Risk Factors for the Development of High-Titer Inhibitors in 260 Children with Severe Hemophilia a Born Between 1990 and 2009: The Remain Study
Authors: Mancuso Maria Elisa , Fischer Kathelijn , Santagostino Elena , Oldenburg Johannes , Platokouki Helen , Königs Christoph , Escuriola Carmen , Rivard Georges-Etienne , Cid Ana , Carcao Manuel , Ljung Rolf , Petrini Pia , Rafowicz Anne , Altisent Carmen , Kenet Gili , Liesner Raina , Kurnik Karin , Van Geet Christel , Alvarez-Roman Teresa , Yee Tin Tin , Auerswald Guenter , Perez-Garrido Rosario , Nolan Beatrice , Chambost Hervé , Makipernaa Anne , Molinari Angelo Claudio , Thomas Angela , Chalmers Elizabeth , Williams Mike , Kobelt Rainer , Van den Berg Marijke 
Published: October 2019

Abstract

The development of anti-FVIII antibodies (i.e., inhibitors) is the major side effect of severe hemophilia A treatment. Inhibitors mainly develop in children during the first 50 exposure days and are classified in low-and high-titer (i.e., peak titer < or > 5 UB/ml). High-titer inhibitors have the major clinical impact. At diagnosis however, the real nature of the antibody is not clear in all patients, since some low-titer inhibitors may progress to high-titer. The determinants of the evolution from low- to high-titer inhibitors are still unclear and the aim of the present study was to investigate potential risk factors associated with the progression from low- to high-titer inhibitors. This study is a follow-up study of the PedNet Registry and includes 260 children with severe hemophilia A and clinically relevant inhibitors, born between 1990 and 2009 and consecutively recruited from 31 hemophilia centers in 16 countries. Clinical and laboratory data were collected from the date of first positive inhibitor test and covered a minimum of 3-years follow-up. Factors potentially associated with progression from low- to high-titer inhibitor development were analyzed using univariate and multivariate logistic regression. F8 mutation type was known in 247 patients (95%), including 202 (82%) null mutations (i.e., large deletions, nonsense mutations and inversions). Positive family history of inhibitors was present in 37 of 99 (37%) with positive family history of hemophilia. At diagnosis 49% (n=127) had low-titer inhibitors, however, upon FVIII re-exposure, 50% of low-titer inhibitors progressed to high-titer and only 25% of patients (n=69) had persistent low-titer inhibitors. Within the first 3 years of follow-up, immune tolerance induction (ITI) was equally implemented in around 80% of low-and high-titer patients but it was started later in children with high-titers (median time to ITI start 4.5 vs 0.3 months; p<0.001) in whom daily regimens and high-dose FVIII were more frequently adopted (89, 67% vs 41, 50% and 98, 74% vs 35, 43%; p=0.01 and <0.001, respectively). Overall high-titer inhibitor development was associated with null F8 mutations (OR 2.8, 95%CI 1.4-5.5) and family history of inhibitors (OR 3.9, 95%CI 1.2-12.6). The progression from low- to high-titer inhibitors during follow up, was associated with the use of high-dose ITI regimens (i.e., >100 IU/kg/day) with an OR of 3.9 (95%CI 1.5-10.0), independent from the effects of F8 mutation type (adjusted OR 3.6, 95%CI 1.4-9.8) and family history of inhibitors (adjusted OR 6.7, 95%CI 1.1-42.6). No difference was found by comparing the use of daily versus non-daily ITI. In conclusion, in a cohort of 260 children with severe hemophilia A and inhibitors, 49% presented with low-titers at diagnosis and 46% of them progressed to high-titers during follow-up. Progression to high-titer inhibitors was associated with the use of high-dose ITI. These results suggest that intensive ITI should be avoided as initial strategy in low-titer inhibitor patients.

Disclosures
Mancuso: Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sobi/Biogen Idec: Consultancy, Speakers Bureau; Novo Nordisk: Consultancy, Speakers Bureau; CSL Behring: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Baxalta: Consultancy, Speakers Bureau; Bayer Healthcare: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kedrion: Consultancy. Fischer:Wyeth/Pfizer: Research Funding; Biogen: Consultancy; NovoNordisk: Consultancy, Research Funding, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; Biotest Octapharma: Speakers Bureau; CSL Behring: Speakers Bureau; Baxter: Consultancy, Research Funding, Speakers Bureau; Freeline: Consultancy; Bayer: Consultancy, Research Funding, Speakers Bureau. Santagostino:Octapharma: Consultancy; Novo Nordisk: Consultancy; Kedrion: Consultancy; Sobi: Consultancy; Biogen Idec: Consultancy; Roche: Consultancy; Grifols: Consultancy; Pfizer: Consultancy; Baxalta: Consultancy; CSL Behring: Consultancy; Bayer: Consultancy. Escuriola:Baxalta, now part of Shire: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Investigator Clinical Studies, Research Funding; Bayer: Consultancy, Honoraria, Research Funding; Biotest: Consultancy, Honoraria, Research Funding; CSL Behring: Consultancy, Honoraria, Research Funding; Grifols: Consultancy, Honoraria, Research Funding; Octapharma: Consultancy, Honoraria, Research Funding; NovoNordisk: Consultancy, Honoraria, Research Funding. Liesner:BPL: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Honoraria, Speakers Bureau; Cangene: Research Funding; CSL Behring: Consultancy, Honoraria, Research Funding; Baxalta Innovations GmbH, now a part of Shire: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; SOBI: Consultancy, Honoraria, Research Funding, Speakers Bureau; Octapharma: Consultancy, Honoraria, Research Funding, Speakers Bureau; Biogen: Consultancy, Honoraria, Research Funding; Grifols: Consultancy, Honoraria. Nolan:Sobi: Research Funding; Biogen: Research Funding.