肿瘤细胞治疗研究
英文原题：Clonal Hematopoiesis and Inflammation Predict Hematologic Toxicity and Secondary Myeloid Malignancies after B-Cell Maturation Antigen-Directed Chimeric Antigen Receptor T-cell Therapy.
本研究强调了血液学毒性和克隆性造血对 B 细胞成熟抗原 CAR-T 结局的影响，并提示 CAR-T 可能影响 TP53 克隆动态和髓系疾病发展的潜在作用。
目的：CAR-T 已显示出治疗多发性骨髓瘤的显著疗效，但长期血液学毒性仍是常见不良事件，继发性髓系恶性肿瘤也是重要安全性问题。实验设计：研究评估了本中心接受 B 细胞成熟抗原靶向 CAR-T 治疗的 213 例骨髓瘤患者，旨在描述与血液学毒性相关的临床、炎症及髓系克隆特征。结果：第 100 天仍有持续 3 级中性粒细胞减少或血小板减少的患者占 19%，其无进展生存期较短（P = 0.0003），总生存期也较短（P < 0.0001）；在持续缓解者中，64% 在 1 年后仍出现长期高级别血细胞减少。基线炎症是血液学毒性的风险因素，而潜在克隆性造血（CH）会调节这一风险；CH 与铁蛋白升高并存可高度预测恢复延迟（校正 HR 0.38，P = 0.006）。髓系恢复延迟患者的血清细胞因子分析显示持续炎症和内皮功能障碍特征。最终，9% 患者发生继发性髓系疾病，其中 5% 发生需要治疗的高级别骨髓增生异常综合征（MDS）；CAR-T 后发生中位时间为 14.5 个月。MDS 与潜在 TP53 突变 CH 的克隆扩增相关，变异等位基因频率中位数从 CAR-T 前的 3.4% 升至 44.0%。基线存在 TP53 突变 CH 的患者表现出克隆演化和较高 MDS 发生率（67%），而 CAR-T 后其他 CH 突变未显示类似扩增（P > 0.99）。结论：本研究强调血液学毒性和 CH 对 B 细胞成熟抗原 CAR-T 疗效结局的影响，并提示 CAR-T 可能影响 TP53 克隆动态及髓系疾病发生。
PURPOSE: Chimeric antigen receptor T cells (CAR-T) have demonstrated remarkable efficacy in multiple myeloma, but prolonged hematologic toxicity remains a common adverse event, and secondary myeloid malignancies are a significant safety concern. EXPERIMENTAL DESIGN: We evaluated 213 patients with myeloma treated with B-cell maturation antigen-directed CAR-T at our center to characterize clinical, inflammatory, and myeloid clonal features associated with hematologic toxicity. RESULTS: Patients with persistent grade 3 neutropenia or thrombocytopenia at day 100 (19%) had shorter progression-free survival (P = 0.0003) and overall survival (P < 0.0001), and among those with continued remissions, 64% developed prolonged high-grade cytopenias beyond 1 year. Whereas baseline inflammation is a risk factor for hematologic toxicity, underlying clonal hematopoiesis (CH) modulated this risk, and the combination of CH and elevated ferritin was highly predictive of delayed recovery (adjusted HR, 0.38, P = 0.006). Serum cytokine analysis in patients with delayed myeloid recovery showed a signature of persistent inflammation and endothelial dysfunction. Finally, 9% developed secondary myeloid diseases, including 5% with high-grade myelodysplastic syndrome (MDS) requiring therapy, a median of 14.5 months after CAR-T. MDS was associated with clonal expansion of underlying TP53-mutated CH from a median variant allele frequency of 3.4% before CAR-T to 44.0%. Whereas patients with baseline TP53-mutated CH exhibited clonal evolution and a high incidence of MDS (67%), other CH mutations did not show similar expansion after CAR-T (P > 0.99). CONCLUSIONS: This study underscores the impact of hematologic toxicity and CH on B-cell maturation antigen CAR-T outcomes and suggests a potential role of CAR-T in influencing TP53 clonal dynamics and myeloid disease development.
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