Presentation is loading. Please wait.

Presentation is loading. Please wait.

Inhibitors in hemophilia

Similar presentations

Presentation on theme: "Inhibitors in hemophilia"— Presentation transcript:

1 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

2 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

3 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

4 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. Anti-A2 e -A3 inhibitors disrupt the interaction FVIIIa with FIXa destabilizing FVIIIa within the Xase complex. Flora Peyvandi

5 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 B-lymphocytes FVIII antibodies Exogenous FVIII Flora Peyvandi (Astermark J hemophilia 2006;12, Suppl.3:52-60)

6 The development of inhibitory antibodies
The infused factor binds to the surface of the APC internalized by endocytosis and proteolytically cleaved in the endocytic processing pathway linear peptides of 13–18 amino acids bind to the major histocompatibility complex (MHC) class II molecules Transferred to the cell surface for interaction with T-cell receptor (TCR-CD3) on CD4+ Flora Peyvandi

7 The development of inhibitory antibodies
TH-cells released cytokines IL-4, IL-5, IL-6 and IL-10 promote B-cells activation and mediate the humoral response Cytokines secreted by TH2 cells also mediate the characteristic immunoglobulin (Ig) class-switching to IgG4 Flora Peyvandi

8 Factors influencing inhibitor development
8 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

9 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], and OR 1.4, 95% CI, , respectively) intron 1 inversions and splice-site mutations were equal (pooled OR 0.9; 95% CI, and OR 1.0; 95% CI, ) small deletions/insertions and missense mutations showed a lower risk (pooled OR 0.5; 95% CI, and OR 0.3; 95% CI, , respectively) (Gouw SC et al, Blood 2012; 119: ) Flora Peyvandi

10 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 164 HA patients in 78 unrelated families (77 inhibitor positive) IL1beta RFLP - Astermark et al Blood 2006 IL4 1 SNP IL10 STR Allele 134 bp CA repeats 164 HA patients in 78 unrelated families (77 inhibitor positive) HLA class I/II 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 833 subjects from 3 independent cohorts (457 inhibitor positive) 1 081 genes SNPs 13 SNPs located in: MAPK9, DOCK2, CD44, IQGAP2, CSF1R PDGFRB, PCGF2, HSP90B1, F13A1, IGSF2, ALOX5AP, MAP2K4, PTPRN2 Astermark et al Blood 2013 362 severe HA patients (99 inhibitor positive) HMOX1 STR, 2 SNPs Allele >30 GT repeats Repessè et al Haematologica 2013 85 severe HA patients (36 inhibitor positive) FCGR 5 SNPs FCGR2A (131HH allele) Eckhardt et al J Thromb Haemost 2014 Induction of heme oxygenase-1, a stress-inducible enzyme with anti-inflammatory activity, reduces the immunogenicity of therapeutic factor VIII in experimental hemophilia A. In humans, heme oxygenase-1 expression is modulated by polymorphisms in the promoter of the heme oxygenase-1-encoding gene (HMOX1). We investigated the relationship between polymorphisms in the HMOX1 promoter and factor VIII inhibitor development in severe hemophilia A. We performed a case-control study on 99 inhibitor-positive patients and 263 patients who did not develop inhibitors within the first 150 cumulative days of exposure to therapeutic factor VIII. Our results demonstrate that inhibitor-positive patients had a higher frequency of alleles with large (GT)n repeats (L: n≥30), which are associated with lesser heme oxygenase-1 expression (odds ratio 2.31; 95% confidence interval ; P<0.001].

11 Hemophilia Growth and Development Study (HGDS)
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 SNPs from genes, primarily immune response and immune modifier genes Flora Peyvandi

12 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

13 Ethnicity and inhibitor development
Recombinate Ô Kogenate Ô US Retrospective Study* Total patients (≤2%) 72 64 89 African American 9 8 10 with inhibitors 5 (55,5%) 4 (50%) 5 (50%) Caucasian and others 63 56 79 17 (27,4%) 14 (25%) 20 (25%) * 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: ) (Viel KR et al, N Englan J Med 2009;360: ) Flora Peyvandi

14 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: ) (Santagostino et al. Br J Haematol 2005) Flora Peyvandi

15 ‘Age at first exposure’ CANAL cohort study
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 after adjustment for treatment intensity, this association largely disappeared (Gouw SC et al, Blood 2007;109: )

16 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: )

17 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

18 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

19 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: ) (Suzuki et al. Thromb Haemost 1996;76: ) (Delignant et al. Haemophilia 2012;18: ) Flora Peyvandi

20 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)

21 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

22 recombinant better | recombinant worse
Relative risk or odds ratio Adjusted Unadjusted * * p< 0.05 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 MODIFICATO: sfondo nero Flora Peyvandi

23 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

24 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, months) Flora Peyvandi

25 The CANAL study: results
the risk of inhibitor development was not clearly lower in plasma-derived compared with recombinant factor VIII products (relative risk [RR], 0.8; 95% confidence interval [CI], ). the inhibitor risk was similar in plasma-derived products containing considerable quantities of VWF (RR, 1.0; CI, ), and it was 70% decreased in plasma-derived products containing small quantities of VWF (RR, 0.3; CI, ).

26 Multicenter (29 hemophilia centers in Europe, Israel and Canada) cohort study
Included 574 PUPs, median age 4.6 ( ), 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

27 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 (cumulative incidence, 22.4%; 95% CI, 18.8 to 26.0) 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

28 The RODIN study: results
Absence of an evident difference in inhibitor incidences between plasma-derived and recombinant FVIII products (adjusted hazard ratio as compared with recombinant products, 0.96; 95% confidence interval [CI], 0.62 to 1.49) 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) 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.

29 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

30 Seminars in Thrombosis & Hemostasis, Sept 2013
data from 28 prospective studies evaluating the incidence of inhibitors in 1421 PUPs rates of inhibitors were 23% ( ) for pd-FVIII and 29% ( ) for rFVIII products Inhibitor rate incidence no statistically significant differences were observed in the inhibitor incidence between pdFVIII and rFVIII concentrates Flora Peyvandi

31 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

32 (Survey of Inhibitors in Plasma-Product Exposed Toddlers)
The SIPPET study: (Survey of Inhibitors in Plasma-Product Exposed Toddlers) MODIFICATO: titolo dello studio Flora Peyvandi

33 Study objective To compare the immunogenicity of the class of plasma- derived 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

34 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

35 Patients recruitment with geographic distribution
279 patients recruited 19 pts 20 pts 38 pts 96 pts 23 pts 83 pts Flora Peyvandi 35

36 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

Download ppt "Inhibitors in hemophilia"

Similar presentations

Ads by Google