Efficacy and safety of the polatuzumab, acalabrutinib, rituximab, and lenalidomide (Pola-AR2) regimen as first-line therapy in unfit or frail patients with diffuse large B-cell lymphoma

Abstract Background Elderly patients often present with multiple comorbidities due to age-related decline in physiological function, leading to significantly reduced tolerance to conventional cytotoxic chemotherapy. This frequently results in severe adverse events such as myelosuppression, necessitating treatment interruption or dose reduction, which compromises efficacy. Recent breakthroughs in molecularly targeted therapies, characterized by their tumor cell-specific cytotoxicity and reduced systemic toxicity, offer superior and better-tolerated treatment options for elderly and frail patients, substantially improving their quality of life and prognosis. Methods This study reports on 13 patients newly diagnosed with diffuse large B-cell lymphoma (DLBCL). All patients, comprehensively assessed as unfit or frail and deemed unsuitable for standard chemotherapy regimens, received first-line treatment with the Pola-AR2 regimen. Treatment was administered every 21 days for up to 6 cycles, followed by acalabrutinib maintenance therapy for one year. The dosing schedule was as follows: Polatuzumab vedotin 1.8 mg/kg intravenously on Day 1 of each cycle; Rituximab 375 mg/m² on Day 2 of each cycle; Acalabrutinib 100 mg orally twice daily from Days 1 to 21; Lenalidomide 25 mg orally once daily from Days 1 to 10. Treatment response was assessed by positron emission tomography/computed tomography (PET/CT) after four cycles. Patients achieving complete response (CR) or partial response (PR) after 4 cycles received two additional cycles followed by end-of-treatment PET/CT assessment. Patients not achieving response after 4 cycles discontinued the regimen and received second-line therapy. Results Between July 2024 and July 2025, 13 patients received the Pola-AR2 regimen at our center and were evaluable for efficacy. The median age was 79 years (range: 67-88), with 7 males and 6 females. Eleven patients (84.6%) had advanced-stage disease (Ann Arbor stage III-IV), and 10 patients (76.9%) had an International Prognostic Index (IPI) score of 3-5. Nine patients (69.2%) were classified as having the non-germinal center B-cell-like (non-GCB) subtype, and 6 patients (46.2%) exhibited BCL2/MYC double-expression. To date, 9 patients (69.2%) have completed all 6 cycles of treatment and undergone end-of-treatment assessment. Within this cohort, 9 patients (69.2%) achieved CR, 3 patients (23.1%) achieved PR, and 1 patient (7.7%) experienced progressive disease (PD). The complete response rate (CRR) was 69.2% (9/13), and the overall response rate (ORR) was 92.3% (12/13). No significant adverse events, such as febrile neutropenia, severe vomiting, prolonged neutropenia, or organ dysfunction, were observed in any patient. Conclusion The Pola-AR2 regimen demonstrates promising efficacy and a favorable safety profile as first-line therapy for elderly and frail patients with newly diagnosed DLBCL. Larger prospective studies are warranted to validate these findings.