Outcome of Extra-Nodal Follicular Lymphoma Affected By Selection of Induction Chemoimmunotherapy and Maintenance Rituximab - Real-World Retrospective Study
Authors: Ng Lawrence Cheng Kiat , Ong Shin Yeu , Huang Xinxin , Ghosh Aditi , Nagarajan Chandramouli , Goh Yeow Tee , Chen Yunxin , Lim Francesca , Lee Xiu Hue , Tan Jing Yuan , Grigoroloupos Nicholas Francis , Hoe Joshua Tian Ming , Chiang Jianbang , Chang Esther , Poon Eileen , Tan Ya Hwee , Somasundaram Nagavalli , Yang Valerie Shiwen , TAO Miriam , Lim Soon Thye , Chan Jason Yongsheng 
Published: December 2024

Background: Extra-nodal involvement is frequently observed in follicular lymphoma, yet there is limited evidence regarding its prognostic significance and optimal treatment strategies. We present our institutional experience treating follicular lymphoma, focusing on the impact of extra-nodal involvement.
Methods: We conducted a retrospective analysis of demographic, treatment, and outcome data from patients with follicular lymphoma treated at two major cancer institutions in Singapore from 2010 to 2023, using registry data. Patients with grade 3B histology were excluded. Progression-free survival (PFS) was defined as the time from treatment initiation to disease progression or death. Overall survival (OS) was defined as the time from treatment initiation to death from any cause. Progression within 24 months (POD24) was defined as disease progression within 24 months from treatment initiation. Survival distributions were estimated using the Kaplan-Meier method. Univariate analysis was performed using the log-rank test, and multivariate analysis was conducted using Cox proportional hazards modelling.
Results: A total of 190 patients were included in the study. The median age was 60 years, with 55% male and 45% female. Stage distribution included 7% stage 1, 14% stage 2, 19% stage 3, and 60% stage 4. According to FLIPI stratification, 22% were low (0-1), 22% intermediate (2), and 54% high (3-5). Histologically, 55% had grade 1/2 and 45% grade 3A disease. Extra-nodal involvement was present in 67% of patients, most commonly affecting bone marrow (43%), skeletal system (10%), liver (6%), and other sites (n=15, including skin, intestine, lung, renal, and breast). The median time from diagnosis to treatment initiation was 25 days (range: 0-1488 days). Treatment regimens included R-CHOP in 44%, BR in 31%, and other treatments in 25% (R-CVP/R-lenalidomide/Rituximab monotherapy). Maintenance Rituximab (MR) was administered to 28% of patients.
With a median follow-up of 70.3 months, median PFS and OS were not reached, with estimated 5-year PFS of 62% and 5-year OS of 85%. POD24 occurred in 15% of patients. The leading causes of death were lymphoma (n=12), unknown (n=11), pneumonia (n=6), secondary malignancy (n=3), and other causes (n=1). Univariate analysis of patients treated with R-CHOP or BR showed significantly inferior PFS in those with extra-nodal involvement (5-year PFS 64% vs. 69%, p=0.041), but no differences in POD24 or OS. FLIPI score showed no prognostic value in PFS (p=0.53) or POD24 (p=0.65), although high FLIPI score correlated with inferior OS (p=0.03), likely due to age-factor within FLIPI. This is because age more than 60 years alone stand out with inferior OS (p=0.03). In multivariate analysis, extra-nodal involvement marginally lost statistical significance for PFS (p=0.057) whereas FLIPI score (p=0.15) and age (p=0.26) do not affect OS on multivariate analysis.
Subgroup analysis of 95 patients with extra-nodal disease treated with R-CHOP or BR showed trends towards superior PFS and lower POD24 with rituximab maintenance (p=0.06 each). R-CHOP was associated with a non-statistically higher risk of POD24 compared to BR (p=0.057), with no impact on OS. No prognostic differences were found based on the number of extra-nodal sites or involvement of solid organs. Among patients with extra-nodal involvement treated with R-CHOP without MR, significantly shorter PFS (p=0.006) and higher POD24 risk (p=0.02) were observed compared to those receiving R-CHOP with MR, translating into inferior OS (p=0.014). This trend was not observed among BR-treated patients without maintenance rituximab.
Conclusion: Extra-nodal involvement in follicular lymphoma appears to confer high-risk status. R-CHOP induction in these patients may result in poorer outcomes unless followed by maintenance rituximab.