Trial of Rituximab Versus Oral Cyclophosphamide to Eradicate or Suppress Autoimmune Anti-Factor VIII Antibodies in Acquired Hemophilia A

Inclusion Criteria:

• Diagnosis of acquired hemophilia A in a previously non-coagulopathic individual.
• Prior treatment with at least 3 weeks of immunosuppressive therapy
• Factor VIII: C levels <50% within 14 days prior to study entry, which do not correct in coagulation assays in which normal plasma is mixed and incubated with patient plasma.
• Measurable anti-factor VIII:C antibody inhibitor activity > 0.6 Bethesda Units/ml.
• Age ³18 years
• Written informed consent
• Use of an effective means to avoid pregnancy, including abstinence, for women of childbearing potential,.
• Serum bilirubin less than or equal to the upper limit of normal (ULN); ALT and AST £2.5´ ULN within 14 days prior to study entry
• Serum creatinine £1.5´ the ULN within 14 days prior to study entry
• Negative serum pregnancy test, for all women of childbearing potential, within 14 days prior to study entry

Exclusion Criteria:

• Continued treatment requirement of prednisone ≥30mg/day or equivalent dosing of other corticosteroid preparations to control serious symptoms of an underlying autoimmune disease state.
• Treatment with cyclophosphamide, danazol, vinca alkaloids, azathioprine, IVIG, or other immunosuppressive, immodulatory, or cytotoxic agents (other than decreasing doses of corticosteroids) within 30 days prior to study entry.
• Anticipated need for repeated extracorporeal plasmapheresis in order to reverse refractory bleeding associated with acquired hemophilia.
• Treatment with other experimental agents within 30 days prior to study entry
• Known sensitivity to murine or chimeric products
• Hepatitis BsAg positivity or high risk for reactivation of Hepatitis B.
• Active infection requiring antibiotic therapy within 7 days prior to study entry
• Current use of any required medications, which in the opinion of the treating physician, could be inducing the formation of auto-FVIII:C inhibitory antibodies
• Prior treatment with rituximab or other monoclonal antibody therapy
• Known HIV antibody positivity
• NCI-CTC Grade ³1 cardiac arrhythmia ( refer to CTC v3)
• Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the results or render the patient at high risk from treatment complications
• Currently pregnant women, lactating women, or women within 12 months of delivery, spontaneous miscarriage, or therapeutic or elective termination of pregnancy.
• Known severe leucopenia (absolute neutrophil count <1000/µL) or thrombocytopenia (<25,000/µL);
• Known pre-existing cystitis or severe urinary outflow obstruction.
• Known history of recurrent severe opportunistic infections, eg. generalized herpes zoster;
• Inability or unwillingness to comply with study design and requirements and follow-up procedures.