急性B淋巴细胞白血病嵌合抗原受体-T细胞免疫治疗后血清细胞因子水平与桥接异基因造血干细胞移植预后的相关研究

Study on the relationship between serum cytokines levels after chimeric antigen receptor (CAR)-T cell immunotherapy and the prognosis of bridged allogeneic hematopoietic stem cell transplantation in acute B lymphoblastic leukemia patients

目的研究急性B淋巴细胞白血病(B-ALL)患者接受嵌合抗原受体(CAR)-T细胞免疫治疗后血清细胞因子和趋化因子水平与其桥接异基因造血干细胞移植术(allo-HSCT)后发生早期急性移植物抗宿主病(aGVHD)及血清细胞因子和趋化因子水平与患者预后关系。方法根据病例对照原则纳入2019年9月18日至2022年5月9日于河北燕达陆道培医院接受CD19-CAR-T细胞免疫治疗且后续均进行allo-HSCT的42例B-ALL患者为研究对象, 采用Mann-WhitneyU检验比较同一时间点不同患者CAR-T细胞免疫治疗后到桥接移植期间aGVHD相关细胞因子以及趋化因子的水平变化, 观测时间点为接受CAR-T治疗前当天, 以及接受CAR-T治疗到桥接移植之间的时间点:接受CAR-T细胞治疗后第4、7、14、21、28天。绘制受试者工作特征(ROC)曲线评估细胞因子及趋化因子预测患者发生aGVHD及aGVHD患者发生死亡的预测价值。采用 Kaplan-Meier法和Log-rank检验进行生存分析。结果入组42例患者, 24例发生aGVHD, 其中11例死于aGVHD, 31例患者存活。接受CAR-T细胞治疗前当天aGVHD组与无aGVHD组患者细胞因子及趋化因子比较, 差异无统计学意义(P>0.05)。第21天时, aGVHD组患者血清弹性蛋白酶特异性抑制剂(Elafin)水平为4 482(2 811, 6 061)ng/L, 较无aGVHD组患者的2 466(1 948, 3 375)ng/L高(Z=3.145, P=0.001);第28天时aGVHD组患者血清Elafin水平为4 391(2 808, 5 594)ng/L, 高于无aGVHD组的2 463(1 658, 2 830)ng/L(Z=2.038, P=0.048)。在第14天时, aGVHD死亡组与aGVHD生存组比较, 血清巨噬细胞炎症蛋白1α(MIP-1α)[21.02(12.36, 30.35)ng/L比5.56(3.64, 10.79)ng/L]、可溶性CD25(sCD25)[422.47(257.99, 1 233.78)IU/ml比 216.11(133.75, 457.39)IU/ml]、Elafin[4 101(2 393, 5 006)ng/L比 2 155(1 781, 3 033)ng/L]、白细胞介素(IL)-6[119.08(23.97, 183.43)ng/L比8.39(2.91, 17.42)ng/L]、IL-8[13.56(12.50, 24.52)ng/L比2.83(1.73, 6.87)ng/L]更高(Z=2.653, P=0.007;Z=2.176, P=0.030;Z=2.058, P=0.041;Z=3.329, P<0.001;Z=3.162, P=0.001)。KM生存曲线显示第14天时血清高MIP-1α、sCD25、Elafin、IL-6、IL-8水平患者的生存率低于血清低MIP-1α、sCD25、Elafin、IL-6、IL-8水平患者, 差异具有统计学意义(χ^(2)=12.353、4.890、6.551、10.563、20.755, P均<0.05)。结论 CAR-T细胞免疫治疗桥接allo-HSCT患者的结局与患者CAR-T细胞免疫治疗到桥接allo-HSCT之间的血清MIP-1α、sCD25、Elafin、IL-6、IL-8相关, 高MIP-1α、sCD25、Elafin、IL-6、IL-8水平提示预后不良, 可作为提示临床选择合适疗法的标志物。

Objective To investigate the relationship between the levels of serum cytokines and chemokines and the prognosis of patients with acute B-ALL after receiving chimeric antigen receptor(CAR)-T cell immunotherapy and acute graft-versus-host disease(aGVHD)in patients after bridging allogeneic hematopoietic stem cell transplantation(allo-HSCT).Methods According to the case-control principle,Forty-two patients with B-ALL who received CD19-CAR-T cell immunotherapy bridged to allo-HSCT at Heibei Yanda Ludaopei Hospital from September 18,2019 to May 9,2022 were enrolled.Mann-Whitney U test was used to compare the changes of aGVHD-related cytokines and chemokine levels between CAR-T cell immunotherapy and bridging transplantation in different patients at the same time.Their plasma levels of cytokines and chemokines related to aGVHD were monitored at the day before CAR-T therapy and after CAR-T treatment at day 4,7,14,21,28.The receiver operating characteristic curve was drawn to evaluate the predictive value of cytokines and chemokines in predicting the occurrence and the death of aGVHD patients.Kaplan-Meier method and Log-rank tests were used for Overall survival(OS)analysis.Results Twenty-four of total 42 patients had aGVHD,of which 11 patients died and 31 patients survived.There was no significant difference in cytokines and chemokines between the aGVHD group and the non-aGVHD group on the day before CAR-T cell treatment.According to statistical analysis,the serum Elafin levels of aGVHD group was higher than that of non-aGVHD group at the 21st day[4482(2811,6061)ng/L vs 2466(1948,3375)ng/L,Z=3.145,P=0.001]and the 28st day[4391(2808,5594)ng/L vs 2463(1658,2830)ng/L,Z=2.038,P=0.048]separately.At the 14th day,serum cytokines and chemokines levels between the two group were as follows,MIP-1α[21.02(12.36,30.35)ng/L vs 5.56(3.64,10.79)ng/L],sCD25[422.47(257.99,1233.78)IU/ml vs 216.11(133.75,457.39)IU/ml],Elafin[4101(2393,5006)ng/L vs 2155(1781,3033)ng/L],IL-6[119.08(23.97,183.43)ng/L vs 8.39(2.91,17.42)ng/L]and IL-8[13.56(12.50,24.52)ng/L vs 2.83(1.73,6.87)ng/L]were at higher levels(Z=2.653,P=0.007;Z=2.176,P=0.030;Z=2.058,P=0.041;Z=3.329,P<0.001;Z=3.162,P=0.001).The KM survival curve showed that the cumulative survival rates of patients with higher serum levels of MIP-1α,sCD25,Elafin,IL-6 and IL-8 were lower than those with low levels at day 14,and the difference was statistically significant(χ^(2)=12.353,4.890,6.551,10.563,20.755,P<0.05).Conclusion The outcomes of patients treated with CAR-T cell therapy bridged to allo-HSCT was correlated with serum MIP-1α,sCD25,Elafin,IL-6 and IL-8 levels after receiving CAR-T therapy.High concentrations of MIP-1α,sCD25,Elafin,IL-6 and IL-8 suggest poor prognosis and can be used as biomarkers to suggest appropriate clinical selection of therapy.