New and established treatment options for mycosis fungoides and Sézary syndrome – an update
At the time of diagnosis primary cutaneous lymphomas are limited to the skin. T-cell lymphomas represent at least two thirds of all primary cutaneous lymphomas with mycosis fungoides and Sézary syndrome being the most frequent entities. A precise staging based on clinical, histological, immunohistological and molecular biological criteria is crucial for selecting the appropriate therapy. Since curative treatment is only possible in exceptional cases, the aim of any therapy is to achieve healing of the skin lesions, minimizing relapses, preventing progression and maintaining the quality of life. While in early disease stages skin-directed therapy is being used, in later stages systemic treatments become more important. This work aims to provide an overview of established and new therapies for the treatment of mycosis fungoides and Sézary syndrome.
Primary cutaneous lymphomas are the second most frequent type of extra nodal non-Hodgkin lymphomas with an incidence of approximately 1 per 100.000 inhabitants per year. Depending on the tumor cell type cutaneous lymphomas are classified in different subgroups with cutaneous T-cell lymphomas (CTCL) representing the major part. According to recent epidemiological data, cutaneous B-cell neoplasias only make up 15 % of all cutaneous lymphomas .
For decades classification of cutaneous lymphomas was inconsistent until in 2005 agreement was reached on the WHO/EORTC classification based on clinical, histological, immunohistological, molecular biological as well as on prognostic criteria . Precise diagnosis and exact staging of cutaneous lymphomas is crucial for selecting the appropriate therapy. In this respect we refer to the current guidelines of the „Deutsche Dermatologische Gesellschaft“ (German Dermatological Society), which has been revised on behalf of the German Cancer Society in 2012, as well as to a review published in this journal in January 2014 [3, 4].
This article is to give an overview of the latest developments in the therapy of the two most important types of CTCL, mycosis fungoides (MF) and Sézary syndrome (SS).
Clinically, MF follows consecutive stages in most of the cases beginning with the initial patch stage followed by plaque- and tumor stage as well as erythrodermia (reddening of more than 90 % of the body surface). At any moment there is the risk of blastic transformation worsening the prognosis drastically. Outcome is dependent on tumor stage. In in stage IA (patches and plaques affecting less than 10 % of the body surface) life expectancy is not significantly reduced. When patches und plaques affect more than 10 % of the body surface, approximately 20 % of the patients die within the next 10 years. In tumor stage the 10-year disease-specific survival is 42 %, dropping to about 20% with lymph node involvement [2, 5].
Several clinical and histological types of MF have been described, some of them with therapeutic consequence (for example, folliculotropic MF, pagetoid reticulosis and granulomatous slack skin according to the WHO/EORTC classification).
MF is a disease of clonal mature memory T-cells with atypical convoluted nuclei positive for CD4 and CD3. A rare variant is positive for CD8; however, this is without influence on the clinical course. Another characteristic feature of MF cells is the expression of skin homing factors such as CCR4, CCR6, CCR10 and the cutaneous lymphocyte antigen (CLA) which help explain that that even though MF is a systemic disease, in the beginning it is limited to the skin exclusively. Already in the early stages malignant clones can be detected in peripheral blood with molecular biological techniques. CLA as a ligand for E-selectin on cutaneous endothelial cells is highly expressed on the neoplastic cells of MF. Interestingly, the expression of CLA decreases with disease progression fitting with decline of epidermotropism in tumor stage as well as the increased risk for visceral and leukemic involvement .
SS is characterized by erythrodermia, severe pruritus, generalized lymphadenopathy and proof of neoplastic T cells in blood and skin. In contrast to SS, erythrodermic MF does not fulfill the hematological criteria and thus can be differentiated from SS. Sometimes SS has been described as leukemic variant of MF due to cytomorphologic similarity of the neoplastic cells and the CD3+, CD4+ phenotype. Recent molecular genetic studies show that SS and MF are two different diseases that are not biologically related. In contrast to the effector-memory tumor cells in MF being located in the skin, tumor cells of SS do not show a distinct epidermotropism but have characteristic features for the lymph node (CCR7 and L-selectin) and express CD27. Thus the SS cell rather corresponds with a central memory T cell. So far it remains uncertain whether cases of SS preceded by a typical MF have to be judged differently [7-11].
With a median survival of 2–4 years the outcome of SS is poor. Just as in MF, opportunistic infections are the most common cause of death.
Established and new treatment options
Although MF accounts for approximately 50 % of all cutaneous lymphomas, it still is a rarely observed disease. For this reason clinical studies are generally based on small numbers of cases and only very few prospective, randomized therapeutic studies with an appropriate level of evidence can be found. Since no reliable statements concerning dose, therapy time or therapy combination are available and cure is unlikely, a moderate, stage-dependent therapeutic approach is recommended (For overview see Table 1 and 2 as well as ).
Table 1. Treatment recommendations for MF and special types of MF 
|IA Unilesional MF, pagetoid reticulosis||Corticosteroids class III—IV PUVA/UVB-311 nm Local radiotherapy (>30 Gy)|| |
▸ Topical BCNU/carmustine
▸ Local PUVA PUVA/UVB-311 nm
▸ Corticosteroids class III–IV
|In juveniles with circumscribed MF These clinical pictures are to be considered as special types of MF stage IA|
▸ PUVA + IFN-α
▸PUVA + bexarotene
▸(Whole-body electron beam irradiation)
|IIB||PUVA, if necessary combined with IFN-α, bexarotene and RT for tumors|| |
▸ Low-dose MTX and RT for tumors
▸Oral bexarotene and RT for tumors
▸HDAC-inhibitor (SAHA, romidepsin)
▸Whole-body irradiation with electrons
|Many of these substances are not approved for this indication in Germany or Europe|
|III*||PUVA, if necessary combined with IFN-α, bexarotene Photopheresis, if necessary combined with IFN-α, MTX, bexarotene or PUVA||▸ See stage IIB|| |
|IVA||PUVA, if necessary combined with IFN-α, bexarotene RT for tumors||▸ See stage IIB|| |
|IVB||PUVA, if necessary combined with IFN-α, bexarotene Chlorambucil/corticosteroids RT for tumors|| |
▸ See stage IIB
▸Cladribine, fludarabine, cyclophosphamide
|If necessary maintenance therapy with PUVA + IFN-α after reaching remission|
Table 2. Treatment recommendations for Sézary syndrome 
▸ Extracorporeal photopheresis (ECP), if necessary combined with PUVA, IFN-α and/or bexarotene
▸ PUVA combined with IFN-α and/or bexarotene
▸ Chlorambucil/corticosteroids (Winkelmann scheme)
▸ Low-dose methotrexate
▸ Denileukin diftitox
▸ Whole-body electron beam irradiation
▸ Alemtuzumab i. v. or low-dose subq (anti-CD52-antibody)
▸ Vorinostat, romidepsin (HDAC inhibitors)
▸ Fludarabine, cladribine, gemcitabine
Aggressive treatments, especially chemotherapy, do not improve the outcome of patients with MF and are thus reserved for patients with a very aggressive disease course . A good chance for healing exists with unilesional MF as well as for progressive MF when being treated with very aggressive therapies. Between the two lies the large spectrum of palliative treatment options based on the principle not to compromise the patient by pharmaceutical side effects while delaying or even stopping the disease's progress at the same time. Sometimes, even in these stages, complete remission can be achieved, but only very rarely this is permanent.
Many patients with MF or SS also suffer from extreme dryness and scaling of the skin as well as from severe pruritus. In these cases moisturizing substances as well as treatment with oral antihistamines, gabapentin, mirtazapine or aprepitant should be taken into consideration [12, 14]. The following sections will emphasize the lymphoma-specific treatment options.
Skin-directed topical treatment
Early stages are usually treated topically or with phototherapy. Skin-directed therapies can achieve a long-lasting remission in approximately 60 % of the patients with MF in patch or plaque stage.
Highly potent topical corticosteroids are counted among the first-line topical therapies and serve as benchmark for all other topical treatment options. The effect is based on the induction of apoptosis and the influence on lymphocyte adhesion to endothelium as well as on the reducing influence of the production of different cytokines, adhesion molecules and growth factors [15-17].
Long experience exists in the treatment of early stage MF with topical nitrogen mustard. Applied topically, this alkylating agent affects the interaction between keratinocytes, Langerhans cells and T cells [18, 19]. In 2013 a 0.016 % gel preparation was approved by the Food and Drug Administration (FDA) achieving cure rates similar to those of topical corticosteroids for patients with MF stages IA/IB, who had been treated previously with other skin-directed therapies (Valchlor (mechlorethamine) Gel®) [20, 21]. Currently, the company is seeking approval for other countries. If approved, topical nitrogen mustard may represent a relevant alternative to topical corticosteroids, particularly due to the available clinical long-term experience . Healing of lesions can take over six months and frequent side effects include burning, pruritus and dermatitis. Moreover, there is a slightly increased risk for non-melanoma skin cancer (1–5 %) especially when the patient is treated with PUVA or radiotherapy simultaneously .
Other topical treatment options
The topical retinoid bexarotene (Targretin Gel®) is effective in approximately 50 % of the patients, especially when they do not respond to topical corticosteroids . Local irritation is observed frequently and so far no reliable study data exist concerning the long-term side effects of topical bexarotene. To date Targretin Gel® is approved by the FDA only and it remains uncertain in how far efforts are being made for a European approval application. Another retinoid, alitretinoin (Panretin Gel®), was approved for the treatment of Kaposi sarcoma in patients with HIV. Although isolated reports showed a successful treatment in patients with MF , further researches still focused on bexarotene gel.
Other treatment options include topical cytostatics such as carmustine (BCNU) or topical immune modulators (for example imiquimod) . Both preparations are approved in Germany and may be applied off-label. Long-term experience is available for carmustine (Carmubris®). The powder for injections must be mixed with a hydrophilic ointment base (for example Ungt. Cordes) and applied on the whole body . A ready-to use product is not available.
Along with topical corticosteroids, UV phototherapy (systemic or topical PUVA, UV-B 311 nm- or UVB-therapy) is another established pivotal component for the treatment of CTCL leading to response rates of approximately 70 % with long-lasting complete remission rates of 10 years and longer especially in patients with MF in patch stage [27-29]. 8-methoxypsoralen (Meladinine®) is approved for the treatment of CTCL in Germany. Long-term risks include light-induced aging and photo carcinogenesis. UV phototherapy is often combined with systemic therapies such as oral retinoids or interferon-α, also in order to reduce the cumulative light dose.
Since the tumor cells are generally very radiosensitive, radiotherapy has its firm place in the treatment of CTCL. One differentiates between local radiation and a whole body irradiation with high-velocity electrons.
Local radiation: Local radiation can be performed with fast electrons or photons or with soft X-rays. For unilesional MF radiation represents a curative approach. A dose of up to 40 Gy is considered to be sufficient. If possible, a minimum safety distance of 3–5 cm should be maintained. Response rates are high (up to 100 %), one study including 18 cases revealed only 2 relapses [30-32].
Radiation of isolated tumor nodules in progressive MF is of palliative character. Even though it has no effect on the outcome, individual nodules may show a good response and complications such as painful ulceration and wound infections (which in patients with weakened immune defense may be fatal) can be avoided.
Low-dose palliative radiation using only 8 Gy applied in one or two sessions represents a new therapeutic approach and is almost free from side effects. In one study 82 plaques and tumors in patients with MF were irradiated with a response rates of 92 % [31, 33]. Moreover, a low-dose intravenous therapy with histone deacetylase inhibitors (HDI) has been recently tested in patients with progressive MF in order to reduce the dose of a subsequent radiation. HDI leads to an arrest of the cell cycle in the G1 and G2/M phase in tumor lymphocytes and induce apoptosis, thus causing an increased radio sensitivity of the tumor cells. In small case series, synergetic effects of HDI and radiation have been demonstrated [34, 35]. Treating CTCL with HDI exclusively will be discussed in detail under systemic therapy.
Whole-body irradiation with electrons: Whole-body irradiation with electrons has been established in the treatment of MF for a long time, but since this option is technically difficult it is only available in few centers. Due to a deeper penetration into the skin, the whole-body radiation reduces circulating, highly radiosensitive malignant T cells in the dermal vessels more efficiently than topical therapy or phototherapy. With increasing experience, the treatment becomes more and more tolerable with less complications observed. A very well tolerated radiation regime with a target dose of 36 Gy was presented in 2009 .
The whole-body radiation is especially indicated for early stages of MF as described by the EORTC in 2002  but it also has its place in the treatment of late stages. A large study with 68 patients in stage I and II was performed in 2009 revealing a complete remission rate of 97 %, but with half of the patients suffering from relapse within 1.8 years on average. 31 % of the patients were free from relapse even after 10 years .
In progressive stages, whole body radiation can be performed as a palliative treatment option. The complete remission rate is generally lower in patients with stage IIB to IV but still was 50 % in a recent study. In 16 of the 18 patients (89 %) symptoms were alleviated and one quarter of the patients did not show any progression of disease one year later .
Whole-body radiation is also helpful in SS. In a case series with 4 patients, all achieved complete remission of skin lesions and an improvement of tumor burden in the peripheral blood following whole-body radiation .
Long-term side effects include alopecia, anhidrosis, xerosis and skin atrophy . Systemic side effects are unusual due to the superficial mode of action.
A patient with MF in the USA was described who was stable after three years therapy with PUVA and oral bexarotene. Due to a national delivery problem for psoralens, treatment was continued with UVB-311 nm resulting in a massive flare. Treatment was switched to a 308 nm- excimer laser, which lead to successful healing of all plaques .
In case of widespread skin involvement, inadequate response to skin-directed therapies, progressive disease or in order to reduce the phototherapy dose, systemic therapies are indicated, mainly consisting of immune modulators such as IFN-α or retinoids. Monoclonal antibodies seem to have a positive effect in erythrodermal types of CTCL. Chemotherapy and allogeneic stem cell transplantation are generally reserved for refractory and rapidly progressive types of skin lymphomas. Very often therapy schedules are graduated and include a combination of different topical and systemic treatment options.
Interferon-alpha: IFN-α increases the body's own Th1-cell-mediated immune response against tumor lymphocytes and shows good benefit in monotherapy in all stages of CTCL. IFN-α-2a is approved for the treatment of CTCL and is available under the name Roferon®. Although both the optimal doses as well as the duration of therapy remain uncertain, usually IFN-α is recommended for long-term treatment, starting with an initial dose of 1–3 million units three times a week, being increased up to 9–12 million units daily, depending on tolerability . After reaching remission, therapy should be continued for at least three months before starting to reduce the dose continuously over another 6–12 months. Combination with PUVA increases the response rate reaching complete remission rates of 70 % . Decreased effects due to dose-dependent neutralizing antibodies are found less often when used in combination with other therapies. In cases of MF/SS being refractory to IFN-α, treatment with IFN-γ may represent a promising alternative .
Retinoids: Over decades retinoids have been used in the treatment of MF. Case reports have been published showing successful use of alitretinoin (Toctino®) in patients with MF/SS in off-label use, combined with different UV therapies [45, 46]. No controlled studies are available.
Bexarotene (Targretin®), a ligand of the retinoid-x-receptor, is approved for the treatment of CTCL and has effects on cell differentiation and apoptosis influencing cell migration of malignant T cells in the skin via down-regulation of CCR4 and e-selectin expression . It is generally administered orally but it can also be applied topically—an uncommon approach in Germany. Bexarotene has shown good benefit in early as well as in progressive stages for both MF and SS. Response rates for early stage MF are between 37 % and 47 % in monotherapy and 67 % when combined with PUVA. In late stages the combination of bexarotene with IFN-α, extracorporeal photopheresis (ECP) or UV-light therapy seems to have no advantage compared to monotherapy . Expression of CD30 seems to be a prognostic marker for the therapeutic response. Mild side effects are very frequent; hyperlipidemia and hypothyroidism are found in almost all cases. Both side effects can be treated easily with fenofibrate and thyroxine and do not necessarily require discontinuation of therapy. Evaluation of the data obtained from the Tarado phase IV study in Germany performed by the „Arbeitsgemeinschaft Dermatologische Onkologie“ (ADO), prospectively examining the efficacy and side effect profile of bexarotene in monotherapy in 200 patients, showed a response rate for MF and SS of 37 % and 33 % . Moreover, in September the BexaCOS study was started, in which the maintenance therapy with bexarotene is to be investigated.
Extracorporeal photopheresis: ECP is effective in erythrodermic types of MF and SS and can be combined with IFN-α or bexarotene for synergistic effects. ECP extracts circulating mononuclear cells from the patient's blood, which are then mixed with 8-methoxypsoralen (Uvadex®) before being irradiated with UVA light. The treated cells are then re-infused. Although in use for many years, the exact mode of action still is not fully understood. It appears that by induction of apoptosis in the tumor cells, tumor antigens are released which activate a systemic anti-tumor immune response . ECP is performed over at least 6 months with treatment sessions on two consecutive days every 2–4 weeks. For further details see the published guidelines from January 2014 .
Monoclonal antibodies: Alemtuzumab is a CD52-antibody expressed on both mature, mainly CD4-positive T cells and mature B cells. It has proven to be beneficial in early and progressive stages of MF. Recently, a case series of 19 patients with erythrodermic MF or SS has been published. The response rate was high with 84 % and a complete remission rate of 47 % . In another study observing a similar patient collective the response rate was 38 % . When administered in high doses, alemtuzumab caused severe infections, above all fungal and viral infections as well as fungal sepsis. The introduction of an infection prophylaxis could already reduce these risks. A lower dose also seems to be effective with less side effects being observed . Unfortunately, Lemtrada® can only be used off-label. It was removed from the market for this indication since its use for the treatment of multiple sclerosis seemed to be more lucrative.
Zanolimumab is a monoclonal CD4-antibody, interrupting the T-cell activation, thus leading to a reduction of T-cells. Its efficacy in MF has been shown in two separate phase II studies. The European Medicines Agency (EMA) classified HuMax-CD4® as orphan drug for the treatment of peripheral T-cell lymphomas. A phase III study was not completed. The response rate observed in the present studies was 56 % for therapy refractory MF. In one patient with therapy refractory SS who did not respond to alemtuzumab, zanolimumab achieved an almost complete remission after 4 months . Side effects include infections and dermatitis .
A new substance mogamulizumab was developed as a monoclonal anti-CCR4 antibody with a defucosylated Fc-region increasing the antibody-dependant cellular cytotoxicity. In-vitro investigations and In-vivo studies in the mouse model revealed that mogamulizumab has a strong anti-tumor effect on T-cell lymphoma cell lines and tumor cells from patients. A Japanese phase II study published in March 2014 that included 37 patients (but only 8 of them with CTCL) revealed a response rate of 38 % for the CTCL patients and a progression-free time of three months for all patients. The most common side effects in this study included hematological changes, fever and different skin diseases but all of them were treatable and reversible . The substance was approved in Japan in the year 2012 for the treatment of adult T-cell leukemia under the name Poteligeo®.
Histone deacetylase inhibitors (HDI): Histone deacetylase regulates gene expression via epigenetic mechanisms. The increased histone deacetylase activity in tumor cells can be suppressed by these new targeted inhibitors. Its principle of efficacy was proven in cell culture models. HDI can cause cell death of tumor cell lines.
Vorinostat (Zolinza®) is an oral HDI that in patients with MF shows response rates of 29.7 % to 34 % (stage IB to IVA). Several side effects have been observed, including diarrhea, nausea, fatigue and ECG changes . The substance has been approved by the FDA for the treatment of CTCL, within the EU it has an orphan drug designation for the therapy of multiple myeloma. In the meantime the pharmaceutical company has withdrawn the approval application at the EMA for the treatment of cutaneous T-cell lymphomas due to a negative benefit/risk assessment.
Another drug of this group is romidepsin, which so far has been examined within two phase II studies for CTCL [59, 60]. Response rates of 34–38 % were found in patients with therapy refractory CTCL. Improvement of symptoms, especially of pruritus, was observed in 43 % . Side effects are frequent and often include thrombopenia and granulocytopenia as well as flu-like symptoms. Romidepsin (Istodax®) has been approved by the FDA in November 2009, the application for approval in the EU however, was rejected by the EMA in 2012.
Denileukin diftitox: Denileukin diftitox (Ontak®) is a toxic fusion protein (IL-2 linked to diphtheria toxin), targeting the IL-2 receptor (CD25), which is expressed on malignant T cells. The cytotoxic drug is approved in the USA and selectively affects cells being positive for IL-2, which include tumor cells but also other activated T cells, B cells and NK cells. Several phase III studies have been performed and recently data of three studies were published with 263 patients altogether versus 44 patients treated with placebo. The response rate was 38 %. Treatment was more efficient in early than in progressive stages. This study also revealed a positive effect for patients with a low expression of CD25 in the skin lesions . 89 % of the patients suffered from side effects, some of them being severe; problems included fever, arthralgia, headache, myalgia, gastrointestinal symptoms, lymphocytopenia with infections and capillary leak syndrome. These problems plus the relative lack of effectiveness explain why denileukin diftitox, did not be established as standard therapy for MF. Moreover, since 2011, this drug was taken off the market.
Some other substances (for example lenalidomide (thalidomide analog), toll-like-receptor agonists, bortezomib (proteasome inhibitor), brentuximab vedotin (directed against CD30), anti-PD-1 (programmed cell death protein) antibodies, phosphoinositide-3-kinase-inhibitors or protein kinase C inhibitors) are under development and are currently being tested for the treatment primarily of refractory stages of CTCL.
Anti-folic acid drugs: Anti-folic acid agents mediate their effects via the inhibition of the dihydrofolate reductase, inhibiting mitosis and DNA synthesis. Methotrexate and a newer substance pralatrexate are administered mainly for erythrodermic types of CTCL and show response rates depending on dose and tumor stage between 33 % and 82 %. Gastrointestinal, hematological and hepatic side effects are rarely observed when administered in a usual dose of 10–30 mg methotrexate per week . However, a cumulative life dose of 2 g and more increases the risk for liver cirrhosis. Methotrexate is approved in Germany for the treatment of non-Hodgkin lymphoma. Pralatrexate (Folotyn®) was declared as orphan drug for the treatment of peripheral T-cell lymphomas in 2007. The EMA did not recommend approval in 2012 due to a negative benefit/risk assessment.
Non-pegylated liposomal doxorubicin: Mono-chemotherapy with pegylated liposomal doxorubicin (Caelyx®) is recommended as important second-line therapy for progressive CTCL. It is used off-label. Complete remissions are achieved in 42 % with response rates of 84 %. The effects last on average for 13 months, which is comparatively long. Even in therapy-refractory progressive MF, response rates of up to 56 % can be reached. Since Caelyx® was unavailable for a longer period of time, the efficacy of the non-pegylated liposomal doxorubicin (Myocet®) has been tested as a possible therapeutic alternative. The substance is approved for the treatment of patients with metastatic breast cancer in Germany. The anti-tumor efficacy of non-pegylated liposomal doxorubicin seems to be comparable to that of the pegylated form with significantly reduced cardiac toxicity .
Gemcitabine: Studies reveal response rates of approximately 51–70 % for progressive MF, with complete remission rates in 16 % of the cases. In Germany gemcitabine is used off-label in the treatment of CTCL. Severe hematotoxicity has been described as well as hemolytic uremic syndrome and capillary-leak-syndrome. Moreover, cardiac problems have been observed in one- quarter of the patients; this being the main the reason why gemcitabine is not recommended as first-line treatment in the absence of long-term studies [64, 65].
Poly-chemotherapy regimens with cyclophosphamide, doxorubicin, vincristine and prednisone showed comparable response rates to mono-chemotherapy agents but with higher toxicity.
Hematopoietic stem cell transplantation
Autologous stem cell transplantation in patients with progressive cutaneous T-cell lymphomas is frustrating and associated with high rates of relapse. Allogeneic stem cell transplantation in contrast may lead via the graft-versus-lymphoma effect to long-lasting remissions in patients with MF. The complete remission rate lasting for up to six years was 58 % [14, 66]. Since the treatment-related mortality is approximately 30 %, the non-myeloablative (mini) allogeneic stem cell transplantation can represent a possible therapeutic alternative, achieving a graft-versus-lymphoma effect with reduced therapeutic toxicity .
Despite guidelines and development of new and promising therapeutic approaches, the treatment of MF and SS remains individual. The variety of clinical features makes a stratified approach difficult. Very often the selection and sequence of therapy reflects the source of training and experience of the physician. However, since early stages can be well treated with therapies having few side effects and for progressive stages there is lack of consistent treatment recommendations, this individual therapeutic approach has no disadvantages for the patient. Cures can only be achieved in exceptional cases. For this reason the aim of any therapy is to achieve remission of both skin and non-cutaneous involvement, as well as to delay or prevent disease progression and to improve quality of life, which very often is restricted due to pruritus and xerosis. Systemic therapeutic approaches are best delivered within clinical studies in order to develop evidence-based therapies for these rare diseases.
Conflict of interest