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The R-CHOP immunochemotherapy protocol has been the first-line (1L) standard of care (SOC) for diffuse large B-cell lymphoma (DLBCL) patients for decades and is curative in approximately two-thirds of patients. Numerous randomized phase III trials, most of them in an “R-CHOP ± X” design, failed to further improve outcomes. This was mainly due to increased toxicity, the large proportion of patients not in need of more than R-CHOP, and the extensive molecular heterogeneity of the disease, raising the bar for “one-size-fits-all” concepts. Recently, an R-CHP regimen extended by the anti-CD79b antibody–drug conjugate (ADC) Polatuzumab Vedotin proved superior to R-CHOP in terms of progression-free survival (PFS) in the POLARIX phase III trial. Moreover, a number of targeted agents, especially the Bruton’s tyrosine kinase (BTK) inhibitor Ibrutinib, seem to have activity in certain patient subsets in 1L and are currently being tested in front-line regimens. Chimeric antigen receptor (CAR) T-cells, achieving remarkable results in ≥3L scenarios, are being exploited in earlier lines of therapy, while T-cell-engaging bispecific antibodies emerge as conceptual competitors of CAR T-cells. Hence, we present here the findings and lessons learnt from phase III 1L trials and piloting phase II studies in relapsed/refractory (R/R) and 1L settings, and survey chemotherapy-free regimens with respect to their efficacy and future potential in 1L. Novel agents and their mode of action will be discussed in light of the molecular landscape of DLBCL and personalized 1L perspectives for the challenging patient population not cured by the SOC.

DLBCL 1L—What to Expect beyond R-CHOP?