Mohammad Ayman, Mascarenhas John, Marcellino Bridget K, Nathan Daniel I
Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Tisch Cancer Institute, Division of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Blood Rev. 2025 Jul 25:101323. doi: 10.1016/j.blre.2025.101323.
Clonal hematopoiesis (CH) is defined by the expansion of hematopoietic stem and progenitor cells (HSPCs) harboring somatic mutations that confer a competitive advantage. Clonal cytopenia of undetermined significance (CCUS), a subtype of CH characterized by cytopenias, represents a high-risk precursor to myeloid malignancies and is increasingly associated with cardiovascular disease, thrombosis, and chronic inflammatory conditions. Despite its clinical significance, therapeutic strategies for CCUS remain limited, and prospective trial frameworks are still evolving. In this review, we outline emerging therapeutic opportunities in CCUS, including inflammatory targets (e.g., NLRP3, IL-1β, IL-6), epigenetic modulators (e.g., hypomethylating agents, Vitamin C), mutation-specific inhibitors (e.g., JAK2, IDH1/2), and repurposed agents (e.g., statins, metformin, colchicine). We also discuss key elements of early-phase clinical trial design, such as risk stratification, endpoint selection, and ethical enrollment of at-risk individuals. CCUS offers a unique window for preventive intervention before the onset of overt malignancy or irreversible end-organ damage. Realizing this potential will require translating biologic insights into well-designed randomized clinical trials that incorporate careful patient selection, ethical enrollment practices, and clinically relevant endpoints. Establishing such frameworks will be essential to developing effective, targeted strategies in this high-risk population.
克隆性造血（CH）的定义是携带具有竞争优势的体细胞突变的造血干细胞和祖细胞（HSPCs）的扩增。意义未明的克隆性血细胞减少症（CCUS）是CH的一种亚型，其特征为血细胞减少，是髓系恶性肿瘤的高危前驱病变，且越来越多地与心血管疾病、血栓形成和慢性炎症性疾病相关。尽管其具有临床意义，但CCUS的治疗策略仍然有限，前瞻性试验框架仍在不断发展。在本综述中，我们概述了CCUS中新兴的治疗机会，包括炎症靶点（如NLRP3、IL-1β、IL-6）、表观遗传调节剂（如低甲基化剂、维生素C）、突变特异性抑制剂（如JAK2、IDH1/2）和重新利用的药物（如他汀类药物、二甲双胍、秋水仙碱）。我们还讨论了早期临床试验设计的关键要素，如风险分层、终点选择以及高危个体的伦理入组。CCUS为在明显恶性肿瘤或不可逆终末器官损伤发生之前进行预防性干预提供了一个独特的窗口。要实现这一潜力，需要将生物学见解转化为精心设计的随机临床试验，其中包括仔细的患者选择、伦理入组实践和临床相关终点。建立这样的框架对于在这一高危人群中制定有效的靶向策略至关重要。
