Treatment of CTCL depends on the stage of the disease. The current staging of this disease was first presented at the International Consensus Conference on CTCL in 1997. The staging attempts to show the complex interaction between the various outward symptoms of the disease and prognosis. The system has seven clinical stages based on skin involvement (tumor = T), lymph node involvement (LN), and presence of visceral metastases (M).

The first stage, IA, is characterized by plaques covering less than 10% of the body (T1) and no visceral involvement (M0). Lymph node condition at this stage can be uninvolved, reactive to the skin disease, or dermatopathic (biopsies showing CTCL involvement) but not enlarged (LN0-2). The shorthand expression of this stage is therefore T1, LN0-2, M0. The next stage, IB, differs from IA in that greater than 10% of the body is covered by plaques (T2, LN0-2, M0). Stage IIA occurs with any amount of plaques in addition to the ability to palpate the lymph node and the lymph uninvolved, reactive, or dermatopathic (T1-2, LN0-2, M0).

Treatments applied to the skin are preferred for patients having these preliminary stages of the disease, commonly topical chemotherapy with mechlorethamine hydrochloride (nitrogen mustard) or phototherapy of psoralen plus ultraviolet A (PUVA). Topical chemotherapy involves application to the skin of nitrogen mustard, an alkylating agent, in a concentration of 10–20 mg/dL in an aqueous or ointment base. Treatment of affected skin is suggested at a minimum and application over the entire skin surface is often recommended. Care needs to be taken that coverage of involved skin is adequate, as patients who self-apply the drug often cannot reach all affected areas. The most common side effect is skin hypersensitivity to the drug. Nearly all patients respond favorably to this treatment, with a 32–61% complete response rate, based on amount of skin involvement. Unfortunately, only 10–15% of patients maintain a complete response rate after discontinuing the treatment.

Phototherapy involves treatment with an orally administered drug, 8-methyloxypsoralen, that renders the skin sensitive to long-wave ultraviolet light (UVA), followed by controlled exposure to the radiation. During the initial treatment period, which may last as long as six months, patients are treated two to three times weekly. This is reduced to about once monthly after initial clearing of the lesions. Redness of the skin and blistering are the most common side effects of the treatment and are much more common in patients presenting with overall skin redness, or erythroderma, so lower intensities of light are usually used in this case. About 50% of all patients experience complete clearance with this treatment. Some patients with very fair skin and limited skin involvement can successfully treat themselves at home with special lamps and no psoralen.

The next stage, IIB, involves one or more cutaneous tumors, in combination with absent or present palpable lymph nodes, lymph uninvolved, reactive, or dermatopathic, and no visceral involvement (T3, LN0-2, M0). Stage III is characterized by erythroderma, an abnormal redness over widespread areas of the skin (T4, LN0-2, M0).

For more extensive disease, radiation therapy is an effective treatment option. It is generally used after the topical treatments have proven ineffective. Individual plaques or tumors can be treated using electrons, orthovoltage x rays, or megavoltage photons with exposure in the range of 15 to 25 Gy. Photon therapy has proven particularly useful once the lymph nodes are involved. Another possibility is total-skin electron beam therapy (TSEB), although the availability of this treatment method is limited. It involves irradiation of the entire body with energized electrons. Side effects of this treatment include loss of finger and toe nails, acute redness of the skin, and inability to sweat for about six to 12 months after therapy. Almost all patients respond favorably to radiation treatment and any reoccurrence is usually much less severe.

Combinations of different types of treatments is a very common approach to the management of CTCL. Topical nitrogen mustard or PUVA is often used after completion of radiation treatment to prolong the effects. The addition of genetically engineered interferon to PUVA therapy significantly increases the percentage of patients showing a complete response. Furthermore, although treatments using chemotherapy drugs alone, such as deoxycofomycin or etretinate, have been disappointing for CTCL, combining these drugs with interferon has shown promising results. Interferon has also been combined with retinoid treatments, although the mechanism of action of retinoids (Vitamin A analogues) against CTCL is unknown.

The final two stages of the disease are IVA and IVB. IVA presents as any amount of skin involvement, absent or present palpable lymph nodes, no visceral involvement, and lymph that contains large clusters of convoluted cells or obliterated nodes (T1-4, LN3-4). IVB differs in the addition of palpable lymph nodes and visceral involvement (T1-4, LN3-4, M1). All of the treatment methods described above are appropriate for the final two stages of the disease.

A newer drug that has been used to treat CTCL is bexarotene, a topical gel that is a synthetic retinoid analog. Bexarotene has been shown to be effective in clinical trials for stage IA or IB CTCL, and has fewer side effects than topical nitrogen mustard or electron beam radiotherapy. Another team of researchers at the University of Pennsylvania reported in 2003 that bexarotene combined with psoralen and UVA therapy is also effective in treating patients with advanced CTCL.

A treatment for advanced CTCL that is considered experimental as of mid-2003 is alemtuzumab, a monoclonal antibody. A Swedish study of 22 patients with advanced CTCL and Sézary syndrome found that alemtuzumab relieved symptoms in 55% of patients, with 32% in complete remission and 23% in partial remission.