Polatuzumab vedotin plus R-CHP demonstrates high efficacy with manageable toxicity in treatment-Naïve dual-expressor DLBCL (DEL): Real-world analysis with focus on elderly high-risk patients

Abstract

Abstract Background: Dual-expressor DLBCL (DEL), characterized by MYC/BCL2 co-expression (20-30% of cases), demonstrates inferior outcomes with R-CHOP (3-year PFS 30-40%). The POLARIX trial established pola-R-CHP superiority in high-risk DLBCL, with DEL subgroups showing improved 2-year PFS (64.2% vs 48.6%; HR 0.65, 0.42-0.99). While phase II data suggest promising activity (ORR 75-80%, CR 50-55%), real-world experience with frontline pola-R-CHP-like regimens remains limited, particularly regarding optimal dosing and toxicity management in elderly DEL patients. These knowledge gaps underscore the need for DEL-specific prospective studies to define pola's therapeutic role. Methods This study analyzed 41 consecutive treatment-naïve DEL-DLBCL patients receiving physician-selected pola-R-CHP regimens ( pola-R-CHP, pola-R-EPCH, pola-R-miniCHP) with polatuzumab vedotin 1.8mg/kg day 1 every 21 days (planned 6 cycles), assessing response by Lugano 2014 criteria via local PET-CT and safety per CTCAE v5.0, with particular attention to elderly patients (36.6% ≥65 years) where chemotherapy dose reductions were permitted while maintaining full anti-CD79b antibody dosing, reflecting real-world treatment heterogeneity. Results Among 41 evaluable treatment-naïve DEL-DLBCL patients receiving pola-R-CHP-based regimens (pola-R-CHP: 78.0% [32/41]; pola-R-EPCH: 7.3% [3/41]; pola-R-miniCHP: 14.6% [6/41]), baseline characteristics revealed advanced disease (median stage IV [range 2-4]), with 92.7% (38/41) showing extranodal involvement including 36.6% (15/41) with ≥3 extranodal sites. IPI scores were distributed as 31.7% (13/41) IPI 2 and 53.7% (22/41) IPI 3-5. TP53 mutations and concurrent CNS/systemic involvement were each observed in 4.9% (2/41) of patients. With a median follow-up of 10 months (range 2-27) and median 6 treatment cycles (range 2-8), we observed high response rates (ORR: 95.1% [39/41]; CR: 90.2% [37/41]). Early relapse occurred in 12.2% (5/41) of CR patients, all presenting with stage IV disease, IPI ≥3, extensive extranodal involvement, and age >60 years. Relapse patterns included CNS involvement (7.3% [3/41], with 1 mortality and 2 achieving CAR-T-induced CR) and systemic relapse (4.9% [2/41], including 1 glofitamab-induced CR and 1 pending case). Median PFS and OS were not reached. The elderly subgroup (≥65 years, 36.6% [15/41]) exhibited distinct features: non-GCB subtype (60.0% [9/15]), high-risk IPI ≥3 (73.3% [11/15]), and multiple extranodal sites (46.7% [7/15]). Despite comparable treatment intensity (median 6 cycles [range 2-8]), this population showed higher early treatment failure rates (26.7% [4/15]). Safety analysis revealed increased but manageable toxicities: peripheral neuropathy (40.0% [6/15], all grade 1-2), grade 3-4 neutropenia (46.7% [7/15]), and infections (26.7% [4/15], all grade 1-2). Most patients <75 years with ECOG 0-2 maintained full treatment intensity, while dose reduction (preserving anti-CD79b antibody dose) was implemented for frail patients (ECOG ≥3, age ≥75 years, or significant comorbidities). Conclusions:Pola-R-CHP demonstrates promising efficacy in DEL-DLBCL, with particular clinical relevance for elderly patients. While maintaining therapeutic activity in this vulnerable population, the regimen requires careful toxicity monitoring and dose optimization. The observed early failure rate underscores the need for improved risk stratification in elderly DEL-DLBCL patients. These findings support pola-R-CHP as a valuable treatment option while highlighting the importance of age-adapted therapeutic strategies in this high-risk disease.