循环肿瘤DNA检测嵌合抗原受体T细胞治疗弥漫大B细胞淋巴瘤患者基因突变的可行性及其预后预测价值分析

Analysis of the feasibility and prognostic value of circulating tumor DNA monitoring in detecting gene mutations in patients with diffuse large B-cell lymphoma receiving chimeric antigen receptor Tcell therapy

目的探讨循环肿瘤DNA(ctDNA)检测在嵌合抗原受体T细胞(CAR-T细胞)治疗难治复发弥漫大B细胞淋巴瘤(R/R DLBCL)中的预后预测价值,为CAR-T细胞治疗失败患者的预防和后续治疗提供一定指导。方法纳入2017年12月至2022年3月在浙江大学医学院附属第一医院接受CAR-T细胞治疗的48例R/R DLBCL患者。对患者治疗前外周血进行187个淋巴瘤相关基因集的ctDNA检测。将患者分为完全缓解(CR)和未达完全缓解(nonCR)两组。使用卡方检验和t检验比较组间临床特征的差异,使用Log-rank检验比较组间生存差异。结果CAR-T细胞治疗R/R DLBCL nonCR患者中,突变频率最高的10个基因由高到低依次为TP53(41%)、TTN(36%)、BCR(27%)、KMT2D(27%)、IGLL5(23%)、KMT2C(23%)、MYD88(23%)、BTG2(18%)、MUC16(18%)、SGK1(18%)。Kaplan-Meier生存分析结果表明相较于ctDNA突变基因数≤10的患者,ctDNA突变基因数>10的患者总生存(OS)(1年OS率:0对73.8%,P<0.001)和无进展生存(PFS)较差(1年PFS率:0对51.8%,P=0.011)。治疗前MUC16突变阳性的患者OS更好(2年OS率:56.8%对26.7%,P=0.046),而BTG2突变阳性的患者OS较差(1年OS率:0对72.5%,P=0.005)。结论ctDNA检测可以作为评估CAR-T细胞治疗R/R DLBCL患者疗效的工具,治疗前的基因突变负荷、MUC16以及BTG2的突变具有潜在的预后预测价值。

Objective To explore the prognostic value of circulating tumor DNA(ctDNA)testing in patients with refractory/relapsed diffuse large B-cell lymphoma(R/R DLBCL)undergoing chimeric antigen receptor T-cell(CAR-T)therapy,and to guide the prevention and subsequent treatment of CAR-T-cell therapy failure.Methods In this study,48 patients with R/R DLBCL who received CAR-T-cell therapy at the First Affiliated Hospital of Zhejiang University School of Medicine between December 2017 and March 2022 were included.Furthermore,ctDNA testing of 187 lymphoma-related gene sets was performed on peripheral blood samples obtained before treatment.The patients were divided into complete remission and noncomplete remission groups.The chi-square test and t-test were used to compare group differences,and the Log-rank test was used to compare the differences in survival.Results Among the patients who highest mutation frequencies were TP53(41%),TTN(36%),BCR(27%),KMT2D(27%),IGLL5(23%),KMT2C(23%),MYD88(23%),BTG2(18%),MUC16(18%),and SGK1(18%).Kaplan-Meier survival analysis revealed that patients with ctDNA mutation genes>10 had poorer overall survival(OS)rate(1-year OS rate:0 vs 73.8%,P<0.001)and progression-free survival(PFS)rate(1-year PFS rate:0 vs 51.8%,P=0.011)compared with patients with ctDNA mutation genes≤10.Moreover,patients with MUC16 mutation positivity before treatment had better OS(2-year OS rate:56.8%vs 26.7%,P=0.046),whereas patients with BTG2 mutation positivity had poorer OS(1-year OS rate:0 vs 72.5%,P=0.005).Conclusion ctDNA detection can serve as a tool for evaluating the efficacy of CAR-T-cell therapy in patients with R/R DLBCL.The pretreatment gene mutation burden,mutations in MUC16 and BTG2 have potential prognostic value.