2003; baxter - Supplements - Haematologica

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[Acquired Inhibitors in Non-Hemophiliacs]review paperTen years experience withimmune tolerance inductiontherapy in acquired hemophiliahaematologica 2003; 88(suppl. n. 12):106-110http://www.haematologica.org/free/immunotolerance2001.pdfLASZLO NEMES,* ERVIN PITLIK°*National Hemophilia Center, National Medical Center°Semmelweis University, 2 nd Department of InternalMedicine, Budapest, HungaryObjective. The primary aim of long-term managementin acquired hemophilia is to eradicate the FVIIIautoantibody so that further bleeding can be prevented.ITI regimens with human FVIII concentratesuntil recently were rarely implemented in adultpatients with autoantibody-inhibitors even thoughthey have been used with increasing frequency foralloantibody suppression primarily in young childrenwith congenital hemophilia. In the ITI treatment ofacquired hemophilia the FVIII administration servesto enhance the stimulation of the autoantibody-producinglymphocyte clones and is a useful adjuvant toimmunosuppressive therapy. For successful ITI inautoantibody patients, small, repeated FVIII dosesseem to provide the adequate stimulation for thesubsequent successful immunosuppression andthere is no obvious need for the exhaustive high-doseFVIII administration, as in the original Bonn andMalmö protocols. We evaluated the results of 20consecutive non-hemophiliac patients with factor VIIIautoantibody treated in a single center with our ITIprotocol between 1992 and 2001, comparing themto 6 historical control patients treated with the traditionalimmunosuppressive therapy (steroid and/orcyclophosphamide) between 1988 and 1992 in thesame setting. The sex ratio, mean age at the diagnosis,the initial and peak inhibitor titers and residualFVIII:C values were similar in the two groups.Study design. Our ITI protocol consists of 3 weeks oftreatment with 1) human FVIII concentrates (30U/kg/day for the1st week, 20 U/kg/day for the 2ndweek, and 15 U/kg/day for the 3rd week, plus 2) iv.cyclophosphamide (200 mg/day to a total dose of2-3 grams), plus 3) methylprednisolone (100mg/day iv. for one week and then tapering down thedose gradually over the next two weeks). After thedisappearance of the inhibitor no further maintenanceimmunosuppression was given. The laborato-Correspondence: Dr. Laszlo Nemes, National Hemophilia CenterNational Medical Center Vagany u. 2. 1135, Budapest,Hungary. Phone: international +36.1.32034973504760/ext.1882, 1884. Fax: international +36.1.3297097. E-mail:lnemes@hiete.hury follow up consisted of aPTT and mixing tests beforeand after two hours of incubation, Bethesda inhibitorassay, porcine FVIII cross-reactivity, FVIII:C before andafter FVIII administration (recovery), three times aweek. The definition of success was the disappearanceof the inhibitor in the Bethesda assay systemand the persistent normalization of the FVIII:C value(i.e. >70% activity of the normal).Results. Eradication of the inhibitor occurred in18(19)/20 patients in the ITI group versus 4/6patients in the control group. (One patient achievedcomplete remission only after a second course ofITI.)Conclusions. The main difference between the twogroups was in the time needed for the complete disappearanceof the inhibitor (4,7 weeks for ITI vs. 28.3weeks for controls). No bleeding-related mortalityoccurred in the ITI group in contrast to that of 33%in the controls.©2003, Ferrata Storti FoundationKey words: acquired hemophilia, factor VIIIautoantibodies, immunosuppression,immune tolerance induction therapy.Acquired hemophilia is a rare, usually severebleeding disorder characterized by the formationof IgG1-IgG4 autoantibodiesagainst the factor VIII (FVIII) procoagulant activity.The FVIII autoantibodies occur either spontaneously(idiopathic cases) or in connection withpregnancy (postpartum cases), various autoimmune,dermatological and malignant diseasesand drug therapy. 1,2 The management of acquiredhemophilia serves for dual goals: the promotionof hemostasis by the treatment of the acute bleedingepisodes and the elimination of the FVIIIautoantibody by long-term eradication therapyfor consequent cure of the condition.Whereas the principles of the management ofacute bleedings are comparable in allo- andautoantibody patients, the methods used in theeradication therapy differ more fundamentally.In contrast to congenital hemophilia withalloantibody inhibitors, acquired inhibitors tohaematologica vol. 88(supplement n. 12):september 2003
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
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