Download PDF
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
1   New York Presbyterian Hospital, Weill Medical of College of Cornell, New York, NY, USA
,
B.L. Kroner
1   New York Presbyterian Hospital, Weill Medical of College of Cornell, New York, NY, USA
,
The North American Immune Tolerance Study Group › Author Affiliations
Further Information

Publication History

Received 09 July 2001

Accepted after revision 27 September 2001

Publication Date:
13 December 2017 (online)

Also available at
    Permissions and Reprints

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

* North American Immune Tolerance Study Group: (US) Adair, S., Addiego, J., Anderson, V., Barbosa, J., Blatt, P., Bockenstedt, P., Castle, V., Chenaille, P., Cohen, J., Czapek, E., Davis, J., Davignon, G., de Alarcon, P., DiMichele, D., Dubowy, R., DuCore, J., Dugdale, M., Ewenstein, B., Fahner, J., Gribble, T. J., Gnarra, D., Gruppo, R., Hakami, N., Hanna, M., Hanna, W., Haut, P., Heggie, G., Homans, A., Hutter, J., Johnson, C., Kajani, M., Karpatkin, M., Kasper, C., Katz, J., Kessler, C., Key, N., Koerper, M., Konkle, B., Kosinski, R., Lazerson, J., Lightsey, A., Loew, T., Lusher, J., MacLaughlin, W., Manco-Johnson, M., Manno, C., McRedmond, K., Phatak, P., Powell, J., Ragni, M., Rosenfield, C., Sanders J., Santiago-Borrero, P., Saidi, P., Seeler, R., Seremetis, S., Sexauer, J., Travis, S., Valdez, L., Warner, E., White, G., (Canada) Barnard, D., Drown, J., Herst, J., Inwood, M., Lillicrap, D., Rivard, G., Rubin, S., Stranczyniski, H., Teitel, J.


 

  • 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.
    CrossrefPubMedGoogle Scholar
  • 2 Briet E, Reisner HM, Roberts HR. Inhibitors in Christmas disease. Prog Clin Biol Res 1984; 150: 123-9.
    PubMedGoogle Scholar
  • 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.
    PubMedGoogle Scholar
  • 4 Brackmann HH, Gormsen J. Massive FVIII infusion in a haemophiliac with FVIII inhibitor, high responder (letter). Lancet 1977; 02 8044 933.
    PubMedGoogle Scholar
  • 5 Brackmann HH. Induced immunotolerance in FVIII inhibitor patients. Prog Clin Biol Res 1984; 150: 181-95.
    PubMedGoogle Scholar
  • 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.
    PubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 8 Ewing NP, Sanders NL, Dietrich SL, Kasper CK. Induction of immune tolerance to FVIII in hemophiliacs with inhibitors. JAMA 1988; 259: 65-8.
    CrossrefPubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 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.
    PubMedGoogle Scholar
  • 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.
    PubMedGoogle Scholar
  • 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.
    PubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 15 Freiburghaus C, Berntorp E, Ekman M. et al. Tolerance induction using the Malmo treatment model 1982-1995. Haemophilia 1999; 05: 32-9.
    CrossrefPubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 18 Mariani G, Ghirardini A, Bellocco R. Immune tolerance in hemophilia. Principal results from the international registry. Thromb Haemost 1994; 72 (01) 155-8.
    PubMedGoogle Scholar
  • 19 Mariani G, Kroner B. International immune tolerance registry, 1997 update. Vox Sang 1999; 77 (01) 25-7.
    CrossrefPubMedGoogle Scholar
  • 20 Kroner B. Comparison of the international immune tolerance registry and the North American immune tolerance registry. Vox Sang 1999; 77 (01) 33-7.
    CrossrefPubMedGoogle Scholar
  • 21 Data supplied by the National Hemophilia Foundation (US).
    PubMed
  • 22 Data supplied by the Canadian Hemophilia Society.
    PubMed
  • 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.
    PubMedGoogle Scholar
  • 24 Addiego Jr JE, Kasper C. et al. Increased frequency of inhibitors in African American hemophilia A patients. Blood 1994; (Suppl. 01) 239a.
    PubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 26 Warrier I. FIX antibody and immune tolerance. Vox Sang 1999; 77 (01) 70-1.
    CrossrefPubMedGoogle Scholar
  • 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.
    PubMedGoogle Scholar