Autologous Peripheral Blood Stem Cell Transplantation in Patients With Life Threatening Autoimmune Diseases
Autologous Peripheral Blood Stem Cell Transplantation in Patients With Life Threatening Autoimmune Diseases
OBJECTIVES: I. Determine whether there is prompt engraftment after autologous peripheral
 blood stem cell transplantation using filgrastim (G-CSF) mobilization in patients with life
 threatening autoimmune diseases.

 II. Determine the kinetics of T- and B-cell immune reconstitution after a combination of
 timed plasmapheresis, high dose cyclophosphamide and total lymphoid irradiation, and
 posttransplant immunosuppression with cyclosporine in these patients.

 III. Determine whether this treatment regimen beneficially influences the clinical course of
 these patients.
PROTOCOL OUTLINE: Patients receive filgrastim (G-CSF) SC daily until peripheral blood stem
 cells (PBSC) are collected. On the fifth day of G-CSF therapy, PBSC are collected. Patients
 undergo plasmapheresis on days -9 to -7. Patients receive cyclophosphamide IV on days -6 to
 -3 and total lymphoid irradiation on day -1. PBSC are reinfused on day 0. Following PBSC
 reinfusion, patients receive prophylaxis with oral prednisone or methylprednisolone IV on
 days -1 to 28, antithymocyte globulin IV on days 1-3, and cyclosporine every 12 hours on days
 1-60.

 Patients with autoimmune thrombocytopenia purpura, autoimmune hemolytic anemia, or pure red
 cell aplasia are followed on days 7, 14, 21, 28, 60, and 100, 6 months, and 1, 2, and 5
 years. Patients with rheumatoid arthritis, juvenile rheumatoid arthritis, or systemic lupus
 erythematosus are followed on days 14, 28, 60, and 100, and then every 6 months. Patients
 with vasculitis are monitored for abnormal clinical and laboratory parameters characteristic
 of the individual type of vasculitis.
Autoimmune thrombocytopenia purpura: platelet count less than 20,000/mm3 Adequate or
 increased marrow megakaryocytes Presence of detectable platelet associated immunoglobulins
 not due to alloreactive antibodies or posttransfusion purpura Prior response to
 immunosuppressive therapy Platelet count chronically less than 20,000/mm3 with petechial
 bleeding or less than 50,000/mm3 with other bleeding OR Any history of life threatening
 hemorrhage Refractory to conventional therapy for at least 21 days Splenectomy At least 1
 additional immunosuppressive therapy applied after splenectomy OR Controlled on
 conventional therapy but at price of unacceptable toxicity: Serious steroid related
 toxicity Absolute neutrophil count less than 500/mm3 25% of time, pure red blood cell
 transfusion dependent or other toxicities (e.g., hemorrhagic cystitis) that are a
 consequence of chronic or cytotoxic therapy Unable to wean from chronic daily or
 intermittent cytotoxic therapy

 Autoimmune hemolytic anemia or pure red cell aplasia, AIHA: Hemolytic anemia Hemoglobin
 less than 10.0 g/dL without transfusion Hemolysis as evidenced by both: Sustained
 reticulocytosis (greater than 125,000/mm3) without evidence of active bleeding or
 increasing hemoglobin Laboratory evidence of hemolysis Positive direct antiglobulin test or
 equivalent immune adherence test No evidence for paroxysmal nocturnal hemoglobinuria
 Negative Ham's test and sucrose hemolysis. For PRCA: Anemia due to selective decrease in
 marrow erythroid precursors Hemoglobin less than 10.0 g/dL without transfusion Severe
 reticulocytopenia (less than 20,000/mm3 despite anemia) Severely decreased marrow erythroid
 precursors Positive marrow coculture with serum or cells or response to immunosuppression
 No evidence for PNH Negative Ham's test and sucrose hemolysis Severe disease: Chronic
 (i.e., greater than 1 year) Transfusion dependent or untransfused hemoglobin less than 8.0
 g/dL Ferritin greater than 2,000 or evidence of organ dysfunction due to iron overload
 Refractory to conventional therapy after all 3 of the following: High dose steroids (at
 least 1 mg/kg) for at least 21 days Splenectomy (except cold reactive antibodies) 1
 additional immunosuppressive therapy OR Controlled on conventional therapy but at price of
 unacceptable toxicity

 Rheumatoid arthritis: Morning stiffness for at least 6 weeks Arthritis of 3 or more joint
 areas Arthritis of hand joints Symmetric arthritis Rheumatoid nodules Serum rheumatoid
 factor Radiographic changes Active rheumatoid disease as evidenced by all of the following:
 Elevated Westergren erythrocyte sedimentation rate Minimum of 16 swollen or tender joints
 using the 28 joint count method Must be at high risk for developing deforming joint disease
 as defined by at least 2 of the following: High titer IgM-IgG rheumatoid factor
 Radiographic evidence of erosive arthritis developing within the first 24 months of
 clinical disease Functional class II or III Refractory to conventional therapy after 12
 months of: Methotrexate used in combination with cyclosporine, hydroxychloroquine, or
 sulfasalazine OR Intramuscular gold therapy (total dose greater than 1.0 g and duration at
 least 6 months) OR Controlled on conventional therapy but at price of unacceptable toxicity

 Juvenile rheumatoid arthritis: Under 16 years of age at onset Arthritis in 1 or more joints
 as defined by swelling or effusion, or presence of 2 or more of the following: Limitation
 of range of motion Tenderness or pain on motion Increased heat Duration of disease 6 weeks
 or longer Onset type defined by type of disease in first 6 months: Polyarthritis (i.e., 5
 or more inflamed joints) Oligoarthritis (i.e., less than 5 inflamed joints) Systemic (i.e.,
 arthritis with characteristic fever) Exclusion of other forms of juvenile arthritis Active
 disease evidenced by 1 of the following: Minimum of 2 swollen or tender joints using the 71
 joint count method Endocardial or myocardial disease, or serositis Anemia or thrombocytosis
 of chronic disease High risk for developing deforming joint disease or evidence of
 potential life threatening involvement for at least 1 internal organ system Radiographic
 evidence of erosive arthritis developing within first 24 months of clinical disease
 Functional class II or III Endocardial, myocardial, pericardial, and/or pleural disease
 Hemoglobin less than 10.0 g/dL or platelet count greater than 600,000/mm3 Refractory to
 conventional therapy after 12 months of methotrexate used in combination with
 hydroxychloroquine, sulfasalazine, azathioprine, cyclosporine, or cyclophosphamide OR
 Controlled on conventional therapy but at price of unacceptable toxicity

 Systemic lupus erythematosus: Malar rash Discoid rash Photosensitivity Oral ulcers
 Arthritis Serositis Renal disorder Neurologic disorder Hematologic disorder Immunologic
 disorder Antinuclear antibody Must have at least 4 of 7 variables on the lupus activity
 scale measured Evidence of potential life threatening involvement of at least 1 internal
 organ system Endocardial and/or myocardial disease Central nervous system disease Pulmonary
 parenchymal disease Renal disease defined as WHO III, IV or V and a high activity and low
 chronicity index Immune mediated cytopenias Refractory to conventional therapy after
 attempts to control disease with at least 2 drugs, including prednisone and 1 of the
 following: Azathioprine Cyclophosphamide (greater than 500 mg/m2 monthly for 6 months)
 Cyclosporine OR Controlled on conventional therapy but at price of unacceptable toxicity

 Vasculitis Definitive diagnosis of 1 of the following forms: Churg-Strauss syndrome Giant
 cell arteritis Henoch-Schonlein purpura Hypersensitivity vasculitis Polyarteritis nodosa
 Takayasu arteritis Wegener's granulomatosis Evidence of active disease defined as
 reversible manifestations of the underlying inflammatory process Must have 1 or more of the
 following: Elevated Westergren erythrocyte sedimentation rate Elevated C reactive protein
 Decrease serum complement levels Evidence of potential life threatening involvement of at
 least 1 internal organ system Endocardial and/or myocardial disease Central nervous system
 disease Pulmonary parenchymal disease Renal disease defined as WHO III, IV or V and a high
 activity and low chronicity index Immune mediated cytopenias Refractory to conventional
 therapy (i.e., failed or relapsed within 6 months) after attempts to control disease with
 at least 2 drugs, including prednisone and 1 of the following: Methotrexate Azathioprine
 Cyclophosphamide Cyclosporine OR Controlled on conventional therapy but at price of
 unacceptable toxicity

 Performance status: ECOG 0-1 ECOG 2 allowed provided symptoms directly related to
 autoimmune disease Hepatic: No history of severe, prior or ongoing chronic liver disease
 Bilirubin less than 2.0 mg/dL AST less than 2 times upper limit of normal (ULN) Alkaline
 phosphatase less than 2 times ULN Renal: Creatinine less than 2.5 mg/dL OR Creatinine no
 greater than 2 times normal baseline for age in pediatric patients Cardiovascular: No
 symptoms of cardiac disease No active ischemic heart disease Ejection fraction greater than
 45% by MUGA No uncontrolled hypertension Pulmonary: FEV1/FVC at least 60% OR Resting PO2 at
 least 80 mm Hg DLCO greater than 50% predicted O2 saturations greater than 94% in children
 unable to perform PFTs Neurologic: No active or ongoing ischemic or degenerative CNS
 disease not attributable to underlying disease Other: Not pregnant No poorly controlled
 diabetes HIV negative