Lay Summary: Stem cell transplantation in the hope of modifying disease activity in scleroderma is under active clinical investigational.
Immunosuppressive agents such as cyclophosphamide have long been used to treat autoimmune disease, but the dose is often limited by bone marrow suppression. More than ten years ago several groups considered adopting the oncological approach of myeloablative therapy followed by haematological ‘rescue’ using either autologous or allogeneic hematopoietic stem cells to treat severe, therapy-resistant autoimmune disease. The concept was supported by animal model data, suggesting tolerance induction in a rat arthritis model and cases of patients receiving an hematopoietic stem cell transplantation (HSCT) for conventional indications and in whom a coincidental autoimmune disease was improved or eradicated.
After several international meetings, consensus guidelines were developed and the first published case of a patient receiving an HSCT as treatment for an autoimmune disease alone was published in October 1996. Since then, over 1000 patients have been transplanted for autoimmune disease, the majority within the context of phase I/II trials and more recently within phase III prospective randomized studies.
The recent phase 3 Autologous Stem Cell Transplantation International Scleroderma (ASTIS) open-label, parallel-group trial included 29 clinical centers in 10 countries. During a median follow-up of 5.8 years, there were a total of 53 events: 22 in the HSCT group (19 deaths and 3 irreversible organ failures) and 31 in the control group (23 deaths and 8 irreversible organ failures). During the first year, more events occurred in the HSCT group (13 events [16.5%], including 8 treatment-related deaths) than in the control group (8 events [10.4%], with no treatment-related deaths). At 2 years, the HSCT group experienced 14 events (17.7%) vs 14 events (18.2%) in the control group. At 4 years, a total of 15 events (19%) had occurred in the HSCT group vs 20 events (26%) in the control group. At 4 years, time-varying hazard ratios (modeled with treatment × time interaction) for event-free survival were 0.35 (95% confidence interval, 0.16 – 0.74) and 0.34 (95% confidence interval, 0.16 – 0.74) at 2 years. Transplant was more effective than cyclophosphamide alone. It was reported in JAMA. 2014;311:2485-2487, with an supportive editorial on pp. 2490-2498 and there is a recently supportive NEJM article referenced below.
Autologous stem cell transplantation is well supported and has become standard in poorly responding scleroderma cases.
Sullivan KM, Goldmuntz EA, Keyes-Elstein L, et al. Myeloablative autologous stem-cell transplantation for severe scleroderma. N Engl J Med 2018;378:35-47
Nash RA, McSweeney PA, Crofford LJ, et al. High-dose immunosuppressive therapy and autologous hematopoietic cell transplantation for severe systemic sclerosis: long-term follow-up of the U.S. multicenter pilot study. Blood 2007; 23 April
van Laar JM, Farge D, Sont JK, et al. Autologous hematopoietic stem cell transplantation vs intravenous pulse cyclophosphamide in diffuse cutaneous systemic sclerosis: a randomized clinical trial. JAMA 2014;311:2490-2498.
van Laar JM, Tyndall A. Adult stem cells in the treatment of autoimmune diseases. Rheumatology (Oxford) 2006; 45:1187-1193.
Alan Tyndall; Daniel E. Furst Adult Stem Cell Treatment of Scleroderma Curr Opin Rheumatol. 2007;19(6):604-610
Jacob M. van Laar Kamran Naraghi Alan Tyndall, Haematopoietic stem cell transplantation for poor-prognosis systemic sclerosis. Rheumatology (Oxford) (2015) 54 (12): 2126-2133.