Daniel P. Hart

Introduction: The UK National Haemophilia Database (NHD) collects data from all UK persons with haemophilia A with inhibitors (PwHA‐I). It is well‐placed to investigate patient selection, clinical outcomes, drug safety and other issues not addressed in clinical trials of emicizumab.Aims: To determine safety, bleeding outcomes and early effects on joint health of emicizumab prophylaxis in a large, unselected cohort using national registry and patient reported Haemtrack (HT) data between 01 January 2018 and 30 September 2021.Methods: Prospectively collected bleeding outcomes were analysed in people with ≥6 months emicizumab HT data and compared with previous treatment if available. Change in paired Haemophilia Joint Health Scores (HJHS) were analysed in a subgroup. Adverse events (AEs) reports were collected and adjudicated centrally.Results: This analysis includes 117 PwHA‐I. Mean annualised bleeding rate (ABR) was .32 (95% CI, .18; .39) over a median 42 months treatment with emicizumab. Within‐person comparison (n = 74) demonstrated an 89% reduction in ABR after switching to emicizumab and an increase in zero treated bleed rate from 45 to 88% (p < .01). In a subgroup of 37 people, total HJHS improved in 36%, remained stable in 46% and deteriorated in 18%, with a median (IQR) within‐person change of −2.0 (−9, 1.5) (p = .04). Three arterial thrombotic events were reported, two possibly drug related. Other AEs were generally non‐severe and usually limited to early treatment, included cutaneous reactions (3.6%), headaches (1.4%), nausea (2.8%) and arthralgia (1.4%).Conclusions: Emicizumab prophylaxis is associated with sustained low bleeding rates and was generally well‐tolerated in people with haemophilia A and inhibitors.

Recent advances in therapeutics are now providing a wide range of options for adults and children living with hemophilia. Although therapeutic choices are also increasing for the youngest individuals with severe disease, challenges remain about early management decisions, as supporting data are currently limited. Parents and healthcare professionals are tasked with helping children achieve an inclusive quality of life and maintain good joint health into adulthood. Primary prophylaxis is the gold standard to optimize outcomes and is recommended to start before 2 years of age. A range of topics need to be discussed with parents to aid their understanding of the decisions they can make and how these will affect the management of their child/children. For those with a family history of hemophilia, prenatal considerations include the possibility of genetic counseling, prenatal investigations, and planning for delivery, together with monitoring of the mother and neonate, as well as diagnosis of the newborn and treatment of any birth-associated bleeding. Subsequent considerations, which are also applicable to families where infant bleeding has resulted in a new diagnosis of sporadic hemophilia, involve explaining bleed recognition and treatment options, practical aspects of initiating/continuing prophylaxis, dealing with bleeds, and ongoing aspects of treatment, including possible inhibitor development. Over time, optimizing treatment efficacy, in which individualizing therapy around activities can play a role, and long-term considerations, including retaining joint health and tolerance maintenance, become increasingly important. The evolving treatment landscape is creating a need for continually updated guidance. Multidisciplinary teams and peers from patient organizations can help provide relevant information. Easily accessible, multidisciplinary comprehensive care remains a foundation to care. Equipping parents early with the knowledge to facilitate truly informed decision-making will help achieve the best possible longer-term health equity and quality of life for the child and family living with hemophilia. Plain language summary: Points to be taken into account to help families make decisions to best care for children born with hemophilia Medical advances are providing a range of treatment options for adults and children with hemophilia. There is, however, relatively limited information about managing newborns with the condition. Doctors and nurses can help parents to understand the choices for infants born with hemophilia. We describe the various points doctors and nurses should ideally discuss with families to enable informed decision-making. We focus on infants who require early treatment to prevent spontaneous or traumatic bleeding (prophylaxis), which is recommended to start before 2 years of age. Families with a history of hemophilia may benefit from discussions before pregnancy, including how an affected child would be treated to protect against bleeds. When mothers are pregnant, doctors can explain investigations that can provide information about their unborn child, plan for the birth, and monitor mother and baby to minimize bleed risks at delivery. Testing will confirm whether the baby is affected by hemophilia. Not all infants with hemophilia will be born to families with a history of the condition. Identification of hemophilia for the first time in a family (which is ‘sporadic hemophilia’) occurs in previously undiagnosed infants who have bleeds requiring medical advice and possibly hospital treatment. Before any mothers and babies with hemophilia are discharged from hospital, doctors and nurses will explain to parents how to recognize bleeding and available treatment options can be discussed. Over time, ongoing discussions will help parents to make informed treatment decisions: • When and how to start, then continue, prophylaxis. • How to deal with bleeds (reinforcing previous discussions about bleed recognition and treatment) and other ongoing aspects of treatment. ○ For instance, children may develop neutralizing antibodies (inhibitors) to treatment they are receiving, requiring a change to the planned approach. • Ensuring treatment remains effective as their child grows, considering the varied needs and activities of their child.

Haemophilia B is a rare X-linked genetic deficiency of coagulation factor IX (FIX) that, if untreated, can cause recurrent and disabling bleeding, potentially leading to severe arthropathy and/or life-threatening haemorrhage. Recent decades have brought significant improvements in haemophilia B management, including the advent of recombinant FIX and extended half-life FIX. This therapeutic landscape continues to evolve with several non-factor replacement therapies and gene therapies under investigation. Given the rarity of haemophilia B, the evidence base and clinical experience on which to establish clinical guidelines are relatively sparse and are further challenged by features that are distinct from haemophilia A, precluding extrapolation of existing haemophilia A guidelines. Due to the paucity of formal haemophilia B-specific clinical guidance, an international Author Group was convened to develop a clinical practice framework. The group comprised 15 haematology specialists from Europe, Australia, Japan, Latin America and North America, covering adult and paediatric haematology, laboratory medicine and biomedical science. A hybrid approach combining a systematic review of haemophilia B literature with discussion of clinical experience utilized a modified Delphi format to develop a comprehensive set of clinical recommendations. This approach resulted in 29 recommendations for the clinical management of haemophilia B across five topics, including product treatment choice, therapeutic agent laboratory monitoring, pharmacokinetics considerations, inhibitor management and preparing for gene therapy. It is anticipated that this clinical practice framework will complement existing guidelines in the management of people with haemophilia B in routine clinical practice and could be adapted and applied across different regions and countries.

Background: Increasing survival among people with haemophilia means that more individuals are at risk of developing age-related morbidity. Little is known about morbidity and health-related quality of life (HRQoL) in different age groups within a single large population of people with haemophilia. Aim: This study aimed to explore the association between increasing age and comorbidity among people with haemophilia and to compare their HRQoL with that of a sample of the general population in England. Methods: The prevalence of comorbidity recorded in medical records and HRQoL assessed by EQ-5D were compared by age group in participants in the Cost of Haemophilia in Europe: A Socioeconomic Survey study (CHESS) in Europe. HRQoL was compared with that of a sample of the general population taken from the 2012 Health Survey for England (HSE). Results: Younger adults in CHESS were more likely to have received prophylaxis from an early age. The mean number of affected joints in younger adults was 1.0; participants aged 41–50 (1.25) and 51–60 years (1.41) had the highest mean number of affected joints. The prevalence of comorbidity was 36% in patients aged 18–30, 61% in 31–60-year-olds and 68% in those aged 61+. HRQoL impairment in young adults with haemophilia was comparable with that in the HSE population aged over 60. Conclusions: Older people with haemophilia have impaired quality of life compared with younger adults and an increasing prevalence of several age-related disorders affecting mental health and cardiovascular and bone health. Young adults with haemophilia report impaired HRQoL comparable with that in a general population aged 61+.

Introduction: Adeno‐associated virus (AAV)‐based gene therapy for haemophilia presents a challenge to the existing structure of haemophilia centres and requires a rethink of current collaboration and information exchange with the aim of ensuring a system that is fit‐for‐purpose for advanced therapies to maximise benefits and minimise risks. In Europe, a certification process based on the number of patients and facilities is offered to the haemophilia centres by European Haemophilia Network (EUHANET).Aim and methods: This joint European Association for Haemophilia and Allied Disorders (EAHAD) and European Haemophilia Consortium (EHC) publication describes criteria for centres participating in gene therapy care that require a reassessment of the infrastructure of comprehensive care and provides an outlook on how these criteria can be implemented in the future work of haemophilia centres.Results: The core definition of a haemophilia treatment centre remains, but additional roles could be implemented. A modifiable ‘hub‐and‐spoke’ model addresses all aspects associated with gene therapy, including preparation and administration of the gene therapy product, determination of coagulation and immunological parameters, joint score and function, and liver health. This will also include the strategy on how to follow‐up patients for a long‐term safety and efficacy surveillance.Conclusion: We propose a modifiable, networked ‘hub and spoke’ model with a long term safety and efficacy surveillance system. This approach will be progressively developed with the goal of making haemophilia centres better qualified to deliver gene therapy and to make gene therapy accessible to all persons with haemophilia, irrespective of their country or centre of origin.

Introduction: In good risk patients (historic inhibitor peak < 200BU), the International Immune Tolerance Study demonstrated equal efficacy to induce tolerance between high (200iu/kg/day) and low dose (50iu/kg ×3 times/week) immune tolerance induction (ITI) regimens. However, the trial stopped early on account of the excessive bleed rate in the low dose ITI arm.Methods: United Kingdom Haemophilia Centre Doctors’ Organization (UKHCDO) Paediatric and Inhibitor working parties considered available ITI data alongside the bi‐phenotypic antibody emicizumab (Hemlibra®) efficacy and safety data to develop a consensus guideline for the future UK ITI guideline.Results: This revision of UKHCDO ITI guidance incorporates the recommendation to use emicizumab as a prophylaxis haemostatic agent to reduce bleeding rates and to facilitate low dose and reduced frequency of FVIII CFC for ITI in the majority of children.Conclusion: This consensus protocol will facilitate future evaluation of ITI outcomes in the evolving landscape of haemophilia therapeutics and ITI strategies.

Background: For communities of people living with hemophilia and other genetic conditions, gene therapy could represent a paradigm shift in treatment strategies. As investigational therapeutic modalities such as gene therapy become more widely used and discussed, there is a critical need for all stakeholders to communicate using a lexicon that is intelligible, accurate, consistent, and representative of novel treatments. In doing so, expectations can be more carefully managed and potential risks, benefits, and limitations better understood. In recognition of this need, a first-ever study of gene therapy lexicon was conducted using established methods of market research and linguistic analysis.Methods: Ninety-four participants representing hematologists, nurses, caregivers, and people with hemophilia A, in six countries (US, UK, Spain, Germany, France, Italy) took part in a series of in-depth interviews, face-to-face focus groups, an advisory board meeting, and online group interviews to develop, refine, and test verbal, written, and pictorial language concepts through a three-phase iterative process. Sessions were conducted in local languages using detailed discussion guides. Feedback from participants was captured using real-time instant-response dial testing to measure moment-by-moment emotional responses to language stimuli. Semiquantitative analysis of the responses informed selection of preferred language concepts for final testing, and qualitative discussion explored preference rationale. Participants also completed polling and forced rank and choice written exercises.Results: Study feedback showed that the hemophilia community has preferences around consistent lexicon to describe hemophilia and its management. Expert linguistic analysis of feedback from the three phases enabled agreement of a consensus lexicon of vocabulary and an optimized summary narrative for talking about gene therapy amongst people affected by hemophilia A. Preferences were largely consistent across audiences and countries, although some country-specific recommendations were made. A representative summary phrase was agreed: “Gene therapy is being studied in clinical trials with the aim to allow the body to produce factor VIII protein on its own”.Conclusions: The use of preferred language across different stakeholders increases understanding and comfort during discussions of novel and complex therapeutic modalities such as gene therapy. Consistent use of community-informed lexicon minimizes miscommunication and facilitates informed decision-making regarding potential future treatment opportunities.