Rituximab for the Treatment of High Titer Acquired Factor VIII Inhibitors Refractory to Conventional Chemotherapy.

Acquired factor VIII inhibitors are a rare cause of serious bleeding which are associated with a high mortality rate. Individuals with high titer antibodies (>100 Bethesda units) often have difficulty achieving a complete sustained remission and although different treatment strategies have been advocated for these patients, no approach has been well defined. Rituximab is a monoclonal antibody targeting the CD20 antigen on B lymphocytes which has demonstrated efficacy in the treatment of a variety of immune-mediated hematologic diseases including patients with acquired factor VIII inhibitors. However, there is limited data in patients with high titer inhibitor antibodies. In this study, we prospectively studied 4 patients with acquired high titer factor VIII inhibitors who have had long-term follow up. All patients were resistant to initial therapy with cyclophosphamide, vincristine, and prednisone. The patients ranged from 40 to 71 years of age and three of the four were women. The male patient had an associated autoimmune disease but the other patients were thought to have an idiopathic inhibitor. The patient’s inhibitor titers ranged from 249 BU to 836 BU at the time of treatment with rituximab and all received 4 weekly infusions of rituximab at 375 mg/kg. No significant treatment-related complications were noted. Each patient initially responded to rituximab therapy with a decline in inhibitor titer. Subsequently, three of the four patients relapsed. The relapses occurred 4, 8 and 15 months following rituximab therapy and were associated with an elevation in inhibitor titers and clinically significant bleeding in all 3 patients. The individual who did not relapse achieved a partial response with a decline in her inhibitor titer from 836 BU to 5 BU over 13 months and then died of causes unrelated to her coagulopathy. After control of the clinical bleeding, the three remaining patients received an additional course of rituximab with responses observed in all patients. One patient has been in a sustained remission for 19 months following the second dose of rituximab. A second patient had a notable improvement in his inhibitor titers from 418 BU to 10 BU over 9 months after the second dose. The third patient continues to have high inhibitor titers with intermittent bleeding following the additional dose. We conclude that in patients with acquired high titer acquired factor VIII inhibitors, treatment with rituximab alone results in improvement of inhibitor titers but is not sufficient to achieve a sustained response. Rituximab in combination with other therapies may provide a better result in this high risk population.