Differential prognostic impact of chromatin modifier mutations in peripheral T-cell lymphoma: KMT2A emerges as a critical biomarker

Abstract Background: Peripheral T-cell lymphomas (PTCLs) remain one of the most challenging lymphoma subtypes to treat, with consistently poor outcomes across different populations. Although mutations in genes like TET2, DNMT3A, and KMT2A have been reported in Western cohorts, we still don't fully understand their relevance in Asian patients. We sought to map the genetic landscape of PTCL in Korean patients using targeted sequencing and determine which mutations actually affect survival. Methods: We reviewed 55 adults diagnosed with PTCL at Yeouido St. Mary's Hospital between September 2020 and September 2024. Our cohort included 23 patients with PTCL-NOS (42%), 14 with angioimmunoblastic T-cell lymphoma (25%), 11 with extranodal NK/T-cell lymphoma (20%), and 7 with other subtypes (13%). We performed targeted sequencing on tumor tissue using a 146-gene lymphoma panel and classified variants according to AMP/ASCO/CAP criteria. We collected clinical information including patient characteristics, treatments received, and responses based on Lugano 2014 criteria. For survival analysis, we used Kaplan-Meier curves and Cox regression models to identify factors associated with progression-free survival (PFS) and overall survival (OS). Results: Our patients had a median age of 62 years (range 28-81), with 60% being male. Most had advanced disease at diagnosis—71% were stage III-IV and 65% had intermediate-high or high IPI scores. After a median follow-up of 21 months, the 2-year OS was 57.3%. When we looked at the mutation patterns, ATR was mutated most often (30%), followed by KMT3A (29%) and TP53 (27%). What stood out was KMT2A—mutated in 15 patients (27%)—which was strongly linked to worse survival. Patients with KMT2A mutations had a median OS of just 10.7 months compared to 30.8 months for those without (p=0.043). We found a similar pattern with DNMT3A mutations, present in 7 patients, where median OS was only 12.3 months (p=0.027). Interestingly, TET2 mutations didn't affect survival at all despite being present in 9 patients (p=0.9). Ten patients got brentuximab vedotin as part of their initial treatment, but this didn't improve outcomes compared to standard CHOP chemotherapy. When we adjusted for other factors like IPI score and histology, KMT2A mutations remained a strong predictor of death (HR 2.8, p=0.018). The four patients who had both KMT2A and DNMT3A mutations did particularly poorly, with a median survival of only 8.2 months. Conclusions: Our study reveals that KMT2A mutations occur in about a quarter of Asian PTCL patients and predict significantly worse outcomes. This finding, along with the poor prognosis associated with DNMT3A mutations, suggests these genetic alterations could help identify patients who need more aggressive or experimental treatments upfront. The fact that TET2 mutations didn't affect survival, despite being frequently studied in PTCL, shows that not all epigenetic mutations are equal. Moving forward, we believe NGS testing should become standard practice for PTCL patients to better stratify risk. These patients with KMT2A mutations clearly need different treatment strategies, and clinical trials specifically targeting this high-risk group should be prioritized.