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Inhibitors in hemophilia Flora Peyvandi Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico.

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Presentation on theme: "Inhibitors in hemophilia Flora Peyvandi Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico."— 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 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 Treatment complication Flora Peyvandi

3 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 Inhibitors 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) Flora Peyvandi 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.

5 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 The development of inhibitory antibodies (Astermark J hemophilia 2006;12, Suppl.3:52-60) Flora Peyvandi

6 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

7 The development of inhibitory antibodies Flora Peyvandi 5.T H -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

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], 2.3-5.7 and OR 1.4, 95% CI, 1.1- 1.8, 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

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 patientsHLA class IIHLA allelesDQA1*0102 allele Hay et al. Thromb Haemost 1997 164 HA patients in 78 unrelated families (77 inhibitor positive) IL1betaRFLP- Astermark et al. Blood 2006 IL41 SNP- IL10STRAllele 134 bp CA repeats 164 HA patients in 78 unrelated families (77 inhibitor positive) HLA class I/IIHLA alleles- Astermark et al. Blood 2006 TNFa4 SNPs-308 A/G 124 severe HA patients in 60 unrelated families (63 inhibitor patients) CTLA42 SNPs -318 C/T Astermark et al. J Thromb Haemost 2007 915 severe HA patients (282 inhibitor positive) 21 candidate genes372 SNPsIL1, IL2, IL12 Lozier et al. hemophilia 2011 833 subjects from 3 independent cohorts (457 inhibitor positive) 1 081 genes13 331 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) HMOX1STR, 2 SNPsAllele >30 GT repeats Repessè et al. Haematologica 2013 85 severe HA patients (36 inhibitor positive) FCGR5 SNPsFCGR2A (131HH allele) Eckhardt et al. J Thromb Haemost 2014

11 833 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

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 Flora Peyvandi - 13 SNPs passing the meta P<.001 - 8 SNPs significant in discordant pairs

13 Ethnicity and inhibitor development * Study subjects received either cryoprecipitate or intermediate purity FVIII concentrates Flora Peyvandi Black patients with hemophilia A are twice as likely as white patients to produce inhibitors against factor VIII proteins given as replacement therapy. Recombinate  Kogenate  US Retrospective Study* Total patients (≤2%)726489 African American9810 with inhibitors5 (55,5%)4 (50%)5 (50%) Caucasian and others635679 with inhibitors17 (27,4%)14 (25%)20 (25%) (Scharrer et al, Haemophilia 1999; 5:145-154) (Viel KR et al, N Englan J Med 2009;360:1618-27)

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 Flora Peyvandi (Lorenzo et al. Br J Haematol 2001;113: 600-603) (Santagostino et al. Br J Haematol 2005)

15 ‘Age at first exposure’ CANAL cohort study (Gouw SC et al, Blood 2007;109:4648-4654) 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

16 Intensity of treatment Intermediate frequency: 10 to 50 days High frequency: <10 days 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 (Gouw SC & Fijnvandraat K, Semin Thromb Hemost 2013;39:740-751) Flora Peyvandi

17 Clinical data 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 Type of FVIII concentrates 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 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 VWF and FVIII immunogenicity Flora Peyvandi (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)

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 Flora Peyvandi

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

23 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

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, 10-22 months) Flora Peyvandi

25 1.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], 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). The CANAL study: results

26 Flora Peyvandi 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

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 1.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) 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. The RODIN study: results

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% (0.15- 0.33) for pd-FVIII and 29% (0.26- 0.32) for rFVIII products no statistically significant differences were observed in the inhibitor incidence between pdFVIII and rFVIII concentrates Inhibitor rate incidence 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 The SIPPET study: (Survey of Inhibitors in Plasma-Product Exposed Toddlers) Flora Peyvandi

33 Multicentre, international (Europe, America, Africa, Asia), open-label, controlled, randomised trial Approximately 300 patients will be enrolled 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. Flora Peyvandi

34 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 Treatment Flora Peyvandi

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

36 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 Consideration Flora Peyvandi

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