Adverse events associated with systemic cutaneous T-cell lymphoma therapies: a narrative review.

Background: Mycosis fungoides (MF) and Sézary syndrome (SS) are the most prevalent subtypes of cutaneous T-cell lymphoma (CTCL). Systemic therapies span multiple drug classes, and as most are administered with palliative intent over prolonged periods, the adverse event (AE) profile of each agent is as clinically important as its efficacy. No comprehensive narrative review has synthesized AE data across all National Comprehensive Cancer Network (NCCN)-recommended systemic therapies for MF/SS. Objectives: To summarize and compare the AE profiles of all 14 NCCN guideline-recommended systemic therapies for MF and SS, with emphasis on cutaneous toxicities and their distinction from active disease. Methods: Systemic therapies were identified from Version 2.2026 NCCN Guidelines for Cutaneous Lymphomas. Safety data were abstracted from available Phase II and III trials supporting guideline inclusion, with attention to AE frequency, severity, dose-limiting toxicities, and treatment discontinuation rates. PubMed and Scopus were searched for case reports and series capturing rare or delayed toxicities not represented in prospective trials. Data were narratively synthesized given heterogeneity across study designs and reporting practices. Results: Fourteen NCCN-recommended systemic agents were reviewed, spanning antibody-drug conjugates, monoclonal antibodies, histone deacetylase (HDAC) inhibitors, retinoids, antifolates, immunotoxins, cytotoxic chemotherapies, interferons, and immune checkpoint inhibitors. Toxicity profiles varied substantially by drug class. Peripheral neuropathy was the defining AE of brentuximab vedotin. Mogamulizumab was distinguished by mogamulizumab-associated rash, a treatment-emergent immune reaction that closely mimics CTCL progression. Bexarotene required proactive management of hypertriglyceridemia and central hypothyroidism. HDAC inhibitors carried gastrointestinal, hematologic, and cardiac risks, while cytotoxic agents posed variable risks of myelosuppression, mucositis, and hepatotoxicity. Immunomodulatory agents introduced risks of opportunistic infection and paradoxical disease flares. Conclusions: Systemic therapies for MF/SS carry distinct AE profiles that should inform treatment selection, patient counseling, and monitoring. A recurring challenge is distinguishing cutaneous drug toxicity from CTCL progression, underscoring the importance of therapy-specific toxicity awareness. Standardized AE reporting and patient-centered outcome measures are needed to optimize long-term care in this population.