Management of Refractory Early-Stage Cutaneous T-Cell Lymphoma
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Cutaneous T-cell lymphoma (CTCL) is a heterogeneous group of non-Hodgkin’s lymphomas that manifest primarily in the skin. Mycosis fungoides is recognized as the most common type of CTCL. Patients with early-stage CTCL usually have a benign and chronic disease course. However, although there is a wide array of therapeutic options for early-stage CTCL, not all patients respond to these individual therapies, resulting in refractory cutaneous disease over time. Refractory early-stage CTCL poses an important therapeutic challenge, as one of the principal treatment goals is to keep the disease confined to the skin, thereby preventing disease progression.
Much of the focus of current research has been on the evaluation of already available skin-directed therapies and biologic response modifiers and combination regimens thereof, such as the combination of psoralen and UVA (PUVA) with interferon-α or retinoids. Recent novel developments include oral bexarotene, a retinoid X receptor-selective retinoid that has activity in all stages of CTCL and has been shown to be effective in patients with refractory early-stage disease as well as advanced-stage disease. Likewise, the topical gel formulation of bexarotene has proved to be an important therapeutic option in patients with refractory or relapsed lesions. Oral bexarotene and topical bexarotene have been approved by the US FDA for the treatment of refractory CTCL. Systemic chemotherapy is typically reserved for advanced-stage CTCL and is usually not recommended for early-stage, skin-limited disease. However, recent exploratory studies indicate that low-dose methotrexate may represent an overall well tolerated therapy in a subset of patients with refractory early-stage CTCL, as may pegylated liposomal doxorubicin, which is currently being investigated in this specific clinical setting. Another recently FDA-approved therapy is the interleukin-2 fusion toxin denileukin diftitox, which is now well established to play a role in the treatment of refractory CTCL, including early-stage extensive plaque disease. The value of other agents, such as topical tazarotene, topical methotrexate, and topical imiquimod, and of novel immunomodulatory approaches including monoclonal antibodies, still needs to be assessed for refractory early-stage CTCL.
KeywordsRetinoid Imiquimod Mycosis Fungoides Etretinate Tazarotene
Primary cutaneous T-cell lymphomas (CTCL) represent a heterogeneous group of non-Hodgkin’s lymphomas, defined as clonal proliferation of skin-infiltrating T lymphocytes primarily presenting in the cutaneous compartment. Primary cutaneous lymphomas have to date been classified according to systems such as the European Organization for Research and Treatment of Cancer (EORTC) and WHO classifications. However, a new system, called the WHO-EORTC classification, has now been developed. This new classification system distinguishes between CTCL with indolent clinical behavior (including mycosis fungoides, mycosis fungoides variants and subtypes [folliculotropic mycosis fungoides, pagetoid reticulosis, granulomatous slack skin]), primary cutaneous CD30-positive lymphoproliferative disorders (primary cutaneous anaplastic large cell lymphoma, lymphomatoid papulosis), and CTCL with aggressive clinical behavior (including Sezary syndrome, nasal-type primary cutaneous natural killer/T-cell lymphoma, unspecified primary cutaneous peripheral T-cell lymphoma and subtypes).
Mycosis fungoides is recognized as the most common type of CTCL and accounts for almost 50% of all primary cutaneous lymphomas, according to data from 1905 patients with a primary CTCL registered by the Dutch and Austrian Cutaneous Lymphoma Group between 1986 and 2002. Mycosis fungoides is a low-grade lymphoma caused by an epidermotropic infiltrate of atypical, cerebriform CD4+ helper T cell clones that may form cutaneous patches, plaques, and tumors. The pathogenesis of mycosis fungoides has not been elucidated in detail. It is not yet clear whether the disorder represents a malignant neoplastic process de novo or a reaction of activated T cells to foreign (viral, superantigen) or autoantigens that ultimately results in overt malignant lymphoma.[6,7] The accumulation of T lymphocytes in the skin seems to occur due to a lack of apoptosis rather than an increase in proliferation. Moreover, there is growing evidence for a role of the tumor microenvironment in the growth maintenance of mycosis fungoides. Mycosis fungoides represents the most frequent clinical subset of refractory early-stage CTCL, and in this review the term ‘CTCL’ refers to mycosis fungoides unless otherwise stated.
Several large studies have assessed the prognosis, disease course, and long-term survival of patients with CTCL. In general, the prognosis of CTCL has been shown to vary with the clinical stage at the time of diagnosis. Zackheim et al. reported the long-term survival of 489 patients with CTCL by skin (T) stage relative to an age-, sex-, and race-matched population. Ten-year survival was similar to that of the control population in patients with T1 limited patch/plaque-stage disease (clinical stage IA), 67.4% in patients with T2 generalized patch/plaque-stage disease, 39.2% in those with T3 tumor-stage disease, and 41.0% in those with T4 erythrodermic-stage disease. Other studies have shown that the risk of disease progression increases with advanced-stage disease. A multicenter retrospective cohort analysis by the Dutch Cutaneous Lymphoma Group studied the disease course of 309 patients with mycosis fungoides. The risk of disease progression at 5 and 10 years gradually increased from 4% to 10% in patients with T1 skin-stage disease, from 21% to 39% in those with T2 skin-stage disease, from 32% to 60% in those with T3 skin-stage disease, and was as high as 70% in patients with T4 skin-stage disease. Another study demonstrated that approximately 24% of patients with T2 skin-stage mycosis fungoides experienced disease progression, and that these patients exhibited in general a lower complete response rate to initial therapy than other patients.
Collectively, these data reflect the overall refractoriness of CTCL to therapy, which is first seen in the early stages of the disease and becomes increasingly common in the advanced and late stages. In view of this, refractory early-stage CTCL poses an important therapeutic challenge because one of the principal treatment goals in the early stages — apart from induction of complete remission, reduction of tumor burden, and disease-related symptoms — is to prevent disease progression. As long as the disease can be kept confined to the skin, the outlook for long-term survival remains very favorable. Although there are a number of treatment modalities for early-stage mycosis fungoides, not all patients respond to these individual therapies, and cutaneous disease often becomes refractory to specific therapies over time. Thus, there is still a need for alternative treatment modalities, especially for these refractory cases.
This article discusses current standard and investigational treatment options for early-stage CTCL (as identified by a comprehensive literature search of Medline) with a focus on the management of refractory early-stage CTCL and on drug therapy. It is important to note that the term ‘refractory’ in this review refers to disease progression after one therapy.
2. Topical Therapies
Patients with early-stage patch/plaque mycosis fungoides usually have a benign and chronic disease course as long as the disease remains confined to the skin. In a randomized study comparing various local treatment approaches according to clinical stage, including phototherapy and chlormethine (mechlorethamine, nitrogen mustard) with more aggressive combined electron beam radiation and chemotherapy for early mycosis fungoides, the combined regimen was associated with more severe adverse effects and conferred no benefit in terms of disease-free or overall survival at a median follow-up of 75 months. Therefore, a relatively mild, stage-adapted therapy is recommended for mycosis fungoides and this recommendation should, in our opinion, also apply to the clinical scenario of recurrent or refractory lesions.
2.1 Topical Corticosteroids
Corticosteroids inhibit intracellular adhesion and lymphocyte binding to the endothelium and induce apoptosis of lymphoid cells. Topical corticosteroids have demonstrated efficacy in the treatment of early patch/plaque-stage CTCL.[20,21] A retrospective study of 79 patients with early-stage mycosis fungoides demonstrated that 63% of 51 patients with T1-stage disease (<10% of skin involved) achieved complete remission, with a total response rate of 94%. Of 28 patients with T2-stage disease (>10% of skin involved), 25% achieved complete remission, with a total response rate of 82%. The same authors recently reported that since the 1998 study, approximately 200 patients have been treated with high-potency class I topical corticosteroids. The overall response rates have continued to be >90% in stage T1 patients and >80% in stage T2 patients.
Although topical corticosteroids are generally well tolerated, their potential adverse effects — especially with more prolonged periods of treatment — include irritant dermatitis, purpura, cutaneous atrophy, and striae. In addition, percutaneous absorption of corticosteroids can temporarily depress the hypothalamic-pituitary-adrenal axis, resulting in adrenal insufficiency. However, this has not been observed in the 200 CTCL patients in the above-mentioned study.
While no studies to date have investigated the use of topical corticosteroids in the treatment of refractory early-stage CTCL, it has been suggested that a further trial of topical therapy with corticosteroids should be considered in patients who have not previously responded to this therapeutic modality, particularly in view of the lower incidence of adverse effects and ease of application of this form of therapy compared with other treatment options. It should also be mentioned that treatment with topical corticosteroids is the most inexpensive therapy for early mycosis fungoides.
While corticosteroids qualify for primary therapy in stage IA disease, where complete remission has been observed in up to 60%, in the more advanced stages (clinical stage IB) or refractory cases, they should be applied adjuvantly.[1,22]
2.2 Topical Chemotherapy
2.2.1 Chlormethine (Mechlorethamine, Nitrogen Mustard)
Chlormethine is an alkylating agent with proven cytotoxic and immunogenic effects that is a commonly used first-line therapy in the treatment of patch- and plaque-stage CTCL.[12,23,24] It can be compounded in an ointment or in an aqueous base at a concentration of 10–20 mg/dL. In a recent retrospective study by Kim et al. of 203 patients with mycosis fungoides who received topical chlormethine as initial therapy, 93% of those with T1 disease achieved a response, with a complete response rate of 65%, while in patients with T2 disease the overall response and complete response rates were 72% and 34%, respectively. A similar clinical response was seen in patients with clinical stage IIA disease. Importantly, the freedom-from-progression rates (no progression to higher T classification or worse clinical stage) were 92% and 85% at 5 and 10 years, respectively, in patients with T1 disease, and 83% at both 5 and 10 years in patients with T2 disease. The most commonly reported adverse effects were contact hypersensitivity reactions (i.e. toxic or allergic contact dermatitis), which were reported in <10% of patients treated with topical chlormethine in an ointment preparation. The risk of developing hypersensitivity reactions can thus be minimized when chlormethine is compounded into an ointment form. Other potential adverse effects include hyperpigmentation, erythema, telangiectasias, and an increased risk of secondary cutaneous carcinogenesis. However, in the study by Kim et al., only 4% of the 203 patients developed secondary cutaneous malignancies, none of which was attributable to topical chlormethine monotherapy.
2.2.2 Carmustine (Bischlorethylnitrosurea)
Topical carmustine (bischlorethylnitrosurea), another alkylating agent, is a nitrosurea compound that is also used to treat early-stage CTCL, though less often than chlormethine. Similar to the latter, it is available as an aqueous solution or ointment at a concentration of 10–20 mg/dL. Topical carmustine has been associated with complete response rates of 86% in patients with T1 skin-stage disease and 47% in those with T2 skin-stage disease. Adverse effects include erythema following topical application of carmustine, which may subside within a few weeks or may also be followed by severe telangiectasia that can persist for a few months or even for years before gradually involuting. In a recent study, myelosuppression with mild leukopenia occurred in 3.7% of 188 patients using carmustine solution. Irritant or allergic dermatitis occurred in <10% of patients.
2.2.3 Role of Topical Chemotherapy
Collectively, both of the locally applied cytostatic agents chlormethine and carmustine are associated with noticeable response rates in early-stage CTCL and can therefore be considered as first-line therapies.[22,27] However, use of these drugs may be limited by their complex administration procedures (e.g. carmustine is a carcinogen and exposure to its vapors should be avoided during preparation of the solution; application of the solution should be made with plastic gloves; particular care should be used when treating the face), and considerable adverse effects, which consist mainly of hypersensitivity reactions following treatment with both agents. Also, no US FDA-approved chlormethine or carmustine formulations are currently readily available.
Although no studies have specifically addressed the efficacy of topical chemotherapy in the management of refractory early-stage CTCL, it has been shown that patients who relapsed after initial therapy with chlormethine responded as well to subsequent treatments with chlormethine as they did to initial treatment.[12,25]
2.3 Topical Retinoids
Retinoids belong to the steroid hormone family and are recognized as regulators of many physiological processes such as embryonic development, vision, reproduction, bone formation, metabolism, hematopoiesis, differentiation, proliferation, and apoptosis. The biologic effects of retinoids are mediated by two distinct families of intracellular receptors: the retinoid acid receptor (RAR) and the retinoid X receptor (RXR), both of which are ligand-activated, DNA-binding, trans-acting, transcription-modulating proteins. Retinoids exert some of their effects by binding to RARs or RXRs in the nuclei, which in turn bind as heterodimers to particular DNA sequences, the so-called retinoic acid response elements. RXRs can also form homodimers or heterodimerize with other nuclear receptors, e.g. thyroid hormone receptors and the vitamin D receptor. Together, RXRs and RARs play a central role in hormone signaling by transcriptional regulation of a wide range of target genes, which again allows them to influence multiple signaling pathways that are critical for proliferiation, and apoptosis. The antitumoral effects of retinoids depend on modulation of growth and differentiation in a variety of human tumors, specifically inhibition of cell growth by arresting cells in the G1-phase or inducing apoptosis. In addition, retinoids also exert immunomodulatory effects, e.g. by upregulation of antigen presentation by Langerhans cells and surface expression of HLA-DR and CD11c, a β-2 integrin critically involved in T-cell activation.
While various retinoids derived from retinoic acid have been used for the treatment of CTCL, bexarotene, a synthetic retinoid, is the first highly selective RXR retinoid (rexinoid) to be studied in humans. Bexarotene induces in vitro apoptosis in CTCL lines and is available for oral and topical administration. Because superficial malignancies are easily accessible by topical treatment modalities, it was assumed that topical application of retinoids may be an effective approach in early CTCL stages. Bexarotene as topical gel has been evaluated in phase I, II, and III studies. In a dose-ranging phase I–II trial of bexarotene administered in concentrations from 0.01% to 1.0% to 67 patients with early-stage CTCL (TNM stages IA, IB and IIA), the complete and partial response rates were 21% and 42%, respectively. There was a dose-response effect, with greater efficacy seen at higher concentrations, greater frequency of application, and greater duration of use. Most patients tolerated topical bexarotene at a concentration of 1% applied twice daily for routine use. The median response duration from the start of therapy was 99 weeks. Notably, 55 patients had received one to six therapies before entering this study, with 24 patients being recorded as ‘refractory’ to corticosteroids, 15 to chlormethine, 14 to UVB or psoralen plus UVA (PUVA), four to radiation, and one to carmustine. Patients who had not previously received CTCL therapy had a higher response rate (75%) than patients who had previously received topical or radiation therapies (67%). However, of 42 responding patients (63%), 22 were refractory or intolerant to between one and three previous therapies. Likewise, of 14 patients achieving a complete response (21%), ten had received previous therapies that were unsatisfactory because of incomplete response, intolerance, or relapse. In a recent multicenter, multinational, open-label, phase III trial, 50 patients with refractory stage IA, IB, or IIA CTCL applied 1% bexarotene gel with increasing frequency up to four times daily. The overall response rate in this study was 44% according to the physician’s global assessment of clinical condition. In both studies, bexarotene gel had an overall tolerable safety profile, with adverse events generally being restricted to the site of application. Importantly, some patients in these trials responded to bexarotene gel whether or not they had undergone previous therapies for refractory CTCL and even if they were resistant to previously used agents. Adverse effects deemed at least possibly related to therapy were rash/irritation, pruritus, pain, and headache.[30,31] Most of these adverse effects are temporary and easily managed by dose modification, decreasing the frequency of application, or short-term addition of topical corticosteroids.
Bexarotene gel can be considered a therapeutic alternative in early-stage disease. Moreover, the risk-benefit profile may support this agent as an important therapeutic option in patients with refractory or relapsed lesions. One percent bexarotene gel is approved by the FDA for the topical treatment of cutaneous lesions in patients with CTCL (stages IA and IB) who have refractory or persistent disease after other therapies or who have not tolerated other therapies.
Tazarotene, a synthetic RAR-β, γ-selective retinoid, is widely used for the treatment of psoriasis and acne. Recently, it was suggested that tazarotene exerts its molecular action by normalization of epidermal differentiation and reduction of cytokines and adhesion molecules found both in psoriasis and in mycosis fungoides lesions. A recent open-label pilot study evaluated the efficacy and tolerability of topical use of 0.1% tazarotene in 20 patients with early-stage mycosis fungoides (clinical stage IA and IB) lesions that were either stable or refractory to therapy for at least 8 weeks. One percent tazarotene gel was applied to mycosis fungoides lesions once daily for 24 weeks. The overall response rate was 58%, with 35% of refractory index lesions clearing completely. Adverse effects consisted mainly of local skin irritations (erythema, burning, and peeling) that could be controlled by addition of local corticosteroids but were dose-limiting in some cases. Interestingly, eight patients who had a partial response on the basis of total body surface area improvement applied a midpotency topical corticosteroid for amelioration of the tazarotene-induced irritation, and five of those eight patients had been refractory to topical corticosteroids immediately before study entry. Thus, tazarotene cleared mycosis fungoides lesions that were refractory to topical corticosteroids, application of a topical corticosteroid in combination with tazarotene helped to alleviate local irritation, and use of the two agents together may have had synergistic effects.
Tazarotene may be an effective adjuvant topical treatment for refractory early-stage mycosis fungoides lesions, although larger placebo-controlled studies and direct comparative studies with topical bexarotene are required.
2.4 Other Topical Therapies
Two other experimental topical agents, topical methotrexate and imiquimod, have recently been reported to have potential efficacy in CTCL.
Methotrexate is a common component of systemic chemotherapy regimens for the treatment of CTCL. However, its use may be limited by acute toxicities. Thus, application of topical forms of methotrexate that would not involve the risk of systemic adverse effects has been advocated. In a recent phase I–II pilot study, a topical gel formulation combining methotrexate and laurocapram (a lipophilic vehicle enabling methotrexate to penetrate epidermal barriers) was applied once daily to ten patients with histologically confirmed stage IA or IB mycosis fungoides. At the end of the treatment phase (week 24), seven of nine patients demonstrated a slight-to-moderate response to therapy with methotrexate-laurocapram. Adverse effects consisted of skin reactions of mild severity. Based on these findings, it was proposed that topical methotrexate might represent a new therapeutic option for patients with mycosis fungoides.
Imiquimod is a topical immunomodulatory agent approved for the treatment of external genital warts. By binding to Toll-like receptors 7 and 8, it induces T helper cell (Th)-1 cytokines, including interferon-α. In view of these findings, a PUVA- and retinoid-resistant plaque on the face of a patient with mycosis fungoides otherwise responsive to PUVA therapy combined with low-dose retinoids was treated with 5% imiquimod cream daily for 2 weeks. Local imiquimod treatment resulted in complete clearance of the plaque followed by complete remission lasting at least 12 months. Likewise, an open-label pilot study evaluating 5% imiquimod cream in six patients with stage IA to IIB mycosis fungoides showed that this agent was well tolerated and induced a clinical response rate of 50% in these patients.
2.4.3 Role of Methotrexate and Imiquimod
Clearly, more research needs to be done to determine whether topical methotrexate and imiquimod will ultimately play a role in the treatment of CTCL and, finally, whether both may represent new options for the management of refractory early-stage disease.
Phototherapy and photochemotherapy have been utilized for decades in the treatment of CTCL. As this very important topic has been covered by several recent reviews[36, 37, 38] and, moreover, as the present review focuses on drug therapy, the different phototherapeutic modalities will be described only briefly here. However, patch/plaque disease that is refractory to photo(chemo)therapies often responds to the addition of a biologic response modifier such as interferon-α or bexarotene. These combination regimens, which are relevant to the management of refractory early-stage CTCL, are reviewed in section 8.
3.1 UVB Phototherapy
UVB was the first artificial UV light source to be employed in the management of CTCL, specifically mycosis fungoides. While the exact mechanism of action of UVB in the treatment of CTCL remains unclear to date, evidence has accumulated that UVB-induced T-cell apoptosis may be the reason for its efficacy.
Several clinical studies of broadband UVB therapy (with a wavelength of 290–320nm) in early-stage CTCL demonstrated up to 74% complete remission rates in patients with stage I disease.[12,23,40, 41, 42] Notably, patients with patch disease responded significantly better, suggesting that UVB does not penetrate deeply enough to treat infiltrates in the deep dermis. Although UVB is a relatively well tolerated treatment, possible adverse effects include phototoxicity, actinic skin damage, and an increased incidence of other skin cancers.
Narrow-band UVB with a wavelength of 311–312nm has also recently been used to treat early-stage CTCL. Complete remission rates of up to 83% have been reported in patients with patch-stage CTCL.[43,44] In a recent study involving 21 patients (mycosis fungoides stage IA and IB) treated with narrow-band UVB, the complete remission rate was 81%, with a mean relapse-free interval of 24.5 months. One limitation of narrow-band UVB is the shorter treatment intervals (<10 days) required to prevent phototoxicity with its long-term risks of photoaging and photo-carcinogenesis, although there is evidence that narrow-band UVB may be less carcinogenic than broad-band UVB.
3.2 Psoralen Plus UVA Photochemotherapy (PUVA)
Photochemotherapy with PUVA is an accepted first-line treatment for early-stage CTCL. Psoralen (5-methoxypsoralen), a photosensitizing substance, is administered orally, followed by exposure of the skin to UVA. The proposed mechanism of this therapy involves the formation of DNA crosslinks in cutaneous T-cells by UVA-activated psoralen, which may result in mitotic inhibition and, finally, impairment of T-cell survival at the tissue level.[12,36] In an analysis of 82 patients with mycosis fungoides (83% with stage IA or IB) treated with PUVA, the overall response rate was 95%. Most responses are seen in clinical stage IA to IIA CTCL, including both patch and plaque disease. The duration of disease-free survival is usually long in these early stages, with a mean of 43 months (3.6 years) reported in one study. There are a number of potential adverse effects of UVA, including increased risk of developing non-melanoma skin cancer, melanoma, benign pigmentary lesions such as lentigines, hyperpigmentation or tanning and, less frequently, vitiligo-like localized leukoderma and leukotrichia. Adverse effects related to systemic psoralen are nausea, vomiting, and prolonged ocular and cutaneous photosensitivity. The latter can be avoided by administering topical PUVA, involving either the application of a topical formulation of psoralen to the affected skin areas or immersion in a psoralen bath, followed by UVA radiation. However, the efficacy of topical PUVA in mycosis fungoides treatment is so far not sufficiently established.
While it is clear that monotherapy with PUVA is beneficial for early-stage mycosis fungoides, its efficacy can be further improved if it is used in conjunction with other treatment modalities such as interferon-α or retinoids. Some of these combination regimens have been demonstrated to be more effective than PUVA alone, in that complete remission was observed in patients with previously refractory CTCL (see section 8.1 and section 8.2).
3.3 Photodynamic Therapy
Photodynamic therapy using topically applied 5-aminolevulinic acid followed by exposure to 630 ± 15nm wavelength light was recently reported to be effective in CTCL patients with limited patch/plaque disease refractory to other forms of skin-directed therapy such as topical corticosteroids, topical chemotherapy, or UVA/UVB phototherapy.[48,49] However, while photodynamic therapy with 5-aminolevulinic acid may be a useful addition to the therapeutic options for individual refractory patches/plaques in early-stage CTCL, further studies are required to define optimal treatment protocols.
3.4 Extracorporeal Photochemotherapy
Conceptually derived from PUVA therapy, extracorporeal photochemotherapy involves the extracorporeal exposure of peripheral blood mononuclear cells to photoactivated 8-methoxypsoralen and their subsequent return to the patient. It has been demonstrated that light-activated psoralen causes apoptosis of the extracorporeally treated cells. Moreover, the immune response of the host is mounted against these damaged pathogenic T-cell clones upon reinfusion of the photoirradiated blood. Since the introduction of extracorporeal photochemotherapy, numerous studies have documented its efficacy, particularly in a specific subset of patients with CTCL. Today, extracorporeal photochemotherapy is considered by most leading authorities to be a first-line treatment, to be used alone or in combination with other therapeutic modalities, for advanced, erythrodermic CTCL (skin-stage T4, clinical stage III). However, use of extracorporeal photochemotherapy in early-stage CTCL remains controversial. In different studies, a total of 25 patients with stage IB CTCL showed an overall response of 64%, and 28% achieved a complete response. Likewise, of 25 patients with stage IIA CTCL, 56% responded and 24% had a complete response. However, it is not known whether these patients had evidence of T-cell clones in gene rearrangement studies of peripheral blood. Therefore, it cannot be concluded that blood involvement is not necessary to achieve a response to extracorporeal photochemotherapy. Also, it was noted that whenever the frequency of extracorporeal photochemotherapy was reduced in a cohort of eight stage IB patients, relapse or progression of the disease was recorded in all cases. Collectively, these observations raise questions about the use of extracorporeal photochemotherapy to treat early-stage CTCL, especially when less expensive and more accessible therapies are available.
4. Total Skin Electron Beam Radiation
As this review focuses on drug therapy, total skin electron beam therapy (TSEB) will be described only briefly in this section. Electron beam radiation is a technically challenging modality involving treatment with low-energy electrons (4–9 MeV) generated from linear accelerators. Electron beam therapy can be used either in a localized fashion for the treatment of single refractory plaques of mycosis fungoides or applied to the entire skin surface (TSEB). Initial response rates tend to be high, with complete remission rates of 96% for stage IA, 56% for stage IB, and 63% for stage IIA disease being reported in a study of 241 CTCL patients treated with TSEB alone. However, relapses are common, especially in patients with stage IB or higher CTCL. In patients with generalized T2-stage disease, the disease-free interval can be prolonged by adjuvant therapy with chlormethine after TSEB remission. Adverse effects from TSEB can be severe and either temporary (such as temporary alopecia, nail dystrophy, swelling of the hands and feet, temporary anhidrosis, and blistering on the fingers and toes) or chronic (such as persistent nail dystrophy, xerosis, telangiectasia, permanent partial alopecia, fingertip anesthesia, and infertility in male patients).
Because a variety of less toxic therapies have similar long-term efficacy to that of TSEB in patients with limited patch/plaque disease (clinical stage IA), TSEB is generally reserved for patients with more extensive involvement. Indeed, in light of its potential toxicity, TSEB should be reserved for the initial therapy of patients with very thickened, infiltrated plaques involving >10% of the body surface area (stage IB, IIA) or for generalized, more superficial patch/plaque disease in the latter clinical stages that is refractory to standard treatment regimens.
TSEB has recently been the subject of a consensus report from the EORTC, the Cutaneous Lymphoma Group, and experts from radiotherapy centers in North America. The aim of this report was to achieve a consensus on acceptable methods and clinical indications for TSEB in the treatment of mycosis fungoides. According to this consensus, the early stages of mycosis fungoides remain the main indications for TSEB, but in other stages of the disease, TSEB has a palliative action and may be part of a combined regimen.
5. Biologic Response Modifiers
In CTCL, there is an imbalance of immune regulation due to increased production of Th2 cytokines such as interleukin (IL)-5, IL-10 and IL-13 by proliferating malignant CD4 cells. Biologic response modifiers including interferons, interleukins, and members of the tumor necrosis factor family target not only the malignant cells (e.g. by direct antiproliferative effects) but can also correct this immune dysregulation in CTCL by supporting a cytotoxic Th1 immune response.[1,55]
Of the three major types of interferons (interferon-α, interferon-β, and interferon-γ), interferon-α has primarily been used for the treatment of CTCL. The rationale for the use of interferon-α has been its well-defined enhancement of cell-mediated cytotoxicity and its antiproliferative effects on a variety of tumor cell lines in vitro. Interferon-α is usually administered subcutaneously at doses of 3–18 × 106 U three times weekly. Although it seems to have efficacy across all stages of CTCL, the response rates to interferon-α tend to be higher in patients with early-stage CTCL, in whom complete remission rates as high as 62.5% have been reported in patients with stage I disease. The adverse effects seen with interferon-α are distinctly either acute or chronic in nature. The rather common acute ‘flu-like’ adverse effects of fever, chills, arthralgias, myalgias, and malaise usually dissipate over the first weeks of treatment and can be easily controlled by pretreatment with acetaminophen (paracetamol) or administration of the drug at bedtime. Chronic constitutional adverse effects include fatigue, anorexia, weight loss, diarrhea, hair loss, depression and, rarely, thyroid dysfunction. Laboratory abnormalities such as leukocytopenia, thrombocytopenia, and elevation of liver function tests are also frequent but generally not dose limiting.
As monotherapy, interferon-α shows less efficacy in heavily treated patients with refractory CTCL than as part of a combination therapy (see section 8.1), and there is also evidence for the development of anti-interferon antibodies, which can induce intolerance and resistance to therapy with this agent. Concurrent therapy with PUVA, however, may reduce the development of neutralizing interferon antibodies. Combined therapies that lower the incidence of interferon antibodies in CTCL may then have synergistic effects. For the treatment of refractory early-stage CTCL, interferon-α should be used in conjunction with either skin-directed therapies (e.g. PUVA) or other biologic response modifiers (see section 8).
Pegylated (polyethylenglycol) interferon-α, which is currently being studied in other diseases as well as CTCL, may prove to be a more active and better tolerated form of interferon.
5.2 Retinoic Acid Receptor Retinoids
Three oral retinoids, isotretinoin, etretinate, and acitretin, work through RARs and have been used in the treatment of CTCL. Cumulative data from studies of isotretinoin and etretinate as monotherapy have yielded estimates of a complete remission rate of 19% and an overall response rate of 58%, with a median response duration ranging from 3 to 13 months. In an effort to increase the response rates in CTCL, RAR retinoids have also been combined with other therapies such as interferon-α or PUVA. Thomsen and coworkers showed that the combination of isotretinoin or etretinate with PUVA achieved response rates equal to those with PUVA alone but had the advantage of lower UVA dosage requirements and prolonged duration of remission. The efficacy of acitretin plus PUVA seems comparable to that of etretinate plus PUVA. The most commonly reported adverse effects of isotretinoin and other RAR retinoids are dryness of the skin and mucous membranes (resulting in cheilitis and conjunctivitis), pruritus, elevation of liver enzyme levels, transient hypertriglyceridemia and hypercholesterolemia, axial osteoarthropathy with bone pain, arthralgias/myalgias, and hair loss. Transient hypertriglyceridemia may rarely lead to acute pancreatitis, which can be prevented by dose reduction or administration of a lipid-lowering agent. It must also be noted that retinoids are potent teratogens.
Mono- or combination therapies with traditional RAR retinoids play an important role in the treatment of CTCL. For the management of refractory early-stage CTCL, however, new agents like bexarotene seem to be more efficient (see section 5.3).
5.3 Retinoid X Receptor Selective Retinoids (Rexinoids)
Bexarotene is the first RXR-selective agonist to be investigated clinically as a treatment for CTCL. In vitro studies have shown that bexarotene at clinically relevant concentrations causes apoptosis of CTCL cell lines with downregulation of its cognate receptor RXR-α, RAR-α, anti-apoptotic protein, and survivin, together with activation of caspase-3.[28,29] As systemic therapy, bexarotene is administered orally, with an optimal dose being 300 mg/m2/day, based on response and safety profile.
Two phase II–III, multicenter, open-label trials of bexarotene have been conducted in early- and late-stage mycosis fungoides patients who were refractory to other therapies. In the early-stage trial involving 58 patients, response rates of 20%, 54%, and 67% were achieved with bexarotene 6.5 mg/m2/day, 300 mg/m2/day, and 650 mg/m2/day, respectively. In the advanced-stage trial, patients receiving bexarotene 300 and 650 mg/m2/day achieved response rates of 45% and 55%, respectively. Overall, the 300 mg/m2/day dose displayed an optimal balance between response and tolerability, with an overall response rate of 48% in the combined group of patients. Importantly, the response rate was identical in both patients who had and those who had not received prior therapy with RAR retinoids.
The most common significant adverse events of bexarotene experienced in these trials were hypertriglyceridemia (82%), hypercholesterolemia (30%), central hypothyroidism (29%), and leukopenia (11%).[28,63,64] Hypertriglyceridemia, which can occur within days of starting therapy with bexarotene, can be successfully managed with concomitant administration of the lipid-lowering agents fenofibrate and an HMG-CoA reductase inhibitor (statin) such as atorvastatin. Gemfibrozil inhibits cytochrome P450 3A4, which metabolizes bexarotene, resulting in increasing blood levels of bexarotene and increased lipid levels. Therefore, this agent should not be used to control bexarotene-induced hypertriglyceridemia. Suppressed thyrotropin secretion results in bexarotene-induced central hypothyroidism, which can be controlled by thyroid hormone replacement therapy. Because thyroid hormone enhances lipid clearance, thyroid supplementation may be helpful in reducing hypertriglyceridemia during bexarotene therapy.
Bexarotene has been shown to be effective in patients with refractory early-stage and advanced-stage CTCL. The FDA has approved bexarotene as an oral therapy for refractory CTCL in all stages. While bexarotene is clearly a useful drug in the management of refractory CTCL, some questions, such as the optimal length of treatment and how best to taper the drug, have yet to be clarified.
5.4 Other Biologic Response Modifiers
A number of other biologic response modifiers, including IL-2, IL-12, and an anti-CD52 monoclonal antibody, have been proposed for the treatment of CTCL.
IL-2 is a cytokine secreted by Th1 cells which has been used in smaller studies of CTCL therapy. It has been recommended that IL-2 be used only in the context of clinical trials, mainly for patients with advanced disease. The role of denileukin diftitox (DAB-IL-2), a novel fusion protein consisting of the receptor-binding domain of IL-2 and diphtheria toxin, is discussed in section 7.
IL-12 is a heterodimeric cytokine that is able to orchestrate a Th1-weighted immune response. Recent observations in a phase I dose escalation trial indicated that IL-12, when administered subcutaneously or intralesionally, had promising local and systemic effects in patients with CTCL. In a phase II trial of IL-12 in CTCL, 23 patients with clinical stage I–IIA disease received IL-12 100 ng/kg twice weekly for 2 weeks followed by 300 ng/kg twice weekly for 24 weeks. The response rate was 43%.
Currently available monoclonal antibodies for the treatment of CTCL identify T-cell antigens, such as CD25 and CD52, that are broadly expressed on different T-cell subtypes. Alemtuzumab is a humanized anti-CD52 antibody that has been reported to have significant activity in advanced-stage mycosis fungoides or Sezary syndrome. Because of serious adverse effects such as infections and cardiotoxicity in the form of arrhythmias and congestive heart failure, alemtuzumab has not been widely used in refractory mycosis fungoides, but studies are under way.
In summary, all of these novel immunomodulatory approaches may offer new possibilities for molecular intervention in patients with CTCL. However, they also carry significant toxicity and their role in treating CTCL, particularly refractory early-stage CTCL, is unclear at present.
Systemic chemotherapy is typically reserved for relapsed or refractory advanced-stage CTCL (clinical stages IIB and III) and for nodal and/or visceral involvement (clinical stages IVA and IVB) and large-cell transformation.[12,23,24,69] While single-agent chemotherapy can be effective, the response rates are generally modest and the duration of the response is usually <6 months.
6.1 Single-Agent Chemotherapy
Among the single-agent chemotherapies, gemcitabine, a novel pyrimidine antimetabolite, has shown effectiveness in the treatment of refractory CTCL. In one trial of 44 patients with either relapsed mycosis fungoides or peripheral T-cell lymphoma, treatment with gemcitabine 1200 mg/m2 on days 1, 8, and 15 of a 28-day cycle resulted in an overall response rate of 70%. Pentostatin, a potent inhibitor of adenosine deaminase, has demonstrated activity in patients with advanced and refractory CTCL.[71,72] A phase II study reported a 41% overall response rate with manageable toxicities for pentostatin in combination with high-dose interferon-α. Fludarabine, another purine analog, has also been used in patients with advanced mycosis fungoides or Sezary syndrome, with an overall response rate of 29%; a higher response rate was observed in patients with Sezary syndrome than in those with mycosis fungoides. When fludarabine was combined with photopheresis, the response rate was significantly higher. In another study, fludarabine was shown to be more effective in advanced/refractory CTCL when combined with low-dose interferon-α.
6.2 Combination Regimens
Although multi-agent regimens such as cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) and cyclophosphamide, vincristine, methotrexate, and prednisone (COMP) may result in higher response rates, overall, no specific regimen has been found to significantly increase survival in CTCL patients. On the other hand, another multi-agent regimen consisting of cyclophosphamide, methotrexate, etoposide, and dexamethasone (CMED) has been reported to be effective in aggressive nasal natural killer/T-cell lymphoma, with an improvement in overall survival.
Systemic chemotherapy weakens an already compromised immune system and can therefore cause significant adverse effects, i.e. myelosuppression, opportunistic infections, sepsis, and death from immunosuppression. Many authors have suggested that in view of the potential toxicities and short duration of response, systemic chemotherapy should not be recommended for patients with early-stage, skin-limited disease. However, recent exploratory studies have identified agents that may play a role in the therapy of refractory CTCL.
6.3 Low-Dose Methotrexate
Systemic low-dose methotrexate has been shown to be particularly effective in patients with erythrodermic mycosis fungoides (skin-stage T4, clinical stage III).[1,78] As methotrexate is a relatively well tolerated and effective chemotherapeutic agent, its use has been suggested for refractory early-stage CTCL. In a recent study, Zackheim et al. treated 69 patients with refractory patch/plaque and tumor-stage mycosis fungoides with methotrexate (median dose approximately 25mg once weekly). Of the 60 patients with stage T2 disease (>10% skin involvement), 12% achieved complete remission and 22% partial remission, giving a total response rate of 33%. Oral mucositis was the most frequent adverse effect (17.4% of all patients), followed by gastrointestinal disturbances, bone marrow depression, minor neurologic symptoms, elevated transaminase levels and, rarely, pneumonitis and drug eruption. In addition, Sarris et al. recently obtained favorable results with the lipophilic antifolate trimetrexate in patients with relapsed T-cell lymphoma.
A subset of patients with refractory early-stage CTCL may respond well to methotrexate, which represents an easily administered and overall well tolerated therapy with a low frequency of major adverse effects compared with other chemotherapeutic agents. Clearly, more studies addressing the use of methotrexate for the treatment of refractory early-stage CTCL are required.
6.4 Pegylated Liposomal Doxorubicin
Pegylated liposomes are stable, long-circulating carriers that render delivery of cytotoxic agents to tumor sites with lower toxicity and greater efficacy than the free drug. Addition of polyethylene glycol to the liposome means the drug can selectively accumulate in the skin, resulting in greater tumor cell uptake compared with normal cell uptake.[69,77] In a pilot study, six patients with relapsing or refractory mycosis fungoides (clinical stage IB or IIB) received pegylated doxorubicin 20 mg/m2 once every 4 weeks. Four patients achieved complete remission and one had a partial response, for an overall response rate of 83%. In another study of ten patients with relapsing or refractory CTCL (of whom five had early-stage disease at clinical stages IB [n = 3] and IIA [n = 2], respectively), liposomal doxorubicin administered at the same dose as in the previously discussed study resulted in complete remission in six patients and a partial response in two patients, with an overall response rate of 80%. The progression-free survival was calculated as 18.2 ± 6.5 months. The most frequent adverse effects were anemia and lymphopenia without the need for supportive treatment or dose reduction. These results were recently updated in 34 patients, of whom 15 (44%) achieved complete remission, with an overall response rate of 88%. The high response rates and the low toxicity associated with pegylated liposomal doxorubicin make this a promising agent for patients with refractory CTCL, and one that is worthy of further investigation in this specific clinical setting.
7. Denileukin Diftitox
Denileukin diftitox is a novel, genetically engineered fusion protein that combines the full-length sequences for the receptorbinding domain of IL-2 and the enzymatically active cytotoxic moiety of diphtheria toxin. This chimeric protein targets lymphoma cells expressing the high-affinity IL-2 receptor (IL-2R) consisting of the α/p55/CD25, β/p75/CD122, and γ/p64/CD132 chains. Upon internalization of denileukin diftitox by endocytosis, the diphtheria toxin is cleaved and exerts its cytotoxic effect by inhibiting protein synthesis, resulting in apoptosis of the target cell. IL-2R expression has been demonstrated in skin biopsies in 50–60% of patients with CTCL.
A phase III trial of denileukin diftitox enrolled 73 patients with stage IB–IVA refractory CTCL. Immunohistochemical expression of CD25 on at least 20% of tumor cells in the skin biopsy was required for entry into the study. All patients were randomized to a low-dose (9 μg/kg/day) or high-dose (18 μg/kg/day) schedule of denileukin diftitox on 5 consecutive days for 21-day cycles. All patients were heavily pretreated, having received three or more prior therapies. The overall response rate was 30%, with 10% having complete remission and 20% having partial responses. Responses were noted in the early and advanced stages, including in ten patients who had refractory early-stage plaque disease (stages IB-IIA). The predominant toxicities associated with administration of denileukin diftitox were fever, arthralgias, headache and, in some patients, a form of hypersensitivity reaction with hypotension, dyspnea, angioedema, pruritus, and a transient rash. Mild vascular or capillary leak syndrome occurred in 25% of patients. Importantly, an improved overall response rate of 60%, with considerably fewer adverse effects, was noted with the use of corticosteroid premedication before therapy with denileukin diftitox.
As it has been postulated that upregulation of IL-2R expression might enhance the efficacy and specificity of IL-2R-directed therapies, several studies have evaluated modulation of IL-2R expression by other agents used for the treatment of CTCL. It has been demonstrated that retinoids, including bexarotene, are capable of increasing p55 and p75 expression in human T-cell leukemia cell lines, thus enhancing their susceptibility to denileukin diftitox. Interestingly, in a very recent phase I trial, 14 patients with relapsed or refractory CTCL were treated with escalating doses of bexarotene (75–300 mg/day) and denileukin diftitox (18 μg/kg/day for 3 days every 21 days). The overall response rate was 67%, with modulation of IL-2R expression observed at a bexarotene dose of ≥150 mg/day. This study demonstrates that the combination of denileukin diftitox and bexarotene is well tolerated and that even low doses of bexarotene are capable of in vivo upregulation of CD25 expression on circulating leukemia cells.
Denileukin diftitox now has a well established role in the treatment of refractory CTCL, including early-stage extensive plaque disease (stages IB and IIA).
8. Combination Therapy
Early-stage CTCL that is refractory to skin-directed therapies may respond to a regimen that combines different therapeutic modalities, i.e. skin-directed therapies such as PUVA combined with biologic response modifiers such as interferon-α or retinoids.
Combining primary skin-targeted therapies with primary systemic approaches is gaining increasing importance, as recent studies have demonstrated the early occurrence of circulating clonal T cells in CTCL, which may again reflect the refractoriness already observed in early stages of the disease. So far, there is a host of possible combinations that have been reported to be effective in CTCL. In a large study of 95 patients with early- and late-stage mycosis fungoides, a combined modality protocol (interferon-α and oral isotretinoin, followed by TSEB and long-term maintenance therapy with topical chlormethine and interferon-α; patients with late-stage disease received additional chemotherapy before TSEB) resulted in higher response rates and disease-free survival than TSEB alone.
In sections 8.1 and 8.2, we focus on regimens that have been used for the treatment of refractory early-stage CTCL.
8.1 PUVA and Interferon-α
Many clinical trials have corroborated that PUVA plus interferon-α represents a highly effective combination that allows the use of lower doses of both therapies. Moreover, this regimen has demonstrated superior results over PUVA alone, in that complete remission was observed in patients who were previously refractory to PUVA therapy.[12,23,36] This is based on reports such as that by Kuzel et al., who reported on the first large series of 39 patients with all stages of mycosis fungoides and Sezary syndrome treated with PUVA photochemotherapy plus systemic interferon-α. Mostow et al. also demonstrated that five patients with stage IA or IB CTCL who were refractory to PUVA alone achieved complete remission with PUVA plus interferon-α. In addition, a study comparing PUVA plus interferon-α with acitretin plus interferon-α in the treatment of patients with early-stage CTCL demonstrated better responses in the group of patients treated with PUVA plus interferon-α, who had complete remission and overall response rates of 70% and 80%, respectively, compared with 38% and 50%, respectively, in the group treated with acitretin plus interferon-α).
8.2 PUVA and Retinoids/Rexinoids
Although the response rates achieved with PUVA plus retinoids do not differ from those achieved with PUVA alone, it has been demonstrated that RAR-selective retinoids (e.g. etretinate and isotretinoin) reduce PUVA dosage requirements and produce longer remissions when used as maintenance therapy. Some authors have also considered this regimen to be particularly effective in the management of refractory or relapsing stage I–II disease. Recently, bexarotene was added to the list of agents that show promise when combined with PUVA therapy. It has been shown previously that bexarotene can be combined safely with several therapeutic modalities such as PUVA, interferon-α, extracorporeal photochemotherapy, and denileukin diftitox, resulting in favorable responses even in patients who were refractory to one agent alone.[28,65] In a recent case report, a patient with long-standing early-stage mycosis fungoides that was refractory to established skin-directed treatment regimens, including PUVA therapy, responded rapidly to therapy with a combination of oral bexarotene and PUVA bath therapy. Likewise, a retrospective analysis of eight patients with CTCL ranging from stage IA to stage IIB, who had failed multiple single-agent treatment modalities, demonstrated complete remission in five patients following low-dose oral bexarotene and PUVA combination therapy. Although these results are anecdotal, prospective studies (e.g. by the EORTC) are under way to expand on the role of combination therapy with PUVA and oral bexarotene in treating patients with refractory CTCL.
9. Treatment Options for Refractory Early-Stage Cutaneous T-Cell Lymphoma by Clinical Stages
In recent years, substantial progress has been made in the treatment of CTCL. While more effective therapies are emerging for early-stage disease, not all patients respond to these individual therapies, and cutaneous disease often becomes refractory. The management of refractory early-stage CTCL poses an important therapeutic challenge, as there are often no or insufficient data determining the suitability and comparing the efficacy of the available therapies in this distinct clinical situation. Among the novel therapies for CTCL is bexarotene, an RXR-selective agonist that has demonstrated efficacy in early refractory CTCL. Other agents that are under investigation for refractory disease include methotrexate and pegylated liposomal doxorubicin, as well as novel immunomodulators such as denileukin diftitox, one of the recent promising additions to the CTCL therapeutic armamentarium. PUVA combined with interferon-α has been proven to be effective in refractory early-stage CTCL, and the combination of PUVA with bexarotene is currently being assessed in clinical trials.
No sources of funding were used to assist in the preparation of this review. The authors have no conflicts of interest that are directly relevant to the content of the review.
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