Gastroenterology

Gastroenterology

Volume 128, Issue 3, March 2005, Pages 552-563
Gastroenterology

Clinical-alimentary tract
Autologous hematopoietic stem cell transplantation in patients with refractory Crohn’s disease

https://doi.org/10.1053/j.gastro.2004.11.051Get rights and content

Background & Aims: Crohn’s disease (CD) is an immunologically mediated inflammatory disease of the gastrointestinal tract. Due to a high morbidity and/or an increase in mortality in refractory cases, a new treatment approach is needed. In theory, maximum immune ablation by autologous hematopoietic stem cell transplantation (HSCT) can induce a remission. Methods: We conducted a phase 1 HSCT study in 12 patients with refractory CD. Candidates were younger than 60 years of age with a Crohn’s Disease Activity Index (CDAI) of 250–400 despite conventional therapies including infliximab. Peripheral blood stem cells were mobilized with cyclophosphamide and granulocyte colony-stimulating factor and CD34+ enriched. The immune ablative (conditioning) regimen consisted of 200 mg/kg cyclophosphamide and 90 mg/kg equine antithymocyte globulin. Results: The procedure was well tolerated with anticipated cytopenias, neutropenic fever, and disease-related fever, diarrhea, anorexia, nausea, and vomiting. The median days for neutrophil and platelet engraftment were 9.5 (range, 8–11) and 9 (range, 9–18), respectively. The initial median CDAI was 291 (range, 250–358). Symptoms and CDAI improved before hospital discharge, whereas radiographic and colonoscopy findings improved gradually over months to years following HSCT. Eleven of 12 patients entered a sustained remission defined by a CDAI ≤150. After a median follow-up of 18.5 months (range, 7–37 months), only one patient has developed a recurrence of active CD, which occurred 15 months after HSCT. Conclusions: Autologous HSCT may be performed safely and has a marked salutary effect on CD activity. A randomized study will be needed to confirm the efficacy of this therapy.

Section snippets

Study design

This is a pilot study designed to investigate the safety and efficacy of HSCT utilizing high-dose cyclophosphamide, equine antithymocyte globulin, and autologous T cell-depleted (CD34+ cell-enriched) HSCT in patients with chronic active CD refractory to conventional therapies including infliximab. Primary end points were treatment-related toxicity and engraftment. Secondary end points were an HSC mobilization and disease response.

Patient selection

Patients and/or parents read and signed an informed consent form

Patient demographics and pre-HSCT disease manifestations

Twelve white patients (6 female and 6 male patients) with a median age of 27 years (range, 15–38 years) were enrolled. Five patients had significant pre-HSCT complications from standard immunosuppressive therapies. Three patients had either anaphylaxis or an anaphylactoid reaction from infliximab, while 6-mercaptopurine caused pancreatitis in 1 patient and prolonged cytopenias due to bone marrow suppression in another patient. The median duration of disease was 10 years (range, 1.5–20 years).

Discussion

The etiology of CD is unknown. No intestinal self-antigen (initiating or spread epitope) that is pathogenic has been identified. On the other hand, several animal gene knockout models suggest that inflammatory bowel disease may be a result of immune dysregulation between Th1 and Th2 cytokines. Deficiency of multiple Th2 cytokines may cause colitis in animal models. Interleukin 10-deficient mice develop acute and chronic colitis. 22 Interleukin 2-deficient, 23 double mutant interleukin 2- and

References (32)

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Supported by a grant from the Broad Foundation (Los Angeles, CA).

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