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Key Points Cleaved HK is observed in many patients with cancer, suggesting activation of the contact system.EVs from cancer cell lines or patients with cancer express polyphosphate, bind and activate FXII, and are prothrombotic., Visual Abstract, Extracellular vesicles (EV) have been implicated in diverse biological processes, including intracellular communication, transport of nucleic acids, and regulation of vascular function. Levels of EVs are elevated in cancer, and studies suggest that EV may stimulate thrombosis in patients with cancer through expression of tissue factor. However, limited data also implicate EV in the activation of the contact pathway of coagulation through activation of factor XII (FXII) to FXIIa. To better define the ability of EV to initiate contact activation, we compared the ability of EV derived from different cancer cell lines to activate FXII. EV from all cell lines activated FXII, with those derived from pancreatic and lung cancer cell lines demonstrating the most potent activity. Concordant with the activation of FXII, EV induced the cleavage of high molecular weight kininogen (HK) to cleaved kininogen. We also observed that EVs from patients with cancer stimulated FXII activation and HK cleavage. To define the mechanisms of FXII activation by EV, EV were treated with calf intestinal alkaline phosphatase or Escherichia coli exopolyphosphatase to degrade polyphosphate; this treatment blocked binding of FXII to EVs and the ability of EV to mediate FXII activation. In vivo, EV induced pulmonary thrombosis in wild-type mice, with protection conferred by a deficiency in FXII, HK, or prekallikrein. Moreover, pretreatment of EVs with calf intestinal alkaline phosphatase inhibited their prothrombotic effect. These results indicate that polyphosphate mediates the binding of contact factors to EV and that EV-associated polyphosphate may contribute to the prothrombotic effects of EV in cancer.

Background: The relationship between venous thromboembolism (VTE) and lymphoma is well established. In recent years, direct oral anticoagulants (DOACs) have been adopted as a treatment option for cancer associated thrombosis, however the majority of data using DOACs is in solid tumor patients. Here, we report the risk of recurrent VTE, bleeding outcomes, and effect of VTE on survival among lymphoma patients treated in a large centralized cancer associated thrombosis clinic. Methods: We prospectively followed lymphoma patients referred to our clinic from 8/2014-01/2021. VTE events including deep venous thrombosis (DVT), pulmonary embolism (PE), and visceral vein thrombosis (VVT), were noted. Overall survival (OS) was estimated by Kaplan-Meier and compared using log rank test. Cumulative incidence rate of VTE was estimated and compared using Gray's method. Results: A total of 103 patients were referred to our clinic due to clinical suspicion of VTE, of whom 40 (38.8%) were diagnosed with an acute VTE. The median age of the study population was66 (range 19-88), 61.2% were male and 16.5% had prior VTE. Non-Hodgkin Lymphoma (NHL) compromised 87.4%, with diffuse large b-cell lymphoma (DLBCL) being the most common subtype. Most patients had stage 4 disease (55.34%), had high grade lymphoma (defined as grade 3-4) (51.46%), and were on antineoplastic treatment (71.67%) at the time of VTE diagnosis. Site of VTE was DVT in 35.9%, PE in 5.8%, both DVT and PE in 2.9% and VVT in 0.97% of patients. Of these, 21 (20.39%) received a (DOAC), 14(13.59%) received enoxaparin, and 2(1.94) had IVC filter placed due to contraindication to anticoagulation. VTE recurrence occurred in 10% patients (total n=4; 2 were on enoxaparin and 2 were on rivaroxaban). Cumulative incidence of VTE in all patients at 6 months was 1% (95% CI: 0-2.9%), at 1 year was 3% (95% CI: 0-6.4%) with no significant difference in VTE or bleeding rates between lymphoma types or grade groups (P >0.05) (Table 1). Of 37 patients on anticoagulation, 10.8% experienced bleeding events (n=4) , of which 1 (2.7%) had major bleeding on IVC filter and 3 (8.1%) had CRNMB (2 on enoxaparin and 1 on rivaroxaban) at 6 month follow-up. Median follow-up was 35.9 months (range: 0.4-77.7 months) and median 2 year OS was 76%, 95% CI (68-85%). Overall survival was negatively impacted by age (patients over age 65 had a 2 year OS rate of 67%95% CI (0.56-0.81), p=0.01). Lymphoma grade had no impact on OS (2-year OS rate= 0.69, 95% CI (0.57-0.84), P=0.1132) Conclusion: High grade and low grade lymphoma patients treated in our centralized cancer thrombosis clinic had a 10% chance of VTE recurrence when treated with DOAC or enoxaparin. Bleeding rates were low in both groups; however, we saw decreased overall survival in those treated with DOACs. This data adds to the growing knowledge of treating hematologic malignancies with direct oral anticoagulants, but larger studies are needed to study the safety and efficacy of these agents in lymphoma patients. Figure 1 Figure 1. Disclosures Khorana: Halozyme: Consultancy, Honoraria; Anthos: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Bayer: Consultancy, Honoraria. Angelini: Sanofi: Membership on an entity's Board of Directors or advisory committees.

Introduction Venous thromboembolism (VTE) is a common complication of both solid and hematologic malignancies. Risk factors for VTE and standard recommendations for prevention and treatment primarily pertain to solid tumor patients. There are fewer data in patients who have undergone allogeneic hematopoietic cell transplant (HCT). Therefore, we studied the incidence, risk factors, and impact of VTE on post-HCT outcomes. Methods We retrospectively reviewed 431 patients who underwent allogeneic HCT between 1/2014 and 8/2019 to identify patients with VTE. VTE was estimated with cumulative incidence methods. Risk factors for VTE were identified with Fine and Gray regression and results are reported as hazard ratio (HR) with a 95% confidence interval (CI). An apriori list of potential risk factors for VTE included age, gender, race, performance status, co-morbidity index, number of prior chemotherapy regimens, history of VTE, disease risk, donor/graft source, transplant conditioning regimen, and acute or chronic graft vs. host disease (GVHD). VTE was analyzed as a time-dependent covariate relative to other post-HCT outcomes. Results Patient characteristics are shown in the Table. The median age at time of transplant was 59 years, (range 18-76); 55.5% were male, the majority (90.7%) were White. The most common indication for transplant was acute myelogenous leukemia and myelodysplastic syndrome (70.3%). Within our cohort, 64 patients (14.8%) developed VTE after allogeneic HCT. The cumulative incidence of VTE at 1 year was 9% (CI 7-12%). Median time to VTE was 9.8 months (range 0.7-74.0) (Figure). Thrombosis site breakdown included the following: lower deep vein thrombosis (DVT) n=47 (74%), catheter related DVT n=12 (19%), DVT and pulmonary embolism (PE) n=12 (19%), PE alone n=4 (6%). Patients were most commonly treated with a direct oral anticoagulant (n=27, 42%), followed by enoxaparin (n=15, 23.4%). The majority of patients (n=38, 58%) were treated with anticoagulation for more than 6 months. Six (9.4%) patients had recurrent thrombosis after completion of anticoagulation therapy from the time of transplant until last known follow-up. Only 9 (14%) had an inferior vena cava filter placed due to contraindications for anticoagulation. In patients treated with anticoagulation, there was a low overall incidence of clinically significant bleeding (n=3, 5%). In multivariable analysis, age (HR 1.36 per 10-year increase, CI 1.09-1.70, P=0.006), history of VTE (HR 1.95, CI 1.09-3.48, P=0.024), and grade 2-4 acute GVHD (HR 1.75, CI 1.05-2.94, P=0.033) were significantly associated with VTE. VTE was not associated with relapse mortality (HR 0.95, CI 0.44-2.04, P=0.89), however VTE was significantly associated with an increased risk of non VTE-associated non-relapse mortality (NRM) (HR 4.09, CI 2.47-6.74, P Discussion VTE is an important complication after allogeneic HCT and is associated with significantly increased NRM and inferior OS. Older patients, those with a prior history of VTE, and patients with acute GVHD are at increased risk for development of VTE after HCT. We found an overall low risk of bleeding with anticoagulation and further study to investigate the role of prophylaxis in this high-risk cohort is needed. Figure 1 Figure 1. Disclosures Sobecks: CareDX: Membership on an entity's Board of Directors or advisory committees. Majhail: Incyte Corporation: Consultancy; Anthem, Inc: Consultancy. Angelini: Sanofi: Membership on an entity's Board of Directors or advisory committees. Hamilton: Syndax: Membership on an entity's Board of Directors or advisory committees; Equilium: Membership on an entity's Board of Directors or advisory committees.

Background: Patients with renal cell carcinoma (RCC) are at a higher risk of thromboembolism (TE) compared to other cancers. Immunotherapy (IO) is a mainstay in the treatment of advanced or metastatic RCC (aRCC). It is still unknown whether IO further increases the hypercoagulable status in this already high risk population. We present the first analysis of the incidence and outcomes of venous (VTE) and arterial (ATE) events in patients with aRCC treated with immunotherapy. Methods: All patients with aRCC treated with IO at the Cleveland Clinic from 1/2015 to 12/2019 were identified. Cumulative incidence analysis was done to calculate rates of TE over time, and Gray's test was used to determine difference in rates of TE among groups. Factors associated with overall survival (OS) were identified using Cox proportional hazards regression, and the impact of TE on OS was evaluated with TE analyzed as a time dependent covariate. Results: Of 351 pts, 75% were men (median age 65 years, 92% white). 81% had clear cell histology and 77% had International Metastatic RCC Database Consortium intermediate to poor risk disease. Median follow up 12.8 months (range 0.1-53 months). From RCC diagnosis to IO initiation, the cumulative incidence of TE was 6.1% (95%CI 3.3-9.1) at 6 months and 6.1% (95%CI 3.8-9.1 months) at 12 months. At the time of IO start, 12% of patients were on anticoagulation, not specifically for TE related events. IO was used as first line therapy in 43% of patients (median doses 8, range 1-81) and included single agent (54% nivolumab, 13% pembrolizumab, 0.6% durvalumab, 1% atezolizumab, 0.2% avelumab) or doublet (30% ipilimuamb and nivolumab). VTE occurred in 11% (n=37), of which 62% were DVT, 27% PE, or 11% both. DVT locations were 74% lower limb, 7% upper limb, 19% visceral vein. ATE occurred in 2% (n=6), 4 had cerebral vascular events and 2 had myocardial infarctions. There was no difference in TE rates in patients receiving single versus doublet IO (p= 0.7475) For all patients, the incidence of TE after initiation of IO was 4.4% (95%CI 2.6%-6.9%) at 6 months and 9.8% (95%CI 6.8%-13.4%) at 12 months. Of all TE events, 72% resulted in hospitalization (mean duration of hospitalization 4 days), 9% of which resulted in clot related mortality. TE related dose delay occurred in 21% of patients (mean delay of 13 days). There were no TE-related IO discontinuations. The impact of IMDC score and Khorana score with respect to OS were evaluated in separate multivariable models given overlap in variables for score calculation. TE (HR 3.23, 95% CI 2.07-5.03, p Conclusion: Patients treated with IO therapy had a high incidence of TE at 12 months from treatment initiation. TE is associated with risk of treatment delay, hospitalization and mortality. TE, IMDC poor risk, and Khorana score ≥ 2 are associated with poorer survival. Further investigations into IO-associated TE are needed to identify benefit from primary thromboprophylaxis. Disclosures Gupta: Astra Zeneca: Consultancy; BMS: Consultancy; Merck: Consultancy; Pfizer: Consultancy; Seattle Genetics: Consultancy; Exelixis: Other; Janssen: Other. Khorana:Leap: Research Funding; BMS: Honoraria, Research Funding; Merck: Research Funding; Array: Other: Research funding (to institution); Janssen: Honoraria; Bayer: Honoraria; Pfizer: Honoraria; Sanofi: Honoraria; Medscape: Honoraria; Leo Pharma: Honoraria; Seattle Genetics: Honoraria; Pharmacyte: Honoraria; Pharmacyclics: Honoraria.

Background: The treatment paradigm for cancer associated thrombosis (CAT) has evolved over recent years from using low molecular weight heparin (LMWH) to direct oral anticoagulants (DOACs). Some randomized trials suggest decreased rates of recurrent venous thromboembolism (VTE) in CAT patients treated with DOACs compared to LMWH but also reported increased rates of bleeding. The Cleveland Clinic Taussig Cancer Center has been treating cancer thrombosis in a centralized CAT clinic since 2014. Here we report our rates of bleeding and recurrent VTE in cancer patients treated with anticoagulation. Methods: We prospectively followed cancer patients referred to our clinic from 8/2014-10/2019. A total of 1548 patients were referred to the clinic, of whom 462 were diagnosed with an acute VTE. VTE events, including deep venous thrombosis, pulmonary embolism, and visceral thrombosis, were noted. The comparison of bleeding rates (defined using ISTH criteria for major and clinically relevant non major bleeding, CRNMB) among treatment groups (LMWH vs DOACs) was examined using chi-square test. Rate of recurrent VTE was analyzed using a competing model in which death was treated as a competing risk. Results: The study population comprised 462 patients with acute VTE with a mean age of 62.67±12.23 and 51.8 % males. Of these, 234 (52.9%) received LMWH, 161(36.4%) received DOACs, and 47 (10.6%) received other agents including warfarin for initial anticoagulation. Overall, the 6-month, 1 year, and 2-year VTE recurrence rate was 5.9%, 6.6%, 7.9%, respectively. Recurrent VTE rates were similar for LMWHs, DOACs and other agents (P>0.05). Of 368 patients for whom follow-up data was available, 74 (16.7%) had bleeding event , of which 25 (33.8%) had major bleeding and 49 (66.4%) had CRNMB at 6 month follow-up with no difference across three treatment groups (p=0.56). Conclusion: In this real-world practice setting, rates of recurrent VTE and bleeding were similar for DOACs and LMWH suggesting that with careful patient selection the concern for higher bleeding with DOACs in cancer patients can be safely overcome. Disclosures McCrae: Momenta Pharmaceuticals: Consultancy; Novartis: Honoraria; Rigel: Consultancy; Dova: Consultancy. Khorana:Merck: Research Funding; Medscape: Honoraria; Leo Pharma: Honoraria; Seattle Genetics: Honoraria; Pharmacyte: Honoraria; Pharmacyclics: Honoraria; Array: Other: Research funding (to institution); Janssen: Honoraria; Bayer: Honoraria; Pfizer: Honoraria; Sanofi: Honoraria; BMS: Honoraria, Research Funding; Leap: Research Funding.

Introduction: In recent years, direct oral anticoagulants (DOACs) have been adopted as a treatment option for cancer associated thrombosis (CAT). Randomized trials comparing anti-Xa drugs to low molecular weight heparin (LMWH) showed treatment with DOACs conferred less risk of recurrent venous thromboembolism (VTE), but found higher rates of clinically important bleeding, especially in patients with gastrointestinal (GI) malignancies. Given these findings, there is a need for additional data regarding the safety of DOAC use in GI malignancies. Here, we report bleeding events of GI cancer patients treated with anticoagulation in a large centralized CAT clinic. Methods: We evaluated a prospective cohort of patients referred to our CAT clinic from 8/2014-10/2019. Patients with primary gastrointestinal malignancies treated with therapeutic anticoagulation with LMWH or a DOAC for acute VTE were included. Bleeding was defined using the ISTH criteria for major and clinically relevant non-major bleeding (CRNMB). Bleeding rates were compared between luminal [anus/anal, colon, esophagus, rectal, stomach] and extraluminal GI cancers [gallbladder, liver/bile duct, and pancreas]. Patient characteristics associated with bleeding were evaluated with Fisher's exact test and the association of age with bleeding was analyzed by Wilcoxan rank sum test. Results: Of 463 patients with acute VTE, 73 patients (15.8%) with primary GI tumors were included in the analysis. Males comprised 57.5% of the population, median age was 62 (range 36-86), and 61.6% had stage 4 disease. Figure 1 shows a breakdown of tumor types. Enoxaparin was the most commonly used anticoagulant (n=48, 65.8%), followed by DOAC (n=25, 34.2%). Overall, 16 (21.9%) patients had a bleeding event within 6 months of treatment (7 major bleeds and 9 CRNMB). There was no difference in 6-month bleeding rate between patients treated with LMWH (n= 9, 18.8%) vs. DOAC (n=7, 28.0%), p=0.39. None of the clinical factors analyzed were significantly associated with bleeding (Table 1). There was no difference in bleeding rate in patients with luminal GI cancers vs. extraluminal GI cancers and no difference was found in a three-way association between site, treatment, and bleeding, p=0.40 (Table 2). Conclusions: In our centralized cancer thrombosis clinic, patients with GI malignancies had similar rates of major and CRNMB when treated with LMWH or DOAC. In both cohorts, bleeding rates were high within 6 months of starting anticoagulation. There were no statistically significant differences in bleeding rates based on several clinical characteristics evaluated in this study. Although limited by a small patient population, this study adds to the knowledge of treating GI malignancies with DOACs. There is a need for further prospective evaluations regarding the safety of DOAC use in GI cancer patients and there remains an unmet need for antithrombotic treatments that do not increase bleeding potential. Disclosures McCrae: Novartis: Honoraria; Momenta Pharmaceuticals: Consultancy; Rigel: Consultancy; Dova: Consultancy. Khorana:Bayer: Honoraria; Pharmacyte: Honoraria; Pharmacyclics: Honoraria; Array: Other: Research funding (to institution); Merck: Research Funding; Leap: Research Funding; BMS: Honoraria, Research Funding; Seattle Genetics: Honoraria; Pfizer: Honoraria; Sanofi: Honoraria; Medscape: Honoraria; Leo Pharma: Honoraria; Janssen: Honoraria.

Background:Patients with cancer are at high risk of both venous thromboembolism (VTE) and arterial events, however, little is known about the association between venous and arterial thromboembolic events in patients with cancer. In this study, we evaluated the incidence and relative risk of subsequent arterial thromboembolism in patients with a confirmed diagnosis of acute cancer-associated VTE. Methods:We conducted a retrospective cohort study at the Cleveland Clinic Taussig Cancer Institute of cancer patients with confirmed VTE who were referred to a centralized thrombosis clinic between January 2017-October 2019 with at least 6 months of follow-up. Arterial thrombotic events (ATE), including myocardial infarction, peripheral arterial thrombosis, and ischemic stroke, were identified by manual review of electronic medical records. The cumulative incidence rate of each ATE event was calculated. Results:The study population comprised 294 patients with a median age of (63.5) years (range 27-90), and 49.7 % were male. The cumulative incidence rate of overall ATE during the 6-month, 1-year, and 2-year follow-up period was 3.07%, 3.42%, and 3.42%, respectively. A total of 10 patients who experienced arterial events of whom 7 had ischemic stroke, 2 had myocardial infarction, 2 had peripheral arterial thrombosis where one patient had two arterial events of myocardial infarction and peripheral arterial thrombosis(Table 1 shows the incidence rates of arterial events). Amongst patients with ATE, 30 % were active smokers (n=3), 90% had hypertension (n=9), 20% had diabetes mellitus (n=2), 50% had a family history of coronary artery disease (n=5), 40% were on statin and daily aspirin use (n=4), 40% were obese with BMI >30 (n=4). 40% of ATE patients(n=4) were on a therapeutic anticoagulant therapy at the time of arterial thrombotic event (3 on enoxaparin, 1 on apixaban) Conclusion:Cancer patients with acute VTE have a substantial increased risk of subsequent arterial thromboembolism particularly in the first six months after VTE. Ischemic stroke was the most frequent arterial event and ATE events occured despite therapeutic anticoagulation in a large subset of our cohort. Further prospective studies are needed to better understand the risk of ATE in cancer patients, and further studies should be designed to mitigate the risk of arterial events in this patient population. Disclosures McCrae: Momenta Pharmaceuticals:Consultancy;Novartis:Honoraria;Rigel:Consultancy;Dova:Consultancy.Khorana:Pharmacyclics:Honoraria;Pharmacyte:Honoraria;Seattle Genetics:Honoraria;Leo Pharma:Honoraria;Medscape:Honoraria;Sanofi:Honoraria;Pfizer:Honoraria;Bayer:Honoraria;Janssen:Honoraria;Array:Other: Research funding (to institution);Merck:Research Funding;BMS:Honoraria, Research Funding;Leap:Research Funding.

Background: Venous thromboembolism (VTE) is a prevalent cause of morbidity in MM patients. The IMPEDE VTE score was recently proposed by Sanfilippo KM et al. in 2018 ASH annual meeting to predict VTE in MM. Herein, we report on the external validation of this score. Methods: We reviewed consecutive newly diagnosed MM patients who were treated at the Cleveland Clinic between 2010 and 2012. All treatment variables were collected as time-varying variables. Poor cytogenetic features were defined as monosomy 13 or 17, t(4;14), or t(4;16). We calculated the total IMPEDE VTE score for each patient as previously defined; immunomodulatory drug (IMiD) use (+3), BMI >25 kg/m2 (+1), pathologic pelvis/femur fracture (+2), erythropoiesis-stimulating agent use (+1), low/high dexamethasone use (+2/+4), doxorubicin use (+2), Asian race (-3), history of VTE (+3), central venous catheter use (+2), prophylactic aspirin or enoxaparin (-2), therapeutic anticoagulation (-5). Patients with IMPEDE VTE score of 6 were defined as low-, intermediate-, and high-risk groups, respectively. Cumulative incidence of symptomatic VTE after initiation of systemic treatment was calculated with death as competing risk and compared with the Gray's test. Overall survival (OS) was estimated by the Kaplan-Meier method and compared with the log-rank test. Multivariable Cox analysis was used to identify independent predictors of OS. Results: We identified 210 MM patients, 102 (49%) were female, 31 (15%) were black, and median age at diagnosis was 63 years (range: 30 - 91). Fifteen (7%) patients had VTE prior to MM diagnosis and 30 (14%) patients had pathologic pelvic or femur fracture at or after MM diagnosis. Poor cytogenetic features were seen in 65 (31%) patients. ECOG performance status at diagnosis was ≥2 for 33 (16%) patients. Sixty-seven (32%), 65 (31%), and 57 (27%) patients had ISS stage I, II, and III disease, respectively. MM subtypes were IgG, IgA, and light-chain disease for 109 (52%), 46 (22%), and 52 (25%) patients, respectively. IMiDs and low-dose dexamethasone were given to 145 (69%) and 205 (98%) patients, respectively. Seventy-seven (37%) patients underwent autologous hematopoietic cell transplant. Patient and treatment characteristics were compared between patients with and without VTE after MM diagnosis in Table 1. Twenty-two (10%) patients had symptomatic VTE within 6 months after initiation of systemic treatment for MM. When IMPEDE VTE score was calculated based on the risk factors during this time period, 37 (18%), 157 (75%), and 16 (8%) patients were in low-, intermediate- and high-risk groups, respectively. Six-months cumulative incidence of VTE in low-, intermediate- and high-risk groups were 2.7% (95% CI: 0 - 7.9), 10.8% (95% CI: 6.0 - 15.7), and 25% (95% CI: 3.8 - 46.2), respectively (p=0.011) (Figure 1A). Whereas, 39 (19%) patients were diagnosed with symptomatic VTE during median follow-up of 86 months. When the highest IMPEDE VTE score for each patient was calculated based on the risk factors at any time after initiation of treatment, 16 (8%), 151 (72%), and 43 (20%) patients were in low-, intermediate-, and high-risk groups, respectively. Seven-year cumulative incidence of VTE in low-, intermediate- and high-risk groups were 9.0% (95% CI: 0 - 25.7), 16.3% (95% CI: 10.3 - 22.3), and 29.3 (95% CI: 15.2 - 43.3), respectively (p=0.014) (Figure 1B). Seven-year OS of patients with and without VTE within 6 months after initiation of treatment was 50% (95% CI: 32% - 79%) and 46% (95% CI: 39% - 55%), respectively (p=0.4). On multivariable analysis, VTE vs no VTE within 6 months after initiation of treatment did not predict OS (HR 1.10, 95% CI: 0.46 - 2.66, p=0.8), whereas each 1-year increase in age (HR 0.99, 95% CI: 0.96 - 1.02, p=0.61), each 1 increase in ECOG performance status (HR 1.77, 95% CI: 1.24 - 2.53, p=0.002) and ISS stage (HR 1.50, 95% CI: 1.06 - 1.14, p=0.024), poor vs non-poor cytogenetics features (HR 4.38, 95% CI: 2.25 - 8.57, p Conclusion: In this cohort of MM patients, we showed that IMPEDE VTE score was able to stratify patients into distinct risk groups and can be a helpful tool to provide personalized strategies for thromboprophylaxis. Disclosures Anwer: In-Cyte: Speakers Bureau; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees. Valent:Takeda pharmaceuticals: Speakers Bureau; Amgen corporation: Speakers Bureau; Celgene corporation: Speakers Bureau.

Introduction Randomized trials of venous thromboembolism (VTE) treatment in cancer have primarily focused on the initial 6-month period and the risk/benefit of additional anticoagulant therapy beyond this time point has not been fully evaluated. Current guidelines recommend continuing full dose anticoagulation after 6 months in patients who have ongoing active cancer and/or those undergoing anti-neoplastic treatment. This recommendation, however, is based on little evidence. Here, we describe clinical outcomes of patients who have completed at least 6 months of anticoagulation. Our aim was to compare VTE recurrence, bleeding rate, and overall survival in patients who continued vs. discontinued anticoagulation after the initial 6-month treatment period. Methods We evaluated a prospective cohort of patients referred to the Cleveland Clinic cancer-associated thrombosis clinic from 8/2014-12/2018. We evaluated clinical characteristics, VTE recurrence, bleeding (major or clinically relevant non-major bleeding (CRNMB) as defined by ISTH criteria), and overall survival in patients who continued vs. discontinued anticoagulation after 6 months. Low-risk for recurrent VTE was defined as not having active cancer and not receiving systemic therapy. Statistical methods included t-tests, chi-squared tests, Cox model, and log rank test where appropriate. Multivariable analysis was performed to analyze outcomes of interest. Results The study population was comprised 284 (73.2%) patients who were followed 6 months after the initial VTE event. Of these, 93 (32.7%) did not continue anticoagulation beyond 6 months, and 191 (67.3%) continued anticoagulation treatment (table 1). Anticoagulation was discontinued for the following reasons: low risk (n=33, 35.5%), bleeding (n=12, 12.9%), clinical decision (n=4, 4.3%) and other including financial reasons (n=43, 46.2%; table 2). In patients who continued anticoagulation, 86/191 (45%) had stage IV disease and the most frequent cancers were hematologic malignancies (58/191, 30.4%) and gastrointestinal cancers (37/191, 19.4%). Low molecular weight heparin was the most commonly prescribed anticoagulant (110/191; 57.6%) followed by direct oral anticoagulants (68/191, 35.6%). There was no difference in the rate of recurrent VTE in patients who remained on treatment beyond six months (23/191; 12%) vs. those who stopped treatment at six months (11/93; 11.8%; p= 0.81; figure 1). In patients who continued anticoagulation 6-12 months after the initial treatment period, 13/191 (6.8%) had a bleeding event (major bleeding n=4, CRNMB n=9). There was 1 major bleed and no CRNMB in the group that stopped anticoagulation. After multivariable analysis, recurrent VTE was associated with worse overall survival [hazard ratio (HR) 1.88; 95% Confidence Interval (CI) 1.06-3.35, p=0.03]. Discussion This prospective analysis found no difference in the rate of recurrent VTE and more bleeding in patients who continued anticoagulation, although recurrent VTE rates were high in both cohorts. Furthermore, a recurrent VTE event was associated with worse overall survival. Emerging data with DOACs may alter recurrence rates and the ability to continue treatment beyond 6 months. Although limited by a small study population, this study adds to available data regarding outcomes beyond six months of treatment. Future studies should focus on exploring the outcomes of extending anticoagulation and better identifying patients at risk for recurrent VTE. Disclosures McCrae: Rigel Pharmaceutical: Membership on an entity's Board of Directors or advisory committees; Pfizer Pharmaceutical: Membership on an entity's Board of Directors or advisory committees; Dova Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Sanofi Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Khorana:Janssen: Consultancy; Bayer: Consultancy; Pfizer: Consultancy; Sanofi: Consultancy.

Background: Current guidelines recommend anticoagulation for the treatment of cancer associated thrombosis (CAT). In addition to risk of recurrent VTE, cancer patients are also at risk of bleeding complications. However, little is described in regards to bleeding risk, especially in the direct oral anticoagulant (DOAC) era. Although clinical trials have captured bleeding rates with low molecular weight heparin (LMWH) and DOACs, they have not described fatality rates due to bleeding events vs. progression of acute VTE. To better understand whether or not patients are more likely to die from a VTE occurrence or from a fatal major bleed with anticoagulation treatment, we sought to analyze the cause of death in cancer patients from a thrombotic event vs. a bleeding event within 90 days of diagnosis of CAT. Methods: We evaluated a prospective cohort of patients referred to our centralized CAT clinic at the Cleveland Clinic Taussig Cancer Institute from 8/2014-5/2018. We evaluated clinical characteristics, anticoagulation prescription, and death from cancer progression, VTE or major bleed within 90 days of initial VTE diagnosis. Date of death was determined by documented date of death or date of last contact. Major bleed was defined using the ISTH definition for major bleeding. Statistical methods included wilcoxon rank sum tests and fisher's exact tests where appropriate. Multivariable analysis was performed to identify risk factors associated with the cause of death within 90 days. Results: Data from 1100 patients were included in the analysis, of which 103 (9.4%) patients died during the follow up period. Of these patients, 46 died within 90 days of an acute VTE event which represents our study cohort. Average age was 68.7 years [SD 9.7] and 95.7% of patients had stage 4 disease. Isolated distal DVT events comprised 46.0% of our cohort and 54.0% were proximal events. Enoxaparin was used in 60.9% of cases, rivaroxaban in 23.9%, warfarin in 4.3%, and no anticoagulation (due to contraindication) in 10.9%. Cause of death was determined to be secondary to cancer progression in 80.4%, VTE in 6.5% and major bleed in 13.0%. After multivariable analysis, older age was associated with a higher risk of death from a major bleed (p=0.01). Proximal VTE events were associated with a higher risk of VTE related death compared to distal thrombosis (p Conclusions: This study demonstrates that cancer patients with VTE occurrence are at high risk of death within 90 days. Notable characteristics of our patient cohort were advanced age and stage 4 disease. There was no notable difference in cause of death regardless of type of anticoagulant used or gender. Bleeding related death was notably higher than VTE related death in our patient population, specifically in older individuals. We intend to further evaluate these findings in a larger cohort. This study adds to the limited literature of bleeding events during the treatment of CAT in the DOAC era. Disclosures Khorana: Bayer: Consultancy; Sanofi: Consultancy; Pfizer: Consultancy; Janssen: Consultancy.

Introduction: Although a randomized trial showed no difference in progression of VTE in patients with isolated distal deep vein thrombosis (IDDVT) treated with anticoagulation vs. serial ultrasound monitoring, cancer patients were excluded from this study and remain a high risk population. Furthermore, studies to evaluate the long-term clinical outcomes of IDDVT in cancer patients have been limited. Here we report patient outcomes from our experience in treating cancer-associated IDDVT. Methods: We evaluated a prospective cohort of patients referred to our centralized cancer-associated thrombosis (CAT) clinic at the Cleveland Clinic Taussig Cancer Institute from 8/2014-5/2018. We evaluated clinical characteristics, anticoagulation prescription, venous thromboembolism (VTE) recurrence rate, major bleeding, hospital admission, and overall survival in patients diagnosed with IDDVT compared to those with proximal events. Statistical methods included t-tests, chi-squared tests, Cox model and competing risks model where appropriate. Multivariable analysis was performed to identify risk factors associated with overall survival and recurrence rate. Results: Data from 1100 patients were included in the analysis. After excluding upper extremity DVT, a total of 302 (27.5%) VTE events were diagnosed, 122 (40.4%) of which were IDDVT. Of patients diagnosed with IDDVT, 14 (11.7%) had a history of prior VTE and 48 (55.8%) had documented stage 4 cancer (see table 1). Low molecular weight heparin (LMWH) was the most commonly prescribed anticoagulant (50.8%) followed by rivaroxaban (35.2%). Seven patients (5.7%) did not receive anticoagulation due to contraindication. Proximal events were seen more often in males vs. females (110/180 (61.1%) vs. 70/180 (38.9%), p=0.027 and in those with stage 4 disease vs. stage 0-3 (95/120 (79.2%) vs. 25/120 (20.8%), p=0.001. Rate of VTE recurrence (see figure 2) in patients initially diagnosed with IDDVT was similar to the rate of VTE recurrence in proximal DVT or pulmonary embolism (PE), with 1-year incident rate of 12.7% and 8%, respectively, (HR 1.31, 95% CI, 0.54 - 3.15, p= 0.55). There was no difference in rate of major bleeding 6 months after the initial event between patients with IDDVT and proximal events, 4/17 (23.5%) vs. 7/30 (23.3%), respectively, p=1.0. There was no difference in subsequent hospital admission between those with IDDVT and proximal events 48/122 (39.3%) vs. 73/175 (41.7%), respectively, p=0.77. After multivariable analysis, there was no difference in overall survival between IDDVT vs. proximal events HR 1.43 (95% CI 0.88-2.32), p=0.15 (see figure 1). Overall survival was negatively impacted in patients with stage 4 disease, hematologic malignancy, male gender, and symptomatic VTE. Discussion: This study demonstrates that cancer patients with IDDVT have a similar rate of VTE recurrence, subsequent hospital admission, rate of major bleeding, and overall survival compared to those with proximal events. These findings, if validated, suggest that treatment of cancer-associated IDDVT should mirror treatment of proximal events. Disclosures Khorana: Janssen: Consultancy; Bayer: Consultancy; Pfizer: Consultancy; Sanofi: Consultancy.

Background: Emerging data suggest that treatment of cancer-associated venous thromboembolism (VTE) with direct oral anticoagulants (DOACs) results in lower recurrence rate compared to low molecular weight heparins (LMWHs) at 6 months but with concern for increase in bleeding risks. The objective of this study was to determine occurrence of major bleeding as well as recurrent VTE events on treatment with DOACs or LMWHs in a cohort study. Methods: The cancer-associated thrombosis (CAT) clinic is a centralized service for care of cancer patients with suspected deep venous thrombosis (DVT) and/or pulmonary embolism (PE) established at the Tausig Cancer Institute of the Cleveland Clinic. We conducted a prospective cohort study of patients referred to this clinic between 8/2014 through 1/2018. The demographics, cancer types, VTE characteristics, treatment courses, and outcomes (VTE recurrence, major or clinically relevant nonmajor [CRNM] bleeding) were recorded for these patients. Standards of treatment at the CAT clinic shifted in late 2017 from use of LMWH, enoxaparin, to a DOAC, rivaroxaban for cancer-associated VTE. Current exclusion criteria for rivaroxaban use include recent active bleeding, GFR < 30 mL/min, severe hepatic impairment, thrombocytopenia (platelet count < 50,000), and/or expected malabsorption at the level of stomach or small bowel. For cancer patients considered at higher risk of bleeding, including patients with luminal gastrointestinal cancers with an intact primary; cancers at risk of bleeding from genitourinary tract, bladder or nephrostomy tubes; or patients with active mucosal abnormalities such as duodenal ulcers, gastritis/esophagitis or colitis, treatment with LMWHs is preferred. Major or CRNM bleeding was determined according to definitions outlined by the International Society on Thrombosis and Haemostasis. Results: The study population included 258 patients with acute VTE. Of these, 239 patients had DVT (93%), 34 had PE (14%), 15 had both (6.2%), and 3 had visceral vein thromboses (1.2%). The patients were 53% male with a median age of 65 ± 16 years. The most common cancer types were hematologic malignancies (19.5%, n = 50), primary brain tumors (11.2%, n = 29), lung (8.5%, n = 22), breast (7.0%, n = 18), and pancreatic cancers (6.6%, n = 17). Enoxaparin monotherapy was prescribed for 72.1% (n = 179 of 248) of patients. Other treatments included rivaroxaban (17.3%, n = 43), apixaban (0.8%, n = 2), warfarin (2.8%, n = 7), dalteparin (0.4%, n = 1), or no anticoagulation (3.2%, n = 8). Major bleeding occurred in 5% (n = 12 of 241) of patients treated with anticoagulation at 6 months of the initial event, including 5.0% (n = 9 of 179) of patients on enoxaparin and 4.7% (n = 2 of 43) of patients on rivaroxaban, and these differences were not significant (p > 0.95) (Figure 1). CRNM bleeding was observed in 16.2% (n = 29 of 179) of patients on enoxaparin and 11.6% (n = 5 of 43) of patients on rivaroxaban. The common cancer types for patients with major bleeding events included primary brain tumors (n = 4), genitourinary cancers (n = 2) and gastrointestinal cancers (n = 2) (Table 1). The 1-year incident rate of recurrent VTE was 11% for patients treated with enoxaparin and 9% for those treated with DOACs, and 2-year rate was 13% and 11%, respectively (Figure 2). Overall, there was no significant difference in the VTE recurrence rate calculated by the competing risk model between patients on enoxaparin compared to rivaroxaban (p = 0.19). Conclusions: Bleeding events of patients treated with enoxaparin was comparable to rivaroxaban for both major and CRNM bleeding events in this carefully selected real-world population. Patients receiving rivaroxaban reported a statistically insignificant but lower rate of recurrent VTE compared to those receiving enoxaparin. These findings support a recent change in ISTH guidance recommending rivaroxaban or edoxaban as initial treatment of cancer-associated VTE in selected patients. Disclosures Khorana: Sanofi: Consultancy; Bayer: Consultancy; Janssen: Consultancy; Pfizer: Consultancy.

Background : Selectins, among other adhesion-mediated functions, facilitate and augment thrombosis; standard anticoagulants address thrombosis but also increase bleeding risk. Previous work in animal models showed inhibiting E-selectin decreases venous thrombosis (VTE) and vein wall inflammation without adverse bleeding events, making E-selectin inhibition a favorable therapeutic candidate for VTE. GMI-1271 is a potent, specific E-selectin antagonist. Here we report final analysis of safety, PK, biomarker and bleeding risk profile for GMI-1271 in 2 phase 1 studies of healthy subjects. Methods: The first study was a blinded single ascending dose (SAD) evaluation of 2, 5, 20, or 40mg/kg of GMI-1271 (n=4/cohort), vs placebo control saline (n=4) or active control Lovenox 1mg/kg (n=4). The second was an open-label multiple ascending dose (MAD) study of 10 (n=3) or 20mg/kg (n=3) of GMI-1271 QD d 1-5 vs Lovenox 1mg/kg (n=2) d 1-5. Assessments included safety (adverse events [AEs], clinical labs, bleeding time, PT/PTT, vitals, exam); PK (plasma and urine); and biomarkers. Biomarkers included ELISAs (CRP, D-dimer, IL-10, MPO, Prothrombin fragment 1.2, soluble E-selectin (sEsel), soluble P-selectin (sPsel), sICAM, Thrombin-antithrombin complex (TAT), Tissue Factor (TF), TNFα, VWF activity, and sCD40L); PicoGreen Assay for circulating DNA; flow cytometry (Platelet Monocyte Aggregates (PMA), Mac-1, LFA-1, and CD44) and Thromboelastography (TEG). See Table 1 for functional description. SAD remains blinded to GMI-1271 or placebo (GMI-1271/p). In SAD, we measured biomarker values at baseline, 8 and 24 h after dosing. Analysis was performed of biomarkers at each dose level and then pooled by GMI-1271/p vs Lovenox. In MAD, we measured biomarker values at baseline and day 4. Comparisons were made using unpaired t-test. Results: In total, 32 subjects enrolled and received GMI-1271/placebo (GMI-1271/p; 20), GMI-1271 (6) or Lovenox (L; 6). Safety: All subjects completed dosing uneventfully. Safety findings for GMI-1271/p were unremarkable. No moderate or serious AE were seen. AE overall were as expected in healthy volunteers. In SAD, only 1/20 GMI-1271/p subjects experienced an AE possibly related to study drug (mild transient headache); 0/6 in MAD. In the L group we saw expected mild transaminitis and injection site bruising. In all studies, GMI-1271 had no effect on bleeding time, PT, or PTT. PK: Plasma levels, Cmax, and AUC increased in a linear manner. Cl, Vz, and t ½ were not dose dependent; no accumulation was seen with multiple dosing (Fig 1 and 2). TEG: In SAD, there was a tendency to increase R, K, and decrease A and MA with no change in % lysis in L vs GMI-1271/p. In MAD, we saw a similar trend as SAD except for an increase in % lysis in L. In the pooled SAD analysis, there was a statistically significant difference between GMI-1271/p and L (higher values) for R (p sEsel: In SAD, there was a trend for sEsel to decrease with treatment in all cohorts (combined GMI-1271/p vs L p= 0.017). In MAD, there was non-significant trend for sEsel to decrease between Day 0 and Day 4 in GMI-1271; sEsel levels trended upward with L in comparison. MPO: In SAD, there was a trend for increased values in L vs GMI-1271/p, except for the 40mg/kg cohort. When pooled, there was a significant difference between GMI-1271/p vs L (higher levels) p MAC-1 In SAD, there was no change. In MAD, there was a significant decrease in MAC-1 at the 10mg/kg dose (p No other notable trend was seen in the other biomarkers measured. Conclusion: We report a favorable safety, biomarker and bleeding profile for the E-selectin antagonist GMI-1271 in healthy subjects. There is no signal to suggest GMI-1271 increases bleeding potential based on adverse events, PT, PTT, bleeding time, and TEG values, unlike traditional anticoagulants. An additional unblinded analysis of the biomarkers will be presented at ASH. We note a trend for sE-sel to decrease with GMI-1271 treatment even in this healthy volunteer population, consistent with previous experience and as expected based on mechanism of action. A phase 1 study of GMI-1271 is currently ongoing to evaluate the safety and efficacy of E-selectin antagonism for the treatment of patients with calf vein DVT. PK Figures: Figure 1: SAD; Figure 2: MAD. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures Hemmer: GlycoMimetics, Inc.: Employment, Equity Ownership. Flanner:GlycoMimetics, Inc.: Employment. Parker:GlycoMimetics, Inc.: Employment. Li:GlycoMimetics, Inc.: Employment, Equity Ownership. Froehlich:Novartis: Consultancy; Janssen: Consultancy; Pfizer: Membership on an entity's Board of Directors or advisory committees; Boehringer-Ingelheim: Membership on an entity's Board of Directors or advisory committees; Fibromuscular Disease Society of America: Research Funding; Blue Cross/Blue Shield of Michigan: Research Funding; Merck: Consultancy. Magnani:GlycoMimetics: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Thackray:GlycoMimetics: Employment, Equity Ownership. Sood:Bayer: Research Funding.

Background Current guidelines recommend all cancer inpatients receive pharmacologic VTE prophylaxis in the absence of contraindications. This is extrapolated from trials showing the benefit of VTE prophylaxis in general medical inpatients and the known increased risk of VTE in cancer patients. However, given the increased risk of bleeding in cancer patients on anticoagulation (AC), it is vital to better define a subpopulation of cancer inpatients who most benefit from VTE prophylaxis. Current inpatient VTE risk models, including Padua, Caprini and IMPROVE, contain cancer as a variable and thus are not discriminative among cancer patients. Although the Khorana score (KS) stratifies VTE risk by cancer type, it was originally derived for cancer outpatients, and has yet to be validated for inpatients. Using a large multi-center cohort, we developed a novel VTE risk assessment model (RAM) specific to cancer inpatients, the CANclot score. Methods The Michigan Hospital Medicine Safety Consortium, a 49 hospital collaborative, established a multicenter retrospective cohort of medical inpatients > 18 years of age. Exclusion criteria include surgical patients, pregnancy, admission to the ICU or for palliative care, therapeutic AC, diagnosis of acute VTE, history of VTE within 6 months, and length of stay < 2 days. Patient demographics, clinical characteristics, and VTE events (both hospital associated and 90 day post discharge) were recorded. The CANclot risk assessment model was derived from logistic regression analyses of an apriori list of risk factors. Significant risk factors included in the CANclot scale were weighted based on the respective odds ratio estimates and an optimal cut-off was chosen. Model discrimination of the CANclot score was compared with other published risk models. Results Between 7/2012-7/2015, 18,956 cancer admissions were included. 2,464 (13%) had a pre-defined contraindication to prophylaxis (active bleed within 3 months, coagulopathy, or high risk brain metastasis). Of all admissions, 52.8% received VTE prophylaxis. A total of 327 (1.7%) VTE events were observed; 51/327 (15.6%) VTE events occurred during admission and 276/327 (84.4%) within 90 day f/u. When comparing AUC's of different risk models, CANclot ≥ 3 was superior to Padua ≥ 4 (p=0.01), Caprini ≥ 5 (p=0.01) and IMPROVE ≥ 2 (p=0.02). In our dataset 4,695 (25%) of patients had a CANclot score ≥ 3. Conclusion: The CANclot score is a novel VTE risk assessment tool derived specifically for cancer inpatients. Compared to other published risk prediction tools used in the general population, CANclot ≥ 3 shows an improved predictive ability for VTE and good yield, applying to 25% of the population. Improving VTE prediction in hospitalized cancer patients is crucial because targeting only those at highest risk may spare low risk patients from untoward bleeding complications from AC. Additionally, we found the majority of VTE events occurred during the 90 day followup period which calls for further attention to the possible need for extended prophylaxis in this population. Limitations to our study include a low overall rate of VTE, lack of some cancer specific variables, and that risk score values have not yet been corrected for optimism. The CANclot VTE risk score is a promising new tool for cancer inpatients that warrants further validation. 1 Patell R et al. JCO 34, 2016 (suppl; abstr 6598) Disclosures Flanders: Blue Cross Blue Shield: Research Funding; Wiley Publishing: Patents & Royalties. Sood:Bayer: Research Funding.

Introduction: Despite efforts toward prevention, thousands of patients suffer from venous thromboembolic disease (VTE), consisting of deep vein thrombosis (DVT) and pulmonary embolism (PE), each year; this results in significant morbidity and mortality. Clinical prediction rules, such as the Wells score, in conjunction with biomarkers like the D-dimer, are suggested by national guidelines to aide in evaluating for DVT. Substantial interest exists in developing improved diagnostic testing strategies and algorithms to limit the need for more costly, time consuming, and/or invasive testing. Novel biomarkers, like the soluble P selectin (sP-Sel), a cell adhesion molecule that functions to mediate thrombus formation and amplification, have shown promise in this area. While cancer patients suffer from a high burden of VTE, the D-dimer and Wells score are less helpful in this group. This is due to non-specific D-dimer elevations in these patients, and cancer being part of the Wells risk stratification schema. We sought to identify a more specific combination of biomarkers and Wells score, for the diagnosis of DVT that would apply to cancer patients as well. Methods: We previously performed a prospective cohort study of adults presenting with symptoms of DVT afflicting the upper or lower extremities (Vandy et al. J Vasc Surg Venous Lymphat Disord., 2013). Patients were enrolled from December 2008 to July 2013. Those with isolated calf DVT, superficial venous thrombosis, pregnant or breastfeeding, on therapeutic anticoagulation, or with symptoms of simultaneous upper and lower DVT were excluded. After informed consent was obtained, clinical characteristics and biomarkers (D-dimer, C-reactive protein (CRP), Von Willebrand Factor activity (VWF), and sP-Sel) were collected, and duplex ultrasonography was performed to determine if DVT was present. In this subset analysis, cancer patients were compared to non-cancer patients with regards to thrombotic risk factors, biomarker values, and to assess the test characteristics of various combinations of biomarkers and Wells score. Results: A total of 373 patients were enrolled, 151 (40%) in the cancer group, compared to 222 (60%) in the non-cancer group. Cancer patients were more likely to have a DVT on confirmatory testing (58.9% vs. 43.2%). Cancer patients tended to be older, male, have a lower BMI, more recent acute illness, and more central lines, relative to the non-cancer group. Non-cancer patients were more likely to have other potential risk factors for thrombosis, i.e. recent surgery, oral contraceptive use, and a family history of thrombosis. Biomarker values for CRP and sP-Sel were similar, however VWF and D-dimer values were significantly higher in the cancer patients (see table). D-Dimer > 500 with Wells score ≥ 2 was less specific for the diagnosis of DVT among cancer patients compared to non-cancer patients (p=0.003). However, D-Dimer ≥ 500 with sP-Sel ≥ 90 showed not only high specificity, but that specificity was not different between the cancer and non-cancer populations (p=0.88). sP-Sel ≥ 90 and Wells ≥ 2 had similar performance characteristics in both groups as well (p=0.54 for specificity, p=0.14 for positive predictive value (PPV)). Conclusion: Co-morbid risk factors for thrombosis among cancer patients included an older age, male gender, and an increased use of central lines. This group was less likely to have other potential thrombotic risk factors like family history or recent surgery. Our results concur with the finding that the D-dimer, combined with a clinical prediction rule, is not as helpful for DVT in cancer patients. Moreover, this study further supports sP-Sel as a specific test for DVT, that can be combined with clinical information (Wells score) or other laboratory data (D-dimer) to reflect the presence of DVT and potentially rule in clot; the test seems equally useful for both cancer and non-cancer populations. This could potentially be used to guide initial patient management in scenarios where imaging or further testing is not immediately available, such as in an outpatient clinic or rural area. Further exploration of the optimal strategy for utilizing biomarkers and clinical prediction rules in the diagnosis of DVT in cancer is needed. Table Table. Disclosures Sood: Bayer: Research Funding.

Introduction: VTE affects 1.6-1.8/1000 hospitalized patients per year; active cancer increases the rate of VTE 6-fold. Despite the high risk of VTE, studies show cancer patients receive inpatient VTE prophylaxis at a lower rate than general medical patients. In addition, VTE prophylaxis is often held for a platelet value of Methods: The Michigan Hospital Medicine Safety Consortium, a 49 hospital quality collaborative, has prospectively collected data on VTE risk factors and outcomes in medical patients > 18 years of age. Exclusion criteria include surgical patients, pregnancy, admission to the ICU or for palliative care, therapeutic anticoagulation, diagnosis of acute thrombus, history of VTE within 6 months, and length of stay < 2 days. We compared rates of VTE prophylaxis, bleeding and new VTE between cancer and general medicine patients who were eligible for prophylaxis (i.e. no contraindications including active bleed within 3 months, coagulopathy, or high risk brain metastasis). Student's t-test was used for continuous variables and chi-square for categorical data. Logistic regression was used to calculate odds ratio (OR). The number needed to treat and number needed to harm were used to derive a risk:benefit ratio. Results: Between 7/2012-7/2015, 86,634 admissions were captured in the cohort; 70,086 were eligible for VTE prophylaxis and included in this analysis. 22% of cases had a diagnosis of cancer. Table 1. Demographics on Admission Cancer (n= 15,166), % General Medicine (n=54,920), % p Race (Caucasian) 82.3 74.3 Of cancer admissions, 89.5% had solid tumors, 13.5% hematologic malignancies, 3.4% both and 20% metastatic disease. Active treatment for cancer was delivered 12 mo in 44.4% and no treatment or unknown in 20.3%. When compared to general medical admissions, cancer admissions were more likely to receive VTE prophylaxis (72.16% vs 69.21%, p Table 2. The Number Needed to Treat (NNT) to Prevent One VTE During Admission or 90 Days Post Discharge and Number Needed to Harm (NNH) to Cause One Major Bleed During Admission with Risk:Benefit Ratio (NNH:NNT) General Medicine Cancer NNT 1428 NNT 1000 NNH 2500 NNH 277.9 NNH:NNT 1.75 NNH:NNT 0.28 Conclusions: In this prospective inpatient cohort, we compared general medicine to cancer cases and found cancer admissions received VTE prophylaxis at a higher rate. This is different than previously reported data, likely due to the exclusion of patients with contraindications to prophylaxis. However, despite prophylaxis, cancer patients had a higher rate of VTE during admission and 90 days post discharge as well as more bleeding complications. The risk:benefit ratio of VTE prophylaxis is 6 times worse in cancer patients due to bleeding. While bleeding occurs more frequently in cancer patients with platelet count Disclosures Flanders: Institute for Healthcare Improvement and the Society of Hospital Medicine: Consultancy; Wiley Publishing: Patents & Royalties; CDC Foundation: Research Funding; Blue Cross Blue Shield of Michigan: Research Funding; Michigan Hospital Association: Research Funding. Sood:Bayer: Research Funding.

Background: GMI-1271 is a potent, specific E-selectin antagonist which targets interactions between cancer cells and the bone marrow niche thereby increasing tumor sensitivity to chemotherapy; avoids HSC mobilization; and inhibits thrombosis without increasing bleeding risk. Delayed inflammatory cell recruitment into the vein wall post thrombus induction indicates a possible decrease in leukocyte activation, which may be crucial in treating both acute and cancer associated thrombosis. Here we report first-in-human evaluation of GMI-1271 for safety (including bleeding), PK, and biomarker data for effects on adhesion and mobilization. Methods: Two Phase I single dose escalation DBRCT in healthy subjects evaluated 2, 5, 10, and 20 mg/kg IV doses of GMI-1271. Study 1 is complete and unblinded (GMI-1271 vs placebo). Study 2 is ongoing, remains blinded (GMI-1271 vs placebo) with open-label positive control (Lovenox), and is reported in aggregate. In both studies, assessments included safety (adverse events [AEs], clinical labs, bleeding time, PT/PTT, vitals, and exam); PK (drug levels in plasma and urine); and biomarkers (plasma soluble E-selectin [sEsel], sPsel, sICAM-1 levels; and blood CD34+ counts). Only sEsel and CD34+ are reported for Study 1; sEsel, sPsel, sICAM-1 for Study 2. Comparisons to baseline were made by ANOVA and paired t-test models; PK analyses were for total clearance (CL), volume of distribution (Vz), elimination half-life (t½), fraction excreted (Fe), and renal clearance (CLr). Results: Forty-six subjects enrolled; 30 received GMI-1271 (10 each at 2 and 5 mg/kg; 6 at 10 mg/kg; and 4 at 20 mg/kg) and 16 received control (13 placebo, 3 Lovenox). Safety: All subjects completed the studies; labs, vitals, and exam were unremarkable. Bleeding times and PT/PTT were unaffected by E-selectin inhibition. No serious AEs were seen. For Study 1, AEs were seen in 12/18 (66.7%) of those on GMI-1271 and 5/10 (50%) on placebo. AEs were mostly mild events at the infusion site (i.e. tenderness or erythema), and occurred in both groups. One moderate AE occurred (vasovagal reaction) in the 2 mg/kg GMI-1271 cohort. Three AEs were possibly related to drug: 2 in the 2 mg/kg cohort (infusion site bruise, lightheaded), and 1 in the 5 mg/kg cohort (metallic taste). For Study 2, AEs were seen in 12/15 (80%) of those on GMI-1271/placebo and 3/3 (100%) on Lovenox. All AEs were mild. In GMI-1271/placebo group, all AEs were considered unrelated to study drug; 3 were infusion site bruise (1 per dose level). In the Lovenox group, AEs were bruise at injection site (related) and blood in urine (possibly related). PK: Plasma levels, Cmax, and AUC increased in a consistent dose-related manner in both studies (figure). CL, Vz, and t½ were not dose dependent; the latter averaged ~2.3 hours. ~66% of the dose was excreted unchanged in the urine independent of dose level, and CLr averaged 86 mL/min, less than estimated CrCl, suggesting tubular reabsorption is one component of CLr. Biomarkers: In Study 1, the absolute CD34+ and %CD34+ cell counts were normal across all cohorts. There was no dose-response for changes in peripheral CD34+ counts after administration of GMI-1271 (doses 2-10 mg/kg). Plasma concentrations of sEsel were relatively constant in the placebo and GMI-1271 2 mg/kg cohorts, with significant reduction (vs baseline, p=0.012) at 48hrs post-2mg/kg dose only. In the 5 and 10 mg/kg cohorts sEsel decreased significantly post-dose (p Conclusion: First-in-human experience with the potent E-selectin antagonist GMI-1271 demonstrated favorable safety and PK at single doses up to 20 mg/kg. These findings are consistent with the glycomimetic class for safety at anticipated therapeutic levels. Biomarkers of physiologic effect demonstrated clear reductions in sEsel/sPsel; decreased leukocyte adhesion with lower sICAM-1 levels; and no CD34+ rise indicating no mobilization of HSCs. Studies of GMI-1271 are ongoing to evaluate activity in hematologic malignancies and thrombosis. Figure 1. Plasma concentrations and Cmax are consistent for GMI-1271 between Phase 1 studies. Figure 1. Plasma concentrations and Cmax are consistent for GMI-1271 between Phase 1 studies. Disclosures Sood: Bayer: Research Funding. Hemmer:GlycoMimetics: Employment, Equity Ownership. Flanner:GlycoMimetics: Employment, Equity Ownership. Kramer:GlycoMimetics: Consultancy. Nietubicz:GlycoMimetics: Employment, Equity Ownership. Myers:GlycoMimetics: Research Funding. Wakefield:GlycoMimetics: Research Funding. Magnani:GlycoMimetics: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Thackray:GlycoMimetics: Employment, Equity Ownership.

Introduction: Accurate and rapid diagnosis is essential in acute venous thromboembolism (VTE) to help prevent significant morbidity and mortality. Soluble P-selectin (sP-sel) is a cell surface ligand that aids in cell adhesion. It is released from activated platelets and damaged endothelial cells resulting in release of procoagulant molecules from leukocytes and aiding in thrombus generation. Our lab has previously shown elevated sP-sel is highly predictive of VTE in combination with clinical probability (Wells score). Current standards for ruling out VTE include combining Wells Score and plasma D-dimer; however, D-dimer increases with age and is less useful in the elderly. Age adjusted D-dimer, defined as 10*age in patients ≥50 years old, has been described as being more sensitive, which could rule out more clots in the elderly, sparing them from other diagnostic tests. Methods: We performed a prospective cohort study of patients ≥18 years old who presented with symptoms of deep venous thrombosis (DVT) in upper or lower extremities from December 2008 to July 2013. Exclusion criteria included isolated calf DVT, superficial thrombosis, indeterminate duplex scans, pregnancy or nursing mothers, therapeutic anticoagulation, and symptoms of simultaneous upper and lower extremity (LE) clot. After informed consent was obtained, biomarkers were drawn and duplex ultrasound was used to confirm or deny presence of acute clot. Our objective was to examine the accuracy of biomarker combinations and clinical probability score to rule in or rule out acute venous thrombus. Results: We recruited 461 patients to the study. Patients with positive lower extremity DVT were significantly more likely to be male, have a prior history of DVT, have active cancer or history of cancer, and be inpatient. Table 1: Biomarkers and Clinical Probability Score of Patients Presenting with Symptoms of LE DVT Table 1:. Biomarkers and Clinical Probability Score of Patients Presenting with Symptoms of LE DVT There were no significant differences in biomarkers between upper and lower extremity VTE aside from non-significance of sP-sel in upper extremity clots. We calculated the specificity, sensitivity, positive predictive value (PPV), and negative predictive value (NPV) of several combinations of biomarkers and clinical probability assessment. Table 2: Specificity and PPV Table 2:. Specificity and PPV Table 3: Sensitivity and NPV Table 3:. Sensitivity and NPV Using the age adjusted D-dimer did not improve the overall sensitivity when compared to the traditional cut off. However, sub-analysis demonstrated using D-dimer Conclusions: We found Wells ≥ 2 and sP-sel ≥ 90 ng/mL had the highest specificity of any combination of biomarkers, highlighting its clinical utility as a predictive biomarker of thrombosis. Using this combination would allow clinicians to accurately rule in venous thrombus without need for further imaging. In this study, we would have successfully identified 48 (25%) patients with acute thrombus without duplex ultrasound. Compared to the traditional cut off value, age adjusted D-dimer did not increase sensitivity in those >age 50, but its utility increased with age, making it a promising biomarker to safely rule out thrombosis in the elderly. Disclosures No relevant conflicts of interest to declare.