Targeted and Immune-Based Therapies in Cutaneous T-Cell Lymphomas

Importance: Advanced cutaneous T-cell lymphomas (CTCLs), including mycosis fungoides (MF) and Sézary syndrome (SS), are associated with substantial morbidity and limited durable treatment options. Although several targeted and immune-based therapies have emerged, their comparative efficacy, durability, and safety have not been comprehensively synthesized. Objective: To evaluate the efficacy and safety of targeted and immune-based monotherapies for CTCL and characterize subtype-specific outcomes in MF and SS. Data Sources: MEDLINE, Embase, and CENTRAL databases were searched from inception to April 10, 2026. Study Selection: Studies reporting efficacy or safety outcomes in patients with CTCL treated with targeted or immune-based monotherapy were included. Two reviewers independently screened studies and extracted data. Data Extraction and Synthesis: Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guidelines were followed and risk of bias was assessed using the Joanna Briggs Institute tool. Random-effects meta-analyses were performed to estimate pooled overall response rates (ORRs) with 95% CIs. Main Outcomes and Measures: Pooled ORR; secondary outcomes were duration of response, progression-free survival, time to response, treatment-related adverse events (AEs), grade 3 or greater AEs, treatment discontinuations, recurrence, and subtype-specific response rates. Results: The analysis included 41 studies comprising 1660 patients with a mean (SD) age of 61.6 (12.6) years; of the 1460 with reported sex, 647 were female (44.3%) and 813 male (55.7%) individuals. Pooled ORRs varied across therapeutic cohorts, led by brentuximab vedotin (69%; 95% CI, 62%-75%; n = 510), interferon alfa (68%; 95% CI, 32%-90%; n = 59), alemtuzumab (65%; 95% CI, 45%-80%; n = 96), mogamulizumab (45%; 95% CI, 35%-56%; n = 514), denileukin diftitox (39%; 95% CI, 33%-46%; n = 341), and pembrolizumab (34%; 95% CI, 20%-51%; n = 33). Among MF cohorts, pooled ORRs ranged from 38% to 66% across evaluated therapies. Among SS cohorts, pooled ORRs ranged from 60% to 74% across evaluated therapies. Sample-size-weighted means of study-reported median duration of response ranged from 4.7 to 9.4 months across reported therapies, while median progression-free survival ranged from 14.4 to 23.3 months. Grade 3 or greater AE rates varied across therapies, ranging from 15% (95% CI, 11%-21%) with mogamulizumab to 26% (95% CI, 7%-64%) with denileukin diftitox. Conclusions and Relevance: In this systematic review and meta-analysis, targeted and immune-based therapies demonstrated clinically meaningful activity in CTCL, although important differences existed in response rates, response durability, and toxic effect profiles across therapeutic cohorts. Therapeutic activity also varied according to disease subtype, highlighting the importance of individualized treatment selection. These findings support incorporating disease subtype, anticipated durability of response, and toxicity considerations into treatment decision-making for patients with CTCL.