Therapy options in cutaneous T-cell lymphoma

Review

Therapy options in cutaneous T-cell lymphoma Narin Apisarnthanarax and Madeleine Duvic†

Expert opinion

The treatment of cutaneous T-cell lymphoma (CTCL) is continually evolving, as new and emerging drugs are added to the growing arsenal of CTCL therapy. The availability of newly approved investigational therapies, such as bexarotene, denileukin diftitox (DAB389IL2), monoclonal antibodies and novel chemotherapeutic agents, adds complexity to decisions on the management and treatment of CTCL patients. In formulating a treatment plan, therapeutic options are best approached through consideration of overall clinical staging (stage IA–IVB) and skin staging (T1–T4), which affect prognosis and the characteristics of each individual patient’s disease. This article will present and discuss the optimal therapeutic agents for all clinical stages of CTCL patients, based on currently available and investigational agents.

Early-stage disease

Expert Rev. Anticancer Ther. 1(3), 403–420 (2001)

CONTENTS Prognosis

Late-stage disease

pheresis, therapies have not yet been shown to improve overall survival in the late stages of disease. However, long-term remissions with therapies that palliate the disease manifestations are attainable for most patients.

KEYWORDS: bexarotene, chemotherapy, cutaneous T-cell lymphoma, denileukin diftitox, electron beam therapy, interferon, monoclonal antibodies, mycosis fungoides, photopheresis, phototherapy, retinoids, Sezary syndrome

Cutaneous T-cell lymphomas (CTCLs) are among the extranodal, non-Hodgkin’s lymphomas and are characterized by clonal T-cell malignancies with primary cutaneous manifestations. The classical subsets of CTCL include the more indolent mycosis fungoides (MF), characterized histologically by atypical epidermotropic CD4+ helper T-cell clone infiltrates that may form Pautrier’s microabscesses and Sezary syndrome (SS), the erythrodermic and leukemic variant. CTCLs also include anaplastic large cell lymphoma and rare subsets of cutaneous peripheral T-cell lymphomas, best classified by histology, T-cell markers and clinical presentation. MF is the most common CTCL with an incidence rate of 0.45 per 100,000 person-years [1]. Since other CTCLs are much less common than MF, further discussion of CTCL will focus on MF. While the most recent data disclose a 22% improvement in mortality rates between 1979 and 1991, it is likely that diagnosis of MF in an earlier stage of disease is a major contributing factor. Unfortunately, at this time there is no standard or curative therapy for this disease. Randomized trials have been difficult to accomplish because of the small numbers of patients and their heterogeneity at presentation. With the exception of photo-

Prognosis and survival of the MF variant of CTCL are associated with overall clinical stage at presentation, which is based on the MF Cooperative Group TNM criteria [2]. Generally, stage IA patients have similar survival as agematched controls and stage IB–IVB patients have progressively shorter overall survival (TABLE 1) [3–7]. However, the prognosis of stage IA patients may be affected by the age of disease onset and duration of disease, as the lifespan of young patients may be altered by long-standing refractory disease. Also prognostic, the clinical extent of skin involvement is classified by T-stage. Five-year overall survival rates are 95% for T1-limited patch/plaque stage, 70% for T2-generalized patch/plaque stage and 40% for T3-tumor or T4-erythrodermic stages [3–7]. These survival data reflect the refractoriness of MF to therapy, especially in the advanced and late stages of disease. The other forms of CTCL are staged using the Ann Arbor staging method, which classifies patients

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New & investigational skin-directed therapies New & investigational systemic therapies Summary & conclusions Expert opinion & five-year view Key issues Information resources References

†Author for correspondence

Department of Dermatology, MD Anderson Cancer Center, 1515 Holcombe Boulevard, Box 434, Houston, TX. 77030-4095, USA Tel.: +1 713 745 1113 Fax: +1 713 745 3597 [email protected]

Prognosis

Apisarnthanarax & Duvic

with skin lesions in more than one area as stage IV [8]. However, this staging does not accurately represent overall prognosis in these patients, especially for anaplastic large cell lymphoma patients, who have a favorable prognosis and most often relapse in skin following therapy.

Table 2. Early-stage CTCL treatment options. Stage IA (T1) Less severe:

Topical corticosteroids Topical bexarotene

Expert opinion

Despite the improved response rates of current therapies, relapses of MF are common and few are cured with the exception of some who undergo total body skin electron beam therapy early in the disease course. Successful treatment of MF has yet to translate into improved long-term survival or cures. However, since the disease is indolent in most patients and their prognosis is favorable, therapeutic options should be determined primarily by overall clinical staging and T-stage (TABLE 2,3). Within each clinical stage, consideration must also be given to the degree of disease involvement and nature of the lesions. Stage IA patients should be treated very conservatively as though they have chronic eczema or psoriasis. Stage IB patients with 15% body surface area (BSA) involvement may require different treatment options than patients with 75% BSA involvement. Patch and plaque stage patients require different forms of phototherapy. Likewise, the treatment of stage IIB patients with one tumor differs from those with 30 tumors where local versus total-body electron beam therapy may be the best selection. Consideration must also be given to disease tempo, as rapidly progressive or accelerating disease may warrant more aggressive therapy choices. Since patients with early-stage MF (stage IA–IIA) usually have a benign and chronic course, they may be treated with sequential, conservative therapies applied to local lesions. Patients with advanced disease (stage IIB–IVB) require the addition of systemic therapies, especially biological response modifiers. Although systemic chemotherapy has frequently been selected in the past, it often results in further immunocompromise and may precipitate sepsis, the most common

UVB phototherapy (patch)

More severe:

Topical mechlorethamine PUVA phototherapy (plaque)

Stage IB (T2) Less severe:

Topical corticosteroids Topical bexarotene Topical mechlorethamine UVB phototherapy PUVA phototherapy

More severe:

IFN-α ± other Oral RAR retinoids ± other Oral bexarotene ± other Total-skin electron beam therapy MDACC combined modality

Stage IIA (T1, T2) IFN-α ± other Oral RAR retinoids ± other Oral bexarotene ± other Total-skin electron beam therapy Denileukin diftitox (DAB389-IL2) MDACC combined modality MDACC: MD Anderson Cancer Center; PUVA: Psoralen-ultraviolet A; RAR: Retinoic acid receptor; UVB: Ultraviolet B.

Table 1. Overall clinical staging and survival. Stage

Clinical description

T

N

M

MS (yr)

Stage IA

Limited patch/plaque < 10%

1

0

0

N/A§

Stage IB

Generalized patch/ plaque > 10%

2

0

0

12.8

1-2

1

0

10

Stage IIB Tumors ± adenopathy§§ 3

0-1

0

3.2

Stage III

4

0-1

0

4.6

Stage IVA Histologically + nodes

1-4

2-3

0

2.5

Stage IVB Visceral involvement

1-4

0-3

1

2.5

Stage IIA Patch/plaque + adenopathy§§

Erythroderma ± adenopathy§§

§ Stage IA survival similar to age-matched controls; §§Adenopathy: dermatopathic/reactive, histologically negative lymph nodes

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cause of demise. Novel therapies, such as the recombinant fusion toxin ONTAK (DAB389-IL2) and oral bexarotene, a rexinoid, are also effective in the treatment of late-stage patients and are treatments of choice prior to chemotherapy. Patients who are refractory to initial conventional therapies should receive investigational agents. This review will provide a general treatment guide for MF and discuss therapeutic strategies for the various MF disease stages, based on the most efficacious therapies that are currently available (FIGURE 1). Early-stage disease Stage IA–IIA disease

Patients with stage IA disease, by definition, have skin-limited T1 disease with excellent prognosis. While most stage IA patients will live with unaltered lifespans even with persisting disease, approximately 10% of these patients may progress to

Expert Rev. Anticancer Ther. 1(3), (2001)

CTCL treatment

Table 3. Late-stage CTCL treatment options. Stage IIB (T3) Oral bexarotene Total-skin electron beam therapy Denileukin diftitox (DAB389-IL2) MDACC combined modality Experimental therapies: (gemcitabine)

Stage III (T4) Extracorporeal photopheresis§ Total-skin electron beam thearpy Oral bexarotene Denileukin diftitox (DAB389-IL2) MDACC combined modality Experimental therapies (deoxcycoformycin)

Stage IVA/IVB§§ (T1, T2, T3, T4) Oral bexarotene Denileukin diftitox (DAB389-IL2) Chemotherapy (single- or multiagent) MDACC combined modality Experimental therapies First-choice therapy; §§In addition to T-stage specific therapy MDACC: MD Anderson Cancer Center.

§

more advanced disease [5]. Up to 50% of early patients will have blood involvement detected by sensitive PCR for the Tcell receptor, showing that MF is a blood disease that presents in the skin-homing lymphocyte population [9]. The goal of therapy in this group of patients is to lessen tumor burden to prevent disease progression, to improve cosmesis and to alleviate disease-associated discomfort and pruritus. Patients who have active folliculitis or bright red lesions or erythroderma should be cultured for Staphylococcus colonization in skin and nose. MF patients have a high rate of colonization by Staphylococcus aureus, which is able to produce superantigens driving T-cell proliferation [10]. Chronic oral and topical antibiotics (mupirocin) are often effective in providing partial or complete remissions and are important aspects of disease stabilization for patients at all stages of the disease (TALPUR ET AL., UNPUBLISHED OBSERVATION). Patients with stage IA MF often achieve durable complete or partial remissions using skin-directed therapies. These include sequentially potent topical corticosteroids or retinoids and local phototherapy. Refractory cases – or cases with more extensive disease involvement (approaching 10% body surface area) – may require, topical chemotherapy with mechlorethamine or nitrogen mustard (HN2), full-body ultraviolet B (UVB) phototherapy in


patch-stage patients or psoralen-ultraviolet A (PUVA) phototherapy in plaque-stage patients. Recalcitrant or plaque-stage lesions may also benefit from the addition of topical or systemic retinoids as well as interferon (IFN)-α [3,11]. Other topical agents that are currently under investigation and that may prove of some benefit are topical tazarotene (an RAR selective retinoid), hypericin (St. John’s wort, a photosensitizer) and methotrexate. The failure of conservative topical therapies may necessitate the use of more extensive skin-directed therapies that are usually employed in stage IB disease therapy, such as total-skin electron beam therapy. Stage IB patients have more extensive skin involvement (T2, greater than 10% body surface area) than stage IA patients and consequently require more extensive topical or systemic treatments. Similar to stage IA patients, stage IB patients with less severe patch-stage skin involvement may be treated with topical corticosteroids and topical HN2. Most stage IB patients, however, will require UVB (for patch disease) or PUVA phototherapy in combination with biological response modifiers. Stage IIA patients have reactive adenopathy that is not involved histologically with lymphoma. The adenopathy may resolve with therapy or even with antibiotics and topical steroids. If the adenopathy persists, these patients should be viewed as having the potential for developing more aggressive disease. Thus, these patients should receive systemic, aggressive stage IB therapies and combination therapies, such as PUVA plus IFN-α, total-skin electron beam therapy (TSEB), oral bexarotene or combined modality. At MD Anderson Cancer Center (Houston, TX, USA; MDACC), several stage IIA patients have had durable complete remissions (>3 years) using bexarotene as a single agent (DUVIC, UNPUBLISHED OBSERVATION). The more severe, extensive stage IB–IIA cases require more aggressive therapies, such as TSEB and biological response modifiers, such as IFN-α and oral RAR retinoids, which are most effective in combination with other therapies, such as PUVA. A combined modality protocol utilizing IFN-α, oral isotretinoin, TSEB and topical HN2 has been in use at MDACC for the past 15 years and has demonstrated remarkable success in stage IB patients, with several long-term complete responses (CRs). Another alternative is the new oral retinoid (or rexinoid), bexarotene, which is also very effective when used alone or in combination. Bexarotene therapy does not require iv. lines or catheters, but requires close monitoring of thyroid function and hypertriglyceridemia during therapy. These therapies are discussed in further detail. Topical corticosteroids

Topical corticosteroids (CSs) are the most commonly used initial therapy for early-stage MF and may be very effective. Most patients receive topical CSs before the diagnosis of their disease has been clearly established by pathology. Topical CSs of high potency used with occlusion achieve a 94% overall response rate (OR) with a 63% CR rate in T1 patch stage patients [12]. This effectiveness applies predominantly to patients with patch-stage disease, as topical CSs may not adequately penetrate into the reticular dermis.

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IA (limited patch, plaque)

IB, IIA (generalized patch, plaque)

IIB (tumors)

III (erythroderma)

IVA, IVB (nodal/visceral involvement)

Topical corticosteroids

Photopheresis

Bexarotene gel

Therapy failures

Nitrogen mustard UVB PUVA PUVA + IFN/other Electron beam

Oral bexarotene

Denileukin diftitox

Chemotherapy

Figure 1. CTCL primary treatment map. Based on stage and refractoriness of disease, this treatment map depicts the recommended general approach to the treatment and management of CTCL; treatment figure shapes correspond to treatment applicability in each disease stage, with larger areas signifying higher expected response rates and efficacy.

Topical CSs are generally well-tolerated with a few potential side effects, including ecchymoses (20%), mild contact dermatitis (3%) and skin atrophy and striae (1%) with chronic use [12]. Percutaneous absorption of topical CSs applied over large cutaneous areas may temporarily depress the serum cortisol level and the hypothalamus-pituitary-adrenal axis in approximately 13% of cases. Although these changes are usually asymptomatic, iatrogenic secondary adrenal insufficiency may arise from full body, long-term use. It is advisable to begin with the lowest potency CSs that are effective to avoid these side effects. Potency may be increased or occlusion may be added as required. Use of topical retinoids with steroids may ameliorate the steroid-induced atrophy, may to some degree lessen the retinoid irritations and are an effective alternative therapy to steroids for localized lesions. Topical retinoids

While oral retinoids are common therapies for more extensive CTCL, either alone or in combination with other therapies, topical forms of retinoids have only recently been developed for CTCL therapy. Retinoids are thought to induce their effects by decreasing proliferation, increasing differentiation and inducing apoptosis and they may effect T-cell immunity as

406

well. Bexarotene is the first retinoid X receptor (RXR) retinoid to be approved by the FDA for the treatment of CTCL and is available for oral or topical administration. Topical bexarotene gel has been evaluated in a Phase II doseranging study of concentrations of 0.01–1.0% (BRENNEMAN ET AL., IN PRESS), as well as in a placebo-controlled, Phase III study (HEALD ET AL., UNPUBLISHED OBSERVATION). The Phase I–II trial involving 67 stage IA–IIA patients demonstrated CR in 21% and partial response (PR) in 42% of patients. The median time-to-response was approximately 20 weeks. Topical bexarotene displayed a dose response effect with greater efficacy at higher concentrations and frequencies of application. In the Phase III trial of refractory stage IA, IB and IIA patients, bexarotene gel 1% was applied topically every other day with increasing frequency up to four times a day as tolerated and demonstrated a 44% response rate (8% CR). The response rate was even higher in the group of previously untreated patients. Histologically, topical bexarotene decreases T-cell infiltrates in treated mycosis fungoides lesions and induces apoptosis in CTCL lines in vitro (DUVIC, UNPUBLISHED OBSERVATION). Similar to other topical retinoids, bexarotene induces local irritation in approximately 70% of treated patients, with most cases being mild-to-moderate in severity. This irritation is easily managed


CTCL treatment

by lessening the amount of drug applied, using it less frequently or by combining it with a low- to mid-potency topical corticosteroid. Despite bexarotene’s effectiveness, the cost of the drug precludes its use over large areas of the body. Ultraviolet B phototherapy

UVB light phototherapy has been proven safe and effective in the treatment of early patch-stage CTCL, especially for stage IA patients with more extensive involvement. Phototherapy with UVB induces apoptosis of malignant cutaneous T-cells and may work through this and other mechanisms. UVB phototherapy has a CR rate as high as 74% in stage I patients, with a median time-to-remission of approximately 5 months [13]. Generally, these remissions are also long-lasting with a median duration of 22–51 months. Most responses occur in patients with patch-stage disease, indicating that UVB therapy does not penetrate the skin enough to treat cells in the deeper dermis. After clearing, UVB should be tapered gradually to a maintenance schedule. Fair-skinned patients respond better than blacks to phototherapy, although they are also more susceptible to actinic skin damage and the risks of nonmelanoma skin cancers. In MF patients who have dysplastic nevi and are at risk for developing melanomas, suspicious lesions should be removed or followed closely. Although burning may occur with UVB therapy, the treatment is relatively safe, with nonmelanoma skin cancers occurring infrequently. Topical mechlorethamine

Topical mechlorethamine or nitrogen mustard (HN2), an alkylating agent, has been used to treat CTCL since 1959 and remains a first-line skin directed topical therapy in early-stage MF. It is used in corticosteroid or UVB refractory stage IA patients to produce long-lasting remissions of MF. It is a frequently selected first therapy for patients with stage IB–IIA disease, as it is convenient to use at home. Topical HN2 may be used in concentrations of 10–20 mg/dl and may be compounded in either aquaphor ointment or water [14]. Stage I patients treated with topical HN2 achieve CR rates of 63– 75% with an 11% rate of curability [14,15]. Nitrogen mustard therapy requires prolonged use over 1–2 years or more to achieve a lasting response and should be tapered rather than discontinued when the patient achieves a remission. The value of topical HN2 is also well-established as maintenance therapy after remission, prolonging disease-free survival (DFS) to a median of 7.3 years [14]. Unfortunately, the success of HN2 in early disease is not reproducible in tumor and erythrodermic patients [14]. Topical HN2 is generally well-tolerated, without the toxicity of systemic chemotherapy administration. In addition to the benign effect of cutaneous hyperpigmentation, there is a 35– 60% rate of allergic dermatitis associated with aqueous-based drug application, occurring within days to months after initiation of therapy [14]. Allergic reactions tend to occur less frequently with an incidence of less than 5% when HN2 is compounded into ointment-form with aquaphor. Sensitization


may actually induce a favorable response to the therapy, as disease often clears after the dermatitis has subsided. Another potential long-term complication of topical HN2 treatment is the development of nonmelanoma skin cancers, which occur at a rate of 11% with long-term use [14–16]. This incidence may rise in patients who receive other carcinogenic therapies in their treatment course, such as PUVA phototherapy and totalskin electron beam therapy. Nitrogen mustard should not be combined with phototherapy given at the same time. Topical BCNU (bischlorethylnitrosurea), a nitrosurea compound, is another topical chemotherapy that is similar to topical HN2 in effectiveness. However, topical BCNU is used less often then HN2 due to its disadvantage of causing residual telangiectasias and myelosuppression. Psoralen-ultraviolet A photochemotherapy

PUVA is an often used, first-line treatment for plaque-stage CTCL, especially in patients with stage IB disease. PUVA has been shown to be more effective than UVB in one retrospective analysis [17]. Oral psoralen (5- or 8-methoxypsoralen), a plantderived or synthesized photosensitizing drug, is activated by UVA light in the 320 to 400 nm range and is administered orally at doses of 0.6 mg/kg, 1.5 h before phototherapy [16]. UVA penetrates deeper into plaques, which would otherwise be recalcitrant to UVB therapy. PUVA is typically given two to three times a week in the USA, as opposed to four times a week in European protocols and requires a high degree of patient compliance in making multiple outpatient office visits. A review of 244 patients treated with PUVA in five clinical studies has demonstrated a 95% overall response and CR rate of 74% [16]. The median time to complete clearing is 3 months. Most responses are seen in stage IA–IIA patients with both patch and plaque disease. Although late-stage patients (stage IIB–IVB) may also respond to PUVA, most of these responses are nondurable. Generally, however, tumor and erythrodermic/ Sezary patients respond poorly to PUVA. Thus, PUVA is only recommended as palliative therapy in the setting of advanced disease and should be combined with a biological response modifier. Disease-free survival durations for stage IA and IB patients are usually long (mean 43 months) and long-term remission or ‘cures’ are possible [18]. However, relapse rates for all stages of disease are generally high (31% for stage IA), so tapering to a maintenance dose is advised to avoid relapse. In comparison to UVB therapy, PUVA is associated with more adverse effects, including more intense and longer lasting dose-related acute burning and erythema (10–20%), psoraleninduced nausea (4–17%), accelerated photoaging and freckling and increased risk of nonmelanoma skin cancers (8%) after several years of therapy [16]. One study has suggested that PUVA may be associated with a 6-fold increased risk of melanoma, while other studies have not confirmed this finding [19]. A history of topical HN2 or total-skin electron beam therapy amplifies this risk. CTCL patients undergoing these therapies must have careful surveillance for malignant melanoma and other skin cancers.

407


As a method of reducing exposure dosages and improving response, other treatment modalities are often used in conjunction with PUVA. PUVA plus IFN-α is a highly effective combination that allows dose reduction of both therapies, thereby reducing adverse effects and produces 96% OR and 76% CR rates in early-stage patients [20]. This combination is more effective than PUVA alone, IFN-α alone or the combination of IFN plus retinoids [21,22]. Limited data on rePUVA demonstrate that the combination does not improve response rates as compared to PUVA alone [23]. However, the combination lowers the frequency and dosage of PUVA required to achieve remission. PUVA plus bexarotene is currently being studied. Interferons

The interferons are biological response modifiers that have antiproliferative, cytotoxic and immunomodulating effects [22]. IFN-α, IFN-β and IFN-γ are the different existing forms of IFN. Recombinant IFN-α has been best studied, as IFN-β and IFN-γ have shown greater toxicity and no benefits over IFN-α [22]. IFN-α is further divided into the 2a and 2b subtypes, which demonstrate no apparent differences. Usually given subcutaneously, IFN-α has an overall response rate (all stages) of 54% with 17% CR and a low median duration of response (4– 28 months) [15,22]. There is greater efficacy for skin-limited disease with higher CR rates in stage I patients (62% CR) compared to stage III–IV patients (16%) [24]. Duration of disease may also be a predictor of response, as patients who have had the disease longer and who are more heavily treated, may perform less well on IFN-α. In addition, there is evidence for the development of antiIFN antibodies, which may induce tolerance and resistance to response in patients receiving IFN therapy [25]. As experience in IFN-α has increased during the past 15 years, the dosage of IFN-α administration has trended towards lower doses. The initial trial by Bunn et al. used a dose of 50 MU/m2 three times weekly; however, the side effects of IFN-α at such high doses are generally intolerable. Doses as low as 3 MU daily or three times weekly are now thought to be as effective [15,22,26]. Intralesional IFN-α is also effective in clearing 83% of injected plaques [27]. As previously discussed, the combination of PUVA and IFNα appears to produce the greatest response rates. IFN-α has also been evaluated in combination with retinoids, demonstrating an 11% CR and 60% OR rate, similar to either modality when used alone [15,22,28]. However, one recent study using IFN-α and etretinate demonstrated a higher 83% CR rate in 12 refractory late-stage patients along with a prolonged median remission of 17.8 months with IFN-α maintenance therapy [29]. Side effects of IFN-α occur frequently and include initial flulike symptoms consisting of fever, chills, myalgias and malaise during the first week of therapy [22,30]. Some symptoms may continue during therapy, occurring after each sc. injection. Other side effects are dose-related, such as fatigue, anorexia, diarrhea, leukopenia, thrombocytopenia, hepatitis, telogen effluvium and mental status changes. IFN-α may also cause thyroid dysfunction, with a 6% incidence [31]. These toxicities

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may be severe and dose-limiting, making this modality a poor choice in older and already debilitated patients. RAR retinoids: isotretinoin, etretinate, acitretin

Retinoids are vitamin A analogs, which also have biological response modifying activities. In vitro, retinoids display antiproliferative and immunomodulating properties and promote differentiation [32]. The three oral retinoids isotretinoin, etretinate and acitretin, which have been used in CTCL treatment, are metabolized to RAR receptor agonists. Most data are available for etretinate and isotretinoin, which demonstrate no differences in response or toxicity. Etretinate has been largely replaced by acitretin because of its long half-life, long-term storage issues and prolonged risk of teratogenicity in women. When used alone, retinoids produce overall response rates around 50%, similar to IFN-α. Cumulative data on isotretinoin and etretinate therapy show 19% CR and 58% OR with a median response duration ranging 3–13 months [15,32]. For this reason, retinoids are also often used in combination with other therapies, such as IFN-α and PUVA, as discussed. Systemic chemotherapy plus retinoids has also been evaluated, although no significant differences in response rate could be determined when compared to systemic chemotherapy alone [33]. The dosedependent toxicities of oral RAR retinoids include dry skin, cheilosis, conjunctivitis, fatigue, arthralgia, myalgia, mental status changes, bone changes and headache [32]. The most potentially serious side effect of retinoid therapy is transient hypertriglyceridemia, which may be controlled by dose reduction or gemfibrozil therapy. Oral bexarotene

Oral bexarotene is the first of a novel class of synthetic RXR selective retinoids called ‘rexinoids’. Bexarotene was approved by the FDA in December 1999 for the treatment of early-stage CTCL patients who are unable to tolerate other therapies, or who have refractory or resistant disease and refractory advanced-stage patients. The mechanism of action of bexarotene is unknown, although it is thought that the drug has both apoptotic and antiproliferative effects. Bexarotene displays a dose-response effect, with a recommended optimal dose of 300 mg/m2/day based on the drug’s safety profile [11,34,35]. A Phase II–III multicenter open-label trial on 58 refractory early-stage (IA–IIA) patients evaluated drug administration at three randomized dose levels (6.5, 300 and 650 mg/m2/day) 2 [34]. As the studies proceeded, an optimal dose of 300 mg/m / day was selected. Hypertriglyceridemia with pancreatitis was experienced in patients at the higher dose level and the response at the low level was significantly lower. Patients at the 6.5, 300 and 650 mg/m2/day doses achieved response rates of 20, 54 and 67%, respectively. Overall, the 300 mg/m2/day dose level displayed an optimal balance between response and tolerability, with a response rate of 54%. Bexarotene takes several months to induce remissions and if it is tapered too quickly the disease may reoccur. After inducing a complete durable remission of 12 months duration, we have found it


CTCL treatment

possible to reduce the dose to a maintenance level of 75– 300 mg. Initial experiences with bexarotene in combination with IFN, PUVA, extracorporeal photopheresis and denileukin diftitox, support its safe use in combination and it may augment the activity of other modalities [36]. The side effects of bexarotene are usually dose-dependent and manageable using the combination of lipid-lowering agents, such as statins and thyroid replacement. The most common significant side effects in the pivotal trials were hypertriglyceridemia (79%), hypercholesterolemia (32%), central hypothyroidism (29%) and leukopenia (17%). Hypertriglyceridemia is the most frequent dose-limiting toxicity and most patients require concomitant lipid-lowering agents: fenofibrate and HMG-CoA reductase inhibitors or ‘statins’. We have used atorvastatin (Lipitor™) up to 80 mg or fenofibrate (Tricor™) up to 200 mg as single agents. We have also used the two drugs at maximum doses in combination, although rhabdomyolysis can potentially occur in this setting. An algorithm for using bexarotene is shown in FIGURE 2. During the trials, it was discovered that gemfibrozil, while effective for isotretinoin-induced hypertriglyceridemia, was paradoxically associated with higher bexarotene levels, increased hypertriglyceridemia and increased risk for pancreatitis. Given these results, gemfibrozil should not be used with bexarotene. Bexarotene-induced central hypothyroidism is due to suppressed thyrotropin secretion with low TSH and T4 levels [37]. Patients feel better on thyroid replacement, which also assists in lipid clearance. The condition is reversible upon discontinuation of therapy and normalization of thyroid function occurs in as early as 8 days. At MDACC, serum thyrotropin levels were decreased in 26 of 27 CTCL patients taking bexarotene with 19 patients becoming symptomatic. The side effect profile of bexarotene, while manageable, requires a high degree of patient understanding and compliance in order to maintain safe and proper management of toxicities. Additionally, the current high cost of bexarotene capsules is limiting to some patients who remain on long-term treatment.

Baseline labs: Complete blood count, liver function tests, creatine phosphokinase, lipid panel, thyroid stimulating hormone (TSH), free T4 (FT4) , pregnancy test Patient education

TSH > 6.0 mcu/ml, Triglycerides Triglycerides FT4 < 0.7 ng/dl < 250 mg/dl > 250 mg/dl Start levothyroxine, Start low dose lipid- Normalize lipids with lowering agent (LLA) LLA before initiating 0.025 mg/day bexarotene

Start bexarotene in 1 week Dose 300 mg/m2/day (recommended dose)

Start bexarotene Dose 100-200 mg/m2/day (low dose)

Monitor all labs weekly

FT4 < 0.7 ng/dl TG > 400-800 mg/dl TG > 800 mg/dl Increase levothyroxine Increase LLA dose Hold bexarotene, by 0.025 mg/day increase LLA dose until FT4 normal Resume bexarotene at same or lower dose when TG < 400 mg/dl

Labs stable Monitor labs monthly

Figure 2. Bexarotene algorithm. Depicts the management of bexaroteneinduced toxicity and proper courses of action for hypertriglyceridemia and central hypothyroidism.

Total-skin electron beam therapy

Mycosis fungoides is radiosensitive and radiotherapy was first used for the disease in 1902 [38]. Electron beam therapy, optimal for superficially treating the wide field volumes of the skin, came into use for MF in 1952. Currently, total-skin electron beam therapy (TSEB) is perhaps the most effective single skin-directed therapy for skin-limited disease, including tumor-stage disease and has produced very long-lasting remissions in some individuals. Its use is limited by the availability of the procedure, cost and its side effects. Electron beam therapy is typically given through a six-field technique with 4–9 MeV energy at doses totaling 3200–4000 cGy, usually fractionated two to four times a week. In world data on 1165 patients on TSEB therapy, presented by Jones et al., TSEB techniques varied at different institutions and over time [38]. At Stanford, early methods in the 1960s used low total doses of 800 cGy, delivered at 400 cGy in four fractions


per week. Therapy evolved in the 1970s to a higher standard dose of 3600 cGy, given at the same rate. While 6 MeV were usually used, energy was boosted to 9 MeV for tumors or thick lesions. In contrast, 3–4 MeV were used at Hamilton. Generally, there are variations in dose per fraction, numbers of fractions, total time and the use of shielding, patching and boosting among different treatment centers. The world data on TSEB demonstrate CR rates of approximately 90% in T1 patients and 70% in T2 patients [38]. However, the use of TSEB in patients with limited stage IA, T1 disease is now uncommon, given their already favorable prognosis. Remissions induced by TSEB for disease stages greater than stage IA are prone to relapse and require maintenance therapy, particularly with topical HN2. In generalized T2 disease, adjuvant HN2 after TSEB remission can increase disease-free survival from approximately 15–55% at 5 years [39]. Furthermore,

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there is evidence that cutaneous immunological suppression induced by TSEB therapy may lead to a lower frequency of HN2 allergic reactions [40,41]. The addition of adjuvant PUVA after TSEB in T1 and T2 patients also yields a statistically significant improvement in disease-free survival [42]. The use of both modalities may amplify the risk of skin cancers, though the risk of melanoma is less clear. Although TSEB offers the advantage of superficial and skinlimited effects, discomfort from TSEB-induced skin changes can be severe and may include swelling, dry and moist exfoliation, erythema, tenderness, blister formation, alopecia, anhidrosis and loss of nails. These effects are usually transient and are ultimately relatively benign, but may cause patients considerable morbidity and cosmetic distress. There is also a reported 6–25% rate of developing nonmelanoma skin cancers, especially with HN2 or PUVA therapy as previously discussed [43]. A second course of TSEB can be given to selected patients if the disease relapses after years. Combined modality therapy: early-stage regimen

Various combinations of the previously discussed therapies can be used to try to improve treatment efficacy. Over the past 15 years, one particular multiphased combined modality regimen has been used at MDACC to treat both early- and latestage patients. In the treatment arm for early-stage (stage IA– IIA) patients, the regimen used a 4-month induction phase in the form of sc. IFN-α and oral isotretinoin, a 2-month radiotherapy phase with TSEB therapy and a maintenance therapy phase with IFN (for 1 year) and topical HN2 (for 2 years) [44]. Although the study was nonrandomized, this combined modality regimen displayed efficacy in 50 early-stage patients with an overall response rate of 94%, a CR rate of 76%, a disease-free survival of more than 29.2 months and a sustained 5-year disease-free survival rate of 18% (DUVIC, UNPUBLISHED OBSERVATION). Stage IB patients on the MDACC regimen experienced higher 5-year disease-free survival (43%) than historical controls of patients receiving TSEB therapy alone (25%). While most stage IA patients usually do not require such aggressive combination therapy, stage IB and IIA patients are likely to receive the greatest benefit from this regimen. Late-stage disease Stage IIB, IVA, IVB disease

Stage IIB patients have T3 tumor involvement and tend to have aggressive disease with poor prognosis, despite being free of visceral or nodal disease. In some cases, the development of tumors is a manifestation of large cell transformation in the skin, which incurs an even worse prognosis [45]. While some patients with only one or two tumors may do well with local radiotherapy combined with other T-stage-specific therapies, most stage IIB cases require more aggressive therapy to clear tumors. Previously discussed, TSEB therapy remains one of the best therapies for inducing response in stage IIB disease and has CR rates ranging from 44–74% [3,38,39,46]. Unfortunately, responses may be shortlived, with only a 2–23% disease-free survival at 5 years [38].

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Oral bexarotene may also be effective in tumor reduction, even in patients with large cell transformation [35]. The novel fusion toxin protein DAB389-IL2 (ONTAK) is a potential option that is less immunosuppressive than chemotherapy and has been shown to be effective against tumor-stage disease. In the Phase III clinical trial, the higher dose of DAB389-IL2 (18 µg/kg/day) gave a significantly higher response rate 38% than the lower 9 µg/kg/day dose (10%) in stage IIB–IVA patients [47]. In most cases, single- or multiagent chemotherapy should be reserved for cases that are refractory to these previous therapies, given the risks of immunosuppression. However, the late-stage treatment arm of the MDACC combined modality regimen effectively incorporates six cycles of CMED (cyclophosphamide, methotrexate, etoposide and dexamethasone) chemotherapy before the TSEB phase of therapy while maintaining acceptable risk. Stage IV patients have visceral and nodal involvement and have the worst prognosis of all disease stages. Like other late stage patients, these patients require aggressive systemic therapy with or without T-stage specific, skin-directed therapies. While some patients may respond to oral bexarotene or DAB389-IL2 therapy, in most cases, these patients will ultimately require systemic chemotherapy, given alone or as a part of combined modality therapy. Stage IV patients are often refractory to conventional therapy and should be offered investigational therapies, including systemic cytokines, chemotherapeutic agents, monoclonal antibodies and bone marrow or stem cell transplantation. Oral bexarotene

Late-stage CTCL trials demonstrate that oral bexarotene is a well-tolerated systemic agent that is effective in treating T3 and T4 patients. In these trials, 94 stage IIB or greater CTCL patients were treated at the 300 mg/m2/day dose and the 650 mg/m2/day dose and achieved response rates of 45 and 55%, respectively [35]. Oral bexarotene exhibited activity in tumor and lymph node reduction and was also surprisingly effective in treating patients with large-cell transformation. Bexarotene also displayed efficacy in controlling, stabilizing or resolving the erythroderma of Sezary and erythrodermic MF patients. In a subset of erythrodermic patients, 44% showed remissions on bexarotene oral capsules alone (DUVIC, UNPUBLISHED OBSERVATION) and there have been durable almost complete responders to bexarotene monotherapy. Bexarotene is a safe and effective therapy for erythrodermic patients because it does not require catheters or lines that put these patients at risk for sepsis. These results suggest that oral bexarotene retains therapeutic efficacy in late stages that is similar to responses seen in early stage disease. When bexarotene is combined with other active agents or with ECP, we have found response rates to be 67% in a study of 15 patients [36]. Denileukin diftitox (DAB389-IL2; ONTAK)

DAB389-IL2, approved by the FDA in 1998 for relapsed CTCL, is the first of a novel class of fusion toxin proteins. The


CTCL treatment

fusion toxin protein consists of the IL-2 coding sequences combined with those for diptheria toxin A chain. DAB389-IL2 utilizes the T-cell targeting activity of IL-2 and the cytotoxic properties of diptheria toxin to kill lymphoma cells expressing the CD25 component of the IL-2 receptor (IL-2R). Once the DAB389-IL2 molecule is internalized into the targeted T-cell by endocytosis, the activity of diptheria toxin inhibits protein synthesis, thereby inducing cell death [48]. While the drug was originally developed as DAB489-IL2, the smaller DAB389-IL2 molecule has greater affinity to the IL-2 receptor, a longer half-life and an improved response and toxicity profile [48,49]. The DAB389-IL2 Phase I study demonstrated a 37% response rate with 14% CR in 35 CTCL patients. Responses occurred rapidly within the first two cycles of therapy and lasted a median of 15 months for CR and 3 months for PR [48,50]. The results prompted a subsequent Phase III trial of DAB389-IL2 in 73 refractory, heavily pretreated patients. Patients were randomized to either a low-dose (9 mcg/kg/day) or high-dose (18 mcg/kg/ day) schedule administered on 5 consecutive days in a 21-day course. The results of this trial confirmed the activity of DAB389-IL2 in CTCL, with a 30% OR, 10% CR and a median duration of response of 4.4 months from time of first response or 6.9 months from time of first dose [47–49]. Higher response rates (38%) were seen in stage IB–IVA patients treated at the higher 18 mcg/kg/day dose than at the lower dose (10%) [47]. DAB389-IL2 may have particularly high efficacy in stage IIB tumor patients, as these patients exhibited a higher response rate (OR 50%) at the 18 mcg/kg/day dose [47–49,51]. Significant improvements in the patients’ quality of life and pruritus were observed as well (DUVIC, UNPUBLISHED OBSERVATION) [47–49,52]. There were no significant differences between the low- and high-dose arms overall, although there may be a dose-response effect for advanced-disease patients. DAB389-IL2 causes acute constitutional and gastrointestinal symptoms, such as fevers/chills, asthenia, nausea/vomiting, myalgias, arthralgias, headache, diarrhea and anorexia in 92% of patients [47–49]. Rash occurs in 35% and transient elevations of hepatic transaminases occurs in 17% of patients. Mild vascular or capillary leak syndrome, which includes edema, hypoalbuminemia and hypotension, does occur in 25% of patients [47]. Patients receiving DAB389-IL2 should have a serum albumin level greater than 3.0 mg/dl, as these patients may be associated with a greater risk of capillary leak syndrome. In contrast to systemic chemotherapy agents, DAB389-IL2 usually does not induce myelosuppression and the incidence of toxicities diminish after the first course of therapy [47–49]. Premedication with systemic corticosteroids has been shown to decrease the incidence of acute hypersensitivity reactions and adverse events [53]. In addition, it has been observed that a post-infusion hydration with saline after DAB389-IL2 infusion may decrease the incidence of capillary leak syndrome and other toxicities (Frankel AE, personal communication and observation, 2000). At MDACC, 15 heavily pretreated refractory patients, with a median of four previous treatments, have been treated with DAB389-IL2. Eight had partial responses (53% response rate)


and two patients progressed [54]. Seven of these patients were treated on a Phase III trial of DAB389-IL2 treated with corticosteroid premedication consisting of a 14-day tapered regimen of oral dexamethasone, 8 mg/day, starting 1 day prior to administration. Although six patients on corticosteroids still developed capillary leak syndrome, it did not occur in patients with postDAB389-IL2 saline infusion [54]. A Phase III doubleblinded, placebo-controlled study of DAB389-IL2 is still underway, as there is still much to be learned about the drug’s efficacy, dosing and management of toxicity. Currently, the relationship between CD25 positivity and response to DAB389-IL2 is not well understood. In the Phase III randomized, two-arm trial, patients were required to display at least 20% CD25 positivity of neoplastic cells on a pretreatment diagnostic biopsy [47]. However, CD25 is only one component of the IL-2 receptor and the percentage of CD25positive cells in patients may be highly variable over time. Responses have also been demonstrated in patients who are negative for CD25 expression. An open-label study of CD25negative patients without corticosteroid premedication and a blinded study are currently underway to determine the importance of CD25 positivity. Single- and multiagent chemotherapy

While systemic chemotherapy was the primary treatment of late-stage CTCL in the past, new and less toxic therapies, such as oral bexarotene and DAB389-IL2 have taken its place. Despite its toxicities, however, systemic chemotherapy still has a role in the treatment of refractory patients. Multiagent regimens, such as CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) demonstrate slightly better results than single-agent regimens with 81% OR rate and 38% CR [15,55]. The median response durations of multiagent regimen trials range from 5–41 months, with the results of most trials at the lower end of this range. Overall, no single- or multiagent regimen appears to produce better responses than the others [15,56]. The myelosuppressive properties of systemic chemotherapeutic agents are well-known and opportunistic infections, sepsis and death may result from the immunosuppression. On occasion, the development of acute myelogenous leukemia may also occur [57]. Given these toxicities and the short durations of response, systemic chemotherapy should be reserved for refractory patients or patients with the most extensive visceral and nodal disease. Combined modality in late-stage disease

There have been attempts at combining TSEB and chemotherapy to improve response, survival and disease-free survival in late-stage CTCL. Kaye et al. conducted the only randomized trial to date comparing combined modality with topical sequential conservative therapy and found that although combined modality produced higher CR rates, the disease-free survival and overall survival was not different from sequential conservative therapy, including topical HN2, PUVA, TSEB and oral methotrexate [58]. In the previously discussed MDACC

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combined modality protocol using an induction phase and CMED chemotherapy followed by TSEB and maintenance therapy, 38 late-stage CTCL patients exhibited a 80% overall response rate and 33% CR rate with a median disease-free survival of 9.9 months (DUVIC, UNPUBLISHED OBSERVATION). This regimen demonstrated improved response rates in stage IIB and IV patients and improved disease-free survival in IVA patients over TSEB alone, based on historical controls. The MDACC combined modality regimen exhibited a 7% sustained 5-year disease-free survival rate in late-stage CTCL patients and a 100% 5-year survival rate of stage IIA and IVB patients. Given these results, this combined modality regimen should be considered in late stage patients, particularly in stage IIB, IVA and IVB disease. Stage III disease

Sezary syndrome and stage III erythrodermic MF are indistinguishable clinically as both present with exfoliative erythroderma and pruritus. Sezary syndrome should be defined as the leukemic form of MF with a significant population (10–20%) of circulating atypical lymphocytes identified on peripheral blood smear or by flow cytometry [59]. These patients are particularly challenging, given their total body erythroderma, leukemic blood involvement and high incidence of staphylococcal infection and colonization, which appears to drive the erythroderma and possibly even the T-cell expansion in some patients [10]. These patients can be significantly improved if kept on oral antibiotics, to clear staphylococcus, combined with topical triamcinolone 0.1% used with wet wraps on a daily basis and doxepin for pruritus. Extracorporeal photopheresis has been a breakthrough development that is considered firstline therapy for erythrodermic MF/SS patients. Extracorporeal photopheresis

First evaluated in the late 1980s by Edelson et al., extracorporeal photopheresis (ECP) is one of the few disease-modifying CTCL treatments to be associated with improved overall survival [46,60– 62]. An intact immune response is thought to be a prerequisite for the success of ECP, as the mechanism of ECP may involve a CD8+ cell-mediated anticlonotypic immune reaction that is akin to vaccination. The host’s immune response is mounted against reinfused pathogenic T-cell clones, which are damaged by photoirradiation. ECP also reverses Th1/Th2 imbalance and induces lymphoid cell apoptosis [63,64]. The immunomodulation is associated with a decrease in the CD4+:CD8+ ratio, which is correlated with disease response [60,65]. In the Edelson et al. data, erythrodermic patients had prolonged survival (median 60 months) when compared to historical control groups (median 30 months) [60,62]. In recent years, however, the efficacy of ECP in SS patients has become a widely debated issue, with one controversial study by FraserAndrews et al. reporting that ECP does not prolong survival in erythrodermic patients with a demonstrated peripheral blood T-cell clone. In this retrospective study, the survival of 29 SS patients who received ECP (median 39 months) was found not

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to be statistically significant when compared to two other groups of a total of 15 patients who did not receive ECP (median 22 and 27.5 months) [66]. Other investigators have pointed out that the low number of subjects in this study led to inadequate statistical power and that the study patients were given inadequate treatment regimens (less than 8 weeks therapy) [67]. Additionally, the ECP-treated group of patients may have had worse disease as they were more heavily treated before ECP and had a higher percentage of nodal lymphoma. Some of the study patients also received concomitant systemic corticosteroids and prior systemic chemotherapy prior to ECP, which as Edelson and other investigators have indicated, may have caused immunosuppression, blunting their responses to ECP [67,68]. Russell-Jones has, in turn, countered that other study populations, such as the original study group of Edelson et al. have also been treated with chemotherapy prior to ECP and that the subjects in the Fraser-Andrews study group had cytotoxic CD8 counts that were near normal [69]. However, proponents of both sides of these issues agree that preservation of the immune system is likely favorable for ECP and that ECP should be given prior to immunosuppressive therapies. It appears that only prospective randomized trials will be able to clarify the activity of ECP in SS patients. Since the overall response rate for photopheresis for T4 erythrodermic patients is approximately 50% with CRs limited in the 15% range, there is a need to develop better combinations to use with ECP [60–62,65,70]. When photopheresis fails to induce a response, biologic response modifiers (IFN-α or bexarotene) should be added to photopheresis [71,72]. Patients with T4 erythrodermic MF may have prolonged remissions and improved survival when ECP is combined with TSEB therapy [73]. The use of ECP as maintenance therapy following TSEB may also improve survival [45]. Patients who are most likely to respond to therapy are those who have presence of modest or small numbers of peripheral Sezary cells (10–20%), a short duration of disease, normal numbers of cytotoxic T-cell and NK-cell activity, normal serum IgG levels, no prior history of intensive chemotherapy and absence of lymphadenopathy or visceral disease [74]. The side effects of ECP are relatively minimal. Patients often experience nausea related to oral psoralen ingestion, although ECP systems using methoxsalen in the extracorporeal circuit may bypass the use of an oral photosensitizer. Catheter-related sepsis is a potentially serious complication seen with the use of indwelling lines in erythrodermic patients [70]. These patients have a high rate of colonization by S. aureus and may be septic in the setting of hypothermia [10]. Patients may experience transient hypotension during the procedure and post-reinfusion fever and increased erythema. Unfortunately, limitations often exist in access to ECP, as it is available in few major academic medical centers. New & investigational skin-directed therapies

Tazarotene is a topical retinoid, which is approved for the treatment of psoriasis and acne [75,76]. At MDACC, an openlabel pilot study has studied the effectiveness of a 6-month


CTCL treatment

course of topical tazarotene gel applied daily. Of 16 evaluable stage IA and IB stable or refractory mycosis fungoides patients with less than 20% cutaneous disease involvement, 12 (75%) achieved at least a moderate (50%) global improvement in their target lesions and 35 of 88 (40%) of target lesions cleared completely [77]. Similar to the effects of other topical retinoids, topical tazarotene therapy is associated with local irritation in 79% of patients, which may be relieved by local corticosteroids with or without reduction in frequency of drug application. Tazarotene may prove to be a less costly alternative to topical bexarotene gel. Visible light may be effective in treating CTCL when combined with a topically applied, photodynamic compound, such as hypericin [78]. Hypericin, or St. John’s Wort, is a natural compound found in plants that has been shown to induce apoptosis in malignant T-cells in vitro. Hypericin is a photoactive agent that absorbs light in the range of 570–650 nm and acts as a photosensitizer. Topical hypericin-activated by visible fluorescent light-is currently being compared to placebo for psoriasis, mycosis fungoides and warts. In this trial, 0.5 or 1.0% hypericin or placebo is applied to lesions and irradiated with light twice a week. In one MF patient, one of three index lesions resolved on this therapy, with one lesion partially responding and one lesion remaining stable. Two patients had dose-limiting local reactions. Hypericin may be more attractive than ultraviolet phototherapy, as the risk of skin cancer should be reduced with the use of visible light. Methotrexate (MTX) is a common component of systemic chemotherapy regimens in the treatment of CTCL. As with other systemic chemotherapeutic agents, MTX is limited by its acute toxicities. Topical MTX would provide the potential for lesion-specific therapy without the risk of systemic toxicity. However, MTX penetrates the skin only to a limited extent and a threshold concentration is required for MTX to produce its inhibition effects on epidermal DNA synthesis [79]. Thus, the efficacy of topical MTX is dependent upon the ability of its vehicle to penetrate epidermal barriers. Topical MTX formulations containing laurocapram, a lipophilic vehicle, have demonstrated efficacy in the treatment of psoriasis with 50% improvement in erythema, scale and elevation scores [80]. Mycosis fungoides trials of this formulation are currently underway. Narrowband UVB or TL-01 UVB phototherapy (311 nm), which has been used effectively for psoriasis treatment, has been studied for CTCL therapy in recent years. Clark et al. studied narrowband UVB therapy in eight patch-stage patients and achieved a 75% CR rate lasting an average of more than 20 months in duration [81]. Similar to broadband UVB, narrowband UVB therapy induces erythema, pruritus and photoaging. In contrast, however, there is no correlation between skin phototype and response. Experience in psoriasis therapy has demonstrated that narrowband UVB is more effective than broadband UVB and may be nearly as effective as PUVA with several advantages over PUVA [82]. Narrowband UVB avoids the adverse effects associated with psoralen ingestion, namely


nausea, headaches and light-headedness. Also, there is no need for protective eyewear after treatment, therapy may be given during pregnancy and there may be less photocarcinogenic risk than PUVA. Narrowband UVB seems to have similar prospects for CTCL therapy, although more experience is needed. New & investigational systemic therapies Pegylated interferon

Pegylated IFN, a new form of IFN attached to polyethylene glycol molecules, has been shown to have a longer half-life than standard IFN and can consequently be given as once weekly dosing. While no studies have been performed in MF or CTCL patients, recent trials in hepatitis C patients have demonstrated that pegylated IFN-α produces higher response rates over standard IFN-α without additional toxicity [83]. These results suggest that pegylated IFN-α could also hold advantages over standard IFN-α in the treatment of MF patients. Interleukins

IL-2 is a glycoprotein product of activated T-cell lymphocytes and is a major T-cell growth factor that promotes further Tcell activation and proliferation. In anticancer therapy, it is presumed that recombinant IL-2 (rIL-2) therapy induces Tcell expansion against a specific cell-surface tumor antigen to mediate tumor regression. In one CTCL trial, seven advanced-stage (stage III–IVA) patients were treated with high-dose rIL-2, achieving CR in three patients (43%), PR in two patients (29%) and progressive disease in two patients [84]. Responses occurred expeditiously within the first three courses and two remissions were durable with one ongoing after 62 months and one relapsing after 56 months [85]. IL-2 therapy is accompanied by significant toxicity and is administered in an intensive care setting. Classical side effects are chills, nausea and vomiting, diarrhea, weight gain, creatinine elevation, hypotension, anemia and thrombocytopenia. Fever and grade 1 hypotension are very common Among the many cytokine profile alterations associated with CTCL, a defect in IL-12 production may play a significant role in the disease, as IL-12 is critical for antitumor cytotoxic T-cell response. Recombinant IL-12 therapy is effective in CTCL, restoring CD8 cells in lesions and suppresses the production of IL-4 by Sezary cells in vitro. A Phase I trial of sc. IL12 using twice weekly escalating doses (50, 100 and 300 ng/kg), demonstrated 56% OR and 22% CR rates in ten plaque, tumor and Sezary patients [86]. Intralesional therapy also produced responses with two out of two patients experiencing tumor regression. Skin biopsies from treated patients displayed increased numbers of CD8+ cells. A subsequent Phase II multicenter IL-12 trial was conducted with an overall response rate of 43% at doses of 300 ng/kg twice weekly for 24 weeks [87]. The side effects of IL-12 are similar to IFN-α including lowgrade fever, myalgia, headache, mild anemia and leukopenia and depression. The side effects may be dose limiting in elderly patients. One case of fatal hemolytic anemia occurred in an elderly MF patient on the Phase II trial.

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Nuceloside analogs

Gemcitabine is a promising, novel pyrimidine antimetabolite that has shown significant activity against solid tumors and is FDA-approved for the treatment of pancreatic cancer. As a chemotherapeutic agent, gemcitabine is valued for its low toxicity profile and dose scheduling (once a week for 3 consecutive weeks every 4 weeks). In the only significant published experience with CTCL, Zinzani et al. used gemcitabine in 30 pretreated T3 and T4 mycosis fungoides patients, resulting in a 70% overall response with a 10% CR rate [88]. Side effects were minimal with no nausea or vomiting and no severe hematologic toxicity. An ongoing investigational trial is being conducted at MDACC. Twelve stage IB–IVA CTCL patients, including three peripheral T-cell lymphoma patients, have been treated to date, with one CR, four PR responses and three near-partial responses for a 42% OR rate (APISARNTHANARAX, UNPUBLISHED OBSERVATION). Improvements were observed after only one or two cycles of therapy. One patient developed an erythematous maculopapular rash in lesions during two cycles of therapy that may represent radiation recall reaction. Resolution of these flares has been followed by an improvement in skin disease. Other side effects have most frequently involved bone marrow suppression, particularly leukopenia, with cutaneous hyperpigmentation occurring in two patients and hepatic transaminase elevations in one patient. As a drug that is well-tolerated and that works expeditiously, gemcitabine may prove effective in CTCL therapy. Pentostatin or 2´-deoxycoformycin was the first of a novel group of purine analogs to be approved for hairy cell leukemia and studied in CTCL. Pentostatin exerts T-cell selective lymphotoxic effects through the inhibition of adenosine deaminase. Recent multicenter Phase II trials of pentostatin in the treatment of 94 CTCL patients has yielded 40% OR and 7% CR rates [89]. Kurzrock et al. reported better results in 14 Sezary and six tumor stage patients with a 70% OR and 25% CR rate, although median response durations were extremely short: 2 months in tumor-stage and 3.5 months in Sezary patients [90]. Only one patient has had a durable long-lasting response. The combination of pentostatin and IFN-α prolongs response duration to a median of 13.1 months, but does not appear to increase response rates [91]. Overall, studies point towards greater efficacy of pentostatin in erythrodermic MF and Sezary syndrome than in tumor-stage disease. While pentostatin is relatively safe and well-tolerated below a dose of 4 mg/m2/day, dose-dependent toxicities are common [92]. The most frequent side effect is hematologic toxicity, including granulocytopenia and thrombocytopenia (33%) [89]. Prolonged CD4 lymphopenia occurs after therapy. Kurzrock et al. reported a 19% rate of Herpes zoster outbreaks within 1 year of therapy. Given the frequency of immunosuppresion in pentostatin-treated patients, prophylactic antiviral therapy and Pneumocystis carinii pneumonia prophylaxis should be considered. Nausea and renal insufficiency also occur with frequencies of 18 and 7%, respectively [89]. Neurotoxicity and cardiotoxicity

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are also seen. Transient disease flares may occur after pentostatin administration, although a response to therapy often follows [90]. Fludarabine is the fluorinated derivative of vidarabine and induces its lymphocytic effects through its resistance to adenosine deaminase and subsequent inhibition of DNA synthesis and repair. It is one of the least active nucleoside analogs and is associated with a high rate of immunosuppression in CTCL patients. One study group treated 30 MF patients with fludarabine with only one CR and five PR responses [93]. The combination of fludarabine plus IFN-α produces higher response rates (51% OR, 11% CR) with CRs seen in Sezary syndrome and tumor-stage patients [94]. Fludarabine induces immunosuppression and hematologic toxicity that is more severe than pentostatin, as it suppresses both T- and B-cells. There is a 17% rate of sepsis and 14% rate of opportunistic infections when used with IFN-α. Currently, fludarabine therapy cannot be recommended in the treatment of CTCL, although it may be selected in patients undergoing allogeneic bone marrow as a preparative regimen. The most recent purine analog to be developed is 2-chlorodeoxyadenosine (2-CDA), which is preferentially toxic to T-cell lymphocytes. The largest study of 2-CDA for treatment of CTCL involved 21 patients with relapsed or refractory MF/SS patients and yielded a 28% OR and 14% CR rate with a median duration of response of 4.5 months [95]. Similar to the other purine analogs, toxicity involves myelosuppression and related infectious complications. In the 21 patients treated by Kuzel et al., 62% experienced myelosuppression and infectious complications. However, 38% of patients experienced no severe toxicity from 2-CDA. Temozolomide

Temozolomide is a new alkylating agent that has been used in one advanced refractory MF patient in a Phase I trial [96]. A total of 1000 mg/m2 oral temozolomide was administered over 5 days and achieved a CR lasting 7 months, followed by relapse and a second remission after retreatment. Myelosuppression is the most significant adverse effect and occurs at doses greater than 750 mg/m2. Temozolomide may have particular efficacy in MF due to the unusual lack of O6-alkylguanine-DNA alkyltransferase (AGT), which is a DNA repair protein that is associated with resistance to alkylating drug activity [97]. Phase II trials of temozolomide treatment of CTCL are pending. Pegylated liposomal anthracyclines

Pegylated liposomal doxorubicin (PLD), currently used in the treatment of Kaposi’s sarcoma and some solid tumors, has recently been investigated for use in MF. While the liposomal form of doxorubicin already allows for reduced toxicity and improved efficacy, the attachment of polyethylene glycol to the liposome induces a longer half-life and increased concentration in tumor cells [98]. In one pilot study, ten relapsing or recalcitrant MF patients were treated with 20 mg/m2 PLD and achieved an 80% response rate with 60% CR [99]. Similar to standard doxorubicin, the pegylated liposomal form of the drug


CTCL treatment

causes myelosuppression as well as cardiotoxicity, which limits the lifetime dose of the drug. While the ten studied patients were pretreated mostly with extracorporeal photopheresis and IFN-α and had never been treated on systemic chemotherapy, another investigator reported no success with PLD in two patients who previously had poor response to systemic chemotherapy [100]. Further studies will be required to evaluate the efficacy of PLD, especially in patients who are refractory to other systemic chemotherapy. Monoclonal antibodies

Monoclonal antibodies have been developed in the search for a ‘magic bullet’, an effective treatment that will target specific malignant cells and spare normal tissues. Earlier monoclonal antibodies, such as T101 (antiCD5) and its radioimmunoconjugates, were developed with murine components [101]. Unfortunately, the effectiveness of these murine-based therapies was limited by the development of human antimouse antibodies. The chimeric antiCD4 antibody, containing both human and murine components, was developed to try to circumvent this problem. The most recent study in a group of eight MF patients yielded only seven minor responses [102]. The experience with the antiCD5 HG5-RTA immunoconjugate and the anti-idiotypic antibody have yielded few responses with extremely short response durations. Most recently, monoclonal antibody trials have turned towards human antibodies. CAMPATH-1H is a human immunoglobulin G1 antiCD52 monoclonal antibody that binds to nearly all B-cell and T-cell lymphomas. A Phase II trial of CAMPATH-1H was recently conducted in 50 advanced, lowgrade non-Hodgkin’s lymphoma patients, including eight MF patients, yielding a 50% OR rate with two CRs in the MF patients [103]. Remarkably, CR was achieved in the blood and bone marrow in 94 and 32% of patients, respectively, although the authors did not indicate how many of these responses were MF patients. However, CAMPATH-1H was associated with significant immunosuppression, including lymphopenia in all patients and WHO grade 4 neutropenia in 28% of patients. Cases of opportunistic infections and bacterial sepsis were also observed, some of which were fatal. While CAMPATH-1H appears to have improved efficacy over previous monoclonal antibody treatments, its use may be limited by its severe immunosuppression. Of note, five patients who were treated with CAMPATH-1H at MDACC developed severe cardiac dysfunction, including congestive heart failure and arrhythmias. No responses were seen among these MF patients. Bone marrow transplantation

Bone marrow transplantation (BMT), widely used in the treatment of leukemias, lymphomas and hematologic disorders, is a therapeutic option that has not been widely used in CTCL due to the relatively indolent nature of the disease. Transplantation of stem cells may be either autologous or allogeneic and is preceded by myeloablative chemotherapy or chemoradiotherapy conditioning. In the experience at MDACC, autologous BMT


has not produced long-lasting remissions in CTCL patients. In a published autologous BMT trial, five of six advanced-stage MF patients achieved CR [104]. However, three of the responses lasted less than 100 days with the remaining two being diseasefree 1 year after treatment. Sustained responses may be difficult to achieve with autologous BMT because it is likely that all the malignant T-cells are not eradicated from the marrow or from the skin. Allogenic transplantation could overcome this problem if a ‘curative’ preparatory therapy were available. However, the use of donor stem cells incurs a high risk of graft versus host disease that can be more devastating than MF. If the prevention and treatment of graft versus host disease can be improved, allogenic BMT has high potential for success in CTCL treatment, as demonstrated in one report of a refractory Sezary syndrome patient who attained a durable remission [105]. In recent years, there has been a trend towards the use of peripheral blood or umbilical cord blood instead of the bone marrow as a source of stem cells. Although there are no published data, stem cell transplantation is also feasible in CTCL. Mini-allogeneic transplantation is a recent development that uses less severe nonmyeloablative pretransplant radiation and chemotherapy regimens to minimize toxicity and immunosuppression to allow engraftment and enhancement of graftversus-tumor effects. Mini-allogeneic transplantation is still experimental and data on efficacy are still scarce. Summary & conclusions

The wide array of available therapeutic options can make choices in CTCL treatment rather complex. The management of CTCL is best approached by tailoring the treatment plan according to the unique disease characteristics and needs of each CTCL patient. The choice of therapy depends upon such factors as overall clinical stage, skin stage, lesional thickness (patch versus plaque), degree of cutaneous involvement, tolerance of treatment toxicities, geographic constraints, affordability and patient compliance. There have been many recent milestone additions to CTCL therapy, including ECP, bexarotene and DAB389-IL2. However, the advanced stages of disease remain resistant to durable responses and therapies for these stages require much more development, as most have so far proven ineffective or too toxic, especially in the case of monoclonal antibodies. Therapeutic combinations, such as IFN-α plus PUVA or bexarotene combinations offer the potential for more immediate improvements in therapy. Expert opinion & five-year view

CTCL is a rare disease that is not curable and lacks large multicenter trial data to support rational approaches to therapy. Therapy of the future will still be selected based on the patient’s stage and age and should be as conservative as possible initially. In the past 5 years we have seen the development of two new agents (ONTAK and bexarotene) that received FDA approval for treatment of CTCL. In the next 5 years, we will learn how to use them more effectively not only as monotherapy but in combination with other active agents. New biological response

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modifiers, such as IL-2, IL-12 and pegylated IFN and more selective retinoids may also become available and will be tested in CTCL. New immunomodulatory agents and monoclonal antibodies to T-cells that are being tested in psoriasis and other autoimmune diseases will be tested in CTCL patients with potential to improve or worsen the disease. Agents that selectively induce T-cell apoptosis or newer nucleoside analogs also may offer an exciting new therapeutic approach to the disease. Finally, mini-allogeneic bone marrow or stem cell transplantation will be tested to see if this disease can be cured. Approaches to augment the host’s cellular immune system should also lead to novel treatments and prolonged survival for CTCL patients. Information resources

The treatment of CTCL is a continually evolving field, so textbooks tend not to be the best sources of information. Although six years old, the October 1995, Volume 9 issue of Hematology/ Oncology Clinics of North America is devoted to CTCL and serves as a good comprehensive review. Other recent key journal review articles include the following: • Duvic M, Cather JC. Emerging new therapies for cutaneous T-cell lymphoma. Dermatol. Clin. 18, 147–156 (2000). • Siegel RS, Pandolfino T, Guitart J, Rosen S, Kuzel T. Primary cutaneous T-cell lymphoma: review and current concepts. J. Clin. Oncol. 18(15), 2908–2925 (2000). • Foss FM. DAB389-IL2 (ONTAK): A novel fusion toxin therapy for lymphoma. Clin. Lymphoma 1, 110–116 (2000). • Kim YH, Hoppe RT. Mycosis fungoides and the Sezary syndrome. Semin. Oncol. 26, 276–289 (1999). • Diamandidou E, Cohen PR, Kurzrock R. Mycosis fungoides and Sezary syndrome. Blood 88, 2385–409 (1996). • Bunn PA, Jr., Hoffman SJ, Norris D, Golitz LE, Aeling JL. Systemic therapy of cutaneous T-cell lymphomas (mycosis fungoides and Sezary syndrome). Ann. Intern. Med. 121, 592–602 (1994). In addition, some useful CTCL websites include: • www.CTCLconsult.com • www.mffoundation.org • www.lymphomainfo.net • www.cutaneouslymphoma.org

2

Bunn P, Lamberg S. Report of the committee on staging and classification of cutaneous T-cell lymphoma. Cancer

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• Cutaneous T-cell lymphoma (CTCL) treatment options are determined by overall clinical staging, T-stage and the nature and degree of disease involvement. • Mycosis fungoides (MF) is often exacerbated by infections that must be treated for the disease to improve. • Stage IA patients have survival that is similar to age-matched controls and should be treated conservatively. • In severe or aggressive disease, combinations of skin-directed therapies and biological response modifiers improve response rates. • In late-stage patients, aggressive chemotherapy does not improve overall survival over conservative sequential therapies and may precipitate opportunistic infections. • With the exception of extracorporeal photopheresis for Sezary syndrome, no treatments have been shown to improve survival in late-stage CTCL. • After remission has been achieved, use maintenance therapy with topical corticosteroids, topical mechlorethamine, IFN-α, or phototherapy to prevent disease relapse. • Patients receiving topical mechlorethamine, phototherapy and total-skin electron beam therapy should be monitored for the development of skin cancers and malignant melanomas. • Two new agents are approved for CTCL (bexarotene, a rexinoid or RXR-selective retinoid) and ONTAK, a fusion protein directed to the IL-2 receptor. • Bexarotene oral capsules are for all stages of CTCL. The gel is available for localized lesions. • Oral bexarotene therapy avoids catheters and line infections, but requires monitoring triglycerides and use of concomitant lipidlowering agents and thyroid replacement in most patients. • ONTAK, approved for CD25+ CTCL, is associated with capillary leak syndrome (20–30%) and acute hypersensitivity reactions, ameliorated by hydration and steroids. • Further developments for MF may include more selective immunomodulatory agents, monoclonal antibodies and bone marrow transplantation. • Further research and drug development need to continue in order to find a cure for CTCL.

Treatment Reports. 63, 725–728 (1979).

References

Papers of special note have been highlighted as: • of interest •• of considerable interest Weinstock MA, Gardstein B. Twenty-year 1 trends in the reported incidence of mycosis fungoides and associated mortality. Am. J. Public Health 89, 1240–1244 (1999).

Key issues

3

Kim YH, Hoppe RT. Mycosis fungoides and the sezary syndrome. Semin. Oncol. 26, 276–289 (1999).

4

Foss FM, Sausville EA. Prognosis and staging of cutaneous T-cell Lymphoma. Hematol. Oncol. Clin. N. Am. 9, 1011– 1019 (1995).

5

Kim YH, Jensen RA, Watanabe GL et al. Clinical stage Ia (limited patch and plaque)

mycosis fungoides: a long-term outcome analysis. Arch. Dermatol. 132, 1309–1313 (1996). 6

Kim YH, Chow S, Varghese A et al. Clinical characteristics and long-term outcome of patients with generalized patch or plaque (T2) mycosis fungoides. Arch. Dermatol. 135, 26–32 (1999).

7

Zackheim HS, Amin S, Mohammed KS et al. Prognosis in cutaneous T-cell lymphoma by skin stage: long-term survival Expert Rev. Anticancer Ther. 1(3), (2001)

CTCL treatment

Dermatologia e Venereologia 125, 91–95 (1990).

in 489 patients. J. Am. Acad. Dermatol. 40, 418–425 (1999). 8

Rosenberg S. Validity of the Ann Arbor staging classification for the non-Hodgkin’s lymphomas. Cancer Treat. Rep. 61, 1023 (1977).

Muche JM, Lukowsky A, Asadullah K, Gellrich S, Sterry W. Demonstration of frequent occurrence of clonal T-cells in the peripheral blood of patients with primary cutaneous T-cell lymphoma. Blood 90(4), 1636–1642 (1997). •• Establishes the presence of peripheral blood involvement even in patients with limited early-stage disease. 10 Jackow CM, Cather JC, Hearne V et al. Association of erythrodermic cutaneous Tcell lymphoma, superantigen-positive Staphylococcus aureus and oligoclonal T-cell receptor V-β gene expansion. Blood 89, 32– 40 (1997). •• Suggests that infection, especially with Staphylococcus aureus, may play a role in stimulating clonal expansion and erythrodermic manifestations in CTCL. 11 Duvic M, Cather JC. Emerging new therapies for cutaneous T-cell lymphoma. Dermatol. Clin. 18, 147–156 (2000).

18

9

12

13

Zackheim HS, Kashani-Sabet M, Amin S. Topical corticosteroids for mycosis fungoides: experience in 79 patients. Arch. Dermatol. 134, 949–954 (1988). Herrmann JJ, Roenigk HH, Jr., Honigsmann H. Ultraviolet radiation for treatment of cutaneous T-cell lymphoma. Hematol. Oncol. Clin. N. Am. 9, 1077– 1088 (1995).

19

20

21

•

22

23

Hermann JJ, Roenigk HH, Jr., Hurria A et al. Treatment of mycosis fungoides with photochemotherapy (PUVA): long-term follow-up. J. Am. Acad. Dermatol. 33, 234– 242 (1995). Stern RS, Nichols KT, Vakeva LH. Malignant melanoma in patients treated for psoriasis with methoxsalen (psoralen) and ultraviolet A radiation (PUVA): the PUVA follow-up study. N. Engl. J. Med. 336, 1041–1045 (1997). Rupoli S, Barulli S, Guiducci B et al. Low dose interferon-α2b combined with PUVA is an effective treatment of early stage mycosis fungoides: results of a multicenter study. Cutaneous T-cell lymphoma multicenter study group. Haematologica 84, 809–813 (1999). Stadler R, Otte HG, Luger T, Henz BM, Kuhl P, Zwingers T. Prospective randomized multicenter clinical trial on the use of interferon-2a plus acitretin versus interferon-2a plus PUVA in patients with cutaneous T-cell lymphoma stages I and II. Blood 92, 3578–3581 (1998). Randomized trial that establishes the high efficacy of the interferon and PUVA combination. Olsen E, Bunn PA. Interferon in the treatment of cutaneous T-cell lymphoma. Hematol. Oncol. Clin. N. Am. 9, 1089– 1107 (1995). Thomsen K, Hammar H, Molin L et al. Retinoids plus PUVA (RePUVA) and PUVA in mycosis fungoides, plaue stage. A report from the Scandinavian Mycosis Fungoides Group. Acta Derm. Venereol. 69, 536–538 (1989).

Ramsay DL, Meller JA, Zackheim HS. Topical treatment of early cutaneous T-cell lymphoma. Hematol. Oncol. Clin. N. Am. 9, 1031–1055 (1995).

24

15

Bunn PA, Jr., Hoffman SJ, Norris D, Golitz LE, Aeling JL. Systemic therapy of cutaneous T-cell lymphomas (mycosis fungoides and Sezary syndrome). Ann. Intern. Med. 121, 592–602 (1994).

Jumbou O, N’guyen JM, Tessier MH, Legoux B, Dreno B. Long-term follow-up in 51 pateints with mycosis fungoides and Sezary syndrome treated by interferon-α. Br. J. Dermatol. 140, 427–431 (1999).

25

16

Abel EA, Sendagorta E, Hoppe RT. Cutaneous malignancies and metastatic squamous cell carcinoma following topical therapies for mycosis fungoides. J. Am. Acad. Dermatol. 14, 1029–1038 (1986).

Steis RG, Smith JW, Urba WJ et al. Resistance to recombinant interferon α-2a in hairy cell leukemia associated with neutralizing anti-interferon antibodies. N. Engl. J Med. 318, 1409–1413 (1988).

26

17

Piccino R, Caccialanza M, Mainardi L. Comparison of the results obtained with ultraviolet radiation and photochemotherapy in the early stages of mycosis fungoides. Giornale Italiano di

VanderMolen LA, Steis RG, Duffey PL, Foon KA, Smith JW, Clark JW. Low-versus high-dose interferon α-2a in relapsed indolent non-Hodgkin’s lymphoma. J. Natl Cancer Inst. 82, 235–238 (1990).

27

Wolff JM, Zitelli JA, Rabin BS et al.

14


Intralesional interferon in the treatment of early mycosis fungoides. J. Am. Acad. Dermatol. 13, 604–612 (1985). 28

Thestrup-Pederson K, Hammer R, Kaltoft K, Sogaard H, Zachariae H. Treatment of mycosis fungoides with recombinant interferon-α2a alone and in combination with etretinate. Br. J. Dermatol. 118, 811– 818 (1988).

29

Aviles A, Guzman R, Garcia EL, DiazMaqueo JC. Biological modifiers (etretinate and α 2a) in the treatment of refractory cutaneous T-cell lymphoma. Cancer Biotherapy Radio. 11, 21–24 (1996).

30

Quesada JR, Talpaz M, Rios A et al. Clinical toxicity of interferons in cancer patients: a review. J. Clin. Oncol. 4, 234– 243 (1986).

31

Koh LK, Greenspan FS, Yeo PP. Interferonα induced thyroid dysfunction: three clinical presentations and a review of the literature. Thyroid 7, 891–896 (1997).

32

Kessler JF, Jones SE, Levine N, Lynch PJ, Booth AR. Isotretinoin and cutaneous helperT-cell lymphoma (mycosis fungoides). Arch. Dermatol. 123, 201–204 (1987).

33

Molin L, Thomsen K, Volden G et al. Retinoids and systemic chemotherapy in cases of advanced mycosis fungoides. A report from the Scandinavian Mycosis Fungoides Group. Acta Derm. Venereol. 67, 179-182 (1987).

34

Duvic M, Martin A, Kim Y et al. Phase II and III clinical trial of oral bexarotene (Targretin capsules) for the treatment of refractory or persistent early-stage cutaneous T-cell lymphoma. Arch. Dermatol. 137(5), 581–593 (2001). This article describes the multidose level trial demonstrating the effectiveness of bexarotene in refractory early-stage CTCL therapy and also details drug-related toxicities, such as central hypothyroidism and hypertrigylceridemia and their management.

•

35

•

Duvic M, Hymes K, Heald P et al. Bexarotene is effective and safe for treatment of refractory advanced-stage cutaneous T-cell lymphoma: multinational Phase II–III trial results. J. Clin. Oncol. 19(9), 2456–2471 (2001). This article describes the multidose level trial demonstrating the effectiveness and toxicity of bexarotene in late-stage CTCL therapy, including potential efficacy in the treatment of tumor and erythrodermicstage patients.

417


36

Talpur RS, Ward S, Apisarnthanarax N, Duvic M. Bexarotene combination therapy for cutaneous T-cell lymphoma. Society for Investigative Dermatology 62nd Annual Meeting. Washington D.C., USA, May (2001). (Abstract).

37

Sherman SI, Gopal J, Haugen BR et al. Central hypothyroidism associated wth retinoid X receptor-selective ligands. N. Engl. J. Med. 340, 1075–1079 (1999).

38

•

39

40

Jones GW, Hoppe RT, Glatstein E. Electron beam treatment for cutaneous Tcell lymphoma. Hem. Oncol. Clin. 9, 1057– 1075 (1995). A comprehensive overview of the Stanford, Hamilton and world data on total-skin electron beam therapy up until 1995. Chinn DM, Chow S, Kim YH, Hoppe RT. Total skin electron beam therapy with or without adjuvant topical nitrogen mustard or nitrogen mustard alone as initial treatment of T2 and T3 mycosis fungoides. Int. J. Radiat. Oncol. 43, 951–958 (1999).

Duvic M, Apisarnthanarax N, Sung HG et al. An analysis of long-term outcomes of combined modality therapy for cutaneous T-cell lymphoma. (in preparation).

42

Quiros PA, Jones GW, Kacinski BM et al. Total skin electron beam therapy followed by adjuvant psoralen/ultraviolet-A light in the management of patients with T1 and T2 cutaneous T-cell lymphoma (mycosis fungoides). Int. J. Rad. Oncol. Biol. Phys 38, 1027–1035 (1997).

44

45

Wilson LD, Licata Al, Braverman IM. Systemic chemotherapy and extracorporeal photochemotherapy for T3 and T4 cutaneous T-cell lymphoma patients who have achieved a complete response to total skin electron beam therapy. Int. J. Rad. Oncol. Biol. Phys 32, 987–995 (1995).

55

Fierro MT, Quaglino P, Savoia P, Verrone A, Bernengo MG. Systemic polychemotherapy in the treatment of primary cutaneous lymphomas: a clinical follow-up study of 81 patients treated with COP or CHOP. Leuk. Lymphoma 31, 583– 588 (1998).

47

Olsen EA, Duvic M, Frankel et al. Pivotal Phase III trial of two dose levels of denileukin diftitox for the treatment of cutaneous T-cell lymphoma. J. Clin. Oncol. 19, 376–388 (2001). A key trial on DAB389-IL2, the first genetically engineered CTCL celltargeting drug to be FDA-approved; the article discusses response characteristics, pharmokinetics, drug safety profile and the differences between low and high dosing levels. Foss FM. DAB389IL-2 (ONTAK): A novel fusion toxin therapy for lymphoma. Clin. Lymphoma 1, 110–116, (2000).

56

Rosen ST, Foss FM. Chemotherapy for mycosis fungoides and the Sezary syndrome. Hem. Oncol. Clin. 9, 1109– 1116 (1995).

57

Waddell CC, Zubler MA, Gore WS. Acute myeloblastic leukemia following chemotherapy for mycosis fungoides. Arch. Dermatol. 118, 179–182 (1982).

•

48

49

Duvic M, Cather J. Immunotoxin DAB389-interleukin-2 (Ontak) in the management of cutaneous T-cell lymphoma. Curr. Pract. Med. 2, 7–9 (1999).

50

LeMaistre CF, Saleh MN, Kuzel TM et al. Phase I trial of a ligand fusion protein (DAB389IL-2) in lymphomas expressing the receptor for interleukin-2. Blood 91, 399–405 (1998).

51

Duvic M, Cather J, Mazie J et al. DAB389IL2 diptheria fusion toxin produces responses in tumor stage cutaneous T-cell lymphoma. Am. J. Hem. 58, 87–90 (1998).

Price NM, Hoppe RT, Deneau DG. Ointment-based mechlorethamine treatment for mycosis fungoides. Cancer 52, 2214–2219 (1983).

41

43

46

Licata AG, Wilson LD, Braverman, IM, Feldman AM, Kacinski BM. Malignant melanoma and other second cutaneous malignanacies in cutaneous T-cell lymphoma: the influence of additional therapy after total skin electron beam radiation. Arch. Dermatol. 131, 432–435 (1995). Duvic M, Lemak NA, Redman JR et al. Combined modality therapy for cutaneous T-cell lymphoma. J. Am. Acad. Dermatol. 34, 1022–1029 (1996). Diamandidou E, Colome-Grimme M, Fayad L, Duvic M, Kurzrock R. Transformation of mycosis fungoides/ Sezary syndrome: clinical characteristics and prognosis. Blood 92, 1150–1159 (1998).

418

52

53

54

Duvic M, Kuzel TM, Olsen E et al. Quality of life is significantly improved in CTCL pastients who responded to DAB389-IL2 (ONTAK) fusion protein (abstract). Blood 92(10 Suppl. 1), 624a (1998). Foss FM, Bacha P, Kuzel TM. Biological correlates of acute hypersensitivity events with DAB389IL-2 (denileukin diftitox, ONTAK) in cutaneous T-cell lymphoma: decreased frequency and severity with steroid premedication. Clin. Lymphoma 1, 298–302 (2001). Duvic M, Talpur R, Boh E, Sidique Y, Stevens V. Improved tolerability of ONTAK (denileukin diftitox) with corticosteroid premedication patients with CTCL. American Society of Hematology 43rd Annual Meeting. Orlando, USA, (2001). (Abstract)

Kaye FJ, Bunn PA, Steinberg SM et al. A randomized trial comparing combination electron beam radiation and chemotherapy with topical therapy in the initial treatment of mycosis fungoides. N. Engl. J. Med. 321, 1784–1790 (1989). •• The only controlled, randomized trial demonstrating that aggressive systemic chemotherapy does not improve overall survival in comparison to sequential conservative therapy.

58

59

Vonderheid E, Bernengo MG, Burg G. Update on erythrodermic cutaneous T-cell lymphoma: report of the International Society for Cutaneous Lymphomas. J. Am. Acad. Dermatol. (In Press).

60

Edelson R, Berger C, Gasparro F et al. Treatment of cutaneous T-cell lymphoma by extracorporeal photochemotherapy. N. Engl. J. Med. 316, 297–303 (1987).

61

Heald PW, Rook A, Perez MI et al. Treatment of erythrodermic cutaneous Tcell lymphoma with extracorporeal photochemotherapy. J. Am. Acad. Dermatol. 27, 427–433 (1992). Follow-up on the original Edelson et al. data demonstrating improved overall survival of CTCL patients with extracorporeal photopheresis therapy. Lim HW, Edelson RL. Photopheresis for the treatment of cutaneous T-cell lymphoma. Hematol. Oncol. Clin. N. Am. 9, 1117–1126 (1995).

•

62

63

Di Renzo M, Rubegni P, De Aloe G et al. Extracorporeal photochemotherapy restores Th1/Th2 imbalance in patients with early stage cutaneous T-cell lymphoma. Immunology 92, 99–103 (1997).

64

Miracco C, Rubegni P, De Aloe G et al. Extracorporeal photochemotherapy induces apoptosis of infiltrating lymphoid cells in


CTCL treatment

patients with mycosis fungoides in early stages. A quantitative histological study. Br. J. Dermatol. 137, 549–557 (1997). 65

66

•

67

Jiang SB, Dietz SB, Kim M, Lim HW. Extracorporeal photochemotherapy for cutaneous T-cell lymphoma: a 9.7-year experience. Photoderm. Photoimmunol. Photomed. 15(5), 161–165 (1999). Fraser-Andrews E, Seed P, Whittaker S, Russell-Jones R. Extracorporeal photopheresis in Sezary syndrome: No significant effect in the survival of 44 patients with a peripheral blood T-cell clone. Arch. Dermatol. 134, 1001–1005 (1998). The trial that instigated a controversial debate on the efficacy of extracorporeal photopheresis in Sezary syndrome. Stevens S, Bowen G, Duvic M et al. Effectiveness of photopheresis in Sezary syndrome. Arch. Dermatol. 135, 995–997 (1999).

68

Edelson RL. Sezary syndrome, cutaneous T-cell lymphoma and extracorporeal photopheresis. Arch. Dermatol. 135, 600– 601 (1999).

69

Russell-Jones R. Extracorporeal photopheresis in cutaneous T-cell lymphoma: Inconsistent data underline the need for randomized structures. Br. J. Dermatol. 142, 16–21 (2000).

70

71

72

73

74

Duvic M, Hester JP, Lemak NA Photopheresis therapy for cutaneous T-cell lymphoma. J. Am. Acad. Dermatol. 35, 573–579 (1996). Bisaccia E, Gonzalez J, Palangio M et al. Extracorporeal photochemotherapy alone or with adjuvant therapy in the treatment of cutaneous T-cell lymphoma: a 9-year retrospective study at a single institution. J. Am. Acad. Dermatol. 43, 263–271 (2000). Gottlieb SL, Wolfe JT, Fox FE et al. Treatment of cutaneous T-cell lymphoma with extracorporeal photopheresis monotherapy and in combination with recombinant interferon-α: a 10-year experience at a single institution. J. Am. Acad. Dermatol. 35(6), 946–957 (1996). Wilson LD, Jones GW, Kim D et al. Experience with total skin electron beam therapy in combination with extracorporeal photopheresis in the management of patients with erythrodermic (T4) mycosis fungoides. J. Am. Acad. Dermatol. 43, 54– 60 (2000). Rook AH, Suchin KR, Kao DMF et al.


Photopheresis: clinical applications and mechanism of action. J. Invest. Dermatol. Symp. Proc. 4, 85–90 (1999). 75

76

77

78

79

Weinstein GD, Krueger GG, Lowe NJ et al. Tazarotene gel, a new retinoid, for topical therapy of psoriasis: vehiclecontrolled study of safety, efficacy and duration of therapeutic effect. J. Am. Acad. Dermatol. 37(1), 85–92 (1997). Shalita AR, Chalker DK, Griffith RF et al. Tazarotene gel is safe and effective in the treatment of acne vulgaris: a multicenter, double-blind, vehicle-controlled study. Cutis 63(6), 349–354 (1999). Apisarnthanarax N, Talpur R, Ward S, Duvic M. Tazarotene 0.1% gel in the treatment of refractory mycosis fungoides: an open-label pilot study. American Academy of Dermatology Summer Meeting. Anaheim, USA, (2001). (Abstract). Fox E, Niu Z, Tobia A et al. Photoactivated hypericin is an antiproliferative agent that induces a high rate of apoptotic death of normal, transformed and malignant Tlymphocytes: implications for the treatment of lymphoproliferative and inflammatory disorders. J. Invest. Dermatol. 111, 327–332 (1998). Chabner BA, Young RC. Threshold methotrexate concentration for in vivo inhibition of DNA synthesis in normal and tumorous target tissues. J. Clin. Invest. 52, 1804–1811 (1973).

85

Baccard M, Marolleau JP, Rybojad M. Middle-term evolution of patients with advanced cutaneous T-cell lymphoma treated with high-dose recombinant interleukin-2. Arch. Dermatol. 133, 656 (1997).

86

Rook AH, Wood GS, Yoo EK et al. Interleukin-12 therapy of cutaneous T-cell lymphoma induces lesion regression and cytotoxic T-cell responses. Blood 94, 902– 908 (1999).

87

Duvic M, Phillips R, Yoon L et al. Interleukin-12 therapy in early mycosis fungoides is associated with reduced expression of lesional cytokines. Society of Investigative Dermatology 62nd Annual Meeting. Chicago, USA, (2000). (Abstract).

88

Zinzani PL, Baliva G, Magagnoli M et al. Gemcitabine treatment in pretreated cutaneous T-cell lymphoma: experience in 44 patients. J. Clin. Oncol. 18, 2603–2606 (2000).

89

Foss FM. Activity of pentostatin (Nipent) in cutaneous T-cell lymphoma: single-agent and combination studies. Semin. Oncol. 27(Suppl.), 58–63 (2000).

90

Kurzrock R, Pilat S, Duvic M. Pentostatin therapy of T-cell lymphomas with cutaneous manifestations. J. Clin. Oncol. 17, 3117–3121 (1999).

91

Foss FM, Ihde D, Breneman DL et al. Phase II study of pentostatin and intermittent high-dose recombinant interferon α-2a in advanced mycosis fungoides/Sezary syndrome. J. Clin. Oncol. 10, 1907–1913 (1992).

80

Weinstein GD, McCullough JL, Olsen E. Topical methotrexate therapy for psoriasis. Arch. Dermatol. 125, 227–230 (1989).

81

Clark C, Dawe RS, Evas AT et al. Narrowband TL-01 Phototherapy for patch-stage mycosis fungoides. Arch. Dermatol. 136, 748–752 (2000).

92

Margolis J, Grever MR. Pentostatin (Nipent): a review of potential toxicity and its management. Semin. Oncol. 27(Suppl. 5), 9–14 (2000).

82

Coven T, Burack LH, Gilleaudeau P et al. Narrowband UV-B produces clinical and histological resolution of moderate to severe psoriasis in patients compared with broadband UV-B. Arch. Dermatol. 133, 1514–1522 (1997).

93

Von Hoff D, Dahlberg S, Hartstock R et al. Activity of fludarabine monophosphate in patients with advanced mycosis fungoides: a Southwest Oncology Group study. J. Natl Cancer Inst. 82, 1353–1355 (1990).

94

83

Lindsay KL. A randomized, double-blind trial comparing pegylated interferon α-2b to interferon α-2b as initial treatment for chronic hepatitis C. Hepatology 34, 395– 403 (2001).

Foss F, Ihde D, Linnoila IR et al. Phase II study of fludarabine phosphate and interferon α-2a in advanced mycosis fungoides/Sezary syndrome. J. Clin. Oncol. 12, 2051–2059 (1994).

95

84

Marolleau JP, Baccard M, Flageul B et al. High-dose recombinant interleukin-2 in advanced cutaneous T-cell lymphoma. Arch. Dermatol. 131, 574–579 (1995).

Kuzel TM, Hurria A, Samuelson E et al. Phase II trial of 2-chlorodeoxyadenosine for the treatment of cutaneous T-cell lymphoma. Blood 87, 906–911 (1996).

96

Newlands ES, Blackledge GRP, Slack JA

419


et al. Phase I trial of temozolomide (CCRG 81045: M&B 39831: NSC 362856). Br. J. Cancer 65, 287–291 (1992). 97

98

99

Dolan ME, McRae BL, Ferries-Rowe E et al. O6-Alkylguanine-DNA alkyltransferase in cutaneous T-cell lymphoma: implications for treatment with alkylating agents. Clin. Cancer Res. 5, 2059–2064 (1999). Gabizon AA. Selective tumor localization and improved therapeutic index of anthracyclines encapsulated in longcirculating liposomes. Cancer Res. 52, 891– 896 (1992). Wollina U. Pegylated doxorubicin for primary cutaneous T-cell lymphoma: a report on ten patients with follow-up. J.

420

Cancer Res. Clin. Oncol. 127, 128–134 (2001). 100

Prince HM, Seymour JF, Ryan G, McCormack C. Pegylated liposomal doxorubicin in the treatment of cutaneous T-cell lymphoma. J. Am. Acad. Dermatol. 44, (2001)

101

Bunn PA, Jr., Norris DA. The therapeutic role of interferons and monoclonal antibodies in cutaneous T-cell lymphomas. J. Invest. Dermatol. 95(Suppl.), 209S–12S (1990).

102

Knox S, Hoppe RT, Maloney D et al. Treatment of cutaneous T-cell lymphoma with chimeric antiCD4 monoclonal antibody. Blood 87, 893–899 (1996).

103

Lundin J, Osterborg A, Brittinger G et al. CAMPATH-1H monoclonal antibody in therapy for previously treated low-grade non-Hodgkin’s lymphomas: a Phase II multicenter study. European Study Group of CAMPATH-1H Ttreatment in lowgrade Non-Hodgkin’s lymphoma. J. Clin. Oncol. 16, 3257–3263 (1998).

104

Bigler RD, Crilley P, Micaily B et al. Autologous bone marrow transplantation for advanced stage mycosis fungoides. Bone Marrow Transplant. 7, 133–137 (1991).

105

Molina A, Nademanee A, Arber DA et al. Remission of refractory Sezary syndrome after bone marrow transplantation from a matched unrelated donor. Biol. Blood Marr. Transpl. 5, 400–404 (1999).
