95% confidence intervals) and p values for surgery, medical hospitalization, and active cancer were 1.5 (0.7-3.1), p=0.30; 1.1 (0.6-2.1), p=0.74; and 1.4 (0.6-3.2), p=0.46 respectively. Compared to the entire Olmsted County population, the odds of VTE associated with surgery, hospitalization, and cancer are surprisingly much lower for NH residents. Additional investigation is needed to characterize the subset of NH residents at increased risk of VTE. Disclosures: No relevant conflicts of interest to declare.