Longitudinal Evaluation of Immunological Biomarkers in Previously Untreated/Minimally Treated Patients With Severe and Moderately Severe Haemophilia A During Exposure to Factor VIII: Results From the HEMFIL Study

Background Haemophilia A (HA) is an inherited bleeding disorder due to Factor VIII (FVIII) deficiency. Treatment with FVIII can activate immune mechanisms, which may lead to inhibitor development. Objectives This study aimed to perform a longitudinal and exploratory analysis of immunological biomarkers during replacement with FVIII concentrate and after immune tolerance induction (ITI) in patients who developed a high-responding inhibitor. Methods Biological samples and clinical data from severe and moderately severe persons with HA (PwHA; FVIII < 0.02 IU/mL) were obtained before any or after minimal exposure (<= 5 days) to FVIII (T0), at inhibitor development (INB+), at 75 exposure days (ED) without inhibitor (INB-) (T1) and at end of ITI (T2). Biomarkers were assessed at T0, T1 and T2. Results One hundred patients were analysed, of whom 32 (86.5%) developed high-responding inhibitor and underwent ITI. We found no difference in the plasma concentration of the 15 immunological biomarkers at T0 or at T1 versus T2 in INB+ compared with INB-. However, at T1, PwHA INB+ who failed ITI had higher median concentration of interleukin (IL)-2 (3.50 vs. 0.85 pg/mL; q = 0.016), IL-10 (3.46 vs. 0.74 pg/mL; q = 0.035), tumour necrosis factor (TNF) (11.18 vs. 0.93 pg/mL; q = 0.016), interferon-gamma (INF-gamma) (98.57 vs. 3.57 pg/mL; q = 0.035) and CCL5 (5245.11 vs. 3107.86 pg/mL; p = 0.037) compared with those who achieved complete response, respectively. Conclusions Patients who failed ITI had higher concentration of IL-2, IL-10, TNF, INF-gamma and CCL5 in comparison with complete responders, suggesting that these biomarkers could be potential predictors of ITI outcome.