Introduction: Outcomes for FL have markedly improved, and the 10-year (yr) overall survival (OS) for patients (pts) diagnosed in the rituximab era is about 80%. Historically, FL is the leading cause of death in the first decade after diagnosis (dx); however, modern outcomes beyond 10 yrs after dx remain unknown. Here we report long-term outcomes of FL from a large prospective cohort of pts with FL from the rituximab era.

Methods: Pts with biopsy-proven FL 1-3A at dx were prospectively enrolled within 9 months of dx from 2002-2015 in the MER. Outcomes of interest were OS, event-free survival (EFS), histologic transformation (HT), and cause of death. HT was defined as subsequent biopsy-proven FL 3B, diffuse large B cell lymphoma, or high-grade B cell lymphoma. Analyses were performed using Cox models and KM curves; cause of death was evaluated using a competing risk approach. A subset analysis was performed in younger (18-59 yrs) vs older (60+ yrs) pts. A landmark analysis was conducted in pts alive at 10 yrs.

Results: 1,155 pts with FL 1-3A were enrolled in the MER from 2002-2015. Median age at dx was 60 yrs (IQR 51-69). Clinical characteristics were: 67% stage III/IV, 12% grade 3A, 4% ECOG PS 2-4, and 19% elevated LDH. Initial management was 35% observation (obs), 12% R-monotherapy (R-mono), 39% immunochemotherapy (IC; 43% R-CHOP, 28% R-CVP, 27% BR), and 14% other. FLIPI scores were 40% low, 33% intermediate (int), and 27% high; FLIPI24 risk categories were 49% low, 25% int, and 26% high. At a median follow-up of 14 yrs (IQR 11-18 yrs), 751 events, 148 HTs, and 402 deaths were observed.

EFS estimates (95% CI) were: 10-yr: 40% (37-43), 15-yr: 31% (28-35), and 18-yr: 27% (24-31). 15 yr & 18 yr EFS by initial txs were 22% (18-27) & 18% (14-25) for obs, 30% (23-40) & 18% (11-30) for R-mono, and 40% (35-46) & 38% (33-45) for IC.

The incidence (95% CI) of HT was 12% (10-14) at 10 yrs, 13% (11-16) at 15 yrs, and 14% (12-17) at 18 yrs. OS (95% CI) for the entire cohort was 77% (75-80%) at 10 yrs, 63% (60-66) at 15 yrs, and 55% (51-59) at 18 yrs. The incidence of non-lymphoma-related death (non-LRD) surpassed lymphoma-related death (LRD) after 12 yrs in pts with known cause of death. Estimates (95% CI) for LRD were 11% (10-13) at 10 yrs, 14% (12-17) at 15 yrs, and 16% (14-19) at 18 yrs, while estimates for non-LRD were at 8% (7-10) at 10 yrs, 17% (15-20) at 15 yrs, and 22% (19-26) at 18 yrs.

Among pts diagnosed before age 60, LRD remained the predominant cause of mortality into the second decade following dx, with incidences (95% CI) of LRD vs. non-LRD of 7% (5-9) vs 3% (2-4) at 10 yrs, 10% (8-13) vs 5% (3-8) at 15 yrs, and 13% (9-17) vs 6% (4-10) at 18 yrs, respectively. In patients age >60 non-LRD was the predominant cause of mortality in the second decade. Incidence of LRD vs. non-LRD in those aged ≥60 at dx were 15% (13-19) vs 13% (10-16) at 10 yrs, 18% (15-22) vs 28% (24-32) at 15 yrs, and 20% (16-24) vs 35% (31-41) at 18 yrs, respectively.

In the landmark analysis of pts alive at 10 yrs from dx (n=720), median age was 69 yrs (IQR 60-77). 63 pts (9%) had HT prior to landmark. The median number of prior treatments was 1 (IQR 1-2, range 1-8). Risk of death (95% CI) was 19% (15-22) in the next 5 yrs (i.e. 15 yrs from dx) and 29% (24-33) in the next 8 yrs (18 yrs from dx). The risk of LRD vs non-LRD was 4% (3-6) vs 12% (9-15) at 5 yrs and 7% (3-9) vs 18% (10-23) at 8 yrs.Conclusions: Long-term outcomes for pts with FL remain excellent into the second decade from dx. HT risk decreases significantly after 10 yrs, though late HTs still occur. At 15 yrs from dx, 40% of pts remained alive and event-free after 1L IC. Nearly a quarter of pts observed at dx remained treatment-free. The most common cause of death after 10 yrs from dx was from non-lymphoma causes, notably in older pts aging into their 70s and 80s. While younger pts have a lower overall risk of LRD compared to older pts, FL represents the leading cause of death in this population during the second decade following dx. These results provide critical insights into the natural history of FL diagnosed in the modern era.

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2025
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