Longitudinal ctDNA tracking by low-pass whole-genome sequencing predicts CAR-T outcomes in B-cell lymphomas

Current PET/CT monitoring for relapsed/refractory B-cell lymphomas treated with CAR-T therapy often lacks specificity. We evaluated longitudinal low-pass whole-genome sequencing (LP-WGS) of circulating tumor DNA (ctDNA) in 11 patients with B-cell lymphoma receiving axicabtagene ciloleucel to assess treatment response and prognosis. We found that lower baseline tumor fraction correlated with complete remission (CR), and ctDNA positivity at baseline or 1-month post-infusion significantly predicted inferior survival outcomes. Combining ctDNA with PET/CT refined risk stratification, distinguishing high-risk patients more accurately than imaging alone. Furthermore, specific genomic features, such as 17p deletion and high copy number variation burden, were associated with poor prognosis. We conclude that LP-WGS of ctDNA shows promise as a complementary tool to PET/CT for response evaluation and risk stratification in CAR-T-treated B-cell lymphomas, highlighting its potential to guide personalized clinical management in lymphoma care.