Impact of tumor mutational burden on the response to immunochemotherapy in follicular lymphoma

Introduction: Follicular lymphoma (FL) is the second most common subtype of non-Hodgkin lymphoma. It is typically an indolent entity, however, patients who progress or relapse within 24 months of front-line immunochemotherapy (ICT), have a poor outcome. Tumor mutational burden (TMB) is defined as the number of somatic mutations/megabase (mut/Mb) and has been proposed as a biomarker for predicting response to immune checkpoint inhibitors in some cancers. This study aimed to explore the role of TMB in FL. Methods: The study included 51 patients with FL grade 1–3a treated with first line ICT (rituximab, R-CHOP, R-CVP or R-bendamustine). TMB was determined in diagnostic lymph node biopsies by Next Generation Sequencing (NGS), using the Oncomine Tumor Mutational Load Assay (Thermo Fisher), which covers 409 genes. Sequencing was performed on the Ion GeneStudio S5 system with >300X mean coverage. In addition, the mutational profile of 27 of the 51 patients was analyzed using a QIAgen custom DNA panel which covered 64 genes frequently mutated in FL. Sequencing was performed using MiSeq (Illumina) with >3000X mean coverage. Variants were analyzed and interpreted for pathogenicity using several databases. Results: Median age at time of treatment was 64 years (mean 62; range 24–83), with 84% of patients diagnosed with stage III-IV disease. All patients presented at least one mutation using the custom panel, and showed a median TMB value of 5.22 mut/Mb (range 1.69–14.66 mut/Mb). The number of mutations identified correlated with TMB value at diagnosis (p = 0.003). We did not find statistically significant differences in clinical parameters according to basal TMB. However, patients harboring the t(14;18)(q32;q21) translocation and patients with mutations in genes involved in migration, had a higher TMB at diagnosis (mean 6.57 vs. 4.18 mut/Mb, p = 0.017; 8.52 vs. 4.74 mut/Mb, p < 0.001, respectively). Moreover, patients with mutations in genes involved in the BCR pathway showed a trend towards a higher TMB (6.79 vs. 4.73 mut/Mb, p = 0.061). Patients were then stratified in two groups according to their basal TMB value, with a cutoff of 8 mut/Mb that corresponded to the upper quartile. The high-TMB group was enriched in patients harboring mutations in BCR signaling pathway or migration genes (p = 0.016, p = 0.009 respectively) and showed a trend towards having the t(14;18) translocation or mTORC1 pathway mutations (p = 0.106, p = 0.144 respectively). Patients in the high-TMB subgroup had a trend towards a longer progression free survival (PFS) (p = 0.17) (Figure 1). 5-years PFS was 88.9% (95% CI: 10.5–70.6) in high-TMB patients and 61.1% (95% CI: 46.0–81.2) in low-TMB patients. The research was funded by: FIS/FEDER PI19/00034, ISCIII Spanish Ministry of Education (FPU21/02671) Keywords: diagnostic and prognostic biomarkers, genomics, epigenomics, and other -omics, indolent non-Hodgkin lymphoma No conflicts of interests pertinent to the abstract.