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

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) BCL2 mutations at activation-induced cytidine deaminase (AICDA) sites, we examined 11 AICDA mutational targets, including BCL2, BCL6, PAX5, PIM1, RHOH, SOCS1, and MYC, 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.]]>
Inclusion Criteria:Patients with newly diagnosed grade 1 or 2 follicular lymphoma ]]>
This study was reviewed and approved by the Mayo Clinic Institutional Review Board. Samples were obtained from 199 patients with newly diagnosed grade 1 or 2 FL who consented to enrollment in the Molecular Epidemiology Resource (MER) of the University of Iowa/Mayo Clinic Lymphoma Specialized Program of Research Excellence (SPORE) and were treated at the Mayo Clinic between 2002 and 2009. All patients had formalin fixed paraffin embedded (FFPE) biopsy samples available from initial diagnosis and a minimum follow-up of five years in 2014 when the cohort was assembled, i.e., prior to bendamustine approval.These patients were divided into groups that i) received first-line therapy with rituximab, R-CHOP5 or R-CVP (“Rituximab-treated”), with only 3 patients (1 R-mono and 2 R-CVP) receiving R maintenance; ii) were observed or received localized radiation as their initial treatment (“No systemic treatment”); or iii) received systemic treatment without rituximab (“Other”). FFPE lymph nodes from initial diagnosis were reviewed to confirm the presence of FL and estimate tumor content (median 70%, range 50-90%). All participants were contacted every 6 months for the first three years after diagnosis and annually thereafter to determine disease progression/relapse, retreatment, and transformation. All events, as well as deaths (including cause of death) were validated against medical records.]]>