ALBERT

Description: Abstract 1515 Poster Board I-538 BACKGROUND Acute chest syndrome (ACS) is a common cause of morbidity and mortality for individuals with sickle cell disease (SCD). The treatment of ACS is mainly supportive. Prior studies have shown that intravenous pulse-dose corticosteroids, such as dexamethasone, can decrease the duration and morbidity of ACS. However, such treatment may also precipitate ‘rebound‘ episodes of vaso-occlusive pain in some individuals that might negate the overall benefit of corticosteroids. Tapered corticosteroid therapy might decrease the rebound effect while maintaining therapeutic benefit. Therefore, we designed a prospective study to begin to test this hypothesis and to assess biomarkers that might clarify the therapeutic and toxic mechanisms of corticosteroids in SCD, predict outcome, and guide therapy. METHODS We conducted a multi-center, placebo-controlled pilot study to test the feasibility and safety of high-dose oral dexamethasone followed by a taper for ACS. Children and adults with SCD and ACS of any severity were randomized to dexamethasone (0.3 mg/kg q12h x 2, 0.3 mg/kg q24h x 2, 0.2 mg/kg q24h x 2, 0.1 mg/kg q24h x2, then stop) or placebo to start within 24 hours of diagnosis. All subjects received standard, protocol-directed supportive care for ACS. We defined the duration of ACS using a novel, objective tool that assessed rate and effort of breathing, oxygen saturation in room air, thoracic pain, and use of supplemental oxygen and ventilatory support. The primary outcomes were the duration of ACS and the duration of hospitalization for ACS. We also measured a panel of biomarkers before, during and after therapy. Inflammatory biomarkers included high sensitivity C-reactive protein and secretory phospholipase A2 (sPLA2). White cell and endothelial activation markers included sVCAM-1, sICAM-1, vWF:Ag and vWF:RCoF, sE-selectin, sP-selectin, sL-selectin, nitric oxide metabolites (NO), and whole blood tissue factor. We used generalized linear mixed models controlling for age to test for differences between treatment groups. RESULTS We enrolled 12 subjects (9 children, 3 adults; mean age 17.3 years, range 5 - 45) with homozygous sickle cell anemia at 4 centers and randomized 11 (1 drop-out) to either dexamethasone (N=5) or placebo (N=6). The objective ACS assessment tool was completed on all subjects without difficulty. In this pilot study, dexamethasone reduced the duration of hospitalization (41.5 vs 62.3 hrs; P=0.024), but not the duration of ACS (log of duration 2.4 vs 3.5 hrs; P=0.127), supplemental oxygen (17.5 vs 41.2 hrs; P=0.876), hypoxemia (13.8 vs 34.3 hrs; P=0.770), or total opioid usage in morphine equivalents (54.4 vs 68.8 mg; P=0.885). There were no statistically significant differences in adverse events between arms. However, 3 patients treated with dexamethasone had a painful event in the 2 weeks after hospital discharge (1 required re-hospitalization), compared to 1 patient in the placebo group (0 re-hospitalizations). No marked leukocytosis occurred in either treatment group, but the leukocyte count at 1-week follow-up had decreased less from baseline in the dexamethasone group compared to placebo (-17.7 vs -37.6%; P=0.028). The baseline sPLA2 concentration was 3 100 ng/mL in 4/5 and 4/6 patients in the dexamethasone and placebo arms. The white cell activation marker, sL-selectin was significantly decreased at 1-week follow-up in the dexamethasone group compared to placebo (573.8 ng/mL vs 742.8; change from baseline -121.2 vs 57.2; P

Description: Introduction: The pan-selectin antagonist rivipansel (GMI-1070) reduced intravascular arrest of red/white blood cell aggregates and improved blood flow and survival in a mouse model of sickle cell disease vaso-occlusive crisis (SCD VOC). In a Phase 1 study of GMI-1070 infusion in SCD adults at steady state (not in VOC), GMI-1070 decreased markers of cellular activation including neutrophil integrins, platelet/neutrophil aggregates, soluble adhesion molecule concentration; and markers of hemostatic activation. Furthermore, in a randomized Phase 2 study of SCD patients, treatment of VOC with GMI-1070 improved clinical outcomes such as time to resolution of crisis, time to discharge, and IV opioid use. Herein we report on the effect of GMI-1070 on biomarkers of cellular and hemostatic cascade activation from this Phase 2 trial. Methods: Patients in VOC enrolled in a prospective, randomized multi-center double-blind Phase 2 trial, ages 12-60 with HbSS or HbSB0thalassemia were treated with GMI-1070 q12h or placebo, in addition to standard treatment per institutional practice, until resolution of VOC. Clinical outcomes and pharmacokinetics have been previously reported (ASH 2013 Abstracts 775, 776, and 2206). Biomarker blood samples were drawn prior to study drug, and on a sparse sampling basis at times starting 30 minutes after initial dose and continuing until 36 hours after the last dose. Analytes measured included: soluble adhesion molecules E-selectin (sEsel), P-selectin, L-selectin, intercellular adhesion molecules 1 and 3, vascular cell adhesion molecule-1; and tissue factor and thrombin-antithrombin complexes by ELISA. At some sites, surface expression of monocyte b2 integrins MAC-1 & LFA-1 and platelet-monocyte aggregates were also measured by flow cytometry. Comparisons were made between the GMI-1070 and placebo groups, and serial expression levels were compared over time. Subgroup analyses were performed by hydroxyurea (HU) use, age group, baseline WBC, and responders' based on clinical outcomes. A mixed effect model was used to test the LS means difference at each time point and ANCOVA model was used to analyze the nadir, peak, and last dose values. Results: ELISA and flow cytometry samples were collected from 70 and 15 subjects, respectively. Soluble E-selectin levels were reduced for the group on GMI-1070 compared to placebo throughout hospitalization, and the differences were statistically significant at some time-points (Figure 1). Baseline sEsel levels were similar; but the peak, nadir, and level at last dose were all lower in the GMI-1070 group (Figure 2). Exploratory subgroup analysis by HU use, age group, response as measured by visual analog scale or opiate use, frequency of VOC in the past, and baseline white blood cell count revealed consistently lower sEsel levels in the GMI-1070 group. Many, but not all, of these differences reached statistical significance. Conclusion: GMI-1070 use during VOC resulted in consistent and significant reductions of sEsel, overall and in sub-groups as compared to placebo. These findings are consistent with the hypothesized effect of GMI-1070 on endothelial activation and/or apoptosis, mediated by inhibition of E-selectin, although an effect on sEsel clearance cannot be excluded. A Phase 3 study is planned to evaluate efficacy and safety of GMI-1070 as treatment for VOC. Soluble E-selectin concentrations may be useful as a biomarker of pharmacodynamic effect. Figure 1: sE-sel was reduced in the GMI-1070 group at all timepoints tested. Comparison to placebo for change from baseline over time is shown. *p

Description: A population-based cohort was used to determine the incidence and risk factors associated with development of venous thromboembolism (VTE) among Californians diagnosed with acute leukemia between 1993 to 1999. Principal outcomes were deep vein thrombosis in both the lower and upper extremities, pulmonary embolism, and mortality. Among 5394 cases with acute myelogenous leukemia (AML), the 2-year cumulative incidence of VTE was 281 (5.2%). Sixty-four percent of the VTE events occurred within 3 months of AML diagnosis. In AML patients, female sex, older age, number of chronic comorbidities, and presence of a catheter were significant predictors of development of VTE within 1 year. A diagnosis of VTE was not associated with reduced survival in AML patients. Among 2482 cases with acute lymphoblastic leukemia (ALL), the 2-year incidence of VTE in ALL was 4.5%. Risk factors for VTE were presence of a central venous catheter, older age, and number of chronic comorbidities. In the patients with ALL, development of VTE was associated with a 40% increase in the risk of dying within 1 year. The incidence of VTE in acute leukemia is appreciable, and is comparable with the incidence in many solid tumors.

Description: Background: Heparin induced thrombocytopenia (HIT) is a potentially life threatening complication of heparin administration caused by antibodies directed to the heparin-platelet factor 4 (PF4) complex and characterized by thrombocytopenia with a seemingly paradoxical high risk of thrombosis. Diagnosis is challenging, and is based on both clinical suspicion and laboratory detection of heparin-PF4 antibodies. The Warkentin 4 T’s “pre-test” probability and Chong’s “post-test” probability models have been developed to aid the diagnosis of HIT. Enzyme-linked immunoabosorbant assay (ELISA) laboratory measurement of heparin-PF4 antibodies is commonly used but has a low positive predictive value for thrombosis. Recent reports suggest that using an ELISA optical density (OD) value of ≥ 1 may improve the predictive value for thrombosis. Methods: We performed a retrospective analysis of 105 patients with suspected HIT who were treated with a direct thrombin inhibitor and evaluated the anti-heparin-PF4 ELISA OD values and Warkentin 4 T’s scores for sensitivity, specificity, and positive and negative predictive values (PPV and NPV, respectively) using the Chong’s score to define HITBoth the manufacturer’s OD threshold of 0.4 and ≥ 1 were evaluated. Table 1. Comparison of sensitivity, specificity, and predictive values for 4 T’s and OD levels, alone and in combination Sensitivity (%) Specificity (%) NPV (%) PPV (%) For calculations, Chong’s categories of definite/probable and unlikely were used to define presence or absence of HIT. 4T’s score (high and low) 81 100 80 100 OD level 0.4 69 75 65 78 OD level ≥1 38 85 52 77 4T’s + OD 0.4 94 100 94 100 4T’s +OD ≥1 69 85 81 75 Results: The sensitivity, specificity and predictive value of ELISA alone were inferior to the 4 T’s clinical scorings system. The sensitivity and negative predictive values of the 4T’s score were improved by considering positive or negative ELISA test results. Conclusions: Consistent with previous reports, the PPV of a high probability 4T score alone was 100%. Thus, ELISA results might not change clinical decisions in this situation. Alternative anticoagulation might be inappropriately withheld in 20% of patients if a low probability 4T score alone were to be used for decision-making. The addition of ELISA data using an OD level of 0.4 increased the NPV to a threshold that might be considered clinically acceptable (94%) to withhold therapy. Addition of an OD level of ≥ 1 did not improve the PV of the 4 T’s. However, in contrast to other studies that found better predictive value to using this higher OD threshold, our study group was limited to people considered high risk for HIT. Validation of this strategy in a prospective trial with clinical endpoints should be considered.

Description: Abstract 1632 GMI-1070 is a pan-selectin inhibitor that targets E-, P-, and L-selectins and has shown activity in multiple animal models of disease. Sickle cell disease (SCD) is characterized by periodic vaso-occlusive (VOC) episodes in which cell adhesion and aggregation play a crucial role. GMI-1070 has previously been shown to restore blood flow and improve survival in a mouse model of VOC, and safety and PK have been evaluated in normal, healthy volunteers in phase 1. Here we report clinical, safety, and PK results from the first study of GMI-1070 in individuals with SCD. Methods: An open-label phase 1/2 study was performed, enrolling adults with SCD at steady state. GMI-1070 was administered in two IV doses given on the same day: 20 mg/kg in the first dose, followed 10 hours later by 10 mg/kg. Patients were evaluated for safety on days 0, 1, 2, 7 and 28, including adverse events (AEs), routine clinical labs, and clinical exam. Plasma and urine concentrations of GMI-1070 were measured on days 0, 1, and 2, and PK parameters calculated and compared with those from healthy volunteers. Results: Fifteen adults were enrolled at three centers; 13 with HbSS, 2 with HbSB0thal. All were African-American, 9 were male, mean age was 32 years (range 18–50), mean weight was 64.7 kg; 4 were on hydroxyurea. In the past year, 6 had experienced VOC requiring medical care; 2 had ACS; 2 required transfusions; and 1 had an episode of priapism. Five were hospitalized in the past year; 12 were hospitalized in the past 5 years. All subjects received both doses of study drug; all but one were followed for 28 days. The PK in adults with SCD was in good agreement with that in the controls. The elimination half-life of GMI-1070 averaged 7.73 ± 2.45 hours (Figure). Renal clearance averaged 18.0 ± 7.93 mL/min and accounted for essentially all elimination. Physical exam parameters after dosing were unchanged, and all infusions were well tolerated. Four subjects reported headache within 24 hours of dosing, all of which were mild or moderate and resolved within 24 hours. Two subjects experienced VOC not requiring hospitalization, at 2 and 4 weeks after dosing. One subject had worsening anemia requiring transfusion 5 days after dosing. Other adverse events typical of SCD were reported without apparent association with study drug; none were serious adverse events. Routine labs demonstrated no changes from baseline (Hb, reticulocytes, platelets, electrolytes, glucose, ALT, LDH, BUN, Cr, bilirubin, urinalysis) with the exception of white blood cell counts (WBC) and absolute neutrophil counts (ANC). At 24 hours, mean WBC change from baseline was 1.9K/mm3, or 20% (p=0.076, using parametric test with mixed model); mean ANC change was 2.7, or 67% (p=0.019); all returned to baseline by 7 days. One individual had marked leukocytosis 24 hours after dosing (from 10.4 to 28K/mm3), returning to baseline by day 7; no other effects were observed in this subject. Mean C-reactive protein (CRP) increased at 24 and 48 hours, returning to baseline by day 7. Two subjects had marked increases in CRP: one exhibited leukocytosis with dosing and the other had a high baseline WBC count. There was otherwise no apparent correlation between PK, WBC/ANC, hydroxyurea use, or adverse events. In conclusion, GMI-1070, a pan-selectin inhibitor, when administered to adults with SCD at steady state, has a similar safety and PK profile to that in healthy volunteers. However, SCD patients had moderate WBC and ANC increases at 24–48 hours after dosing, which return to baseline without other observed symptomatic adverse events. This study supports further evaluation of GMI-1070 for the treatment of vaso-occlusive crisis. Disclosures: Styles: GlycoMimetics: Consultancy, clinical trial sponsorship. Wun:GlycoMimetics: Consultancy, clinical trial sponsorship. De Castro:GlycoMimetics: clinical trial sponsorship. Telen:GlycoMimetics: Consultancy, clinical trial sponsorship. Kramer:GlycoMimetics: Consultancy. Flanner:GlycoMimetics: Employment, Equity Ownership. Magnani:GlycoMimetics: Employment, Equity Ownership. Thackray:GlycoMimetics: Employment, Equity Ownership. Off Label Use: This drug (GMI-1070) has not been approved for any clinical indication.

Description: Abstract 851FN2 Introduction: E-selectin expression by endothelium plays dual roles in inflammation by supporting slow rolling and subsequently eliciting integrin activation and arrest of leukocytes. This process may be important for immune surveillance. In a previous mouse model of sickle cell disease, E-selectin mediated outside-in signaling results in upregulated leukocyte Mac-1 and increased red cell capture, exacerbating vaso-occlusion. This process was attenuated by infusion of GMI-1070, a novel synthetic small molecule pan-selectin antagonist. GMI-1070 is now in Phase II clinical trial to determine efficacy in treatment of vaso-occlusive crisis (VOC) of sickle cell disease (SCD). Here, we studied its dose dependent effects in SCD subjects not in VOC on neutrophil activation and its effects on E-selectin mediated β2 integrin activation and rolling and arrest in shear flow. Methods: Samples were obtained from 4 SCD subjects not in VOC enrolled in a Phase I study of the effects of GMI-1070, a pan-selectin antagonist that preferentially inhibits E-selectin. An intravenous (IV) loading dose of 20 mg/kg was followed 10 hours later by a dose of 10 mg/kg. Samples were drawn before the loading dose, then 4 and 8 hours after the initial infusion. Polymorphonuclear Neutrophil (PMN) activation was analyzed in whole blood and isolated cell assays. Monoclonal antibodies and fluorescent-activated cell sorting (FACS) were used to assay expression of CD11b/CD18 (Mac-1), CD62L (L-selectin), and the high affinity active conformation of CD18 (327C) as markers of neutrophil activation. E-selectin mediated activation of CD18 was achieved in isolated PMN by incubating with E-selectin-IgG and goat antibody F(ab')2 fragment to crosslink E-selectin-IgG PMN activation was assessed by surface expression of high affinity CD18 by the mAb 327C and FACS in the presence of various concentrations of GMI-1070. PMN rolling and arrest on an inflammatory substrate was quantified using a lab on a chip assay. Whole blood or isolated PMN were perfused through a microfluidic flow chamber at a shear stress of 2 dynes/cm2. The flow chamber had immobilized E-selectin and ICAM-1 to support PMN rolling and adhesion. Video recordings of PMN interacting with this substrate were taken to quantify the number of rolling versus arrested cells and to measure rolling velocity in the presence of GMI-1070. Results: An inverse relationship between the serum concentration of GMI-1070 and either activated CD18 or upregulated CD11b was observed. In the flow chamber assays, 6 of 7 samples showed GMI-1070 diminished PMN arrest that also correlated with diminished integrin activation. Incubation of PMN with GMI-1070 blocked CD18 activation in response to E-selectin-IgG cross-linking, with an IC50 of 0.5 mM. PMN rolling and arrest was measured following shearing of isolated PMN on E-selectin and ICAM-1 using a lab on a chip assay. The mean rolling velocity of 2 mm/sec was increased to 6 mm/sec at a GMI-1070 concentration of 20 mM, with an IC50 of 5.5 mM for the increase in rolling velocity. In contrast, an IC50 = 0.8 mM was required to antagonize the fraction converting from rolling to arrest under shear flow. Summary and Conclusions: There was a dose dependent inhibitory effect on PMN activation after IV administration of GMI-1070 as measured in ex vivo whole blood samples in a small cohort of SCD subjects at steady state. A systematic study of the activity of GMI-1070 on isolated PMN revealed two distinct patterns of inhibition. At low concentrations (IC50 = 0.5mM), GMI-1070 effectively blocked the capacity of E-selectin to activate CD18, in response to cross-linked ligands, and mediate arrest. Only at higher concentrations (IC50 = 5.5mM) did we observe a significant alteration in the capacity of GMI-1070 to increase the rolling velocity and frequency of capture on a substrate of E-selectin under fluid shear stress. This differential capacity to alter function reveals that slow rolling, which is mediated by recognition of a number of sialylated ligands on the surface of PMN can be distinguished from the processes associated with the transition to arrest. Thus, treatment with GMI-1070 at doses that efficiently block vascular occlusion may spare some PMN rolling and immune surveillance function. Disclosures: Simon: GlycoMimetics Inc.: Research Funding. Chase:GlycoMimetics Inc.: Research Funding. Thackray:GlycoMimetics, Inc.: Employment, Equity Ownership. Magnani:GlycoMimetics, Inc.: Employment, Equity Ownership.

Description: Background: Previous data has shown that cancer-related VTE is associated with reduced two-year survival for patients with several tumor types. The reason for the survival difference is not clear. Methods: Using the California cancer registry and hospital discharge data, we identified all cases diagnosed with colon, breast and lung cancer over a 6-year period. Patients with local or regional stage cancer who developed incident VTE within 2 years after the diagnosis of cancer were identified. The cause of death was determined using a master death registry. Each VTE case was compared to 4 case-controls without VTE after matching for age, race, sex, stage and number of medical co-morbidities. The odds ratio (OR) for dying from any cause and dying due to the underlying cancer in the subsequent 2 years was calculated. Results (Table): Approximately 40% of all deaths occurred 〈 30 days of the VTE diagnosis for all cancers. The longer the time interval between cancer diagnosis and VTE, the greater the relative risk of dying of cancer. Conclusions: Patients with lung, breast and colon cancer who developed VTE 〈 2 years after cancer diagnosis were significantly more likely to die, and death was attributed to the underlying cancer in a sizable percentage of these cases. This indicates that among patients initially diagnosed with local or regional stage cancer of the breast, colon or lung, VTE is frequently a harbinger or consequence of metastatic stage. Odds Ratio (OR) for Death and Death Due to Cancer VTE Cases 〈 2 Years From Cancer Dx N Died 〈 2 Years From Date of VTE (%) OR (CI) For Death in VTE Cases 〈 2 Years Cancer As the Cause of Death N (%) OR (CI) for VTE Cases to Die of Cancer % Deaths Due to Cancer CI = Confidence Interval Local Stage     Breast 545 85 (16) 4.1 (3.0 – 5.6) 30 (6) 4.5 (2.7 – 7.7) 53     Colon 377 130 (35) 3.9 (3.0 – 5.1) 58 (15) 5.0 (3.3 – 7.5) 45     Lung 234 150 (64) 3.7 (2.6 – 5.5) 110 (45) 3.0 (2.0 – 4.4) 73 Regional Disease     Breast 493 116 (24) 3.4 (2.6 – 4.4) 73 (15) 2.8 (2.1 – 3.9) 63     Colon 887 375 (42) 2.1 (1.9 – 2.6) 273 (31) 2.1 (1.8 – 2.5) 73     Lung 485 386 (80) 3.7 (2.8 – 5.0) 320 (66) 2.5 (2.0 – 3.3) 66

Description: Background: Ambulatory cancer patients at high-risk for venous thromboembolism (VTE) can be identified using a validated risk score. We evaluated the benefit of outpatient thromboprophylaxis with dalteparin in such high-risk patients in a multicenter randomized controlled trial. Methods: Cancer patients at high risk for VTE (Khorana score ≥3) and initiating a new systemic chemotherapy regimen were screened for VTE and, if negative, randomized to either dalteparin 5000 units daily subcutaneously or no prophylactic anticoagulation for 12 weeks. Subjects in both arms were screened with lower extremity ultrasounds every 4 weeks on study. Primary efficacy endpoint was any VTE over 12 weeks and primary safety endpoint was clinically relevant bleeding events over 13 weeks. The study was terminated due to poor accrual. Results: Of 117 enrolled patients, 19 were not randomized due to the presence of VTE on initial screening (N=10, 8.5%) or for other reasons (N=9). The mean age was 59 years with 46% female and 54% male, similar in both arms. The most common primary sites of cancer were pancreas, gastro-esophageal junction, lung and lymphoma. Over three-fourths of patients in each arm had an ECOG performance status of 0 or 1.Of 98 patients randomized, VTE occurred in 12% (N=6/50) of patients on the dalteparin arm and 21% (N=10/48) on the control arm (hazard ratio, HR 0.69, 95% CI 0.23-1.89) (absolute risk reduction 9%, relative risk reduction 42%, number needed to treat = 12). Major bleeding was similar (N=1) in each arm but clinically relevant bleeding was higher in the dalteparin arm (N=7 versus 1 in the control arm) (HR = 7.0, 95% CI 1.2-131.6). There was no difference in overall survival. Conclusions: Thromboprophylaxis is associated with a non-significant reduced risk of VTE with no effect on major bleeding or survival but increased risk of clinically relevant bleeding in this underpowered study population. The Khorana score successfully identifies patients with high incidence of VTE both at baseline and during study. The high incidence of baseline VTE suggests that consideration should be given to screening high-risk patients in clinical practice prior to starting systemic therapy. Future studies should continue to focus on risk-adapted approaches to reduce the burden of VTE in cancer. (Funded by NIH/NHLBI R01HL095109; clinicaltrials.gov identifier: NCT00876915). Table 1. Baseline Characteristics of Patients Enrolled in the PHACS trial Dalteparin Observation Total Enrolled (n) Baseline VTE, n (%) DVT PE Other reasons for not randomizing Randomized (n) Age, mean (SD), y --- --- --- --- --- 50 60 (10) --- --- --- --- --- 48 58 (12) 117 10 (9%) 6* (5%) 4 (3%) 9 98 59 (11) Gender, n (%) Female 21 (42%) 24 (50%) 45 (46%) Male 29 (58%) 24 (50%) 53 (54%) Primary Tumor Site, No. (%) Gynecologic 4 (8%) 4 (8%) 8 (8%) Colorectal 1 (2%) 3 (6%) 4 (4%) GE junction 8 (16%) 4 (8%) 12 (25%) Lung 6 (12%) 7(15%) 13 (27%) Genitourinary 2 (4%) 0 (0%) 2 (2%) Lymphoma 5 (10%) 2 (4%) 7 (15%) Breast 1 (2%) 1 (2%) 2 (2%) Pancreatic 19 (38%) 17 (35%) 36 (37%) Gastric 4 (8%) 6 (13%) 10 (10%) Other 0 (0%) 4 (8%) 4 (4%) Previous history of VTE, n (%) 4 (8%) 2 (4%) 6 (6%) *NOTE: 1 subject had both DVT and PE at baseline screening Abbreviations: DVT, deep vein thrombosis; PE pulmonary embolism; VTE, venous thromboembolism; ECOG: Eastern Cooperative Oncology Group Figure 1. Cumulative Incidence Curves for the Primary Efficacy Outcome in the Intention-to-Treat Population, According to Study Arm. Figure 1. Cumulative Incidence Curves for the Primary Efficacy Outcome in the Intention-to-Treat Population, According to Study Arm. Disclosures Khorana: Leo Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Boehringer-Ingelheim: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria; sanofi: Consultancy, Honoraria. Off Label Use: Randomized trial of dalteparin as prophylaxis. The drug is approved for treatment of cancer-associated thrombosis but not for prophylaxis.. Francis:Eisai: Consultancy, Research Funding; Portola: Consultancy, Honoraria; NHLBI: Consultancy; Lilly: Consultancy. Kuderer:Hospira: Consultancy; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Daiichi Sankyo: Consultancy. Carrier:Leo Pharma: Consultancy, Research Funding; BMS: Research Funding; Bayer: Consultancy, Honoraria; Pfizer: Consultancy. Ortel:Instrumentation Laboratory: Consultancy; Instrumentation Laboratory: Research Funding; Eisai: Research Funding; Daiichi Sankyo: Consultancy. Wun:Janssen: Consultancy. Iyer:Ipsen Pharmaceuticals: Consultancy; Genentec: Research Funding; Bristol Myers Squibb: Honoraria. Lyman:Amgen: Research Funding.

Description: Abstract 4854 Peptides are promising cancer-targeting agents—they are small, chemically stable, easy to synthesize and can be readily conjugated to toxins, radionucleotides, or drugs. The “one-bead one-compound” (OBOC) combinatorial libraries developed in the Lam lab consist of millions of beads, each displaying one unique peptide entity. Through high throughput screening peptide combinatorial libraries against cancer cell lines, peptides can be selected and engineered to recognize some certain receptors on the cell surface. From our previous screen, we observed that the LLP2A peptide sequence bound to the α4β1 integrin on the cell surface of a variety of malignant lymphoid cell lines. We hypothesize that more specific ligands against the α4β1 integrin on human patient lymphoma cells could be identified through screening focused LLP2A libraries. Two OBOC-focused combinatorial libraries based on the LLP2A peptide sequence were designed, synthesized and screened against human patient lymphoma cells to search for ligands with higher binding affinity. We selected the candidate peptide sequences that displayed a higher strength for the patient lymphoma cells using the whole cell binding assay, an in vitro approach for quantitating the strength of peptide interaction with cell surface molecules on the cancer cells. We are currently analyzing the data to determine the specific sequence requirements for higher affinity binding. Further assessment of the affinity and kinetics of integrin-peptide binding will be performed using flow cytometry. Disclosures: No relevant conflicts of interest to declare.

Description: Abstract 1413 Poster Board I-436 Objectives: There are relatively few centers across the United States that either specialize in SCD care or have day hospitals where patients can be evaluated and urgently treated for acute pain crises. While most patients come to the ED for management of an acute pain crisis, SCD patients are at risk for many life-threatening complications. Most patients with SCD require an ED visit at some point. The complexity of SCD warrants a comprehensive assessment in the emergency department. While it may be challenging to conduct such an assessment in the ED, a succinct decision support tool may help guide clinicians in the performance of such an assessment. The benefits of such an assessment would identify unmet patient needs and help guide ED management and referrals. The goal of this project was to develop a brief, easy to use tool that guides the emergency clinicians in the identification of such needs and aid in accomplishing the following goals: 1) rapidly and aggressively manage ED pain, 2) identify other life-threatening conditions, 3) decrease hospital admission rates, 4) decrease return visits to the ED, 5) identify and increase the number of referrals made from the ED setting, and 6) increase both patient and clinician satisfaction with the ED experience. Methods: A series of seven clinician and patient focus groups were conducted in four cities across the United States (Chicago, Denver, Durham, and New York) to obtain key stakeholder input. Visits at three SCD centers of excellence (University of Colorado Denver, Duke University, Virginia Commonwealth University) were conducted, a literature search was conducted, and the PI attended SCD clinics to observe practice patterns with sickle cell experts at the University of Illinois and University of Chicago sickle cell clinics. Focus group data was analyzed using qualitative methods and is reported elsewhere. All data was synthesized and a draft tool was created and reviewed by outside experts. Revisions were made. Results: The following six key decisions were identified as being critical in achieving the tools aims: (1) what is the correct triage level, (2) how should pain be treated, (3) does the patient require a diagnostic work-up, (4) should the patient be admitted to the hospital, (5) if discharged home, is there a need for analgesic prescriptions, and (6) does the patient need a referral to a sickle cell expert or mental health or social services? Supporting data elements for each decision were also identified and included as part of the tool which will be formulated into an easy to use algorithm. Data elements include key history and physical indicators of a potential high risk situation necessitating further evaluation, pain assessment and history of analgesic use, relationship with a sickle cell expert, ED and hospital utilization history, and evaluation of psychosocial needs (self-report of anxiety or depression, work/employment status, home situation). Conclusions: Critical decisions and associated supporting elements to facilitate ED management were identified. Future work will involve finalizing and testing this communimetric tool, which will guide emergency department evaluation and management, as well as guide analgesic management in real time. Disclosures: Tanabe: NIH, and Mayday Fund: Research Funding. Todd: NIH: Research Funding; Xanodyne: Consultancy; Merck: Consultancy; Alpharma: Consultancy; Abbott: Consultancy; Baxter Healthcare: Consultancy; Fralex Therapeutics: Consultancy; Intranasal Therapeutics: Consultancy; Baxter Health: Research Funding; Roxro: Consultancy.