Inhibitors, what is the risk of treatment intensity?

Abstract

The formation of an allo‐antibody that inhibits factor (F) VIII is the most significant treatment‐related complication in people with hemophilia A who have access to safe and adequate supplies of FVIII concentrate. Inhibitor formation most commonly occurs in patients with severe hemophilia during their early treatment history [1Wight J. Paisley S. The epidemiology of inhibitors in haemophilia A: a systematic review.Haemophilia. 2003; 9: 418-35Crossref PubMed Google Scholar]. Whilst some inhibitors are clinically insignificant because they are low titer and transient, a significant proportion are persistent and compromise standard treatment regimens by preventing optimal therapy with FVIII [1Wight J. Paisley S. The epidemiology of inhibitors in haemophilia A: a systematic review.Haemophilia. 2003; 9: 418-35Crossref PubMed Google Scholar, 2Dimichele D. Inhibitors: resolving diagnostic and therapeutic dilemmas.Haemophilia. 2002; 8: 280-7Crossref PubMed Scopus (123) Google Scholar]. Although the use of bypassing agents has been shown to provide good hemostasis for the majority of bleeds and their use is recommended treatment in patients unresponsive to FVIII [3Hay C.R. Brown S. Collins P.W. Keeling D.M. Liesner R. The diagnosis and management of factor VIII and IX inhibitors: a guideline from the United Kingdom Haemophilia Centre Doctors Organisation.Br J Haematol. 2006; 133: 591-605Crossref PubMed Scopus (272) Google Scholar], their efficacy is not as predictable as FVIII, treatment failures can occur, prophylaxis is a less available treatment option, and a validated method for laboratory monitoring has not been established. This means that people with hemophilia and inhibitors are more likely to have recurrent bleeding episodes, resulting in long‐term complications such as hemophilic arthropathy [4Scalone L. Mantovani L.G. Mannucci P.M. Gringeri A. The I, C.S. Quality of life is associated to the orthopaedic status in haemophilic patients with inhibitors.Haemophilia. 2006; 12: 154-62Crossref PubMed Scopus (123) Google Scholar] and severe bleeding episodes that are difficult to treat and may be life‐threatening. Furthermore, the cost of treatment with bypassing agents and by immune tolerance places strains on health‐care providers and, as a result, optimal treatment is not always available. Decreasing the rate of inhibitor formation is therefore an important goal. There has been significant progress in defining potential risk factors for inhibitor formation in patients with congenital hemophilia A. It is generally accepted that there is interaction between inherited risk factors, which predispose to inhibitor formation, and environmental factors, which trigger an inhibitor in susceptible individuals [2Dimichele D. Inhibitors: resolving diagnostic and therapeutic dilemmas.Haemophilia. 2002; 8: 280-7Crossref PubMed Scopus (123) Google Scholar, 5Astermark J. Why do inhibitors develop?.Principles of and factors influencing the risk for inhibitor development in haemophilia Haemophilia. 2006; 12: 52-60Crossref PubMed Scopus (0) Google Scholar]. Whilst the inherited risk factors cannot be changed, it is possible that knowledge about environmental or acquired risk factors may lead to strategies that can decrease the risk of inhibitor formation. Data on environmental risk factors are therefore extremely important and have the potential to inform future studies designed to alter the risk of inhibitor formation. The manuscript by Gouw et al. [6Gouw S.C. Van Den Berg H.M. Le Cessiw S. Van Der Bom .J.G. Treatment characteristics and the risk of inhibitor development: a multicenter cohort study among previously untreated patients with severe hemophilia A.J Thromb Haemost. 2007; 5: 1383-90Abstract Full Text Full Text PDF PubMed Scopus (126) Google Scholar] in this issue of the journal investigates the role of potential environmental risk factors in the formation of inhibitors in previously untreated patients (PUPs) and minimally treated patients (MTPs) with severe hemophilia A, and contributes significant new insights. One of the limiting factors of research in hemophilia is the relative rarity of the disorder and the associated difficulty in recruiting sufficient patients. In this report, the data from four recombinant FVIII PUP studies (Recombinate, Kogenate, Kogenate Bayer, and Refacto) have been combined, allowing 236 patients to be included. Each study was designed to investigate inhibitor formation as a major outcome, and combination of the databases is therefore a valid approach that allows more robust conclusions to be drawn. Patients were investigated during their first 50 exposure days in a rigorous statistical model that took into account the changing risk of inhibitor formation with increasing exposure days. The main novel finding is that intensive treatment episodes were associated with an increased risk of inhibitor formation even when adjusted for other potential risk factors such as ethnicity, baseline FVIII, age at first exposure, and family history of inhibitors. This finding was true for both all and high titer inhibitors when the intensive treatment of five or more days was the first exposure to FVIII. There are some discrepancies in the trend in risk of inhibitor formation between patients who received three to four days of treatment and those that had five or more days when the intensive treatment was not at the first exposure, but it is likely that this is due to the relatively small numbers of patients available in subgroup analysis. The fundamental finding that intensive treatment is related to an increased risk of inhibitor formation is convincing. Further analysis showed that decreasing time between exposure days was also associated with increased inhibitor formation, again suggesting a role for intensity of treatment. The most significant data relate to the finding that intensive treatment in the context of surgery is a major risk factor for both all and high titer inhibitors. This finding is important and may relate to the tissue trauma and exposure to infection associated with surgery priming the immune system to respond to the infusion of large amounts of FVIII. It will be important to know whether intensive treatment of bleeds and intensive treatment at the time of surgery have different risks of inhibitor formation. The obvious corollary to these findings is whether avoiding intensive treatment episodes early in a patient’s treatment history decreases the rate of inhibitor formation or merely delays the onset. Elective surgery can potentially be delayed, although avoiding intensive treatment once a major bleed has occurred is not an option. One possible strategy of avoiding FVIII is to use recombinant activated FVII rather than FVIII early in a patient’s treatment history; however, a prospective study did not provide evidence to support this approach [7Rivard G.E. Lillicrap D. Poon M.C. Demers C. Lepine M. St L.o.u.i.s. .J. Warner M. Can activated recombinant factor VII be used to postpone the exposure of infants to factor VIII until after 2 years of age?.Haemophilia. 2005; 11: 335-9Crossref PubMed Scopus (0) Google Scholar]. An alternative strategy for reducing the need for intensive treatment episodes for bleeds is the early use of prophylaxis. The impact of prophylaxis could not be investigated in Gouw’s study because insufficient patients started prophylaxis before the median time of onset of inhibitor formation. Early prophylaxis would be expected to decrease the need for intensive treatment for bleeding episodes, but conversely may be associated with increased surgery for central venous access. The balance of these two risk factors needs to be assessed. It would be interesting to know how many operations in the studies were for the placement of central venous catheters. If it is shown that this procedure is associated with an increased risk of inhibitor formation, then parents and clinicians will need to take this into account when deciding on whether central catheter placement is the best course of action to take for individual patients. Interestingly, the study did not find an association between early FVIII replacement and inhibitor formation. This finding is in keeping with other recent publications [8Chalmers E.A. Brown S.A. Keeling D. Liesner R. Richards M. Stirling D. Thomas A. Vidler V. Young D. Paediatric Working Party of UKHCDOEarly factor VIII exposure and subsequent inhibitor development in children with severe haemophilia A.Haemophilia. 2007; 13: 149-55Crossref PubMed Scopus (151) Google Scholar, 9Santagostino E. Mancuso M.E. Rocino A. Mancuso G. Mazzucconi M.G. Tagliaferri A. Messina M. Mannucci P.M. Environmental risk factors for inhibitor development in children with haemophilia A: a case‐control study.Br J Haematol. 2005; 130: 422-7Crossref PubMed Scopus (0) Google Scholar]. However, one drawback of the use of cohorts from pharmaceutical initiated PUP studies is that some groups of patients are excluded. For example, patients who are treated at birth, either for a bleed or as prophylaxis, are unlikely to be included and this may, to some extent, bias the data relating inhibitor risk to age at first treatment. As with all cohorts, the inclusion and exclusion criteria need to be considered when the results are interpreted. The study of Gouw et al. also confirms previously reported data (e.g. the finding that ethnicity is a risk factor for inhibitor formation), and this strengthens the novel findings. Inevitably there are weaknesses because the databases were not set up to answer the specific questions addressed in the study. The most important gap in the data is the lack of FVIII genotype data. It is well recognized that some mutations that cause severe hemophilia A are associated with a higher risk of inhibitor formation [10Oldenburg J. Pavolva A. Genetic risk factors for inhibitors to factor VIII and IX.Haemophilia. 2006; 12: 15-22Crossref PubMed Scopus (0) Google Scholar]. It would have been very valuable to link genotype data with environmental risk factors. This is particularly relevant because the study reports that the risk of inhibitor formation was the same for patients with a FVIII <1 IU dL−1 and those with a FVIII of 1–2 IU dL−1, although in subgroup analysis relatively small numbers were involved. It is very likely that these subgroups have different types of mutations and it is a finding that is difficult to explain except on the basis of small numbers. An analysis based on FVIII mutations was not possible because not all the studies collected the data, and this will have to be addressed in future studies. Research in the field of hemophilia is hampered by the difficulties of recruiting large enough cohorts of patients to adequately answer important clinical questions. The use of cohorts of patients recruited into studies whose primary aim is to demonstrate the safety and efficacy of a new product is an efficient use of resources and the investigators should be congratulated on their success in coordinating the study, and the pharmaceutical companies should be commended for their willingness to release data for independent analysis. Further studies that investigate cohorts of patients recruited into studies initiated by pharmaceutical companies should be encouraged so that the maximum benefit can be obtained from the data collected from recruited patients. The findings presented in this study, relating inhibitor formation to intensive treatment and surgery, need to be replicated in other cohorts controlled for other known risk factors, and, if confirmed, will be a major advance. Encouragingly, similar results have been found by the same group in the Canal study [11Gouw S.C. Van Der Bom J.G. Van Den Berg .H.M. Treatment‐related risk factors of inhibitor development in previously untreated patients with hemophilia A: the CANAL cohort study.Blood. 2007; 109: 4648-54Crossref PubMed Scopus (0) Google Scholar]. This should lead to studies that investigate regimens of early FVIII replacement in MTPs that reduce exposure to known environmental risk factors in order to establish whether this reduces or merely delays inhibitor formation. The paper by Gouw et al. is an important contribution to the field and should encourage and inform further clinical studies into an important area of clinical hemophilia research. The author states that he has no conflict of interest.