Challenges identifying DLBCL patients with poor outcomes to upfront chemoimmunotherapy and its impact on frontline clinical trials

Diffuse large B cell lymphoma (DLBCL) has a variable course of disease among patients as it consists of subgroups that are clinically, biologically and molecularly heterogeneous. In this review, we will discuss how this heterogeneity has likely hindered the ability of traditional prognostic models to identify DLBCL patients at high risk of having poor outcomes with conventional upfront chemoimmunotherapy. We will highlight the challenges and downsides of using these models for risk stratification in clinical trials. Also, we present some of the novel prognosticators that have shown a prognostic value independently or when incorporated into existing prognostic models. Additionally, since the failure of frontline clinical trials to improve outcomes beyond R-CHOP chemoimmunotherapy may be at least partially explained by the restrictive eligibility criteria, risk stratification methods and the selection bias encountered due to the complexed logistics of clinical trials; we will discuss strategies to refine and modernize clinical trial design.