Emicizumab for the Treatment of Acquired Hemophilia A: Lessons Learned from 4 very Different Cases
13 February 2019 (online)
Acquired hemophilia A (AHA) is a severe bleeding disorder caused by inhibiting autoantibodies to FVIII. For hemostatic treatment bypassing agents (recombinant activated FVII (rhFVIIa), activated prothrombin complex), human or porcine FVIII are currently standard of care. Although highly effective, these need frequent iv. infusions, have high costs and some risk of thromboembolism. Emicizumab is a bispecific, FVIII-mimetic therapeutic antibody that has considerably reduced the annualized bleeding rates in congenital hemophiliacs with and without inhibitors, for the latter it is already approved. Preclinical data and pathophysiology suggest efficacy also in AHA.
Here we report on 4 patients with AHA,2 male, 2 female, age 62.3 years (50–78) (means, range), treated with emicizumab. All patients gave informed consent. The initial FVIII activity was < 1%, the max. inhibitor 54.3 BU/mL (3.1–81.6). 3 patients had severe bleeding (2 after major surgery), requiring RBC transfusions and therapy with rhFVIIa prior to emicizumab (mean dose 48 mg/d, range 24–72 mg/d), one patient had extensive skin hematomas, but did not receive bypassing therapy. Emicizumab was given at 3 mg/kg sc. weekly for 4 weeks, followed by 1.5 mg/kg weekly. For FVIII monitoring a chromogenic assay with reagents from human origin (FVIII:chr) was used.
APTT normalized 1–3 days after the first dose, FVIII:chr exceeded 10% after 13 (7–18) days. Hemostatic efficacy was obtained, bypassing therapy was stopped after 4 (2–9) days after the first emicizumab. FVIII:chr exceeded 50%, indicating complete remission, after 24 and 42 days (n = 2), and emicizumab could be stopped after 3 and 6 injections. In the remaining patients these thresholds were not reached at the time of abstract submission. One female patient (80 years, severe comorbidities, major abdominal surgery) experienced minor stroke after the third emicizumab dose (FVIII:chr 10%) in association with concomitant rhFVIIa therapy for surgery. No other adverse events associated with hemostatic therapy were observed. All patients received immunosuppression with steroids, 3 were also treated with rituximab. Patients were discharged after 2 weeks (5–30 days) after the first emicizumab injection.
In conclusion, emicizumab seems to be an effective hemostatic therapy for AHA, with several advantages: weekly sc. therapy, good hemostatic efficacy, possible outpatient therapy, option to reduce the immunosuppressive therapy to avoid side effects, and seems even to be more cost effective than bypassing agents. Special attention is needed on the use of appropriate laboratory assays, the artificial effects on APTT and Bethesda assays, the recognition of remission, and to avoid the concomitant use of APCC. Strategies for patients with comorbidities, severe over- or underweight, after, or in need for major surgery, concomitant risk of thromboembolism need to be developed, and a clinical trial comparing emicizumab with the current standards of care is warranted.