Final Progress Report
Proposal No. IBD-0004
Principal Investigator: Robert M. Craig, M.D.
Applicant Organization: Northwestern University (Chicago, Illinois, U.S.A.)
Project Title: Immune ablation and hematopoietic peripheral stem cell support in patients with severe Crohn's disease
Period of Award: March 1, 2002 - February 29, 2004
The specific aims of the study were to investigate the safety and efficacy of treating severe Crohn’s disease with high dose cyclophosphamide and antithymocyte globulin rescued with T-cell depleted autologous peripheral stem cells. The data obtained from this component of the study are to be used as preliminary data for a phase 2 - 3 protocol. The second aim was to note whether peripheral stem cell transplantation promotes a remission in severe Crohn’s disease. We hypothesize that this unique therapy does indeed produce a remission and might result in a permanent cure of Crohn’s disease in some patients.
Twelve patients with severe Crohn’s disease who had failed all standard therapy including 5-amino salicylic acid, antibiotics, cortico steroids, immuno suppression and Infliximab were recruited for the study. Each of the patients’ Crohn’s disease activity indexes was greater than 250. Stem cells were mobilized from the peripheral blood by using cyclophosphamide and granulocyte cell stimulating factor. The cells were enriched by selecting CD-34 cells by the isolex system. After immune conditioning by cyclophosphamide and anti thymocyte globulin, the cells were reinfused.
All 12 patients tolerated the therapy well. Only culture negative fever ensued as a complicating problem in the patients. In most circumstances, the patients’ diarrhea and abdominal pain resolved prior to hospital discharge. Perianal fistulae remained a problem in some patients. Colonic strictures in general improved, however, one patient with a small intestinal stricture had a progression of the stricture requiring surgical resection. All of the patients continued to improve over the course of observation over three years, although small ulcerations continued to be present and resolution of perianal disease in general did not occur. The Crohn’s disease activity index fell to below 100 in all patients, fulfilling a definition of remission in accordance with this index. Continued improvement in serum albumin, hemoglobin, weight, sedimentation rate and c-reactive proteins were regularly noted.
This preliminary experience in the first 12 patients who have received this unique therapy continues to be encouraging. The depth and the length of this clinical remission remain to be determined.
Lay summary of this report:
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 reinfused after the chemotherapy. All of the patients tolerated this procedure quite well, and each of the twelve is currently being followed by our group. The patients have all improved, although some have improved more than others. The longest patients have been treated for three years and continue to show evidence of improvement.