Autologous Stem-Cell Treatment Validated in Systemic Sclerosis

June 30, 2014

In long-awaited results of a randomized trial against cyclophosphamide, autologous hematopoetic stem cells provided longer survival for patients with systemic sclerosis, after a risky first year.

Dinesh Khanna D, Georges GE, Couriel DR. Autologous Hematopoietic Stem Cell Therapy in Severe Systemic Sclerosis: Ready for Clinical Practice?JAMA (2014) 311:2485-2487. June 25, 2014 doi:10.1001/jama.2014.6369.

van Laar JM, Farge Sont JK, ET AL., for the EBMT/EULAR Scleroderma Study Group. Autologous Hematopoietic Stem Cell Transplantation vs Intravenous Pulse Cyclophosphamide in Diffuse Cutaneous Systemic Sclerosis: A Randomized Clinical TrialJAMA (2014) 311:2490-2498. June 25, 2014 doi:10.1001/jama.2014.6368.

For patients with systemic sclerosis (SSc), long-term survival was significantly higher after autologous hematopoetic stem cell transplantation (HSCT) than with conventional cyclophosphamide-based treatment – as long as they survived the first year’s treatment-related mortality. This supports the prospects of HSCT becoming a standard treatment for immunological diseases, just as it is for some cancers.

Rheumatologists and neurologists have been awaiting the result of this European trial, the Autologous Stem Cell Transplantation International Scleroderma (ASTIS) trial, because it is one of two large, randomized controlled trials testing the "immune reset" for immune diseases. When the immune system regenerates itself, the trigger may not be there to provoke autoimmune disease. This has worked in small trials, in which 30-50% of patients with lupus, multiple sclerosis (MS) and scleroderma were in remission for up to 8 years of followup. (See News Focus: Immunology: Replacing an Immune System Gone Haywire, by Jennifer Couzin-Frankel, Science, 12 February 2010, 327 (5967) 772-774. doi: 10.1126/science.327.5967.772)

Results are expected in about two years for the other ongoing trial, the Scleroderma: Cyclophosphamide or Transplantation (SCOT), involving 114 patient in the US. SCOT uses a more aggressive treatment, including radiation, more like the aggressive HSCT treatments used by oncologists.

The main reason rheumatologists have resisted HSCT is the high risk of treatment-related death. For aggressive leukemias, hich have a five-year survival rate beow 50%, a 5% risk of treatment-related mortality as the price of a cure is a good bet. But for autoimmune diseases like lupus, with modern treatments offering the prospect of a near-normal lifespan, rheumatologists have been reluctant to recommend such a risky procedure. That’s why the first two large trials of autoimmune disease are for SSc.

The other problem with HSCT is that, as the ASTIS trial has confirmed, treatment-related survival is highest early in the disease, and much lower after organs have been damaged (particularly the heart). So patients can’t wait for this treatment until the disease has progressed and they’ve run out of options. They must make a decision soon after SSc is diagnosed.

Conversely, treatment-related survival should be better for well-selected patients. For example, the 55% who are current and former smokers did much worse.

In ASTIS, 156 patients were randomized to HSCT or cyclophosphamide. The primary end point was event-free survival, defined as time to death or persistent major organ failure. Those events occurred in 22 of the HSCT group and 31 of the cyclophosphamide group (HR 0.34, 95% CI 0.16-0.74, p=0.006).

The secondary endpoint was overall survival. At a median followup of six years, there were 19 deaths in the HSCT group and 23 deaths in the cyclophosphamide group (hazard ratio 0.29, 95% confidence interval 0.13-0.64, p=0.002).

As expected, mortality was higher in the HSCT group in the first year, because of treatment-related complications. There were 11 first-year deaths in the HCST group (14%), including eight (10%) judged treatment-related, and seven (9%) in the cyclophosphamide group, none of the latter treatment-related. Then the survival curves crossed over and were better for the HCST group for the rest of the study.