Autologous non-myeloablative hematopoietic stem cell transplantation for diffuse scleroderma

Abstract

Patients with diffuse cutaneous scleroderma with visceral involvement have an overall 10-year survival of 35–68%. There is no known therapy that is able to alter the natural course of the disease. Here we report outcomes of autologous HSCT phase I study utilizing non-myeloablative lymphoablative conditioning regimen. Nine patients with diffuse scleroderma and poor clinical features were enrolled. Candidates were less than 65 years old and had either Rodnan skin score of more than 14 or lung diffusion capacity of carbon monoxide (DLCO) less than 80%, interstitial lung disease, elevated ESR, renal involvement, or abnormal electrocardiogram. Patients with pulmonary hypertension (pulmonary artery systolic pressure >45 mmHg) were excluded. Peripheral blood stem cells were mobilized with intravenous (IV) cyclophosphamide (CY) 2g/m2 and subcutaneous granulocyte colony-stimulating factor 10 mcg/kg daily. The graft was not manipulated. The conditioning regimen consisted of CY 200 mg/kg and rabbit antithymocyte globulin (rATG) 7.5 mg/kg. The procedure was well tolerated. Anticipated cytopenias, neutropenic fever, and mild fluid overload were easily controlled. White blood cells and platelets both engrafted on average day 8 (range days 7–9 and days 0–10, respectively). The median numbers of infused CD34+ and CD3+ cells were 8.31 × 106/kg (range 2.35–14.7 × 106/kg) and 2.03 × 108/kg (range 0.41–6.83 × 108/kg), respectively. We observed a marked improvement of skin score in all subjects, whereas cardiac function (ejection fraction, pulmonary artery systolic pressure), pulmonary function (DLCO) and renal function (creatinine) remained stable. One patient with advanced disease and poor performance status died 2 years after the transplant from progressive disease. Two patients developed recurrence of skin tightness without compromising organ function, however, with institution of mycophenolate mofetil both showed gradual improvement of skin scores. After median follow-up of 20 (range 5–32) months, the overall survival is 89% (8 out of 9 patients) and progression-free survival with continuing improvement is 67% (6 out of 9 patients). Autologous HSCT with CY/rATG conditioning regimen is safe and effective. A randomized study (ASSIST: American Scleroderma Stem Cell vs Immune Suppression Trial), comparing HSCT to IV pulse CY is now enrolling patients. Patients with diffuse cutaneous scleroderma with visceral involvement have an overall 10-year survival of 35–68%. There is no known therapy that is able to alter the natural course of the disease. Here we report outcomes of autologous HSCT phase I study utilizing non-myeloablative lymphoablative conditioning regimen. Nine patients with diffuse scleroderma and poor clinical features were enrolled. Candidates were less than 65 years old and had either Rodnan skin score of more than 14 or lung diffusion capacity of carbon monoxide (DLCO) less than 80%, interstitial lung disease, elevated ESR, renal involvement, or abnormal electrocardiogram. Patients with pulmonary hypertension (pulmonary artery systolic pressure >45 mmHg) were excluded. Peripheral blood stem cells were mobilized with intravenous (IV) cyclophosphamide (CY) 2g/m2 and subcutaneous granulocyte colony-stimulating factor 10 mcg/kg daily. The graft was not manipulated. The conditioning regimen consisted of CY 200 mg/kg and rabbit antithymocyte globulin (rATG) 7.5 mg/kg. The procedure was well tolerated. Anticipated cytopenias, neutropenic fever, and mild fluid overload were easily controlled. White blood cells and platelets both engrafted on average day 8 (range days 7–9 and days 0–10, respectively). The median numbers of infused CD34+ and CD3+ cells were 8.31 × 106/kg (range 2.35–14.7 × 106/kg) and 2.03 × 108/kg (range 0.41–6.83 × 108/kg), respectively. We observed a marked improvement of skin score in all subjects, whereas cardiac function (ejection fraction, pulmonary artery systolic pressure), pulmonary function (DLCO) and renal function (creatinine) remained stable. One patient with advanced disease and poor performance status died 2 years after the transplant from progressive disease. Two patients developed recurrence of skin tightness without compromising organ function, however, with institution of mycophenolate mofetil both showed gradual improvement of skin scores. After median follow-up of 20 (range 5–32) months, the overall survival is 89% (8 out of 9 patients) and progression-free survival with continuing improvement is 67% (6 out of 9 patients). Autologous HSCT with CY/rATG conditioning regimen is safe and effective. A randomized study (ASSIST: American Scleroderma Stem Cell vs Immune Suppression Trial), comparing HSCT to IV pulse CY is now enrolling patients.