Usefulness of Emicizumab Associated with Immune Tolerance Induction in Patient with Hemophilia a and Inhibitors: Experience in Cuenca-Ecuador

Background: Referring to the World Federation of Hemophilia (WFH) 2020 Annual Global Survey Report published in October 2021: In Ecuador, with a population of 17,643,060 inhabitants, there are 1,708 cases of hemophilia, 99 cases of Von Willebrand disease, and 7 cases of other coagulation disorders. Within the hemophilia A group, 21 patients have active inhibitors, and there is a record of 2 new cases of inhibitors in relation to the previous notification.

Emicizumab is a bispecific, humanized monoclonal antibody that binds activated FIX and factor X (FX) resulting in the generation of activated FX (FXa) which then catalyzes the formation of thrombin from prothrombin.

Based on the HAVEN 1-4 clinical trials, the FDA and EMA approved the use of Emicizumab as prophylaxis in Hemophilia A (with and without inhibitors) in both adults/adolescents (>12 years) and pediatrics (<12 years). In both the primary analyzes and long-term follow-up, emicizumab produced statistically and clinically significant reductions in annual bleeding rates compared with Factor VIII prophylaxis (in patients without inhibitors); and with bypassing agents (in patients with inhibitors). These trials excluded patients in immune tolerance (ITI).

Keywords: emicizumab, immune tolerance, hemophilia.

Objectives: -Assess the usefulness of Emicizumab in immune tolerance in terms of bleeding control, osteoarticular health and functional activity

Materials and Methods: 1) The evaluation was carried out in a 9-year-old patient (boy) with severe Hemophilia A and high titer inhibitors who, prior to the start of ITI, had predictive factors of high risk and poor prognosis (historical peak 234 UB, 5 years since inhibitor screening) with 4-8 joint bleeds per year. The ITI scheme used was with plasmatic Factor VIII 100 IU/Kg 3 times a week with management with bypass agents on demand (ITI duration: 3 years) and inclusion of emicizumab 2 years after starting the strategy

2) The analysis was determined based on periodic clinical evaluations, osteoarticular status was assessed through the Hemophilia Joint Health Score 2.1 (HJHS), Disease Activity Score (DAS28); and functional activity through Functional Independence Score in Hemophilia (FISH), and Health Assessment Questionnaire (HAQ). An analysis was made prior to the start of immune tolerance and after reaching immunological tolerance.

Results: 1) This strategy contributed to better control of joint bleeding, and therefore to the inhibitor eradication process.

2) Improved the evolutionary course of his osteoarticular state:

- Prior to ITI: DAS28: 4.26 (moderate activity), HJHS 33. Target joints: left knee and ankle.

- After immunological tolerance: DAS28: 1.87 (clinical remission), HJHS 12.

3) Favorable progression of his functional status, despite slight limitation of his left knee in flexion (sequel to recurrent episodes of hemarthrosis):

- Prior to the start of ITI: FISH 14, HAQ: 1.50 (severely affected functional capacity), functional scale IV (use of a wheelchair).

- After immunological tolerance: FISH 27, HAQ: 1.00, functional scale II (able to carry out activities of daily living with slight difficulty).

Conclusions: 1) Larger-scale studies and accumulated evidence are needed that allow us to establish the usefulness of Emicizumab in ITI and therefore corroborate these results.

2) We must establish the best clinical application profile and the economic impact of these therapies; especially in health systems like ours, in which accessibility to drugs is complex and optimization of resources is the norm.

Bibliography: 1. Alvarez Roman M: Guías Españolas para el manejo de la hemophilia. 2022, 1-190.

2. Callaghan M, Negrier C, Paz-Priel I, Chang T, Chebon S y col: Long-term outcomes with emicizumab prophylaxis for hemophilia A with or without FVIII inhibitors from the HAVEN 1-4 studies. 2021;137(16):2231-2242

3. Carcao M, Escurriola C, Santagostina E, Oldenburg J, Liesner R y col: The changing face of immune tolerance induction 3. Hematology Am Soc Hematol Educ Program. 2021, Dec 10;2021(1):219-225.

4. Young G: Management of children with hemophilia A: How emicizumab has changed the landscape. Journal of Thrombosis and Haemostasis. 2021 Jul;19(7):1629-1637

No relevant conflicts of interest to declare.

Emicizumab associated with immunotolerance in patients with Hemophilia A and Inhibitors