Isolated A1-domain F8 large deletions are associated with favorable immune tolerance induction outcomes in children with severe hemophilia A.

BACKGROUND

Large F8 deletions are generally associated with unfavorable immune tolerance induction (ITI) outcomes in children with severe hemophilia A. Whether intragenic deletion location further stratifies ITI outcomes remains unclear.

OBJECTIVES

To evaluate the association between the location of F8 large deletion and ITI outcome in children with severe hemophilia A and to exploratorily assess residual F8 expression across patients with different deletion locations.

METHODS

This single-center, retrospective cohort included 34 children with severe hemophilia A, F8 large deletions, inhibitors, and evaluable ITI outcomes. Deletions were mapped to factor VIII (FVIII) domains and categorized as isolated A1-domain or nonisolated A1-domain deletions. Exploratory F8 mRNA and protein analyses were performed in patients with available blood samples.

RESULTS

Thirteen patients achieved ITI success or partial success, and 21 experienced ITI failure. Success or partial success was more frequent with isolated A1-domain than nonisolated A1-domain deletions (8/9 vs 5/25; P < .001). Higher historical peak, pre-ITI, and on-ITI peak inhibitor titers were associated with failure in univariate analyses. After multivariable adjustment, isolated A1-domain deletion remained associated with higher odds of success or partial success (adjusted odds ratio, 21.59; 95% confidence interval, 1.24-375.60; P = .035). Residual downstream F8 transcripts were detected in the isolated A1-domain subgroup; their biological relevance remains uncertain.

CONCLUSIONS

Intragenic location of F8 large deletions was associated with ITI outcome in this cohort. Isolated A1-domain deletions may identify patients with a more favorable ITI prognosis. Exploratory expression findings require confirmation in larger studies using physiologically relevant models.