A variety of therapeutic modalities produce remissions in most patients with MF. In general, MF therapy is divided into (1) skin-directed therapy (SDT) and (2) systemic therapy (Table 103–5). SDT is the mainstream therapy in early disease but also is used as an adjunct in systemic disease. Therapeutic decisions may be difficult and heavily depend on the stage at presentation. Revised practice guidelines are available on National Comprehensive Cancer Network (NCCN) website (www.nccn.org). See Fig. 103–6 for an overview of the treatment algorithm for MF/SS. In view of the protracted course of the disease and lack of curative therapies, therapeutic decisions should generally be focused on induction of long-term remissions with the least toxic agents and regimens. A number of highly effective monotherapies were recently shown to be safe and effective in patients with MF and SS in prospective clinical trials, leading to their approval by the FDA in the United States and abroad. Several novel agents are in clinical trials to test for their efficacy as monotherapy for MF. In addition, there are number of promising combination regimens being tested in clinical trials examining systemic multiagent therapies in advanced MF or SS to guide therapeutic decisions.
Cutaneous T-cell lymphoma treatment algorithm. NBUVB, narrowband ultraviolet B; PUVA, psoralen ultraviolet A; TSEB, total-skin electron beam; UVB, ultraviolet B.
Table 103–5.Therapeutic Option for Mycosis Fungoides and Sézary Syndrome ||Download (.pdf) Table 103–5. Therapeutic Option for Mycosis Fungoides and Sézary Syndrome
|Skin-Directed Therapy ||Systemic Therapy |
|Topical therapy ||Immunomodulators |
| Topical glucocorticoids || Interferon-α |
Nitrogen mustard (mechlorethamine)
Carmustine (BCNU, nitrosourea)
Extracorporeal photophoresis (ECP)
| Retinoids (bexarotene, tretinoin) || Denileukin diftitox (ONTAK, DAB389–IL-2) |
| Topical tacrolimus (Protopic) || Alemtuzumab (Campath) |
| Imiquimod (Aldara) ||Retinoids |
|Light therapy || Oral bexarotene (Targretin) |
| UVB and PUVA || Acitretin (Soriatane) |
| Photodynamic therapy || Isotretinoin (Accutane) |
| Electron beam ||Histone deacetylase inhibitors |
| Localized || Vorinostat (Zolinza) |
| Total-skin || Romidepsin (Istodax) |
| ||Chemotherapy (alone or in combinations) |
| || Oral prednisone, methotrexate, doxorubicin, cyclophosphamide; chlorambucil; pentostatin, cladribine, fludarabine, pralatrexate, several others |
These agents are effective during early stages of MF. They are limited to temporary short-term use because of suppression of collagen synthesis (skin atrophy), striae formation, skin fragility, and secondary infections. The class of topical preparation depends on the area and the site of involvement. Ultrapotent topical glucocorticoids should not be used on the face, neck, and intertriginous areas. Topical steroids are rarely used as monotherapy, but may be effective as an additional modality for symptomatic relieve of pruritus.
Topical Tacrolimus (Protopic) Topical tacrolimus has been approved for use in atopic dermatitis. It is as effective as mid- to low-potency glucocorticoids for use on facial skin and intertriginous areas in patients with MF. A major advantage of tacrolimus compared with steroids is that it does not suppress collagen synthesis and therefore does not cause skin atrophy.82 However, because the use of calcineurin inhibitors in CTCL is controversial,83 tacrolimus use should be limited to short-term use on small areas.
Topical Nitrogen Mustard (Mechlorethamine Hydrochloride) Topical nitrogen mustard is a topical alkylating agent used predominantly in patients with early stages of the disease (stages IA and IB), but can be used as a part of combination therapy with systemic agents in advanced stages. Prior to FDA-approval of mechlorethamine hydrochloride 0.02 percent gel in 2013,84 it was only available through certified compounding pharmacies in forms of solution, cream or ointment of various concentrations (0.01 to 0.04 percent). The major advantage of this topical therapy is its relatively low toxicity. Disadvantages include the inconvenience of daily application to large areas of skin, allergic reactions in up to half of cases,85 the potential for development of skin cancer,86 and the inability to cure the disease. Therapy is usually continued for up to 12 months in responders. Frequency then is reduced to every other day for an additional 1 to 2 years. Therapy is discontinued after 3 years or when cutaneous lesions disappear completely. Mechlorethamine should not be used together with ultraviolet A (UVA) or ultraviolet B (UVB) therapy because of cumulative carcinogenic effects on the skin and significant increase in risk for skin cancer and melanoma.
Topical Carmustine (Bis-Chloroethylnitrosourea [BCNU]) BCNU is not currently widely used for treatment of MF because of its severe irritant reactions and its absorption from the skin that results in systemic toxicity. The preparation ranges from 20 to 40 mg/dL in petrolatum ointment. It is applied at night and washed off in the morning. Monitoring includes biweekly complete blood counts to identify marrow suppression. Carmustine causes irreversible skin thinning, telangiectasias, and hyperpigmentation.87
Topical Retinoids Bexarotene (Targretin) 1 percent gel, is a topical retinoid (rexinoid) FDA-approved for treatment of MF patients who are refractory to at least one other topical therapy. It is a small lipophilic molecule related to vitamin A. It readily crosses the cytoplasmic membrane and binds to nuclear receptors (retinoid X receptors [RXRs]), resulting in changes in gene expression mediated through specific intracellular receptors, leading to maturating and apoptosis of malignant cells.88 Complete responses of 20 percent and overall responses of 60 percent are reported.89,90 It is applied in a thin layer to the patches and plaques twice daily. The major toxicity is irritation at the site. Oral administration of bexarotene is associated with severe birth defects. Considering potential absorption of the drug from the skin surface, bexarotene should not be given to pregnant women.
Phototherapy Phototherapy is a well-established effective treatment for MF, utilizing ultraviolet radiation of the UVA and UVB spectra. It is not FDA-approved for treatment of MF and SS because of a lack of prospective clinical trials, but is considered to be one of the most effective therapies for early disease (mainly patches and thin plaques). Phototherapy may result in complete clearing of the lesions. It was hypothesized that the mechanism of action of this therapy is Langerhans’ cells depletion from the epidermis.91
The peak of therapeutic effectiveness of UVB is within 295 to 313 nm. Conventional broad band UVB lamps emit wavelengths ranging from 280 to 330 nm, but narrow band UVB (NBUVB) emits only wavelengths 311 to 312 nm, eliminating harmful UV rays below 300 nm, which can cause erythema or severe burning and increase the risk of skin cancer.92,93,94 Similarly, excimer lasers emitting at 308 nm can be successfully used for hard to reach areas resistant to other therapy.95 NBUVB may be a viable alternative to psoralen with UVA radiation (PUVA) with similar response rates in a small cohort.96 Therapy should be instituted three times per week. On average, 6 to 12 weeks are required to achieve response. Maintenance therapy is required after a response occurs for at least 2 more months, but thereafter the maintenance regimen for various light sources is not well established and depends on the personal experience of the treating physician.
The UVA spectrum ranges from 320 to 400 nm, therefore UVA light penetrates deeper than UVB, into the dermis. Phototherapy involving UVA radiation is used with psoralen and is referred to as PUVA. Psoralen is a phototoxic furocoumarin activated by UVA light. In its active form, psoralen bonds covalently and irreversibly to DNA. Therefore, psoralen activated by UVA light affects cells primarily in the epidermis and papillary dermis. A 60 percent complete remission rate and long-term remissions (>10 years) have been reported with PUVA; patients with generalized erythroderma and tumors have lower response rates than patients with plaques.97,98,99 Psoralen usually is given at a dose of 0.6 mg/kg orally, 2 hours before the UVA light therapy. Treatments initially are given three times per week. Maintenance therapy may be given every 2 to 4 weeks for an indefinite period. Adverse effects of PUVA therapy include mild nausea, pruritus, and sunburn-like changes, with atrophy and dry skin. PUVA is not cross-resistant with other treatment modalities. Disadvantages of PUVA therapy are its necessity to visit doctor’s office frequently (from three times a week to once a month) and its expense. Long-term side effects include an increased incidence of skin cancers and melanoma.100
Photodynamic Therapy Photodynamic therapy is a photochemotherapy that utilizes two properties of porphyrins: their selective accumulation in tumor sites (e.g., 5-aminolevulinic acid) and their ability to generate cytotoxic oxygen species at the tumor site after red-light irradiation. 5-Aminolevulinic acid is a natural porphyrin precursor and upon irradiation is converted in the tumor to the highly photoactive endogenous protoporphyrin IX. Red-light irradiation is safe and penetrates deep in the tissue, allowing for treatment of thick tumors. Photodynamic therapy is especially useful in patients with limited skin area involved by few tumors. The main problem with the treatment is that the pain induced during irradiation limits its use for larger areas.101,102 It is used for therapy of MF off-label.
Electron Beam Therapy Electron beam therapy is a highly effective form of treatment of MF and can be used as a localized therapy (LEBT) to specific sites or lesions, or as radiation of the entire skin surface (total skin electron beam therapy [TSEBT]). It delivers a uniform dose from the surface to a specific depth, after which the dose falls off rapidly, sparing deeper normal tissues. It is usually delivered to penetrate only into the dermis, systemic effects are minimal, and the complete remission rate is 80 percent.3,103,104 Twenty percent of patients remain relapse free after 3 years. The relapse rate depends on the stage of the disease, and the relapse usually is short lived (may be as short as 2 to 3 weeks) in patients with erythroderma or numerous tumors. In the past, the treatment regimen was 4 Gy per week to a total dose of 36 Gy in 8 to 9 weeks. However, low-dose electron beam therapy has been shown to be nearly as effective, eliminating the usual side effects, such as alopecia, skin atrophy, destruction of skin adnexa, dermatitis, and increased risk of cutaneous malignancy.105,106,107,108 The advantage of electron beam therapy is the high frequency of durable complete responses without systemic toxicity. Up to three courses of electron beam therapy can be safely administered when used in a highly fractionated fashion (1 Gy per dose).
Imiquimod (Aldara) Imiquimod is a topical immunomodulator that is extremely effective in the treatment of condylomata acuminata, actinic keratoses, basal cell carcinomas, keratoacanthomas, and other cutaneous malignancies. The mode of action is not known but is thought to be related to induction of tumor necrosis factor-α and interferons resulting in activation of a Th1-type immune response and rejection of cancer or virally infected cells. Several groups reported the effectiveness of imiquimod in early patch MF.109,110 It should be used three times per week for 3 months. It is not FDA-approved for therapy of MF and SS.
Bexarotene (Targretin) is an FDA-approved RXR-selective retinoid, or “rexinoid,” for therapy of the MF. It is a first-line systemic agent for patients without contraindications to retinoids. At the currently FDA-approved dose of 300 mg/m2/day the overall response rate to bexarotene monotherapy ranges from 45 to 57 percent with at least 2 percent complete responses.111,112 Higher doses are associated with higher response rates and shorter time to response, but also with a higher incidence of adverse events. All patients on bexarotene rapidly develop central hypothyroidism and hyperlipidemia (most significantly hypertriglyceridemia), requiring coadministration of thyroid supplements and lipid-lowering agents. Other rare adverse events include headaches, possibly a result of pseudotumor cerebri, leucopenia, and pruritus. The majority of side effects are laboratory findings and dose-dependent; bexarotene is usually well tolerated by the patients. Its use is recommended beginning with refractory or persistent stage IA disease as well as in more advanced stages (NCCN guidelines). Standard procedures for management of patients on bexarotene therapy are reviewed.113 Bexarotene is safe to use long-term for maintenance therapy. Bexarotene and other retinoids are labeled pregnancy Category X, and must not be given to a pregnant woman or a woman who intends to become pregnant.
Other retinoids have been used for treatment of MF and SS, including isotretinoin, acitretin, etretinate (not available in United States), and all-trans retinoic acid (ATRA). Activity of these compounds in MF/SS has been demonstrated in case series or small open-label pilot studies, but there are no prospective studies formally evaluating these drugs.114
Histone Deacetylase Inhibitors Vorinostat is an oral histone deacetylase inhibitor (HDACi), which was FDA-approved for treatment of cutaneous manifestations of recurrent, refractory or persistent MF and SS in 2008 at the dose of 400 mg by mouth daily.115 Vorinostat was evaluated in an open-label phase IIb clinical trial and was shown to have an overall response rate of 30 percent. No complete responses were observed on the clinical trial. Median time to relapse in patients with advanced disease was 56 days. Median time to progression was 4.9 months overall, and 9.8 months for stage IIB or higher responders. Overall, 32 percent of patients had pruritus relief. The most common drug-related adverse events were diarrhea (49 percent), fatigue (46 percent), nausea (43 percent), and anorexia (26 percent); most were grade 2 or lower but those grade 3 or higher included fatigue (5 percent), pulmonary embolism (5 percent), thrombocytopenia (5 percent), and nausea (4 percent).
Romidepsin is a selective HDACi given as an intravenous infusion. Romidepsin was FDA-approved for therapy of CTCL based on a phase IIB clinical trial documenting an overall response rate of 34 percent, with 6 percent complete responses.116 The median duration of response was 13.7 months. Toxicities included nausea, vomiting, fatigue, and transient thrombocytopenia and granulocytopenia. Romidepsin was shown to have single-agent clinical activity with significant and durable responses in patients with CTCL.116 HDACi may be excellent combinational agents, potentiating effects of other therapies, possessing a radio- and photosensitizing effects. Several clinical trials are on the way examining potential combinations, including electron beam.106
Interferon-α Interferon-α can be used as a single agent or combined with other systemic therapies. The response rate when interferon-α is used as a monotherapy is 50 to 70 percent at doses beginning at 3 to 5 × 106 units/day or three times per week, either subcutaneously or intralesionally.117 Toxicity includes acute flu-like symptoms and fatigue. It is commonly used in combination with other immunotherapies (such as extracorporeal photopheresis [ECP] and phototherapy), but this practice is based on small case series and small prospective studies. It is not clear if combinations truly result in improved clinical outcomes.10,118,119
Extracorporeal Photopheresis PUVA can be delivered by an extracorporeal technique.120,121 White cells are collected by leukapheresis, exposed to a photoactivating drug, and irradiated with UVA. The cells then are reinfused into the patient. The effect may be both a direct cytotoxic effect on the tumor cells and an immunologic effect by activating lymphocytes against the tumor cells. Photopheresis typically is administered every 2 to 4 weeks until clearance of disease. Side effects are minimal and may be related to fluid shifts during the procedure.100 A recent retrospective review suggested a survival advantage for patients treated with ECP122 and beneficial responses in patients with early stage MF.123
Monoclonal Antibodies Alemtuzumab (Campath-1H) is a humanized IgG1 monoclonal antibody that targets the CD52 antigen. A response rate of 50 percent has been reported in a small cohort of patients.124,125 Low-dose alemtuzumab was shown to be safe and effective in very elderly SS patients.126 Alemtuzumab effectively depletes leukemic cells from blood of these patients. Very low doses on an as needed basis were reported to be effective long-term in SS patients.127 Numerous monoclonal antibodies are in clinical trials now as single agents and in combinations, including anti–PD-1 antibodies and anti-CCR4 antibody.
Monoclonal Antibody Conjugates Brentuximab vedotin (SGN-35) is an anti-CD30 antibody conjugated via a protease-cleavable linker to the potent antimicrotubule agent monomethyl auristatin E (MMAE). Following binding to CD30, brentuximab vedotin is rapidly internalized and transported to lysosomes where MMAE is released and binds to tubulin, leading to cell-cycle arrest and apoptosis. Brentuximab was recently FDA-approved for CD30+ cutaneous T-cell lymphomas, showing durable antitumor activity with a manageable safety profile in patients with relapsed/refractory primary cutaneous CD30-positive lymphoproliferative disorders.128 The overall response rate was 73 percent, with 54 percent for MF and 100 percent for all other tumor types (LyP and primary cutaneous anaplastic large cell lymphoma [PCALCL]). Response was not correlated with level of CD30 expression at baseline in MF. Peripheral sensory neuropathy is a significant adverse event associated with brentuximab vedotin administration. Neuropathy symptoms are cumulative and dose related. Multiple ongoing trials are currently evaluating brentuximab vedotin alone or in combination with other agents in relapsed/refractory patients, as well as patients with newly diagnosed disease.
Recombinant Fusion Proteins Denileukin diftitox (DD) is an IL-2 diphtheria toxin fusion protein, which had full FDA approval in October 2008 following a phase III randomized, double-blind, placebo-controlled trial.129 The overall response rate was 37 percent at a dose of 9 μg/kg/day and 46 percent with 18 μg/kg/day, which was statistically significant (p = 0.002) compared to placebo. Patients receiving 18 μg/kg/day had a progression-free survival of 971+ days and duration of response of 220 days. Time to response was 92 days; time to treatment failure was 169 days. Importantly, 45 percent of best responses occurred during cycle 4 and beyond, suggesting that an appropriate trial of the drug is necessary to achieve optimal responses. All complete responses occurred after four or more cycles.129 Side effects were numerous, including a capillary leak syndrome, infection, hepatitis, increased fluid retention, rash, shortness of breath, and flu-like symptoms such as chills, fever, weakness, bone and muscle pain, headache, nausea, and vomiting. Cardiac arrhythmias and thrombotic emergencies have been reported occasionally. Usually, adverse events are most severe during the first two cycles, diminishing as the treatments continue. DD manufacturing was discontinued and a new formulation of the same product is in clinical trials at this time.
Chemotherapy Several agents have been FDA-approved for therapy of various subsets of MF and SS.
Pralatrexate is a novel antifolate with high affinity for reduced folate carrier-1, which was recently FDA-approved for therapy of transformed MF (tMF). The recommended regimen was identified as 15 mg/m2 a week for 3 of 4 weeks; the response rate was 45 percent.130 The most common grade 3 adverse event (AE) was mucositis (17 percent); the only grade 4 AE was leukopenia (3 percent). MF patients were not able to tolerate the “lymphoma” dosage of pralatrexate (30 mg/m2 a week for 6 of 7 weeks) because of intolerable toxicities, including severe mucositis. It was hypothesized that the higher incidence of mucositis was a result of distribution of malignant cells from the skin and mucosal surfaces beyond visible lesions resulting in “localized” tumor necrosis in the skin with collateral damage to surrounding tissues. Administration of a single 10 to 15 mg dose of leucovorin 24 hours following pralatrexate infusion, completely abrogated these side effects and allowed therapy with 30 mg/m2 without sacrificing efficacy.131
Alkylating agents used to treat MF and SS include nitrogen mustard topically or systemic cyclophosphamide, or chlorambucil. Response rates of 60 percent, with 15 percent complete remissions, have been reported.132,133 Similar results are obtained with methotrexate 2.5 to 10 mg/day orally134; bleomycin 7.5 to 15 mg intramuscularly given twice weekly; and doxorubicin 60 mg/m2 intravenously given once per month.135,136 Pegylated doxorubicin used in advanced MF has resulted in an overall response of 88 percent.137 Purine analogues including fludarabine and pentostatin have response rates as high as 50 percent.138,139,140 Gemcitabine has a similar response rate.141 Neither single-agent or multiagent therapy cures MF. Chemotherapy with a single agent and polychemotherapy result in a higher incidence of transformation to large cell lymphoma, which carries a worse prognosis than the original diagnosis.142,143 Because responses to therapy are generally higher after combination therapy, single-agent chemotherapy is used rarely. However, use of multiagent chemotherapy results in increased immunosuppression and an increased risk of serious infections, leading to death in the majority of patients who develop this complication.144 Combination therapy produces objective responses in greater than 80 percent of patients and complete responses in approximately one fourth of cases.99,145 The duration of remission varies, with a median of approximately 1 year. No long-term disease-free survival has been reported.
Combined Modality Therapy Several multidrug regimens reportedly improve clinical response in patients with MF, including combination of extracorporeal photophoresis with low-dose interferon-α and oral bexarotene; prednisone and fludarabine; and PUVA and oral bexarotene.3,146
Because in general MF is an indolent malignancy of T cells with excellent prognosis in early stages, the treatment should be conservative, with skin-directed therapies (nitrogen mustard, topical glucocorticoids, topical bexarotene) combined with light therapy, low-dose interferon, low-dose methotrexate, or other single-agent chemotherapy. The survival of patients treated with aggressive chemotherapy is not different from the survival of patients treated conservatively, but aggressive chemotherapy results in greater toxicity. Because no curative therapy exists, the goal of therapy is to prevent progression to more advanced stages and to preserve the patient’s quality of life for as long as possible.