LOW-DOSE IMMUNE TOLERANCE INDUCTION WITH EMICIZUMAB PROPHYLAXIS IN HEMOPHILIA A PATIENTS WITH HIGH-TITER INHIBITORS: PRELIMINARY RESULTS FROM THE BRAZILIAN EXPERIENCE

Abstract

Background: Hemophilia A (HA) treatment primarily involves factor VIII (FVIII) replacement therapy, but the development of inhibitors hampers management and leads to increased morbidity and mortality. Immune tolerance induction (ITI) is employed to restore the effectiveness of FVIII, although the process is lengthy, costly, and its success rate is variable. Combining ITI with emicizumab prophylaxis could potentially shorten the duration of ITI, reduce bleeding rates, and improve both cost-effectiveness and quality of life for patients. This study aims to evaluate the safety and efficacy of this combination therapy in HA patients who have developed high-titer inhibitors. Aims: This prospective study describes the efficacy of low-dose ITI combined with emicizumab prophylaxis. Methods: Ten severe HA patients with high-responding inhibitors and no prior ITI were included in the study. Following a 4-week loading dose of emicizumab (3 mg/kg), patients received low-dose ITI, consisting of FVIII at 50 IU/kg three times per week, along with a maintenance dose of emicizumab at 1.5 mg/kg weekly. Once tolerance was achieved, patients continued on emicizumab prophylaxis for an additional year, with the FVIII dose reduced to 25 IU/kg once weekly. Results: Ten participants, including nine children, were enrolled in the study between August 2021 and February 2023. The mean age at the start of immune tolerance induction (ITI) was 3.2-years (range 1.1‒30.7-years). The median historical peak inhibitor level before ITI was 49 Bethesda Units (BU) (IQR 19.9‒117.2). At the initiation of ITI, the median inhibitor titer was 2.8 BU (IQR 1.4‒11.5), with 70% of patients having titers below 10 BU. Central venous catheter implantation was required in three cases. Seven patients were on prophylaxis with bypassing agents before ITI. Six patients (60%) achieved complete ITI success within a median of 33-weeks (IQR 21.7‒56). Three patients (30%) did not achieve ITI success, and one remained on ongoing ITI with a low-titer inhibitor. Among those who achieved ITI success, the median time to becoming inhibitor-negative was 20-weeks (IQR 4‒47), which was significantly shorter compared to a cohort of 11 historical pediatric patients from the same center who underwent a first low-dose ITI attempt, requiring a median of 72-weeks (IQR 32‒147) to become inhibitor-negative (p = 0.03). All patients who achieved complete success remained inhibitor-negative up to 10-months post-success. The study also observed a significant reduction in the median Annual Bleeding Rate (ABR), which dropped to 0 (range 0‒2) compared to 4 (range 2‒28) during the 12-months preceding ITI (p = 0.003). Additionally, the median annual joint bleeding rate (AJBR) decreased to 0 (range 0‒0) from 1 (range 0‒14) before ITI (p = 0.03). Conclusions: Preliminary findings from this prospective ITI protocol combined with emicizumab prophylaxis demonstrate promising outcomes. Notably, 60% of patients met success criteria within 56-weeks of the first ITI attempt. As expected, emicizumab prophylaxis was significantly associated with reduced bleeding episodes. Additionally, we observed early inhibitor negativity with emicizumab compared to historical first-attempt low-dose ITI in pediatric patients.