Abstract
Congential hemophilia B (HemB) is one fifth as common as hemophilia A. The development of inhibitors in Hem B is also less common (3–5%) than observed with hemophilia A and is associated with the absence of factor IX (FIX) antigen caused by large or complete deletions or major derangements of the FIX gene. These mutations have been linked to severe anaphylactic reactions upon re-exposure to factor IX (FIX). This has compromised attempts at immune tolerance induction with FIX products and has also been associated with the onset of nephrotic syndrome. The presence of FIX within activated prothrombin complex concentrates, precludes the use of these agents in this unique patient population. Thus, patients with HemB and inhibitors (HemBwI) are managed with recombinant VIIa (rVIIa, NovoSeven®), some for close to a decade since its original FDA approval. The rFVIIa dosing typically used is less well understood, as is the relationship between anaphylaxis to FIX exposure and rFVIIa dosing.
The HTRS registry records data regarding the treatment of acute bleeding episodes in those with hemophilia A or B and related hemorrhagic disorders, with focus on congenital hemophilia complicated by inhibitors. From data collected between January 2004 and March 2008, all patients with HemBwI that were treated at least in part with rFVIIa for acute bleeds were examined for their initial and total dose, number of doses, and number of days on rFVIIa therapy. Due to significant outlier bleeds, median values and interquartile ranges (IQR) are reported for many parameters.
There were 287 patients with HemB and 33 with HemBwI. Of over 2,532 bleeds treated with rFVIIa, 353 bleeds were reported in 12 individuals with HemBwI treated with 4,254 doses of rFVIIa. One patient had 102 bleeds recorded. The mean age was 13.2 years (range 0.6–55.9 years). Mean titers of anti-FIX alloantibodies were 11.8 BU (median, 4.3; range, 0–55.5).
Bleeding Sites N (%) Treatment Location N (%) Joint 234 (66%) Home 306 (87%) Target joint 70 (20%) Hospital, inpatient 25 (7%) Muscle 67 (19%) Hospital, ER 8 (2%) Mucosal 12 (3%) HTC 8 (2%) Subcutaneous 11 (3%) Head 4 (1%) Bleeding Type N (%) Spontaneous 243 (69%) Traumatic 84 (24%) Mean (Median) IQR Range Total dose (mcg/kg) 1,514 (720) 360–1600 54–43,200 Initial dose (mcg/kg) 142.8 (120) 99–180 53–400 # Doses 12 (6) 3–11 1–480 Joint Target Joint Muscle Initial dose - mean (median) 145.1 (120) 121.6 (120) 143.9 (120) Total dose - mean (median) 1306 (840) 953 (840) 2510 (480)
Overall efficacy as assessed by physician report of “bleeding stopped” was 82% (joint, 84%; target joint, 91%; muscle, 73%). Most other bleeds were categorized as “bleeding slowed” (53 of 62, 18%) and “no improvement” (9 of 53, 3%), however none of those patients switched medications and treatment was self-limited suggesting all patients ultimately had resolution of their bleeds. There were 44 single dose treatments including 31 joint bleeds. Mean (median, range) dose was 142.8 mcg/kg (120, 53–400). Physicians reported “bleeding stopped” in 43 (98%).
There were no serious adverse drug reactions or thromboembolic events related to rFVIIa associated with the bleeding episodes analyzed.
While registries admittedly only capture those data reported in a selected and potentially biased manner, the 2004–2008 data from HTRS provide the largest single source of data on the real world dosing, safety and efficacy of rFVIIa in HemBwI in a predominantly home setting. Dosing was similar between joint, target joint and muscle bleeds, and similar to reported dosing in HemAwI. Clinical efficacy appeared greatest for target joint bleeds, although no patients switched to other medications to control bleeding. Further analysis on HemBwI patients to assess differences in dosing for patients with history of anaphylactic responses to FIX will be important to understand this patient group better.
Peripheral transvenular delivery of adeno-associated viral vectors to skeletal muscle as a novel therapy for hemophilia B
