ORLANDO, Fla. — Recombinant Factor VIII replacement products for severe hemophilia A appeared to increase inhibitor development 1.87-fold compared with products in the plasma-derived class, according to study results presented during the plenary session of the ASH Annual Meeting and Exposition.
Flora Peyvandi, MD, PhD, associate professor of internal medicine at University of Milan and head of the internal medicine department and of the Angelo Bianchi Bonomi Haemophilia and Thrombosis Centre of Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico in Milan, Italy, and colleagues conducted this multicenter, open-label, randomized study to evaluate whether the rate of inhibitory alloantibody development differed based on the source of Factor VIII replacement — plasma-derived or recombinant — in previously untreated patients with severe hemophilia A.
“One of the most important complications in the management of severe hemophilia A is the development of inhibitors present in almost one-third of the children,” Peyvandi said during her presentation during the plenary session. “That is a major challenge — to identify the risk factor for the development of inhibitors.
“Some of the risk factors, like Factor VIII gene mutation, are well-established,” she added. “However, some other risk factors related to the treatment regarding exposure during the treatment and the intensity of the treatment are still a matter of discussion. [We wanted to look] at the type of Factor VIII concentrate and its relation to the development of inhibitors.”
The researchers enrolled 303 previously untreated patients between 2010 and 2014 who were screened at one of 42 participating centers in 14 countries.
After 39 screening failures and 13 exclusions, researchers evaluated data from 251 patients aged 0 to 81 months (median age, 14 months). From that group, 35 had shortened follow-up due to study dropout or termination
Researchers randomly assigned patients 1:1 to receive one product within the plasma-derived (n = 125) or the recombinant (n = 126) Factor VIII class. The product selected from the class was allocated based on site licensing and availability.
Researchers then monitored patients for inhibitor development, which served as the study’s primary endpoint (≥ 0.4 BU/mL). The development of high-titred inhibitors (peak levels ˃ 5 BU/mL) served as a secondary outcome.
Patients received between one and 50 infusions (median, 22) of Factor VIII concentrates.
Overall, 76 patients developed an inhibitor — 50 of which were high-titred for a cumulative inhibitor incidence of 35.4% (95% CI, 28.9-41.9). Ninety percent of the inhibitors developed within 20 exposure days.
Among patients who did not develop an inhibitor, more than 70% had at least 20 exposure days.
Inhibitors developed in 29 patients in the plasma-derived cohort (20 high-titred) and 47 patients (30 high-titred) in the recombinant cohort. These data equated to a cumulative inhibitor incidence of 26.7% (95% CI, 18.3-35.1) for plasma-derived Factor VIII replacement and 44.5% (95% CI, 34.7-54.3) for recombinant Factor VIII replacement.
The cumulative incidence of only high-titre inhibitors was 18.5% (95% CI, 12.1-26.9) in the plasma-derived cohort and 28.4% (95% CI, 19.6-37.2) in the recombinant cohort.
Results of a univariate analysis indicated recombinant replacement increased inhibitor development 87% compared with plasma-derived products (HR = 1.87; 95% CI, 1.18-2.97). Further, recombinant replacement appeared associated with a 70% increase in high-titre inhibitor development (HR = 1.7; 95% CI, 0.96-2.99).
These rates appeared comparable in adjusted models and analyses of sites that did not randomly assign patients to one of the study arms.
“We can say that patients treated with recombinant factor VIII have an 87% higher risk to develop inhibitors than those treated with plasma-derived containing von Willebrand factor,” Peyvandi said. “This difference remained even when second-generation, full-length recombinant Factor VIII concentrate was excluded from the analysis.
“Finally, these findings are clinically important due to the development of inhibitors, [which is] the major thrombotic complication in hemophilia A and causes a marked increase in morbidity, mortality and treatment cost.” – by Anthony SanFilippo
Peyvandi F, et al. Abstract 5. Presented at: ASH Annual Meeting and Exposition; Dec. 5-8, 2015; Orlando, Fla.
Disclosure: This study was funded in part by Grifols, Kedrion and LFB. Peyvandi reports research funding and honoraria from, consultant/advisory roles with, and other financial relationships with Bayer, CSL Behring, Kedrion, LFB, Novo Nordisk, Octapharma and Roche. Please see the abstract for a list of all other researchers’ relevant financial disclosures.