Early FVIII Prophylaxis Improves Long-Term 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 (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 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–factor-based 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.