Factor VIII inhibitors in hemophilia A treated with emicizumab: longitudinal follow-up of outcomes

Sarina Levy-Mendelovich; Nitzan Atia; Ivan Budnik; Assaf Arie Barg; Einat Avishai; Omri Cohen; Tami Brutman-Barazani; Tami Livnat; Gili Kenet

doi:10.1016/j.rpth.2023.100278

Factor VIII inhibitors in hemophilia A treated with emicizumab: longitudinal follow-up of outcomes

Res Pract Thromb Haemost. 2023 Jun 14;7(4):100278. doi: 10.1016/j.rpth.2023.100278. eCollection 2023 May.

Authors

Sarina Levy-Mendelovich^{1

2

3}, Nitzan Atia^{1

2}, Ivan Budnik⁴, Assaf Arie Barg^{1

2}, Einat Avishai^{1

2}, Omri Cohen^{1

2}, Tami Brutman-Barazani^{1

2}, Tami Livnat^{1

2}, Gili Kenet^{1

2}

Affiliations

¹ National Hemophilia Center and Coagulation Unit, Sheba Medical Center, Tel Hashomer, Israel.
² Amalia Biron Research Institute of Thrombosis and Hemostasis, Sheba Medical Center, Tel Hashomer and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
³ The Sheba Talpiot Medical Leadership Program, Sheba Medical Center, Tel Hashomer, Israel.
⁴ Department of Internal Medicine, Division of Hematology/Oncology, University of Iowa, Iowa City, Iowa, USA.

Abstract

Background: Using emicizumab in lieu of immune tolerance induction (ITI) for patients with hemophilia A (HA) and factor (F)VIII inhibitors has been well described. However, decisions regarding ITI initiation, regimen, and preservation of tolerance remain to be elucidated.

Objectives: To study the course of FVIII inhibitors in patients with HA and a history of FVIII inhibitors receiving emicizumab prophylaxis.

Methods: Patients with HA, with and without FVIII inhibitors, initiating emicizumab prophylaxis were prospectively followed up in our center. All patients with current or previous inhibitors were included in this analysis. Plasma samples for FVIII inhibitor assays were obtained every 3 to 6 months or following FVIII exposure. Patients documented annual bleeding rate and any FVIII exposure days (EDs).

Results: Of 162 emicizumab-treated participants, 51 met the inclusion criteria. A decrease in annual bleeding rate was observed in all 51 participants followed up for a median of 3.3 years, with 31 breakthrough bleeding episodes reported in 22 of 51 participants. FVIII inhibitor level transiently increased following FVIII exposures in 5 of 15 failed ITI participants. Eight of 21 participants who did not undergo ITI were exposed to FVIII (1-2 EDs)), and 1 of these 8 participants demonstrated increased FVIII inhibitor levels after head trauma (following 1 ED). Among participants who underwent successful ITI, 8 of 15 patients were exposed to FVIII over a total of 13 EDs (1-2 ED(s) each) for traumatic breakthrough bleeds. In all these participants, inhibitor levels remained zero, indicating successful tolerance maintenance.

Conclusion: Our longitudinal follow-up of emicizumab-treated patients with HA and FVIII inhibitors shows that occasional exposure to FVIII may induce a transient anamnestic response. Nonetheless, no FVIII inhibitor recurrence was noted following FVIII exposures in patients who underwent successful ITI.

Keywords: FVIII; FVIII inhibitor; emicizumab; hemophilia A; immune tolerance induction.