Emicizumab for the Treatment of Acquired Hemophilia_A: Lessons Learned from 4 Very Different Cases
Authors: Knoebl Paul , Sperr Wolfgang R. , Schellongowski Peter , Staudinger Thomas , Jilma-Stohlawetz Petra , Quehenberger Peter , Koder Silvia , Ay Cihan , Gleixner Karoline V. 
Published: October 2019

Abstract
Acquired hemophilia A (AHA) is a severe bleeding disorder caused by autoantibodies inhibiting coagulation factor VIII. For hemostatic treatment bypassing agents (recombinant activated human factor VII (rhFVIIa), activated prothrombin complex concentrates (APCC)), human or porcine FVIII concentrates are currently standard of care. Although highly effective, these options have the disadvantages of frequent iv. infusions, high costs, and some risk of thromboembolic complications. 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 and available. Preclinical data and the pathophysiological concept suggest efficacy also in AHA.
Here we report the cases of 4 patients with AHA, treated with emicizumab in an individual named patient program. All patients gave informed consent to that treatment. Mean age was 62.3 years (50-78), 2 males, 2 females. The initial FVIII activity (FVIII:C) was < 1%, the maximum inhibitor titers 54.3 BU/mL (3.1-81.6); all data given as means and range. Three patients had severe bleeding (2 after large surgery), requiring red blood cell transfusions and daily therapy with rhFVIIa prior to emicizumab therapy (mean daily dose 48 mg, range 24-72 mg per day), one patient had extensive skin hematomas and a high risk for more bleeding, but did not receive bypassing therapy. Emicizumab was given at 3 mg/kg adjusted body weight (in one severely overweight patient the dose was reduced to 60%) subcutaneously once weekly for 4 consecutive weeks, followed by 1.5 mg/kg weekly. FVIII activity monitoring was done with a chromogenic assay with reagents from human origin (FVIII:chrom).
APTT normalized 1-3 days after the first dose, FVIII:chrom exceeded 10% after 13 days (mean; range: 7-18 days). Hemostatic efficacy was obtained after 14 days (stable hemoglobin, no more blood transfusions, reduction in hematoma size), and bypassing therapy was stopped after 4 days (mean; range: 2-9 days) after the first emicizumab injection. FVIII:chrom exceeded 50%, indicating complete remission after 24 and 42 days (n=2), and emicizumab could be terminated in after 4 injections (median; range: 3-6; n=3). In the remaining patients these thresholds were not reached at the time of abstract submission). One female patient (age 80 years, severe comorbidities, major abdominal surgery) experienced minor thromboembolic stroke after the third emicizumab dose (FVIII:chrom = 10%) in association with concomitant rhFVIIa therapy for surgery. No other adverse events associated with any hemostatic therapy were observed in the other patients. All patients received immunosuppression with steroids, 3 were also treated with rituximab. The patients were discharged after 2 weeks (range 5-25 days) days after the first emicizumab injection, one patient was still in hospital at the time of abstract submission (at day 25).
In conclusion, emiczumab seems to be an effective hemostatic therapy also for AHA, which offers several advantages: subcutaneous weekly therapy, good hemostatic efficacy, possible outpatient therapy, the option to reduce the intensity of immunosuppressive therapy to avoid side effects (as the patients are protected from bleeding), and seems even to be more cost effective than bypassing agents. However, special attention is necessary on the use of appropriate lab assays (chromogenic FVIII assays), the artificial effects on APTT and Bethesda assays, the recognition of the remission, and to avoid the concomitant use of APCC. Moreover, strategies for special patients (i.e., patients with comorbidities, severe over- or underweight, after (or in need) for major surgery, concomitant risk for thromboembolism, etc.) need to be developed, and a clinical trial comparing emicizumab with the current standards of care is warranted.

Disclosures
Knoebl: Novo Nordisk: Consultancy, Honoraria; Shire: Consultancy, Honoraria. Sperr:Novartis: Honoraria; Pfizer: Honoraria; Daiichi Sankyo: Honoraria.