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. 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 with granulocyte colony-stimulating factor (G-CSF) 5 μg/kg) and stem-cell harvest (minimum 2·0 × 10 CD34 cells per kg), before conditioning (fludarabine 125 mg/m, 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. 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. 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. Efficacy and Mechanism Evaluation Programme, a Medical Research Council and National Institute for Health Research partnership.

中文翻译：

---

低剂量环磷酰胺动员和降低强度调节的自体造血干细胞移植与标准护理治疗难治性克罗恩病的安全性和有效性 (ASTIClite)：一项开放标签、多中心、随机对照试验

先前对难治性克罗恩病患者进行的自体造血干细胞移植（HSCT）对照试验未达到其主要终点，并报告了高毒性。我们的目的是评估该患者群体中使用强度降低的免疫消融方案与标准护理相比的 HSCT 的安全性和有效性。这项开放标签、多中心、随机对照试验是在英国九家国家卫生服务信托医院进行的。内镜检查患有活动性克罗恩病的成人（18-60 岁）（克罗恩病简化内镜评分 [SES-CD] 溃疡分值≥2），对两类或更多类别的生物治疗无效，且无肛周或肛内治疗招募了腹部脓毒症或临床显着合并症的患者。参与者被集中随机分配 (2:1) 接受减少环磷酰胺剂量的 HSCT（干预组）或标准治疗（对照组）。通过使用大小为 3 和 6 的随机排列块，按试验地点进行随机分组。干预组的患者接受干细胞动员（环磷酰胺 1 g/m 与粒细胞集落刺激因子 (G-CSF) 5 μg/kg）和干细胞收获（每公斤至少 2·0 × 10 个 CD34 细胞），预处理前（氟达拉滨 125 mg/m、环磷酰胺 120 mg/kg、兔抗胸腺细胞球蛋白 [胸腺球蛋白] 7·5 mg/kg） ）以及随后由 G-CSF 支持的干细胞回输。对照组患者继续任何可用的常规、生物或营养疗法。主要结局是在第 48 周时未进行内镜下溃疡（SES-CD 溃疡分值为 0）或死亡，通过中心读数在意向治疗人群中进行分析。该试验在 ISRCTN 登记处注册，编号为 17160440。2018 年 10 月 18 日至 2019 年 11 月 8 日期间，对 49 名患者进行了资格筛查，其中 23 名患者 (47%) 被随机分配： 13 名患者 (57%) 被分配到干预组对照组有 10 名（43%）。在干预组中，10 名（77%）参与者接受了 HSCT，9 名（69%）参与者进行了 48 周随访；在对照组中，九人（90%）达到了 48 周的随访。由于干预组中 6 名（46%）患者出现 9 例疑似意外严重不良反应，该试验被暂停，其中包括 3 名受试者因证实的血栓性微血管病导致肾衰竭以及 1 名受试者因肺静脉闭塞性疾病死亡。在第 48 周时，干预组 7 名参与者中的 3 名 (43%) 报告没有内镜下溃疡，无需手术或死亡，而对照组的 6 名参与者中无一人报告有可用数据。干预组（13 例 [100%] 患者中出现 38 例）严重不良事件发生率高于对照组（4 例 [40%] 患者中出现 16 例）。干预组中的第二名患者在第 48 周后因呼吸和肾衰竭死亡。尽管采用降低强度的免疫消融方案的 HSCT 降低了内镜下疾病活动性，但显着的不良事件认为该方案不适合未来临床用于难治性克罗恩病患者。功效和机制评估计划，是医学研究委员会和国家健康研究所的合作伙伴。