Case-Control Pilot Study of the Immune Modulating Effect of FEIBA® on Patients with Haemophilia a and Inhibitors
Authors: Fernandez Bello Ihosvany , Álvarez Román María Teresa , Jiménez Yuste Victor , Martín Salces Monica , Iruin Gemma , Bonanad Santiago , López Fernández María Fernanda , Altisent Carmen , García Candel Faustino , Rivas Pollmar María Isabel , Canales Miguel , Butta Nora 
Published: October 2019

Abstract
Background: Immune tolerance therapy (ITT) is the only available therapy for eliminating the inhibitor in patients with haemophilia and high-responding inhibitors. However, it is a very expensive treatment with an efficacy of up to 60%-75%. Factors influencing the outcome of ITT are not completely understood. Some studies have suggested that plasma derived factor VIII (FVIII) concentrates might offer certain advantages in the elimination of the inhibitor when compared with recombinant derivatives. The presence of von Willebrand factor (Auerswald et al,Haematologica 2003;88:EREP05; Kreuz et al,Haematologica 2001;86:16-20) and some molecules with immunomodulatory effect like anti-idiotype antibodies, transforming growth factor-β, HLA type I molecules and soluble FAS ligand in plasma derived concentrates may be involved in such effect (Berntorp et al,Haemophilia 2001;7:109-13; Hodge et al,Br J Haematol 2001;115:376-81; Hodge et al, Haemophilia 2006;12:133-9; Ghio et al, Thromb Haemost 2003;89:365-73). The activated prothrombin complex concentrate (FEIBA®) is a plasma derived product used for bleeding control in patients with haemophilia A and high-responding inhibitors. We hypothesize that FEIBA® may have an immunomodulatory activity due to its plasmatic origin. This effect might be observed in patients with intense treatment with FEIBA® (e.g. prophylaxis treatment) by the reduction in levels of antibodies against FVIII compared with patients on demand treatment with this product.
Objective: The aim of this study was to compare levels of inhibitors in patients with severe haemophilia A and inhibitors on demand or under prophylactic treatment with FEIBA®.
Methods and results: This was a prospective, observational and multicenter study. A total of 12 adult patients with severe haemophilia A and high-responding inhibitors (6 patients on demand and 6 patients under prophylaxis treatment with FEIBA®) were included. All patients had normal levels of serum creatinine, serum alanine aminotransferase and CD4+ lymphocyte counts at inclusion. Levels of inhibitors were determined by Bethesda assay. Levels of inhibitors in patients on prophylaxis with FEIBA® were lower than those observed in patients on demand treatment but differences were not statistical significant. In most of the patients on prophylaxis, levels of inhibitors went down along the prophylaxis regimen.
Table. Medical history of patients. Patient Nº Age Type of treatment Usual dose (IU/kg) Frecuency Titer (BU) Time frame with start of prophylaxis (months)** 480101 53 Prophylaxis 60 Three times a week 64* 4.4 80 4.1 96 1.3 250 -1.3 480102 58 Prophylaxis 55 Three times a week 5* 3.3 12 2.1 7 -3.8 12 -6.1 150101 UNK Prophylaxis 60 Three times a week 4* 3.0 5 -6.0 6 -8.0 280101 28 Prophylaxis 56 Every other day 109* 7.3 77 4.1 101 -8.3 101 -9.7 280102 57 On Demand 56 x 8 doses N/A 174* N/A 37 N/A 83 N/A 21 N/A 25 N/A 184 N/A 280103 57 On Demand 55 x 6 doses N/A 8000* N/A 64 N/A 5 N/A 21 N/A 280104 58 On Demand 68 x 6 doses N/A 152* N/A 280105 23 On Demand 68 x 3 doses 40 x 6 doses N/A 30* N/A 080101 28 On Demand 50 x 5 doses N/A 5.2* N/A 7.0 7.2 4.0 7.8 460101 37 Prophylaxis 66 every 48h Negative 21,0 460102 57 On demand 70 2 doses/ bleeding usually 66.5* More than 20 years 300001 50 Prophylaxis 85 Three times a week 8* 3 *Titer at inclusion. **Positive values represent number of months after starting prophylaxis and negative values are referred to number of months before starting prophylaxis. For example, the patient number 480101 had 250 BU at 1.3 months before starting prophylaxis (in the table= -1.3 months) and 64 UB at month 4.4 after initiation of prophylaxis (in the table= 4.4 months). N/A: not applicable.
Conclusion: Prophylaxis with FEIBA® might decrease levels of inhibitors in patients with severe haemophilia A and high-responding inhibitors. However, a broader study is needed to confirm this result.

Disclosures
Iruin: Baxalta: Research Funding. Bonanad:Baxalta: Research Funding. López Fernández:Baxalta: Research Funding. Altisent:Baxalta: Research Funding. García Candel:Baxalta: Research Funding. Rivas Pollmar:Baxalta: Research Funding. Canales:Baxalta: Research Funding.