Extracorporeal Photopheresis for the Treatment of Cutaneous T-Cell Lymphoma

Cutaneous T-cell lymphoma (CTCL) is the general term used to describe extracutaneous non-Hodgkin’s lymphomas characterized by monoclonal expansion of skin-homing malignant T cells that can further be defined by the use of immunophenotypic markers and the presence of specific rearrangements of the T-cell receptor. The most frequently diagnosed form of CTCL is mycosis fungoides (MF) and its leukemic variant, Sezary syndrome (SS). MF most often presents as chronic eczematous or psoriasiform patches or plaques and can remain stable for many years. In some patients, MF progresses to involve lymph nodes, peripheral blood, bone marrow, and visceral organs. SS may present de novo with persistent exfoliative erythroderma accompanied by staphylococcal colonization, perivascular atypical lymphocytes in the dermis, and ‡1000 atypical T lymphocytes/mm in the blood, a criterion recently defined as a B2 blood rating by the International Society for Cutaneous Lymphomas. Extracorporeal photopheresis (ECP) combines blood apheresis with ultraviolet-A irradiation of psoralen-photosensitized peripheral blood mononuclear cells. ECP was first introduced in 1987 for the treatment of erythrodermic MF and SS. ECP was the first therapy to receive FDA approval for the treatment of CTCL based on a multicenter trial. Twenty-seven of 37 patients (76%) achieved a 25%–100% reduction in their erythroderma skin score. The Yale–New Haven Hospital experience has been reviewed by Heald et al. who treated 32 patients with ECP. Of 19 erythrodermic patients who were treated with ECP as their first therapy at Yale, five had greater than 75% improvement of their skin score, ten had 25%– 50% improvement, and four had less than 25% improvement. The majority of patients had improved quality of life. Heald et al. also evaluated long-term followup in 29 original CTCL patients in the original multicenter study. Their mean survival from the time of diagnosis was 60.3 months and from beginning of therapy it was 47.9 months, which exceeds their expected mean overall survival of 24–30 months reported in the literature. Four of six patients in the original study had prolonged responses. Favorable prognostic factors in both analyses were normal CD4-to-CD8 ratios at baseline suggesting that the presence of CD8+ cytotoxic T cells is required for response. Other studies conducted by investigators around the world have verified the initial study, reporting response rates between 50% and 75%, with complete response rates of 10%–5% (Table I). In patients with stable disease, investigators have claimed that photopheresis improves overall patient survival, improves quality of life, and extends response to total body skin electron beam radiation. This is in contrast to chemotherapy that does not increase overall survival if used as front-line therapy for CTCL patients. Although approved for treatment of erythrodermic patients (T4 skin rating), ECP has also produced remissions in patients with clinically early MF and with tumor phase disease. The addition of biological response modifiers, such as interferon a, granulocyte macrophage colony stimulating factor (GM-CSF), and retinoids, to ECP has been shown to result in higher response rates as reviewed by Rook et al. Gottlieb et al. reported a ten-year experience at the University of Pennsylvania using ECP alone and in combination with rIFN-a. Thirty-one of the 41 patients with CTCL who received more than six months of photopheresis therapy had evaluable disease. Twentyeight of the 31 patients had ECP monotherapy, with the following results: 7 of 28 patients had complete remission (25%), 13 of 28 patients had partial remissions (46%), and 8 out of 28 were nonresponders (29%). Seventy-one percent of the patients had greater than 50% clearing. This study found an overall intent-to-treat response rate of 48%, with 17% complete responses and 31% partial responses. A favorable response predictor was the presence of Sezary cells in the peripheral blood at onset of therapy. The median time to treatment failure was 18 months. The median survival from initiation of therapy was 77 months. The median survival from diagnosis was greater than 100 months and 77 months from initiation of ECP, suggesting that photopheresis increased overall survival in advanced patients.