Factor VIII Gene Variants Predict Immune Tolerance Induction Outcomes

In patients with severe hemophilia A with high-responding inhibitors, large deletions in the factor VIII (FVIII) gene (F8) were shown to be independent predictors of immune tolerance induction (ITI) therapy failure. Conversely, inversion of intron 22 type 2 (Inv22-2) was “likely to be a predictor of successful ITI,” according to retrospective analysis presented at the 65th American Society of Hematology Annual Meeting & Exhibition in San Diego, California.

“We found a correspondence between variants classified as high-risk and intermediate-risk to inhibitor development with ITI failure and success, respectively,” summarized lead author, Luciana Zuccherato, PhD, from the Universidade Federal de Minas Gerais in Belo Horizonte, Brazil.

The study’s authors enrolled 158 patients with severe and moderately-severe hemophilia A and high-responding inhibitors who completed ITI therapy in the HEMFIL and BrazIT studies. The cohort had a median age of 6.6 years at time of ITI therapy, and 90.5% were classified as severe.

Investigators used polymerase chain reaction and high-throughput sequencing to assess Inv22 and F8 variants, respectively. Associations between pathogenic variants of F8 and ITI therapy outcomes were adjusted for inhibitor levels.

According to the data, Inv22 was the most prevalent F8 variant at 55.1%. Compared with patients with Inv22 type 1, those with large F8 deletions had a nine-fold increased risk of ITI therapy failure (adjusted odds ratio [aOR], 9.29; 95% CI, 1.95-53.70). Patients with Inv22-2 were associated with favorable ITI therapy outcomes in both univariate (OR, 0.15; 95% CI, 0.01-0.84) and adjusted analysis (aOR, 0.32; 95% CI, 0.02-1.96)

Dr. Zuccherato also reported that F8 variants associated with inhibitor development that previous studies categorized as high- and intermediate-risk corresponded with ITI therapy failure and success, respectively.

Ultimately, “we suggest that F8 genotyping should be considered before indication of ITI, as ITI outcome can vary according to individual variant burden,” the study’s authors suggested.

Reference

Zuccherato LW, Souza RP, Camelo RM, et al. Large deletion in the factor VIII gene is a predictor of immune tolerance induction failure in people with severe and moderately-severe hemophilia A and high-responding inhibitors. Abstract #1245. Presented at the 65th ASH Annual Meeting & Exposition; December 9-12, 2023; San Diego, California.