Cyclophosphamide Efficacy and Toxicities in the First Line Treatment of Acquired Hemophilia

Background: Acquired hemophilia is a rare bleeding disorder caused by antibodies against factor VIII. Patients without a personal or family history of coagulopathy may present with significant bleeding symptoms, often later in life. Acquired hemophilia has been associated with pregnancy, malignancy, and autoimmune disorders, but in approximately 50% of cases no clear etiology is identified. The two goals of treatment include control of bleeding and eradication of the antibody. Current recommendations based on data from large registries suggest that cyclophosphamide and high-dose steroids should be the first-line treatment of acquired hemophilia.

The objective of our study was to describe our experience with cyclophosphamide and steroids for the initial treatment of acquired hemophilia.

Methods: We conducted a retrospective chart review of patients with acquired hemophilia presenting to an urban tertiary referral center over 12 months. Data included gender, age, comorbidities, symptoms, factor VIII activity, and Bethesda Unit inhibitor titers (BU) at presentation. We documented the type of agents administered to control bleeding. We recorded type, dosing, duration and complications of immunosuppressive treatments. Complete blood counts, factor VIII activity, and inhibitor titers were checked weekly at clinic visits. Goals of immunosuppression treatment were the resolution of bleeding symptoms, factor VIII activity >50%, and a BU titer < 1.

Results: We identified six patients with acquired hemophilia (2 males, 4 females). The median age was 78.5 years, range 51-94. Four patients presented with muscular hematomas of the extremities, one with diffuse bruising, and one with a lower intestinal bleed. One patient had HIV and was on anti-retroviral therapy, one patient had advanced breast cancer, and four patients had no significant co-morbidities. Five of 6 patients had undetectable factor VIII activity by one-stage chromogenic activity assay (<1%), one patient presented with Factor VIII activity of 18%. The median BU titer was 57.5 (range 3.1-691). One of five patients had a low titer BU < 5.

Five out of 6 patients received FEIBA for control of acute bleeding at diagnosis, one patient did not require hemostatic agents because bleeding was judged to be minor. Five of six patients were treated with daily oral cyclophosphamide at a median dose of 1.94 mg/kg (range 1.4-2.6 mg/kg) and prednisone at 1mg/kg. One patient received six doses of rituximab followed by cyclophosphamide. Compliance and side effects from oral cyclophosphamide and steroid treatments were assessed at weekly visits. Steroids were tapered based on clinician judgment. The median time to a factor VIII > 50% and to a BU titer <1 were 38.5 days (range 19-87) and 51.5 days (range 19-92) respectively. Four of six patients required dose reduction or interruption of cyclophosphamide for neutropenia (ANC < 1000; n=3) or lymphopenia (CD4 count <100; n=1). The median time to cytopenias requiring dose reduction was 48.5 days (range 43-50 ). Two patients with neutropenia presented to the ED with fevers and required GCSF for neutropenia.

Conclusions: Weight-based oral cyclophosphamide with steroids resulted in remission of acquired hemophilia in 4 of 6 patients. Factor VIII recovery occurred within two weeks, inhibitor eradication took twice as long and usually disappeared around the time of the development of febrile neutropenia. Our case series underscores the need for caution with cyclophosphamide in older patients. Given the risk of infection and sepsis from immunosuppression in this older population, regular clinical monitoring including weekly CBCs and cyclophosphamide dose reduction may be required. Additional first-line therapies should be explored in this older population in well-designed multicenter clinical trials.