High Dose Cyclophosphamide for Treatment of Scleroderma

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.

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