肿瘤细胞治疗研究
英文原题：Persistent and pathogen-specific infection risk during long-term survivorship after CD19 chimeric antigen receptor T-cell therapy: an Australian multicentre cohort study.
Persistent and pathogen-specific infection risk during long-term survivorship after CD19 chimeric antigen receptor T-cell therapy: an Australian multicentre cohort study.
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晚期感染常见且具有临床意义，其中 RVI 仍是发病的主要原因。
感染仍是CD19CAR-T 细胞治疗后非复发死亡的首要原因。然而，迟发性感染，尤其输注后1年以上感染的病因和风险尚未得到充分界定。
本项全国多中心回顾性队列研究纳入2019至2023年间在澳大利亚5家中心接受标准治疗CD19 CAR-T 的侵袭性淋巴瘤成人患者，随访至2025年3月。按照共识定义，将感染分类为微生物学确诊或临床定义感染。结局包括感染发生率、时间、微生物病因及病原体特异性危险因素。采用以死亡为竞争风险的原因特异性Cox比例风险回归，评估微生物学确诊感染及早期（第0–30天）、中期（第31–365天）和晚期（>365天）感染风险，并以Firth回归开展敏感性分析。
291例患者中，49.5%（144/291）至少发生1次感染，共249次感染事件；36%（106/291）发生重度感染（3级不良事件通用术语标准[CTCAE]），5%（16/291）发生致死性感染。在可评估1年后感染的146例患者中（中位随访600天；四分位距420–900天），40%发生晚期感染（57/146），18%发生重度晚期感染（27/146）。呼吸道病毒感染是最常见晚期感染（89次事件中37次），且重度呼吸道病毒感染比例未随时间下降。早期感染与第31至365天期间感染相关（OR 2.96；95% CI 1.32–6.87；p=0.009）。未发现输注后1年以上感染的预测因素。真菌感染较少见（占队列6%，17/291），但危险因素谱具有特异性。多变量分析中，地塞米松累积暴露和既往细菌感染与侵袭性真菌病相关（p<0.05）。治疗最初28天内地塞米松等效剂量达到56 mg可预测真菌感染风险（95% CI 1.6–27.1；曲线下面积0.71；p=0.015）。
迟发性感染常见且具有临床意义，呼吸道病毒感染仍是重要发病原因。真菌感染风险与皮质类固醇暴露有关，支持在输注后第一年以后继续开展感染监测和预防。
Infection remains the leading cause of nonrelapse mortality after CD19 chimeric antigen receptor T-cell (CAR-T) therapy. However, the aetiology and risk of late infections, particularly beyond 1 year after infusion, remain poorly defined.
This national multicentre retrospective cohort study included adults receiving standard-of-care CD19 CAR-T for aggressive lymphoma across five Australian centres between 2019 and 2023, with follow-up to March 2025. Infections were classified as microbiologically confirmed or clinically defined using consensus definitions. Outcomes included infection incidence, timing, microbiological aetiology, and pathogen-specific risk factors. Cause-specific Cox proportional hazards regression, with death as a competing risk, evaluated risks for microbiologically confirmed infections and early (day 0-30), medium (day 31-365), and late ( 365 days) infection events, with Firth regression used for sensitivity analyses.
Among 291 patients, 49.5% (144/291) experienced 1 infection (249 events); 36% (106/291) developed a severe infection (grade 3 Common Terminology Criteria for Adverse Events [CTCAE] and 5% (16/291) suffered a fatal infection. Of 146 patients evaluable after 1 year (median follow-up, 600 days; interquartile range, 420-900), 40% experienced a late infection (57/146) and 18% (27/146) a severe late infection. Respiratory viral infections (RVIs) were the most common late infections (37/89 events), and the proportion of severe RVIs did not decline over time. Early infection (OR, 2.96; 95% CI, 1.32-6.87; p 0.009) was associated with infection between days 31 and 365. No predictors of infections beyond 1 year were identified. Fungal infections were uncommon (6% of cohort, 17/291) but showed a distinct risk profile. Cumulative dexamethasone exposure and antecedent bacterial infection were associated with invasive fungal disease in multivariable analysis (p <0.05). A threshold of 56 mg dexamethasone-equivalent within the first 28 days predicted fungal risk (95% CI, 1.6-27.1; area under the curve, 0.71; p 0.015).
Late infections were common and clinically significant, with RVIs remaining a major source of morbidity. Fungal infection risk was associated with corticosteroid exposure extending beyond 6 months, supporting ongoing infection surveillance and prevention strategies beyond the first postinfusion year.
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