Background

Acquired hemophilia A is a rare bleeding disorder caused by autoantibodies that inhibit coagulation factor VIII (FVIII). The disorder is understudied given its rarity and there are no randomized prospective trials to guide therapy. In practice, treatment involves attaining hemostasis and eliminating the FVIII inhibitor, typically with high-dose steroids (1 mg/kg daily) and either cyclophosphamide or rituximab. However, current approaches carry risk of significant adverse events and delayed or inadequate responses. Emicizumab is a bispecific antibody that targets coagulation factors IXa and X to recapitulate the function of endogenous FVIII. We present a case series of patients with acquired hemophilia A who were successfully treated with a regimen consisting of rituximab and emicizumab.

Methods

We identified patients >18 years who were diagnosed with acquired hemophilia A and received treatment with rituximab and emicizumab at Brigham and Women's Hospital between 2019 and 2020. We performed a retrospective chart review. Data collected included the patients' clinical presentation, laboratory studies (including coagulation testing, FVIII activity, and FVIII inhibitor titer), and treatments received (including systemic therapies, recombinant factor VIIa [rFVIIa], red blood cell [RBC] transfusions, and vascular embolization). We recorded the time to normalization of the activated partial thromboplastin time (aPTT) and chromogenic FVIII activity following emicizumab and rituximab initiation, respectively. Activated prothrombin complex concentrate was avoided given the use of emicizumab.

Results

We identified 8 patients with acquired hemophilia A who received treatment with emicizumab and rituximab. The median patient age was 81 (range 47-93). All patients sought medical attention for extensive ecchymoses or bleeding and were found to have prolonged aPTT leading to FVIII inhibitor identification (Table 1). The median inhibitor titer was 18 Bethesda units (range 9.2-107.5). Patients concurrently received 4 weekly doses of rituximab 375mg/m2 and 4 weekly loading doses of emicizumab 3mg/kg. Patient (Pt) #1 continued emicizumab 3mg/kg every two weeks to complete three months of treatment. Pts #2, #3, and #8 received high-dose prednisone (1mg/kg) at the start of treatment for a range of 10-14 days. Pt #8 received 7 additional days of prednisone for an initial aPTT of 60.7 seconds before starting emicizumab and rituximab; she had no clinical response when treated with prednisone alone. Pts #2, #5, and #7 required vascular embolization. 7 patients (Pts #2 through #8) had aPTT retested within 1 week of starting emicizumab, and the aPTT for these patients normalized within 10 days of starting emicizumab (i.e. after only 1-2 doses; Figure 1). Except for Pt #5 who had recurrent hematuria from a persistent anatomic bladder defect that eventually required prostatic artery embolization, patients did not require rFVIIa or RBC transfusions for more than 7 days after starting emicizumab. Except for Pt #5 who required 28 doses of rFVIIa and 3 units of RBC transfusions after starting emicizumab, the median number of rFVIIa doses and RBC units given to the remaining 7 patients was zero (range 0-6 doses) and zero (range 0-4 units), respectively. Pts #2 and #3 had chromogenic FVIII levels obtained >30 days after starting rituximab with improvement in FVIII activity to 29% (day 71) and 86% (day 91), respectively. During a median follow-up of 102 days, no patients experienced recurrent bleeding. However, Pt #3 exhibited a slowly increasing aPTT that reached 46.3 seconds on day 233 of follow-up without symptoms; further diagnostic testing is pending.

Conclusion

Our case series demonstrates that the combination of rituximab and emicizumab can be an effective and safe regimen for the treatment of acquired hemophilia A. No thrombotic events or thrombotic microangiopathy occurred. Treatment with weekly emicizumab led to aPTT normalization after 1-2 doses and facilitated hemostasis, as reflected by a median usage of zero rFVIIA doses and zero RBC transfusions after starting emicizumab when excluding one patient with hematuria from an anatomic defect. This compares favorably to historical reports. While no patient has had recurrent bleeding, additional chromogenic FVIII activity testing for patients is needed to confirm long-term normalization of FVIII activity.

Disclosures

Gibson:Ampressa therapeutics: Current equity holder in private company; nference: Consultancy, Current equity holder in private company; ImmPACT-Bio: Consultancy; Boston Clinical Research Institute: Consultancy. Parnes:Bayer: Consultancy; I-Mab: Consultancy; Sunovion: Consultancy; UniQure: Consultancy; Sigilon: Consultancy; Shire/Takeda: Consultancy, Research Funding; Genentech: Research Funding; Geron: Current equity holder in publicly-traded company.

OffLabel Disclosure:

Emicizumab is used off-label in our case series for the treatment of acquired hemophilia A.

Author notes

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Asterisk with author names denotes non-ASH members.