2003; baxter - Supplements - Haematologica

IV International Workshop on Immune Tolerance in Hemophilia 107FVIII represent a rather heterogeneous group ofpatients with different basic and accompanyingdiseases and prognostic factors. Therefore, thedetailed assessment of the patient’s individualcharacteristics (e.g. location and severity of thebleeding at presentation, underlying disorder, ageand clinical condition of the patient, accompanyingdiseases, expected response to immunosuppression,and initial and peak human and porcineinhibitor titers) is essential before the decision onthe particular therapeutic interventions is made. 3The primary aim of long-term management inacquired hemophilia is to eradicate the FVIIIautoantibody so that further bleeding can be prevented.This can be achieved through immunomodulationby immunosuppressive drugs, intravenousgammaglobulin (IVIG), and by immunetolerance induction (ITI) regimens. AlthoughFVIII autoantibodies may remit spontaneously, 2clinical studies indicate that early initiation oferadication treatment is advantageous. 1,4 Dramaticand life-threatening bleeding complicationsare experienced in 80-90% of patients at sometime in the course of their disease. The 10-22%mortality rate for this disorder is directly or indirectlyattributable to the inhibitor. 1,4 Most publishedtherapeutic guidelines and algorithms recommendthat eradication therapy should be institutedas soon as the diagnosis has been established.5,6 It is possible that different strategies forlong-term management may be suitable for thevarious subgroups of patients. 7 A conservativewatch and wait approach for children, peripartum,and drug-induced cases in whom spontaneousremission can be reasonably expected may bemore appropriate than the combined immunomodulatorytherapies for idiopathic, autoimmune-and malignancy-associated cases. 3 In anycase, individuals presenting with acquired hemophiliaand severe hemorrhage need rapid andeffective treatment.Immunosuppressive therapy with steroid or thecombination of steroid plus cyclophosphamid hasbeen the mainstream of traditional eradicationtreatment for FVIII autoantibody patients. 8,9 ITIregimens with human FVIII concentrates untilrecently were rarely implemented in adult patientswith autoantibody-inhibitors even though theyhave been used with increasing frequency foralloantibody suppression primarily in young childrenwith congenital hemophilia. 10 Although ITIcould be utilized in the management of both conditions,the actual mechanisms of the effect anddosage schedules should be fundamentally different.ITI for alloantibodies is a typical desensitizingtherapy in the immunological sense; so large dailydoses of FVIII are given for a prolonged periodaiming at exhausting the alloantibody-producingclones. The duration of ITI is generally betweensome months to one year, and the addition of vigorousimmunosuppressive therapy is of doubtfulimportance. On the other hand, in the ITI treatmentof acquired hemophilia the FVIII administrationserves to enhance the stimulation of theautoantibody-producing lymphocyte clones and isa useful adjuvant to immunosuppression. Theduration of therapy is limited to some weeks. Forsuccessful ITI in autoantibody patients, small,repeated FVIII doses seem to provide the adequatestimulation for the subsequent successful immunosuppressionand there is no obvious need forthe exhaustive high-dose FVIII administration, as inthe original Bonn 11 and Malmö 12 protocols.The theoretical basis for the development of ITIin acquired hemophilia was derived from the successesof plasma exchange therapy for progressiveautoimmune disorders unresponsive to conventionalimmunosupressive treatment. 13,14,15 It washypothesized that plasmapheresis induced proliferationof the pathogenic clones and subsequentpartial clonal depletion could be produced by givinglarge doses of cytotoxic drugs during theassumed period of increased B-cell vulnerability.The stimulation induced by plasma exchange wassynchronized with pulse immunosuppressive therapy.14,15 Similarly, in ITI of autoantibodyinhibitors, exogenous FVIII administration mayresult in additional stimulation with a correspondingincrease in the susceptibility of theimmunocytes to the effect of the cytotoxic drugs. 16In other words, the repeated administration of theantigen (FVIII) causes extra stimulation of theinhibitor-producing B-cell clones, making themmore susceptible to immunosuppression. In theoriginal case report of Green, 16 massive doses ofFVIII were given simultaneously with 1.5 g intravenouscyclophosphamide to an acquiredinhibitor patient previously unresponsive to combinedimmunosuppressive medication. In thisreport, the distinction between the acute treatmentof bleeding and eradication of inhibitor asthe aim of the administration of high-dose FVIIIwas not yet completely clear. In a later trial in1989, Lian et al. 17 used a combination of singlehigh-dose FVIII bolus followed by a modifiedcyclophosphamide, vincristine, and prednisonecytostatic protocol for the treatment of seriousacute bleeding in acquired hemophilia. 17 In 1996,two other successful applications of the same protocolwere published. 18,19 On the basis of these earlierexperiences, we have developed a new aggressiveprotocol for the management of patients withacquired FVIII inhibitor.Design and MethodsWe evaluated the results of 20 consecutive nonhemophiliacpatients with factor VIII autoantibodytreated in a single center with our ITI protocolbetween 1992 and 2001, comparing them to6 historical control patients treated with the traditionalimmunosuppressive therapy (steroidand/or cyclophosphamide) between 1988 and1992 in the same setting.In the two study groups similar treatmentmodalities were used for the management of acutebleeding episodes (traditional and activated prothrombincomplex concentrates, recombinantactivated FVII, porcine and human FVIII concen-haematologica vol. 88(supplement n. 12):september 2003