Background: CD5+ DLBCL comprises 5-10% of DLBCL and is characterized by various aggressive clinical features and frequent CNS relapse. Our previous retrospective study (Miyazaki et al. Ann Oncol 2011) revealed that the 2-year (yr) PFS and CNS relapse rates in patients (pts) with newly diagnosed stage II-IV CD5+ DLBCL were 51% and 15%, respectively. An interim analysis of our multicenter phase II study for newly diagnosed stage II-IV CD5+ DLBCL (PEARL5 study) revealed that DA-EPOCH-R/HD-MTX provided a high CR rate (91%) with manageable toxicity (Miyazaki et al. ASH 2016). Methods: Pts with newly diagnosed stage II-IV CD5+ DLBCL between 20-75 yrs old and ECOG PS of 0-3 were eligible. Four cycles of DA-EPOCH-R followed by 2 cycles of HD-MTX (3.5 g/m²) and additional 4 cycles of DA-EPOCH-R were planned as the protocol treatment. Cell-of-origin of DLBCL was determined by means of NanoString analysis system. The primary endpoint was 2-yr PFS. Results: From Aug 2012 to Nov 2015, 47 pts were enrolled in the study. AII the pts were eligible and exhibited the following features: age, 37-74 yrs (median 62); M:F = 18:29; ECOG PS > 1, 4%; stage III/IV, 53%; IPI HI/H, 47%; and ABC/GCB/unclassified, 39/4/3 (n = 46). With a median follow-up of 3.1 yrs (range, 2.0-4.9), the 2-yr PFS rate was 79% (95% CI, 64-88%). This compared favorably with the historical control of conventional R-chemotherapy (51%). The 2-yr OS rate was 89%. One pt in CR died in a traffic accident 0.8 yr after enrollment. The 2-yr CNS relapse rate was 9% (95% CI, 3-21%; n = 4). Among the 4 pts, 1 pt had primary testicular DLBCL. The remaining 3 pts experienced CNS relapse before HD-MTX. Two of these pts had high-grade B-cell lymphoma, NOS (WHO 2016) with MYC rearrangement, and the other pt discontinued the protocol treatment after the 1st rituximab due to grade 4 tumor lysis syndrome. The 2-yr PFS and OS rates in CD5+ ABC DLBCL (n = 39) were 77% and 87%, respectively. Conclusions: DA-EPOCH-R/HD-MTX is an effective treatment for newly diagnosed stage II-IV CD5+ DLBCL. Long-term efficacy and toxicity will be evaluated in a 5-yr follow-up in Nov 2021. Clinical trial information: UMIN000008507.