Investigating Prognostic Value of Immunoglobulin Next-Generation Sequencing in B Cell Non-Hodgkin Lymphoma Patients Undergoing Chimeric Antigen Receptor T-Cell Therapy

Background

In B cell non-hodgkin lymphoma (B-NHL), circulating tumor DNA (ctDNA)-based liquid biopsy for minimal residual disease (MRD) detection correlates strongly with post-treatment relapse. Immunoglobulin next-generation sequencing (Ig-NGS) is more sensitive and cost-effective compared to targeted capture sequencing. Improved biomarkers are essential to guide autologous chimeric antigen receptor T-cell (CAR-T) therapy, particularly in early stages. Currently, there is a lack of research on the prognostic value of Ig-NGS MRD in B-NHL patients undergoing CAR-T therapy.

Method

We recruited B-NHL patients scheduled for CAR-T therapy, collecting tissue and/or peripheral blood samples prior to leukapheresis. Plasma and peripheral blood mononuclear cells were immediately separated and used for dominant clonotypes identified by Ig-NGS assay (Origimed, Shanghai, China) as the baseline assessment. Post-therapy, serial peripheral blood samples were collected at days 7, 14, 28, and every 3 months for MRD assessment via Ig-NGS assay. Imaging examinations were performed at 3, 6 and 12 months after therapy.

Result

In a cohort of 51 B-NHL patients treated with CAR-T therapy, including 45 diffuse large B-cell lymphoma patients, two follicular lymphoma patients, two primary bone marrow B-cell lymphoma patients, and two high-grade B-cell patients, clonality was identified in 94% (48/51) of patients, with at least one identifiable clonotype (median 2; range 1-3). In matched baseline samples, the dominant clonotypes identified in tissue samples were detectable in 83% (19/23) of ctDNA samples and 71% (15/21) of gDNA samples. After a median follow-up of 12 months post-treatment, the objective response rate was 78% (40/51). In post-CAR-T therapy surveillance, MRD was detected in 50% (11/22) of patients, significantly correlated with poorer progression-free survival than MRD negative patients (1-year PFS: 36% vs. 100%, P<0.001). MRD positivity had a sensitivity and specificity for progression of 64% (7/11) and 100% (11/11), respectively. The median lead time from MRD detection to clinical relapse was 23 days (range: 2-166 days).

Conclusion

Our research provides substantive evidence that Ig-NGS testing on ctDNA, rather than gDNA from peripheral blood, is more suitable for MRD monitoring. ctDNA effectively serves as a reliable indicator for impending disease progression. A positive plasma MRD result directly correlates with a significantly heightened risk of disease progression. Consequently, MRD surveillance following CAR-T therapy holds potential for timely evaluation and early re-initiation of treatment upon molecular relapse, thereby optimizing therapeutic strategies.

No relevant conflicts of interest to declare.