1. WFH Bangkok 2004 Factor VIII-Von Willebrand Factor Inhibitors and Immune Tolerance Inhibitor Elimination Immune Tolerance Induction (ITI)

2. WFH Bangkok 2004 Immune Tolerance Induction (ITI) Induction of tolerance to FVIII in haemophiliacs with inhibitors (ITI) by regular administration of FVIII over a prolonged period of time began in Bonn, Germany, in the late 1970s Immunosupressive and immunomodulatory regimens were introduced in Malmö in the 1980s Treatment strategies vary according to the inhibitor level at time of treatment and the type of response on challenge

3. WFH Bangkok 2004 Immune Tolerance Induction (ITI) In inhibitors which have not been boostered, saturation of the inhibitor is possible and clinical levels of factor can be obtained Patients with high titre inhibitors may require so-called bypassing agents or extracorporeal removal of the inhibitor Treatment protocols vary considerably with regard to dosage, e.g. 300 FVIII IU/kg BW/day A high success rate is generally ascribed to ITI in haemophilia A with low/moderate response High-responding inhibitors are more difficult to overcome In haemophilia B, the success rate of ITI is considered to be lower than in haemophilia A

4. WFH Bangkok 2004 Immune Tolerance Induction (ITI): Protocols FVIII ITI ProtocolCharacteristics “Low dose” 25 FVIII IU/kg every other day, 1 – 12 months “Intermediate dose” 50 FVIII IU/kg daily, corticosteroids, 1 – 12 months High dose (Bonn Protocol) 200 – 300 FVIII IU/kg daily, APCC, several months to years High dose (Malmö Protocol) FVIII, immunosuppressives/ cytotoxics, IVIG, 1 – 2 months

5. WFH Bangkok 2004 ITI: Bonn Protocol 1st phase –100 IU FVIII/kg BW plus –40-60 U APCC/kg BW, every 12 hours 2nd phase –Inhibitor levels ~ 1 BU –150 IU FVIII/kg BW, daily 3rd phase –Inhibitor undetectable –FVIII prophylaxis: 20-40 IU/kg BW, 3 x per week

6. WFH Bangkok 2004 ITI: Malmö Protocol 1st phase –Inhibitor levels > 10 BU reduced with immune adsorption using protein A sepharose 2nd phase –High dose FVIII, to sustain a measurable level –Cyclophosphamide, 12-15 mg/kg BW, Iv for 2 days then –Cyclophosphamide, 2-3 mg/kg BW, orally for 8-10 days –Intravenous immunoglobulin (IVIG) 0.4g/kg BW/day for 5 days, beginning on the 4th day of FVIII treatment 3rd phase –Low dose FVIII prophylaxis

7. WFH Bangkok 2004 Outcome of ITI: Bonn Protocol Most patients treated with the Bonn protocol achieve inhibitor elimination Inhibitor levels peak within the first 1-2 months then fall rapidly Some patients require years of treatment

8. WFH Bangkok 2004 Outcome of ITI acc. to Bonn Protocol (1) Haemophilia 1995; 1: 24-32 Patient Factor VIII Inhibitor Titre (BU) FVIII Dose (IU/kg/d) Time Between Inhibitor Detection and ITI Start Inhibitor Elimin- ation Time (months) StartMaximumEndMonths Exposure Days 10.86503003.070.5 21715303008.561.2 3788302001.75122.0 42.81203001.093.0 538253003001.5124.0 691102000.2574.0 7133202000.7564.0

9. WFH Bangkok 2004 Outcome of ITI acc. to Bonn Protocol (2) Haemophilia 1995; 1: 24-32 Patient Factor VIII Inhibitor Titre (BU) FVIII Dose (IU/kg/d) Time Between Inhibitor Detection and ITI Start Inhibitor Elimin- ation Time (months) StartMaximumEndMonths Exposure Days 821240030015.0154.1 9254402000.7564.5 101335501001.5215.0 11582670500.578.0 12224802002.25189.0 13619602001.54014.0 141052107005017.08242.0 1563106893001.539No 16312157023502.024No

10. WFH Bangkok 2004 Outcome of ITI: Malmö Protocol In one study, 9/11 patients achieved inhibitor elimination after 2-3 weeks following the Malmö protocol Other outcomes (Info)

11. WFH Bangkok 2004 Haemophilia 1995; 1: 24-32 Immune tolerance therapy in paediatric haemophiliacs with factor FVIII inhibitors: 14 years follow-up Kreuz W, Ehrenforth S, Funk M, Auerswald G, Mentzer D, Joseph-Steiner J, Beeg T, Klarmann D, Scharrer I, Kornhuber B

12. WFH Bangkok 2004 Criteria for Ending ITI Definition of success: –Inhibitor titre = 0 (3 consecutive tests) –Normal 12 hour recovery –Normal half-life for 6-8 weeks End ITI by continuous reduction of FVIII dosage by 10 % each week until normal prophylactic regime established No reappearance of inhibitor Haemophilia (1995), 1, 24-32

13. WFH Bangkok 2004 Criteria for Discontinuing ITI Discontinue ITI after 1 year if –Inhibitor titre no longer falling –Normal 12 hour recovery not achieved –Specific haemorrhagic problems arise Haemophilia (1995), 1, 24-32

14. WFH Bangkok 2004 Success Variables in ITI Dose of FVIII Maximum inhibitor titre Inhibitor titre at start of ITI Age at which ITI is carried out Time between inhibitor detection and start of ITI Interruption of therapy Haemophilia (1995), 1, 24-32

15. WFH Bangkok 2004 Factor VIII Dose in ITI High dose FVIII correlates with –Short inhibitor elimination time –Higher success rate Median Time for immune tolerance induction – 300 IU/kg/day3.0 months(0.5 - 4.1) – 200 IU/kg/day4.25 months(2.0 - 14) –< 100 IU/kg/day20 months(5.0 - 42 or failure) Results from > 200 patients included in the International Registry of Immune Tolerance Protocols Haemophilia (1995), 1, 24-32

16. WFH Bangkok 2004 Maximum Inhibitor Titre in ITI Patients with a maximum inhibitor titre higher than 600 BU may fail or take a very long time to achieve immune tolerance In patients with a maximum inhibitor titre of < 600 BU, there is no correlation between titre and time needed to achieve tolerance Haemophilia (1995), 1, 24-32

17. WFH Bangkok 2004 Inhibitor Titre and Age at Start of ITI Patients with higher inhibitor titres at the start of ITI require longer treatment The age of the patient at the beginning of therapy does not influence the outcome Haemophilia (1995), 1, 24-32

18. WFH Bangkok 2004 Inhibitor Detection and Start of ITI Times Results of ITI are influenced by the number of exposure days (ED) between initial detection of inhibitor and initiation of treatment Time to inhibitor eradication –< 14 ED 0.5 - 8.0 months –14-21 ED 4.1 - 9.0 months –15-21 ED 14.0 - 42 months (or failure) Haemophilia (1995), 1, 24-32

19. WFH Bangkok 2004 Interruption of ITI In 5 patients in whom FVIII treatment was interrupted the outcome of therapy was significantly worse –Prolonged inhibitor elimination time (3 of 5) –Failure (2 of 5) Haemophilia (1995), 1, 24-32

20. WFH Bangkok 2004 Influence of Factor VIII Product on ITI Factor VIII concentrates containing von Willebrand factor (VWF) can influence the success of ITI (Info)