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Immune Tolerance and the Treatment of Hemophilacs with an Inhibitor 53 exposure to factor VIII should be avoided or minimized by treating bleeding, on-demand, using bypass-therapy, preferably recombinant VIIa (Novoseven, Novo, Denmark). If ITI is started at the first opportunity, as is common current practice, ITI will often start shortly after some earlier treatment with factor VIII, during a secondary immune response to factor VIII and when the inhibitor titer may be rising rapidly. This may reduce the chance of achieving successful ITI. Treatment in which ITI was deferred until the inhibitor titer was
54 C.R.M. Hay Logistic barriers to conducting a randomized trial of ITI Patient numbers The literature is disparate, which makes an accurate estimation of the power of the study difficult. However, using a crude meta-analysis of the available studies suggests that about seventy patients may be required in each treatment arm. A further three patients are required per arm to compensate for the loss of statistical power introduced by the two interim safety analyses. This gives a total sample size of about 75 per treatment-arm. To recruit such a large number is clearly challenging. The size of the problem is well illustrated by considering the potential for recruitment from a single country, the United States of America. In the USA about 200 PUPS a year are born with severe hemophilia. At least 20 % will develop persistent inhibitors i.e. 40 patients per year. About 70% of these are estimated to be eligible for the study giving a potential total of 56 patients over two years. Clearly, multinational collaboration is required for such a study to be completed within a reasonable time. It is therefore, proposed to conduct this study throughout North America and Canada, throughout Western, Northern and Southern Europe, Israel, Australia, New Zealand and possibly Japan. Factor VIII shortages The study permits the use of any brand of factor VIII for ITI, from intermediate-purity plasmaderived concentrates to second-generation B- domain deleted recombinants. The choice of product is left to the managing clinician, the only stipulation in the protocol being that we would not wish a change of product during ITI. [The clinician is not obliged to tolerize using the same product that the patient was using when the inhibitor was first detected, although they commonly would.] Despite reports suggesting that intermediate-purity products are more effective for ITI, 13 there is no convincing evidence that product type affects the outcome of ITI and there are several reports of good results using high-purity or recombinant factor VIII for ITI. 9,10,14 We anticipate that most clinicians will choose to induce tolerance using recombinant factor VIII because most children in the participating countries are treated using these products. Demand for recombinant factor VIII has outstripped supply, and increasing production capacity is a very slow process with a very long lead-in time. Some manufacturers are rationing their products on a world-wide basis and have refused to supply recombinant factor VIII for immune tolerance because they have already too small an allocation for their existing customers. We estimate that the average patient tolerized using the van Creveld regime will require about 0.25M units compared to 1.0M units required for the average patient tolerized using the Bonn regime. We have deliberately deferred starting this study for over a year now because the supply of recombinant factor VIII was insufficient to sustain the study. It would appear that the supply of recombinant will soon ease, permitting the study to start. The recent opening of Baxter’s Thousand Oaks Plant, licensing of Refacto (Wyeth/GI B-domain deleted factor VIII) and imminent licensing of Kogenate SF should all lead to an easing in supply from the end of the first quarter of the year 2000. We hope to start our study at about that time. Further information on this study is available from haemophilia@man.ac.uk, dmdimich@mail.med.cornell.edu or http://www.itistudy.com. REFERENCES 1. Mauser-Bunschoten EP, Niewenhuis HK, Roosendaal G, van den Berg HM. Low-dose immune tolerance induction in haemophilia A patients with inhibitors. Blood 1995; 86:983-8. 2. Nilsson IM, Berntorp E, Zettervall 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; 318:947-50. 3. Brackmann HH, Oldenburg J, Schwaab R. Immune tolerance for the treatment of factor VIII inhibitors – twenty years of the Bonn Protocol. Vox Sanguinis 1996; 70: (Suppl):30-5. 4. Kreutz W, Ehrenforth S, Funk M, et al. Immune-tolerance therapy in paediatric haemophiliacs with factor VIII inhibitors: 14 years follow-up. Haemophilia 1995; 1:24-32. 5. Mariani G, Ghirardini A, Belloco R. Immune-tolerance in hemophilia: principal results from the international registry. Thromb Haemost 1994; 72:155-8. 6. Mariani G, Kroner BL. International Immune Tolerance Registry, 1997 update. Vox Sang 1999; 77:25-7. 7. DiMichele DM, Kroner BL, and the ISTH Factor VIII/IX Subcommittee. Analysis of the North American Immune Tolerance Registry (1993-970: current practice implications. Vox Sang 1999; 77:31-2. 8. DiMichele DM, Kroner B. Analysis of the North American Immune Tolerance Registry (NAITR) 1993-1997: current practice implications. ISTH Factor VIII/IX Subcommittee Members. Vox Sang 1999; 77 (Suppl 1):31-2. 9. Lenk H and the Study Group of German Haemophilia Centres. The German National Immune Tolerance Registry, 1997 update. Vox Sang1999; 77:28-30. 10. Kroner B. Comparison of the International Immune Haematologica vol. 85(supplement to n. 10):October 2000
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Acknowledgments We wish to thank th
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Page 25 and 26: 22 CRM Hay Side effects of Hyate:C
Page 27 and 28: 24 CRM Hay tion by porcine factor V
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II Immune Tolerance and the Treatme
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