Background

Donors other than matched siblings and low-intensity conditioning regimens are increasingly used in haematopoietic stem cell transplantation. We aimed to compare the relative risk of donor type and conditioning regimen intensity on the transplantation outcomes of in patients with sickle cell disease.

Methods

For this retrospective cohort study, we collected data from 90 US centres reported to the Center for International Blood and Marrow Transplant Research. Eligible patients were younger than 50 years, had genetically confirmed sickle cell disease (Hb SS) or sickle beta thalassemia (Hb Sβ), and underwent allogeneic haematopoietic cell transplantation between Jan 15, 2008, and Dec 28, 2017. We considered transplants from donor-recipient pairs matched at the allele-level (HLA-A, HLA-B, HLA-C, and HLA-DRB1), including HLA-matched sibling donors, haploidentical related donors, matched unrelated donors, or mismatched unrelated donors. The main outcome was event-free survival. The effect of donor type, conditioning regimen intensity (myeloablative, non-myeloablative, and reduced-intensity regimens), age (≤12 or 13-49 years), sex, performance score, comorbidity index, recipient cytomegalovirus serostatus, graft type (bone marrow, peripheral blood, or umbilical cord blood), and transplantation period (2008–12 and 2013–17) on outcomes was studied using Cox regression models.

Findings

Of 996 patients with sickle cell disease and who underwent transplantation in 2008–17, 910 (91%) were included (558 [61%] patients had HLA-matched sibling donors, 137 [15%] haploidentical related donors, 111 [12%] matched unrelated donors, and 104 [11%] mismatched unrelated donors). The median follow-up was 36 months (IQR 18–60) after transplantation from HLA-matched siblings, 25 months (12–48) after transplantation from haploidentical related donors, 37 months (23–60) after transplantation from HLA-matched unrelated donors, and 47 months (24–72) after transplantation from mismatched unrelated donors. Event-free survival was worse in recipients aged 13 years or older than in those younger than 13 years (hazard ratio 1·74, 95% CI 1·24–2·45; p=0·0014) and in those who received a transplant from haploidentical related donors (5·30, 3·17–8·86; p<0·0001), matched unrelated donors (3·71, 2·39–5·75; p<0·0001), and mismatched unrelated donors (4·34, 2·58–7·32; p<0·0001) than in patients who received a transplant from matched siblings. There was no significant difference in event-free survival between recipients of transplants from non-sibling donors: haploidentical related donors (1·43, 0·81–2·50; p=0·21) or mismatched unrelated donors (1·17, 0·67–2·05; p=0·58) versus HLA-matched unrelated donors, or mismatched unrelated donors versus haploidentical related donors (1·22, 0·65–2·27; p=0·98). Event-free survival was also worse in patients conditioned with reduced-intensity regimens (1·97, 1·15–3·36; p=0·013) than in those conditioned with non-myeloablative regimens, but did not differ between those who received myeloablative compared with non-myeloablative regimens (1·57, 0·95–2·61; p=0·079). Interpretation Our data suggest that event-free survival is improved in patients with sickle cell disease who receive an allogenic transplantation at age 12 years or younger and those with an HLA-matched sibling donor. For patients without a matched sibling available for transplantation, our data do not favour one alternative donor type over another in this setting.

Funding

National Institutes of Health and US Health Services Research Administration, Department of Health and Human Services.

中文翻译：

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供体类型和条件治疗强度对镰状细胞病患者同种异体移植结局的影响：一项回顾性多中心队列研究

背景

除同胞兄弟姐妹和低强度条件疗法外，其他捐赠者也越来越多地用于造血干细胞移植。我们旨在比较供体类型和条件疗法强度对镰状细胞病患者移植结局的相对风险。

方法

对于这项回顾性队列研究，我们收集了90个美国中心的数据，这些中心已报告给国际血液和骨髓移植研究中心。符合条件的患者年龄小于50岁，在2008年1月15日至2017年12月28日之间进行了遗传学确认的镰状细胞病（Hb SS）或镰状β地中海贫血（HbSβ），并接受了同种异体造血细胞移植。等位基因水平（HLA-A，HLA-B，HLA-C和HLA-DRB1），包括与HLA匹配的同胞供体，与单性相关的供体，匹配的不相关供体或不匹配的不相关供体。主要结果是无事件生存。供体类型，调节方案强度（清髓，非清髓和强度降低方案），年龄（≤12或13-49岁），性别，性能评分，合并症指数，受体巨细胞病毒血清状况，移植物类型（骨）的影响使用Cox回归模型研究了骨髓，外周血或脐带血）以及移植期（2008-12和2013-17）的结局。

发现

在2008-17年度有996例镰状细胞病患者中接受移植，其中910例（91％）被纳入研究（558 [61％]患者为HLA匹配的同胞供体，137 [15％]个与单身相关的供体，111 [12％] ]匹配的无关捐赠者，以及104 [11％]个不匹配的无关捐赠者）。从HLA匹配的同胞移植后，中位随访时间为36个月（IQR 18-60），从单倍体相关供体移植后，中位随访时间为25个月（12-48），从HLA匹配的非亲缘关系移植后37个月（23-60）供体，以及不匹配的不相关供体移植后47个月（24-72）。13岁或13岁以上的接受者的无事件生存期比13岁以下的接受者的无事件生存期更差（危险比1·74，95％CI 1·24-2·45； p = 0·0014）和接受单倍体相关供体的移植（5·30、3·17-8·86； p < 0·0001），匹配的无关供体（3·71、2·39-5·75； p <0·0001）和不匹配的无关供体（4·34、2·58-7·32； p <0·0001 ），而不是从同胞兄弟姐妹那里接受移植手术的患者。非同胞供体的移植受者之间的无事件存活率无显着差异：单倍相关供体（1·43，0·81–2·50; p = 0·21）或不匹配的不相关供体（1·17） ，0·67–2·05; p = 0·58）与HLA匹配的无关供体，或不匹配的无关的供体与单倍相关的供体（1·22，0·65-2·27; p = 0·98）。强度降低的患者（1·97、1·15–3·36； p = 0·013）的无事件生存率也比非清髓治疗的患者差，但两者之间无差异与非清髓疗法相比，接受清髓疗法的患者（1·57、0·95–2·61；p = 0·079）。解释我们的数据表明，镰状细胞病患者（年龄在12岁以下）和HLA匹配的同胞供者移植后，无事件生存率均得到改善。对于没有可匹配兄弟姐妹进行移植的患者，在这种情况下，我们的数据不赞成一种供体替代另一种供体。

资金

美国国立卫生研究院和美国卫生服务研究局，卫生与公共服务部。