A sudden increase in factor VIII inhibitor development in multitransfused hemophilia A patients in The Netherlands. Dutch Hemophilia Study Group

Abstract

The development of antibodies to factor VIII (inhibitors) in response to clotting-factor concentrates administration in hemophilia is common during the first few years of treatment but rare in multitransfused patients. We have investigated the possible association of a recently introduced factor VIII concentrate (Factor VIII CPS-P) in The Netherlands with the occurrence of inhibitors. To this effect, we conducted two studies. First, we performed a national multicenter study in which clinical information and inhibitor test results were obtained for 447 hemophilia A patients over the period 1988 through 1991. Secondly, for a baseline comparison we estimated the frequency of inhibitor development in a closely followed cohort of 144 patients, from 1984 through 1989. Before the introduction of Factor VIII CPS-P, the incidence of new inhibitors was 4.4/1,000 patient-years in the national study from March 1988 through May 1990, and 3.9/1,000 patient- years in the cohort followed from 1984 through 1989. These figures are similar to the incidence of new inhibitors that was found in a large cohort of patients in the United States followed in the 1970s. In the period that the new concentrate Factor VIII CPS-P was on the market, from June 1990 through November 1991, 11 clinically relevant inhibitors were detected, which yielded an incidence over this interval of 20.1/1,000 patient-years, a 4.5-fold increase compared with the previous interval (C195: 1.4 to 14.3). Nine of these 11 patients had in their lifetime received over 250 infusions with factor VIII preparations. whereas all of the inhibitors detected in the previous time interval, and all of the 24 inhibitor patients described in the US study, had received less than 250 infusions in their lifetime. All patients who developed inhibitors after June 1990 had been exposed to Factor VIII CPS-P, whereas only 75% of the patients who did not develop an inhibitor had been exposed to this product. In a prospective extension of the study, with a second inhibitor measurement after 3 months, we found that one additional inhibitor had developed during 52.5 patient-years of Factor VIII CPS-P use. In conclusion, there has been a sudden increase in the frequency of inhibitor patients, for a large part among multitransfused patients. It seems more than likely that this increase is associated with the introduction of a new factor VIII concentrate in The Netherlands.(ABSTRACT TRUNCATED AT 400 WORDS)

Human recombinant DNA‐derived antihaemophilic factor (factor VIII) in the treatment of haemophilia A: conclusions of a 5‐year study of home therapy

“…The overall mean was 2.48% IU −1 kg −1 for all 885 studies, with the same mean recovery of 2.55% IU −1 kg −1 for all studies during the first and fifth year. The lack of evidence for inhibitor formation is in contrast to recent reports on two plasma‐derived FVIII products which were found to be immunogenic in previously treated patients shortly after introduction and were withdrawn from clinical use [ 19, 20].…”

“…There were no new seroconversions to HIV, and none of the HIV‐positive individuals died during the course of the study. Analysis of CD4 and CD8 cell changes after 3.5 years of study was previously reported on 54 subjects (23 HIV‐positive and 31 HIV‐negative) who had been followed on study for more than 2 years and had at least three lymphocyte subset counts [ 20]. Data through year 5 is now available on 21 of the 23 HIV‐positive patients and 29 of the 31 HIV‐negative patients.…”

European principles of haemophilia care

“…Power calculations show that to detect an increase in inhibitors in previously treated patients of 1–3% with an α of 0.05 and a power (1 − β) of 90%, a sample size of at least 430 patients is needed. This is illustrated by the Dutch study detecting increased inhibitor incidence after introduction of a new FVIII concentrate [5] and the Canadian surveillance of the effects of switching to recombinant concentrate [6]. Inhibitor incidence in previously untreated patients is a particularly important issue at the time of introduction of new concentrates.…”

Clinical assessment of Optivate®, a high-purity concentrate of factor VIII with von Willebrand factor, in the management of patients with haemophilia A

“…Nowadays, the development of inhibitor antibodies remains a concern with new FVIII products. In the late 1980s and early 1990s, two outbreaks of inhibitors amongst previously treated patients (PTPs) treated with new concentrates showed that changes in manufacturing processes could result in the formation of neoantigens leading to inhibitor formation [22–25]. Since then, it has been essential to evaluate all new FVIII concentrates in PTPs to establish whether they are unusually antigenic.…”