Combined anti-CD20 and mTOR inhibition with factor VIII for immune tolerance induction in hemophilia A patients with refractory inhibitors.

BACKGROUND

Hemophilia A (HA) inhibitor patients that fail traditional immune tolerance induction (ITI) have increased morbidity and mortality. Preclinical studies support factor VIII (FVIII) tolerance induction with a combined approach of anti-CD20 mediated transient B cell depletion and rapamycin mediated regulatory T cell (Treg) induction.

METHODS

Two refractory HA inhibitor patients were treated with rituximab, rapamycin, and FVIII ITI. Their clinical course, anti-FVIII immunoglobulins, cytokines, and select lymphocytes were followed.

RESULTS

One patient achieved complete and the other partial FVIII tolerance; both had marked annualized bleeding rate improvement. FVIII-specific immunoglobulins, but not total Treg counts, correlated with tolerance induction. IL-6 and IL-21 correlation with complete tolerance induction may support that down-regulation of T effectors and IgG4 production, respectively, contribute to the pathogenesis of tolerance induction.

CONCLUSIONS

This regimen may be considered to induce FVIII tolerance in HA patients with refractory inhibitors. Further characterization of the FVIII-specific immune response is necessary to clarify the mechanism of immune tolerance.