2003; baxter - Supplements - Haematologica

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[Round Table on Immune Tolerance Treatment]Twenty years of experience withlow dose immune tolerancereview paperhaematologica 2003; 88(suppl. n. 12):34-39http://www.haematologica.org/free/immunotolerance2001.pdfEVELIEN P. MAUSER-BUNSCHOTEN,H. MARIJIKE VAN DEN BERG, GORIS ROOSENDAALVan Creveldkliniek, Univerisity Medical Center Utrecht,The NetherlandsCorrespondence: Evelien P. Mauser-Bunschoten, Van Creveldkliniek,University Medical Center Utrecht, Postbox 85000,C01-425, 3508 CX Utrecht, The Netherlands.Phone:international +31.30.2508449. Fax:international+31.30.2503854. E-mail: E.Mauserbunschoten@digd.azu.nlSome patients with inhibitors develop a hightiter antibody, having a brisk anamnesticresponse following infusion with any factorVIII material. In some of these patients theinhibitor disappears spontaneously after stoppingfactor VIII, but will relapse after the nextfactor VIII infusion. 1,2 For this reason factor VIIItherapy was stopped as soon as a hemophiliapatient developed an inhibitor until 1980.In 1974 Brackmann made a first serious protocolfor the irradiation of inhibitors in hemophiliaA by designing the so called Bonn protocolfor induction of immune tolerance in thesepatients. 3 The protocol originally daily infusionswith high dose factor VIII were given in combinationwith activated prothrombin complexconcentrate (APPC, FEIBA). This regimen wassuccessful in patients with low and extreme hightiter inhibitors. Since the beginning of the 1980svarious regimens for the introduction ofimmune tolerance were introduced. 4,8 Sometimesplasmapheresis, cyclophosphamide, gammaglobulinor corticosteroids were added tothese regimens. 9,10 All these strategies had incommon that they were not based on any quantitativeresearch and that nobody understood themechanism of successful treatment.Low dose immune tolerance therapyLow dose immune tolerance therapy wasdeveloped because this was thought to be lessdemanding for patients and staff becausepatients have to be infused only 2-3,5 timesweekly. Also the amount of factor VIII infused islow, making it for economical reasons moreattractive.In the Netherlands this low dose immune toleranceregimen was first introduced in 1981 inthree young patients with life threatening bleeds.Dosage regimenIn patients in whom factor VIII was startedwith the only aim of obtaining immune tolerance,the factor VIII dosage was 25-50 Units factorVIII per kilogram bodyweight (U FVIII/kgbw) every other day or three times a week, inde-pendent of their inhibitor titer. Initially in veryyoung children in whom venous access was difficult,factor VIII was injected twice weekly. Since1990 in these patients an intravenous catheter(Port-a-Cath system, PAC) is implanted in orderto obtain adequate venous access.)When factor VIII treatment was startedbecause of an operation or life-threateningbleeding and the inhibitor was less than 10BU/mL, an initial high dose of factor VIII wasgiven to neutralize the antibodies. The neutralizingdosage was calculated as follows: 112 × BW 80 x (100-Ht) × I100where BW is body weight in kilograms, Ht ishematocrit, and I is inhibitor in BethesdaUnits/mL.The initial high dose was followed by infusion25 U FVIII/kg bw twice daily for one or twoweeks, depending on the clinical status of thepatients and the anamnestic response to factorVIII. After this period factor VII was continued 3times a week or every other day in a dosage of25-50 U FVIII/kg bw.Dose adjustmentWhen factor VIII antibodies decreased and factorVIII recovery was restored, or when ananamnestic response was lacking, factor VIII wastapered down each time the absolute factor VIIIrecovery was higher than 30% until a standardprophylactic dosage of 10-15 units FVIII/kg bwwas reached. Since 1997 standard prophylacticdose in children may be, depending of its clinicaleffect, a similar doses of 25 U FVIII/kg bw 3times a week. 12In patients in whom the inhibitor titer showedno tendency to decrease over a period of 6months or longer and in patients with a highbleeding frequency, the factor VIII dosage wasincreased to 50-100 U factor VIII 3 times a weekor every other day. In those patients in whomthe inhibitor remained high despite 2 years ofhaematologica vol. 88(supplement n. 12):september 2003
IV International Workshop on Immune Tolerance in Hemophilia35low dose ITT, high dose ITT was started accordingto the Malmö protocol. 10Choice of productThe choice of factor VIII product varied withtime. Different factor VIII products were used:cryoprecipitate and intermediate purified product,with and without vonWillebrand factor, aswell as monoclonal-purified and recombinantfactor VIII.PatientsPatients are considered to have a type Ainhibitor when recovery of 50% or less is measured,with or without the clinical evidence of aninhibitor. Patients are considered to have transient(type B) inhibitors when the second sampletested negative for antibodies and a normalrecovery was found. 13 Type B inhibitors wereexcluded from the study. Twenty-seven patientswith persistent antibodies were included into thestudy.Informed consentFrom all patients informed consent wasobtained.Laboratory AssaysPlasma sampling. Plasma samples for factor VIIIand inhibitor assays were collected according tostandard techniques; 4.5 mL of venous blood wasdrawn with a disposable needle into a siliconetreated Vacutainer in which 0.5 mL of 3.8%(0.13M) sodium citrate was added. Immediateafter collection, samples were carefully mixedand centrifuged at 3000 × g for 15 minutes at4°C. The platelet poor plasma was carefullypipetted off and stored in a plastic tube at minus20°C. All samples were analyzed at the coagulationlaboratory of the University Medical CenterUtrecht (head Prof. dr. JWN Akkerman).Inhibitor assayInhibitor measurements were performed usingthe Bethesda method as described by Kasper etal. 14 Inhibitor titers of 1 Bethesda Unit per milliliter(BU/mL) or more were considered positive. 5After 1997 inhibitor measurement were performedusing the modified Nijmegen assay. 15Using this method, inhibitors higher than 0.3BU/mL are considered positive.Stored blood samples from all patients tolerizedbefore 1997 were tested for inhibitors usingthe Njmegen method. The results were comparablewith those using the original Bethesdainhibitor assay.In patients with positive inhibitor tests, bloodsamples for inhibitor measurement were subsequentlytaken every 4-8 weeks.Factor VIII assayFactor VIII assays were performed using the onestage method based on the kaolin-activated partialprothrombin time and expressed as a percentageof factor VIII present in pooled humanplasma. 16In vivo recoveryBlood samples for factor VIII assays were takenbefore and 15 minutes after infusion with factorVIII. Recovery was defined as the percentageof factor VIII measured and the expected levelcalculated by the method according to Lee et al. 17Definition of successOriginally immune tolerance was consideredto be clinically successful when the inhibitordecreased to < 2 BU/mL, with a factor VIII recoveryof at least 50% of normal and a half-life of 6hrs or more and the absence of an anamnesticresponse after infusion with factor VIII. Since1997, after the introduction of the inhibitormeasurement according to the modifiedNijmegen method, an inhibitor of less than 0.4BU/mL was taken as cut-off. Clinical success waschosen as an endpoint because these patients canbe treated with prophylaxis to prevent bleeds, andbleeds can be treated adequately with factor VIII.Complete success was defined as absence ofinhibitor, normal recovery and half-life time.Follow-upAfter start of ITT patients were seen at leastevery month. During follow-up visits samples forantibody test were taken. When the inhibitor wasless than 2 BU/mL recoveries were also performedafter infusion with the dosage factor VIIIa patient was currently using for ITT. When theinhibitor was less than 1 BU/mL (Kasper) or lessthan 0.4 BU/mL in the Nijmegen assay, and arecovery of more than 50% was measured, halflifewas performed after infusion with 50 U/kgbw. Once a patient was tolerized, blood samplesfor inhibitor measurement and recovery weretaken at least twice a year. The date of the lastinhibitor assay was taken as the end-point forevaluation.Treatment of bleeds during ITTBleeds in patients with active inhibitors weretreated with 50 U/kg bw APCC (FEIBA) or 90 µgfactor VIIa (NOVOSEVEN). When a patient hada factor VIII recovery, bleeds were treated with(increased) doses of factor VIII. Infusion withclotting factor was repeated depending on theclinical situation of the patient.Statistical analysisProbabilities of disappearance of the inhibitorover time were estimated with the product limitof Kaplan and Meier and were compared usingthe log-rank statistic. The time lapse until disappearanceof the inhibitor was also examined byunivariate stepwise Cox regression analyses. Allvariables found to have p values of less than 0.10in univariate were considered candidate variablesfor multivariate analyses.haematologica vol. 88(supplement n. 12):september 2003
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Index of authorsAhmad, R.U., 56Albe
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