Relationship between BCL2 mutations and follicular lymphoma outcome in the chemoimmunotherapy era

Abstract

How to identify follicular lymphoma (FL) patients with low disease burden but high risk for early progression is unclear. Building on a prior study demonstrating the early transformation of 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, SOCS, and MYC, in 199 newly diagnosed grade 1 and 2 FLs. BCL2 mutations with VAF ≥20% occurred in 52% of cases. Among 97 FL patients who did not initially receive rituximab-containing therapy, nonsynonymous BCL2 mutations at VAF ≥20% were associated with increased transformation risk (HR 3.01, 95% CI 1.04-8.78, p = 0.043) and a trend toward shorter event-free survival (EFS, median 20 months with mutations versus 54 months without, p = 0.052). Other sequenced genes were less frequently mutated and did not increase the prognostic value of the panel. Across the entire population, nonsynonymous BCL2 mutations at VAF ≥20% were associated with decreased EFS (HR 1.55, 95% CI 1.02-2.35, p = 0.043 after correction for FLIPI and treatment) and decreased overall survival after median 14-year follow-up (HR 1.82, 95% CI 1.05-3.17, p = 0.034). Thus, high VAF nonsynonymous BCL2 mutations remain prognostic even in the chemoimmunotherapy era.

Fig. 1. Somatic mutational profiles in FL.

A Percentage of FL patients with somatic BCL2 SNVs at different variant allele frequencies. B BCL2 mutations per case in 103 samples harboring BCL2 mutations with VAF ≥20%. C Pie chart representing somatic mutation types: Synonymous, nonsynonymous (missense and nonsense), and presence in untranslated regions (urt) in 103 samples harboring BCL2 mutations with VAF ≥20%. D Distribution of nonsynonymous SNVs with VAF ≥20% along the BCL2 coding exons (2 and 3). Missense (orange) and nonsense (red) mutations are shown. An analysis showing results with VAF ≥5% is found in Supplemental Fig. S3.

Fig. 2. Relationship between prevalent nonsynonymous BCL2 mutations detected at diagnosis and FL EFS.

A–C Kaplan–Meier plots showing the impact of nonsynonymous BCL2 mutations with VAF ≥20% on EFS for all patients (A), patients who did not receive systemic therapy initially, i.e., were observed or treated with local radiation (B), and those treated initially with rituximab, R-CVP or R-CHOP (C). D, E Kaplan–Meier plots showing the relationship between nonsynonymous BCL2 mutations with VAF ≥5% (D) or any BCL2 mutation (synonymous or nonsynonymous) with VAF ≥20% (E) and EFS for patients who did not receive systemic therapy initially.

Fig. 3. Relationship between prevalent nonsynonymous BCL2 mutations detected at diagnosis and TTT or OS.

A, B Kaplan–Meier plots showing the impact of BCL2 nonsynonymous mutations with VAF ≥20% on TTT and time to death for patients who did not receive systemic therapy initially (A) or patients treated initially with rituximab, R-CVP, or R-CHOP (B). C Kaplan–Meier plot showing the impact of prevalent nonsynonymous BCL2 mutations on OS for all FL patients. D, E, Kaplan–Meier plots showing the relationship between any BCL2 mutation (synonymous or nonsynonymous) with VAF ≥20% (D) or nonsynonymous BCL2 mutations with VAF ≥5% (E) and OS for all FL patients studied.