背景:改进的治疗方案,例如降低强度的调理,使老年患者能够接受潜在治愈性异基因造血细胞移植(HCT).这一进展增加了对老年HLA匹配同胞供体的使用。与老年供体相关的意外潜在风险是将具有克隆造血(CH)的供体细胞移植到患者体内。
目的:我们旨在确定移植前HLA匹配的老年同胞供者中CH的患病率,并评估供者移植的CH对HCT结局的临床影响。
方法:这是一项观察性研究,使用来自国际血液和骨髓移植研究中心资料库的供体外周血样本,与相应的接受者结果相关。探讨HCT后CH突变的植入效率和进化,包括通过骨髓移植临床试验网络(#1202)获得的受体随访样本.接受首次降低强度HCT治疗骨髓性恶性肿瘤的老年供体和患者(均≥55岁)符合资格。来自存档的供体血液样品的DNA用于靶向深度测序以鉴定CH。捐赠者CH状态和接受者结果之间的关联,包括急性GVHD(aGVHD),慢性移植物抗宿主病(cGVHD),总生存率,复发,非复发死亡率,无病生存,无GVHD和无复发的复合生存率,无CGVHD和无复发生存率,进行了分析。
结果:总共299个供体成功测序以检测CH。在变异等位基因频率≥2%时,13.7%(41/299)的HLA匹配同胞供者有44个CH突变.CH主要涉及DNMT3A(27,61.4%)和TET2(9,20.5%)。来自13个受者的HCT后样本也进行了测序,其中7个有CH+供体。在HCT后第56天或第90天在受体中检测到所有供体CH突变(7/7,100%)。总的来说,突变VAF保持相对恒定直到HCT后第90天(中值变化0.005,范围-0.008-0.024)。受体第56天和第90天数据的加倍时间分析表明,供体嫁接的CH突变最初扩展,然后减少到稳定的VAF;种系突变比CH突变具有更长的倍增时间。在第100天,II-IV级aGVHD的累积发病率在有CH供体的接受者中较高(37.5%vs.25.1%);然而,供者CH状态的aGVHD风险未达到统计学意义(HR1.35,95%CI0.61-3.01,p=0.47).cGVHD的累积发生率或任何次要结局在供体CH状态方面没有统计学上的显着差异。在子集分析中,与没有DNMT3A-CH的供体相比,有DNMT3A-CH的供体的cGVHD发生率较低(34.4%vs57%,p=0.035)。在任何供体-受体对中均未报告供体细胞白血病。
结论:CH在老年HLA匹配的同胞供者中是相对常见的,并且成功移植并在受体中持续存在。在同质人群中(骨髓性恶性肿瘤,年长的捐赠者和接受者,降低强度的调理,非环磷酰胺的GVHD预防),我们未检测到cGVHD风险或其他次要结局的差异(根据供者CH状态).亚组分析表明,临床特征和CH突变可能会产生不同的影响。需要更大规模的前瞻性研究来可靠地确定哪些患者亚群和CH突变会对临床结果产生有意义的影响。
Improved treatment options, such as reduced-intensity conditioning (RIC), enable older patients to receive potentially curative allogeneic hematopoietic cell transplantation (HCT). This progress has led to increased use of older HLA-matched sibling donors. An unintended potential risk associated with older donors is transplantation of donor cells with clonal hematopoiesis (CH) into patients. We aimed to determine the prevalence of CH in older HLA-matched sibling donors pretransplantation and to assess the clinical impact of donor-engrafted CH on HCT outcomes. This was an observational study using donor peripheral blood samples from the Center for International Blood and Marrow Transplant Research repository, linked with corresponding recipient outcomes. To explore engraftment efficiency and evolution of CH mutations following HCT, recipient follow-up samples available through the Bone Marrow Transplant Clinical Trials Network (Protocol 1202) were included. Older donors and patients (both ≥55 years) receiving first RIC HCT for myeloid malignancies were eligible. DNA from archived donor blood samples was used for targeted deep sequencing to identify CH. The associations between donor CH status and recipient outcomes, including acute graft-versus-host disease (aGVHD), chronic GVHD (cGVHD), overall survival, relapse, nonrelapse mortality, disease-free survival, composite GVHD-free and relapse-free survival, and cGVHD-free and relapse-free survival, were analyzed. A total of 299 donors were successfully sequenced to detect CH. At a variant allele frequency (VAF) ≥2%, there were 44 CH mutations in 13.7% (41 of 299) of HLA-matched sibling donors. CH mostly involved DNMT3A (n = 27; 61.4%) and TET2 (n= 9; 20.5%). Post-HCT samples from 13 recipients were also sequenced, of whom 7 had CH+ donors. All of the donor CH mutations (n = 7/7; 100%) were detected in recipients at day 56 or day 90 post-HCT. Overall, mutation VAFs remained relatively constant up to day 90 post-HCT (median change, .005; range, -.008 to .024). Doubling time analysis of recipient day 56 and day 90 data showed that donor-engrafted CH mutations initially expand then decrease to a stable VAF; germline mutations had longer doubling times than CH mutations. The cumulative incidence of grade II-IV aGVHD at day 100 was higher in HCT recipients with CH+ donors (37.5% versus 25.1%); however, the risk for aGVHD by donor CH status did not reach statistical significance (hazard ratio, 1.35; 95% confidence interval, .61 to 3.01; P = .47). There were no statistically significant differences in the cumulative incidence of cGVHD or any secondary outcomes by donor CH status. In subset analysis, the incidence of cGVHD was lower in recipients of grafts from DNMT3A CH+ donors versus donors without DNMT3A CH (34.4% versus 57%; P = .035). Donor cell leukemia was not reported in any donor-recipient pairs. CH in older HLA-matched sibling donors is relatively common and successfully engrafts and persists in recipients. In a homogenous population (myeloid malignancies, older donors and recipients, RICr, non-cyclophosphamide-containing GVHD prophylaxis), we did not detect a difference in cGVHD risk or other secondary outcomes by donor CH status. Subgroup analyses suggest potential differential effects by clinical characteristics and CH mutations. Larger prospective studies are needed to robustly determine which subsets of patients and CH mutations elicit meaningful impacts on clinical outcomes.