Selection of the Regimen for Immunosuppressive Therapy
Cyclophosphamide with ATG is a common conditioning regimen with two decades of experience in the treatment of aplastic anemia, and has been used safely without reported mortality in the treatment of autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis.Cy / ATG is not associated with late malignancies or cataracts. Both cyclophosphamide and anti-thymocyte globulin (horse or rabbit ATG) are potent immunosuppressive agents. ATG contributes additional immunosuppression without additional cytotoxicity. ATG given shortly pre-transplant will contribute to the elimination of host T lymphocytes that survive cyclophosphamide SLE, an autoimmune disease responsive to cyclophosphamide, responds well to a CY / ATG conditioning regimen, but we have recently found that patients with either systemic lupus erythematosus (SLE) or neuromyelitis optica respond faster and may have more durable remissions to a regimen of "rituxan sandwich" in which rituxan is infused before and after standard cytoxan, rATG. For these reasons, "rituxan sandwich" will be the conditioning regimen utilized in this study.
5.2 Method of Harvesting Stem Cells
Based on the experience of the pilot studies, the current protocol will mobilize stem cells with granulocyte-colony stimulating factor (G-CSF) and collect stem cells by apheresis, with subsequent bone marrow harvest performed only if needed to supplement the peripheral blood stem cells (PBSC). Based on experience of autoimmune flares in patients receiving G-CSF alone for mobilization, patients will be mobilized with cyclophosphamide 2.0 g/m2 and G-CSF 5-10 mcg/kg.
5.3 Cyclophosphamide
Cyclophosphamide (CY) is an active agent in patients with a wide variety of malignancies. It is used frequently in the therapy of lymphoid malignancies and has potent immunosuppressive activity. It is frequently used as a cytotoxic and immunosuppressive agent in patients undergoing marrow transplants and as a treatment for patients with autoimmune diseases. It is an alkylating agent that requires hepatic metabolism to the active metabolites, phosphoramide mustard and acrolein. These active metabolites react with nucleophilic groups. It is available as an oral or intravenous preparation. Bioavailability is 90% when given orally. The half-life of the parent compound is 5.3 hours in adults, and the half-life of the major metabolite phosphoramide mustard is 8.5 hours. Liver or renal dysfunction will lead to prolonged serum half-life. CY is administered intravenously at a dosage of 50 mg/kg on each of 4 successive days (use adjusted ideal body weight if patient's actual body weight is greater than 100% ideal body weight). The major dose limiting side effect at high doses is cardiac necrosis. Hemorrhagic cystitis can occur and is mediated by the acrolein metabolite.This can be prevented by co-administration of MESNA or bladder irrigation. Other notable side effects include nausea, vomiting, alopecia, myelosuppression and SIADH. Refer to institutional manuals for more information about administration, toxicity and complications.
5.4 Rabbit-Derived Anti-Thymocyte Globulin (rATG)
Rabbit-derived anti-human thymocyte globulin (rATG) is a gamma globulin preparation obtained from hyperimmune serum of rabbits immunized with human thymocytes. rATG has been used predominately in solid organ transplant immunosuppressive regimens. rATG is a predominantly lymphocyte-specific immunosuppressive agent. It contains antibodies specific to the antigens commonly found on the surface of T cells. After binding to these surface molecules, rATG promotes the depletion of T cells from the circulation through mechanisms which include opsonization and complement-assisted, antibody-dependent, cell-mediated cytotoxicity. The plasma half-life ranges from 1.5 12 days. rATG is administered intravenously at a dose of 0.5 mg/kg recipient body weight on day -6 and at a dose of 1.0 mg/kg recipient body weight on days -5, -4, -3, -2, and -1. Unlike equine ATG, rabbit ATG does not require a pre-infusion skin test to check for hypersensitivity. Methylprednisolone 250 mg will be given before every dose of rATG. Additional medications such as diphenhydramine may be given at the discretion of the attending physician. Although rare, the major toxicity is anaphylaxis; chills, fever, pruritus or serum sickness may occur.
5.5 Rituxan Rituximab is a chimeric monoclonal antibody used in the treatment of B cell non-Hodgkin's lymphoma, B cell leukemia, and numerous autoimmune disorders. The recommended adult dosage for patients with low grade or follicular non-Hodgkin's lymphoma (NHL) is 375 mg/m2 infused intravenously and for adult patients with autoimmune diseases a standard 500 mg is generally given intravenously. The infusion may be given at weekly intervals for four total dosages or once every 2 weeks and repeated 2-3 times. Acetaminophen and diphenhydramine hydrochoride are given 30-60 minutes before the infusion to help reduce side effects. If given as a retreatment the dosage is the same. The majority of side effects occur after or during the first infusion of the drug. Some common side effects include dizziness, feeling of swelling of tongue or throat, fever and chills, flushing of face, headache, itching, nausea and vomiting, runny nose, shortness of breath, skin rash, and fatigue.
