2003; baxter - Supplements - Haematologica

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108L. Nemes et al.trates, plasmapheresis and transfusions).Our ITI protocol consists of 3 weeks of treatmentwithI. human FVIII:1 st week: 30 U/kg/day;2 nd week: 20 U/kg/day;3 rd week: 15 U/kg/day;II. cyclophosphamide:200 mg/day to a total dose of 2-3 grams;III. methylprednisolone:1 st week: 100 mg/day intravenously;2-3 rd week: tapering of the dose gradually.I and II were immediately discontinued ifFVIII:C has been normalized within the 3 weeks oftreatment. After the disappearance of the inhibitorno further maintenance immunosuppression wasgiven. Different high purity (Beriate-P, HaemoctinSDH, Koate-HP, Koate DVI) and ultra-high purity(Octonativ-M, Hemofil-M) FVIII concentrateswere used for the ITI. The laboratory follow upconsisted of aPTT and mixing tests before andafter two hours of incubation, Bethesda inhibitorassay, porcine FVIII cross-reactivity, FVIII:C beforeand after FVIII administration (recovery), threetimes a week.The definition of success was the disappearanceof the inhibitor in the Bethesda assay system andthe persistent normalization of the FVIII:C value(i.e. >70% activity of the normal). The sex ratio,mean age at the diagnosis, the initial and peakinhibitor titers and residual FVIII:C values weresimilar in the two groups. The summarized meanvalues for the entire cohort of the 26 inhibitorpatients are shown in Table 1. The characteristicsof the control and the ITI groups are demonstratedin Tables 2 and 3.Table 1. Summary of the patients’ mean values.Female/male 13/13Age at diagnosis 62 years (27-85 years)Residual FVIII:C 3.94% (1-16%)Initial human inhibitor titer 277,3 BU (2,2-3200 BU)Peak human inhibitor titer 288,5 BU (8-3200 BU)(maximal value after FVIII challenge)Initial porcine cross-reactivity 12,4 IU/mL (0-104 IU/mL)(measured in 11 patients)Peak porcine cross-reactivity 12,7 IU/mL (0-104 IU/mL)(measured in 11 patients)ResultsEradication of the inhibitor occurred in18(19)/20 patients in the ITI group versus 4/6patients in the control group. (One patientachieved complete remission only after a secondcourse of ITI.) The comparison of the results of thecontrol and ITI groups is shown in the Table 4.The main difference between the two groupswas in the time needed for the complete disappearanceof the inhibitor (4,7 weeks for ITI vs.28,3 weeks for controls). In the ITI group we haveobserved only two relapses during the relative longmean follow up period (26,2 months), in whichcases the same re-induction protocol was successfulagain. No bleeding-related mortalityoccurred in the ITI group in contrast to that of33% in the controls. Apart from the well-knownadverse effects of glucocorticoid therapy, we haveobserved only one patient with transient cytopenia,which resolved spontaneously without anyfurther consequence. We have not seen anyadverse event, which could be attributed to theuse of FVIII concentrates.DiscussionOn the basis of some earlier experiences withFVIII administration in autoantibody patients, anew aggressive protocol has been developed in1992 for the ITI treatment of acquired hemophiliapatients presenting with serious bleeds. 20 ThisBudapest protocol consists of three weeks of treatmentwith 1) human FVIII concentrates (30IU/kg/day for the 1 st week, 20 IU/kg/day for the2 nd and 15 IU/kg/day for the 3 rd week), plus 2)intravenous cyclophosphamide (200 mg/day to aTable 2. Control group.initials sex F/M age at Dx underlying condition initial bleeding res.FVIII:C(%) initial BIA rem.time* rem.duration° eradication1. J.H. F 36 PSS sc.,musc.hematomas 1 3200 − 3 CPH+steroid2. M.O. F 66 idiopathic sc.,musc.hematomas 2 610 8 36 steroid3. B.K.V F 27 postpartum uterine 2 5.5 3 1 steroid4. M.M. F 85 idiopathic hematuria 1 15 107 12 steroid5. S.B. M 69 idiopathic pharyngeal 5 20 2 3 steroid6. A.Cs. M 62 idiopathic femoral 1 437 − − CPH+steroidMean 57.5 2 714 28.25 13*remission time: time needed to achieve remission in weeks; °remission duration: duration of remission (follow-up) in months; BIA: Bethesda inhibitor assay; CPH: cyclophosphamide;PSS: progressive systemic sclerosis.haematologica vol. 88(supplement n. 12):september <strong>2003</strong>
IV International Workshop on Immune Tolerance in Hemophilia 109Table 3. ITI group.initials sex F/M age at Dx underlying condition initial bleeding res.FVIII:C(%) initial BIA rem.time* rem.duration°1. J.M. M 70 idiopathic sc.,musc.hematomas 3,5 21 3 932. I.T. F 53 idiopathic sc.,musc.hematomas 4 20 4 233. P.D. F 62 idiopathic sc.,musc.hematomas 3,5 8 3 534. F.R. M 74 gastric cc. sc.,musc.hematomas 1,4 19 2 205. Gy. Sz. M 55 renal cc.+IFNα tx retroperitoneal 5 320 10 246. P.F. M 79 gastric cc. retroperitoneal 4 22 10 367. L.L. M 65 idiopathic sc.,musc.hematomas 2 30 3 358. E.B. M 58 psoriasis pharyngeal 1 60 3 439. I.J. F 65 psoriasis retroperitoneal 1 1128 − − remission after 2 nd course10. J.B. F 49 idiopathic+MGUS retroperitoneal 7 64 12 1511. K.L. F 75 idiopathic femoral hematoma 14 28 3 2512. M.K. F 60 PSS brachial hematoma 16 10,3 2 2613. J.A. F 57 idiopathic CNS, intraabdominal 9 6 4 714. A.P. M 74 idiopathic femoral hematoma 2 58 5 1515. J.P. F 30 postpartum hematuria,fem.hemat. 1 33 2 1916. M.B M 50 idiopathic sc.musc.hematoma 1 1050 − −17. E.N. F 64 idiopathic thoracal 1 9 3 14 relapsus 1×18. J.T. M 80 idiopathic femoral hematoma, GI 6 2,2 9 3 relapsus 1×19. K.B. M 22 TTP, pheresis sc.musc.hematoma 6 4,7 2 1920. J. B. M 70 idiopathic, MGUS femoral hematoma 2 28 4 2Mean 60,6 4,52 146,06 4,67 26,22*remission time: time needed to achieve remission in weeks; °remission duration: duration of remission (follow-up) in months; BIA: Bethesda inhibitor assay; cc.: carcinoma;IFN: interferon; MGUS: monoclonal gammopathy of unknown significance; TTP: thrombotic thrombocytopenic purpura.total dose of 2-3 grams), plus 3) methylprednisolone(100 mg/day intravenously for the 1stweek and then tapering the dose gradually overthe next two weeks). After the completion of thethree weeks of ITI treatment, no further maintenanceimmunosuppression is given. In contrastto the earlier reports mentioned above, in thisregime FVIII is administered daily in lower doses,simultaneously with cyclophosphamide andsteroids, aiming for the rapid disappearance of theinhibitor. ITI resulted in eradication of the autoantibodyin 95% (19/20) of the cases. The maindifference between patients treated by ITI versustraditional immunosuppression was in the timeneeded for complete disappearance of theinhibitor (4.7 weeks versus 28.3 weeks). Nobleeding-related mortality occurred.We concluded that the ITI protocol describedabove is highly effective for the treatment ofacquired hemophilia, induces exceptionally rapidtherapeutic responses and advantageously influencesthe underlying autoimmune disorder. HoweverITI should be reserved for the eradication ofidiopathic, autoimmune- and malignancy-associatedFVIII autoantibodies in patients presentingwith severe bleeding or as a second line therapy ofother autoantibody inhibitors resistant to moreconservative approaches. It will be necessary toconfirm these initial promising results in furthermulti-center prospective studies.In the late 1990s three leading German hemophiliacenters (Bonn, Frankfurt and Heidelberg)also adopted the concept of ITI in the managementof acquired hemophilia. Brackmann et al. 11introduced a modified Malmö protocol consistingof long-term immunoadsorption by Ig-apheresis,plus high-dose (100-200 IU/kg/day) humanFVIII, plus high-dose IVIG, plus cyclophosphamide,plus steroids, and rFVIIa for acute hemorrhages.In the Heidelberg modification of thisregime FVIII is given as a 200 IU/kg bolus followedby high-dose continuous infusion aiming toachieve a FVIII:C level greater than 60% of normal.Recently, an oral ITI regimen also has beenreported in acquired hemophilia 21 . These preliminarydata indicate that ITI regimens may beapplied successfully in acquired hemophilia, butfurther studies are warranted to establish feasibilityand cost-benefit relationships. 22Table 4. Comparison of the control and ITI groups.ControlNumber of patients 4/6 18/20who achieved remission (19/20)Time needed 28,3 (2-107) 4,67 (2-12)to achieve remission (weeks)Duration of remission 13 (1-36) 26,22 (2-93)follow-up (months)Mortality rate 3/6 4/20Bleeding-related mortality 2/6 0/20ITIhaematologica vol. 88(supplement n. 12):september <strong>2003</strong>
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