Treatment of Cutaneous T Cell Lymphoma

Abstract

The treatment of cutaneous T cell lymphoma (CTCL), which includes mycosis fungoides and Sezary syndrome, has been in a state of continual change over recent decades, as new therapies are constantly emerging in the search for more effective treatments for the disease. However, prognosis and survival of patients with CTCL remains dependent upon overall clinical stage (stage IA-IVB) at presentation, as well as response to therapy. Past therapies have been limited by toxicity or the lack of consistently durable responses, and few treatments have been shown to actually alter survival, especially in the late stages of disease. Even aggressive chemotherapy has not been shown to improve overall survival compared to conservative sequential therapy in advanced disease, and adds the risk of immunosuppressive complications. Over the last decade, extracorporeal photopheresis has been the only single treatment that has been shown to improve survival in patients with Sezary syndrome, although its true efficacy and place in combination therapy remain unclear. Much of the focus of current research has been on combinations of skin-directed therapies and biological response modifiers, which improve response rates. The results of various trials over the years have also brought into favor the use of post-remission maintenance therapy with topical corticosteroids, topical mechlorethamine (nitrogen mustard), interferon-alpha, or phototherapy to prevent disease relapse. Recent novel developments in CTCL therapy include oral bexarotene, a retinoid X receptor-selective retinoid that has activity in all stages of CTCL, and the topical gel formulation of bexarotene, which plays a role in treating localized lesions. US Food and Drug Administration (FDA)-approved, oral systemic bexarotene has the advantage of a 48% overall response rate at a dosage of 300 mg/m(2)/day, and avoids immunosuppression and risk of central line and catheter-related infectious complications that are associated with other systemic therapies. Monitoring of triglycerides and use of concomitant lipid-lowering agents and thyroid replacement is required in most patients. Also recently FDA-approved, denileukin diftitox is the first of a novel class of fusion toxin proteins and is selective for interleukin-2R (CD25+) T cells, targeting the malignant T cell clones in CTCL. Denileukin diftitox is associated with capillary leak syndrome in 20 to 30% of patients, which may be ameliorated by hydration and corticosteroids. Higher response rates are possible by combining bexarotene with "statin" drugs and active CTCL therapies. Studies are being conducted on combining bexarotene and denileukin diftitox with other modalities. Biological response modifier therapies that are in current or future investigational trials include topical tazarotene, pegylated interferon, interleukin-2, and interleukin-12. At the forefront of systemic chemotherapy development, pegylated liposomal doxorubicin, gemcitabine, and pentostatin appear to have the greatest potential for success in CTCL therapy. Bo...

Treatment of Transformed Mycosis Fungoides with Intermittent Low-Dose Gemcitabine

“…First-line therapy consists of topical corticosteroids, bexarotene gel, topical mechlorethamine and UVB phototherapy. More advanced MF is treated with PUVA plus biological response modifiers such as interferon or oral retinoids such as the RXR agonist bexarotene or the RAR agonist soriatane, total body skin electron beam therapy and targeted denileukin diftitox [1]. Advanced MF (IIB–IVB) is substantially more difficult to put into remission and durable complete responses (CR) are obtained only in a minority of patients with curative therapy being less common [13].…”

“…Late-stage disease has been treated with systemic monotherapy or combined chemotherapy [1], with the greatest wealth of literature pertaining to the cytotoxic agents [14]. Cytotoxic chemotherapies, alone or in combination, have been associated with response rates of 20–60%, typically lasting for a short duration (4–6 months) [15, 16].…”

“…The pyrimidine antimetabolite has recently gained attention as a promising agent for the treatment of advanced MF/SS, not only for its reported efficacy but also for its attractive low-toxicity profile and appealing dose scheduling, often given once a week for 3 consecutive weeks every month [1]. Studies investigating the efficacy of gemcitabine monotherapy (1,000–1,200 mg/m 2 on days 1, 8 and 15 of a 28-day cycle) for refractory or relapsed CTCL have reported response rates of 68–70.5% (11–11.4% CR) [27, 28].…”

“…Cutaneous T cell lymphomas (CTCLs) include heterogeneous extranodal lymphoproliferative disorders characterized by malignant T cells localized in the skin [1]. In the most common type of CTCL, mycosis fungoides (MF), malignant cells are clonal CD4+ CD45RO+ helper T cells exhibiting epidermotropism and inducing skin lesions.…”

Familial Cutaneous Mycosis fungoides: Successful Treatment with a Combination of Gemcitabine and Alemtuzumab

“…Gemcitabine, a new nucleoside analogue, has shown some activity in the treatment of MF and is generally well tolerated [16, 17, 18, 19]. In the largest phase II study, 30 patients with MF were treated with gemcitabine as a single agent at a dose of 1,200 mg/m 2 intravenously over 30 min on days 1, 8 and 15 of a 28- day schedule.…”