Circulating tumor DNA-based minimal residual disease assessment predicts progression-free survival in diffuse large B-cell lymphoma: A systematic review and meta-analysis

Abstract Circulating Tumor DNA-Based Minimal Residual Disease Assessment Predicts Progression-Free Survival in Diffuse Large B-Cell Lymphoma: A Systematic Review and Meta-Analysis Background: Minimal residual disease (MRD) detection via circulating tumor DNA (ctDNA) offers a sensitive approach to identify subclinical disease in diffuse large B-cell lymphoma (DLBCL). Compared to conventional imaging modalities like PET-CT, ctDNA MRD provides molecular-level insights into disease persistence. We conducted a systematic review and meta-analysis to assess the prognostic impact of ctDNA MRD status at the end of treatment (EOT) on progression-free survival (PFS) in DLBCL. Methods A systematic search of PubMed, Embase, and Cochrane databases identified studies reporting PFS outcomes stratified by EOT ctDNA MRD status in DLBCL patients. Studies with data on MRD-positive and MRD-negative PFS rates, hazard ratios (HR), or risk ratios (RR) were included. PFS percentages were pooled using a random-effects model. Risk ratios comparing MRD-positive to MRD-negative groups were calculated. Comparative PET scan outcomes were qualitatively analyzed where available. Results A total of eight studies encompassing 490 patients were included in the meta-analysis evaluating the prognostic significance of ctDNA-based minimal residual disease (MRD) status at the end of treatment (EOT) in diffuse large B-cell lymphoma (DLBCL). The pooled analysis demonstrated that MRD-positive patients had a significantly inferior progression-free survival (PFS) compared to MRD-negative patients. The forest plot analysis revealed a consistent association across studies, with MRD-positive status conferring a markedly increased risk of disease progression. The pooled risk ratio (RR) for PFS in MRD-positive versus MRD-negative patients was RR = 0.27; 95% CI: 0.19-0.40; p 0.001, indicating a 73% higher risk of progression in patients with detectable ctDNA at EOT. All individual studies showed a consistent direction of effect favoring MRD-negative status, though the magnitude varied across cohorts. Substantial heterogeneity was observed (I² = 75%), likely reflecting differences in MRD detection techniques, follow-up durations, and population characteristics. Subgroup analyses revealed that ctDNA MRD identified residual disease in a subset of patients who were PET-negative, highlighting its superior prognostic sensitivity over imaging modalities. Conclusions End-of-treatment ctDNA MRD positivity is a strong predictor of inferior progression-free survival in DLBCL, outperforming PET-CT in detecting subclinical disease. Integration of ctDNA MRD assessment into post-treatment surveillance strategies could enable earlier identification of high-risk patients, guiding tailored therapeutic interventions.