Mutations and Outcomes in Slovenian nTCL Cohort. Insights into Nodal T-Follicular Helper Cell Lymphomas and Peripheral T-Cell Lymphomas, Not Otherwise Specified, in Slovenian Patients: Mutational Landscape, Clinicopathological Characteristics, and Outcomes

Nodal T-follicular helper (TFH) cell lymphomas (nTFHLs) are the most common mature nodal T-cell lymphomas (nTCL) in Europe, characterized by an aggressive course, poor prognosis, and recurrent expression of TFH markers. Despite this, their mutational landscape and the impact of mutations on survival outcomes remain underexplored. In this study, we aimed to better depict nTCLs' features within a Slovenian cohort. We analyzed 108 patients diagnosed with nTCL through immunohistochemistry, clonality testing, and high-throughput sequencing using a lymphoma panel targeting 172 genes. Clinical and mutational characteristics were correlated with survival outcomes. Our cohort (50 females, 58 males) consisted of 91 nTFHL, 9 peripheral TCL, not otherwise specified (PTCL-NOS), and 8 composite lymphomas (CL; co-occurrence of nTFHL, angioimmunoblastic type (nTFHL-AI) and monoclonal B-cell proliferation), and was followed up for a median of 23 months. Most patients received COP/ COP-like treatment regimens. The mutational analysis uncovered TET2 (43%), RHOA (26%), IDH2 (9%), PLCG1 (8%), and DNMT3A (6%) as the most commonly mutated genes, found exclusively in nTFHL. RHOA mutations were associated with TET2, IDH2, and DNMT3A mutations, and CD10 expression was linked to mutations in TET2. Simultaneous presence of ≥2 mutations, along with a high International Prognostic Index, progressive disease after first-line treatment, and the absence of autologous stem cell transplantation (ASCT) as consolidation therapy were all linked to shorter overall survival, with all being independent adverse prognostic factors. To date, this study is one of the largest nTCL series, confirming that nTFHLs outnumber PTCL-NOS (92% vs. 8%). Our findings underscore the complex role of genetic factors in nTCL's clinical behavior and emphasize the importance of ASCT. We also highlight the need for prospective clinical trials, which explore tailored therapeutic interventions, such as hypomethylating agents or IDH inhibitors, for improving survival in specific genetic contexts.