High Dose Cyclophosphamide for Treatment of Scleroderma
Condition: Scleroderma
MeSH terms: Scleroderma, Systemic; Scleroderma, Diffuse; Scleroderma, Localized
Intervention: IV Cyclophosphamide
Intervention description: Cyclophosphamide (50 mg/kg) intravenously daily for 4 consecutive days (total 200 mg/kg) followed by granulocyte colony-stimulating factor (5 µg/kg/day)
Intervention MeSH terms: Cyclophosphamide
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 6.0
Sex: All
Minimum age: 18 Years
Maximum age: 70 Years
Healthy volunteers: No
Keywords: High Dose Cyclophosphamide; Systemic Sclerosis; Scleroderma; immunoablation

Summary:

      Systemic Sclerosis (Scleroderma) varies greatly in clinical manifestations, mode of
      presentation, and course. The natural history of this chronic autoimmune disease ranges from
      benign to fatal. Patients are classified into limited and diffuse scleroderma defined by the
      degree of skin involvement. Patients with limited disease (e.g. the C.R.E.S.T. syndrome)
      generally have mild disease and normal survival. However, patients with diffuse cutaneous
      scleroderma often have severe multi-system disease that is not only devastating emotionally
      and physically but is associated with a 60-70% five year survival and a 40-50% 10 year
      survival. No therapies have proven effective in the treatment of scleroderma. Strategy to
      treat scleroderma have included attempts to prevent fibrosis with drugs that interfere with
      collagen metabolism, attempts to modify the disease process by immunosuppression and attempts
      to alter the disease by vasoactive drugs. High dose of corticosteroids and other
      immunosuppressive drugs (e.g. chlorambucil, 5-fluorouracil, methotrexate, cyclophosphamide,
      cyclosporine) used at conventional doses have not proven curative, but have shown some
      benefit for inflammatory features of the disease (e.g. arthritis, myositis, fibrosing
      alveolitis).

      Both allogeneic and autologous bone marrow transplantation (BMT) have shown to modify and in
      some instances reverse a variety of animal models of autoimmune disease. This has prompted
      many investigators to propose the use of peripheral blood stem cell transplantation (PBSCT)
      for the treatment of autoimmune disease including scleroderma. Unfortunately, this approach
      risks infusing untreated autoreactive lymphocyte clones after the immunoablative preparative
      regimen. We have previously demonstrated that high-dose cyclophosphamide without BMT can
      induce durable and complete remissions in another autoimmune disease, severe aplastic anemia.
      Recent data with high dose cyclophosphamide show that it can induce complete remissions in
      other autoimmune hematologic disorders. The objective of this study is to determine whether
      high dose cyclophosphamide can induce a durable remission in scleroderma patients with
      life-threatening disease, and to determine toxicity of high dose cyclophosphamide in high
      risk scleroderma patients.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Meet established criteria for a diagnosis of diffuse cutaneous scleroderma and have
             evidence of moderately severe organ damage and clinical evidence of active disease.

          -  Patients with diffuse scleroderma who have evidence of active fibrosing alveolitis
             manifested by either a greater than 10% decline in the forced vital capacity or the
             diffusing capacity from the defined normal values or from baseline measurements.

          -  Patients with severe deforming localized scleroderma (generalized morphea, liner
             morphea, keloid or bullous scleroderma) that threatens their capacity to function
             normally in society.

        Exclusion Criteria:

          -  Age less than 18 years and over 70 years

          -  Any risk of pregnancy

          -  Cardiac ejection fraction of < 45%

          -  Serum creatinine > 3.0

          -  Patients who are pre-terminal or moribund

          -  Bilirubin > 2.0, transaminases > 2x normal

          -  Forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1), (5/30/01) <
             50% predicted