A prospective, multicenter, randomized, controlled clinical trial comparing polatuzumab vedotin, zanubrutinib, lenalidomide, and rituximab (Pola-ZR2) versus zanubrutinib, lenalidomide, and rituximab (ZR2) in the treatment of previously untreated, eld

Abstract Background: Elderly patients with diffuse large B-cell lymphoma (DLBCL) often tolerate standard chemoimmunotherapy poorly, emphasizing the need for less toxic treatments. This study aims to compare the efficacy and safety of Polatuzumab Vedotin, Zanubrutinib, Lenalidomide, and Rituximab (Pola-ZR2) versus Zanubrutinib, Lenalidomide, and Rituximab (ZR2) in this population (NCT06522555). Methods This prospective, multicenter, randomized, controlled phase II/III trial enrolled previously untreated elderly DLBCL patients aged ≥ 80 years or 70-79 years assessed as unfit or frail via comprehensive geriatric assessment. Participants who met the inclusion/exclusion criteria were randomized 1:1 according to international prognosis index (IPI) score (IPI 2-3 vs IPI 4-5). After signing the informed consent form, participants receive Pola-ZR2 or ZR2 regimen every 21 days for 6 cycles. Polatuzumab vedotin was given at a dosage of 1.8 mg/kg intravenously on day 2 on the first cycle and on day 1 on the second to sixth cycle, zanubrutinib was given 160 mg orally twice a day from day 1 to day 21, lenalidomide was given 25 mg orally once a day from day 2 to day 11, and rituximab was administered at a dosage of 375 mg/m² intravenously on day 1. A PET/CT scan was used to evaluate interim and final therapeutic effects after 3 cycles and 6 cycles. The primary endpoint is two years progression-free survival (PFS). Key secondary endpoints include PFS, overall survival (OS), overall response rate (ORR), complete response (CR) rate, and safety/tolerability, with a specific focus on rates of grade ≥3 adverse events, treatment discontinuations, and infections. Results Between July 2024 and March 2025, a total of 67 newly diagnosed older DLBCL patients were enrolled. Among them, 32(47.8%) received Pola-ZR2 regimen and 35 (52.2%) received ZR2 regimen. The median age was 78 years (range 71-88) in Pola-ZR2 group and 77 years (range 70-89) in ZR2 group. 18 (56.3%) and 23 (65.7%) patients were male in Pola-ZR2 and ZR2 group respectively. 18 (56.3%) patients in Pola-ZR2 group and 19 (54.3%) patients in ZR2 group had advanced stage (Ann Arbor stage III-IV) diseases. 17 (53.1%) patients in Pola-ZR2 group and 20 (57.1%) patients in ZR2 group had an IPI score of 3 to 5. 20 (62.5%) patients in Pola-ZR2 and 23 (65.7%) in ZR2 group were classified as non-germinal center B-cell-like (non-GCB) subtype. Besides, 9 (28.1%) patients in Pola-ZR2 and 9 (25.7%) patients in ZR2 group had BCL2/MYC double expression. With a median follow-up of 7.0 months, 8 (22.9%) patients in the ZR2 arm discontinued due to no response, including 7 progressive disease (PD) and 1 stable disease (SD), while 1 (3.1%) patient in the Pola-ZR2 arm discontinued because of PD. Conclusion We observed the efficacy of these chemo-free regimens in elderly patients, especially the benefit of Pola-ZR2 regimen in unfit and frail patients. Furthermore, the distinct genomic and microenvironmental profiles between responders and non-responders underscore the need for deeper exploration.