Emicizumab for acquired hemophilia A: Report of two cases and dosing strategies

Abstract Acquired hemophilia A (AHA) is a rare autoimmune bleeding disorder caused by autoantibodies against FVIII. Severe AHA is life‐threatening. Currently, licensed hemostatic agents for the treatment of severe AHA have short half‐lives and require intravenous administration, leading to a need for hospitalization, higher costs, and negative effects on quality of life. We present two cases of severe AHA with high inhibitor titers where emicizumab was safely and effectively used with intensive immunosuppression. These reports suggest in vivo efficacy even in high inhibitor environments. The optimal dosing regimen (accelerated vs. standard loading, maintenance frequency) is unknown and we discuss the current approaches.


INTRODUCTION
Acquired hemophilia A (AHA) is a rare acquired bleeding disorder involving the generation of autoantibodies against FVIII [1].AHA is not inherited and incidence increases with age; estimated at 1-2 cases per million [2].Patients often present with spontaneous or provoked bleeding that is cutaneous, intramuscular, or retroperitoneal in location [3].Following stabilization of initial hemorrhage, rebleeding occurs in approximately 50% of patients and this risk remains significant until near-normal FVIII levels are attained [4].Hemorrhage in AHA can be limb-, organ-, or life-threatening [5].
Standard therapy includes 1) immunosuppressive therapy (corticosteroids, rituximab, and cyclophosphamide) to suppress inhibitor formation and 2) agents for hemostasis such as recombinant activated human Factor VII (rFVIIa), activated prothrombin complex concentrate (aPCC), and recombinant porcine FVIII concentrate (rpFVIII) [6,7].These treatments are limited by short half-lives and intravenous route of administration.Both rFVIIa and aPCC require hospitalization, leading to increased cost and decreased quality of life.Some patients with AHA have cross-reactive antibodies to rpFVIII, while those who do not, often develop anti-FVIII alloantibodies with repeated rpFVIII exposure [8].
Emicizumab is a humanized, recombinant antibody with bispecific properties that mimic the role of coagulation FVIII [9].
While emicizumab has been Food and Drug Administration-licensed for use in bleeding prevention for patients with congenital Hemophilia A (CHA) with and without inhibitors, it has not been approved for use in AHA.There are emerging reports of patients with AHA who show significant clinical improvement on emicizumab; optimal dosing and activity remain unknown, especially in severe AHA [10].Here, we discuss two cases of severe AHA effectively managed with emicizumab treatment without any adverse events and complete remission without rebleeding.

Case 1
A 66-year-old Hispanic male with gout and hypertension pre-

Case 2
A 64-year-old Hispanic male with a past medical history of type 2 diabetes, chronic kidney disease, gout, and nonalcoholic steatohepatitis presented with calf pain after mild blunt trauma to the left leg.He denied any personal or family history of bleeding disorders or malignancy.On physical exam, he had significant ecchymoses on both lower extremities (Figure 1C).Hemoglobin was 5.

Treatment and monitoring
Recombinant Factor VIIa 90 mcg/kg/dose was used every 2 to 4 h to stabilize bleeding; immunosuppression was initiated using prednisone 1 mg/kg daily and cyclophosphamide 100 mg daily, continued for six weeks, with rituximab 375 mg/m 2 weekly for four doses.
Patient 1 transitioned to rpFVIII while we investigated treatment on a clinical trial; unfortunately, due to location in El Paso, TX this was not possible.Both patients decided for off-label treatment with emicizumab protocol of loading dose 3 mg/kg subcutaneously for 2-3 weekly doses followed by maintenance 1.5 mg/kg every 1 to 3 weeks adjusting frequency to maintain lowest effective FVIII activity with no breakthrough bleeding [9].During maintenance, weekly monitoring was recommended with dosing frequency: administer dose of 1.5 mg/kg for FVIII < 10%, prolong the interval for FVIII activity 10%-30%, and hold dosing at higher levels.

Outcomes
Both patients had steady recovery with no rebleeding, rehospitalization, and no adverse effects of any type.Figure 2 summarizes treatment courses.For Case

DISCUSSION
Management of severe AHA with high inhibitor titers is complex and anxiety-provoking for patients and providers.Emicizumab is a bispecific recombinant monoclonal antibody containing two different antigen-binding fragments [9].One fragment recognizes Factor IXa and the other recognizes Factor X, resulting in spatial approximation and activation of Factor X and mimicking in vivo FVIII activity [10].With a long half-life, emicizumab can be administered outpatient and has reduced the annualized bleeding rates in congenital hemophiliacs with and without inhibitors.
In 2021, Knoebl et al. reported emicizumab use for AHA in Austria [9].Our approach followed this dosing regimen as detailed above with the exception that our patients were younger with good performance status and received concurrent intensive immunosuppression.While the cases presented above had higher maximum inhibitor titers, outcomes were similar, suggesting emicizumab maintains in vivo efficacy even in high FVIII inhibitor environments.This dosing regimen is limited by sample size but appears to have excellent hemostatic activity with clinical control of bleeding, no bleeding mortality and low thromboembolic rates (Table 1).Even low emicizumab plasma concentrations therefore appear to protect from bleeding [9].
In 2023, two studies (AGEHA, Japan and GTH-AHA-EMI, Germany and Austria) were reported using emicizumab with limited or TA B L E 1 Summary of prospective studies using different emicizumab dosing and immunosuppression strategies for the treatment of acquired hemophilia A (AHA).All patients in this study were reported to have had comorbidities that prevented intensive immunosuppressive therapy.

Study
sented with spontaneous bruising, inability to walk, and unintentional weight loss.He had no personal or family history of bleeding disorders, malignancy, or autoimmune disease.A physical exam showed ecchymosis along his right arm, tracking down to the flanks, thighs, and calves.Computed tomography (CT) imaging showed intramuscular hematoma in the posterior compartment of the left thigh and active bleeding from the left inferior gluteal vessels (Figure 1A,B).Activated partial thromboplastin time (APTT) was prolonged at 70.5 s (ref: 23.3-38.6 s) and did not correct with mixing study (53.8 s).FVIII activity was undetectable at < 1%; maximum FVIII inhibitor titer was 430 BU/mL (ref: < 0.6 BU/mL) using Nijmegen-Bethesda assay.
2 g/dL with hypotension requiring vasopressor management.CT imaging demonstrated retroperitoneal hematoma tracking into the left thigh.APTT was prolonged at 52.2 s (ref: 23.3-38.6 s) and did not correct with mixing study (53.3 s).FVIII activity was undetectable at < 1% with maximum inhibitor titer 353 BU/mL.

After 3
weekly loading doses, Patient 1 began to walk independently with no new bruising and resolution of old bruising and resumed light work as an accountant.Patient 2 began emicizumab earlier without rpFVIII and rapidly improved clinically after 2 weekly loading F I G U R E 2 Factor VIII activity and inhibitor titers before, during, and after emicizumab treatment.doses.After 3 and 2 weeks respectively, both transitioned to maintenance treatment with monitoring.While on emicizumab, the Factor VIII activity chromogenic assay using bovine reagents was employed (normal range 50%-160%; Quest Diagnostics Nichols Institute, San Juan Capistrano, CA 92675).Emicizumab dose was adjusted for changes in weight of ±20%.Patients came to the infusion center with each treatment, obtaining clinical and laboratory monitoring with nursing staff, and hematology clinic follow up every 4-6 weeks.
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© 2024 The Authors.eJHaem published by British Society for Haematology and John Wiley & Sons Ltd.