Recombinant versus plasma-derived factor VIII products and the development of inhibitors in previously untreated patients with severe hemophilia A: the CANAL cohort study

Abstract

It has been suggested that plasma-derived factor VIII products induce fewer inhibitors than recombinant factor VIII products. We investigated the relationship of factor VIII product type and switching between factor VIII products with the risk to develop inhibitors. This multicenter retrospective cohort study included 316 patients with severe hemophilia A born between 1990 and 2000. The outcome was clinically relevant inhibitor development, defined as the occurrence of at least 2 positive inhibitor titers with decreased recovery. The risk of inhibitor development was not clearly lower in plasma-derived compared with recombinant factor VIII products (relative risk [RR], 0.8; 95% confidence interval [CI], 0.5-1.3). Among high-titer inhibitors, the possible reduction in risk was even less pronounced (RR, 0.9; CI, 0.5-1.5). Plasma-derived products with considerable quantities of von Willebrand factor (VWF) carried the same risk for inhibitor development as recombinant factor VIII products (RR, 1.0; CI, 0.6-1.6). Switching between factor VIII products did not increase the risk for inhibitors (RR, 1.1; CI, 0.6-1.8). In conclusion, our findings support neither the notion that plasmaderived factor VIII products with considerable concentrations of VWF confer a lower risk to develop inhibitory antibodies than recombinant factor VIII products, nor that switching between factor VIII product brands increases inhibitor risks in previously untreated patients with severe hemophilia A. IntroductionAt present, the main concern in the treatment of children with severe hemophilia A is the development of inhibitory antibodies that neutralize infused factor VIII, occurring in 10% to 30% of patients. 1 Several patient-related factors have been associated with the risk of developing inhibitors, such as factor VIII gene mutation, 2-4 other genetic factors, 5-8 family history of inhibitors, 9-11 and ethnicity. 11,12 In addition to these determinants, a number of treatment-related factors have been suggested to affect the risk of inhibitor development, such as prophylaxis, 13,14 age at first exposure, 15,16 and intensity of treatment. 17 One of the most intensively discussed potential risk factors is the factor VIII product type.Indications for a potential role of the factor VIII product type in inhibitor development arose when prospective registration studies of recombinant factor VIII products among previously untreated hemophilia A patients reported inhibitor incidences between 29% and 32%. [18][19][20][21][22][23] These incidences were considerably higher than the previously observed 0% to 12% in patients treated with single plasma-derived products. 1,24 However, methodologic differences between studies rendered comparisons inconclusive. 25 More convincing were the findings of a recent comparative study in which the inhibitor risk in patients treated with full-length recombinant factor VIII was again higher than the risk in patients treated with a high-purity plasma-derived factor VIII product containing von Willebrand factor (VWF)...

Current Controversies in the Formation and Treatment of Alloantibodies to Factor VIII in Congenital Hemophilia A

“…The Italian multicenter experience of hemophilia A (FVIII 1%-2%) patients showed a significantly smaller risk for inhibitor development in those treated with prophylaxis over on-demand treatment, 2 a trend that was also confirmed in the CANAL study 6 but not in the UK study. 3 In a prospective study of hemophilia A (FVIII Յ 2%), boys Ͻ 30 months of age were randomized to receive 25 IU/kg of FVIII every other day versus on-demand treatment.…”

“…This was particularly true at higher (Ͼ 50 IU/kg) doses and when the first treatment was for surgery rather than for bleeds or prophylaxis. 6 The above-mentioned retrospective case control study in the United Kingdom examined early treatment patterns in severe hemophilia A (FVIII Յ 1%) in 78 (63 high-titer) inhibitor patients and agematched controls and found that high frequency treatment (FVIII on Ͼ 50% of days) increased inhibitor risk by approximately 2.5-fold. Similarly, high treatment intensity per episode resulted in increased inhibitor risk: the overall risk for more than 5 exposure days per episode was 2.7 and for more than 10 exposure days, it was 5.5.…”

“…5 This trend was again demonstrated in a larger multicenter review of 366 patients with severe hemophilia A in the Netherlands (the CANAL cohort study), but disappeared when adjusting for confounding factors, especially intensity at first treatment. 6 This study selected for symptomatic patients (decreased FVIII half-life) but did not account for a large heterogeneity in FVIII products used.…”

How we treat a hemophilia A patient with a factor VIII inhibitor

“…In a cohort of 316 subjects, Gouw et al found that there was no association between the type of product used and inhibitor development. 32 In addition, since the rate of nontransient inhibitor development in prospective trials of new recombinant products was similar to studies using plasmaderived products 33,34 ; and inhibitor formation is rare in previously treated patients who are switched to recombinant products 33,35,36 ; we believe the overall weight of the data suggests that there is no association between the type of fVIII product and inhibitor formation. Thus, we do not consider the risk of inhibitor formation when selecting a fVIII product to use for an individual patient.…”

Back to the future: a recent history of haemophilia treatment

“…In the last few years, experimental data [21] and two retrospective cohort studies [22,23], carried out in previously untreated boys with severe haemophilia A, have raised the suspicion that the cumulative incidence of inhibitors is higher with recombinant FVIII than with plasma-derived products containing, besides other proteins, large amounts of von Willebrand factor, the carrier and stabilizer of FVIII. There is also a published cohort study that demonstrates comparable immunogenicity of the two forms of treatment [24]; accordingly, this issue is likely to remain unsettled until randomized clinical trials are performed [25].…”