Inhibitor incidence in an unselected cohort of previously untreated patients with severe haemophilia B: a PedNet study

Abstract

The incidence of FIX inhibitors in severe hemophilia B (SHB) is not well defined. Frequencies of 3-5% have been reported but most studies to date were small, including patients with different severities, and without prospective follow-up for inhibitor incidence. Study objective was to investigate inhibitor incidence in patients with SHB followed up to 500 exposure days (ED), the frequency of allergic reactions, and the relationship with genotypes. Consecutive previously untreated patients (PUPs) with SHB enrolled into the PedNet cohort were included. Detailed data was collected for the first 50 ED, followed by annual collection of inhibitor status and allergic reactions. Presence of inhibitors was defined by at least two consecutive positive samples. Additionally, data on factor IX gene mutation was collected. 154 PUPs with SHB were included; 75% were followed until 75 ED, and 43% until 500 ED. Inhibitors developed in 14 patients (7 high-titre). Median number of ED at inhibitor manifestation was 11 (IQR 6.5-36.5). Cumulative inhibitor incidence was 9.3% (95%CI 4.4-14.1) at 75 ED, and 10.2% (5.1-15.3) at 500 ED. Allergic reactions occurred in 4 (28.6%) inhibitor patients. Missense mutations were most frequent (46.8%) overall but not associated with inhibitors. Nonsense mutations and deletions with large structural changes comprised all mutations among inhibitor patients and were associated with an inhibitor risk of 26.9% and 33.3%, respectively. In an unselected, well-defined cohort of PUPs with SHB, cumulative inhibitor incidence was 10.2% at 500 ED. Nonsense mutations and large deletions were strongly associated with the risk of inhibitor development. The PedNet Registry is registered at clinicaltrials.gov; identifier: NCT02979119

The German Hemophilia Registry: Growing with Its Tasks

“…A subgroup especially relevant to post-marketing surveillance are PUPs, as with the end of mandatory clinical trials in PUPs with hemophilia, post-marketing data captured in hemophilia registries will become increasingly important to optimize hemophilia treatment for PUPs as compared to PTPs. One major difference between PUPs and PTPs is inhibitor risk, which is highest in PUPs just beginning treatment and much lower in PTPs [ 58 , 59 , 60 , 61 , 62 , 63 ]. To ensure relevance and completeness of patient data captured in this early stage of treatment, the dhr was harmonized with the designated PUP registries PedNet and GEPHARD.…”

Genetic analysis of carrier status in female members of Japanese hemophilia families

“…The distribution of point mutations was almost similar to those reported in other countries. 14,23 Since the early 1980s, when Sanger capillary sequencing made it possible to establish carrier status, DNA direct sequencing has evolved from haplotyping to mutation analysis, 24,25 offering certainty about the carrier status. [26][27][28] Arg226Gln, generated the site of activation peptide known to play a critical role in cleavage by factor XIa or factor VIIa/tissue factor.…”

Nonacog beta pegol (N9‐GP) in hemophilia B: First report on safety and efficacy in previously untreated and minimally treated patients

“…Recently, a systematic review analyzed seven studies (including data from European Haemophilia Safety Surveillance) comprising 176 PUPs with severe hemophilia B, reporting an overall anti‐FIX inhibitory antibody rate of 10.2% (interstudy range, 5%‐14%; one outlier study reported a rate of 37%) 26,27 . Further studies in PUPs with severe hemophilia B found anti‐FIX inhibitory antibody incidences of 11.8%, 28 19%, 29 and 10.2; 30 the last of these also reported a 26.9% increased inhibitor risk associated with nonsense mutations. Therefore, the anti‐FIX inhibitory antibody incidence of 6.1% is within the expected range for this patient population.…”