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Abstract
Cutaneous T-cell lymphomas (CTCLs) comprise a clinicopathologically heterogeneous group of uncommon non-Hodgkin lymphomas that manifest primarily in the skin but also may involve lymph nodes, blood, bone marrow and viscera. CTCLs are generally considered incurable unless allogeneic stem cell transplantation is implemented. Goals of therapy are to control symptoms, maintain cosmesis and improve survival by maximally reducing the tumor burden. Current treatment consists of skin-directed therapy for early stage disease and systemic therapy for advanced stage or refractory early stage disease. Despite the availability of a number of active systemic therapeutic strategies, including biological therapy, cytotoxic chemotherapy and extracorporeal photophoresis, there is an unmet need for targeted therapies, with favorable therapeutic indices, for the treatment of advanced and refractory CTCLs, which often render patients highly susceptible to infection. This review will discuss targeted therapy for the two most extensively studied subtypes of CTCL, mycosis fungoides and Sézary syndrome.
Financial & competing interests disclosure
J Guitart has been a consultant for Celgene, Actelion and Seattle Genetics. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.
Key issues
Cutaneous T-cell lymphomas (CTCLs) comprise a heterogeneous group of uncommon non-Hodgkin lymphomas that manifest primarily in the skin but also may involve lymph nodes, blood, bone marrow and viscera.
The most commonly studied CTCLs are mycosis fungoides (MF) and Sézary syndrome, an erythrodermic and leukemic form of CTCL.
Multiple deregulated cell signaling pathways have been observed in CTCL and likely contribute to its pathogenesis.
Treatment of early stage MF, which often behaves indolently, usually involves skin-directed therapy with or without systemic therapy or just observation.
Advanced stage MF (IIB–IV) and Sézary syndrome are usually treated with systemic therapies, with an intent to achieve maximal duration of response and ideally improve survival.
Certain types of CTCL, such as adult T-cell leukemia/lymphoma and advanced extranodal NK/T lymphoma, nasal type, are typically treated with aggressive combination chemotherapy, with the latter type often being treated with autologous hematopoietic transplantation after induction therapy. Many cases of localized primary cutaneous anaplastic T-cell lymphoma are treated with surgical excision with or without radiotherapy.
Monoclonal antibodies, either unconjugated or conjugated to a cytotoxic agent (referred to as an immunoconjugate), typically target cell surface antigens and may exert their cytotoxic effects by a variety of mechanisms.
Histone deacetylase inhibitors are a class of epigenetic-modifying agents, including the US FDA-approved drugs vorinostat and romidepsin, which may lead to durable responses and clinically meaningful pruritus reduction in patients with CTCL. Belinostat and panobinostat are novel histone deacetylase inhibitors undergoing investigation.
Pralatrexate (PDX) is a novel antifolate analog that is FDA-approved for the treatment of PTCL.
Forodesine (BCX1777) is a transition-state analog for purine nucleoside phosphorylase (PNP) and leads to cytotoxicity by causing intracellular accumulation of deoxyguanosine.
The immunomodulatory agent lenalidomide and the proteasome inhibitor bortezomib, both of which are approved for use in multiple myeloma and mantle cell lymphoma, have shown activity in the treatment of CTCL.
Preclinical data support the role of immune checkpoint blockade to control the proliferation of CTCL cells in vitro, and therefore the clinical study of immune checkpoint inhibitors in treating CTCL is warranted.
Multiple other classes of targeted therapy are undergoing clinical trial investigation for the treatment of CTCL.
Notes
†These subtypes are still considered by WHO-European Organization for Research and Treatment of Cancer to be provisional entities.
Data taken from Citation[2].