Haematologica 2000;85:supplement to no. 10 - Supplements ...

More documents

Recommendations

Info

Immune Tolerance and the Treatment of Hemophilacs with an Inhibitor 47 one year. Table 2 shows the comparison of group 1 with full success with groups 2 and 3 without full success. The significance of the parameters does not change when groups 1 and 2 with full and partial success are evaluated composed against group 3 together. Discussion ITT is now the most accepted method of eliminating inhibitors, especially high titer, in hemophilia A. In Germany immune tolerance induction generally follows the Bonn protocol. 1 This means that patients are mostly treated with a high dose regimen. Statistical evaluation of high against low dosage therapy therefore is not possible in the patients included here. The registry contains all patients of the participating centers from the start of this method of treatment. Consequently, the age distribution of the patients treated in the ‘70s and ‘80s is shifted in the direction of older patients compared to the mostly young children which tend to dominate nowadays. Inhibitor titer The importance of the inhibitor titer as a predictor of the success was noted from when the registry was established. Other registries also show the strong influence of titer on outcome, 2,3 although it is not easy to compare outcome results of different studies 4,5 because inclusion criteria are not similar. The ITT outcome was 79% of complete success in our patients. If only patients with inhibitor titers below 100 BU are included the success rate of ITT is 89%. The success rate also depends on the criteria chosen to define success. The patients in our group 2 became mild low responders with inhibitor values constantly below 2 BU without an increase at FVIII challenge. Treatment with FVIII is possible again. If patients with full and partial success are counted together the overall success rate is 87%. Time from diagnosis to start of ITT There has always been discussion about the importance of the interval between diagnosis of the inhibitor and start of ITT. The advantages of an early eradication of the inhibitor after its detection, especially in children, is obvious. The danger of bleeding is diminished, joints can be protected by prophylactic treatment again and the costs of ITT are lower because of the low body weight. However, the time interval between inhibitor detection and start of ITT or the number of exposure days in this interval does not significantly influence success in our registry. In the international 3 and North American immune tolerance registry 2,4 only patients who started ITT more than 5 years after inhibitor detection had a significantly worse outcome; starting earlier did not influence success rate. A high inhibitor titer at the start of ITT is significantly related to a negative outcome. It may, therefore, be better to wait in such cases until the inhibitor titer is reduced so that treatment can be commenced under more favorable conditions. REFERENCES 1. Brackmann HH, Lenk H, Scharrer I, Auerswald G, Kreuz W. German recommendations for immune tolerance therapy in type A haemophiliacs with antibodies. Haemophilia 1999; 5:203-6. 2. DiMichele DM, Kroner BL. Analysis of the North American immune tolerance registry (NAITR) 1993 - 1997: current practice implications. Vox Sang 1999; 77 suppl. 1:31-2. 3. Mariani G, Kroner B. International immune tolerance registry, 1997 update. Vox Sang 1999; 77 (Suppl 1) :25- 7. 4. Kroner BL. Comparison of the international immune tolerance registry and the North American immune tolerance registry. Vox Sang 1999; 77 (Suppl 1):33-7. 5. Mauser-Bunschoten EP, Nieuwenhuis HK, Roosendaal G, van den Berg HM. Low dose immune tolerance induction in hemophilia A patients with inhibitors. Blood 1995; 86:983-8. Haematologica vol. 85(supplement to n. 10):October 2000
Haematologica 2000; 85(suppl. to n.10) p. 48-51 Registries of Immunotolerance Protocol Malmö protocol update ERIK BERNTORP, JAN ASTERMARK, EBBA CARLBORG Department for Coagulation Disorders, University of Lund, Malmö University Hospital, Malmö, Sweden Abstract The Malmö protocol for immune tolerance induction includes high doses of Factor VIII/IX, intravenous IgG and cyclophosphamide. If the inhibitor titer exceeds 10 Bethesda units at start, extracorporeal adsorption of IgG is performed using protein A. The protocol sometimes has to be repeated. A successful response may occur within a few weeks. In hemophilia A the success rate so far is 10/17 patients (15 high-responders, 2 low-responders) or 59%, whereas in hemophilia B 6/9 patients (8 high-responders, 1 low-responder), or 67%, have become tolerant. In one hemophilia B patient, a relapse occurred after 6 months. During a second treatment episode he developed an acute myocardial infarction, probably caused by replacement with prothrombin complex concentrate. We conclude that the Malmö protocol is efficient for induction of immune tolerance but the patients must be selected particularly with regard to inhibitor duration and time of last booster. ©2000, Ferrata Storti Foundation Key words: hemophilia A, hemophilia B, immune tolerance, protein A adsorption, factor VIII, factor IX Professor Inga Marie Nilsson developed the Malmö protocol for immune tolerance induction during the 1980s after the clinical observation of a patient with hemophilia B and a high responding inhibitor. 1 The protocol has since then been used both in hemophilia A and hemophilia B and the purpose of this report is to give an update of the results. The Malmö treatment model for induction of immune tolerance The protocol If the inhibitor titer is above 10 Bethesda inhibitor units (BU) immune tolerance induction (IT) is preceded by extracorporeal adsorption of inhibitor to protein A (CITEM 10 Excorim KB, Lund, Sweden) in order to reduce the inhibitor to 3 BU or below. 2-4 Cyclophosphamide is given from the first day of treatment, first intravenously at daily doses of 12-15 mg/kg bodyweight (bw) Correspondence: Erik Berntorp, Dept for Coagulation Disorders, Malmö University Hospital, SE-205 02 Malmö, Sweden. Phone: international +46.40.332392 - Fax: international +46.40.336255 – E-mail: erik.berntorp@medforsk.mas.lu.se for 2 days and then orally at daily doses of 2-3 mg/kg bw for 8-10 days, the time period depending on the development of low leukocyte counts. The initial dose of factor VIII (FVIII) for hemophilia A or factor IX (FIX) for hemophilia B varies, as it is necessary to increase the VIII:C/IX:C levels to about 40-100 units/dL. FVIII/IX is then given at intervals of 8-12 hours to maintain the VIII:C/IX:C concentration at a level of 30-80 units/dL. When the VIII:C/IX:C levels decrease, usually after one week, shortening of the interval between doses, usually 6 hours, increases the total daily dosage of FVIII/IX. Beginning on day 4 of treatment, IgG is given intravenously at daily doses of 0.4 g/kg bw for 5 days. After disappearance of the inhibitor, regular FVIII/IX treatment (around 30 units/kg bw) is given 2-3 times a week according to the usual prophylaxis protocol (Nilsson, 1992). At the start of immune tolerance induction hydrocortisone (100 mg) is usually given i.v. daily for the first two days in order to prevent sideeffects such as allergic reactions caused by the drugs. In children Uromitexan ® is given in order to counteract toxicity to the urinary bladder by cyclophosphamide. Strategy for the use of the Malmö model for inhibitor treatment In the most recent comprehensive follow-up of the Malmö protocol, Freiburghaus et al. 4 analyzed the prognostic factors for success. The most important factors seem to be the following: low current inhibitor titer, low historical peak and long interval since previous replacement therapy. It also seems to be important that the patient at the start of immune tolerance induction should be in a steady state without any ongoing reactive process. Based on these factors we have developed a strategy for the Malmö inhibitor treatment, which is shown in Figure 1. Thus, IT is started when the inhibitor has not been boostered in at least 6 months. If still above 10 BU, protein A adsorption is included in the protocol. If the treatment is successful, the patient continues with ordinary prophylaxis; if not successful the treatment is repeated after 6-12 months. In the meantime recombinant FVI- Haematologica vol. 85(supplement to n. 10):October 2000
Page 1 and 2: Haematologica established in 1920 e
Page 3 and 4: Acknowledgments We wish to thank th
Page 5 and 6: Haematologica 2000; 85(suppl. to n.
Page 7 and 8: 4 J.M. Lusher (range 1-34) for pati
Page 9 and 10: 6 J.M. Lusher ALEDORT: I’d just l
Page 11 and 12: 8 J. Oldenburg et al. Tuddenham et
Page 13 and 14: 10 J. Oldenburg et al. Table 4. Mut
Page 15 and 16: 12 J. Oldenburg et al. reactions ac
Page 17 and 18: 14 J. Oldenburg et al. Dr. Schwaab
Page 19 and 20: 16 J. Ingerslev be established more
Page 21 and 22: 18 J. Ingerslev sion monitoring dem
Page 23 and 24: 20 J. Ingerslev REFERENCES 1. Hay C
Page 25 and 26: 22 CRM Hay Side effects of Hyate:C
Page 27 and 28: 24 CRM Hay tion by porcine factor V
Page 31 and 32: 28 P. Lollar these epitopes by site
Page 33 and 34: 30 P. Lollar titer and an anti-porc
Page 35 and 36: 32 Immune Tolerance and the Treatme
Page 37 and 38: 34 Immune Tolerance and the Treatme
Page 39 and 40: 36 B.M. Ewenstein et al. exposed, 7
Page 41 and 42: 38 B.M. Ewenstein et al. Table 1. H
Page 45 and 46: 42 D. DiMichele et al. Discussion T
Page 47 and 48: 44 D. DiMichele et al. Italy and in
Page 49: 46 H. Lenk et al. Figure 1. Maximum
Page 53 and 54: 50 E. Berntorp et al. standing inhi
Page 57 and 58: 54 C.R.M. Hay Logistic barriers to
Page 59 and 60: 56 C.R.M. Hay ed to go for a fully
Page 61 and 62: 58 C.M. Kessler hemophilia A, have
Page 63 and 64: 60 C.M. Kessler in eradicating allo
Page 65 and 66: 62 C.M. Kessler ously. Do you see d
Page 69 and 70: 66 L. Nemes et al. Figure 1. A gian
Page 71 and 72: 68 L. Nemes et al. trast to the ear
Page 73 and 74: 70 E. Berntorp Hemophilia A severe
Page 75 and 76: 72 E. Berntorp VIII. MARIANI: It wo
Page 77 and 78: 74 R. Landolfi et al. Table 1. Resu
Page 79 and 80: 76 H-H. Brackmann et al. Table 1a.
Page 83 and 84: 80 R.B. Butler of progress and perm
Page 85 and 86: 82 B. Gargallo emotional consequenc
Page 87 and 88: 84 L.M. Aledort et al. Success rate
Page 91 and 92: 88 D. Scandella et al. Seven non-in
Page 93 and 94: 90 S. Lacroix-Desmazes et al. demon
Page 95 and 96: 92 S. Lacroix-Desmazes et al. 244:1
Page 97 and 98: 94 J-M.R. Saint-Remy linking of sur
Page 99 and 100: 96 J-M.R. Saint-Remy identification
Page 101 and 102:
98 M.D. Kazatchkine et al. normal l
Page 103 and 104:
Haematologica 2000; 85(suppl. to n.
Page 105 and 106:
102 L.W. Hoyer et al. have prevente
Page 107 and 108:
104 J.G. Gilles et al. Table 1. The
Page 109 and 110:
106 J.G. Gilles et al. typic intera
Page 111 and 112:
Haematologica 2000; 85(suppl. to n.
Page 113 and 114:
110 D. Lillicrap a transgene in tis
Page 115 and 116:
112 D. Lillicrap DI MICHELE: I am a
Page 117 and 118:
114 G.C. White et al. cost, time, a
Page 119 and 120:
116 G.C. White et al. Blood 62:141-
Page 121:
II Immune Tolerance and the Treatme
show all

Haematologica 2000;85:supplement to no. 10 - Supplements ...

Create successful ePaper yourself

Delete template?

Save as template?