BACKGROUND Benefits of cord blood transplantation include low rates of relapse and chronic graft-versus-host disease (GVHD). However, the use of cord blood is rapidly declining because of the high incidence of infections, severe acute GVHD, and transplant-related mortality. UM171, a haematopoietic stem cell self-renewal agonist, has been shown to expand cord blood stem cells and enhance multilineage blood cell reconstitution in mice. We aimed to investigate the safety and feasibility of single UM171-expanded cord blood transplantation in patients with haematological malignancies who do not have a suitable HLA-matched donor. METHODS This single-arm, open-label, phase 1-2 safety and feasibility study was done at two hospitals in Canada. The study had two parts. In part 1, patients received two cord blood units (one expanded with UM171 and one unmanipulated cord blood) until UM171-expanded cord blood demonstrated engraftment. Once engraftment was documented we initiated part 2, reported here, in which patients received a single UM171-expanded cord blood unit with a dose de-escalation design to determine the minimal cord blood unit cell dose that achieved prompt engraftment. Eligible patients were aged 3-64 years, weighed 12 kg or more, had a haematological malignancy with an indication for allogeneic hematopoietic stem cell transplant and did not have a suitable HLA-matched donor, and a had a Karnofsky performance status score of 70% or more. Five clinical sites were planned to participate in the study; however, only two study sites opened, both of which only treated adult patients, thus no paediatric patients (aged <18 years) were recruited. Patients aged younger than 50 years without comorbidities received a myeloablative conditioning regimen (cyclophosphamide 120 mg/kg, fludarabine 75 mg/m2, and 12 Gy total body irradiation) and patients aged older than 50 years and those with comorbidities received a less myeloablative conditioning regimen (cyclophosphamide 50 mg/kg, thiotepa 10 mg/kg, fludarabine 150 mg/m2, and 4 Gy total body irradiation). Patients were infused with the 7-day UM171-expanded CD34-positive cells and the lymphocyte-containing CD34-negative fraction. The primary endpoints were feasibility of UM171 expansion, safety of the transplant, kinetics of hematopoietic reconstitution (time to neutrophil and platelet engraftment) of UM171-expanded cord blood, and minimal pre-expansion cord blood unit cell dose that achieved prompt engraftment. We analysed feasibility in all enrolled patients and all other primary outcomes were analysed per protocol, in all patients who received single UM171-expanded cord blood transplantation. This trial has been completed and was registered with ClinicalTrials.gov, NCT02668315. FINDINGS Between Feb 17, 2016, and Nov 11, 2018, we enrolled 27 patients, four of whom received two cord blood units for safety purposes in part 1 of the study. 23 patients were subsequently enrolled in part 2 to receive a single UM171-expanded cord blood transplant and 22 patients received a single UM171-expanded cord blood transplantation. At data cutoff (Dec 31, 2018), median follow-up was 18 months (IQR 12-22). The minimal cord blood unit cell dose at thaw that achieved prompt engraftment as a single cord transplant after UM171 expansion was 0·52 × 105 CD34-positive cells. We successfully expanded 26 (96%) of 27 cord blood units with UM171. Among the 22 patients who received single UM171-expanded cord blood transplantation, median time to engraftment of 100 neutrophils per μL was 9·5 days (IQR 8-12), median time to engraftment of 500 neutrophils per μL was 18 days (12·5-20·0), and no graft failure occurred. Median time to platelet recovery was 42 days (IQR 35-47). The most common non-haematological adverse events were grade 3 febrile neutropenia (16 [73%] of 22 patients) and bacteraemia (nine [41%]). No unexpected adverse events were observed. One (5%) of 22 patients died due to treatment-related diffuse alveolar haemorrhage. INTERPRETATION Our preliminary findings suggest that UM171 cord blood stem cell expansion is feasible, safe, and allows for the use of small single cords without compromising engraftment. UM171-expanded cord blood might have the potential to overcome the disadvantages of other cord blood transplants while maintaining the benefits of low risk of chronic GVHD and relapse, and warrants further investigation in randomised trials. FUNDING Canadian Institutes of Health Research, Canadian Cancer Society and Stem Cell Network.

中文翻译：

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使用单UM171扩增脐带血进行造血干细胞移植：单臂1-2期安全性和可行性研究。

背景技术脐带血移植的益处包括低复发率和慢性移植物抗宿主病（GVHD）。但是，由于感染率高，严重的急性GVHD和与移植相关的死亡率高，脐带血的使用量正在迅速下降。UM171是一种造血干细胞自我更新激动剂，已显示可在小鼠中扩增脐带血干细胞并增强多谱系血细胞重构。我们旨在研究单次UM171脐​​带血移植在没有合适的HLA匹配供体的血液系统恶性肿瘤患者中的安全性和可行性。方法这项单臂，开放标签的1-2期安全性和可行性研究是在加拿大的两家医院进行的。该研究分为两个部分。在第1部分中 患者接受了两个脐带血单位（一个用UM171扩增，一个未处理的脐带血），直到UM171扩增的脐带血被证实植入为止。一旦记录了植入情况，我们便开始在此处进行报告的第2部分，其中患者接受单UM171扩展的脐带血单位，并采用剂量降级设计，以确定实现快速植入的最小脐带血单位细胞剂量。符合条件的患者年龄在3-64岁，体重在12 kg或以上，患有血液系统恶性肿瘤，具有同种异体造血干细胞移植的适应症，并且没有合适的HLA匹配供体，其Karnofsky行为状态评分为70％或者更多。计划有五个临床站点参与该研究。但是，只有两个研究站点开放，两个站点都只治疗成年患者，因此，未招募任何小于18岁的小儿患者。年龄小于50岁且无合并症的患者接受清髓性调理方案（环磷酰胺120 mg / kg，氟达拉滨75 mg / m2和12 Gy全身照射）和年龄大于50岁且合并症的患者接受清髓性调理方案较少（环磷酰胺50 mg / kg，噻替帕10 mg / kg，氟达拉滨150 mg / m2和4 Gy全身照射）。患者接受了为期7天的UM171扩增的CD34阳性细胞和含淋巴细胞的CD34阴性组分的输注。主要终点是UM171扩增脐带血的可行性，移植的安全性，造血重建的动力学（中性粒细胞和血小板植入的时间），和最少的扩增前脐血单位细胞剂量，即可迅速植入。我们分析了所有入组患者的可行性，并对所有接受单次UM171扩增脐带血移植的患者均按方案分析了所有其他主要结局。该试验已经完成，并已在ClinicalTrials.gov上注册，编号NCT02668315。研究结果在2016年2月17日至2018年11月11日之间，我们招募了27位患者，其中4位出于安全目的在研究的第一部分中接受了两个脐带血单位。随后将23例患者纳入第2部分，以接受单次UM171扩增的脐血移植，而22例患者接受单次UM171扩增的脐血移植。在数据截止日（2018年12月31日），中位随访时间为18个月（IQR 12-22）。在UM171扩增后，作为单条脐带移植迅速植入的融化后的脐带血最小单细胞剂量为0·52×105 CD34阳性细胞。我们使用UM171成功扩大了27个脐带血单位中的26个（96％）。在接受单次UM171扩增的脐血移植的22例患者中，每μL植入100个中性粒细胞的中位时间为9·5天（IQR 8-12），每μL植入500个中性粒细胞的中位时间为18天（12· 5-20·0），并且没有发生移植失败。血小板恢复的中位时间为42天（IQR 35-47）。最常见的非血液学不良事件为3级发热性中性粒细胞减少（22例患者中的16例[73％]）和菌血症（9例[41％]）。没有观察到意外的不良事件。22名患者中有1名（5％）因与治疗有关的弥漫性肺泡出血而死亡。解释我们的初步发现表明，UM171脐​​带血干细胞扩增是可行，安全的，并允许使用小的单根脐带而不损害植入。UM171扩增的脐带血可能具有克服其他脐带血移植的弊端的潜力，同时保持了慢性GVHD和复发的低风险优势，因此有必要在随机试验中进行进一步研究。资金加拿大卫生研究所，加拿大癌症协会和干细胞网络。UM171扩增的脐带血可能具有克服其他脐带血移植的弊端的潜力，同时保持了慢性GVHD和复发的低风险优势，因此有必要在随机试验中进行进一步研究。资金加拿大卫生研究所，加拿大癌症协会和干细胞网络。UM171扩增的脐带血可能具有克服其他脐带血移植的弊端的潜力，同时保持了慢性GVHD和复发的低风险优势，因此有必要在随机试验中进行进一步研究。资金加拿大卫生研究所，加拿大癌症协会和干细胞网络。