Prophylactic bypassing agent use before and during immune tolerance induction in patients with haemophilia A and inhibitors to FVIII

Abstract

The development of high-titre inhibitory antibodies (inhibitors) against factor VIII (FVIII) remains a challenge in the management of patients with haemophilia A (HA). Patients with high-titre inhibitors are more likely to experience uncontrolled bleeding, physical disability from chronic arthropathy and premature death compared with those without this complication. Immune tolerance induction (ITI), utilizing repeated infusions of FVIII, is an effective therapeutic approach to eliminating inhibitory antibodies. This strategy can eradicate FVIII inhibitors, so that FVIII-specific tolerance is induced. However, patients undergoing ITI are still vulnerable to the development of serious and/or repeated bleeding events. The efficacy of bypassing agents in preventing bleeding episodes has been widely proven in patients with HA and inhibitors to FVIII. Evidence suggests that reducing bleeding during ITI can also shorten the time to tolerance. There are concerns with the use of bypassing agents, including the cost of treatment, short half-life, management of non-responders and the risk of thrombosis. Despite these concerns, and the still limited evidence from prospective studies and consensus reports, the use of prophylaxis with bypassing agents during ITI has been gaining support. This review presents a rationale and current data supporting the use of prophylactic bypassing agents as effective and safe therapies to reduce the incidence of joint bleeding due to inhibitors and improve quality of life in patients with HA undergoing ITI.

Assessing the value of bypassing agent therapy used prophylactic versus on-demand, during immune tolerance induction for treatment of inhibitors: a retrospective chart review

“…There is limited literature available that specifically evaluates the use of prophylaxis with BPA prior to or while patients are receiving ITI and to the authors' best knowledge, no comparative trials of bypassing agents used as prophylaxis in patients with Haemophilia A and inhibitors to FVIII are currently available in the literature. Evidence from the study data that is available has demonstrated that concomitant administration of BPA prophylaxis during ITI leads to a decrease in bleeding events [11][12][13]. Published case reports second this by providing evidence of successful use of prophylaxis in patients prior to or during ITI, contradictory to our findings.…”

“…One study reported the bleeding rates of prophylaxis and on-demand cohorts with BPA for six months, and found that with the prophylaxis BPA cohort bleeding rates were significantly reduced compared to the on-demand cohort [ 10 ]. Similarly, according to the literature, patients with Haemophilia A and inhibitors to FVIII who experience acute bleeding events during ITI and are managed with on-demand bypassing therapies will almost inevitably lead to the development and/or worsening of haemophilic arthropathy [ 11 ]. Looking at the baseline results of the patients in this study, the prophylaxis cohort had higher mean bleeding and joint bleeding events prior to the most recent inhibitor (as shown in Table 1 ).…”

“…This is mirrored in the outcomes between the prophylaxis and on-demand cohorts. Additionally, patients have been found to have less predictable responses to bypassing agents compared with factor replacement therapy and some inhibitor patients respond better to some bypass agents compared to others during serious bleed events [ 11 , 23 ]. So, although it can be inferred that this study shows that the treatment pathway of BPA concomitant with ITI results in a higher bleeding and joint bleeding rate on average during treatment for an inhibitor to FVIII replacement therapy, there are multiple contextual factors to take into consideration that may support the opposite claim.…”

“…Published case reports second this by providing evidence of successful use of prophylaxis in patients prior to or during ITI, contradictory to our findings. [11,[14][15][16][17][18][19][20][21][22].…”

A Thrombin-Activatable Factor X Variant Corrects Hemostasis in a Mouse Model for Hemophilia A

“…7,8 Prophylactic use with these compounds indeed reduces the annual bleeding rate in these inhibitor patients. [9][10][11][12] It should be noted that the circulatory halflives of these products are relatively short (4-7 hours for FEIBA and 1.5-2.7 hours for NovoSeven), albeit that extravasation of rFVIIa may prolong its clinical efficiency. 13 More recently, other therapeutic approaches have been developed, including the bispecific antibody Emicizumab (Hemlibra, F. Hoffmann-La Roche, Ltd, Basel, Switzerland) and Fitusiran (Sanofi-Genzyme/Alnylam, Cambridge, Massachusetts, United States), a small interfering RNA (siRNA) approach that reduces antithrombin expression.…”