Haematologica 2000;85:supplement to no. 10 - Supplements ...

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Immune Tolerance and the Treatment of Hemophilacs with an Inhibitor 49 300 5 Yes 7.7 2 2 150 12 Yes, relapse Relapse after 6 months 3 1 >300 14 After 6 months 16 4 1 >600 10 Yes 13.6 5 1 120 46 Yes Not known 6 1 100 22 Yes 9 7 3 >300 5 No Not tolerant 8 2 429 1.6 No Not tolerant 9 1 3 29 No Not tolerant Haematologica vol. 85(supplement to n. 10):October 2000
50 E. Berntorp et al. standing inhibitor, prior to immune tolerance induction. In several patients it is evident that frequent treatment with FVIII alone or in combination with cyclophosphamide attenuated the anamnestic response. Thus the historical peak is probably not really relevant to the type of immune response in certain patients entering the Malmö protocol. This might explain the apparent decrease in the success rate during recent years. An alternative explanation may be that a switch from intermediate purity products to ultrapure or recombinant products has occurred, especially during the last decade. Whether product purity has an impact on IT tolerance outcome remains an open question, however. Our IT regimen for hemophilia A has changed somewhat, because of the observation that important factors for a successful outcome are, among others, low current inhibitor titer and long intervals since previous replacement therapy. This means that in a small child who develops an inhibitor, the optimal use of the Malmö protocol would require a long waiting period before IT is implemented. This could jeopardize the child´s health, due to recurrent hemorrhages. Therefore, in children with a newly detected inhibitor we prefer to start immediately with a Bonn-like regimen, giving at least 200 units of FVIII per kg bw daily. The Malmö protocol is mainly reserved for patients with longstanding inhibitors prior to IT. For hemophilia B, we have treated 9 patients as of October 1999. The study material and the results are shown in Table 2, from which it can be seen that one relapse occurred after 6 months. This patient received another course of treatment, which was terminated when the patient developed signs of an acute myocardial infarction. He later developed cardiac failure and expired from heart failure several years later. The treatment given was the full protocol including protein A adsorption. The FIX concentrate used was a prothrombin complex concentrate. Thus, of the 9 patients treated of whom one had a low-responding inhibitor, tolerance was achieved in 6 (67%). Relapse occurred in one patient so the final success rate was 5/9 (56%). The conclusions drawn from treatment of patients with hemophilia B are that the Malmö model gives a comparatively high response rate in the treatment of high-responding FIX inhibitors, and that only purified FIX concentrate should be used, in order to minimize the risk of thromboembolic complications. In addition, the short treatment period used for the Malmö protocol should, from a theoretical point of view, minimize the risk of developing nephrotic syndrome, a known complication of long-term high-dose FIX treatment. 5 REFERENCES 1. Nilsson IM, Jonsson S, Sundqvist SB, Ahlberg Å, Bergentz SE. A procedure for removing high titer antibodies by extracorporeal protein sepharose A adsorption in hemophilia: substitution therapy and surgery in patients with hemophilia B and antibodies. Blood 1981; 58:38-44. 2. Nilsson IM, Berntorp E, Zettervall O. Induction of split tolerance and clinical cure in high-responding hemophiliacs with factor IX antibodies. Proc Natl Acad Sci USA 1986; 83:9169-73. 3. Nilsson IM, Berntorp E, Zettervall O. Induction of immune tolerance in patients with hemophilia and antibodies to factor VIII by combined treatment with intravenous IgG, cyclophosphamide, and factor VIII. N Engl J Med 1988; 318:947-50. 4. Freiburghaus C, Berntorp E, Ekman M, Gunnarsson M, Kjellberg BM, Nilsson IM. Immunoadsorption for removal of inhibitors: update on treatment in Malmö- Lund between 1980 and 1995. Haemophilia 1998; 4: 16-20. 5. Warrier I. Management of haemophilia B patients with inhibitors and anaphylaxis. Haemophilia 1998; 4: 574-6. DISCUSSION 6 The Malmö Protocol Update Berntorp E (Malmö, Sweden) DI MICHELE: I would like to make a comment and ask a question with respect to the hemophilia B data. If you look at your success rates and the relapse in six months, I’m not convinced that you shouldn’t consider it five successes out of nine patients. What is more important is that if you count up the number of courses of treatment that they were required to achieve those successes, what you really have are seven successful courses out of a total of thirteen. Most of us were presenting success in terms of immune tolerance perceived success in terms of a single course of therapy. You have multiple courses here. BERNTORP: In a few patients we gave multiple courses. It is very important to look at the economic aspects here. We have always stressed that these courses sometimes have to be repeated. There is a big difference between a median of twelve months immune tolerance induction Haematologica vol. 85(supplement to n. 10):October 2000
Page 1 and 2: Haematologica established in 1920 e
Page 3 and 4: Acknowledgments We wish to thank th
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Page 7 and 8: 4 J.M. Lusher (range 1-34) for pati
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Page 19 and 20: 16 J. Ingerslev be established more
Page 21 and 22: 18 J. Ingerslev sion monitoring dem
Page 23 and 24: 20 J. Ingerslev REFERENCES 1. Hay C
Page 25 and 26: 22 CRM Hay Side effects of Hyate:C
Page 27 and 28: 24 CRM Hay tion by porcine factor V
Page 31 and 32: 28 P. Lollar these epitopes by site
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Page 73 and 74: 70 E. Berntorp Hemophilia A severe
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116 G.C. White et al. Blood 62:141-
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II Immune Tolerance and the Treatme
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