According to research published in the Journal of Blood Medicine, immune tolerance induction (ITI) therapy with ADVATE® (antihemophilic factor [recombinant] [rAHF]) was effective and resulted in no unexpected safety signals in patients with hemophilia A and neutralizing antibodies to coagulation factor VIII (FVIII inhibitors).

The conclusions come from the final results of the Prospective ADVATE Immune Tolerance Induction Registry (PAIR) study, an international, multicenter, open-label, prospective observational study in patients with hemophilia A of any severity and inhibitors who were prescribed rAHF ITI therapy in clinical practice (PASS-INT-004, a noninterventional postauthorization study initiated in 2007).

The investigators reported the incidence of adverse events (AEs) possibly related to rAHF during ITI therapy as the primary endpoint and included incidence of central venous access device-related complications and success rates of ITI therapy as secondary endpoints. They also monitored maintenance of immune tolerance for 12 months post-ITI therapy.

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All 44 participants completed the study. Of those, 36 (81.8%) completed ITI therapy, and 31 (70.5%) completed the 12-month follow-up period. The median age at enrollment was 23.5 months (range, 1.0-676). Overall, 86.4% and 13.6% of patients had severe (baseline FVIII level ≤1%; 38/44) and nonsevere hemophilia A (baseline FVIII level >1%; 6/44), respectively.  

Most patients (59.1%) received an rAHF dose ranging from 90 to 130 IU/kg/day. The mean number of doses was 6.0 doses per week. Following PAIR study enrollment, the median duration of rAHF ITI therapy was 600 days.

A total of 284 AEs were reported. Of these, 56 AEs (19.7%) were serious; none of these were considered related to rAHF ITI therapy. Of the 228 nonserious AEs, 14 AEs, which occurred in 6 patients (13.6%), were deemed related to rAHF ITI therapy. These included pyrexia (n=1), urticaria (n=1), nausea (n=2), catheter site pain (n=1), upper respiratory tract infection (n=1), arthralgia (n=2), hemarthrosis (n=2), and increase of FVIII inhibitors titer due to anamnestic response (n=4). Central venous access device-related complications (≥1) occurred in 18 patients.

Of the 36 patients who completed therapy, 21 (58%) achieved a negative inhibitor titer, and the Kaplan-Meier estimate of success for achievement of first negative titer at 18 months was 68.3% (95% confidence interval, 51.8-83.6). Among those with partial or complete success following therapy, 87% (20/23) maintained immune tolerance at the 12-month follow up.

Limitations of the study included the possibility that not all data were entered into the database, the wide patient age range, small/variable sample sizes in subgroups, and the difference in protocol and current definitions for hemophilia severity (namely, severe hemophilia now defined as baseline FVIII level <1%).  

“The observational PAIR study provides important real-world data on a widely used recombinant factor VIII concentrate,” the authors wrote. “Future prospective studies may further define factors associated with ITI therapy success and failure in patients with hemophilia A.”

Disclosure: This research was funded by Baxalta US Inc., a Takeda company, Lexington, MA, USA. Please see the original reference for a full list of disclosures.


Shapiro AD, Fernandez A, Teitel J, Botha J, Khair K. Final results of the prospective ADVATE® immune tolerance induction registry (PAIR) study with plasma- and albumin-free recombinant factor VIII. J Blood Med. 2021;12:991-1001. doi:10.2147/JBM.S329883