Nodal peripheral T-cell lymphomas (nPTCL) constitute a heterogeneous group of rare malignancies with aggressive biological behavior and poor prognosis. Epigenetic phenomena involving genes that control DNA-methylation and histone deacetylation, such as IDH2, DNMT3A, TET2 and RhoA, play a central role in their pathogenesis. Tumor mutation burden (TMB) has emerged as a prognostic biomarker in numerous solid neoplasms. Furthermore, TMB reflects the process of clonal evolution, with progressive acquisition of additional molecular-genetic abnormalities. Recent studies were capable to establish a relationship between TMB and response to anti-cancer treatments. In 2021 Fachi et cols. established a correlation between high TMB in epigenetic regulatory genes and higher response rates to 5-azacytidine and romidepsin in nPTCL. However, the potential prognostic impact of epigenetic TMB remains unknown in nPTCL. Based on this premise, here we aimed, in a pioneering way, to search for a correlation between epigenetic high TMB and adverse prognosis in nPTCL.

This is a retrospective, observational and single-center study, involving 59 patients with nPTCL diagnosed and treated at the Department of Hematology, University of São Paulo, Brazil, from January 2000 to December 2019. FFPE diagnostic tumor samples were submitted to Sanger sequencing with a target-panel, involving IDH2, DNMT3A, TET2 and RhoA genes to search for recurrent mutations.

The median age was 50 years (IqR 38-61), and 57.6% (34/59) were male. Thirty-nine percent (23/59) had bulky disease ≥ 7 cm, 83% (49/59) had B-symptoms, 94.9% (56/59) had advanced stage III/IV, 27.1% (16/59) had ECOG ≥ 2, 27.1% (16/59) had ≥ 2 extranodal sites involved by lymphoma, and 55.9% (33/59) had intermediate-high/high-risk IPI. Seventy-six percent (45/59) received up-front therapy with CHOP-like regimens (CHOP or CHOEP), 23.7% (14/59) experienced radiotherapy, and 33.3% (20/59) were consolidated with ASCT. With a median follow-up of 3.7 years (95% CI: 0.9-12.4), the estimated 2-year OS and PFS were 57.1% (95% CI: 45.5-70.4) and 49.2% (95% CI: 34.0-59.2), respectively. Missense, non-sense or frameshift mutations in the IDH2 gene were observed in 3.3% (2/59) of cases, DNMT3A in 3.3% (2/59), RhoA in 23.7% (14/59) and TET2 in 37.2% (22/59). Among the 59 patients included, 23/59 (38.9%) had no mutations in the target-genes, 25/59 (42.4%) had 1 mutation, and 11/59 (18.6%) had two or more mutations. Therefore, the cases were categorized into low TMB (< 2 mutations) [n = 48/59 – 81.3%] or high TMB (≥ 2 mutations) [n = 11/59 – 18.7%]. The median overall survival was 51.4 months (95% CI: 0-124.1) for low TMB and only 3.1 months (95% CI: 3.1-15.2) for high TMB, p = 0.08. The estimated 2-year OS was 64.3% (95% CI: 50.6-78.0) for low TMB and 36.4% (95% CI: 8.0-65.0) for high TMB. Similarly, median progression-free survival was 13.3 months (95% CI: 0-29.4) for low TMB and 6.3 months (95% CI: 0.9-11.6) for high TMB, p = 0.319. The estimated 2-year PFS was 46.1% (95% CI: 20.0-72.1) for low TMB and 25.0% (95% CI: 17.5-67.5) for high TMB.

In a pioneering way, we demonstrated that the high epigenectic TMB, defined by the presence of 2 or more mutations involving epigenetic regulatory genes, was associated with decreased overall survival in Brazilian patients with nodal PTCL. Although preliminary, these data support the potential impact of epigenetic TMB as a prognostic biomarker in nPTCL.