Although the exact mechanism of action of mechlorethamine is unknown, when administered systematically, it acts as an alkylating agent with an antimitotic effect. Its topical activity, however, appears to be mediated by immune mechanisms or by interaction with Langerhans cells. The drug is usually used as an aqueous solution with a strength of 10-20mg/100mL or as a gel (10-20mg/100g petroleum jelly).9–15 An ongoing randomized, double-blind, multicenter trial is comparing the safety and efficacy of 2 preparations of nitrogen mustard (0.02% in propylene glycol and 0.02% in petroleum jelly) in patients with stage I or IIA MF refractory to topical corticosteroids.16 The preliminary results have shown similar efficacy (overall response rate [ORR] of around 70%) and a good safety profile (no systemic absorption was seen) for both preparations. In clinical practice, the drug is initially applied daily until the lesions have cleared (in 3 to 6 months with the solution and 6 to 12 months with the gel). An intermittent maintenance regimen is followed thereafter. Application to the entire body surface is usually recommended, though avoiding intertriginous areas. However, the need to treat unaffected areas is not very clear. Response varies between 50% and 75% in stage T1 and 25% and 50% in stage T2. Contact dermatitis (allergic or irritant) may arise, particularly when using the aqueous solution (30% vs <5% with the gel). Urticaria and anaphylactic reactions have also been reported. Prolonged use increases the risk of nonmelanoma skin cancer, particularly if the patients have received prior PUVA or total skin electron beam therapy. In general, myelosuppression or other systemic effects do not occur. Efficacy appears to be similar for the 2 preparations (solution and gel), although prospective studies comparing the 2, other than the one described above,16 have not been undertaken. In recent years, the availability of mechlorethamine in hospital pharmacies has been limited, and so it is unfortunately being used less and less despite its efficacy.

Several studies have shown the usefulness of narrow-band UV-B phototherapy in the initial stages of MF (CR rates of around 75%, with a mean response duration of 51 months).21–26 The risk of skin cancer is increased, however, and therapy is only effective in MF with incipient lesions with little or no infiltration, given the limited penetration of the radiation. This type of therapy is considered particularly useful in those patients who do not tolerate psoralens, those with very light skin, and those with very incipient lesions.27

PUVA is the classic treatment in the early stages of lymphatic disease.20,29–34 Usually, the patient starts with 2 to 3 weekly sessions, with the interval between sessions being reduced according to response. There is no consensus about whether it is necessary to follow a maintenance regimen once CR has been achieved.35 In a study of 82 patients with MF in the form of superficial plaques and/or palpable plaques, CR was obtained in 65% and PR in 30%, with a mean response duration of 43 months.28 Chronic actinic damage was observed in 10% of the patients, with the appearance of carcinomas in 6 patients: 3 with basal cell carcinoma and 3 with squamous cell carcinoma. Although there are studies that show a statistically significant increase in carcinogenesis, including melanoma, we believe that this risk is more theoretical than real, at least in this group of patients. According to the most recent studies, the disease-free interval is related to a higher cumulative dose of PUVA and longer treatment times.27,35 Although late recurrences are seen, between 30% and 50% of patients in stages IA, IB, and IIA can maintain CR for periods of up to 10 years. The disease-free survival at 5 and 10 years for patients in stage IA was 56% and 30%, respectively. For those patients in stages IB/IIA, 5- and 10-year disease-free survival was 74% and 50%, respectively. However, the overall survival did not vary significantly between those with recurrences and those without.

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  Extracorporeal photopheresis.36–39 In a modification of PUVA, after ingestion of psoralen, circulating mononuclear cells from the patient are exposed to UV-A. The main drawback of this approach is the high cost and, in addition, efficacy is no better than other treatments. The best responses are obtained in patients with early-stage SS who have normal CD8 counts and have not received prior aggressive therapies.

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  Hypericin. This new photodynamic plant derivative induces T-lymphocyte apoptosis in association with visible or UV-A light. If preliminary results are confirmed, this option could be better than the other forms of phototherapy,40 as visible light does not increase the risk of skin cancer.

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  Photodynamic therapy. The use of photodynamic therapy with derivatives of 5-aminolevulinic acid could be particularly appropriate in patients with few lesions or lesions on the scalp.41

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  Monochromatic excimer laser light. Excimer lasers at a wavelength of 308nm have also been used and are approved by the US Food and Drug Administration (FDA) for psoriasis and vitiligo. Passeron et al.42,43 have performed a clinical trial in which good responses were obtained in very incipient lesions. This approach can therefore be considered in areas that are not usually accessible with phototherapy.

The evidence to support these approaches is, however, limited. Likewise, there is little evidence with regard to other therapeutic options.

Conventional radiotherapy is used for highly infiltrated plaques or localized MF tumors refractory to other treatments.44 It is particularly indicated as front-line treatment of cutaneous marginal zone B-cell lymphoma and follicle center lymphoma along with excision.45,56 The recurrence rate is higher if doses less than 30Gy are used. Local radiotherapy has also been used in solitary MF lesions with impressive results.47

An electron beam is the treatment of choice for patients with MF with infiltrated plaques or small generalized tumors. The most widely used voltage is 6 MeV, and therapy is applied 4 days per week for a total dose of 3600 cGy in 10 weeks.48 The treatment can be repeated several times if reduced doses are used. Adverse effects include generalized erythema, edema, scaling and exudation, apparent worsening of existing lesions, total loss of skin appendages, transverse melanonychia and, less frequently, blistering. Hair loss is usually reversible if the total dose administered has not exceeded 2500 cGy. In the longer term, patients may develop edema, hyperpigmentation, telangiectasia, and persistent xerosis, while men may become sterile.48–50

The disease-free interval can be extended according to some authors by subsequent maintenance therapy, either with mustard derivatives or PUVA.48,49,51,52 The recommendations of the EORTC on total skin electron radiation in MF were published in 2002.53 The procedure is not recommended for erythrodermic CTCL (T3) given the risk of severe scaling and because the CR rates are higher in the earlier stages (CR of 90% in T1 and 70% in T2 disease) than in the more advanced stages, where the effect is only palliative.

It is known that CR rate depends on the stage of the disease, the dose applied, and the electron energy.51 Overall, CR rates of 96% are obtained in patients with stage IA, IB, and IIA disease; of 36% in those with stage IIB disease; and of 60% or less in patients with stage III disease. CR rates are also related to total dose (32-36Gy) and electron energy (4-6 MeV).52,53

Isotretinoin and etretinate have been used in the treatment of MF to similar effect. Their usefulness as monotherapy is limited, as it was seen that atypical cells were still present according to the pathology study even though the lesions had apparently healed. These agents have been combined with PUVA and interferon alfa (IFN-α). When combined with PUVA, they seem to be able to reduce the UV-A dose while with IFN-α they seem to enhance the response to interferon in early but not late disease stages. However, there are no randomized studies that compare IFN-α and IFN-α in combination with retinoids.54

Bexarotene is a new retinoid (more specifically a rexinoid) whose exact mechanism of action is unknown although it inhibits growth of tumor lymphocytes and also enhances apoptosis in vitro.55 Bexarotene selectively activates RXR receptors (a type of nuclear receptor activated by retinoic acid), acting as a regulator of cell differentiation and proliferation. In 2002, the FDA approved the compound, both for topical use as a 1% gel (which has so far not been marketed in Spain but can be obtained as an imported medicine) and for systemic use at an optimum dose of 300mg/m2/d. Regular laboratory testing should be performed during treatment, focusing mainly on triglyceride levels and thyroid hormones. Bexarotene induces hypertriglyceridemia, which can be marked at times. Preventive treatment should therefore be given the preceding week with statins or a fenofibrate but not with gemfibrozil as this fibrate increases the levels of bexarotene in blood, probably through inhibition of cytochrome P450. Hypothyroidism is another common adverse effect that can be controlled with administration of thyroid hormone. Bexarotene can be combined with other treatments such as PUVA or IFN-α. It may also find uses in a maintenance regimen after more aggressive therapies in patients with more advanced disease. As with other retinoids, it requires contraceptive measures in view of the risk of malformations.56–61

IFN-α is used as monotherapy administered subcutaneously (although intramuscular and intralesional administration is also possible) at a dose of 3 to 20 million units per day, 3 days a week, with a good (dose-dependent) response, particularly in early-stage disease (ORR of approximately 70%) or in combination with other therapies such as PUVA (apparently the most effective combination), retinoids, or purine analogs (fludarabine) with apparent benefit (studies that compare these options with IFN-α monotherapy are lacking). Adverse effects include flu-like syndrome, gastrointestinal disorders, bone marrow suppression, and elevated transaminases. The agent can be used for years as maintenance in patients who showed a good response and are at risk of relapse, although there is a risk of developing autoimmune diseases such as diabetes mellitus, thyroiditis, or hemolytic anemia.62–64

Denileukin diftitox (DAB389-interleukin 2 [IL-2]) is the first fusion cytotoxin approved by the FDA for the treatment of CTCL.65,66 It acts as a specific cytotoxin for cells that express the IL-2 receptor. It is obtained by expression in Escherichia coli of the product of fusion of the human IL-2 receptor genes with cytotoxic sequences of diphtheria toxin. The agent binds to the IL-2 receptor (CD25) of T lymphocytes, thereby inhibiting protein synthesis, and is administered intravenously at a dose of 9 or 18mg/kg/d in 5-day cycles every 3 weeks. It has been shown to be particularly effective in stage IIB MF (response rate, 38%). Transient flu-like syndrome is reported in 60% to 70% of the patients, a similar figure to that seen with IFN-α. Other adverse effects such as urticaria, anaphylaxis, or vascular leak syndrome have also been reported. Some patients developed anti-DAB389 or anti-IL-2 antibodies in the first cycle, but there was no correlation with either toxicity or response. Efficacy has been boosted in recent studies through the concomitant use of oral bexarotene, particularly in patients with low or nonexistent expression of the IL-2 receptor.67,68 Combination therapy enabled lower doses of the 2 treatments to be used. The agent has been used in monotherapy in CTCLs other than MF,69 and in combination with radiotherapy.70

Methotrexate is the first-choice treatment in CD30+ CTCL, particularly when the patient has multiple lesions (radiotherapy is the best alternative in solitary lesions).96 High weekly doses are required in some cases to achieve CR, with a higher risk of adverse effects.

Recently, 2 other chemotherapies (gemcitabine and pegylated liposomal doxorubicin [DOX-PEG]) have been shown to be useful in monotherapy.

Gemcitabine is a pyrimidine antimetabolite indicated for solid tumors traditionally considered resistant to conventional treatment such as lung cancer, ovarian cancer, pancreatic cancer, and urinary bladder cancer. Its effectiveness in cutaneous lymphomas has been investigated in 2 studies. The first to these was a series of 32 patients (mostly with MF).97 CR was achieved by 22% (7 patients) while PR was achieved by 53% (17 patients). Unfortunately, the study used standard criteria for assessing response as if the patients had common forms of non-Hodgkin lymphoma and not specifically cutaneous lymphoma (severity-weighted assessment tool). Response was achieved by 73% of those with MF (26 patients), with 23% with CR and 50% with PR. The only patient included with SS did not respond. The median duration of CR was 10 months (range, 4-22 months). Gemcitabine was administered as an intravenous infusion at a dose of 1200 mg/m2 for 30minutes in cycles of 28 days (total of 6 cycles) on days 1, 8, and 15 of each cycle. The most frequently reported adverse effects were cytopenias. Reversible liver toxicity was the most frequently reported nonhematologic adverse effect (13 patients, 40%). No treatment-related deaths were reported. The second study was a series of 33 patients, most of whom had heavily pretreated MF (median of 5 prior regimens) (31 patients).98 Two patients had anaplastic CD30+ T-cell lymphoma. Compared to the first study, a higher dose of gemcitabine was used (1000mg/m2) but the schedule of administration and number of cycles were the same. Response was assessed using variables that included the area of skin involved, size of lymph nodes, and peripheral blood cytometry. Response was achieved by 68% of the patients (2 with CR). Myelosuppression was the most frequently observed adverse effect (grade 3 in 8 of the 33 patients) and 2 characteristic uremic hemolytic syndromes were diagnosed in patients with SS. Other adverse effects were elevated transaminase liver enzymes, mucositis, lethargy, fever, hyperpigmentation, infusion-related maculopapular rash, and different types of cardiovascular events. Another more recent multicenter study reported similar outcomes to the studies already discussed, but with significantly greater toxicity.99

DOX-PEG is approved for the treatment of advanced ovarian cancer, relapsed multiple myeloma after hematopoietic stem cell transplantation, and AIDS-associated Kaposi sarcoma. The usefulness of DOX-PEG has also been demonstrated in patients with CTCL in observational and retrospective studies. Recently, a prospective, multicenter study analyzed use of this agent in 25 patients with MF and/or SS in stages ≥II refractory to at least 2 prior lines of treatment and in patients with CD30+ large-cell CTCL.100 DOX-PEG was administered intravenously every 4 weeks at a dose of 40mg/m2/d for up to 8 cycles. An objective ORR of 56% was reported (14/25 patients with CR and 9/25 with PR). Response rates were high in patients with SS, with 6 of the 10 (60%) responding. One of these responses was a CR. Response rates were also high in transformed CTCL, and 50% of these responses were a CR. In general, more adverse effects were seen than in the previous studies, with 4 episodes of serious infection and some cardiac events. DOX-PEG has also been shown to have good activity in 5 CBCLs (1 with marginal zone disease and 4 diffuse large-cell lymphomas, leg-type) in an Italian phase II pilot study (dose of 20mg/m2 every 3 or 4 weeks). An impressive prolonged CR was obtained in 4 of these patients (80%).101 In another study published recently, excellent outcomes were obtained with DOX-PEG in combination with bleomycin, vinblastine, and dacarbazine (CBVD regimen) in 37 patients with advanced PCL, both of T-cell origin (19 patients) and B-cell origin (18 patients).102 CR rates of 88.8% and 100%, respectively, were obtained. Between 4 and 6 cycles of CBVD were administered in the group of CTCL whereas those with CBCL received between 2 and 6 cycles (with rituximab added to the chemotherapy: R-CBVD). The safety profile was good. Subsequent allogeneic hematopoietic stem cell transplantation was performed in 3 patients (2 with CTCL and 1 with CBCL).