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Keywords:

  • transplantation;
  • autologous transplantation;
  • Crohn's disease;
  • inflammatory bowel disease;
  • immunosuppression

Abstract

  1. Top of page
  2. Abstract
  3. CASE REPORT
  4. DISCUSSION
  5. Acknowledgements
  6. References

Crohn's disease usually runs a chronic relapsing and remitting course, characterized by a repeated need for immunosuppressive drug therapy or often surgery, and is considered to be incurable by standard treatment. We report a case of successful long-term disease control of Crohn's disease following autologous bone marrow transplantation. This case provides further support for the concept that some forms of severe immune-mediated diseases may be amenable to treatment by high-dose therapy with autologous stem cell support.

One current conceptual view of Crohn's disease is that it is a chronic autoimmune disease ( Sartor, 1995). It has been theorized that this disease may be induced by the exposure of the intestine to an antigen or antigens similar in structure to intestinal antigens resulting in loss of tolerance and subsequent immunologically mediated attack on the bowel. Although the basic mechanisms have not been clearly elucidated, aberrant T-cell function may be involved and therapy often involves immunosuppression ( Sartor, 1995; Glickman, 1998; Hanauer, 1996). We describe a patient with long-standing coincidental active Crohn's disease who underwent autologous bone marrow transplantation (ABMT) for non-Hodgkin's lymphoma (NHL). Both diseases have been in remission for 7 years after ABMT. This is the first case report, with long-term follow-up, which suggests that Crohn's disease could be controlled by ABMT.

CASE REPORT

  1. Top of page
  2. Abstract
  3. CASE REPORT
  4. DISCUSSION
  5. Acknowledgements
  6. References

A 13-year-old male was first diagnosed with Crohn's disease after a 4-year history of bowel cramps and diarrhoea. For the next 6 years he received intermittent treatment with prednisone and 6-mercaptopurine, achieving general disease control. At the age of 19, incision and drainage and antibiotics were used to treat a peri-rectal abscess. One year later, another Crohn's disease flare resulted in small bowel obstruction complicated by an intra-vesicular fistula requiring resection of the caecum, appendix, a Meckels diverticulum and the terminal ileum.

At the age of 20 he developed night sweats, weight loss and generalized lymphadenopathy. Flow cytometry, performed from a fine-needle aspiration of a cervical lymph node, CT and gallium scans, and bone marrow aspiration and biopsy confirmed the presence of stage IVB T-cell, large cell, NHL. The patient was treated with one cycle of bleomycin, cyclophosphamide and VP-16, in order to establish initial tumour control. This was followed by eight cycles of M-BACOD (methotrexate, bleomycin, adriamycin, cyclophosphamide, vincristine and dexamethasone) chemotherapy and five (monthly) cycles of CNS chemo-prophylaxis with intrathecal cytosine arabinoside and hydrocortisone, culminating in first complete remission. Autologous peripheral blood stem cells were collected and cryopreserved in preparation for ABMT. However, this was postponed because of the development of a peri-anal fistula and a 2 cm peri-rectal mass consistent with persistent Crohn's disease. This was treated with prednisone. Within 1 year, abdominal and chest CT scans and bone marrow biopsy confirmed relapse of NHL. ABMT was performed after one cycle of DHAP (dexamethasone, high-dose Ara-C, platinum) salvage chemotherapy. Dose-intensive therapy consisted of fractionated total body irradiation (200 cGy × six doses), VP-16 (60 mg/kg) and cyclophosphamide (100 mg/kg), followed by reinfusion of 9.8 × 108 unmanipulated mononuclear cells/kg. RhG-CSF was given after transplantation to enhance haemopoietic recovery. The patient had an unremarkable course and has been followed regularly as an outpatient since that time. There has been no clinical or laboratory evidence of recurrence of either NHL or Crohn's disease in the 7 years following transplantation.

DISCUSSION

  1. Top of page
  2. Abstract
  3. CASE REPORT
  4. DISCUSSION
  5. Acknowledgements
  6. References

The natural history of Crohn's disease is very variable. The clinical course may be persistent, progressive, or may improve or go into remission. A typical patient has waxing and waning of his illness, throughout his life, with medical therapy adjusted to match the frequency and severity of presentations. Although Crohn's disease often responds to immunosuppressive medications, such as corticosteroids, azathioprine and cyclosporine, and to anti-inflammatory and antimicrobial agents, no therapy has been found to be generally curative ( Sartor, 1995; Glickman, 1998; Hanauer, 1996). The fluctuating nature of this disease also makes analysis of clinical trials difficult. Large long-term studies suggest that Crohn's disease carries a significant disease-associated mortality rate in the order of 6–24% at 13–20 years of median follow-up ( Farmer et al, 1985 ; Trnka et al, 1982 ; Cooke et al, 1980 ). Additionally, the need for surgery may identify a subgroup of patients who have a more aggressive form of the disease with a higher disease-related mortality ( Farmer et al, 1985 ; Glotzer, 1995). During the 7-year post-transplant course of this patient there were no signs or symptoms of Crohn's disease. The numerous flares of disease, requiring immunosuppressive therapies and extensive surgery, prior to ABMT, is testament to the activity of his disease. Although we recognize that it would have been ideal to perform follow-up intestinal biopsies and other invasive studies in this patient, the lack of any symptoms or signs consistent with Crohn's disease strongly argues for its disappearance. The long-term remission, seen in this patient, would be highly unusual with standard treatment.

Bone marrow transplantation has been proposed as a potentially curative treatment for severe autoimmune diseases characterized by significant morbidity and mortality such as rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis and systemic sclerosis ( Marmont & Van Bekkum, 1995). Recently, patients with Crohn's disease who appeared to enter long-term remission after performance of allogeneic transplantation for malignancy have been described ( Lopez-Cubero et al, 1998 ). Of five long-term survivors, four remained in remission of Crohn's disease. One patient who remained a donor–host chimaera after transplantation and had recurrence of chronic myeloid leukaemia, continued to have active Crohn's disease before his death. Another patient, a disease-free survivor, died of myocardial infarction 4.5 years after transplantation without evidence of Crohn's disease. There has been one previous case report of autologous transplantation of a patient with malignancy and coincidental Crohn's disease ( Drakos et al, 1993 ). However, it is difficult to draw any conclusions regarding efficacy from this report, as the post-transplant follow-up of this patient was only 6 months.

It has been hypothesized that the conditioning regimen employed to perform ABMT results in eradication or near eradication of the cells causing immune-mediated disease manifestations. This hypothesis pre-supposes that local tissue disturbances will not, by themselves, be sufficient to cause reactivation of sustained inflammation after the immune system is reconstituted by the growth of transplanted stem cells. For this approach to be curative, it must also be assumed that the factors that initiated the disease process are no longer present and that recovering autologous derived lymphohaemopoietic cells cannot reactivate disease ( Tyndall & Gratwohl, 1997).

The acute mortality rate of ABMT is now <5% for patients with malignancy; due principally to infectious complications and treatment-related organ toxicity such as veno-occlusive disease of the liver ( Weaver et al, 1997 ). This decreased toxicity has resulted in the application of ABMT to a much wider patient population. Pilot clinical trials of ABMT in patients with severe autoimmune diseases are now in progress and these could include patients with Crohn's disease. However, it must be emphasized that ABMT, with its attendant risks, is an experimental therapy in this setting.

Acknowledgements

  1. Top of page
  2. Abstract
  3. CASE REPORT
  4. DISCUSSION
  5. Acknowledgements
  6. References

This work was supported in part by United States Public Service Grants NCI PPG CA 30206 and NCI CA 33572.

References

  1. Top of page
  2. Abstract
  3. CASE REPORT
  4. DISCUSSION
  5. Acknowledgements
  6. References
  • 1
    Cooke, W.T., Mallas, E., Prior, P., Allan, R.N. (1980) Crohn's disease: course, treatment and long-term prognosis. Journal of Medicine, 195, 363 384.
  • 2
    Drakos, P.E., Nagler, A., Or, R. (1993) Case of Crohn's disease in bone marrow transplantation. (Letter), American Journal of Hematology, 43, 157 158.
  • 3
    Farmer, R.G., Whelan, G., Fazio, V.W. (1985) Long-term follow-up of patients with Crohn's disease: relationship of the clinical pattern and prognosis. Gastroenterology, 88, 1818 1825.
  • 4
    Glickman, R.M. (1998) Inflammatory bowel disease: ulcerative colitis and Crohn's disease. Harrison's Principles of Internal Medicine, pp. 1633 1645.
  • 5
    Glotzer, D.J. (1995) Surgical therapy for Crohn's disease. Gastroenterology Clinics of North America, 24, 577 596.
  • 6
    Hanauer, S.B. (1996) Inflammatory bowel disease. New England Journal of Medicine, 334, 841 848.
  • 7
    Lopez-Cubero, S.O., Sullivan, K.M., McDonald, G.B. (1998) Course of Crohn's disease after allogeneic marrow transplantation. Gastroenterology, 114, 433 440.
  • 8
    Marmont, A.M. & Van Bekkum, D.W. (1995) Stem cell transplantation for severe autoimmune diseases: new proposals but still unanswered questions. Bone Marrow Transplantation, 16, 497 498.
  • 9
    Sartor, R.B. (1995) Current concepts of the etiology and pathogenesis of ulcerative colitis and Crohn's disease. Gastroenterology Clinics of North America, 24, 475 507.
  • 10
    Trnka, Y.M., Glotzer, D.J., Kasdon, E.J., Goldman, H., Steer, M.L., Goldman, L.D. (1982) The long-term outcome of restorative operation in Crohn's disease. Annals of Surgery, 196, 345 354.
  • 11
    Tyndall, A. & Gratwohl, A. (1997) Blood and marrow stem cell transplants in autoimmune disease: a consensus report written on behalf of the European League against Rheumatism (EULAR) and the European Group for Blood and Marrow Transplantation (EBMT). Bone Marrow Transplantation, 19, 643 645.
  • 12
    Weaver, C.H., Schwartzberg, L.S., Hainsworth, J., Greco, F.A., Li, W., Buckner, C.D., West, W.H. (1997) Treatment-related mortality in 1000 consecutive patients receiving high-dose chemotherapy and peripheral blood progenitor cell transplantation in community cancer centers. Bone Marrow Transplantation, 19, 671 678.