INHIBITOR TO ANTIHEMOPHILIC FACTOR

Djajadiman GatotDivision of Hematology Oncology

Department of Child Health

FMUI - CMGH

What is inhibitor?(to factor VIII)

Inhibitor are polyclonal allo-antibodies of the IgG molecules predominantly of the IgG4 subclass that directed to FVIII

Highly heterogeneous among patients Display changes in epitope specificity over time Its synthesis requires activated CD4+ cells Neutralized the procoagulant activity of FVIII

and render infusion of FVIII inefficient

How do inhibitor develop?

• FVIII is a soluble glycoprotein; its adminis-tration to an individual with normal immunocompetence will results in immune response

• The FVIII genotype has major influence for the development of inhibitors

Who will develop inhibitor?

FVIII genotype and the risk of developing

inhibitor:

- large deletion ( 88%)

- nonsense mutations ( 60%)

- intron-22 inversion ( 21%)

- small deletions/insertions ( 20%)

- missense mutations ( 5%)

InhibitorInhibitor

Location of major factor VIII inhibitory epitopes

Who will develop inhibitor?

HLA and the risk of developing inhibitor ethnic group, African-American 2x than whites

family history of antibodies to FVIII inherited predisposition

hemophilic siblings >> extended hemophilic relatives

any severe hemophilia

When will inhibitor develop?

The majority of inhibitors develop during childhood, at an average of 12 years

Reported studies:

Inhibitor development occurred between the age of 1 – 2 yrs, after an average of 10 treatments with rFVIII

Inhibitor risk is greatest during the first 50 exposures to rFVIII

What is the incidence of inhibitor?

Inhibitors of FVIII develop in up to 30% of hemophilia A patients and significantly more frequent in severe hemophilia

Why ‘only’ 30% of hemophilia patients have inhibitor?

There are several possible mechanisms:1) anti-FVIII antibodies are neutralized in the

periphery,

2) B cells (and T cells) can be rendered anergic by intrinsic mechanism,

3) any antibodies produced are primarily directed towards sites of the FVIII molecule that are not involved in its function

InhibitorInhibitor

ClassificationClassification TreatmentTreatment

Low titer (< 5 BU)Low titer (< 5 BU) Higher/more frequent Higher/more frequent dose of factor dose of factor concentrateconcentrate

High titer (> 5 BU)High titer (> 5 BU) By-passing agentBy-passing agent

Immune tolerance Immune tolerance inductioninduction

Rituximab (?)Rituximab (?)

Haemophilia 2006;12:7–18.Haemophilia 2006;12:218–22.

Management of bleeding in patient with inhibitor

The ultimate goals of treatment are:1. Resolution of bleeding diathesis

2. The elimination of the inhibitor

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Inhibitor Development WithrFVIII & pdFVIII: PUPs

Survival without inhibitor

1.0

0.5

0.0

0 20 40 60 80 100

Cumulative exposure days

p=0.006

End points: All inhibitors

148 106 88 74 65 58No. patients at risk:

pdFVIII(historical control)

rFVIII

Goudemand J et al. Blood. 2006;107:46-51.

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AIM

To investigate

Whether plasma products induce fewer inhibitors than recombinant products

Whether plasma products with a higher VWF factor have a lower inhibitor incidence

Impact of switching products

Gouw SC et al. Blood, 2007;109:4693-4697

CANAL Study

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CANAL Study

Study design Multi-centre retrospective cohort study 13 European and 1 Canadian hemophilia centre

Study population FVIII activity <0.02 IU/mL Born 1990 and 2000 Treated with FVIII for 50 exposure days

Gouw SC et al. Blood, 2007;109:4693-4697

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All products divided according to VWF:Ag content of FVIII concentrates

No VWF:Ag

-Kogenate

-Kogenate FS

-Recombinate

-Refacto

Low VWF:Ag

<0.01 IU VWF:Ag per IU FVIII

All monoclonallypurified plasma derived FVIII products

High VWF:Ag

>0.01 IU VWF:Ag per IU FVIII

-All other plasma derived FVIII products

Gouw SC et al. Blood, 2007;109:4693-4697

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Total Inhibitor incidenceRecombinant vs plasma products

0%

5%

10%

15%

20%

25%

30%

35%

Recomb Low VWF High VWF

Crude 0.3Adj 0.4

Crude 1.0Adj 0.8

N=181 N=33 N=102

Crude RR 1.0Adj 1.0

Gouw SC et al. Blood, 2007;109:4693-4697

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Cumulative incidence of clinically relevant inhibitor development according to switching products

Gouw SC et al. Blood, 2007;109:4693-4697

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Summary CANAL StudyProduct related factors

Similar inhibitor incidence in recombinant vs plasma products

No increased risk after switching of product

Gouw SC et al. Blood, 2007;109:4693-4697

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Efficacy: Treatment of Bleeding Episodes

875 (100)1710 (100)Total

42 (4.8)19 (1.1)≥5

16 (1.8)21 (1.2)4

24 (2.7)47 (2.7)3

137 (15.7)210 (12.3)2

656 (75.0)1413 (82.6)1

European patients, n (%)

North American patients, n (%)

Bleeding episodes

Number of infusions

Overall, 80.0% of bleeds were treated with 1 infusion

93.5% of bleeds were treated with 1 or 2 infusions

Patients assessed the response to the first infusion as “excellent” or “good” in 80.5% of bleeding episodes

Abshire TC, et al. Thromb Haemost. 2000;83(6):811-816.

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Safety Summary

No viral seroconversions to hepatitis B or C or to HIV observed

1 patient had detectable inhibitors (≥0.6 BU)Measurable baseline inhibitor titer (0.39 BU) at

enrollment, not de novo No clinically significant immune response to murine, baby

hamster kidney, or FVIIII proteins A total of 24 events in 13 patients described as remotely

related to study drug One patient experienced palpitations classified as severe,

which ceased after treatment with analgesics

Abshire TC, et al. Thromb Haemost. 2000;83(6):811-816.

Resolution of Bleeding Diathesis

• Replacement therapy: ~ human FVIII (high-dose) ~ recombinant FVIII (2nd and 3rd generation) ~ porcine FVIII

• Bypass therapy: ~ prothrombin complex concentrate (PCC) ~ activated PCC ~ recombinant FVIIa

Contact activation

XIa

IXa+VIII APCTM

TF-VIIa Xa+V IIa Fibrin Fibrinolysis

TAFITFPITM

The elimination of inhibitor

• Immune tolerance induction (ITI), - may take up to 1 – 3 years to achieve tolerance - very high cost - successfully eradicating up to 90% of FVIII inhibitor

• Immunomodulation, + cytostatics: cyclophosphamide, 6-mercaptopurine + immunosuppressant: azathioprine, cyclosporin + corticosteroids

+ gamma globulin + plasmapheresis

Immune tolerance induction

The dose:

High level inhibitors (>100 BU), treated with high-dose regimen:

100-200 IU kg-1day-1

Low titer inhibitors (5-100 BU), treated either with high- or low-dose regimen:

50 IU kg-1, 3 times per week

Immune tolerance induction

The cost:

British: 0.25 – 1 million £ per patient

Italy: 18,000 € per patient, monthly

USA: 1,7 million $ per patient

Thank You