Minimal residual disease in diffuse large B‐cell lymphoma after first‐line therapy: Defining the continuum from metabolic remission to molecular clearance

Response assessment in diffuse large B-cell lymphoma (DLBCL) has traditionally relied on anatomical and metabolic imaging, with fluorodeoxyglucose positron emission tomography (FDG-PET)–defined complete metabolic remission representing the principal end-point of first-line therapy. However, growing evidence indicates that metabolic control does not necessarily correspond to clonal eradication. Circulating tumour deoxyribonucleic acid (ctDNA)–based minimal residual disease (MRD) assessment offers a complementary perspective by detecting systemic clonal persistence rather than localized tumour burden. In this review, we synthesize biological, methodological and clinical evidence showing that PET and MRD capture distinct and only partially overlapping dimensions of treatment response. We discuss biological implications of PET-negative/MRD-positive status, which may represent occult residual disease driven by subthreshold metabolic activity, diffuse low-volume dissemination or microenvironment-mediated resistance. MRD may therefore refine prognostic stratification beyond PET, particularly among patients achieving complete metabolic responses. Nevertheless, technical variability, limited standardization and insufficient prospective validation currently limit its use as a routine therapeutic decision trigger. Emerging frameworks integrating PET and MRD, especially within adaptive clinical trials, conceptualize response as a dynamic biological process rather than a static classification. Overall, metabolic remission likely reflects control of dominant tumour compartments, whereas MRD detection identifies persisting therapy-resistant clones. Integrating both dimensions may improve interpretation and guide therapeutic strategies.