Cutaneous T-Cell Lymphoma Treatment & Management

Updated: Jun 23, 2017
  • Author: Lauren C Pinter-Brown, MD; Chief Editor: Emmanuel C Besa, MD  more...
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Treatment

Approach Considerations

The evaluation and treatment of individuals with mycosis fungoides is usually conducted on an outpatient basis. Symptomatic treatments (eg, emollients, antipruritics) are used in combination with specific topical and systemic treatments.

Mycosis fungoides treatment selection should be based on the stage and previous treatment history. In general, topical therapies are indicated for stage I patients, and systemic therapies or combinations of topical and systemic therapies are indicated for patients with stage IIB disease or greater, or for patients with stage I mycosis fungoides who are intolerant of topical treatments or whose condition has failed to respond to such treatments. [7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17]

Sequential therapies that are stage appropriate are selected on the basis of convenience and availability to the patient, as well as on short- and long-term toxicity profiles. Therapies may also be selected based on the probability that a given patient's condition will respond and on the rapidity of onset of that response.

Clinicians should encourage the use of supportive treatments to decrease pruritus and to lubricate the skin in patients with mycosis fungoides. Nonspecific antipruritic treatments are useful and often necessary adjuncts to more specific therapies. Patients should avoid sun exposure and should remain in a cool environment.

Treatment of localized mycosis fungoides

Localized mycosis fungoides may benefit from a number of therapeutic modalities, including radiotherapy, intralesional steroids, or surgical excision. One option is to excise a patch or plaque with a 0.5-cm margin and then control subsequent disease using one of the following treatment modalities [96] :

  • Irradiation
  • Photochemotherapy using ultraviolet A (UV-A) light treatment enhanced with psoralen (PUVA)
  • Photodynamic therapy
  • Carbon dioxide laser surgery

Localized radiation or a surgical approach to localized mycosis fungoides can be used. The advantage of using surgery first is that a full dose of radiation can be delivered in the same location at a later time, thus preserving options for future therapy.

A retrospective review by Thomas et al indicated that the use of a single dose of radiation (700-800 cGy) in place of multiple-fraction radiation treatment still results in excellent palliation in patients with cutaneous T-cell lymphoma. The investigators reviewed the results of radiation treatment in 270 lesions in a total of 58 patients (most of whom had mycosis fungoides); 97% of the lesions had been treated with 700 cGy or more of radiation. [97]

Over a mean follow-up period of 41.3 months, Thomas et al noted a complete response occurred in 255 (94.4%) lesions and a partial response rate occurred in 10 (3.7%) lesions. Four lesions (1.5%) demonstrated a partial response that, following a second treatment, became a complete response. Only one lesion (0.4%) showed no response. [97]

The investigators also found the following results:

  • A lower complete-response rate in the lower extremities than in other parts of the body
  • A lower complete-response rate in lesions treated with photons than in those treated with electrons
  • A lower complete-response rate in patients whose lesions demonstrated large-cell transformation and tumor morphology
  • A significantly lower overall survival rate in patients with Sézary syndrome and erythroderma than in other patients

Thomas et al also determined that the cost of multiple-fraction radiation treatment was more than 200% greater than it was for single-fraction therapy.

See also the clinical guideline summary, Guidelines for topical photodynamic therapy: update, from the British Association of Dermatologists.

Extracorporeal photophoresis

Extracorporeal photopheresis, either alone or in combination with other treatment modalities (eg, interferon alfa), is an effective treatment for Sézary syndrome and for erythrodermic mycosis fungoides, with overall response rates of 30-80% and complete response rates of 14-25%. [18] The alleged superiority of extracorporeal photopheresis over the traditional low-dose chemotherapy regimens has not been proven.

Cord blood transplantation

Unrelated cord blood transplantation is a possible therapeutic option. [19] In one patient, it was performed following myeloablative conditioning and brought a complete remission. Although a relapse occurred 3 months later, discontinuation of immunosuppressant therapy led to mycosis fungoides regression and a second complete remission that continued for more than 23 months. Reduced-intensity umbilical cord blood transplantation is another option for advanced mycosis fungoides. [98]

Bone marrow transplantation

Allogeneic transplants are reported in the literature as case reports or in small groups of patients. [99, 7] A German study suggested that allogeneic stem cell transplantation may be an important alternative option for young patients with treatment-refractory mycosis fungoides, because "complete clinical remission can be obtained even in advanced stages." [7]

Combination chemotherapy

Combination chemotherapy is generally not used in mycosis fungoides, because the infectious complications of this treatment, as well as the short response duration, outweigh the modest response rates (compared with those of other non-Hodgkin lymphomas) seen in this disease. Increased survival is not demonstrated with the use of combination chemotherapy relative to sequential topical agents.

However, multiagent chemotherapy is used with unequivocal lymph node or systemic involvement or in cases with widespread tumor-stage mycosis fungoides that is refractory to skin-targeted therapies and is not early patch/plaque-stage disease.

Consultations

Consultations with a dermatologist, medical oncologist, and/or radiation oncologist may aid clinicians in the management of patients with mycosis fungoides.

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Topical Therapy

Topical mycosis fungoides treatments, such as topical steroids, topical retinoids, topical chemotherapy, and light treatment that may be enhanced by the ingestion of psoralen, are used to induce remissions, which may be lengthy in patients whose disease is largely confined to the skin. In the patch or plaque stage of the disease, the following topical treatments are generally used:

  • Topical steroids
  • Topical retinoids
  • Topical chemotherapy - Eg, nitrogen mustard or bischloroethylnitrosourea (BCNU)
  • Ultraviolet B (UV-B) light treatment or UV-A light treatment enhanced with psoralen (PUVA)
  • Total-body electron beam radiation

These modalities are also used in combination with systemic modalities (eg, PUVA plus interferon) for higher-stage disease.

A majority of patients in the patch stage will have a response, usually to class I (highest potency) steroids; steroids lyse T lymphocytes and block cytokine secretion. Most cases of patch- or plaque-stage disease will respond to PUVA (76-90% complete responses); psoralens inhibit DNA synthesis in tissues exposed to psoralen and UV-A. In addition, most cases of patch- or plaque-stage disease will respond to topical chemotherapy agents, which inhibit cell growth and proliferation (complete response rate, 60%).

Retinoids are vitamin A analogues involved in the modulation of cell growth, division, reproduction, and differentiation. [100] Their biologic effects result from alterations in gene expressions that are mediated through 2 major types of nuclear receptors, the retinoic acid receptor and the retinoic X receptor. Each receptor subtype likely controls the expression of unique and common genes. Subclass-specific retinoids are available.

Mechlorethamine topical (Valchlor) was approved in August 2013 for mycosis fungoides–type cutaneous T-cell lymphoma (MF-type CTCL). Approval was based on a trial in patients with refractory stage IA-IIA MF-type CTCL, in which 60% of patients treated with mechlorethamine had a confirmed response at 12 months, compared with 48% of those treated with a pharmacy-compounded mechlorethamine preparation. [101, 102, 103]

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Systemic Therapy

Systemic treatment, such as oral retinoids, recombinant interferon alfa, fusion toxins, monoclonal antibodies, and single-agent chemotherapy, can be used sequentially to palliate symptoms from more advanced mycosis fungoides. Many active agents exist, including antimetabolites, alkylating agents, topoisomerase II inhibitors, anthracyclines, and purine analogues. The most extensive data exist for the use of methotrexate. [104]

Other examples of systemic treatment for mycosis fungoides include the following:

  • Extracorporeal photopheresis - Leukapheresis with UV-A light treatment enhanced with psoralen (PUVA) for the collected white blood cells, with reinfusion of treated cells
  • Oral retinoids
  • Fusion toxin treatment - Recombinant toxins are generated by fusion of a plant or bacterial toxin gene to a receptor ligand; the first such toxin to enter clinical trial was DAB-interleukin 2 (DAB-IL2)
  • Histone deacetylase inhibitor treatment - These agents may inhibit gene transcription

Biologic response modifiers may inhibit the proliferative capacity of malignant T cells by modulating cytokine production. These agents may also enhance the antitumor immune response by augmenting cell-mediated cytotoxicity.

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Specific Therapies

When mycosis fungoides is confined to the skin (cutaneous T-cell lymphoma [CTCL]), skin-targeted therapies, such as the following, are often effective in controlling manifestations [105] :

  • Topical corticosteroids
  • Heliotherapy
  • Photochemotherapy - Eg, psoralen plus UV-A (PUVA)
  • Topical application of nitrogen mustard (mechlorethamine) or carmustine (BCNU)
  • Radiotherapy - Including total skin electron beam irradiation

Bexarotene is also sometimes used for disease confined to the skin. Beneficial effects of bexarotene and of alemtuzumab (anti-CD52) have been noted, but the long-term effects of these therapies remain to be established. [106]

Psoriatic doses of methotrexate have been used, but some concern exists relating to large cell transformation occasionally observed in these patients. Narrowband UV-B therapy is another option. [107]

Treatment of stages T1 and T2 mycosis fungoides with total skin electron beam therapy is highly effective without adjuvant therapy. Management of relapses with local radiotherapy or a second round of total skin electron beam irradiation is feasible, timesaving, and cost-effective. [108] In patients with limited patch-stage mycosis fungoides, topical steroids or bexarotene gel can be used.

Tazarotene, long-term and low-dose oral etoposide, and imiquimod may be of value in the treatment of early cutaneous T-cell lymphoma. [109, 110] One small pilot study showed tazarotene 0.1% gel to be a well-tolerated and effective adjuvant topical therapy for the treatment of refractory mycosis fungoides. [111]

Biologic agents such as interferon alfa and other cytokines (eg, IL-2), traditional and newer retinoids such as bexarotene, and receptor-targeted cytotoxic fusion proteins (eg, DAB389IL-2) are increasingly being used. The fusion protein, denileukin, was discontinued in January 2014. Combination therapy with bexarotene and PUVA should be considered for patients with treatment-resistant cutaneous T-cell lymphoma that is refractory to monotherapy. [112] However, the precise use of these newer treatments, either as single-agent therapy or in combination with other therapies (eg, PUVA) in the treatment of mycosis fungoides, remains to be established.

Beneficial results have been described with interferon alfa, either alone or in combination with PUVA therapy, prolonged treatment with a combination of low-dose chlorambucil (2-4 mg/day) and prednisone (10-20 mg/day), or methotrexate (MTX) (5-25 mg/wk), but complete responses are uncommon.

As previously mentioned, multiagent chemotherapy is used with unequivocal lymph node or systemic involvement or in cases with widespread tumor-stage mycosis fungoides that is refractory to skin-targeted therapies and is not early patch/plaque-stage disease.

Subcutaneous panniculitis-like T cell lymphoma usually responds poorly to chemotherapy. Cyclosporine A has shown some efficacy for cases that relapse after chemotherapy, and a case report of a long-term complete remission with cyclosporine A as a first-line therapy has been published. [113] Systemic corticosteroids have also been found effective for first-line single-agent therapy, inducing complete remission in four of five patients in one study. [114]

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Treatment of Sézary Syndrome

The treatment of Sézary syndrome should be predicated on disease burden and rapidity of progression. [20] Because infection is the major cause of death in patients with mycosis Sézary syndrome, one should attempt to preserve immune response, use immunomodulatory therapy before chemotherapy unless the disease burden or therapeutic failure requires otherwise, and consider combination therapy, particularly systemic immunomodulatory therapy plus skin-directed treatments, as a better option than monotherapy.

Because Staphylococcus infection may be associated with a disease flare, systemic antibiotics should be administered when in doubt to prevent life-threatening sepsis. Pruritus treatment is an important quality-of-life consideration and should not be neglected. [115] It can be so severe that special itch-targeted therapies may need to be devised.

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Treatment of Folliculotropic Mycosis Fungoides

Perifollicular localization of the dermal infiltrates in folliculotropic mycosis fungoides is often less responsive to skin-targeted therapies (eg, PUVA, topical nitrogen mustard) than is classic plaque-stage mycosis fungoides; total skin electron beam irradiation is superior. [116] However, because sustained complete remissions are rarely achieved with electron beam therapy, PUVA combined with retinoids or interferon alfa should be considered, although persistent tumors can be effectively treated with local radiotherapy.

Follicular mycosis fungoides may benefit from isotretinoin for persistent cysts and comedones. [117] Many patients benefit from PUVA therapy, although they may not respond as well as patients with classic mycosis fungoides do. [63] Early syringotropic cutaneous T-cell lymphoma may be treated with local radiotherapy, with excellent local control. [118]

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