Best evidence on B‐domain deletion and the immunogenicity of recombinant factor VIII

Abstract

To cite this article: Aledort LM, Navickis RJ, Wilkes MM. Best evidence on B-domain deletion and the immunogenicity of recombinant factor VIII. J Thromb Haemost 2011; 9: 2325-7.See also Aledort LM, Navickis RJ, Wilkes MM. Can B-domain deletion alter the immunogenicity of recombinant factor VIII? A meta-analysis of prospective clinical studies. This issue, pp 2180-92; Mannucci PM. Factor VIII inhibitors in previously treated hemophilic patients. This issue, pp 2328-9.Development of inhibitors to factor VIII (FVIII) is recognized as the most serious complication of hemophilia A therapy. Attendant morbidity risk, quality of life impairment and treatment costs are high. Accordingly, the assessment of potentially avoidable risk factors such as use of more highly immunogenic FVIII products remains a high priority. Timely evaluation of accumulating evidence on such risk factors is essential, and meta-analysis can serve as a valuable tool in this endeavor.In our meta-analysis of 29 prospective clinical studies with over 3000 previously treated patients [1], de novo inhibitors of any titer were seven times as frequent after exposure to Bdomain-deleted recombinant FVIII (BDD-rFVIII) as fulllength recombinant FVIII (FL-rFVIII). High-titer de novo inhibitors (> 5 Bethesda units) were 11 times as frequent. These differences were highly statistically significant. The robustness of these observations is supported by several methodological features of the meta-analysis, as outlined in our paper. First, only prospective clinical studies were included. Second, Cox regression was employed to account fully for length of follow-up. Third, intent-to-treat analyses were performed. Lastly, sensitivity analyses were used to rule out confounding by other variables.We nevertheless urged caution in interpreting our results, chiefly because the included studies predominantly involved single cohorts with no control group. However, while limitations of our meta-analysis should be recognized, they should not be exaggerated, as have Iorio and colleagues in their commentary [2]. They wrongly contend that most of the included studies were Ôretrospective assessments of prospectively collected case recordsÕ. In fact, nearly all the included studies were clearly well-designed and rigorously conducted prospective investigations. As indicated in our paper, the suppliers of the evaluated recombinant FVIII (rFVIII) products were direct participants and/or sponsors for at least 79% of the studies. Seven were formal pivotal prospective studies in support of product licensure: six of them multinational trials and one a multicenter study in China [3][4][5][6][7][8][9][10][11][12][13]. Six were prospective multinational pharmacosurveillance studies [14][15][16][17][18][19]. Five were prospective multicenter pharmacosurveillance studies in Germany [20,21] and Japan [22][23][24]. rFVIII efficacy and safety were the subject of three multicenter studies in Italy [25], Japan [26] and Taiwan [27] and a single-center study in the Netherlands [28]. Five studies were...

Clotting factor concentrate switching and inhibitor development in hemophilia A

“…As already noted, even with large transnational (pooled) datasets, it would be almost impossible to perform a multivariable analysis powerful enough to identify risk factors for inhibitor development. 67,69 Actually, in a prospective uncontrolled cohort, to detect a 2-fold increase in the rate measured by Hay (Table 2) with a power of at least 80% and an ␣ level of 0.05, we would need 2589 patients, whereas the power of detecting the same increase in a registration trial of 100 patients would be 2%; an observational controlled study would require 5065 patients per arm.…”

Factor VIII inhibitors in previously treated hemophilic patients

“…The most striking and novel finding reported by Aledort et al [1] is a dramatic difference between brands of recombinant FVIII products for the magnitude of risk of de novo inhibitors, because there was a seven-to 10-fold increased risk in patients treated with BDD-rFVIII compared with those treated with FL-rFVIII. These huge differences in risk between the two rFVIII moieties were statistically significant, with Pvalues of 0.0016 for all de novo inhibitors and of 0.0037 for the more clinically relevant high-titer inhibitors [1].…”

“…These huge differences in risk between the two rFVIII moieties were statistically significant, with Pvalues of 0.0016 for all de novo inhibitors and of 0.0037 for the more clinically relevant high-titer inhibitors [1]. Impressed by these very high hazard ratios (HRs) and corresponding Pvalues, I could not help notice that the CIs of the HRs are extremely wide (2.12-24.9 for all inhibitors, 2.77-53.7 for highrisk inhibitors), giving the impression that results carry some degree of statistical instability and uncertainty.…”

“…The main and most important message that as a clinician I get from Aledort et al [1] is that the development of inhibitors in PTP is a relatively rare event [1.25%, with a 95% confidence interval (CI) as narrow as 0.63-1.88%]. This message is substantially confirmatory of the low risk of new inhibitors in patients exposed to FVIII who switch to other products, in agreement with the results of several previous smaller studies [3][4][5], which supported the safety of switching when changes are justified by clinical advantages for patients.…”

“…In this issue of the Journal of Thrombosis and Haemostasis, Aledort et al [1] carried out a meta-analysis that evaluated the cumulative incidence of de novo factor (F)VIII inhibitors in previously treated patients (PTPs) with severe hemophilia A. They compared PTPs who, being under regular replacement therapy with various types of FVIII products, switched to recombinant products, either full length (FL-rFVIII) or B-domain deleted (BDD-rFVIII).…”