Targeted Therapies and Immunotherapies for Diffuse Large B-Cell Lymphoma Across Lines of Treatment: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Abstract

Background: Many targeted therapies and immunotherapies have been compared with standard treatment for diffuse large B-cell lymphoma (DLBCL), with discordant results across lines of therapy.

Objective: To estimate their effects on survival, response and serious toxicity and to test whether setting or mechanism modifies them.

Methods: PubMed/MEDLINE, Europe PMC, OpenAlex and Scopus were searched for randomized trials comparing a regimen containing a novel targeted agent or immunotherapy with standard therapy in adults with DLBCL. Hazard ratios (HR) and risk ratios (RR) with 95% confidence intervals (CI) were pooled with random-effects models; certainty was rated with GRADE.

Results: Thirty-eight trials (14,001 participants) were included. Progression-free survival improved in relapsed or refractory disease (HR 0.54, 95% CI 0.44 to 0.68; moderate certainty), most in transplant-ineligible patients (HR 0.42, 95% CI 0.38 to 0.47), and modestly in first-line induction (HR 0.84, 95% CI 0.76 to 0.94; moderate certainty); the setting modified the effect (p<0.001), whereas immunotherapies and targeted therapies did not differ (p=0.55). Overall survival improved in relapsed or refractory disease (HR 0.72, 95% CI 0.60 to 0.87) but not significantly in first-line induction (HR 0.88, 95% CI 0.77 to 1.01); the difference between settings was not significant (p=0.13). Grade ≥3 adverse events (RR 1.10, 95% CI 1.04 to 1.16) and fatal adverse events (RR 1.34, 95% CI 1.08 to 1.66) increased.

Conclusion: The benefit of novel agents in DLBCL differed between lines of treatment but not between mechanisms: substantial in relapsed or refractory disease and modest in first-line therapy, where it must be weighed against more fatal toxicity.