Regular Replacement Therapy as Prophylaxis In Severe Forms of Von Willebrand Disease: Initial Results From the Von Willebrand Disease Prophylaxis Network (VWD PN) Study Group

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 236-236
Author(s):  
Erik Berntorp ◽  
Thomas C. Abshire ◽  
Augusto B. Federici
Keyword(s):  
Quality Of Life ◽  
Research Funding ◽  
Von Willebrand Disease ◽  
Gi Bleeding ◽  
Total Group ◽  
Primary Indication ◽  
Type 3 ◽  
Von Willebrand

Abstract 236 The bleeding patterns of severe von Willebrand Disease (VWD), mainly type 3, adversely affect short- and long-term quality of life, and may be life threatening. The index case of VWD, described by Erik von Willebrand in 1926, was a girl who had a history of serious bleeds from mucous membranes and ankles, and died during her fourth menstrual period. There is no doubt that there is a role for long-term prophylaxis with VWF-containing concentrates, but the experience is scarce and restricted to a retrospective follow-up of 37 patients in Sweden, and a few other small cohorts in Europe. All studies have shown favorable results; however, unresolved issues remain, such as to whom prophylaxis should be given, optimal dose and dose interval, and when to start. The von Willebrand Disease Prophylaxis Network (VWD PN) was formed to investigate the role of prophylaxis in clinically severe VWD that is non-responsive to other treatment(s). The VWD International Prophylaxis (VIP) Study, a combination of prospective and retrospective studies, is an initiative of the VWD PN. Using a retrospective study design, the effect of prophylaxis on bleeding frequency was studied among 39 individuals enrolled from 11 centers in Europe and North America. Data were collected from center records, diaries, and bleeding logs. The period of study was one year prior to start of prophylaxis plus at least 6 months following onset of treatment. Subject demographics, VWD type, and primary bleeding indication for prophylaxis were collected. Annualized bleeding rates were calculated for the period prior to onset of prophylaxis, during prophylaxis for the total group, and by primary bleeding indication defined as the most frequent bleeding symptom. In 4 cases, data were not available to identify the primary indication. Differences (after – before) were calculated. The Wilcoxan Signed Rank test of the differences in the medians was used. The median age (range) at onset of prophylaxis was 29 years (2 to 76). Fifty-one percent were female and 49% male. The vast majority were of European descent, 84.6%, with 12.8% and 2.6% reported as Hispanic and of African descent, respectively. Type 3 VWD accounted for the largest number: 24 (61.5%). Two subjects (5.1%) were type 1, 7 (18.0%) type 2A, 5 (12.8%) type 2B, and 1 (2.6%) type 2M. The usual number of infusions of VWF during prophylaxis was 2 to 3 times per week, with a median usual dose of 45 U VWF:RCo per kg per infusion. The median (range) number of bleeding episodes per year prior to the onset of prophylaxis was 12 (2 – 54), compared to a median (range) of 4 (0 – 24) during prophylaxis, p<0.0001. Changes in bleeding for the total group, as well as the most common primary indications for prophylaxis, are shown in the figure. In 7 cases (not included in the figure) the bleeding pattern was mixed with no primary indication (N=3), or the primary indications occurred with low frequency (N=4). Annualized bleeding rates were lower during prophylaxis for all primary indications, and significantly so (p<0.05) for joint bleeding, epistaxis and GI bleeding. When we examined the effect of prophylaxis by age for subjects <18, and those ≥18, we found that it was similar in both groups. The median number of bleeds per year during prophylaxis was significantly lower, p=0.001 and p<0.0001 respectively, compared to the number prior to prophylaxis. While the primary indications of epistaxis and joint bleeding occurred with similar frequency in both age groups, GI bleeding and menorrhagia were not reported as the primary bleeding indication for prophylaxis for anyone <18. We conclude from this international, multi-center cohort that prophylactic treatment of VWD is efficacious. A network-initiated prospective study is underway, the objectives of which are to provide guidelines for dosing, and address issues of cost-effectiveness and quality of life. Disclosures: Berntorp: CSL Behring: Honoraria, Research Funding. Abshire:CSL Behring: Honoraria, Research Funding. Federici:CSL Behring: Honoraria, Research Funding.

scholarly journals Wish-Qol Study - Assessment of Health-Related Quality of Life (HRQoL) and Health-Economic Aspects in Patients with Von Willebrand Disease (VWD) in France: Results of the Women Cohort

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1395-1395
Author(s):  
Annie Borel-Derlon ◽  
Jenny Goudemand ◽  
Dominique Desprez ◽  
Fabienne Volot ◽  
Yves Gruel ◽  
...  
Keyword(s):  
Interim Analysis ◽  
Research Funding ◽  
Von Willebrand Disease ◽  
Female Group ◽  
Bleeding Score ◽  
Type 3 ◽  
Von Willebrand

Abstract Background: Von Willebrand disease (VWD) is the most common inherited bleeding disorder with a prevalence of 1% in the general population. VWD results from a deficiency in or a dysfunction of von Willebrand factor which is a protein that is necessary for normal platelet adhesion and protection of factor VIII from proteolysis in the circulation. Nevertheless, prevalence of the most symptomatic forms such as bleeds requiring replacement treatment and /or hospitalization is about 0.01%. Although VWD affects both genders, there is a higher proportion in females than in males.VWD seems to be more symptomatic in women because of their reproductive life. Women with VWD have an increased bleeding risk in numerous situations including anemia, menorrhagia, bleeding during pregnancy, postpartum hemorrhage and impairments in their quality of life (QoL).The prevalence of menorrhagia in women with VWD is 74-92%. According to the Francecoag Network, the referral-based prevalence of moderate-to-severe VWD patients is about 1,750 cases in France. Aim: Since the disease and its treatment can affect every-day life of patients and their families, a French HRQoL Study (WiSH-QoL) exploring this impact started 22 months ago. Methods: This non-interventional 5-year study evaluates patients HRQoL and costs of care in France. At least 350 patients will be followed for 24 months in minimum 30 centers. HRQoL is assessed with the generic SF-36 and the disease-specific VWD-QoL questionnaires. Bleeding severity was measured using the Tosetto Bleeding Score (BS). Results: Since October 2014, 245 patients have been included. We present here the first interim analysis with a focus on the female group. At the first interim analysis, data from 140 patients were documented: 91 adults with a median age of 40.0 years [18.3-78.0] and 49 children with a median age of 10.1 years [2.9-17.5]. VWD Types were already identified for 122 (87%) of these patients: 33 with VWD type 1 (27%) including 5 type 1 Vicenza; 76 type 2 (62%) and 13 type 3 (11%). The median Tosetto bleeding score reported for 124 patients (males and females) was +7 ranging from -1 to +28. From the 95 female patients, 70 were aged ≥18 years, 21 were adolescents between 8-17 years and 4 were girls below 4 years of age. Median age was 29.4 (range 4.3-78.0) years. A total of 25 women had type 1 VWD (31%), 49 had type 2 VWD (60%), and 7 had type 3 VWD (9%), for 14 patients VWD type is undetermined. The median Tosetto bleeding score of the female group was +8 ranging from -1 to +28. Out of 95 patients, 45 patients (47.4%) have received a concomitant treatment due to menorrhagia, such as iron therapy, oral contraceptive, levonorgestrel intrauterin system: 5/21 patients in the group between 8 and 17 years and 40/70 in the group ≥18 years. Out of the 60 women of childbearing potential defined as age between 15-50 years, 6 women were pregnant at time of inclusion. A total of 46 patients, aged 18 years or more have had obstetrical history prior to study inclusion. The mean number of childbirth was more than 2 i.e 2.39 range (1-8) per woman, 75% of these deliveries were natural delivery and 25% were caesarean section. Out of 108 deliveries, 28 (26%) were experienced with post-partum hemorrhages. Conclusions: With the results of the WiSH-QoL study, the first prospective study of von Willebrand disease conducted in France, especially the VWD-specific evaluation of HRQoL and treatment satisfaction a deeper insight will be gathered into the patients' daily life, their perception of well-being and their specific health care needs. With the additional domain 'pregnancy' included in the French version of the VWD-QoL questionnaire for female adult patients, it will possible to better understand how women may be affected by VWD during childbearing years. Disclosures Borel-Derlon: LFB: Other: Reference expert and national coordinator for VWD; Octapharma: Research Funding; NovoNordisk: Other: Expert for scientific committee; Shire - Baxalta: Research Funding. Chatelanaz:LFB Biomedicaments: Employment. Doriat-Robin:LFB Biomedicaments: Employment. von Mackensen:SOBI: Research Funding; Shire: Research Funding.

Willebrand in the Netherlands: WiN Study. Background and Study Design

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4510-4510
Author(s):  
Eva M. De Wee ◽  
Eveline P. Mauser-Bunschoten ◽  
Anske G. Van der Bom ◽  
Jeroen C.J. Eikenboom ◽  
Karin J. Fijn van Draat ◽  
...  
Keyword(s):  
Quality Of Life ◽  
The Netherlands ◽  
Clinical Presentation ◽  
Von Willebrand Disease ◽  
Hemophilia Treatment Centers ◽  
Type 3 ◽  
Von Willebrand ◽  
The Impact

Abstract The clinical presentation of patients with Willebrand Disease (VWD) is highly variable, and not always predictable upon laboratory measurements. The mechanism of this clinical variability is unknown. Also the impact of VWD on the quality of life is highly variable between patients. This ongoing study aims to register and investigate all patients in the Netherlands with moderate and severe von Willebrand Disease to assess clinical presentation, treatment and related complications of treatment. One of the aims is to assess which factors influence the bleeding phenotype. Another goal is to investigate the influence of von Willebrand Disease on quality of life. We have identified 1071 eligible patients. All patients are known at 12 hemophilia treatment centers. Inclusion criteria are moderate or severe VWD defined as; VWF antigen or activity ≤ 30% and/or FVIII:C ≤ 40%. The patients will be sent a questionnaire and a blood sample will be obtained for plasma and DNA. The characteristics of the patients are the following: median age is 34 years (range 0–86) in males and 42 years (range 1–92) in females. 192 children are included (&lt;18 years). Sixty-one percent is female. In this cohort 59% has type 1, 30% has type 2, 4,5% has type 3, 0.5% is compound heterozygote and 6% is non-specified. Among type 2 we identified 50% 2A, 26% 2B, 10% 2M, 6% 2N, and 8% non-specified. In this cohort 45% has blood group 0, 29% non-0 and in 26% this is unknown. The VWF:Ag, VWF:Act (CB or RCo) and FVIII:C levels are mentioned in table 1. Conclusion: The WiN study has identified 1071 moderate to severe VWD patients in the Netherlands who will form the basis for further research that will result in more insight into the clinical features and quality of life in VWD. Table 1: VWF:Ag VWF:Act* FVIII:C * VWF:CB of VWF:RCo &lt;0.10 IU/mL 91 (9%) 246 (23%) 62 (6%) 0.10 – 0.19 IU/mL 157 (15%) 368 (34%) 63 (6%) 0.20 – 0.29 IU/mL 287 (27%) 332 (31%) 137 (13%) &gt;0.30 IU/mL 527 (49%) 119 (11%) 799 (75%) Missing data 9 (1%) 6 (1%) 10 (1%)

scholarly journals Efficacy of emicizumab in a pediatric patient with type 3 von Willebrand disease and alloantibodies

2019 ◽  
Vol 3 (18) ◽  
pp. 2748-2750 ◽  
Author(s):  
Angela C. Weyand ◽  
Veronica H. Flood ◽  
Jordan A. Shavit ◽  
Steven W. Pipe
Keyword(s):  
Quality Of Life ◽  
Pediatric Patient ◽  
Lower Cost ◽  
Treatment Options ◽  
Von Willebrand Disease ◽  
Rare Clinical Entity ◽  
Key Points ◽  
Type 3 ◽  
Von Willebrand

Key Points Type 3 von Willebrand disease with alloantibodies is a rare clinical entity with few treatment options. Emicizumab prophylaxis in such patients may result in improved hemarthrosis control, lower cost, and enhanced quality of life.

Joint bleeds in von Willebrand disease patients have significant impact on quality of life and joint integrity: a cross-sectional study

Haemophilia ◽  
2015 ◽  
Vol 21 (3) ◽  
pp. e185-e192 ◽  
Author(s):  
K. P. M. van Galen ◽  
Y. V. Sanders ◽  
U. Vojinovic ◽  
J. Eikenboom ◽  
M. H. Cnossen ◽  
...  
Keyword(s):  
Quality Of Life ◽  
Cross Sectional Study ◽  
Von Willebrand Disease ◽  
Sectional Study ◽  
Cross Sectional ◽  
Von Willebrand ◽  
Joint Integrity

Clinical Joint Outcome after Joint Bleeds in Patients with Von Willebrand Disease Is Comparable to Moderate and Severe Hemophilia A Despite Fewer Joint Bleeds

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3789-3789 ◽  
Author(s):  
Karin PM van Galen ◽  
Merel Timmer ◽  
Piet de Kleijn ◽  
Frank W.G. Leebeek ◽  
Roger E.G. Schutgens ◽  
...  
Keyword(s):  
Physical Examination ◽  
Research Funding ◽  
Functional Limitations ◽  
Joint Damage ◽  
Von Willebrand Disease ◽  
X Rays ◽  
X Ray ◽  
History Of ◽  
Type 3 ◽  
Von Willebrand

Abstract Background Recurrent joint bleeds are the main cause of joint deterioration (hemophilic arthropathy) in patients with hemophilia. To what extent arthropathy occurs following joint bleeds in patients with Von Willebrand disease (VWD) compared to hemophilia has never been studied. Objectives The primary objective was to compare joint outcome by physical examination between adults with VWD and moderate and severe hemophilia A (HA). The main secondary objectives were to compare joint bleed frequency, radiological joint damage and self-reported functional limitations between VWD and moderate and severe HA. Methods We selected adult patients with VWD (VWF activity <30%) and moderate or severe HA, who had a medical history of treatment for joint bleeds, for this post hoc analysis. To compare joint outcome we used the Hemophilia Joint Health Score (HJHS range 0-124, obtained by physical examination), X-ray Pettersson scores of ankles, knees and elbows (PS range 0-13 per joint) and Hemophilia Activities List scores, a patient administered questionnaire measuring functional limitations (HAL range 0-100). Univariate analyses were performed using Mann Whitney U and Chi2. For multivariate analysis we used negative binomial regression analysis (HJHS) and logistic regression (dichotomized PS>3 and HAL<95) adjusted for age. We performed a subgroup analysis of the patients with type 3 VWD. Results We included 48 patients with VWD, 39 with moderate and 59 with severe HA. The mean age was 45, 38 and 26 years, respectively. Fewer patients with VWD than HA had a lifetime history of more than 5 joint bleeds (56% VWD vs. 77% moderate HA vs. 98% severe HA, p<0.001). Joint dysfunction at physical examination was comparable between the patients with VWD and moderate HA (median HJHS 5 vs. 5.5, p=0.65) but slightly better in VWD compared to severe HA (median HJHS 5 vs. 9, p=0.02). Apparent joint damage on X rays (PS>3 of one or more joints) occurred in 12/46 patients with VWD compared to 27/40 patients with severe HA (26% vs. 68%: OR 0.09; 95%CI 0.03-0.34, p<0.001). In moderate HA insufficient X rays were available for analyses. Functional limitations according to the HAL were comparable between patients with VWD and moderate and severe HA (VWD median HAL total score 88 vs. 95 in both moderate and severe HA, p=0.35). The subgroup analysis of joint dysfunction in patients with type 3 VWD (n=19, median age 40) showed clinical changes comparable to severe HA (median HJHS 14 vs. 9, p=0.83). We found a trend towards less radiological joint damage in type 3 VWD compared to severe HA (PS>3: 47% vs. 68%, OR 0.28; 95%CI 0.07-1.12, p=0.07). However, patients with type 3 VWD reported more functional limitations compared to those with moderate or severe HA (median HAL total score 77 vs. 95, p=0.01; adjusted for age OR 0.38; 95%CI 0.1-1.2, p=0.10). Conclusions Despite fewer joint bleeds, joint function according to the HJHS was comparable between adult patients with VWD and moderate HA with a history of treatment for joint bleeds. Apparent X ray joint damage occurred less often in patients with VWD compared to those with severe HA. The HJHS of patients with type 3 VWD was comparable to those with severe HA, but the patients with type 3 VWD reported more functional limitations, partly explained by their higher age. Knowledge of similarities and differences in joint outcome between VWD and hemophilia can be helpful to improve the awareness and treatment of joint bleeds in VWD to prevent arthropathy and functional limitations. Disclosures van Galen: Bayer: Research Funding; CSL Behring: Research Funding; Baxter: Research Funding. Leebeek:CSL Behring: Research Funding; Baxter: Research Funding. Schutgens:Sanquin: Research Funding; CSL Behring: Research Funding. Fischer:Baxalta/Baxter: Consultancy, Research Funding, Speakers Bureau; Pfizer: Consultancy, Research Funding, Speakers Bureau; CSL Behring: Consultancy, Speakers Bureau; NovoNordisk: Consultancy, Research Funding, Speakers Bureau; Octapharma: Speakers Bureau; Baxter: Consultancy, Research Funding, Speakers Bureau; Wyeth: Research Funding; Biogen: Consultancy; Biotest: Consultancy, Speakers Bureau; Bayer: Consultancy, Research Funding, Speakers Bureau; Freeline: Consultancy. Mauser-Bunschoten:CSL Behring: Research Funding; Bayer: Research Funding; Baxter: Research Funding; Griffols: Research Funding; Novo Nordisk: Research Funding; Pfizer: Research Funding; Biovitrum: Research Funding; Saquin: Research Funding.

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

Blood ◽  
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.

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

Blood ◽  
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.

scholarly journals Opportunities for Improvement: The Lot of the Inhibitor Patient Is Not a Happy One

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5040-5040
Author(s):  
Frank V. McL. Booth ◽  
Johnny Mahlangu ◽  
Howard Levy
Keyword(s):  
Quality Of Life ◽  
Half Life ◽  
Research Funding ◽  
Hemophilia A ◽  
Assessment Tools ◽  
Life Assessment ◽  
Breakthrough Bleeding ◽  
Present Trial

Abstract INTRODUCTION: Hemophilia A or B carries significant morbidity - progressive throughout life. The mainstay of treatment is regular factor replacement to treat or prevent bleeding episodes. Up to 30% of Hemophilia A and up to 5% of Hemophilia B develop neutralizing antibodies (inhibitors) rendering factor replacement therapy ineffective. Hemophilia patients with inhibitors are managed with bypassing agents for treatment or prevention of bleeds. Prophylaxis is not adequate in inhibitor patients using currently available bypassing products due to their very short half-life (2-3 hours for rFVIIa; 5-6 hours for aPCC) so they are treated on an episodic basis for bleeds. On-demand treatment results in poor quality of life, significantly higher mortality and inferior musculoskeletal outcomes in inhibitor patients when compared to patients without inhibitors. The quality of life of hemophilia has been evaluated using EQ-5D and Haem-A-QOL and impaired activity has been measured with Haemophilia Activity List (HAL). The EQ-5D is a widely used internationally validated general-purpose quality of life instrument however it lacks granularity and is not specific to Hemophilia. Haem A-QOL (Mackensen et al 2004) and Hemophilia Activities List (HAL) (Van Genderen FR et al 2006.) were developed and validated specifically to address the typical disabilities and life issues faced by patients with Hemophilia. Marzeptacog alfa (activated) (MarzAA) was created using a structure-based rational protein design and has 4 amino acid substitutions to enhance the biological properties of FVIIa. This variant molecule has substantially (6-7x) greater potency than wild-type FVIIa, a greater half-life and sufficient bioavailability when given subcutaneously (SQ). There is currently a paucity of data on quality of life (QoL) of inhibitor patients. We evaluated the baseline QoL and functional activity of inhibitor patients enrolled in the MAA-201 study using the EQ-5D , Haem-A-QoL and HAL compared the results to those of reference hemophilia patients without inhibitors. METHODS A phase 2 / 3 open-label study evaluating safety and efficacy of MarzAA in hemophilia patients with inhibitors is underway MAA-201, (NCT03407651) Subject eligibility required an annualized bleeding rate of >12 and documented inhibitor to replacement factor. The primary aim of the trial was the complete prevention of breakthrough bleeding for 50 days by the daily administration of a fixed SQ dose of MarzAA. If breakthrough bleeding occurred, up to three dose escalations were permitted. At baseline and study conclusion, each subject completed quality of life assessment tools the EQ-5D, Haem-A-QOL and the Hemophilia Activities List Haem-A-QOL assesses subjects across ten domains and provides a summarized score. Subjects in the present trial (MARZAAPOP) were compared to baseline values for subjects with severe hemophilia but without inhibitors recruited into a long-term prophylaxis trial (The A-LONG trial - ALONGREFPOP). Mean baseline Haem-A-QOL summed score in the A-LONG trial was 29.3 ±15.7 contrasting sharply with a mean baseline summed score of 42 ±15.2 for subjects in the present trial (Table 1) HAL is more motor function oriented and assesses patients across ten domains of which seven assess basic functionality and three are composites intended to assess disability in performing complex tasks. HAL provides both raw and normalized scores. Normalized scores provide meaningful output in the case of missing data elements. For each domain and for the sum score, a raw score of 0 and a normalized score of 100 indicates no functional deficit. Figure 1 provides a visual comparison between recruited subjects (MARZAAPOP) in the present trial and the population used to validate the HAL tool. (HALREFPOP). CONCLUSION: In examining recruits into the present trial, it is clear that inhibitor patients have generally worse functional scores than either of two reference groups. Effective long-term prophylaxis is expected to produce measurable improvement in QOL scores in this hard-to-treat population. Disclosures Booth: Catalyst Biosciences: Consultancy. Mahlangu:Sanofi: Research Funding, Speakers Bureau; Roche: Consultancy, Research Funding, Speakers Bureau; LFB: Consultancy; NovoNordisk: Consultancy, Research Funding, Speakers Bureau; CSL Behring: Consultancy, Research Funding, Speakers Bureau; Chugai: Consultancy; Catalyst Biosciences: Consultancy, Research Funding; Biomarin: Research Funding, Speakers Bureau; Biogen: Research Funding, Speakers Bureau; Bayer: Research Funding; Amgen: Consultancy; Alnylam: Consultancy, Research Funding, Speakers Bureau; Shire: Consultancy, Research Funding, Speakers Bureau; Sobi: Research Funding, Speakers Bureau; Spark: Consultancy, Research Funding. Levy:Catalyst Biosciences: Employment, Equity Ownership.

scholarly journals Semiautomatic VWF Multimer Densitometric Analysis: Validation of the Clinical Accuracy and Clinical Implications in Von Willebrand Disease

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 15-16
Author(s):  
Ferdows Atiq ◽  
Johan Boender ◽  
Marjon H. Cnossen ◽  
Johanna G van der Bom ◽  
Karin Fijnvandraat ◽  
...  
Keyword(s):  
Clinical Practice ◽  
Research Funding ◽  
Von Willebrand Disease ◽  
Densitometric Analysis ◽  
Travel Grant ◽  
Bleeding Score ◽  
Type 3 ◽  
Von Willebrand

Introduction Von Willebrand factor (VWF) multimer analysis is an essential tool in the diagnosis and classification of von Willebrand disease (VWD). Current visual VWF multimer analysis is observer dependent, time consuming and is inaccurate in detecting subtle changes in multimer patterns. Therefore, recent studies have investigated VWF multimer quantification using semiautomatic densitometric analysis. The accuracy of VWF multimer densitometric analysis in clinical practice needs further investigation before it can be widely used. The aim of the study was to validate the accuracy of VWF multimer densitometric analysis in clinical practice. Additionally, we aimed to identify patient characteristics associated with VWF multimer densitometry outcomes in type 1 and type 2 VWD patients, and we investigated whether subtle differences in VWF multimer pattern are associated with the bleeding phenotype of VWD patients. Methods We included patients from the nationwide Willebrand in the Netherlands (WiN) study. The inclusion criteria of the WiN study were a personal hemorrhagic diathesis or family history of VWD, and historically lowest VWF antigen (VWF:Ag), VWF activity (measured with the monoclonal antibody assay: VWF:Ab) or VWF collagen binding (VWF:CB) ≤0.30 IU/mL or FVIII activity (FVIII:C) ≤0.40 IU/mL in case of type 2N VWD. At inclusion in the WiN study, blood was drawn and patients filled in an extensive questionnaire containing a self-administered Tosetto bleeding score (BS). For multimer analysis, citrated blood samples were separated on 0.9% agarose gel and visualized by Western blotting. We used IMAGEJ for densitometric analysis. The five smallest bands on densitometric images were defined as small multimers, next five bands were defined as medium multimers and the remaining bands were defined as large multimers. Medium-large VWF multimer index was calculated by dividing the patient's multimer ratio (intensity of the medium and large multimers divided by the total intensity of all multimers) by the multimer ratio of a normal control in the same western blot. If no multimers could be detected, the multimer index was set as 0. Results We included 561 VWD patients: 328 type 1, 211 type 2 and 21 type 3 patients. The median age was 44 [IQR 29-58] and 351 patients (62.7%) were female (Table 1). Figure 1 illustrates typical densitometric outcomes of a type 1 VWD patient with normal VWF multimers (A) and a type 2A patient with reduced high-molecular-weight (HMW) VWF multimers (B). Medium-large VWF multimer index was 1.06 [0.99-1.12] in type 1 and 0.53 [0.29-0.89] in type 2 and 0.00 [0.00-0.00] in type 3 VWD. Medium-large VWF multimer index was in patients visually classified as normal, reduced and absent HMW VWF multimers, respectively 1.07 [1.02-1.12], 0.84 [0.71-0.91] and 0.31 [0.20-0.44] (p&lt;0.001, Figure 2A). With visual examination as gold standard, medium-large VWF multimer index had a very good accuracy in distinguishing normal VWF multimers from reduced HMW VWF multimers (AUC: 0.96 (0.94-0.98) p&lt;0.001, Figure 2B). It could also accurately distinguish reduced HMW VWF multimers from absence of HMW multimers, with an AUC of 0.95 (0.92-0.97, p&lt;0.001), and type 2A and 2B from type 2M and 2N (AUC: 0.96 (0.94-0.99), p&lt;0.001, Figure 2C and 2D). From VWF activity measurements, medium-large VWF multimer index was strongest correlated with VWF:CB (ρ=0.79, p&lt;0.001). From the ratio of the various functional VWF measurements (divided by VWF:Ag), the strongest correlation was again found for VWF:CB/VWF:Ag ratio (ρ=0.80, p&lt;0.001). In type 1 VWD, an increased clearance of VWF (defined as VWFpropeptide/VWF:Ag ratio ≥2.2) was independently associated with lower medium-large VWF multimer index (β=-0.10 (-0.14; -0.07), p&lt;0.001). Also, type 1 VWD patients with a VWF gene variant had relatively lower medium-large VWF multimer index compared to type 1 patients without a VWF variant, respectively 1.03 [0.95-1.10] vs 1.08 [1.04-1.12] (p&lt;0.001). In the total population, higher medium-large VWF multimer index was associated with a lower bleeding score: β=-4.6 (-7.2; -2.0), p=0.001, adjusted for age, sex, blood group and type of VWD. Conclusion Semiautomatic densitometric analysis of VWF multimers has an excellent accuracy in clinical practice, and may have an additional value in providing a better understanding of the clinical features such as the bleeding phenotype of VWD patients. Disclosures Atiq: CSL Behring: Research Funding; SOBI: Other: travel grant. Boender:SOBI: Current Employment; CSL Behring: Research Funding. Cnossen:Bayer: Research Funding; Novo Nordisk: Research Funding; Nordic Pharma: Research Funding; Sobi: Research Funding; Takeda: Research Funding; CSL behring: Research Funding; Pfizer: Research Funding; Shire: Research Funding; Baxter: Research Funding. van der Bom:Bayer: Speakers Bureau. Fijnvandraat:SOBI: Research Funding; NovoNordisk: Consultancy; Grifols: Consultancy; Takeda: Consultancy; Roche: Consultancy; CSL Behring: Research Funding; NovoNordisk: Research Funding. Van Galen:Bayer: Research Funding; Takeda: Speakers Bureau; CSL Behring: Research Funding. Laros-Van Gorkom:Baxter: Other: Educational grant; CSL Behring: Other: Educational grant. Meijer:Bayer: Research Funding; Sanquin: Research Funding; Pfizer: Research Funding; Bayer: Speakers Bureau; Sanquin: Speakers Bureau; Boehringer Ingelheim: Speakers Bureau; BMS: Speakers Bureau; Aspen: Speakers Bureau; Uniqure: Consultancy. Eikenboom:CSL Behring: Research Funding; Roche: Other: Teacher on educational activities. Leebeek:Roche: Other: DSMB member for a study; SOBI: Other: Travel grant; Novo Nordisk: Consultancy; Shire/Takeda: Consultancy; Uniqure: Consultancy; Shire/Takeda: Research Funding; CSL Behring: Research Funding.

scholarly journals Quality of Life and Life Satisfaction in AML Long-Term Survivors: Primary Results of the AMLCG-Survivorship Study

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2289-2289
Author(s):  
Eva Telzerow ◽  
Dennis Görlich ◽  
Maja Rothenberg-Thurley ◽  
Maria Cristina Sauerland ◽  
Anna Sophia Moret ◽  
...  
Keyword(s):  
Quality Of Life ◽  
Life Satisfaction ◽  
General Population ◽  
Research Funding ◽  
Well Being ◽  
Advisory Committees ◽  
Health Related ◽  
Long Term Survivors

Abstract Introduction An increasing proportion of patients with Acute Myeloid Leukemia (AML) become long-term survivors. Somatic and psycho-social outcomes are therefore becoming increasingly important, but little is known about the long-term effects of the disease and its treatment. Methods We designed a comprehensive analysis of AML survivorship outcomes including psycho-social well-being and somatic health status and conducted a questionnaire-based study collecting data from AML long term survivors (AML-LTS) and their physicians. This report focuses on overall and health-related quality of life. Somatic, especially cardiovascular, morbidity in AML-LTS are reported separately (Moret et al.). The primary aim of this study was to compare quality of life (QoL, measured by the FACT-G questionnaire) and general and health-related life satisfaction (gLS/hLS, measured by the FLZ-M questionnaire) of AML-LTS with normative data of German adults who were not diagnosed with AML (Holzner et al. 2009; Daig et al. 2009). FLZ-M and FACT-G scores were standardized relative to the normal population mean and standard deviation, stratified by sex and age. These z-scores were then tested against the fixed value 0 (indicating no difference between AML-LTS and the general population) using Mann-Whitney U-tests. Our statistical design incorporated a sequentially rejective testing procedure to maintain the multiple testing significance level at 5%, using a graphical model as described by Bretz et al. (2009). Results 427 former AML patients who had been enrolled in AMLCG trials (AMLCG-1999, AMLCG-2004, AMLCG-2008) or the AMLCG patient registry, participated in this study between 5 and 18.6 years [y] after their initial AML diagnosis (median, 11.3y). Median age of AML-LTS was 61y (range 28y-93y), and 56% were female. Thirty-eight percent of participants had been treated with chemotherapy alone, while 62% received at least one allogeneic stem cell transplant (alloSCT). A relapse occurred in 24% of the participants. Unexpectedly, quality of life and general life satisfaction summary scores were significantly higher in AML-LTS (p&lt;.001) compared to adults without the diagnosis of AML, although most differences on QoL subscales relative to the general population were small and very likely not clinically relevant. No statistical difference between AML-LTS and normal adults was found for health-related life satisfaction (hLS). Notably, a subgroup of participants (26%) reported poor physical well-being (PWB), indicated by a FACT PWB subscore more than one standard deviation (SD) below the age- and sex-matched general population value (Figure A). This resulted in poor overall QoL (i.e. &gt;1 SD below normal) for 13% of the participants (Figure B). To identify factors potentially associated with poor overall QoL, we constructed a logistic regression model including pre-specified cofactors (age, sex, time since initial diagnosis, relapse and alloSCT) and additional covariables that associated with QoL in univariate analyses (Table C). We found that participants with younger age, male sex, lower educational level, shorter time since diagnosis and a altered financial situation reported significantly lower QoL. No influence was found for other characteristics including treatment (alloSCT vs. no alloSCT), previous relapse, or de novo vs. secondary or therapy-related AML. Discussion Unlike previous studies of AML survivorship, our large cohort included a diverse spectrum of patients regarding age, time since diagnosis, and treatment modalities, which allows for new insight into long-term quality of life. Our study establishes that overall QoL in AML long-term survivors is comparable to the general population. Improvement of QoL continues beyond five years post diagnosis. Importantly, disease- and treatment-related factors, such as prior relapse or status post allogeneic transplantation, are not associated with overall QoL. However, we were able to identify risk factors for worse QoL (younger age, male sex, alteration of the financial situation), delineating a subgroup of patients that may still have a need for targeted psycho-social interventions five or more years after an AML diagnosis. Figure 1 Figure 1. Disclosures Berdel: Philogen S.p.A.: Consultancy, Current equity holder in publicly-traded company, Honoraria, Membership on an entity's Board of Directors or advisory committees. Hiddemann: Janssen: Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding. Metzeler: AbbVie: Honoraria; Astellas: Honoraria; Daiichi Sankyo: Honoraria; Novartis: Consultancy; Jazz Pharmaceuticals: Consultancy; Pfizer: Consultancy; Celgene/BMS: Consultancy, Honoraria, Research Funding.

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