Biologicals and Beyond
Stem Cells as Treatment in Inflammatory Bowel DiseaseHawkey C.J.
Nottingham Digestive Diseases Centre, Nottingham, UK
Do you have an account?
- Rent for 48h to view
- Buy Cloud Access for unlimited viewing via different devices
- Synchronizing in the ReadCube Cloud
- Printing and saving restrictions apply
Rental: USD 8.50
Cloud: USD 20.00
Background: The Autologous Stem Cell Transplantation International Crohn’s Disease (ASTIC) trial is a randomised controlled evaluation of the proposition that immunoablation and haemopoietic stem cell transplantation improves the course of Crohn’s disease. Recruitment of all 48 patients in the trial will be completed in early 2012 and the results to date are descriptively presented here. Methods: Patients with an impaired quality of life due to active Crohn’s disease, despite the administration of at least 3 immunosuppressive agents, all received mobilisation treatment (cyclophosphamide 4 g/m2 over 2 days followed by recombinant human granulocyte colony stimulating factor (filgrastim) 10 µg/kg daily before randomisation to immediate (after 1 month) or delayed (after 1 year) immunoablation and stem cell transplantation. The conditioning regime was cyclophosphamide 50 mg/kg/day for 4 days, anti-thymocyte globulin 2.5 mg/kg/day and methylprednisolone 1 mg/kg on days 3–5. The bone marrow was reconstituted by the infusion of an unselected graft of 3–8 × 106/kg CD34-positive stem cells. Results were compared 1 year after mobilisation alone or after transplantation. Results: Twelve months after stem cell transplantation (early or delayed) the Crohn’s Disease Activity Index (CDAI) fell from 324 (median, interquartile range 229–411) to 161 (85–257, n = 17) compared to 351 (287–443) to 272 (214–331) following mobilisation alone (n = 11). Six patients had a normal CDAI after transplantation versus 1 after mobilisation. C-reactive protein fell from 16.6 (6.7–32.0) to 6.5 (3.5–12.5) mg/l versus 14 (8.0–27.0) to 9.0 (2.0–23.4) mg/l following mobilisation alone. The Crohn’s Disease Endoscopic Index of Severity (CDEIS) (aggregate for upper and lower endoscopy) fell from 18 (10–25) to 5 (1–11) following transplantation versus 14 (12–16) to 9 (4–22) following mobilisation. Three patients achieved the goal of a normal CDAI, no drug therapy and normal upper and lower endoscopy 1 year after transplantation, but so did 1 patient following mobilisation alone. Serious adverse events were common (n = 100 to date) with 42 infective episodes requiring or prolonging hospitalisation, following both mobilisation and conditioning and transplantation. There were 7 episodes of viral (re)activation. Temporary flare of Crohn’s disease activity or a need for surgery occurred in 8 patients. Conclusions: Immunoablation and haemopoietic stem cell transplantation appear to be an effective treatment for some patients with Crohn’s disease, although full results will be required for a firm conclusion. The risks are significant, making it potentially suitable for only a limited number of patients. Data from the whole trial will be needed to judge whether mobilisation alone has any benefits.
© 2012 S. Karger AG, Basel
- Lopez-Cubero SO, Sullivan KM, McDonald GB: Course of Crohn’s disease after allogenic marrow transplantation. Gastroenterology 1998;114:433–440.
- Ditschkowski M, Einsele H, Schwerdtfeger R, et al: Improvement of inflammatory bowel disease after allogenic stem-cell transplantation. Transplantation 2003;75:1745–1747.
- Sonwalkar SA, James RM, Ahmad T, Zhang L, Verbeke CS, Barnard DL, Jewell DP, Hull MA: Fulminant Crohn’s colitis after allogeneic stem cell transplantation. Gut 2003;52:1518–1521.
- Glocker EO, Frede N, Perro M, Sebire N, Elawad M, Shah N: Grimbacher B infant colitis – it’s in the genes. Lancet 2010;376:1272.
Elawad M: Personal communication.
- Drakos PE, Nagler A, Or R: Case of Crohn’s disease in bone marrow transplantation. Am J Hematol 1993;43:157–158.
Castro J, Bentch H, Smith L, et al: Prolonged clinical remission in patients with inflammatory bowel disease (IBD) after high dose chemotherapy (HDC) and autologous blood stem cell transplantation. Blood 1996;88(suppl):133A.
- Kashyap A, Forman SJ: Autologous bone marrow transplantation for non-Hodgkin’s lymphoma resulting in long-term remission of coincidental Crohn’s disease. Br J Haematol 1998;103:651–652.
- Talbot DC, Montes A, Teh WL, Nandi A, Powles RI: Remission of Crohn’s disease following allogenic bone marrow transplant for acute leukaemia. Hosp Med 1998;59:580–581.
- Musso M, Porretto F, Crescimanno A, et al: Crohn’s disease complicated by relapsed extranodal Hodgkin’s lymphoma: prolonged complete remission after unmanipulated PBPC autotransplant. Bone Marrow Transplant 2000;26:921–923.
- Marti JI, Mayordomo JI, Isla MD, et al: PBSC autotransplant for inflammatory bowel disease (IBD): a case of ulcerative colitis. Bone Marrow Transplant 2001;28:109–110.
- Solderholm JD, Malm C, Juliusson G, Sjodahl R: Long term endoscopic remission of Crohn’s disease after autologous stem cell transplantation for acute myeloid leukaemia. Scand J Gastroenterol 2002;37:613–616.
- Hawkey CJ: Stem cell transplantation for Crohn’s disease. Best Pract Res Clin Haematol 2004;17:317–325.
- Anumakonda V, Hayee B, Chung-Faye G: Remission and relapse of Crohn’s disease following autologous haematopoietic stem cell transplantation for non-Hodgkin’s lymphoma. Gut 2007;56:1325.
- Tyndall A: Successes and failures of stem cell transplantation in autoimmune diseases. Hematology 2011;280–284.
- Kreisel W, Potthoff K, Bertz H, et al: Complete remission of Crohn’s disease after high-dose cyclophosphamide and autologous stem cell transplantation. Bone Marrow Transplant 2003;32:337–340.
- Scime R, Cavalllaro AM, Tringali S, et al: Complete clinical remission after high dose immune suppression and autologous hematopoietic stem cell transplantation in severe Crohn’s disease refractory to immunosuppressive and immunomodulator therapy. Inflamm Bowel Dis 2004;10:892–894.
- Oyama Y, Craig RM, Traynor AE, et al: Autologous hematopoietic stem cell transplantation in patients with refractory Crohn’s disease. Gastroenterology 2005;128:552–563.
- Cassinotti A, Annaloro C, Ardizzone S, et al: Autologous haematopoietic stem cell transplantation without CD34+ cell selection in refractory Crohn’s disease. Gut 2008;57:211–217.
- Burt RK, Craig RM, Milanetti F, Quigley K, Gozdziak P, Bucha J, Testori A, Halverson A, Verda L, de Villiers WJ, Jovanovic B, Oyama Y: Autologous nonmyeloablative hematopoietic stem cell transplantation in patients with severe anti-TNF refractory Crohn disease: long-term follow-up. Blood 2010;116:6123–6132.
- Kountouras J, Sakellari I, Tsarouchas G, Tsiaousi E, Michael S, Zavos C, Anastasiadou K, Stergiopoulos C, Anagnostopoulos A: Autologous haematopoietic stem cell transplantation in a patient with refractory Crohn’s disease. J Crohn Colitis 2011;5:275–276.
- Hommes DW, Duijvestein M, Zelinkova Z, Stokkers PC, Ley MH, Stoker J, Voermans C, van Oers MH, Kersten MJ: Long-term follow-up of autologous hematopoietic stem cell transplantation for severe refractory Crohn’s disease. J Crohn Colitis 2011;5:543–549.
Hasselblatt P, Drognitz K, Potthoff K, Bertz H, Kruis W, Schmidt C, Stallmach A, Finke J, Kreisel W: High-dose cyclophosphamide and autologous hematopoietic cell transplantation for inflammatory bowel disease – a single center experience. Falk Symp, Basel 2012, poster 33.
- Brittan M, Hunt T, Jeffery R, Poulsom R, Forbes SJ, Hodivala-Dilke K, Goldman J, Alison MR, Wright NA: Bone marrow derivation of pericryptal myofibroblasts in the mouse and human small intestine and colon. Gut 2002;50:752–757.
- Garcia-Gomez I, Elvira G, Zapata AG, Lamana ML, Ramirez M, Castro JG, Arranz MG, Vicente A, Bueren J, Garcia-Olmo D: Mesenchymal stem cells: biological properties and clinical applications. Expert Opin Biol Ther 2010;10:1453–1468.
Ratajczak MZ, Suszynska M, Pedziwiatr D, Mierzejewska K, Greco NJ: Umbilical cord blood-derived very small embryonic like stem cells (VSELs) as a source of pluripotent stem cells for regenerative medicine. Pediatr Endocrinol Rev. 2012;9:639–643.
- van der Flier LG, Clevers H: Stem cells, self-renewal, and differentiation in the intestinal epithelium. Ann Rev Physiol 2009;71:241–260.
Article / Publication Details
Copyright / Drug Dosage / DisclaimerCopyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.