Autologous HSCT: toward scleroderma treatment

The article by Nash and colleagues in this issue of Blood extends reported clinical experience with autologous hematopoietic stem cell transplantation (HSCT) in severe systemic sclerosis (SSc) by describing the outcome of 27 patients with at least 1 year of follow-up, providing a rather good estimation of long-term outcome and treatment effects at 4 years. The authors observed a significant decrease in the clinical and histological degree of dermal fibrosis, with improved overall functional status and stabilization of lung, heart, and kidney functions. Although these results were issued from nonrandomized, multicentric pilot studies, they illustrate the encouraging risk-to-benefit ratio after HSCT in rapidly progressive diffuse SSc patients selected for their 5-year mortality risk of 50% under conventional treatment.

Since 1996, approximately 1000 HSCTs for autoimmune diseases were reported worldwide. Early results from phase 1 and 2 clinical trials showed that HSCT is feasible in carefully selected patients with diffuse SSc, although transplant-related mortality (TRM) appeared higher than the 3% reported in non-autoimmune disease (AID) patients and varied according to conditioning regimen.^1,2  McSweeney et al¹  originally reported 3 fatal treatment-related complications and 1 posttransplantation lymphoproliferative disorder among the first 19 patients treated with high-dose immunosuppressive therapy (HDIT) using fractionated total body irradiation (TBI; 800 cGy), cyclophosphamide (CY; 120 mg/kg), and equine anti-thymocyte globulin (ATG; 90 mg/kg) plus methylprednisolone (1 mg/kg). Using a similar mobilization regimen, other groups reported lower TRM in SSc patients receiving CY (200 mg/kg) alone or in addition to ATG, with only one TRM among 12 SSc patients in the French multicenter study and 5 TRMs among 57 patients analyzed in the follow-up report from the EBMT-EULAR (European Group for Bone and Marrow Transplantation-European League Against Rheumatism) study.^2,3  Nash and colleagues used lung shielding for a total dose of 200 cGy to prevent the fatal pulmonary toxicities observed by McSweeney et al¹  in 2 of 8 patients, but 6 patients developed renal crisis or dysfunction, with 4 requiring dialysis and 3 dying. Lower steroid doses and earlier effective blood pressure control with converting enzyme inhibitors may decrease risk of renal crisis, but future studies should consider renal shielding during TBI in these SSc patients. Factors other than type of conditioning influence HSCT results. When analyzing the EBMT database of 473 AID patients treated by HSCT, 7% TRM at 3 years was directly related to the type of AID disease (SSc and systemic lupus erythematosis [SLE] were higher risk), the year of transplant with a learning curve, and the intensity of conditioning (HDIT had a higher risk of TRM but lower probability of disease progression).⁴ 

The positive effect of HSCT on survival rate should be interpreted carefully, due to the wide range of follow-up duration (1 to 8 years) with only 17 out of 27 assessable patients surviving 1 year after HSCT. More importantly, as previously reported,⁵  autologous HSCT induced a major regression of SSc dermal fibrosis, which had never been reported with other treatments. Such findings underline the importance of ongoing randomized trials comparing autologous HSCT with (the US SCOT [Scleroderma: Cyclophosphamide or Transplant] study) or without (the European ASTIS [Autologous Stem Cell Transplantation International Scleroderma] trial) TBI to monthly intravenous cyclophosphamide.