The Addition of Interferon Gamma to Oral Bexarotene Therapy With Photopheresis for Sézary Syndrome

A 53-year-old white woman presented to our clinic with Sézary syndrome. A buffy coat analysis of multiple fixed slides revealed a circulating Sézary cell count of 40% to 55%. Flow cytometry revealed an elevated CD4:CD8 ratio of 30:1. Therapy was begun with extracorporeal photopheresis, psoralen–UV-A, and interferon alfa-2b, 1.8 million units injected subcutaneously 3 times weekly. Oral bexarotene, 150 mg daily, was added 2 months later. On this regimen, the patient’s erythroderma and pruritus improved over a period of 3 months.

Three months later, the patient’s erythroderma and pruritus recurred and was associated with the appearance of large cells on peripheral smear, eosinophilia, and a rising Sézary cell count. Treatment with psoralen–UV-A was discontinued, and the patient began a 4-week course of total skin electron beam radiation. Three weeks after completion of this treatment, she presented with profound total body erythroderma and edema with severe fissuring of the palms and soles. A complete blood cell count revealed eosinophilia (33%), and results from buffy coat analysis showed a Sézary cell count of 30% to 36%. She was completely disabled owing to severe fatigue and had difficulty ambulating. She was referred for considpara>Interferon gamma, 40 μg administered subcutaneously 3 times weekly, was substituted for interferon alfa-2b, while photopheresis and bexarotene therapies were continued. Typically, dosing is increased to 100 μg 3 times weekly as soon as tolerated; however, 1 month later the patient’s skin was already clear and the Sézary count was 5% to 10%. At a 3-year follow-up examination, her skin remained clear and the Sézary cell count was below 5%, while findings from flow cytometry were normal (Figure 1). Adverse effects of interferon gamma have been mild and limited to a transient episode of neutropenia.

Prior to initiation of treatment with interferon gamma, a variety of cellular immune functions, including natural killer cell activity and interleukin (IL) 12 production, were determined to be markedly depressed compared with the normal means for the laboratory findings. During therapy with interferon gamma, peripheral blood natural killer cell activity and IL-12 production rose significantly over time (Figure 2).

Treatment of advanced refractory cutaneous T-cell lymphoma is difficult and often ineffective.¹ Our patient experienced progressive disease despite an aggressive regimen of concomitantly administered total skin electron beam radiation, photopheresis, bexarotene, interferon alfa-2b, and psoralen–UV-A.

Cutaneous T-cell lymphoma is characterized by the clonal proliferation of CD4⁺ lymphocytes displaying the T_H2 cytokine profile.^{2 - 3} As a result, excess amounts of IL-4, IL-5, and IL-10 are produced. The overproduction of these cytokines leads to a defined constellation of immune abnormalities, in which the net result is suppressed antitumor immunity and further propagation of the malignant clone. For example, IL-10 has been shown to antagonize the biological activity and decrease the production of interferon gamma and IL-12.

Conversely, interferon gamma can inhibit the biological activity of IL-4 and stimulate cytotoxic T cells.⁴ Given the ability of interferon gamma to counteract at least some of the T_H2 cytokine immune abnormalities, in vivo administration should help to restore antitumor immunity and thereby inhibit clonal expansion. Indeed, in concert with the decline of peripheral blood Sézary cell counts while receiving treatment with interferon gamma, natural killer cell activity and other immune functions improved.

There is limited evidence exploring the use of recombinant interferon gamma in advanced cutaneous T-cell lymphoma. Kaplan et al⁵ conducted a phase 2 study that included 16 patients with advanced stages of cutaneous T-cell lymphoma, most of whom had been heavily pretreated with combination chemotherapy, which is immunosuppressive. A dose of 250 μg/m² increased to 500 μg/m² on day 8 injected intramuscularly daily for 8 weeks was used. No concurrent therapies were allowed. There was a 31% partial remission rate, but no complete remission was observed.

In comparison with the phase 2 study,⁵ our patient was continued on concurrent therapies, including photopheresis and oral bexarotene. However, these therapies remained a constant factor, while the marked clinical and immunologic improvement directly coincided with the substitution of interferon gamma for interferon alfa-2b. We believe that biological response modifier therapies such as photopheresis, interferon, and retinoids are most effective when used in combination, with each treatment targeting different arms of the immune response. Thus, the success of interferon gamma in this case may be due in part to its incorporation into a multimodality treatment regimen in the absence of prior chemotherapy, which can suppress the host antitumor response. Additional research and controlled clinical trials are needed to further elucidate the underlying biological mechanisms as well as to better define the most effective clinical regimen.

Correspondence: Dr Rook, Department of Dermatology, 2 Rhoads Pavilion, Hospital of the University of Pennsylvania, 3600 Spruce St, Philadelphia, PA 19104-4283 (arook@mail.med.upenn.edu).

Financial Disclosure: None.