Outcomes of immune tolerance induction with rituximab to eradicate high-titer inhibitor of hemophilia A: depicted by exponential decay model and the gene expression profile of different outcomes by RNA-sequencing.

Background: Eradication of inhibitors is still a desirable goal for patients with hemophilia A inhibitors. Combining rituximab with immune tolerance induction (ITI) is the secondline regimen, but data and predictors are limited.

Objectives: To evaluate the efficacy of ITI-rituximab and to identify the predictors of prognosis.

Methods: In total, 76 children with high-titer inhibitor prospectively using low-dose ITI together with 1-3 round(s) of rituximab were evaluated for outcomes: success or failure and rapidity (rapid or slow) of inhibitor negativity (ie, inhibitor titers turned negative, inhibitor negativity [IN]). The whole-transcriptome RNA-sequencing (RNA-seq) was used to analyze the gene expression profile of 4 failure patients (excluding F8 large deletion) and 4 rapid success-IN patients.

Results: Success IN was achieved in 41 of 76 (53.9%) patients after first-round of rituximab, 50 of 76 (65.8%) after second-round of rituximab, and 51 of 76 (67.1%) after third-round of rituximab. Profile of inhibitor decay followed an exponential decay curve. Time to a given inhibitor titer during ITI-rituximab could be estimated by the model t=ln(Y0-PlateauY-Plateau)k. The newly observed poor prognostic factors included relapse after the first-round of rituximab and early occurence of poor-outcome events. RNA-seq analysis showed 186 upregulated differential expressed genes (DEGs) and 176 downregulated DEGs in failure subjects compared with those in patients with rapid success IN. The upregulated DEGs included CXCL8, NLRP6, CHI3L1, CLEC9A, THBD, and PROS1. The downregulated DEGs included STAT1, TLR7, C1Q, C2, IDO1, and CD38.

Conclusion: Success IN was achieved in 67% of children with hemophilia A with high-titer inhibitor treated by ITI-rituximab. A model based on the profile of inhibitor-titer decay can be used for predicting outcomes. Humoral immune response and complement and coagulation cascades may act as signals that influence ITI outcomes (ClinicalTrials.gov: NCT03598725).