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

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