Pomalidomide, rituximab, and orelabrutinib in combination with polatuzumab vedotin for newly diagnosed diffuse large B-cell lymphoma in elderly, unfit, or frail patients:a prospective phase II study

Abstract Background The management of newly diagnosed diffuse large B-cell lymphoma (DLBCL) in elderly, unfit or frail patients requires careful balancing of potential therapeutic benefits against the risks of treatment-related morbidity and mortality, given their high comorbidities and poor tolerance to standard-dose chemotherapy. There is an urgent need for novel therapeutic strategies, and research in this area is actively ongoing. Our prior study demonstrated that a regimen combining pomalidomide, rituximab, and orelabrutinib (PRO) with reduced-dose cyclophosphamide, doxorubicin, vincristine, and prednisone (miniCHOP) represents a promising treatment option for elderly DLBCL patients, showing favorable efficacy and acceptable safety profiles—particularly among those who responded to PRO induction therapy. Polatuzumab vedotin (Pola) is a CD79b-targeted antibody-drug conjugate (ADC) that induces apoptosis by releasing monomethyl auristatin E (MMAE), a microtubule-disrupting agent that disrupts microtubule dynamics. Compared with conventional chemotherapy, this targeted delivery mechanism minimizes systemic toxicity. Aims This study aimed to evaluate the efficacy and safety of the PRO-Pola regimen in elderly, unfit, or frail patients with newly diagnosed DLBCL. Methods This was an open-label, single-arm, phase II study (NCT07072208). Eligible patients (aged ≥70 years with unfit or frail status) received 1 cycle of induction therapy with PRO (pomalidomide 4 mg on days 1–7; rituximab 375 mg/m² on day 1; orelabrutinib 150 mg once daily) over a 21-day period. Subsequently, patients who achieved at least a minimal response (miniR, defined as a 25%–50% reduction in tumor lesions) were administered an additional 6 cycles of PRO-Pola (the PRO regimen plus polatuzumab vedotin 1.8 mg/kg on day 1 of each cycle). After completion of PRO-Pola therapy, patients with a complete response discontinued treatment, while those with a partial response initiated 2 years of pomalidomide maintenance therapy. The primary endpoint was the complete response rate (CRR) after 6 cycles of PRO-Pola. Secondary endpoints included the overall response rate (ORR) after 6 cycles of PRO-Pola, 2-year progression-free survival (PFS), 2-year overall survival (OS), and safety. Resullts As of August 1, 2025, a total of 14 patients were enrolled, including 10 males and 4 females, with a median age of 78 years (range, 72–91 years). Baseline characteristics of the enrolled patients were as follows: 85.7% had an International Prognostic Index score of 3–5; 57.1% had MYC/BCL-2 double-expression lymphoma; 78.6% presented with extranodal involvement; and 50.0% were classified as having a non-germinal center B-cell-like subtype. All patients (100%) achieved at least a miniR after PRO induction therapy, including 3 with complete response (CR), 6 with partial response (PR), and 5 with miniR. Nine patients completed ≥3 cycles of PRO-Pola, achieving a CRR of 77.8% and an ORR of 100.0%. Among the 5 patients who completed all 6 cycles of PRO-Pola, both the CRR and ORR reached 100.0%. At a median follow-up of 5.6 months, the median PFS and median OS had not yet been reached. Adverse events (AEs) were reported in 13 patients (92.9%), with 7 patients (50%) experiencing grade ≥3 AEs. The most common AEs and grade ≥3 AEs were as follows: neutropenia (71.4% overall; 50% grade ≥3), anemia (64.3% overall; 0% grade ≥3), thrombocytopenia (21.4% overall; 0% grade ≥3), elevated alanine aminotransferase/aspartate aminotransferase (28.6% overall; 0% grade ≥3), elevated creatinine (21.4% overall; 0% grade ≥3), venous thrombosis (14.3% overall; 0% grade ≥3), and rash (4.1% overall; 0% grade ≥3). There were no occurrence of atrial fibrillation, infection and hemorrhage. All toxicities were transient and reversible. Summary/Conclusion These preliminary results suggest that the PRO-Pola regimen is a potential treatment option for elderly, unfit, or frail patients with DLBCL, exhibiting promising efficacy and an acceptable safety profile—particularly in those who responded to PRO induction therapy. Further data will be updated as this ongoing study progresses.