Assessing the Safety of Various VWF Regimens in Patients with Clinically Severe VWD: A Natural History Study

Background: Von Willebrand disease (VWD) is the most common inherited bleeding disorder in humans affecting up to 1% of the population, while symptomatic prevalence is likely closer to 0.1%. A deficiency of von Willebrand factor (VWF) can be quantitative (type 1 or type 3) or qualitative (type 2) and lead to a bleeding diathesis of variable intensity roughly correlating with functional activity. Diagnosis can be challenging due to variable penetrance and large influence of multiple pre-analytic variables and a wide testing coefficient of variation. Treatment for VWD is focused on replacement of defective or deficient VWF with a plasma-derived or recombinant VWF-containing product, release and elevation of endogenous stores of VWF with Desmopressin (DDAVP), or prevention of premature fibrinolysis with an antifibrinolytic, such as aminocaproic acid. Although there is relative consensus on the management of mild VWD, there is scarce literature about the optimal treatment of patients with severe disease, especially in regard to factor replacement. Real World evidence for the use of primary (prior to significant bleeding) or secondary (following development of significant bleeding) prophylaxis is lacking with the majority of studies relying heavily on retrospective data. Additionally, ongoing VWD prophylaxis studies typically only allow participants to enroll if they previously have not been on prophylaxis, limiting our ability to learn about this growing population of patients. Study Design and Methods: Approximately 1,900 VWD patients were identified in the ATHNdataset with a VWF:Ag or VWF:RCo of ≤ 30%, with ~170 of these on prophylaxis. This group, in addition to those VWD patients with clinically significant bleeding and ≤ 40% of normal VWF:Ag or VWF:RCo, provide a potential unmet opportunity to examine prophylaxis and treatment patterns. Furthermore, a standardized laboratory assessment (including a standardized diagnostic battery, genetic evaluation of VWF gene, and inhibitor testing) will provide significant enrichment of the ATHNdataset by fully characterizing patients that are highly likely to utilize factor concentrates. Inclusion criteria are patients with severe VWD defined as type 3 VWD, or VWF:RCo, VWF:GP1bM or VWF:Ag≤ 30%, patients with clinically severe VWD as defined by VWF:Rco, VWF:GP1bM or VWF:Ag ≤ 40% with severe bleeding phenotype requiring recurrent use of factor concentrates, and co-enrollment in the ATHNdataset. Patients with platelet-type or acquired VWD are excluded. The primary objective is to assess the safety of various VWF regimens for different indications (on-demand, surgery, and prophylaxis) in adult and pediatric patients with clinically severe VWD. Safety is measured by the number of reported events as defined by the European Haemophilia Safety Surveillance (EUHASS) program. Secondary objectives are to enrich and analyze data from clinically severe congenital VWD patients by collecting laboratory data; to establish sub-studies for patients who are treated with VWF products on demand or who have started on or switched to a particular VWF containing product; to evaluate the use of factor replacement as prophylaxis in a cohort of severe VWD participants over 6 month time periods; to describe bleeding events, changes in overall bleeding, and annualized bleed rate as measured by the International Society on Thrombosis and Haemostasis (ISTH) Bleeding Assessment Tool (BAT) and if applicable the Pictorial Bleed Assessment Chart (PBAC); and to describe real-world effectiveness of VWD treatment as measured by health care utilization and quality of life measures (PROMIS® and V-WIQ questionnaires). Descriptive statistics will be calculated to analyze the primary and secondary outcomes. For each categorical variable, its frequency and percentage will be reported. In terms of a continuous measurement, its mean, median, standard deviation, interquartile range, minimum, and maximum values will be disclosed. The study will attempt to enroll a target number of at least 50 participants who are receiving VONVENDI but will not mandate the use of VONVENDI. More study design details are outlined in Table 1. Disclosures Sidonio: 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; Grifols: Membership on an entity's Board of Directors or advisory committees, Research Funding; Biomarin: Membership on an entity's Board of Directors or advisory committees; 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; Kedrion: Research Funding.

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Clustering of Bleeding Symptoms in Patients Previously Diagnosed As Type 3 Von Willebrand Disease: Results from a Large Cohort of Type 3 Von Willebrand Disease (the 3Winters-Ips Project)

Blood ◽

10.1182/blood-2018-99-113996 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 2465-2465

Author(s):

Alberto Tosetto ◽

Zahra Badiee ◽

Mohammad-Reza Baghaipour ◽

Luciano Baronciani ◽

Javier Battle ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Advisory Board ◽

Von Willebrand Disease ◽

Severe Bleeding ◽

Advisory Committees ◽

Bleeding Score ◽

Type 3 ◽

Von Willebrand

Abstract Patients with type 3 von Willebrand Disease (VWD) usually have markedly reduced FVIII/VWF levels and very severe bleeding manifestations but, because of their rarity, their bleeding phenotype is poorly described. We aimed at evaluating the distribution of bleeding symptoms in patients with type 3 VWD, comparing them with previously available data from a cohort of type 1 patients, and describing site-specific clustering of bleeding symptoms in these patients. We analyzed clinical data from the type 3 Von Willebrand International RegistrieS Inhibitor Prospective Study (3WINTERS-IPS),a no-profit, investigators initiated, multicenter, European-Iranian observational, retrospective and prospective study on patients with diagnosis of type 3 VWD. Aims of the 3WINTERS-IPS is 3-fold: a) to identify the main phenotypic and molecular characteristics of a large cohort of VWD patients; b) to evaluate the risk factors responsible for the severe bleeding phenotype; c) to assess the efficacy and safety of the treatment with VWF concentrates with or without FVIII including the risk of anti-VWF antibodies. Retrospective information on bleeding symptoms at presentation was collected using the MCMDM-1 VWD bleeding questionnaire, and bleeding severity summarized as bleeding score. Individual bleeding symptoms were considered as relevant when having a score >1 (hence requiring medical attention). Data was compared with that retrieved from the MCMDM-1 VWD study database on patients affected by type 1 VWD (index cases and affected family members). The study enrolled a total of 260 patients, of which we analysed 243 patients with available bleeding score at recruitment. The median age at study inclusion was 29 years (interquantile range, 26.5 years); 140 were females (53.8%). There were 108 patients of Iranian descent, while the remaining of patients were from Europe. The median number of bleeding symptoms was 5, and the median bleeding score was 15 (interquantile range, 13). Only 7/243 patients (2.8%) had a single bleeding symptom. Epistaxis was the most frequent relevant symptom, being present in 195 patients (80.2%), followed by menorrhagia in 99 females (70.7%). Males had a higher frequency of hemarthroses and hematomas than females (53.4% vs 42.1% and 40.8% vs 27.1%, respectively). When comparing the clinical presentation of type 3 vs. type 1 VWD, clearly increased bleeding scores were evident for all age-classes and even in paediatric cases. The association between symptoms having a relative frequency >20% is presented in the circle diagram, showing that some symptoms appeared to cluster with others in a variable degree (e.g., menorrhagia with epistaxis, hemarthrosis or oral cavity bleeding; post-extraction bleeding again with epistaxis, hemarthrosis or oral cavity bleeding; surgical bleeding or gastrointestinal bleeding with epistaxis alone). These findings confirm the severity of type 3 VWD and extend the knowledge of symptoms distribution in the widest available cohort of type 3 VWD patients. Disclosures Tosetto: Stago, Novo-Nordisk, BMS: Speakers Bureau; Werfen: Other: Member of Advisory Board, Speakers Bureau. Berntorp:Octapharma: Consultancy; CSL Behring: Consultancy; Shire: Consultancy, Other: honoraria for lecturing . Eikenboom:CSL: Research Funding. Mazzucconi:Baxalta-Shire: Consultancy, Speakers Bureau; Bayer: Consultancy, Speakers Bureau; Novartis,: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Novo Nordisk: Consultancy, Speakers Bureau; CSL Behring: Consultancy, Speakers Bureau. Oldenburg:Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Biogen Idec: Honoraria, Membership on an entity's Board of Directors or advisory committees; Chugai: Honoraria, Membership on an entity's Board of Directors or advisory committees; Grifols: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Shire: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Octapharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL Behring: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Biotest: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Swedish Orphan Biovitrum: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Peyvandi:Kedrion: Consultancy; Ablynx: Other: Member of Advisory Board, Speakers Bureau; Shire: Speakers Bureau; Roche: Speakers Bureau; Shire: Speakers Bureau; Kedrion: Consultancy; Kedrion: Consultancy; Ablynx: Other: Member of Advisory Board, Speakers Bureau; Grifols: Speakers Bureau; Roche: Speakers Bureau; Octapharma US: Honoraria; Octapharma US: Honoraria; Sobi: Speakers Bureau; Ablynx: Other: Member of Advisory Board, Speakers Bureau; Kedrion: Consultancy; Shire: Speakers Bureau; Roche: Speakers Bureau; Roche: Speakers Bureau; Novo Nordisk: Speakers Bureau; Shire: Speakers Bureau; Ablynx: Other: Member of Advisory Board, Speakers Bureau; Grifols: Speakers Bureau; Shire: Speakers Bureau; Ablynx: Other: Member of Advisory Board, Speakers Bureau; Grifols: Speakers Bureau; Novo Nordisk: Speakers Bureau; Octapharma US: Honoraria; Octapharma US: Honoraria; Sobi: Speakers Bureau; Grifols: Speakers Bureau; Grifols: Speakers Bureau; Kedrion: Consultancy; Sobi: Speakers Bureau; Roche: Speakers Bureau; Novo Nordisk: Speakers Bureau; Novo Nordisk: Speakers Bureau; Novo Nordisk: Speakers Bureau; Sobi: Speakers Bureau; Octapharma US: Honoraria; Sobi: Speakers Bureau. Schneppenheim:SHIRE: Consultancy; CSL Behring: Consultancy. Tiede:Alnylam, Bayer, Biogen Idec, Biotest, Bristol-Myers-Squibb, Boehringer Ingelheim, CSL Behring, Leo Pharma, Novo Nordisk, Octapharma, Pfizer, Roche, Shire, and SOBI: Consultancy; Alnylam, Bayer, Biogen Idec, Biotest, Bristol-Myers-Squibb, Boehringer Ingelheim, CSL Behring, Leo Pharma, Novo Nordisk, Octapharma, Pfizer, Roche, Shire, and SOBI: Honoraria; Alnylam, Bayer, Biogen Idec, Biotest, Bristol-Myers-Squibb, Boehringer Ingelheim, CSL Behring, Leo Pharma, Novo Nordisk, Octapharma, Pfizer, Roche, Shire, and SOBI: Research Funding.

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Bleeding in Patients with Clinically Severe Von Willebrand Disease: Preliminary Results of Athn 9, a Natural History Study of the Safety, Effectiveness, and Practice of Treatment for People with Severe Von Willebrand Disease (VWD)

Blood ◽

10.1182/blood-2020-137124 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 27-28

Author(s):

Angela C. Weyand ◽

Kenneth D Friedman ◽

Sweta Gupta ◽

Kristina M. Haley ◽

Chunla He ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Von Willebrand Disease ◽

Heavy Menstrual Bleeding ◽

Severe Bleeding ◽

Advisory Committees ◽

Type 3 ◽

Von Willebrand

Background: Von Willebrand Disease (VWD) is the most common inherited bleeding disorder, thought to occur in ~0.1% of the population. VWD results from a quantitative (Type 1 or 3) or qualitative (Type 2) defect in von Willebrand Factor (VWF), a multifunctional plasma protein involved in primary and secondary hemostasis. Diagnosis of VWD can be difficult due to pre-analytical variables, a wide coefficient of variation in testing, and incomplete penetrance. Treatment of VWD is aimed at replacement of the defective or missing protein through plasma derived or recombinant VWF, release of endogenous VWF through desmopressin (DDAVP) or clot stabilization with anti-fibrinolytic therapy. Though individuals with mild VWD and bleeding symptoms are common, less is known regarding individuals with VWD and a clinically severe bleeding phenotype. Aims: To characterize the bleeding phenotype and treatment regimens in patients with clinically severe VWD in the United States. Study Design and Methods: ATHN 9 is sponsored by the American Thrombosis and Hemostasis Network (ATHN) and is being conducted at ATHN-affiliated sites across the US. Participants were identified by the site investigators with the projected goal to enroll 130 individuals. Inclusion criteria were patients with severe VWD defined as type 3 VWD, or VWF:RCo, VWF:GPIbM or VWF:Ag≤ 30% or patients with "clinically severe VWD" defined by VWF:RCo, VWF:GPIbM or VWF:Ag ≤ 40% a with severe bleeding phenotype (need for recurrent use of factor concentrates) and prior enrollment in the ATHN dataset national surveillance data collection project. Patients with platelet-type or acquired VWD were excluded. Laboratory assessment including a standardized diagnostic battery, VWF genetic analysis, and inhibitor testing, was performed by a central laboratory. Bleeding was assessed using the International Society for Thrombosis and Haemostasis (ISTH) Bleeding Assessment Tool (BAT) (normal adult 0-4, normal score <18 years 0-2) and the Pictorial Bleeding Assessment Chart (PBAC) if applicable. Results: Initial data on 35 participants was analyzed. Most were adult (69%), female (66%), Caucasian (86%) and non-Hispanic (89%). Just less than half (16/35, 45.7%) have completed diagnostic testing (Table 1). Half of the patients had Type 1, a quarter Type 3, and the remaining had Type 2 or unknown. The majority of patients (69%) had VWF GPIbM activity <30IU/dL, while 44% had an abnormally low FVIII level as well. The majority (26/35, 74.3%) had a known family history of VWD. Slightly over half (19/35, 54.2%) had previous surgery. Few participants (4/35, 11.4%) reported the presence of a target joint at enrollment, ankle being most common. The bleeding phenotype was significant but variable with a mean ISTH BAT score of 10.6 (range 0-39). With the exception of the youngest cohort (0-5 years of age, mean BAT score of 6, range 3-8), bleeding scores increased with age and all participants had abnormal scores. The most commonly endorsed symptoms were epistaxis, heavy menstrual bleeding (HMB), and post-surgical bleeding. The PBAC was performed on 4/10 participants in reference to their last period with a median score of 36 and range of 0-112 (>150 is abnormal). The majority (3/4) of participants filling out the PBAC received VWF concentrate prophylaxis for HMB. The majority (23 participants, 66%) utilized factor concentrates for prophylaxis or on-demand treatment; six patients (17%) were on continuous prophylaxis, while 12 (34%) were on event-based or HMB prophylaxis while the remainder received episodic treatment. Participants most commonly used plasma derived VWF concentrate (93.9%) with the remainder using recombinant VWF. Discussion: Initial evaluation of 35 participants with clinically severe VWD demonstrated a predominance of mucosal bleeding with a minority of participants endorsing joint bleeds at enrollment. Despite abnormal ISTH BAT scores in all participants, PBAC scores were within normal range, likely reflecting appropriate management of HMB with most participants receiving VWF concentrate for HMB prophylaxis. In contrast to patients with mild disease where antifibrinolytics and desmopressin are frequently used, factor replacement was the most common treatment modality. Future analysis will focus on laboratory evaluation, bleeding phenotype, response to factor replacement therapy and quality of life. Disclosures Weyand: Shire: Membership on an entity's Board of Directors or advisory committees; Kedrion: Membership on an entity's Board of Directors or advisory committees; Aptevo: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees. Friedman:Alexion: Speakers Bureau; Bayer: Consultancy; Instrumentation Laboratories: Consultancy; Alexion: Consultancy. Haley:ATHN: Research Funding. Roberts:Sanofi: Consultancy, Speakers Bureau; Novo Nordisk: Consultancy, Speakers Bureau; Pfizer: Consultancy; Takeda: Consultancy, Research Funding, Speakers Bureau; uniQure: Consultancy; Octapharma: Consultancy, Speakers Bureau. Sidonio:Genentech: Membership on an entity's Board of Directors or advisory committees; Sanofi/Bioverativ: Membership on an entity's Board of Directors or advisory committees; Octapharma: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees; Uniqure: Membership on an entity's Board of Directors or advisory committees; Biomarin: Membership on an entity's Board of Directors or advisory committees; Catalyst Sciences: Membership on an entity's Board of Directors or advisory committees; Emergent Solutions: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Kedrion: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees; Octapharma: Research Funding; Grifols: Research Funding; Grifols: Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: VWF concentrates used for heavy menstrual bleeding

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Profile of Mutations Identified in the 3WINTERS-IPS Project on European & Iranian Patients with Previously Diagnosed Type 3 Von Willebrand Disease.

Blood ◽

10.1182/blood-2018-99-114702 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 1184-1184

Author(s):

Luciano Baronciani ◽

Flora Peyvandi ◽

Anne Goodeve ◽

Reinhard Schneppenheim ◽

Zahra Badiee ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Advisory Board ◽

Von Willebrand Disease ◽

Compound Heterozygous ◽

Advisory Committees ◽

Type 3 ◽

Von Willebrand ◽

Two Populations ◽

Iranian Patients

Abstract Background: The type 3 Von Willebrand International RegistrieSInhibitor Prospective Study (3WINTERS-IPS) is a no-profit, investigator initiated, multicenter, European-Iranian observational, retrospective and prospective study on patients with diagnosis of type 3 VWD. Patients with type 3 von Willebrand Disease (VWD3) have markedly reduced levels of von Willebrand factor (VWF) and very severe bleeding phenotype. Due to the recessive inheritance pattern, VWD3 is by definition a rare bleeding disorder (1:Million) but its prevalence may increase in countries like Iran with consanguineous marriages. Aim: To identify the VWF genetic defects in a cohort of European and Iranian patients with previously diagnosed VWD3 enrolled into the 3WINTERS-IPS project. Methods: Patients classified locally as VWD3 were enrolled in the study following informed consent. 141 patients were from 9 different European countries and 119 patients were from the Islamic Republic of Iran. Plasma/buffy-coat samples were sent to expert labs to confirm patient's laboratory phenotype and to perform molecular analysis. PCR and Sanger sequencing/ next generation sequencing and multiplex-ligation dependent probe amplification were used in Hamburg, Sheffield and Milan to confirm previously identified variants or to seek previously unidentified variants. Results: DNA samples from 122 patients from Europe and 114 patients from Iran were analyzed at the molecular level. Of the 236 VWD3 patients under evaluation 24 are still in progress. Of the 212 fully evaluated patients 139 were homozygous (EU/IR=46/93) and 43 were compound heterozygous (EU/IR=36/7). In the remaining 30 patients no variants were identified in 19 samples (EU/IR=6/13) and only one variant was found in the remaining 11 cases (EU/IR=10/1). 135 (EU/IR=82/53) different gene defects were identified among the 375 (EU/IR=174/201) alleles found in this study. Of these 135 variants identified 51(EU/IR=22/29) were not reported on the www.ensembl.org database. The distribution of the different type of variants identified in the two populations is shown in the Figure. The two charts are showing quite similar percentages of the variants identified, with a main exception for the Small deletions and Small insertions. Only five variants are shared among the two populations. Three of these are the "hotspot" variants at the Arg codon, p.Arg1659* (EU/IR=9/8), p.Arg1853* (EU/IR=2/3) and p.Arg2535* (EU/IR=1/2). However, a missense variant , p.Cys275Ser (EU/IR=1/2) and a large deletion, delEx1_Ex5 (EU/IR=1/2) were also found in both populations. Fifteen variants were recurrent and were found in 154 alleles, whereas 49 variants were found only once in the heterozygous state (EU/IR=40/9) and 50 variants were found only twice, mainly in the homozygous state (EU/IR=25/25). Six large deletions were identified (delEx1_Ex3, delEx1_Ex5, delEx14_Ex15, delEx17, delEx35_Ex52 and delEx1_Ex52) and a duplication (dupEx1_Ex28), nevertheless 52 alleles with missense variants were identified (EU/IR=20/32). Discussion: As expected, the majority of the Iranian patients were found to be homozygous (Homozygous/Compound Heterozygous=93/7) reflecting a high rate of consanguinity, nevertheless half of the European patients were found to be homozygous (Homozygous/Compound Heterozygous=46/36). The European populations demonstrated a higher heterogeneity of variants with 82 different variants among the 175 mutated alleles vs 53 different variants among the 201 mutated alleles identified in the Iranian population. Nevertheless, a higher number of previously unreported variants was found in the Iranian population (29) vs the European one (22), probably due to bias of previous investigations performed in European patients. Figure Figure. Disclosures Peyvandi: Ablynx: Other: Member of Advisory Board, Speakers Bureau; Shire: Speakers Bureau; Roche: Speakers Bureau; Grifols: Speakers Bureau; Grifols: Speakers Bureau; Novo Nordisk: Speakers Bureau; Sobi: Speakers Bureau; Sobi: Speakers Bureau; Novo Nordisk: Speakers Bureau; Kedrion: Consultancy; Novo Nordisk: Speakers Bureau; Octapharma US: Honoraria; Novo Nordisk: Speakers Bureau; Sobi: Speakers Bureau; Ablynx: Other: Member of Advisory Board, Speakers Bureau; Kedrion: Consultancy; Novo Nordisk: Speakers Bureau; Kedrion: Consultancy; Ablynx: Other: Member of Advisory Board, Speakers Bureau; Octapharma US: Honoraria; Shire: Speakers Bureau; Roche: Speakers Bureau; Kedrion: Consultancy; Kedrion: Consultancy; Ablynx: Other: Member of Advisory Board, Speakers Bureau; Octapharma US: Honoraria; Octapharma US: Honoraria; Sobi: Speakers Bureau; Roche: Speakers Bureau; Octapharma US: Honoraria; Shire: Speakers Bureau; Sobi: Speakers Bureau; Roche: Speakers Bureau; Roche: Speakers Bureau; Shire: Speakers Bureau; Ablynx: Other: Member of Advisory Board, Speakers Bureau; Grifols: Speakers Bureau; Grifols: Speakers Bureau; Grifols: Speakers Bureau; Shire: Speakers Bureau. Schneppenheim:CSL Behring: Consultancy; SHIRE: Consultancy. Berntorp:Octapharma: Consultancy; CSL Behring: Consultancy; Shire: Consultancy, Other: honoraria for lecturing . Eikenboom:CSL: Research Funding. Mannucci:Bayer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kedrion: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Grifols: Speakers Bureau; Alexion: Speakers Bureau; Baxalta/Shire: Speakers Bureau; Novo Nordisk: Speakers Bureau. Mazzucconi:Baxalta-Shire: Consultancy, Speakers Bureau; Bayer: Consultancy, Speakers Bureau; Novartis,: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Novo Nordisk: Consultancy, Speakers Bureau; CSL Behring: Consultancy, Speakers Bureau. Oldenburg:Swedish Orphan Biovitrum: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Shire: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Grifols: Honoraria, Membership on an entity's Board of Directors or advisory committees; Biogen Idec: Honoraria, Membership on an entity's Board of Directors or advisory committees; Chugai: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Biotest: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL Behring: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Octapharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Clinical Study to Investigate the Efficacy and Safety of Wilate during Prophylaxis in Previously Treated Patients with Von Willebrand Disease (VWD)

Blood ◽

10.1182/blood-2019-128339 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4931-4931

Author(s):

Robert F. Sidonio ◽

Bruce A. Schwartz

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Prophylactic Treatment ◽

Von Willebrand Disease ◽

Advisory Committees ◽

Previously Treated Patients ◽

Previously Treated ◽

Type 3 ◽

Von Willebrand

Background: Inherited von Willebrand disease (VWD) is the most common inherited hemorrhagic disorder, with an estimated prevalence of 1 in every 100 individuals. Type 1 and type 3 (the most severe form) are characterized by a quantitative deficiency of von Willebrand factor (VWF) and type 2 arises from a qualitative deficiency of VWF. Treatment of VWD depends on the type and severity of the disease. Severe bleeding is reported in patients with all subtypes, leading to progressive joint disease as well as diminished quality of life (QoL). VWF/factor VIII (FVIII) concentrates have become the mainstay of VWD treatment for these patients with severe disease or for those patients in whom other treatments (e.g., desmopressin) are ineffective or contraindicated but this is broadly applicable only for on demand treatment. Aims: The primary objective of this study is to determine the efficacy of VWF/FVIIII concentrate in the prophylactic treatment of previously treated patients with type 3, type 2 (except 2N), or severe type 1 VWD. Secondary objectives of this study will be to collect data to 1) Assess the VWF:Ac and VWF:Ag incremental IVR of VWF/FVIIII concentrate over time and, 2) Assess the safety and tolerability of VWF/FVIIII concentrate in this indication. The study will also examine, the efficacy of VWF/FVIIII concentratein the treatment of breakthrough bleeding episodes (BEs), and in surgical prophylaxis, as well as the QoL during prophylaxis with VWF/FVIIII concentrate. Methods: The study is planned to enroll 28 patients aged ≥6 years and with VWD type 1, 2A, 2B, 2M, or 3. Eligible patients must be receiving on-demand treatment with a VWF-containing product, with at least 1, and an average of ≥2, documented spontaneous BEs per month in the preceding 6 months requiring treatment with a VWF-containing product. This will be assessed as part of a run-in observational study to collect the bleeding profile prior to the start of prophylaxis. From the beginning of the study, patients will receive prophylactic treatment with VWF/FVIIII concentrate for 12 months and record all BEs in a patient diary. Based on these data, the frequency of BEs and the annualized bleeding rate (ABR) under prophylactic treatment will be calculated. Treatment efficacy of BEs will be assessed by the patient (together with the investigator in case of on-site treatment) using a 4-point scale (excellent, good, moderate, none) In patients that undergo surgeries, efficacy of VWF/FVIIII concentratewill be assessed at the end of surgery by the surgeon and at the end of the postoperative period by the haematologist. In both cases, predefined assessment criteria will be used. In addition, an overall assessment of efficacy will be made at the end of the postoperative period by the investigator. Results: Data will be monitored on an ongoing basis and the study is expected to end Q2 2021. Conclusions: Prophylactic treatment in other congenital bleeding disorders is widely accepted as the standard of care to prevent bleeding and preserve QoL in patients but to date, this form of treatment in VWD is not well characterized. This study will provide data on the efficacy of prophylactic treatment in reducing the rate of bleeding and on the impact of prophylaxis on the QoL in VWD patients. Disclosures Sidonio: 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; Biomarin: Membership on an entity's Board of Directors or advisory committees; Octapharma: 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; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees; Grifols: Membership on an entity's Board of Directors or advisory committees, Research Funding; Kedrion: Research Funding; Uniqure: Membership on an entity's Board of Directors or advisory committees. Schwartz:Octapharma: Employment.

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Genetic Analysis of Von Willebrand Disease By Using the Exome Sequencing Approach

Blood ◽

10.1182/blood.v126.23.1097.1097 ◽

2015 ◽

Vol 126 (23) ◽

pp. 1097-1097

Author(s):

Naomi Sanda ◽

Nobuaki Suzuki ◽

Takeshi Kanematsu ◽

Mika Ogawa ◽

Mayuko Kishimoto ◽

...

Keyword(s):

Exome Sequencing ◽

Board Of Directors ◽

Research Funding ◽

Sanger Sequencing ◽

Gene Mutations ◽

Causative Gene ◽

Advisory Committees ◽

Type 3 ◽

Von Willebrand

Abstract Background: Von Willebrand disease (VWD) is the most common inherited bleeding disorder characterized by quantitative and/or qualitative von Willebrand factor (VWF) abnormalities. VWF gene is a large gene consists of 52 exons, wheras its pseudogene corresponds to exons 23-34 that makes the analysis much complicated. In this study, we performed genetic analyses of the VWF gene from 20 Japanese VWD patients, aimed to find the causative genetic mutations by using various techniques including the exome sequencing approach, and to explore the diversity of yet unknown VWD pathogenetic mechanisms. Methods: Patients' samples were collected after the written informed consent has been obtained. First, we analyzed exon 28 of VWF genes from peripheral blood genomic DNA of the patients by PCR using allele-specific primers, and analyzed DNA sequences of the patients by Sanger sequencing method. If patients show the type 3 phenotype, the possibility of deletion or insertion of the gene was taken into consideration, then MLPA method was selected. In cases the gene mutation was not detected by exon 28 sequencing or MLPA, we analyzed all exons of VWF by Sanger method. In selected patients, the exome sequencing was employed by using the next-generation sequencer Hi-Seq 2500 (Illumina) and exomes were captured using SureSelect XT Human All Exon V5+UTRs kit (Agilent Technologies). Results: Twenty VWD cases were studied. As a result of the VWF exon 28 sequencing, we identified causative gene mutation in 12 cases (10 cases were type 2, 2 cases were type 1). Gene mutations found in exon 28 were p.R1308C, p.R1315C, p.V1316M, p.R1334W, p.A1461D, p.L1503R, p.S1506L, p.R1597Q, p.G1609R. In one case and her sister of type 3, MLPA could not detect the large deletions or insertions. Sanger sequencing showed the they were compound heterozygous for an p.E2341X (c.7021G>T) mutation in exon 41 and a p.Y2631X (c.7892-7893insA) mutation in exon 48. In another case of type 3, we used exome sequencing and found a novel homozygous gene mutation p.G2752S (c.8254G>A) in exon 52. The mutation was confirmed by Sanger sequencing and the propositus was homozygote for the mutation, while the parents and two sons had the same mutation in the heterozygote. In the multimer analysis of plasma, multimers larger than the dimer in size were hardly visible, but there was a faint monomer band was present in the plasma. Multimeric patterns of his family were normal. Discussion: We analyzed the VWF genes of 20 VWD cases and identified causative gene mutations in 14 cases including three novel mutations (p.E2341X, p.Y2631X, p.G2752S). We previously demonstrated BOECs established from the type 3 patient (p.E2341X and p.Y2631X) reproduced the phenotype of the disease (ASH 2014). Meanwhile, G2752S mutation is located in CTCK domain, therefore possibly it affects the VWF dimer formation. However, the causative gene mutations were not detected in 6 cases (5 cases were type 1, 1 case was type 2) by exome sequencing. Although previous observations have pointed out that causative VWF gene mutations are not detectable in about 30 % of entire type 1 cases, a newer approach would be needed to elucidate molecular pathogenesis of VWD. Disclosures Suzuki: Baxalta: Honoraria; Novo Nordisk Pharma: Honoraria; Bayer Healthcare: Honoraria. Matsushita:Biogen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Baxalta: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bayer Healthcare: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Asahi Kasei Pharma: Honoraria, Research Funding, Speakers Bureau; Kaketsuken: Honoraria, Research Funding, Speakers Bureau; Seamens: Speakers Bureau; Japan Blood Products Organization: Honoraria, Research Funding; Kyowa-Kirin: Honoraria, Research Funding; Novartis Pharma: Honoraria, Speakers Bureau; Sysmex: Speakers Bureau; Chugai Pharmaceutical Co., Ltd.: Research Funding; Novo Nordisk Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Eisai: Research Funding; Nihon Pharmaceutical: Honoraria, Research Funding, Speakers Bureau; Octapharma AG: Honoraria; CLS-Behling: Research Funding.

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Depression and Anxiety in Persons with Von Willebrand Disease

Blood ◽

10.1182/blood-2021-151625 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 4052-4052

Author(s):

Jonathan C. Roberts ◽

Roshni Kulkarni ◽

Peter A. Kouides ◽

Robert F. Sidonio ◽

Shannon L Carpenter ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Clinical Characteristics ◽

Important Variable ◽

Von Willebrand Disease ◽

Depression And Anxiety ◽

Advisory Committees ◽

Type 3 ◽

Von Willebrand

Abstract Background: Depression and anxiety are associated with poor health-related quality of life (HRQoL), lower functioning and decreased treatment adherence. In 2019, 7% adults in the US had moderate/severe symptoms of depression, while <5% had anxiety. Impacts of depression and anxiety in persons with von Willebrand disease (VWD) are unclear and less studied. Objective: We assessed sociodemographic and clinical characteristics associated with depression and anxiety in a geographically diverse cohort of individuals with VWD obtaining care at seven US Hemophilia Treatment Centers (HTCs). Methods: The study enrolled and collected data on individuals age ≥12 with VWD Type 1 (VWF:Ag/RCo: ≤30%), low VWF(VWF:Ag/RCo: 30-50%), Type 2, and type 3 between September 2018-June 2021. Participants completed a survey at enrollment to collect sociodemographic and clinical characteristics, self-reported pain, joint problems and HRQoL measured by the EQ-5D-3L. A quarterly survey administered one year post-enrollment collected similar data. The patient health questionnaire (PHQ-8) and the generalized anxiety disorder (GAD-7) were administered with the last follow-up survey after August 2019. Chart reviews abstracted VWD type information. The association of sociodemographic and clinical characteristics with depression or anxiety was assessed using Chi-square tests for categorical variables, as well as logistic regression models with stepwise selection. Results: We analyzed data from 77 participants who completed both baseline and last follow-up surveys. Mean age was 34.2 (standard deviation (SD)=18.8) years, 74.0% were adults ≥18 years, 79.2% were female, 60.8% had Type 1/low VWF, and 3.9% had Type 3 VWD. Mean age at VWD diagnosis was 13.9 (SD=13.2) years. Overall reported depression rate was 63.4%, and 58.3% for anxiety (values ≥10 on either PHQ-8 or GAD-7). Proportion of those with depression (75% vs. 62%) or anxiety (58% vs. 58%) prior to and during the COVID-19 pandemic were not significantly different. Persons with low VWF had higher rates of depression (86.7%) or anxiety (69.2%) as compared to those with type 1 VWD (55.3% for depression, 52.8% for anxiety) or types 2 and 3 (62.5%, 60.9%, p=0.10, not significant (NS) for depression and p=0.56, NS for anxiety, respectively). Females reported a higher rate of anxiety (61.4%) than males (46.7%, p=0.30, NS). When compared to individuals who rated their general health as the same or better than 3-months ago, those who rated their health as worse had significantly higher rates of depression (92.3% vs. 57.8%, p=0.02) and anxiety (83.3% vs. 53.3%, p=0.05). Participants with chronic pain reported a significantly higher depression rate (81.6% vs. 36.8%, p=0.0003). Those who reported having joint problems also reported depression at a significantly higher rate (82.4% vs. 48.8%, p=0.002) or anxiety (74.1% vs. 46.3%, p=0.02) than those without joint problems. Logistic regression analyses demonstrated that among adults or parents of pediatric patients, being single or not with a partner was the most important variable associated with depression (odds ratio (OR)=7.0, confidence interval (CI): 1.7-29.0), followed by having joint problems (OR=6.3, CI=2.0-20.1). The most important variable associated with anxiety was being a youth aged 12-18 years old (OR=6.7, CI=1.6-26.9), followed by being single or not with a partner (OR=10.8, CI=2.5-47.5), or having worse health compared to 3-months prior (OR=12.3, CI=1.3-116.2). Mean covariates adjusted EQ index scores were lower among persons with depression (0.75±standard error (SE) 0.03 vs. 0.83±0.04, p=0.06 NS) or anxiety (0.75±0.03 vs. 0.82±0.04, p=0.7 NS) than among those without depression or anxiety. As compared to individuals without depression or anxiety, mean covariates adjusted EQ VAS was significantly lower in persons with depression (68.7±3.1 vs. 77.6±4.2, p=0.03), but not among those with anxiety (69.3±3.7 vs. 71.3±4.3, p=0.66 NS). Conclusions: Our study revealed higher rates of major depression and anxiety in this VWD sample than the general US population. Depression had a significant negative impact on HRQoL. Mental health screening is imperative for persons with VWD, especially those with low VWF, chronic pain or joint problems. Special attention should be paid to women and youth. This study underscores the need for a multidisciplinary approach in the comprehensive care of patients seen at HTCs. Disclosures Roberts: Genentech, Novo Nordisk, Octapharma, Pfizer, Sanofi, Takeda, uniQure: Consultancy; Takeda; Speakers Bureau: Novo Nordisk, Octapharma, Sanofi, Takeda.: Research Funding. Kulkarni: Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees; CSL Behring: Honoraria, Membership on an entity's Board of Directors or advisory committees; Shire/Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi Genzyme: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Octapharma: Honoraria, Membership on an entity's Board of Directors or advisory committees. Sidonio: Bayer: Consultancy; Catalyst: Consultancy; Genentech: Consultancy, Research Funding; Novo Nordisk: Consultancy; Guardian Therapeutics: Consultancy; Octapharma: Consultancy, Research Funding; Biomarin: Consultancy; Pfizer: Consultancy; Takeda: Consultancy, Research Funding. Carpenter: Genentech: Honoraria; Novo Nordisk: Honoraria; Kedrion Pharmaceuticals: Honoraria; Hemophilia and Thrombosis Research Society: Membership on an entity's Board of Directors or advisory committees. Konkle: Pfizer, Sangamo, Sanofi, Sigilon, Spark, Takeda and Uniqure: Research Funding; BioMarin, Pfizer and Sigilon: Consultancy. Wu: Baxalta US Inc., Bannockburn, IL (a Takeda Company), CSL Behring L.L.C., Octapharma USA, Inc., Genentech Inc.: Research Funding. Curtis: Pfizer, Bayer, and Novo Nordisk: Consultancy; University of Southern California: Consultancy. Nichol: Pfizer, Genentech Inc., Baxalta US Inc., Bannockburn, IL (a Takeda Company), Octapharma, CSL Behring, Global Blood Therapeutics, and Novo Nordisk: Research Funding.

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Characterization of Bleeding in Hemophilia Carriers and Comparison to Women with Type 1 Von Willebrand Disease, Type 3 Von Willebrand Disease Obligate Carriers and Controls

Blood ◽

10.1182/blood.v128.22.875.875 ◽

2016 ◽

Vol 128 (22) ◽

pp. 875-875

Author(s):

Natasha Amrita Satkunam ◽

Johnny Mahlangu ◽

Christoph Bidlingmaier ◽

Maria Eva Mingot-Castellano ◽

Meera B. Chitlur ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Von Willebrand Disease ◽

Advisory Committees ◽

Type 3 ◽

Von Willebrand ◽

Hemophilia Carriers ◽

Normal Controls ◽

Mucocutaneous Bleeding

Abstract Background: Hemophilia carriers report abnormal bleeding, even when factor VIII or IX levels are normal. Information comparing bleeding events between carriers and women with other inherited bleeding disorders is lacking. Purpose: The purpose of our study was to characterize bleeding in hemophilia carriers using the International Society on Thrombosis and Hemostasis Bleeding Assessment Tool (ISTH-BAT) and to compare it with bleeding in normal controls, women with Type 1 VWD and Type 3 VWD obligate carriers (OC). Method: This was a prospective, observational, cross-sectional study performed by members of GEHEP (Global Emerging HEmostasis Panel). Study participants were recruited from GEHEP members' clinics in North America (Kingston, Canada, Detroit and Philadelphia, USA), Europe (Malaga, Spain; Milan, Italy; Munich, Germany; Oslo, Norway) and South Africa (Johannesburg). Potential participants were identified through local patient databases and approached during clinic visits. All participants signed informed consent. Hemophilia carriers were defined by a documented FVIII or FIX mutation and/or by an appropriate family history (daughter of a man with hemophilia or mother of two sons with hemophilia or mother of one son with hemophilia with at least one other affected male relative). Demographic information was collected using a CRF and the ISTH-BAT was completed for each participant by study personnel. Existing ISTH-BAT data for women with Type 1 VWD, Type 3 VWD OC and age-matched female controls were used for comparison. Results: A total of 329 participants were included in this study; 168 hemophilia carriers, 83 women with Type 1 VWD, 32 Type 3 VWD OC and 46 female normal controls. Hemophilia carriers and normal controls were similar in age (40.1 vs 41.6, p=0.445). The mean overall ISTH-BAT bleeding score (BS) was significantly higher in carriers than in controls (5.7 vs 2.48, p<0.0001). Carriers reported significantly more bleeding in the categories of cutaneous, minor wounds, oral cavity bleeding, post-dental bleeding, surgical bleeding, menorrhagia, post-partum bleeding and other when compared with controls. Carriers were older than Type 1 VWD patients (40.1 vs 36.4 years, p=0.042). While women with Type 1 VWD had higher total ISTH-BAT BS (8.7 vs 5.7, p<0.0001) as well as higher scores for epistaxis, cutaneous bleeding, minor wounds, oral cavity bleeding and menorrhagia, hemophilia carriers had significantly higher scores for muscle hematomas and hemarthrosis. Carriers were younger than Type 3 VWD OC (40.1 vs 45.2 years, p = 0.02), had higher overall ISTH-BAT BS (5.7 vs 3.0, p=0.009) and reported more bleeding in the following categories: total score, epistaxis, hematuria, dental, muscle hematomas, hemarthrosis, and other. In fact, hemophilia carriers reported more musculoskeletal bleeding than all other groups. Importantly, given the concern about over-reporting of joint bleeds by hemophilia carriers because of familiarity with hemarthrosis in affected male relatives, no Type 3 VWD OC reported joint bleeds. See Table 1 for detailed results. Conclusion: In summary, our study showed that hemophilia carriers report significantly more bleeding by overall ISTH-BAT BS than age-matched female controls. Carriers experience both mucocutaneous bleeding as well as musculoskeletal bleeding. They score higher for mucocutaneous bleeding when compared with controls and when compared with Type 3 VWD OC. Overall Type 1 VWD patients experience more severe mucocutaneous bleeding than hemophilia carriers. However, hemophilia carriers report more musculoskeletal bleeding in the form of hemarthrosis and hematomas than all other groups. A comparison of overall ISTH-BAT BS between groups shows that bleeding in women with Type 1 VWD > hemophilia carriers > Type 3 VWD OC > controls. Additional research into the underlying pathophysiology of this abnormal bleeding is a critical next step in understanding and determining how to appropriately manage these patients. Disclosures Bidlingmaier: Novo Nordisk: Honoraria; Sobi: Honoraria; Pfizer: Honoraria; Biotest: Honoraria; Baxalta: Honoraria; Bayer: Honoraria; CSL Behring: Honoraria, Research Funding. Mingot-Castellano:Amgen: Consultancy; Pfizer: Consultancy; Novo Nordisk: Consultancy, Research Funding; Baxalta: Consultancy, Research Funding; Novartis: Consultancy; Bayer: Consultancy, Research Funding. Chitlur:Novo Nordisk: Consultancy; Baxalta: Honoraria; Bayer: Honoraria; Biogen-Idec: Honoraria; Pfizer: Honoraria. Fogarty:Bayer Healthcare: Membership on an entity's Board of Directors or advisory committees, Research Funding; Baxter/Baxalta: Membership on an entity's Board of Directors or advisory committees, Research Funding; Biogen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Chugai: 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; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees; Pfizer: Employment, Membership on an entity's Board of Directors or advisory committees, Research Funding; Spark Therapeutics: Research Funding. Cuker:T2 Biosystems: Research Funding; Genzyme: Consultancy; Biogen-Idec: Consultancy, Research Funding; Amgen: Consultancy; Stago: Consultancy. Mancuso:Bayer Healthcare: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Baxalta: Consultancy, Speakers Bureau; CSL Behring: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novo Nordisk: Consultancy, Speakers Bureau; Sobi/Biogen Idec: Consultancy, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kedrion: Consultancy. Holme:Baxalta, now part of Shire: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Investigator Clinical Studies. Mathew:Bayer: Employment. James:CSL Behring: Research Funding; Octapharma: Research Funding; Biogen: Consultancy; Basalt: Consultancy; Bayer: Research Funding.

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Observational Study on Safety and Efficacy of Factor Replacement Therapy in the Management of Von Willebrand Disease Patients - Results from an Ongoing Study with a VWF/FVIII Concentrate

Blood ◽

10.1182/blood.v128.22.4968.4968 ◽

2016 ◽

Vol 128 (22) ◽

pp. 4968-4968

Author(s):

Hassan M. Yaish ◽

Kate Khair ◽

Mario von Depka ◽

Maria Sol Cruz ◽

Sylvia Werner ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Von Willebrand Disease ◽

Ongoing Study ◽

Advisory Committees ◽

Safety And Efficacy ◽

On Demand ◽

Study Investigator ◽

Post Marketing Surveillance ◽

Von Willebrand

Abstract Introduction and Objective Prospective surveillance studies are a useful tool to monitor drug safety and efficacy in the post-approval period and provide treaters and caregivers with real-life information about von Willebrand disease (VWD) treatment. This ongoing study aims to demonstrate consistency of safety and efficacy data of a VWF/FVIII concentrate with a 1:1 ratio (wilate®) used in routine clinical practice with data obtained in previous clinical studies. Methods This non-interventional post-marketing surveillance study was designed to document the safety, tolerability, and efficacy of a 1:1 VWF/FVIII concentrate in the prophylaxis and treatment of bleeding, as well as in the perioperative bleeding management in VWD patients. Treatment regimens and dosages were at the discretion of the investigators. The primary endpoints were tolerability assessment on a 3-point verbal rating scale and the incidence of investigator reported adverse drug reactions (ADRs). Additionally, the efficacy was assessed using a pre-defined 4-point haemostatic scale for on-demand treatment and surgeries, and the frequency of breakthrough bleeding events (BEs) for prophylaxis. Results Eighty-nine patients qualified as safety population, having received at least one infusion of the VWF/FVIII concentrate. Tolerability was rated 'excellent' for 4261/4450 (96%) assessed infusions. No development of clinically relevant VWF inhibitors or thrombotic events occurred. ADRs were reported in 6 of 89 patients (6.7%). The efficacy population comprised 47 patients undergoing 74 surgeries, 22 patients treated on-demand for 93 BEs, 12 patients on continuous prophylactic treatment, and 4 patients treated for 20 menstrual BEs. Some patients were assessed in more than one treatment group. 100% of rated bleeds in patients on on-demand treatment were assessed as 'excellent/good', receiving a mean total dose per BE of 111.4 (+/-69.78) IU/kg. Of the 44 minor and 31 major surgeries, 73 (99%) were rated as 'excellent/good' efficacy and one (1%) as 'moderate'. Mean dose of VWF/FVIII concentrate used was 78.6 (+/-126.16) IU/kg and 132.4 (+/-102.71) IU/kg for minor and major surgeries, respectively. Patients on continuous prophylaxis received a mean of 111.4 (+/-69.78) IU/kg in a mean of 2.4 (+/-0.86) infusions per week and experienced a median annualized bleeding rate of 2.3 (mean 3.3±5.6; range 0-19.7) for spontaneous bleeds and 2.5 (mean 4.8±6.2; range 0-19.7) for all types of bleeds. Efficacy for menstrual bleeding was rated as excellent or good in 100% of rated episodes (16/20). Conclusion The data confirm the safety, tolerability and efficacy of the 1:1 VWF/FVIII concentrate in the treatment of VWD patients in routine clinical conditions. Disclosures Yaish: Octapharma: Other: Study investigator. Khair:Pfizer: Research Funding; NovoNordisk: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Baxalta, now part of Shire: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Study Investigator, Research Funding; Octapharma: Consultancy, Equity Ownership, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Study Investigator, Patents & Royalties, Research Funding, Speakers Bureau; Sobi/Biogen: Research Funding. von Depka:Octapharma: Other: Study Investigator, Speakers Bureau. Cruz:Octapharma: Other: Study Investigator. Werner:Octapharma: Employment. Knaub:Octapharma: Employment. Rodgers:Octapharma: Other: Study Investigator.

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Emicizumab-Kxwh for Previously Untreated Patients with Haemophilia: The Conversation Begins

Blood ◽

10.1182/blood-2019-127270 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2409-2409

Author(s):

Tiffany Lin Lucas ◽

Shveta Gupta ◽

Joanna A. Davis ◽

Fernando F. Corrales-Medina

Keyword(s):

Board Of Directors ◽

Real World ◽

Research Funding ◽

Hemophilia A ◽

The United States ◽

Haemophilia A ◽

Advisory Committees ◽

Inhibitor Development ◽

Increased Risk ◽

Prophylaxis Therapy

Introduction: With the Federal Drug and Administration approval of the use of emicizumab from birth to adulthood, clinicians will now grapple with when to choose and offer emicizumab for routine prophylaxis, especially in previously untreated patients (PUPs). Given the overall limited real-world reported data and experience using emicizumab in PUPs, we created and administered a survey to medical providers in the United States who care for paediatric patients with haemophilia to investigate real-world practice strategies and treatment selection for PUPs. Methods: After review and endorsement by the Haemostasis and Thrombosis Research Society (HTRS), the survey was electronically distributed by e-mail to all providers included in the HTRS core member list. The survey was also sent to those providers included in a list of Haemophilia Treatment Centre (HTC) physicians (with duplicate emails reconciled). Providers needed to self-identify as ones that treat pediatric patients to be included. The survey was developed as a tiered survey with questions presented to each recipient based on their prior responses. Results: Seventy-seven completed surveys were included and analysed. All participants were active providers at a comprehensive HTC and the majority (93.4%) were practicing at an academically affiliated site. In terms of characteristics of those that answered the survey, forty-eight percent of responders reported that 1-20% of their patients had expressed interest in emicizumab. 46% of participants (34/74) reported that they would personally consider emicizumab as their prophylaxis recommendation for the majority (>50%) of their hemophilia A patients without inhibitors. 57% (44/76) reported that 1-10% of their non-inhibitor hemophilia A patients were already prescribed emicizumab prophylaxis. Each participant was then asked about his or her consideration of emicizumab as prophylaxis therapy for a 2 month old PUP. Just over the majority were unsure or said no to this consideration (51.3%) and their concerns were lack of information on safety and efficacy in this young age group and increased risk for inhibitor development. If the 2 month old PUP had a high risk of inhibitor, the majority of providers who initially were hesitant to start emicizumab prophylaxis would remain so. Of note, those providers went on to be asked if the patient had gone on to complete 50 exposure days without inhibitor development, they would then become more likely to initiate emicizumab prophylaxis therapy. Use of concurrent factor replacement was posed to all participants and there were varied responses. Discussion: Overall, our results reflect a widespread practice variation and a not yet well-standardized or defined approach for the use of emicizumab in PUPs with haemophilia A. In this survey, patient preference and individual bleeding risk were the top reasons for which a provider would consider using switching to emicizumab prophylaxis in both severe and mild/moderate haemophilia A patients. This pattern of practice reflects the current era of individualized medicine. Overall, our findings reinforce the need for more studies to investigate the outcomes of a combined treatment approach with FVIII concentrates and emicizumab focusing in the potential benefit of this approach in decreasing the risk for inhibitor development PUPs. Clinicians also feel the need for further data to help clarifying the safety of emicizumab in this population. Figure Disclosures Gupta: Novartis: Honoraria, Speakers Bureau; CSL Behring: Research Funding; Novo Nordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Octapharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda-Shire: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Davis:Sanofi: Membership on an entity's Board of Directors or advisory committees; Kedrion: Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees; CSL Behring: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda Shire: Consultancy; Spark Therapeutics: Consultancy. Corrales-Medina: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; Octapharma: Membership on an entity's Board of Directors or advisory committees.

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Severe Bleeding Events in Hemophilia Α Patients Receiving Emicizumab Prophylaxis

Blood ◽

10.1182/blood-2019-126659 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1126-1126

Author(s):

Karen L. Zimowski ◽

Glaivy M. Batsuli ◽

Paulette Bryant ◽

Jenny McDaniel ◽

Kelly Tickle ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Hemophilia A ◽

Severe Bleeding ◽

Severe Hemophilia ◽

Bleeding Events ◽

Advisory Committees ◽

Acute Bleeding ◽

Fviii Activity ◽

Bleeding Episodes

Introduction : Emicizumab is a novel humanized bispecific antibody that mimics the function of activated coagulation factor VIII (fVIII). It has significantly changed the management of patients with hemophilia A and inhibitors by achieving baseline hemostatic control. Based on the HAVEN studies, emicizumab markedly reduces annualized bleeding rates and is FDA-approved for prophylaxis in hemophilia A patients of all ages, regardless of inhibitor status. In the HAVEN2 interim analysis, only 3/57 pediatric patients receiving emicizumab prophylaxis required treatment for an acute bleeding event after a 9-week median observation time. We report 3 patients with severe hemophilia A and a history of inhibitors receiving emicizumab prophylaxis with severe or refractory bleeding episodes to highlight the importance of vigilance and surveillance of children with severe hemophilia A on emicizumab. Methods: This retrospective analysis includes patients between 0-21 years of age with severe hemophilia A (fVIII activity < 1%) receiving emicizumab prophylaxis and admitted for the management of an acute bleeding episode following emicizumab's FDA approval in November 2017. Patients were followed at the Pediatric Hemophilia Treatment Center at the Hemophilia of Georgia Center for Bleeding & Clotting Disorders of Emory and the St. Jude Affiliate Clinic at Novant Health Hemby Children's Hospital. Data collected included demographics, past medical history including inhibitor status, bleeding history, and treatment modalities, and details regarding the presentation, management, and outcome of acute severe bleeding events. Due to the nature of the study, descriptive statistics were primarily used for data analysis. Results: Three patients with severe hemophilia A receiving emicizumab prophylaxis were admitted for the management of 4 severe bleeding episodes. All patients had a history of a fVIII inhibitor. Three of the 4 bleeding episodes were trauma-induced while 1 occurred spontaneously. For the traumatic episodes, all patients presented with worsening symptoms approximately 1 week following the inciting event. All patients had a normal aPTT at the time of presentation, ruling out a significant anti-drug antibody (emicizumab level not available). A patient with a low-titer inhibitor developed an epidural hematoma following a trampoline injury and was treated with continuous infusion of recombinant factor VIII (rfVIII), adjusting the rate to achieve chromogenic fVIII activity of 100% for 14 days. Following 14 days, he was started on rfVIII 50 IU/kg Q12 hours with a goal fVIII activity of 50%. His rfVIII dosing interval was gradually weaned to every other day while in inpatient rehabilitation. As outlined in Table 1, the remaining 3 bleeding events were initially managed with recombinant activated factor VII (rfVIIa) dosed at 80-90 mcg/kg/dose with escalating frequency for an average of 8 days. However, due to lack of improvement, treatment was changed to low-dose activated prothrombin complex concentrates (aPCC; 10-15 IU/kg/dose Q12-24 hours for an average of 7 days). In all 3 of these events, the hematomas improved after treatment with aPCC. No patient experienced thrombotic microangiopathy, thrombosis, or had evidence of DIC while receiving these treatment regimens. Discussion/Conclusion: Pharmacokinetic analysis of emicizumab suggests that following the standard 4-week loading phase, trough plasma emicizumab concentrations obtained prior to a 1.5 mg/kg once weekly maintenance dose correlates with at least 10-15 IU/dL equivalent fVIII activity. This degree of thrombin generation should be sufficient to prevent severe spontaneous bleeding episodes in most patients. However it does not preclude significant trauma-induced bleeding or spontaneous bleeding in inhibitor patients. Based on our cases, providers should maintain a high index of suspicion for acute bleeding in patients receiving emicizumab prophylaxis. Serious bleeding events, although rare, may have a more insidious onset in patients receiving emicizumab. Furthermore, despite the baseline hemostasis achieved with emicizumab, acute bleeding events may still require aggressive therapy. Our cases suggest that low-dose aPCC or continuous infusion fVIII may be feasible options for treating acute bleeding events in patients with hemophilia A and inhibitors receiving emicizumab prophylaxis. Disclosures Zimowski: Pfizer: Research Funding; National Hemophilia Foundation: Other: Medical Loan Reimbursement, Research Funding. Batsuli:Octapharma: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Genetech: Membership on an entity's Board of Directors or advisory committees. Bryant:Novo Nordisk: Other: PI on Novo Nordisk sponsored Studies. McDaniel:Genentech: Membership on an entity's Board of Directors or advisory committees. Tickle:National Hemophilia Foundation: Research Funding. Meeks:Bayer: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees; Bioverativ: Membership on an entity's Board of Directors or advisory committees; Takeda-Shire: Membership on an entity's Board of Directors or advisory committees; HEMA Biologics: Membership on an entity's Board of Directors or advisory committees. Sidonio: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; Grifols: Membership on an entity's Board of Directors or advisory committees, Research Funding; Biomarin: Membership on an entity's Board of Directors or advisory committees; 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; Kedrion: Research Funding.

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