Clinical efficacy and safety of polatuzumab vedotin, rituximab, and zanubrutinib (POLA-Z-R) therapy in treatment of super-elderly patients with DLBCL: A real-world retrospective study

Abstract Background: Super-elderly patients (≥80 years) with Diffuse Large B-cell Lymphoma (DLBCL) represent a significant therapeutic challenge due to frailty, comorbidities, and poor tolerance to standard R-CHOP chemoimmunotherapy. There is a critical unmet need for effective, less toxic, chemotherapy-free regimens for this population. The novel combination of polatuzumab vedotin (Pola), an anti-CD79b antibody-drug conjugate, rituximab, and the BTK inhibitor zanubrutinib offers a targeted, chemotherapy-free approach. We report the first real-world data on the efficacy and safety of the POLA-Z-R regimen in this vulnerable group. Methods: We conducted a single-center, retrospective analysis of super-elderly patients (≥82 years) with DLBCL who received at least one cycle of the POLA-Z-R regimen between March 2024 and July 2025. Data on baseline clinico-pathological characteristics, treatment exposure, and outcomes were collected from medical records. The primary endpoint was Overall Response Rate (ORR), defined as the proportion of patients achieving Complete Response (CR) or Partial Response (PR). Secondary endpoints included CR rate, safety, and survival. Results: Eight patients were included, with a median age of 85 years (range, 82-94). The cohort was characterized by very high-risk features: 87.5% (7/8) had Ann Arbor stage IV disease, and the median IPI score was 4.5 (range, 2-5). All patients had an ECOG performance status of 1 (62.5%) or 2 (37.5%). Pathological data, where available, indicated a poor prognosis, with 100% (5/5) being of the non-GCB subtype and 75% (3/4) exhibiting dual-expression of BCL-2 and MYC. Seven patients (87.5%) were treatment-naïve. After a median of 4 cycles of therapy, the Overall Response Rate (ORR) was 87.5% (7/8), with a Complete Response (CR) rate of 37.5% (3/8) and a Partial Response (PR) rate of 50% (4/8). At the time of data cutoff, all 8 patients were alive, and only one patient (12.5%) had experienced disease progression after an initial response. The regimen was generally well-tolerated. Notable Grade ≥2 adverse events included peripheral neuropathy (Grade 2, n=1, 12.5%), thrombosis (Grade 2, n=1, 12.5%), and fever (Grade 3, n=1, 12.5%). No treatment-related deaths occurred. Conclusion: In this real-world cohort of very high-risk, super-elderly DLBCL patients, the chemotherapy-free POLA-Z-R regimen demonstrated promising anti-tumor activity and a manageable safety profile. These preliminary findings suggest that this targeted combination represents a potential new therapeutic option for this frail, difficult-to-treat population. These results warrant validation in larger, prospective studies to establish the role of POLA-Z-R in the treatment algorithm for super-elderly DLBCL patients. RX and QH contributed equally as co-first authors.