Beruflich Dokumente
Kultur Dokumente
n e w e ng l a n d j o u r na l
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original article
A bs t r ac t
Background
We evaluated 574 consecutive patients with severe hemophilia A (factor VIII activity,
<0.01 IU per milliliter) who were born between 2000 and 2010 and collected data on
all clotting-factor administration for up to 75 exposure days. The primary outcome
was inhibitor development, which was defined as at least two positive inhibitor tests
with decreased in vivo recovery of factor VIII levels.
Results
Conclusions
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Me thods
Patients
We enrolled consecutive, previously untreated patients with severe hemophilia A (factor VIII activity, <0.01 IU per milliliter) that had been diagnosed in 1 of the 29 participating hemophilia
treatment centers. All the children in the study
were born between January 1, 2000, and January
1, 2010. Children who had been referred to the
centers because of the presence of inhibitory antibodies were excluded from the study. Approval
was obtained from the institutional review board
at each study center. Parents or guardians of all
children provided written informed consent.
Data Collection
We uniformly collected detailed data on all infusions of factor VIII for up to 75 exposure days or
until the development of inhibitory antibodies,
including dates of infusion, doses and brands of
factor VIII products, reasons for treatment, types
of bleeding, extravasation of products, and surgery.
Patients were followed until the development
of a clinically relevant inhibitory antibody or a
cumulative number of 75 exposure days. (After
75 exposure days, inhibitor development becomes
rare [approximately 2 to 5 cases per 1000 patientyears]).27
Outcomes
We assessed the incidence of inhibitor development according to the type of product used at
subsequent exposure days (time-varying determinant). We categorized factor VIII products in several ways. First, we compared the inhibitor risk
between plasma-derived factor VIII products and
recombinant products. Second, to investigate
whether the content of von Willebrand factor was
associated with the risk of inhibitor development,
we categorized factor VIII products into products
containing no von Willebrand factor (all recombinant products), products containing less than
0.01 IU of von Willebrand factor antigen per international unit of factor VIII antigen (monoclonal
antibodypurified plasma-derived products), and
products containing 0.01 IU or more of von Willebrand factor per international unit of factor VIII
antigen (other plasma-derived products).30 Third,
we compared inhibitor incidence among the following categories of factor VIII products: plasmaderived products, first-generation full-length recombinant product (derived from the full-length
complementary DNA sequence of human factor
VIII) (Recombinate, Baxter BioScience), secondgeneration B-domaindeleted recombinant product, and second- and third-generation full-length
recombinant products.
We did not evaluate Kogenate (Bayer Healthcare), a first-generation full-length recombinant
product, or Refacto AF (Pfizer), a third-generation
B-domaindeleted product, because of the small
numbers of patients who received these products
(10 patients [7 as first-use product] and 3 patients [3 as first-use product], respectively). The
product type that was used most frequently was
selected as the reference category.
Switching among Products
still receiving a plasma-derived product. We similarly assessed the association between switching
among various types of factor VIII products and
the development of inhibitory antibodies.
Study Conduct
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25 Were excluded
5 Did not provide informed consent
10 Did not have available data
8 Were lost to follow-up
1 Died from intracranial hemorrhage
1 Had unknown reason
17 Had pending informed consent
R e sult s
Patients
Plasma-derived products were used on 4018 exposure days, and recombinant products were used
on 25,661 exposure days. Plasma-derived products
carried a risk of inhibitor development that was
similar to the risk with recombinant products (adjusted hazard ratio as compared with recombinant
products, 0.96; 95% CI, 0.62 to 1.49) (Table 2 and
Fig. 2).
provided in the Supplementary Appendix, available with the full text of this article at NEJM.org.
To assess whether our findings were robust,
we also compared the incidence of inhibitor development according to the product brands used
at the first exposure to factor VIII (a time-fixed
determinant). We repeated the analyses in the
subgroup of patients who were not included in
registration trials (primary studies of safety and
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41 (22.4)
21 (11.5)
33 (18.0)
64 (37.7)
40 (25.2)
4.6 (3.56.5)
137 (87.3)
71 (45.2)
64 (40.8)
22 (14.0)
95 (60.5)
45 (28.7)
9.9 (5.313.5)
110 (70.1)
17.0 (9.825.3)
40 (25.5)
28 (17.8)
46 (29.3)
41 (28.2)
25 (17.9)
Second-Generation
Full-Length
(N=183)
4 (2.5)
0
Third-Generation
Full-Length
(N=157)
17 (29.0)
14 (24.6)
15 (25.4)
9 (15.3)
18 (30.5)
18.0 (11.331.8)
40 (67.8)
35 (59.3)
18 (30.5)
9.7 (3.811.6)
21 (35.6)
11 (18.6)
27 (45.8)
9.3 (8.410.8)
54 (91.5)
25 (42.4)
0
First-Generation
Full-Length
(N=59)
Recombinant Product*
23 (30.3)
13 (18.0)
20 (26.0)
14 (18.2)
28 (36.4)
18.5 (8.026.3)
62 (80.5)
37 (48.1)
20 (26.0)
8.8 (2.914.0)
21 (27.3)
14 (18.2)
42 (54.5)
9.1 (5.710.5)
73 (94.8)
15 (19.5)
1 (1.3)
Second-Generation
B-DomainDeleted
(N=77)
29 (33.1)
21 (25.7)
30 (34.1)
24 (27.3)
16 (18.2)
12 (521)
67 (76.1)
56 (63.6)
28 (31.8)
7.9 (3.712.8)
24 (27.3)
20 (22.7)
44 (50.0)
6.4 (4.29.6)
81 (92.0)
28 (31.8)
17 (19.3)
Plasma-Derived
Product (N=88)
177 (32.4)
116 (22.4)
149 (26.0)
98 (17.1)
144 (25.1)
15 (725)
411 (71.6)
331 (57.7)
172 (30.0)
9.8 (5.413.5)
187 (32.6)
83 (14.5)
304 (53.0)
6.4 (4.08.9)
521 (90.8)
94 (16.4)
20 (3.5)
* Among the recombinant products, data are not included for seven patients who were first treated with Kogenate (Bayer Healthcare), a first-generation full-length product, and three patients
who were first treated with Refacto AF (Wyeth), a third-generation B-domaindeleted product. However, these patients are included in the total number of patients who received any product.
Race was self-reported.
Low-risk genotypes included those with small deletions and insertions, missense mutations, and splice-site mutations. High-risk genotypes included those with large deletions, nonsense mutations, and intron 1 and 22 inversions.
The start of regular prophylaxis was defined as the moment at which at least three consecutive prophylactic infusions of factor VIII had been given within a period of at least 15 days.
A peak treatment episode was defined as treatment with factor VIII for bleeding or for surgery on either at least 3 consecutive days or at least 5 consecutive days.
The values for inhibitor development are cumulative incidences, which were calculated by means of the KaplanMeier method.
Characteristic
Table 1. Characteristics of the Patients and the Type of Factor VIII Product Administered during the First Treatment.
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0.92
0.51
1.23 (0.672.28)
0.97 (0.491.91)
1.51 (0.842.71)
0.17
0.93 (0.481.79)
0.56
1.16 (0.701.92)
0.27
4,018
0.97
1.01 (0.601.70)
0.99
1.31 (0.812.11)
4,018
4,491
Plasma-derived
Second-generation B-domaindeleted
1.00 (0.601.65)
4,491
0.82
0.02
0.53
1.26 (0.612.61)
1.79 (1.092.94)
0.12
0.31
1.47 (0.912.38)
1.44 (0.712.90)
9,143
1.12 (0.612.04)
2,464
0.02
0.96
1.60 (1.082.37)
0.99 (0.531.83)
0.11
0.72
1.37 (0.932.01)
9,143
2,464
Second-generation full-length
1.00
NA
1.00
9,297
NA
1.00
NA
1.00
9,297
Third-generation full-length
Recombinant
Specific products
First-generation full-length
NA
0.85
NA
1.00
0.95 (0.561.61)
4,018
NA
1.00
1.24 (0.752.03)
25,661
NA
0.87
1.00
0.96 (0.621.49)
NA
0.54
1.00
4,018
1.14 (0.751.72)
25,661
Recombinant
Plasma-derived
0.40
No. of
Exposure Days
Product
Table 2. Risk of Inhibitor Development, According to the Type of Factor VIII Product.*
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Discussion
In this cohort study involving 574 consecutive,
previously untreated children with severe hemophilia A who were born between 2000 and 2010,
recombinant factor VIII products conferred a risk
of inhibitor development that was similar to the
risk conferred by plasma-derived products. The
von Willebrand factor content in factor VIII products was not associated with inhibitor development. Second-generation full-length recombinant
products were associated with a higher risk of
inhibitor development than were third-generation
full-length products. Switching from a plasmaderived product to a recombinant product or
switching among brands of factor VIII products
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Group25,34 have not shown significant differences in the risk of inhibitor development
among various recombinant factor VIII products.
In the registration studies, the incidence of inhibitor development may have been underestimated because of the inclusion of patients who
had already been treated with factor VIII on several exposure days and a short follow-up period
for the subgroup of patients who were still at
risk for inhibitor development. There is no
straightforward biologic explanation for a difference in immunogenicity among recombinant
factor VIII products. Further studies are needed
to verify these observations and to identify biologic explanations.
In conclusion, the use of recombinant factor
VIII products in children with severe hemophilia A
did not have a significant effect on the risk of
inhibitor development, as compared with the use
of plasma-derived products, nor was the von
Willebrand factor content of the products or
switching among them associated with the risk
of inhibitor development. An unexpected finding was that second-generation full-length recombinant products were associated with an
increased risk of inhibitor development, as
compared with third-generation products.
Supported by unrestricted research grants from Bayer
Healthcare and Baxter BioScience.
Disclosure forms provided by the authors are available with
the full text of this article at NEJM.org.
We thank the study coordinator, Ella Smink; Emma Smid and
Mojtaba Hashemi for their support in data cleaning; Yves Guillaume, Kate Khair, Karin Lindvall, Monique Spoor, and Bep
Verkerk for their assistance in the study; and J. Michael Soucie
(Division of Blood Disorders, National Center on Birth Defects
and Developmental Disabilities, Centers for Disease Control and
Prevention) for repeating the analyses.
Appendix
The authors affiliations are as follows: the Department of Pediatrics, Wilhelmina Childrens Hospital (S.C.G.), and the Julius Center
for Health Sciences and Primary Care, University Medical Center Utrecht (S.C.G., H.M.B.), Utrecht, and the Department of Clinical
Epidemiology, Leiden University Medical Center, and the Center for Clinical Transfusion Research, Sanquin Foundation, Leiden (J.G.B.)
all in the Netherlands; Lund University, Department of Pediatrics and Malm Center for Thrombosis and Hemostasis, Sknes Universitetssjukhus, Malm, Sweden (R.L.); Department of Pediatrics, J.W. Goethe University Hospital, Frankfurt, Germany (C.E.); Unidad
de Hemostasia y Trombosis, Hospital Universitario y Politcnico La Fe, Valencia, Spain (A.R.C.); Centre Regional dHemophilie, Centre
Hospitalier Universitaire, Toulouse, France (S.C.-D.); the Department of Pediatrics, University Hospitals Leuven, and the Department of
Cardiovascular Sciences, KU Leuven both in Leuven, Belgium (C.G.); National Hemophilia Center, Ministry of Health, Sheba Medical
Center, Tel Hashomer, Israel (G.K.); Hospital for Children and Adolescents, University of Helsinki, Helsinki (A.M.); Dipartimento di
Ematologia ed Oncologia, Unit Trombosi ed Emostasi, Ospedale Pediatrico Giannina Gaslini, Genoa (A.C.M.), and Angelo Bianchi
Bonomi Hemophilia and Thrombosis Center, Fondazione IRCCS Ca Granda, Ospedale Maggiore Policlinico, Milan (E.S.) both in
Italy; Universittsklinik fr Kinder- und Jugendheilkunde, Graz, Austria (W.M.); Hmophiliezentrum, Wabern and Childrens Hospital
of the University of Bern, Bern, Switzerland (R.K.); Division of Hematology/Oncology, Hpital St. Justine, Montreal (G.R.); and Royal
Hospital for Sick Children, Edinburgh (A.T.).
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