CAR-T（CAR-T）细胞疗法在非肿瘤性疾病中的应用
Chimeric antigen receptor T (CAR-T) cell therapy in non-oncological diseases.
CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
CAR-HEMATOTOX：复发/难治性大 B 细胞淋巴瘤 CAR-T 细胞相关血液学毒性的模型
英文原题：CAR-HEMATOTOX: a model for CAR T-cell-related hematologic toxicity in relapsed/refractory large B-cell lymphoma.
查看英文原题
CAR-HEMATOTOX: a model for CAR T-cell-related hematologic toxicity in relapsed/refractory large B-cell lymphoma.
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中文摘要
血液毒性是嵌合抗原受体（CAR）T 细胞治疗常见的不良事件，其机制仍未充分阐明。本多中心分析研究了 258 例接受 axicabtagene ciloleucel（axi-cel）或 tisagenlecleucel（tisa-cel）治疗复发/难治性大 B 细胞淋巴瘤患者的造血重建模式，并评估潜在预测标志物。72% 患者出现严重中性粒细胞减少（绝对中性粒细胞计数 [ANC]<100 个/μL），64% 出现持续性中性粒细胞减少（≥21 天）。重度中性粒细胞减少（ANC<500 个/μL）中位持续 9 天。研究以截至第 +60 天重度中性粒细胞减少持续时间为主要终点，寻找血液毒性预测生物标志物。在训练队列（n=58）中，基线血小板减少（r=−0.43；P=0.001）和高铁蛋白血症（r=0.54；P<0.0001）在单变量和多变量分析中均显著相关。
细胞因子释放综合征、免疫效应细胞相关神经毒性综合征的发生率和严重程度，以及细胞因子峰值水平均与主要终点无关。研究者建立 CAR-HEMATOTOX 模型，纳入造血储备标志物（如血小板、血红蛋白和 ANC）及基线炎症标志物（如 C 反应蛋白和铁蛋白）。该模型在欧洲（n=91）和美国（n=109）两个独立队列中得到验证，可区分严重中性粒细胞减少持续时间≥14 天与<14 天的患者（合并验证队列 AUC 0.89，敏感度 89%，特异度 68%）。CAR-HEMATOTOX 高分患者中性粒细胞减少时间更长（12 对 5.5 天；P<0.001），重度血小板减少（87% 对 34%；P<0.001）和贫血（96% 对 40%；P<0.001）发生率更高。该评分表明 CAR-T 治疗前骨髓储备和炎症是迟发性血细胞减少的重要相关特征，可用于血液毒性的风险适应性管理。
展开英文摘要原文
Hematotoxicity represents a frequent chimeric antigen receptor (CAR) T-cell-related adverse event and remains poorly understood. In this multicenter analysis, we studied patterns of hematopoietic reconstitution and evaluated potential predictive markers in 258 patients receiving axicabtagene ciloleucel (axi-cel) or tisagenlecleucel (tisa-cel) for relapsed/refractory large B-cell lymphoma.
We observed profound (absolute neutrophil count [ANC] <100 cells per L) neutropenia in 72% of patients and prolonged (21 days or longer) neutropenia in 64% of patients. The median duration of severe neutropenia (ANC < 500 cells per L) was 9 days.
We aimed to identify predictive biomarkers of hematotoxicity using the duration of severe neutropenia until day +60 as the primary end point. In the training cohort (n = 58), we observed a significant correlation with baseline thrombocytopenia (r = -0. 43; P = . 001) and hyperferritinemia (r = 0. 54; P < . 0001) on univariate and multivariate analysis. Incidence and severity of cytokine-release syndrome, immune effector cell-associated neurotoxicity syndrome, and peak cytokine levels were not associated with the primary end point.
We created the CAR-HEMATOTOX model, which included markers associated with hematopoietic reserve (eg, platelet count, hemoglobin, and ANC) and baseline inflammation (eg, C-reactive protein and ferritin). This model was validated in independent cohorts, one from Europe (n = 91) and one from the United States (n = 109) and discriminated patients with severe neutropenia 14 days to <14 days (pooled validation: area under the curve, 0.
89; sensitivity, 89%; specificity, 68%). A high CAR-HEMATOTOX score resulted in a longer duration of neutropenia (12 vs 5. 5 days; P < . 001) and a higher incidence of severe thrombocytopenia (87% vs 34%; P < . 001) and anemia (96% vs 40%; P < . 001). The score implicates bone marrow reserve and inflammation prior to CAR T-cell therapy as key features associated with delayed cytopenia and will be useful for risk-adapted management of hematotoxicity.
论文信息
- 作者
- Rejeski K、Perez A、Sesques P、Hoster E、Berger C、Jentzsch L、Mougiakakos D、Frölich L
- 单位
- Department of Medicine III, University Hospital, Ludwig Maximilian University (LMU) Munich, Munich, Germany.Germany
- 文献类型
- 多中心研究 · 观察性研究 · 非美国政府资助研究
- 期刊
- Blood2021 Dec 16
- 原文标识
- PubMed 34166502 · DOI 10.1182/blood.2020010543
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