改良细胞输注法降低CD19嵌合抗原受体T细胞治疗相关发热非溶血性输血反应临床观察

The evaluation of modified cell infusion method to reduce febrile non-hemolytic transfusion reaction in CD19 chimeric antigen receptor T cell threapy

目的探讨改良的嵌合抗原受体(CAR)T细胞输注法降低治疗相关的发热非溶血性输血反应(FNHTR)发生率的有效性及安全性。方法纳入2017年2月—2018年10月天津市第一中心医院血液科CD19 CAR-T治疗临床试验病例69例。改良CAR-T细胞输注法的试验组(38例)CAR-T细胞培养成熟后以生理盐水重悬细胞,添加人血白蛋白2 mg/1×106 CAR-T细胞,终体积20 ml,静脉推注;对照组(31例)以100 ml生理盐水重悬细胞,静脉输注。观察改良输注法对CAR-T细胞体内增殖率、治疗相关FNHTR发生率、细胞因子释放综合征(CRS)级别、细胞因子释放及疗效的影响。结果(1)试验组FNHTR发生率低于对照组[21.1%(13/38)比87.1%(27/31),P=0.000]。(2)试验组CAR-T细胞输注后第4、7、14、21天的外周血CAR-T细胞比例与对照组相比,差异无统计学意义(P=0.801、0.071、0.095、0.588)。(3)试验组与对照组的CRS分级的差异无统计学意义(P=0.767);试验组与对照组输注CAR-T细胞后第4、7、14、21天的外周血白细胞介素-2受体(IL-2R)、白细胞介素-6(IL-6)和肿瘤坏死因子α(TNFα)水平的差异均无统计学意义。(4)试验组CRP水平在第4和7天低于对照组,差异有统计学意义(P=0.026,0.007)。(5)试验组与对照组中急性淋巴细胞白血病(ALL)与非霍奇金淋巴瘤(NHL)患者各疗效层次构成比的差异均无统计学意义(ALL,P=0.842;NHL,P=0.866)。结论改良CD19 CAR-T细胞输注法可有效降低治疗相关FNHTR发生率,而对CAR-T细胞的体内增殖、CRS发生率、严重级别及CAR-T细胞疗效无明显影响。

Objective To retrospectively analyze the efficacy and safety of modified cell infusion method in reducing the incidence of febrile non-hemolytic transfusion reaction (FNHTR). Methods A total of 69 patients were enrolled in the clinical trial of CD19 chimeric antigen receptor T (CAR-T) cell treatment from February 2017 to October 2018. Study group received the modified cell infusion method, that 1×106 CAR-T cells were re-suspended in 2 mg human serum albumin with total volume of 20 ml and injected intravenously. The control group was intravenously administrated with CAR-T cell in 100 ml normal saline. The incidence of FNHTR, cytokine releasing syndrome (CRS) grade, cytokine level and efficacy were compared. Results (1)The incidence of FNHTR in the study group was 21.1%, significantly lower than that in the control group (71%)(P=0.000).(2)There was no statistical difference in cell proliferation between the study group and the control group on day 4, 7, 14 and 21 after CAR-T cell infusion (P=10.223, 3.254, 5.551, 7.605).(3)There was no statistical difference in CRS grading between the study group and the control group (P=0.767). There was no statistical difference in the levels of interleukin 2 receptor (IL-2R), IL-6, tumor necrosis factor (TNF)-α between the two groups.(4)The C-reaction protein (CRP) level of the study group was lower than that of the control group on day 4 and 7 (P=0.026, 0.007).(5)There was no statistical difference of response rates in acute lymphocytic leukemia (ALL) and non-Hodgkin lymphoma (NHL) patients between the two groups (PALL=0.842;PNHL=0.866). Conclusion The modified cell infusion method in CD19 CAR-T cell treatment reduces the incidence of treatment-related FNHTR. It does not affect the proliferation of CAR-T cells in vivo, the grading of CRS and the response rates.