Subclonal TP53 mutation are frequent and predict resistance to radio-immunotherapy in follicular lymphoma.

Although TP53 is commonly mutated in transformed follicular lymphoma, mutations are reported in fewer than 5% of pre-treatment follicular lymphoma (FL) specimens. We assayed archival follicular B-cell non-Hodgkin lymphoma specimens from a completed clinical trial, SWOG S0016, a phase III randomized intergroup trial of CHOP chemotherapy plus rituximab (R-CHOP) compared with CHOP chemotherapy plus 131-iodine tositumomab (radio-immunotherapy (RIT)-CHOP). Subclonal TP53 mutation (median allele frequency 0.02) were found in 25% of diagnostic FL specimens and 27% of a separate validation cohort. In the R-CHOP arm, pathogenic TP53 mutations were not associated with progression-free survival (PFS) (10-year PFS 43% vs 44%). In contrast, among patients with no detectable pathogenic TP53 mutation, RIT-CHOP was associated with a longer PFS than R-CHOP (10 year PFS 67% vs 44%; HR=0.49; p=0.008). No relationship was detected between PFS and the extent of Activation-induced cytidine deaminase (AICDA)-mediated heterogeneity. In summary, subclonal TP53 mutations are common in FL and are a distinct phenomenon from AICDA-mediated genetic heterogeneity. The absence of a detectable subclonal mutation in TP53 defined a population that particularly benefited from RIT.