ECOG/ACRIN 1412 (E1412) is a randomized, phase II open-label study of lenalidomide/RCHOP vs. RCHOP alone in adults with newly diagnosed de novo diffuse large B-cell lymphoma (DLBCL) and requires NanoString gene expression profiling (GEP) for cell-of-origin testing. Because of high ineligibility rate on retrospective expert central pathology review (ECPR), real-time (RT) ECPR was instituted to confirm diagnosis and ensure adequate tissue for GEP prior to study enrollment. Goal was notification of eligibility within 2 working days (WD). Initially, 208 patients were enrolled, 74 (35.6%) of whom were deemed ineligible by retrospective ECPR. After initiation of RT-ECPR, 219 patients were registered. Of these, 73 (33.3%) were ineligible and were declined enrollment; 47 (21.5% of total) had an ineligible diagnosis on RT-ECPR, and 26 (11.9% of total) had inadequate tissue. Because the 73 ineligible patients were never enrolled, no study slots were "lost" during this phase. Notification of eligibility occurred in an average of 1 WD (Range 0-4) with 97.3% within 2 WD. This novel RT-ECPR serves as a model for future lymphoma trials. Real-time ECPR can help to reduce costs and ensure that study slots accurately reflect the targeted population. In the precision-medicine era, rapid collection of relevant pathology/biomarker data is essential to trial success.