Intensity of factor VIII treatment and inhibitor development in children with severe hemophilia A: the RODIN study

Abstract

Key Points• High-dose intensive factor VIII treatment increases the risk for inhibitor development in patients with severe hemophilia A.• In patients with severe hemophilia A, factor VIII prophylaxis decreases inhibitor risk, especially in patients with low-risk F8 mutations.The objective of this study was to examine the association of the intensity of treatment, ranging from high-dose intensive factor VIII (FVIII) treatment to prophylactic treatment, with the inhibitor incidence among previously untreated patients with severe hemophilia A. This cohort study aimed to include consecutive patients with a FVIII activity < 0.01 IU/mL, born between 2000 and 2010, and observed during their first 75 FVIII exposure days. Intensive FVIII treatment of hemorrhages or surgery at the start of treatment was associated with an increased inhibitor risk (adjusted hazard ratio [aHR], 2.0; 95% confidence interval [CI], 1.3-3.0). High-dose FVIII treatment was associated with a higher inhibitor risk than low-dose FVIII treatment (aHR, 2.3; 95% CI, 1.0-4.8). Prophylaxis was only associated with a decreased overall inhibitor incidence after 20 exposure days of FVIII. The association with prophylaxis was more pronounced in patients with low-risk F8 genotypes than in patients with high-risk F8 genotypes (aHR, 0.61, 95% CI, 0.85, 95% CI, respectively). In conclusion, our findings suggest that in previously untreated patients with severe hemophilia A, high-dosed intensive FVIII treatment increases inhibitor risk and prophylactic FVIII treatment decreases inhibitor risk, especially in patients with low-risk F8 mutations. (Blood. 2013;121(20):4046-4055)

Targeting of Antithrombin in Hemophilia A or B with RNAi Therapy

“…Finally, treatment with factor-replacement products can result in the development of inhibitory alloantibodies in up to 30% of patients with severe hemophilia A 19 and in 5% of those with hemophilia B, 20 which renders factor treatment ineffective. 21 Thus, there remains a major unmet need for new therapeutic agents that can provide safe, effective, and consistent prevention of bleeding, including in patients with inhibitory alloantibodies, while avoiding the development of such antibodies and reducing the treatment burden.…”

Correlation between phenotype and genotype in a large unselected cohort of children with severe hemophilia A

“…The details of inhibitor development and correlation with factor VIII product type and with intensity of treatment and start of prophylaxis can be found in 2 recently published papers. 10,11 Regular prophylaxis was started in 439 patients (70.7% of entire cohort) at a median age of 16.7 months (IQR, 11.9-24.9 months). Excluding the 112 patients who developed an inhibitor before ever starting on prophylaxis, 86.2% of the remaining 509 patients started prophylaxis.…”

Safety surveillance in haemophilia and allied disorders

“…This is a prospective registry of new patients with severe Table 2 The Phases of clinical trials I -small groups of patients for testing drug safety II -small group of patients for testing drug effectiveness III -larger study to confirm safety and effectiveness before approval for a relatively short follow-up IV -postmarketing studies in special populations and postmarketing surveillance studies haemophilia, mostly from Europe, who are being followed to their 75th exposure day [13,18,25,26]. In the RODIN study, risk factors for inhibitor development in previously untreated patients (PUPs) have been reported, together with rates of inhibitor development according to product, and most controversially a potential difference between second-and third-generation recombinant products has been observed [13].…”