Lymphoma Continues to be Main Cause of Death in Follicular Lymphoma, New Pooled Analysis Finds

A new pooled analysis concluded that the leading cause of death in patients with follicular lymphoma continues to be lymphoma, despite the widespread improvements in overall survival (OS) demonstrated with rituximab (Rituxan).¹

According to the authors, who were led by Clementine Sarkozy, MD, of the Hospices Civils de Lyon, patients are most vulnerable to dying of follicular lymphoma in the first 10 years post-diagnosis. “This is particularly true for patients who present with a high FLIPI (Follicular Lymphoma International Prognostic Index) score, for those with transformed disease, and for those who did not achieve EFS12/EFS24 (event-free survival for 12 or 24 months),” they wrote in theJournal of Clinical Oncology. “Deaths related to treatment seem to also be a significant burden and new, less toxic treatment options need to be investigated.”

The investigators pooled 2 cohorts of patients who had been recently diagnosed with follicular lymphoma, grades 1 to 3A. Patients from 2 French institutions were enrolled between 2001 and 2013 (n = 734). A comparable American cohort was enrolled from 2002 to 2012 (n = 920). The composition of both cohorts was comparable in patient age and sex, Ann Arbor stage, and FLIPI score.

The 10-year OS rate was comparable in each cohort, at approximately 80%. After a median follow-up of 89 months in the French cohort, there were 113 deaths (15.4%). At a median follow-up of 84 months in the US cohort, 170 deaths had occurred (18.5%).

Sarkozy et al had previously defined the inability to reach EFS24 as early failure among patients first treated with immunochemotherapy. Among patients with other initial management strategies, including watchful waiting, they considered the early failure point to be EFS12. In the current trial, 69.9% of patients in each cohort were able to achieve EFS24.

Of the 283 patients who died, the investigators were able to identify the cause of death in 248 patients (88%). They classified these deaths as being due to either lymphoma, treatment-related causes, other malignancies, other causes or unknown causes.

Death from lymphoma was the most common cause of death, with a cumulative incidence of 10.3% at 10 years (95% CI, 8.6%-12.2%). Seventy patients from each cohort died of lymphoma, yielding a combined total of 56.5% lymphoma-related deaths. About half of these patients (n = 77) had experienced disease transformation.

Treatment-related mortality was deemed the second-leading cause of death, with a cumulative incidence of 3.0% at 10 years (95% CI, 2.2%-4.1%). A total of 42 patients (16.9%) died from their treatments. Therapy-related infections were the leading culprit (n = 20), followed by myelodysplastic syndrome/acute myeloid leukemia (n = 12). Cardiac treatments (n = 6) and other treatments (n = 4) accounted for the remaining treatment-related mortalities.

The cumulative incidence for other malignancies was 2.9% (95% CI, 2.0% to 4.2%), accounting for 33 deaths, or 13.3% of the total. Thirty-three patients died of other causes (95% CI, 1.5%-3.1%).

The authors also modeled the cumulative incidence for each cause of death category for key subgroups defined on clinical characteristics and demographics like patient age. For example, the 10-year cumulative incidence of death resulting from 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% vs 16.6%).

The 10-year incidence of death from lymphoma or treatment was also higher than death as a result of any other causes for FLIPI score 3 to 5 (27.4% vs 5.2%), but not FLIPI score 0 to 1 (4.0% vs 3.7%). Likewise, patients who failed to achieve event-free survival within 24 months from diagnosis had a higher incidence of death from lymphoma (36.1% vs 7.0%), but patients who achieved event-free survival within 24 months of diagnosis did not (6.7% vs 5.7%).

The 10-year incidence of death from lymphoma was dramatically higher for patients with a history of transformed FL (45.9% vs 4.7%), but not among patients without (8.1% vs 6.2%). This led the authors to conclude that the “important notion that transformation in follicular lymphoma is the major cause of lymphoma-related death should provide a framework for future specific approaches.”

Sarkozy et al also called for more research to establish less-toxic treatment paradigms in follicular lymphoma. They based this call on their data showing that the cumulative risk of mortality as a result of lymphoma of 1.3% at 10 years ballooned to a cumulative risk of 13.3% when combined with treatment-related mortality, the second-leading cause of death in the study.

They noted that, in contrast, the cumulative risk of mortality as a result of all non-lymphoma-related causes was only 5.1% at 10 years following diagnosis.

Reference:

Sarkozy C, Maurer MJ, Link BK, et al. Cause of death in follicular lymphoma in the first decade of the rituximab era: a pooled analysis of French and US cohorts [published online November 27, 2018]. J Clin Oncol. doi: 10.1200/JCO.18.00400.