Abstract
Objective: This study aims to explore the utility of low-pass whole-genome sequencing (LP-WGS) for serial peripheral blood circulating tumor DNA (ctDNA) detection in monitoring treatment response to CD19 chimeric antigen receptor T-cell (CAR-T) therapy among patients with B-cell lymphomas (BCL) patients, investigate the relationship between the dynamic changes of ctDNA and the prognosis of patients, as well as the role of ctDNA and Fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) in stratifying the prognosis of patients.Methods: We included 11 patients with B-cell lymphomas who received commercial CD19 CAR-T cell therapy in the First Affiliated Hospital of Zhengzhou University from June 2023 to May 2024. Peripheral blood samples were collected at the predetermined time points: (1) on the day of lymphodepletion (baseline); (2) one month after CAR-T cell infusion (M1); (3) three months after CAR-T cell infusion (M3). A total of 33 peripheral blood ctDNA samples from 11 patients were detected by LP-WGS, and tumor fraction (TF) was used to quantify the ctDNA level. Results: The 1-year PFS, OS and EFS rates were 64%, 82% and 45%, respectively. The best overall response and best complete response rates were 73% and 64%, respectively.The median TF values were 0.154%, 0.091% and 0.114% at lymphodepletion, 1 month and 3 months after CAR-T cell infusion, respectively. The baseline TF value and peak TF value of patients who achieved CR at the last assessment were lower than those of patients who did not achieve CR (P = 0.045 and P = 0.036). The PFS (P = 0.042 and P = 0.042), EFS (P = 0.015 and P = 0.015) and OS (P < 0.001 and P < 0.001) of patients with negative peripheral-blood based residual disease (PRD) at baseline and M1 were better than those of patients with positive PRD. Patients were divided into four subgroups according to PRD and PET/CT results. At baseline, M1, and M3, PFS (P = 0.09, P = 0.051 and P = 0.013) and EFS (P = 0.025, P < 0.001 and P < 0.001) of PET/CT-/PRD- patients were better than those of PET/CT+/PRD- or PET/CT+/PRD+ patients. Compared with PET/CT-/PRD- or PET/CT+/PRD- patients, PET/CT+/PRD+ patients had poorer OS at baseline, M1, and M3 (P < 0.01, P < 0.001, and P < 0.001).Conclusions: ctDNA detected by LP-WGS can be used to assess the efficacy of CD19 CAR-T cell therapy in patients with BCL. The baseline TF value and peak TF value of patients who achieved CR at the last evaluation were lower. The prognosis of PRD-negative patients after infusion is better, while the prognosis of PRD-positive patients, especially those with persistently elevated TF value, is worse. ctDNA can increase the specificity of PET/CT in assessment, and further risk stratification in patients with PET/CT positive. LP-WGS has a broad application prospect in lymphoma treatment monitoring. Serial ctDNA assessment before and after CAR-T cell infusion holds significant clinical value, which is helpful to accurately evaluate the treatment response and predict prognosis.
