ORLANDO – Immunoablation and hematopoietic stem cell transplantation is highly effective – but also risky – for patients with intractable Crohn’s disease, according to interim findings from the randomized controlled ASTIC (Autologous Stem Cell Transplantation International Crohn’s Disease) trial.

At 1-year follow-up in the 5-year study, the treatment was associated with significant improvements as measured by the Crohn’s Disease Activity Index (CDAI) and Simple Endoscopic Score for Crohn’s Disease (SES-CD), Dr. Christopher J. Hawkey reported at the annual Digestive Disease Week. However, patients experienced more than three serious adverse events per person, and one death occurred 2 weeks after transplantation, he said.

Of 45 patients with impaired quality of life due to moderate to severe Crohn’s disease activity despite treatment with at least three immunosuppressive agents, all underwent stem cell mobilization treatment and were then randomized to receive either immediate or delayed immunoablation and hematopoietic stem cell transplantation (HSCT). The delayed-treatment group served as a control group.

In 22 patients who received immediate treatment and survived until 1-year follow-up, the CDAI score was halved to a median value of 162, compared with only about a 50-point drop in 13 patients in the control group who continued in the study (9 patients withdrew early – mainly because of disease worsening – and some went on to early HSCT). Furthermore, an "encouraging number" of patients in the treatment group were able to discontinue all immunosuppressive drugs and steroids (about two-thirds of patients, compared with 15% in the control group), said Dr. Hawkey of the University of Nottingham, England.

Almost half of the patients in the treatment group achieved a CDAI score of 150 or less, signaling clinical remission.

"Strikingly, most of these patients were not taking any drugs at the time, either," Dr. Hawkey said.

The SES-CD score also decreased markedly in the treatment group, falling from a mean of 13 to 4 points, with four patients achieving complete absence of any evidence of involvement or ulceration, compared with no patients in the control group.

Complete mucosal healing, defined as lack of erosions or ulcerations on endoscopy, occurred in 40% of treatment-group patients, compared with only 15% of control-group patients, but several of these patients were still taking anti–tumor necrosis factor (anti-TNF) drugs or steroids, Dr. Hawkey said.

"Nevertheless, these are quite substantial findings," he said.

Patients included in the trial were adults who had undergone up to 12 surgeries each but who still had disease-related impairments to quality of life.

"For such an extreme technique, we wanted to enroll the most resistant patients," Dr. Hawkey said.

The treatment and control groups were well matched with respect to major demographics as well as CDAI and SES-CD scores, and patients were relatively young, having been diagnosed with Crohn’s disease at an early age, he noted.

Stem cell mobilization was achieved using 4 g/m² of intravenous cyclophosphamide delivered over 2 days, followed by 10 mcg/kg filgrastim daily until randomization. The conditioning regimen in the treatment group was 50 mg/kg per day of intravenous cyclophosphamide for 4 days, 2.5 mg/kg per day of antithymocyte globulin, and 1 mg/kg of methyl prednisolone on days 3-5. The bone marrow was reconstituted by infusion of an unselected graft of 3-8 × 10⁶ CD34-positive cells/kg.

One patient in the treatment group died 2 weeks after HSCT due to sepsis, and a significantly greater number of serious adverse events – usually infectious – occurred during follow-up in the treatment group than in the control group (an average of 3.3 per person).

The findings could have important implications for the treatment of Crohn’s disease.

"Immunoablation and repopulation of the bone marrow by uncommitted stem cells has excited a lot of interest in Crohn’s disease lately, and some of the case reports are undoubtedly so dramatic that it’s reasonable to talk about a cure in those patients," Dr. Hawkey said.

HSCT has been shown in controlled clinical trials to be effective – albeit with major toxicities – in systemic sclerosis and multiple sclerosis, but this is the first randomized controlled trial to evaluate the technique in Crohn’s disease.

"Our goal was quite an ambitious one. If we could achieve clinical remission, and patients were off drugs, that would be something of a game-changer," he said.

Indeed, the findings thus far suggest that stem cell transplantation is highly effective for patients with resistant Crohn’s disease, but in most cases, there is evidence of disease persistence.

"So this is seldom a cure, although sometimes it clearly is," he said, adding that given the significant number of serious adverse events, weighing the risks and benefits will be the key to successful clinical use in the future.

Outcomes following HSCT in the delayed-treatment group will be presented at a later date, he said.

Dr. Hawkey serves on advisory committees or review panels for Atlantic Healthcare, Bayer AG, GlaxoSmithKline, Novartis Pharmaceuticals, Boehringer Ingelheim, and Takeda Pharmaceuticals.

Stem cell transplantation offers hope for resistant Crohn's