2003; baxter - Supplements - Haematologica

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82L. Hess et al.36 months (median 28, minimum 1 month).None of the patients exhibited another bleedingtendency or inhibitor activity. Of these 17patients three died due to events not related tobleedings; one after 1 month, one after 10months, and one after 20 months.Figure 3.Treatment failures during MBM-ProtocolIn one case, inhibitor elimination failed despiteintensive therapeutic efforts. Unlike the previouslymentioned patients this 47-year-old manwas not in an acute bleeding interval at thebeginning of treatment. However, his medicalhistory revealed several severe bleedings in thearea of the lower extremities. Treatment extendedover a period of 75 days of hospitalizationincluding 62 apheresis days. The inhibitor withan initial value of 3,556 BU was reduced to 6 BU.One reason for the patient´s failure to respondto the therapy may have been the presence ofsevere adiposity (160 cm, 144 kg), which duringthe course of treatment progressed to 155 kg. Therequired factor VIII dosages per kg body weight aswell as the dosages of immunosuppressants werenot achieved; in addition the adsorption timesand as a result the plasma volumes were reducedto 50% of the target value.Follow-up of MBM-ProtocolFor the 17 successfully treated patients a meanfollow-up period (end of July 2001) of 31months was reached. The longest follow-up wasApplication of recombinant factor VIIa duringMBM ProtocolFactor VIIa was used in six cases, for a medianduration not exceeding three apheresis days(mean 3, minimum 1, maximum 5 days). Medianconsumption was 12,000 KIU (mean 15,000;maximum 30,000; minimum 2,200). Applicationwas indicated in five patients due to acutetreatment started in the peripheral hospital andcontinued until hospitalization in our clinic. Inone case, it was only indicated as a first-line treatmentand bleeding prophylaxis for the placementof a central venous catheter in the presence ofsevere adiposity.Factor VIII application during MBM ProtocolAs regards the life-threatening condition, allpatients exhibit a similar clinical picture and hightiterinhibitor irrespective of the treatment regimen.Factor VIII application was a mean of 552,000units in those patients (n=17) who received theentire scope of the MBM Protocol. One caserequired infusion of 2 million units. The median,which is 384,000 units, on the other handindicates a lower factor consumption. Onepatient required only 134,000 factor VIII units.Results of conventional inhibitor therapyOf the five patients who were treated usingimmunosuppressive or immunomodulatorystrategies inhibitor elimination was achieved inone patient (SG) after 15 months (see Table 2).The patient exhibited an initially life-threateningbleeding and subsequently four additional softtissuebleedings, some of them with an effect onhemoglobin, under the cyclophosphamide mono-Table 2.haematologica vol. 88(supplement n. 12):september <strong>2003</strong>
IV International Workshop on Immune Tolerance in Hemophilia 83therapy (1 mg/kg/BW) applied. In total 1.8 millionFEIBA units were applied, for vital treatmentas well as for prophylactic treatment of furtherbleedings. Today, 9 years after normalization ofplasma activity, the patient does not exhibit anynew inhibitor activity.Another patient (TT) received monotherapywith prednisolone as application of cyclophosphamidehad led to severe leukopenia in severaltreatment attempts. After overcoming the initiallylife-threatening bleeding event, the patientwas treated with FEIBA prophylaxis on an outpatientbasis for almost 10 years.Inhibitor elimination was not achieved withinthat period. Factor requirement during that timewas 15 million FEIBA units. Despite intensivebleeding prophylaxis a total of 15 bleeding eventswere observed in that patient. The patient died ofa disease not associated with any bleeding event.Another three patients (RA, PK, MU) were initiallytreated using conventional combinationtherapies (cyclophosphamide, prednisolone, vincristineand IgG). Two patients additionallyreceived factor VIII within the framework of anITT according to the Bonn Protocol. Initially,these patients also suffered from a life-threateningbleeding event. Duration of treatment was13-67 months (mean 36.7) until these threepatients were switched to treatment according tothe MBM Protocol. During conventional treatmentthe patients received 0.056 to 4.3 millionfactor VIII units (mean 1.78). FEIBA consumptionwas 0.77 to 5.8 million units; however, 1-28(mean 12) additional bleedings were observed.Only one patient (PK) experienced inhibitorremission for the duration of 12 months untilanother life-threatening bleeding occurred,which was the reason for starting MBM-P (seeTable 2).The treatment results of the three patients (RA,PK, MU) who after unsuccessful conventionaltreatment changed to the MBM Protocol areillustrated once more in table 3.Under the MBM Protocol long-term inhibitorelimination was achieved in patients RA and PKDue to the fact that she developed pulmonarycarcinoma as a secondary disease, patient MUdecided to discontinue the therapy, as alreadyexplained above.Comparison of factor concentrate consumption(FVIII and FEIBA) during the conventionaltreatment phase of the two patients RA and PKyields that the MBM Protocol reduces clottingfactor consumption by 1.18 million units (64%).When looking at the procurement costs for FEI-BA and factor VIII the difference between the twotherapies in terms of treatment costs is furtherincreased as the procurement costs for one FEI-BA unit are well above those for factor VIII, andduring the MBM Protocol, application of FEIBAor recombinant FVIIa is almost entirely dispensable.In addition, neither patient (RA or PK)experienced another bleeding event after conclusionof the MBM Protocol. The follow-up periodis currently between 41 and 62 months, duringwhich time no new bleedings and therefore nobleeding-related follow-up costs have occurred.DiscussionThe Modified Bonn-Malmö Protocol presentedhere can be characterized by the following properties.With the MBM Protocol, life-threateningbleeding events can be controlled within 24-48hours. The hemostatic effect of factor VIII underthe MBM Protocol can be described as promptand direct. The high success rate of 94.4% (n=18)illustrates the high reliability of the therapy presentedhere. Considering the long-term follow-upresults (median: 28 months) inhibitor eradicationcan be considered as permanent. Theextremely short treatment period of 16.5 apheresisdays until inhibitor elimination ensures theprevention of undesirable effects (compartmentsyndrome, fistula formation, etc.) as may occurduring immunosuppression with cyclophosphamideor prednisolone over several months. Inaddition, secondary infections, which tend tooccur particularly during long-term immunosuppression,can be avoided. We can also assume lowercosts for short-term treatment with factor FVIII(median: 384,000 units) within the frameworkof the MBM Protocol as compared to conventionaltherapies (up to 4.3 million FVIII units).Argumentation in favor of factor VIII applicationusing apheresis treatment is based on its veryearly hemostatic effect, 24 so that use of othercost-intensive coagulation concentrates (APCCand rFVIIa) can be reduced or entirely eliminated.The costs of an exclusively immunosuppressiveand immunomodulatory treatment aredetermined by the use of APCC and rFVIIa, whichare indispensable for conventional treatment regimens,especially in the presence of bleedingevents. 25,26As far as economic efficiency is concerned, theprocurement costs for APCC and rFVIIa have tobe taken into consideration, which are more thantwice the expenses for factor VIII. In addition,our experience shows that during conventionaltreatment the drugs APCC and rFVIIa have to beapplied in hemostatically effective dosages whichaccount for final costs far exceeding the treatmentcosts associated with the MBM Protocol.Our results also show that the use of APCCwithin the framework of a conventional therapydoes not effectively protect the patients from newbleedings (1-28 bleedings). Under the MBM Protocolon the other hand there was only the primarybleeding event, no re-bleedings.Apart from the hemostaseological necessity offactor VIII therapy the immunological competenceof factor VIII during the three weeks oftreatment according to the MBM Protocol is amatter worthy of discussion.In contrast to inhibitor patients with hemophilia,patients with acquired inhibitors still havethe ability to synthesize their own (endogenous)factor VIII. Exogenous factor application at reg-haematologica vol. 88(supplement n. 12):september <strong>2003</strong>
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