Impaired tolerance in the International Immune Tolerance Induction study due to the presence of very low-titer inhibitors.

BACKGROUND

In persons with hemophilia A (pwHA), development of an inhibitor complicates treatment with factor (F)VIII replacement therapy. Immune tolerance induction (ITI) is used to restore tolerance. However, some pwHA do not reach tolerance despite disappearance of the inhibitor detected with the Nijmegen-modified Bethesda assay (NBA), potentially due to the persistent presence of very low-titer inhibitors.

OBJECTIVES

We determined the presence of very low-titer inhibitors with the Nijmegen ultrasensitive Bethesda assay (NusBA) in the International-ITI study.

METHODS

This study included 115 pwHA with inhibitors (pwHAI). In 53 of these participants, both NBA and NusBA were determined from the same sample measured at 175 time points. Both FVIII half-life and recovery were correlated with NBA and NusBA results, which were used to plot receiver operating characteristic curves, as 50 of 175 concurrent measurements included pharmacokinetic analysis.

RESULTS

NusBA had a stronger correlation with FVIII half-life (r = -.56; 95% CI, -.80 to -.20; P = .004) than NBA (r = -.36; 95% CI, -.67 to -.06; P = .008). Also, the area under the curve of the NusBA (0.79; 95% CI, 0.59-0.98) was higher than the area under the curve of the NBA (0.64; 95% CI, 0.40-0.87), with FVIII half-life of ≥7 hours, indicating tolerance. The NBA was unable to detect very low-titer inhibitor levels in pwHAI with a decreased FVIII half-life. Post-ITI, a positive NusBA was detected in 66% of all samples, which is in contrast to the 42% NBA-positive samples.

CONCLUSION

The NusBA can detect very low-titer inhibitors and correlates with FVIII half-life in the early post-ITI period. The NusBA has added value in pwHAI undergoing ITI to monitor tolerance.