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Cutaneous T-cell lymphoma

Table of Contents

GENERAL INFORMATION
CELLULAR CLASSIFICATION
STAGE INFORMATION
TNM definitions
Stage I
Stage II
Stage III
Stage IV
TREATMENT OPTION OVERVIEW
STAGE I CUTANEOUS T-CELL LYMPHOMA
STAGE II CUTANEOUS T-CELL LYMPHOMA
STAGE III CUTANEOUS T-CELL LYMPHOMA
STAGE IV CUTANEOUS T-CELL LYMPHOMA
RECURRENT CUTANEOUS T-CELL LYMPHOMA

GENERAL INFORMATION

Mycosis fungoides and the Sezary syndrome are neoplasias of malignant T-lymphocytes that usually possess the helper/inducer cell surface phenotype. These neoplasms initially present as skin involvement and as such have been classified as cutaneous T-cell lymphomas (CTCL). These lymphomas are included in the Revised European-American Lymphoma (REAL) classification as low grade T-cell lymphomas, which should be distinguished from other T-cell lymphomas which involve the skin such as peripheral T-cell lymphomas (PTL) or adult T-cell leukemia/lymphoma (ATLL), which are aggressive lymphomas.[1,2] These more aggressive T-cell lymphomas have different staging systems and are generally treated with intensive chemotherapy.

The prognosis of CTCL is based on the extent of disease at presentation (stage).[3] The presence of lymphadenopathy and involvement of peripheral blood and viscera increase in likelihood with worsening cutaneous involvement and define poor prognostic groups. The median survival following diagnosis varies according to stage. Patients with stage IA disease have a median survival of 20 or more years. The majority of deaths for this group are not caused by, nor are they related to, mycosis fungoides.[4] In contrast, more than half of patients with stage III through IV disease die of mycosis fungoides, with a median survival of less than 5 years.[3,4]

Typically, the natural history of mycosis fungoides is indolent. Symptoms of the disease may present for long periods (average of 2-10 years) as waxing and waning cutaneous eruptions prior to biopsy confirmation. CTCL is treatable with available topical and/or systemic therapies. However, curative modalities have thus far proven elusive, with the possible exception of patients with minimal disease confined to the skin.

Cutaneous disease typically progresses from an eczematous patch/plaque stage covering less than 10% of the body surface (T1) to plaque stage covering greater than or equal to 10% of the body surface (T2), and finally to tumors (T3) which frequently undergo necrotic ulceration.[5] The Sezary syndrome is an advanced form of mycosis fungoides with generalized erythroderma (T4) and peripheral blood involvement at presentation. Cytologic transformation from a low-grade to a high-grade lymphoma sometimes occurs during the course of these diseases and is associated with a poor prognosis.[6-8] A common cause of death during the tumor phase is sepsis from Pseudomonas aeruginosa or Staphylococcus aureus due to chronic skin infection with staph species and subsequent systemic infections.[5]

References:

  1. Willemze R, Kerl H, Sterry W, et al.: EORTC classification for primary cutaneous lymphomas: a proposal from the Cutaneous Lymphoma Study Group of the European Organization for Research and Treatment of Cancer. Blood 90(1): 354-371, 1997.

  2. Harris NL, Jaffe ES, Stein H, et al.: A revised European-American classification of lymphoid neoplasms: a proposal from the International Lymphoma Study Group. Blood 84(5): 1361-1392, 1994.

  3. Zackheim HS, Amin S, Kashani-Sabet M, et al.: Prognosis in cutaneous T-cell lymphoma by skin stage: long-term survival in 489 patients. Journal of the American Academy of Dermatology 40(3): 418-425, 1999.

  4. Kim YH, Jensen RA, Watanabe GL, et al.: Clinical stage IA (limited patch and plaque) mycosis fungoides: a long-term outcome analysis. Archives of Dermatology 132(11): 1309-1313, 1996.

  5. Lorincz AL: Cutaneous T-cell lymphoma (mycosis fungoides). Lancet 347(9005): 871-876, 1996.

  6. Schechter GP, Sausville EA, Fischmann AB, et al.: Evaluation of circulating malignant cells provides prognostic information in cutaneous T-cell lymphoma. Blood 69(3): 841-849, 1987.

  7. Dmitrovsky E, Matthews MJ, Bunn PA, et al.: Cytologic transformation in cutaneous T cell lymphoma: a clinicopathologic entity associated with poor prognosis. Journal of Clinical Oncology 5(2): 208-215, 1987.

  8. Kim YH, Bishop K, Varghese A, et al.: Prognostic factors in erythrodermic mycosis fungoides and the Sezary syndrome. Archives of Dermatology 131(9): 1003-1008, 1995.

CELLULAR CLASSIFICATION

The histologic diagnosis of cutaneous T-cell lymphoma (CTCL) is usually difficult in the initial stages of the disease and may require the review of multiple biopsies by an experienced pathologist.

A definitive diagnosis from a skin biopsy requires the presence of mycosis or Sezary cells (convoluted lymphocytes), a band-like upper dermal infiltrate, and epidermal infiltrations with Pautrier's abscesses (collections of neoplastic lymphocytes). A definitive diagnosis of Sezary syndrome may be made from a peripheral blood evaluation when skin biopsies are consistent with the diagnosis.

STAGE INFORMATION

The stages given here are defined by TNM classification. Peripheral blood involvement with mycosis fungoides or Sezary cells is correlated with more advanced skin tumors, lymph node and visceral involvement, and shortened survival, but probably provides no independent prognostic information beyond that associated with TNM staging. In a multivariate analysis, the two most important prognostic factors are the presence of visceral disease and type of skin involvement.[1,2]

TNM definitions

Primary tumor (T)

T1: Eczematous patches, papules, or limited plaques covering less than
10% of the skin surface
T2: Erythematous patches, papules, or generalized plaques covering 10% or
more of the skin surface
T3: Tumors, one or more
T4: Generalized erythroderma

Note: Pathology of T1-T4 is diagnostic of CTCL. When characteristics of more
than one T exist, both are recorded and the highest is used for staging,
for example, T4(3).

Nodal involvement (N):
N0: No clinically abnormal peripheral lymph nodes, pathology negative for
CTCL
N1: Clinically abnormal peripheral lymph nodes, pathology negative for CTCL
N2: No clinically abnormal peripheral lymph nodes, pathology positive for
CTCL
N3: Clinically abnormal peripheral lymph nodes, pathology positive for CTCL

Note: The number of sites of abnormal nodes is recorded. For example,
cervical (left + right), inguinal (left + right), epitrochlear,
submandibular, and so forth. A pathologic classification for lymph node
involvement has been developed by Matthews and Gazdar.[3] The degree of
nodal involvement may have prognostic significance when categorized
according to this system.

Distant metastasis (M)
M0: No involvement of visceral organs
M1: Visceral involvement (must have confirmation of pathology; organ
involved should be specified)

Stage I

Stage IA is defined as the following TNM grouping:

T1, N0, M0

Stage IB is defined as the following TNM grouping:

T2, N0, M0

Stage II

Stage IIA is defined as either of the following TNM groupings:

T1 or T2, N1, M0

Stage IIB is defined as either of the following TNM groupings:

T3, N0 or N1, M0

Stage III

Stage III is defined as either of the following TNM groupings:

T4, N0 or N1, M0

Stage IV

Stage IVA is defined as any of the following TNM groupings:

T1-T4, N2 or N3, M0

Stage IVB is defined as any of the following TNM groupings:

T1-T4, N0-N3, M1

Note: Involvement of peripheral blood is also associated with a shorter survival and an increased risk of nodal and/or visceral involvement. Some studies suggest that patients can be divided into three groups: Stage IA, IB, and IIA, with excellent 5- and 10-year survival; stage IIB and III, with intermediate survival; and stage IVA and IVB, with poor survival. The survival of patients with affected lymph nodes is as poor as those with visceral involvement.

References:

  1. Bunn PA, Lamberg SI: Report of the Committee on Staging and Classification of Cutaneous T-cell Lymphomas. Cancer Treatment Reports 63(4): 725-728, 1979.

  2. Schechter GP, Sausville EA, Fischmann AB, et al.: Evaluation of circulating malignant cells provides prognostic information in cutaneous T-cell lymphoma. Blood 69(3): 841-849, 1987.

  3. Sausville EA, Eddy JL, Makuch RW, et al.: Histopathologic staging at initial diagnosis of mycosis fungoides and the sezary syndrome: definition of three distinctive prognostic groups. Annals of Internal Medicine 109(5): 372-382, 1988.

TREATMENT OPTION OVERVIEW

Treatment of cutaneous T-cell lymphoma (CTCL) includes topical chemotherapy with mechlorethamine (nitrogen mustard) or carmustine (BCNU), psoralen and ultraviolet A radiation (PUVA), total-skin electron-beam irradiation (TSEB), irradiation of symptomatic skin lesions, interferon alfa alone or in combination with topical therapy, single- and multi-agent chemotherapy, and combined modality treatment.[1] These treatments produce remissions, but cure is uncommon and can only be achieved in the earliest stage of disease. Therefore, treatment is considered palliative for most patients, although major symptomatic improvement is regularly achieved. However, survival in excess of 8 years is not uncommon. All patients with CTCL are candidates for clinical trials evaluating new approaches to treatment.

Current areas of interest in clinical trials for CTCL confined to the skin include combined modality therapies containing both topical and systemic agents such as TSEB combined with chemotherapy, topical mechlorethamine or PUVA combined with interferon, or wide-field irradiation techniques with PUVA. There have been reports of activity for extracorporeal photochemotherapy using psoralen; interferon gamma or alfa; pentostatin; retinoids; fludarabine; acyclovir; 2-chlorodeoxyadenosine (2-CdA); serotherapy with unlabeled, toxin-labeled, or radiolabeled monoclonal antibodies; and cell surface receptor ligand-toxin fusion protein.[2-9] Combinations of these agents (such as interferons and retinoids) are also being evaluated.

The designations in PDQ that treatments are "standard" or "under clinical evaluation" are not to be used as a basis for reimbursement determinations.

References:

  1. Bunn PA, Hoffman SJ, Norris D, et al.: Systemic therapy of cutaneous T-cell lymphomas (mycosis fungoides and the Sezary syndrome). Annals of Internal Medicine 121(8): 592-602, 1994.

  2. Kaplan EH, Rosen ST, Norris DB, et al: Phase II study of recombinant human interferon gamma for treatment of cutaneous T-cell lymphoma. Journal of the National Cancer Institute 82(3): 208-212, 1990.

  3. Heald P, Rook A, Perez M, et al.: Treatment of erythrodermic cutaneous T-cell lymphoma with extracorporeal photochemotherapy. Journal of the American Academy of Dermatology 27(3): 427-433, 1992.

  4. Rosen ST, Zimmer AM, Goldman-Leikin R, et al.: Radioimmunodetection and radioimmunotherapy of cutaneous T cell lymphomas using an 131I-labeled monoclonal antibody: an Illinois Cancer Council study. Journal of Clinical Oncology 5(4): 562-573, 1987.

  5. Foss FM, Ihde DC, Breneman DL, et al.: Phase II study of pentostatin and intermittent high-dose recombinant interferon alfa-2a in advanced mycosis fungoides/Sezary syndrome. Journal of Clinical Oncology 10(12): 1907-1913, 1992.

  6. Saven A, Carrera CJ, Carson DA, et al.: 2-Chlorodeoxyadenosine: an active agent in the treatment of cutaneous T-cell lymphoma. Blood 80(3): 587-592, 1992.

  7. Kuzel TM, Roenigk HH, Samuelson E, et al.: Effectiveness of interferon alfa-2a combined with phototherapy for mycosis fungoides and the Sezary syndrome. Journal of Clinical Oncology 13(1): 257-263, 1995.

  8. LeMaistre CF, Saleh MN, Kuzel TM, et al.: Phase I trial of a ligand fusion-protein (DAB389IL-2) in lymphomas expressing the receptor for interleukin-2. Blood 91(2): 399-405, 1998.

  9. Foss FM, Borkowski TA, Gilliom M, et al.: Chimeric fusion protein toxin DAB486IL-2 in advanced mycosis fungoides and the Sezary syndrome: correlation of activity and interleukin-2 receptor expression in a phase II study. Blood 84(6): 1765-1774, 1994.

STAGE I CUTANEOUS T-CELL LYMPHOMA

Since several forms of treatment can produce complete resolution of skin lesions in this stage, the choice of therapy is dependent on local expertise and the facilities available. With therapy, the survival of patients with stage IA disease can be expected to be the same as age and gender-matched controls.[1,2]

Treatment options:

1. PUVA: psoralen + ultraviolet A radiation.
Therapeutic trials with PUVA have shown a 62% to 90% complete remission
rate with early cutaneous stages achieving the best responses.
Continued maintenance therapy with PUVA at more protracted
intervals is generally required to prolong remission duration.[3] PUVA
combined with interferon alfa-2a is associated with a high response
rate.[4]

2. TSEB: total-skin electron-beam irradiation.
Electron irradiation of appropriate energies will penetrate only to the
dermis, and thus the skin alone can be treated without systemic
effects. This therapy requires considerable technical expertise to
deliver, can result in short- and long-term cutaneous toxic effects,
and is not widely available. Based on the long-term survival of these
early stage patients, electron-beam irradiation is sometimes used with
curative intent.[5] Long-term disease-free survival can be achieved in
patients with unilesional mycosis fungoides treated with local radiation
therapy.[6]

3. Topical mechlorethamine (nitrogen mustard).
Topical application of mechlorethamine has produced regression of
cutaneous lesions, with particular efficacy in early stages of disease.
The overall complete remission rate is related to skin stage; 50% to 80%
of TNM classification T1, and 25% to 75% of T2 patients have complete
responses. Treatments are usually continued for 2 to 3 years.
Continuous 5-year disease-free survival may be possible in up to one
third of T1 patients.[7,8]

4. Local electron-beam irradiation or orthovoltage radiation therapy may be used to palliate areas of bulky or symptomatic skin disease.

5. Phototherapy with ultraviolet B is under clinical evaluation.[9]

6. Interferon alfa alone or in combination with topical therapy.[10]

References:

  1. Kim YH, Jensen RA, Watanabe GL, et al.: Clinical stage IA (limited patch and plaque) mycosis fungoides: a long-term outcome analysis. Archives of Dermatology 132(11): 1309-1313, 1996.

  2. Zackheim HS, Amin S, Kashani-Sabet M, et al.: Prognosis in cutaneous T-cell lymphoma by skin stage: long-term survival in 489 patients. Journal of the American Academy of Dermatology 40(3): 418-425, 1999.

  3. Herrmann JJ, Roenigk HH, Hurria A, et al.: Treatment of mycosis fungoides with photochemotherapy (PUVA): long-term follow-up. Journal of the American Academy of Dermatology 33(2, Part 1): 234-242, 1995.

  4. Kuzel TM, Roenigk HH, Samuelson E, et al.: Effectiveness of interferon alfa-2a combined with phototherapy for mycosis fungoides and the Sezary syndrome. Journal of Clinical Oncology 13(1): 257-263, 1995.

  5. Jones GW, Hoppe RT, Glatstein E: Electron beam treatment for cutaneous T-cell lymphoma. Hematology/Oncology Clinics of North America 9(5): 1057-1076, 1995.

  6. Micaily B, Miyamoto C, Kantor G, et al.: Radiotherapy for unilesional mycosis fungoides. International Journal of Radiation Oncology, Biology, Physics 42(2) 361-364, 1998.

  7. Vonderheid EC, Tan ET, Kantor AF, et al.: Long-term efficacy, curative potential, and carcinogenicity of topical mechlorethamine chemotherapy in cutaneous T cell lymphoma. Journal of the American Academy of Dermatology 20(3): 416-428, 1989.

  8. Hoppe RT, Abel EA, Deneau DG, et al.: Mycosis fungoides: management with topical nitrogen mustard. Journal of Clinical Oncology 5(11): 1796-1803, 1987.

  9. Ramsey DL, Lish KM, Yalowitz CB, et al.: Ultraviolet-B phototherapy for early-stage cutaneous T-cell lymphoma. Archives of Dermatology 128(7): 931-933, 1992.

  10. Kuzel TM, Eastern Cooperative Oncology Group: Phase III Study of Topical Therapy of Psoralen With Phototherapy (PUVA), Nitrogen Mustard (Mechlorethamine HCL) Chemotherapy, or Total Skin Electron Beam (TSE) Alone vs One Topical Therapy Combined With Interferon Alfa-2b for Cutaneous T-Cell Lymphoma (CTCL) (Summary Last Modified 06/1999), E-1495, clinical trial, closed, 04/22/1999.

STAGE II CUTANEOUS T-CELL LYMPHOMA

No curative therapy exists for stage II disease. Therefore, the choice of initial palliative therapy is dependent on the patients symptoms and the local expertise with each modality. A randomized study compared combined total-skin electron-beam irradiation (TSEB) plus combination chemotherapy to conservation therapy consisting of sequential topical therapies in 103 patients. In the latter group, combination chemotherapy was reserved for symptomatic extracutaneous disease or for disease refractory to topical therapies. Patients of any stage were eligible. Although the complete response rate was higher with combined therapy, toxic effects were considerably greater and there was no difference in disease-free or overall survival between the two groups.[1]

Treatment options:

1. PUVA: psoralen + ultraviolet A radiation.
Therapeutic trials with PUVA have shown a 62% to 90% complete remission
rate with early cutaneous stages achieving the best responses.
Maintenance therapy with PUVA is generally required to prolong
remission duration.[2] PUVA combined with interferon alfa-2a is
associated with a high response rate.[3]

2. TSEB: total-skin electron-beam irradiation.
Electron irradiation of appropriate energies will penetrate only to
to the dermis, and thus the skin alone can be treated without systemic
effects. This therapy requires a radiation therapy facility with
physics support, considerable technical expertise, and precise
dosimetry. It can provide excellent palliation with complete response
rates of 40% to 80%.[4]

3. Topical mechlorethamine (nitrogen mustard).
Topical application of mechlorethamine has produced regression of
cutaneous lesions, with particular efficacy in early stages of disease.
The overall complete remission rate is related to skin stage; 25% to 75%
of TNM classification T2 and 0-50% of T3 patients have complete
responses. Treatments are usually continued for 2 to 3 years.[5,6]

4. Local electron-beam irradiation or orthovoltage radiation therapy may also be used to palliate areas of bulky or symptomatic disease.

5. Interferon alfa alone or in combination with topical therapy.[7,8]

References:

  1. Kaye FJ, Bunn PA, Steinberg SM, et al.: A randomized trial comparing combination electron-beam radiation and chemotherapy with topical therapy in the initial treatment of mycosis fungoides. New England Journal of Medicine 321(26): 1784-1790, 1989.

  2. Herrmann JJ, Roenigk HH, Hurria A, et al.: Treatment of mycosis fungoides with photochemotherapy (PUVA): long-term follow-up. Journal of the American Academy of Dermatology 33(2, Part 1): 234-242, 1995.

  3. Kuzel TM, Roenigk HH, Samuelson E, et al.: Effectiveness of interferon alfa-2a combined with phototherapy for mycosis fungoides and the Sezary syndrome. Journal of Clinical Oncology 13(1): 257-263, 1995.

  4. Jones GW, Hoppe RT, Glatstein E: Electron beam treatment for cutaneous T-cell lymphoma. Hematology/Oncology Clinics of North America 9(5): 1057-1076, 1995.

  5. Vonderheid EC, Tan ET, Kantor AF, et al.: Long-term efficacy, curative potential, and carcinogenicity of topical mechlorethamine chemotherapy in cutaneous T cell lymphoma. Journal of the American Academy of Dermatology 20(3): 416-428, 1989.

  6. Hoppe RT, Abel EA, Deneau DG, et al.: Mycosis fungoides: management with topical nitrogen mustard. Journal of Clinical Oncology 5(11): 1796-1803, 1987.

  7. Foss FM, Ihde DC, Breneman DL, et al.: Phase II study of pentostatin and intermittent high-dose recombinant interferon alfa-2a in advanced mycosis fungoides/Sezary syndrome. Journal of Clinical Oncology 10(12): 1907-1913, 1992.

  8. Kuzel TM, Eastern Cooperative Oncology Group: Phase III Study of Topical Therapy of Psoralen With Phototherapy (PUVA), Nitrogen Mustard (Mechlorethamine HCL) Chemotherapy, or Total Skin Electron Beam (TSE) Alone vs One Topical Therapy Combined With Interferon Alfa-2b for Cutaneous T-Cell Lymphoma (CTCL) (Summary Last Modified 06/1999), E-1495, clinical trial, closed, 04/22/1999.

STAGE III CUTANEOUS T-CELL LYMPHOMA

No curative treatment exists for stage III disease. Therefore, the initial choice of palliative therapy is dependent on the local expertise with each modality. In patients with the Sezary syndrome, there is a high probability of extracutaneous involvement, and therefore systemic chemotherapy is often given, although there is no proof that this affects survival. A randomized study compared combined total-skin electron-beam irradiation (TSEB) plus combination chemotherapy to conservation therapy consisting of sequential topical therapies in 103 patients. In the latter group, combination chemotherapy was reserved for symptomatic extracutaneous disease or for disease refractory to topical therapies. Patients of any stage were eligible. Although the complete response rate was higher with combined therapy, toxic effects were considerably greater, and there was no difference in disease-free or overall survival between the two groups.[1]

Treatment options (note that in this clinical setting, the skin is easily injured; any of the topical therapies must be administered with extreme caution):

1. PUVA: psoralen + ultraviolet A radiation.
Therapeutic trials with PUVA have shown a 62% to 90% complete remission
rate with early cutaneous stages achieving the best responses. It may
be used in conjunction with systemic treatment. Maintenance therapy
with PUVA is generally required to prolong remission duration.[2]
PUVA combined with interferon alfa-2a is associated with a high
response rate.[3]

2. TSEB: total-skin electron-beam irradiation.
Electron irradiation of appropriate energies will penetrate only to
the dermis, and thus the skin alone can be treated without systemic
effects. This therapy requires an excellent radiation therapy facility
with physics support, considerable technical expertise, and precise
dosimetry. This therapy can produce excellent palliation with complete
response rates of 40% to 80%.[4]

3. Topical mechlorethamine (nitrogen mustard).
This form of treatment may be used palliatively or to supplement
therapeutic approaches directed against nodal or visceral disease. The
overall complete remission rate of TNM classification T4 patients is
20% to 40%. Treatments are usually continued for 2 to 3 years.[5]

4. Local electron-beam irradiation or orthovoltage radiation therapy may also be used to palliate areas of bulky or symptomatic disease.

5. Systemic chemotherapy (single agent or combination) often combined with treatment directed at the skin.

6. Fludarabine, 2-chlorodeoxyadenosine, and pentostatin are active agents for mycosis fungoides and Sezary syndrome.[6-8]

7. Extracorporeal photochemotherapy.[9,10]

8. Interferon alfa alone or in combination with topical therapy.[7,11]

9. Retinoids.[12]

References:

  1. Kaye FJ, Bunn PA, Steinberg SM, et al.: A randomized trial comparing combination electron-beam radiation and chemotherapy with topical therapy in the initial treatment of mycosis fungoides. New England Journal of Medicine 321(26): 1784-1790, 1989.

  2. Herrmann JJ, Roenigk HH, Hurria A, et al.: Treatment of mycosis fungoides with photochemotherapy (PUVA): long-term follow-up. Journal of the American Academy of Dermatology 33(2, Part 1): 234-242, 1995.

  3. Kuzel TM, Roenigk HH, Samuelson E, et al.: Effectiveness of interferon alfa-2a combined with phototherapy for mycosis fungoides and the Sezary syndrome. Journal of Clinical Oncology 13(1): 257-263, 1995.

  4. Jones GW, Hoppe RT, Glatstein E: Electron beam treatment for cutaneous T-cell lymphoma. Hematology/Oncology Clinics of North America 9(5): 1057-1076, 1995.

  5. Vonderheid EC, Tan ET, Kantor AF, et al.: Long-term efficacy, curative potential, and carcinogenicity of topical mechlorethamine chemotherapy in cutaneous T cell lymphoma. Journal of the American Academy of Dermatology 20(3): 416-428, 1989.

  6. Saven A, Carrera CJ, Carson DA, et al.: 2-Chlorodeoxyadenosine: an active agent in the treatment of cutaneous T-cell lymphoma. Blood 80(3): 587-592, 1992.

  7. Foss FM, Ihde DC, Breneman DL, et al.: Phase II study of pentostatin and intermittent high-dose recombinant interferon alfa-2a in advanced mycosis fungoides/Sezary syndrome. Journal of Clinical Oncology 10(12): 1907-1913, 1992.

  8. Foss FM, Ihde DC, Linnoila IR, et al.: Phase II trial of fludarabine phosphate and interferon alfa-2a in advanced mycosis fungoides/Sezary syndrome. Journal of Clinical Oncology 12(10): 2051-2059, 1994.

  9. Edelson R, Berger C, Gasparro F, et al.: Treatment of cutaneous T-cell lymphoma by extracorporeal photochemotherapy. New England Journal of Medicine 316(6): 297-303, 1987.

  10. Heald PW, Perez MI, McKiernan G, et al.: Extracorporeal photochemotherapy for CTCL. Progress in Clinical and Biological Research 337: 443-447, 1990.

  11. Kuzel TM, Eastern Cooperative Oncology Group: Phase III Study of Topical Therapy of Psoralen With Phototherapy (PUVA), Nitrogen Mustard (Mechlorethamine HCL) Chemotherapy, or Total Skin Electron Beam (TSE) Alone vs One Topical Therapy Combined With Interferon Alfa-2b for Cutaneous T-Cell Lymphoma (CTCL) (Summary Last Modified 06/1999), E-1495, clinical trial, closed, 04/22/1999.

  12. Bunn PA, Hoffman SJ, Norris D, et al.: Systemic therapy of cutaneous T-cell lymphomas (mycosis fungoides and the Sezary syndrome). Annals of Internal Medicine 121(8): 592-602, 1994.

STAGE IV CUTANEOUS T-CELL LYMPHOMA

The use of single alkylating agents has produced objective responses in 60% of patients with a duration of less than 6 months. One of the alkylating agents (mechlorethamine, cyclophosphamide, or chlorambucil), or the antimetabolite methotrexate is the most frequently used. Single agents have not been shown to cure any patients, and insufficient data exist to determine whether these agents prolong survival. Combination chemotherapy is not definitely superior to single agents. Even in stage IV disease, treatments directed at the skin may provide significant palliation. A randomized study compared combined total-skin electron-beam irradiation (TSEB) plus combination chemotherapy to conservation therapy consisting of sequential topical therapies in 103 patients. In the latter group, combination chemotherapy was reserved for symptomatic extracutaneous disease or for disease refractory to topical therapies. Patients of any stage were eligible. Although the complete response rate was higher with combined therapy, toxic effects were considerably greater and there was no difference in disease-free or overall survival between the two groups.[1]

Treatment options:

1. Systemic chemotherapy:
chlorambucil + prednisone, mechlorethamine, cyclophosphamide,
methotrexate, combination chemotherapy [1]

2. Topical mechlorethamine (nitrogen mustard).
This form of treatment may be used palliatively or to supplement
therapeutic approaches directed against nodal or visceral disease. The
overall complete remission rate in 243 patients was 64% and was related
to stage; up to 35% of stage IV patients had complete responses.
Treatments are usually continued for 2 to 3 years.[2]

3. TSEB: total-skin electron-beam irradiation.
Electron irradiation of appropriate energies will penetrate only to the
dermis, and thus the skin alone can be treated without systemic
effects. This therapy requires an excellent radiation therapy facility
with physics support, considerable technical expertise, and precise
dosimetry. This therapy can produce excellent palliation and may be
combined with systemic treatment.[3]

4. PUVA: psoralen + ultraviolet A radiation.
Therapeutic trials with PUVA have shown a 62% to 90% complete remission
rate with early cutaneous stages achieving the best responses. It may
be used in conjunction with systemic treatment. Maintenance therapy
with PUVA is generally required to prolong remission duration.[4]
PUVA combined with interferon alfa-2a is associated with a high
response rate.[5]

5. Local electron-beam irradiation or orthovoltage radiation therapy may also be used to palliate areas of bulky or symptomatic disease.

6. Fludarabine, 2-chlorodeoxyadenosine, and pentostatin are active agents for mycosis fungoides and Sezary syndrome.[6-8]

7. Extracorporeal photochemotherapy.[9,10]

8. Interferon alfa alone or in combination with topical therapy.[7,11,12]

9. Serotherapy with monoclonal antibodies.[13,14]

10. Retinoids.[15]

References:

  1. Kaye FJ, Bunn PA, Steinberg SM, et al.: A randomized trial comparing combination electron-beam radiation and chemotherapy with topical therapy in the initial treatment of mycosis fungoides. New England Journal of Medicine 321(26): 1784-1790, 1989.

  2. Vonderheid EC, Tan ET, Kantor AF, et al.: Long-term efficacy, curative potential, and carcinogenicity of topical mechlorethamine chemotherapy in cutaneous T cell lymphoma. Journal of the American Academy of Dermatology 20(3): 416-428, 1989.

  3. Jones GW, Hoppe RT, Glatstein E: Electron beam treatment for cutaneous T-cell lymphoma. Hematology/Oncology Clinics of North America 9(5): 1057-1076, 1995.

  4. Herrmann JJ, Roenigk HH, Hurria A, et al.: Treatment of mycosis fungoides with photochemotherapy (PUVA): long-term follow-up. Journal of the American Academy of Dermatology 33(2, Part 1): 234-242, 1995.

  5. Kuzel TM, Roenigk HH, Samuelson E, et al.: Effectiveness of interferon alfa-2a combined with phototherapy for mycosis fungoides and the Sezary syndrome. Journal of Clinical Oncology 13(1): 257-263, 1995.

  6. Saven A, Carrera CJ, Carson DA, et al.: 2-Chlorodeoxyadenosine: an active agent in the treatment of cutaneous T-cell lymphoma. Blood 80(3): 587-592, 1992.

  7. Foss FM, Ihde DC, Breneman DL, et al.: Phase II study of pentostatin and intermittent high-dose recombinant interferon alfa-2a in advanced mycosis fungoides/Sezary syndrome. Journal of Clinical Oncology 10(12): 1907-1913, 1992.

  8. Foss FM, Ihde DC, Linnoila IR, et al.: Phase II trial of fludarabine phosphate and interferon alfa-2a in advanced mycosis fungoides/Sezary syndrome. Journal of Clinical Oncology 12(10): 2051-2059, 1994.

  9. Edelson R, Berger C, Gasparro F, et al.: Treatment of cutaneous T-cell lymphoma by extracorporeal photochemotherapy. New England Journal of Medicine 316(6): 297-303, 1987.

  10. Heald PW, Perez MI, McKiernan G, et al.: Extracorporeal photochemotherapy for CTCL. Progress in Clinical and Biological Research 337: 443-447, 1990.

  11. Bunn PA, Foon KA, Ihde DC, et al.: Recombinant leukocyte A interferon: an active agent in advanced cutaneous T-cell lymphomas. Annals of Internal Medicine 101: 484-487, 1984.

  12. Kuzel TM, Eastern Cooperative Oncology Group: Phase III Study of Topical Therapy of Psoralen With Phototherapy (PUVA), Nitrogen Mustard (Mechlorethamine HCL) Chemotherapy, or Total Skin Electron Beam (TSE) Alone vs One Topical Therapy Combined With Interferon Alfa-2b for Cutaneous T-Cell Lymphoma (CTCL) (Summary Last Modified 06/1999), E-1495, clinical trial, closed, 04/22/1999.

  13. Knox SJ, Levy R, Hodgkinson S, et al.: Observations on the effect of chimeric anti-CD4 monoclonal antibody in patients with mycosis fungoides. Blood 77(1): 20-30, 1991.

  14. Rosen ST, Zimmer AM, Goldman-Leikin R, et al.: Radioimmunodetection and radioimmunotherapy of cutaneous T cell lymphomas using an 131I-labeled monoclonal antibody: an Illinois Cancer Council study. Journal of Clinical Oncology 5(4): 562-573, 1987.

  15. Bunn PA, Hoffman SJ, Norris D, et al.: Systemic therapy of cutaneous T-cell lymphomas (mycosis fungoides and the Sezary syndrome). Annals of Internal Medicine 121(8): 592-602, 1994.

RECURRENT CUTANEOUS T-CELL LYMPHOMA

The treatment of relapsed patients with cutaneous T-cell lymphomas involves the joint decisions of the dermatologist, medical oncologist, and radiation oncologist. It may be possible to re-treat localized areas of relapse with additional electron-beam irradiation or possibly to repeat TSEB therapy. Photon irradiation to bulky skin or nodal masses may prove beneficial. If these options are not possible, then continued topical treatment with other modalities such as mechlorethamine or PUVA may be warranted to relieve cutaneous symptoms. Systemic chemotherapy or clinical trials, if possible, should be considered as the next therapeutic option. PUVA combined with interferon alfa-2a is associated with a high response rate.[1] Extracorporeal photochemotherapy has produced tumor regression in patients resistant to other therapies.[2,3] Radioimmunotherapy using a 131I-labeled monoclonal antibody directed against a T-cell antigen has produced brief responses in a clinical trial.[4] Fludarabine, 2-chlorodeoxyadenosine, and pentostatin are active agents for mycosis fungoides and Sezary syndrome.[5-7] Cell surface receptor ligand-toxin fusion proteins are under evaluation.[8] Allogeneic or autologous bone marrow transplantation is also under clinical evaluation.

References:

  1. Kuzel TM, Roenigk HH, Samuelson E, et al.: Effectiveness of interferon alfa-2a combined with phototherapy for mycosis fungoides and the Sezary syndrome. Journal of Clinical Oncology 13(1): 257-263, 1995.

  2. Edelson R, Berger C, Gasparro F, et al.: Treatment of cutaneous T-cell lymphoma by extracorporeal photochemotherapy. New England Journal of Medicine 316(6): 297-303, 1987.

  3. Heald PW, Perez MI, McKiernan G, et al.: Extracorporeal photochemotherapy for CTCL. Progress in Clinical and Biological Research 337: 443-447, 1990.

  4. Rosen ST, Zimmer AM, Goldman-Leikin R, et al.: Radioimmunodetection and radioimmunotherapy of cutaneous T cell lymphomas using an 131I-labeled monoclonal antibody: an Illinois Cancer Council study. Journal of Clinical Oncology 5(4): 562-573, 1987.

  5. Saven A, Carrera CJ, Carson DA, et al.: 2-Chlorodeoxyadenosine: an active agent in the treatment of cutaneous T-cell lymphoma. Blood 80(3): 587-592, 1992.

  6. Foss FM, Ihde DC, Breneman DL, et al.: Phase II study of pentostatin and intermittent high-dose recombinant interferon alfa-2a in advanced mycosis fungoides/Sezary syndrome. Journal of Clinical Oncology 10(12): 1907-1913, 1992.

  7. Foss FM, Ihde DC, Linnoila IR, et al.: Phase II trial of fludarabine phosphate and interferon alfa-2a in advanced mycosis fungoides/Sezary syndrome. Journal of Clinical Oncology 12(10): 2051-2059, 1994.

  8. LeMaistre CF, Saleh MN, Kuzel TM, et al.: Phase I trial of a ligand fusion-protein (DAB389IL-2) in lymphomas expressing the receptor for interleukin-2. Blood 91(2): 399-405, 1998.

Date Last Modified: 11/1999


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