Challenges in the Management of Hemophilia B with Inhibitor

Abstract

Development of factor IX (FIX) inhibitor is a rare but challenging complication in hemophilia B. In addition to inefficacy of specific replacement therapy, FIX inhibitors increase morbidity due to serious allergic reactions/anaphylaxis upon treatment with FIX. Limited experience with immune tolerance induction (ITI) shows a high risk of nephrotic syndrome development and poor ITI outcomes. Recently, immunomodulation therapy has been used in ITI regimens in hemophilia B; however, relevant guidelines for ITI in hemophilia B are still lacking. We describe a 7-year-old hemophilia B patient with "null" mutation Arg29 stop who underwent surgery and massive transfusion therapy in the neonatal period and developed an FIX inhibitor after consecutive 20 exposures to FIX concentrate. At the age of 6 years, a high-dose ITI was commenced combined with immunomodulation therapy including rituximab, dexamethasone, and intravenous immunoglobulin. Allergic reactions that occurred in the third week of ITI were resolved by premedication with antihistamines and continued immunomodulation protocol without any need for ITI interruption. Inhibitor was negative from week 10; however, doses of FIX continued unchanged until pharmacokinetic criteria for success were met at month 9 of ITI. One year after the start of ITI, the patient started regular prophylaxis with FIX 41 IU/kg three times a week. No further allergic reactions or any signs of nephrotic syndrome have occurred.

Clinical Care of Bone Health in Patients on the Immune Tolerance Induction’s Protocols With an Immunosuppressive Agent for Inhibitor Eradication in Hemophilia

“…The whole 96 original articles were read. As reflected in the flow diagram of the study, 51 surveys had used at least one of the immunosuppressive agents in their ITI protocols, 37 , 51 - 99 while 45 studies had used a version of ITI without any immunosuppressive agent ( Figure 1 ). Among the 51 reported studies on the eradication of inhibitors in hemophilia A and B using an immunosuppressive agent or combination of them, the used immunosuppressive agents included mycophenolate mofetil, corticosteroid, rituximab, rapamycin, Solumedrol, dexamethasone, hydrocortisone, prednisolone, prednisone, cyclophosphamide, methylprednisolone, fluprednisolone, and cyclosporine A ( Table 1 ).…”

Current animal models of hemophilia: the state of the art

“…Translational data produced from hemophilia B dogs have supported the development of long-acting FIX [ 29 , 30 ] with accompanying recent human clinical trials [ 12 , 31 – 34 ]. In contrast to the higher success ITI rate in hemophilia A, the ITI outcome in hemophilia B patients with FIX inhibitors is poor and research in this area remains in its infancy [ 35 ]. Recently, an ITI strategy using AAV liver expression of a FIX variant, FIX-Padua was successfully applied to hemophilia B dogs prone to inhibitors.…”