In a separate document, we have provided specific guidance on performing individual pharmacokinetic (PK) studies using limited samples in persons with hemophilia with the goal to optimize prophylaxis ...with clotting factor concentrates. This paper, intended for clinicians, aims to describe how to interpret and apply PK properties obtained in persons with hemophilia.
The members of the Working Party on population PK (PopPK) of the ISTH SSC Subcommittee on Factor VIII and IX and rare bleeding disorders, together with additional hemophilia and PK experts, completed a survey and ranking exercise whereby key areas of interest in the field were identified. The group had regular web conferences to refine the manuscript’s scope and structure, taking into account comments from the external feedback to the earlier document.
Many clinical decisions in hemophilia are based on some form of explicit or implicit PK assessment. Individual patient PK profiles can be analyzed through traditional or PopPK methods, with the latter providing the advantage of fewer samples needing to be collected on any prophylaxis regimen, and without the need the for a washout period. The most useful presentation of PK results for clinical decision making are a curve of the factor activity level over time, the time to achieve a certain activity level, or related parameters like half‐life or exposure (AUC). Software platforms have been developed to deliver this information to clinicians at the point of care. Key characteristics of studies measuring average PK parameters were reviewed, outlining what makes a credible head‐to‐head comparison among different concentrates. Large data collections of PK and treatment outcomes currently ongoing will advance care in the future.
Traditionally used to compare different concentrates, PK can support tailoring of hemophilia treatment by individual profiling, which is greatly simplified by adopting a PopPK/Bayesian method and limited sampling protocol.
Background
The relative safety and efficacy of recombinant activated coagulation factor VII (rFVIIa, NovoSeven® RT) across pediatric age cohorts is poorly defined. The objective of this analysis was ...to assess the safety and efficacy of rFVIIa in pediatric patients with congenital hemophilia with inhibitors (CHwI) in the clinical studies supporting the U.S. labeling.
Procedure
Pediatric data were derived from seven studies (five acute and two perioperative treatments) and pooled. All data were stratified by age (<2, 2 to <6, 6 to <12, and 12–16 years) and study category (acute treatment of bleeding episodes or surgery).
Results
The pediatric dataset included 172 patients; 144 received rFVIIa for the treatment of bleeding episodes and 28 for the control of bleeding perioperatively. Recombinant FVIIa was effective for 95.4% (1,026/1,076) of the evaluable bleeding episodes and had similar treatment effectiveness across pediatric age groups (range, 94.1–97.2%). The majority received doses of 90 mcg/kg. rFVIIa was effective in achieving perioperative hemostasis across pediatric age groups (range, 91–100%), with greater efficacy observed with the recommended (90 mcg/kg) versus lower dose (35 mcg/kg). A total of 88 pediatric patients experienced a total of 285 adverse drug reactions, similar in type to those reported among adult patients. A total of seven thrombotic events were recorded in seven pediatric patients; only one was confirmed related to rFVIIa upon individual case review.
Conclusions
rFVIIa is safe and effective in the treatment of bleeding episodes and prevention of periprocedure bleeding in CHwI with no apparent differences observed among pediatric age groups.
Introduction
Haemophilia B (HB) is less well studied than haemophilia A (HA); despite similarities between the two inherited bleeding disorders, important differences remain that require further ...research.
Aim
B‐Natural is a multi‐centre, prospective, observational study of HB, designed to increase understanding of clinical manifestations, treatment, quality‐of‐life (QoL), inhibitor development, immune tolerance induction (ITI) outcome, renal function and create a biorepository for future investigations.
Methods
Participants include sibling pairs/groups without a current/history of inhibitors and singletons or siblings with a current/history of inhibitors followed for six months. Demographics, medical, social history and treatment were recorded. A physical examination including joint range of motion (ROM) was performed; QoL was assessed. Samples were collected for F9 gene mutation, HLA typing, non‐inhibitory antibodies and renal function testing.
Results
Twenty‐four centres enrolled 224 individuals from 107 families including 29 with current/history of inhibitors. Of these, 68, 30.4%, had severe (<1% FIX level of normal); 114, 50.9%, moderate (1%‐5%); and 42, 18.8%, mild (>5‐<40%) disease. At enrolment, 53.1% had 50 + exposure days to exogenous FIX. Comparison of joint scores showed significant (P < .05) differences between those with severe (with/without inhibitors), and those with moderate/mild disease. The majority with severe disease, 80.0% with current/history of inhibitors and 64.3% of those without, were treated with prophylaxis.
Conclusion
B‐Natural provides data supporting an increased understanding of HB and its impact throughout life. The need for optimal disease control to normalize physical and psychosocial outcomes is underscored, and further analyses will contribute to an increased understanding of critical issues in HB.
Research is critical to advancing the diagnosis and care of people with inherited bleeding disorders (PWIBD). This research requires significant infrastructure, including people and resources. ...Hemophilia treatment centers (HTC) need many different skilled care professionals including doctors, nurses, and other providers; also statisticians, data managers, and other experts to process patients' clinical information into research. Attracting diverse qualified professionals to the clinical and research work requires long-term planning, recruiting individuals in training programs and retaining them as they become experts. Research infrastructure includes physical servers running database software, networks that link them, and the environment in which these components function. US Centers for Disease Control and Prevention (CDC) and American Thrombosis and Hemostasis Network (ATHN) coordinate and fund data collection at HTCs on the health and well-being of thousands of PWIBD into a registry used in research studies.
National Hemophilia Foundation (NHF) and ATHN asked our group of health care professionals, technology experts, and lived experience experts (LEE) to identify the infrastructure, workforce, and resources needed to do the research most important to PWIBD. We identified the types of CDC/ATHN studies all HTCs should be able to perform, and the physical and human infrastructure this requires. We prioritized finding the best clinical trial designs to study inherited bleeding disorders, identifying ways to share personnel and tools between HTCs, and innovating how research is governed and funded. Involving LEEs in designing, managing, and carrying out research will be key in conducting research to improve the lives of PWIBD.
The National Hemophilia Foundation (NHF) conducted extensive, inclusive community consultations to guide prioritization of research in coming decades in alignment with its mission to find cures and address and prevent complications enabling people and families with blood disorders to thrive.
With the American Thrombosis and Hemostasis Network, NHF recruited multidisciplinary expert working groups (WG) to distill the community-identified priorities into concrete research questions and score their feasibility, impact, and risk. WG6 was charged with identifying the infrastructure, workforce development, and funding and resources to facilitate the prioritized research. Community input on conclusions was gathered at the NHF State of the Science Research Summit.
WG6 detailed a minimal research capacity infrastructure threshold, and opportunities to enable its attainment, for bleeding disorders centers to participate in prospective, multicenter national registries. They identified challenges and opportunities to recruit, retain, and train the diverse multidisciplinary care and research workforce required into the future. Innovative collaborative approaches to trial design, resource networking, and funding to surmount obstacles facing research in rare disorders were elucidated.
The innovations in infrastructure, workforce development, and resources and funding proposed herein may contribute to facilitating a National Research Blueprint for Inherited Bleeding Disorders.
Introduction: Low VWF is an intermediate reduction in VWF between the normal range and type 1 VWD. Assessment of the clinical relevance of low VWF is difficult due to the wide interpatient ...variability in bleeding phenotype, especially in children who often have no prior hemostatic challenges. A standard approach to diagnosing and treating low VWF in pediatric patients is lacking. This study aims to characterize the archetypes of pediatric patients with low VWF and create a diagnostic and therapeutic workflow for subsequent prospective validation.
Methods: A retrospective review of pediatric outpatients with abnormal VW panels evaluated by Boston Children's hematology between 1/1/2015 and 5/31/2019 was conducted following IRB approval. Pediatric patients with low VWF laboratory values without a VWD diagnosis or alternate bleeding disorder were included in the study population. Demographics, blood type, laboratory results, personal and family bleeding history, procedure history, and treatment plan were recorded for each patient. Patients were categorized based on bleeding history and laboratory results and analyzed within each group.
Results: Low VWF study population included 293 patients, Table 1. Since 2015, 234 new patients were seen by hematology for low VWF, with at least 40 new low VWF patients each year. Of the 235 patients reporting a personal history of bleeding, the most common bleeding symptoms were epistaxis (56%), easy bruising (48%), and gingival bleeding (29%). Among the 148 female patients in this group, 65% reported heavy menstrual bleeding. Patients segregated into 4 main groups: (1) concordant decrease in VWF antigen (Ag) and VWF ristocetin cofactor activity (RCoF) (21%), (2) low Ag with RCoF:Ag≤0.7 (low ratio) (5%), (3) normal Ag and isolated low RCoF (29%), (4) normal Ag with a low ratio (44%). Type O blood group predominated in each category.
For patients reporting any bleeding history, the majority (72%) had a normal Ag and an isolated low RCoF. Nearly 60% of this group also had a low ratio, with only 53 (44%) patients in this subgroup evaluated for type 2 VWD and 38 (32%) assessed for a benign variant. A benign variant was identified in 22 patients (58%) by exon 28 sequencing and/or normalization of VWF activity with GP1bM testing, Table 2. Of the 42 patients with a low ratio evaluated for a benign variant, regardless of bleeding history, 26 (62%) were identified. In total, a benign variant was identified in 18% of the 142 patients with a low ratio. 42% of this benign variant population were of non-black/Hispanic race.
Management recommendations were generally similar for each of the 4 groups with any bleeding history, with most patients (~57%) instructed to return for assessment with injury or future procedures. Approximately 25% of patients had an explicit bleed treatment plan in place, and about 18% did not have a defined treatment or follow up plan. Notably, for patients with a bleeding history and a concordant decrease in Ag and RCoF with a low ratio, most patients (83%) were told to return for future procedures or injuries, while 8% had an explicit bleed treatment plan and 8% were evaluated for other bleeding disorders. In contrast, individuals identified to have a benign variant or diagnosed “normal for blood type” were generally not given specific treatment plans and instead discharged from hematology clinic, ~80%; however, some underwent additional hemostatic evaluation.
Conclusion: Although many patients reported a personal or family bleeding history, interpretation of providers' assessment of the significance was difficult. Implementation of an electronic, self-scoring bleeding assessment tool may more explicitly quantify and discriminate between low-risk and potentially clinically relevant bleeding symptoms. Investigation for a benign variant contributing to isolated low RCoF or low ratio, first with exon 28 sequencing and now with the GPIbM functional assay, has resulted in increased reported prevalence. This identification is particularly important as it may facilitate the discharge of asymptomatic patients from routine hematology follow-up and limit unnecessary therapy. Additionally, for symptomatic patients, it may suggest the need for further hemostatic testing.
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Croteau:Bayer: Consultancy, Honoraria; CSL Behring: Consultancy, Honoraria; Shire: Consultancy, Honoraria; Novo Nordisk: Consultancy, Honoraria, Research Funding; Spark Therapeutics: Research Funding; Pfizer: Research Funding; Genentech: Consultancy, Honoraria; Octapharma: Honoraria.
Introduction: As the first in a new class of substitutive, non-factor hemophilia A therapy, acceptance of emicizumab by patients with hemophilia is unclear. Impact of emicizumab on treatment ...adherence, pursuit of athletic activity, psychosocial connection to the hemophilia patient community, and patient satisfaction have not been assessed. Additionally, reasons for choosing to initiate or not initiate emicizumab in patients who have been offered it have not been evaluated. This patient survey study addresses these questions.
Methods: A voluntary, anonymous 22-item survey was electronically distributed to hemophilia patients throughout the United States through hemophilia treatment centers and the National Hemophilia Foundation. Recipients were instructed to take the survey only if they were a patient with hemophilia A who has been offered bleeding prophylaxis (or the parent of such a patient under age 18). Skip logic was employed such that individual respondents answered 15 or fewer items based on their familiarity with and use of emicizumab. Results to items utilizing a 5-point Likert scale were converted to weighted average scores (ranging from 1, lowest to 5, highest) for comparison between groups of respondents.
Results: 126 respondents (67 adults and 59 parents of children age <18) answered the survey, 82% without an inhibitor and 18% who currently have an inhibitor (Table 1). 89% of respondents were familiar with emicizumab, of whom 43% were using and 57% had never used emicizumab. Table 1 describes respondent demographics and baseline bleeding and prophylaxis characteristics by emicizumab use and inhibitor status. Patients using emicizumab had higher reported median annualized bleeding rates (ABR) prior to emicizumab than those not using emicizumab regardless of inhibitor status (5 bleeds/year vs. 2 bleeds/year) and patients using emicizumab reported lower adherence with prior factor prophylaxis than current emicizumab prophylaxis (76.7% vs. 96.8 described adherence as good or excellent). Non-inhibitor patients emphasized subcutaneous administration score 4.33, 21% cited as most important reason (MIR) for initiating emicizumab and ability to dose ≤1 time per week (4.24, 6%) as equally or more important than safety (4.27, 15%) and effectiveness in bleed prevention (4.15, 24%), Table 2. By contrast, the top concern of inhibitor patients was effectiveness in bleed prevention (4.27, 46%) and safety (4.18, 9%), with lifestyle concerns such as subcutaneous administration (3.82, 0%) less important. In consideration of the impact of emicizumab on wellbeing, most patients were highly satisfied with their decision to start emicizumab (Table 3). Emicizumab use did not result in perceived distancing from the hemophilia patient community. Non-inhibitor patients deciding not to initiate emicizumab (Table 4) cited safety concerns (score 4.38, MIR 45%), unknowns of a new treatment (4.22, 33%), and lack of lab monitoring of emicizumab effect (4.10, 15%) as the primary reasons to forego emicizumab; effectiveness (3.35, 0%) was not a major concern. Of the 64 respondents not using emicizumab, 60% had discussed it with their hemophilia doctor; of these patients, 90% chose to wait for more experience with its use and 10% would have started it but could not due to insurance denial. Of the 40% who had not discussed emicizumab with their hemophilia doctor, 67% felt they learned enough about emicizumab from patient groups or marketing and had decided not to begin the agent; 33% felt they did not have enough information to make a decision about using it.
Conclusions: Most U.S. hemophilia A patients requiring prophylaxis are familiar with emicizumab. Regardless of inhibitor status, patients with higher ABR and worse compliance with infusion-based prophylaxis are more likely to use emicizumab. From the non-inhibitor patient perspective, ease of administration with subcutaneous dosing ≤1 time per week was at least as important as effectiveness and safety of the drug in their decision to switch to emicizumab, whereas this was much less important to inhibitor patients. Patients using emicizumab were highly satisfied with their decision to switch to this agent. Patients choosing not to switch to emicizumab are concerned about safety, unknowns with a new treatment, and lack of lab monitoring, although one-third of patients felt they lacked the information to decide whether to use it.
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Al-Samkari:Dova: Consultancy, Research Funding; Agios: Consultancy, Research Funding; Moderna: Consultancy. Croteau:Octapharma: Honoraria; Bayer: Consultancy, Honoraria; Pfizer: Research Funding; Genentech: Consultancy, Honoraria; Spark Therapeutics: Research Funding; CSL Behring: Consultancy, Honoraria; Shire: Consultancy, Honoraria; Novo Nordisk: Consultancy, Honoraria, Research Funding.
Emergence of population pharmacokinetic models for prediction of individual pharmacokinetic (PK) profiles facilitates individualization of prescribed prophylactic therapy for patients with hemophilia ...A and B and may have a favorable impact on clinical outcomes and annual factor utilization. How providers approach the integration and application of these data into routine clinical practice is not clear.
To explore the potential application of and barriers to incorporating PK profiles into current hemophilia prophylaxis decision making.
A facilitated group discussion of hematologists practicing within the federally‐supported United States Hemophilia Treatment Center Network was conducted. Separately, a group of parents of patients with severe hemophilia less than 18 years of age participated in a focus group on individualizing prophylactic factor regimens with the use of PK data.
Physician participants constructed a conceptual model for factors that determined their selection of hemophilia prophylaxis. These factors clustered in five groupings. When charged with creating a prophylaxis regimen for a specific clinical case including PK data, eight of nine providers generated a unique regimen. Parent focus group supported PK data use as they preferred data driven treatment decisions.
Clinician application of PK data for prophylaxis decision making is heterogeneous. Prospective evaluation of the use of PK‐tailored prophylaxis in routine care and its impact on patient outcomes is needed. Parents perceived that, while obtaining blood draws could be challenging, images of factor activity decay informed their decisions about physical activity timing and provided an opportunity for partnership and shared decision making with their provider.
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