Emerging Therapeutic Strategies in Cutaneous T-Cell Lymphoma: A Comprehensive Review of Clinical Trials

Cutaneous T-cell lymphomas (CTCL), including mycosis fungoides (MF) and Sézary syndrome (SS), are rare non-Hodgkin lymphomas characterized by skin-homing malignant T cells. While early-stage disease carries favorable prognosis, advanced-stage CTCL has limited treatment options with historically modest response rates and no demonstrated overall survival benefit from systemic therapies.

To comprehensively review interventional clinical trials in CTCL registered between January 2015 and December 2025, with emphasis on developments during the last 5 years.

We conducted a systematic search of ClinicalTrials.gov, supplemented by review of conference proceedings from American Society of Hematology (ASH), American Academy of Dermatology (AAD), and European Organization for Research and Treatment of Cancer Cutaneous Lymphoma Group (EORTC-CLG) meetings (2020-2025). Of 181 studies identified, 134 met inclusion criteria after excluding withdrawn, terminated, duplicate, and supportive care trials.

The 134 included trials spanned antibody and biologic therapies (n = 31), including payload-delivering agents, immune-engaging antibodies, and bispecific constructs; epigenetic modifiers (n = 20); signaling pathway inhibitors (n = 21); apoptosis modulators and protein degraders (n = 10); immunotherapy (n = 26); cellular therapies (n = 10); and skin-directed modalities (n = 16). Major regulatory milestones included Food and Drug Administration (FDA) approval of denileukin diftitox-cxdl (August 2024) for relapsed/refractory CTCL and breakthrough therapy designation for lacutamab (February 2025) for Sézary syndrome. Lacutamab demonstrated 43% overall response rate with median duration of response of 25.6 months in SS. Chimeric antigen receptor T-cell (CAR-T) therapy overcame the historical barrier of T-cell fratricide, with CTX130 (CD70-directed allogeneic CAR-T) achieving 46% overall response rates (ORR) in patients who were heavily pretreated. Combination strategies pairing histone deacetylase (HDAC) inhibitors with PI3K inhibitors (tenalisib, duvelisib, linperlisib) achieved 50-60% response rates in refractory cases. For early-stage disease, HyBryte (synthetic hypericin) visible light-activated photodynamic therapy demonstrated efficacy in the Phase 3 FLASH trial. The RESMAIN trial, despite meeting its primary PFS endpoint, failed to achieve regulatory approval due to quality-of-life detriments from gastrointestinal toxicity, highlighting the importance of incorporating patient-reported outcomes alongside efficacy measures in this disease setting.

The 2020-2025 period brought meaningful therapeutic advances for CTCL, including new FDA approvals, breakthrough designations, and emergence of cellular therapy. Future development should prioritize patient-reported outcomes as co-primary endpoints, prospective biomarker validation, and combination strategies with non-overlapping toxicity profiles.