LAUSR

Amaral and Garbe discuss the impressive developments in targeted therapy for non-melanoma skin cancers (NMSCs) such as basal cell carcinoma and squamous cell carcinoma [1]. Systemic targeted therapy for cutaneous T-cell lymphoma (CTCL), another subset of NMSC that includes mycosis fungoides (MF) and Sézary syndrome (SS), remains equally exciting. MF is an extranodal, non-Hodgkin lymphoma characterized by the cutaneous infiltration of neoplastic CD4+ T lymphocytes. SS represents the erythrodermic and leukemic form ofMF. Treatment depends on the stage of disease and degree of response to previous therapies. Early-stage MF is treated with skin-directed therapy, whereas advanced disease requires systemic agents such as oral retinoids, extracorporeal photopheresis, and cytotoxic chemotherapy. Barring allogeneic stem cell transplantation, advanced CTCL is considered incurable. As such, goals of therapy include alleviating symptoms, inducing remission, and preventing progression. In recent years, the development of systemic targeted therapy has significantly improved and broadened the therapeutic options for CTCL. A number of monoclonal antibodies have shown promise in CTCL. Alemtuzumab is an approved agent that targets CD52 on both normal and malignant lymphocytes. Brentuximab vedotin is amonoclonal antibody–drug conjugate directed against CD30, expressed in MF with large-cell transformation. A recent phase III study yielded encouraging results [2]. Mogamulizumab targets C-C chemokine receptor 4 (CCR4) [3], which lends malignant T cells their skin-homing capacity, and is currently being evaluated in a phase III trial [4]. Lastly, immune checkpoint inhibitors, such as the programmed cell death protein-1 (PD-1) inhibitors nivolumab and pembrolizumab, represent emerging therapies. Histone deacetylase inhibitors (HDACis) have also become popular agents in treating CTCL. They promote cell cycle arrest and apoptosis by modifying the expression of tumor suppressor genes. Approved HDACis include vorinostat and romidepsin, and others including belinostat, panobinostat, and resminostat are under investigation. Several other targeted agents are being studied. Pralatrexate, a novel folic acid inhibitor preferentially affectingmalignant cells, demonstrated significant clinical activity in a phase I/II trial [5]. Denileukin diftitox is an interleukin-2 (IL-2)–diphtheria toxin fusion protein that targets the IL-2 receptor on malignant T cells [6]. A phase III trial of a purified version, E7777, is ongoing. Lastly, the proteasome inhibitor bortezomib, the transition-state analog forodesine [7] and the immunomodulatory agent lenalidomide have all shown activity in phase II trials. We arewitnessing remarkable progress in CTCL research. These targeted agents represent only a fraction of those that have led to improved disease management and quality of life with advanced CTCL (Table 1). Ongoing discoveries involving the genetic and