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

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Haematologica 2000; 85(suppl. to n.10) p. 69-72 Clinical and Organizational Aspects Related to Immunotolerance Protocols Regimens of factor VIII administration – continuous infusion vs. bolus ERIK BERNTORP Department for Coagulation Disorders, University of Lund, Malmö University Hospital, Malmö, Sweden Abstract The Malmö protocol for immune tolerance induction uses intermittent injections of factor VIII/IX together with intravenous IgG and cyclophosphamide. In order to increase the production of antigen-antibody complexes, and also to improve cost-efficacy, we applied continuous infusion instead of intermittent injection in 5 high-responders (3 hemophilia A and 2 hemophilia B). All treatment attempts failed. However, we conclude that continuous infusion may play a role in immune tolerance induction, and the treatment failures in our study could probably be explained by the fact that the patients were partially selected to be resistant cases. ©2000, Ferrata Storti Foundation Key words: continuous infusion, factor VIII, factor IX, hemophilia A, hemophilia B The Malmö protocol for immune tolerance induction (IT) includes high doses of factor VIII or IX (FVIII/IX), intravenous IgG and cyclophosphamide. 1 When the inhibitor level is at or above 10 Bethesda units (BU) at the start of treatment, the IT protocol is preceded by extracorporeal adsorption to protein A. In accordance with the results of the IT registry 2 we believe that it is important to administer high doses of FVIII/IX concentrates. This is done from the start of treatment, and when the inhibitor returns after about a week the dose should be increased, usually by shortening the interval between infusions. In this way the immune system is exposed to high antigen levels. In order to ensure constant high antigen levels, continuous infusion during IT is an attractive approach. In addition, delivery via a pump would facilitate product administration. In terms of pharmacoeconomics, constant infusion should also be an advantage for several reasons. It is superior to intermittent injections as it saves concentrate, as shown for surgery in hemophilia. 3 In particular, Correspondence: Erik Berntorp, Department 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 in products with a short half-life, constant infusion saves concentrate for pharmacokinetic reasons and is more cost-effective during regular prophylaxis. 4 In patients with an inhibitor, the half-life of FVIII/IX is very short and thus there is a pharmacoeconomic rationale for using constant infusion for IT. In the present study, the primary goal was to see whether constant infusion could be a way to induce IT in patients who either had been resistant to the traditional Malmö protocol or could be anticipated to be difficult to tolerize. Design and Methods The study material comprised 3 patients with severe hemophilia A (FVIII
70 E. Berntorp Hemophilia A severe 4 years, 15 kg. High-responder >450 BU. Malmö protocol with continuous infusion of FVIII (Recombinate). Attempt 1(2) BU/FVIII:C IU/dL 900 800 700 600 500 400 300 200 100 0 0 2 4 6 8 10 12 14 16 FVIII IVGG CTX Inhibitor BU FVIII:C IU/dL Intermittent Day Cont. Infusion 5.3-13.3 IU/kg/h (127-319 IU/kg/24 h) injection Figure 1A. Severe hemophilia A, 4 years, 15 kg. Highresponder >450 BU. Malmö protocol with continuous infusion of FVIII (Recombinate). Attempt 1 (2). Hemophilia A severe 8 years, 23 kg. High-responder >450 BU. Modified Malmö protocol (CTX replaced by prednisone 60mg/m2/day po) (Recombinate). Attempt 2(2) BU/FVIII:C (IU/dL) 700 600 500 400 300 200 100 0 0 2 4 6 8 10 12 IVGG x 5 Pred x 10 FVIII Day Inhibitor BU FVIII:C IU/dL Intermittent injection Cont. Infusion 27-54 IU/kg/h (648-1296 IU/kg/24 h) Figure 1B. Hemophilia A severe 8 years, 23 kg. Highresponder >450 BU. Modified Malmö protocol (CTX replaced by prednisone 60 mg/m2/day p.o.) (Recombinate). Results Hemophilia A Three hemophilia A patients were treated. In one patient, who was a high-responder with a historical peak above 450 BU, the first attempt was performed using the original Malmö protocol with cyclophosphamide but with the intermittent injections replaced by continuous infusion (Figure 1A). The inhibitor reappeared after 6 days and had increased to 800 BU after 2 weeks. The number of FVIII units given was 5.3-13.3 units per kg per hour. Four years later, this patient was treated again but now the protocol was modified to include prednisone instead of cyclophosphamide (Figure 1B). The FVIII level during the first few days was kept higher than during the first attempt, approximating 3 IU/mL, which was achieved by giving a continuous infusion of 27 units per kg per hour. However, the VIII:C level dropped after only 4-5 days. The infusion was doubled but a brisk anamnestic response was seen, reaching a peak of around 600 BU, and remaining at this level until day 13 of the observation period. As in the first attempt the treatment was discontinued, as the IT was obviously a failure, according to previous experience with the Malmö protocol. 5 Of the other 2 hemophilia A patients, one was a high responder with more than 300 BU. He was treated using protein A adsorption followed by continuous infusion of IVgG and cyclophosphamide. The VIII:C level went up to more than 2 IU/mL during the first days but then declined. The inhibitor reappeared after 6 days and peaked at 1,000 BU. The treatment was discontinued after 8 days, as it was an obvious failure in this case also. The number of units of FVIII Hemophilia B severe. 5 years, 24 kg. Highresponder >90 BU. Malmö protocol with continuous infusion of FIX BU/FIX:C IU/dL) 500 450 400 350 300 250 200 150 100 50 0 Protein A ads IVGGxV CTXxX -3 -2 -1 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 FIX Inhibitor BU FIX:C IU/dL Intermittent injedction Day Cont.infusion 5-13 IU/kg/h (125-305 IU/kg/24 h) Figure 2. Hemophilia B severe. 5 years, 24 kg. Highresponder >90 BU. Malmö protocol with continuous infusion of FIX. given was 6-29 per kg per hour. In the third patient cyclophosphamide was replaced by prednisone. The VIII:C level was kept very high, around 5 units per ml during the first 6 days, but the inhibitor reappeared after a week and peaked at 70 BU on day 14, exceeding the historical peak of 47 BU. The inhibitor declined to a plateau of around 40 BU, and the patient was kept on a Bonn-like regimen. He became tolerant one year after start of treatment. Haemophilia B Two patients were treated as reported earlier. 6 Both patients had already been treated unsuccessfully according to the Malmö protocol. Both Haematologica vol. 85(supplement to n. 10):October 2000
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Acknowledgments We wish to thank th
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4 J.M. Lusher (range 1-34) for pati
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6 J.M. Lusher ALEDORT: I’d just l
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8 J. Oldenburg et al. Tuddenham et
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10 J. Oldenburg et al. Table 4. Mut
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12 J. Oldenburg et al. reactions ac
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