The German National Immune Tolerance Registry, 1997 Update

Abstract

Haemophilia treatment has overcome many obstacles and risks, but the appearance of inhibitors to coagulation factors VIII (FVIII) and IX (FIX) remains a difficult problem. The special treatment to eradicate inhibitors in haemophilia has a long tradition in Germany, starting at the haemophilia centre in Bonn with the first patients successfully treated. Afterwards, many other centres in Germany have also performed this method to induce tolerance. German treatment centres wanted to have an overview about all their results in the large number of ITTs which were performed here. Therefore, 22 treatment centres have participated in the study. Immune tolerance therapy had been performed on 118 patients of these centres. Only 20 of the patients were low–responders, all the others were high responders with different inhibitor levels (fig. 1). The age distribution shows, that they came from all age groups up to 50 and 60 years, however, over two–thirds of the patients were young children.All the 118 patients were classified into five types. Classification type ‘1’ means, that the therapy is finished with normal recovery and half–life, type ‘2’ means the therapy is finished, the inhibitor is below 2 Bethesda units (BU) and also recovery and half–life are not 100% normal. Type ‘3’ means therapy is finished without success for different reasons. In type ‘4’ the therapy is not finished, the inhibitor level is below 2 BU, that means clinically there is quite a good result in comparison to the high inhibitor at start, but the therapy is ongoing. In type ‘5’ the therapy is not finished and the inhibitor level is higher. Factor IX (FIX) inhibitors are also included here. We have only four patients with FIX inhibitors reported to us who had ITT, and out of this in two the therapy failed and in the other two the therapy is ongoing.In group 4 and 5 we have altogether 12 patients, 8 and 4 respectively, in group 4, 4 patients are below 2 years in treatment, and in group 5, there are 3 of 4 below 2 years in treatment. So we can hope that this treatment will end at least in some of them being successful too. These 12 patients out of the 118 are not mentioned further. The additional considerations are done only with the first three groups – on these groups, where the therapy is really finished.Out of the 106 patients with completed treatment, 86 (81%) had a full success, 4% had a clinical success but a remaining shortened half–life, and in 15% the therapy failed (table 1).If low (≤5 BU) and high responders (>5 BU) are observed separately, one can see that the treatment success rate in the low responders was 94%, that means only one of 18 treatments failed. But even in the high–responders we had nearly 80% success and if we take the patients of group 1 and 2 together, we have a good clinical result in 83% of patients with inhibitor titres above 5 BU.A very important issue from this clinical point of view are the variables, which can affect the outcome of immune tolerance therapy. These are: age, characteristics of inhibitor as high or low–responder, the interval between detection of inhibitor and start of treatment, exposure to FVIII or FIX in this interval, ITT dosage, additional administration of APCC, interruptions of therapy, maximum inhibitor level, maximum inhibitor level during ITT, inhibitor level at start of therapy and others. It was our aim to show the influence of these variables on our patients outcome.Figure 2 shows the influence of the maximum inhibitor level on the outcome. If the inhibitor level remains below 100 BU, the success is nearly complete. We have a success rate of 94, 100 and 93% if the inhibitor is below 5, 10 or 100 BU respectively. But in the range with inhibitor titres above 100 BU the success rate falls rapidly towards 60% and if maximum titres are above 1000 BU only a few more than half of the patients reach tolerance.If we take the initial inhibitor increase to a maximum during ITT as a prognostic sign, the phenomenon of bad success is even a bit more pronounced in the high inhibitor ranges.We were also looking on the influence of the inhibitor levels at start of ITT. We had bad success rates when a very high inhibitor level at start was registered.Logistic regression analysis with backward variable selection shows, that the really significant variable in this test was the maximum inhibitor level with a very low p–value (table 2). Not significant variables were the interval between detection of inhibitor and ITT, exposure days between detection of inhibitor and ITT, the administration of APCC concentrates and the age at start of ITT.Most patients were treated with dosages of 200 or 300 U/kg per day. There was no significant difference in the success rates of these two dosages, but comparing the duration of ITT until patients succeeded in getting either 200 or 300 U/kg, we found a duration of 109 weeks and only 53 week respectively.What about the influence of dosage and maximum inhibitor levels during ITT on outcome? With 100 U FVIII/kg daily or less, we have only a few patients, most of the patients were treated with 200 or 300 units. If the maximum inhibitor level did not exceed 100 Bethesda units, treatments with nearly all dosages were successful. In the patients with inhibitor titre of more than 100 Bethesda units the success rate was lower and it was not really increasing with a higher dosage. Because only 11 out of 53 patients were treated with 100 U/kg or less it is not possible to do a statistical analysis. In some patients which were successfully treated a high dosage was chosen after a low dosage failedThe influence of time interval between detection of the inhibitor and start of ITT on the outcome is a further important question (fig. 3). We formed four groups: all of patients that started therapy instantly after detection of the inhibitor, within one month, within two and 12 months and all others who started therapy after one year (fig. 3). In our patients ,statistically there are no significant differences between the groups.The influence of exposure days between detection of the inhibitor and start of ITT also was statistically not significant. There is only a certain trend for a somewhat better success when ITT starts without many exposure days than if it starts later.It is really very interesting to look for patients having an interruption of therapy. In 18 out of the 102 patients an interruption of the treatment was reported. In nearly half of these patients (in 8 of 18) therapy failed. This is a success rate of 55% only. The success rate in patients with continuous therapy was in contrary 88%. The difference was statistically significant (table 3).