Polatuzumab vedotin, zanubrutinib, rituximab, lenalidomide, and prednisone (Pola-ZR2P) as frontline immunochemotherapy in previously untreated DLBCL patients

Abstract Background: Suboptimal cure rates with frontline therapy and limited treatment tolerance in elderly and frail patients were two major challenges in diffuse large B-cell lymphoma (DLBCL). We evaluated a novel chemotherapy-free regimen including polatuzumab vedotin, zanubrutinib, rituximab, lenalidomide and prednisone (Pola-ZR2P) as induction therapy for previously untreated patients with DLBCL to investigate its efficacy and safety. Methods: Newly diagnosed patients with DLBCL were enrolled and received Pola-ZR2P regimen every 21 days for 6 cycles. Polatuzumab vedotin was given at a dosage of 1.8 mg/kg intravenously on day 1, 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 1 to day 14, rituximab was administered at a dosage of 375 mg/m2 intravenously on day 1 and prednisone was given 60 mg/m2 orally once a day, from day 1 to day 5. Positron emission tomography/computed tomography (PET/CT) scan was used to evaluate interim therapeutic effects. If patients received complete response (CR) or partial response (PR) after 2-4 cycles, remaining cycles will be finished. Overall response rate (ORR) and adverse events were evaluated.(NCT06664411) Results: Between October 2024 and July 2025, 4 newly diagnosed DLBCL patients were enrolled. Patient 1 was a 72-year-old female patient diagnosed with de novo DLBCL NOS, stage IVB, high-risk (IPI score 5), GCB subtype, genetically classified as BN2. The patient was complicated with hereditary hemorrhagic telangiectasia and pulmonary hypertensionPET-CT evaluation after 3 cycles of Pola-ZR2P showed complete response (CR). Treatment was interrupted after cycle 1 due to gastrointestinal bleeding and intestinal infection (Candida albicans), and after cycle 2 due to grade 4 myelosuppression, but resumed in the subsequent cycle successfully. Patient 2was a 38-year-old female patient diagnosed with de novo DLBCL NOS, stage IA, low-risk (IPI score 0), GCB subtype, with no definitive genetic mutations identified. PET-CT evaluation after 4 cycles of Pola-ZR2P showed CR. During cycle 1, the patient developed septic shock and recovered following anti-infective therapy. Patient 3 was a 63-year-old female patient diagnosed with de novo DLBCL NOS, stage IVA, high-risk (IPI score 5), GCB subtype, genetically classified as EZB. She had a history of arrhythmia managed with intermittent propafenone. PET-CT evaluations after both cycle 3 and cycle 6 confirmed CR. During cycle 1, she developed rash and pruritusand resolved by anti-allergy treatment, and During cycle 3, she developed COVID-19 and recovered following antiviral therapy. Patient 4 was a 68-year-old male patient diagnosed with DLBCL NOS transformed from follicular lymphoma, stage IIIB, high-risk (IPI score 5), non-GCB subtype, genetically classified as ST2 and TP53. The patient was complicated with coronary artery disease and hypertension. The patient has completed 6 cycles to date. PET-CT evaluation after 3 cycles of Pola-ZR2P showed CR, and assessment after cycle 6 is pending. Treatment was interruptedduring cycle 1 due to severe pulmonary infection (Citrobacter braakii, HHV-6B, Mycoplasma), and resumed treatment at cycle 2 following anti-infective therapy. In conclusion, all 4 patients achieved complete response (CR) (3 at interim assessment, 1 at EOT assessment). The most common grade ≥3 adverse events (AEs) were infection, neutropenia and gastrointestinal bleeding, and most occurred after the first cycle. Grade 1 skin hyperpigmentation, potentially treatment-related, was observed in all patients. Treatment was interrupted due to AEs in two patients but was successfully resumed in the subsequent cycle. No fatal AEs were observed. Conclusion: Pola-ZR2P regimen demonstrated promising efficacy and a manageable safety profile in this cohort of previously untreated DLBCL patients. This report provides clinical evidence on the efficacy and safety of Pola-ZR2P regimen as the frontline immunochemotherapy in previously untreated DLBCL patients. Further enrollment of more patients is necessary to better clarify the effectiveness and safety of Pola-ZR2P regimen as the frontline chemotherapy in DLBCL patients.