Immune Toleration Induction with Emicizumab in Hemophilia a Patients with Inhibitors: A Systematic Review

Background: Up to 30% of patients with severe hemophilia A, factor VIII (FVIII) activity <1%, will develop inhibitors against FVIII. Immune tolerance induction (ITI) has been used historically to eradicate inhibitors but can pose undue burden on patients and families due to frequent intravenous FVIII infusions requiring central venous access devices (CVAD) and increased CVAD-associated complications. Emicizumab is a bispecific antibody administered subcutaneously that significantly reduces bleeding rates in patients with inhibitors. The Atlanta Protocol was first described in 2018 as the concurrent use of ITI with emicizumab as an alternative and less burdensome approach to ITI. We aimed to describe tolerance outcomes from existing studies that employed concurrent ITI and emicizumab in persons with hemophilia A.

Methods: We collected data from single-center and multi-center international studies that utilized ITI combining FVIII with emicizumab to eradicate inhibitors or maintain tolerance in pediatric and adult patients with hemophilia A. Achievement of a negative inhibitor titer (<0.6 BU/ml), normal FVIII recovery ≥66% of expected, and reported bleeding complications were analyzed. Pooled estimates were calculated as part of the meta-analysis.

Results: We identified 12 studies that met inclusion criteria, most of which were prospective cohort design. These studies were conducted between 2019-2024 with the majority conducted in Europe and rare examples of studies performed exclusively in Asia, South America, and North America. Additionally, we included interim analysis data from the ongoing MOdern Treatment of Inhibitor-positiVe pATiEnts with haemophilia A (MOTIVATE) trial that includes centers across several continents. The age range of patients in these studies was 6 months to 54 years of age. All patients were male and all but one had a diagnosis of severe hemophilia A. One patient had moderate hemophilia A with a baseline FVIII activity of 3% prior to inhibitor onset. A total of 71 pediatric patients (≤18 years of age) and 4 adult patients (>18 years) were included across the 12 studies. The negative inhibitor titer pooled incidence rate estimate was 46 per 100 person-years (95% CI: 34, 58), FVIII recovery pooled incidence rate estimate was 46 per 100 person-years (95% CI: 32, 61), and bleeding event pooled incidence rate estimate was 24 per 100 person-years (95% CI: 15, 37). Overall, there were variable proportions of patients that had negative inhibitor titers and appropriate FVIII recovery. There was a total of 30 bleeds among 15 patients, but the number of reported severe bleeds was minimal. There were no episodes of thrombosis or thrombotic microangiopathy. The studies reported good compliance with emicizumab and ITI among participants.

Conclusion: Systematic review of concurrent emicizumab and ITI in patients with hemophilia A suggests favorable clinical and laboratory outcomes. However, there is still limited data on this alternative approach that warrants further investigation on long-term outcomes, feasibility, and safety.