Abstract Number: PB0563
Meeting: ISTH 2021 Congress
Background: Despite the prophylactic efficacy of emicizumab, eradicating inhibitors to restore the efficacy of factor VIII (FVIII) is a desirable treatment goal for patients with severe hemophilia A (SHA) and inhibitors, as this enables treatment of bleeding episodes with FVIII concentrates. However, since immune tolerance induction (ITI) is a burdensome and costly treatment, it is important to identify determinants for ITI success to individualize ITI treatment. Perhaps this has never been so crucial as now as many patients/clinicians may feel that it may not be worth trying ITI if emicizumab is available.
Aims: The aim of this study is to identify genetic/clinical determinants for ITI outcome in patients with SHA.
Methods: Dutch and Canadian patients with SHA (FVIII:C<0.01 IU/mL) who underwent ITI were included. The primary outcome was successful ITI, defined by a negative inhibitor titer and an adequate clinical response to standard doses of FVIII. We analyzed both clinical and genetic determinants (FCGR2A (p.His166Arg, p.Gln62Trp, c.777+1G>A), FCGR2B (p.Ile232Thr, promotor haplotypes 2B.1/2B.4), FCGR2C (p.Gln57Ter, promotor haplotypes 2B.1/2B.2), FCGR3A (p.Val176Phe), FCGR3B (haplotypes NA1/NA2), CTLA-4 (rs5742909 -318C/T) and TNFɑ (rs1800629 -308G/A)). Proportions of determinants were compared between patients with ITI success and failure in univariate analysis.
Results: 76 patients were included. Baseline characteristics are in Table 1. Most patients were Caucasian and 46/76 had the intron-22 inversion mutation. 62 (82%) patients achieved ITI success. Risk factors for ITI failure were >3 months between inhibitor detection and ITI start, pre-ITI inhibitor titer >5 BU/ml and peak inhibitor titer >200 BU/ml (Table 2). We did not find an association between ethnicity, F8 genotype and the investigated genetic variations with ITI outcome.
|F8 genotype, n (%)||Intron-22 inversion||46 (61)|
|Ethnicity, n (%)||Caucasian||52 (68)|
|FVIII product at start ITI, n (%)FVIII product at start ITI, n (%)||Recombinant||41 (54)|
|Interval inhibitor detection – ITI start, weeks (IQR)||8.1 (1.0-28.5)|
|Age at start ITI, years (IQR)||2 (1 – 4)|
|Inhibitor titer, BU/ml (IQR)||At first detection||4.7 (1.3-14.9)|
|Inhibitor titer at first detection||<5 BU/ml||33||6||*|
|Interval between inhibitor detection and ITI start||<3 months||36||3||*|
|Pre-ITI inhibitor titer||<5 BU/ml||28||2||*|
|Peak inhibitor titer||<200 BU/ml||52||5||*|
|* Reference group|
Conclusions: Our results confirm that clinical determinants are associated with ITI outcome but did not show a role of genetic variation in FCGR, CTLA-4 and TNFɑ genes on ITI outcome. The cohort will be expanded to 200-250 patients.
To cite this abstract in AMA style:Abdi A, Oomen I, Nagelkerke SQ, Fischer K, Carcao M, Rivard GE, Rydz N, Eikenboom J, Mohseny AB, Schols S, Leebeek FWG, Geissler J, Tanck MW, Lillicrap D, Voorberg J, Kuijpers TW, Fijnvandraat K, Gouw SC, International GO-ITI study group . Genetic and Clinical Determinants for the Outcome of Immune Tolerance Induction in Severe Hemophilia A – Preliminary Results [abstract]. Res Pract Thromb Haemost. 2021; 5 (Suppl 2). https://abstracts.isth.org/abstract/genetic-and-clinical-determinants-for-the-outcome-of-immune-tolerance-induction-in-severe-hemophilia-a-preliminary-results/. Accessed January 23, 2022.
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