Impact of Hemophilia a Inhibitor on Joint Health and Health-Related Quality of Life from the Hemophilia Utilization Group Studies Part VIII in the U.S

Introduction: Persons with hemophilia A (PwHA) and Factor VIII inhibitors experience significant economic burden associated with high treatment costs and compromised physical and psychosocial health. Few studies have compared burden of illness for PwHA with active inhibitors to those with tolerized or no inhibitor. We describe clinical and treatment outcomes, and health-related quality of life (HRQoL) in PwHA with and without inhibitors using the Hemophilia Utilization Group Studies Part VIII (HUGS VIII) baseline cross-sectional data. Methods: HUGS VIII prospectively examines the cost and burden of hemophilia care, including HRQoL, arthropathy, and psychosocial impact in PwHA aged ≥2 years. The study enrolled PwHA with inhibitors and without inhibitor at a 1:2 ratio. Participants were classified to three groups: 1) active inhibitor (FVIII≥1.0 Bethesda Units within six months of data extraction), 2) presumably tolerized inhibitor (history of immune tolerance induction, ITI, and using factor VIII for prophylaxis), and 3) no inhibitor. Parents/adult participants completed a standardized interview at enrollment (baseline) to collect sociodemographic and clinical data, self-reported pain, joint health, and HRQoL measured by the EQ-5D-3L. Clinical chart review documented hemophilic severity, inhibitor level and treatment regimen. Associations between participants' characteristics and inhibitor status were assessed using Chi-square tests. Results: Data from 73 participants with complete baseline information were analyzed. Mean age was 24.8 (standard deviation (SD)=14.1) years, 65.8% were adults, 87.7% had severe hemophilia A, and 87.1% self-reported receiving prophylactic treatment. The three groups of participants were: non-inhibitor (n=42, 57.5%); tolerized inhibitor (n=23, 31.5%); and active inhibitor (n=8, 11.0%). Mean age among the tolerized inhibitor group was significantly younger (17.3, SD=9.3 years) than active inhibitor (22.6, SD=20.4) or non-inhibitor groups (29.3, SD=13.3), p=0.02. Among individuals with inhibitors, 78.6% had undergone ITI which was successful in 72.2%. Adult participants/parents in the active inhibitor group reported a lower rate of full-time employment (42.9%) compared to the non-inhibitor (58.5%) or tolerized inhibitor (55.7%) groups, p=0.03. Compared to those without inhibitors or tolerized inhibitors, those with active inhibitors showed lower HRQoL with lower covariates adjusted mean EQ-5D Visual Analogue Scale (73.1 vs. 83.6, 80.2, P=0.21) or index score (0.80 vs. 0.87, 0.88, P=0.57). Participants with active inhibitors and those without inhibitors were more likely to report having joint pain (85.7%, 75.6% non-inhibitors, vs. 59.1% tolerized inhibitors, p=0.26), or very stiff joints upon arising (71.4%, 73.2%, vs. 27.3%, p=0.002) or during the day (71.4%, 63.4% vs. 27.3%, p=0.01) than those with a tolerized inhibitor, likely due to younger age and earlier institution of long-term effective prophylaxis after ITI. Conclusions: While the study is limited to a small sample with a skew to younger age in persons with tolerized inhibitors, preliminary analyses indicate that individuals with active inhibitors experienced greater negative impacts on employment and HRQoL than PwHA with no or tolerized inhibitors. Younger persons with tolerized inhibitors showed better joint health (less pain, stiffness) than older persons with active or no inhibitor. Future research using longitudinal data on these participants will examine whether individuals in the tolerized inhibitor group with successful ITI continue with long-term prophylaxis and achieve positive joint health outcomes. Disclosures Roberts: uniQure: Consultancy; Takeda: Consultancy, Research Funding, Speakers Bureau; Pfizer: Consultancy; Novo Nordisk: Consultancy, Speakers Bureau; Sanofi: Consultancy, Speakers Bureau; Octapharma: Consultancy, Speakers Bureau. Khairnar:Genentech, Inc.: Current Employment, Current equity holder in publicly-traded company; F Hoffmann-La Roche Ltd: Current equity holder in publicly-traded company. Wu:Baxalta US Inc., Bannockburn, IL (a Takeda Company), CSL Behring L.L.C., and Octapharma USA, Inc.: Research Funding. Carrasco:Baxalta US Inc., Bannockburn, IL (a Takeda Company), CSL Behring L.L.C., and Octapharma USA, Inc.: Research Funding. Curtis:Bayer: Consultancy; USC Hemophilia Utilization Group Study (HUGS): Consultancy; Novo Nordisk: Consultancy; Patient Reported Outcomes, Burdens and Experiences: Consultancy. Tran:Bioverativ: Consultancy; Novo Nordisk: Consultancy; Bayer: Consultancy; Takeda: Consultancy. Nichol:Pfizer: Research Funding; Octapharma: Research Funding; CSL Behring: Research Funding; Global Blood Therapeutics: Research Funding; Baxalta US Inc., Bannockburn, IL (a Takeda Company): Research Funding; Genentech Inc.: Research Funding.

Download Full-text

Fitusiran Treatment Impacts on Health-Related Quality of Life in Subjects with Hemophilia A and B with Inhibitors Assessed with the Haemophilia Quality of Life Questionnaire for Adults (Haem-A-QoL)

Blood ◽

10.1182/blood-2020-142266 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 23-24

Author(s):

Sylvia Von Mackensen ◽

Pratima Chowdary ◽

Sarah Mangles ◽

Qifeng Yu ◽

Baisong Mei ◽

...

Keyword(s):

Quality Of Life ◽

Hemophilia A ◽

Phase 1 ◽

Phase 2 ◽

Publicly Traded ◽

Advisory Committees ◽

Related Quality ◽

Health Related ◽

Dose Dependent

Background: Fitusiran, an investigational RNA interference treatment for people with hemophilia A or B (PwH), with or without inhibitors, has shown dose-dependent lowering of antithrombin, increase in thrombin generation, and decrease in bleeding frequency in clinical trials. The novel mechanism of action and long pharmacodynamic effect enables once-monthly subcutaneous administration. This sustained hemostatic protection and less burdensome administration may improve patient-reported outcomes (PRO). Objective: To evaluate changes in PRO in terms of patient-relevant improvements in health-related quality of life (HRQoL) in PwH with inhibitors (PwHI) on prophylactic fitusiran treatment. Methods: Fitusiran was evaluated in a phase 1 dose-escalation study (NCT02035605) followed by a phase 2 open-label extension (OLE) study (NCT02554773) with monthly subcutaneous fixed doses of 50 mg or 80 mg. HRQoL was assessed using the Haem-A-QoL and the EuroQol 5 Dimensions (EQ-5D) questionnaires at baseline and at end of study in a cohort of 17 PwHI (Hemophilia A, n=15; Hemophilia B, n=2) from the phase 1 study. Results: Subjects previously treated on-demand or prophylactically had a mean (standard deviation [SD]) age of 34.6 (10.3) years and a mean (SD) number of bleeding episodes in the 6 months before baseline of 16.6 (10.7). Mean (SD) changes from baseline to end of study (day 84 or later) in Haem-A-QoL total (-9.2 [11.2]) and physical health (−12.3 [15.1]) domain scores suggest clinically meaningful improvement (lower scores indicate better HRQoL). Numeric reduction (i.e., improvement) in all other domains appeared to be dose-dependent (greater improvement in the 80 mg group) (Table 1). Changes in EQ-5D utility and EQ-VAS scores were not clinically meaningful. Further analyses in PwH with and without inhibitors from the phase 2 OLE will be presented. Conclusions: Fitusiran prophylaxis may improve HRQoL - particularly the Haem-A-QoL 'Physical health' domain (painful swelling, joint pain, pain with movement, difficulty walking, and time to get ready) as shown in a cohort of 17 PwHI . Additional analyses from ongoing OLE and phase 3 studies are planned to quantify the patient-relevant changes with fitusiran treatment in all hemophilia patients over time. Disclosures Von Mackensen: Sanofi, Bayer, Sobi, Chugai, Kedrion, Spark: Consultancy; Biotest, Sobi, CSL Behring: Honoraria; Novo Nordisk, Sobi: Research Funding. Chowdary:BioMarin: Honoraria; Bayer, CSL Behring, Freeline, Novo Nordisk, Pfizer and Sobi: Research Funding; Chugai, CSL Behring, Novo Nordisk, Pfizer, Roche, Sobi: Speakers Bureau; Bayer, Chugai, CSL Behring, Freeline, Novo Nordisk, Pfizer, Roche, Sanofi, Shire (Baxalta), Sobi, Spark: Membership on an entity's Board of Directors or advisory committees. Mangles:Roche, Takeda, Novo Nordisk: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sobi, Octapharma, Novo Nordisk, Shire and Roche/Chugai: Other: travel funding. Yu:Sanofi: Other: was an employee and stockholder of Sanofi, at the time of study; Albireo Pharmaceuticals, Inc: Current Employment. Mei:Sanofi: Current Employment, Current equity holder in publicly-traded company. Andersson:Sanofi: Current Employment, Current equity holder in publicly-traded company. Dasmahapatra:Sanofi: Current Employment, Current equity holder in publicly-traded company.

Download Full-text

Improvement in Health-Related Quality of Life Measures after Long-Term, Daily, Subcutaneous Concizumab Prophylaxis in Patients with Hemophilia A/B with and without Inhibitors: Results from the Main and Extension Parts of Phase 2 Clinical Trials

Blood ◽

10.1182/blood-2021-152257 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 1041-1041

Author(s):

Mathilde Faller ◽

Sidsel Marie Tønder ◽

Thomas Porstmann

Keyword(s):

Health Care ◽

Prophylactic Treatment ◽

Hemophilia A ◽

Response Threshold ◽

Individual Level ◽

Responder Analysis ◽

Related Quality ◽

Health Related

Abstract Relative to the general population, health-related quality of life (HRQoL) is impaired in patients with hemophilia, who report increased pain and reduced physical activity. It is therefore of interest to assess the change in HRQoL after long-term prophylactic treatment. Concizumab is an anti-tissue factor pathway inhibitor monoclonal antibody in clinical development for a subcutaneous, prophylactic treatment of patients with hemophilia. Here, we present results from exploratory analyses assessing changes in HRQoL after long-term concizumab treatment (≤126 treatment weeks), which includes data from the main and extension parts of explorer4 (NCT03196284) and explorer5 (NCT03196297) phase 2 trials. Both trials comprised a main part (≤24 weeks), and an extension part (explorer4: ≤94 weeks; explorer5: ≤102 weeks). In explorer4, patients with hemophilia A and B with inhibitors (HAwI/HBwI) were recruited and randomized 2:1 to concizumab prophylaxis (n=17) or recombinant activated factor VII on-demand treatment (n=9). Patients in the on-demand arm switched to concizumab prophylaxis in the extension part. Twenty-six patients were recruited for explorer4, 25 patients were exposed to concizumab in the extension part, and 22 patients completed the trial. In explorer5, 36 patients with severe hemophilia A (HA) were recruited, 32 patients entered the extension part, and 30 patients completed the trial. Patients were asked to complete the 36-item Short Form Health Survey (SF-36v2) at baseline (for this analysis, baseline was defined as the last assessment before first treatment with concizumab), and throughout the main and extension parts. Scoring was conducted according to the SF-36v2 scoring software (version 5.0). Only patients who completed the entire trial were included for analysis. T score points of SF-36v2 domains were used to determine clinically meaningful differences at group level from baseline to the end of the extension part, based on minimally important difference criteria (MID; SF-36v2 manual 3rd edition, 2013). At an individual level, a responder analysis was conducted to identify the proportion of patients who had improved scores in the physical component summary (PCS), physical function (PF) and bodily pain (BP) domains, based on the recommended individual-level response threshold of 3.4, 4.3 and 6.2, respectively (based on 2009 United States general population norms; SF-36v2 manual). The results presented here demonstrate the change in HRQoL before and after long-term concizumab use in the main and extension parts of explorer4 and explorer5. For explorer4, 22 patients (14 HAwI; 8 HBwI) were included in the current exploratory analysis, which showed that the difference in improvement from baseline to end of extension part exceeded the MID thresholds for PCS score (Table 1), at group level. Additionally, the MID thresholds were also met for PF, BP, role-physical, general health, vitality, social functioning, and mental health domains in explorer4 (Table 1). At an individual level, the responder analysis revealed that 63.6%, 54.5% and 50.0% of 22 patients had an improvement that met or exceeded the response threshold for PCS, PF and BP scores. In the 30 patients with severe HA included in the explorer5 analysis, PCS score met the MID threshold for difference in improvement from baseline to end of extension, although large standard deviations were observed (Table 1). At an individual level, the responder analysis revealed that 43.3%, 33.3% and 33.3% of 30 patients had an improvement that met or exceeded the response threshold for PCS, PF and BP scores. While these analyses are exploratory and should be interpreted with caution, they illustrated that patients with HAwI/HBwI reported improved HRQoL after long-term, subcutaneous concizumab prophylaxis, particularly in clinically relevant domains such as PF and BP, suggesting a potential positive effect of concizumab prophylaxis on physical functioning and reduced pain. Interestingly, PCS improvement was observed across all hemophilia subgroups, suggesting better functional health, albeit the large standard deviation reported. The potential beneficial effect of concizumab prophylaxis on HRQoL in hemophilia patients is being investigated further in the ongoing phase 3 trials. Figure 1 Figure 1. Disclosures Faller: Novo Nordisk Health Care AG: Current Employment. Marie Tønder: Novo Nordisk Health Care AG: Current Employment. Porstmann: Novo Nordisk Health Care AG: Current Employment.

Download Full-text

Problem Joints and Their Clinical and Humanistic Burden in Children and Adults with Moderate and Severe Hemophilia a: CHESS Paediatrics and CHESS II

Blood ◽

10.1182/blood-2020-140306 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 33-34

Author(s):

Paul McLaughlin ◽

Cedric Hermans ◽

Sohaib Asghar ◽

Tom Burke ◽

Francis Nissen ◽

...

Keyword(s):

Quality Of Life ◽

Research Funding ◽

Hemophilia A ◽

Joint Damage ◽

Severe Hemophilia ◽

Publicly Traded ◽

Hemophilic Arthropathy ◽

Joint Health ◽

Humanistic Burden

Introduction Severe hemophilia A (SHA) is characterized by spontaneous (non-trauma related) bleeding episodes into the joint space and muscle tissue, leading to progressive joint deterioration and chronic pain. Chronic joint damage is most often associated with severe hemophilia, however more recent research has illustrated that people with moderate hemophilia A (MHA) also experience hemophilic arthropathy and functional impairment. The need to measure joint health in children as well as adults, is underscored by findings from the Joint Outcome Continuation Study, which found that FVIII prophylaxis was insufficient to protect joints from damage, from childhood through adolescence in severe HA (Warren et al., 2020). The objective of this analysis is to gain a more patient-centric understanding of the clinical, economic and humanistic burden associated with 'Problem Joints', a measure of joint morbidity developed in consultation with an expert panel to overcome limitations with existing measures, in people with MHA and SHA. Methods A descriptive cohort analysis was conducted, utilizing retrospective, cross-sectional real-world data from the 'Cost of Haemophilia in Europe: a Socioeconomic Survey' (CHESS Paeds and CHESS II), studies of adult and pediatric persons with hemophilia. The analysis population is comprised of children (17 and below) with MHA or SHA in CHESS Paeds, and adults aged 20 and over with MHA or SHA in CHESS II. To account for the possibility that persons aged 18 or 19 in CHESS II may have participated in CHESS Paeds, these individuals were excluded from the analysis. Physician-reported clinical outcome data and patient/caregiver-reported quality of life were analyzed. A problem joint (PJ) is defined as having chronic joint pain and/or limited range of movement due to compromised joint integrity (i.e. chronic synovitis and/or hemophilic arthropathy). Analyses were stratified by number of PJs: none, 1 PJ, and 2+ PJs. We report retrospective data of the 12 months prior to study enrollment, on annualized bleeding rate (ABR), prevalence of target joints (TJ), as defined by the International Society on Thrombosis and Haemostasis, and EQ-5D-/5L/Y/Proxy score. Results are presented as mean (standard deviation) or N (%). Results Among 785 participants (N = 464 SHA; N = 321 MHA) in CHESS Paeds, mean age and BMI were 10.33 (4.63) and 22.50 (17.07), respectively. Of 493 participants (aged 20 and above) in CHESS II (N = 298 SHA; N = 195 MHA), the mean age and BMI were 38.61 (14.06) and 24.55 (2.92), respectively. Current inhibitor to FVIII replacement was more prevalent in children than in adults (10% vs. 5%). In CHESS II, approximately 40% of people with MHA and 49% with SHA had one or more PJs, respectively [1 PJ (23% vs. 28%); 2+ PJs (16% vs. 21%)]. In CHESS Paeds, approximately 14% of children with MHA and 18% with SHA had at least one PJ, respectively [1 PJ (9% vs. 14%); 2+ PJs (5% vs. 3%)]. TJs were less prevalent with MHA in comparison to SHA, in both adults (24% vs. 45%) and children (13% vs. 22%). Clinical burden was higher among both children and adults with PJs compared to those with no PJs. ABR correlates with the number of PJs, in those with MHA and SHA in CHESS II (Figure 1). Similarly, PJs were associated with higher ABR across MHA and SHA in CHESS Paeds (Figure 2). Hemophilia-related hospitalizations were higher in both adult and pediatric participants with PJs. In CHESS II, MHA with no PJs had fewer [0.73 (1.23)] hospitalizations compared to having those with 1 PJ [1.38 (1.11)] or 2+ PJs [1.28 (1.25)]. Similarly, children with MHA with 2+ PJs had 1.60 (1.92) hemophilia-related hospitalizations, compared to 1.38 (1.92) with 1 PJ and 0.71 (1.14) with no PJs. PJs were associated with impaired quality of life. In CHESS II, MHA and SHA EQ-5D-5L values in persons with no PJs were 0.81 (0.19) and 0.79 (0.18), respectively, compared to 0.65 (0.16) and 0.62 (0.23) with 1 PJ, and 0.65 (0.14) and 0.51 (0.33) in with 2+ PJs. A similar trend was observed in EQ-5D-Y and EQ-5D-proxy scores in CHESS Paeds. Conclusions Data from CHESS Paeds and CHESS II demonstrate an association between chronic joint damage, as measured by the 'problem joint' definition, and worsening clinical and quality of life outcomes, across both MHA and SHA. Further analyses will seek to expand upon the initial results presented here, to investigate the wider elements of burden associated with compromised long-term joint health. Disclosures McLaughlin: BioMarin: Consultancy; Novo Nordisk: Consultancy, Speakers Bureau; Sobi: Consultancy, Speakers Bureau; Roche/Chugai: Speakers Bureau; Takeda: Speakers Bureau. Hermans:Novo Nordisk: Consultancy, Speakers Bureau; Roche: Consultancy, Speakers Bureau; Sobi: Consultancy, Research Funding, Speakers Bureau; Biogen: Consultancy, Speakers Bureau; CAF-DCF: Consultancy, Speakers Bureau; CSL Behring: Consultancy, Speakers Bureau; Shire, a Takeda company: Consultancy, Research Funding, Speakers Bureau; Pfizer: Consultancy, Research Funding, Speakers Bureau; Bayer: Consultancy, Research Funding, Speakers Bureau; WFH: Other; EAHAD: Other; Octapharma: Consultancy, Speakers Bureau; Kedrion: Speakers Bureau; LFB: Consultancy, Speakers Bureau. Asghar:HCD Economics: Current Employment. Burke:HCD Economics: Current Employment; University of Chester: Current Employment; F. Hoffmann-La Roche Ltd: Consultancy. Nissen:GSK: Research Funding; Novartis: Research Funding; Actelion: Consultancy; F. Hoffmann-La Roche Ltd: Current Employment. Aizenas:F. Hoffmann-La Roche Ltd: Current Employment, Current equity holder in publicly-traded company. Meier:F. Hoffmann-La Roche Ltd: Current Employment, Current equity holder in publicly-traded company. Dhillon:HCD Economics: Current Employment; F. Hoffmann-La Roche Ltd: Other: All authors received editorial support for this abstract, furnished by Scott Battle, funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland. . O'Hara:F. Hoffmann-La Roche Ltd: Consultancy; HCD Economics: Current Employment, Current equity holder in private company.

Download Full-text

Bone and Joint Health Markers in Persons with Hemophilia A (PwHA) Treated with Emicizumab in HAVEN 3

Blood ◽

10.1182/blood-2019-123689 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 626-626 ◽

Cited By ~ 1

Author(s):

Anna Kiialainen ◽

Markus Niggli ◽

Christine L. Kempton ◽

Giancarlo Castaman ◽

Tiffany Y. Chang ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Hemophilia A ◽

Study Entry ◽

Type I ◽

Healthy Individuals ◽

Advisory Committees ◽

Joint Health ◽

Equity Ownership

Introduction Emicizumab is a recombinant, humanized, bispecific monoclonal antibody that restores the function of missing activated factor VIII (FVIII) by bridging activated FIX and FX in persons with hemophilia A (PwHA). Prophylaxis with emicizumab once weekly or every two weeks resulted in significant reductions in bleeds, including joint bleeds, and a favorable safety profile in PwHA without FVIII inhibitors in the HAVEN 3 study (NCT02847637; Mahlangu et al. 2018). Recurrent joint bleeds in PwHA can lead to hemophilic arthropathy, and hemophilia A has been associated with decreased bone mineral density (Kempton et al. 2014). To explore the potential effect of emicizumab prophylaxis on bone and joint health beyond bleed prevention, we measured joint health scores and bone and joint biomarkers in HAVEN 3. Methods Hemophilia joint health scores (HJHS; v2.1) were evaluated at baseline and Week 49 of emicizumab prophylaxis in 107 PwHA in HAVEN 3. Biomarkers of bone formation (osteocalcin [OC], N-terminal propeptide of type I procollagen [P1NP]), bone resorption (C-terminal telopeptide of type I collagen [CTX-I]), osteoblasts (osteoprotegerin), osteoclastogenesis (soluble receptor activator of nuclear factor- kappaB Ligand [sRANKL]), cartilage turnover (cartilage oligomeric matrix protein [COMP]), and inflammation (interleukin 1 beta, interleukin 6, and tumor necrosis factor) were measured in 117 PwHA (Table 1) receiving emicizumab at baseline and after 3, 6, 12, and 18 months of treatment. In all, 94 of 117 PwHA with samples for biomarker analysis were part of the HJHS evaluation. Results PwHA previously on FVIII prophylaxis and those with no target joints at study entry had lower (indicating healthier) HJHS scores at baseline. Mean improvements from baseline of −2.25 (95% confidence interval [CI]: −4.12, −0.39) in total HJHS and −2.23 (95% CI: −4.07, −0.38) in HJHS joint-specific domain (excluding gait) were observed after 49 weeks of emicizumab prophylaxis in PwHA with one or more target joints at study entry (n=71). Improvement was consistent across HJHS for different locations (knee, ankle, elbow). No significant differences in the measured biomarkers between PwHA previously on FVIII prophylaxis or on on-demand treatment, or in those with or without target joints, were seen at baseline. Mean baseline values of most bone and joint biomarkers were within normal ranges, or similar to published levels in healthy individuals, although large variability was observed between individuals. None of the measured biomarkers changed significantly during emicizumab prophylaxis. Higher OC, P1NP, and CTX-I levels were observed in adolescent vs adult PwHA at all time points, which is consistent with reported increases of these biomarkers during skeletal growth. Data suggest a potential association of COMP levels with HJHS scores at baseline (Pearson correlation coefficient 0.46, p=0.0001). Data on two additional cartilage biomarkers, CTX-II (C-terminal telopeptide of type II collagen) and CS-846 (a chondroitin sulfate epitope) are being generated. Conclusions Reduction in joint bleeds was previously reported in HAVEN 3, including over 99% target joint resolution with long-term follow up (Callaghan et al. 2019). This analysis provides further evidence of the positive effect of emicizumab on joint health, showing significant and clinically relevant improvements in HJHS (defined as a ≥2-point reduction in HJHS joints domain [Kuijlaars et al. 2017]) after as few as 49 weeks of emicizumab prophylaxis. The biomarkers measured in blood as surrogates of bone and joint health did not show significant changes over the first 18 months of emicizumab prophylaxis. This may reflect heterogeneity between individuals, and effects on the measured biomarkers by factors other than joint health. However, improvement in bone and joint biomarkers would have been unexpected as the observed means at baseline were already similar to levels reported in healthy individuals. Although data from animal models have suggested that FVIII may play a role in bone health beyond protection against bleeds, in this study we observed no indication of worsening in any of the measured bone and joint health markers that might have resulted from reduced exposure to FVIII in PwHA who switched to emicizumab prophylaxis. Additional data are needed to better understand the long-term effect of emicizumab prophylaxis on bone and joint health. Disclosures Kiialainen: F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Niggli:F. Hoffmann-La Roche Ltd: Employment. Kempton:Novo Nordisk: Research Funding; Octapharma: Honoraria; Pfizer: Honoraria; Genentech, Inc.: Honoraria. Castaman:Sanofi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bayer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Uniqure: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Kedrion: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Werfen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda (SHIRE): Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sobi: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Research Funding; CSL Behring: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Chang:Genentech/Roche: Equity Ownership; Genentech, Inc.: Employment. Paz-Priel:Genentech, Inc.: Employment. Adamkewicz:F. Hoffmann-La Roche Ltd: Equity Ownership; Genentech, Inc.: Employment. Levy:F. Hoffman La Roche: Equity Ownership; Genentech, Inc: Employment.

Download Full-text

Effectiveness and Safety Outcomes in Patients with Hemophilia a Receiving Antihemophilic Factor (Recombinant) for at Least 5 Years in a Real-World Setting: 6-Year Interim Analysis of the Ahead International and German Studies

Blood ◽

10.1182/blood-2020-139873 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 1-1

Author(s):

Dimitrios A. Tsakiris ◽

Johannes Oldenburg ◽

Robert Klamroth ◽

Benoît Guillet ◽

Kate Khair ◽

...

Keyword(s):

Clinical Practice ◽

Real World ◽

Interim Analysis ◽

Research Funding ◽

Hemophilia A ◽

Routine Clinical Practice ◽

Publicly Traded ◽

Real World Setting ◽

Antihemophilic Factor

Introduction: Long-term effectiveness and safety data in patients treated in routine clinical practice settings can be captured from real-world studies. The international (INT) and German (GER) Antihemophilic factor (recombinant; rAHF) Hemophilia A (HA) outcome Database (AHEAD) studies assess long-term effectiveness and safety outcomes in patients with moderate HA (factor VIII level 1-5%) or severe HA (factor VIII <1%) receiving rAHF (ADVATE®; Baxalta US Inc., a Takeda company, Lexington, MA, USA) in routine clinical practice. Methods: These are non-interventional, prospective, long-term, multicenter studies (INT: NCT02078427; GER: DRKS 00000556). Key outcomes include Gilbert scores (primary endpoint; pain scored 0-3; bleeding scored 0-3, and physical exam scored 0-12), annualized bleeding rates (ABRs) by disease severity, and adverse events (AEs). Findings reported here are from the 6-year interim analysis (data cut-off: July 15, 2019), and focus on patients who have received rAHF prophylaxis or on-demand (OD) treatment for ≥5 years in the studies. All data are reported for the safety analysis set (SAS), which comprised patients who passed screening and were assigned to a treatment group or regimen in the INT study, or were enrolled and have received ≥1 dose of rAHF since study enrollment in the GER study. Results: At the time of analysis, the INT study SAS comprised 707 patients, 156 of whom had received ≥5 years of rAHF treatment during the study. The GER study SAS comprised 382 patients, 231 of whom had received ≥5 years of rAHF treatment. Average Gilbert scores (all joints) were consistently low (years 1-6: median 0-1.0; mean 0-1.3) for both children aged 2 to <12 years and adolescents aged 12 to <18 years receiving rAHF prophylaxis within both studies. In the INT study, average Gilbert scores were lower with prophylaxis than with OD therapy in adults (aged ≥18 years) throughout the observation period (years 1-6: median: 0.9-1.4 [n=8-25] vs 1.4-6.3 [n=2-8], respectively; mean: 1.4-2.2 vs 2.1-6.3; respectively); significant differences (P<0.05) between mean values were observed for years 3, 4, and 6. In the GER study, average Gilbert scores were slightly higher with prophylaxis than with OD in adults (years 1-6: median: 0.7-2.2 [n=12-37] vs 0.3-1.4 [n=2-15], respectively; mean: 1.0-2.7 vs 0.5-2.2, respectively; P-values not available). In the INT study, ABRs were consistently lower in patients receiving rAHF prophylaxis than in those receiving rAHF OD, irrespective of disease severity (Table). A similar trend was observed in the GER study in patients with severe HA, whereas ABRs were similar for both treatment regimens in patients with moderate HA. In both studies, greater proportions of patients with moderate or severe HA receiving rAHF prophylaxis had 0 bleeds than those receiving rAHF OD (Table). In the INT study, 842 AEs were reported in 116/156 (74.4%) patients, including 2 treatment-related serious AEs in 2 (1.3%) patients. In the GER study, 1321 AEs were reported in 197/231 (85.3%) patients, including 29 treatment-related serious AEs in 14 (6.1%) patients. Conclusions: These findings in patients receiving rAHF for ≥5 years in a real-world setting corroborate previous data on the long-term efficacy and tolerability of rAHF in patients with moderate or severe HA. rAHF demonstrated effectiveness in maintaining joint health (as measured by Gilbert scores) in adult patients. Table Disclosures Tsakiris: Roche: Research Funding; Shire, a Takeda company: Research Funding; Sobi: Research Funding; Bayer: Research Funding; CSL Behring: Research Funding; Novo Nordisk: Research Funding; Pfizer: Research Funding; Octapharma: Research Funding. Oldenburg:Sobi: Consultancy, Speakers Bureau; Bayer: Consultancy, Research Funding, Speakers Bureau; Biotest: Consultancy, Research Funding, Speakers Bureau; CSL Behring: Consultancy, Research Funding, Speakers Bureau; Novo Nordisk: Consultancy, Research Funding, Speakers Bureau; Octapharma: Consultancy, Research Funding, Speakers Bureau; Pfizer: Consultancy, Research Funding, Speakers Bureau; Shire, a Takeda company: Consultancy, Research Funding, Speakers Bureau; Biogen: Consultancy, Speakers Bureau; Chugai: Consultancy, Speakers Bureau; Grifols: Consultancy, Speakers Bureau; Roche: Consultancy, Speakers Bureau. Klamroth:Pfizer: Consultancy, Research Funding, Speakers Bureau; Biotest: Speakers Bureau; Grifols: Speakers Bureau; Takeda/Shire: Consultancy, Research Funding, Speakers Bureau; Octapharma: Consultancy, Research Funding, Speakers Bureau; Novo Nordisk: Consultancy, Research Funding, Speakers Bureau; Biomarin: Consultancy, Research Funding, Speakers Bureau; CSL Behring: Research Funding, Speakers Bureau; Roche: Consultancy, Speakers Bureau; Sobi: Consultancy, Speakers Bureau; Bayer: Consultancy, Research Funding, Speakers Bureau. Guillet:CSL Behring: Research Funding, Speakers Bureau; Octapharma: Research Funding; Bayer: Consultancy; Novo Nordisk: Consultancy, Speakers Bureau; Shire, a Takeda company: Consultancy, Speakers Bureau; Roche-Chugai: Consultancy, Speakers Bureau. Khair:Shire, a Takeda company: Consultancy, Speakers Bureau; Novo Nordisk: Consultancy, Research Funding, Speakers Bureau; Pfizer: Research Funding, Speakers Bureau; Roche: Consultancy, Speakers Bureau; Sobi: Consultancy, Research Funding, Speakers Bureau; Bayer: Consultancy, Speakers Bureau; Baxalta/Shire, Takeda companies: Research Funding. Huth-Kühne:Bayer: Consultancy; CSL Behring: Consultancy; Shire, a Takeda company: Consultancy; Sobi: Consultancy. Kurnik:Sobi: Consultancy, Research Funding; Biotest: Consultancy, Speakers Bureau; Bayer: Consultancy, Research Funding, Speakers Bureau; CSL Behring: Consultancy, Research Funding, Speakers Bureau; Novo Nordisk: Consultancy, Research Funding, Speakers Bureau; Pfizer: Research Funding; Roche: Consultancy, Research Funding, Speakers Bureau; Shire, a Takeda company: Consultancy, Research Funding, Speakers Bureau. Regensburger:Takeda Pharma Vertrieb GmbH & Co. KG: Current Employment, Current equity holder in publicly-traded company. Botha:Takeda Pharmaceutical International AG: Current Employment, Current equity holder in publicly-traded company. Fernandez:Takeda Pharmaceutical International AG: Current Employment, Current equity holder in publicly-traded company. Tang:Takeda Pharmaceutical International AG: Current Employment, Current equity holder in publicly-traded company. Ozelo:Pfizer: Consultancy, Research Funding; Shire/Takeda: Consultancy, Research Funding, Speakers Bureau; Roche: Consultancy, Research Funding, Speakers Bureau; Bioverativ/Sanofi: Consultancy, Research Funding; BioMarin: Consultancy, Research Funding, Speakers Bureau; Novo Nordisk: Consultancy, Research Funding, Speakers Bureau.

Download Full-text

Symptoms, Health-Related Quality of Life, and Tolerability of Loncastuximab Tesirine in Patients with Relapsed or Refractory Diffuse Large B Cell Lymphoma

Blood ◽

10.1182/blood-2020-139571 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 3-4

Author(s):

Alexander I. Spira ◽

Lei Chen ◽

Xiaolei Zhou ◽

Ari Gnanasakthy ◽

Luqiang Wang ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

B Cell Lymphoma ◽

Patient Reported Outcome ◽

Publicly Traded ◽

Advisory Committees ◽

Patient Reported ◽

Related Quality ◽

Health Related ◽

Night Sweats

Introduction In the ongoing single-arm, open-label phase 2 ADCT-402-201 study (LOTIS 2, NCT03589469), loncastuximab tesirine has shown substantial antitumor activity with a manageable toxicity profile in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) who had failed ≥ 2 prior therapies, including activity in patients with high-risk disease characteristics. The overall response rate was 48.3% (based on positron emission tomography-computed tomography [PET-CT] assessed by independent review according to Lugano response criteria), and the median duration of response was 10.25 months. This analysis examined symptoms, health-related quality of life (HRQoL), and tolerability using validated patient-reported outcome instruments. Methods Enrolled patients aged ≥18 years received loncastuximab tesirine as an intravenous infusion on day 1 of each 3-week treatment cycle. Responders were defined as patients with a best overall response of complete or partial response. Patient-reported symptoms and HRQoL were measured using the Functional Assessment of Cancer Treatment-Lymphoma (FACT-Lym) and EQ-5D 5 Levels (EQ-5D-5L) instruments at baseline, day 1 of each cycle while patients were treated, and at the end-of-treatment visit. Descriptive statistics for change from baseline scores and percentages of patients with improved, stable, or worsened symptoms were summarized by visit and clinical response. Analysis was conducted using data collected from study initiation (1 August 2018) through 6 April 2020. Results The 145 patients enrolled in this study had a median age of 66 years (range, 23-94). Patients were heavily pretreated, with a median of 3 (range, 2-7) prior systemic therapies. A baseline patient-reported outcome score and at least one post-baseline score were available for 130 patients. Completion rates among patients treated at each visit were ≥ 92% for EQ-5D-5L and ≥ 88% for FACT-Lym up to cycle 9, day 1 (24 weeks). After cycle 9, fewer than 20 patients had patient-reported outcome scores available for analysis. For symptoms assessed in the FACT-Lym lymphoma subscale, pain in certain parts of the body, lumps/swelling, trouble sleeping at night, and fatigue were the most frequently reported symptoms at baseline (34%-59% reported "somewhat" to "very much"). Most patients (≥ 80%) reported "not at all" or "a little bit" at baseline for fever, night sweats, losing weight, itching, and loss of appetite. During the course of treatment, higher percentages of patients reported improvement than worsening for pain and lumps/swelling for the majority of visits. Fever, night sweats, and losing weight did not change for most patients. Itching was the only symptom for which more patients experienced worsening than improvement. For other symptoms, similar percentages of patients reported improvement and worsening. The mean change from baseline in EQ-5D Visual Analog Scale (VAS) score showed a trend of improvement in overall health over time (see figure). The mean VAS change reached the minimally important difference of 7 points at cycle 8, day 1. This improvement was associated with clinical response. When patients were asked how much they were bothered by side effects of treatment, most patients (> 60%) reported "not at all" or "a little bit" for all visits throughout the treatment. Conclusions Results of this analysis suggest that patients who responded to treatment with loncastuximab tesirine generally had stable or improved symptoms and overall HRQoL. The treatment was well tolerated by patients. These findings further support the clinical use of loncastuximab tesirine for the treatment of relapsed or refractory DLBCL. Disclosures Spira: ADCT:Research Funding;Janssen:Consultancy;Incyte:Consultancy;BMS:Consultancy;Merck:Consultancy;Novartis:Consultancy;Takeda:Consultancy;Cardiff Oncology:Research Funding.Chen:ADCT:Current Employment, Current equity holder in publicly-traded company.Zhou:ADCT:Research Funding.Gnanasakthy:ADCT:Research Funding.Wang:ADC Therapeutics America, inc:Current Employment, Current equity holder in publicly-traded company.Ungar:ADC Therapeutics:Current Employment, Current equity holder in publicly-traded company.Curiel:ADCT:Current Employment, Current equity holder in publicly-traded company.Radford:GlaxoSmithKline:Current equity holder in publicly-traded company, Other: Spouse;AstraZeneca:Current equity holder in publicly-traded company, Other: Spouse;Takeda:Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau;Pfizer:Research Funding;ADCT:Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding;BMS:Consultancy, Honoraria, Speakers Bureau;Novartis:Consultancy, Honoraria;Seattle Genetics:Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.Kahl:AstraZeneca Pharmaceuticals LP:Consultancy, Membership on an entity's Board of Directors or advisory committees;Celgene Corporation:Consultancy;Genentech:Consultancy;Pharmacyclics LLC:Consultancy;Roche Laboratories Inc:Consultancy;BeiGene:Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding;Janssen:Consultancy, Membership on an entity's Board of Directors or advisory committees;Acerta:Consultancy, Research Funding;ADC Therapeutics:Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding;AbbVie:Consultancy.

Download Full-text

Modeling Minimally-Effective FVIII Trough Levels in Hemophilia a Patients on PK-Guided Prophylaxis

Blood ◽

10.1182/blood.v124.21.689.689 ◽

2014 ◽

Vol 124 (21) ◽

pp. 689-689 ◽

Cited By ~ 1

Author(s):

Gerald Spotts ◽

Steven W. Pipe ◽

Erik Berntorp ◽

Peter W. Collins ◽

Victor S. Blanchette ◽

...

Keyword(s):

Research Funding ◽

Hemophilia A ◽

Bleeding Risk ◽

Valuable Insight ◽

Risk Modeling ◽

Bleeding Events ◽

Joint Health ◽

Post Infusion ◽

The Ideal

Abstract Background: The aim of FVIII prophylaxis in Hemophilia A management is the reduction of risk for any bleed events (BE) in order to preserve long-term joint health and QOL. One proposed measure of the ideal prophylactic outcome is the virtual elimination of all BE not associated with trauma and/or of spontaneous etiology. Given the wide inter-patient variance in PK parameters, long-term prophylaxis outcomes and costs of therapy, PK-guided dosing has become an attractive approach to add more precision to dosing decisions and improve outcomes. Knowledge of the appropriate FVIII trough target for each individual patient to achieve a bleed-free outcome is needed however to design the ideal personalized PK-guided regimen. Objective: Model individual FVIII trough targets for achieving ideal outcomes in hemophilia A patients prescribed PK-guided prophylaxis every third day. Methods: FVIII infusion and BE records, and PK parameters from each subject participating in the 12-month PK-guided dosing arm of the randomized rAHF-PFM prophylaxis study (Valentino et al, 2012) were used to determine the predicted FVIII level at time of each BE. Median and maximum predicted FVIII values at time of spontaneous/non-trauma BE for all sites, and for joint and non-joint sites were estimated per subject. Number (%) of subjects with any spontaneous/non-trauma BE that occurred at predicted FVIII levels (maximum value and/or median value for those with more than one bleed) above and below specific theoretical FVIII trough values was modeled. Results: Of 34 subjects on PK-guided prophylaxis with rAHF-PFM targeting 1% trough every third day, 19 (56%) had no spontaneous BE during one year observation at FVIII levels (median) above the theoretical trough value of 1%. The number (%) of subjects with no spontaneous/non-trauma BE at FVIII levels (median) above the theoretical trough value of 3%, 5%, 10%, 15% and 20% levels increased to 71%, 79%, 31 91%, 97%, and 100%, respectively (Figure 1). All 57 spontaneous/non-trauma BE occurred at predicted FVIII levels ≤30%. Figure 1 Figure 1. Conclusions: Evaluation of individual bleeding events and treatment records for this prophylaxis study population, most of which had pre-established hemophilic arthropathy, suggests that some patients may require higher trough targets to achieve an ideal outcome. Targeting a 1% trough FVIII level every 72 hrs was effective with 56% of subjects achieving a full year with no spontaneous BE. Modeling showed that targeting a 3 - 5% FVIII trough level would have led to more than 75% overall achieving zero spontaneous annual bleed rate (ABR), and that others may have benefitted from trough targets even as high as ≥15%. While this study could not necessarily account for or examine the role of differing levels of physical activity and/or arthropathy on levels of bleeding risk, modeling of FVIII levels post-infusion using individual PK parameters and infusion records along with the contemporaneous overlay of BE should provide valuable insight when designing the optimal, personalized prophylaxis regimen for patients. Valentino LA, Mamonov V, Hellmann A, et al. J Thromb Haemost 2012 Mar; 10(3): 359-67. Disclosures Spotts: Baxter Healthcare Corporation: Employment, Equity Ownership. Pipe:Baxter: Consultancy, Honoraria. Berntorp:Baxter: Honoraria. Collins:Baxter: Consultancy, Honoraria. Oh:Baxter: Employment. Valentino:Baxter: Consultancy, Employment, Honoraria, Research Funding; Bayer: Consultancy, Honoraria, Research Funding; Biogen: Consultancy, Honoraria, Research Funding; CSL Behring: Consultancy, Honoraria, Research Funding; GTC Biotherapeutics: Consultancy, Honoraria, Research Funding; rEVO Biologics: Consultancy, Honoraria; Inspiration Bioscience: Consultancy, Honoraria, Research Funding; NovoNordisk: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding.

Download Full-text

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

Blood ◽

10.1182/blood-2020-143055 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 3-4

Author(s):

Jonathan C. Roberts ◽

Roshni Kulkarni ◽

Peter A. Kouides ◽

Robert F. Sidonio ◽

Shannon L Carpenter ◽

...

Keyword(s):

Board Of Directors ◽

Healthcare Utilization ◽

Research Funding ◽

Von Willebrand Disease ◽

Advisory Committees ◽

Related Quality ◽

Joint Health ◽

Health Related ◽

The Impact

Background: von Willebrand disease (VWD) is the most common inherited bleeding disorder. Questions remain regarding the impact of VWD related bleeding phenotype on healthcare utilization, joint health, and health-related quality of life (HRQoL) in the US. Objective: Our study investigated the impact of VWD bleeding phenotype on healthcare utilization, joint health, and HRQoL in a geographically diverse cohort of individuals with VWD who obtain care at seven US Hemophilia Treatment Centers (HTCs). Methods: Hematology Utilization Group Studies (HUGS) prospectively examined the cost and burden of illness in persons with VWD. The current study enrolled individuals age ≥12 with VWD Type 1 (VWF:Ag/RCo: ≤30%), low VWF (VWF:Ag/RCo: 30-50%), Type 2, and 3. Participants completed a standardized interview to collect sociodemographic and clinical data, self-reported healthcare utilization and bleeding in last 6 months, self-reported pain, joint health and HRQoL measured by EQ-5D-3L. Clinical chart reviews abstracted information about VWD type and treatment. Association of bleeding and VWD type with healthcare utilization, joint health, and HRQoL were assessed using Chi-square or Fisher exact tests for categorical variables and Student T-tests or one-way ANOVA for continuous variables. P value ≥0.05 indicates not statistically significant (NS). Results: We analyzed 100 participants with complete baseline information. Mean age was 31.7 (SD=18.6) years, 67.0% were adults ≥18 years, 80.0% were female, 67.7% had Type 1/low VWF, and 3.0% had Type 3 VWD. Mean age at VWD diagnosis was 13.6 (SD=13.0) years. Persons with low VWF were diagnosed and received VWD treatment at an older age (mean 19.2, SD=11.8; 19.4, SD=11.9 years for diagnosis and treatment respectively) than those with Type 1 (13.7, SD=12.7; 15.6, SD=13.7), or Types 2&3 (9.4, SD=12.9; 13.3, SD=16.6), p=0.03 and p=NS. As compared to individuals without bleeding in the previous 6 months, those reported bleeding had significantly higher rate of medical procedures related to treating bleeding events (42.5% vs. 13.3%, p=0.001), and overnight hospitalization (20.0% vs. 3.3%, p<0.01). The individuals with recent bleeding also reported higher proportion of emergency room visits (25.0% vs. 11.9%, p=NS), physician visits (55.0% vs. 38.3%, p=NS), joint pain (48.7% vs. 40.0%, p=NS), and joint range of motion limitation (35.9% vs. 20.0%, p=NS) than those without bleeding, although the differences were not statistically significant. Those with recent bleeding reported more problems in EQ-5D mobility (33.3% vs. 15.0%, p=0.03) and usual activities (41.0% vs. 26.7%, p=NS) than those without recent bleeding. EQ VAS (71.6 vs. 75.2, p=NS) and EQ index scores (0.79 vs. 0.83, p=NS) were not significantly different between persons with and without recent bleeding. Those with Types 2&3 VWD were more likely to have hospitalization (25.0% vs. 5.0%, 2.1%, p<0.01), bleeding (50.0% vs. 35.0%, 36.2%, p=NS), joint pain (53.1% vs. 30.0%, 41.3%, p=NS), joint range of motion limitation (40.6% vs. 20.0%, 19.6%, p=NS) than those with low VWF or Type 1 VWD. Individuals with low VWF (50.0%) reported higher rate of anxiety or depression per EQ-5D than Type 1 (34.8%) or Type 2&3 (40.6%), p=NS. Covariate-adjusted EQ-5D VAS or index score were lower among persons with low VWF (64.7±8.2 for VAS, 0.76±0.07 for EQ-index) than those with Type 1 (77.3±7.6, 0.84±0.06) or Types 2&3 (78.7±7.4, 0.84±0.66), p values=NS. Conclusions: Our study demonstrates that persons with VWD who obtain care at US HTCs experience significant illness burden regardless of severity. Self-reported recent bleeding as expected was associated with increased healthcare utilization and negative impact on joint health and HRQoL. Bleeding phenotype was significantly associated with healthcare utilization differences. Delayed diagnosis and treatment for persons with low VWF may impact their HRQoL, and if confirmed in a larger sample size would underscore the fact that low VWF is not necessarily a mild disorder compared to other VWD subtypes. Disclosures Roberts: Octapharma: Consultancy, Speakers Bureau; Sanofi: Consultancy, Speakers Bureau; Novo Nordisk: Consultancy, Speakers Bureau; Pfizer: Consultancy; Takeda: Consultancy, Research Funding, Speakers Bureau; uniQure: Consultancy. Kulkarni:Bioverativ/Sanofi, BPL, Genentech, Kedrion, Novo Nordisk, Octapharma, Pfizer, Takeda, Catalyst Bioscience Bayer: Membership on an entity's Board of Directors or advisory committees; Sanofi/ Bioverativ, Bayer, Biomarin, Shire/Takeda, Novo Nordisk, Freeline: Other: clinical trial research grants . Sidonio:Octapharma, Grifols, Takeda and Genentech: Research Funding; Bayer, Bioverativ/Sanofi, Novo Nordisk, Takeda, Uniqure, Biomarin, Octapharma, Catalyst, Grifols, Sigilon, Tremeau, Genentech/Roche: Consultancy. Carpenter:Kedrion: Honoraria; Novo Nordisk: Honoraria; Genentech, Inc.: Honoraria; American Thrombosis and Hemostasis Network: Membership on an entity's Board of Directors or advisory committees; CSL Behring: Research Funding; Shire: Research Funding; Hemostasis & Thrombosis Research Society: Membership on an entity's Board of Directors or advisory committees; American Academy of Pediatrics: Other: PREP Heme/Onc editorial board. Konkle:Sigilon: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; BioMarin: Consultancy; Sanofi: Consultancy, Research Funding; Takeda: Research Funding; Uniquire: Research Funding; CSL Behring: Consultancy; Roche: Consultancy; Baxalta: Research Funding; Spark: Consultancy, Research Funding. Wu:Baxalta US Inc., Bannockburn, IL (a Takeda Company), CSL Behring L.L.C., and Octapharma USA, Inc.: Research Funding. Curtis:USC Hemophilia Utilization Group Study (HUGS): Consultancy; Bayer: Consultancy; Novo Nordisk: Consultancy; Patient Reported Outcomes, Burdens and Experiences: Consultancy. Carrasco:Baxalta US Inc., Bannockburn, IL (a Takeda Company), CSL Behring L.L.C., and Octapharma USA, Inc.: Research Funding. Tran:Novo Nordisk: Consultancy; Bioverativ: Consultancy; Takeda: Consultancy; Bayer: Consultancy. Nichol:Global Blood Therapeutics: Research Funding; Octapharma: Research Funding; CSL Behring: Research Funding; Pfizer: Research Funding; Baxalta US Inc., Bannockburn, IL (a Takeda Company): Research Funding; Genentech Inc.: Research Funding.

Download Full-text

Association of Hemophilia a Inhibitor Status and Patient-Reported Outcomes with Work Productivity and Health-Related Quality of Life

Blood ◽

10.1182/blood-2021-153410 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 4069-4069

Author(s):

Megan M. Ullman ◽

Marilyn J Manco-Johnson ◽

Jonathan C. Roberts ◽

Nicole Crook ◽

Rahul Khairnar ◽

...

Keyword(s):

Chronic Pain ◽

Research Funding ◽

Patient Reported Outcomes ◽

Work Productivity ◽

Joint Stiffness ◽

Activity Impairment ◽

Active Inhibitor ◽

Patient Reported ◽

Related Quality ◽

Health Related

Abstract Introduction: Persons with hemophilia suffer from recurrent bleeds, especially hemarthrosis, which results in joint damage. Hemophilia inhibitor status impacts bleeding, which is associated with acute and chronic pain. To better characterize the impact of inhibitor status, we compared patient-reported outcomes (bleed rate, pain, and joint health), work productivity and activity impairment (WPAI), and health-related quality of life (HRQoL) by inhibitor status, and investigated the correlation of patient-reported outcomes with WPAI and HRQoL. Methods: The U.S. Hematology Utilization Group Studies Part VIII prospectively collected data to examine the cost and burden of hemophilia in persons with hemophilia A (PwHA) aged ≥2 years obtaining care at four federally-supported hemophilia treatment centers. From April 2019 to May 2021 we enrolled PwHA with and without inhibitors at a 1:2 ratio. Parents/adult participants completed a survey at enrollment to collect sociodemographic and clinical characteristics, self-reported bleeds in the last month, pain, and joint stiffness (5-item scale). We also measured WPAI and HRQoL using EQ-5D-3L. Clinical chart review documented hemophilic severity, inhibitor level and treatment regimen. Participants were classified into three groups: 1) active inhibitor (inhibitor titer ≥1.0 Bethesda Units (BU) six months prior to enrollment), 2) tolerized inhibitor (history of inhibitor titer ≥1.0 BU, immune tolerance induction (ITI) and/or currently using factor VIII for prophylaxis), and 3) no inhibitor. Patient-reported data were compared across these groups using Chi-square tests for categorical variables and generalized linear models for continuous variables. Association of bleeds, pain, and joint stiffness with HRQoL and WPAI were assessed using Pearson correlation. Results: Among 80 PwHA enrolled, 9 (11%) had active inhibitors, 22 (27.5%) had tolerized inhibitors, and 49 (61.3%) had no inhibitors. Mean age was 24.9±14.3 (standard deviation) years, 66.3% were adults, 87.5% had severe hemophilia, and 87.5% used prophylaxis. Mean age of the non-inhibitor group (29.3±13.5) was older than the tolerized inhibitor group (16.3±9.5 years, p<0.05) or the active inhibitor group (21.9±19.1, p>0.05). The non-inhibitor group had a lower rate of severe hemophilia (81.6%) or prophylactic treatment (81.6%) than those in the active (100%) or tolerized groups (95.5%, p=0.13). Larger proportions of participants with active inhibitors (66.7%) and no inhibitors (57.1%) reported having bleeds in the last month compared to those with tolerized inhibitors (22.7%, p=0.01). Participants without inhibitors had a greater mean number of bleeding episodes (1.09±standard error (SE) 0.26 vs. 0.23±0.38, p=0.03), specifically joint bleeds (0.58±0.16 vs. 0.08±0.24, p=0.03,) than the tolerized group. Those with active inhibitors reported significantly higher mean joint stiffness scores (35.1±2.6 vs. 27.5±1.9, p=0.006) or more joint pain (77.8% vs. 54.5%, p=0.23) than the tolerized group. Mean EQ-5D index score was significantly lower in the active inhibitor group (0.79±SE (0.07) than in the tolerized group (0.96±0.05, p=0.03). Joint bleeding, chronic pain, and joint stiffness were negatively correlated with the EQ-5D visual analogue scale, and index scores (all correlation coefficients |r|>0.43, all p<0.001). Number of bleeds and the joint stiffness score in children were positively correlated with their parents' level of impairment while working (r=0.41, p=0.04; r=0.62, p=0.001) and overall work impairment (r=0.41, p=0.046; r=0.60, p=0.002). Joint bleeding, chronic pain, and joint stiffness in adults were positively correlated with proportion of work time missed (r=0.31, p=0.03; r=0.39, p=0.006; r=0.48, p=0.0004), overall work impairment (r=0.37, p=0.007; r=0.41, p=0.003; r=0.42, p=0.002), and activity impairment (r=0.33, p=0.02; r=0.63, p<0.0001; r=0.59, p<0.0001), respectively. Conclusions: This study is limited to a small sample skewed toward a younger age in the tolerized inhibitor group. PwHA in the active and no inhibitor groups experienced greater clinical burden as measured by bleeds compared to the tolerized group. Those with active inhibitor displayed lower HRQoL scores than the tolerized inhibitor group. Bleeds, chronic pain and joint stiffness were inversely correlated with HRQoL, resulting in lower work productivity and activity. Figure 1 Figure 1. Disclosures Roberts: Takeda; Speakers Bureau: Novo Nordisk, Octapharma, Sanofi, Takeda.: Research Funding; Genentech, Novo Nordisk, Octapharma, Pfizer, Sanofi, Takeda, uniQure: Consultancy. Khairnar: University of Maryland, Baltimore: Ended employment in the past 24 months; Roche: Current equity holder in publicly-traded company; Genentech Inc - A Member of The Roche Group: Current Employment. Decker-Palmer: Genentech Inc. --A member of the Roche Group.: Current Employment, Current equity holder in publicly-traded company. Curtis: Pfizer, Bayer, and Novo Nordisk: Consultancy; University of Southern California: Consultancy. Wu: Baxalta US Inc., Bannockburn, IL (a Takeda Company), CSL Behring L.L.C., Octapharma USA, Inc., Genentech Inc.: Research Funding. Nichol: Pfizer, Genentech Inc., Baxalta US Inc., Bannockburn, IL (a Takeda Company), Octapharma, CSL Behring, Global Blood Therapeutics, and Novo Nordisk: Research Funding.

Download Full-text