Polatuzumab Vedotin, Zanubrutinib, Rituximab and Lenalidomide (Pola-ZR2) Regimen in the Treatment of Unfit or Frail Patients with Diffuse Large B-Cell Lymphoma

Background: The therapeutic arsenal for unfit or frail patients with diffuse large B-cell lymphoma (DLBCL) is limited, emphasizing the need for treatments that offer a better balance of efficacy and safety. We applied polatuzumab vedotin, zanubrutinib, rituximab, and lenalidomide (Pola-ZR2) regimen in unfit or frail patients with DLBCL, aiming to explore the efficacy of the quadruplet regimen in this population. Methods: Here, we reported the preliminary results of 22 unfit or frail (categorized via comprehensive geriatric assessment) patients with DLBCL who received Pola-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 positron emission tomography/computed tomography (PET/CT) scan was used to evaluate interim therapeutic effects after 3 cycles. If patients have complete response (CR) or partial response (PR) after 3 cycles, he or she will receive another 3 cycles and have a final evaluation via PET/CT scan. The complete response (CR) rate will be calculated as the proportion of participants with CR at the end of evaluation, and the overall response rate (ORR) will be calculated as the proportion of patients having CR or PR at the end of evaluation. Results: Between April 2023 and March 2024, a total of 22 patients in our center received the Pola-ZR2 regimen. Among them, 17 (77%) were newly diagnosed patients, and 5 (23%) were patients with relapsed or refractory (R/R) diseases. The median age was 75 years (range 70-88). Thirteen (59%) patients were male, and 9 (41%) patients were female. Seventeen (77%) patients had advanced stage (Ann Arbor stage III to IV) diseases, and 17 (77%) patients had an international prognosis index (IPI) score of 3 to 5. Thirteen (59%) patients were classified as non-germinal center B-cell-like (non-GCB) subtype, and 8 (36%) patients had BCL2/MYC double expression. So far, 19 (86%) patients have completed treatment and have obtained their end-of-treatment evaluations, while 3 (14%) patients were still under treatment but have obtained their interim evaluation results after 3 cycles. Up to now, 17 (77%) patients received CR (3 for interim evaluation after 3 cycles, and 14 for final evaluation), 2 (9%) patients received PR, 1 (5%) patient had stable disease (SD), and 2 (9%) patients had progressive disease (PD). The CR rate was 77% (17/22), and ORR was 86% (19/22) in this cohort. In conclusion, the Pola-ZR2 regimen demonstrates promising efficacy in unfit or frail patients with DLBCL. Though with high-risk clinicopathological characteristics, both de novo or R/R unfit or frail patients benefit from this potent quadruplet regimen. Conclusion: This report provides clinical evidence on the efficacy of the Pola-ZR2 regimen in DLBCL patients who are deemed unfit or frail. A phase 2, single-arm trial is ongoing to further evaluate the efficacy and safety of the Pola-ZR2 regimen as first-line treatment in those patients and to explore the potential therapeutic mechanism of this treatment combination.