Photo courtesy of ASH
ORLANDO, FL—The source of factor VIII (FVIII) replacement therapy affects the risk of inhibitor development in previously untreated patients with severe hemophilia A, according to a prospective, randomized trial.
Results of the SIPPET study indicate that receiving recombinant FVIII is associated with a nearly 2-fold higher risk of developing inhibitory alloantibodies than receiving plasma-derived FVIII.
These results have implications for the choice of therapy for previously untreated patients, as inhibitor development remains a major challenge in the management of hemophilia A, said Flora Peyvandi, MD, PhD, of Angelo Bianchi Bonomi Hemophilia and Thrombosis Center in Milan, Italy.
Dr Peyvandi presented results of the SIPPET study during the plenary session of the 2015 ASH Annual Meeting (abstract 5*).
She noted that 13 previous observational studies indicated an increased risk of inhibitor formation with recombinant FVIII. But 2 consecutive, multicenter, observational trials (CANAL and RODIN) suggested there was no difference in immunogenicity between recombinant and plasma-derived FVIII.
A few meta-analyses showed a higher risk of inhibitors with recombinant FVIII, but the difference between recombinant and plasma-derived FVIII was attenuated after researchers adjusted for confounding factors.
In an attempt to obtain some conclusive results, Dr Peyvandi and her colleagues conducted the SIPPET study. It is the first randomized clinical trial in hemophilia with the goal of comparing the immunogenicity of FVIII product classes—plasma-derived FVIII products with von Willebrand factor and recombinant FVIII products.
Study design
Between 2010 and 2014, the researchers enrolled patients from 42 sites in 14 countries from Africa, the Americas, Asia, and Europe.
The all-male patients were younger than 6 years of age at enrollment. They had severe hemophilia A, negative inhibitor measurement at enrollment, and no or minimal exposure (less than 5 exposure days) to blood products.
The patients were randomized to either a single plasma-derived FVIII product containing von Willebrand factor or a single recombinant FVIII product. The treatment was at the discretion of the local physician.
Patients were treated for 50 exposure days, 3 years, or until inhibitor development.
The primary outcome was any FVIII inhibitor at titers ≥ 0.4 BU/mL. High-titer inhibitors (≥ 5 BU/mL) were a secondary outcome. Transient inhibitors were defined as those that spontaneously disappeared within 6 months.
Patients were assessed every 3 to 5 exposure days in the first 20 exposure days, then every 10 exposure days or every 3 months and every 2 weeks during prophylaxis.
“Every time a clinician had some doubt about the development of inhibitors, this [was] measured and also confirmed at the central lab in Milan,” Dr Peyvandi noted.
Results
In all, 251 patients were analyzed—126 randomized to recombinant FVIII and 125 to plasma-derived FVIII.
Dr Peyvandi pointed out that confounders—such as family history, previous exposure, and surgery—were equally distributed between the treatment arms thanks to the randomization. The same was true for the treatment type—on-demand, standard prophylaxis, etc.
Overall, 76 patients developed inhibitors, for a cumulative incidence of 35.4%. Fifty patients had high-titer inhibitors, for a cumulative incidence of 23.3%.
The cumulative incidence of all inhibitors was 44.5% (n=47) in the recombinant FVIII arm and 26.8% (n=29) in the plasma-derived FVIII arm. The cumulative incidence of high-titer inhibitors was 28.4% (n=30) and 18.6% (n=20), respectively.
More than 73% of all inhibitors were non-transient in both arms.
By univariate Cox regression analysis, recombinant FVIII was associated with an 87% higher incidence of inhibitors than plasma-derived FVIII (hazard ratio [HR]=1.87). And recombinant FVIII was associated with a 69% higher incidence of high-titer inhibitors (HR=1.69).
The researchers also adjusted their analysis for range of potential confounders to see how the randomization worked.
“None of this adjustment made any difference, as you would expect from a randomized study,” Dr Peyvandi said.
She went on to highlight a study published in NEJM in 2013, which suggested that second-generation, full-length FVIII products were associated with an increased risk of inhibitor development when compared to third-generation FVIII products.
Based on this finding, the World Federation of Hemophilia recommended against using second-generation products in previously untreated patients.
So Dr Peyvandi and her colleagues stopped the use of those products during the course of the SIPPET study. And they adjusted their analysis to ensure their observations were not due to any confounding effects of the products.
After excluding second-generation, full-length recombinant FVIII from their analysis, the researchers still observed an increased risk of inhibitor development with recombinant FVIII. The HRs were 1.98 for all inhibitors and 2.59 for high-titer inhibitors.
In closing, Dr Peyvandi said these findings are clinically important because inhibitors are the major therapeutic complication in hemophilia A and can cause a marked increase in morbidity, mortality, and treatment costs.
*Data in the abstract differ from data presented at the meeting.