PB1273 - Inhibitor Recurrence on Emicizumab Prophylaxis in Tolerized Patients with Severe Hemophilia A

Background: Emicizumab, a non-factor therapy (NFT), is a highly effective hemostatic treatment for hemophilia A patients. However, in patients tolerized to factor-VIII (FVIII), concern of inhibitor recurrence when initiating NFT exists.

Aims: To report our inhibitor monitoring observations in two tolerized patients and experience with different approaches to tolerance maintenance after NFT initiation.

Methods: FVIII inhibitor titers were measured prior to commencement of emicizumab, then repeated monthly in the first 3 months, then every 3-6 months afterwards (July 2020 – December 2022). Inhibitor titers were measured by Nijmegen modified Bethesda assay using chromogenic reagents and results were extracted from the patients’ electronic medical records.

Results: Inhibitor monitoring in two tolerized patients (Table 1) revealed recurrence of FVIII inhibitors. The patient with partial success of immune tolerance induction (ITI) (Bethesda negative, normal FVIII recovery for about 3 years, FVIII half-life of 4-5h) had a recurrence 2 months after initiating NFT, without regular FVIII exposure to maintain tolerance, however, with 4 exposure days of plasma-derived FVIII for a bleeding event. The patient with complete success of ITI had a recurrence 10 months after initiating NFT, with regular exposure to recombinant-factor-VIII (rFVIII). Both patients showed low-titer inhibitor recurrence during 20-month follow-up (Table 2). After 28-month follow-up, the successfully tolerized patient had negative inhibitor titer (confirmed in two samples) with concomitant administration of rFVIII and emicizumab. The presence of inhibitors was not associated with any bleeding requiring hemostatic therapy in both patients.

Conclusion(s): Transition from FVIII therapy to NFT presents a challenge in maintaining tolerance to FVIII. Our observations concur with the consensus protocols suggesting that concomitant use of FVIII with emicizumab are potentially advantageous in maintaining tolerance during the transition. Nevertheless, reports suggest that emicizumab alone is safe and inhibitor-recurrence-free. Further research in needed to evaluate inhibitor recurrence and the best approach for maintaining tolerance in the long-term.