US Hemophilia Treatment Centers Research Articles

Race and ethnicity reporting and representation in hemophilia clinical trials

AbstractRacial and ethnic representativeness in clinical trials is crucial to mitigate disparities in outcomes, however, diversity among hemophilia trials is unknown. The aim of this study is to examine the reporting and representation of race and ethnicity in trials of people with hemophilia (PwH). In this cross-sectional study, the ClinicalTrials.gov database was queried in April 2023 for interventional clinical trials involving PwH between 2007 and 2022. The distribution of participants (observed) was compared with expected proportions based on US Hemophilia Treatment Center (HTC) and country–specific census data with observed-to-expected ratios (OERs). Of 129 trials included, 94.6% were industry sponsored, with a mean of 62 participants and mean age of 26.8 years. Overall, 52.0% (n = 66) of trials reported data on race and ethnicity, increasing from 13.9% in 2007-2012 to 22.5% in 2013-2016 to 100% in 2017-2022 (P = .001). Among these 66 trials, 65.8%, 22.8%, 5.1%, 3.9% of participants were White, Asian, Hispanic, and Black, respectively. OERs were 10% to 20% lower for White participants vs US HTC, and US, UK, and Canadian census populations and ∼75% lower for Black or Hispanic participants when compared with US HTC and US census population. OERs for Asian participants were 1.6 to 3 times higher than Canada, US, and UK census populations. The reporting of race and ethnicity in hemophilia trials has drastically improved, however, Black and Hispanic PwH remain especially underrepresented. To address these disparities, stakeholders across the clinical trial enterprise need to implement strategies to ensure equitable participation.

Clinical and treatment characteristics of infants and toddlers less than 2 years of age with hemophilia

AbstractInfants and toddlers (ITs) with hemophilia have unique bleeding features. Factor prophylaxis has been shown to decrease the risk of intracranial hemorrhage (ICH), which supports recommendations to begin at a young age. Clinical and demographic characteristics were analyzed for 883 ITs ≤2 years old with hemophilia A and B, seen at US Hemophilia Treatment Centers and enrolled in the Community Counts Registry, a surveillance program of the Centers for Disease Control and Prevention. ICH in the first 2 years of life was seen in 68 of 883 (7.7%) ITs, of whom 8 of 68 (11.8%) were on continuous prophylaxis at the time of ICH. ITs in this study usually started prophylaxis within the first year of life (mean, 10.3 months), with earlier ages of prophylaxis initiation in later birth cohorts in ITs with hemophilia A. Compared with those without a family history (FH) of hemophilia, known positive FH of hemophilia was associated with earlier age of diagnosis (P ≤ .0001) and decreased rates of vaginal delivery (P = .0006). The use of factor VIII mimetics and extended half-life clotting factor prophylaxis increased with later birth cohorts for ITs with hemophilia A and B. The study highlights that ICH rates in ITs with hemophilia remains substantial and underscores the need for further research to identify modifiable risk factors to prevent ICH by earlier diagnosis and initiating prophylaxis early, even within the first month of life.

Defining the impact of immune tolerance induction on clinically relevant outcomes in a US cohort of severe hemophilia A

AbstractAlthough the near-term benefit of immune tolerance induction (ITI) for the treatment of people with severe hemophilia A with inhibitor is apparent, the magnitude of the longer-term impact of ITI on clinical outcomes remains undefined. We examined the association between receiving ITI and the success of ITI on clinical outcomes including (1) clinical events, (2) health care use, (3) quality of life/function, (4) socioeconomic status, and (5) death, using the Community Counts (CC) registry of US Hemophilia Treatment Centers between 2013 and 2017. Multivariate logistic regression, negative binomial, and Poisson models were used. Included in this study were 3659 people with severe hemophilia A with median age of 21 years when entering the CC registry. Among 576 participants with inhibitors, 485 had received ITI (84%). ITI was successful in 299 (61.7%) and partially successful or failed in 95 (19.5%) or 91 (18.7%), respectively. Those that received ITI had fewer treated bleeds, less chronic pain, better function, and higher educational attainment than those not receiving ITI. Successful vs partially successful and failed ITI was associated with fewer treated bleeds, less health care use, less chronic pain, better function, and fewer missed days of school or work. Mortality was not associated with ITI, regardless of its success. Those with successful ITI had similar rates of treated bleeds, chronic pain, and health care use as those with no inhibitors. Undergoing ITI, particularly if successful, improved clinical outcomes but not mortality. These findings support decision making regarding initiation of ITI and inform future clinical trials.

A pilot study of US HTC physical therapists' concordance of PT MASAC recommendations and educational needs.

Physical therapists (PTs) are essential providers within the Hemophilia Treatment Centers (HTCs) team caring for persons with inherited blood disorders (PWBD). Little is known regarding PTs understanding and concordance of MASAC PT Recommendations (MASAC#238), educational resources used to maintain competency and support for a mentorship programme. PTs at federally funded HTCs were eligible to participate in a descriptive non-validated study exploring: (i) demographics, (ii) educational background, (iii) experience in evaluation and treatment of PWBD, (iv) practice patterns indicative of concordance with MASAC#238 and (v) opinion regarding PT mentorship. Respondents experience caring for PWBD ranged 1-36 years, treating both adults and children. Although most acknowledged awareness of MASAC#238, dropout (14/44, 31.8%) was noted; 28/30 (93.3%) who continued were aware of the recommendations. Level of concordance with MASAC#238 varied (range 64.3%-96.2%) regarding: signs/symptoms, treatment of muscle/joint bleeding and pre/post synovectomy and knee replacement treatment. Many PTs identified patients as individual and unique, thus not all recommendations may apply. PTs utilised available educational programmes. No relationships were noted regarding years of practice, education and years caring for PWBD. All respondents favoured a mentorship programme citing benefits, but also outlined barriers. Provision of necessary financial support for optimal function of a full-time PT within the HTC can enhance standards of care for PWBD. Supporting educational opportunities may enhance concordance with current MASAC PT Recommendations. Respondents valued development of a structured, hands-on mentorship programme. MASAC#23 has recently been updated in May 2023 to MASAC#275.

Development of a haemophilia A gene therapy shared decision-making tool for clinicians.

As gene therapies are incorporated into clinical practice, shared decision-making (SDM) is recommended for implementation. To inform development of a clinician SDM tool for haemophilia A gene therapy. Clinicians at US Hemophilia Treatment Centers completed semi-structured interviews about their experience with SDM and provided feedback on a clinician SDM tool prototype. Interviews were transcribed verbatim for coding and thematic content analysis. Ten participants enrolled, eight physicians and two haemophilia nurses. All participants care for adults with haemophilia (1-27 years of experience) and 7 have gene therapy trials open at their institution. Confidence in having a clinical discussion about gene therapy included none (N=1), slight (N=3), moderate (N=5) and high (N=1). All participants reported familiarity with SDM and agreed that the tool would be useful for their clinical practice. Key themes in participant feedback for the tool were (1) language and presentation; (2) content; and (3) implementation. Participants highlighted the importance of providing unbiased information and having companion tools with patient-centric language. These data highlight the need for SDM tools for haemophilia A gene therapy. Key information to include in the tool are safety, efficacy, cost and detailed information on the gene therapy process. Data should be provided in an unbiased format and allow comparison to other treatments. The tool will be evaluated in clinical practice and refined as clinical trial data and real-world experience mature.

Depression and anxiety in persons with Von Willebrand disease.

We assessed sociodemographic and clinical characteristics associated with depression and anxiety in individuals with Von Willebrand disease (VWD) aged ≥12years. The study collected data on patients' sociodemographic, joint problems and health-related quality of life (HRQoL) using EQ-5D-3L, 8-item patient health questionnaire for depression and 7-item Generalized Anxiety Disorder Questionnaire from participants in seven geographically diverse US haemophilia treatment centres. Analyses included 77 participants. The rates of depression and anxiety were 63.6% and 58.3%, respectively. Persons with low VWF displayed higher rates of depression (86.7%) or anxiety (69.2%) compared to those with VWD (58.1%, p=.04 for depression, and 55.9%, p=.38 for anxiety). Logistic regression analyses demonstrated that having joint problems (odds ratio [OR]=6.3, confidence interval [CI]=2.0-20.1) was the most important variable associated with depression, followed by being single, divorced, widowed, or separated in adult participants or parents of participants age<18 years (OR=7.0, CI=1.7-29.0. The most important variable associated with anxiety was being single or lacking a partner (OR=10.8, CI=2.5-47.5), followed by age 12-17years old (OR=6.7, CI=1.6-26.9), or having worse health compared to 3-months ago (OR=12.3, CI=1.3-116.2). Mean covariates adjusted EQ visual analogue scale score was significantly lower among persons with depression (68.77±3.15 vs. 77.58±4.24, p=.03) than those without depression. Our study revealed concerning levels of depression and anxiety in this VWD sample. Lack of social support was determined an important factor associated with depression and anxiety in this sample. Mental health screening is critical in VWD clinical evaluation and care.

Results of genetic analysis of 11 341 participants enrolled in the My Life, Our Future hemophilia genotyping initiative in the United States

BackgroundHemophilia A (HA) and hemophilia B (HB) are rare inherited bleeding disorders. Although causative genetic variants are clinically relevant, in 2012 only 20% of US patients had been genotyped. ObjectivesMy Life, Our Future (MLOF) was a multisector cross‐sectional US initiative to improve our understanding of hemophilia through widespread genotyping. MethodsSubjects and potential genetic carriers were enrolled at US hemophilia treatment centers (HTCs). Bloodworks performed genotyping and returned results to providers. Clinical data were abstracted from the American Thrombosis and Hemostasis Network dataset. Community education was provided by the National Hemophilia Foundation. ResultsFrom 2013 to 2017, 107 HTCs enrolled 11 341 subjects (68.8% male, 31.2% female) for testing for HA (n = 8976), HB (n = 2358), HA/HB (n = 3), and hemophilia not otherwise specified (n = 4). Variants were detected in most male patients (98.2%% HA, 98.1% HB). 1914 unique variants were found (1482 F8, 431 F9); 744 were novel (610 F8, 134 F9). Inhibitor data were available for 6986 subjects (5583 HA; 1403 HB). In severe HA, genotypes with the highest inhibitor rates were large deletions (77/80), complex intron 22 inversions (9/17), and no variant found (7/14). In severe HB, the highest rates were large deletions (24/42). Inhibitors were reported in 27.3% of Black versus 16.2% of White patients. ConclusionsThe findings of MLOF are reported, the largest hemophilia genotyping project performed to date. The results support the need for comprehensive genetic approaches in hemophilia. This effort has contributed significantly towards better understanding variation in the F8 and F9 genes in hemophilia and risks of inhibitor formation.

Genome-Wide Association Study and Gene-Based Analysis of Participants With Hemophilia A and Inhibitors in the My Life, Our Future Research Repository.

IntroductionUp to 30% of individuals with hemophilia A develop inhibitors to replacement factor VIII (FVIII), rendering the treatment ineffective. The underlying mechanism of inhibitor development remains poorly understood. The My Life, Our Future Research Repository (MLOF RR) has gathered F8 and F9 mutational information, phenotypic data, and biological material from over 11,000 participants with hemophilia A (HA) and B as well as carriers enrolled across US hemophilia treatment centers, including over 5,000 whole-genome sequences. Identifying genes associated with inhibitors may contribute to our understanding of why certain patients develop those neutralizing antibodies.Aim and MethodsHere, we performed a genome-wide association study and gene-based analyses to identify genes associated with inhibitors in participants with HA from the MLOF RR.ResultsWe identify a genome-wide significant association within the human leukocyte antigen (HLA) locus in participants with HA with F8 intronic inversions. HLA typing revealed independent associations with the HLA alleles major histocompatibility complex, class II, DR beta 1 (HLA DRB1*15:01) and major histocompatibility complex, class II, DQ beta 1 (DQB1*03:03). Variant aggregation tests further identified low-frequency variants within GRID2IP (glutamate receptor, ionotropic, delta 2 [GRID2] interacting protein 1) significantly associated with inhibitors.ConclusionOverall, our study confirms the association of DRB1*15:01 with FVIII inhibitors and identifies a novel association of DQB1*03:03 in individuals with HA carrying intronic inversions of F8. In addition, our results implicate GRID2IP, encoding GRID2-interacting protein, with the development of inhibitors, and suggest an unrecognized role of this gene in autoimmunity.

The GOAL-Hēm journey: Shared decision making and patient-centred outcomes.

IntroductionGOAL‐Hēm is a novel, haemophilia‐specific, patient‐centred outcome measure (PCOM) based on goal attainment scaling, allowing people with haemophilia (PwH) to set and monitor the attainment of individualized goals for treatment.AimTo provide a thorough overview of the creation, validation, and development of GOAL‐Hēm.MethodsClinician workshops were held to develop a haemophilia‐specific goal menu. Qualitative data from semistructured interviews with PwH and their caregivers guided further revisions to the goal menu (i.e., goal domains and descriptors). A feasibility study was performed including a 12‐week, prospective, noninterventional evaluation involving clinicians and PwH at four US haemophilia treatment centres. Finally, the Patient Voice Study gathered feedback from PwH and their caregivers via an online survey, interviews, and a focus group.ResultsThe feasibility study validated GOAL‐Hēm with successful outcomes in construct/content validity and responsiveness, including a large effect in patient‐ and clinician‐rated goal attainments. The Patient Voice Study led to significant refinement of GOAL‐Hēm goals and descriptors, resulting in a more straightforward and relatable menu for PwH and their caregivers. Overall, GOAL‐Hēm captured qualitative data in areas important to PwH and employed quantitative methods to evaluate meaningful changes in those areas. The individualized tool was well equipped to handle the complex and chronic nature of haemophilia and was endorsed by PwH, their caregivers, and clinicians.ConclusionThe GOAL‐Hēm development journey may serve as a roadmap for other PCOMs in a variety of settings, including clinical studies, haemophilia treatment centres for care planning, and as a tool to gather real‐world evidence.

Reduced Dosing Frequency Following a Switch to Rix-FP for the Treatment of Hemophilia B: Results from the Athn 2 Study

Reduced Dosing Frequency Following a Switch to Rix-FP for the Treatment of Hemophilia B: Results from the Athn 2 Study

Emicizumab for the Treatment of Acquired Hemophilia a: A Multicenter US Case Series

Emicizumab for the Treatment of Acquired Hemophilia a: A Multicenter US Case Series

Depression and Anxiety in Persons with Von Willebrand Disease

Depression and Anxiety in Persons with Von Willebrand Disease

Symptoms in Infants and Toddlers With von Willebrand Disease

Source: Dupervil B, Abe K, O’Brien SH, et al. Characteristics, complications, and sites of bleeding among infants and toddlers less than 2 years of age with VWD. Blood Adv. 2021;5(8):2079-2086; doi:10.1182/bloodadvances.2020004141Investigators from multiple institutions conducted a retrospective study to describe the diagnosis and bleeding history among infants and toddlers with von Willebrand disease (VWD). For the study, data from the CDC Universal Data Collection (UDC) surveillance system established in the US Hemophilia Treatment Center (HTC) Network were reviewed. Children <24 months old, diagnosed with VWD and treated at one of 135 HTCs from 2003 to 2011 were enrolled. For the UDC, data on demographics, VWD diagnosis, family history of bleeding disorders, and history and treatment of bleeding episodes were collected at enrollment and regularly scheduled visits in a systematic manner. VWD type (1, 2, or 3) was classified based on the diagnosis made by the treating physician at the HTC. Descriptive statistics were used to characterize demographics, age at diagnosis, reason for diagnosis (family history or unusual bleeding), and number and anatomic location of bleeding episodes. Chi-square, Fisher exact, or Wilcoxon rank sum tests were used to assess differences when groups were compared.Data on 105 infant and toddlers were analyzed. The mean age of enrollment was 14 months, and 61 (58%) of the patients were male. Among these infants and toddlers, 63% had VWD type 1, 28% type 2, and 9% type 3. There was a family history of bleeding disorders in 79.1%. A family history of VWD prompted diagnostic testing in 68% of study patients; 93% of children diagnosed with type 2 disease had a family history of VWD, compared to 77% of those with type 1 and 44% of those with type 3 (P = 0.02). The mean age at diagnosis of all study patients was 7 months. Children with type 2 VWD were diagnosed at a significantly younger age than those with types 1 and 3 (mean age, 4.7, 8.0, and 6.8 months, respectively; P = 0.04).Among study participants, 22% experienced a bleeding episode before the diagnosis of VWD, 22% were diagnosed at the time of an episode, and approximately 50% were diagnosed before their first notable bleeding event (with testing done because of a family history). Overall, 274 bleeding events were documented in 73 patients. The most common types of bleeding episodes were oral/nasal bleeds (166 episodes, 60.6%) and soft-tissue hematomas (57 episodes, 20.8%); 9 boys (14.8%) experienced unusual bleeding with circumcision. There were 7 episodes of subdural hemorrhages among the study children, occurring both after trauma and spontaneously.The authors conclude that the majority of infants and toddlers with VWD have a family history of the disease, and bleeding episodes are common.Dr Hogan has disclosed no financial relationship relevant to this commentary. This commentary does not contain a discussion of an unapproved/investigative use of a commercial product/device.Von Willebrand disease affects up to 1% of the U.S. population.1 Von Willedbrand Factor (VWF) is an acute-phase reactive glycoprotein that aggregates and adheres platelets to damaged blood vessel walls.2 Many with Type 1 VWD, a partial VWF deficiency associated with autosomal dominant inheritance, are unaware of their bleeding disorder due to mild gum bleeding, epistaxis, petechiae, bruising, gastrointestinal bleeding, and heavy menses often attributable to co-morbidities, medications, or trauma (See AAP Grand Rounds. 2020;44[5]:54.)3 Those with subtypes of type 2 VWD, due to different qualitative VWF defects, have variable inheritance and bleeding symptoms.4 Those with the rarest, type 3 VWD, due to an autosomal recessive inheritance manifesting with an absence of VWF, have severe bleeding symptoms.4In older children, teens, and adults, screening for bleeding disorders includes family history and symptom scores using the International Society on Thrombosis and Haemostasis Bleeding Assessment Tool.5 Falsely abnormal or normal blood test results for CBC, PT, PTT, VWF antigen, VWF activity, Factor VIII, and multimeric analysis arise due to issues with phlebotomy, specimen handling, and assay variability.6 Interpretation of diagnostic test results are affected by blood type, hormones, and concurrent stressors such as fear, exercise, or infection.2 Currently, complex genetic testing plays a limited role in diagnosis and clinical severity in some type 2 VWD cases.7The current investigators review a large cohort of newborns, infants, and toddlers with VWD and describe bleeding episodes, which occur most often before 1 year of age. Limitations of this study include overrepresentation of non-Hispanic whites and missing data for bleeding characteristics or scores, VWF antigen/activity levels, and vitamin K administration at birth. No control cohort with or without bleeding symptoms was available for comparison.A family history of VWD or personal history of oropharyngeal, circumcision-related, hematomas, or intracranial bleeds in children <2 years of age indicate the need for evaluation for VWD.

Evolution of haemophilia integrated care in the era of gene therapy: Treatment centre's readiness in United States and EU.

Evolution of haemophilia integrated care in the era of gene therapy: Treatment centre's readiness in United States and EU.

Characteristics, complications, and sites of bleeding among infants and toddlers less than 2 years of age with VWD

AbstractData on infants and toddlers (ITs) with von Willebrand disease (VWD) are lacking. We used data collected in the US Hemophilia Treatment Center Network (USHTCN) to describe birth characteristics, bleeding episodes, and complications experienced by 105 patients with VWD who were <2 years of age. In 68% of the patients, the reason for diagnostic testing was a family history of a bleeding disorder. The mean age at diagnosis was 7 months, with little variation by sex. Patients with type 2 VWD were diagnosed earlier than those with types 1 or 3 (P = .04), and those with a family history were diagnosed ∼4 months earlier than those with none (P < .001). Among the patients who experienced a bleeding event (70%), oral mucosa was the most common site of the initial bleeding episode (32%), followed by circumcision-related (12%) and intracranial/extracranial bleeding (10%). Forty-one percent of the initial bleeding events occurred before 6 months of age, and 68% of them occurred before the age of 1 year. Approximately 5% of the cohort experienced an intracranial hemorrhage; however, none was associated with delivery at birth. Bleeding patterns and rates were similar by sex (P = .40) and VWD type (P = .10). Forty-seven percent were treated with plasma-derived von Willebrand factor VIII concentrates. The results of this study indicate that a high percentage of ITs diagnosed with VWD and receiving care within the multidisciplinary structure of the USHTCN have a family history of VWD. In addition, bleeding events such as circumcision-related, oropharyngeal, and intracranial or extracranial episodes are common and are leading indicators for treatment.

Hematology Utilization Group Studies Part VII (HUGS VII): Costs and Impact of Disease in Older Persons with Hemophilia

BACKGROUD Improved care and prophylactic factor replacement therapy have lengthened life expectancy for persons with hemophilia (PWH). These advancements have created a new hemophilia cohort of senior persons not seen since the previous human immunodeficiency viruses (HIV) years, and little is known about their age-related health outcomes. OBJECTIVES We describe the impact of hemophilia on comorbidities, joint problems, healthcare utilization and health related quality of life (HRQoL) from the HUGS VII baseline data. METHODS HUGS VII prospectively examines the cost and burden of hemophilia, including HRQoL, arthropathy, and economic impact in persons with hemophilia A or B age ≥ 40 years who obtained care from three US Hemophilia Treatment Centers. Participants completed a standardized interview to collect clinical and sociodemographic characteristics, hemophilia treatment regimen, pain, joint problems, comorbidities, and HRQoL using EQ-5D-3L. Clinical chart reviews documented hemophilic severity and treatment. Participants' characteristics were compared between two age groups: 40-49 years and ≥ 50 years using Chi-square tests for categorical variables and T-tests for continuous variables. RESULTS This analysis includes a total of 70 male with hemophilia, 64.3% aged ≥50 years, 75.7% with hemophilia A. Individuals ≥ 50 years had higher rates of being married or with a partner (71.11% vs. 56.0%, P=0.20), retired/not employed (66.7% vs. 28.0%, P=0.002), and having mild or moderate hemophilia (68.9% vs. 40.0%, P=0.02) than those 40-49 years old. Use of prophylaxis was similar among age groups in severe hemophilia but lower for older mild/moderate PWH. Among persons with mild/moderate hemophilia, those ≥ 50 years old reported a higher rate of joint pain (83.8% vs 70.0%, P=0.37) or range of motion limitation (73.3% vs, 60.0%, p=0.45) than the younger group, although the differences were not statistically significant. Compared to those 40-49 years old, individuals ≥ 50 years old reported fewer emergency room visits (4.6% vs. 20.8%, P=0.03), and physical therapy visits (16.0% vs. 41.7%, P=0.06). The older age group had significantly higher rates of self-reported myocardial infarction (11.6% vs. 0%, P=0.08) and diabetes (24.4% vs. 4.0%, P=0.03) than those 40-49 years. Self-reported comorbidities were measured by asking "Has a doctor ever told you that you have certain conditions?" The most frequently reported comorbidities were hepatitis C infection (75.7%, 79.3% of persons with infected hepatitis C had been treated and, 82.7% cleared the hepatitis C virus), hypertension (47.1%), depression (23.2%) and anxiety (21.7%). Mean covariates adjusted EQ-5D index score was lower in older persons (0.79 vs. 0.87, P=0.09). CONCLUSIONS Older PWH are over-represented by individuals with mild/moderate disease, potentially due to premature death among those with severe disease. Although this group included a larger proportion of mild disease than younger PWH, it presented prevalent comorbidities both of aging and of hemophilic arthropathy, despite lower rates of healthcare utilization and use of preventive therapies. Disclosures Curtis: USC Hemophilia Utilization Group Study (HUGS): Consultancy; Patient Reported Outcomes, Burdens and Experiences: Consultancy; Bayer: Consultancy; Novo Nordisk: Consultancy. Konkle:Pfizer: Consultancy, Research Funding; Roche: Consultancy; BioMarin: Consultancy; Sigilon: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding; Takeda: Research Funding; Uniquire: Research Funding; CSL Behring: Consultancy; Baxalta: Research Funding; Spark: Consultancy, Research Funding. Kulkarni:Sanofi/ Bioverativ, Bayer, Biomarin, Shire/Takeda, Novo Nordisk, Freeline: Other: clinical trial research grants ; Bioverativ/Sanofi, BPL, Genentech, Kedrion, Novo Nordisk, Octapharma, Pfizer, Takeda, Catalyst Bioscience Bayer: Membership on an entity's Board of Directors or advisory committees. Wu:Baxalta US Inc., Bannockburn, IL (a Takeda Company), CSL Behring L.L.C., and Octapharma USA, Inc.: Research Funding. Tran:Takeda: Consultancy; Novo Nordisk: Consultancy; Bayer: Consultancy; Bioverativ: Consultancy. Nichol:Global Blood Therapeutics: Research Funding; CSL Behring: Research Funding; Octapharma: Research Funding; Genentech Inc.: Research Funding; Baxalta US Inc., Bannockburn, IL (a Takeda Company): Research Funding; Pfizer: Research Funding.

Healthcare Utilization and Health Related Quality of Life in Persons with Von Willebrand Disease

Healthcare Utilization and Health Related Quality of Life in Persons with Von Willebrand Disease

Patient satisfaction with US Hemophilia Treatment Center Care, Teams and Services: The First National Survey.

Patient satisfaction with health care is a key quality metric, associated with adherence and better outcomes. However, satisfaction with US Hemophilia Treatment Centers (HTC) is unknown. To assess patient satisfaction with US Hemophilia Treatment Centers. A nationally uniform survey was conducted using the US HTC Network's regional infrastructure. Satisfaction with multidisciplinary team members, services and care processes was assessed. The anonymous survey, in English and Spanish, was disseminated to 28289 households. Data were aggregated using 4 standard US Census regions. 5006 individuals (17.7%) who obtained care from 133 (96.4%) of 138 HTCs in 2014 responded. Satisfaction with overall HTC care at 'always' or 'usually' (A/U) levels ranged 94.2%-97.9% regardless of patient gender, age, race, ethnicity, language, diagnosis, severity, region or frequency of HTC contact. A/U satisfaction with HTC haematologist, nurse, social worker or physical therapist, individually, ranged 95.1%-97.3% nationally. A/U satisfaction with three HTC services was 89.5%-96.9% and 94.9%-98.0% for five HTC care processes nationally. Regional satisfaction at A/U levels was at least 87.0%. Nationally, 26.4% and 21.2% rated insurance and language, respectively, as A/U problems in getting needed HTC services. Patient satisfaction with US Hemophilia Treatment Center care, multi-disciplinary teams, services and processes was consistently high, documenting the value patients place on HTCs. The successful survey administration demonstrates the capability of the Network's regional infrastructure. Access to the US HTC Network is particularly critical to ongoing health in this new era of novel and gene therapies.

Immune Tolerance Induction (ITI) with a Plasma-Derived Factor VIII for Patients with Hemophilia a and Inhibitors: A Retrospective Study

Introduction: A serious complication in hemophilia A is the formation of inhibitors to clotting factors. The primary means for eradicating inhibitors is immune tolerance induction (ITI) therapy. Antihemophilic factor (human) (Koate®-DVI) is a purified dried concentrate indicated for the treatment of hemophilia A with insufficient activity of Factor VIII (FVIII). Although other plasma-derived concentrates containing von Willebrand factor have been utilized successfully for ITI, studies evaluating this product for ITI therapy have not been published. An evaluation of patient- and treatment-related factors associated with outcomes following primary or rescue ITI with antihemophilic factor (human) in patients with hemophilia A and inhibitors was conducted in this retrospective multicenter chart review project. Methods: An evaluation of medical records of 13 inhibitor patients treated with antihemophilic factor (human) for primary or rescue ITI therapy between January 1, 2012, and July 31, 2017, was conducted in five US hemophilia treatment centers. To be eligible for inclusion, patients were required to have a diagnosis of hemophilia A of any severity level, inhibitor to FVIII at the time of treatment initiation with antihemophilic factor (human), and ongoing treatment with antihemophilic factor (human) for primary or rescue ITI. Data were de-identified and analyzed descriptively. Outcome measures were defined, per the International Immune Tolerance consensus recommendations, as "complete success" (inhibitor titer &lt;0.6 Bethesda Units [BU] at 33 months of ITI, FVIII recovery ≥66% and half-life ≥6 hours), "partial success" (a reduction in inhibitor titer to &lt;5 BU mL with FVIII recovery &lt;66% and/or FVIII half-life &lt;6 hours associated with clinical response to FVIII therapy not followed by a treatment-limiting anamnestic rise in inhibitors to &gt;5 BU mL), or "failure" (neither complete nor partial success). Results: All (N=13) patients who met the inclusion criteria were males with severe hemophilia, with the exception of one with moderate hemophilia. Six patients were African American, four were Hispanic, two Caucasian, and one was Asian. They were diagnosed with inhibitors between the ages of 8 months and 39 years and were 5 to 53 years old upon ITI with antihemophilic factor (human). Ten of 13 patients (76.9%) had successful ITI; seven with complete success and three with partial success (Table). Three patients failed ITI. As primary therapy, complete success was obtained with all but one of the six patients treated with antihemophilic factor (human). These six patients were all older than 7 at the initiation of ITI, a risk factor for poor ITI. Seven of the 13 total patients had a combined previous 12 attempts at ITI with other products (plasma derived and/or recombinant). Of these seven rescue patients, ITI with antihemophilic factor (human) was completely successful in two and partially successful in three. Adverse events reported once in separate patients during treatment with antihemophilic factor (human) included catheter infection, portal infection, bacteremia, peritonitis due to a ruptured appendix, and complications in treatment. One patient had several adverse events, including cellulitis at the port site, abdominal wall hematoma, right thumb fracture and hematoma, and left shoulder hemarthrosis. Conclusions: While retrospective data has limitations, real-world evidence demonstrates that ITI with antihemophilic factor (human) concentrate can be successful or partially successful in diverse populations of moderately complex patients with hemophilia A and inhibitors. The data suggest that antihemophilic factor (human) may be most appropriate for patients when used as primary ITI, as even patients older than 7 years achieved complete success. Additional patients need to be evaluated to make a definitive conclusion regarding the impact of age on success of ITI therapy in addition to other risk factors. Disclosures Escobar: Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; National Hemophilia Foundation: 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; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Consultancy, Membership on an entity's Board of Directors or advisory committees. Rajan:Bayer, Octapharma: Consultancy, Honoraria, Research Funding, Speakers Bureau. Amega:Kedrion Biopharma: Employment. OffLabel Disclosure: Koate is not approved to treat vWD, nor, cTTP however, based on some published reports using kotae for these indications, we are anticipating those type of off label inquiries. I will clearly disclose to the participants that these are off label indications.

Spontaneous Bleeding and Poor Bleeding Response with Extended Half-Life Factor IX Products: A Survey of Select US and Canadian Hemophilia Treatment Centers

Background: Factor IX (FIX) has distinct pharmacokinetic properties compared to factor VIII including significant distribution to the extravascular space. Extravascular distribution and binding to type IV collagen is important in hemostasis but not readily measureable in clinical practice for patients with hemophilia B receiving factor products. We previously reported data regarding use of EHL-FIX products in a cohort of patients who demonstrated issues with spontaneous bleeding and poorly controlled bleeding events; we now report data from an expanded cohort including performance of all EHL-FIX products available in US and Canada. Aims: To characterize the use and performance of EHL-FIX in clinical practice at six hemophilia treatment centers (HTCs). Methods: An electronic survey regarding center specific use of EHL-FIX amongst patients with severe hemophilia B (HB) was sent in summer 2019, including 4 previously surveyed centers and 2 additional centers. Providers were asked if patients utilizing EHL-FIX for prophylaxis had experienced 1) spontaneous/minimally traumatic bleeding events at factor levels &gt;10% or 2) poorly controlled bleeding events requiring more frequent/higher doses of EHL-FIX than anticipated in addition to patterns of EHL-FIX product switching. Results: Surveyed HTCs cared for 90 patients with HB including 67 (74%) who utilized EHL-FIX, including 26 (39%) recombinant factor IX (FIX) albumin fusion protein (rFIX-FP), 37 (55%) recombinant factor IX Fc fusion protein (rFIXFc), and 4 (6%) received glycopegylated recombinant FIX (rFIX-GP). All patients had severe hemophilia B with the exception of one smaller center also contributing data regarding moderate HB patients on prophylaxis. All centers reported having patients with unexpected spontaneous/minimally traumatic bleeding and poorly controlled bleeding which did not seem to be dependent on age (median age 14.5 years, range 1.4-44). This occurred in 18 patients on prophylaxis, including 16 of 26 (62%) patients using rFIX-FP, and 2 of 4 (50%) of patients using rFIX-GP. Conclusions: Although plasma FIX activity levels have driven prophylaxis and bleed management decisions, clinical experience suggests novel properties of EHL-FIX may impact hemostasis. Although achieving seemingly adequate FIX plasma troughs (&gt;10%), limited clinical experience suggests patients with SHB may have a differential response to EHL-FIX, noted in our cohort with FIX-FP and rFIX-GP. Successful bleed prevention or control in SHB may be predicted by the distribution of FIX in circulation and extravascular space, and the presence of FIX in tissues at time of injury. These data demonstrate the importance of real-world monitoring of efficacy of new FIX products and suggest the need for more robust mechanisms to understand the hemostatic performance of products. Disclosures Malec: Bayer: Honoraria; Spark: Honoraria; CSL: Honoraria; Sanofi: Consultancy, Honoraria, Speakers Bureau; Takeda: Honoraria. Croteau:Novo Nordisk: Consultancy, Honoraria, Research Funding; Shire: Consultancy, Honoraria; Bayer: Consultancy, Honoraria; Bayer: Consultancy, Honoraria; Octapharma: Honoraria; Octapharma: Honoraria; Genentech: Consultancy, Honoraria; Pfizer: Research Funding; Spark Therapeutics: Research Funding; Novo Nordisk: Consultancy, Honoraria, Research Funding; Spark Therapeutics: Research Funding; Pfizer: Research Funding; Genentech: Consultancy, Honoraria; CSL Behring: Consultancy, Honoraria; CSL Behring: Consultancy, Honoraria; Shire: Consultancy, Honoraria. Callaghan:Biomarin, Bioverativ, Grifols, Kedrion, Pfizer, Roche/Genentech, Shire, and Spark Therapeutics: Consultancy; Alnylum: Equity Ownership; Bayer: Consultancy, Speakers Bureau; Takeda: Consultancy, Research Funding; Sanofi: Consultancy; Global Blood Therapeutics: Consultancy; Novonordisk: Consultancy, Speakers Bureau; Octapharma: Consultancy; Pfizer: Research Funding; Roche: Research Funding; Shire/Takeda: Speakers Bureau; Roche/Genentech: Speakers Bureau. Matino:Bayer: Honoraria, Research Funding; Sobi: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Roche: Research Funding; Bioviiix: Honoraria; Sanofi: Honoraria. Friedman:CSL: Consultancy; Bayer: Consultancy; Genentech: Consultancy; Instrumentation Laboratory: Consultancy; Siemens: Consultancy. Sidonio:Grifols: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genetech: 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; Bioverativ: Membership on an entity's Board of Directors or advisory committees, Research Funding; Octapharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Uniqure: Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees; Biomarin: Membership on an entity's Board of Directors or advisory committees; Kedrion: Research Funding.