Outcomes and prognostic factors in patients with follicular lymphoma treated with front-line bendamustine and rituximab

Abstract

Abstract Background Combination therapy with bendamustine and rituximab (BR) is a safe and effective front-line regimen in patients with follicular lymphoma (FL) (Rummel, Lancet 2013; Flinn, Blood 2014). Long-term data regarding the outcomes of FL patients treated with BR have largely been limited to randomized trials, and there is limited insight into the outcomes and prognostic factors of patients treated off of clinical trials with this regimen. Methods We retrospectively identified consecutive adult patients with FL (grades 1-3A) who were treated at Dana-Farber Cancer Institute with front-line BR from January 1, 2013 to June 1, 2024. Baseline demographic, clinical and radiographic characteristics were collected from the medical records. Progression free survival (PFS), overall survival (OS), and cumulative incidence of histological transformation (CIHT) were calculated using standard definitions from time of treatment start, with death considered a competing cause for CIHT. Response outcomes and other categorical variables were tested for association with continuous and other categorical baseline variables using Wilcoxon rank-sum (or Kruskal-Wallis for three or more groups) or Fisher's exact tests, respectively. Results A total of 194 patients were identified. The median age of the cohort was 61 years (range 27-91), and 52% of patients were male. More than half (54%) of patients presented with stage IV disease (37% with stage III), and 86% of patients had grade 1-2 FL. The median Ki-67 and largest SUVmax at diagnosis were 15% (interquartile range [IQR] 10-30%) and 10.0 (IQR 7.5-15.1), respectively. 33 patients (17%) had a reduction in bendamustine dosing with advanced patient age being noted as the most common reason for modification. Among patients receiving dose modifications for advanced age, 10/13 (77%) were empirically given reduced-dose bendamustine in cycle 1. N patients (86%) received all 6 planned cycles of BR. 167 pts (36%) received growth factor support during treatment of which 84% was given as primary prophylaxis. Patients receiving primary prophylaxis were generally older with a median age of 66 years. 22% of patients received maintenance rituximab (median of 10 maintenance cycles). At the end of treatment, 151 patients (78%) underwent repeat PET/CT evaluation. Among these patients, the overall (ORR) and complete response (CR) rates were 89% and 80%, respectively. Among 33 patients who underwent evaluation with CT, the ORR and CR were 90% and 70%, respectively. With a median follow-up of 65.1 months, the median PFS was 66.9 months, the median time-to-next-treatment (TTNT) and the median OS were not reached. The 6-year TTNT and OS were 56% (95% confidence interval [95% CI] 48-64%) and 78% (95% CI 70%-84%), respectively. There were 5 deaths potentially related to treatment, all due to infection. 42 patients (22%) experienced disease progression within 24 months (POD24), of whom 27 (64%) had biopsy-proven evidence of histologic transformation at the time of progression.The CIHT for total cohort at 2 years and 6 years were 13% and 17%, respectively. In univariate analysis, factors associated with worse PFS included age (hazard ratio [HR] 1.24 per 10-year increase, 95% CI 1.02-1.49), elevated LDH (HR 4.69, 95% CI 2.64-8.33), SUVmax (HR 1.04 per 1-unit increase, 95% CI: 1.01-1.07), and reduction in cycle 1 bendamustine dose (HR 3.05, 95% CI: 1.85 to 5.02) by Cox regression. Elevated LDH (HR 2.72, 95% CI: 1.05 to 6.70) was associated with increased risk of transformation. We additionally examined the impact of elevated SUVmax at baseline with a cutoff of 15 based on prior literature (Rossi, Haematologica 2020), which was associated with numerically shorter PFS (median 33.3 months vs. 83.8 months, p=0.20), shorter time-to-next-treatment (median 34.1 months vs. 103.9 months, p=0.04), and increased CIT at 2 years (23% vs 6%) and 6 years (37% vs 11%) in comparison to patients with SUV≤15 at baseline (p<0.01). Conclusions This represents one of the largest real-world analysis of outcomes of patients with FL treated with frontline BR. These data redemonstrate BR is an effective first-line regimen with favorable long-term results. Notably, an elevated baseline SUVmax was associated with shorter PFS and increased risk of transformation in line with prior analysis of FL patients (Strati, Haematologica 2019), which suggest a subset of patients that may benefit from consideration of alternative therapeutic strategies.