Abstract

Safety and efficacy of autologous haematopoietic stem-cell transplantation with low-dose cyclophosphamide mobilisation and reduced intensity conditioning versus standard of care in refractory Crohn's disease (ASTIClite): an open-label, multicentre, randomised controlled trial

Lancet Gastroenterol Hepatol. 2024 Apr;9(4):333-345.doi: 10.1016/S2468-1253(23)00460-0. Epub 2024 Feb 7.

 

James O Lindsay 1Daniel Hind 2Lizzie Swaby 2Hannah Berntsson 2Mike Bradburn 2Uday Bannur C 3Jennifer Byrne 4Christopher Clarke 3Lauren Desoysa 2Ben Dickins 5Shahida Din 6Richard Emsley 7Gemma A Foulds 5John Gribben 8Christopher Hawkey 9Peter M Irving 10Majid Kazmi 11Ellen Lee 2Amanda Loban 2Alan Lobo 12Yashwant Mahida 9Gordon W Moran 9Diana Papaioannou 2Miles Parkes 13Andrew Peniket 14A Graham Pockley 5Jack Satsangi 15Sreedhar Subramanian 16Simon Travis 17Emily Turton 2Ben Uttenthal 18Sergio Rutella 5John A Snowden 19

 
     

Author information

1Centre for Immunobiology, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK. Electronic address: james.lindsay8@nhs.net.

2Sheffield Clinical Trials Research Unit, University of Sheffield, Sheffield, UK.

3Department of Radiology, Nottingham University Hospitals NHS Trust, Nottingham, UK.

4Department of Haematology, Nottingham University Hospitals NHS Trust, Nottingham, UK.

5John van Geest Cancer Research Centre, School of Science and Technology, Nottingham Trent University, Nottingham, UK.

6Department of Gastroenterology, Western General Hospital, Edinburgh, UK.

7Department of Biostatistics & Health Informatics, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK.

8Barts Cancer Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.

9NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust, Nottingham, UK; Translational Medical Sciences, School of Medicine, Faculty of Medicine and Health Sciences, University of Nottingham, Nottingham, UK.

10Department of Gastroenterology, Guy's and Saint Thomas' Hospitals NHS Trust, London, UK.

11King's College Hospital NHS Foundation Trust, London, UK.

12Department of Gastroenterology, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK.

13Department of Medicine, University of Cambridge, Cambridge, UK.

14Department of Haematology, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.

15NIHR Oxford Biomedical Research Centre, Oxford University Hospitals NHS Foundation Trust, John Radcliffe Hospital, Oxford, UK.

16Liverpool University Hospitals NHS Foundation Trust, Liverpool, UK.

17NIHR Biomedical Research Centre, Translational Gastroenterology Unit, Nuffield Department of Experimental Medicine, University of Oxford, Oxford, UK.

18Department of Clinical Haematology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.

19Division of Clinical Medicine, School of Medicine and Population Health, University of Sheffield, Sheffield, UK; Department of Haematology, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK.

 

Abstract

Background: A previous controlled trial of autologous haematopoietic stem-cell transplantation (HSCT) in patients with refractory Crohn's disease did not meet its primary endpoint and reported high toxicity. We aimed to assess the safety and efficacy of HSCT with an immune-ablative regimen of reduced intensity versus standard of care in this patient population.

Methods: This open-label, multicentre, randomised controlled trial was conducted in nine National Health Service hospital trusts across the UK. Adults (aged 18-60 years) with active Crohn's disease on endoscopy (Simplified Endoscopic Score for Crohn's Disease [SES-CD] ulcer sub-score of ≥2) refractory to two or more classes of biological therapy, with no perianal or intra-abdominal sepsis or clinically significant comorbidity, were recruited. Participants were centrally randomly assigned (2:1) to either HSCT with a reduced dose of cyclophosphamide (intervention group) or standard care (control group). Randomisation was stratified by trial site by use of random permuted blocks of size 3 and 6. Patients in the intervention group underwent stem-cell mobilisation (cyclophosphamide 1 g/m2 with granulocyte colony-stimulating factor (G-CSF) 5 μg/kg) and stem-cell harvest (minimum 2·0 × 106 CD34+ cells per kg), before conditioning (fludarabine 125 mg/m2, cyclophosphamide 120 mg/kg, and rabbit anti-thymocyte globulin [thymoglobulin] 7·5 mg/kg in total) and subsequent stem-cell reinfusion supported by G-CSF. Patients in the control group continued any available conventional, biological, or nutritional therapy. The primary outcome was absence of endoscopic ulceration (SES-CD ulcer sub-score of 0) without surgery or death at week 48, analysed in the intention-to-treat population by central reading. This trial is registered with the ISRCTN registry, 17160440.

Findings: Between Oct 18, 2018, and Nov 8, 2019, 49 patients were screened for eligibility, of whom 23 (47%) were randomly assigned: 13 (57%) to the intervention group and ten (43%) to the control group. In the intervention group, ten (77%) participants underwent HSCT and nine (69%) reached 48-week follow-up; in the control group, nine (90%) reached 48-week follow-up. The trial was halted in response to nine reported suspected unexpected serious adverse reactions in six (46%) patients in the intervention group, including renal failure due to proven thrombotic microangiopathy in three participants and one death due to pulmonary veno-occlusive disease. At week 48, absence of endoscopic ulceration without surgery or death was reported in three (43%) of seven participants in the intervention group and in none of six participants in the control group with available data. Serious adverse events were more frequent in the intervention group (38 in 13 [100%] patients) than in the control group (16 in four [40%] patients). A second patient in the intervention group died after week 48 of respiratory and renal failure.

Interpretation: Although HSCT with an immune-ablative regimen of reduced intensity decreased endoscopic disease activity, significant adverse events deem this regimen unsuitable for future clinical use in patients with refractory Crohn's disease.

Funding: Efficacy and Mechanism Evaluation Programme, a Medical Research Council and National Institute for Health Research partnership.

© Copyright 2013-2024 GI Health Foundation. All rights reserved.
This site is maintained as an educational resource for US healthcare providers only. Use of this website is governed by the GIHF terms of use and privacy statement.