Effectiveness of Monthly Low-Dose Emicizumab Prophylaxis without 4-Week Loading Doses Among Patients with Hemophilia a with and without Inhibitor: A Case Series Report

Introduction: Emicizumab is a humanized, bispecific, monoclonal antibody proven as an effective prophylaxis for patients with hemophilia A with and without inhibitor. After the weekly loading of 3 mg/kg for 4 doses followed by maintenance dose of 1.5 to 6 mg/kg at 1 to 4-week intervals, the equivalent factor VIII was maintained at approximately 15% and showed an effective prophylaxis in reducing annual bleeding rate. Due to the health care resource constraint, the dose of emicizumab was reduced to maintain the prophylaxis factor VIII at 1-3%.

Methods: The effectiveness of monthly low dose emicizumab prophylaxis without 4 loading doses was evaluated among patients with hemophilia A with and without inhibitor for at least 6 months. The bone mineral density (BMD), ultrasonography of bilateral ankle, elbow and knee as well as Hemophilia Joint Health Score (HJHS) were initially evaluated and planned to be repeated after one year treatment. The vitamin D level was determined initially, and vitamin D supplement was prescribed for 3 patients with low vitamin D levels at 13.3, 23.2 and 24.6 ng/mL. Moreover, the quality of life assessment using Hemo-QoL and CHO-KLAT was performed in 3-month intervals.

Results: Five patients without inhibitor (3 severe, 2 moderate) and 1 patient with severe hemophilia A with inhibitor enrolled in the study. They all behaved in low bleeding risk circumstances such as avoidance of contact sport. Their ages ranged from 4 to 40 years of age. The youngest boy had difficulty at peripheral venous access for regular prophylaxis while the remaining 4 patients without inhibitor experienced frequent breakthrough bleeding episodes while receiving a low dose prophylaxis at 500 to 1,000 units of factor VIII concentrate twice weekly. All refused to receive more frequent prophylaxis. For patient with inhibitor, the high inhibitor titer of 65 Bethesda units (BU) declined during the 2 years of immune tolerance induction (ITI) at the intermediate dose of 100 units/kg of extended half-life factor VIII concentrate 3 times weekly. His lowest inhibitor was at 10 BU and was documented as failed ITI. He experienced frequent bleeding at the muscles and joints for which bypassing agents could not be adequately provided.

For the baseline study, 2 patients had low BMD Z score ≤-2.0 while the remaining 4 patients had normalized BMD Z score >-2.0. The ultrasonography of bilateral ankle, elbow and knee at anterior, medial, lateral and posterior/inferior spaces revealed joint distension reflecting varying-degree synovial hypertrophy and/or bleeding component of 0-14.0, 0-9.8, 0-9.4, 0-12.8; 0-14.4, 0-17.8, 0-10.7, 0-18.6 and 0-23.8, 0-15.3, 0-17.1, 0-12.9 millimeter, respectively. Varying-degree hyperemia from the ultrasonography reflecting active inflammation of synovium was found in 4 ankles, 6 elbows and 4 knees of the total 36 joints in 4 of 6 patients. The HJHS scores ranged from 6 in the youngest patient to 56 in the patient with inhibitor. All patients except the 4-year-old boy had 1 to 3 target joints.

All the studied patients received 1 each of the whole vial of emicizumab at 30, 75, 105 mg monthly except 3 patients receiving 60 mg monthly which was equal to 1.1 to 1.6 mg/kg of emicizumab. The monthly trough levels of emicizumab determined by a modified one stage factor VIII assay using emicizumab calibrator were maintained at 3.8 to 9.8 µg/ml which were equivalent to the levels of FVIII at 1 to 3% (0.3% FVIII per µg/ml of emicizumab). The bleeding rate was markedly decreased from 4-8 episodes monthly to 0-1 episode monthly. The monthly zero bleeding rate was found among 4 patients. Moreover, the swollen target joint gradually dissolved. Their quality of life markedly improved evaluated by the Hemo-QoL and CHO-KLAT. They could attend regular school and work happily. The HJHS and ultrasonography have not been repeated yet.

Conclusion: The monthly low dose emicizumab prophylaxis of the whole vial at 1.1 to 1.6 mg/kg without loading dose could achieve emicizumab trough levels at 3.8 to 9.8 µg/ml which were equivalent to the levels of FVIII at 1 to 3%. It showed effective prophylaxis among patients with hemophilia with and without inhibitor who performed low bleeding risk activity. The 3 aspects of body functions and structures, activities and participation were gradually improved.