Topical Imiquimod Therapy for Cutaneous T-Cell Lymphoma

A 74-year-old Caucasian woman presented with a 2-year history of pruritic, erythematous patches and plaques on the lateral trunk and medial thighs. Skin biopsy specimens of three lesions on her back were consistent with cutaneous T-cell lymphoma (CTCL). On physical examination, she had erythematous patches and plaques with ill-defined borders over most of her lateral torso bilaterally, proximal extremities, lumbosacral area, and the lower portion of the abdomen anteriorly (Figure 1A and 1B, top; Figure 1C, left). There was no dermal thickening or ulcerations. No lymphadenopathy or hepatosplenomegaly was noted. A chest roentgenogram revealed no abnormalities. A Sézary preparation was negative, and results of a serum protein electrophoresis, CD4/CD8 ratio, complete blood count, and complete metabolic panel were normal. These findings were consistent with stage IB (T2N0M0) CTCL according to tumor, node, metastasis (TNM) classification. The patient was initially treated with desoximetasone 0.25% ointment b.i.d. and then clobetasol propionate 0.05% cream b.i.d. Other medications included atorvastatin and conjugated estrogen. On follow-up several months later, the patient's existing patches appeared somewhat improved, but pruritus was persistent. At that time, she was prescribed tretinoin 0.05% cream nightly and loratadine for relief of her pruritus. Three months later, the patient's condition had not changed significantly, so the tretinoin and loratadine were discontinued. The patient's treatment was changed to doxepin 50 mg q.h.s., hydroxyzine 10 mg b.i.d., and 0.1% nitrogen mustard in Aquaphor base daily in addition to clobetasol propionate 0.05% cream b.i.d. Two months later, the patient returned with new lesions on her left thigh and enlarging lesions on her knees, which were diagnosed as verruca plana, likely a complication of nitrogen mustard therapy. The warts were treated with tretinoin 0.05% cream and cryotherapy. At a follow-up visit 5 months later, she had new erythematous patches on her inner thighs and was prescribed desoximetasone and hydrocortisone valerate ointments. After 4 months, she presented with new lesions on her back and lower thighs, as well as evidence of steroid-induced atrophy and purpura, and the desoximetasone ointment was discontinued. After the topical steroids were discontinued, treatment with topical 5% imiquimod cream three times per week was started for 2 weeks, advancing to daily application thereafter. She was instructed to apply the cream to lesions q.d. without occlusion. One month later, the patient noted some improvement of her CTCL lesions with no irritation at the application sites. After 4 weeks of additional once-daily therapy, the patient developed a new rash on the right anterior chest, which she assumed was CTCL, and she treated the area with imiquimod cream. She developed an application-site reaction with ulcerations and erythema, and, at a subsequent office visit, the eruption was diagnosed clinically and via Tzanck preparation as herpes zoster (Figure 2, top). Imiquimod was discontinued. The herpes zoster resolved without any complications or postherpetic neuralgia (Figure 2, bottom). At this time, repeated skin biopsies of residual skin lesions revealed no evidence of CTCL, and 8 weeks later, there was no clinical evidence of disease on her legs. Lesions on her proximal extremities, lumbosacral area, and trunk were substantially improved (Figure 1A and 1B, bottom; Figure 1C, right). These lesions eventually resolved with no residual erythema or postinflammatory hyperpigmentation. Treatment with desoximetasone 0.25% cream and cetirizine 10 mg q.d. was initiated. One month later, a biopsy of a livedoid knee lesion was negative for CTCL. Since then, the patient has had a few scattered patches and plaques of CTCL and continues to complain of intermittent but tolerable pruritus. She has been treated with desoximetasone 0.25% cream, doxepin 50 mg q.h.s., and fexofenadine 180 mg q.d. Repeated CD4/CD8 ratios have been normal, and multiple Sézary preparations have been negative. Overall, the patient's stage IB CTCL exhibited a strong clinical response to imiquimod therapy. The resolution of CTCL lesions during therapy suggested that topical imiquimod induced regression of existing CTCL lesions. The use of imiquimod on herpes zoster lesions resulted in erosions and ulcerations that necessitated therapy cessation. After discontinuing imiquimod because of this dose-limiting toxicity, the patient maintained this clinical response for approximately 12 weeks before a relapse in CTCL, which was controlled with topical corticosteroids.

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Left arm (A, top), lumbosacral area (B, top), and right posterior shoulder (C, left) before and 2 months after (A, bottom; B, bottom; and C, right) 8 weeks of topical imiquimod therapy.

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Therapy-limiting application-site reaction on upper right chest at site of herpes zoster infection after patient applied imiquimod cream to area (top) and temporary residual erythema after imiquimod treatment was discontinued (bottom).

Cutaneous T-cell lymphoma (CTCL) is a chronic, often smoldering disease that can progress to life-threatening systemic involvement. The goal of therapy is to arrest or slow disease progression. Topical treatments play an important role in early disease. Current mainstays of treatment, including potent topical steroids and nitrogen mustard, are associated with adverse effects such as cutaneous atrophy, systemic absorption, and allergic and irritant contact dermatitis. Elucidation of the role of CD4+ T-helper cells and associated cytokines in the pathogenesis of CTCL has revealed a potential role for topical immune modulators in early

disease. Topical imiquimod, which inhibits cytokine activity associated with T-helper-2 cells and promotes a cytotoxic antitumor effect, is a promising treatment option for early-stage CTCL.

CTCL, the most predominant variant of primary non-Hodgkin's lymphoma, encompasses both mycosis fungoides and Sézary syndrome.^[1,2] CTCL comprises primarily CD3+ CD4+ memory T-helper lymphocytes that initially exhibit epidermotropism.^[3,4] Patients with lesions confined solely to the skin have a variable clinical course and survival rate.^[5] Extracutaneous manifestations represent advanced metastatic disease, with a worsening prognosis.

The histopathologic criteria for CTCL have been refined, leading to enhanced detection of early-stage disease. A modified staging classification system that includes the depth of the infiltrate has been proposed.^[6] In addition, important cytokines and tumor-specific antigens involved in the molecular biological basis of CTCL have been identified.^[7,8] Despite these advances, CTCL remains a chronic, incurable, and potentially fatal disease with treatment modalities limited by their efficacy and toxicity. Immunomodulators, such as interferon, retinoids, and interleukins, have become increasingly popular therapeutic options for CTCL treatment.^[9] Novel immune response modifiers may offer valuable treatment alternatives for CTCL.

Topical 5% imiquimod cream may play such a role in early-stage CTCL. Imiquimod has been effective in the treatment of CTCL in a patient with stage IA disease.^[10] The Food and Drug Administration has approved topical imiquimod therapy for treatment of external anogenital warts.^[11] Additionally, imiquimod has been demonstrated to have antiviral and antitumor activity in animal models. The maturation of human epidermal Langerhans cells into functional antigen-presenting cells is enhanced by imiquimod. Stimulation of the T-helper-1 lymphocyte response with increased production of key cytokines such as interleukin-2 and interferon-gamma is seen in imiquimod-treated Langerhans cells.^[12] Other cytokines induced include interleukin-6, interleukin-8, interferon- , and tumor necrosis factor- .^[13] Of these, interferon-gamma demonstrates potent antiviral properties. By these mechanisms, imiquimod modifies both the innate and cell-mediated

branches of the immune system.^[14] Adverse skin reactions include localized erythema, erosions, and scarring as a consequence of cytokineinduced inflammation.^[15] In addition to stimulating the release of predominantly T-helper-1 cytokines, imiquimod has been shown to increase levels of prostaglandin E₂, which has been associated with the activation of herpes simplex virus (HSV).^[16] Imiquimod therapy has been associated with recurrences of HSV in patients with a history of facial HSV.^[17] It is possible that our patient's herpes zoster eruption was related to use of imiquimod, although the outbreak may also have been coincidental, since the incidence of herpes zoster increases with age and with underlying conditions such as lymphoma.

Successful treatment of cutaneous viral infections and tumors with topical imiquimod cream has been reported.^[11] Imiquimod has been effective in the treatment of chronic molluscum contagiosum in a severely immunocompromised individual.^[13] Premalignant lesions, such as actinic keratoses and Bowen's disease, as well as high-grade genital intraepithelial neoplasias have responded well to topical imiquimod therapy.^{[15,17,18,19,20]} Imiquimod also appears promising in the treatment of lentigo maligna and cutaneous melanoma metastasis.^[21,22]

CTCL is considered a chronic, incurable illness. The goal of treatment is to control the rate of disease progression with escalating treatment regimens based on disease extent and symptoms. Our patient experienced clinical clearing of stage IB CTCL during imiquimod therapy. Our observations suggest that topical 5% imiquimod cream appears beneficial for early stage disease. However, placebo-controlled, randomized clinical trials with larger numbers of patients are needed to confirm the role of imiquimod therapy in early stage CTCL.

Skinmed. 2003;2(5) © 2003 Le Jacq Communications, Inc.

Cite this: Topical Imiquimod Therapy for Cutaneous T-Cell Lymphoma - Medscape - Sep 01, 2003.