Impact of <i>KMT2A</i> Rearrangement on Peripheral T‑Cell Lymphoma, Not Otherwise Specified, and Angioimmunoblastic T‑Cell Lymphoma

Background: 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 KMT2A rearrangement (KMT2A‑r) in nodal PTCL remains undefined. We aimed to investigate the clinicogenomic features and prognostic impact of KMT2A-r in AITL and PTCL-NOS. Methods: 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. Results: Overall, 37 patients were included (AITL: 14; PTCL‑NOS: 23), with similar baseline clinical characteristics. In AITL, TFH markers were more frequently expressed, and RHOA mutations were enriched. KMT2A‑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%; P=0.040) but similar progression-free survival (PFS). Univariate analysis revealed that KMT2A‑r, lactate dehydrogenase elevation, and bone‑marrow involvement predicted inferior PFS (Hazard ratio for KMT2A‑r: 2.56). Median PFS was 5.9 versus 12.5 months in the KMT2A‑r and non‑KMT2A‑r groups, respectively (P=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 KMT2A‑r subset. Conclusions: KMT2A‑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.