Phase I/II trial of autologous stem cell transplantation in systemic sclerosis: procedure related mortality and impact on skin disease

Background-Systemic sclerosis (SSc, scleroderma) in either its diffuse or l imited skin forms has a high mortality when vital organs are affected. No t reatment has been shown to influence the outcome or significantly affect th e skin score, though many forms of immunosuppression have been tried. Recen t developments in haemopoietic stem cell transplantation (HSCT) have allowe d the application of profound immunosuppression followed by HSCT, or rescue , to autoimmune diseases such as SSc. Methods-Results for 41 patients included in continuing multicentre open pha se I/II studies using HSCT in the treatment of poor prognosis SSc are repor ted; Thirty seven patients had a predominantly diffuse skin form of the dis ease and four the limited form, with some clinical overlap. Median age was 41 years with a 5:1 female to male ratio. The skin score was >50% of maximu m in 20/33 (61%) patients, with some lung disease attributable to SSc in 28 /37 (76%), the forced vital capacity being <70% of the predicted value in 1 8/36 (50%). Pulmonary hypertension was described in 7/37 (19%) patients and renal disease in 5/37 (14%). The Scl-70 antibody was positive in 18/32 (56 %) and the anticentromere antibody in 10% of evaluable patients. Peripheral blood stem cell mobilisation was performed with cyclophosphamide or granul ocyte colony stimulating factor, alone or in combination. Thirty eight pati ents had ex vivo CD34 stem cell selection, with additional T cell depletion in seven. Seven conditioning regimens were used, but six of these used hae moimmunoablative doses of cyclophosphamide +/- anti-thymocyte globulin +/- total body irradiation. The median duration of follow up was 12 months (3-5 5). Results-An improvement in skin score of >25% after transplantation occurred in 20/29 (69%) evaluable patients, and deterioration in 2/29 (7%). Lung fu nction did not change significantly after transplantation. One of five rena l cases deteriorated but with no new occurrences of renal disease after HSC T, and the pulmonary hypertension did not progress in the evaluable cases. Disease progression was seen in 7/37 (19%) patients after HSCT with a media n period of 67 (range 49-255) days. Eleven (27%) patients had died at censu s and seven (17%) deaths were considered to be related to the procedure (di rect organ toxicity in four, haemorrhage in two, and infection/neutropenic fever in one). The cumulative probability of survival at one year was 73% ( 95% CI 58 to 88) by Kaplan-Meier analysis. Conclusion-Despite a higher procedure related mortality rate from HSCT in S Sc compared with patients with breast cancer and non-Hodgkin's lymphoma, th e marked impact on skin scare, a surrogate marker of mortality, the trend t owards stabilisation of lung involvement, and lack of other treatment alter natives justify further carefully designed studies. If future trials incorp orate inclusion and exclusion criteria based on this preliminary experience , the predicted procedure related mortality should be around 10%.