Retinoids are derivatives of vitamin A that inhibit proliferation and induce differentiation in different tumours. In MF, etretinate, its metabolite acitretin and mostly bexarotene have been used.

Combined treatment of acitretin + PUVA achieves the same response of PUVA alone (73 % vs. 72 % CRs, respectively), but the cumulative dose of PUVA to achieve CR was lower in the combined treatment group [25]. Combination is recommended as second-line therapy in MF stages Ia to IIa and as first line for MF IIb or III [4].

Bexarotene (Bxt) is a rexinoid (specific agonist of RXR receptors). Bxt has multiple activities (blocks tumour growth, induces apoptosis, blocks NFKB, modifies microenvironment, etc.). Oral Bxt has been approved by FDA for resistant, recurrent MF (EMEA label includes “advanced”).

It is recommended to start with 150 mg/m² and increase to 300 mg/m², if possible.

In monotherapy, response rates in refractory early MF are 54 %, with 7 % of CRs. Median time to response is about 8 weeks. Response rates in refractory advanced MF are 45 % with 2 % of CRs. Median time to response is >20 weeks [26, 27].

Most common adverse event is hypertriglyceridemia appearing between 80 and 100 % of cases. It is the most dose-limiting toxicity of Bxt. It usually starts 1–2 days after beginning and disappears 2–4 days after withdrawal of bexarotene. Second most common AE is central hypothyroidism, appearing between 70 and 80 % of cases. It starts and disappears 2–4 days after beginning and withdrawal of Bxt, respectively.

Other adverse events appearing in >20 % of cases are neutropenia (usually late), skin peeling, leukopenia, elevated LDH, headache and hypercholesterolemia. Very importantly, it does not produce photosensitivity, allowing combination with PUVA.

It is recommended to normalise serum lipids and thyroid function before starting Bxt. One or two hypolipidemic agents should be introduced one week before Bxt (fenofibrate ± statin are the most usual). Gemfibrozil is contraindicated because it produces paradoxical hypertriglyceridemia when combined with Bxt.

Most authors recommend to associate thyroid hormone replacement from the beginning (50μg/day) but is not always needed.

Blood tests should include lipid profile, free T4 (not TSH), muscle enzymes (to detect early myopathy induced by hypolipidemics) and pancreatic enzymes (to detect pancreatitis) and should be performed periodically, starting 1 week before and at 7, 14 and 28 days time points; after that, monthly [28, 29].

Bxt can be combined with different therapies as PUVA, IFN, extracorporeal photopheresis or denileukin diftitox.

Different series reporting combination of PUVA + Bxt have been published. In global, response rates vary from 60 to 78 % depending on the dosage of Bxt [30, 31]. A randomised clinical trial with PUVA + two different doses of Bxt (150 vs. 300 mg/day) (MILL-61896) did not find differences in response rate. Interestingly, patients included in the trial seemed to need less UVA irradiation than historical doses needed in the centre that performed the study [32]. The EORTC CLTF has finished a randomised clinical trial (EORTC 21011) comparing Bxt+PUVA vs. Bxt alone. The study was underpowered but no significant differences in response rate or response duration was observed. There was a trend towards fewer PUVA sessions and lower UVA dose required to achieve CCR in the combination arm (PUVA + bexarotene) [3, 19, 30, 80].

A phase II clinical trial [33] reported that responses of the combination of IFN+Bxt were similar to Bxt alone. However, clinical practice shows that frequently patients achieving a tableau with Bxt or IFN alone respond with the combination [34].

ECP is an immunomodulatory therapy involving leukapheresis. Lymphocytes are treated ex vivo with 8-methoxypsoralen + UVA irradiation and reinfused to the patient. First reported in 1987 [35], it was approved by FDA 1 year later for treatment of CTCL. More than 1,000 patients have been published with CTCL treated with ECP. RRs of 43–100 % and CRs from 0 to 62 % have been reported. Recently, UK consensus on the use of ECP has been published [36].

Mechanism of action is not well understood, but clinical and laboratory findings support the hypothesis of a vaccination-like effect. It seems that malignant T lymphocytes suffer cell cycle stop and apoptosis. After that, phagocytosis, antigen presentation and elicitation of specific immune responses mediated through cytotoxic T lymphocytes with antitumour specificity would occur.

ECP should be restricted to erythrodermic CTCL, either stage III or IVa demonstrating a peripheral blood involvement with T-cell clone and/or circulating Sézary cells >10 % and/or CD4/CD8 ratio >10. Patch/plaque or tumoural stages are not suitable for ECP. Treatment of stage IVb or erythrodermic patients without peripheral blood involvement is not recommended following UK consensus, but there are some publications reporting response in some of these patients. Patients with very high tumour burden in peripheral blood respond poorly and should be considered for combination (e.g. alemtuzumab) or alternative treatments.

Schedule includes 1–2 cycles per month (two procedures performed on two consecutive days per cycle).

Adverse events are rare. Venous access can originate infections.

UK consensus recommends maintaining treatment for at least 6 months. If no response is achieved, combination with other drugs (Bxt, IFN or multiple combinations are frequently used) [37–39] is done for three additional months. If no response, treatment should be stopped. International guidelines are under preparation (several workshops held to date in Minden and Lisbon) that probably could modify these recommendations. ECP treatment is recommended early as patients become more immunosuppressed with time.

Median time to maximum response is 10 months. Patients achieving response should be maintained with the same schedule and eventually reduce frequency (every 6–12 weeks) before stopping. Median time to treatment failure is 18 months.

Transimmunisation is a modification of ECP consisting in incubating overnight at body temperature the buffy coat after photoactivation. This allows co-incubation of the apoptotic malignant T cells with the newly formed antigen-presenting cells prior to reinfusion [40].

Denileukin diftitox (Ontak™, Onzar™), DAB389–IL-2, is a recombinant fusion protein that selectively binds high-affinity IL-2 receptor (CD25). The molecule consists of sequences for the enzymatically active domain of diphtheria toxin and the IL2. After joining receptor, DAB389-IL2 is internalised in the cell, diphtheria toxin is released and protein synthesis is blocked, resulting in cell death.

Denileukin diftitox was approved by FDA in 1999 (not by EMEA) for resistant, recurrent MF expressing IL2. Dose schedule is 18 mcg/kg/day by IV infusion once daily for 5 days every 3 weeks for up to 8 cycles.

Phase III clinical trials [41, 42] including patients with stages Ib-IVa and at least 20 % of cells expressing IL2 have reported RRs between 30 and 49 % with 10 % of CRs. Median time to response is 3–4 months and median duration of response is 6.9 months.

Most common adverse events are fever, myalgia, chills, nausea and vomiting and a mild increase in transaminase levels. Acute hypersensitivity occurs in 60 %, always in the first 24 h and during the initial infusion. Vascular leak syndrome (hypotension, hypoalbuminaemia and oedema) occurs in 25 % of cases within the first 14 days of a given dose. Myelosuppression is very rare. Adverse events drop and response rates increase to 60 % if patients are pretreated with corticosteroids [43].

Response rate is higher in CD25+ MF cases. Different papers have reported 30–78 % of response in cases with >20 % of cells expressing CD25 and 20–30 % in cases with low CD25 expression. However, a recent review considering only patients achieving CR with denileukin diftitox did not find differences between CD25 +ve and −ve cases. More than 36 % of patients relapsing after a first course of denileukin diftitox treatment respond again to this drug [44–46].

Combination of denileukin diftitox with bexarotene is based on the rationale that Bxt can induce expression of IL2 on malignant T cells. A phase I clinical trial combining Ontak + Bxt reported 67 % of RR [47].

Alemtuzumab (Campath™) is a humanised monoclonal antibody that targets CD52. CD52 is found in normal and malignant B and T cells. Granulocytes, macrophages or thrombocytes do not express CD52. Alemtuzumab is usually administered at a dose of 30 mg intravenously three times per week, for up to 12 weeks.

A phase II clinical trial [48] with 22 patients with heavily pretreated MF or SS patients reported an ORR of 55 % with 32 % of CRs. Sézary cells were cleared from the blood in 6 of 7 (86 %) patients, and CR in lymph nodes was observed in 6 of 11 (55 %) patients. The effect was better on erythroderma (OR, 69 %) than on plaque or skin tumours (OR, 40 %) and in patients who had received 1 to 2 previous regimens (OR, 80 %) than in those who had received 3 or more prior regimens (OR, 33 %). Time to treatment failure was 12 months.

The main problem with alemtuzumab is the severe immunosuppression produced, with high-risk viral, bacterial and fungal infectious complications that may be life-threatening [49].

Patients should be monitored for CMV reactivation using periodically PCR studies every 2–3 weeks. If viremia is increasing, ganciclovir should be recommended. On the other hand, acyclovir and sulfamethoxazole trimethoprim to prevent herpes virus and Pneumocystis carinii pneumonia should be given to patients. Mantoux test with booster and chest X-ray to detect latent infection by Mycobacterium tuberculosis should be performed. Active or latent hepatitis B or C infections should be treated before using alemtuzumab. Serology for Strongyloides is recommended for patients living in endemic areas.

Recently, a new approach with low subcutaneous dose (10 mg s.c. eod) has been reported with very good results (14 patients, 3 CRs and 9 PRs) and very importantly, without infectious complications [50].

Finally, patients should have cardiac monitorisation. In a series of patients treated with standard IV dose, 4 of 8 patients with no prior history of cardiac problems developed significant cardiac toxicity (congestive heart failure or arrhythmia) that mostly improved after alemtuzumab discontinuation [51].

Other monoclonal antibodies are under investigation.

Zanolimumab is a fully human anti-CD4 antibody directed against CD4 molecules on surface of T cells. There are 2 phase II clinical trials finished, including 47 patients [52]. Patients were initially treated with intravenous zanolimumab at a dose of 280 mg/week, which was increased to 560 mg/week in early-stage patients and 980 mg/week in patients with advanced disease. In MF, RRs were low in the low dose (15 %) vs. high dose (56 % of RR with 2 CRs and 10 PRs). In SS, RR was only 22 % with high dose, showing a greater efficacy of zanolimumab in MF compared to SS.

In the high-dose arm, median time to response was less than 8 weeks and median response duration, 81 weeks. Most frequent adverse events are eczematous dermatitis, low-grade infections, flu-like symptoms and asthenia. Zanolimumab produces a very prolonged CD4 reduction, lasting even >24 months. There is an ongoing pivotal phase III clinical trial comparing 3 dose levels (4 vs. 8 vs. 14 mg/kg). The first two doses were stopped because of low RRs. Trial was stopped in Europe but is ongoing in the USA.

Recombinant CD3 immunotoxin (A-dmDT(390)-bisFv(UCHT1)) is composed of the catalytic and translocation domains of diphtheria toxin fused to two single-chain Fv fragments of an anti-CD3 epsilon monoclonal antibody. The drug was administered to 5 MF patients. Two of them had PR lasting 1 and >6 months [53].

SGN30 and a more active drug (SGN35, brentuximab vedotin (BV)) are anti CD30 monoclonal antibodies. Brentuximab vedotin is a chimeric protein targeting CD30 on cell surface. The molecule is conjugated with monomethyl auristatin E (MMAE), a microtubule disruptor. After joining receptor, MMAE is internalized and blocks mitosis. In two different trials recently reported, ORR is between 40 and 68 % depending on the level of CD30 expression. Time to response was 6-10.5 weeks. Most frequent adverse events are peripheral neuropathy, rash, fatigue and diarrhea. Neutropenia can be severe [54, 96, 97].

Mogamulizumab (KW-061), a humanized, defucosilated monoclonal antibody targeting CCR4 produces antibody dependent cellular cytotoxicity. ORR in a recent phase II clinical trial was 37 % (29 % in mycosis fungoides, 47 % in Sézary syndrome).

HDACi are a new group of compounds involved in the balance of acetylation/deacetylation of proteins within the cell. Histones are the main proteic component of the chromatin. Its main function is to allow DNA strand to roll around and form nucleosomes. Protein queues of histones can suffer different chemical modifications (phosphorylation, methylation, acetylation, etc.). Depending on the level of histone acetylation, chromatin has a more or less relaxed or packed disposition. Relaxed chromatin allows gene expression, while packed chromatin does not. HDACi produce histone hyperacetylation, chromatin has a more relaxed disposition, and cells modify their behaviour.

Very importantly many other proteins in the cell can suffer acetylation/deacetylation (p53, bcl6, cMyc, NFKB, HSP90, etc.). In global all these proteins are called acetiloma. The final result of HDACi is a group of transcriptional and non-transcriptional effects with cell cycle stop, induction of apoptosis, increase of immunogenicity, antiangiogenic activity, chaperone inhibition, mitotic catastrophe, autophagy and senescence [55–57].

Vorinostat (Zolinza™) is the first HDACi approved by FDA in 2006 (not approved by EMEA) for the treatment of CTCL progressive, persistent or recurrent after two systemic therapies. Recommended dose is 400 mg daily, oral [58, 59].

Phase IIb clinical trial with 74 patients (most of them stage at least IIb) showed a RR of 29.7 % without CRs (including 30 % of showed a RR in advanced disease, a 33 % of RR in Sézary syndrome and a 22 % of RR in tumoural stage). Median time to response was around 2 months and time to progression, 4.9 months (in cases with stage at least IIb median time to progression was 9.8 months).

The most common adverse events (AE) were diarrhoea (49 %), fatigue (46 %), nausea (43 %) and anorexia (26 %); most were grade 2 or lower but those grade 3 or higher included fatigue (5 %), pulmonary embolism (5 %), thrombocytopenia (5 %) and nausea (4 %).

Post hoc analysis has demonstrated safety of vorinostat after at least 2 years of long-term maintenance [60].

Immunohistochemical analysis of STAT1 and phosphorylated STAT3 (pSTAT3) in skin biopsies obtained from CTCL patients enrolled in the vorinostat phase IIb trial showed that nuclear accumulation of STAT1 and high levels of nuclear pSTAT3 in malignant T cells correlate with a lack of clinical response [61]. On the other hand, HR23B expression pretreatment is considered a biomarker for response to vorinostat [62].

Romidepsin (Istodax ^®) is the second HDACi approved by FDA (2009) for the treatment of adult patients with cutaneous T-cell lymphoma (CTCL) or peripheral T-cell lymphoma (PTCL) who have received at least one prior systemic therapy. Romidepsin is given IV at a dose of 14 mg/m² on days 1, 8 and 15 every 28 days [63, 64].

Pooled analysis of 2 clinical trials included 167 (71  +  96) patients, 76 % of them at least stage IIb. RR was 41 % with 6 % of CRs. RR in Sézary syndrome was 58 %.

A clinically meaningful improvement in pruritus was observed in 43 % of patients, including patients who did not achieve an objective response.

Time to response was 2 months and median duration of response was 15 months.

Very interestingly, it has been shown that romidepsin increases CD25 expression, giving a rational basis to possible future treatments combined with denileukin diftitox.

Most common drug-related adverse events (AE), all grades, included nausea (67 %), fatigue (49 %), anorexia (37 %), ECG T-wave changes (29 %), anaemia (26 %), dysgeusia (23 %), neutropenia (22 %) and leukopenia (20 %).

Other HDACi are under investigation. Panobinostat (20 mg, oral, days 1, 3 and 5 of every week). A phase II clinical trial reported with Seventy-nine bexarotene-exposed and 60 bexarotene-naïve patients. The ORR was 17.3 % (15.2 % and 20.0 % in the bexarotene-exposed and -naïve groups, respectively). The most common adverse events were thrombocytopenia, diarrhoea, fatigue and nausea [65].

Bortezomib is a reversible inhibitor of the 26S proteasome in mammalian cells that degrades ubiquitinated proteins, thereby maintaining homeostasis within cells. Inhibition of the 26S proteasome can affect multiple signalling cascades within the cell, produces stress of the endoplasmic reticulum and can lead to cell death [66].

Bortezomib is FDA approved for the treatment of multiple myeloma patients and mantle cell lymphoma patients who have received at least 1 prior therapy.

In MF, a phase II study [67] with 12 previously treated CTCL (stage III or IVb) patients who received bortezomib as monotherapy for a total of six cycles (1.3 mg/m² iv, days 1, 4, 8 and 11 out of 21). The overall response rate was 67 %, with two (17 %) CRs and six (50 %) PRs. All responses were durable, lasting from 7 to 14 or more months. The most common grade 3 toxicities were neutropenia (n  =  2), thrombocytopenia (n  =  2) and sensory neuropathy (n  =  1).

MF is relatively chemoresistant due to the low proliferative rate that frequently have the tumour cells. Both single and multiagent chemotherapy have been used in MF. Chemotherapy should be restricted for advanced MF (stages IIb–IV). There is evidence against its use in early MF. Kaye et al. reported a randomised clinical trial comparing chemotherapy: cyclophosphamide, adriamycin, vincristine and etoposide (CAVE)  +  total skin electron beam irradiation (TSEB) vs. conservative palliative therapy, consisting of topical mechlorethamine, superficial radiotherapy and phototherapy. RR was better in the chemotherapy group (38 % vs. 18 %), but very importantly, there were no significant differences in disease-free survival or overall survival between the two groups. Toxicity was much higher in the aggressive arm [68].

Autologous stem cell transplantation (SCT) is not recommended for MF because, although patients achieve response, usually it is very transient, with disease progression occurring within months after the procedure [84]. Even after careful manipulation of the stem cell harvest, most cases present the T-cell clone in the reinfusion sample. Interestingly, the presence or not of the clone does not predict duration of response [85]. A meta-analysis performed to compare the outcome of allogeneic vs. autologous SCT in patients with MF/Sézary syndrome showed a more favourable outcome of patients who received allogeneic SCT [86].