Somatic mutations are frequently reported in individuals with cytopenia but without a confirmed haematological diagnosis (clonal cytopenia of undetermined significance; CCUS). These patients have an increased risk of progression to a myeloid malignancy and worse overall survival than those with no such mutations. To date, studies have been limited by retrospective analysis or small patient numbers. We aimed to establish the natural history of CCUS by prospectively investigating outcome in a large, well defined patient cohort. This prospective cohort study was conducted at the Haematological Malignancy Diagnostic Service, a diagnostic laboratory in Leeds, UK. Patients aged at least 18 years who were referred for investigation of cytopenia were eligible for inclusion; those with a history of myeloid malignancy were not eligible. Targeted sequencing was conducted alongside routine clinical testing. Baseline mutation analysis was then correlated with the main study outcomes: longitudinal blood counts, disease progression to a myeloid malignancy, and overall survival with a median follow-up of 4·54 years (IQR 4·03–5·04). Data were collected manually from hospital records or extracted from laboratory or clinical outcome databases. Bone marrow samples from 2348 patients were received at the Haematological Malignancy Diagnostic Service between July 1, 2014, and July 31, 2016. Of these, 2083 patients (median age 72 years [IQR 63–80, range 18–99]; 854 [41·0%] female and 1229 [59·0%] male) met the inclusion criteria and had samples of sufficient quality for further analysis. 598 (28·7%) patients received a diagnosis on the basis of their biopsy sample, whereas 1485 (71·3%) samples were classified as non-diagnostic; of these, CCUS was confirmed in 400 (26·9%) patients (256 [64·0%] male and 144 [36·0%] female). and were the most frequently mutated genes in patients with CCUS, with 320 (80%) of 400 patients harbouring a mutation in at least one of these genes. Age (p<0·0001), sex (p=0·0027), and mutations in (p=0·0009), (p=0·0056), and (p=0·0055) correlated with a worse overall survival; however, the number of mutations was the strongest predictor for progression to a myeloid malignancy (two mutations, p=0·0024; three or more mutations, p=0·0004). Extended sequencing of samples from a subgroup of patients with sequential samples and no mutations in the initial myeloid gene panel showed recurrent mutations in both and , suggesting that these genes should be included in clinical test panels. Mutation analysis is advised in patients who have undergone bone marrow examination and have an otherwise-unexplained cytopenia. High-risk genetic mutations and increased numbers of mutations are predictive of both survival and progression within 5 years of presentation, warranting clinical surveillance and, when necessary, intervention. MDS Foundation.

中文翻译：

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预测意义未明的克隆性血细胞减少症患者的血细胞减少症、进展和生存：一项前瞻性队列研究

体细胞突变常见于患有血细胞减少症但没有确诊的血液学诊断的个体（意义未定的克隆性血细胞减少症；CCUS）。与没有此类突变的患者相比，这些患者进展为骨髓恶性肿瘤的风险增加，总体生存率更差。迄今为止，研究受到回顾性分析或患者数量较少的限制。我们的目的是通过前瞻性调查大型、明确的患者队列的结果来建立 CCUS 的自然史。这项前瞻性队列研究是在英国利兹的诊断实验室血液恶性肿瘤诊断服务中心进行的。被转诊进行血细胞减少症检查的年龄至少 18 岁的患者有资格纳入；有骨髓恶性肿瘤病史的人不符合资格。靶向测序与常规临床测试同时进行。然后将基线突变分析与主要研究结果相关联：纵向血细胞计数、骨髓恶性肿瘤的疾病进展以及中位随访 4·54 年的总生存期 (IQR 4·03–5·04)。数据是从医院记录中手动收集的，或者是从实验室或临床结果数据库中提取的。血液恶性肿瘤诊断服务中心于 2014 年 7 月 1 日至 2016 年 7 月 31 日期间收集了 2348 名患者的骨髓样本。其中，2083 名患者（中位年龄 72 岁 [IQR 63-80，范围 18-99]；854 41·0%] 女性和 1229 [59·0%] 男性）符合纳入标准，并且样本质量足以进行进一步分析。 598 (28·7%) 名患者根据活检样本获得诊断，而 1485 (71·3%) 样本被归类为非诊断；其中，400 名 (26·9%) 患者（256 [64·0%] 男性和 144 [36·0%] 女性）确诊为 CCUS。和 是 CCUS 患者中最常见的突变基因，400 名患者中有 320 名 (80%) 至少存在其中一个基因突变。年龄 (p<0·0001)、性别 (p=0·0027) 以及 (p=0·0009)、(p=0·0056) 和 (p=0·0055) 的突变与较差的整体相关生存；然而，突变数量是进展为骨髓恶性肿瘤的最强预测因子（两个突变，p=0·0024；三个或更多突变，p=0·0004）。对来自具有连续样本且初始髓系基因组中没有突变的患者亚组的样本进行扩展测序显示 和 中均出现复发突变，表明这些基因应包含在临床测试组中。建议对接受过骨髓检查并出现无法解释的血细胞减少症的患者进行突变分析。高风险基因突变和突变数量增加可预测出现后 5 年内的生存和进展，需要进行临床监测，并在必要时进行干预。 MDS 基金会。