A Novel Approach to Immune Tolerance Induction in Hemophilia Α with Factor VIII Inhibitor
Authors: Thornburg Courtney D. , Ducore Jonathan M. 
Published: October 2019

Abstract
Factor VIII (FVIII) inhibitors are currently the most significant complication of hemophilia A therapy. Immune tolerance induction (ITI) is the treatment of choice for inhibitor eradication. However, the optimal ITI regimen has not been identified. We describe an ITI approach for an adolescent male with severe hemophilia A and recurrent and refractory high-titer FVIII inhibitor. This strategy is now being tested in a randomized, controlled trial (NCT03204539).
A 1-year-old white, Hispanic male with severe hemophilia A, intron 22 inversion, developed a FVIII inhibitor while receiving on-demand treatment with recombinant FVIII (rFVIII). Due to life-threatening bleeding despite bypassing agents, he was immediately started on ITI with daily rFVIII along with intravenous immunoglobulin (IVIg), solumedrol, and rituximab. He achieved tolerance after 15 months and was switched to every-other-day dosing for prophylaxis. Unfortunately, on prophylaxis he had breakthrough bleeding and inhibitor recurrence, and has required additional ITI regimens over the past 14 years (Table 1).
Most recently, the family agreed to switch to Wilate® [von Willebrand Factor/Coagulation Factor VIII Complex (Human); Octapharma USA, Inc.; Hoboken, NJ; U.S. License No. 1646] as an alternative von Willebrand factor (VWF)/FVIII concentrate since he was unable to achieve tolerance on prior plasma-derived (pd) VWF/FVIII concentrate at 100 international units (IU)/kg daily for ~4 years. Wilate® was started when inhibitor titer was 1.5 Bethesda Units (BU). Initial FVIII recovery was 30% and 24-hour trough level was 1%. After several months, blood samples were sent to a diagnostic laboratory at Haemophilie-Zentrum Rhein Main GmbH for lot selection. Lot selection entails measuring residual FVIII activity when patient plasma is mixed with different lots of VWF/FVIII in vitro. This involves using the modified New Oxford method to measure residual FVIII activity after incubation of a FVIII source (lot) with the inhibitor patient plasma. The inhibitor titer is the reciprocal of the dilution of patient plasma that results in 50% of residual FVIII, similar to the Bethesda Unit. Ideally, the lot providing the highest residual FVIII activity will more effectively challenge the immune system, provide better prevention and control of bleeding, and have shorter time to tolerance. Investigators have demonstrated the utility of lot section in in vitro studies. The patient's plasma was tested against 6 lots of Wilate® and the lot with the lowest inhibitor activity was selected for prescription. This lot was allocated to this patient, and the prescribing physician included the lot number on the factor prescription for distribution to the patient via the patient's specialty pharmacy. The patient received Wilate® from the same lot for ~11 months. During that time, his inhibitor decreased from 2.6 BU to 0 after 5 months. A new plasma sample was tested against an additional 5 lots of Wilate®. Inhibitor was negative at that time and all lots of Wilate® revealed a negative inhibitory activity. One lot was selected for ongoing treatment. After 18 months his 48-hour trough FVIII level was detectable. He had blood drawn for pharmacokinetic analysis, which showed FVIII recovery of 55% and an estimated half-life of 6.75 hours. He was switched to every-other-day dosing and has had only one trauma-induced soft-tissue bleed despite increased physical activity, with negative inhibitor and a 48-hour trough of 2%.

Disclosures
Thornburg: Shire: Research Funding; CSL Behring: Research Funding; ATHN: Research Funding; Bayer Pharmaceuticals: Research Funding; Octapharma: Research Funding; Bioverativ: Consultancy; Genentech: Speakers Bureau; Biomarin: Consultancy; Bluebird Bio: Consultancy; NovoNordisk: Research Funding; Johns Hopkins All Children's Hospital: Research Funding. Ducore:OPKO: Other: investigator; HemaBiologics: Consultancy, Other: investigator, travel support; Shire: Consultancy, Other: travel support, investigator; Biomarin: Other: investigator; Octapharma: Consultancy, Other: travel support, investigator , Research Funding; Bayer Healthcare: Consultancy, Other: travel support, investigator; Pfizer: Other: investigator; Spark Therapeutics: Consultancy, Other: investigator; CSL Behring: Other: investigator.