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TO THE EDITOR: The introduction of plasmapheresis with plasma exchange has increased survival in patients with thrombotic thrombocytopenic purpura (TTP) from

Introduction The United States Thrombotic Microangiopathy (USTMA) Consortium consists of high-volume US referral centers that are committed to collaborative research in TMAs. The USTMA Immune Thrombotic Thrombocytopenic Purpura (iTTP) registry has compiled retrospective data on demographics, treatments and outcomes in patients with iTTP to create the world's largest database of patients with this rare disease. While there is consensus on the use of therapeutic plasma exchange (TPE) for treatment of iTTP, there are no large randomized trials on which to base use of rituximab. The drug is frequently used for refractory or relapsed iTTP, but is currently being used more frequently for de novo (first episode) iTTP. We queried the USTMA iTTP registry to determine whether relapse free survival (RFS) is superior when rituximab is added to TPE and corticosteroids for treatment of iTTP. We hypothesized that the addition of rituximab would improve RFS at 5 years in both de novo and relapsing iTTP. Methods Following IRB approval at each institution, investigators independently reviewed individual patient records to confirm diagnostic criteria and entered demographic, treatment and outcomes data into the REDCap database housed at the University of North Carolina. The diagnosis of iTTP was defined as ADAMTS13 < 10% or ADAMTS13 < 20% with an inhibitor or antibody detected at any point or a clinical diagnosis of iTTP based on presenting characteristics, response to treatment and/or relapsing phenotype before ADAMTS13 testing became available (N=173). Relapse was defined as a recurrence of iTTP after at least 30 days of remission (recurrence within 30 days was considered an exacerbation, or continuation of the prior episode). To explore the effect of rituximab added to TPE and corticosteroids, we first assessed the treatment effect in de novo iTTP patients and then separately in relapse. We constructed Kaplan-Meier curves to compare RFS for patients treated with rituximab plus corticosteroids versus corticosteroids alone in both groups, and compared RFS at specific time points using the Klein method. To better understand whether other patient variables had an effect on RFS in both de novo episodes and relapses, ordinary (time-to-event) and mixed-effects (recurrent time-to-event) Cox proportional hazards models were used to examine the relationships of treatment, race/ethnicity, sex, age, treatment year, and presenting signs/symptoms with the outcome. Analyses were conducted using R version 3.5.2 (R Foundation for Statistical Computing, Vienna, Austria). Results As of July, 2019, the USTMA database contains 775 unique study patients with a confirmed diagnosis of iTTP with 1397 unique iTTP episodes. The treatment of patients' de novo iTTP episode was available for analysis in 375 patients, 188 of whom were treated with corticosteroids alone, 131 with corticosteroids plus rituximab, and 56 with other therapies. RFS was significantly higher in patients treated with corticosteroids and rituximab compared to those treated with corticosteroids alone at 1 year (0.93 vs. 0.78, p=0.0002) and 3 years (0.82 vs. 0.66, p=0.004) but not 5 years (0.60 vs. 0.56, p=0.39). In addition, the risk of relapse decreased with later treatment year for de novo iTTP (hazard ratio (HR) 0.95, 95% CI 0.92-0.99, p=0.03), consistent with rituximab use increasing over time, and was increased in African Americans compared with Caucasians (HR 1.83, 1.10-3.06, p=0.02). We then explored the treatment effect in all iTTP relapses (743 relapses in 426 patients). Here, a significant (p=0.0007) interaction between treatment and race was found. Among African Americans, we found no difference in RFS when rituximab was added (HR 1.15, 0.81-1.62, p=0.43). However, among Caucasians, RFS was significantly improved when rituximab was added (HR 0.15, 0.06-0.35, p Conclusions For de novo iTTP, adding rituximab to corticosteroids for immunosuppression likely delays but does not prevent relapse. Unlike in de novo disease, in patients with relapsed iTTP, we found a novel and significant interaction between race and treatment: while Caucasians had significantly improved RFS with the addition of rituximab, there was no effect on RFS in African Americans. Further investigation is warranted to determine the mechanisms of this difference in the response to rituximab in relapsed iTTP to improve outcomes in African Americans. Figure Disclosures Marshall: Sanofi: Membership on an entity's Board of Directors or advisory committees. Farland:Sanofi: Membership on an entity's Board of Directors or advisory committees. Metjian:Sanofi: Membership on an entity's Board of Directors or advisory committees. Raval:Bayer, Inc: Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees. Liles:Imara: Other: PI on Clinical trial- Sickle cell ; Shire: Other: PI on clinical trial Sickle cell ; Novartis: Other: PI on clinical trial Sickle cell . Baumann Kreuziger:CSL Behring: Consultancy; Vaccine Injury Compensation Program: Consultancy. McCrae:Rigel Pharmaceutical: Membership on an entity's Board of Directors or advisory committees; Sanofi Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Dova Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Pfizer Pharmaceutical: Membership on an entity's Board of Directors or advisory committees. Chaturvedi:Shire/Takeda: Research Funding; Sanofi: Consultancy; Alexion: Consultancy. Zheng:Clotsolution: Other: Co-Founder; Shire/Takeda: Research Funding; Ablynx/Sanofi: Consultancy, Speakers Bureau; Alexion: Speakers Bureau. Cataland:Ablynx/Sanofi: Consultancy, Research Funding; Alexion: Consultancy, Research Funding. Off Label Disclosure: rituximab for immunosuppression in TTP.

Background: Immune thrombotic thrombocytopenic purpura (iTTP) is a potentially fatal hematologic disorder characterized by thrombocytopenia, microangiopathic hemolytic anemia, and ischemic organ impairment. The incidence of iTTP is higher among African-Americans (AA), however, differences in presentation and outcomes have not been fully investigated. In a multi-center cohort of patients with iTTP from the United States Thrombotic Microangiopathy (USTMA) Consortium, we tested the hypothesis that AA race is an independent predictor of poor outcomes including iTTP related mortality and relapse. Methods: We queried data from the USTMA iTTP registry, which currently includes data from 785 individual patients from 15 institutions across the United States. Data from at least one iTTP episode are available for 734 patients. The cohort is 35.1% (N = 272) White, 58.7% (N = 455) African American, 0.4% (N=3) Asian, 1.8% (N=14) Hispanic, and 4.0 % (N=31) other/unknown race. We restricted our analyses to AA and White participants because of small numbers in the other groups. We compared presenting features and treatments using the chi-squared test and t-test for categorical and continuous variables, respectively. A relapse was defined as a recurrent iTTP episode occurring at least 30 days after last therapeutic plasma exchange. To evaluate relapse-free survival, we included only patients enrolled in the registry at their first TTP episode (144 White and 246 AA) since patients presenting with a relapse as their index episode are already confirmed to have relapsing iTTP. Kaplan Meier analysis was used to compare relapse-free survival in White and AA patients, and a Cox regression model was developed to evaluate the independent effect of race on relapse, adjusting for potential confounders including age, sex, and the use of rituximab. Results: Demographics and presenting features of 390 individuals (144 White and 246 AA) presenting with a first episode of iTTP are shown in Table 1. Presenting symptoms including fever, confusion, seizure, memory deficits, stupor, headache, stroke, chest pain, abdominal pain, fatigue, and dark urine were similar between Whites and AA except for petechiae, which were more frequently documented in Whites (28.8% vs 17.7%, p=0.011). Presenting laboratory studies were also comparable though AA had a higher rate of elevated serum troponin (50.6% vs 32.5%, p=0.003), lower hemoglobin level (8.27 ± 0.13 vs 8.81 ± 0.19, p=0.0176) and platelet count (20.3 ± 1.2 vs 26.2 ± 3.2, p=0.0432). In addition to therapeutic plasma exchange and corticosteroids, rituximab was administered to 23.7% of White patients and 22.7% of AA during their first iTTP episode (P=0.815). Median time to platelet count recovery (days of daily plasma exchange until normal platelet count for two consecutive days) was shorter in AA compared with White patients [5 (IQR 4, 10) vs. 8 (IQR 5, 14), log rank P = 0.004]. AA race remained a significant predictor of the shorter time to platelet count recovery [HR 1.44 (95% CI 1.12, 1.85), P=0.004] after adjusting for rituximab therapy [HR 0.60 (95% CI 0.0.46, 0.80), P Relapse-free survival after the first episode of iTTP was lower in AA than White patients (Figure 1). AA race was associated with the reduced relapse free survival [HR 1.79 (95% CI 1.08, 2.98), P=0.024] in a Cox regression model adjusted for age [HR 1.00 (95% CI 0.98, 1.01), P=0.683], sex [HR 0.96 (95% CI 0.60, 1.54), P=0.867], and rituximab therapy [HR 0.93 (95% CI 0.55, 1.59), P=0.806]. Conclusion: African Americans with iTTP have a higher relapse rate and shorter relapse free survival after the first episode of the disease compared with Caucasian patients, which is independent of age, sex and rituximab therapy. Contrary to our hypothesis, acute outcomes of iTTP (time to platelet count recovery and mortality) were not worse in AA patients. The factors contributing to the higher relapse rate in AA with iTTP need to be further investigated. Our findings suggest that AA patients may also benefit from closer follow up. Disclosures Farland: Sanofi: Membership on an entity's Board of Directors or advisory committees. Metjian:Sanofi: Membership on an entity's Board of Directors or advisory committees. Raval:Bayer, Inc: Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees. Liles:Shire: Other: PI on clinical trial Sickle cell ; Imara: Other: PI on Clinical trial- Sickle cell ; Novartis: Other: PI on clinical trial Sickle cell . Baumann Kreuziger:CSL Behring: Consultancy; Vaccine Injury Compensation Program: Consultancy. McCrae:Dova Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Pfizer Pharmaceutical: Membership on an entity's Board of Directors or advisory committees; Rigel Pharmaceutical: Membership on an entity's Board of Directors or advisory committees; Sanofi Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Zheng:Alexion: Speakers Bureau; Ablynx/Sanofi: Consultancy, Speakers Bureau; Clotsolution: Other: Co-Founder; Shire/Takeda: Research Funding. Cataland:Alexion: Consultancy, Research Funding; Ablynx/Sanofi: Consultancy, Research Funding. Chaturvedi:Shire/Takeda: Research Funding; Sanofi: Consultancy; Alexion: Consultancy.

Introduction:Acquired thrombotic thrombocytopenic purpura (TTP) is caused by autoantibodies against ADAMTS13 that prevent the cleavage of von Willebrand factor and allow the growth of microvascular thrombi, causing microangiopathic hemolysis and severe thrombocytopenia. Untreated TTP is almost always fatal but plasma exchange enables ~80% of patients to survive. Those who respond often have exacerbations or relapses that require more therapy. Exacerbations and refractory TTP usually can be treated effectively by combining plasma exchange, corticosteroids, and rituximab. A typical regimen for TTP is 4 weekly doses of rituximab 375 mg/m2, which is borrowed from protocols for B cell lymphomas. However, the pathogenic B cell mass in TTP is much less than in lymphoma and lower doses of rituximab may be enough. For example, case reports in TTP and studies in immune thrombocytopenia suggest that fixed doses of 100 mg and conventional doses of 375 mg/m2 have similar efficacy. Methods:The ART study (Adjuvant Rituximab in TTP, NCT01554514) was designed as a pilot safety/efficacy study of low dose rituximab (100 mg/week x 4 doses) plus standard plasma exchange and corticosteroids for TTP. The study enrolled at Washington University, Beth-Israel Deaconess Medical Center, Emory University, and Duke University. Eligibility criteria include age ≥18 years with acute TTP and ADAMTS13 Results:19 patients were enrolled. Two patients were subsequently excluded: 1 proved to have congenital TTP and was ineligible, 1 was withdrawn for protocol violations during the first week. The 17 evaluable patients have a median age of 48 years (range 30-71), 14 (82%) are African-American and 11 (65%) are female. All had a treatment response in a median of 5 days (range 3-16 days). 13 patients achieved normal ADAMTS13 levels after treatment, 2 had persistent severe ADAMTS13 deficiency, and 2 patients have yet to be assessed for ADAMTS13 responses. No patients had refractory disease and 2 had exacerbations; both achieved Durable Treatment Responses after 29 and 35 days. No patient died of TTP; 1 patient died of metastatic cancer. To date, 13 patients have completed 2 years of follow up and 3 (23%)have relapsed at 11, 19, and 22 months. For comparison, among 54 episodes of TTP at Washington University treated without rituximab, the primary endpoint occurred in 26 (48%). These included exacerbation in 23 (43%), refractory disease in 9 (17%), and both in 6 (11%). 6 patients died, and the incidence of relapse within 2 years was 51%. Treatment with low dose rituximab (100 mg) was associated with a significant decrease in the primary endpoint from 48% to 12% (P= 0.01, Fisher's exact test) and an encouraging decrease in 2-year relapse rate from 51% to 23% (P= 0.06). Conclusions:These results with low dose rituximab (100 mg x 4 doses) are consistent with reports that immediate treatment of TTP with standard dose rituximab (375 mg/m2x 4 doses) reduces the incidence of exacerbation and refractory disease, and prevents or delays relapses. A direct comparison of these regimens would be useful to establish whether low dose rituximab has similar efficacy with greater ease of administration, less cost, and less risk of infusion reactions and late complications. Disclosures Sadler: Ablynx: Consultancy. Zwicker:Quercegen: Research Funding; Daiichi: Honoraria; Parexel: Consultancy; Incyte: Research Funding.

Introduction: Acute myeloid leukemia (AML) is one of the most lethal types of adult cancer, with 10,460 deaths among 18,860 diagnoses in 2014. Although some patients are cured with induction and consolidation chemotherapy with or without stem cell transplantation (SCT), between 50-80% of patients will either fail to obtain a complete remission (CR; primary refractory AML) or will relapse. The median overall survival (OS) for relapsed and refractory AML patients is dismal, and there is no clear consensus on the management of relapsed/refractory AML. In this study, with extended follow-up, we set out to look at our own experience with primary refractory and relapsed AML patients in order to try to identify the best therapy and factors associated with improved outcomes. Methods: This retrospective study in AML patients seen at Emory University Hospital (EUH) was IRB approved. Descriptive statistics were used to characterize the demographic and clinical variables. Cytogenetic and molecular signatures were defined based upon the European Leukemia Network and Southwest Oncology group classifications (Döhner et al. 2010, Slovak et al. 2000). Response criteria were based upon the revised recommendations of the International Working Group (Cheson et al. 2003). The combined prognostic score was created using previously validated prognostic variables including age (< 60 vs. >/= 60), Eastern Cooperative Oncology Group Performance Status (ECOG PS; 0-1 vs. >/= 2), and cytogenetic and molecular signatures (favorable vs unfavorable). A score of 0 was termed "favorable" and a score of 1 or greater was termed "unfavorable." The Kaplan-Meier and Cox proportional hazard statistical methods were used to estimate OS. Results: Review of electronic medical records identified 67 consecutive patients between January 1st 2008 and December 31st 2012 diagnosed with primary refractory or relapsed AML. Median age was 56 (range 18-81). Cytogenetic/molecular signatures were favorable in 6%, intermediate in 60%, and unfavorable in 34%, and PS was 0-1 in 34% and 2 in 66%. The majority of patients had a combined prognostic score of unfavorable (n = 53, 79%). Among the 67 patients, 17 (25%) achieved CR with salvage therapy, with 13 (76%) of those able to undergo SCT. With an extended follow-up of approximately 5.6 years, the median OS of our refractory/relapsed AML cohort was 4 months (95% CI 2.2-5.8), with 8% of patients living at least 5 years from their date of relapse. Univariate analysis identified the following factors to be associated with a significantly worse median OS: Secondary AML at initial diagnosis (2.0 vs 5.0 months; p = 0.005), unfavorable cytogenetic/molecular signature at initial diagnosis (3.0 vs 6.0 months; p = 0.014), ECOG PS of 2 or greater at relapse (2.0 vs. 7.0 months; p< 0.001), an unfavorable combined prognostic score at relapse (3.0 vs 18.0 months; p < 0.001), lack of SCT after salvage (3.0 vs. 39.0 months; p < 0.001), lack of treatment in the refractory/relapsed setting with the combination of induction chemotherapy and hypomethylating agents (1.0 vs 8.0 months; p < 0.001), and lack of attainment of CR in the refractory/relapsed setting (3.0 vs. 40.0 months; p < 0.001). In the final multivariable model, only a favorable combined prognostic score at relapse (hazard ratio, HR 0.5; 95% CI 0-0.8; p = 0.02; Figure 1) and ECOG PS of 0-1 (HR 0.42; 95% CI 0.1-0.8; p=0.04) were associated with an improved OS, while the lack of attainment of a CR in the refractory/relapsed setting (HR 15.9; 95%CI 15.2-16.6; p < 0.001; Figure 2) was associated with a worse OS. Conclusion: In our cohort, the median OS among all patients diagnosed with primary refractory/relapsed AML was dismal. Despite the incorporation of novel agents and treatment approaches among this vulnerable patient population, there remains significant heterogeneity in patient outcomes within the first year, with only a small minority having a significantly longer OS. Similarly to patients with newly diagnosed AML, the most important prognostic variables among our refractory/relapsed AML cohort appears to be their combined prognostic score and their ability to achieve a CR in the salvage setting. It may be beneficial for future studies to focus on improving both, modifiable patient prognostic factors (i.e., PS) and treatment approaches in order to achieve CR in the refractory/relapsed setting. Figure 1. Figure 1. Figure 2. Figure 2. Disclosures Kota: Pfizer: Membership on an entity's Board of Directors or advisory committees; Leukemia Lymphoma Society: Research Funding.

Background: Numeracy, defined as the ability to handle basic probability and numerical concepts including computation, estimation, logic, and problem solving, is an under-recognized component of health literacy. Numeracy has been shown to influence performance of health tasks in non-hemophilia populations. Little is known about numeracy in the hemophilia population. Since hemophilia treatment requires understanding of numerical concepts to manage factor replacement, it is likely that numeracy also influences performance of health tasks by patients with hemophilia. A greater understanding of numeracy status and the characteristics influencing numeracy in the hemophilia population may allow healthcare providers to better influence health task performance. The objective of this study is to explore numeracy in the hemophilia population using two different tests of numeracy and to evaluate characteristics that are associated with low numeracy. Methods: Using a cross-sectional design, adults with moderate or severe hemophilia A or B who spoke and read English were enrolled at their annual visit at the Emory/Children's Health Care of Atlanta Hemophilia Treatment Center (HTC). Numeracy was measured using the validated Schwartz Woloshin (SW) test requiring answers in words and the unvalidated stick figure test requiring answers using images. Subjects were considered numerate with the SW numeracy test if all three questions were answered correctly or with the stick figure numeracy test if all four questions were answered correctly. Demographic and socioeconomic characteristics collected included age, race, ethnicity, household income (more or less than $50,000), level of education completed (more or less than completion of college), and duration of time followed at this HTC. Clinical information including type and severity of hemophilia, history of viral infections, history of depression, and use of chronic medication were abstracted from the medical records. Descriptive statistics of each variable and bivariate associations between numerate status and each dependent variable were calculated. Multivariable modeling using logistic regression was performed using the validated SW numeracy test as the dependent variable. Results: Of 91 enrolled participants with complete data, all were men. Most had hemophilia A [n=82 (90%)] and severe disease [69 (76%)]. Median age was 34 years [interquartile range (IQR) 18]. Sixty-three (69%) were Caucasian; 5 (6%) were Hispanic; 55 (61%) reported income of On bivariable analysis, SW numeracy was associated with higher education (p Conclusion: Among patients with hemophilia, a significant proportion of patients were not numerate. Patients with less than a college education were more likely to not be numerate. Accordingly, many patients with less than a college education may struggle to understand basic numeracy concepts and this may influence their understanding of dosing, factor pharmacokinetics and probability. The impact of numeracy on health outcomes and the utility of the SW and stick figure numeracy tests to help guide patient-centered discussions that involve mathematical concepts are important areas of future research. Disclosures Tran: Novo Nordisk: Honoraria. Kempton:Baxter Biopharmaceuticals: Honoraria; Biogen Idec: Honoraria; Kedrion Biopharma: Honoraria; CSL Behring: Honoraria.

Background: Distress can affect a patient's ability to cope with and manage disease. Patients may feel uncomfortable initiating conversations about distress with their provider. Systematic screening for distress in patients with bleeding disorders may help identify distressed patients and guide treatment services planning. Objectives: Describe prevalence of distress in adult patients with bleeding disorders and the specific problems, health characteristics, and behaviors most associated with distress in this population. Methods: Patients who attended the Emory Comprehensive Bleeding Disorder Clinic for a regularly scheduled visit between January 1st, 2012 through February 28th, 2014 and who completed a distress screen, pain screen, and clinic questionnaire during the visit were evaluated cross-sectionally. Distress was measured by the National Comprehensive Cancer Network Distress Management Tool which allowed patients to rate recent distress on a 0-10 point scale and also asked patients to identify from a checklist whether any of 38 specific issues among 5 different categories were recently problematic. A distress rating of 5 or more was categorized as high distress, 1-4 as mild/moderate distress, and 0 as no distress. Pain was measured by the Brief Pain Inventory Short Form which asked patients to rate their various pain types on 0-10 point scales. Patients reported current behavioral and demographic information including employment status, alcohol, and tobacco use on the clinic questionnaire. Depressive symptoms were measured on a 0-6 point scale using the Patient Health Questionnaire-2 screening tool. Primary diagnosis, age, prophylaxis use, and HIV and HCV status were taken from medical records. Unadjusted logistic regression models to identify predictors of high distress were used. Adjusted logistic regression models that controlled for possible confounders were used to examine whether diagnosis and employment were associated with high distress. In the adjusted model examining employment, because depression and pain were collinear, we ran two models; one including depression and one including pain. Results: Of the 168 patients who formed the cohort, most were male (69%) and most had hemophilia as the primary diagnosis (67%). Nearly three-quarters identified as White race with one-quarter Black or African-American. Average patient age was 36 years and ranged from 18 to 83 years. HCV and HIV prevalence in the cohort were 35% and 13%, respectively. High distress prevalence (distress rating ≥ 5) was 31.6% (Figure 1). Patients who reported at least one emotional concern from the problem checklist were more likely to report high distress (Figure 2). In unadjusted analyses, patients who were older, unemployed or disabled, required assistance in daily life activities, reported opioid use, used crutches, had higher depressive symptoms, exercised less, and who reported high pain levels were more likely to report high distress. Diagnosis, gender, race, alcohol consumption, tobacco use, prophylaxis use, and HIV and HCV status were not associated with high distress. Unemployment, disability, higher depression symptoms, and high pain were associated with high distress in multivariate models (Table 1). Conclusions: Nearly one-third of patients with bleeding disorders reported high distress while an additional 40% reported mild/moderate distress. Further study is needed to determine if high distress impacts clinical outcomes of patients with bleeding disorders as has been demonstrated in other chronic disorders. Table 1 Multivariate analysis results Adjusted Odds Ratios for High Distress (95% CI) Predictor Model 1 (n=148) Model 2 (n=126) Model 3 (n=137) Diagnosis Severe/moderate hemophilia 1.0 Mild hemophilia 1.91 (0.53 – 6.85) Other bleeding disorders 1.02 (0.28 – 3.74) Employment Work full-time 1.0 1.0 Student, part-time, retired, homemaker, other 0.51 (0.14 – 1.86) 0.29 (0.07 – 1.18) Unemployed 6.15 (1.33 – 28.44) 5.49 (1.09 – 27.82) Disabled 3.41 (1.08 – 10.78) 2.37 (0.64 – 8.87) Age 1.02 (0.99 – 1.05) 1.02 (0.99 – 1.05) 1.02 (0.99 – 1.06) Pain Score 0 (no pain) 1.0 1-4 (low pain) 1.12 (0.34 – 3.73) 5-10 (high pain) 4.85 (1.29 – 18.33) Depression score 2.61 (1.78 – 3.83) 2.29 (1.52 – 3.45) All models also adjusted for race and HIV/HCV positivity Figure 1 Figure 1. Figure 2 Figure 2. Disclosures No relevant conflicts of interest to declare.

Background: Health literacy (HL) is the degree to which individuals have the capacity to obtain, process, and understand basic health information and services needed to make appropriate health decisions. Numeracy, a component of HL, is defined as the ability to handle numerical concepts. Both low HL and low numeracy have been associated with poor adherence to treatment regimens in a variety of chronic diseases. For the management of hemophilia, a chronic bleeding disorder, adherence to treatment regimens can be difficult and requires completion of multiple complex tasks. We hypothesized that lower HL and lower numeracy are associated with decreased adherence to treatment in persons with hemophilia (PWH). A secondary aim of this study was to evaluate other demographic and clinical characteristics that may be associated with adherence. Methods: In a cross-sectional study, adult PWH completed questionnaires to assess the main outcome variable, adherence measured by the validated hemophilia regimen treatment adherence scale (VERITAS) and the primary independent variables, HL as measured by the shortened Test of Functional Health Literacy in Adults (sTOFHLA) and numeracy as measured by the Schwartz-Woloshin questions. Other potential independent or confounding variables including general demographic and clinical information, the General Self-Efficacy (GSE) Scale, the Wake Forest Physician Trust Scale (WFPTS), and the Haem-A-QoL were also collected. Analysis proceeded from descriptive statistics to bivariable associations using simple linear regression and multivariable analysis using multiple linear regression. Results: All were men (n=99); 91% had hemophilia A and 78% had severe disease. Mean age was 34 years (standard deviation (SD) 11.5). White race was reported by 69% and 6% were Hispanic. Income was reported to be ≥$50,000 in 39%; and 37% had received an undergraduate degree or higher. Mean length of time seen at the Hemophilia Treatment Center (HTC) was 16.0 years (SD 11). HIV infection was noted in 26%, and 59% were HCV positive; depression history was reported in 21%; 49% infused replacement factor prophylactically. Most of the study population (95%) had high HL; but only 23% were numerate. The mean VERITAS-Pro was 45.6 (SD 12.7) and mean VERITAS-PRN was 51.0 (SD 11.2) with a lower score indicating greater adherence. On bivariable analysis, adherence was significantly associated with depression history, GSE score, WFPTS score, and Haem-A-QoL score (p < 0.05). On multivariable analysis, HL score and numerate status were not significantly associated with adherence (see Table). Being on any chronic medication, longer time seen at HTC, higher physician trust, and better quality of life were significantly associated with higher adherence. Depression history was significantly associated with lower adherence. This model overall accounted for a moderate proportion of the variability of adherence between subjects (adjusted R2 = 0.296). Conclusion: In this study population, HL and numeracy were not associated with adherence. A large majority of the PWH in our study were health literate; however, the study population was limited to those who made it to their scheduled HTC appointments and were sufficiently on time to allow completion of study questionnaires which may have biased this study toward a more literate population. This study population did show that being on any chronic medication, longer time seen at the HTC, higher physician trust, and better quality of life were significantly associated with better adherence. Depression history was significantly associated with lower adherence. These factors provide a better understanding of characteristics that influence adherence and may prove important for optimizing the care of PWH. Table: Multivariable Linear Regression of the Association of Adherence with Predictors (n=91) Predictor Beta Coefficient Standard Error p-value* sTOFHLA score† -0.09 0.22 0.67 Numerate 1.04 3.01 0.73 On chronic medication(s) -5.13 2.47 0.041 Depression history 6.89 3.02 0.025 Time seen at HTC -0.27 0.11 0.022 WFPTS score† -0.51 0.18 0.006 Haem-A-QoL score‡ 0.12 0.038 0.0024 *Significant if < 0.05 †sTOFHLA: The higher the score, the better the HL; WFPTS: The higher the score, the higher the physician trust ‡ Haem-A-QoL: The lower the score, the better the quality of life Disclosures No relevant conflicts of interest to declare.

Introduction The formation of Factor VIII (FVIII) inhibitory antibodies is a major complication of hemophilia A. Currently immune tolerance induction (ITI) is successful in up to 70% of patients. Outside of the International Immune Tolerance Registry, where 6 of 128 patients had a recurrent inhibitor between 1 and 6 years, little is known about the probability of inhibitor recurrence following successful ITI. Objective To determine the probability of inhibitor recurrence and the influence of adherence to post-ITI prophylaxis on inhibitor recurrence following successful ITI. Methods All persons with hemophilia A (FVIII level < 50%) who completed ITI (defined as inhibitor titer 6 hours and/or FVIII recovery > 66% in addition to inhibitor titer < 0.6 BU/ml, information was also collected on post-ITI prophylaxis regimen, adherence to post-ITI prophylaxis, and the presence of a recurrent inhibitor titer (≥ 0.6 BU/ml) or last inhibitor titer prior to 8/15/2011. Adherence during the 6 months prior to inhibitor recurrence or last inhibitor titer was determined by review of pharmacy and infusion logs compared with prescribed treatment regimen. Follow-up time started when the subject was considered tolerized (normalized half-life or recovery if half-life not performed) and ended at the time of inhibitor recurrence or the last recorded inhibitor titer. Estimates of the probability of remaining inhibitor-free at 1, 3 and 5 years were calculated with the Kaplan-Meier method. The association between adherence (completing >80% of prescribed infusions vs. < 80% of prescribed infusions) and inhibitor recurrence was assessed using the chi-square test. Results Eighty-three male subjects were enrolled. The median age at start of ITI was 3.3 years (range: 0.08 - 39). The majority of the subjects were white (73%) and non-Hispanic (73.5%). Seventy-one (85.6%) had severe hemophilia. The median peak inhibitor titer was 8.5 BU/ml (range: 0.6 - 950). Four subjects (5%) had a prior unsuccessful course of ITI. FVIII alone was used in 85% of subjects. Sixty-seven (80.7%) met criteria for tolerance and 64 had follow-up data available, with a median follow up time of 3.4 years (range: 0.08-12.4). Forty-four subjects (68.7%) remained tolerant without a recurrent inhibitor titer after a median 4.7 years (range: 0.25-12.4) of follow-up. Twenty subjects (31.3%) had at least one inhibitor titer ≥ 0.6 BU/ml after a median of 1.6 years (range 0.08-5.7). The probability of recurrent inhibitor at 1 year is 0.15 (95% CI: [0.05, 0.20]); at 3 years is 0.30 (95% CI: [0.2, 0.4]) and 5 years is 0.35 (95% CI: [0.2, 0.5]) (Figure 1). Four subjects discontinued post-ITI prophylaxis anywhere from 6 months to greater than 6 years after tolerance was achieved, of whom 2 (50%) developed a recurrent inhibitor. Of those that remained on post-ITI prophylaxis, 41 subjects (64.1%) were adherent (took >80% of prescribed infusions) to their post-ITI prophylaxis regimen, of whom 13 (31.7%) developed a recurrent inhibitor. Twenty-three (35.9%) who were non-adherent (took Conclusion ITI is currently the most effective treatment to eradicate FVIII inhibitors, however 5 years after completion, 30-35% of patients will have at least one inhibitor titer ≥ 0.6 BU/ml. A recurrent inhibitor is unlikely after 5 years. Adherence to post-ITI prophylaxis does not appear to be a major driver of inhibitor recurrence. It is imperative to elucidate the factors that influence the durability of successful ITI to improve quality of life and cost of treatment in these patients. Disclosures: Monahan: Baxter: Consultancy, Honoraria, Research Funding, travel support, travel support Other; Bayer: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Novo Nordisk: Consultancy, Honoraria, Research Funding; Pfizer: Honoraria; Prolor Biotech: Research Funding; Asklepios: Consultancy, Research Funding, travel support Other. Manco-Johnson:Eisai: Research Funding; Novo Nordisk: Membership on an entity’s Board of Directors or advisory committees; Biogen Idec: Membership on an entity’s Board of Directors or advisory committees; Baxter BioScience: Membership on an entity’s Board of Directors or advisory committees; CSL Behring: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Bayer HealthCare: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Carpenter:Novo Nordisk: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; CSL Behring: Honoraria, Research Funding; Grifols: Honoraria, Research Funding. Kruse-Jarres:Bayer HealthCare: Consultancy; Biogen IDEC: Consultancy; Grifols: Consultancy; Kedrion: Consultancy; Novo Nordisk: Consultancy; Baxter Healthcare: Consultancy. Ragni:Novo Nordisk: Research Funding; Merck: Research Funding; CSL Behring: Research Funding; Bayer: Research Funding; Baxter: Research Funding; Tacere Benitec: Consultancy; Smith Kline Glaxo: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Biogen Idec: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding. Kempton:Novo Nordisk: Research Funding; Baxter Healthcare: Membership on an entity’s Board of Directors or advisory committees.

Abstract 219 The immune response to factor VIII (fVIII) currently is the most significant complication in the management of patients with hemophilia A. In addition, antibodies to fVIII can develop in non-hemophiliacs, producing acquired hemophilia A, which frequently produces life- or limb-threatening bleeding. In either congenital or acquired hemophilia A, the majority of inhibitory antibodies are directed at either the 40-kDa A2 or the 15-kDa C2 domains of fVIII. Classical anti-C2 antibodies inhibit the binding of fVIII and activated fVIII to phospholipid membranes. These antibodies bind to hydrophobic feet in the C2 domain that include loops containing M2199-F2000 and L2251-L2252. Non-classical anti-C2 antibodies inhibit the activation of fVIII by thrombin and factor Xa. They bind to the beta sheet that comprises the front face of the C2 domain that is remote from the phospholipid binding region. In the Bethesda assay, non-classical anti-C2 antibodies inhibit fVIII incompletely at saturating concentrations and thus are type II inhibitors. However, they have inhibitory titers on an equimolar basis that are usually at least 10-fold higher than classical anti-C2 antibodies. von Willebrand factor (VWF) competes with classical but not non-classical anti-C2 bodies for binding to fVIII. We recently found that the binding of classical anti-C2 antibodies to fVIII in a direct ELISA was increased in the presence non-classical anti-C2 antibodies, suggesting the presence of a cooperative interaction between fVIII antibody epitopes. In the present study, we characterized the interaction of highly-purified recombinant full-length human fVIII with a classical anti-C2 antibody, ESH4, in the presence and absence of a non-classical anti-C2 antibody, G99, by surface plasmon resonance spectroscopy. The ligand, ESH4, was covalently attached to a Biacore CM5 biosensor chip and the kinetics of binding of the analyte, fVIII, at concentrations of 10, 20 and 30 nM were measured at 25 °C. When present, G99 (60 nM) was pre-mixed with fVIII for 30 min before the start of the kinetic experiment. In both the presence and absence of G99, global nonlinear least-squares analysis indicated that the binding of fVIII to ESH4 was first-order in both the adsorption and desorption phases, consistent with a 1:1 reversible bimolecular interaction (Fig. 1). Both the association and dissociation rates were slower in the presence of G99. Estimated phenomenological association and dissociation rate constants were 0.5 × 105 M−1 sec−1 and 1.5 × 10−4 sec−1 and 1.7 × 105 M−1 sec−1 and 4.4 × 10−4 sec−1 in the presence and absence of G99, respectively. The clinical implication of these results is that infusion of recombinant fVIII (which does not contain VWF) or plasma-derived fVIII (which is bound to VWF) may result in complex kinetic interactions that are significantly influenced by cooperative interactions between anti-C2 antibodies and competitive interactions involving VWF. Disclosures: No relevant conflicts of interest to declare.

The BCL6 oncogenic transcriptional repressor is constitutively expressed in about 60% of Diffuse Large B-cell Lymphomas (DLBCLs). We previously developed a recombinant inhibitor peptide that specifically blocks the ability of BCL6 to mediate transcriptional repression. Based on this peptide, we developed a novel retro-Inverso peptidomimetic inhibitor called BPI (BCL6 Peptidomimetic Inhibitor) that is far more potent and stable than its prototype. We have treated a large panel of DLBCL cell lines with BPI to determine the spectrum and mechanisms of sensitivity and resistance to this agent. BPI (1 to 20 μM) caused dose dependent killing of 6 of 10 DLBCL cell lines in vitro. Sensitive DLBCL cell lines display a high percentage of necrotic and apoptotic cells as shown by 7-ADD and Annexin-V staining. Additionally, by BrdU incorporation plus PI staining, we demonstrated that cells undergo cell cycle arrest before the death pathway is initiated. Since BCL6 represses genes involved in DNA repair checkpoints, cell cycle and protein ubiquitylation and degradation, we predicted that combination therapy with cytotoxic drugs or drugs that alter cellular protein metabolism might synergize with BPI to kill DLBCL cells. We performed combinatorial therapy studies where additional drugs were administered 24 hours after BPI and cells were evaluated for viability in several different assays. We found an additive to synergistic effect of BPI with several cytotoxic drugs commonly used in lymphoma therapy (such as doxorubicin, alkylating agents, etoposide and dexamethasone), as well as bortezomib (a proteasome inhibitor). In vivo xenotransplantation studies with the BPI sensitive cell lines Ly1, Ly7, SUDHL4 and SUDHL6 showed a marked decrease in tumor size and weight (p=0.03 for control vs BPI, T-test), as well as serum β2-microglobulin (BPI: 6.5 ± 2 μg/ml vs control: 14.3 ± 2.5 μg/ml, p=0.02), even when BPI was administered at very low doses (150 μg per day). The tumor remnants from BPI treated animals showed extensive induction of apoptosis (determined by TUNEL), a lower mitotic index (2 ± 0.8/100 cells vs 4.8 ± 0.9/100 cells, for BPI vs. control respectively, p