OR06 - Update on inhibitor development for individual FVIII concentrates in PUPs with severe hemophilia A in the PedNet registry.

OR06

Update on inhibitor development for individual FVIII concentrates in PUPs with severe hemophilia A in the PedNet registry.

K. Fischer^1,², M. de Kovel², M. Olivieri^3,*, S. Ranta^4,⁵, J. Motwani⁶, F. Pinto⁷, V. Labarque⁸, G. Kenet⁹, C. Königs¹⁰, B. Nolan¹¹, J. Blatný¹², M. Carcao¹³, C. Van Geet⁸, N. G. Andersson^14,¹⁵ on behalf of The PedNet Study Group

¹Van Creveld Kliniek, University Medical center Utrecht, Utrecht, ²PedNet Haemophilia Research Foundation, Baarn, Netherlands, ³Pediatric Thrombosis and Hemostasis Unit, Pediatric Hemophilia Center, Dr. von Hauner Children's Hospital, LMU Munich, Munich, Germany, ⁴Pediatric Coagulation Unit, Astrid Lindgren Children’s Hospital, Karolinska University Hospital, ⁵Pediatric Oncology, Department of Women’s and Children’s Health, Karolinska Institutet, Stockholm, Sweden, ⁶Department of Haematology, The Children's Hospital, Birmingham, ⁷Department of Haematology, Royal Hospital for Sick Children, Yorkhill, Glasgow, United Kingdom, ⁸Service of Pediatric Haematology, University Hospitals Leuven, Leuven, Belgium, ⁹National Hemophilia Center Sheba Medical Center, Tel Hashomer & Amalia Biron Research Institute of Thrombosis & Hemostasis, Tel Aviv University, Tel Hashomer, Israel, ¹⁰Department of Paediatrics and Adolescent Medicine, University Hospital Frankfurt, Frankfurt, Germany, ¹¹Department of Paediatric Haematology, Children's Coagulation Centre, Children's Health Ireland at Crumlin, Dublin, Ireland, ¹²HCCC, Centre for Thrombosis and Haemothasis at the Department of Paediatric Haematology and Biochemistry, University Hospital Brno, Brno, Czech Republic, ¹³Division of Haematology/Oncology, Department of Paediatrics, Hospital for Sick Children, Toronto, Canada, ¹⁴Department of Clinical Sciences, Lund University, Lund, ¹⁵Department of Pediatrics and Malmö Centre for Thrombosis and Haemostasis, Skane University Hospital, Malmö, Sweden

Introduction: Severe Hemophilia A (SHA) requires replacement FVIII therapy for treatment of bleeding episodes and/or prophylaxis. This treatment is complicated by development of neutralizing inhibitors in ±30% of patients during the first 50 exposure days (EDs). Information on inhibitor risks on individual FVIII concentrates is valuable, as FVIII is the most effective treatment for breakthrough bleeds and surgery. Despite extensive research, inhibitor risk of individual FVIII concentrates remains to be elucidated. The PedNet prospective registry has detailed information on inhibitor development and its risk factors since 2000. Aim: to analyze inhibitor development according to (classes of) individual FVIII concentrates in previously untreated patients (PUPs) with SHA.

Methods: PUPs with SHA born between 2000-2024 were followed until inhibitor development or 50 EDs. Inhibitor development according to classes of FVIII concentrates, i.e. plasma derived (pdFVIII) vs recombinant (rFVIII), standard vs extended half-life (SHL- vs EHL-rFVIII), and individual concentrates used by ≥40 PUPs were compared using multivariate Cox regression adjusted for differences in follow-up and other risk factors for inhibitor development, incl. use of emicizumab prophylaxis (generating rate ratios (RR) with 95% Confidence Intervals (CI)).

Results: 1503 PUPs were included. Inhibitors developed in 444 patients after 12 EDs (median; 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 FVIII concentrates (5 SHL-rFVIII, 1 EHL-rFVIII, 3 pdFVIII) were compared using Advate (n=392) as reference (concentrate with most available data). Only KogenateFS/HelixateNexGen (307 PUPs, RR 1.40; CI 1.07-1.82, p=0.013) and Fanhdi (50 PUPs, RR 1.72; CI 1.11-2.68, p=0.024) showed a statistically significant increased inhibitor risk.

Discussion/Conclusion: The incidence of inhibitor development was similar across SHL-rFVIII, EHL-rFVIII, and pdFVIII classes. Analysis of individual concentrates showed higher inhibitor risk in PUPs with KogenateFS/HelixateNexGen and, for the first time, for pdFVIII Fanhdi. Although exposure to FVIII will be delayed in the era of emicizumab and PUP studies are no longer mandatory for new concentrates, PedNet will continue to evaluate inhibitor risk according to individual FVIII concentrates.

Disclosure of Interest: K. Fischer Grant/Research support from: speakers fees from CSL Behring, Novo Nordisk. Consultancy fees from Biogen, CSL Behring, Freeline, Novo Nordisk, Roche and SOBI; research support from Bayer, Pfizer, and Novo Nordisk. Epidemiologist for the EUHASS and the PedNet Registry, M. de Kovel: None declared, M. Olivieri Grant/Research support from: Grants/research support from Bayer, Takeda, CSL Behring, Pfizer and Swedish Orphan Biovitrum. Consultancy and speaker fees from Bayer, Biomarin, Biotest, Novo Nordisk, Takeda, CSL Behring, Pfizer, Roche, Stago and Swedish Orphan Biovitrum, S. Ranta Grant/Research support from: Investigator in clinical trials (payment to institution, not to author) sponsored by Novo Nordisk, Roche, Sobi, Boehringer Ingelheim. Grants for research from the Childhood Cancer Foundation, Stockholm County Council and Ellen Bachrach memorial Fund. Member of a study steering committee for Roche, J. Motwani Grant/Research support from: Speaker fees, educational grant, honoraria from Roche, SOBI, CSL Behring, Bayer, F. Pinto Grant/Research support from: Financial support from Roche for participating in advisory board and for attending meeting, V. Labarque Grant/Research support from: Speaker and/or adivsor for Bayer, Novartis, Novo Nordisk, Octapharma, Roche, Sobi, and Takeda, and has received financial support for travel, accomodations, and expenses from Jazz Pharmaceuticals, Roche, CAF-DCF, and Sobi, G. Kenet Grant/Research support from: Research grant support from: BSF, Novonordisk, Pfizer, Roche, Tel Aviv University. Consultant: ASC therapeutics, Novonordisk, Pfizer, Roche, Sanofi- Genzyme, Takeda. Advisory boards and honoraria for lectures: Bayer, BioMarin, CSL, Pfizer, Sanofi- Genzyme, Sobi, Spark, Uniquore, C. Königs Grant/Research support from: fees for clinical trials and research to Goethe university from Bayer, Biotest, CSL Behring, Intersero, Novo Nordisk, Pfizer, Roche/Chugai, Takeda, Sobi/Sanofi, EU H2020 ITN, State of Hesse, FUSE e.V.; Consultations and Speaker’s fees from: Bayer, CSL Behring, Florio, MSD, Novo Nordisk, Roche/Chugai, Sobi/Sanofi, Takeda. , B. Nolan Grant/Research support from: Speaker fees, advisory board SOBI, principal investigator for clinical trials for Alnylam, SOBI, Sanofi, Bioverativ, CSL Behring, Takeda, Bayer, NovoNordisk, J. Blatný Grant/Research support from: Potential COI: Consultation and/or speakers fee for Roche, Sobi, NovoNordisk, Pfizer, Takeda, Octapharma, CSL Behring) Supported by Ministry of Health, Czech Republic - conceptual development of research organization (FNBr, 65269705), M. Carcao Grant/Research support from: research support from Novartis, Novo Nordisk, Pfizer, Roche, Sanofi and Takeda and honoraria for speaking/participating in advisory boards from Bayer, LFB, Novo Nordisk, Pfizer, Roche, Sanofi and Takeda., C. Van Geet Grant/Research support from: Grant support from Bayer, CSL Behring and Aventis, not related to this work, N. Andersson Grant/Research support from: speaker for lectures, educational courses and/or on Advisory Boards for CSL Behring, Octapharma and Sobi/Sanofi and received grants/research support to the institution from NovoNordisk and Sanofi.