Inhibitor development according to FVIII concentrates in previously untreated patients with severe hemophilia A: update from the PedNet registry

BACKGROUND: Treatment of severe hemophilia A (SHA) with FVIII concentrates is complicated by the development of neutralizing inhibitors in about 30% during the first 50 exposure days (EDs). Despite extensive research, inhibitor risk of different FVIII concentrates remains to be elucidated.

OBJECTIVES: This study aimed to analyze inhibitor development according to (classes of) individual FVIII concentrates in previously untreated patients (PUPs) with SHA.

METHODS: PUPs with SHA born between 2000 and 2024 were followed until inhibitor development or 50 EDs. Inhibitor development according to classes of FVIII concentrates (ie, plasma-derived [pdFVIII] vs recombinant [rFVIII] and standard vs extended half-life [SHL-rFVIII vs EHL-rFVIII]) and individual concentrates used by ≥40 PUPs were compared using multivariable Cox regression (generating rate ratios [RR] with 95% CIs).

RESULTS: One thousand five hundred three PUPs were included. Inhibitors developed in 444 PUPs after a median of 12 EDs (cumulative incidence, 31.0%; CI, 28.6%-33.4%). Compared to SHL-rFVIII, inhibitor risk was similar for pdFVIII (RR, 0.89; CI, 0.69-1.14) and EHL-rFVIII (RR, 1.10; CI, 0.75-1.61). Nine individual FVIII concentrates (5 SHL-rFVIII, 1 EHL-rFVIII, and 3 pdFVIII) were compare to Advate (n = 392): only KogenateFS/HelixateNexGen (n = 307; RR, 1.40; CI, 1.07-1.82, P, .013) and Fanhdi (n = 50; RR, 1.72; CI, 1.11-2.68; P, .024) showed increased inhibitor risk.

CONCLUSION: Inhibitor development occurred in 31.0% of PUPs, with similar incidence across SHL-rFVIII, EHL-rFVIII, and pdFVIII. Analysis of individual concentrates showed increased inhibitor risk for Kogenate FS/Helixate NexGen (SHL-rFVIII) and for the first time for Fanhdi (pdFVIII). In the absence of formal PUP studies, PedNet will continue evaluating the inhibitor risk according to individual FVIII concentrates.