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

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Immune Tolerance and the Treatment of Hemophilacs with an Inhibitor 85 national Registry: report of the Factor VIII and IX Subcommittee. Thromb Haemost 1994; 72:1:155-8. 3. DiMichele DM, Kroner BL. Analysis of the North American Immune Tolerance Registry (NAITR) (1993- 1997): current practice implications. Blood 1997; 90:10:Suppl 1:156a. 4. Colowick AB, Bohn R, Avorn JL, Ewenstein BM. Immune tolerance induction for hemophilia A patients with inhibitors: a cost-effectiveness analysis. Blood 1998; 92:10:553a. 5. Aledort LM and the Baxter Previously Untreated Patient Study Group. Immune tolerance induction in hemophiliacs: can we afford it Is it worth it Transfusion 1999; 39:1034-5. DISCUSSION 17 Economic and organizational issues Mariani G (Palermo, Italy), Aledort L (New York, USA) BERNTORP: I would like to reiterate the fact that the treatment of hemophilia is one of the most cost-effective treatments that we have. In Sweden the total cost for arterial hypertension is about fifteen times that of hemophilia care. So, I think it’s important to look at the tremendous costs in that perspective. DI MICHELE: I’d like to comment on the data that Dr.Mariani has just presented; I think that we will hopefully have a chance in the prospective study to assess the prognostications that you predict in terms of patients with favorable predictors versus those who do not have favorable predictors. I think that we will be starting tolerance much earlier than your data indicate based on your weight assessments of 25 kilos; it’s very possible that the average weight that we calculated was probably closer to 12 kilos. The cost of that may well be half which is good news that in terms of the high-dose arm that 75% of our patients should achieve tolerance within a year and this will also depend on their pre-titer. I think we have seen some rather favorable predictions and it will be very interesting to see what happens in the study with regard to those patients who fulfill your criteria. MARIANI: Yes. These are just calculations and yet I think it is important to state that what we have identified as additional costs might not turn out to be additional costs because the patient has to be treated anyway. Nursing problems and venous success are certainly notable costs for an inhibitor patient who is not on IT in the first case. All the other costs such as recombinant factor VIIa are still costs for a patient who is not on IT. I would keep the attention focused on the real costs which are mostly for factor VIII. DI MICHELE: To play devil’s advocate, I would like to point out that you arbitrarily picked a time of one year. Remember the overall cost of tolerance has not only to do with the size of the child and the ultimate dosage but really the dosage over time. I think one of the important aspects is that of using less factor even if it may take a longer time to achieve tolerance. Does it end up being more cost effective than higher doses over a shorter period of time Those are questions that can’t really be addressed unless they are studied prospectively. MARIANI: We have to be on the safe side because if you use a lower dosage it could be that it takes more time. I think that it’s preferable to start with a high dose and reduce the duration of treatment; it’s also a matter of the quality of life. BEARDLEY: We have done an analysis of some of our inhibitor patients. Some of them are acquired hemophiliacs but once they have a bleeding episode it becomes a kind of a gamble because those patients cost us around $20,000 per day of hospitalization for their blood product usage and you can have astronomical costs for individual patients if they happen to have a compartment syndrome or intercranial bleed. I am very much in favor of the cost-effectiveness of preventing those kinds of episodes. MARIANI: Reducing costs has to be considered as a very important aspect because the patient not on ITI has more bleedings and so ITI in the long run might cost less. If you treat a patient while he is young and with a favorable prognosis, this should be the best choice ALEDORT: I think that’s the nice part of the Harvard model which is going to be refined. It’s going to be important to put real data and not just modeling into the costs of care both before and after ITI. MARTINOWITZ: I would like to stress the cost of regular treatment of inhibitor patients and of course the patients with the burnt out joints which it must be said are relatively rare. In these patients the cost effectiveness will be low. But then we have to think about children who are bleeding every day or every other day. We have two children and one of these children costs £!,000,000 a year and the other costs close to $4,000,000 a year. These are children who weigh 40 and 20 kilos. If you take this into account then the cost effectiveness of immune tolerance is so clear. Haematologica vol. 85(supplement to n. 10):October 2000
Haematologica 2000; 85(suppl. to n.10) p. 86-88 Immunetolerance: Molecular and biological aspects Characterization of antibodies to factor VIII in hemophilia A patients treated by immune tolerance therapy DOROTHEA SCANDELLA, HERBERT REYES, MATTHEW FELCH, YOSHIHIKO SAKURAI American Red Cross, Holland Laboratory, Rockville, MD, USA Abstract The treatment of hemophilia A patients has improved in this decade by production of recombinant factor VIII (FVIII) in mammalian cells, which has significantly reduced contamination by infectious agents. A remaining serious problem in 25- 30% of patients with severe hemophilia A is the appearance of antibodies that inactivate FVIII. The present therapy for this condition is frequent treatment with high doses of FVIII to induce tolerance, which is defined as a negative Bethesda assay. Serial plasma samples from 50 evaluable patients in a large study of 72 previously untreated patients were tested to determine whether tolerized patients have actually lost all their anti-FVIII by using a 10 fold more sensitive immunoprecipitation (IP) method of measuring all anti-FVIII antibodies. Six of the 22 patients with inhibitors were given tolerance therapy, and 3 of them were only partially tolerized as determined by IP assay. Seven patients with 1-11 BU/mL lost their inhibitor spontaneously, while 5 non-inhibitor patients with low level immune responses similarly became antibody negative. In a smaller study, a tolerized patient with 0 BU/mL had remaining non-inhibitory antibody levels high enough to reduce the FVIII half-life significantly. Plasmas from 2 patients who were not tolerized, were tested by the IP assay for the A2 and/or C2 domain specificity of the anti-FVIII over time.The antibodies detected were directed against both the heavy and light chains of FVIII, and they increased and decreased at the same rate before and during tolerance therapy ©2000, Ferrata Storti Foundation Key words: factor VIII, hemophilia A, immune tolerance, anti-Factor VIII antibody Treatment of individuals with hemophilia A in past decades was often compromised by factor VIII (FVIII) contamination with infectious agents from the human plasma used for the purification of FVIII. Both hepatitis A and AIDS viral infections were detected in a significant portion of these patients. Within the past few years the FVIII therapeutic products Correspondence: D. Scandella, Ph.D., American Red Cross, 15601 Crabbs Branch Way, Rockville, MD 20855, USA, Phone: international +001-301-738-0750, Fax: international +1-301-738-0794 given for therapy of hemophilia A have been improved by better viral inactivation steps and by production of recombinant factor VIII in mammalian, non-human cell lines. 1,2 So far the recombinant FVIIIs have not caused the previous problems or any new ones. The most serious remaining problem of FVIII therapy is the production of anti-FVIII inhibitor antibodies that arise in about 25-30% of individuals with severe hemophilia (1-2% FVIII) 3 and less often in those with mild and moderate hemophilia. As these antibodies can inactivate FVIII and are consequently referred to as inhibitors, they represent a serious challenge to effective therapy. Patients with a common FVIII gene inversion, large deletions, and some nonsense mutations 4 are more likely to develop anti- FVIII antibodies because they have no circulating FVIII antigen and are therefore not tolerant to FVIII infusion. The current clinical strategy for significantly reducing or eliminating anti-FVIII is to give frequent doses of FVIII in low, medium, or high doses that eventually reduce antibody levels to very low or non-existent levels, as measured by the Bethesda assay. 5 A study using low FVIII doses (25 U/kg every other day) led to immune tolerance in 21 of 24 patients. 6 Another study treated high titer inhibitor patients with FVIII doses of 100 U/kg/day and FEIBA, a source of factor IXa. Twelve of the 15 patients had inhibitor titers that dropped to ≤1 BU/mL, and their FVIII recovery and half-life was normal. 7 We examined the status of antibody development in several studies of previously untreated patients who received treatment with recombinant FVIII and others who used either plasmaderived or recombinant FVIII. We particularly focused on those patients who had immune tolerance therapy to determine whether all their antibodies disappeared by using a highly sensitive immunoprecipitation assay. Using this method we also tested patient plasmas with low or no Bethesda titer to determine whether such titers corresponded to significant amounts of antibody and whether the BU negative individuals ever had low level immune responses to FVIII. Haematologica vol. 85(supplement to n. 10):October 2000
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Acknowledgments We wish to thank th
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