Background: Patients with diffuse large B-cell lymphoma (DLBCL) in the elderly face challenges in treatment due to comorbidities and tolerance of chemotherapy. Age >60 years is an unfavorable risk factor of outcome in DLBCL in the International Prognostic Index (IPI) system. Besides, increased proportion of ABC/non-GCB subgroups, complex molecular features associated with unfavorable prognosis are also present with increased frequency with advancing age. These characteristics foreshadow distinct biological or immune microenvironment features of DLBCL in the elderly. Although clinical benefit of single-agent anti-PD-1 antibody in DLBCL was not obvious, pre-use anti-PD-1 antibody as first-line may be an opportune for elderly DLBCL. Additionally, the activated B-cell-like subtype may exhibit programmed death ligand 1 (PD-L1) overexpression through genetic alterations, further facilitating immune evasion. These findings rationalize investigating programmed death 1 (PD-1) blockade combination therapy in the frontline setting to enhance therapeutic efficacy in extranodal DLBCL At the 2022 ASH meeting, we presented results from 37 patients. This time, we provide an update with data from a larger cohort.

Methods: Patients aged 60-85 years, ECOG 0-2 with untreated DLBCL and at least one measurable or evaluable lesion were enrolled. Patients received 2 cycles of Toripalimab (RP2D) plus Rituximab (375mg/m2) every 3 weeks. They allowed to accept two additional cycles of Toripalimab plus Rituximab (To-Ri) if they got complete response (CR) after the first 2 cycles. To-Ri followed by R-CHOP (21) up to 6 cycles then Toripalimab (RP2D) maintenance 6 cycles (q 30 days) after CR or CMR post R-CHOP. The primary endpoints were objective response rate (ORR) based on Lugano 2016 criteria and clinical benefit rate. Secondary endpoints were progression-free survival (PFS), overall survival (OS) and safety. Simon's two-stage design was used in Phase II study. According to previous studies, we assumed that P1 = 0.86 (expected CR rate), P0 = 0.76 (minimum CR rate), α = 0.05, β = 0.8. The best two-stage design was (36/46，95/118). A total of 140 patients were enrolled. Adverse events (AEs) were defined according to CTCAE 5.0. This trial was registered at ClinicalTrials.gov (NCT04058470).

Results:

From December 2020 to July 2025, 114 eligible patients were enrolled. Key baseline characteristics included a median age of 66 years (range: 60-83) with balanced sex distribution (50% male). ECOG socre >1 was observed at 8.8% (n=10), while 66.7% (n=76) exhibited extranodal involvement. The most frequent single extranodal sites were stomach (15.8%, n=18), nasal cavity/nasopharynx (10.5%, n=12), and intestine (5.3%, n=6); 14.0% (n=16) had >2 involved organs. An IPI score ≥3 was present in 38.9% (n=41). Molecular subtyping distribution was: GCB 26.4% (n=29), non-GCB 51.8% (n=57), double-expressor DLBCL 18.2% (n=20), double-hit DLBCL 2.7% (n=3), and triple-hit DLBCL 0.9% (n=1). All patients were evaluable for To-Ri regimen response, receiving a median of 2 cycles (range 1-4). The ORR was 64.0% (73/114) with CR in 36.8% (42/114). Subtype-specific ORR/CR rates were: GCB 58.6%/34.5%, non-GCB 63.2%/38.6%, double-expressor DLBCL 65.0%/30.0%, double-hit DLBCL 100%/33.3%, and triple-hit DLBCL 100%/100%. By involved site, nasal/nasopharyngeal disease showed the highest ORR (83.8%, 10/12), followed by gastric (66.7%, 12/18) and testicular involvement (60.0%, 3/5). Among 110 patients receiving To-Ri plus R-CHOP, significantly higher response rates were achieved (ORR 94.6%, CR 89.1%). With median follow-up of 19.8 months, estimated 2-year progression-free survival (PFS) was 79.0% (95% CI: 68.3-86.5%) and overall survival (OS) 88.9% (95% CI: 80.1-93.9%). Treatment-emergent adverse events (TRAEs) were documented in 110 (96.5%) patients. The most frequently observed (≥10%) TRAEs were neutropenia (40.9%), lymphopenia (27.2%), anemia (26.3%), thrombocytopenia (18.2%), abnormal liver function (17.2%), hypothyroidism (11.8%).

Conclusion: The current CR rate in our study exceeds the prespecified efficacy threshold. Toripalimab plus Rituximab as a first-line treatment then followed by R-CHOP yielded high CR rate and manageable toxicities in newly diagnosedelderly DLBCL, especially for patients with extranodal disease and high grade lymphoma. This treatment strategy deserves further study.

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2025
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