Stem Cell Transplantation Shows Promise in Scleroderma

Kate Johnson

June 08, 2012

June 8, 2012 (Berlin, Germany) — Autologous stem cell transplantation increased long-term survival in patients with early diffuse cutaneous systemic sclerosis, researchers reported here at the European League Against Rheumatism (EULAR) Congress 2012.

However, the therapy carries inherent risks — a 100-day treatment-related mortality rate of 10%, said Jacob van Laar, MD, PhD, during a EULAR press conference.

"We accept that patients in the transplant arm have a higher risk of dying upfront of complications from the transplant but that their survival in the long run will be better than control patients," explained Dr. van Laar, who is professor of clinical rheumatology at the Newcastle University in the United Kingdom.

The ASTIS (Autologous Stem cell Transplantation International Scleroderma) trial is the first international, investigator-initiated, phase 3 stem cell transplant trial in early diffuse cutaneous systemic sclerosis; it involved 10 countries and 27 centers.

"We specifically targeted patients with early disease because we thought that was the stage of the disease where we could make a difference," said Dr. van Laar. "In late-stage disease, it's probably not possible to change the disease course, but in the early stages of the disease, inflammation still plays a significant role, and this treatment targets inflammation," said Dr. van Laar. He added that diffuse cutaneous systemic sclerosis has a mortality rate similar to that of lymphoma.

The researchers randomized 156 patients with a maximum disease duration of 4 years (mean, 1.4 years) to receive either autologous stem cell transplantation (n = 79) or standard therapy (n = 77), which involved 12 monthly pulses of intravenous cyclophosphamide.

Stem cell transplantation included high-dose cyclophosphamide and lymphoablative antibodies to kill immune cells, he noted.

Although these drugs pose the risks of infertility, hair loss, nausea, infection, bladder bleeding, heart and lung failure, and malignancies, "the idea is that stem cell transplantation, although riskier, is more effective [than standard treatment], so the benefits will outweigh the risks," he said.

After a median follow-up of 33 months in the transplant group and 27 months in the control group, there were 42 deaths — 16 in the transplant group and 26 in the control group. Disease progression was seen in 5 patients in the transplant group and in 15 in the control group. Major organ failure was seen in 1 patient in the transplant group and in 3 patients in the control group.

Half the 16 deaths in the transplant group were deemed by an independent data monitoring committee to be related to the procedure. This indicates a 100-day treatment-related mortality rate of 10% (8 of 79), said Dr. van Laar.

"This is exactly what we anticipated at the onset of the trial. We expected that we would lose a few patients from transplant-related complications, but that there would be a long-term survival benefit."

The researchers are looking into what factors might help them identify which patients will benefit most from transplant therapy. Preliminary data suggest that smoking is one factor working against this treatment approach.

It is already known that response to any form of transplantation is better in nonsmokers than in smokers. This was also true in the ASTIS trial; nonsmokers benefited more in terms of event-free and overall survival, said Dr. van Laar.

Asked to comment on the findings, Xavier Mariette, MD, PhD, from Hôpital Bicêtre in Paris, France, and EULAR scientific chair, said that it is unclear whether it is the transplant itself or the accompanying high-dose chemotherapy that is responsible for the benefits.

"We have some data in lupus that high-dose cyclophosphamide alone is as efficient as high-dose cyclophosphamide followed by transplant," he said in an interview with Medscape Medical News.

However, such high-dose therapy alone can result in cytopenia, necessitating the transplant, he explained. "Stem cell transplantation is only a means for giving the cyclophosphamide."

He believes it is unlikely that the transplantation itself is beneficial.

"I don't see how these stem cells could be curative," he said. "It is autologous stem cell transplantation, using the stem cells of the patient — and the patient is sick — so the stem cells you reinject have seen the disease previously.... In my opinion, it is likely that the high-dose cyclophosphamide is curative, not the stem cells."

But Dr. van Laar said it is possible that both theories are valid.

"The point that it is the high-dose chemotherapy that mediates the effects of stem cell transplantation is actually not very clear in the setting of autoimmune diseases," he said. "There is a lot of rationale for thinking that, but it might be that stem cell transplantation itself also mediates immune effects."

Dr. van Laar and Dr. Mariette have disclosed no relevant financial relationships.

European League Against Rheumatism (EULAR) Congress 2012: Abstract LB0002. Presented June 7, 2012.

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