Cohen Sandra, Roy Jean, Lachance Silvy, Delisle Jean-Sébastien, Marinier Anne, Busque Lambert, Roy Denis-Claude, Barabé Frédéric, Ahmad Imran, Bambace Nadia, Bernard Léa, Kiss Thomas, Bouchard Philippe, Caudrelier Pierre, Landais Sévérine, Larochelle Fannie, Chagraoui Jalila, Lehnertz Bernhard, Corneau Sophie, Tomellini Elisa, van Kampen Jeroen J A, Cornelissen Jan J, Dumont-Lagacé Maude, Tanguay Mégane, Li Qi, Lemieux Sébastien, Zandstra Peter W, Sauvageau Guy
Division of Hematology, Maisonneuve-Rosemont Hospital, Montreal, QC, Canada; Department of Medicine, Montreal, QC, Canada.
Division of Hematology, Maisonneuve-Rosemont Hospital, Montreal, QC, Canada; Department of Medicine, Montreal, QC, Canada.
Lancet Haematol. 2020 Feb;7(2):e134-e145. doi: 10.1016/S2352-3026(19)30202-9. Epub 2019 Nov 6.
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.
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/m, 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/m, 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.
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 × 10 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.
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.
Canadian Institutes of Health Research, Canadian Cancer Society and Stem Cell Network.
脐血移植的益处包括复发率低和慢性移植物抗宿主病（GVHD）发生率低。然而，由于感染、严重急性GVHD和移植相关死亡率的高发生率，脐血的使用正在迅速下降。UM171是一种造血干细胞自我更新激动剂，已被证明可在小鼠中扩增脐血干细胞并增强多系血细胞重建。我们旨在研究单份经UM171扩增的脐血移植在没有合适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。
这项单臂、开放标签的1-2期安全性和可行性研究在加拿大的两家医院进行。该研究分为两个部分。在第1部分中，患者接受两份脐血单位（一份用UM171扩增，一份未处理的脐血），直到经UM171扩增的脐血显示植入。一旦记录到植入，我们就启动了第2部分，即本文所报告的部分，其中患者接受单份经UM171扩增的脐血单位，并采用剂量递减设计以确定实现快速植入所需的最小脐血单位细胞剂量。符合条件的患者年龄在3至64岁之间，体重12千克或以上，患有血液系统恶性肿瘤且有同种异体造血干细胞移植指征，没有合适的HLA匹配供体，且卡诺夫斯基表现状态评分在70%或以上。计划有五个临床地点参与该研究；然而，仅两个研究地点开放，且这两个地点仅治疗成年患者，因此未招募儿科患者（年龄<18岁）。年龄小于50岁且无合并症的患者接受清髓性预处理方案（环磷酰胺120mg/kg、氟达拉滨75mg/m²和全身照射12Gy），年龄大于50岁及有合并症的患者接受强度较低的预处理方案（环磷酰胺50mg/kg、噻替派10mg/kg、氟达拉滨150mg/m²和全身照射4Gy）。患者输注经UM171扩增7天的CD34阳性细胞和含淋巴细胞的CD34阴性部分。主要终点是UM171扩增的可行性、移植的安全性、经UM171扩增的脐血造血重建动力学（中性粒细胞和血小板植入时间）以及实现快速植入所需的最小预扩增脐血单位细胞剂量。我们分析了所有入组患者的可行性，所有其他主要结局在所有接受单份经UM171扩增的脐血移植的患者中按照方案进行分析。该试验已完成，并在ClinicalTrials.gov上注册，注册号为NCT02668315。
在2016年2月17日至2018年11月11日期间，我们招募了27名患者，其中4名患者在研究的第1部分中出于安全目的接受了两份脐血单位。随后有23名患者进入第2部分接受单份经UM171扩增的脐血移植，22名患者接受了单份经UM171扩增的脐血移植。在数据截止（2018年12月31日）时，中位随访时间为18个月（四分位间距12 - 22个月）。经UM171扩增后作为单份脐血移植实现快速植入所需的解冻时最小脐血单位细胞剂量为0.52×10⁶个CD34阳性细胞。我们成功地用UM171扩增了27份脐血单位中的26份（96%）。在22名接受单份经UM171扩增的脐血移植的患者中，每微升100个中性粒细胞的中位植入时间为9.5天（四分位间距8 - 12天），每微升500个中性粒细胞的中位植入时间为18天（12.5 - 20.0天），且未发生移植失败。血小板恢复的中位时间为42天（四分位间距35 - 47天）。最常见的非血液学不良事件是3级发热性中性粒细胞减少（22名患者中的16名[73%]）和菌血症（9名[41%]）。未观察到意外不良事件。22名患者中有1名（5%）因治疗相关的弥漫性肺泡出血死亡。
我们的初步研究结果表明，UM171扩增脐血干细胞是可行、安全的，并且允许使用小份单份脐血而不影响植入。经UM171扩增的脐血可能有潜力克服其他脐血移植的缺点，同时保持慢性GVHD和复发风险低的益处，值得在随机试验中进一步研究。
加拿大卫生研究院、加拿大癌症协会和干细胞网络。
