The North American Immune Tolerance Registry: Practices, Outcomes, Outcome Predictors

D. M. DiMichele; B.L. Kroner; The North American Immune Tolerance Study Group

doi:10.1055/s-0037-1612943

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2002; 87(01): 52-57
DOI: 10.1055/s-0037-1612943

Review Article

Schattauer GmbH

The North American Immune Tolerance Registry: Practices, Outcomes, Outcome Predictors

D. M. DiMichele

¹New York Presbyterian Hospital, Weill Medical of College of Cornell, New York, NY, USA

,

B.L. Kroner

¹New York Presbyterian Hospital, Weill Medical of College of Cornell, New York, NY, USA

,

The North American Immune Tolerance Study Group

› Author Affiliations

Abstract

Summary

The North American Immune Tolerance Registry was initiated to study of immune tolerance (ITT) in Canada and the United States with respect to: 1) therapeutic regimens in use for haemophilia A (HA) and B (HB) inhibitor patients; 2) therapeutic outcomes; 3) potential predictors of successful outcome and 4) complications of therapy. Data on 188 ITT courses was collected by questionnaire from 60 haemophilia centers from 1993-99. Among the completed courses, the overall ITT success rate was 70% (115/164) for all HA and 31% (5/16) for all HB. Outcome parameters noted to be predictive of ITT success for all HA were 1) pre-ITT induction (p = 0.003), 2) ITT peak (p = 0.007) and 3) historical pre ITT peak (p = 0.04) inhibitor titres. An inverse correlation between total daily dose (units/kg/day) and success: (80% with under 50; 71% with 50-99; 73% with 100-199; and 41% with ≥ 200, p = 0.01) was found. Outcome predictors were not evaluable for HB, although adverse reactions to therapy, including nephrotic syndrome, and access complications were more common among failed courses. Infection most often complicated the use of access catheters. These results are discussed within the context of the international ITT registry and upcoming prospective ITT study.

Keywords

Hemophilia A - hemophilia B - inhibitor therapy - immune tolerance

Full Text

References

References
1 Ehrenforth S, Kreutz W, Scharrer I. et al. Incidence of development of FVIII and FIX inhibitors in haemophiliacs. Lancet 1992; 339: 594-8.
2 Briet E, Reisner HM, Roberts HR. Inhibitors in Christmas disease. Prog Clin Biol Res 1984; 150: 123-9.
3 Aledort LM, Cohen M, Hilgartner M, Lipton R. Treatment of hemophiliacs with inhibitors: cost and effect on blood resources. Prog Clin Biol Res 1984; 150: 353-65.
4 Brackmann HH, Gormsen J. Massive FVIII infusion in a haemophiliac with FVIII inhibitor, high responder (letter). Lancet 1977; 02 8044 933.
5 Brackmann HH. Induced immunotolerance in FVIII inhibitor patients. Prog Clin Biol Res 1984; 150: 181-95.
6 Aznar JA, Jorquera JI, Peiro A. et al. The importance of corticoids added to continued treatment with FVIII concentrates in the suppression of inhibitors in hemophilia A. Thromb Haemost 1984; 51: 217-121.
7 Van Leeuwen EF, Mauser-Bunschoten EP, van Dijken PJ, Kok AJ, Sjamsvedin-Visset EJM, Sixma JJ. Disappearance of FVIII:C antibodies in patients with haemophilia upon frequent administration of FVIII in intermediate or low dose. Br J Haematol 1986; 64: 291-7.
8 Ewing NP, Sanders NL, Dietrich SL, Kasper CK. Induction of immune tolerance to FVIII in hemophiliacs with inhibitors. JAMA 1988; 259: 65-8.
9 Nilsson IM, Berntorp E, Zettervall O. Induction of immune tolerance in patients with hemophilia and antibodies to FVIII by combined treatment with intravenous IgG, cyclophosphamide and FVIII. N. Engl J Med 1988; 318: 947-50.
10 Gruppo RA, Valdez LP, Stout RD. Induction of immune tolerance in patients with hemophilia A and inhibitors. Am J Pediatr Hematol Oncol 1992; 14: 82-7.
11 Mauser-Bunschoten EP, Nieuwenhuis HK, Roosendaal G, van den Berg HM. Low dose immune tolerance induction in hemophilia A patients with inhibitors. Blood 1995; 86 (03) 983-8.
12 Kreuz W, Ehrenforth S, Funk M. et al. Immune tolerance therapy in paediatric hemophiliacs with FVIII inhibitors: 14 years follow up. Haemophilia 1995; 01: 24-32.
13 Brackmann HH, Oldenburg J, Schwaab R. Immune tolerance for the treatment of FVIII inhibitors – twenty years’ ‘Bonn Protocol’. Vox Sang 1996; 70: 30-5.
14 Frieburghaus C, Berntorp E, Ekman M. et al. Immunoadsorption for removal of inhibitors: update on treatments in Malmo-Lund between 1980 and 1995. Haemophilia 1998; 04: 16-20.
15 Freiburghaus C, Berntorp E, Ekman M. et al. Tolerance induction using the Malmo treatment model 1982-1995. Haemophilia 1999; 05: 32-9.
16 Oldenburg J, Schwaab R, Brackmann HH. Induction of immune tolerance in HA inhibitor patients by the ‘Bonn Protocol’: Predictive parameter for therapy duration and outcome. Vox Sang 1999; 77 (01) 49-54.
17 Nilsson IM, Berntorp E, Zetterval O. Induction of split tolerance and clinical cure in high-responding hemophiliacs with FIX antibodies. Proc Natl Acad Sci USA 1986; 83: 9169-73.
18 Mariani G, Ghirardini A, Bellocco R. Immune tolerance in hemophilia. Principal results from the international registry. Thromb Haemost 1994; 72 (01) 155-8.
19 Mariani G, Kroner B. International immune tolerance registry, 1997 update. Vox Sang 1999; 77 (01) 25-7.
20 Kroner B. Comparison of the international immune tolerance registry and the North American immune tolerance registry. Vox Sang 1999; 77 (01) 33-7.
21 Data supplied by the National Hemophilia Foundation (US).
22 Data supplied by the Canadian Hemophilia Society.
23 Gill FM. et al. The natural history of FVIII inhibitors in patients with hemophilia A. Progress in Clinical & Biological Research 1984; 150: 19-29.
24 Addiego Jr JE, Kasper C. et al. Increased frequency of inhibitors in African American hemophilia A patients. Blood 1994; (Suppl. 01) 239a.
25 Warrier I, Ewenstein BM, Koerper M. et al. FIX inhibitors and anaphylaxis in hemophilia B. Am J Pediatr Hematol Oncol 1997; 19 (01) 23-7.
26 Warrier I. FIX antibody and immune tolerance. Vox Sang 1999; 77 (01) 70-1.
27 Ewenstein BM, Takemoto C, Warrier I. et al. Nephrotic syndrome as a complication of immune tolerance in hemophilia B (letter). Blood 1997; 89 (03) 1115-6.