In children with severe hemophilia A (SHA) with high-titer inhibitors, the type of F8 mutation is a key predictor of the success of low-dose immune tolerance induction (ITI) and the time to success, according to the results of a single-center, retrospective cohort study published in the journal Research & Practice in Thrombosis & Haemostasis.

To date, no study has explored the role played by F8 mutation in outcomes among individuals with SHA treated with low-dose ITI. It is well known that inhibitors against coagulation factor VIII typically develop in 25%-35% of those with SHA in the first 50 exposure days, with these individuals experiencing a higher risk for disability, worse quality of life, and higher rates of death compared with those without developing inhibitors.

The current study was conducted on children with SHA and high-titer inhibitors who were admitted between January 2015 and May 2022 to Beijing Children’s Hospital in China. Study inclusion criteria were (1) established diagnosis of SHA, (2) aged less than14 years, (3) inhibitor titers of at least 5 BU/mL on at least 1 occasion, (4) receiving a low-dose ITI regimen alone or with immunosuppressants for longer than 1 year, and (5) having undergone F8 gene analysis.


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Based on risk for inhibitors, F8 mutations were classified into a high-risk group or a non–high-risk group. Rapid tolerance and final ITI outcomes were evaluated at 12 months and 24 months of treatment, respectively, and outcome predictors were examined.

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A total of 104 unrelated children with SHA and high-titer inhibitors were enrolled in the current study with 101 having F8 mutations detected. All of the participants received ITI therapy at a median age of 3.2 years, which followed a median interval time of 5.3 months from inhibitor diagnosis. Of them, 60 patients received the ITI plus immunosuppressant regimen. 

Study results showed that those participants with non-high-risk mutations exhibited a significantly higher rate of rapid tolerance compared with those with high-risk mutations (61.0% vs 29.2%; P =.006). Among 72 children who were beyond 24 months of receiving ITI, 55 attained success, 3 achieved partial success, and 14 failed. Participants in the non–high-risk arm demonstrated a significantly higher success rate than those in the high-risk arm (86.8% vs 43.8%; P =.001) and a significantly shorter time to achieving success (mean time, 9.3 months vs 13.2 months; P =.04).

Per multivariable regression, the presence of F8 mutations was an independent predictor of ITI success (non-high-risk group vs high-risk group: adjusted odds ratio [aOR], 20.3; 95% CI, 3.5 to 117.8), as was the interval from inhibitor diagnosis to initiation of ITI (aOR, 0.95; 95% CI, 0.90 to 0.99).

The investigators concluded that “This study provided a solid context for future research, which can combine F8 genotyping with clinical predictors to develop tools . . . that can identify high-risk patients with poor prognosis to optimize clinical choices.”

Reference

Sun J, Li Z, Li G, et al. Low-dose immune tolerance induction in children with severe hemophilia A with high-titer inhibitors: type of factor 8 mutation and outcomes. Res Pract Thromb Haemost. Published online October 26, 2022. doi:10.1002/rth2.12824