OC 41.2 - F8 mutations involving deletion of the F8B gene increase inhibitor risk for hemophilia A

Monday, June 24, 2024

15:00 – 15:15 ICT

Room: Ballroom B1

Presenting Author(s)

Jie Sun, MD

Hemophilia Comprehensive Care Center, Beijing Children’s Hospital, Capital Medical University
Hemophilia Comprehensive Care Center,Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health
Beijing, Beijing, China (People's Republic)

Co-Author(s)

Zekun Li, PhD

Ph.D.
Department II of Hematology Center, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, Beijing, 100045, China
Beijing, Beijing, China (People's Republic)
Jialu Zhang

Resident physician
Department II of Hematology Center, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, Beijing, 100045, China
Beijing, Beijing, China (People's Republic)
Zhenping Chen

Associate professor
Hematologic Diseases Laboratory, Hematology Center, Beijing Pediatric Research Institute, Beijing Children's Hospital, Capital Medical University, National Center for Children’s Health, Beijing, 100045, ChinaChildren’s Health, Beijing, 100045, China
Beijing, Beijing, China (People's Republic)
Runhui Wu, PhD, MD

Professor
Department of Hematology, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, Beijing, 100045, China
Beijing, Beijing, China (People's Republic)

Background: The deleterious mutations in F8 gene, including large deletions, nonsense and frameshift mutations, severely disrupt FVIII expression, resulting in a rather high risk of inhibitor development in hemophilia A patients. Moreover, the transcription or translation of the F8B gene, which encompasses F8 exons 23-26, may depend on the location of the mutation, leading to differential immune responses to exogenous FVIII in patients.

Aims: To explore the association between F8B gene and inhibitor development, inhibitor titer, immune tolerance induction (ITI) response.

Methods: Patients with identified F8 variants involving deleted FVIII domains, including large deletions, nonsense and frameshift mutations, were included in this retrospective study. According to the deletion region, F8 mutation types were classified into two groups: mutation outside and within F8B gene. The ITI outcomes were assessed at twenty-fourth month of treatment, and ITI success were defined as negative inhibitor titer and FVIII recovery>66% of expected. Clinical characteristics between mutation outside and within F8B gene were compared and analyzed.

Results: A total of 145 eligible patients were included. The patients carrying mutations within F8B presented a significantly higher frequency of inhibitor than those carrying mutations outside F8B [14/15 (93.3%) vs 87/130 (66.9%), p=0.035, Table1]. Only 49 patients received adequate ITI therapy (greater than 24 months), and patients with mutations within F8B developed significantly higher historical peak titers compared to patients with mutations outside F8B [median titer, 80 BU/mL vs 25.8 BU/mL; p=0.036, Table1 and Figure 1A]. In addition, patients carrying mutations within F8B showed a lower ITI success rate [4/9 (44.4%) vs 33/87 (82.5%), P=0.029, Table1] and a longer time to success (p=0.043, Figure 1B).

Conclusion(s): Hemophilia A patients carrying F8 mutations causing deletion involving F8B gene have a higher inhibitor risk, titer, and worse prognosis, which may be due to the absence of a tolerizing second transcript FVIIIB.