GENETIC AND NON-GENETIC DETERMINANTS OF SUCCESSFUL IMMUNE TOLERANCE INDUCTION IN PEOPLE WITH SEVERE HEMOPHILIA A

Abstract

Background: Eradicating inhibitors to restore the effectiveness of Factor VIII (FVIII) is a desirable treatment goal for People with Severe Hemophilia A (PwSHA) and inhibitors, as this enables treatment of bleeding episodes with FVIII concentrates. However, since Immune Tolerance Induction (ITI) is a burdensome and costly treatment, it is important to identify determinants for ITI success to decide if it is worth undertaking ITI. For more effective treatment allocation, there is a need to identify which persons will or will not benefit from ITI. Aim: We aimed to identify determinants of successful ITI in PwSHA and to use these determinants in a clinical prediction model. Methods: German, Brazilian, Dutch, Canadian, and Italian PwSHA who underwent ITI were included. The primary outcome was clinical ITI success, defined by (1) a negative inhibitor titer, and (2) an adequate clinical response to FVIII concentrates. Clinical determinants included F8 genotype, race, age, cumulative exposure days to FVIII, inhibitor titers, and ITI regimen. Genetic determinants included in the analyses were FCGR gene, IL10 CA short tandem repeat, and gene variants. Crude Relative Risks (RR) were calculated for ITI success with 95% Confidence Intervals (95% CI). Results: In total, 224 PwSHA were included (61 German, 51 Brazilian, 45 Dutch, 39 Canadian, and 28 Italian). The median ages at inhibitor development and ITI start were 2-years (Interquartile Range [IQR 1‒3]) and 2-years (IQR 1‒6). The median interval between inhibitor diagnosis and ITI start was 17-weeks (IQR 2‒64). Most ITI trials started with recombinant FVIII (130; 58%) and the median prescribed regimen at ITI start was 43 IU/kg/day (IQR 21‒200). The need for adjuvant therapy and central venous access infection were related to failure, while inhibitor titer at detection < 10 BU/mL, inhibitor titer immediately before ITI start < 10 BU/mL, and peak inhibitor titer ever measured < 100 BU/mL were related to success. Inhibitor peak titer below 100 BU/mL showed the highest chance for ITI success (OR = 11.5, 95% CI 5.5‒24.3, p < 0.001). Conclusion: Historical peak titer below 100 BU/mL was the strongest determinant for ITI success. Genetic analyses will be available by the due date, and we will develop a prediction model to estimate the chance of success.