Inhibitors in Severe Hemophilia A: 25-Year Experience in Slovakia

Abstract

We present 25-year experience with inhibitors in previously untreated patients (PUPs) with severe hemophilia A in Slovakia, where safe factor VIII (FVIII) concentrates have been used since 1990. A prospective study focused on inhibitor incidence in PUPs was established in 1997. Out of a total 61 PUPs born between January 1997 and October 2015, 59 were eligible for evaluation; 50 and 9 were treated with > 20 exposure days (ED) of plasma-derived FVIII (pdFVIII) and recombinant FVIII (rFVIII) products, respectively. In the entire group 13/59 (22%) PUPs developed inhibitors; i.e. 7/50 (14%) and 6/9 (67%) treated with pdFVIII and rFVIII, respectively. Univariate analysis of inhibitor risk factors in patient groups with and without inhibitors showed the rFVIII and serious/ recurrent infections within the first 50 EDs to be associated with inhibitor development (OR of 12.3 [95% CI 2.48-60.83; p ¼ 0.002] and 5.0; [95% CI 1.16-21.9; p ¼ 0.03), respectively]). Also, in multivariate Cox regression analysis, peak treatment ! 5 EDs reached statistical significance. The hazard ratio (HR) was 7.15 (95% CI 1.65-31.36) p ¼ 0.0086 for rFVIII and 4.38 (95% CI 1.02-18.67) p ¼ 0.046 for intensive treatment. Between 1993 and 2015, 21 immune tolerance inductions (ITIs) in 19 inhibitor patients were performed in the two largest hemophilia centers in Slovakia. In all but one ITI courses pdFVIII containing von Willebrand factor (FVIII/VWF) was used with preferred use of high-dose ITI (HD ITI) in high responders (HRs). Complete or partial success was achieved in 17/19 (89.5%) patients. Evaluating only the patients who already completed ITI, the success rate was even higher (15/16; 94%), including 7/7 low responders and

Product type and other environmental risk factors for inhibitor development in severe hemophilia A

“…In a report by Chalmers et al., the exposure to FVIII throughout the neonatal period showed no association with a higher incidence of inhibitors than in patients treated later during the first year of life. Two additional studies published most recently found no association between age of therapy initiation and inhibitor formation during the first years of life . To sum up, the data reported in the literature are discordant, in all likelihood owing to the observational nature of the studies, and thus fail to support firmly the hypothesis that a first replacement therapy at an early age increases the risk of inhibitor formation.…”

“…Two additional studies published most recently found no association between age of therapy initiation and inhibitor formation during the first years of life. 46,61 To sum up, the data reported in the literature are discordant, in all likelihood owing to the observational nature of the studies, and thus fail to support firmly the hypothesis that a first replacement therapy at an early age increases the risk of inhibitor formation.…”

2019 Eberhard F. Mammen Award Announcements: Part I—Most Popular Articles

“…►Table 2 lists the top 20 downloaded "open-access" articles from STH (2017 and 2018 inclusive), as eligible for the "Open Access" award. [20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39] ►Table 3 lists the top 20 downloaded nonopen-access articles from STH (2017 and 2018 inclusive), as otherwise eligible for the "General category" award. [40][41][42][43][44][45][46][47][48][49][50][51][52][53][54][55][56][57][58][59] Accordingly, the 2018 Eberhard F. Mammen award winners for most popular article (2017/2018 inclusive) are:…”

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“…2 In the frame of the multifactorial pathogenesis involving many factors, both genetic (unmodifiable) and environmental (including treatment, potentially modifiable), Batorova and coworkers add their contribution to the never-ending debate regarding the role in inhibitor development of the type of FVIII concentrate. 21 In a prospective analysis of all 61 PUPs born and treated in Slovakia since the introduction of safe FVIII concentrates in 1990, they report a significantly higher inhibitor risk in PUPs receiving recombinant products versus those treated with plasma-derived ones. Moreover, most inhibitor patients were tolerized after immune tolerance induction with plasma-derived FVIII concentrates.…”

“…These intriguing results, however, should be interpreted cautiously, in particular due to the small study population with few patients on recombinant products. 21 In previously treated patients (PTPs), the incidence of inhibitors is much lower and, even in this setting, the role of treatmentrelated factors is still debated, with many patients and physicians concerned about risk in switching FVIII products. Product changes may occur because of the development of new concentrates considered safer, as well fewer side effects, convenience issues, or economic reasons.…”