Single‐center experience with rituximab as first‐line immunosuppression for acquired hemophilia

Acquired hemophilia (AH) is a rare, life-threatening bleeding disorder with an estimated incidence of 1.48 patients per million per year and a median age at presentation of 78 years [1]. It is caused by the development of autoantibodies directed against coagulation factor VIII (FVIII), with resultant low FVIII activity levels [2]. AH has a significant mortality rate that has been estimated to be between 8% and 22%, and approximately 90% of patients experience severe bleeding episodes [3,4]. Although the majority of cases of AH are felt to be idiopathic, up to 50% of cases are associated with underlying conditions such as autoimmune disorders, the postpartum state, current or past malignancy, infection, or certain medications [2]. Inhibitors may spontaneously remit or may resolve following treatment of the underlying condition [3,5]. Athough spontaneous remissions may occur in patients with AH, it is generally accepted that patients should be treated with immunosuppression to reduce the length of time for which they are at risk for severe bleeding. The use of corticosteroids has been associated with inhibitor resolution in 30–70% of patients, and when they are added to cyclophosphamide, the remission rate approaches 60–80% [1,6]. Chronic use of corticosteroids is often associated with significant adverse affects. Our experience, as well as that described by Collins et al. [1], suggests that this iatrogenic toxicity in a typically elderly population has previously been underestimated in the literature. This impression led us to consider other, potentially less toxic, immunosuppressive therapies for these patients. Rituximab has been reported in the successful treatment of various non-neoplastic immunologic disorders, including AH, where its use has recently been reviewed [7]. However, in many of these case series, rituximab was used in combination with corticosteroids or as a second or later line of therapy. Since August 2005, we have chosen to use rituximab as a single firstline agent in all patients presenting with AH requiring inhibitor eradication. Steroids are not routinely employed, but additional immunosuppressive agents are added when the FVIII inhibitor titer is not felt to be responding adequately, and are instituted at the treating provider s discretion. This was typically performed if the Bethesda Units (BU) titer did not decline significantly within 4–8 weeks of initiation of rituximab. We identified all patients seen at the University of North Carolina for AH from August 2005 through January 2011. Complete remission (CR) was defined as FVIII:C > 70 IU dL or undetectable FVIII inhibitor titer (< 0.4 BU mL). Rituximab was administered intravenously at a dose of 375 mg m weekly for four consecutive weeks (days 1, 8, 15 and 22) upon laboratory confirmation of AH. If corticosteroid therapy had already been instituted prior to transfer to our facility, it was rapidly tapered once rituximab was initiated. This single-center experience includes data on 22 patients (see Table 1 for patient details, including available outcome data). One patient was lost to follow-up after initial hospitalization. Six additional patients died during their initial hospitalization or were discharged to hospices (see Table 1 for details related to death/hospice transfer); five of the six had been started on immunosuppression. Four of these patients had been started on prednisone prior to transfer, andwere therefore treated with both rituximab and prednisone. None of these patients completed all four infusions of rituximab. There were no statistically significant differences between these groups with regard to baseline FVIII levels or FVIII inhibitor titers. Thus, 15 patients were evaluable for response to an initial immunosuppressive regimen. Of these, 12 received rituximab as a single agent, and three received a combination of rituximab and corticosteroids (initiated prior to referral). Of the 12 individuals who received rituximab alone, seven achieved CR, and one achieved partial remission ( PR) with resolution of bleeding symptoms. The remaining four patients required additional immunosuppressive agents to achieve CR. The following associated conditions were noted: infection (8%), past malignancy (12%), active or suspected malignancy (24%), autoimmune disorder (20%), postpartum (4%), and idiopathic (32%). Those patients who achieved CR or PR on rituximab alone had a median baseline FVIII inhibitor titer of 22 BU mL (range 1–163, interquartile range [IQR] 5–113), whereas those who achieved CR with multiple lines of therapy had a median Correspondence: Alice D. Ma, Harold R. Roberts Comprehensive Hemophilia Treatment Center, Division of Hematology/Oncology, Department of Medicine, University of North Carolina at Chapel Hill, Physicians Office Building 3rd Floor CB# 7305, 170 Manning Drive, Chapel Hill, NC 27599-7305, USA. Tel. : +1 919 843 9779; fax: +1 919 966 6735. E-mail: alice_ma@med.unc. edu