Introduction: Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma, occurring preferentially in individuals aged 60 or over. Elderly DLBCL presents high-risk molecular abnormalities, greater association with EBV infection, higher rates of chemoresistance, lower tolerability to cytotoxic drugs and worse outcomes. Excluding new chemo-free treatments applied in clinical trial settings, the cornerstone of elderly DLBCL therapy is immunochemotherapy based on anthracyclines. Therefore, in addition to full-dose R-CHOP regimen, attenuated protocols, such as R-miniCHOP (containing doxorubicin 25/sqm) and Elderly-R-miniCHOP (rituximab 375 mg/sqm, cyclophosphamide 400 mg/sqm, doxorubicin 25 mg/sqm, vincristine 1 mg fixed dose, and prednisone 40 mg/sqm) have emerged for this particularly fragile population. This study aims to assess long-term outcomes, determine survival predictors, and compare responses and toxicities between different R-CHOP-like protocols in a large real-world cohort. Methods: Retrospective, observational, and single-center study involving 568 DLBCL, NOS patients aged ≥ 60 years, treated at University of São Paulo, Brazil, between January 2009 and December 2023. End-points included ORR, OS, and EFS. Survival curves were constructed using KM method, and Log-Rank test was used to access relationship between variables and outcomes. Chi-square test and Kruskal-Wallis test were used to access statistically significant differences between clinical-demographic variables, adverse event profile, and responses among different therapeutic modalities. Univariate and multivariate analysis to identify prognostic factors were performed using Cox regression method. Results were presented as HR, 95% CI, and a p-value ≤ 0.05 was considered statistically significant. Results: The median age at diagnosis was 70 years (60-97) and 52.3% were female. Comorbidities were prevalent, including 27.8% of immobility, 28.1% of malnutrition and 25% of polypharmacy. Advanced clinical stage (III/IV) was observed in 79% of cases, 50.4% had bulk disease ≥ 7 cm and 70.3% had IPI ≥ 3. Among 518 (91.1%) cases effectively treated, 66.2% (343) received full-dose R-CHOP, 18.7% (97) R-miniCHOP, 11.4% (59) Elderly-R-miniCHOP, and 3.7% (19) anthracycline-free protocols. ORR for the whole cohort was 90.1% (95% CI: 86.9-92.6%), with 79.9% (95% CI: 75.8-83.5%) achieving CR. ORR was 92.4% for R-CHOP, 89% for R-miniCHOP, and 75.7% for Elderly-R-miniCHOP, p=0.011. Overall mortality (p=0.010) and induction mortality (p=0.002) rates were significantly lower in patients treated with full-dose R-CHOP. With a median follow-up of 72.3 months, estimated 5-year OS and EFS were 51.3% (95% CI: 47.1-56%) and 47.5% (95% CI: 43.3-52.2%), respectively. The estimated 5-year OS and EFS were 61.7% (95% CI: 56.5-67.5%) and 57.7% (95% CI: 52.4-63.5%) for full-dose R-CHOP, 47.2% (95% CI: 37.1-59.9%) and 42.1% (95% CI: 32.4-54.8%) for R-miniCHOP, and 36.1% (95% CI: 24.1-54%) and 33.7% (95% CI: 22.5-50.4%) for Elderly-R-miniCHOP, p<0.0001 for both outcomes. Additionally, very-elderly (≥80 years) and frail (KPS<50) patients had markedly decreased OS and EFS compared to younger groups (60-79 years) and fit cases (KPS 50-70 and >70), p<0.0001. Despite having promoted an improvement in outcomes compared to attenuated doxorubicin-based immunochemotherapeutic protocols, full-dose R-CHOP regimen was associated with higher rates of neutropenia (p<0.0001), not translated into an increase in treatment discontinuation rates (p=0.155) or microbiologically documented infections (p=0.063). In multivariate analysis age ≥ 70 years, congestive heart failure, KPS < 70, involvement ≥ 2 extranodal areas, Elderly-IPI int-high/high-risk, increased LDH and β2-microglobulin values were independent predictors for decreased survival. Conclusion: Although a significant proportion of DLBCL patients older than 60 years are considered frail and ineligible for full-dose anthracycline-based regimens, attenuated immunochemotherapeutic protocols, such as R-miniCHOP and Elderly-R-miniCHOP provided markedly inferior long-term outcomes in our large and long-term cohort. Therefore, we concluded that outside clinical trials settings, full-dose R-CHOP regimen is nowadays still considered as first-choice therapy for up-front management of elderly DLBCL, being associated with greater efficacy, better outcomes and a relatively safe adverse event profile.

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2025
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