Introduction: Diffuse large B-cell lymphoma (DLBCL) is most diagnosed among patients aged over 65 years old, however, the 5-year overall survival was merely 55.8%. First-line regimen incorporating efficacy with fewer toxicities is needed for this population. Following the approval of polatuzumab vedotin in April 2023 in China, we introduced a combination of polatuzumab vedotin, zanubrutinib and rituximab (Pola-ZR) in untreated elderly and frail DLBCL patients that the complete response (CR) rate reached 83% in the retrospective study (Yuhong Ren et al., Ann Hematol, 2025). To further elucidate the efficacy and safety of Pola-ZR, we initiated a prospective phase 2 clinical trial (NCT05940064) with revised prophylaxis for infections. We reported the preliminary efficacy results at European Hematology Association 2025 Congress (PF943). Here we update the molecular features and latest follow-up outcomes.

Methods: Untreated DLBCL patients aged over 70 years old or aged between 60 to 69 years old with a performance status score of 2 to 4 were enrolled in this study. Central nervous system involvement was excluded. The treatment and follow-up procedures remained consistent with our previous reports. The primary endpoint was CR rate after 6 cycles of Pola-ZR. The secondary endpoints were safety, overall response rate, and 24-month progression-free survival (PFS). Peripheral blood was tested for circulating tumor DNA (ctDNA) at baseline, cycle 4, cycle 7, and end-of-treatment by KAPA Hyper Prep Kit. Fresh tissue specimens were obtained at baseline and examined by whole-exome sequencing (WES) and RNA sequencing to explore the molecular features. Sequencing was performed using an Illumina Novaseq 6000 following Illumina-provided protocols for 2×150 paired-end sequencing.

Results: Thirty-two DLBCL patients were screened from December 20, 2023, to January 3, 2025, and thirty patients were enrolled. The median age was 72 years old (range: 67-83). Twenty-four (80.0%) patients were aged over 70 years old. Fourteen (46.7%) patients were female. Twenty-two (73.3%) patients had an international prognostic index score of 3 to 5. Eleven (36.7%) patients were GCB subtype, and nineteen (63.3%) patients were non-GCB. At the cut-off date August 4, 2025, the median cycle of treatment was 10.5 (range: 3-12). Twenty-eight patients were evaluable for the primary endpoint. Th preliminary results showed a CR rate of 71.4% after 6 cycles of Pola-ZR. After a median follow-up of 11.6 months (95% Confidence Interval: 10.637-12.563), the median PFS was 18.5 months (95% Confidence Interval: 6.579-30.421) and the median overall survival was not reached. Grade 3 to 4 lung infection remained 10.0% as previously reported under mandatory prophylaxis for pneumocystis jirovecii pneumonia (PJP). Treatment-related leukopenia remained 26.7% and was all in grade 1 to 2. Dose de-escalation or discontinuation of polatuzumab vedotin was still not observed. A total of 22 samples were validated for WES analysis, of which 21 were successfully genotyped, including 6 cases of A53 subtype, 5 cases of MCD subtype, 3 cases of N1 subtype, 4 cases of ST2 subtype, 2 cases of BN2 subtype and 1 case of EZB subtype. A total of 20 samples were validated for RNA sequencing, of which 8 cases were GCB subtype, 10 cases were ABC subtype, and 2 cases were unclassified.

Conclusions: Pola-ZR showed sustained efficacy in untreated elderly and frail DLBCL patients in this prospective clinical trial. Safety profiles were manageable, as lung infection was brought under control by mandatory prophylaxis for PJP. Preliminary WES and RNA sequencing results showed consistency with our clinical findings. Ongoing treatment, follow-up, and molecular mechanism analysis will be further updated.

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2025
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