The current landscape of frontline large B-cell lymphoma trials

At least 25% to 35% of patients with large B-cell lymphoma (LBCL) are not cured with frontline treatment, with generally poor subsequent outcomes. This motivates ongoing and intense interest in improving the frontline treatment of this disease. R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) has remained the standard of care for 20 years despite dozens of trials aiming to improve upon this regimen, and only recently has a novel regimen (pola-R-CHP [polatuzumab vedotin, rituximab, cyclophosphamide, doxorubicin, and prednisone]) challenged its supremacy. Fortunately, at least 15 promising randomized trials evaluating new treatments in frontline LBCL treatment are underway. They differ not only in the therapy evaluated in the experimental arm, but in the choice of control arm, primary end point, and patient selection strategy, with some targeting specific biologic subtypes, some focusing on specific high-risk patient populations, and others enrolling older or frail patients. Novel response-adapted strategies leveraging circulating tumor DNA are also underway. Although this variety of approaches provides a welcome increase in the overall likelihood of success, it will also present challenges if several of these trials are successful and we must choose among multiple potential treatment options that were not all tested in the same fashion. In this review, we summarize the main ongoing frontline randomized trials and discuss some of the questions that we will face in interpreting and applying their results in clinical practice in the next few years.