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.

Conflict of interest statement

Conflict-of-interest disclosure: B.B.W. has received research funding from the HTRS/Novo Nordisk Clinical Fellowship Award, the Bayer Hemophilia Awards Program Fellowship Project Award, and the CSL Behring Professor Heimburger Award, and has served as a consultant for Bayer Healthcare. M.R. receives research support from Bioverativ, Genentech, Novo Nordisk, and Shire, and serves on consulting/advisory boards for Bioverativ, CSL Behring, Genentech, Kedrion, Novo Nordisk, Pfizer, Shire, and uniQure. S.F. serves on a speakers’ bureau for Sanofi Genzyme. M.J.M.-J. has received research support from Bayer and serves on advisory boards for CSL Behring, HEMA Biologics, Genentech, Novo Nordisk, and Shire. The remaining authors declare no competing financial interests.

© 2020 by The American Society of Hematology.

Figures

Graphical abstract

Figure 1.

Follow-up and analysis of study participants. All participants of the JOS were eligible to enroll in the JOS-C prior to age 18 years. CI, confidence interval; QOD, every other day; RR, relative risk.

Figure 2.

Repeated measures correlation between individual joint ABR and eMRI scores at age 18 years. (A) Early prophylaxis group. (B) Delayed prophylaxis group. Each color represents a participant, each dot represents an index joint, each colored solid line represents the summary correlation for that participant, and the gray dotted line represents the summary correlation for all data. (C) Additional repeated measures correlations with CPJAS scores.

Figure 3.

Longitudinal comparison. Average joint MRI scores (A) and physical examination scores (B) at JOS exit, JOS-C entry, and JOS-C exit between early prophylaxis (blue) and delayed prophylaxis (red) groups. Table column headers also reflect radiograph time-point labels for graphs. Error bars represent standard error mean.