ABSTRACT Polatuzumab vedotin plus R‐CHP (Pola‐R‐CHP) is approved as a new standard first‐line therapy for diffuse large B‐cell lymphoma (DLBCL) based on the POLARIX trial. However, real‐world data on its efficacy and safety in unselected patients is lacking. We conducted a retrospective cohort study to evaluate Pola‐R‐CHP versus R‐CHOP outcomes in routine clinical practice in China. This is a multi‐institutional retrospective cohort study and included all consecutive patients that received at least one dose of polatuzumab vedotin up until February 2024. A total of 600 eligible patients from 6 centers were identified, 131 receiving Pola‐R‐CHP and 469 R‐CHOP. After 1:2 propensity score matching, 128 pairs were obtained for further survival and prognosis analysis. With a median follow‐up of 12.8 months, 12‐month progression‐free survival (PFS) was numerically higher with Pola‐R‐CHP versus R‐CHOP (90.3% vs. 84.1%, p = 0.18). Benefits were consistently observed across molecular subgroups, especially advanced stage, ECOG ≥ 2, extranodal involvement ≥ 2 and non‐GCB group. The complete response rate of the Pola‐R‐CHP group was higher than that of the RCHOP group (86.8% vs. 79.7%; p = 0.09), but there was no statistical difference. Safety profiles were comparable, with no new concerns. Among 128 patients treated with Pola‐R‐CHP, 96 underwent gene sequencing analysis: MCD (25.0%), EZB (13.5%), combined subtype (12.5%), ST2 (9.4%), and other/unclassifiable subtype (30.2%). The most common mutations (> 25% of cases) were PIM1, TP53, BCL‐6, KMT2D, SOCS1, BCL‐2. Genetic testing results show the correlation between genotyping, gene mutations in PIM1/TP53 and therapeutic efficacy. This large real‐world study supports Pola‐R‐CHP as an effective frontline option for DLBCL, with sustained efficacy versus R‐CHOP observed in unselected populations. While 12‐month PFS failed to reach statistical significance, subgroup analyses favor Pola‐R‐CHP. Further research with a wider population, longer follow‐up, and screening of advantageous groups are warranted.
