Follicular lymphoma in the modern era: survival, treatment outcomes, and identification of high-risk subgroups

Abstract

Patients with follicular lymphoma (FL) frequently require multiple treatments during their disease course; however, survival based on lines of treatment remains poorly described in the post-rituximab era. Also, the Follicular Lymphoma International Prognostic Index (FLIPI) score was developed to predict survival at diagnosis, yet it remains unknown whether increase in FLIPI score following an initial observation period is associated with less-favorable outcomes. To address these knowledge gaps, we retrospectively studied 1088 patients with FL grade 1-3A managed between 1998 and 2009 at our institution. Median overall survival (OS) and progression-free survival (PFS) after first-line treatment were not reached and 4.73 years, respectively. Following successive lines of treatment, years of median OS and PFS were, respectively: after second-line, 11.7 and 1.5; third-line, 8.8 and 1.1; fourth-line, 5.3 and 0.9; fifth-line, 3.1 and 0.6; sixth-line, 1.9 and 0.5. In initially observed, subsequently treated patients, FLIPI score increase after observation was associated with inferior survival following first-line treatment. The reduced survival we observed after second-line and later therapy supports the development of new treatments for relapsed patients and benchmarks historical targets for clinical endpoints. This study also highlights the utility of changes in FLIPI score at diagnosis and after observation in identifying patients likely to have worse outcomes.

Fig. 1. Flow diagram of FL patients included in our analysis.

Patients diagnosed during the years 1998−2009 were assessed for eligibility. We analyzed 1088 patients while excluding 358 patients for active concurrent malignancy, a composite histology at diagnosis, grade 3B histology, or inadequate follow-up. Nine hundred and twenty-four patients were treated, either initially or after an observation period, and 164 patients never required treatment.

Fig. 2. Survival outcomes.

a OS from time of diagnosis for 1088 patients. b OS from time of diagnosis for 1078 patients based on stage at diagnosis. Ten patients excluded for an unknown stage at diagnosis. Stage III disease included patients with provisional stage III, as bone marrow biopsy was not performed for 21% of all patients. c OS from time of diagnosis for 851 patients with FLIPI score at time of diagnosis; FLIPI score at diagnosis unknown for 237 patients. d OS from time of first-line treatment for 731 patients with FLIPI score at time of first treatment; FLIPI score at treatment unknown for 191 patients while 2 patients had incomplete data for survival analysis.

Fig. 3. OS, PFS, and EFS outcomes based on lines of therapy for 922 patients.

a OS from commencement of line of therapy. b PFS from commencement of line of therapy. c EFS from commencement of line of therapy.

Fig. 4. Flow diagram of patients for stable vs increased FLIPI analysis.

a Treated patients with FLIPI score at time of diagnosis and treatment (n = 684) were excluded if they were treated within 6 months or had unknown treatment dates (n = 496). Stable FLIPI included patients whose FLIPI risk category did not change between diagnosis and first treatment (low to low, or intermediate to intermediate). Increased FLIPI included patients whose FLIPI score increased between diagnosis and first treatment (low to intermediate, low to high, or intermediate to high). We excluded patients whose FLIPI score decreased between diagnosis and first treatment or remained high (high to high, high to intermediate, high to low, or intermediate to low). Patients observed ≥6 months (n = 188) and ≥12 months (n = 146) were evaluated for stable or increased FLIPI scores. b Patients who never required treatment were evaluated using FLIPI at diagnosis and the highest FLIPI during the initial 5 years of observation to obtain their status of stable or increased FLIPI.

Fig. 5. Comparison of outcomes for patients with stable vs dynamic FLIPI.

a OS from time of diagnosis in patients who were never treated and had an annual FLIPI score within first 5 years of observation. b OS since time of first-line treatment in treated patients observed ≥6 months. c PFS since time of first-line treatment in treated patients observed ≥6 months. d OS since time of first-line treatment in treated patients observed ≥12 months. e PFS since time of first-line treatment in treated patients observed ≥12 months.