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

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Immune Tolerance and the Treatment of Hemophilacs with an Inhibitor 51 with 200 units per kg bw versus two or three courses with the Malmö protocol but it is true that sometimes that courses have to be repeated. DI MICHELE: I’m just looking at the overall success rates and not quibbling over the cost effectiveness. My second comment refers to the nephrotic syndrome. You didn’t mention whether any of the patients in your cohort were allergic phenotype patients because those are the ones in whom the nephrotic syndrome with immune tolerance has been reported. In the American registry five out of the seven failures were patients who had this allergic phenotype and failed immune tolerance whereas only one of the four successes had this phenotype. There were a total of six out of the eleven patients who were tolerized as part of the North American Registry that had this phenotype and so we may be looking at somewhat different populations. I’m not sure that we can compare the tolerance rates in the North American Registry with the data you have presented here unless there were allergic phenotype patients. BERNTORP: We had one patient who failed who had the allergic phenotype. He developed this allergy and the nephrotic syndrome when we continued with the long-term high dose regimen.There is also the case of another patient who has been subjected to the Malmö protocol who also developed this allergic phenotype in the long term treatment. He was a failure with the Malmö protocol and then he continued. MARIANI: Your data concerning the fact that you start with the lowest possible inhibitor titer either by letting the titer go down because you don’t treat the patient or by using the sepharose column fits very well with the statistical analysis showing that the pre-titer is a very important predictor of outcome. MARTINOWITZ: We had a few patients who failed with the Malmö protocol. We hired a team and a machine which is a very complicated military operation to bring togheter. In two of the five patients we found that there was a change in the pattern of the inhibitor. I believe one had a remaining titer of 20 and the other of 10. They couldn’t have been treated with continuous infusion of factor VIII because the inhibitor became more like a type two inhibitor with much lower avidity and affidity. I don’t know if you have had such experience or if you tested the patients. In all the protocols we should check the inhibitor pattern at the end because if you can treat the patient with factor VIII successfully even for surgical procedures by continuous infusion, then the definition should be changed. BERNTORP: That is not exactly our experience but we have patients on high dose regimens. At the present time we have one small child who has been on 200 units per kg bw for a long time and indeed his bleedings have entirely disappeared. Therefore I agree with you that factor VIII may have a hemostatic effect despite the fact that you measure a rather high inhibitor titer in vitro. HUGHWORTH: As for nephrotic syndrome I’m not absolutely certain that it is always associated with the Ig. We were referred a patient to go on the FVII a surgical trial for renal biopsy who had developed nephrotic syndrome, who had no prior history of anaphylactoid reactions whatsoever and had been on it for about six and a half months. On laproscopic biopsy of the kidney we found focal-sclerosis and glomerulonephritis. Thus I’m not entirely convinced that you have to have a prior Ig event to get nephritic syndrome. It may well be related to the stoichiomotry of nine versus eight in that you’re giving fifty fold greater amounts of protein to treat therapeutically the same number of units. HYBERG: How many absorptions do you perform and how fast does the inhibitor titer rise after the absorption BERNTORP: Usually, we perform two; one absorption each during two consecutive days and two to three plasma volumes are processed each day. The typical pattern is that you take down the inhibitor within the first absorption to, for example, ten Bethesda units and the next morning it will have risen and therefore you perform a new absorption and then you can come close to zero in the average patient. If you then give the patient factor VIII for treatment of a bleed as we have done sometimes, and you do not start with an immune tolerance induction dose then the inhibitor comes back within approximately seven days. MAUSER: We have one hemophilia B patient who was tolerized with the low dose Dutch regimen with 50 I.U of factor IX every other day and he had no anaphylaxis in his history, but after about five years of tolerance induction regime he developed nephritic syndrome while he was on a thousand units every other day of factor IX monoclonally purified. He had a very low dose of factor IX if you consider that he was a patient of 80 kg. BERNTORP: Had he been an inhibitor patient five years before MAUSER: Yes. Haematologica vol. 85(supplement to n. 10):October 2000
Haematologica 2000; 85(suppl. to n.10) p. 52-56 Registries of Immunotolerance Protocol Immune tolerance induction: prospective clinical trials CHARLES RM HAY University Dept. of Hematology, Manchester Royal Infirmary, Oxford Road, Manchester, UK ABSTRACT Successful immune tolerance induction (ITI) relates significantly to the starting inhibitor titer but not the peak historical inhibitor titer. Below a starting titer of 10 BU/mL success appears to be unrelated to the dose of factor VIII (FVIII) used for ITI. Above this starting titer, larger doses of FVIII may be associated with a better outcome from ITI. Opinion on the importance of the dose of FVIII used for ITI is polarized and there is no agreement on the optimal regimen for ITI. A prospective randomized clinical trial is proposed in which patients will initially be treated on demand with bypass therapy until the inhibitor titer has fallen below 10 BU/mL. Patients will then be randomized to receive a high or lowdose regime. Efficacy, cost-effectiveness and morbidity will be compared. ©2000, Ferrata Storti Foundation Our current knowledge of immune tolerance induction is not derived from prospective comparative clinical trials but from several series of patients treated with various single regimens, reported partly retrospectively and partly prospectively, 1-4 and from three retrospective surveys or registries. 5-9 The former studies report the single center experience of individual regimes. Although all used a similar pharmacokinetic definition of success (restoration of normal half-life and recovery), patient-selection varied from study to study and in some cases the regime evolved during the course of the study. 1-4 Although the VanCreveld 1 and Malmö 2 studies are both true cohort studies, the Bonn series excluded low level inhibitors and the precise inclusion criteria are unclear. 3 These differences render a valid direct comparison of the regimes difficult, even though the reported success-rate from the three centers is very similar. The registries were set up to determine predictors of success or failure of ITI and to provide some comparison between regimes. The registries differ in their method of data collection Correspondence: CRM Hay, M.D., University Dept of Haematology, Manchester Royal Infirmary, Oxford Road, Manchester M13 9WL, UK. Phone: international +44-161-2764727 Fax: international +44- 161-2764814 – E-mail: haemophilia@man.ac.uk and even their end points and this limits the extent to which their data may be compared. All are retrospective surveys in which the data are relatively soft and reporting bias cannot be excluded. Although all three registries use a standardized questionnaire, this is not standardized between the registries. The North American Registry (NAITR) 7,8 appears to have a softer definition of success than the other registries. The German Registry 9 collected no data on the use of low-dose regimens and so can provide no insight into their efficacy. Despite these limitations the registries have established most of the predictors of successful ITI, although a number of questions remain unanswered or a source of controversy. ITI is successful in up to 90% of patients although it is not agreed how these patients should be selected or which regime should be used. Both the International Immune Tolerance Registry (IITR) and the NAITR showed that the most important predictor of successful ITI was the inhibitor titer at the start of ITI, which affected both the likelihood of success and the time taken to achieve tolerance. 5-8 An inhibitor titer 500 BU/mL to predict a poor outcome. Since the starting inhibitor titer is far more predictive of outcome than the peak inhibitor titer, the chance of successful ITI may be enhanced by deliberately deferring the initiation of ITI until the inhibitor titer has declined below 10BU/mL. During this interval, Haematologica vol. 85(supplement to n. 10):October 2000
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Haematologica established in 1920 e
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II Immune Tolerance and the Treatme
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