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.

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/m ² with granulocyte colony-stimulating factor (G-CSF) 5 μg/kg) and stem-cell harvest (minimum 2·0 × 10 ⁶ CD34 ⁺ cells per kg), before conditioning (fludarabine 125 mg/m ² , 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.
Competing Interests: Declaration of interests JOL reports grants for investigator-initiated research from the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation research grant for the current project, AbbVie, Gilead Sciences, Takeda UK, and Shire; honoraria for consulting or advisory boards from AbbVie, Allergan, Atlantic Healthcare, Bristol Meyers Squibb, Celgene, Celltrion, Lilly, Ferring Pharmaceuticals, Galapagos NV, Gilead Sciences, GlaxoSmithKline, Janssen, MSD, Napp Pharmaceuticals, Norgine BV, Pfizer, Shire, Takeda UK, and Vifor Pharma Management; honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from AbbVie, Bristol Meyers Squibb, Ferring Pharmaceuticals, Galapagos NV, Janssen, Norgine BV, Pfizer, Shire, Takeda UK, and Cornerstone Healthcare Group; and support for attending meetings, travel, or both from AbbVie, Takeda UK, MSD, Ferring Pharmaceuticals, and Janssen, outside the submitted work. DH reports part funding for salary through the NIHR Efficacy and Mechanism Evaluation research grant for this project. RE reports participation in the NIHR Clinical Trials Unit Standing Advisory Committee (2020 to present), and the Health Technology Assessment Clinical Evaluation and Trials Committee (2017–21). LD reports various NIHR grants, none of which relate to Crohn's disease or investigate treatments similar to those in ASTIClite. SD reports salary funding from NHS Research Scotland via NHS Lothian to support clinical trial work; grants from the Edinburgh & Lothian Health Foundations Award, the Pathological Society of Great Britain & Northern Ireland, Helmsley Charitable Trust–Gut Cell Atlas Normal and Crohn's Disease, and Helmsley Charitable Trust CDTREAT and BIOPIC studies; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Jannsen, Ferring, Takeda, and AbbVie; and support for attending meetings, travel, or both from Janssen, Dr Falk Symposium, and AbbVie. SD also reports participation on a data safety monitoring board or advisory board for AbbVie and MHRA; and leadership or fiduciary role on other board, society, committee, or advocacy groups for the British Society of Gastroenterology, the Royal College of Physicians of Edinburgh, and the Scottish Government. JG reports consulting fees from AbbVie, AstraZeneca, Bristol Meyers Squibb, Gilead Sciences, Janssen, MorphoSys AG, and Novartis AG; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from AbbVie, Bristol Meyers Squibb, Gilead Sciences, and Janssen; and participation on a data safety monitoring board or advisory board for AstraZeneca, outside the submitted work. PI reports grants or contracts from MSD, Takeda UK, Celltrion, and Pfizer; consulting fees from Bristol Meyers Squibb, AbbVie, Arena, Boehringer-Ingelheim, Celgene, Celltrion, Genentech, Gilead, Hospira, Janssen, Lilly, MSD, Pfizer, Pharmacosmos, Prometheus, Roche, Sandoz, Samsung Bioepis, Takeda, Topivert, VH2, Vifor Pharma, and Warner Chilcott; and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from AbbVie, Bristol Meyers Squibb, Celgene, Celltrion, Dr Falk Pharma GmbH, Ferring Pharmaceuticals, Galapagos NV, Gilead Sciences, MSD, Janssen, Pfizer, Takeda UK, Tillotts Pharma AG, Sapphire Medical, Sandoz, Shire, and Warner Chilcott UK, outside the submitted work. EL reports various other NIHR grants, none of which relate to Crohn's disease or investigate treatments similar to those in ASTIClite; and participation in two data monitoring and ethics committees and two trial steering committees for NIHR trials outside the submitted work, none of which relate to Crohn's disease. MP reports grants or contracts from Pfizer, Gilead Sciences, and Crohn's & Colitis UK, outside the submitted work; and a leadership role as Director of Cambridge Biomedical Research Centre, outside the submitted work (2020 to present). AL reports consulting fees from Takeda UK, Vifor Pharma Management, Janssen, and PredictImmune; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Takeda UK, Janssen, and Celltrion; support for attending meetings, travel, or both from Janssen, Tillotts Pharma AG, Takeda UK, and Vifor Pharma Management; and is Director of the non-executive IBD Registry Board. AGP reports being the Chief Executive Officer of multimmune GmbH, Chief Scientific Officer of Alphageneron Pharmaceuticals, and a member of the scientific advisory board of Cytomos, none of which relate to Crohn's disease and all are outside the submitted work. SS reports grants or contracts from Crohn's & Colitis UK and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Takeda UK, Janssen, AbbVie, Celltrion, Boehringer Ingelheim International GmbH, and Bristol Meyers Squibb, outside the submitted work; and participation on a data safety monitoring board or advisory board for Takeda UK, Janssen, AbbVie, Celltrion, Boehringer Ingelheim International GmbH, Bristol Meyers Squibb, and Vifor Pharma Management, outside the submitted work. JS reports grant funding for IBD research from the European Crohn's & Colitis Organization (ECCO), The Leona M and Harry B Helmsley Charitable Trust, Crohn's & Colitis UK, Crohn's & Colitis Foundation, Action Medical Research, the NIHR Efficacy and Mechanism Evaluation, European Commission FP-7, and Horizon 2020 programmes, outside the submitted work; and payment or honoraria for a lecture for the Falk Foundation, and a leadership role on the UK IBD Registry Management Board. ST reports grants or contracts from ECCO, the Leona M and Harry B Helmsley Charitable Trust, Ferring Pharmaceuticals, Janssen, Lilly, Pfizer, Takeda UK, and the Norman Collisson Charitable Trust; and consulting fees from ai4gi Joint Venture, Allergan, Amgen, Arena Pharmaceuticals, AstraZeneca, Biogen, Boehringer Ingelheim International GmbH, Bristol Meyers Squibb, Bühlmann Laboratories AG, Celgene, ChemoCentryx, Cosmo Pharmaceuticals NV, Enterome, Equillium, Ferring Pharmaceuticals, Genentech–Roche, Gilead Sciences, Glenmark Pharmaceuticals, Grünenthal, GlaxoSmithKline, Immunometabolism, Indigo Diabetes, Janssen, Lilly, Merck KGaA, Mestag Therapeutics, Novartis AG, Pfizer, PharmaVentures, Phesi, Satisfai Health, Sensyne Health, Sorriso, SynDermix, Synthon, Takeda UK, Topivert, UCB SA, Vertex Pharmaceuticals, VHsquared, and Vifor Pharma Management, outside the submitted work. ST also reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from AbbVie, Amgen, Biogen, Dr Falk Pharma GmbH, Ferring Pharmaceuticals, Janssen, Pfizer, Shire, Takeda UK, and UCB SA; payment for expert testimony from Cosmo; support for attending meetings, travel, or both from AbbVie, Amgen, Biogen, Dr Falk Pharma GmbH, Ferring Pharmaceuticals, Janssen, Pfizer, Shire, Takeda UK, and UCB SA; and participation on a data safety monitoring board or advisory board for Amgen, outside the submitted work. SR reports research funding from MacroGenics and Kura Oncology, outside the submitted work. BU reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events for Gilead and Novartis; and support for attending meetings, travel, or both from Takeda and Gilead. JS reports support for the current work through a NIHR Efficacy and Mechanism Evaluation grant; consulting fees from Medac (not directly related to Crohn's disease); and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Jazz Pharmaceuticals, Mallinckrodt Pharmaceuticals, Janssen, Gilead Sciences, Vertex, and Actelion, none of which directly relate to Crohn's disease, outside the submitted work. JS also reports participation on the Kiadis Pharma trial Independent Data Monitoring Committee, which does not directly relate to Crohn's disease, outside the submitted work. All other authors declare no competing interests.
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