Perioperative Management of Hemostasis with Recombinant FIX Fc Fusion Protein in Subjects Undergoing Surgery in the B-YOND Study

Background: The phase 3 B-LONG (adults/adolescents ≥12 years of age) and Kids B-LONG (children <12 years of age) studies demonstrated the safety and efficacy of recombinant FIX Fc fusion protein (rFIXFc) for the control and prevention of bleeding episodes in subjects with severe hemophilia B (FIX levels ≤2 IU/dL).  Eligible subjects from either study could continue rFIXFc treatment in the ongoing extension study, B-YOND, during which surgical procedures were allowed.

Aims: To describe rFIXFc efficacy and safety in B-YOND subjects undergoing surgery.

Methods: B-YOND subjects who underwent surgery received an investigator-determined rFIXFc regimen.  Major surgery endpoints included rFIXFc dosing, investigator/surgeon assessment of hemostatic response (4-point scale: excellent, good, fair, poor/none), blood loss, number of transfusions, and safety.  For minor surgeries, hemostatic response and dosing are summarized.  Surgeries performed up to cutoff for the interim analysis (17 October 2014) were included.  For safety analyses, the surgery subgroup included subjects who underwent major surgery during B-YOND and those who underwent major surgery in the parent study but had their surgical/rehabilitation period during B-YOND.

Results: Fifteen major surgeries were performed in 8 subjects (7 adults/adolescents and 1 child <12 years of age), most commonly orthopedic procedures (9/15 surgeries).  In adults/adolescents undergoing major surgery, the median total rFIXFc dose on the day of surgery was 135.92 IU/kg (range, 60.6-317.9 IU/kg); 12 of these 14 surgeries required a single rFIXFc infusion to maintain hemostasis during surgery.  The number of adults and adolescents undergoing major surgery who required an infusion decreased from Day 0 to Day 14.  A single rFIXFc infusion of 99.43 IU/kg was required on the day of surgery for the single major surgery in a pediatric subject (tonsillectomy).  Of 15 major surgeries, 14 surgeries were assessed for hemostatic response to rFIXFc and all were rated as excellent (n = 13, including the single pediatric surgery) or good (n = 1).  Among 12 major surgeries with estimates, blood loss ranged from 0-1,000 mL intraoperatively and 0-1,000 mL postoperatively (for the single pediatric subject, blood loss was 50 mL intraoperatively and 0 mL postoperatively).  One additional subject had an estimated intraoperative blood loss of 5,000 mL during liver transplantation and was the only subject who required transfusion (6 units of packed cells, 4 units of platelet concentrate, and 4 units of fresh frozen plasma intraoperatively), consistent with previously reported blood loss for this procedure in the general population (Yuasa et al. Transfusion 2005;45:879).  Hemostatic response for this surgery was rated as excellent.  No subject reported a bleeding episode during the postoperative/rehabilitation period.  Among 12 subjects in the surgery subgroup (8 with major surgery during B-YOND; 4 with major surgery in B-LONG and a surgical/rehabilitation period during B-YOND), 3 subjects (25%) reported ≥1 adverse event (AE) during the perioperative management period.  One subject who underwent major surgery experienced 2 serious AEs (anal sphincter atony and epididymitis; considered unrelated to treatment) during the perioperative management period.  All AEs were assessed by the investigator as unrelated to treatment and resolved.

Of 25 minor surgeries performed in 17 adults/adolescents (none in children), approximately half were dental procedures (12/25 surgeries).  No rFIXFc was administered on the day of surgery for 2 minor surgeries.  For the other 23 surgeries, the median number of rFIXFc infusions was 1.0 (range, 1-3) and the median total dose of rFIXFc was 79.84 IU/kg (range, 38.5-200.0).  Hemostatic response was assessed in 10 of 25 minor surgeries; all were rated as excellent (n = 9) or good (n = 1). 

Summary/Conclusion: Hemostasis with rFIXFc during surgery was rated favorably by investigators/surgeons, with comparable blood loss to what would be expected for subjects without hemophilia.  Taken together with results from the B-LONG and Kids B-LONG studies, these data indicate that rFIXFc is well-tolerated and efficacious for the management of perioperative hemostasis in individuals with severe hemophilia B.