Characterizing the Use of Direct Oral Anticoagulants in Children Using the American Thrombosis and Hemostasis Network Dataset (ATHNdataset)

Background: The incidence of venous thromboembolism (VTE) in children has risen significantly. (Raffini, Huang et al. 2009) There are currently four direct oral anticoagulants (DOACs) - apixaban, dabigatran, edoxaban, and rivaroxaban - approved for the acute treatment and prevention of VTE in adults. Advantages of these medications over the traditionally used anticoagulants, enoxaparin and warfarin, include fixed dosing, no need for routine laboratory monitoring, few drug interactions and no dietary restrictions. Despite lack of information on the safety and efficacy of these agents in children, pediatric hematologists across the United States are using DOACs in their patients based on extrapolated data from adult studies. The American Thrombosis and Hemostasis Network (ATHN) is a nonprofit network of over 140 federally funded Hemophilia Treatment Centers (HTCs) which provides the infrastructure for clinical and surveillance-based research. ATHN maintains the ATHNdataset (ADS), a "limited dataset" free of protected health information, with data collected on patients with bleeding and clotting disorders at participating HTCs within the Human Resources and Services Administration (HRSA)-supported regional hemophilia networks across the US. The authors acknowledge ATHN, the ATHN-affiliated U. S. Hemophilia Treatment Centers and their 39,000+ patients who have contributed their demographic, clinical, and genetic information to the ATHNdataset. Methods: The objective of this study was to describe the characteristics of pediatric patients diagnosed with VTE in the ADS, focusing on those patients who received a DOAC. Data were abstracted for patients in the ADS who had acute VTE at age <21 years from January 2010 to March 2019. Data extraction included basic demographics and information about VTE and treatment. Results : A total of 1,094 pediatric VTE cases were captured in the ADS. 577 (52.7%) were male. Caucasians were the most prevalent racial group (n = 809; 74%), followed by African-Americans (n = 203; 18.6%).14.9% (n = 163) were Hispanic. Deep venous thrombosis (DVT) was the most prevalent pediatric VTE reported in the ADS (n=889, 81.3%), followed by pulmonary embolism and cerebral venous thrombosis (n=130, 11.9% and n=40, 3.7% respectively). VTE location by age group is listed in Table 1. The most common DVT location was the lower extremities or pelvis, comprising 37.5% (n = 333) of all reported DVTs. Upper extremities or upper thorax DVT occurred less often (n = 211; 23.8 %). 345 (38.8 %) cases were reported only as "DVT" without a specific thrombus location. We reviewed 1,051 anticoagulant prescriptions for 650 VTE patients (mean 1.6 prescriptions per person). Enoxaparin was the most commonly prescribed anticoagulant (n = 676 prescriptions; 64.3%) followed by warfarin (n = 178 prescriptions, 16.9%). Interestingly, 116 (11%) patients, from 21 HTCs, had a DOAC prescribed as their anticoagulant regimen. Anticoagulant prescription by anticoagulant starting age is shown in Table 2. Further analysis of the DOAC subgroup showed that rivaroxaban was the most prescribed DOAC with 77.6% (n = 90/116) of the patients using this agent. Apixaban and dabigatran use was also reported (n= 23, 19.8% and n= 3, 2.6% respectively). The majority of DOACs were prescribed for patients older than 13 years of (111/116, 95.7 %). In children between 3 to 6 years of age (n = 3), rivaroxaban was the only DOAC prescribed. DOACs were primarily used to treat DVT of the extremities (84/116 patients). Other scenarios in which DOACs were also prescribed were PE and abdominal venous thrombosis patients (26, and 4 patients, respectively). Anticoagulant prescription by anticoagulant starting age is shown in Table 2. Conclusion: DVT of the lower extremities and pelvis is the most prevalent pediatric VTE in the ADS. Enoxaparin and warfarin remain the main anticoagulant agents used for pediatric VTE treatment. Despite lack of an FDA-approved pediatric indication, hematologists in US-based HTCs are already using DOACs in pediatric patients with VTE. As further characterization of DOAC use in children is needed, the authors, in collaboration with ATHN, are currently building a multi-institutional retrospective and prospective registry, ATHN 15. This registry will serve as a resource for pediatric hematologists to collect real-world use of DOACs in children, as we await the results of prospective clinical trials. Disclosures Davila: Octapharma: Other: Grant to attend VWD meeting ; Genentech: Other: Advisory board; Spire Learning: Speakers Bureau. Raffini:Bayer: Other: Advisory Board; CSL Behring: Other: Advisory Board; Roche: Other: Advisory Board. Thornburg:Sanofi Genzyme: Research Funding; Bluebird bio: Other: Data Safety Monitoring Board; Genentech: Speakers Bureau; NovoNordisk: Research Funding; Ironwood: Other: Data Safety Monitoring Board; Sanofi Genzyme: Other: Data Safety Monitoring Board. Corrales-Medina:Octapharma: Membership on an entity's Board of Directors or advisory committees; Kedrion: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda-Shire: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Electronic Health Record Tools to Promote Transition Readiness and Knowledge for Adolescents and Young Adults with Hemophilia

Introduction: Challenges to the transition of care for adolescents and young adults with bleeding disorders negatively impact clinical outcomes. Transition of care is a Healthy People 2020 measure, and many Hemophilia Treatment Centers (HTCs) in the United States are developing a systematic approach based on the Got TransitionTM framework, which includes six core elements designed to aid patients and their families during this vulnerable period. To improve the quality of care delivered to transition-aged individuals with hemophilia, we developed a quality improvement initiative (QI) to track and monitor transition, to assess transition readiness, and to provide education based on patient-centered goals. Our global aim is to improve transition readiness and rate of successful transfer to an adult hemophilia provider by age 18-21y. We report results for the specific aim to increase the percentage of transition-aged individuals who complete transition readiness assessments and receive patient-centered goals education at annual comprehensive clinic appointments over a six-month cycle from 0 to 80%. Methods: We developed metrics and reports in Epic (electronic health record system) to track patients with hemophilia aged 12y and older who are eligible to begin the transition process. We also developed a Transition Readiness Assessment and a 15-question hemophilia-specific Skills Practicum to be completed by the patient in EPIC during their appointment. Based on responses to the Transition Readiness Assessment, patients select 2-3 goals for the year. Each selected goal generates a corresponding education handout. The tools are completed by patients with hemophilia between the ages of 12-21y at the time of rooming by the medical assistant for the annual comprehensive clinic appointment. Patients are excluded if they have significant developmental delays. During the appointment, the child life specialist for the HTC reviews the results of the Skills Practicum with the patient, and the HTC nurse reviews the Transition Readiness Assessment and the education handouts with the patient. Descriptive statistics were used to analyze the population and the results. Results: During the QI cycle, 20 of 43 transition-aged patients attended a comprehensive clinic visit and 17/20 (85%) completed all age-appropriate assessments. Patient characteristics and transition readiness results are shown in Table 1. The most frequently selected patient goals were "know my doctors' and nurses' names and roles" (29%), "know my doctor's phone number and call my doctor's office to make or change an appointment" (65%), and "have access to MyChart account and check MyChart" (47%). Four questions on the Skills Practicum test how to read a prescription. Five patients (29%) correctly answered all four questions. Conclusions: In summary, the Epic transition tools were successfully integrated into the HTC comprehensive clinic workflow, and 85% of eligible patients completed the assigned assessments. Utilization of MyChart is low, and access to MyChart was a frequently selected goal. Further work is underway to increase MyChart utilization which would facilitate workflow changes such that assessments may be completed in MyChart before the visit and educational and other resources can be accessed in MyChart. Achievement of patient goals, improvements in knowledge (e.g. how to read a prescription), and successful transfer are being tracked over time. Disclosures Thornburg: Sanofi Genzyme: Other: Data Safety Monitoring Board; Sanofi Genzyme: Research Funding; NovoNordisk: Research Funding; Genentech: Speakers Bureau; Bluebird bio: Other: Data Safety Monitoring Board; Ironwood: Other: Data Safety Monitoring Board.

Incidence of Germline ATM Variants in a Consecutive Clinical Cohort of CLL Patients

Background The pathogenesis of chronic lymphocytic leukemia (CLL) remains unknown, but first-degree relatives of affected patients (pts) have a 3-to-8-fold increased risk of developing CLL, suggesting an inherited component. Previously, we performed an exome-wide comparison of rare germline variants (vts) among CLL pts compared to controls and identified a 1.8X increased risk of any rare germline ATM vt in CLL pts. Certain vts had much higher relative risk; for example, ATM p.L2307F was associated with a 10X increased risk of CLL (Tiao Leukemia 2017). ATM p.F858L and p.P1054R also imparted a 2X increased risk of CLL in a candidate gene association study (Rudd Blood 2006). Most ATM missense vts have not been fully characterized and are classified as vts of uncertain significance (VUS) in clinical testing. We observed that ATM missense vts were common in our CLL clinic and sought to formally test the hypothesis of association by examining the frequency of ATM missense vts identified by next-generation-sequencing (NGS) routinely sent on hematologic malignancy pts seen at our institution. These pts served as a population with well-characterized diagnoses whose genetics had been uniformly determined by a CLIA-certified lab, allowing us to directly ask whether ATM VUS are enriched in CLL compared to other hematologic malignancies, and whether CLL characteristics differ between pts with and without ATM VUS. Methods The Brigham and Women's Hospital Rapid Heme Panel (RHP) is an NGS assay that interrogates 95 cancer-related genes, including the entire coding sequence of ATM. RHP results were aggregated for all 999 pts who had the test sent from the DFCI Lymphoma clinic (excluding T-PLL) between 7/1/2014 and 5/25/2018. RHP data were also aggregated for 876 pts seen by 3 physicians over the same time in the DFCI Leukemia clinic (acute leukemia and other myeloid disorders). Only vts with a total population allelic frequency (PAF) of <1% are included in RHP results, restricting our analysis to less common vts. Statistical analysis was performed in R. Results Out of 384 pts with CLL or monoclonal B lymphocytosis, 99 pts (25.8%, 95% CI 21.5-30.5%) had at least one ATM vt. 71 different ATM vts were seen, with 10 (14%) deemed pathogenic (nonsense mutations, internal insertions or deletions). All remaining 61 vts were missense vts, and the majority were likely germline: 43 are in the gnomAD germline vt database, and of the other 18, 8 had allele frequencies in blood between 40 and 60%. The most common vts were p.S707P (n = 11 pts), p.L2307F (n=9), p.F858L (n=8), and p.D1853V (n=8), all of which are known to be germline. ATM missense vts were more frequent in CLL (97 pts with missense vts out of 384 total, 25.3%) than in non-CLL lymphomas (91 out of 615, 14.8%, p=0.00006). No other individual lymphoma type had a higher frequency of ATM missense vts than CLL. Missense vts were also more frequent in CLL than in pts seen in the myeloid malignancy clinic (143 out of 876, 16.3%, p=0.0003). When restricting analysis to missense vts with PAFs reported in gnomAD, we found a higher percentage of extremely rare vts (PAFs <0.001%) in CLL pts (7 out of 42 vts, 16.7%) compared to the myeloid malignancy group (2 out of 55, 3.6%, p=0.04); the non-CLL lymphoma pts had a similar frequency of extremely rare vts (5 out of 39, 12.8%, p=0.12). Consistent with a biologic role for these vts, 32% of CLL pts with missense vts had 11q-deleted disease, while only 10.5% of pts without missense vts had 11q-deleted disease (p=3*10-6). Pts with missense vts were also significantly less likely to have TP53-aberrant disease, 10.9% vs. 20.7% (p=0.04), consistent with a mutually exclusive role for ATM and TP53. There was no difference in IGHV mutation status between CLL pts with and without missense vts (56.6% vs 53.4% unmutated, respectively). Conclusion One in 4 CLL pts has an ATM missense vt; these are more frequent in CLL than in other lymphoid or myeloid disorders. Most of these are germline and have previously been classified as VUS. CLL pts with missense vts have a higher frequency of 11q-deleted disease. These results highlight an important role for germline ATM missense vts as contributors to the inherited risk for developing CLL and emphasize the importance of analyzing VUS and constitutional data generated by NGS assays, the latter typically not reported by most laboratories. Disclosures Kim: Papgene, Inc: Consultancy; Quanterix, Inc: Consultancy; LabCorp, Inc: Consultancy. Brown:Juno/Celgene: Consultancy; AbbVie: Consultancy; Acerta Pharma: Consultancy; TG Therapeutics: Consultancy; Verastem: Consultancy, Research Funding; Teva: Honoraria; Janssen: Honoraria; Catapult Therapeutics: Consultancy; Dynamo Therapeutics: Consultancy; BeiGene: Consultancy; AstraZeneca: Consultancy; Octapharma: Consultancy; Invectys: Other: Data safety monitoring board; Morphosys: Other: Data safety monitoring board; Sun Pharmaceuticals: Research Funding; Sunesis: Consultancy; Pharmacyclics: Consultancy; Loxo: Consultancy, Research Funding; Novartis: Consultancy; Pfizer: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding; Genentech/Roche: Consultancy; Gilead: Consultancy, Research Funding.

Patient Reported Financial Toxicity in Acute Leukemia

Background: Financial Toxicity (FT) is increasingly recognized as a major contributor to morbidity and mortality in a variety of cancers. Treatment of acute leukemia is associated with heavy healthcare utilization and high costs. The purpose of this study was to define rates, risk factors, and mortality implications for FT in patients with acute leukemia using patient reported data. Methods: All patients seen at the Levine Cancer Institute, a tertiary hospital-based leukemia practice, were surveyed prior to each visit over a six-month period. All patients were aged ≥18 years and were diagnosed with acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL). The survey consisted of the PROMIS Global-10 measure and two questions from the COST measure. FT was defined as scoring 4 or less (maximum: 10) in agreement with the COST questions: "I know that I have enough money in savings, retirement, or assets to cover the costs of my treatment" and "I am satisfied with my current financial situation." Demographic data and disease characteristics were abstracted from the medical record. Model selection was carried out using logistic regression to identify factors impacting the incidence of financial toxicity. Correlation of numerical financial toxicity scores with PROMIS scores and with mortality data was assessed using linear regression. Results: Of the 106 patients, 58 (54%) met the definition of exhibiting FT. The factors associated with incidence of FT included: age, race, and insurance type. The odds of FT in those patients <65 years of age were 2.7 times the odds of FT in those ≥65, adjusting for race, insurance, and time since first treatment (95% CI: 0.884 - 8.438, p = .081). The odds of FT in African American patients were 4.3 times the odds of FT in Caucasian patients, adjusting for age, insurance, and time since first treatment (CI: 0.408 - 44.824, p = .150). The odds of FT in patients with Medicaid insurance were 14.2 times the odds of FT in patients with commercial insurance, adjusting for age, race, and time since first treatment (CI: 1.658 - 121.862, p = .106). Gender, distance from the hospital, type of acute leukemia, history of blood/marrow transplant, and history of relapsed disease were not found to be significant. There was a significant correlation for both the PROMIS global physical (p < .001) and mental (p < .001) scores with the FT score. Lower FT score (higher degree of FT) was associated with lower mental and physical scores. There was no statistically significant difference in survival between patients with FT scores >4 compared to patients with FT scores <=4; however, there was a trend toward decreased survival in those with lower FT scores (Figures 1 and 2). Conclusions: Patients with acute leukemia represent an extremely vulnerable population for financial toxicity with rates of distress even higher than other reported malignancies. Urgent interventions are indicated in this population. Disclosures Grunwald: Medtronic: Equity Ownership; Cardinal Health: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding; Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees; Forma Therapeutics: Research Funding; Janssen: Research Funding; Incyte Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Alexion: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Ariad: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees. Avalos:Juno: Membership on an entity's Board of Directors or advisory committees. Symanowski:Five Prime Therapeutics: Other: Data Safety Monitoring Board ; Boston Biomedical: Other: Data Safety Monitoring Board ; Eli Lily & Co: Other: Data Safety Monitoring Board; Immatics: Other: Data Safety Monitoring Board.

Evaluation of Intravenous Diphenhydramine Use in Patients with Sickle Cell Vaso-Occlusive Crisis

Inpatient management of sickle cell disease (SCD) vaso-occlusive crisis (VOC) often involves use of high-dose opioids, which may result in opioid-induced pruritus (OIP). This OIP is typically treated with antihistamines like diphenhydramine either orally or intravenously. The oversedation adverse effects of diphenhydramine may be magnified when given in combination with high-dose opioid therapy. Current recommendations made by the National Heart, Lung, and Blood Institute endorse using oral rather than intravenous (IV) antihistamines to avoid the cumulative effect on sedation. Despite this guideline, IV diphenhydramine use is still prevalent in many hospitals that treat persons with SCD. We performed a retrospective, single-center, cohort study comparing rates of oversedation among patients who received IV and oral diphenhydramine for management of opioid-induced pruritus in a large SCD inpatient population. Patients with SCD VOC admitted to an urban hospital between June 1, 2016 to July 30, 2017 were included if they were ≥ 18 years old and received either IV or oral diphenhydramine for OIP. Exclusion criteria: Pregnancy, received <24 hours of diphenhydramine, or <50% of their "as needed" doses of diphenhydramine. Primary endpoint: comparative incidence of oversedation in SCD VOC receiving IV versus oral diphenhydramine. Oversedation was defined as meeting two or more of the following criteria: documentation of oversedation in clinician notes, medication doses held by a nurse due to sedation, a PASERO opioid-sedation score ≤3, or documented hypoxemia with O2 percent saturation ≥ 2 points below baseline. Secondary endpoints included: evaluation of hospital length of stay, amount of diphenhydramine administered per day, indication for IV therapy, and number of days receiving diphenhydramine. Individual admissions were portioned by route of diphenhydramine administration cohorts (IV versus oral). Within each cohort, study endpoints were derived at the patient level. Oversedation was determined at the patient level i.e. experiencing at least one occurrence over the course of their admissions. The number of admissions, length of stay, and days of diphenhydramine treatment were totaled across admissions for each patient. The daily dose of diphenhydramine administration (mg/day) was averaged across the admissions per patient. The proportion of subjects experiencing oversedation was summarized by cohort and compared using Fisher's exact test. Length of stay, number of days on treatment, and average daily dose of diphenhydramine were analyzed with analysis of variance (ANOVA) techniques. Length of stay and number of days on treatment were log-transformed prior to statistical analyses. The number of admissions was analyzed with Poisson regression. Fifty unique patients were included in the analysis representing 121 admissions. Seven patients received both formulations on separate admissions and were included in both groups, 15 received oral diphenhydramine, and 42 received the IV formulation. The percent of patients experiencing oversedation was higher in the IV group, however the difference was not statistically significant (p = 0.312). The average number of admissions was significantly higher in the IV versus oral group (2.45 vs. 1.20; p = 0.005) with average and median length of stay also significantly higher in the IV versus oral group (30.57, 16.0 vs. 10.67, 10.0; p = 0.003). Similarly, the average and median number of days on diphenhydramine treatment in the IV group was significantly higher than in the oral group (28.79, 14.5 vs. 9.73, 7.0; p = 0.001). The average daily dose of diphenhydramine was similar in the two cohorts with no compelling indications documented for use of IV over oral formulation. In summary, while we did not find a statistically significant difference in the rates of oversedation with use of IV versus oral diphenhydramine formulations, patients with SCD VOC who received IV diphenhydramine were more likely to have more frequent admissions, and a longer length of stay. These findings have clear impact on clinical outcomes and cost of care and clinicians may consider oral diphenhydramine preferentially in appropriate patients over IV administration. Larger, prospective studies are needed to evaluate the absolute risk to benefit ratio between the two formulations particularly among person receiving concomitant parenteral opioid therapy. Disclosures Osunkwo: Terumo BCT: Speakers Bureau; Prolog Pharmaceuticals LLC: Consultancy; Novartis Pharmaceuticals LLC: Consultancy, Speakers Bureau. Symanowski:Immatics: Other: Data Safety Monitoring Board; Eli Lily & Co: Other: Data Safety Monitoring Board; Boston Biomedical: Other: Data Safety Monitoring Board ; Five Prime Therapeutics: Other: Data Safety Monitoring Board .

730. Hospital Readmissions Following Laboratory-Confirmed Influenza

Background Further understanding of hospital readmissions after influenza illness could reduce readmissions. The aim of our study was to characterize the morbidity associated with laboratory confirmed influenza hospitalizations. Methods This was a retrospective study using data from 2006 to 2016 from the Tennessee (TN) Emerging Infections Program Influenza Surveillance Network, which prospectively identifies laboratory-confirmed influenza hospitalizations in Nashville, TN and surrounding counties. Using the TN Hospital Discharge Data System, which collects information on all hospitalizations and discharges in TN, cases were linked to subsequent hospitalizations up to 1 year. The International Classification of Diseases was used to define the primary diagnosis associated with each hospitalization. Demographic characteristics and outcomes were compared by using χ2 tests for categorical variables. Multivariable logistic regression was used to compare study outcomes. Results Of the 2,897 patients with a laboratory-confirmed influenza hospitalization, 1,364 (47%) had a hospital readmission during the subsequent year (figure). Multiple readmissions occurred in 740 patients (54%). The readmission group was older, female predominant, and had more comorbidities than patients not re-hospitalized. Acute COPD/asthma exacerbation, pneumonia, septicemia, and acute renal failure were the most common causes for readmission. Underlying cardiovascular disease (OR 1.6), lung disease (OR 1.6), kidney disease (OR 1.7), diabetes (OR 1.3), immunosuppression (OR 1.6), and liver disease (OR 2.1) were associated with increased risk of readmission (table). Conclusion An influenza hospitalization is associated with increased hospital readmissions. Approximately 47% of patients hospitalized with influenza are readmitted within 1 year. Patient comorbidities could be an important link to influenza readmissions. Disclosures W. Schaffner, Merck: Member, Data Safety Monitoring Board, Consulting fee. Pfizer: Member, Data Safety Monitoring Board, Consulting fee. Dynavax: Consultant, Consulting fee. Seqirus: Consultant, Consulting fee. SutroVax: Consultant, Consulting fee. Shionogi: Consultant, Consulting fee. H. K. Talbot, sanofi pasteur: Investigator, Research grant. Gilead: Investigator, Research grant. MedImmune: Investigator, Research grant. Vaxinnate: Safety Board, none. Seqirus: Safety Board, none.