From www.bloodjournal.org by guest on March 9, 2016. For personal use only. BLOOD, 15 OCTOBER 2007 䡠 VOLUME 110, NUMBER 8
CORRESPONDENCE
3085
Response: Immunogenicity of factor VIII concentrates in patients with hemophilia: the next sensible step Ever since the introduction of recombinant factor VIII products in the late 1980s, physicians have wondered whether such products carry a higher risk of inhibitory antibodies than the factor VIII products derived from human plasma. The reported incidences of inhibitors in the cohorts of patients in whom the effectiveness and safety of recombinant products was assessed were higher than the reported incidences in cohorts that were treated with plasmaderived products. Yet, this may have been due to more frequent and more sensitive testing for the presence of inhibitors in the cohorts on recombinant products. At present, the clinical significance of these otherwise undetected inhibitors is unclear. Thus far, 3 observational studies have directly compared the incidence of inhibitors in patients on either product type. All 3 studies revealed a point estimate in the same direction, namely a higher risk of inhibitors in the patients on recombinant products. However, the size of these point estimates differed considerably.1-3 Table 1 presents the risk of developing inhibitors according to the use of plasma-derived or recombinant factor VIII products in the 3 reports. The challenge now is to combine the knowledge derived from these 3 studies in order to increase the relevance of our future studies on the topic. Considering the specific critiques of Gringeri and Mannucci, we agree that our demonstration of equivalent immunogenicity of products with considerable contents of von Willebrand factor compared with recombinant products did not definitively settle the issue of plasmaderived versus recombinant products.3 Yet, our findings clearly show that, on average, the incidence of inhibitors among patients on a large variety of plasma-derived products is not much lower than the incidence among patients on different recombinant products. These findings combined with the know-ledge derived from the studies of Goudemand et al1 and Chalmers et al2 suggest that some, but not all, plasma-derived products may indeed carry a lower risk of inhibitor development than other products. In addition, we have learned from the Concerted Action on Neutralizing Antibodies in severe hemophilia A patients (CANAL) study3 that it may be a fallacy to believe that the presence of von Willebrand factor in a product prevents the occurrence of inhibitors. Gringeri and Mannucci suggest that a randomized clinical trial will provide a definite answer on the comparison of immunogenicities of factor VIII products. In our view, the next relevant question is not whether plasma-derived products have a lower risk of inhibitors but rather which plasma-derived products carry a lower risk of inhibitors and why. It may be worth reanalyzing the CANAL study3 data in order to explore the potential effects
Table 1. Cumulative incidence of inhibitors in patients treated with either plasma-derived or recombinant products in the 3 studies that reported a direct comparison of products Study
Plasma-derived products (%)
Recombinant products (%)
Goudemand et al1
27/86 (31)
7/62 (11)
Chalmers et al2
47/172 (27)
18/132 (14)
CANAL study3
53/181 (29)
29/135 (21)
Patients are categorized according to the products of their first exposure to factor VIII.
of different production processes of the plasma-derived products on the risk of inhibitors. Finally, it may be questioned whether plasma-derived products should be studied for their effects on the risk of developing inhibitors at all. Many countries have abandoned the use of plasma-derived products in young children because of the, albeit small, risk of transmission of infectious agents. It may be more relevant to compare the different recombinant products and to further examine the effect of genetic and nongenetic risk factors for inhibitor development, such as the potentially preventive effect of early prophylaxis. Findings from the latter studies may have a major impact on the prevention of inhibitors of future patients with severe hemophilia. Johanna G. van der Bom, Samantha C. Gouw, and H. Marijke van den Berg Conflict-of-interest disclosure: The three authors have received unrestricted research/educational funding for various projects at the Van Creveldkliniek from the following companies: Bayer, Baxter, ZLB Behring, Novo Nordisk, and Wyeth. Correspondence: Dr Johanna G. van der Bom, Leiden University Medical Center, PO Box 9600, 2300 RC Utrecht, The Netherlands; e-mail:
[email protected].
References 1.
Goudemand J, Rothschild C, Demiguel V, et al. Influence of the type of factor VIII concentrate on the incidence of factor VIII inhibitors in previously untreated patients with severe hemophilia A. Blood. 2006;107:46-51.
2.
Chalmers EA, Brown SA, Keeling D, et al. Early factor VIII exposure and subsequent inhibitor development in children with severe haemophilia A. Haemophilia. 2007;13:149-155.
3.
Gouw SC, Van Der Bom JG, Auerswald G, et al. Recombinant versus plasmaderived factor VIII products and the development of inhibitors in previously untreated patients with severe hemophilia A: the CANAL cohort study. Blood. 2007;109:4693-4697.
To the editor: Chronic megakaryocytic leukemia, misnamed chronic idiopathic myelofibrosis, has neoplastic not hyperplastic megakaryocytopoiesis Ciurea et al1 have provided further confirmatory evidence that a neoplastic accumulation of megakaryocytes is the “pivotal” factor in the pathobiology of what is called in the World Health Organization (WHO) classification by its pseudonym, chronic
idiopathic myelofibrosis, focusing on an epiphenomenon, not the central pathobiologic feature of this clonal myeloid (leukemic) disorder. I would like to make 2 points in this brief letter.
From www.bloodjournal.org by guest on March 9, 2016. For personal use only.
2007 110: 3085 doi:10.1182/blood-2007-07-098384
Response: Immunogenicity of factor VIII concentrates in patients with hemophilia: the next sensible step Johanna G. van der Bom, Samantha C. Gouw and H. Marijke van den Berg
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