Esophagus to Small Intestine
Lancet Gastroenterol Hepatol. 2024;9(4):333–45
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 end point and reported high toxicity. The aim of this study was 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 9 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 subscore of ≥ 2) refractory to 2 or more classes of biological therapy, with no perianal or intraabdominal 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 subscore of 0) without surgery or death at week 48, analysed in the intention-to-treat population by central reading.
Findings: Between October 18, 2018, and November 8, 2019, 49 patients were screened for eligibility, of whom 23 (47%) were randomly assigned: 13 (57%) to the intervention group and 10 (43%) to the control group. In the intervention group, 10 participants (77%) underwent HSCT and 9 (69%) reached 48-week follow-up; in the control group, 9 (90%) reached 48-week follow-up. The trial was halted in response to 9 reported suspected unexpected serious adverse reactions in 6 patients (46%) in the intervention group, including renal failure due to proven thrombotic microangiopathy in 3 participants and 1 death due to pulmonary veno-occlusive disease. At week 48, absence of endoscopic ulceration without surgery or death was reported in 3 of 7 participants (43%) in the intervention group and in 0 of 6 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 4 [40%] patients). A second patient in the intervention group died after week 48 of respiratory and renal failure.
Interpretation: Although haematopoietic stem-cell transplantation 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.