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Prevention of Inhibitors in Hemophilia

Prevention of Inhibitors in Hemophilia. Manuel Carcao MD, MSc Paediatric Hematologist Associate Professor Hospital for Sick Children University of Toronto Toronto, Canada. How to reduce inhibitors.

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Prevention of Inhibitors in Hemophilia

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  1. Prevention of Inhibitors in Hemophilia Manuel Carcao MD, MSc Paediatric Hematologist Associate Professor Hospital for Sick Children University of Toronto Toronto, Canada How to reduce inhibitors

  2. Wish to thank the Organizers, the Lebanese Society of Haematology, the WFH and Bayer for bringing me to Lebanon

  3. Haemophilia at the start of 20th century A terrible disease with no treatment

  4. Tremendous Progress in Hemophilia Care during the 20th Century Discovery of Cryoprecipitate Hemophilia treatment centers Virally inactivated safe factor concentrates Home Care National and International Hemophilia Organizations Discovery of the FVIII and FIX genes Recombinant factors “Prophylaxis superior to on demand therapy” Immune Tolerance Induction

  5. Where are we now in Haemophilia Care •  We have safe factor concentrates  But expensive and hence much of the world has little access to these products  Inhibitors continue to occur with no reduction in their incidence

  6. Inhibitors • Antibodies formed against factor concentrates • Inactivate / neutralize / inhibit the activity of factor • → Patients become refractory to conventional factor replacement → need expensive and less effective alternative bypassing agents Heavy chain Light chain

  7. Inhibitor development is a huge problem Clinical Economic

  8. Inhibitor development is a huge problem • More difficult to treat bleeds • ↑ susceptibility to Life-threatening bleeds e.g. ICH • Worse joint disease • Worse quality of life Clinical

  9. Inhibitor development is a huge problem Economic Bypassing agents $$$ Immune tolerance therapy (to eradicate inhibitors) $$$$$

  10. Why Do Inhibitors Develop? Boy with Severe Haemophilia A “Produces no FVIII” No immune central tolerance Immune system does not see endogenous FVIII

  11. Why Do Inhibitors Develop? Boy with Severe Haemophilia A “Produces no FVIII” Receives exogenous FVIII

  12. Why Do Inhibitors Develop? Boy with Severe Haemophilia A “Produces no FVIII” FVIII Receives exogenous FVIII

  13. Inhibitors develop early in life (usually) • 20-40% in severe haemophilia A Median ≈11 Exposure Days; age 1.5 yrs

  14. Multifactorial Risk Factors for Inhibitor Development GENETIC NON-MODIFIABLE NON-GENETIC POTENTIALLY MODIFIABLE

  15. GENETIC NON-MODIFIABLE • Type of Hemophilia: A >>>B • Hemophilia Severity: • Severe(20-40%) > Moderate (5-10%) >Mild (1-5%) • Mutation: Null(25-50%);non-null(<10%) • Ethnicity: 2X higher in African ancestry • Family History of an inhibitor:  risk by 2-3X • Inherited polymorphisms for immune-modulating genes

  16. NON-GENETIC POTENTIALLY MODIFIABLE • Choice of Factor concentrate: • Unclear if a risk factor • Intense exposure to factor early on in life: • ↑ risk (2-3X) • Early start of Prophylaxis: • ↓ risk by 40-60%

  17. A Case of 2 brothers with severe hemophilia A 1) Ben 2) Nathan

  18. Intense exposure 1) Ben

  19. Bypassing therapy & ITT X 1.5 yrs & Port Intense exposure 1) Ben

  20. 2) Nathan

  21. Interventions to reduce inhibitors Which factor to use? How can we expose him in the least immunogenic way?

  22. Interventions to reduce inhibitors Is there a factor that has less inhibitors? Which factor to use?

  23. Type of Factor Recombinant (r) FVIII Plasma derived (PD) FVIII

  24. Type of Factor Recombinant (r) FVIII Plasma derived (PD) FVIII Some studies suggest lower incidence of inhibitors

  25. Type of Factor • But confounding variables • Differences in how Inhibitor surveillance • Different populations - different inhibitor risks • Reporting bias – studies showing low inhibitor incidence more likely to be reported Recombinant (r) FVIII Plasma derived (PD) FVIII Some studies suggest lower incidence of inhibitors

  26. Iorio et al. JTH, 2010 24 studies included • Systematic literature review of inhibitor development in Hemophilia A

  27. Iorio et al. JTH, 2010 24 studies included • Systematic literature review of inhibitor development in Hemophilia A

  28. Iorio et al. JTH, 2010 • Most of the difference explained by • Testing frequency • “more recent studies (usually with rFVIII) have tested more frequently and consequently find more inhibitors” • Follow-up time • “if patients are followed for a longer time more inhibitors will be found” • “factor type was not a statistically significant determinant of inhibitor development” 24 studies included • Systematic literature review of inhibitor development in Hemophilia A

  29. Iorio et al. JTH, 2010 24 studies included “..not possible to prove or disprove the hypothesis that there is a higher risk of inhibitor development associated with the use of recombinant vs. Plasma derived FVIII” • Systematic literature review of inhibitor development in Hemophilia A • Most of the variability explained by • Testing frequency • “more recent studies have tested more and find more inhibitors” • Follow-up time • When taken into account factor type not statistical significance

  30. Randomized head to head comparison Sippet Study (Survey of Inhibitor development in plasma-product exposed toddlers) Is ongoing (150 of 300 patients already enrolled) • Systematic literature review of inhibitor development

  31. Interventions to reduce inhibitors How can we expose him in the least immunogenic way Early prophylaxis & avoidance of intense exposure

  32. Can introduction of early prophylaxis reduce risk of inhibitor? • Is there an explanation as to why early start of prophylaxis may reduce inhibitor incidence? • Is there any evidence that it does?

  33. 1. Possible explanation “The Danger Signal Theory” Signal 2 Signal 1  Risk FVIII Danger Inflammation Severe bleed (ICH) Surgery •  Cytokine production •  Activation of Antigen Presenting Cells •  Activation of T lymphocytes • Antibody prod. by B lymphocytes Baseline genetic risk Matzinger P. The danger model: a renewed sense of self. Science 2002; 296:301-5.

  34. 1. Possible explanation “The Danger Signal Theory” Signal 2 Signal 1  Risk FVIII Danger Inflammation Severe bleed (ICH) Surgery Signal 1 No Danger Signal FVIII  Risk Baseline genetic risk Prophylaxis

  35. 2. EVIDENCE: early introduction of prophylaxis  inhibitor risk • Morado 2005 Spain • Santagostino 2005 Italy • Gouw 2007 Multi-Europe + Canada • Gouw 2007 Netherlands • Ragni 2009 USA • Kurnik 2010 Germany • MacLean 2011 UK

  36. 2. EVIDENCE: early introduction of prophylaxis  inhibitor risk • Morado 2005 Spain • Santagostino 2005 Italy • Gouw 2007 Multi-Europe + Canada • Gouw 2007 Netherlands • Ragni 2009 USA • Kurnik 2010 Germany • MacLean 2011 UK Largest Interventional

  37. #3) Gouw et al (CANAL study) (2007) A large study Gouw SC et al. Blood. 2007;109(11):4648-4654.

  38. #3) Gouw et al (CANAL study) (2007) Gouw SC et al. Blood. 2007;109(11):4648-4654.

  39. #7) Kurnik et al. (2010) (Bremen & Munich) Interventional PILOT Study to explore whether early start of prophylaxis would reduce inhibitor development Kurnik K et al. Haemophilia 2010; 16:256-62.

  40. #7) Kurnik et al. (2010) (Bremen & Munich) Findings Kurnik K et al. Haemophilia 2010; 16:256-62.

  41. #7) Kurnik et al. (2010) (Bremen & Munich) Findings Kurnik K et al. Haemophilia 2010; 16:256-62.

  42. Conclusions from these studies Early start of prophylaxis protects against inhibitor development It permits children to be exposed to FVIII without any danger signals for inhibitor development

  43. What happened to Nathan? • At 8 months of age • Parents asked is there anything that we can do to reduce Nathan’s chances of developing an inhibitor

  44. What happened to Nathan? • 8 mo: Started on Early Low dose “Prophylaxis” with PD FVIII 25 U/kg every 2 wks - peripheral IV • 18 mo:  to 1 / wk prophylaxis • 25 mo:  to 2 / wk prophylaxis • Now 34 mo: Has had > 75 ED No Inhibitor

  45. What happened to Nathan? • Why did he not get an inhibitor? • Choice of Factor? • Early Prophylaxis? • Luck? We will never know from one case alone!

  46. Summary • Inhibitor Development is a major problem • Reducing inhibitors is critical • Non genetic inhibitor risk factors are important and may be modifiable • We must try to reduce inhibitor development

  47. Thank-you for your attention Thank-you for the kind invitation to come to Beirut

  48. Do I believe that exposing children with severe hemophilia A at very young ages to factor in the least immunogenic way will result in less inhibitors? YES

  49. Inhibitor Risk in PUPs: High titer(≥5 BU) only Multiple PD FVIII Single rFVIII Single PD FVIII Wight J, Paisley S. Haemophilia 2003;9:318-35

  50. Inhibitor Risk in PUPs: High titer(≥5 BU) only Multiple PD FVIII No difference Single rFVIII Single PD FVIII Wight J, Paisley S. Haemophilia 2003;9:318-35

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