Case Report

Bone Marrow Transplantation (2003) 32, 337–340. doi:10.1038/sj.bmt.1704134

Complete remission of Crohn's disease after high-dose cyclophosphamide and autologous stem cell transplantation

W Kreisel1, K Potthoff2, H Bertz2, A Schmitt-Graeff3, G Ruf4, J Rasenack1 and J Finke2

  1. 1Medical Clinic, Department of Gastroenterology, Hepatology and Endocrinology, University of Freiburg, Freiburg, Germany
  2. 2Medical Clinic, Department of Haematology and Oncology, University of Freiburg, Freiburg, Germany
  3. 3Institute of Pathology, University of Freiburg, Freiburg, Germany
  4. 4Surgical Clinic, University of Freiburg, Freiburg, Germany

Correspondence: Professor Dr W Kreisel, Medical Clinic, Department of Gastroenterology, Hepatology and Endocrinology, University of Freiburg, Hugstetter Strasse 55, D-79106 Freiburg, Germany

Received 3 December 2002; Accepted 17 February 2003.



In a 36-year-old male with ileocolic Crohn's disease (CD) no long-lasting remission was obtained by treatment with corticosteroids, mesalazine, azathioprine and antibiotics. Surgical interventions due to relapsing fistulae and abscesses resulted in the removal of >1.5 m of small bowel and left only 40 cm of large bowel. In July 2000, a new fistula and abscess developed. The combination of corticosteroids, mesalazine, ciprofloxacin, metronidazol, azathioprine, formula diet and anti-TNF-alpha antibody largely reduced clinical activity, and resection of fistula and abscess were successful. Despite clinical remission, histology showed activity in the small bowel and the colon. In March 2001, stem cell mobilization chemotherapy with cyclophosphamide was performed. It induced an endoscopic remission for 9 months, which was maintained on azathioprine and corticosteroids. After relapse, in March 2002, high-dose chemotherapy with cyclophosphamide and reinfusion of T-cell-depleted autologous peripheral CD34+ blood stem cells were performed. This led to a complete clinical, endoscopical and histological remission for 9 months without any treatment. Thereafter, endoscopy showed initial aphthous lesions with minimal histological signs of inflammation. The patient is asymptomatic, but low-dose prednisolone and methotrexate are prophylactically given. Immunoablative chemotherapy followed by autologous peripheral blood stem cell transplantation may be a beneficial therapeutic option in complicated refractory CD.


Crohn's disease, autologous peripheral stem cell transplantation, cyclophosphamide, immunoablative therapy, autoimmunity

Genetic predisposition, socioeconomical and environmental factors, mucosal permeability, nutrition and intestinal microflora contribute to the complex pathogenesis of chronic inflammatory bowel diseases (IBD).1,2 Mutations in the NOD2-gene influencing immune reaction towards bacterial antigens are involved in Crohn's disease (CD). Several triggering factors may influence the clinical manifestation. Whatever may be the sequence of events, the common denominator is a dysbalance of the mucosa-associated immune system and an upregulation of T cell activity. In CD, reactive T cells are mainly of the Th1 type. IBD therapy aims to suppress the disturbed immune reactions. This is achieved by corticosteroids, aminosalicylates and immunosuppressors. During the past years, the spectrum of therapeutic options has been broadened by the introduction of various biological agents.3 However, there are rare cases of patients with CD, in whom current medical and surgical therapy cannot lead to a continuing remission.

In this case report, we describe a patient with complicated and refractory CD. High-dose immunoablative chemotherapy followed by autologous peripheral blood stem cell transplantation (aPBSCT) was given as a last resort and led to a beneficial outcome.


Clinical course

We report a case of a 36-year-old male patient with CD involving the terminal ileum and colon. The clinical course is shown in Figure 1. Since 1988, he had been treated with multiple courses of corticosteroids and sulfasalazine for several disease exacerbations. In 1994, a subtotal colectomy and ileosigmoidostomy was performed. A perianal fistula was resected in 1997. In September 1999, the patient was referred to our clinic for enterocutaneous fistulae and abscess formation involving the left M. psoas. The patient again underwent surgical interventions. In July 2000, new fistulae and abscesses were observed. Therapy with corticosteroids, mesalazine, ciprofloxacin, metronidazole, azathioprine, balanced formula diet and anti-TNF-alpha antibody (5 mg/kg of body weight) largely reduced clinical activity. A resection of the fistula, stricturoplasty of the remaining small bowel and drainage of the abscess were successful. Therapy with corticosteroids, mesalazine and azathioprine was continued. Despite clinical and endoscopical remission, histology of the remaining small and large bowel revealed persistent inflammation.

Figure 1.
Figure 1 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact or the author

Clinical course of the patient. Ci=ciprofloxacin; Me=metronidazole, SASP=salazosulfapyridine/sulfasalazine, Corticoster/Cort=corticosteroids, CD=Crohn's disease, Form. diet=formula diet, MTX=methotrexate.

Full figure and legend (44K)

Since standard medical and surgical treatment had not led to a remission lasting more than a few months, and the quality of life had been poor due to multiple relapses of the disease that were difficult to treat, we discussed high-dose chemotherapy and aPBSCT with the patient as a therapeutic option. After approval from our local Ethics Committee and informed consent, the patient was readmitted to re-evaluate the activity of CD and to check the overall condition. On gastroscopy, no Crohn-type lesions were seen. Colonoscopy showed a diffuse colitis with mucosal erythema, edema and aphthoid lesions of the remaining rectum and sigmoid colon and the 40 cm of small bowel that could be inspected. Histology revealed typical signs of Crohn's enterocolitis. MRI of the abdomen, indirect perineal MRI fistulography and a leukocyte scintigraphy did not show any evidence of abscess formation or fistula. The cardiac checkup and the laboratory data showed normal findings. This clinical situation was regarded as optimal condition to perform a stem cell mobilization chemotherapy.

In March 2001, mobilization chemotherapy with cyclophosphamide 2 g/m2/day was given on two successive days (days 1 and 2) followed by G-CSF (filgrastim, 480 mug/day subcutanously) for 9 days beginning on day 5. More than 13 times 106 peripheral CD34+ cells per kilogram of body weight (bw) were harvested on day 14. Enrichment for CD34+ cells with 103-fold T cell depletion was performed using CliniMACS cell separation systems (Miltenyi, Bergisch Gladbach, Germany). No flare-up of CD was induced by G-CSF. A short episode of neutropenic fever was empirically treated with ceftazidime. The chemotherapy led to a clinical but not to a histological remission of CD on maintenance therapy with 7.5 mg prednisolone, 2.5 mg/kg bw azathioprine and topical mesalazine. We decided to preserve the stem cells for later high-dose therapy and aPBSCT at the time of any subsequent relapse.

In January 2002, the patient developed diarrhea and abdominal pain. Recurrent CD was confirmed by endoscopy and histology. After increasing prednisolone to 50 mg/day, the inflammation decreased and azathioprine was terminated. In March 2002, high-dose cyclophosphamide 50 mg/kg bw/day was given from day -5 to day -2 followed by retransfusion of 6.4 times 106/kg bw CD34+ autologous stem cells. The post-transplant course was uneventful with a neutropenic episode lasting six days. G-CSF (filgrastim) 480 mug/day was applicated from day +7 to day +9. Leukocyte (>1000/mul) and platelet engraftment (>20 000/mul) occurred at day +9. Lymphocyte reconstitution data are shown in Figure 2. Prednisolone was tapered and stopped 2 weeks after aPBSCT. The patient achieved a complete clinical, endoscopical and histological remission, which continued for 9 months without any anti-inflammatory medication (Figure 3). Thereafter, endoscopy showed few initial aphthous lesions and minimal histological signs of inflammation without any clinical symptoms. Prophylactically, therapy with 5 mg prednisolone/day and methotrexate (MTX) (15 mg weekly) was initiated. At the last endoscopical follow-up examination (28 January 2003), these lesions were constant and the patient was asymptomatic.

Figure 2.
Figure 2 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact or the author

Lymphocyte reconstitution following aPBSCT. Cy=cyclo-phosphamide.

Full figure and legend (27K)

Figure 3.
Figure 3 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact or the author

Endoscopic/macroscopic aspect of the neoterminal ileum. (a) 5 February 2002 (relapse, pre-high-dose cyclophosphamide and aPBSCT); (b) 13 November 2002 (>8 months post aPBSCT.

Full figure and legend (112K)



The elimination of effector cells involved in the pathogenesis of autoimmune diseases by the use of high-dose chemotherapy followed by aPBSCT has been shown to be effective in patients with malignant lymphoma or leukemia and concomitant autoimmune diseases. A complete remission of the malignant disease and of the autoimmune disorder could be observed.4,5 There are several reports describing that autoimmune diseases like multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus or systemic sclerosis can effectively be controlled by aPBSCT.6,7 Therefore, it seems rational to try to control the autoaggressive immune reactions in CD by immunoablative chemotherapy followed by aPBSCT.8 This is supported by promising reports on single BD patients treated by stem cell transplantation – allogeneic or autologous – due to leukemia or malignant lymphomas.9,10,11,12 Recently, two patients with CD have been described in whom, in a period of high clinical activity, (CDAI 308 and 267, respectively) aPBSCT+antithymocyte globulin (ATG) resulted in an impressive response lasting more than 1 year.13 However, there remained a mild to moderate endoscopical and/or histological inflammation. Here we present a further case report of a patient with complicated CD with no additional underlying malignant disease in whom aPBSCT was performed. This case differs in several respects from those described by Burt et al. Initially, our patient had only mild clinical activity. We divided the complete procedure of aPBSCT into two distant phases. Therefore, the effect of the respective therapeutic measures can easily be evaluated. Stem cell mobilization therapy induced an endoscopical, but not histological remission, which could be maintained by low-dose prednisolone and azathioprine. Only after the next relapse, which occurred 9 months later, high-dose immunoablative chemotherapy and autologous stem cell transplantation with CD34+ T cell depleted cells (without ATG) were performed. This high-dose immunosuppression resulted in a complete clinical, endoscopical and histological remission without any further therapy for CD, and which lasted for 9 months. At the end of December 2002, endoscopy showed initial inflammation that remains constant on low-dose prednisolone and MTX. The patient continues to be asymptomatic.

It is improbable that aPBSCT definitively eliminates CD, because the genetic predisposition persists. Nevertheless, aPBSCT might reset the immune system to a premorbid situation allowing for a long-lasting remission. Efforts should be taken to eliminate potential triggers, once a remission has been achieved. The reappearance of pathogenic T cell clones could be slowed or completely suppressed by the redeveloping immune network.

It may be argued whether immunoablative therapy followed by aPBSCT is ever necessary in IBD patients. A more intense chemotherapy alone may be sufficient to induce a long-lasting remission. Our two-step approach suggests a dose–response relation of cytoreductive chemotherapy. The stem cell mobilization chemotherapy is an effective test to evaluate whether it significantly improves the inflammatory process. Provided the patient is free of infectious complications or fistulae this therapy only leads to a short phase of leukopenia with a low probability of harming the patient and enables the collection of (T cell depleted) peripheral CD34+ cells for cryopreservation. In the event of relapse (in our patient 9 months after stem cell mobilization), high-dose chemotherapy and aPBSCT are justified and a long-lasting remission may be predicted. Such a strategy has been employed in a prospective randomized trial of HSCT in rheumatoid arthritis.

If stem cell therapy is ever justified by the severe clinical course of CD itself and not by a different underlying condition (eg leukemia, malignant lymphoma) then autologous PBSCT should be preferred. Using T cell depletion, autoreactive T cell clones can be largely eliminated. Allo-geneic transplantation even from an MHC-matched donor bears the risk of graft-versus-host reaction, which carries a poor prognosis and may involve the gut resembling CD.

For ethical reasons, aPBSCT is not a therapy for CD patients with a benign course. Patients with a severe course often suffer from infectious complications (eg abscesses or fistulae) that exclude a cytoreductive chemotherapy. Therefore, it is desirable to reduce the clinical activity of the IBD and to control effectively any infectious condition as much as possible prior to cyclophosphamide therapy. The present case report documents the proof of principle of immuno-ablative therapy followed by aPBSCT for selected patients who are refractory to available medical therapy or to surgery. We consider the two-step approach, which we have used as a suitable procedure to minimize the risk of aPBSCT in CD. A clinical trial should evaluate the effect of aPBSCT in CD.



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