Management of relapsed/refractory DLBCL in the era of novel agents and new approaches

The therapeutic landscape of relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) is rapidly evolving. Novel immunotherapies and targeted therapies have expanded treatment options and improved outcomes for patients with historically limited effective options. These advances raise important questions regarding sequencing, patient selection, and mechanisms of resistance. At the same time, frontline therapy is shifting toward biomarker-informed and risk-adapted approaches, with interim imaging and circulating tumor DNA increasingly incorporated into trial design. As advanced therapies move earlier in the treatment paradigm, the biology of relapse is expected to evolve, requiring reevaluation of therapeutic sequencing in the R/R setting. This review summarizes relevant prognostic factors and highlights the evolving therapeutic landscape, with a focus on both current practice and future directions in the management of R/R DLBCL.