Unità Operativa di Oncoematologia e Trapianto di Midollo, Ospedale Oncologico 'La Maddalena', Palermo, Italy

Correspondence to: M Musso, Unità Operativa di Oncoematologia e Trapianto di Midollo, Ospedale Oncologico 'La Maddalena' Via S Lorenzo Colli 312, 90146 Palermo, Italy

Crohn's disease and ulcerative colitis are inflammatory bowel diseases (IBD), which are thought to result from an inappropriate immunologic (autoimmune) response to luminal antibodies. Allogeneic stem cell transplantation (SCT) performed for coincidental diseases is able to cure both leukaemia and Crohn's disease. Autologous SCT is currently performed worldwide for severe autoimmune diseases (SADs) because of its reduced transplant-related mortality (TRM). We report the case of a 30-year-old male patient with a 10-year history of severe Crohn's disease, who developed Hodgkin's disease and received an unmanipulated peripheral blood autologous transplant. Three years after the transplant the patient is in complete treatment-free remission of both diseases. Bone Marrow Transplantation (2000) 26, 921-923.

Crohn's disease; Hodgkin's lymphoma; autologous peripheral blood stem cell transplantation

The pathogenic mechanism in Crohn's disease is still unclear. There is some evidence to support the hypothesis that, due to constitutional genetic factors, transmural lesions of inflammatory bowel disease are mediated by environmental stimuli (luminal antigens?) interacting with abnormal T lymphocyte responses.^1,2 Experimental animal data and reports of patients with autoimmune disorders coincident with severe haematological diseases requiring haematopoietic stem cell transplantation (HSCT) suggest that high-dose chemotherapy followed by allogeneic or even autologous HSCT may play an important role in the treatment of patients with severe autoimmune disease (SADs).^3,4,5,6 Clinical case reports have been published and are being collected in the registry of the EBMT/EULAR Autoimmune Disease Stem Cell Project. Recently, long-term remissions in Crohn's disease after allogeneic HSCT for malignancies have been reported.⁷ An increased risk of lymphomas was noted in patients suffering from inflammatory bowel disease. Most lymphomas reported in this setting are of non-Hodgkin's type, but rare cases of Hodgkin's disease have been described.^8,9 We describe the case of a 30-year-old male with a 10 year history of Crohn's disease who achieved long-term CR after unmanipulated PBPC autotransplant for relapsed mixed cellularity Hodgkin's disease (MC-HD).

Case report

In 1987, a 19-year-old male was diagnosed with Crohn's disease by contrast radiography and histology of mucosal biopsy specimens taken at colonoscopy. No alteration of serum alkaline phosphatase levels was noted; however, HLA typing did not show a haplotype previously reported in Crohn's patients (A2 A23 B44 BX BW4, DRB1*03, DB1*10, DRB3*02.^10,11 He was treated with steroids (from 4 mg to 8 mg of methylprednisolone per day) and mesalazine, and achieved resolution of symptoms although he required continuous mesalazine treatment. In 1995, the patient was readmitted to hospital because of an acute terminal ileitis and underwent ileo-coecal resection. Pathologic examination of the surgical specimen showed typical appearances of Crohn's disease in the intestinal wall. Pathological features included inflammation of the submucosa with lymphoid aggregates and noncaseating granulomata. Thrombotic vascular lesions were noted in mucosal, submucosal and serosal venules and capillaries. Deep knife-like features extended from the ulcerated luminal surface into the submucosa.

Unexpected satellite lymphadenopathy was noted and histological examination showed mixed cellularity Hodgkin's disease (MC-HD). Diagnosis of stage II B subphrenic MC-HD was made. The patient received six cycles of MOPP-ABVD-CAD chemotherapy. CR for HD was achieved but he continued to require continuous mesalazine therapy for Crohn's disease. In 1996, the patient relapsed with extranodal pulmonary CM-HD; he was treated with high-dose sequential chemotherapy (HDS) consisting of etoposide 2 g/m², metotrexate 8 g/m² and vincristine 2 mg followed by cyclophosphamide (Cy) 7 g/m² + G-CSF for mobilization.¹² Four weeks after Cy administration he underwent HSCT. Although an improvement in clinical symptoms relating to the Crohn's disease occurred after HDS, at the time of transplant he still required mesalazine and steroid therapy (4 mg methylprednisolone/day).

Conditioning regimen consisting of idarubicin 42 mg/m² i.v. on day -8 and melphalan 180 mg/m² i.v. on day -2 was administered. Unmanipulated PBPC were infused on day 0 (CD34 and CD3 were 3.61 ´ 10⁶/kg and 30.8 ´ 10⁶/kg). A neutrophil count above 0.5 ´ 10⁹/l and platelet count above 20 ´ 10⁹/l were achieved on days 10 and 11. During hospitalisation (24 days) a mild mucositis (WHO: 2) occurred. The patient is now 1155 days after transplant and in CR for both diseases. No particular histological lesions were detected on biopsy specimens taken at colonscopy on days +530, +800 and +1100. Neither methylprednisolone nor mesalazine was administered after the autotransplant.

Discussion

This patient had suffered with Crohn's disease for about 10 years and despite specific therapy required ileocecal resection. He also required continuous mesalazine treatment in spite of the immunosuppressive effect of chemotherapy given prior to HSCT.

Dysregulation of the immune system is considered to play a central role in the pathogenesis as well as in the continuing manifestation of Crohn's disease. It is certain that allogeneic HSCT, generating a 'new' immune system, could represent a theoretically more attractive strategy for the treatment of IBDs and more generally of SADs. Allogeneic HSCT induces powerful immunosuppression by both the conditioning therapy and the immunosuppressive drugs used for prevention and treatment of GVHD. In addition a 'graft-versus-autoimmunity' effect has been postulated through the gradual eradication of T and B autoreactive lymphocytes.¹³ However, for Crohn's patients autologous HSCT could be more appropriate because of the higher risk benefit ratio of allogeneic HSCT. AutoHSCT potentially 'resetting' the immune system might be a valid strategy for treatment of SAD; furthermore, the immunosuppression, probably heightened by the mobilization regimen, is not the only reason for efficacy of HSCT. This impression is supported by the immune recovery pattern, which shows a reduction of CD4⁺ cells and of the CD45RA⁺/CD45RO⁺ ratio.¹⁴ In addition, although reduced Crohn's activity occurred after Cy administration, the patient required continuous mesalazine treatment to the time of transplant. Clinical case reports of autoHSCT for SAD have been published and are being collected in the registry of the EBMT/EULAR Autoimmune Disease Stem Cell Project; transplant-related mortality (TRM) is reported to be 8-9%. However, it can be argued that this risk, which is lower than that of allogeneic SCT, is justified in view of the poor quality of life with intractable Crohn's disease. Furthermore, from our experience of primary SAD patients we suggest that the use of more immunoablative rather than myeloablative conditioning therapy may represent an effective means of inducing immunosuppression without causing severe neutropenia thus reducing TRM.^15,16

The potential impact of autologous HSCT in the treatment of primary inflammatory bowel diseases depends on further clinical experience, and must be carefully compared with other, better known treatments. We agree with other authors¹⁷ who suggest co-operative trials with a multidisciplinary approach as a valuable strategy (EBMT-EULAR and Association des Sociétés Nationales Européennes et Méditerranéennes des Gastroenterologie (ASNEMGE)) in selected patients resistant to first line treatment or with a poor quality of life, in particular patients with fibrotic changes who have repeatedly undergone surgical resection.

Acknowledgements

We thank Prof Alberto M Marmont for fruitful and stimulating discussions.

1 McDonald SA, Palmen MJ, Van Rees EP, MacDonald TT. Characterization of the mucosal cell-mediated immune responce in IL-2 knockout mice before and after onset of colitis. Immunology 1997; 91: 73-80, MEDLINE

2 Elliott DE, Murray JA, Weinstock JV Inflammatory bowel disease and celiac disease. In: Rose NR, Mackay IR (eds). The Autoimmune Disease. Academic Press: San Diego, 1998, 477-509.

3 Marmont AM. New horizons in the treatment of autoimmune diseases: immunoablation and stem cell transplantation. Ann Rev Med 2000; 51: 115-134, MEDLINE

4 Tyndall A, Fassas A, Passweg J et al. Hematopoietic stem cell transplant for autoimmune disease. Bone Marrow Transplant 1999; 24: 729-734, MEDLINE

5 Euler HH, Marmont AM, Bacigalupo A et al. Early recurrence or persistence of autoimmune diseases after unmanipulated autologous stem cell transplantation. Blood 1996; 88: 3621-3625, MEDLINE

6 W Rosler, B Manger, R Repp et al. Autologous PBPCT in a patient with lymphoma and Sjogren's syndrome: complete remission of lymphoma withouth control of the autoimmune disease. Bone Marrow Transplant 1998; 22: 211-214, MEDLINE

7 Lopez-Cubero SO, Sullivan KM, McDonald GB. Course of Crohn's disease after allogeneic marrow transplantation. Gastroenterology 1998; 114: 433-440, MEDLINE

8 Greenstein AJ, Gennuso R, Sachar DB et al. Extraintestinal cancers in inflammatory bowel disease. Cancer 1985; 56: 2914-2921, MEDLINE

9 Kumar S, Fend F, Quintanilla-Martinez L et al. Epstein-Barr virus-positive primary gastrointestinal Hodgkin's disease: association with inflammatory bowels disease and immunosuppression. Am J Surg Pathol 2000; 24: 66-73, MEDLINE

10 Toyoda H, Wang SJ, Yang H et al. Distinct associations of HLA class II genes with inflammatory bowels disease. Gastroenterology 1993; 104: 741-748, MEDLINE

11 Prochazka EJ, Terasaki PI, Park MS et al. Association of primary sclerosing cholangitis with HLA-DRw52a. New Engl J Med 1990; 322: 1842-1844, MEDLINE

12 Gianni AM, Bregni M, Siena S et al. 5-year update of the Milan Cancer Institute randomized trial of high-dose sequential (HDS) vs MACOP-B therapy for diffuse large-cell lymphomas. Proc Am Soc Clin Oncol 1994; 13: 373,

13 Marmont A. Stem cell transplantation for severe autoimmune disorders: progress and problems. Haematologica 1998; 83: 733-743, MEDLINE

14 Cavenagh JD, Milne TM, Macey MG et al. Thymic function in adults: evidence derived from immune recovery patterns following myeloablative chemotherapy and stem cell infusion. Br J Haematol 1997; 97: 673-676, MEDLINE

15 Musso M, Porretto F, Crescimanno A et al. Autologous peripheral blood stem and progenitor (CD34+) cell transplantation for systemic lupus erythematosus complicated by Evans syndrome. Lupus 1998; 7: 1-3, MEDLINE

16 Musso M, Porretto F, Crescimanno A et al. Successful treatment of resistant thrombotic thrombocytopenic purpura/hemolytic uremic syndrome with autologous peripheral blood stem and progenitor (CD34+) cell transplantation. Bone Marrow Transplant 1999; 24: 207-210, MEDLINE

17 Hawkey CJ, Snowden JA, Lobo A et al. Stem cell transplantation for inflammatory bowel disease: practical and ethical issues. Gut 2000; 46: 869-872, MEDLINE