A multicentre phase III clinical trial of dual-epigenetic therapy plus CHOP compared with CHOP in previously untreated patients with peripheral T-cell lymphoma

This phase 3 multicenter trial evaluated the efficacy and safety of adding dual epigenetic agents azacitidine and chidamide to CHOP (AC-CHOP) versus CHOP alone in previously untreated peripheral T-cell lymphoma (PTCL). A total of 128 patients were enrolled from 9 centers in China and assigned according to participating centers (AC-CHOP, N = 84; CHOP, N = 44). Azacitidine 200 mg on days 1–2, 100 mg on day 3 and chidamide 20 mg twice weekly were administered in the AC-CHOP arm. The AC-CHOP arm showed numerically higher ORR (60.7% vs. 54.6%) and CR rate (47.6% vs. 36.4%) than the CHOP arm, although the differences were not statistically significant. A trend toward improved PFS was observed in the AC-CHOP arm (median 10.2 months in the AC-CHOP arm vs . 8.4 months in the CHOP arm, P = 0.093), alongside a significantly improved OS (median 46.2 months vs . 24.1 months, P = 0.023). The safety profile was comparable between the two groups, with hematologic toxicity and infection being the most common adverse events. Genomic profiling showed that DNMT3A mutations were associated with lower response rates, while IDH2 and TP53 mutations were associated with inferior survival outcomes. In conclusion, the addition of chidamide and azacitidine to CHOP did not significantly improve ORR or PFS. Although OS was longer in the AC-CHOP arm, this finding should be interpreted cautiously given the imbalances in post-protocol treatments between the two arms. Integration of molecular profiling may improve risk stratification and inform future biomarker-driven therapeutic strategies in PTCL.