IOURNAL of

the

AmeRiCaN ACaDemy OF

DerMaTOLOGY VOLUME 27

Continuing

NUMBER 3

SEPTEMBER 1992

medical education

Therapeutic alternatives in cutaneous T-cell lymphoma Kathryn B. Holloway, MO,a Franklin P. Flowers, MO,b and Francisco A. Ramos-Caro, MDb, c Gainesville, Florida Mycosis fungoides and S6zary syndrome, collectively referred to as cutaneous T-cell lymphoma, are non-Hodgkin's lymphomas that initially appear in the skin. Early-stage disease, limited to the skin, is best treated with sequential topical therapies such as topical nitrogen mustard, psoralen phototherapy (PUVA), or total-skin electron beam therapy. Photopheresis is the first line of therapy for the patient with erythroderma. Systemic therapy is generally reserved for patients with refractory disease and patients who initially present with extracutaneous involvement. Although there are several treatment options for cutaneous T-cell lymphoma, there have been few randomized comparative trials. (J AM ACAD DERMA. TOL

1992;27:367-78.)

Cutaneous T-cell lymphoma (CTCL) is characterized by a proliferation of T lymphocytes with phenotypic and functional properties of helper T cells. I In a few cases, cytotoxic/suppressor T cells are the malignant clone. 2 CTCL encompasses a spectrum of disease including mycosis fungoides (MF) and S6zary syndrome. Typically, MF initially appears in the skin as patches or plaques. Progression occurs with the development of ulcerating cutaneous tumors and eventual spread to lymph nodes, peripheral blood, and visceral organs. S6zary syndrome is a form of CTCL characterized by generalized erythroderma, lymphadenopathy, and the presence in the blood of circulating atypical mononuclear cells with hyperconvoluted nuclei. I The natural history of CTCL consists of a variable, usually

\tI \J.J

The CME articles are made possible through an educational grant from the Dermatological Division of Ortho Pharma· ceutical Corporation. From the Department of Medicine" and the Division of Dermatology & Cutaneous Surgery,b University of Florida College of Medicine; and the Dermatology & Cutaneous Surgery Section, Veterans Administration Medical Center, Gainesville. c Reprint requests: Franklin P, Flowers, MD, Division of Dermatology, P.O. Box 100277, Gainesville, FL 32610·0277.

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chronic course. Survival is best predicted by the stage of disease (Tables I and II). In a study by the National Cancer Institute,3 good-risk patients, defined as having T I or T 2 skin disease without lymph node, blood, or visceral involvement, had a median survival of more than 12 years. Intermediate-risk patients had a median survival of 5 years and included all other patients except those with lymph node effacement or visceral disease. Patients with visceral involvement or effaced lymph nodes (stage IVa or IVb), the poor-risk group, had a median survival of less than 3 years. The natural course of untreated CTCL is unknown because it is not ethical to withhold palliative or possibly curative treatment from patients with this disease. I The diagnosis of early CTCL is often difficult and delayed for several years. I Once the diagnosis has been established, the extent of skin involvement and disease stage must be determined to select the most appropriate therapy. The associated pruritus and dry skin should be symptomatically treated. Emollients, topical steroids, analgesics, and antihistamines may be beneficiaL Often antibiotics are required for the treatment of secondarily infected ulcerations. In addition to the stage of disease, other

367

368 Holloway et

Journal of the American Academy of Dermatology

at.

Table I. Staging of cutaneous T-cell lymphoma (CTCL): TNM classification*

I

Oassification

Description

T: Skin To

Lesions clinically and/or histopathologically suggestive of CTCL Limited plaques, papules, or eczematous patches covering - 10% of skin surface Tumors Generalized erythroderma

T3 T4

N: Lymph nodes No

No palpable adenopathy, lymph node pathology negative for CTCL Palpable adenopathy, lymph node pathology negative for CTCL No palpable adenopathy, lymph node pathology positive for CTCL Palpable adenopathy, lymph node pathology positive for CTCL

B: Peripheral blood

B1

Atypical circulating cells not present «5%) Atypical circulating cells present (>5%)

M1

No visceral organ involvement Visceral involvement (must have pathology confirmation and organ involved should be specified)

Bo

M: Visceral organs Mo

*Bunn PA, Lamberg 81. Report of the Committee on Staging and Classification of Cutaneous T-cell Lymphomas, Cancer Treat Rep 1979;63:725-8.

Table II. Staging classification of CTCL* Classification Stage

Ia Ib IIa IIb III IVa IVb

I

T

N

M

1 2 1,2 3 4 1-4 1-4

°°

0 0 0 0 0 0 1

1 0,1 0, 1 2, 3 0-3

T, Skin; N, lymph node, M, visceral. *Bunn PA, Lamberg 81. Report of the Committee on Staging and Classification of Cutaneous T-cell Lymphomas. Cancer Treat Rep 1979;63:725-8,

factors that should be considered in selection of treatment include the general health and age of the patient and the availability of various treatment options. These options are reviewed and a suggested treatment algorithm based on stage of disease is provided (Table III). TOPICAL CHEMOTHERAPY

Topical mechlorethamine hydrochloride (topical nitrogen mustard) has been used to treat CTCL for

more than 30 years. 4 The effectiveness of topical mechlorethamine (HN2) in producing a prolonged complete remission in early-stage CTCL has been reported by several investigators. S-12 Most recently, Vonderheid et a1. 12 summarized their experience with topical HN2 in 324 CTCL patients. Complete response rates observed were as follows: stage la, 80% (71 of 89 patients); lb, 68%; IIa, 61%; lIb, 49%; and III, 60%. Attainment of a complete response correlated with increased survival as did early-stage disease. Of the patients achieving a complete response, 34% had remissions of 4 years' duration or longer even with discontinuation of maintenance therapy. Remissions lasting more than 8 years were observed in 10.5% (34 of 324 CTCL patients). Most of these patients (25 of the 34) were in the patch or plaque stage. Because all relapses occurred within 8 years, this 10.5% possibly represents a cure rate. In this study, many patients with slowly responsive disease or extensive disease received local radiotherapy, total-skin electron beam therapy, systemic chemotherapeutic drugs, or phototherapy. However, of the 34 CTCL patients with presumptive cure, none received electron beam therapy or photochemotherapy, whereas nine received systemic drugs. Mainte-

Volume 27 Number 3 September 1992

Therapies for CTCL 369

Table III. Treatment by stage Choice of treatment modality mainly depends on extent and aggressiveness of disease. A physician must also consider age of the patient and presence of concurrent disease, geographic availability of treatment techniques, and patient compliance. Because most of the existing studies are not prospective randomized trials with appropriately matched controls, this table is a suggested treatment algorithm based on available published data. Stage Ia: Limited patch/plaque 1. Generalized topical nitrogen mustard 2. Ifunable to tolerate topical HN2 --->- PUVA or RePUVA37 or topical BCNU16 3. Ifdisease progression or if disease is refractory to treatments already mentioned --->- total skin electron beam therapy or PUVA with interferon-a26 Stage Ib: Generalized patch/plaque Stage IIa: Patch/plaque without histologic node involvement A. Chronic disease --->- as above, topical HN2 or PUVA B. Rapidly progressive disease with thick plaques 1. Total-skin electron beam therapy with optional follow-up therapy such as topical HN2, PUVA, or photopheresis to maintain remissionS! 2. Ifrefractory to these treatments, add systemic drug such as interferon-a, a retinoid, or single agent chemotherapeutic agent (e.g., methotrexate) Stage IIb: Tumors 1. Total-skin electron beam therapy with boost radiation to tumors with optional follow-up topical therapies or photopheresis to maintain response8! 2. Sequential topical therapies for refractory lesions (see Stage Ia) 3. Ifdisease progression --->- photopheresis; if no response, systemic therapy Stage III: Generalized erythroderma without histologic node involvement S6zary syndrome: Erythroderma, lymphadenopathy, and circulating atypical cells 1. Photopheresis 2. Ifdisease progression or if unresponsive --->- add methotrexate to photopheresis8 ! 3. Ifdisease progression - palliative PUVA, palliative topical HN2, interferon-a, systemic chemotherapy, retinoids, experimental protocols such as fiudarabine, monoclonal antibodies, or bone marrow transplant Stage IVa: Histologic lymph node involvement Individualized palliative treatment 1. Interferon-a, systemic chemotherapy 2. Local radiation to local symptomatic disease 3. Photopheresis (response does not correlate with lymph node involvement) 4. Retinoids, experimental protocols as already mentioned Stage IVb: Visceral involvement Individualized palliative treatment 1. Systemic chemotherapy 2. Interferons, retinoids, experimental protocols as already mentioned

nance therapy was discontinued within 6 months after complete response in 10 of these same 34 patients who were without relapse after 8 years. Therefore these investigators 12 surmised that prolonged maintenance therapy is not a necessity for a durable remission. The 5- and la-year survival rates for all patients were 72.6% and 61 %, respectively. Similar complete response rates were attained in a series of 117 CTCL patients reported by Ramsay et a1.!1 In this study, the probability of achieving a complete remission within 2 years was 75.8% for patients with stage I disease, 44.6% for stage II, and 48.6% for stage III. A median of 10.9 months was required to achieve a complete response. When daily topical HN2 was restarted, a second complete

remission was attained in 21 of 29 patients who had had a relapse. The only alternative therapy used was local radiotherapy to skin tumors. In a third large study, Hoppe et al. IO reported complete response rates in 123 patients treated with generalized topical HN2 as follows: TI, 51%; T 2, 26%; T 3, 0%; and T 4, 22%. The lower response rates could have been secondary to the use of an ointment preparation (which was not used by the other investigators) or the lack of concurrent additional therapy that was used in other studies. 12 Relapse occurred in 56% of patients who achieved a complete response. However, 54% of these relapsed patients achieved a second complete response with a second course of topical HN2. A "freedom-from-relapse" curve pre-

370

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Holloway et al.

sented by Hoppe et al. lO supported the observation by Vonderheid et al. l2 that disease relapses did not occur after 8 years and that the probability of a presumptive cure was approximately 11 %. An aqueous solution is prepared daily by the patient at home by dissolving IOta 20 mg of mechlorethamine in 40 to 60 ml of water. This solution is then applied to the entire skin surface once daily until complete remission is achieved. Several months may be required to achieve a complete response. I0-12 Duration and frequency of maintenance therapy are highly variable among institutions. Hoppe et al. 10 continued treatment for 1 to 2 years after a complete response. Ramsay et al. II continued daily treatments for 6 months after skin clearing and then tapered the treatments during the next 1 1/2 years. Vonderheid et al. I2 recommended only 6 months of maintenance therapy. The aqueous solution retains biologic activity for approximately 1 day unless refrigerated. However, the ointment preparation of HN2 has a prolonged shelf life of more than 50 days. 13 An allergic contact dermatitis or delayed hypersensitivity to topical HN2 occurs in 35% to 67% of patients.4·6, 8·12 Most patients can be topically desensitized by a reduction in the concentration of HN2 followed by gradual escalation. A much lower frequency of hypersensitivity has been observed in patients treated with the ointment-based preparation of HN2. 9, 10 Other adverse reactions that may be encountered include a contact irritant dermatitis,4, 6, 8,10 dry skin,4 hyperpigmentation,4, 6,8 telangiectasis formation,8 and an increased risk of cutaneous squamous cell and basal cell carcinomas. 4, 10, 12,14 The recommendation by Vonderheid et al. 12 to limit maintenance therapy to 6 months is an attempt to minimize the carcinogenic effects of topical HN2. Another topical agent that has been shown to be beneficial in the treatment of CTCL is carmustine (BCNU).l5-17 Zackheim et aLi7 recently summarized their long-term data in 143 patients. A complete response was observed as follows: stage la, 86%; stage Ib, 47%; stage IIa, 55%; stage IIb, 17%; stage III, 21 %; and stage IV, 0%. The median time to achieve complete response was 11.5 months. The estimated freedom from relapse at 5 years was 18%. Patients with early-stage disease had significantly increased freedom from relapse and survival. The median follow-up periods were longer than 40 months for the T I and T 2 groups. The complete re-

sponse rate, freedom from relapse rate, and 5-year survival for BCND is similar to topical HN2. IO-l2 , 17 A treatment course generally consists of a 10 mg/60 ml daily dose applied to the entire skin surface for 7 to 14 weeks. Resistant lesions can be treated with a 4 mg/m1 solution. For patients with an inadequate response, treatment is restarted (after a 6-week rest period) with a 20 mg daily dose for a shortened course of 4 to 8 weeks. Patients received a mean of 2.1 treatment courses in the study of Zackheim et al. l ? Maintenance therapy is not used. Therapy is intermittent because of potential bone marrow suppression. Mild bone marrow depression occurred in 7.4% of patients treated with a 10 to 25 mg daily dose of BCND for 3 to 17 weeks. 17 Other side effects include erythema, hyperpigmentation, telangiectases, andskin tenderness. Hypersensitivity reactions were observed in only 7% of patients. Therefore topical BCND is frequently used on patients unable to apply HN2 because of allergic contact dermatitis.

PHOTOTHERAPY Treatment of CTCL with oral psoralen with UVA irradiation (PUVA) has been shown to be efficacious for the early stages of the disease. This was first reported by Gilchrest et aP8 in 1976. An update of this initial clinical trial was published in 1979. 19 Complete clearing was seen in 7 of 11 patients treated with PUVA, whereas a partial response was noted in three. Four patients remained without relapse for more than 3 years while receiving maintenance therapy. Numerous later studies have confirmed the efficacy ofPUVA for clearing early-stage CTCL as well as the benefit of maintenance therapy in prolonging remission. 2o.25 Recently, Roenigk et al. 26 reported long-term data on 82 patients with a mean follow~up period of 45 months. Complete clearing with PDVA was seen in 88% of patients with limited-plaque disease and 51.9% with extensive-plaque disease. No patients with tumor-stage disease had complete clearing. Although some patients with erythroderma responded, most had a relapse while receiving maintenance therapy. Patients with limited-plaque disease remained clear for a mean time of 13 months, whereas those with extensive-plaque involvement had a mean duration of remission of 11 months. A significant frequency of relapse of disease was noted in all stages when PDVA was discontinued or changed to maintenance. Therefore these investigators recommended aggressive continuous maintenance PUVA in all patients even

Volume 27 Number 3 September 1992

when they are clear. In contrast, Honigsmann et al. 27 reported that after cessation of a single PlNA course with no maintenance therapy, 55.6% of stage Ia patients and 38.5% of stage Ib patients had no recurrence of CTCL during a mean follow-up of 44 months. Patients in the early stages of disease required a lower mean total dose of PUVA for complete clearing and had a longer duration of diseasefree interval than patients with advanced disease. 26 Generally, the PUVA treatment consists of an oral 0.6 mg/kg dose of 8-methoxypsoralen (8MOP) 2 hours before treatment. An encapsulated liquid preparation of 8-MOP, Oxsoralen Ultra, induces photosensitivity earlier and UVA irradiation may be begun 1 hour after ingestion of this preparation. 28 The patient's initial dose of UVA is based on the degree of pigmentation before therapy, history of tanning ability, and the type of phototherapy unit to be used. The exposure time is then gradually increased depending on the patient's response and presence of erythema. Usually PUVA is given two or three times a week until the lesions clear. Maintenance therapy can be initiated after complete clearing. 25 ,26, 29 However, not all investigators agree that this is necessary.27 In general, PlNA is well tolerated and few side effects are encountered. Erythema, nausea, and pruritus occur in 10% to 20% of patients.30 Ingestion of the psoralen with food or milk, the use of antiemetics, or division of the dose so that half is given 2 Ih hours and the remainder 2 hours before UVA exposure minimize the nausea. Pruritus can be relieved by emollients or oral antihistamines. Some long-term complications of PUVA that have been observed include an increased risk of squamous cell carcinoma of the skin and male genitalia,31,32 development of pigmented macules,33 cutaneous amyloid deposition,34 nail pigmentation,35 and cataract formation. 3o All patients should be checked regularly for skin cancer, should protect their eyes during and after PUVA therapy, and should have an annual ophthalmologic examination. Given the high relapse rate with PlNA alone, adjunctive treatments have been introduced. Topical nitrogen mustard has been successfully used to clear areas of disease that are relatively shielded from PUVA, often called sanctuary sites. 36 Thomsen et al.37 introduced the use of retinoids in combination with PUVA (RePUVA). The complete response rate of RePUVA was equal to PUVA alone. However, the addition of retinoids reduced signifi-

Therapies for CTCL 371 cantly the number of PUVA treatments required to achieve remission as well as the total UVA dose needed. Although the relapse rate after complete remission was the same for RePUVA and PUVA, the duration of remission seemed more prolonged if maintenance retinoids were given. The retinoids given consisted of etretinate, 0.3 to 1 mg/kg, and isotretinoin, 0.5 to 1.5 mg/kg. Roenigk et al.26 reported the successful use of standard PUVA therapy combined with recombinant interferon alfa-2a given intramuscularly 3 times weekly. A complete response was observed in 80% (12 of 15 patients) and a partial response in 2 of 15 CTCL patients ( 13.3%) for an overall response rate of 93.3% in all stages of disease. Long-term fo1- . lOW-Up is not available. Significant side effects included fever, chills, fatigue, and muscle aches in 93.3% of patients. Acetaminophen taken before treatment partially relieved these symptoms. A confused state or depression was experienced by 33.3% of patients; these resolved with a decreased interferon-a dose. Other side effects included alopecia, nail changes, nausea, vomiting, impotence, and a metallic taste. Laboratory toxicities noted were mild elevations of liver transaminase levels and mild leukopenia. Many patients required dosage reductions because of these side effects. The combination of PUVA and interferon-a appears to be an effective treatment of CTCL but it is associated, with a relatively high incidence of side effects. RADIATION THERAPY

The neoplastic cells of CTCL are radiosensitive. Co:p.ventional x-ray treatment used in the early 1900s was limited because of normal organ toxicity and complications including lymphopenia. 1 Since the 19508, total-skin electron beam (TSEB) therapy has been primarily used for CTCL limited to the skin. This method allows delivery of high-energy electrons to a limited depth of the entire skin surface and therefore prevents systemic toxicity.38 The efficacy of TSEB has been demonstrated in several studies. 39-44 The original clinical trial was reported by Hoppe et al.39 in 1979. Hoppe44 recently updated the Stanford experience with high-dose (>2000 cGy) TSEB in 192 patients with MF limited to the skin who were treated between 1966 and 1987. Although nearly every patient achieved a partial response to treatment, the complete response rates were as follows: limited plaque (Td, 98%; generalized plaque (T2), 71 %; tumor, 36%; anderythro-

372 Holloway et al. derma, 64%. Most patients had a relapse within 5 years. The long-term "freedom-from-relapse" rate is approximately 50% at 10 years for the limitedplaque group and 20% in the generalized-plaque group. In the original report, patients treated with doses greater than or equal to 3000 cGy (rad) had a significantly better survival rate than those treated with doses less than 3000 cGy.39 The initial extent of skin involvement was a significant prognostic factor for survival and freedom from relapse. Prognosis was also adversely affected by increased age and the presence of palpable lymph nodes. Freedom from relapse rate at 5 years for early stage (T1-T2) disease has been observed to be 31% to 44% in other studies. 4o,43 The overall survival rate at 5 years is approXimately 70%40,41 with the 10-year survival rate noted to be 46% by Hoppe et al.39 Patients with limited plaque disease have a lO-year survival rate of 80%.44 The treatment generally involves a total dose of 3000 to 3600 cGy administered in an 8- to lO-week period.39, 41, 44 At Stanford, patients often receive a 1-week split after 1800 to 2000 cGy to relieve some of the associated skin erythema. 44 Tadros et al. 40 administered 3500 cGy in 3 weeks. The eyes are routinely shielded and supplemental treatment is usually administered to "shadowed" areas such as the perineum, soles, and scalp.41, 43, 44 Patients with localized thick plaques or tumors often receive additional treatment to these areas.44 The most common side effects include generalized erythema,40-44 edema,40-43 moist desquamation,40, 42, 44 apparent exacerbation of preexisting lesions,40, 42 total alopecia and nail loss,40-44 and occasional blister formation. 4o,41, 43 Long-term complications include hyperpigmentation,4o, 41, 43 occasional scattered telangiectases,44 and chronic dry skin41 .44 that often requires the use of emollients. The alopecia is usually transient if the scalp dose is limited to 2500 cGy.44 Occasionally patients who are treated primarily by topical chemotherapy or PUVA receiv~local radiotherapy to individual large tumors or thickened plaques. Cotter et al.45 recommend a total tumor dose of at least 3000 cGy at 200 cGy per fraction, five fractions per week, for adequate control of local cutaneous lesions of CTCL. Recently Micaily et al.46 reported the use of combined TSEB radiation and total nodal irradiation for CTCL. They noted an increase in disease-free survival but not in the overall survival rate when com-

Journal of the American Academy of Dermatology

pared with TSEB alone. This was attributed to patient selection and the high incidence of second malignancy observed, which could have been a result of the radiotherapy. Because of the high relapse rate, adjuvant topical therapy (topical HN2 or PUVA) has been recommended after completion of TSEB.39, 44, 47 Patients with erythroderma generally experience severe side effects from TSEB because of their atrophic, sensitive skin and should be treated with other modalities. 44 SYSTEMIC CHEMOTHERAPY

Advanced CTCL often requires systemic therapy. Chemotherapy is used mainly for palliation in patients who have had a relapse or patients who initially appear with nodal or visceral involvement, or both. The single agent and combination chemotherapy regimens have been extensively reviewed. 48 ,49 In general, treatment with single chemotherapeutic agents yielded an objective response (complete response and partial response) rate of 60% to 70% and a complete response rate of 15% to 25% with a median duration ofresponse usually less than 6 months. The agents that have been studied include mechlorethamine, cyclophosphamide, chlorambucil, methotrexate, cisplatin, doxorubicin, VP-16, VM26, fludarabine phosphate, and 2'-deoxycoformycin (pentostatin).48-53 Significantly higher complete response rates and a longer response duration have been reported by McDonald and Bertin054 with the use of moderate dose methotrexate (60.to 240 mg/m2 or 1 to 5 mg/kg intravenously) followed by oral citrovorum factor. Seven of 11 patients had a complete response and 2 of 11 had more than 80% clearing. Remissions of 6 to 30 months were maintained with low to intermediate doses of oral methotrexate weekly. Reviews of the several small trials of different combination chemotherapy regimens48 ,49 reveal objective response rates of 60% to 100%; the complete response rates ranged up to 57% and a median duration of response was approximately 1 year. One exception is the report by Zakem et al. 55 in which 7 of 10 patients with advanced-stage CTCL obtained a histologically documented complete response with a median duration more than 19 months when treated with bleomycin, doxorubicin, and methotrexate with topical nitrogen mustard (BAMM). In addition, three patients with stage IV disease remained in complete remission for more than 3 years. The significance of this is uncertain because these

Volume 27 Number 3 September 1992

three patients were significantly younger and had all undergone splenectomy. This drug regimen was frequently associated with neutropenia and infection. COMBINED MODALITY THERAPY

When the combination of TSEB therapy with combination chemotherapy was initially reported by Griem et al. 56 in 1979, early results suggested that it could achieve longer remissions and increased survival. Their 10-year follow-up results were recently reported for 21 patients with tumor-stage CTCL who were treated with 3200 to 4000 cOy TSEB followed by six monthly cycles of combination chemotherapy. 57 The complete response rate was 52% (11 of 21 patients) with a median diseasefree survival of 12 months. However, all patients had a relapse within 24 months. Many relapses were limited plaques, responded to repeat treatment, and were controlled with maintenance therapy including chemotherapy, PUVA, and topical HN2. The median survival was 6 years with a 1O-year survival rate of 40%. The nonrandomized study by Braverman et al.58 revealed a significant increase in duration of complete clinical remission in early-stage CTCL treated with combined therapy compared with TSEB therapy alone. No difference was observed in advanced disease. The observation of increased disease-free survival in patients with stage I disease (but not in advancedstage disease) treated with combined treatment was also supported by Winkler et al. 59 However, prolonged survival in some patients was achieved with the use ofmaintenance topjcal therapy. 57, 59 Adverse effects of combined modality therapy include the common toxicities of TSEB (erythema, alopecia, dry skin, and edema) and myelosuppression associated with the chemotherapy.56-59 The increased disease-free survival observed in early stage patients treated with combined modality therapy prompted a randomized prospective clinical trial to compare sequential topical therapies versus aggressive treatment consisting of TSEB combined with systemic chemotherapy as initial treatment for CTCL,60 The combination treatment consisted of 3000 cGy of TSEB and parenteral chemotherapy with cyclophosphamide, doxorubicin, etoposide, and vincristine. The "conservative" sequential topical regimen began with topical HN2. The treatment was changed to PUVA if there was disease progres-

Therapies for CTCL 373 sion or severe toxicity to the topical HN2. Ifcutaneous disease became progressive, TSEB therapy was begun, followed by oral methotrexate. Only patients in whom extracutaneous disease developed or who did not respond to the sequential topical therapies received systemic chemotherapy. A higher overall rate of response and a higher rate of complete response were observed with initial combined modality treatment compared with topical therapies. However, there were no statistically significant differences in survival between the two treatment regimens when the overall patient group was analyzed or when the group was analyzed on the basis of stage. Fewer than 10% of the patients remained diseasefree in either treatment group. Patients with tumors and visceral involvement had a substantially improved response with combined therapy. The incidence of side effects was higher with the combined modality regimen. These included myelosuppression, radiodermatitis, neuropathy, and congestive heart failure. With conservative therapy, the most common toxicity was hypersensitivity to topical HN2. INTERFERONS

Interferons are immune glycoproteins produced by recombinant DNA technology and are used as antitumor and antiviral agents. The three major types of interferons are a, {3, and 'Y. The use of systemic interferon alfa-2a for CTCL was first reported by Bunn et al.61,62 In this series of 20 patients with advanced disease refractory to standard therapies, nine patients (45%) had an objective response (three complete responders and six partial responders) to maximally tolerated doses of recombinant interferon alfa-2a, 50 X 106 U 1m2 intramuscularly three times weekly. The median duration of response was 5.5 months. The complete responses lasted more than 1 year while therapy was continued. All patients experienced considerable toxicity, which necessitated dose reductions. The side effects included fever and a flu-like syndrome characterized by fatigue, malaise, lethargy, anorexia, and weight loss. Depression and mental confusion were reported in some patients. There appeared to be tachyphylaxis to both the fever and the flu-like syndrome with subsequent doses. Subsequent studies confirmed the antitumor activity of interferon alfa-2a in advanced CTCL at intermediate (3 to 36 X 106U per day) as well as high doses. 63-67 A review of these studies by Bunn and N orris68 reveals that the overall response

J oumal of the American Academy of Dermatology

374 Holloway et al. rate appears to be about 60% and the complete response rate is approximately 19%. Intralesional injections of recombinant interferon alfa-2a and alfa-2b have a beneficial effect in early plaque-stage CTCL. Interferon alfa-2a 2 X 106 U intralesionally three times weekly for 4 weeks, cleared three of nine lesions completely, and the other six improved. 69 Complete clinical regression was observed in 10 of 12 lesions treated with 1 X 106 U of interferon alfa-2b intralesionally three times weekly for 4 weeks. 70 The use of recombinant interferon-')' for CTCL yielded a partial response in 5 of 16 heavily pretreated, advanced-stage patients (31 %).71 The side effects included fever, weight loss, neutropenia, and increased lactate dehydrogenase and aspartate aminotransferase levels in the serum. Interferons in combination with other treatment modalities have recently been investigated. In two small trials interferon-a combined with retinoids produced a complete response in 3of 14 patients and a partial response in 4. 66,72 PUVA combined with interferon alfa-2a was reported by Roenigk et a1. 26 An overall response rate of 93% was achieved. Complete responses occurred in 12 of 15 patients and partial responses in 2 of 15 patients. These patients had somewhat less extensive disease than those in trials with interferons alone. RETINOIDS

Vitamin A analogs are effective in the treatment of CTCL,37, 73-79 Kessler et aU 3 reported an objective clinical response in 11 of 25 CTCL patients (44%) (stage T2or greater) treated with isotretinoin (l3-cis-retinoic acid). Clinical complete responses (biopsy specimens revealed residual disease) were achieved in three patients. The median duration of response was 8 months. These investigators recommended a starting dose of 1 mg/kg/day orallyin two divided doses. Dosage adjustments were frequently needed because of mucocutaneous drying. The success of isotretinoin in the treatment of CTCL has been confirmed by other investigators. 74, 75 Etretinate at a dose of 0.8 to 1 mg/kg/day was helpful in early-stage CTCL but did not affect latestage disease. 76 The Scandinavian Mycosis Fungoides Group found that the addition of etretinate to a chemotherapy regimen of bleomycin, cyclophosphamide, and prednisolone was advantageous in the treatment of advanced cases when compared with the three-drug chemotherapy combination alone. 77

The addition of etretinate (0.3 to 1 mg/kg) or isotretinoin (0.5 to 1.5 mg/kg) to PUVA (RePUVA) in the treatment of plaque-stage CTCL was successful in decreasing the number of PUVA treatments needed as well as the total UVA dose required to achieve a remission. 37 A newer, more potent retinoid, arotinoid Ro 136298, has been successfully used. 78,79 Five patients with advanced or refractory CTCL were treated with an oral dose of O. 3mg per day.79 Three obtained an objective clinical response and one patient had a complete response. Dosage reductions were generally required because of side effects. The side effects of the various retinoids are similar. Dryness of the skin and mucous membranes is most frequent. Other toxicities are usually mild and include fatigue, arthralgias, myalgias, minor mental changes (usually irritability), headache, and an asymptomatic increase in serum triglyceride levels.?3, 76, 79 PHOTOPHERESIS

Photopheresis, also known as extracorporeal photochemotherapy, was first described as a treatment of CTCL by Edelson et al. 8o in 1987. Although it is relatively new, it is now considered standard therapy for the erythrodermic variants of CTCL. Two hours after an oral 0.6 mg/kg dose of photoactivatable 8-MOP, the patients undergo leukapheresis. The buffy coat lymphocytes are then exposed to UVA light within the photopheresis device, and the photoirradiated cells are reinfused into the patient. This procedure is generally performed on two consecutive days at 4-week intervals with clinical evaluation at 6 months to determine efficacy. Those who demonstrate significant clinical improvement are maintained on this treatment schedule until maximum clearing appears. After this, an additional 6 months of therapy is administered to ensure the stability of the response. The patients are then weaned off photopheresis by gradually increasing the treatment intervals. 8o.83 The side effects of photopheresis are minimal because the treatments are performed ex vivo. Some patients experience nausea, an accentuation of erythema, and approximately 10% of patients experience a transient fever after reinfusion of cells.80 In the original multicenter clinical trial80 64% of the CTCL patients (27 of 37) had a positive response to treatment, including nine patients with a complete or nearly complete clearing of the skin manifesta-

Volume 27 Number 3 September 1992

tions. A positive response is defined as greater than 25% improvement ofskin involvement. Only three of eight patients with localized plaques and tumors responded. However, 24 of 29 patients with generalized exfoliative erythroderma had significant improvement. Patients with lymph node involvement responded as well as those without. Other independent studies have confirmed the efficacy of this therapeutic modality for advanced CTCL.84-86 In a recent update, Edelson et aL82 reported that the median survival time of the original patients with erythroderma treated with photopheresis is now more than 62 months, which is approximately twice as long as patients treated with other modalities. Edelson et aL82 suggested the criteria to determine that an appropriate photopheresis candidate should include a patient who is primarily erythrodermic and immunocompetent with less than 2 years' duration of widespread disease and a near normal absolute CD8 blood cell count. Because up to 25% of patients with CTCL will have a limited response to photopheresis, adjunctive therapies have been introduced. Heald et aL81 reported significant improvement with the addition oflow-dose oral methotrexate in five ofeight patients who did not respond to photopheresis alone. The maximum dose of 1 5 mg, three times a month, was low enough to be relatively nontoxic. Rook et a1. 87 reported almost complete clearing of a patient with rapidly advancing S6zary syndrome when interferon alfa-2b at a dose of 5 million U administered subcutaneously every other day was added to photopheresis treatments. No adverse effects were noted with either of the aforementioned adjunctive therapies. Patients with extensive patch/plaque-stage or tumor-stage CTCL have not been as responsive to photopheresis alone as have the more advanced CTCL patients.80, 81 However, there is evidence that follow-up monthly photopheresis can prolong or maintain remissions induced by radiation therapy in these patients. 81 -83 Armus et a1. 84 reported that photopheresis can be an effective modality for some tumor-stage disease and should be considered. The mechanism of action of photopheresis is not well understood. There is evidence that when the modified, photoirradiated cells are reintroduced to the patient, they stimulate an immune reaction against the malignant clone of T cells, which results in an improved ability of the host immune system to respond to the tumor cells. 80, 83, 88 Therefore, because a patient's response depends on a competent

Therapies for CTCL 375 immune system, concurrent immunosuppressive medications should be avoided. A second hypothesis is that photopheresis induces the release of tumor necrosis factor-a from treated monocytes that may augment the immune system's activity against the malignant cells. 88 ,89 The release of this cytokine corresponds temporally with the fever experienced by many patients. EXPERIMENTAL AND MISCELLANEOUS THERAPIES

Several alternative therapies have been reported for CTCL. Murine monoclonal antibodies, either alone 90-92 or conjugated to radioisotopes 93 , 94 or toxins,95 which react with cell surface antigens ofT cells have been used in the imaging and treatment of patients with CTCL. Regression of skin and lymph node involvement and a reduction in the number of malignant circulating cells have been documented. Objective responses are achieved in only a small percentage of patients and the improvement is generally transient.68 Problems associated with this treatment include rapid modulation or down-regulation of the target antigen and development of human antimouse antibodies. 90-92,94, 95 Methods to alleviate these problems are being explored, including the use of chimeric (murine/human) anti-CD4 monoclonal antibodies that are less likely to promote the development of human antimouse antibodies.68 The side effects of therapy include fever, malaise, pruritus, urticaria, and occasional dysp91 nea. ,92,94,95 Myelosuppression is the limiting toxicity.94 Research and development of improved radioimmunoconjugates are currently under way for testing in future clinical trials. 68 Autologous bone marrow transplant (ABMT) is currently being investigated as a treatment option for advanced CTCL. An initiallirnited pilot study96 demonstrated that CTCL patients do not have an increased risk of developing life-threatening infections during ABMT. Of the six patients who underwent ABMT, only two were alive with no evidence of disease more than 1 year after transplantation. However, different pretransplant treatment regimens were screened. The determination of the efficacy of this treatment awaits further investigation in larger clinical trials. Cyc1osporine has been reported to produce amelioration of the disease for a short duration. 97 ,98 However, this immunosuppressant is also associated with potentially severe side effects and the beneficial

Journal of the American Academy of Dermatology

376 Holloway et at. effect of the drug must be balanced against its toxicity. Several other experimental systemic agents have been evaluated. Beneficial results have been achieved with fludarabine phosphate51 and acyc1ovir. 99 REFERENCES 1. Patterson 1, Edelson R. Cutaneous T-cell lymphoma and other leukemic and lymphomatous infiltrates of the skin. In: Fitzpatrick TB, Eisen AZ, Wolff K, et aI, eds. Dermatology in general medicine. New York: McGraw-Hill, 1987:1086-118.

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