肿瘤细胞治疗研究
英文原题：Prolonged Cytokine Release Syndrome is Associated with Hypofibrinogenemia after CD19-Directed CAR T-Cell Therapy in Adult Patients with Relapsed/Refractory Lymphoma.
Prolonged Cytokine Release Syndrome is Associated with Hypofibrinogenemia after CD19-Directed CAR T-Cell Therapy in Adult Patients with Relapsed/Refractory Lymphoma.
CD19靶向嵌合抗原受体（CAR）T细胞疗法显著改善了复发或难治性B细胞恶性肿瘤患者的结局，尽管以低纤维蛋白原血症为特征的血凝病已日益被认为是CAR T细胞治疗后的并发症。
CD19靶向嵌合抗原受体（CAR）T细胞疗法显著改善了复发或难治性B细胞恶性肿瘤患者的结局，但CAR T细胞治疗后低纤维蛋白原血症这一以纤维蛋白原降低为特征的凝血障碍日益受到关注。其当前真实世界发生率、危险因素和临床影响仍未充分明确。本研究旨在确定复发或难治性B细胞淋巴瘤患者接受CD19靶向CAR T细胞治疗后低纤维蛋白原血症的真实世界发生率、危险因素及临床影响。本回顾性队列研究纳入2019年12月至2024年12月期间在京都大学医院连续接受tisagenlecleucel（tisa-cel）、lisocabtagene maraleucel（liso-cel）或axicabtagene ciloleucel（axi-cel）治疗的所有成年（原文年龄阈值符号缺失，数值为16岁）复发或难治性弥漫大B细胞淋巴瘤（DLBCL）或滤泡性淋巴瘤（FL）患者。我们还依据既往描述的改良CRS分级（m-CRS）详细评估细胞因子释放综合征（CRS）严重程度，其中1级分为1a级（CRS相关症状持续时间≤5天）和1b级（持续时间>5天）；1b级CRS定义为“迁延性CRS”。共纳入111例患者：74例接受tisa-cel（67%），24例接受liso-cel（22%），13例接受axi-cel（12%）。输注后30天内，28例（25%）出现低纤维蛋白原血症（纤维蛋白原≤150 mg/dL），中位起病时间为10.5天。15例患者（14%）接受了新鲜冰冻血浆（FFP）。多变量分析显示，1b级CRS（校正风险比［aHR］4.59；95%置信区间［CI］1.89–11.14；P<0.01）、基线纤维蛋白原较低（每降低10 mg/dL，aHR 1.07；95% CI 1.02–1.14；P=0.01）以及使用axi-cel（相较tisa-cel：aHR 3.29；95% CI 1.38–7.83；P<0.01）均与低纤维蛋白原血症独立相关。队列中未发生致命性出血。低纤维蛋白原血症与总生存期或无进展生存期较差无关。迁延性CRS（1b级）或2级CRS、较低的基线纤维蛋白原以及使用axi-cel均与低纤维蛋白原血症独立相关。根据风险调整纤维蛋白原监测可能有助于识别需要密切监测的患者，及时补充纤维蛋白原或可优化支持治疗。仍需开展多中心研究验证这些发现，并明确低纤维蛋白原血症的临床影响，包括出血结局。
CD19-directed chimeric antigen receptor (CAR) T-cell therapy has markedly improved outcomes for patients with relapsed or refractory B-cell malignancies, although coagulopathy characterized by hypofibrinogenemia has increasingly been recognized as a complication after CAR T-cell therapy. Nevertheless, its contemporary real-world incidence, risk factors, and clinical impact remain incompletely defined. This study aimed to determine the real-world incidence, risk factors, and clinical impact of hypofibrinogenemia following CD19-directed CAR T-cell therapy for relapsed or refractory B-cell lymphoma. This retrospective cohort study included all consecutive adult patients ( 16 years) with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) or follicular lymphoma (FL) who received tisagenlecleucel (tisa-cel), lisocabtagene maraleucel (liso-cel), or axicabtagene ciloleucel (axi-cel) at Kyoto University Hospital between December 2019 and December 2024. We also evaluated detailed CRS severity according to modified CRS grading (m-CRS), in which grade 1 was subdivided into grade 1a (duration of CRS-related symptoms 5 days) and grade 1b (duration of CRS-related symptoms >5 days), as previously described; grade 1b CRS was defined as "prolonged CRS." A total of 111 patients (74 tisagenlecleucel [tisa-cel] [67%], 24 lisocabtagene maraleucel [liso-cel] [22%], and 13 axicabtagene ciloleucel [axi-cel] [12%]) were included. Hypofibrinogenemia (fibrinogen 150 mg/dL) was observed in 28 patients (25%) within 30 days after infusion (median onset, 10.5 days). FFP was administered to 15 patients (14%). Multivariable analysis revealed that grade 1b CRS (adjusted hazard ratio [aHR], 4.59; 95% confidence interval [CI], 1.89 to 11.14; P < .01), lower baseline fibrinogen levels (aHR, 1.07 per 10 mg/dL decrease; 95% CI, 1.02 to 1.14; P = .01), and axi-cel use (versus tisa-cel: aHR, 3.29; 95% CI, 1.38 to 7.83; P < .01) were independently associated with hypofibrinogenemia. In our cohort, no fatal bleeding events occurred. Hypofibrinogenemia was not associated with inferior overall survival or progression-free survival. Prolonged CRS (grade 1b) or grade 2 CRS, lower baseline fibrinogen, and use of axi-cel were independently associated with hypofibrinogenemia. Risk-adapted fibrinogen monitoring may help identify patients who could benefit from closer surveillance, and timely fibrinogen replacement may optimize supportive care. Further multicenter studies are warranted to validate these findings and clarify the clinical impact of hypofibrinogenemia, including hemorrhagic outcomes.
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