Innovative Approaches in Untreated DLBCL

Introduction Diffuse large B-cell lymphoma (DLBCL), the most common lymphoid cancer, is curable but has been treated with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP)-based chemotherapy for decades.1 DLBCL is a heterogeneous disease with distinct subtypes with differential responses to targeted therapy; however, this has not yet translated into standard therapy.2,3 Most frontline DLBCL trials employ an R-CHOP versus R-CHOP + X chemotherapy, which assumes X will either add to or synergize with chemotherapy and not antagonize or have significant added toxicity with chemotherapy.4 Notable examples include lenalidomide, ibrutinib, venetoclax, and bortezomib, among others. Other than rituximab, these trials have been disappointing, despite huge numbers of patients and high response rates in patients with relapsed disease. Moving the field beyond R-CHOP may require a targeted, subgroup-specific approach rather than a one-size-fits-all approach. The analysis of circulating tumor DNA (ctDNA) is a promising technological advance that may enable more flexible/adaptive approaches and should be incorporated into prospective trials.5