Rates of inhibitor development and immune tolerance in children with severe Hemophilia A on emicizumab prophylaxis

Abstract Introduction: Congenital hemophilia A (HA) is a genetically inherited bleeding disorder caused by pathologic variants in the F8 gene, resulting in absent or decreased levels of coagulation factor VIII (FVIII) protein and impairment of physiologic hemostasis. The absence of FVIII results in both trauma-induced and spontaneous bleeding in people with HA (PwHA), which can be life-threatening. Treatment or prevention of bleeding with exogenous FVIII protein infusions can lead to the development of neutralizing anti-FVIII antibodies (“inhibitors”), which render FVIII treatment ineffective. The use of emicizumab, a bispecific antibody which mimics the activity of FVIII, circumvents the need for FVIII prophylactic infusions. In real-world and clinical trial data, bleeding rates and FVIII infusion utilization have decreased in PwHA on emicizumab prophylaxis. Furthermore, historically PwHA with inhibitors were treated with immune tolerance induction (ITI) to eradicate FVIII inhibitors, however, the necessity of ITI in the era of emicizumab is an open question. The rates of inhibitor development and uptake of ITI in this current era of treatment are unknown. Objectives: This study aims to compare PwHA whose initial prophylactic regimen was FVIII compared to those receiving emicizumab as initial prophylaxis. The primary objective was to compare FVIII exposure days (EDs) and inhibitor development between PwHA on FVIII or emicizumab prophylaxis. The secondary objective is to understand the use of ITI treatment in PwHA on either treatment. Methods: A retrospective chart review was performed at the Children's Healthcare of Atlanta (CHOA) Hemophilia Treatment Center under an IRB-approved protocol. PwHA born between 2014 and 2023 with severe disease were included. Demographic data and clinical data (hemophilia mutation as well as inhibitor, ITI, and FVIII ED history) were extracted from the clinical chart. Rates of inhibitor development and ITI usage were compared before and after licensure of emicizumab for all PwHA (2018). Results:A total of 53 males with severe Hemophilia A born between 2014 and 2023 were included in the study. Initial prophylaxis was FVIII in 30 (56.6%) and emicizumab in 23 (43.4%). The study population was 43.6% Black, 41.8% Caucasian, 3.6% Asian, 3.6% multiracial, 7.3% of unknown race, and 25.5% identified as Hispanic. There were no differences in race by initial prophylactic regimen or FVIII inhibitor status. A total of 22 participants developed inhibitors, 15 (68.8%) from the FVIII prophylaxis group and 7 (31.8%) from the emicizumab group. At data cutoff, the incidence of inhibitors was 50% in FVIII group compared to 30.4% in the emicizumab group (odds ratio 2.14, 95% CI 0.69-6.16) at median of 17 (range 3-90) versus 10 (range 4-15) FVIII EDs, respectively (p=0.032, t-test). The median cumulative FVIII EDs in the FVIII group was >150 (range 5 to > 150) and in the emicizumab group was 6 (range 2-112). Of note, 15/23 PwHA with emicizumab prescribed as their initial prophylactic regimen had FVIII exposures prior to emicizumab initiation with a median of 4 FVIII EDs (range 1-13). Consequently, the median age at ED1 was similar between the FVIII and emicizumab groups (9.5 vs 8.6 mo) but median age at ED5 was delayed in the emicizumab group (13.5 vs 17.8 mo, p = 0.011, Mantel-Cox time to event analysis). As expected, emicizumab delayed FVIII EDs as demonstrated by only 1/22 participants in the emicizumab group having surpassed ED20 compared to all 26/30 in the FVIII group (p<0.001, Fisher's exact test) at the last data cutoff. The inhibitor rates in PwHA born before or after 2018 (emicizumab licensure year) were similar at 40.7% and 39.3%, respectively. The rate of ITI usage in PwHA with inhibitors has decreased from 76.9% before emicizumab licensure to 22.2% after. Conclusion:Our data suggest that FVIII inhibitor rates may be lower in PwHA initially started on emicizumab prophylaxis, though these PwHA may not have yet reached sufficient FVIII EDs. In addition, the elevated number of Black study participants adds critical data given racial disparities in research on inhibitor development. Ongoing analyses will include a comparison of the timing of FVIII EDs and inhibitor development in PwHA on emicizumab prophylaxis to determine if inhibitor rates upon reaching 50 FVIII EDs are different than for those on FVIII. Lastly, initiation of ITI appears to be decreased or delayed since the licensure of emicizumab.