The Rodin (Research Of Determinants of INhibitor Development among PUPs with haemophilia) study: the clinical conundrum from the perspective of haemophilia treaters

Abstract

The Rodin study, recently published in the New England Journal of Medicine, has begun to provide some very important answers to several questions pertinent to the quality and safety of replacement therapy to individuals with haemophilia [1]. Probably the most serious complication of modern haemophilia care is currently the development of alloantibody neutralizing inhibitors and considerable recent literature until the Rodin trial had speculated that the recombinant factor (rFVIII) replacement products were more likely than the plasma-derived products to produce this. The Rodin trial has extended our thoughts on this issue because it is a robustly populated prospective observational study, in contrast to previously published results, which have been generated from smaller, retrospective, mostly uncontrolled heterogeneous population studies. Based on the results of 574 previously untreated severe haemophilia A patients (FVIII activity, <0.01 IU mL ), the observations in Rodin indicated that there was no difference in the incidence of alloantibody inhibitors whether patients received plasma-derived or recombinant full-length FVIII products (adjusted hazards ratio = 0.96). Furthermore, among those who developed alloantibody inhibitors while on plasma-derived FVIII concentrates, the content of von Willebrand factor (VWF) did not influence the risk of inhibitor formation (adjusted hazards ratio = 0.90). Lastly, the Rodin population study indicated that switching from a plasma-derived FVIII product (irrespective of relative VWF content) to a full-length rFVIII product did not increase the risk of inhibitor development. These conclusions are extremely cogent to patients and their physicians alike as the possibility that rFVIII products were more immunogenic, that the high content of VWF protein in plasma-derived FVIII products could protect against alloantibody formation, and that product switching would be harmful all were used as rationale to determine the choice of replacement product for previously untreated, slightly previously treated, and even those previously treated individuals with over 150 exposure days. This published report notwithstanding the possibility that it may be underpowered to conduct most of the above comparisons due to the relatively low number of patients treated with plasma-derived molecules has added to the cumulative published data, which tend to discount these concerns when determining product choice for previously untreated patients (PUPs) and others. In fact, several of the haemophilia treaters and haemophilia treatment centres (HTC), who participated in Rodin, had expressed publicly prior to this publication that these same concerns influenced their decision to initiate their PUPs considered at higher risk for inhibitor development on plasma-derived products. The Rodin trial was observational, that is NOT a randomized controlled study, and allowed each HTC to determine independently how it was to treat its PUPs. This approach could have led to an imbalance in the baseline prognostic characteristics of the groups being compared in Rodin and this potential bias could have introduced a significant biostatical flaw into the study design [2].