Young adult outcomes of childhood prophylaxis for severe hemophilia A: results of the Joint Outcome Continuation Study

Abstract

The Joint Outcome Study (JOS), a randomized controlled trial, demonstrated that children with severe hemophilia A (HA) initiating prophylactic factor VIII (FVIII) prior to age 2.5 years had reduced joint damage at age 6 years compared with those treated with episodic FVIII for bleeding. The Joint Outcome Continuation Study (JOS-C) evaluated early vs delayed prophylaxis effects on long-term joint health, following JOS participants to age 18 years in an observational, partially retrospective study. Index joint magnetic resonance imaging (MRI) scores of osteochondral (OC) damage (primary outcome), joint physical examination scores, and annualized rates of joint/other bleeding episodes (secondary outcomes) were collected. Thirty-seven of 65 JOS participants enrolled in JOS-C, including 15 randomized to prophylaxis at mean age 1.3 years (“early prophylaxis”); 18 initially randomized to episodic treatment, starting “delayed prophylaxis” at mean age 7.5 years; and 4 with high-titer inhibitors. At JOS-C exit, MRI OC damage was found in 77% of those on delayed and 35% of those on early prophylaxis for an odds ratio of OC damage, in the delayed vs early prophylaxis group, of 6.3 (95% confidence interval, 1.3, 29.9; P = .02). Annualized bleeding rates were higher with delayed prophylaxis (mean plus or minus standard deviation, 10.6 ± 6.6 vs 3.5 ± 2.1; P < .001), including when only comparing time periods on prophylaxis (6.2 ± 5.3 vs 3.3 ± 1.9; P < .05). In severe HA, early initiation of prophylaxis provided continued protection against joint damage throughout childhood compared with delayed initiation, but early prophylaxis was not sufficient to fully prevent damage. This trial was registered at www.clinicaltrials.gov as #NCT01000844.

2021 clinical trials update: Innovations in hemophilia therapy

“…These patients are also at risk of FVIII or FIX alloantibody formation (inhibitors), which complicate both the approach to prophylaxis as well as bleed management. In our older children and adult patients, the infusion frequency of clotting factor products needed to provide adequate factor activity to eliminate (or even minimize) bleed events remains a barrier to consistent adherence, and an ongoing decline in joint health is observed albeit at a markedly slower pace than without prophylaxis 120 …”

“…Pediatric patients present both a unique challenge and an opportunity as prevention of joint bleeding, particularly at the youngest ages, greatly improves overall joint health 1,120 . Development of therapeutic strategies that are easily administered and provide robust hemostatic protection are appealing.…”

Reimbursing the value of gene therapy care in an era of uncertainty

“…The number of bands can be adapted to each system based on preference with clinicians and patients. In lower bands, PWH with lower levels of factor may still not need prophylactic treatment, although it may be argued that sub‐clinical bleeding may still occur 31 . The details in examples such as this could be agreed to by a Delphi‐like process to achieve expert consensus until population data are available 32 .…”

Prophylaxis for children with moderate hemophilia: Use of a guideline to increase early initiation

“…In 2017, a clinical practice guideline was developed at the University of Colorado Hemophilia and Thrombosis Center to optimize the identification of hemophilia patients eligible for prophylaxis. For patients with baseline factor <2%, full‐dose prophylaxis is recommended by 18‐30 months, 8 or earlier if there is clinically symptomatic bleeding. If the baseline factor level is ≥ 2%, initiation of prophylaxis is recommended when there is: (a) >1 joint bleed in any 12‐month period, (b) participation in high‐risk sports, (c) frequent or persistent joint pain not otherwise explained, (d) any single joint HJHS increased by ≥2 points over 12 months, (e) any single joint HJHS ≥ 5, (f) total HJHS ≥ 18, or (g) patient/parent preference.…”