Population-wide introduction of dose-adjusted EPOCH-R in high-grade B-cell lymphoma with MYC/BCL2 rearrangements, DLBCL morphology.

High-grade B-cell lymphoma with "double-hit" MYC and BCL2 rearrangements (HGBCL-DH-BCL2) is associated with poor outcomes following standard chemoimmunotherapy, prompting dose-intensive regimen use. However, the benefit of intensification is unclear due to rarity precluding randomized trials, and selection bias in retrospective comparisons. In 2015, BC Cancer introduced a provincial guideline recommending dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (DA-EPOCH-R) for fit patients aged ≤75 years with HGBCL-DH-BCL2 identified by routine cytogenetic testing. To assess this guideline's impact, we compared the outcomes of patients with de novo HGBCL-DH-BCL2 tumors of diffuse large B-cell lymphoma (DLBCL) morphology across 2 eras. The DA-EPOCH-R era (2015-2020) included patients diagnosed after guideline implementation. The historic era (2005-2010) included patients identified from a historic province-wide cohort of patients with DLBCL morphology tumors that underwent universal cytogenetic testing in a research setting, predominantly treated with standard chemoimmunotherapy. Two-year overall survival (OS) was significantly improved in the DA-EPOCH-R vs historic era (75% vs 47%, P = .008) in HGBCL-DH-BCL2, whereas OS remained unchanged in DLBCL, not otherwise specified (78% vs 76%, P = .17). Within HGBCL-DH-BCL2, tumors harboring immunoglobulin MYC partner loci (43%) and those expressing the dark-zone signature (77%) were associated with the most substantial survival improvements. In a contemporary cohort of HGBCL-DH-BCL2 histologically transformed from follicular lymphoma (FL) in the DA-EPOCH-R era, outcomes of patients who were chemoimmunotherapy-naïve were comparable to those with de novo disease, whereas patients treated with chemoimmunotherapy for FL prior to transformation had poor outcomes. These data support using DA-EPOCH-R in select patients with HGBCL-DH-BCL2 of DLBCL morphology.