Cutaneous T-Cell Lymphoma/Mycosis Fungoides/Sézary Syndrome

Patients with relapsed or refractory cutaneous T-cell lymphoma (R/R CTCL) face a poor prognosis and limited therapeutic options. Advanced or relapsed disease yields a 5-year overall survival rate of \<50%. Real-world data show that third-line therapy achieves an ORR of only 45-50% with a median PFS of 1.2 years. Chemotherapy remains dominant (43.1% in the third-line) but offers limited, transient efficacy (median time to next treatment: 4 months) and severe toxicities, leaving a critical unmet need for safe, highly specific targeted therapies. Epigenetic dysregulation is central to CTCL pathogenesis, particularly aberrations in the histone methyltransferase EZH2. As the catalytic subunit of PRC2, EZH2 mediates H3K27me3 to repress target gene transcription. In CTCL, EZH2 frequently undergoes copy number amplification or gain-of-function mutations to drive tumor progression. Targeting EZH2 demonstrates high tumor specificity; EZH2 inhibitors like tazemetostat and valemetostat are already approved for epithelioid sarcoma, follicular lymphoma, and peripheral T-cell lymphoma (PTCL). Preclinically, EZH2 is specifically overexpressed in neoplastic CTCL T cells, and EZH2 inhibitors dose-dependently suppress CTCL cell/tumor growth. Given shared pathogenic mechanisms, PTCL data provide strong reference for CTCL. Valemetostat achieved an ORR of 43.7% and median PFS of 5.5 months in R/R PTCL. Zeprumetostat demonstrated superior efficacy (ORR 61%, median PFS 11.1 months) with a favorable safety profile, leading to its 2025 approval in China for R/R PTCL. Therefore, this single-arm, prospective trial evaluates zeprumetostat in R/R CTCL. Given that CTCL shares essential pathogenetic and epigenetic features with PTCL, and leveraging zeprumetostat's established approval in PTCL, this study represents a rational and mechanistically justified therapeutic expansion rather than an unsupported off-label application.