Stem Cell Transplantation Halts Crohn's Disease (original) (raw)

ORLANDO, Florida — Hematopoietic stem cell transplantation can be a highly effective treatment for resistant Crohn's disease, substantially reducing endoscopic evidence of the disease, according to a study by the Autologous Stem Cell Transplantation International Crohn's Disease (ASTIC) Trial group.

ASTIC is the only randomized controlled trial of stem cell transplantation in patients with Crohn's disease. It was designed after case reports and series showed a benefit from immunoablation followed by stem cell transplantation in some patients.

"Immunoablation and repopulation of the bone marrow by uncommitted stem cells has excited a lot of interest in Crohn's disease lately," said Christopher Hawkey, MD, from the University of Nottingham in the United Kingdom. "Some of the case reports are so dramatic that it's reasonable to talk about this being a cure in those patients," he noted.

Dr. Hawkey presented the ASTIC results here at Digestive Disease Week 2013.

In controlled clinical trials, the strategy has been shown to also be effective in systemic sclerosis and multiple sclerosis, but it is associated with major toxicities, he explained. In the largest series reported, patients with Crohn's disease achieved remission, but usually required continued use of immunosuppressive drugs (Blood. 2010;116:6123-6132).

"Against that uncertainty, it was time for a controlled clinical trial," he said.

ASTIC Trial

Dr. Hawkey and his team evaluated stem cell transplantation in 45 patients with moderately to severely active Crohn's disease that was resistant to treatment. Patients had failed at least 3 immunosuppressive drugs, had disease that was not amenable to surgery, and had impaired function and quality of life.

"For such an extreme technique, we wanted to enroll the most resistant patients," he pointed out.

All study participants underwent stem cell mobilization with cyclophosphamide and filgrastim, and were then randomly assigned to immediate stem cell transplantation (at 1 month) or delayed transplantation (at 13 months; control group).

Patients were considered to be in sustained remission if they were not taking immunosuppressive drugs and had a Crohn's Disease Activity Index score below 150 for 3 months prior to 1-year endoscopy or if imaging revealed no evidence of active Crohn's disease.

"Our goal was quite ambitious," he noted. We knew that the achievement of clinical remission and endoscopic remission, and having patients off drugs, would be a "game changer."

Dr. Hawkey presented the 1-year outcomes for the 2 groups; outcomes after delayed transplantation will be presented at a later date.

At 1 year, 22 patients in the treatment group and 13 in the control group were available for assessment. Of the 22 patients originally assigned to the control group, 9 terminated early, largely because of worsening disease, and underwent surgery or accelerated stem cell transplantation.

Objective endoscopic findings were substantially better in the treatment group than in the control group. On the Simple Endoscopic Score for Crohn's Disease, mean lower gastrointestinal score fell from 13 to 4 in the treatment group, whereas it remained unchanged in the control group (9 patients improved and 8 worsened).

Table. ASTIC Trial Outcomes

The decrease in median Crohn's Disease Activity Index score was greater in the treatment group than in the control group (approximately 165 vs 50 points). Two thirds of the treatment group discontinued immunosuppressive drugs and steroids at 1 year, whereas only 15% of the control group did.

"For the nearly 50% of patients in clinical remission, strikingly, most were not taking any drugs at the time," Dr. Hawkey said.

Serious adverse events were, "not surprisingly," higher in the treatment group during the transplant period, but they continued to increase throughout the follow-up period, he pointed out. Most of these were infective episodes. Viral reactivation was also seen. "This is quite a hazardous period of time for these patients," he noted.

Adverse Events

The 1 patient who died during the study was found to have sinusoidal obstructive syndrome. This was either the effect of the transplant or was secondary to sepsis that occurred shortly after transplant, Dr. Hawkey explained.

Because patients with Crohn's disease are susceptible to infections, those in the control group also experienced a high rate of adverse events. The average patient in each group experienced more than 3 serious events.

This is not the first study to evaluate bone marrow transplantation in Crohn's disease, said session moderator Gert Van Assche, MD, from the University of Toronto in Ontario, Canada. "But what is unique is that they did stem cell mobilization on all patients, then half got bone marrow ablation and stem cell rescue. Previous studies have not randomized patients," he said.

However, this is "not a purely controlled trial because some control patients did leave the study and receive hematopoietic stem cell transplantation because they were very sick. The steering group probably decided that they couldn't really do a placebo-controlled trial in this type of patient population," he explained.

Dr. Van Assche noted that the results should interpreted with caution. "Dr. Hawkey himself was cautious, saying there were serious adverse events and many patients were not cured.... We need controlled trials showing a long-term risk/benefit ratio," he said.

Dr. Hawkey reports serving on advisory committees or review panels for Atlantic Healthcare, Bayer AG, GlaxoSmithKline, Novartis, Boehringer Ingelheim GmbH, and Takeda. Dr. Van Assche disclosed no relevant financial relationships.

Digestive Disease Week (DDW) 2013. Abstract 93. Presented May 18, 2013.