International consensus recommendations on the management of people with haemophilia B

Abstract

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.

Preoperative diagnosis and management of inherited bleeding disorders in female adolescents and adults

“…Female hemophilia carriers can be classified as obligate (daughters of affected male, women with > 1 affected son, women with 1 affected son and an affected brother or uncle) or possible (women with 1 affected son and no family history, daughters of an obligate carrier and woman with a maternal family history of hemophilia). A de novo germ cell X chromosome mutation is found in 30%–50% of newborn boys with hemophilia 21 – 26 , 45 – 47 ( Table 1 ).…”

The current challenges faced by people with hemophilia B

“…1,9,10 The decreased frequency of treatment with EHL FIX products has reduced the burden associated with infusion, improved adherence, and has positively impacted the quality of life for PWHB. 9 Currently, factor replacement products are administered intravenously, 1,2 although there is a growing interest in subcutaneous delivery methods. There have been encouraging early results with dalcinonacog alfa, an EHL FIX product with a daily subcutaneous administration route, but its clinical development has been delayed.…”

“…1,2 HA, with a prevalence of 24.6 cases per 100 000, is much more common than HB, which has an estimated prevalence of five cases per 100 000 males globally. 1,2 The management of HA and HB depends on the clinical severity of disease, which has conventionally been categorized by the degree of plasma clotting factor deficiency, ranging from mild (clotting factor level of 5-40 IU/dL, or 5-<40% of normal) to moderate (1-5 IU/dL, or 1-5% of normal) and severe (<1 IU/dL, or <1% of normal). 1 Severe hemophilia is characterized by recurrent spontaneous bleeding into joints, soft tissues, muscles, and internal organs.…”

A new population pharmacokinetic model for recombinant factor IX‐Fc fusion concentrate including young children with haemophilia B

“…When left untreated, these bleeds may be lifethreatening or lead to arthropathy with ultimately long-term disability. 2 FIX replacement therapy-both prophylactically and on demandis mainstay of treatment, leading to a normal life expectancy with good quality of life. 3 Extended half-life (EHL) FIX concentrates have further ameliorated the burden of disease by substantially decreasing the frequency of intravenous FIX concentrate administration to on average once every week.…”

“…Severely and moderately affected haemophilia B patients suffer from spontaneous bleeding or bleeding after minor trauma, especially into joints and muscles. When left untreated, these bleeds may be life‐threatening or lead to arthropathy with ultimately long‐term disability 2 . FIX replacement therapy—both prophylactically and on demand—is mainstay of treatment, leading to a normal life expectancy with good quality of life 3 .…”