Epigenetic-Targeting Regimens vs. Conventional Chemotherapy in Relapsed/Refractory PTCL: A Meta-Analysis

Relapsed/refractory peripheral T-cell lymphoma (R/R PTCL) lacks a uniform salvage standard and outcomes with conventional chemotherapy (CC) remain suboptimal. This meta-analysis compared epigenetic-containing regimens (Epi-Rx) and CC in R/R PTCL.

We searched MEDLINE, Embase, and the Cochrane Library through May 2025 for prospective or retrospective studies evaluating Epi-Rx (≥1 HDAC, DNMT/hypomethylating, or EZH1/2 inhibitor, alone or in combination) or CC without epigenetic agents. Random-effects models pooled single-arm proportions, with prespecified subgroup analyses and meta-regression.

Thirty-eight studies (2,170 patients; 24 Epi-Rx cohorts and 16 CC cohorts) were included. Pooled overall response rate (ORR) was comparable between Epi-Rx and CC (46% [95% CI, 40%-52%] vs. 47% [95% CI, 41%-54%]; p=0.77), whereas 1-year progression-free survival (PFS) rate favored Epi-Rx (28% [95% CI, 24%-32%] vs 20% [95% CI, 16%-23%]; p<0.01). In meta-regression, Epi-Rx was independently associated with improved 1-year PFS (but not ORR) after adjustment for the proportion of T-follicular helper (TFH)-type PTCL, advanced-stage disease, and previous treatment lines. The PFS advantage persisted with epigenetic monotherapy versus CC (26% [95% CI, 21%-31%] vs. 20%; p=0.04) and was most pronounced in cohorts with a median of one prior line (35% [95% CI, 27%-43%] vs. 20% [95% CI, 16%-24%]; p<0.01). One-year overall survival rate favored Epi-Rx (57% [95% CI, 51%-62%] vs. 41% [95% CI, 32%-50%]; p<0.01).

Compared with CC, Epi-Rx may be associated with improved survival outcomes in R/R PTCL. Prospective comparative studies are warranted to confirm this finding.