Immune Tolerance Therapy for Haemophilia A Patients with Acquired Factor VIII Alloantibodies: Comprehensive Analysis of Experience at a Single Institution

Summary

Eleven children with severe haemophilia A associated with the IVS 22 inversion and acquired high titre neutralising antibodies to factor VIII underwent immune tolerance induction. HLA class I and high resolution class II type is detailed for each patient. A three phase approach to immune tolerance induction was used. During phase 1, which lasted a median of six weeks, patients received factor VIII 100 IU/kg twice daily. Phase 2 comprised a factor VIII dose reduction to 100 IU/kg once daily, and continued for a median duration of 14 weeks. Subsequently 10 of the 11 patients satisfied the criteria of absent factor VIII neutralising activity by the Bethesda method, and a factor VIII elimination half life of greater than 5 h, allowing progression to phase 3, a further factor VIII dose reduction to 50 IU/kg three times weekly. A model for dose reduction as factor VIII tolerance evolves, based on pharmacokinetic analysis, is described.

 

• References

• 1 Kreuz W, Escuriola-Ettingshausen C, Martinez-Saguer I, Güngör T, Kornhuber B. Epidemiology of inhibitors in Haemophilia A. Vox Sanguinis 1996; 70 (Suppl. 01) suppl 2-8.
• 2 Ehrenforth S, Kreuz W, Scharrer I, Linde R, Funk M, Güngör T, Krackhardt B, Kornhuber B. Incidence of development of factor VIII and factor IX inhibitors in haemophiliacs. Lancet 1992; 339: 594-8.
• 3 Lusher J, Arkin S, Abildgaard D, Hurst D. Recombinant factor VIII (Kogenate) treatment of previously untreated patients (PUPS) with haemophilia A: Update of safety, efficacy and inhibitor development after seven study years.. Thromb Haemost 1997. (abstr); June suppl 162.
• 4 Kavanaugh ML, Wood CN, Davidson JF. The immunological characterization of human antibodies to factor VIII isolated by immuno-affinity chromatography. Thromb Haemost 1981; 45: 60-4.
• 5 Scandella D, de Graaf Mahoney S, Mattingly M, Roeder D, Timmons L, Fulcher CA. Epitope mapping of human factor VIII inhibitor antibodies by deletion analysis of factor VIII fragments expressed in Escherichia coli. Proc Natl Acad Sci USA 1988; 85: 6152-6.
• 6 Scandella D. Human anti-factor VIII antibodies: Epitope localization and inhibitory function. Vox Sanguinis 1996; 70 suppl 9-14.
• 7 Feinstein I. D. Acquired disorders of haemostasis. In: Haemostasis and Thrombosis: Basic Principles and Practise, Third Edition. Colman RW, Hirsh J, Marder VJ, Salzman EW. (eds). Philadelphia: JB Lippincott Company; 1994: 881-905.
• 8 Ingerslev J, Freidman D, Gastineau D, Gilchrist G, Johnsson H, Lucas G, McPherson J, Preston E, Scheibel E, Shuman M. Major surgery in haemophilic patients with inhibitors using recombinant factor VIIa. Haemostasis 1996; 26 (Suppl. 01) suppl 118-23.
• 9 Kasper CK, Aledort LM, Counts RB, Edson JR, Fratantoni J, Green D, Hampton JW, Hilgartner MW, Lazerson J, Levine PH, McMillan CW, Pool JG, Shapiro NR, van Eys J. A more uniform measurement of factor VIII inhibitors. Thromb Diath Haemorrhag 1975; 34: 875-6.
• 10 Prescott R, Nakai H, Saenko EL, Scharrer I, Nilsson IM, Humphries JE, Hurst D, Bray G, Scandella D. The inhibitor antibody response is more complex in hemophilia A patients than in most nonhemophiliacs with factor VIII antibodies. Blood 1997; 89: 3663-71.
• 11 Levinson B, Kenwrick S, Lakich D, Hammonds G, Gitschier J. A transcribed gene in an intron of the human factor VIII gene. Genomics 1990; 7: 1-11.
• 12 Hay CRM, Ollier W, Pepper L, Cumming A, Keeney S, Goodeve AC, Colvin BT, Hill FGH, Preston FE, Peake IR. from the UKHCDO Working Party. HLA class II profile: a weak determinant of factor VIII inhibitor development in severe haemoplilia A. Thromb Haemost 1997; 77: 234-7.
• 13 Oldenburg J, Picard JK, Schwaab R, Brackmann HH, Tuddenham EGD, Simpson E. HLA genotype of patients with severe haemophilia A due to in-tron 22 inversion with and without inhibitors of factor VIII. Thromb Haemost 1997; 77: 238-42.
• 14 Van Leeuwen EF, Mauser-Bunschoten EP, van Dijken PJ, Kok AJ, Sjamse-din-Visset EJM, Sixma JJ. Disappearance of factor VIII:C antibodies in patients with haemophilia A upon frequent administration of factor VIII in intermediate or low dose. Brit J Haematol 1986; 64: 291-7.
• 15 Brackmann HH, Oldenburg J, Schwaab R. Immune tolerance for the treatment of factor VIII inhibitors – twenty years’ ‘Bonn protocol.’ Vox Sang. 1996; 70 suppl 30-5.
• 16 Nilsson IM, Berntorp E, Zetterall O. Induction of immune tolerance in patients with haemophilia and antibodies to factor VIII by combined treatment with intravenous IgG, cyclophosphamide, and factor VIII. N Eng J Med 1988; 31: 947-50.
• 17 Mariani G, Ghirardini A, Bellocco R. Immune tolerance in haemophilia – principal results from the International Registry. Report of the factor VIII and IX subcommittee. Thromb Haemost 1994; 72: 155-8.
• 18 Dazzi F, Tison T, Vianello F, Radossi P, Zerbinati P, Carraro P, Poletti A, Girolami A. High incidence of anti-FVIII antibodies against non-coagulant epitopes in haemophilia A patients: a possible role for the half-life of transfused FVIII. Brit J Haematol 1996; 93: 688-93.
• 19 Gilles JG, Desqueper B, Lenk H, Vermylen J, Saint-Remy JM. Neutralising antiidiotypic antibodies to factor VIII inhibitors after desentization in patients with haemophilia A. J Clin Invest 1996; 97: 1382-8.
• 20 Gilles JG, Saint-Remy JM. Healthy subjects produce both anti-factor VIII and specific anti-idiotypic antibodies. J Clin Invest 1994; 94: 1496-505.