Genetic subtype-guided immunochemotherapy in diffuse large B cell lymphoma: The randomized GUIDANCE-01 trial.

We report the results of GUIDANCE-01 (NCT04025593), a randomized, phase II trial of R-CHOP alone or combined with targeted agents (R-CHOP-X) guided by genetic subtyping of newly diagnosed, intermediate-risk, or high-risk diffuse large B cell lymphoma (DLBCL). A total of 128 patients were randomized 1:1 to receive R-CHOP-X or R-CHOP. The study achieved the primary endpoint, showing significantly higher complete response rate with R-CHOP-X than R-CHOP (88% vs. 66%, p = 0.003), with overall response rate of 92% vs. 73% (p = 0.005). Two-year progression-free survival rates were 88% vs. 63% (p < 0.001), and 2-year overall survival rates were 94% vs. 77% (p = 0.001). Meanwhile, post hoc RNA-sequencing validated our simplified genetic subtyping algorithm and previously established lymphoma microenvironment subtypes. Our findings highlight the efficacy and safety of R-CHOP-X, a mechanism-based tailored therapy, which dually targeted genetic and microenvironmental alterations in patients with newly diagnosed DLBCL. [Display omitted] • Targeted agents based on genetic subtyping improve R-CHOP efficacy in DLBCL • Inflammatory and immune-depleted tumors have greater sensitivity to therapy • Genetic subtype-guided immunochemotherapy is promising first-line therapy in DLBCL Zhang et al. report findings from the GUIDANCE-01 trial showing genetic subtype-guided immunochemotherapy (R-CHOP-X) improves complete response rate, progression-free and overall survival in diffuse large B cell lymphoma (DLBCL). Among lymphoma microenvironment subtypes, inflammatory and immune-depleted tumors may benefit from R-CHOP-X. This mechanism-based tailored therapy dually targeting genetic and microenvironmental alterations is effective and safe in newly diagnosed DLBCL. [ABSTRACT FROM AUTHOR]