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Transcript
Inhibitors in hemophilia
Flora Peyvandi
Angelo Bianchi Bonomi Hemophilia and Thrombosis Center,
Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico and
University of Milan, Italy
ISTH Advanced Course in Hemostasis and Thrombosis
Moscow 17 – 19 September 2014
Treatment complication
• Inhibitor is the most serious complication associated with the
use of factor concentrates
• Inhibitor neutralizes infused factor, rendering patients resistant
to conventional replacement treatment
• Most inhibitors are transient, i.e. disappear within 6 months from
their occurence, or resolve with immune tolerance therapy
• 20-30% of hemophilia A and 3% of hemophilia B patients show
persistent clinically significant inhibitors which result to severe
morbidity
Flora Peyvandi
Inhibitors
•
Alloantibodies, frequently IgG4 that specifically neutralize
the procoagulant activity of FVIII or FIX
•
Cause serious complication of replacement therapy in
patients with hemophilia
•
Become a long-standing problem that seriously affects
health and quality of life
Flora Peyvandi
The inhibitors interfere with important
interaction of FVIII at various stages of its
functional pathway
Antibodies directed against C2 domain
affect the binding of FVIII to phospholipid
and von Willebrand factor (vWF)
Antibodies directed against C2 domain
interfere with cleavage of FVIII by
thrombin and FXa.
Flora Peyvandi
Anti-A2 e -A3 inhibitors disrupt the interaction
FVIIIa with FIXa destabilizing FVIIIa within the
Xase complex.
The development of inhibitory antibodies
The formation of antibodies against exogenous FVIII is a T-cell
depent event involving antigen-presenting cells (APC), T- and Blymphocytes
Exogenous
FVIII
FVIII antibodies
Flora Peyvandi
(Astermark J hemophilia 2006;12, Suppl.3:52-60)
The development of inhibitory antibodies
1. The infused factor binds to the surface of the APC
2. internalized by endocytosis and proteolytically cleaved in the
endocytic processing pathway
3. linear peptides of 13–18 amino acids bind to the major
histocompatibility complex (MHC) class II molecules
4. Transferred to the cell surface for interaction with T-cell receptor
(TCR-CD3) on CD4+
Flora Peyvandi
The development of inhibitory antibodies
5. TH-cells released cytokines
6. IL-4, IL-5, IL-6 and IL-10 promote B-cells activation and
mediate the humoral response
7. Cytokines secreted by TH2 cells also mediate the
characteristic immunoglobulin (Ig) class-switching
to IgG4
Flora Peyvandi
Factors influencing inhibitor development
Patient-related
FVIII gene mutation
Ethnic origin
Family history of inhibitor
MHC class
Polymorphisms of immune-response genes
(IL10-TNFalfa, regulatory molecules)
Treatment-related
Number of FVIII exposure days
Age at the time of first treatment
Type of FVIII concentrates
Intensity of treatment
Current infection/inflammatory state
Flora Peyvandi
Risk of inhibitor development according to
specific F8 genotype
• meta-analysis of 5383 severe HA patients from 30 selected studies
•
large deletions and nonsense mutations
showed an higher risk than intron 22
inversions (pooled OR 3.6, [95% CI], 2.3-5.7 and OR 1.4, 95% CI, 1.11.8, respectively)
•
intron 1 inversions and splice-site
mutations were equal (pooled OR 0.9; 95% CI, 0.6-1.5 and
OR 1.0; 95% CI, 0.6-1.5)
•
small deletions/insertions and missense
mutations showed a lower risk (pooled OR 0.5; 95%
CI, 0.4-0.6 and OR 0.3; 95% CI, 0.2-0.4, respectively)
(Gouw SC et al, Blood 2012; 119:2922-2934)
Flora Peyvandi
Inhibitor related studies:
Genetic of the immune system
Additional genetic risk factors that have been suggested to influence the inhibitor
development are polymorphic genes in the immune response
SAMPLES
IMMUNE SYSTEMS
RELATED GENES
POLIMORPHISMS
GENOTYPED
POLYMORPHISMS SIGNIFICATIVELY
ASSOCIATED TO INHIBITOR
DEVELOPEMENT
REFERENCES
176 severe HA patients
HLA class II
HLA alleles
DQA1*0102 allele
Hay et al.
Thromb Haemost 1997
IL1beta
RFLP
-
IL4
1 SNP
-
IL10
STR
Allele 134 bp CA repeats
HLA class I/II
HLA alleles
-
TNFa
4 SNPs
-308 A/G
124 severe HA patients in 60 unrelated
families (63 inhibitor patients)
CTLA4
2 SNPs
-318 C/T
Astermark et al.
J Thromb Haemost 2007
915 severe HA patients
(282 inhibitor positive)
21 candidate genes
372 SNPs
IL1, IL2, IL12
Lozier et al.
hemophilia 2011
1 081 genes
13 331 SNPs
13 SNPs located in:
MAPK9, DOCK2, CD44, IQGAP2, CSF1R
PDGFRB, PCGF2, HSP90B1, F13A1,
IGSF2, ALOX5AP, MAP2K4, PTPRN2
Astermark et al.
Blood 2013
HMOX1
STR, 2 SNPs
Allele >30 GT repeats
FCGR
5 SNPs
FCGR2A (131HH allele)
164 HA patients in 78 unrelated families
(77 inhibitor positive)
164 HA patients in 78 unrelated families
(77 inhibitor positive)
833 subjects from 3 independent cohorts
(457 inhibitor positive)
362 severe HA patients
(99 inhibitor positive)
85 severe HA patients
(36 inhibitor positive)
Astermark et al.
Blood 2006
Astermark et al.
Blood 2006
Repessè et al.
Haematologica 2013
Eckhardt et al.
J Thromb Haemost 2014
• 833 subjects from 3 independent cohorts:
- Hemophilia Growth and Development Study (HGDS)
- Malmo International Brother Study (MIBS)
- Hemophilia Inhibitor Genetics Study (HIGS)
• Illumina iSelect platform to genotype 13 331 SNPs from 1 081
genes, primarily immune response and immune modifier genes
Flora Peyvandi
Astermark study
Results
• 53 SNPs significantly associated with inhibitor development
- 13 with p<0.001 in post meta analysis
- 8 significant predictors in discordant brother pairs
- 8 SNPs significant in discordant pairs
- 13 SNPs passing the meta P<.001
Flora Peyvandi
Ethnicity and inhibitor development
Recombinate 
Kogenate 
Total patients (≤2%)
72
64
89
African American
9
8
10
with inhibitors
5 (55,5%)
4 (50%)
5 (50%)
63
56
79
17 (27,4%)
14 (25%)
20 (25%)
Caucasian and others
with inhibitors
US Retrospective Study*
* Study subjects received either cryoprecipitate or intermediate purity FVIII concentrates
Black patients with hemophilia A are twice as likely as white patients to
produce inhibitors against factor VIII proteins given as replacement therapy.
(Scharrer et al, Haemophilia 1999; 5:145-154)
(Viel KR et al, N Englan J Med 2009;360:1618-27)
Flora Peyvandi
Age at first exposure
First replacement therapy at an early age may increase the risk of
inhibitor formation
•
the incidence of inhibitors at 3 years was significantly higher in
those initiating therapy before 6 months of age compared with
patients starting with treatment between 6 and 12 months or those
treated at age >12 months (41% vs. 29% and 12% respectively, P=0.03)
•
children first treated at age <11 months demonstrated a trend
towards an increased risk of inhibitor formation, this data was
not confirmed after adjusting for genetic factors
(Lorenzo et al. Br J Haematol 2001;113: 600-603)
(Santagostino et al. Br J Haematol 2005)
Flora Peyvandi
‘Age at first exposure’
CANAL cohort study
1. the incidence of inhibitors appeared to be associated with age at first
treatment, decreasing from 41% for those treated within the first month
of age to 18% in those treated after 18 months
2. after adjustment for treatment intensity, this association largely
disappeared
(Gouw SC et al, Blood 2007;109:4648-4654)
Intensity of treatment
• the association of a higher frequency of
FVIII treatment and inhibitor risk differed
among studies
• the association that was present
disappeared after adjustment for dose of
FVIII
• the frequency of FVIII treatment was not
independently associated with the risk of
inhibitor development
Intermediate frequency: 10 to 50 days
High frequency: <10 days
Flora Peyvandi
(Gouw SC & Fijnvandraat K, Semin Thromb Hemost 2013;39:740-751)
Type of FVIII concentrates
The most controversal risk factor for the development of inhibitors
in hemophilia patients depends on the type of the therapeutic
molecule used, plasma-derived concentrates or recombinant rFVIII
- Plasma-derived products may vary in purity and VWF content
- Recombinant products produced in mammalian tissue culture are
of high purity and do not contain VWF
Clinical data
Flora Peyvandi
Immunogenic potential of different
source/type FVIII
• The amount of von Willebrand factor (VWF)
• FVIII physical state
• FVIII structural change
• Affinity of FVIII for phospholipids
• posttranslational modifications
(e.g. carboxylation, glycation, sulphation) crucial for
correct functioning of the protein and are specific to the
cell line
Flora Peyvandi
VWF and FVIII immunogenicity
•
Under physiologic conditions, VWF binds to different epitopes in the
A3 and C2 domain of the FVIII molecule and has a protective effect
on these FVIII epitopes against degradation by proteinases
•
In addition, an immunomodulatory effect of VWF has been described
by masking B- and T-cell epitopes
•
VWF is able to block antigen presentation of FVIII by dendritic cells in
a concentration-dependent manner
(Behrmann et al. Thromb Haemost 2002;88:221-229)
(Suzuki et al. Thromb Haemost 1996;76:749-754)
(Delignant et al. Haemophilia 2012;18:248-254)
Flora Peyvandi
Cumulative incidence of FVIII inhibitors
• Incidence rates of inhibitor development in patients treated with
pdFVIII or rFVIII products have been reported in numerous studies
(Mannucci PM hemophilia 2014; 20, Suppl.6:2-16)
Cumulative incidence of FVIII inhibitors
• In previously untreated patients (PUPs) treated with pdFVIII
products, the crude incidence of inhibitor development was 13.8%
• in PUPs treated with recombinant products, the crude incidence
of inhibitors was twofold higher (28.5%)
• the data suggest that plasma-derived products are less
immunogenic than recombinant products but, due to study
heterogeneity, the results cannot be considered conclusive
(Mannucci PM hemophilia 2014; 20, Suppl.6:2-16)
Flora Peyvandi
*
• Calvez et al. has re-examined
the
data
from
four
different retrospective studies
comparing pdFVIII and rFVIII
• The data clearly indicates that
there is an trend indicating that
recombinant products are
more immunogenic
* p< 0.05
*
Relative risk
or odds ratio
Adjusted
Unadjusted
recombinant better | recombinant worse
Flora Peyvandi
• Multicenter (13 European and 1 Canadian center) retrospective cohort
study
• Included 316 previously untreated patients (PUPs) with severe HA born
between 1990 and 2000 who received pdFVIII or rFVIII infusions up to
50 exposure days (EDs) o until inhibitor development
• Describe the inhibitor risk according to different factor VIII product
types
Flora Peyvandi
The CANAL study: results
• Eighty-two patients (26%) developed clinically relevant inhibitors
• High-titer inhibitors developed in 66 patients (21%)
• Patients developed inhibitors after a median of 14 exposure days
(interquartile range [IQR], 8-19 days) and at a median age of 15
months (IQR, 10-22 months)
Flora Peyvandi
The CANAL study: results
1. the risk of inhibitor development was not clearly lower in plasmaderived compared with recombinant factor VIII products (relative risk
[RR], 0.8; 95% confidence interval [CI], 0.5-1.3).
2. the inhibitor risk was similar in plasma-derived products containing
considerable quantities of VWF (RR, 1.0; CI, 0.6-1.6), and it was 70%
decreased in plasma-derived products containing small quantities of
VWF (RR, 0.3; CI, 0.1-1.1).
• Multicenter (29 hemophilia centers in Europe, Israel and
Canada) cohort study
• Included 574 PUPs, median age 4.6 (3.5-6.5), with severe
HA born between 2000 and 2010 who received pdFVIII or
rFVIII infusions up to 75 EDs or until inhibitor development
• Assess whether the types of factor VIII product were
associated with inhibitor development
Flora Peyvandi
The RODIN study: results
• inhibitory antibodies developed in 177 patients (cumulative
incidence, 32.4%; 95% confidence interval [CI], 28.5 to
36.3)
• 116 patients had high-titer inhibitors
incidence, 22.4%; 95% CI, 18.8 to 26.0)
(cumulative
• Inhibitory antibodies developed after a median of 15
exposure days (interquartile range, 10 to 20) at a median
age of 15.5 months (interquartile range, 10.7 to 19.6)
Flora Peyvandi
The RODIN study: results
1. Absence of an evident difference in
inhibitor incidences between plasmaderived and recombinant FVIII products
(adjusted hazard ratio as compared with
recombinant products, 0.96; 95% confidence
interval [CI], 0.62 to 1.49)
2. Second-generation full-length products
were associated with an increased risk of
inhibitor development as compared with
third-generation products (adjusted hazard
ratio, 1.60; 95% CI, 1.08 to 2.37)
3. the content of von Willebrand factor in the
products was not associated with the risk of
inhibitor development.
Adjusted Relative Risk of inhibitor development,
according to the type of FVIII product.
• data from 24 studies comparing pdFVIII
and rFVIII
• 1167 patients treated with pdFVIII and
927 with rFVIII, median age 9.6 months
• pooled incidence rate was 14.3% for
pdFVIII and 27.4% for rFVIII
• after multi-way ANOVA, significant
differences in study design, study period,
testing
frequency
while
type
of
concentrate lost statistical significance*
Flora Peyvandi
*
Seminars in Thrombosis & Hemostasis, Sept 2013
• data from 28 prospective studies
evaluating
the
incidence
of
inhibitors in 1421 PUPs
• rates of inhibitors were 23% (0.150.33) for pd-FVIII and 29% (0.260.32) for rFVIII products
Inhibitor rate incidence
• no statistically significant differences were observed in the inhibitor
incidence between pdFVIII and rFVIII concentrates
Flora Peyvandi
The outcomes of numerous studies and systematic
reviews have been contradictory.
The studies have been limited by the enrollment of
small, heterogeneous study populations and the use
of several factor VIII products, and comparisons
among studies have been difficult because of
different study designs.
THEREFORE…..
Flora Peyvandi
The SIPPET study:
(Survey of Inhibitors in Plasma-Product
Exposed Toddlers)
Flora Peyvandi
Study objective
To compare the immunogenicity of the class of plasmaderived VWF-FVIII concentrates with that of the class of
recombinant FVIII, by determining the frequency of inhibitor
development in PUPs exposed to study products for at least 50
EDs or in the first 3 years from enrollment, whichever comes first.
• Multicentre, international (Europe, America, Africa, Asia),
open-label, controlled, randomised trial
• Approximately 300 patients will be enrolled
Flora Peyvandi
Treatment
• Each patient will be randomly assigned to a treatment with
a single product (pdFVIII or rFVIII)
• Prophylaxis or on-demand regimens will be chosen by the
clinicians according to their guidelines and preferences
Flora Peyvandi
Patients recruitment with
geographic distribution
279 patients recruited
20 pts
19 pts
38 pts
96 pts
23 pts
Flora Peyvandi
83 pts
Consideration
• Inhibitor is a severe complication of FVIII replacement therapy
• the onset of inhibitor is a complex interaction of environmental and
genetic factors
• numerous studies have carefully explored the likelihood of developing
inhibitors related to FVIII product type
• contradictory data have been reported by numerous studies and
systematic reviews
• solid information on the inhibitor risk associated with the use of FVIII
product type are expected to be generated from the randomized
controlled SIPPET study
Flora Peyvandi