Blood Advances in a Different Vein
NEWS
Research from recent issues of Blood Advances
Early FVIII Prophylaxis Improves Joint Outcomes
in Severe Hemophilia A
Joint bleeding results in acute and chronic pain for
patients living with severe hemophilia A, but joint outcomes
improve when prophylactic factor VIII (FVIII) is
started before 2.5 years of age, according to results from
the Joint Outcome Study Continuation (JOS-C), which
updated results from the initial JOS of young boys with
severe hemophilia A.
The findings were published in Blood Advances by
Beth Boulden Warren, MD, from the University of
Colorado Anschutz Medical Center, and co-authors.
The initial JOS, which began in 1996, was a randomized
controlled trial evaluating the effects of FVIII prophylaxis
in 65 young boys with severe hemophilia A. As
reported in 2007 in the New England Journal of Medicine,
the key finding of JOS was that FVIII concentrate administered
every other day starting before 2.5 years of age
led to better joint outcomes at age 6, compared with episodic
treatment for bleeding.
When the study was completed, all participants on
the episodic arm were encouraged to adopt prophylaxis,
the authors explained, “allowing an important
opportunity to compare outcomes relative to prophylaxis
initiation age in the context of a prospective trial.”
The JOS-C followed 37 JOS participants through
adolescence, with a focus on joint outcomes. Four had
a history of high-titer inhibitors, leaving 15 patients
in the prophylaxis group and 18 in the episodic groups
(referred to as “early prophylaxis” and “delayed prophylaxis”
groups, respectively). JOS-C participants
were enrolled between January 2010 and September
2015 and completed the study between December 2012
and September 2017.
Patients were followed for a median of 3.4 years
TABLE. Outcome Data
(range = 0-7.6). Researchers collected data on hemophilia
treatments, bleeding events, hospitalizations,
and surgeries from medical records, and patients completed
surveys about quality of life and participation
in physical activities. Index joint magnetic resonance
imaging (MRI) scores of osteochondral damage served
as the study’s primary outcome. MRIs were scored
according to the extended MRI (eMRI) scale, which
assigns each joint a 9-point score for soft tissue damage
and a 36-point score for osteochondral damage; higher
scores represent more damage. Patients also underwent
physical examination using the 31-point Colorado
Pediatric Joint Assessment Scale.
As seen in the initial JOS, early prophylaxis was
associated with better outcomes at age 6, compared
with delayed prophylaxis (TABLE). These findings were
nearly identical to the original analysis, the authors
reported, but the present study found that the benefits
continued beyond age 6.
At JOS-C exit, when participants turned 18, MRI
scans revealed osteochondral damage in 77% of those
on delayed prophylaxis and 35% of those on early prophylaxis,
for an odds ratio of 6.3 (95% CI 1.3-29.9;
p=0.02). The eMRI total scores were 7.8 (interquartile
range [IQR] = 3.3-25.5) in the early prophylaxis group
and 13.8 (IQR=7.9-37.9) in the delayed-prophylaxis
group. Annualized bleeding rates (ABR) and joint ABRs
also were significantly lower among boys who received
early FVIII prophylaxis – both from birth to 18 years
and when comparing bleeding rates after initiation of
prophylaxis (TABLE).
Data on sports and other physical activity were available
for 24 participants without inhibitors (12 from each
Early Prophylaxis (n=15) Delayed Prophylaxis (n=18) p Value
Age of JOS-C exit, mean 17.5 18.4 0.1
MRI OC damage, %
Participants with OC damage 5/14 (35) 14/18 (77) 0.02
Joints with OC damage 11/84 (13) 26/108 (24) 0.06
Participants with surgery for hemophilic arthropathy 1 2 N/A
No MRI damage (eMRI <1), %
Participants with no damage 2/14 (14) 2/18 (11) 0.79
Joints with no damage 40/84 (48) 48/108 (44) 0.66
eMRI, median (IQR) of participant joint averages
eMRI score 1.3 (0.5-2.2) 2.3 (1.3-5.0) 0.17
OC eMRI score 0.04 (0-0.8) 1.2 (0.3-3.1) 0.08
Lifetime bleeding rates, mean [median (IQR)]
J-ABR 1.5 [1.1 (0.7-2.3)] 4.3 [3.9 (2.4-5.2)] 0.007
ABR 3.5 [2.7 (2.2-4.7)] 10.6 [9.5 (6.5-11.8)] <0.001
After prophylaxis start, mean [median (IQR)]
J-ABR 1.6 [1.1 (0.7-2.6)] 4.0 [2.8 (1.7-4.7)] <0.05
ABR 3.3 [2.7 (2.1-4.7)] 6.2 [4.6 (2.4-8.6)] <0.05
Physical examination score, mean of participant joint averages 2.4 3.2 0.23
OC = osteochondral; ABR = annualized bleeding rate; J-ABR = joint annualized bleeding rate
group). Two-thirds of boys in the early prophylaxis group
experienced no osteochondral damage while playing
moderate- to high-risk sports, compared with just over
one-third of those in the delayed prophylaxis group.
While it appears that early treatment allowed patients to
be more physically active, there were no significant differences
in total scores on quality-of-life scales, including
in physical domains. “Most participant comments
centered on the inconvenience and pain of infusion or
on limitations related to entering certain professions
(e.g., the military),” the authors noted.
As seen in the JOS-C, children who started FVIII prophylaxis
late continued to have significantly increased
risk of MRI osteochondral damage and higher bleeding
rates, the authors concluded, “[which] supports the recommendation
of the World Federation of Hemophilia
that early initiation of prophylaxis, prior to the first
joint bleed, is critical to maintaining joint health in
patients with severe hemophilia.”
“Only a very small proportion of participants and
joints survived to adolescence without damage, despite
full early prophylaxis,” they added. “Equally striking in
both early and delayed prophylaxis groups was the relatively
low individual joint ABR that resulted in joint
damage on MRI and examination, emphasizing that it
is important to prevent every joint bleed.”
Measures of joint damage revealed that damage
increased progressively through childhood and adolescence
and was consistently higher in participants
on delayed prophylaxis. “This suggests that early prophylaxis
is more efficacious than delayed prophylaxis
in limiting joint damage,” they wrote, “but that joint
damage may occur despite early initiation of prophylaxis
using every-other-day prophylaxis with conventional
recombinant FVIII.”
While standard prophylaxis is inadequate to completely
protect joints in patients with severe hemophilia
A, newer hemophilia treatments such as emicizumab may
improve bleeding outcomes. However, this study was
conducted before emicizumab and other non–factorbased
therapies were widely used. “This long-term
study comparing FVIII prophylaxis initiated before
age 2.5 years [versus] after age 6 years provides a critical
baseline against which new therapies can be compared,”
the authors concluded.
The study’s findings also are limited by the small
number of JOS participants who continued in the JOS-C.
In addition, the authors noted that, although bleeding
episode data were corroborated with patient medical
records, it is possible that not all bleeding episodes were
captured, potentially leading to an underestimation of
bleeding rates.
The authors report relationships with Bayer, which
sponsored the study.
Reference
Warren BB, Thornhill D, Stein J, et al. Young adult outcomes of childhood prophylaxis for severe
hemophilia A: results of the Joint Outcome Continuation Study. Blood Adv. 2020;4:2451-2459.
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