2003; baxter - Supplements - Haematologica

IV International Workshop on Immune Tolerance in Hemophilia 79Another treatment option is referred to as immunomodulationusing immunoglobulin substitutionin order to trigger inhibitor elimination. 9 Thepotential to treat acquired hemophilia with FVIIIand cyclophosphamide has been apparent for 30years. 10 In a randomized trial various immunosuppressiveregimens with prednisone and cyclophosphamidereduced inhibitor titers to undetectablelevels in 68% of patients. 11 However theseresults have been partially attributable to concomitanttherapy with coagulation factor concentrates.Furthermore, a complete response toimmunosuppressive therapy in acquired inhibitorpatients may require weeks or months. 11-14Assessment of the current data available is difficultgiven the small number of cases as well asthe inconsistent description of the differenttreatment protocols and experiences with respectto end point definitions of a successful therapy,treatment duration, undesirable effects and especiallythe occurrence of secondary bleedingevents and the amount of activated prothrombincomplex concentrate (aPCC) and recombinantfactor VIIa (rFVIIa) concentrate required. Thesame applies to cost aspects as far as they havebeen considered in publications so far.Availability of immunoadsorption and thus thepossibility of automated antibody reduction inthe patient´s plasma paved the way for the developmentof new treatment cycles. 15,16Based on our experience in the treatment ofpatients both with congenital and with acquiredinhibitors we at the Hemophilia Center in Bonndeveloped a new so-called Modified Bonn-Malmö Protocol (MBM Protocol) from a combinationof the Bonn Protocol (also referred to asImmune Tolerance Therapy, ITT) for the permanentelimination of FVIII inhibitor in patientswith congenital hemophilia A or B, 17-19 and amodified Malmö Protocol (with additional immunoadsorption,oral cyclophosphamide and IgGapplication). 15,20,22 The main focus is on antibodyreduction by means of immunoglobulin columnswhich allow adsorption of all IgG classes, as wellas on immunomodulatory treatment by antigenexposition using factor VIII concentrates 22,23 andapplication of foreign immunoglobulins undersimultaneous immunosuppressive treatmentwith corticosteroids and cyclophosphamide.Medicinal immunosuppression seemed indispensablegiven the experience in the history ofthe treatment of acquired inhibitor diseases.In the following, we will for the first time presentour therapy results achieved in patients withacquired factor VIII inhibitor, treated using conventionalimmunosuppressive or immunomodulatoryregimens as well as the MBM Protocol.MethodsThe MBM ProtocolThe treatment cycle consists of four componentswhich are applied during the course of one week.1. From day 1 to 5 long-term immunoadsorptionwith daily processing of 2.5 times thepatient’s plasma volume.2. Application of factor VIII concentrates,depending on the extent of inhibitor titer andbleeding situation, at a dosage of 100 units/kgbody weight every six hours (in exceptionalcases up to 200 units/kg). Standard dosereduction upon exceeding 100% factor VIIIplasma activity within a six or twelve hourrecovery under consideration of the clinicalrequirements.3. On day 5, 6 and optionally on day 7 applicationof immunoglobulins at a dosage of 0.4mg/kg body weight/day.4. From day 1 to 7 application of cyclophosphamide(2 mg/kg/BW) in combination withprednisolone (1 mg/kg/BW).Upon achieving inhibitor elimination immunosuppressionwas gradually reduced over a periodof six weeks.The treatment cycle is repeated in accordancewith clinical requirements and laboratory results.Application of rFVIIa or aPCC was usually performedprior to transportation to our hospital orprior to the placement of central venous cathetersunder difficult anatomical conditions.Immunoadsorption was accomplished byapheresis with a dual-column system (Ig-Thera-Sorb ® , PlasmaSelect AG, Teterow, Germany) ofsheep-derived polyvalent anti-human immunoglobulinbound to Sepharose CL 4B (AmershamPharmacia Biotech AB, Uppsala, Sweden).Conventional treatment strategies 1986 to 1997Prior to the development of the MBM Protocolour treatment of patients with acquiredinhibitors was guided by our own experience withthe Bonn Protocol as well as the guidelines andtherapy recommendations of current literatureand the clinical requirements.We used cyclophosphamide, prednisolone, vincristine,immunoglobulins, factor VIII concentratesand FEIBA in mono and in combinationtherapies. We also tried induction of immunetolerance by high-dose factor VIII application intwo patients, following therapeutic experiencewith hemophilia patients according to the BonnProtocol. Treatment was modified after sixmonths of unsuccessful therapy at the earliest.DiagnosisAcquired inhibitors were diagnosed by singlefactoranalysis in combination with a plasmaexchange and the Bethesda assay (BU) using theNijmegen method modification.In all patients and for the entire treatmentcycle, factor VIII was invariably determined usingone-stage clotting assay (Immuno) and chromogenicassay (Baxter). Lupus was excluded bymeans of lupus APTT and dRVVT (diluted RussellViper Venom Test).All treatment decisions were based on theresults of the one-stage clotting assay as due tothe high degree of dilution of the plasma samplehaematologica vol. 88(supplement n. 12):september 2003