Outcomes and Toxicity Profile in Elderly and Very-Elderly Diffuse Large B-Cell Lymphoma Patients: A Real-World and Comparative Study Involving Three Different Dose-Modulated Anthracycline-Based Immunochemotherapy Regimens in LATAM

Introduction: Diffuse large B-cell lymphoma (DLBCL) commonly affects the older population. Elderly DLBCL patients often present high-risk molecular profile, lower tolerability to conventional chemotherapy, and poor clinical outcomes. In this setting, attenuated therapeutic regimens, such as R-miniCHOP (R-CHOP with 50% reduction in doxorubicin dose) and R-miniCHOP of the elderly (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 fragile population. Albeit its relevance, response rates, clinical outcomes, and toxicities of these regimens remain poorly understood, because these individuals are usually excluded from controlled clinical trials. Therefore, this study aims to assess the outcomes, determine survival predictors, and compare responses and toxicities between R-CHOP, R-miniCHOP, and R-miniCHOP of the elderly protocols in the up-front management of elderly DLBCL patients.

Methods: This retrospective, observational, and single-center study involved 185 DLBCL patients older than 70 years, treated at the Department of Hematology, University of São Paulo, Brazil, from January 2009 to December 2020. Endpoints included ORR, OS, PFS. Survival curves were constructed using the Kaplan-Meier method and the Log-Rank test was used to assess the relationship between variables and outcomes. The chi-square test and the Kruskal-Wallis test were applied to assess statistically significant differences in clinical-demographic characteristics, adverse event profile, and responses between different treatment modalities. Univariate analysis was performed using the Cox test and multivariate analysis by Cox regression method. The results were presented in HR and 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) with immobility, 28.1% (52/185) with malnutrition and 24.8% (46/185) with polypharmacy. Advanced clinical stage (III/IV) was observed in 72.4% (134/185), 48.6% (90/185) had bulky ≥ 7 cm, 63.2% (117/185) had B-symptoms, and 67.0% (124/185) presented IPI ≥ 3. Among the 182 (98.4%) effectively treated cases, 57.1% (104) received the R-CHOP protocol, 18.0% (51) R-miniCHOP, 13.2% (24) R-miniCHOP of the elderly, and 1.7% (3) were palliated using R-CVP. The ORR for the whole cohort was 68.1% (95% CI: 60.8-74.8%), with CR achieved in 65.9% (95% CI: 58.5-72.7%). ORR was 72.1% for R-CHOP, 70.6% for R-miniCHOP, and 45.6% for R-miniCHOP of the elderly, p=0.040. Although R-miniCHOP of the elderly regimen promoted lower ORR, patients in this group had higher rates of unfavorable clinical-laboratory findings, including hypoalbuminemia (p=0.001), IPI ≥ 3 (p=0.013), and NCCN-IPI ≥ 3 (p=0.002). With a median follow-up of 6.3 years, 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. The estimated 2-year OS was 82.0% (95% CI: 73.9-91.2%) for R-CHOP, 67.5% (95% CI: 51.5-88.4%) for R-miniCHOP, and 48.1% (95% CI: 24.5-94.1%) for R-miniCHOP of the elderly, p=0.003. The estimated 2-year PFS was 61.1% (95% CI: 51.8-72.2%) for R-CHOP, 56.4% (95% CI: 42.1-75.5%) for R-miniCHOP, and 20.5% (95% CI: 6.6-63.5%) for R-miniCHOP of the elderly, p=0.005. Although correlated with increased OS and PFS in comparison to attenuated protocols, R-CHOP regimen was associated with higher rates of severe neutropenia (p=0.003), but not translated into febrile neutropenia (p=0.907), therapy interruption (p=0.671), or higher early mortality rates (p=0.681). In multivariate analysis, age ≥ 75 years (HR: 2.08, p=0.001), neutrophilia (HR: 2.18, p=0.007), low lymphocyte/monocyte ratio (HR: 1.98, p=0.010), and clinical stage III/IV (HR: 2.36, p=0.003) were independent predictors of decreased OS.

Conclusion: In this large and real-life Latin American cohort, we demonstrated that patients with DLBCL older than 70 years still do not have satisfactory clinical outcomes, with half of cases not reaching 5 years of life expectancy after diagnosis. Although a significant portion of older DLBCL patients is highly fragile and ineligible for enhanced regimens, attenuated anthracycle-based protocols promoted remarkably inferior long-term outcomes compared to those achieved by the conventional R-CHOP.