Generalizability of landmark clinical trials in diffuse large B cell lymphoma to real-world patients: a single-center retrospective cohort study

Clinical trials are the gold standard by which therapies in oncology are evaluated and form the basis for approval of novel therapies. However, it is estimated that as little as 3% of cancer patients participate in clinical trials [1]. Furthermore, a recent study showed that up to 40% of cancer patients would be considered trial-ineligible based on common cancer clinical trial eligibility criteria [2]. Appropriate eligibility criteria are required in clinical trials to ensure patient safety by excluding patients at higher risk of adverse events, and to optimize internal validity of results by recruiting a homogenous study population. However, stringent eligibility criteria can form a barrier to enrollment of ‘real-world’ patients, ultimately undermining the external validity and generalizability of trial results to the broader patient population. Diffuse large B-cell lymphoma (DLBCL) is the most common form of aggressive non-Hodgkin lymphoma. Landmark clinical trials in DLBCL have led to a paradigm shift in the treatment of this disease by showing improved clinical outcomes with the addition of antiCD20 monoclonal antibodies to cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP), which is now the standard of care [3,4]. Though up to 40% of patients are not cured by R-CHOP, several subsequent novel therapies have failed to demonstrate benefit in phase 3 clinical trials, including trials of bortezomib (REMoDL-B) [5], bevacizumab (MAIN) [6], and obinutuzumab (GOYA) [7]. We hypothesized that ‘real world’ patients with DLBCL differ from clinical trial populations with trial eligibility excluding the poor-outcome patients who might benefit most from novel therapies. We therefore aimed to determine the eligibility of patients with DLBCL within the Alberta Cancer Registry (ACR) for participation in three landmark clinical trials in DLBCL. To this end, we performed a retrospective chart review of all patients 18 years of age or older who were registered within the ACR with a new diagnosis of DLBCL, between 1 January 2010 and 31 December 2011. Clinical characteristics were reviewed to assess patient eligibility to participate in three landmark clinical trials for DLBCL on the basis of inclusion and exclusion criteria defined by each study. The trials included Pfreundschuh et al. [4] and Coiffier et al. [3], assessed together as representing the landmark studies supporting the addition of rituximab to CHOP, in patients 60 years and younger and those aged 60–80, respectively, and the GOYA trial (2017), as a representative modern trial, which evaluated obinutuzumab-CHOP versus RCHOP [7]. We limited our study to pathology-proven DLBCL. Diagnoses excluded across all three trials were also excluded from our study including primary central nervous system lymphoma (PCNSL), lymphoma unclassifiable, indolent lymphoma, T-cell lymphoma, relapsed DLBCL, previously treated indolent lymphoma, transformed lymphoma, or cases in which a WHO diagnosis could not be confirmed due to sample quality or other technical reasons. Furthermore, we also excluded patients who survived less than 22 days from diagnosis (one cycle length of treatment). For the rituximab trials, we limited assessment of trial eligibility to patients meeting age restrictions for trial inclusion. We present categorical variables as frequencies and percentages. We present nonnormally distributed variables as medians with interquartile ranges (IQRs). Overall survival (OS) estimates were calculated by the Kaplan–Meier method. Survival between groups was compared using the log-rank test. For univariate and multivariate analyses, OS end points were fit using the Cox proportional hazards model using Stata/IC 16.1 for Mac software. We identified 480 patients with a diagnosis of DLBCL within the ACR. A total of 329 patients were eligible for our study, with 14 patients excluded for PCNSL, 29 patients for lymphoma diagnosis not meeting WHO criteria, 17 patients who died within 22 days of the diagnosis, 27 patients with previously treated lymphoma, and 50