Risk stratification integrating genetic data for factor VIII inhibitor development in patients with severe hemophilia A

Abstract

Replacement therapy in severe hemophilia A leads to factor VIII (FVIII) inhibitors in 30% of patients. Factor VIII gene (F8) mutation type, a family history of inhibitors, ethnicity and intensity of treatment are established risk factors, and were included in two published prediction tools based on regression models. Recently investigated immune regulatory genes could also play a part in immunogenicity. Our objective is to identify bio-clinical and genetic markers for FVIII inhibitor development, taking into account potential genetic high order interactions. The study population consisted of 593 and 79 patients with hemophilia A from centers in Bonn and Frankfurt respectively. Data was collected in the European ABIRISK tranSMART database. A subset of 125 severely affected patients from Bonn with reliable information on first treatment was selected as eligible for risk stratification using a hybrid tree-based regression model (GPLTR). In the eligible subset, 58 (46%) patients developed FVIII inhibitors. Among them, 49 (84%) were “high risk” F8 mutation type. 19 (33%) had a family history of inhibitors. The GPLTR model, taking into account F8 mutation risk, family history of inhibitors and product type, distinguishes two groups of patients: a high-risk group for immunogenicity, including patients with positive HLA-DRB1*15 and genotype G/A and A/A for IL-10 rs1800896, and a low-risk group of patients with negative HLA-DRB1*15 / HLA-DQB1*02 and T/T or G/T for CD86 rs2681401. We show associations between genetic factors and the occurrence of FVIII inhibitor development in severe hemophilia A patients taking into account for high-order interactions using a generalized partially linear tree-based approach.

HLA Variants and Inhibitor Development in Hemophilia A: A Retrospective Case-Controlled Study Using the ATHNdataset

“…There is broad recognition that genetic factors play a role in determining which patients develop inhibitors and which do not (3)(4)(5)(6)(7)(8). However, identifying the genetic markers of immunogenicity is challenging.…”

Performance of a clinical risk prediction model for inhibitor formation in severe haemophilia A

“…A different approach would be to incorporate genomic information at baseline, such as HLA class II haplotypes 17 , 18 and/or gene variants of other genes previously associated with inhibitor formation (eg, IL‐10 and CTLA‐4). 19 …”

“…For example, much information could be gained by measuring the antibody response over time, 15 as was done in a recent study by Reipert et al 16 Interestingly, this study found that during treatment, the appearance of IgG1 antibodies, followed by IgG3 antibodies, was a strong biomarker of future inhibitor development. A different approach would be to incorporate genomic information at baseline, such as HLA class II haplotypes 17,18 and/or gene variants of other genes previously associated with inhibitor formation (eg, IL‐10 and CTLA‐4) 19 …”

Factors Involved in the Development of Inhibitory Antibodies in Patients with Hemophilia in Colombia: A Case-Control Study

“…It is unknown whether the patients who developed inhibitors in this cohort were exposed to danger signs such as infections, surgeries or the previous intensity of treatment that could be involved in the generation of immunogenicity against the administered factor VIII. 24,25 It should also be considered that, in real life conditions, patients may not communicate the treatment they were previously receiving to a new clinic responsible for their care if they change institutions; a patient may be treated with a completely different drug, and this is a determining variable.…”