J M Lusher1. 1. Division of Hematology-Oncology, Children's Hospital of Michigan, Detroit 48201, USA. jlusher@med.wayne.edu
Abstract
BACKGROUND AND OBJECTIVES: During the late 1980s, short-term hepatitis safety trials with certain new high purity, virally attenuated plasma derived factor VIII (FVIII) concentrates showed a higher than anticipated percentage of inhibitors in previously untreated patients (PUPs). Thus, the design of prelicensure dinical trials with each of the recombinant (r) FVIII products included prospective evaluations for inhibitors at well-defined time points, to see whether treatment with rFVIII resulted in a higher incidence of inhibitors. DESIGN AND METHODS: Each of several prospective clinical trials with rFVIII preparations is described and analyzed in terms of inhibitor development, patient demographics, and current prevalence of inhibitors in the cohort. RESULTS: In prospective trials with rFVIII preparations (both full length and B domain deleted rFVIII), the percentage of PUPs with severe hemophilia A who developed FVIII inhibitors has varied between 28.3 and 30.6%. Many of the inhibitors have been transient, disappearing while the patient was receiving episodic (on demand) treatment with rFVIII, while others have responded to immune tolerance induction regimens with rFVIII alone. However, many other have persisted. Genetic influences (underlying gene defect and race) were shown to play a role in inhibitor development. In contrast to the experience in the PUPs, in trials with rFVIII preparations in previously treated patients (PTPs), only 0-1 subject per trial developed an inhibitor. INTERPRETATION AND CONCLUSIONS: While the percentage of PUPs developing inhibitors in each of the prospective clinical trials with rFVIII preparations appears high, published data from similarly conducted studies with plasma-derived FVIII products show very similar results. Additionally, only an occasional PTP on rFVIII developed an inhibitor. Thus, none of the rFVIII preparations studied to date appears to be more immunogenic than plasma-derived FVIII.
BACKGROUND AND OBJECTIVES: During the late 1980s, short-term hepatitis safety trials with certain new high purity, virally attenuated plasma derived factor VIII (FVIII) concentrates showed a higher than anticipated percentage of inhibitors in previously untreated patients (PUPs). Thus, the design of prelicensure dinical trials with each of the recombinant (r) FVIII products included prospective evaluations for inhibitors at well-defined time points, to see whether treatment with rFVIII resulted in a higher incidence of inhibitors. DESIGN AND METHODS: Each of several prospective clinical trials with rFVIII preparations is described and analyzed in terms of inhibitor development, patient demographics, and current prevalence of inhibitors in the cohort. RESULTS: In prospective trials with rFVIII preparations (both full length and B domain deleted rFVIII), the percentage of PUPs with severe hemophilia A who developed FVIII inhibitors has varied between 28.3 and 30.6%. Many of the inhibitors have been transient, disappearing while the patient was receiving episodic (on demand) treatment with rFVIII, while others have responded to immune tolerance induction regimens with rFVIII alone. However, many other have persisted. Genetic influences (underlying gene defect and race) were shown to play a role in inhibitor development. In contrast to the experience in the PUPs, in trials with rFVIII preparations in previously treated patients (PTPs), only 0-1 subject per trial developed an inhibitor. INTERPRETATION AND CONCLUSIONS: While the percentage of PUPs developing inhibitors in each of the prospective clinical trials with rFVIII preparations appears high, published data from similarly conducted studies with plasma-derived FVIII products show very similar results. Additionally, only an occasional PTP on rFVIII developed an inhibitor. Thus, none of the rFVIII preparations studied to date appears to be more immunogenic than plasma-derived FVIII.