Cause of Death in Follicular Lymphoma in the First Decade of the Rituximab Era: A Pooled Analysis of French and US Cohorts

Abstract

Purpose: Although the life expectancy of patients with follicular lymphoma (FL) has increased, little is known of their causes of death (CODs) in the rituximab era.

Patients and methods: We pooled two cohorts of newly diagnosed patients with FL grade 1-3A. Patients were enrolled between 2001 and 2013 in two French referral institutions (N = 734; median follow-up 89 months) and 2002 and 2012 in the University of Iowa and Mayo Clinic Specialized Program of Research Excellence (SPORE; N = 920; median follow-up 84 months). COD was classified as being a result of lymphoma, other malignancy, treatment related, or all other causes.

Results: Ten-year overall survival was comparable in the French (80%) and US (77%) cohorts. We were able to classify COD in 248 (88%) of 283 decedents. In the overall cohort, lymphoma was the most common COD, with a cumulative incidence of 10.3% at 10 years, followed by treatment-related mortality (3.0%), other malignancy (2.9%), other causes (2.2%), and unknown (3.0%). The 10-year cumulative incidence of death as a result of lymphoma or treatment was higher than death as a result of all other causes for each age group (including patients ≥ 70 years of age at diagnosis [25.4% v 16.6%]) Follicular Lymphoma International Prognostic Index score 3 to 5 (27.4% v 5.2%), but not Follicular Lymphoma International Prognostic Index score 0 to 1 (4.0% v 3.7%); for patients who failed to achieve event-free survival within 24 months from diagnosis (36.1% v 7.0%), but not for patients who achieved event-free survival within 24 months of diagnosis (6.7% v 5.7%); and for patients with a history of transformed FL (45.9% v 4.7%), but not among patients without (8.1% v 6.2%). Overall, 77 of 140 deaths as a result of lymphoma occurred in patients whose FL transformed after diagnosis.

Conclusion: Despite the improvement in overall survival in patients with FL in the rituximab era, their leading COD remains lymphoma, especially after disease transformation. Treatment-related mortality also represents a concern, which supports the need for less-toxic therapies.

FIG 1.

Cumulative incidence for the competing risks of cause of death in the pooled cohort. (A) Cumulative incidence by cause of death. (B) Cumulative incidence by cause of death with y-axis rescaled.

FIG 2.

Cumulative incidence for the competing risks of cause of death. (A) Cumulative incidence by cause of death for patients age ≤ 60 years. (B) Cumulative incidence by cause of death for patients age 61 to 70 years. (C) Cumulative incidence by cause of death for patients age > 70 years.

FIG 3.

Cumulative incidence for the competing risks of cause of death according to Follicular Lymphoma International Prognostic Index (FLIPI) score. (A) Cumulative incidence by cause of death for patients with FLIPI score 0 to 1. (B) Cumulative incidence by cause of death for patients with FLIPI score 2. (C) Cumulative incidence by cause of death for patients with FLIPI score 3 to 5.

FIG A1.

Overall survival since diagnosis.

FIG A2.

Cumulative incidence for the competing risks of cause of death according to sex. (A) Cumulative incidence by cause of death for male patients. (B) Cumulative incidence by cause of death for female patients.

FIG A3.

Cumulative incidence for the competing risks of cause of death according to disease stage. (A) Cumulative incidence by cause of death for patients with stage I and II disease. (B) Cumulative incidence by cause of death for patients with stage III and IV disease.

FIG A4.

Cumulative incidence for the competing risks of cause of death. (A) Patients treated upfront with immunochemotherapy (IC) who achieved event-free survival within 24 months of diagnosis (EFS24). (B) Patients treated upfront with IC who did not achieve EFS24 diagnosis. (C) Patients not treated with up-front IC (non-IC treated) who achieved EFS12/early event achieve non−IC treated. (D) Patients not treated with up-front IC (non-IC treated) who did not achieve EFS12 (early event)/early event fail non−IC treated.

FIG A5.

Cumulative incidence for the competing risks of cause of death. (A) US cohort patients without follicular lymphoma transformation/US cohort no transformation (B) US cohort patients with follicular lymphoma transformation/US cohort transformation.