Factor IX inhibitors in haemophilia B: A report of National Haemophilia Registry in China

Authors: Dou, X; Zhang, W; Poon, M-C; Zhang, X; Wu, R; Feng, X; Yang, L; Cheng, P; Chen, S; Wang, Y; Zhou, H; Huang, M; Song, Y; Jin, C; Zhang, D; Chen, L; Liu, W; Zhang, L; Xue, F; Yang, R ;

Affiliations: State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin Key Laboratory of Gene Therapy for Blood Diseases, CAMS Key Laboratory of Gene Therapy for Blood Diseases, Tianjin, China. National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China. Departments of Medicine, Pediatrics and Oncology, Cumming School of Medicine, University of Calgary, and the Southern Alberta Rare Blood and Bleeding Disorders Comprehensive Care Program, Foothills Hospital, Alberta Health Services, Calgary, Alberta, Canada. Shandong Hemophilia Treatment Center, Shandong Blood Center, Jinan, China. Beijing Children’s Hospital, Capital Medical University, Beijing, China.

Publication: Haemophilia  October 2022

Abstract: INTRODUCTION The development of inhibitors against factor FIX (FIX) is the most serious complication of FIX replacement therapy in haemophilia B (HB) patients. Currently, only few cohorts of HB inhibitor patients have been reported worldwide. AIM This Chinese nationwide study of HB inhibitor patients explored their risk factors for FIX inhibitor development and experience on their management. METHODS We retrospectively analysed patient characteristics, F9 genotypes, treatment strategies and outcomes of HB inhibitor patients registered to the Chinese National Registry and Patient Organization Registry. RESULTS Forty-four unique HB inhibitor patients were identified in 4485 unique HB patients registered by year 2021 to the two Registries. Inhibitor diagnosis were usually delayed and the low prevalence (.98%) may suggest some inhibitor patients were not identified. Their median age at inhibitor diagnosis was 7.5 (IQR, 3.0-14.8) years. Most patients (95.5%) had high-titre inhibitors. Allergic/Anaphylactic reactions occurred in 59.1% patients. Large deletions and nonsense mutations were the most common F9 mutation types in our FIX inhibitor patients. Patients with large F9 gene deletions were more likely to develop inhibitors (p = .0002), while those with missense mutations had a low risk (p < .0001). Thirteen (29.5%) patients received immune tolerance induction (ITI) therapy using low-dose prothrombin complex concentrate regimens. Twelve completed ITI with three (25.0%) achieving success. Nephrotic syndrome developed in two (16.7%) patients during ITI. CONCLUSION This study reports the largest Chinese cohort of HB inhibitor patients. Large deletions were most significantly associated with inhibitor development. Low-dose ITI might be feasible for FIX inhibitor eradication.