1 Charité - University Medical Center Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany.
2 Berlin Institute of Health, Berlin, Germany.
J Clin Oncol. 2019 Feb 10;37(5):375-385. doi: 10.1200/JCO.2018.79.2184. Epub 2018 Nov 7.
Clonal hematopoiesis of indeterminate potential (CHIP) occurs in the blood of approximately 20% of older persons. CHIP is linked to an increased risk of hematologic malignancies and of all-cause mortality; thus, the eligibility of stem-cell donors with CHIP is questionable. We comprehensively investigated how donor CHIP affects outcome of allogeneic hematopoietic stem-cell transplantation (HSCT).
We collected blood samples from 500 healthy, related HSCT donors (age ≥ 55 years) at the time of stem-cell donation for targeted sequencing with a 66-gene panel. The effect of donor CHIP was assessed on recipient outcomes, including graft-versus-host disease (GVHD), cumulative incidence of relapse/progression (CIR/P), and overall survival (OS).
A total of 92 clonal mutations with a median variant allele frequency of 5.9% were identified in 80 (16.0%) of 500 donors. CHIP prevalence was higher in donors related to patients with myeloid compared with lymphoid malignancies (19.2% v 6.3%; P ≤ .001). In recipients allografted with donor CHIP, we found a high cumulative incidence of chronic GVHD (cGVHD; hazard ratio [HR], 1.73; 95% CI, 1.21 to 2.49; P = .003) and lower CIR/P (univariate: HR, 0.62; 95% CI, 0.40 to 0.97; P = .027; multivariate: HR, 0.63; 95% CI, 0.41 to 0.98; P = .042) but no effect on nonrelapse mortality. Serial quantification of 25 mutations showed engraftment of 24 of 25 clones and disproportionate expansion in half of them. Donor-cell leukemia was observed in two recipients. OS was not affected by donor CHIP status (HR, 0.88; 95% CI, 0.65 to 1.321; P = .434).
Allogeneic HSCT from donors with CHIP seems safe and results in similar survival in the setting of older, related donors. Future studies in younger and unrelated donors are warranted to extend these results. Confirmatory studies and mechanistic experiments are warranted to challenge the hypothesis that donor CHIP might foster cGVHD development and reduce relapse/progression risk.
不确定潜能的克隆性造血（CHIP）发生在大约 20%的老年人的血液中。CHIP 与血液系统恶性肿瘤和全因死亡率的风险增加有关；因此，具有 CHIP 的干细胞供体的资格值得怀疑。我们全面研究了供体 CHIP 如何影响异基因造血干细胞移植（HSCT）的结果。
我们在干细胞捐献时从 500 名健康的相关 HSCT 供体（年龄≥55 岁）中采集血液样本，进行靶向测序，使用 66 个基因panel。评估供体 CHIP 对受者结局的影响，包括移植物抗宿主病（GVHD）、累积复发/进展率（CIR/P）和总生存率（OS）。
在 500 名供体中，共鉴定出 80 名（16.0%）供体中存在中位数变异等位基因频率为 5.9%的 92 个克隆突变。与患有髓系恶性肿瘤的患者相比，与患有淋巴系恶性肿瘤的患者相关的供体 CHIP 发生率更高（19.2%比 6.3%；P≤.001）。在接受供体 CHIP 异基因移植的受者中，我们发现慢性 GVHD（cGVHD）的累积发生率较高（风险比 [HR]，1.73；95%置信区间，1.21 至 2.49；P=.003）和较低的 CIR/P（单变量：HR，0.62；95%置信区间，0.40 至 0.97；P=.027；多变量：HR，0.63；95%置信区间，0.41 至 0.98；P=.042），但非复发死亡率无影响。对 25 个突变的连续定量检测显示，25 个克隆中有 24 个发生了嵌合，其中一半发生了不成比例的扩增。在两名受者中观察到供体细胞白血病。OS 不受供体 CHIP 状态的影响（HR，0.88；95%置信区间，0.65 至 1.321；P=.434）。
来自具有 CHIP 的供体的异基因 HSCT 似乎是安全的，并且在年龄较大的相关供体中导致相似的生存率。需要在年轻和无关供体中进行进一步的研究来扩展这些结果。需要确证性研究和机制实验来挑战供体 CHIP 可能促进 cGVHD 发展并降低复发/进展风险的假说。
