Immune tolerance therapy in paediatric haemophiliacs with factor VIII inhibitors: 14 years follow‐up

Abstract

We report our clinical experience in the immune tolerance (IT) therapy of 21 paediatric haemophiliacs with FVIII inhibitor: high responders (16HR) received initially FVIII twice daily at a dosage of 50-300 U/kg/day, 11/16 received a concomitant treatment with activated prothrombin complex concentrate (100-200 U/kg/day). Low responders (five LR) received 20-100 FVIII U/kg every second or third day. Inhibitor elimination was achieved in 19/21 patients in a median time of 4 months in HR and 1.5 months in LR. The outcome and length of time needed to induce IT was significantly correlated with FVIII exposure between the first inhibitor detection and onset of IT therapy and to interruption of IT therapy. For a rapid elimination of FVIII inhibitors it is important to start continuous administration of high-dose FVIII (≥ 100 FVIII U/kg/day) before repeated exposure to FVIII, in order to prevent rebooster effects, prolongation of elimination time, and to reduce expense.

Immune tolerance induction with a high purity von Willebrand factor/VIII complex concentrate in haemophilia A patients with inhibitors at high risk of a poor response

“…Cumulative evidence stemming from national and international registries [5][6][7][8][9] identified the following as potential prognostic factors for a positive response: young age at ITI, recent onset of inhibitors, low anamnestic peak titres and low titres at ITI start-up. Recently, case series [22,21] and in vitro studies [16,29] have suggested a potential additional role for FVIII concentrates with a high content of VWF in the induction of immune tolerance.…”

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

“…Some studies suggested that tolerance could be induced more easily in younger patients with recently developed inhibitors (Kreuz et al, 1995;Mauser-Bunschoten et al, 1995). The IITR (Mariani & Kroner, 2001) showed significantly lower success rates in patients older than 20 years or with long-standing inhibitors (>5 years after diagnosis), however, these findings were not confirmed in the other Registries.…”

“…This issue has had important implications on the different strategies for discontinuing ITI and maintaining tolerance. At variance with Europe, where ITI has been usually continued for several months after inhibitor eradication and FVIII dose gradually tapered off to standard prophylaxis (Mariani et al, 1994;Kreuz et al, 1995;Brackmann et al, 1996;Astermark et al, 2006c), in North America most patients, at least in past experiences, discontinued ITI and started standard prophylaxis as soon tolerance was achieved (DiMichele & Kroner, 2002). Interestingly, in the NAITR inhibitors relapsed in nine of 27 patients who no longer received regular FVIII infusions, over a median follow-up of 19 months.…”

“…According to the pharmacokinetic criteria adopted in the I-ITI study (Table III), 9 months is the minimum period for assessing ITI failure and 33 months should be the longest duration of treatment. However, in clinical practice, ITI is sometimes continued beyond 33 months as some patients may require longer duration of treatment for achieving tolerance, particularly in the presence of infections (Kreuz et al, 1995;Rocino et al, 2006;Kurth et al, 2008). Moreover, the bleeding tendency and the quality of life during ITI should be considered, in parallel with the economic implications of continuing treatment (DiMichele et al, 2007).…”

Comprehensive management of haemophilia A and B

“…This can only be accomplished through a process called immune tolerance, the goal of which is to render the individual immunologically tolerant to the deficient clotting factor. This therapy requires the regular (daily to weekly) infusions of factor VIII or IX by either bolus injection or continuous infusion for a period of weeks to years, with or without the concomitant use of immunomodulatory therapy, such as low-dose cyclophosphamide, high-dose gamma globulin or prednisolone 43,44 . Although this process has an overall 60-80% success rate, it is time-consuming, associated with central venous access complications and often limited by its prohibitive cost.…”