Retinoids are natural and synthetic analogs of vitamin A that bind to several classes of proteins, including retinoid-binding proteins and nuclear retinoid receptors. They lead to the activation of DNA regulatory regions involved in the regulation of cell growth, differentiation and apoptosis. The nuclear retinoid receptors belong to two families: Retinoic acid receptors (RARs) and retinoid X receptors (RXRs). Isotretinoin is a first-generation non-aromatic retinoid. It was the first retinoid used for the off-label treatment of CTCL. It is used in daily oral doses of 0.2 to 1.0 mg/kg. Adverse events include dry skin and mucous membranes, the elevation of blood lipids and teratogenicity (pregnancy should be avoided for one month after treatment discontinuation).22 Acitretin is a second-generation monoaromatic retinoid. Their structure makes them more lipophilic with greater bioavailability than the first-generation retinoids. It is used in daily oral doses of 0.3–0.5 mg/kg. The safety profile is similar to that of isotretinoin, but pregnancy should be avoided for two to three years after treatment discontinuation.22 Bexarotene is a third-generation polyaromatic retinoid that is highly selective for the RXR receptor. It is administered at a daily oral dose of 300 mg/m2. The safety profile is similar to that of isotretinoin and acitretin, but it has additional adverse events, such as central hypothyroidism and hypertriglyceridemia in most patients. Pregnancy should be avoided for one month after treatment discontinuation.8,23–25

Interferon (IFN) is a Th1 cytokine. There are three types of recombinant interferons (alpha, beta, gamma) currently available for therapeutic use. IFN-α can be found in its pegylated form. All recombinant IFNs are active in the treatment of MF/SS, but IFN-α is the most frequently studied. IFN-α regulates the cell cycle, promotes the suppression of oncogenes and modulates cell adhesion.26 IFN-γ is more frequently studied and used in Japan. Treatment with IFN-α is usually started with a dose of 3 million units via subcutaneous route, three times a week. The dose can be increased up to 9 million units per application. Pegylated IFN-α, a formulation in which the drug is encapsulated in liposomes, resulting in increased half-life and better accumulation in tumor tissues, is administered via subcutaneous route, at a dose of 1.5 μg/kg, once a week.27,28 IFN-γ is administered subcutaneously at a dose of 50 μg/m2 for patients with a body surface area >0.5 m2 and 1.5 μg/kg/dose for patients with a body surface area ≤ 0.5 m2. It is used daily or three times a week.29 Adverse events from interferons are dose-dependent and include flu-like symptoms, thyroid dysfunction, increased transaminases, leukopenia, thrombocytopenia, depression, and arrhythmias.29–31

Doxorubicin is an anthracycline cytotoxic agent. It binds to nucleic acids, inhibiting the progression of topoisomerase II, interrupting the DNA replication process. Pegylated liposomal doxorubicin is encapsulated in liposomes, resulting in increased half-life and better accumulation in tumor tissues. Pegylated liposomal doxorubicin is administered intravenously, at a dose of 20 mg/m2 on days 1 and 15, every 28 days. The main adverse events are usually mild or moderate and include anemia, asthenia, nausea, vomiting, and palmoplantar erythrodysesthesia.8,32,33

Gemcitabine (2',2'-difluorodeoxycytidine) is a classic chemotherapeutic agent from the family of nucleoside analogs. It acts by blocking the formation of new DNA, resulting in cell death. It is administered intravenously, in doses of 1200 mg/m2 on days 1, 8, and 15 of a 28-day regimen. Treatment is well tolerated and the main adverse event is hematological toxicity, which is generally mild.8,34

Chlorambucil is an alkylating agent and forms cross-links in DNA, causing DNA damage and affecting replication and transcription. Chlorambucil can be used orally in a continuous regimen with 2–6 mg/day of chlorambucil plus 20 mg/d of prednisone, or in pulses of 10 to 12 mg/day of chlorambucil for 3 days and fluocortolone, with a dose of 75 mg on the first day, 50 mg on the second day and 25 mg on the third day, every two weeks.35,36 Doses and intervals can be reduced and prolonged as the disease improves. The continuous and prolonged use of chlorambucil increases the risk of myelosuppression and the development of leukemia, especially acute myeloid leukemia.

The most frequently used combinations are Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone (CHOP); Cyclophosphamide, Vincristine, and Prednisone (CVP); Cyclophosphamide, Doxorubicin, Vincristine, and Etoposide (CHOEP); CVP plus Methotrexate (MTX). Combined chemotherapy regimens are associated with high response rates (70%–80%), but often of short duration (around 4 months). Multidrug chemotherapy is also associated with myelosuppression and infectious complications. Therefore, with rare exceptions, the sequential administration of a single chemotherapeutic drug is the strategy of choice.37,38

MTX is an antifolate-type antimetabolite. It competitively inhibits dihydrofolate reductase and, consequently, the folic acid metabolism, acting by inhibiting the synthesis of DNA, RNA, thymidylates and proteins. Low-dose MTX has been used to treat early-stage MF and SS for many years.39 MTX is used in a dose of 10 to 25 mg, once a week, orally or subcutaneously. The adverse effects include gastrointestinal symptoms (nausea, vomiting, stomatitis, diarrhea), anemia, leukopenia, thrombocytopenia, increased transaminases, liver fibrosis, and pneumonitis.8,40 Pralatrexate is also a folate analog with activity demonstrated in patients with MF/SS. It is administered intravenously in a dose of 15 mg / m2 per week for three weeks, in four-week cycles. Adverse events are similar to those seen with MTX, but they tend to be more common and severe. The most common side effects include mucositis, fatigue, nausea, vomiting, anorexia, skin toxicity, epistaxis, and anemia.8,40

Histone Deacetylase (HDAC) is a class of enzymes responsible for catalyzing the removal of acetyl groups from histones, being crucial modulators of transcriptional epigenetic regulation. Two drugs from this class have FDA approval for use in CTCL, mainly in refractory cases: romidepsin and vorinostat.41,42 Romidepsin is administered as a single agent in a dose of 14 mg/m2 intravenously on days 1, 8 and 15 of a 28-day cycle. The most common related adverse events are nausea and fatigue.43 Vorinostat is an oral HDAC inhibitor. It is administered at a daily dose of 400 mg per day. If not tolerated, it can be reduced to 300 mg/day or 300 mg, five days a week. The most common adverse events are diarrhea, fatigue, nausea, and anorexia.43

Alemtuzumab is a humanized anti-CD52 monoclonal antibody. CD52 is a surface glycoprotein present in T and B lymphocytes, monocytes and macrophages. Alemtuzumab binds to CD52, causing destruction of neoplastic cells by antibody-dependent cell cytotoxicity and complement fixation. Response rates are higher in SS than in MF, because alemtuzumab leads to the depletion of central memory T-cells in the blood and skin of patients with SS. On the other hand, the drug does not affect memory/effector T-cells residing on the skin in MF. Recent evidence suggests that alemtuzumab is not effective in tumoral or transformed MF. The standard dose is 30 mg administered intravenously, three times a week, for up to 12 weeks.8,44 Subcutaneous alemtuzumab can also be used in a low-dose regimen of 10 to 15 mg every other day, 3 times a week.45 Infusion reactions (fever, nausea, hypotension, fatigue, rash, hives, bronchospasm) are seen in more than half of the patients. Cytopenias (lymphopenia, neutropenia, anemia, thrombocytopenia) are observed in almost all patients. Severe infections (cytomegalovirus, generalized herpes simplex, fatal aspergillosis, and mycobacterial pneumonia), can be observed, especially in patients heavily pretreated.8 The low-dose regimen can reduce infectious complications in patients with MF.45 The treatment with alemtuzumab requires antibiotic and antiviral prophylaxis, as well as careful observation for the development of cardiac infection and toxicity.8

Brentuximab vedotin (BV) is an antibody-drug conjugate directed to the CD30 molecule. CD30 belongs to the tumor necrosis factor receptor superfamily. The drug in the antibody-drug conjugate is monomethyl auristatin E (MMAE), an anti-tubulin agent. In normal tissues, CD30 has an expression profile that is rather restricted to activated T, B and NK/T-cells, but is highly expressed in Reed Sternberg cells of Hodgkin's lymphoma, in anaplastic large-cell lymphoma and other non-Hodgkin lymphoma subtypes, for instance, in primary cutaneous anaplastic large-cell lymphoma (pcALCL) and certain cases of MF. This expression profile makes CD30 an ideal target for therapies based on monoclonal antibodies. After the binding of BV to CD30 on the surface of neoplastic cells and their internalization, MMAE release occurs. MMAE will then exert its potent cytostatic effect, inhibiting the assemblage of the microtubules, inducing the cell cycle to stop, and resulting in death due to apoptosis of tumor cells. The safety and efficacy of BV were evaluated in the first phase 3 study against a standard therapy (MTX or bexarotene) for CTCL, demonstrating high rates of durable and clinically significant responses. The typical starting dose is 1.8 mg/kg given intravenously every three weeks. The main toxicities are peripheral neuropathy, neutropenia, fatigue, nausea, and alopecia.46

Mogamulizumab is a humanized monoclonal antibody that targets the C-C chemokine receptor type 4 (CCR4) expressed on neoplastic cells. CCR4 is expressed on the surface of tumor cells of most patients with adult T-cell lymphoma/leukemia (ATLL) and is selectively expressed in other subtypes of peripheral T-cell lymphoma and cutaneous T-cell lymphoma. After binding to its target, mogamulizumab acts through antibody-dependent cell-mediated cytotoxicity to destroy tumor cells. Mogamulizumab is administered intravenously in a dose of 1.0 mg/kg weekly, for four weeks, followed by a dose every two weeks until disease progression. Infusion-related and drug-related rashes are common; other toxicities include diarrhea, nausea, thrombocytopenia, dysgeusia, and elevated serum creatinine levels.47

Extracorporeal photopheresis (ECP) is an immunomodulatory therapy in which leukapheresis removes the patient's leukocytes, which are then treated with 8-methoxypsoralen and UVA and reinfused in the patient. It is the first-line treatment for SS and erythrodermic MF.6,48 Each cycle of ECP is generally administered on two consecutive days every two to four weeks for at least six months. With the development of 8-MOP in solution, ECP can be administered directly into the apheresis bag, and the patient is not exposed to the systemic drug absorption, minimizing adverse gastrointestinal effects and systemic photosensitivity. Sporadic side effects include headache, pyrexia, myalgia, mild anemia, thrombocytopenia, and photophobia. Hypotension, vasovagal syncope, infection at the injection site, worsening of skin lesions and sepsis, usually due to central venous access, are rare. There are no reports of opportunistic infections or malignancies, as ECP is not an immunosuppressive treatment.48–51

The combination of treatments is a well-established strategy to increase therapeutic efficacy in treatments for MF. It includes combining skin-directed therapies with systemic ones, or two or more systemic therapies. The most widely used combinations are retinoids and PUVA (RE-PUVA), interferon, and PUVA or ECP with interferon and/or bexarotene.49,52

Allogeneic stem cell transplantation (allo-HSCT) can induce lasting remissions and is the only treatment with curative intent. Due to the high morbidity and mortality rates associated with allo-HSCT, good patient selection is essential for a successful treatment. Careful counseling is necessary and the indication should focus mainly on younger patients with good performance, with advanced stages of the disease and low tumor burden at the time of transplantation and who are aware of the high risk of progression and poor prognosis.53