Final Progress Report
Proposal No. IBD-0170R
Principal Investigator: Robert M. Craig, M.D.
Applicant Organization: Northwestern University (Chicago, Illinois, U.S.A.)
Project Title: Immune ablation and hematopoietic stem cell support in patients with refractory Crohn’s. A randomized, controlled study.
Period of Award: June 1, 2006 – September 30, 2008
Project Aims:
The major aim of our study was to compare immune ablation plus autologous hematopoietic stem cell transplantation to delaying the procedure by a year in subjects with refractory Crohn’s disease in a randomized, controlled study. A secondary aim was to continue to follow the subjects who have received this therapy in an open label study.
Accomplishments and Significant Results:
Our major accomplishment over the past 3 years has been in the following up of subjects in the non-randomized study. We have completed 22 subjects and a manuscript is in preparation on this group. A number of potential subjects have been evaluated, but have not been acceptable for the randomized study as they have not met the CDAI criterion, and the pool of interested patients has shrunk due to competing studies. Only one patient was enrolled in the study, so the randomized study has been abandoned. We shall continue to perform the research protocol for refractory CD in an open-label study and continue to accumulate data on the subjects. The major findings from the non-randomized study are 1. the procedure can be performed safely in an institute that is experienced in bone marrow or stem cell transplantations, 2. most patients have a prolonged salutary experience from the immune ablation and HSCT, but approximately 1/4 relapse, 3. only 3 of our subjects have displayed genetic defects that might predispose them to inflammatory bowel disease, 4. cigarette smoking was related to relapse in some, but not all, of the relapsing subjects, 5. a modified Kaplan-Meyer plot of subjects shows a remission rate of 80%-100% at each study interval (6 mos, and 1, 2, 3, 4, and 5 years), and 6. there was a robust rise in Treg cells following the HSCT, but the rise may be less pronounced in those that relapse.
Lay summary:
Crohn’s disease is due to white blood cells, lymphocytes, that inappropriately attack an individual’s own bowel. Normally these white cells only react against foreign material, but in Crohn’s disease, this process goes amiss. Treatment for Crohn’s disease has mostly been directed at opposing inflammation with aspirin like medications or other anti inflammatory drugs like corticosteroids. In addition, antibiotics which influence bowel activity and agents that oppose the action of these white cells have been utilized. Some patients do poorly on these conventional medicines and require surgery to remove the involved segments. Surgery does not cure the disease as the disease usually returns and surgery leaves the patient with a less functional bowel and may eventually result in the patient having insufficient bowel for nutrient absorption. The current study was developed to provide a new approach for these patients. The patients underwent a type of chemotherapy and had their own stem cells re-infused after the chemotherapy. All of the patients tolerated this procedure quite well, and each of the twenty-two is currently being followed by our group. The patients have all improved, although some have improved more than others. There have also been some relapses. The longest patients have been treated for six years and continue to show evidence of improvement. We also attempted to do a study comparing this experimental therapy to standard therapy, but were unable to access sufficient patients to continue the controlled study. We plan to continue offering the therapy for patients who have failed standard therapy.