It is currently unclear how to identify follicular lymphoma (FL) patients with low disease burden but high risk for early progression. Building on a prior study demonstrating early transformation in FLs with high variant allele frequency (VAF) <a href="https://www.ncbi.nlm.nih.gov/gene/596">BCL2</a> mutations at activation-induced cytidine deaminase (AICDA) sites, we examined 11 AICDA mutational targets, including BCL2, <a href="https://www.ncbi.nlm.nih.gov/gene/604">BCL6</a>, <a href="https://www.ncbi.nlm.nih.gov/gene/5079">PAX5</a>, <a href="https://www.ncbi.nlm.nih.gov/gene/5292">PIM1</a>, <a href="https://www.ncbi.nlm.nih.gov/gene/399">RHOH</a>, <a href="https://www.ncbi.nlm.nih.gov/gene/8651">SOCS1</a>, and <a href="https://www.ncbi.nlm.nih.gov/gene/4609">MYC</a>, in a more contemporary cohort of 199 newly diagnosed grade 1 and grade 2 FLs using targeted capture and massively parallel sequencing. BCL2 mutations with VAF >20% occurred in 52% of cases. Among 97 FLs that did not initially receive rituximab-containing therapy, nonsynonymous BCL2 mutations at VAF >20% were associated with shorter, event-free survival (EFS, median 1.4 years with these mutations versus 4.5 years without, p = 0.048), and increased risk of transformation (HR 3.01, 95% CI 1.03-8.77, p = 0.04). Other sequenced genes were less frequently mutated and did not significantly increase the prognostic value of the panel. Across the entire population, BCL2 mutations at VAF >20% were associated with decreased EFS (HR 1.58, 95% CI 1.03-2.40, p = 0.034 after correction for FLIPI and treatment) and decreased overall survival after median 14-year follow-up (HR 1.86, 95% CI 1.07-3.23, p = 0.029). Thus, high VAF BCL2 mutations remain a prognostic factor for FL even in the chemoimmunotherapy era and might need to be considered in future study design.

Expression of Activation Induced Cytidine Deaminase and Risk of Transformation in Follicular Lymphoma