Value of HSCT for refractory Crohn's questionable: study
By Megan Brooks
NEW YORK (Reuters Health) - A randomized clinical trial questions autologous hematopoietic stem cell transplantation (HSCT) for refractory Crohn's disease not amenable to surgery.
Compared with conventional therapy, HSCT did not lead to significant improvement in sustained disease remission at one year and was associated with significant toxicity, according to the study in JAMA December 15.
HSCT may help a minority of patients with refractory Crohn's disease, but widespread use outside of clinical trials would be premature, first author Dr. Christopher J. Hawkey, of Queens Medical Center in Nottingham, UK, told Reuters Health by email.
Crohn's disease has a "strong polygenic immune component, even though it is not a classic autoimmune condition. Allogeneic HSCT resets the immune system at a genetic level, and autologous HSCT eliminates aberrant clones by immunoablation and replacement with uncommitted stem cells, leading to de novo generation of an altered T-cell repertoire," the authors explain in their article.
Case reports and series have suggested that for some patients, autologous HSCT can induce long-term treatment-free disease regression. Dr. Hawkey and colleagues designed the European multicenter Autologous Stem Cell Transplantation International Crohn Disease (ASTIC) trial to follow up on these promising early data.
"But the treatment is hazardous with major potentially lethal risks, so recruitment to the trial was cautious and only the most resistant cases were studied. And we used the most stringent criteria ever developed for the trial's primary endpoint," Dr. Hawkey told Reuters Health.
The study involved 45 patients with impaired quality of life from refractory Crohn's disease not amenable to surgery. Twenty-three patients underwent autologous HSCT and 22, serving as controls, deferred HSCT for one year. All received standard Crohn's disease therapy as needed.
According to the researchers, there was no statistically significant between-group difference in rates of sustained disease remission at one year. This was achieved by two patients in the HSCT group (8.7%) and by one patient in the control group (4.5%).
"The criteria we used for success were so stringent (no symptoms, no signs of disease on total bowel examination and no need for treatment) that few patients achieved them," Dr. Hawkey said. "Nevertheless, there were improvements in the individual measures underlying this composite endpoint. Objective signs of disease disappeared so that the gut looked normal from mouth to anus in about a quarter of actively treated patients vs no controls. Eight vs two patients were adjudicated free of active disease on endoscopy and radiology at final assessment (p=0.054)."
Some patients were able to come off drug treatments: by the end of one year, 61% of HSCT patients were off immunosuppressive drugs for more than three months vs 23% of controls (p=0.012).
"But treatment was challenging: there were 76 serious adverse events in HSCT patients (particularly infections) vs 38 in controls. One HSCT patient died," Dr. Hawkey noted.
"Because very few patients achieved sustained disease remission, we conclude that HSCT is unlikely to alter the natural history of Crohn's disease, and our findings argue against extension of HSCT to a wider group of patients outside of future additional trials," the authors write in their paper.
"In this group of the most resistant cases of Crohn's disease, HSCT was an effective treatment, but it is not a miracle cure that could be applied to anyone with Crohn's disease because it only seems to work in a minority of patients and the treatment is challenging and hazardous," Dr. Hawkey told Reuters Health.
HSCT is "probably the most effective treatment for Crohn's disease but also the most toxic," he concludes. "It cannot be recommended for widespread use at the present time but may be a risk worth taking for a small number of patients that have run out of treatment options. The challenge now is to find ways to identify those most likely to benefit and those who will not."
Reached for comment, Dr. R. Balfour Sartor, director of the Broad Medical Research Program at the Crohn's & Colitis Foundation of America (CCFA), told Reuters Health by email, "This important study, supported in part by the Broad Medical Research Program, was carefully performed by Dr. Hawkey and colleagues. (Autologous stem cells) did not induce a sustained remission using the extremely stringent criteria of this study, but there was some evidence of clinical response to the stem cell transplant despite the small number of patients studied."
However, this modest improvement was counterbalanced by a substantial increased risk of infections after transplant and even one death," added Dr. Sartor, who is also the Director of the UNC Multidisciplinary Center for IBD Research & Treatment at the University of North Carolina.
"Because of these complications, autologous stem cell transplant cannot be routinely recommended as a routine approach, even in patients with very refractory Crohn's disease," Dr. Sartor said. "Dr. Hawkey and his colleagues should be commended for directly answering an important, clinically relevant question brought up by a number of case reports and small uncontrolled series."
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