Age ≥ 75 Years, Clinical Stage III/IV, Neutrophilia and High Lymphocyte/Monocyte Ratio Predict Decreased Overall Survival in Elderly Patients with DLBCL, NOS Older Than 70 Years

Introduction: Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin's lymphoma, with a wide clinical and biological diversity, as well as a heterogeneous prognosis. It especially affects the elderly population, with an increasing incidence with advancing age. The DLBCL of elderly (≥ 60 years) and very-elderly (≥ 80 years) patients has numerous particularities, including high-risk molecular-genetic findings, greater association with Epstein-Barr (EBV) virus infection, lower tolerability to conventional immunochemotherapy, and poor clinical outcomes. Therefore, alternative therapeutic strategies have emerged for these patients, including immunochemotherapy in reduced doses and regimens without anthracyclines. Based on this premisse, the current study aims to describe clinical and laboratory characteristics, assess outcomes, determine survival predictors and compare responses and toxicities in a large cohort of elderly patients with DLBCL, NOS older than 70 years.

Methods: This is a retrospective, observational and single-center study, involving 185 patients with DLBCL, NOS aged ≥ 70 years, diagnosed and treated at the Department of Hematology, University of São Paulo, Brazil, from January 2009 to December 2020. Survival curves were constructed using the Kaplan-Meier method, and the Log-Rank test was used to establish associations between variables and outcomes. Univariate analysis to determine predictors of survival was performed using the semiparametric Cox test and multivariate analysis by the Cox regression method or proportional ratios model. The results were presented in hazard ratio (HR) and 95% confidence interval (95% CI), and a p-value ≤ 0.05 was considered statistically significant.

Results: The median age at diagnosis was 75 years (70-97) and 58.9% (109/185) were female. Comorbidities were prevalent, including 19.5% (36/185) of immobility, 28.1% (52/185) of desnutrition, and 25% (46/185) of polypharmacy. Advanced clinical stage (III/IV) was observed in 73.6% (134/185), 48.6% (90/185) had bulky disease ≥ 7 cm, 63.2% (117/185) had B-symptoms, 76.2% (141/185) had ≥ 1 extranodal site involved by lymphoma, 67% (124/185) had intermediate-high/high-risk IPI, and 52.3% (57/109) had GCB-like phenotype detected by IHC [Table 1A]. Ninety-eight percent of patients (182/185) received at least one line of therapy, 65.9% (120/182) underwent cytoreduction, 50.5% (92/182) received intrathecal CNS chemoprophylaxis, and 41.8% (76/185) experienced radiotherapy. Table 1B also summarizes the main up-front treatment modalities, characteristics, responses, and toxicities of each treatment arm. The R-miniCHOP elderly regimen had a lower overall response rate (ORR) (p=0.040), however patients in this group had unfavorable clinical and laboratory characteristics, including higher rates of hypoalbuminemia (p=0.001), IPI ≥ 3 (p=0.013) and NCCN-IPI ≥ 3 (p=0.002). For the entire cohort, ORR was 68.1% (95% CI: 60.8-74.8), 13.2% (95% CI: 8.6-18.9) were chemorefractory, early-mortality rate (< 100 days) was 18.7% (95% CI: 13.3-25.1), and overall mortality rate was 52.4% (97/185). With a median follow-up of 6.3 years (95% CI: 5.5-6.7), the estimated 5-year OS and PFS were 50.2% (95% CI: 42.4-57.5) and 44.6% (95% CI: 37.0-51.9), respectively [Figure 1]. In multivariate analysis, age ≥ 75 years [HR 2.22, p=0.001], advanced-stage III/IV [HR 2.36, p=0.003], neutrophilia ≥ 7.0 x 10⁹/L [HR 2.25, p=0.001] and lymphocyte/monocyte ratio > 4 [HR 1.98, p=0.01] were associated with decreased overall survival. Similarly, age ≥ 75 years [HR 2.33, p<0.001], stage III/IV [HR 2.38, p=0.002], B-symptoms [HR 1.62, p=0.032], LDH ≥ 1.5 x UVN [HR 1.09, p=0.047], neutrophilia [HR 2.25, p=0.001] and high lymphocyte/monocyte ratio [HR 2.08, p=0.005] predicted poor PFS.

Conclusion: In the largest real-life Latin American cohort including patients with DLBCL, NOS older than 70 years, age ≥ 75 years, advanced clinical stage III/IV, neutrophilia and high lymphocyte/monocyte ratio were independent predictors associated with decreased overall survival. In future studies, we intend to validate and use these variables to construct a clinical-biological prognostic score capable of predicting survival in elderly patients with DLBCL, NOS up-front treated with R-CHOP-like regimens.