Title: Polatuzumab Vedotin Combined with Orelabrutinib and Rituximab (PRO Regimen) as Frontline Therapy in Elderly and Frail Patients with Diffuse Large B-Cell Lymphoma (DLBCL): Results from a Phase II Study

Background: Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma in the elderly population, with treatment often complicated by frailty, comorbidities, and poor tolerance to standard R-miniCHOP regimens. This Phase II study evaluates the efficacy and safety of the PRO regimen (Polatuzumab + Orelabrutinib + Rituximab) as a frontline therapy in elderly and frail patients with DLBCL, providing a chemotherapy-free alternative suited to this vulnerable population.

Methods: This single-arm, prospective Phase II study enrolled adults aged ≥80 years or those aged 60–79 years classified as unfit or frail based on a simplified geriatric assessment (sGA) with untreated, histologically confirmed DLBCL. Patients with prior lymphoma therapy, significant organ dysfunction, or active infections were excluded. Participants received six 21-day cycles of Polatuzumab vedotin (1.8 mg/kg IV Day 1), Orelabrutinib (150 mg orally daily), and Rituximab (375 mg/m² IV Day 1). Responders (complete response [CR]) entered a maintenance phase with an additional two cycles of Rituximab. Interim assessments via 18F-FDG PET/CT or contrast-enhanced CT scans were scheduled every three cycles. The primary endpoint was CR rate per Lugano 2014 criteria, while secondary endpoints included overall response rate (ORR), progression-free survival (PFS), duration of response (DoR), overall survival (OS), and safety assessment.

Results: Twenty-five patients were enrolled, with a median age of 80 years (range: 73–94); 58% were ≥80 years old, and 68% were male. Most patients (96%) were diagnosed with DLBCL, with 72% classified as non-GCB using the Hans algorithm. Among them, 76% (19/25)had at least one or more underlying comorbidities, such as hyperglycemia, hypertension, atherosclerosis, coronary artery disease, and paroxysmal atrial fibrillation. Advanced-stage disease (Ann Arbor Stage III-IV) was observed in 92%, bulky disease in 12%, and elevated LDH in 60%. ECOG performance status was ≥2 in 60% of patients, and 56% had an International Prognostic Index (IPI) score of 3–5.

At the data cutoff, of the 25 enrolled patients, 18 have completed the interim efficacy assessment, the CR rate was 66.7% (12/18), with an ORR of 94.5%. Among these, 27.8% (5/18) achieved a partial response, while 5.5% (1/18) experienced disease progression. At the completion of combination therapy (C6-response), the CR rate was 100 % (10/10). Subgroup analysis showed consistent response rates irrespective of GCB subtype, age group (<80 vs ≥80), or bulky disease presence. Estimated 6-month PFS was 90%.

The PRO regimen demonstrated a manageable safety profile. Safety analysis identified Pulmonary infections were the most common severe AEs (Grade 3–4), reported in 20% of patients (5/25). Hematological toxicities included lymphopenia (Grade 1/2: 56%), anemia (Grade 1/2: 36%), neutropenia (Grade 1/2: 16%, Grade 3/4: 8%) and thrombocytopenia (Grade 1/2: 16%, Grade 3/4: 4%), all of which were generally manageable with appropriate supportive care.

Conclusion: This Phase II trial highlights the potential of Polatuzumab Vedotin, Orelabrutinib, and Rituximab (PRO regimen) as a well-tolerated, chemotherapy-free frontline treatment for elderly and frail patients with DLBCL. Achieving an impressive CR rate of 66.7% and an ORR of 94.5%, coupled with a favorable safety profile, the PRO regimen addresses a critical unmet need in this vulnerable population. Further investigations with larger cohorts are warranted to confirm these promising results and to evaluate long-term outcomes, including progression-free survival, overall survival, and quality of life improvements.

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2025
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