Tolerance induction using the Malmö treatment model 1982-1995: TOLERANCE INDUCTION, MALMÖ 1982-1995

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Abstract

The ultimate goal in the treatment of haemophilia patients with inhibitors is to eradicate permanently the inhibitor and induce tolerance. Here we summarize our experience at the Malmö centre regarding tolerance induction according to the Malmö Treatment Model. The protocol includes immunoadsorption if needed, neutralization of inhibitor and replacement with factor concentrates, cyclophosphamide intravenously for 2 days (12-15 mg kg-1 bw) and then orally (2-3 mg kg-1 bw) for an additional 8-10 days and intravenous gammaglobulin daily at dosages of 0.4 g kg-1 bw for 5 days. This protocol has been applied in 23 haemophilia patients with inhibitors, 16 haemophilia A patients and seven haemophilia B patients. Altogether 36 attempts have been made to induce tolerance. Ten of the 16 haemophilia A (62.5%) and 6/7 patients with haemophilia B (86%) became tolerant after the treatment. The chances of success or failure are roughly equal, if the series is considered in a historical perspective. The data showed that the chances of success in tolerance induction with the Malmö protocol were best in those patients with low inhibitor titres, with relatively low historical inhibitory peak and with a long interval since the previous replacement therapy. This was especially true where no inflammatory state was present at the start or during tolerance induction. The advantage with this method compared to the high-dose regimen is that in the successful cases tolerance can be achieved within 3-4 weeks.

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Most cited references 24

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HIGH-DOSE INTRAVENOUS GAMMAGLOBULIN FOR IDIOPATHIC THROMBOCYTOPENIC PURPURA IN CHILDHOOD

P Imbach, V D'Apuzzo, A. Hirt … (1981)

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Loss of high-responder inhibitors in patients with severe hemophilia A and human immunodeficiency virus type 1 infection: a report from the Multi-Center Hemophilia Cohort Study.

James J Goedert, Anna B Kroner, M Ragni … (1993)

To evaluate the effects of human immunodeficiency virus type 1 (HIV-1) infection on the loss of factor VIII alloantibodies, we identified 77 patients with a history of inhibitors from among a large cohort of HIV-1-infected participants enrolled in a natural history study of HIV-1 infection in hemophilia. Fifty-six patients were high responders with inhibitors titers greater than 5 Bethesda Units (BU) measured on at least one occasion. From May 1985 to December 1989, 13 of the high-responder patients were rechallenged with factor VIII concentrates after several years of treatment with other plasma products. All exhibited excellent hemostasis upon reinstitution of factor VIII. Seven of the 13 patients (11.3-46.3 years of age) were in the advanced stages of HIV-1 infection at the time of rechallenge. Inhibitor titers measured subsequent to the reinstitution of factor VIII were consistently less than 1 BU in five of these seven patients. The remaining six patients (6.1-57.5 years of age) had mild to moderate CD4+ lymphocyte depletion (absolute CD4+ cells: 262-935/mm3) at the time of factor VIII rechallenge. Follow-up inhibitor titers were negative 7-42 months after consistent factor VIII use in these six patients. The lack of anamnestic response to factor VIII in all 13 patients who were rechallenged indicates that HIV-1-infected patients who have a history of high-responder inhibitors frequently benefit from the reintroduction of factor VIII use for the control of bleeding, regardless of their stage of HIV-1 disease.

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Transient reversal of thrombocytopenia in idiopathic thrombocytopenic purpura by high-dose intravenous gamma globulin.

Lawrence V Hofmann, U Kappeler, J Fehr (1982)

Since recent observations indicate that treatment with high-dose intravenous polyvalent intact immunoglobulin leads to a rapid reversal of thrombocytopenia in the idiopathic thrombocytopenic purpura (ITP) of childhood, we decided to apply this treatment to adults with ITP and to test the possibility that the effect of the immunoglobulin might be attributable to transient blockade of the reticuloendothelial system. Using sequential clearance studies of autologous 99mTc-labeled and anti-Rh(D)-sensitized erythrocytes in four adults with ITP who were treated with total doses of 1 to 1.5 g of immunoglobulin per kilogram of body weight, we found that a transient rise in platelet counts to normal levels within four to five days was accompanied by a marked temporary prolongation of the immune-particle clearance time. These data suggest that commercial intravenous immunoglobulin preparations may interfere with phagocyte Fc-receptor-mediated immune clearance. Since platelets in ITP treated with immunoglobulin were fully hemostatic, this type of therapy may allow surgical procedures to be performed safely in patients with this disease.