Inhibitors in haemophilia A and B: Management of bleeds, inhibitor eradication and strategies for difficult‐to‐treat patients

Abstract

The standard therapy for patients with haemophilia is prophylactic treatment with replacement factor VIII (FVIII) or factor IX (FIX). Patients who develop inhibitors against FVIII/FIX face an increased risk of bleeding, and the likelihood of early development of progressive arthropathy, alongside higher treatment‐related costs. Bypassing agents can be used to prevent and control bleeding, as well as the recently licensed prophylaxis, emicizumab, but their efficacy is less predictable than that of factor replacement therapy. Antibody eradication, by way of immune tolerance induction (ITI), is still the preferred management strategy for treating patients with inhibitors. This approach is successful in most patients, but some are difficult to tolerise and/or are unresponsive to ITI, and they represent the most complicated patients to treat. However, there are limited clinical data and guidelines available to help guide physicians in formulating the next treatment steps in these patients. This review summarises currently available treatment options for patients with inhibitors, focussing on ITI regimens and those ITI strategies that may be used in difficult‐to‐treat patients. Some alternative, non‐ITI approaches for inhibitor management, are also proposed.

Burden on parents of children with haemophilia: The impact of sociodemographic and child's medical condition

“…The strong association between inhibitor development and increased perceived burden for parents of children with haemophilia is not unexpected, and this result is consistent with previous research DeKoven, Karkare, Lee, et al, 2014;DeKoven et al, 2013;Lindvall et al, 2014;Ljung et al, 2019).…”

“…The strong association between inhibitor development and increased perceived burden for parents of children with haemophilia is not unexpected, and this result is consistent with previous research (DeKoven, Karkare, Kelley, et al, ; DeKoven, Karkare, Lee, et al, ; DeKoven et al, ; Lindvall et al, ; Ljung et al, ). Given this, the HCP must recognise and provide sufficient support to parents of children with inhibitors.…”

“…To eradicate inhibitors, the child is given immune tolerance induction treatment. Immune tolerance induction is a demanding treatment which involves daily, or in some cases twice daily, injections of clotting factor in high doses (Ljung et al, 2019). One consequence of the child's illness is personal suffering for the parent.…”

The societal burden of haemophilia A. I – A snapshot of haemophilia A in Australia and beyond

“…Studies undertaken internationally of the lifetime risk (ie the cumulative incidence) show that inhibitors will develop in 25%‐30% of people with severe HA compared with 5%‐12% of those with mild or moderate HA (Table 2). 7‐11 Patients who develop inhibitors typically do so soon after exposure to exogenous FVIII (eg within the first 20 exposure days to FVIII) and often early in the first 2‐3 years of life 6,8,12‐14 . However, recent evidence from the UK suggests that there is a second peak of patients with inhibitors observed in people with severe haemophilia aged over 60 years 15 …”

Bridging the Missing Link with Emicizumab: A Bispecific Antibody for Treatment of Hemophilia A

“…92 However, due to the inferiority of BPAs to FVIII [38][39][40] with regard to treatment of bleeding episodes and possibly serious adverse events when using APCC in a patient receiving emicizumab, the use of APCC should be avoided as much as possible, which is only feasible when patients undergo inhibitor eradication with ITI. 91,93 Another argument in favor of ITI rather than treatment with emicizumab involves a possible future treatment method of hemophilia A-gene therapy. This is discussed below.…”