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 did not achieve complete remission after CAR-T-cell therapy for R/R DLBCL, the top ten genes with the 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.
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。.
Keywords: Chimeric antigen receptor T-cell; Diffuse large B-cell lymphoma; Prognosis; ctDNA.