French and US pooled analysis on cause of death in FL during the rituximab era

On 27 November 2018, Clémentine Sarkozy from the University Hospital Center of Lyon, Lyon, FR, and colleagues, published in the Journal of Clinical Oncology a pooled analysis of French and US follicular lymphoma (FL) patients. The study evaluated the causes of death (CODs) in FL patients during the rituximab era.

FL is the most common indolent lymphoma subtype with lots of research having focused on treatment regimens and the pathology of the disease. There is a lack of data on the precise CODs in FL patients during the modern rituximab treatment era. The aim of this analysis was to contribute information on the exact reasons that FL patients die in France and the US, whilst on rituximab-based therapies.

Study design

• French cohort: N = 734 newly-diagnosed or referred grade 1–3a FL patients, between 2001–2013 (University Hospital Center of Lyon)
• US cohort: N = 920 newly-diagnosed grade 1–3a FL patients, between 2002–2012 (Mayo Clinic and University of Iowa)
• If COD was unclear, the case was discussed and consensus was reached by the investigators
• FL transformation status was mainly confirmed by biopsy or in some cases on previously described clinical criteria
• COD was first categorized into five groups:
  • Lymphoma
  • Treatment
  • Unrelated cancer
  • Other causes
  • Unknown
• A further sub-categorization was also performed based on:
  • Lymphoma-related death (lymphoma- or treatment-related)
  • Unrelated to lymphoma death (other malignancies and causes)
  • Unknown

Results

• French and US patient cohorts had similar baseline characteristics in terms of age, sex distribution, Ann Arbor stage and FL International Prognostic Index (FLIPI) score
• Most common initial therapy:
  • French cohort: immunochemotherapy (IC; 67%)
  • US cohort: IC (38%) and ‘watch and wait’ (36%)
• Deaths:
  • French cohort: n = 113 (median follow-up = 89 months)
  • US cohort: n = 170 (median follow-up = 84 months)
• Ten-year overall survival (OS):
  • French cohort: 8% (median follow-up = 89 months)
  • US cohort: 6% (median follow-up = 84 months)
• Event-free survival at 24 months (EFS24):
  • French cohort: 9%
  • US cohort: 9%
• CODs were evaluated in 88% (n = 248/283) of the deceased patients from both cohorts, with the following ten-year cumulative incidences (most to least frequent):
  • Lymphoma-related: 10.3% (95% CI, 8.6–12.2)
  • Treatment-related mortality (TRM): 3.0% (95% CI, 2.2–4.1)
  • Unknown: 3.0% (95% CI, 2.1–4.4)
  • Other malignancy: 2.9% (95% CI, 2.0–4.2)
  • Other causes: 2.2% (95% CI, 2.1–4.4)
• Among the deceased patients with a known COD:
  • 57% were due to lymphoma
  • 13% were treatment-related
  • 13% were caused by other malignancies
  • 13% were caused by other reasons
• Ten-year cumulative incidence of lymphoma-related death:
  • French cohort: 2% (95% CI, 11.4–17.8)
  • US cohort: 5% (95% CI, 10.2–15.4)
• Ten-year cumulative incidence of death due to other causes:
  • French cohort: 7% (95% CI, 2.3–6.1)
  • US cohort: 1% (95% CI, 4.4–8.4)
• Of the 140 lymphoma-related deaths 55% occurred in FL patients who transformed at some point during the course of the disease
• The cumulative incidence of lymphoma-related (P < 0.001) and non–lymphoma-related (P < 0.001) deaths increased with age of diagnosis
• The 10-year cumulative incidence of lymphoma-related mortality was higher in patients with stage III to IV (15.5%) FL compared to I to II (7.8%; P < 0.001) and in patients with 0–1 FLIPI score (10.0%) compared to 3–5 FLIPI (27.4%; P < 0.001)
• The cumulative incidence of lymphoma-related mortality after FL transformation was greater than that of non–lymphoma-related mortality, something that was not observed for patients without FL transformation (similar values)
  • Ten-year cumulative incidence since transformation was 45.9% for lymphoma-related mortality and 4.7% for non–lymphoma-related mortality

This pooled analysis from French and American FL patients who were treated and diagnosed in the rituximab era, revealed that lymphoma was the main COD during the first ten years since diagnosis. Moreover, lymphoma-related mortality was the main COD irrespective of patient age and was significantly associated with FLIPI score. As expected, the cumulative risk of lymphoma-related death was higher in patients following FL transformation.