Influence of treatment strategies On inhibitor development

1
Influence of treatment strategies On
inhibitor development

• H. Marijke van den Berg
• WFH Global Forum
• September 24-25th 2007

2
Monozygotic twins with severe hemophilia A and an
inversion
3
(No Transcript)
4
Monozygotic twin brothers

• Similar for
• Gene defect
• Clotting product
• HLA
• Vaccinations etc

• Different for
• Age at first treatment
• Severity of bleed
• Intensive treatment
• High versus low titre inhibitor

5
CANAL Study

• Study design
• Multi-centre retrospective cohort study
• 13 European and 1 Canadian hemophilia centre
• Study population
• FVIII activity lt0.02 IU/mL
• Born 1990 and 2000
• Treated with FVIII for ?50 exposure days

6
CANAL Study

• Study outcome
• Clinically relevant inhibitor development
• ? 2 positive inhibitor titres and
  decreased recovery
• High-titre inhibitor development peak titre ?
  5 Bethesda units/mL

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Patient Disposition
381 patients
366 patientsincluded
15 patientsData onpatientcharacteristics
32 patientsData onfirst exposure/ prophylaxis
319 patientsComplete data
8
Cumulative Incidence of Inhibitors per Centre
50
9/20
7/16
17/44
40
5/18
30
8/32
87/366
Percentage
9/41
2/9
7/33
2/10
20
5/29
8/49
4/26
4/39
10
0
Bar
Bre
Fra
GOS
Leu
Mad
Mar
Mil
Mon
RF
Swe
Utr
Val
Total
Large variation between centres due to small
numbers
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Patients With Inhibitors
30
All
(24)
87/366
(79)
High
69 high titre
20
Percentage Inhibitor Development
10
Low

• 18 low titre

(21)
0
30
0
10
20
40
50





















Cumulative Number of Exposure Days
10
Effects of the Very First Treatment With FVIII
32/57
60
50
40
Percentage Inhibitors
30
44/229
7/36
20
10
0
No PeakMoment
Peak Moment 34 d
Peak Moment 5 d
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Canal study IConclusions

• Inhibitor incidence 24 whereof 79 high titre
  and 21 low titre
• Patients treated intensively at first treatment
  had a 3.3 increased relative risk to develop an
  inhibitor
• Early prophylaxis protects against inhibitor
  development 60

Canal study group Blood 2007
12
Canal study II

• 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

Canal study group Blood 2007
13
All products divided according to VWFAg content
FVIII products
Little VWFAg lt0.01 IU VWFAg per IU FVIII All
monoclonally purified plasma derived FVIII
products

• Much VWFAg
• gt0.01 IU VWFAg per IU FVIII
• All other plasma derived FVIII products

• None VWFAg
• Recombinate
• Kogenate
• Helixate
• Refacto
• Kogenate Bayer
• Helixate NexGen

14
Patients

• Data on products upto 50 exposure days were
  available for n322 (88)
• N6 were excluded because they were treated with
  an unknown factor VIII product on one or more
  occasions

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Patients

• Total n316 patients
• Recombinant products n181
• Low-VWF plasma derived n33
• High-VWF plasma derived n 102

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Patient treatment characteristics





Low VWF
High VWF
Recombinant
N181

N33

N102





53 (29)
24 (24)
5 (15)




14 (19)
4 (12)
19 (19)




5 (3)
14 (42)
35 (34)




















17
Data analysis

• Data were adjusted for
• Base line factor VIIIC
• Ethnicity
• Gene mutation
• Age at first exposure
• Duration between exposure days
• Dose of factor VIII
• Prophylaxis

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Total Inhibitor incidenceRecombinant vs plasma
products
Crude RR1.0 Adj 1.0
Crude 1.0 Adj o.8
Crude 0.3 Adj 0.4
N181
N33
N102
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SummaryProduct related factors

• Similar inhibitor incidence in recombinant vs
  plasma products
• Also after adjustment for all other confounders
• High Purity / Low VWF containing products lower
  inhibitor incidence? Numbers to small
• No increased risk after switching of product

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Canal Study Group

• Barcelona Altisent
• Bremen Auerswald
• Frankfurt Escuriola, Kreuz
• Great Liesner
• Ormond
• Leuven v Geet, Peerlinck
• Madrid Villar, Jimenez
• Marseille Chambost

• Milan Santagostino, Mancuso
• Montreal Rivard
• Royal Free Lee, Yee
• Sweden Petrini, Tedgard
• Utrecht vd Berg, Bom, Gouw
• Valencia Cid, Haya

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Thank you
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Danger Model
T Helper
Sig 1
Sig 2 (Co-stimulation)
APC
Alarm signal
Distressedcell
Normalcell
Matzinger P. Science. 2002296301-305.
23
Hypothesis on inhibitor development
Inversions Large deletions IL10
Small deletions Miss mutations CTL4
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Should we have selected patients who never
switched product?

• 3 in recombinant products, 14 in Low VWF, 34
  in High VWF switched
• Patients who develop inhibitors ? less chance to
  switch product
• Subpopulation of pt who never switched?
• selection of inhibitors in High VWF ?
  overestimation of inhibitors in High VWF

25
PUP Studies Treatment at First Exposure Day
60
8/15
Percentage Inhibitors
58/205
40
20
1/16
0
No Peak Moment
Peak Moment 34 d
Peak Moment 5 d
Gouw SC, et al. J Thromb Haemost.
200751383-1390.
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Surgical Procedures in Recombinant PUP Studies
Gouw SC, et al. J Thromb Haemost.
200751383-1390.