Tolerance induction using the Malmö treatment model 1982–1995

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.

The international immune tolerance study: a multicenter prospective randomized trial in progress

“…To date, 14 (31%) have become tolerant after a median of 12 months (range: 5-25) of treatment and have a median FVIII half-life of 7 h (range: 6.5-9.9). Although the two treatment arms cannot yet be compared, the median time to the achievement of each incremental milestone of ITI success for the whole cohort is similar to the data published on patients treated with high-dose ITI [5][6][7][8][9]. To date, seven of 45 subjects (15%) have failed ITI according to study criteria.…”

“…While previous studies have shown that the risk of venous thrombosis (VT) among overweight or obese individuals is increased compared with normal weight individuals [2][3][4][5][6], the risk associated with modest levels of excess weight and with below-normal weight has not been explored in detail. Additionally, little is known about the role of postmenopausal hormone therapy, a known risk factor for VT [7,8], in modifying the association between excess weight and VT risk. Using data from a large, population-based case-control study, we examined (i) whether an increased body mass index (BMI), a proxy for adiposity, increased the risk of VT among postmenopausal women; and (ii) whether hormone therapy modified this association.…”

Optimizing management of immune tolerance induction in patients with severe haemophilia A and inhibitors: towards evidence‐based approaches

“…As reported when the Malmö protocol was increasingly used in patients with poor predictors of success (Freiburghaus et al, 1999) and later in the ITI registries (DiMichele, 2009), no impact on either the success rate or the time to success was shown in patients receiving adjunctive immune modulating treatment. Therefore, no evidence is available to support the role of immune modulating agents or immunoadsorption as first-line components of ITI regimens (DiMichele et al, 2007).…”

Current Controversies in the Formation and Treatment of Alloantibodies to Factor VIII in Congenital Hemophilia A

“…Most patients are then given a single dose of oral corticosteroids (50-150 mg), followed by cyclophosphamide (12-15 mg/kg IV for 2 days, then orally 2-3 mg/kg/d for an additional 8-10 days) and IV immunoglobulin (0.4 mg/kg/d for 5 days) with the start of high daily doses of FVIII. 21 Unanswered is whether the addition of such agents can reduce the time and intensity of ITI needed and whether this would aid in tolerizing individuals who did not succeed with traditional ITI with FVIII alone. There are emerging concerns that one ITI regimen does not fit all; that is, inhibitor immunology is complicated and involves many different pathways.…”