High Dose Cyclophosphamide for Treatment of Scleroderma
Condition: Scleroderma
MeSH terms: Scleroderma, Systemic; Scleroderma, Diffuse; Scleroderma, Localized
Study type: Interventional
Phase: Phase 3

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.
    

Detailed description: 
      Study design

      The study was an open-label, single-site trial of a single exposure to high-dose
      cyclophosphamide without stem cell rescue. Each patient was followed up by the same doctor to
      eliminate interobserver skin score variation. Baseline measurements included comprehensive
      laboratory studies that included complete blood count with differential, comprehensive
      metabolic panel, urine analysis with culture, quantitative immunoglobulins, antibodies to
      hepatitis B core and surface antigens and antibodies to hepatitis C, human immunodeficiency,
      herpes, varicella, Epstein-Barr viruses; rapid plasma reagin test, chest x-ray or
      high-resolution computed tomography (HRCT) scan of the lungs, pulmonary function testing,
      electrocardiogram, and echo or multigated acquisition (MUGA) scan.

      The primary clinical efficacy end point was the modified Rodnan skin score (mRSS).24 A 25%
      sustained improvement in the mRSS at any point in the follow-up was considered clinically
      important and a successful outcome.25 Secondary outcome measures included the Health
      Assessment Questionnaire-Disability Index (HAQ-DI) and physician global assessment (PGA)
      determined by a visual analogue scale on a scale from 0 to 100. Values for the percentage
      predicted lung volumes were referenced from NHANES/Hanikson et al26 and for diffusing
      capacity of the lungs for carbon monoxide (DLCO) from Knudson et al.27 The disease duration
      was defined as the time from the first non-Raynaud's symptom related to scleroderma to study
      entry.

      Treatment protocol

      Cyclophosphamide (50 mg/kg) was administered intravenously over 1 hour daily for four
      consecutive days (200 mg/kg total) through a Hickman catheter. The dose of cyclophosphamide
      was based on the ideal body weight as determined by the Metropolitan Life tables.28 29 If the
      patient's actual weight was less than the ideal body weight, the actual body weight was used
      to calculate the cyclophosphamide dose. Intravenous mesna (10 mg/kg) was given 30 minutes
      before cyclophosphamide and then 3, 6 and 8 hours after cyclophosphamide was administered for
      prophylaxis against haemorrhagic cystitis. Intravenous ondansetron (32 mg) was administered 1
      hour before each dose of cyclophosphamide. Six days after the last dose of cyclophosphamide,
      all patients received granulocyte colony-stimulating factor (5 µg/kg/day) until the
      neutrophil count was 1×109/l for two consecutive days. Prophylactic antibiotic support,
      consisting of fluconazole (400 mg/day), norfloxacin (400 mg/day), and valaciclovir (500 mg
      twice a day, if antibodies to herpes simplex were present), was given beginning the day after
      the last dose of cyclophosphamide and continuing until the neutrophil count exceeded
      0.5×109/l. Dapsone (100 mg three times a week for 6 months) or trimethoprim-sulfamethoxazole
      (80/400 mg three times a week for 6 months) was administered for Pneumocystis carinii
      prophylaxis. Packed red blood cell (leucocyte-poor) transfusions were administered to
      maintain a haematocrit level >25%. Platelet transfusions were given for bleeding or to
      maintain a platelet count >10×109/l, or both. All blood products were irradiated (>2000 rad)
      to prevent graft versus host disease.
    

Intervention name(s): IV Cyclophosphamide
Intervention type(s): Drug
Intervention description(s): Cyclophosphamide (50 mg/kg) intravenously daily for 4 consecutive days (total 200 mg/kg) followed by granulocyte colony-stimulating factor (5 µg/kg/day)
Other intervention name(s): Cytoxan, Neosar
Intervention MeSH terms: Cyclophosphamide
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: High Dose Cyclophosphamide; Systemic Sclerosis; Scleroderma; immunoablation