Impact of KMT2A Rearrangement on Peripheral T-Cell Lymphoma, Not Otherwise Specified, and Angioimmunoblastic T-Cell Lymphoma

<b>Background</b>: Angioimmunoblastic T-cell lymphoma (AITL) and peripheral T-cell lymphomas (PTCL), not otherwise specified (NOS), share overlapping histology and T-follicular helper (TFH) biology but often show divergent outcomes and treatment needs. The clinical significance of <i>KMT2A</i> rearrangement (<i>KMT2A</i>-r) in nodal PTCL remains undefined. We aimed to investigate the clinicogenomic features and prognostic impact of <i>KMT2A</i>-r in AITL and PTCL-NOS. <b>Methods</b>: We retrospectively analyzed consecutive patients diagnosed with AITL or PTCL-NOS between 2021 and 2024 at two centers. All patients underwent 523-gene DNA/RNA next-generation sequencing. Gene co-variation and diagnostic splits were summarized using network and decision-tree analyses. <b>Results</b>: Overall, 37 patients were included (AITL: 14; PTCL-NOS: 23), with similar baseline clinical characteristics. In AITL, TFH markers were more frequently expressed, and <i>RHOA</i> mutations were enriched. <i>KMT2A</i>-r occurred in 24% of cases without histology-specific enrichment. AITL showed better 2-year overall survival (OS) than PTCL-NOS (70.7% vs. 38.8%; <i>p</i> = 0.040) but similar progression-free survival (PFS). Univariate analysis revealed that <i>KMT2A</i>-r, lactate dehydrogenase elevation, and bone-marrow involvement predicted inferior PFS (Hazard ratio for <i>KMT2A</i>-r: 2.56). Median PFS was 5.9 versus 12.5 months in the <i>KMT2A</i>-r and non-<i>KMT2A</i>-r groups, respectively (<i>p</i> = 0.039). Brentuximab vedotin (BV) plus cyclophosphamide, doxorubicin, and prednisone did not significantly improve OS or PFS overall; however, exploratory analysis indicated improved PFS in the <i>KMT2A</i>-r subset. <b>Conclusions</b>: <i>KMT2A</i>-r delineates an adverse-risk biology in nodal PTCL, aligns with non-TFH genomic hubs and markers of tumor burden, and may serve as a stratifier and hypothesis-generating target for BV-based strategies.