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

A Prospective, Phase II/III Randomized, Mult-institutional Controlled, Open-label, Phase II Trial of Rituximab Versus Oral Cyclophosphamide to Eradicate or Suppress Autoimmune Anti-Factor VIII Antibodies in Patients With Acquired Hemophilia A

The purpose of this study is to evaluate the rate of response when administering rituximab to suppress or eliminate the anti-body in a patient's blood that inhibits the effectiveness of their factor replacement product compared to treatment using cyclophosphamide. This is a Phase 2/3 study to find out what effects (good and bad) and response rituximab has on a patient and their anti-Factor VIII antibodies. Also, to compare the effect (good and bad) of the rituximab with cyclophosphamide on a patient and their anti-Factor VIII antibodies to see which is better. This research is being done because we do not know which treatment regimen (rituximab or cyclophosphamide) is more effective in eliminating or suppressing the anti-Factor VIII antibody in patients with acquired Hemophilia A.

This is a prospective Phase II randomized multi-institutional controlled pilot trial comparing the regimen of single agent rituximab with 6 weeks cytotoxic therapy with oral cyclophosphamide to eradicate or suppress autoimmune anti-factor VIII antibodies in individuals with acquired hemophilia A. Patients will be randomized to receive either of these two regimens when their autoimmune anti-factor VIII antibodies prove to be refractory to initial upfront immunosuppressive treatment with oral prednisone 1 mg/kg/day (or equivalent corticosteroid doses) for 3 weeks. Patients will be randomized to the treatment cohorts according to the biostatistical methods.

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, immunomodulatory, 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.