背景:CD19靶向嵌合抗原受体T(CAR-T)细胞疗法是一种革命性的干预措施,在难治性/复发性(R/R)B细胞恶性肿瘤患者中表现出显着的缓解率。然而,治疗的潜在副作用,特别是细胞因子释放综合征(CRS)和感染,由于其重叠的临床特征,构成重大挑战。在CD19靶向CAR-T细胞输注(CTI)后迅速区分CRS和感染仍然是临床上的难题。我们的研究旨在分析感染的发生率,并确定发热患者在CTI后30天内进行B细胞恶性肿瘤早期感染检测的关键指标。
方法:在这项回顾性队列研究中,我们对接受CAR-T治疗的104例R/RB细胞恶性肿瘤患者的队列进行了回顾.临床数据包括年龄,性别,CRS,ICANS,治疗史,感染发生率,并收集治疗反应。血清生物标志物降钙素原(PCT),白细胞介素-6(IL-6),和C反应蛋白(CRP)水平使用化学发光测定法进行分析。统计分析采用皮尔逊卡方检验,t检验,Mann-WhitneyU-test,Kaplan-Meier生存分析,Cox比例风险回归模型,斯皮尔曼等级相关性,和受试者工作特征(ROC)曲线分析,以评估诊断准确性并通过多变量逻辑回归建立预测模型。
结果:在这项研究中,38例患者(36.5%)经历了感染(30例细菌,5真菌,和3病毒)在CART细胞输注的前30天内。总的来说,细菌,真菌,和病毒感染在7,8和9天的中位数检测,分别,CART细胞输注后。先前的异基因造血细胞移植(HCT)是感染的独立危险因素(危险比[HR]:4.432[1.262-15.565],P=0.020)。此外,CRS是两种感染的独立危险因素((HR:2.903[1.577-5.345],P<0.001)和严重感染(9.040[2.256-36.232],P<0.001)。血清PCT,IL-6和CRP在CAR-T治疗后早期感染预测中有价值,特别是PCT,ROC曲线下面积(AUC)最高,为0.897。结合PCT和CRP的诊断模型显示AUC为0.903,灵敏度和特异性高于83%。对于严重的感染,包括CRS严重程度和PCT的模型显示,AUC为0.991,具有完美的敏感性和高特异性.根据上述分析,我们提出了在CAR-T细胞治疗过程中快速识别早期感染的工作流程.
结论:CRS和既往同种异体HCT是发热性B细胞恶性肿瘤患者CTI后感染的独立危险因素。我们使用PCT和CRP预测感染的新模型的鉴定,PCT和CRS用于预测严重感染,提供了指导治疗决策和增强未来CAR-T细胞疗法功效的潜力。
BACKGROUND: CD19-targeted chimeric antigen receptor T (CAR-T) cell therapy stands out as a revolutionary intervention, exhibiting remarkable remission rates in patients with refractory/relapsed (R/R) B-cell malignancies. However, the potential side effects of therapy, particularly cytokine release syndrome (CRS) and infections, pose significant challenges due to their overlapping clinical features. Promptly distinguishing between CRS and infection post CD19 target CAR-T cell infusion (CTI) remains a clinical dilemma. Our study aimed to analyze the incidence of infections and identify key indicators for early infection detection in febrile patients within 30 days post-CTI for B-cell malignancies.
METHODS: In this retrospective cohort study, a cohort of 104 consecutive patients with R/R B-cell malignancies who underwent CAR-T therapy was reviewed. Clinical data including age, gender, CRS, ICANS, treatment history, infection incidence, and treatment responses were collected. Serum biomarkers procalcitonin (PCT), interleukin-6 (IL-6), and C-reactive protein (CRP) levels were analyzed using chemiluminescent assays. Statistical analyses employed Pearson\'s Chi-square test, t-test, Mann-Whitney U-test, Kaplan-Meier survival analysis, Cox proportional hazards regression model, Spearman rank correlation, and receiver operating characteristic (ROC) curve analysis to evaluate diagnostic accuracy and develop predictive models through multivariate logistic regression.
RESULTS: In this study, 38 patients (36.5%) experienced infections (30 bacterial, 5 fungal, and 3 viral) within the first 30 days of CAR T-cell infusion. In general, bacterial, fungal, and viral infections were detected at a median of 7, 8, and 9 days, respectively, after CAR T-cell infusion. Prior allogeneic hematopoietic cell transplantation (HCT) was an independent risk factor for infection (Hazard Ratio [HR]: 4.432 [1.262-15.565], P = 0.020). Furthermore, CRS was an independent risk factor for both infection ((HR: 2.903 [1.577-5.345], P < 0.001) and severe infection (9.040 [2.256-36.232], P < 0.001). Serum PCT, IL-6, and CRP were valuable in early infection prediction post-CAR-T therapy, particularly PCT with the highest area under the ROC curve (AUC) of 0.897. A diagnostic model incorporating PCT and CRP demonstrated an AUC of 0.903 with sensitivity and specificity above 83%. For severe infections, a model including CRS severity and PCT showed an exceptional AUC of 0.991 with perfect sensitivity and high specificity. Based on the aforementioned analysis, we proposed a workflow for the rapid identification of early infection during CAR-T cell therapy.
CONCLUSIONS: CRS and prior allogeneic HCT are independent infection risk factors post-CTI in febrile B-cell malignancy patients. Our identification of novel models using PCT and CRP for predicting infection, and PCT and CRS for predicting severe infection, offers potential to guide therapeutic decisions and enhance the efficacy of CAR-T cell therapy in the future.