Paper Details

ABSTRACT

Background: While follicular lymphoma (FL) has traditionally been considered incurable, emerging long-term data have meaningfully challenged this paradigm. Follow-up from the SWOG S0016 study and the Mayo/Iowa Molecular Epidemiology Resource (MER) cohort demonstrated 15-year overall survival (OS) of 70-80%, with sustained event-free survival (EFS) in 40% of patients (pts) following immunochemotherapy (IC), raising the possibility that a discrete cured fraction exists within FL. Our prior work established that while early progression carries poor outcomes, pts with FL free of progression or transformation at 24 months (having achieved EFS24) have survival indistinguishable from the age and sex-matched U.S. population, and that FLIPI24, a prognostic model using clinical variables at diagnosis, robustly stratifies risk of early events and lymphoma-related death. We hypothesized that among pts subsequently achieving EFS24, those with low baseline FLIPI24 would demonstrate OS consistent with population-normal survival, consistent with a cured fraction within this landmark population.

Methods: We analyzed pts with grade 1-3A FL enrolled at diagnosis in the Lymphoma Epidemiology of Outcomes (LEO) and MER prospective cohorts. We included all pts free of progression, transformation, and/or retreatment at 24 months (achieved EFS24). FLIPI24 risk was calculated at diagnosis and categorized as low, intermediate, or high per the published algorithm. OS was defined from the EFS24 landmark until death from any cause and compared to expected survival in age and sex-matched U.S. general population. Cause of death was evaluated using cumulative incidence with competing risks for lymphoma versus non-lymphoma death. Analyses were performed in all EFS24 achievers, including frontline (IC)-treated and observation/R-mono treated subsets.

Results: 727 pts from MER and 1,077 from LEO achieved EFS24. Median age was 60 in both cohorts. Frontline therapy was 41% IC, 33% observation, 12% R-monotherapy, and 14% other in MER; 41% IC, 30% observation, 12% R-monotherapy, and 18% other in LEO. Baseline FLIPI24 was 39% low, 42% intermediate, 20% high in MER; 41% low, 40% intermediate, 19% high in LEO. Median follow-up from EFS24 was 9 years in MER and 5 years in LEO. Five-year OS (OS5) from EFS24 was 92% (95% CI: 90–94) in MER and 93% (95% CI: 91–94) in LEO.

Pts with low-risk FLIPI24 achieving EFS24 had excellent outcomes: OS5 was 98% in both cohorts [(MER 95% CI: 97–100); (LEO 95% CI: 96-99)], comparable to or exceeding age and sex-matched U.S. general population survival (expected: 95%). Among intermediate-risk FLIPI24 pts achieving EFS24, OS5 was 93% in MER (95% CI: 90–96) and 94% in LEO (95% CI: 91–96), comparable to expected general population survival (92–93%). In contrast, pts with high-risk FLIPI24 had meaningfully lower OS5 after EFS24: 78% in MER (95% CI: 71–85) and 79% in LEO (95% CI: 74–86), below population expectations (83%).

Examination of cause of death showed consistent findings. Lymphoma-related mortality among pts with low-risk FLIPI24 achieving EFS24 was 0.4% (95% CI: 0.1-2.6) at 5 years and 0.9% (95% CI: 0.2-3.8) at 10 years in MER, and 0.3% (95% CI: 0.0-2.2) at 5 years in LEO. Five-year lymphoma-related death was 1.4% (95% CI: 0.5-3.8) in MER and 0.5% (95% CI: 0.1-2.1) in LEO for intermediate-risk, and 3.7% (95% CI: 1.6-8.8) in MER and 4.9% (95% CI: 2.6-9.3) in LEO for high-risk FLIPI24. All results were consistent across frontline therapy subgroups and across 10-year follow-up in MER.

Conclusions: Achieving EFS24 largely mitigates baseline prognostic risk across all FLIPI24 strata in FL. Pts with low and intermediate baseline FLIPI24 achieving EFS24 had very low lymphoma-related mortality (0.3-1.4% at 5 years) and OS comparable to the age and sex-matched general population. Pts with high-risk baseline FLIPI24 achieving EFS24 had slightly lower OS than population expectations, though lymphoma-related death remained uncommon (<5% at 5 years). Results were consistent across frontline therapy subgroups.

These findings suggest FLIPI24 may predict who among EFS24 achievers will have population-normal survival, particularly those with low to intermediate risk at diagnosis. EFS24 may provide a clinically meaningful endpoint in clinical trials among patients with low and intermediate risk FLIPI24.