Mycosis Fungoides and Other Cutaneous T-Cell Lymphomas Treatment (PDQ®): Treatment - Health Professional Information [NCI]

General Information About Mycosis Fungoides and Other Cutaneous T-Cell Lymphomas

Clinical Presentation

Cutaneous T-cell lymphomas, which include mycosis fungoides and Sézary syndrome, are neoplasias of malignant T lymphocytes that usually possess the helper/inducer cell surface phenotype and initially present as skin involvement.[1] Cutaneous T-cell lymphomas should be distinguished from other T-cell lymphomas that involve the skin, such as anaplastic large cell lymphoma (CD30 positive), peripheral T-cell lymphoma (CD30 negative, with no epidermal involvement), or adult T-cell leukemia/lymphoma (usually with systemic involvement).[2,3] For more information about these types of T-cell lymphomas, see Peripheral T-Cell Non-Hodgkin Lymphoma Treatment.

Typically, the natural history of cutaneous T-cell lymphoma is indolent.[4] Symptoms of the disease may be present for long periods, in a range of 2 to 10 years, because cutaneous eruptions wax and wane before being confirmed by biopsy. Cutaneous T-cell lymphomas are treatable with available topical therapy, systemic therapy, or both. Curative modalities have proven elusive, with the possible exception of patients with minimal disease confined to the skin.

In addition, several benign or indolent conditions can be confused with mycosis fungoides. It is important to consult with a pathologist who has expertise in distinguishing these conditions.[1]

Prognosis and Survival

The prognosis of patients with cutaneous T-cell lymphomas is based on the extent of disease (stage) at presentation.[5] The presence of lymphadenopathy and involvement of peripheral blood and viscera increase in likelihood with worsening cutaneous involvement and define poor prognostic groups.[5,6,7,8] The Cutaneous Lymphoma International Consortium retrospectively reviewed 1,275 patients and found that the following four independent prognostic markers indicate a worse survival:[9]

• Stage IV disease.
• Age older than 60 years.
• Large cell transformation.
• Elevated lactate dehydrogenase.

The median survival following diagnosis varies according to stage. Patients with stage IA disease have a median survival of 20 years or more. Most deaths for this group are not caused by, nor are they related to, mycosis fungoides.[10,11] In contrast, more than 50% of patients with stage III through stage IV disease die of mycosis fungoides, with a median survival of approximately 5 years.[7,9,12,13] The Cutaneous Lymphoma International Prognostic index used male sex, age older than 60 years, plaques, lymph nodes, blood involvement, and visceral involvement as poor prognostic factors to define predicted overall survival (OS) and progression-free survival in both early-stage and advanced-stage groups.[14]

A report on 1,798 patients from the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) Program database found an increase in second malignancies in patients with mycosis fungoides (standardized incidence ratio, 1.32; 95% confidence interval [CI], 1.15–1.52), especially for Hodgkin lymphoma, non-Hodgkin lymphoma, and myeloma.[15] Another report on 4,459 patients from the SEER database found that the 19.2% of African American patients with mycosis fungoides had shorter OS, potentially attributable to disease characteristics, socioeconomic status, and type of therapy (hazard ratio, 1.47; 95% CI, 1.25–1.74; P < .001).[16]

Cutaneous disease can manifest as an eczematous patch or plaque stage covering less than 10% of the body surface (T1), a plaque stage covering 10% or more of the body surface (T2), or as tumors (T3) that frequently undergo necrotic ulceration.[17,18] Several retrospective studies showed that 20% of patients have disease that progresses from stage I or II to stage III or IV.[19,20,21] Sézary syndrome presents with generalized erythroderma (T4) and peripheral blood involvement. However, there is some disagreement about whether mycosis fungoides and Sézary syndrome are actually variants of the same disease.[22] The same retrospective study with a median follow-up of 14.5 years found that only 3% of 1,422 patients progressed from mycosis fungoides to Sézary syndrome.[19]

There is consensus that patients with Sézary syndrome (leukemic involvement) have a poor prognosis (median survival, 4 years), with or without the typical generalized erythroderma.[23,24] Cytologic transformation from a low-grade lymphoma to a high-grade lymphoma (large cell transformation) occurs rarely (<5%) during the course of these diseases and is associated with a poor prognosis.[25,26,27] A retrospective analysis of 100 cases with large cell transformation found reduced disease-specific survival with extracutaneous transformation, increased extent of skin lesions, and CD30 negativity.[28] A common cause of death during the tumor phase is septicemia caused by chronic skin infection with staph species, herpes simplex, herpes zoster, and fungal skin infections.[29,30]

Folliculotropic mycosis fungoides is a variant of mycosis fungoides marked by folliculotropic, rather than epidermotropic, neoplastic infiltrates, with preferential location in the head and neck area.[31] Early plaque-stage folliculotropic mycosis fungoides have a very indolent prognosis, while extracutaneous disease portends a very poor prognosis.[31]

References:

1. Wilcox RA: Cutaneous T-cell lymphoma: 2017 update on diagnosis, risk-stratification, and management. Am J Hematol 92 (10): 1085-1102, 2017.
2. 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): 354-71, 1997.
3. 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): 1361-92, 1994.
4. Diamandidou E, Cohen PR, Kurzrock R: Mycosis fungoides and Sezary syndrome. Blood 88 (7): 2385-409, 1996.
5. Agar NS, Wedgeworth E, Crichton S, et al.: Survival outcomes and prognostic factors in mycosis fungoides/Sézary syndrome: validation of the revised International Society for Cutaneous Lymphomas/European Organisation for Research and Treatment of Cancer staging proposal. J Clin Oncol 28 (31): 4730-9, 2010.
6. Talpur R, Singh L, Daulat S, et al.: Long-term outcomes of 1,263 patients with mycosis fungoides and Sézary syndrome from 1982 to 2009. Clin Cancer Res 18 (18): 5051-60, 2012.
7. Kim YH, Liu HL, Mraz-Gernhard S, et al.: Long-term outcome of 525 patients with mycosis fungoides and Sezary syndrome: clinical prognostic factors and risk for disease progression. Arch Dermatol 139 (7): 857-66, 2003.
8. Alberti-Violetti S, Talpur R, Schlichte M, et al.: Advanced-stage mycosis fungoides and Sézary syndrome: survival and response to treatment. Clin Lymphoma Myeloma Leuk 15 (6): e105-12, 2015.
9. Scarisbrick JJ, Prince HM, Vermeer MH, et al.: Cutaneous Lymphoma International Consortium Study of Outcome in Advanced Stages of Mycosis Fungoides and Sézary Syndrome: Effect of Specific Prognostic Markers on Survival and Development of a Prognostic Model. J Clin Oncol 33 (32): 3766-73, 2015.
10. Kim YH, Jensen RA, Watanabe GL, et al.: Clinical stage IA (limited patch and plaque) mycosis fungoides. A long-term outcome analysis. Arch Dermatol 132 (11): 1309-13, 1996.
11. Vollmer RT: A review of survival in mycosis fungoides. Am J Clin Pathol 141 (5): 706-11, 2014.
12. Zackheim HS, Amin S, Kashani-Sabet M, et al.: Prognosis in cutaneous T-cell lymphoma by skin stage: long-term survival in 489 patients. J Am Acad Dermatol 40 (3): 418-25, 1999.
13. de Coninck EC, Kim YH, Varghese A, et al.: Clinical characteristics and outcome of patients with extracutaneous mycosis fungoides. J Clin Oncol 19 (3): 779-84, 2001.
14. Benton EC, Crichton S, Talpur R, et al.: A cutaneous lymphoma international prognostic index (CLIPi) for mycosis fungoides and Sezary syndrome. Eur J Cancer 49 (13): 2859-68, 2013.
15. Huang KP, Weinstock MA, Clarke CA, et al.: Second lymphomas and other malignant neoplasms in patients with mycosis fungoides and Sezary syndrome: evidence from population-based and clinical cohorts. Arch Dermatol 143 (1): 45-50, 2007.
16. Su C, Nguyen KA, Bai HX, et al.: Racial disparity in mycosis fungoides: An analysis of 4495 cases from the US National Cancer Database. J Am Acad Dermatol 77 (3): 497-502.e2, 2017.
17. Siegel RS, Pandolfino T, Guitart J, et al.: Primary cutaneous T-cell lymphoma: review and current concepts. J Clin Oncol 18 (15): 2908-25, 2000.
18. Lorincz AL: Cutaneous T-cell lymphoma (mycosis fungoides) Lancet 347 (9005): 871-6, 1996.
19. Quaglino P, Pimpinelli N, Berti E, et al.: Time course, clinical pathways, and long-term hazards risk trends of disease progression in patients with classic mycosis fungoides: a multicenter, retrospective follow-up study from the Italian Group of Cutaneous Lymphomas. Cancer 118 (23): 5830-9, 2012.
20. Wernham AG, Shah F, Amel-Kashipaz R, et al.: Stage I mycosis fungoides: frequent association with a favourable prognosis but disease progression and disease-specific mortality may occur. Br J Dermatol 173 (5): 1295-7, 2015.
21. Desai M, Liu S, Parker S: Clinical characteristics, prognostic factors, and survival of 393 patients with mycosis fungoides and Sézary syndrome in the southeastern United States: a single-institution cohort. J Am Acad Dermatol 72 (2): 276-85, 2015.
22. Olsen EA, Rook AH, Zic J, et al.: Sézary syndrome: immunopathogenesis, literature review of therapeutic options, and recommendations for therapy by the United States Cutaneous Lymphoma Consortium (USCLC). J Am Acad Dermatol 64 (2): 352-404, 2011.
23. Kubica AW, Davis MD, Weaver AL, et al.: Sézary syndrome: a study of 176 patients at Mayo Clinic. J Am Acad Dermatol 67 (6): 1189-99, 2012.
24. Thompson AK, Killian JM, Weaver AL, et al.: Sézary syndrome without erythroderma: A review of 16 cases at Mayo Clinic. J Am Acad Dermatol 76 (4): 683-688, 2017.
25. Kim YH, Bishop K, Varghese A, et al.: Prognostic factors in erythrodermic mycosis fungoides and the Sézary syndrome. Arch Dermatol 131 (9): 1003-8, 1995.
26. Arulogun SO, Prince HM, Ng J, et al.: Long-term outcomes of patients with advanced-stage cutaneous T-cell lymphoma and large cell transformation. Blood 112 (8): 3082-7, 2008.
27. Kadin ME, Hughey LC, Wood GS: Large-cell transformation of mycosis fungoides-differential diagnosis with implications for clinical management: a consensus statement of the US Cutaneous Lymphoma Consortium. J Am Acad Dermatol 70 (2): 374-6, 2014.
28. Benner MF, Jansen PM, Vermeer MH, et al.: Prognostic factors in transformed mycosis fungoides: a retrospective analysis of 100 cases. Blood 119 (7): 1643-9, 2012.
29. Talpur R, Bassett R, Duvic M: Prevalence and treatment of Staphylococcus aureus colonization in patients with mycosis fungoides and Sézary syndrome. Br J Dermatol 159 (1): 105-12, 2008.
30. Lebas E, Arrese JE, Nikkels AF: Risk Factors for Skin Infections in Mycosis Fungoides. Dermatology 232 (6): 731-737, 2016.
31. van Santen S, Roach RE, van Doorn R, et al.: Clinical Staging and Prognostic Factors in Folliculotropic Mycosis Fungoides. JAMA Dermatol 152 (9): 992-1000, 2016.

Cellular Classification of Mycosis Fungoides and other Cutaneous T-Cell Lymphomas

The histological diagnosis of mycosis fungoides and other cutaneous T-cell lymphomas is usually difficult to determine 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 cutaneous T-cell lymphoma cells (convoluted lymphocytes), a band-like upper dermal infiltrate, and epidermal infiltrations with Pautrier abscesses (collections of neoplastic lymphocytes). A definitive diagnosis of Sézary syndrome may be made from a peripheral blood evaluation when skin biopsies are consistent with the diagnosis. Supportive evidence for circulating Sézary cells is provided by T-cell receptor gene analysis, identification of the atypical lymphocytes with hyperconvoluted or cerebriform nuclei, and flow cytometry with the characteristic deletion of cell surface markers such as CD7 and CD26. However, none of these is individually pathognomonic for lymphoma.[1,2]

References:

1. Olsen EA, Rook AH, Zic J, et al.: Sézary syndrome: immunopathogenesis, literature review of therapeutic options, and recommendations for therapy by the United States Cutaneous Lymphoma Consortium (USCLC). J Am Acad Dermatol 64 (2): 352-404, 2011.
2. Fraser-Andrews EA, Russell-Jones R, Woolford AJ, et al.: Diagnostic and prognostic importance of T-cell receptor gene analysis in patients with Sézary syndrome. Cancer 92 (7): 1745-52, 2001.

Stage Information for Mycosis Fungoides and Other Cutaneous T-Cell Lymphomas

The American Joint Committee on Cancer (AJCC) has designated staging by TNM (tumor, node, metastasis) classification to define cutaneous T-cell lymphomas.[1] Peripheral blood involvement with cutaneous T-cell lymphoma cells is correlated with more advanced skin stage, lymph node and visceral involvement, and shortened survival.

Cutaneous T-cell lymphomas also have a formal staging system proposed by the International Society for Cutaneous Lymphomas and the European Organisation for Research and Treatment of Cancer.[2,3]

References:

1. Primary cutaneous lymphomas. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. Springer; 2017, pp. 967–72.
2. Olsen E, Vonderheid E, Pimpinelli N, et al.: Revisions to the staging and classification of mycosis fungoides and Sezary syndrome: a proposal of the International Society for Cutaneous Lymphomas (ISCL) and the cutaneous lymphoma task force of the European Organization of Research and Treatment of Cancer (EORTC). Blood 110 (6): 1713-22, 2007.
3. Agar NS, Wedgeworth E, Crichton S, et al.: Survival outcomes and prognostic factors in mycosis fungoides/Sézary syndrome: validation of the revised International Society for Cutaneous Lymphomas/European Organisation for Research and Treatment of Cancer staging proposal. J Clin Oncol 28 (31): 4730-9, 2010.

Treatment Option Overview for Mycosis Fungoides and Other Cutaneous T-Cell Lymphomas

Anecdotal responses, some lasting for months, can be seen with aggressive antibiotic treatment of Staphylococcus aureus, with corresponding decreased expression of interleukin-2 receptors, STAT signaling, and T-cell proliferation.[1][Level of evidence C3]

These types of treatments produce remissions, but long-term remissions are uncommon. Therefore, treatment is considered palliative for most patients, although major symptomatic improvement is regularly achieved. Survival in excess of 8 years is common for patients with early stages of disease. All patients with cutaneous T-cell lymphomas are candidates for clinical trials evaluating new approaches to treatment.

References:

1. Lindahl LM, Willerslev-Olsen A, Gjerdrum LMR, et al.: Antibiotics inhibit tumor and disease activity in cutaneous T-cell lymphoma. Blood 134 (13): 1072-1083, 2019.

Treatment of Stage I and Stage II Mycosis Fungoides

Several forms of treatment can produce complete resolution of skin lesions in this stage, so 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 for age- and sex-matched controls.[1,2,3]

There is no curative therapy and no clear difference in overall survival (OS) among the treatment options for patients with stage I and stage II mycosis fungoides.

A randomized study of 103 patients compared combined total-skin electron-beam radiation (TSEB) plus combination chemotherapy with sequential topical therapies.[4] In the latter group, combination chemotherapy was reserved for patients with symptomatic extracutaneous disease or disease that was refractory to topical therapies. Patients with any disease stage were eligible. Although the complete response rate was higher with combined therapy, toxic effects were considerably greater, and no difference was seen in disease-free survival (DFS) or OS between the two groups.[4][Level of evidence A1]

Treatment Options for Stage I and Stage II Mycosis Fungoides

Treatment options for stages I and II mycosis fungoides include the following:[5]

1. Photodynamic therapy.
2. Radiation therapy.
3. Biological therapy.
4. Chemotherapy.
5. Other drug therapy.
6. Targeted therapy.

Photodynamic therapy

1. Psoralen and ultraviolet A (PUVA) radiation therapy.[6,7,8,9,10,11]
   • Therapeutic trials with PUVA have shown an 80% to 90% complete remission rate in patients, with those in early cutaneous stages achieving the best responses. PUVA may be used in conjunction with systemic treatment.[10] Continued maintenance therapy with PUVA at more protracted intervals is generally required to prolong remission duration.[6,7,8,10] PUVA combined with interferon alfa-2a is associated with a high response rate.[9,10]
2. Narrowband ultraviolet B radiation.[12,13]
   • Single-arm and retrospective comparisons confirm the efficacy of narrowband ultraviolet B with 80% to 90% complete remission rates, especially for patients with early cutaneous stages.[12,13]
   • A Cochrane systematic review and meta-analysis compared PUVA with narrowband ultraviolet B radiation in 778 patients with early-stage mycosis fungoides (stage IA, IB, and IIA). Significantly higher complete responses were seen in patients treated with PUVA (73.8% vs. 62.2%; hazard ratio, 1.68; 95% confidence interval [CI], 1.02–2.76; P = .04). There were no significant differences in adverse effects.[11][Level of evidence B3]

Radiation therapy

1. TSEB.[14,15,16,17,18,19]
   • Electron-beam radiation therapy of appropriate energies will penetrate only to the dermis, and thus, the skin alone can be treated without systemic effects. This therapy requires a radiation therapy facility with physics support and considerable technical expertise to deliver precise dosimetry. TSEB can result in short- and long-term cutaneous toxic effects and is not widely available.
   • This therapy can provide excellent palliation, with complete response rates as high as 80%, and may be combined with systemic treatment. Based on the long-term survival of these early-stage patients, electron-beam radiation therapy is sometimes used with curative intent.[14,15,16,17,18] Long-term DFS can be achieved in patients with unilesional mycosis fungoides treated with local radiation therapy.[19]
2. Local electron-beam radiation or orthovoltage radiation therapy may be used to palliate areas of bulky or symptomatic skin disease.[20,21]

Biological therapy

1. Interferon alfa or interferon gamma alone or in combination with topical therapy.[22,23][Level of evidence C3]
   • A retrospective review of 198 patients with mycosis fungoides and Sézary syndrome compared the time-to-next-treatment (TTNT) between patients who received interferon alfa and conventional chemotherapy. Interferon alfa provided a longer TTNT of 8.7 months (95% CI, 6.0–18.0) than did chemotherapy, with a TTNT of 3.9 months (95% CI, 3.2–5.1) (P < .00001).[23][Level of evidence C3]

Chemotherapy

Chemotherapeutic agents generally demonstrate short durations of response. In a retrospective review of 198 patients with advanced-stage disease, the median TTNT was 4 months.[23] However, these comparisons may be confounded by the order in which the agents were introduced.

1. Topical chemotherapy with mechlorethamine.[14,24,25]
   • This form of treatment may be used palliatively or to supplement therapeutic approaches directed against nodal or visceral disease. 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 patients, 25% to 75% of T2 patients, as many as 50% of T3 patients, and 20% to 40% of T4 patients have complete responses. The overall complete remission rate in 243 patients was 64% and was related to stage; as many as 35% of stage IV patients had complete responses. Treatments are usually continued for 2 to 3 years. Continuous 5-year DFS may be possible in as many as 33% of T1 patients.[14,24,25]
2. Oral methotrexate (NCT00425555).[26]
3. Pegylated liposomal doxorubicin.[27,28,29]
4. Fludarabine, cladribine, and pentostatin are active agents for mycosis fungoides.[30,31,32,33]
5. Single-agent chemotherapy or combination systemic chemotherapy (chlorambucil plus prednisone, mechlorethamine, cyclophosphamide, methotrexate) is often combined with treatment directed at the skin.[4,23,34,35]
6. Pralatrexate (folate analogue).[23,36,37]

Other drug therapy

1. Symptomatic management with topical corticosteroids. Low potency steroids can be used on the face with safety and efficacy.[38]
2. Bexarotene, an oral or topical retinoid (NCT00255801).[39,40]
3. Lenalidomide.[41]
4. Vorinostat or romidepsin or other histone deacetylase inhibitors (HDACi).[23,42,43,44][Level of evidence C3]
   • A retrospective review of 198 patients with mycosis fungoides and Sézary syndrome compared TTNT between HDACi and conventional chemotherapy. HDACi provided a longer TTNT of 4.5 months (95% CI, 4.0–6.1) than did chemotherapy, with a TTNT of 3.9 months (95% CI, 3.2–5.1; P = .01).[23][Level of evidence C3]

Targeted therapy

1. Brentuximab vedotin.[45,46]
   • Two phase II trials of 58 patients with variable CD30 expression showed a 50% to 70% response rate with 50% of patients still in remission after 1 year.[45,46][Level of evidence C3]

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References:

1. Kim YH, Jensen RA, Watanabe GL, et al.: Clinical stage IA (limited patch and plaque) mycosis fungoides. A long-term outcome analysis. Arch Dermatol 132 (11): 1309-13, 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. J Am Acad Dermatol 40 (3): 418-25, 1999.
3. Vollmer RT: A review of survival in mycosis fungoides. Am J Clin Pathol 141 (5): 706-11, 2014.
4. 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. N Engl J Med 321 (26): 1784-90, 1989.
5. Trautinger F, Knobler R, Willemze R, et al.: EORTC consensus recommendations for the treatment of mycosis fungoides/Sézary syndrome. Eur J Cancer 42 (8): 1014-30, 2006.
6. Herrmann JJ, Roenigk HH, Hurria A, et al.: Treatment of mycosis fungoides with photochemotherapy (PUVA): long-term follow-up. J Am Acad Dermatol 33 (2 Pt 1): 234-42, 1995.
7. Ramsay DL, Lish KM, Yalowitz CB, et al.: Ultraviolet-B phototherapy for early-stage cutaneous T-cell lymphoma. Arch Dermatol 128 (7): 931-3, 1992.
8. Querfeld C, Rosen ST, Kuzel TM, et al.: Long-term follow-up of patients with early-stage cutaneous T-cell lymphoma who achieved complete remission with psoralen plus UV-A monotherapy. Arch Dermatol 141 (3): 305-11, 2005.
9. Kuzel TM, Roenigk HH, Samuelson E, et al.: Effectiveness of interferon alfa-2a combined with phototherapy for mycosis fungoides and the Sézary syndrome. J Clin Oncol 13 (1): 257-63, 1995.
10. Olsen EA, Hodak E, Anderson T, et al.: Guidelines for phototherapy of mycosis fungoides and Sézary syndrome: A consensus statement of the United States Cutaneous Lymphoma Consortium. J Am Acad Dermatol 74 (1): 27-58, 2016.
11. Phan K, Ramachandran V, Fassihi H, et al.: Comparison of Narrowband UV-B With Psoralen-UV-A Phototherapy for Patients With Early-Stage Mycosis Fungoides: A Systematic Review and Meta-analysis. JAMA Dermatol 155 (3): 335-341, 2019.
12. Almohideb M, Walsh S, Walsh S, et al.: Bath Psoralen-ultraviolet A and Narrowband Ultraviolet B Phototherapy as Initial Therapy for Early-stage Mycosis Fungoides: A Retrospective Cohort of 267 Cases at the University of Toronto. Clin Lymphoma Myeloma Leuk 17 (9): 604-612, 2017.
13. Elcin G, Duman N, Karahan S, et al.: Long-term follow-up of early mycosis fungoides patients treated with narrowband ultraviolet B phototherapy. J Dermatolog Treat 25 (3): 268-73, 2014.
14. Chinn DM, Chow S, Kim YH, et al.: Total skin electron beam therapy with or without adjuvant topical nitrogen mustard or nitrogen mustard alone as initial treatment of T2 and T3 mycosis fungoides. Int J Radiat Oncol Biol Phys 43 (5): 951-8, 1999.
15. Quirós PA, Jones GW, Kacinski BM, et al.: Total skin electron beam therapy followed by adjuvant psoralen/ultraviolet-A light in the management of patients with T1 and T2 cutaneous T-cell lymphoma (mycosis fungoides). Int J Radiat Oncol Biol Phys 38 (5): 1027-35, 1997.
16. Ysebaert L, Truc G, Dalac S, et al.: Ultimate results of radiation therapy for T1-T2 mycosis fungoides (including reirradiation). Int J Radiat Oncol Biol Phys 58 (4): 1128-34, 2004.
17. Jones GW, Rosenthal D, Wilson LD: Total skin electron radiation for patients with erythrodermic cutaneous T-cell lymphoma (mycosis fungoides and the Sézary syndrome). Cancer 85 (9): 1985-95, 1999.
18. Navi D, Riaz N, Levin YS, et al.: The Stanford University experience with conventional-dose, total skin electron-beam therapy in the treatment of generalized patch or plaque (T2) and tumor (T3) mycosis fungoides. Arch Dermatol 147 (5): 561-7, 2011.
19. Micaily B, Miyamoto C, Kantor G, et al.: Radiotherapy for unilesional mycosis fungoides. Int J Radiat Oncol Biol Phys 42 (2): 361-4, 1998.
20. Thomas TO, Agrawal P, Guitart J, et al.: Outcome of patients treated with a single-fraction dose of palliative radiation for cutaneous T-cell lymphoma. Int J Radiat Oncol Biol Phys 85 (3): 747-53, 2013.
21. O'Malley JT, de Masson A, Lowry EL, et al.: Radiotherapy Eradicates Malignant T Cells and Is Associated with Improved Survival in Early-Stage Mycosis Fungoides. Clin Cancer Res 26 (2): 408-418, 2020.
22. Olsen EA, Bunn PA: Interferon in the treatment of cutaneous T-cell lymphoma. Hematol Oncol Clin North Am 9 (5): 1089-107, 1995.
23. Hughes CF, Khot A, McCormack C, et al.: Lack of durable disease control with chemotherapy for mycosis fungoides and Sézary syndrome: a comparative study of systemic therapy. Blood 125 (1): 71-81, 2015.
24. Lessin SR, Duvic M, Guitart J, et al.: Topical chemotherapy in cutaneous T-cell lymphoma: positive results of a randomized, controlled, multicenter trial testing the efficacy and safety of a novel mechlorethamine, 0.02%, gel in mycosis fungoides. JAMA Dermatol 149 (1): 25-32, 2013.
25. de Quatrebarbes J, Estève E, Bagot M, et al.: Treatment of early-stage mycosis fungoides with twice-weekly applications of mechlorethamine and topical corticosteroids: a prospective study. Arch Dermatol 141 (9): 1117-20, 2005.
26. Zackheim HS, Kashani-Sabet M, McMillan A: Low-dose methotrexate to treat mycosis fungoides: a retrospective study in 69 patients. J Am Acad Dermatol 49 (5): 873-8, 2003.
27. Wollina U, Dummer R, Brockmeyer NH, et al.: Multicenter study of pegylated liposomal doxorubicin in patients with cutaneous T-cell lymphoma. Cancer 98 (5): 993-1001, 2003.
28. Dummer R, Quaglino P, Becker JC, et al.: Prospective international multicenter phase II trial of intravenous pegylated liposomal doxorubicin monochemotherapy in patients with stage IIB, IVA, or IVB advanced mycosis fungoides: final results from EORTC 21012. J Clin Oncol 30 (33): 4091-7, 2012.
29. Quereux G, Marques S, Nguyen JM, et al.: Prospective multicenter study of pegylated liposomal doxorubicin treatment in patients with advanced or refractory mycosis fungoides or Sézary syndrome. Arch Dermatol 144 (6): 727-33, 2008.
30. Saven A, Carrera CJ, Carson DA, et al.: 2-Chlorodeoxyadenosine: an active agent in the treatment of cutaneous T-cell lymphoma. Blood 80 (3): 587-92, 1992.
31. 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/Sézary syndrome. J Clin Oncol 10 (12): 1907-13, 1992.
32. Foss FM, Ihde DC, Linnoila IR, et al.: Phase II trial of fludarabine phosphate and interferon alfa-2a in advanced mycosis fungoides/Sézary syndrome. J Clin Oncol 12 (10): 2051-9, 1994.
33. Kurzrock R, Pilat S, Duvic M: Pentostatin therapy of T-cell lymphomas with cutaneous manifestations. J Clin Oncol 17 (10): 3117-21, 1999.
34. Rosen ST, Foss FM: Chemotherapy for mycosis fungoides and the Sézary syndrome. Hematol Oncol Clin North Am 9 (5): 1109-16, 1995.
35. Zackheim HS, Epstein EH: Low-dose methotrexate for the Sézary syndrome. J Am Acad Dermatol 21 (4 Pt 1): 757-62, 1989.
36. Horwitz SM, Kim YH, Foss F, et al.: Identification of an active, well-tolerated dose of pralatrexate in patients with relapsed or refractory cutaneous T-cell lymphoma. Blood 119 (18): 4115-22, 2012.
37. Talpur R, Thompson A, Gangar P, et al.: Pralatrexate alone or in combination with bexarotene: long-term tolerability in relapsed/refractory mycosis fungoides. Clin Lymphoma Myeloma Leuk 14 (4): 297-304, 2014.
38. Duffy R, Jennings T, Kartan S, et al.: Special Considerations in the Treatment of Mycosis Fungoides. Am J Clin Dermatol 20 (4): 571-578, 2019.
39. Duvic M, Hymes K, Heald P, et al.: Bexarotene is effective and safe for treatment of refractory advanced-stage cutaneous T-cell lymphoma: multinational phase II-III trial results. J Clin Oncol 19 (9): 2456-71, 2001.
40. Heald P, Mehlmauer M, Martin AG, et al.: Topical bexarotene therapy for patients with refractory or persistent early-stage cutaneous T-cell lymphoma: results of the phase III clinical trial. J Am Acad Dermatol 49 (5): 801-15, 2003.
41. Querfeld C, Rosen ST, Guitart J, et al.: Results of an open-label multicenter phase 2 trial of lenalidomide monotherapy in refractory mycosis fungoides and Sézary syndrome. Blood 123 (8): 1159-66, 2014.
42. Duvic M, Dummer R, Becker JC, et al.: Panobinostat activity in both bexarotene-exposed and -naïve patients with refractory cutaneous T-cell lymphoma: results of a phase II trial. Eur J Cancer 49 (2): 386-94, 2013.
43. Olsen EA, Kim YH, Kuzel TM, et al.: Phase IIb multicenter trial of vorinostat in patients with persistent, progressive, or treatment refractory cutaneous T-cell lymphoma. J Clin Oncol 25 (21): 3109-15, 2007.
44. Piekarz RL, Frye R, Turner M, et al.: Phase II multi-institutional trial of the histone deacetylase inhibitor romidepsin as monotherapy for patients with cutaneous T-cell lymphoma. J Clin Oncol 27 (32): 5410-7, 2009.
45. Kim YH, Tavallaee M, Sundram U, et al.: Phase II Investigator-Initiated Study of Brentuximab Vedotin in Mycosis Fungoides and Sézary Syndrome With Variable CD30 Expression Level: A Multi-Institution Collaborative Project. J Clin Oncol 33 (32): 3750-8, 2015.
46. Duvic M, Tetzlaff MT, Gangar P, et al.: Results of a Phase II Trial of Brentuximab Vedotin for CD30+ Cutaneous T-Cell Lymphoma and Lymphomatoid Papulosis. J Clin Oncol 33 (32): 3759-65, 2015.

Treatment of Stage III and Stage IV Mycosis Fungoides and Sézary Syndrome

Mycosis Fungoides

There is no curative therapy and no clear difference in overall survival (OS) among the treatment options for patients with stage III and stage IV disease.

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 (e.g., mechlorethamine, cyclophosphamide, or chlorambucil), or the antimetabolite methotrexate is the most frequently used. Single agents have not cured any patients, and insufficient data exist to determine whether these agents prolong survival. Combination chemotherapy is not definitely superior to single agents. Even in patients with stage IV disease, treatments directed at the skin may provide significant palliation.

A randomized study of 103 patients compared combined total-skin electron-beam radiation (TSEB) plus combination chemotherapy with conservation therapy consisting of sequential topical therapies.[1] In the latter group, combination chemotherapy was reserved for patients with symptomatic extracutaneous disease or for disease that was refractory to topical therapies. Patients with any disease stage were eligible. Although the complete response rate was higher with combined therapy, toxic effects were considerably greater, and no difference was seen in disease-free survival (DFS) or OS between the two groups.[1][Level of evidence A1]

Sézary Syndrome

Sézary syndrome is a rare leukemic variant of cutaneous T-cell lymphoma characterized by erythroderma, circulating Sézary cells with cerebriform nuclei, lymphadenopathy, and pruritus.[2] This condition typically progresses rapidly with only short duration of response to most therapies. A retrospective review of 176 patients with Sézary syndrome identified the following poor prognostic factors:[3]

• High lactate dehydrogenase.
• Previous diagnosis of mycosis fungoides.
• Presence of T-cell receptor gene rearrangements in skin, blood, or both.

Remissions attained by using extracorporeal photophoresis, interferon alfa, or retinoids may be followed by allogeneic stem cell transplant. In an anecdotal series of 16 patients with Sézary syndrome after allogeneic transplant, 9 were in complete remission after 4 years.[4]

Treatment Options for Stage III and Stage IV Mycosis Fungoides and Sézary Syndrome

Treatment options for stages III and IV mycosis fungoides and Sézary syndrome include the following (note that in this clinical setting, the skin is easily injured; any of the topical therapies must be administered with extreme caution):[2,5]

1. Photodynamic therapy.
2. Radiation therapy.
3. Biological therapy.
4. Chemotherapy.
5. Other drug therapy.
6. Targeted therapy.
7. Checkpoint inhibitors.

Photodynamic therapy

1. Psoralen and ultraviolet A (PUVA) radiation therapy.[6,7,8,9,10,11]
   • Therapeutic trials with PUVA have shown an 80% to 90% complete remission rate in patients, with those in early cutaneous stages achieving the best responses. PUVA may be used in conjunction with systemic treatment.[10] Continued maintenance therapy with PUVA at more protracted intervals is generally required to prolong remission duration.[6,7,8,10] PUVA combined with interferon alfa-2a is associated with a high response rate.[9,10]
2. Narrowband ultraviolet B radiation.[12,13]
   • Single-arm and retrospective comparisons confirm the efficacy of narrowband ultraviolet B with 80% to 90% complete remission rates, especially for patients with early cutaneous stages.[12,13]
   • A Cochrane systematic review and meta-analysis compared PUVA with narrowband ultraviolet B radiation in 778 patients with early-stage mycosis fungoides (stage IA, IB, and IIA). Significantly higher complete responses were seen in patients treated with PUVA (73.8% vs. 62.2%; hazard ratio, 1.68; 95% confidence interval [CI], 1.02–2.76; P = .04). There were no significant differences in adverse effects.[11][Level of evidence B3]
3. Extracorporeal photophoresis (ECP) alone [14,15,16,17] or in combination with TSEB.[18] ECP is particularly applicable for Sézary syndrome and erythrodermic mycosis fungoides.[17]
   • In a retrospective analysis of 65 patients, with a median follow-up of 48 months, use of ECP in the first to third line of treatment yielded a longer median time-to-next treatment (TTNT) than other systemic options (P < .03).[17][Level of evidence C3]

Radiation therapy

1. TSEB.[19,20,21,22,23,24]
   • Electron-beam radiation therapy of appropriate energies will penetrate only to the dermis, and thus, the skin alone can be treated without systemic effects. This therapy requires a radiation therapy facility with physics support and considerable technical expertise to deliver precise dosimetry. TSEB can result in short- and long-term cutaneous toxic effects and is not widely available.
   • This therapy can provide excellent palliation, with complete response rates as high as 80%, and may be combined with systemic treatment. Based on the long-term survival of these early-stage patients, electron-beam radiation therapy is sometimes used with curative intent.[19,20,21,22,23] Long-term DFS can be achieved in patients with unilesional mycosis fungoides treated with local radiation therapy.[24]
2. Local electron-beam radiation or orthovoltage radiation therapy may be used to palliate areas of bulky or symptomatic disease.[25,26]

Biological therapy

1. Interferon alfa alone or in combination with other agents, such as topical therapy.[27,28]
   • A retrospective review of 198 patients with mycosis fungoides and Sézary syndrome compared the TTNT between patients who received interferon alfa and conventional chemotherapy. Interferon alfa provided a longer TTNT of 8.7 months (95% CI, 6.0–18.0) than did chemotherapy, with a TTNT of 3.9 months (95% CI, 3.2–5.1) (P < .00001).[29][Level of evidence C3]

Chemotherapy

Chemotherapeutic agents generally demonstrate short durations of response. In a retrospective review of 198 patients with advanced-stage disease, the median TTNT was 4 months.[29] However, these comparisons may be confounded by the order in which the agents were introduced.

1. Oral methotrexate (NCT00425555).[30]
2. Fludarabine, cladribine, and pentostatin are active agents for mycosis fungoides and Sézary syndrome.[27,29,31,32,33]
3. Single-agent chemotherapy or combination systemic chemotherapy (chlorambucil plus prednisone, mechlorethamine, cyclophosphamide, methotrexate) often combined with treatment directed at the skin.[1,29,34,35]
4. Topical chemotherapy with mechlorethamine.[36,37]
   • This form of treatment may be used palliatively or to supplement therapeutic approaches directed against nodal or visceral disease. 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 patients, 25% to 75% of T2 patients, as many as 50% of T3 patients, and 20% to 40% of T4 patients have complete responses. The overall complete remission rate in 243 patients was 64% and was related to stage; as many as 35% of stage IV patients had complete responses. Treatments are usually continued for 2 to 3 years. Continuous 5-year DFS may be possible in as many as 33% of T1 patients.[19,36,37]
5. Pegylated liposomal doxorubicin.[38,39,40]
6. Pralatrexate (folate analogue).[29,41,42]

Other drug therapy

1. Symptomatic management with topical corticosteroids. Low potency steroids can be used on the face with safety and efficacy.[43]
2. Lenalidomide.[44]
3. Bexarotene, an oral or topical retinoid.[45,46]
4. Vorinostat or romidepsin or other histone deacetylase inhibitors (HDACi).[2,47,48,49]
   • A retrospective review of 198 patients with mycosis fungoides and Sézary syndrome compared TTNT between HDACi and conventional chemotherapy. HDACi provided a longer TTNT of 4.5 months (95% CI, 4.0–6.1) than did chemotherapy, with a TTNT of 3.9 months (95% CI, 3.2–5.1; P = .01).[29][Level of evidence C3]

Targeted therapy

1. Brentuximab vedotin.[50,51]
   • Two phase II trials of 58 patients with variable CD30 expression showed a 50% to 70% response rate with 50% of patients still in remission after 1 year.[50,51][Level of evidence C3]

Checkpoint inhibitors

1. Pembrolizumab.[52]
   • Anecdotal responses have been seen in patients with advanced relapsed or refractory mycosis fungoides. In a single-arm, multicenter, phase II trial of 24 patients treated with pembrolizumab, the overall response rate was 38%.[52][Level of evidence C3]
   • There are anecdotal reports of hyperprogression of T-cell malignancies following treatment with immune checkpoint inhibitors.[53,54]

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

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. N Engl J Med 321 (26): 1784-90, 1989.
2. Olsen EA, Rook AH, Zic J, et al.: Sézary syndrome: immunopathogenesis, literature review of therapeutic options, and recommendations for therapy by the United States Cutaneous Lymphoma Consortium (USCLC). J Am Acad Dermatol 64 (2): 352-404, 2011.
3. Kubica AW, Davis MD, Weaver AL, et al.: Sézary syndrome: a study of 176 patients at Mayo Clinic. J Am Acad Dermatol 67 (6): 1189-99, 2012.
4. Polansky M, Talpur R, Daulat S, et al.: Long-Term Complete Responses to Combination Therapies and Allogeneic Stem Cell Transplants in Patients With Sézary Syndrome. Clin Lymphoma Myeloma Leuk 15 (5): e83-93, 2015.
5. Trautinger F, Knobler R, Willemze R, et al.: EORTC consensus recommendations for the treatment of mycosis fungoides/Sézary syndrome. Eur J Cancer 42 (8): 1014-30, 2006.
6. Herrmann JJ, Roenigk HH, Hurria A, et al.: Treatment of mycosis fungoides with photochemotherapy (PUVA): long-term follow-up. J Am Acad Dermatol 33 (2 Pt 1): 234-42, 1995.
7. Ramsay DL, Lish KM, Yalowitz CB, et al.: Ultraviolet-B phototherapy for early-stage cutaneous T-cell lymphoma. Arch Dermatol 128 (7): 931-3, 1992.
8. Querfeld C, Rosen ST, Kuzel TM, et al.: Long-term follow-up of patients with early-stage cutaneous T-cell lymphoma who achieved complete remission with psoralen plus UV-A monotherapy. Arch Dermatol 141 (3): 305-11, 2005.
9. Kuzel TM, Roenigk HH, Samuelson E, et al.: Effectiveness of interferon alfa-2a combined with phototherapy for mycosis fungoides and the Sézary syndrome. J Clin Oncol 13 (1): 257-63, 1995.
10. Olsen EA, Hodak E, Anderson T, et al.: Guidelines for phototherapy of mycosis fungoides and Sézary syndrome: A consensus statement of the United States Cutaneous Lymphoma Consortium. J Am Acad Dermatol 74 (1): 27-58, 2016.
11. Phan K, Ramachandran V, Fassihi H, et al.: Comparison of Narrowband UV-B With Psoralen-UV-A Phototherapy for Patients With Early-Stage Mycosis Fungoides: A Systematic Review and Meta-analysis. JAMA Dermatol 155 (3): 335-341, 2019.
12. Almohideb M, Walsh S, Walsh S, et al.: Bath Psoralen-ultraviolet A and Narrowband Ultraviolet B Phototherapy as Initial Therapy for Early-stage Mycosis Fungoides: A Retrospective Cohort of 267 Cases at the University of Toronto. Clin Lymphoma Myeloma Leuk 17 (9): 604-612, 2017.
13. Elcin G, Duman N, Karahan S, et al.: Long-term follow-up of early mycosis fungoides patients treated with narrowband ultraviolet B phototherapy. J Dermatolog Treat 25 (3): 268-73, 2014.
14. Edelson R, Berger C, Gasparro F, et al.: Treatment of cutaneous T-cell lymphoma by extracorporeal photochemotherapy. Preliminary results. N Engl J Med 316 (6): 297-303, 1987.
15. Heald PW, Perez MI, McKiernan G, et al.: Extracorporeal photochemotherapy for CTCL. Prog Clin Biol Res 337: 443-7, 1990.
16. Scarisbrick JJ, Taylor P, Holtick U, et al.: U.K. consensus statement on the use of extracorporeal photopheresis for treatment of cutaneous T-cell lymphoma and chronic graft-versus-host disease. Br J Dermatol 158 (4): 659-78, 2008.
17. Gao C, McCormack C, van der Weyden C, et al.: Prolonged survival with the early use of a novel extracorporeal photopheresis regimen in patients with Sézary syndrome. Blood 134 (16): 1346-1350, 2019.
18. Palareti G, Maccaferri M, Manotti C, et al.: Fibrinogen assays: a collaborative study of six different methods. C.I.S.M.E.L. Comitato Italiano per la Standardizzazione dei Metodi in Ematologia e Laboratorio. Clin Chem 37 (5): 714-9, 1991.
19. Chinn DM, Chow S, Kim YH, et al.: Total skin electron beam therapy with or without adjuvant topical nitrogen mustard or nitrogen mustard alone as initial treatment of T2 and T3 mycosis fungoides. Int J Radiat Oncol Biol Phys 43 (5): 951-8, 1999.
20. Quirós PA, Jones GW, Kacinski BM, et al.: Total skin electron beam therapy followed by adjuvant psoralen/ultraviolet-A light in the management of patients with T1 and T2 cutaneous T-cell lymphoma (mycosis fungoides). Int J Radiat Oncol Biol Phys 38 (5): 1027-35, 1997.
21. Ysebaert L, Truc G, Dalac S, et al.: Ultimate results of radiation therapy for T1-T2 mycosis fungoides (including reirradiation). Int J Radiat Oncol Biol Phys 58 (4): 1128-34, 2004.
22. Jones GW, Rosenthal D, Wilson LD: Total skin electron radiation for patients with erythrodermic cutaneous T-cell lymphoma (mycosis fungoides and the Sézary syndrome). Cancer 85 (9): 1985-95, 1999.
23. Navi D, Riaz N, Levin YS, et al.: The Stanford University experience with conventional-dose, total skin electron-beam therapy in the treatment of generalized patch or plaque (T2) and tumor (T3) mycosis fungoides. Arch Dermatol 147 (5): 561-7, 2011.
24. Micaily B, Miyamoto C, Kantor G, et al.: Radiotherapy for unilesional mycosis fungoides. Int J Radiat Oncol Biol Phys 42 (2): 361-4, 1998.
25. Thomas TO, Agrawal P, Guitart J, et al.: Outcome of patients treated with a single-fraction dose of palliative radiation for cutaneous T-cell lymphoma. Int J Radiat Oncol Biol Phys 85 (3): 747-53, 2013.
26. O'Malley JT, de Masson A, Lowry EL, et al.: Radiotherapy Eradicates Malignant T Cells and Is Associated with Improved Survival in Early-Stage Mycosis Fungoides. Clin Cancer Res 26 (2): 408-418, 2020.
27. 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/Sézary syndrome. J Clin Oncol 10 (12): 1907-13, 1992.
28. Olsen EA, Bunn PA: Interferon in the treatment of cutaneous T-cell lymphoma. Hematol Oncol Clin North Am 9 (5): 1089-107, 1995.
29. Hughes CF, Khot A, McCormack C, et al.: Lack of durable disease control with chemotherapy for mycosis fungoides and Sézary syndrome: a comparative study of systemic therapy. Blood 125 (1): 71-81, 2015.
30. Zackheim HS, Kashani-Sabet M, McMillan A: Low-dose methotrexate to treat mycosis fungoides: a retrospective study in 69 patients. J Am Acad Dermatol 49 (5): 873-8, 2003.
31. Saven A, Carrera CJ, Carson DA, et al.: 2-Chlorodeoxyadenosine: an active agent in the treatment of cutaneous T-cell lymphoma. Blood 80 (3): 587-92, 1992.
32. Foss FM, Ihde DC, Linnoila IR, et al.: Phase II trial of fludarabine phosphate and interferon alfa-2a in advanced mycosis fungoides/Sézary syndrome. J Clin Oncol 12 (10): 2051-9, 1994.
33. Kurzrock R, Pilat S, Duvic M: Pentostatin therapy of T-cell lymphomas with cutaneous manifestations. J Clin Oncol 17 (10): 3117-21, 1999.
34. Rosen ST, Foss FM: Chemotherapy for mycosis fungoides and the Sézary syndrome. Hematol Oncol Clin North Am 9 (5): 1109-16, 1995.
35. Zackheim HS, Epstein EH: Low-dose methotrexate for the Sézary syndrome. J Am Acad Dermatol 21 (4 Pt 1): 757-62, 1989.
36. Lessin SR, Duvic M, Guitart J, et al.: Topical chemotherapy in cutaneous T-cell lymphoma: positive results of a randomized, controlled, multicenter trial testing the efficacy and safety of a novel mechlorethamine, 0.02%, gel in mycosis fungoides. JAMA Dermatol 149 (1): 25-32, 2013.
37. de Quatrebarbes J, Estève E, Bagot M, et al.: Treatment of early-stage mycosis fungoides with twice-weekly applications of mechlorethamine and topical corticosteroids: a prospective study. Arch Dermatol 141 (9): 1117-20, 2005.
38. Dummer R, Quaglino P, Becker JC, et al.: Prospective international multicenter phase II trial of intravenous pegylated liposomal doxorubicin monochemotherapy in patients with stage IIB, IVA, or IVB advanced mycosis fungoides: final results from EORTC 21012. J Clin Oncol 30 (33): 4091-7, 2012.
39. Wollina U, Dummer R, Brockmeyer NH, et al.: Multicenter study of pegylated liposomal doxorubicin in patients with cutaneous T-cell lymphoma. Cancer 98 (5): 993-1001, 2003.
40. Quereux G, Marques S, Nguyen JM, et al.: Prospective multicenter study of pegylated liposomal doxorubicin treatment in patients with advanced or refractory mycosis fungoides or Sézary syndrome. Arch Dermatol 144 (6): 727-33, 2008.
41. Horwitz SM, Kim YH, Foss F, et al.: Identification of an active, well-tolerated dose of pralatrexate in patients with relapsed or refractory cutaneous T-cell lymphoma. Blood 119 (18): 4115-22, 2012.
42. Talpur R, Thompson A, Gangar P, et al.: Pralatrexate alone or in combination with bexarotene: long-term tolerability in relapsed/refractory mycosis fungoides. Clin Lymphoma Myeloma Leuk 14 (4): 297-304, 2014.
43. Duffy R, Jennings T, Kartan S, et al.: Special Considerations in the Treatment of Mycosis Fungoides. Am J Clin Dermatol 20 (4): 571-578, 2019.
44. Querfeld C, Rosen ST, Guitart J, et al.: Results of an open-label multicenter phase 2 trial of lenalidomide monotherapy in refractory mycosis fungoides and Sézary syndrome. Blood 123 (8): 1159-66, 2014.
45. Duvic M, Hymes K, Heald P, et al.: Bexarotene is effective and safe for treatment of refractory advanced-stage cutaneous T-cell lymphoma: multinational phase II-III trial results. J Clin Oncol 19 (9): 2456-71, 2001.
46. Heald P, Mehlmauer M, Martin AG, et al.: Topical bexarotene therapy for patients with refractory or persistent early-stage cutaneous T-cell lymphoma: results of the phase III clinical trial. J Am Acad Dermatol 49 (5): 801-15, 2003.
47. Duvic M, Dummer R, Becker JC, et al.: Panobinostat activity in both bexarotene-exposed and -naïve patients with refractory cutaneous T-cell lymphoma: results of a phase II trial. Eur J Cancer 49 (2): 386-94, 2013.
48. Olsen EA, Kim YH, Kuzel TM, et al.: Phase IIb multicenter trial of vorinostat in patients with persistent, progressive, or treatment refractory cutaneous T-cell lymphoma. J Clin Oncol 25 (21): 3109-15, 2007.
49. Piekarz RL, Frye R, Turner M, et al.: Phase II multi-institutional trial of the histone deacetylase inhibitor romidepsin as monotherapy for patients with cutaneous T-cell lymphoma. J Clin Oncol 27 (32): 5410-7, 2009.
50. Kim YH, Tavallaee M, Sundram U, et al.: Phase II Investigator-Initiated Study of Brentuximab Vedotin in Mycosis Fungoides and Sézary Syndrome With Variable CD30 Expression Level: A Multi-Institution Collaborative Project. J Clin Oncol 33 (32): 3750-8, 2015.
51. Duvic M, Tetzlaff MT, Gangar P, et al.: Results of a Phase II Trial of Brentuximab Vedotin for CD30+ Cutaneous T-Cell Lymphoma and Lymphomatoid Papulosis. J Clin Oncol 33 (32): 3759-65, 2015.
52. Khodadoust MS, Rook AH, Porcu P, et al.: Pembrolizumab in Relapsed and Refractory Mycosis Fungoides and Sézary Syndrome: A Multicenter Phase II Study. J Clin Oncol 38 (1): 20-28, 2020.
53. Ratner L, Waldmann TA, Janakiram M, et al.: Rapid Progression of Adult T-Cell Leukemia-Lymphoma after PD-1 Inhibitor Therapy. N Engl J Med 378 (20): 1947-1948, 2018.
54. Bennani NN, Kim HJ, Pederson LD, et al.: Nivolumab in patients with relapsed or refractory peripheral T-cell lymphoma: modest activity and cases of hyperprogression. J Immunother Cancer 10 (6): , 2022.

Treatment of Recurrent Mycosis Fungoides and Sézary Syndrome

The treatment of patients with relapsed mycosis fungoides and Sézary syndrome involves the joint decisions of the dermatologist, medical oncologist, and radiation oncologist. It may be possible to re-treat localized areas of relapse in the skin with additional electron-beam radiation therapy or to repeat total-skin electron-beam radiation therapy (TSEB).[1] Photon radiation 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 psoralen and ultraviolet A radiation (PUVA) may be warranted to relieve cutaneous symptoms.

Patients should consider clinical trials as a therapeutic option.

Treatment Options for Recurrent Mycosis Fungoides and Sézary Syndrome

Treatment options under clinical evaluation for recurrent mycosis fungoides and Sézary syndrome include the following:[2,3]

1. Radiation therapy.
2. Photodynamic therapy.
3. Chemotherapy.
4. Other drug therapy.
5. Biological therapy.
6. Allogeneic stem cell transplant.
7. Targeted therapy.

Radiation therapy

1. Additional electron-beam radiation therapy or a repeat of TSEB.
   • Electron-beam radiation therapy of appropriate energies will penetrate only to the dermis, and thus, the skin alone can be treated without systemic effects. This therapy requires a radiation therapy facility with physics support and considerable technical expertise to deliver precise dosimetry. TSEB can result in short- and long-term cutaneous toxic effects and is not widely available.
   • This therapy can provide excellent palliation, with complete response rates as high as 80%, and may be combined with systemic treatment. Based on the long-term survival of these early-stage patients, electron-beam radiation therapy is sometimes used with curative intent.[4,5,6,7,8] Long-term disease-free survival (DFS) can be achieved in patients with unilesional mycosis fungoides treated with local radiation therapy.[9]
2. Photon radiation to bulky skin or nodal masses.[10]

Photodynamic therapy

1. PUVA radiation therapy.[11,12,13,14,15,16]
   • Therapeutic trials with PUVA have shown an 80% to 90% complete remission rate in patients, with those in early cutaneous stages achieving the best responses. PUVA may be used in conjunction with systemic treatment.[15] Continued maintenance therapy with PUVA at more protracted intervals is generally required to prolong remission duration.[11,12,13,15] PUVA combined with interferon alfa-2a is associated with a high response rate.[14,15]
2. Narrowband ultraviolet B radiation.[17,18]
   • Single-arm and retrospective comparisons confirm the efficacy of narrowband ultraviolet B with 80% to 90% complete remission rates, especially for patients with early cutaneous stages.[17,18]
   • A Cochrane systematic review and meta-analysis compared PUVA with narrowband ultraviolet B radiation in 778 patients with early-stage mycosis fungoides (stage IA, IB, and IIA). Significantly higher complete response rates were seen in patients treated with PUVA (73.8% vs. 62.2%; hazard ratio [HR], 1.68; 95% confidence interval [CI], 1.02–2.76; P = .04). There were no significant differences in adverse effects.[16][Level of evidence B3]
3. Extracorporeal photophoresis (ECP) has produced tumor regression in patients who are resistant to other therapies.[19,20]
   • In a retrospective analysis of 65 patients, with a median follow-up of 48 months, use of ECP in the first to third line of treatment yielded a longer median time-to-next treatment (TTNT) than other systemic options (P < .03).[21][Level of evidence C3]

Chemotherapy

1. Topical treatment with mechlorethamine or PUVA.
   • This form of treatment may be used palliatively or to supplement therapeutic approaches directed against nodal or visceral disease. 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 patients, 25% to 75% of T2 patients, as many as 50% of T3 patients, and 20% to 40% of T4 patients have complete responses. The overall complete remission rate in 243 patients was 64% and was related to stage; as many as 35% of stage IV patients had complete responses. Treatments are usually continued for 2 to 3 years. Continuous 5-year DFS may be possible in as many as 33% of T1 patients.[4,22,23]
2. Pralatrexate (folate analogue).[24,25]
   • Chemotherapeutic agents generally yield short durations of response. In a retrospective review of 198 patients with advanced-stage disease, the median TTNT was 4 months.[26]
3. Pegylated liposomal doxorubicin.[27,28,29]
4. Systemic chemotherapy: chlorambucil plus prednisone, mechlorethamine, cyclophosphamide, methotrexate, and combination chemotherapy.[26,30,31,32]

Other drug therapy

1. Symptomatic management with topical corticosteroids.
2. Bexarotene, an oral or topical retinoid.[33,34]
3. Lenalidomide.[35]
4. Vorinostat or romidepsin or other histone deacetylase inhibitors (HDACi).[36,37,38]
   • A retrospective review of 198 patients with mycosis fungoides and Sézary syndrome compared the TTNT between HDACi and conventional chemotherapy. HDACi provided a longer TTNT of 4.5 months (95% CI, 4.0–6.1) than did chemotherapy, with a TTNT of 3.9 months (95% CI, 3.2–5.1; P = .01).[26][Level of evidence C3]

Biological therapy

1. Interferon alfa alone or in combination with other agents, such as topical therapy.[39,40]
   • A retrospective review of 198 patients with mycosis fungoides and Sézary syndrome compared the TTNT between patients who received interferon alfa and conventional chemotherapy. Interferon alfa provided a longer TTNT of 8.7 months (95% CI, 6.0–18.0) than did chemotherapy, with a TTNT of 3.9 months (95% CI, 3.2–5.1) (P < .00001).[26][Level of evidence C3]

Allogeneic stem cell transplant

1. Allogeneic stem cell transplant (SCT).[41,42,43,43,44,45]
   • Among highly selected patients, the 5-year overall survival (OS) rate ranges from 30% to 50%, with a relapse-free survival rate of 15% to 25%.[41,42,43,44,45]

Targeted therapy

1. Brentuximab vedotin.[46,47]
   • Two phase II trials of 58 patients with variable CD30 expression showed a 50% to 70% response rate with 50% of patients still in remission after 1 year.[46,47][Level of evidence C3]
2. Mogamulizumab.[48]
   1. In a prospective randomized trial, 372 previously treated patients received either mogamulizumab, a monoclonal antibody directed against C-C chemokine receptor 4, or the HDACi vorinostat.
      • With a median follow-up of 17 months, the median progression-free survival was 7.7 months for patients who received mogamulizumab and 3.1 months for patients who received vorinostat (HR, 0.53; 95% CI, 0.41−0.69; P < .0001).[48][Level of evidence B1]
      • Mogamulizumab appeared to be especially effective in patients with blood involvement, such as those with Sézary syndrome.
      • This preliminary study was not designed to detect differences in OS.

   Mogamulizumab is often avoided in patients scheduled to undergo allogeneic SCT, based on data from a Japanese study that showed an increased risk of severe graft-versus-host disease (GVHD) in patients treated with mogamulizumab beforehand.[49] The relevance of these findings in other countries and the impact of different GVHD prophylaxis regimens in these patients remains to be determined.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References:

1. Becker M, Hoppe RT, Knox SJ: Multiple courses of high-dose total skin electron beam therapy in the management of mycosis fungoides. Int J Radiat Oncol Biol Phys 32 (5): 1445-9, 1995.
2. Trautinger F, Knobler R, Willemze R, et al.: EORTC consensus recommendations for the treatment of mycosis fungoides/Sézary syndrome. Eur J Cancer 42 (8): 1014-30, 2006.
3. Prince HM, Duvic M, Martin A, et al.: Phase III placebo-controlled trial of denileukin diftitox for patients with cutaneous T-cell lymphoma. J Clin Oncol 28 (11): 1870-7, 2010.
4. Chinn DM, Chow S, Kim YH, et al.: Total skin electron beam therapy with or without adjuvant topical nitrogen mustard or nitrogen mustard alone as initial treatment of T2 and T3 mycosis fungoides. Int J Radiat Oncol Biol Phys 43 (5): 951-8, 1999.
5. Quirós PA, Jones GW, Kacinski BM, et al.: Total skin electron beam therapy followed by adjuvant psoralen/ultraviolet-A light in the management of patients with T1 and T2 cutaneous T-cell lymphoma (mycosis fungoides). Int J Radiat Oncol Biol Phys 38 (5): 1027-35, 1997.
6. Ysebaert L, Truc G, Dalac S, et al.: Ultimate results of radiation therapy for T1-T2 mycosis fungoides (including reirradiation). Int J Radiat Oncol Biol Phys 58 (4): 1128-34, 2004.
7. Jones GW, Rosenthal D, Wilson LD: Total skin electron radiation for patients with erythrodermic cutaneous T-cell lymphoma (mycosis fungoides and the Sézary syndrome). Cancer 85 (9): 1985-95, 1999.
8. Navi D, Riaz N, Levin YS, et al.: The Stanford University experience with conventional-dose, total skin electron-beam therapy in the treatment of generalized patch or plaque (T2) and tumor (T3) mycosis fungoides. Arch Dermatol 147 (5): 561-7, 2011.
9. Micaily B, Miyamoto C, Kantor G, et al.: Radiotherapy for unilesional mycosis fungoides. Int J Radiat Oncol Biol Phys 42 (2): 361-4, 1998.
10. Thomas TO, Agrawal P, Guitart J, et al.: Outcome of patients treated with a single-fraction dose of palliative radiation for cutaneous T-cell lymphoma. Int J Radiat Oncol Biol Phys 85 (3): 747-53, 2013.
11. Herrmann JJ, Roenigk HH, Hurria A, et al.: Treatment of mycosis fungoides with photochemotherapy (PUVA): long-term follow-up. J Am Acad Dermatol 33 (2 Pt 1): 234-42, 1995.
12. Ramsay DL, Lish KM, Yalowitz CB, et al.: Ultraviolet-B phototherapy for early-stage cutaneous T-cell lymphoma. Arch Dermatol 128 (7): 931-3, 1992.
13. Querfeld C, Rosen ST, Kuzel TM, et al.: Long-term follow-up of patients with early-stage cutaneous T-cell lymphoma who achieved complete remission with psoralen plus UV-A monotherapy. Arch Dermatol 141 (3): 305-11, 2005.
14. Kuzel TM, Roenigk HH, Samuelson E, et al.: Effectiveness of interferon alfa-2a combined with phototherapy for mycosis fungoides and the Sézary syndrome. J Clin Oncol 13 (1): 257-63, 1995.
15. Olsen EA, Hodak E, Anderson T, et al.: Guidelines for phototherapy of mycosis fungoides and Sézary syndrome: A consensus statement of the United States Cutaneous Lymphoma Consortium. J Am Acad Dermatol 74 (1): 27-58, 2016.
16. Phan K, Ramachandran V, Fassihi H, et al.: Comparison of Narrowband UV-B With Psoralen-UV-A Phototherapy for Patients With Early-Stage Mycosis Fungoides: A Systematic Review and Meta-analysis. JAMA Dermatol 155 (3): 335-341, 2019.
17. Almohideb M, Walsh S, Walsh S, et al.: Bath Psoralen-ultraviolet A and Narrowband Ultraviolet B Phototherapy as Initial Therapy for Early-stage Mycosis Fungoides: A Retrospective Cohort of 267 Cases at the University of Toronto. Clin Lymphoma Myeloma Leuk 17 (9): 604-612, 2017.
18. Elcin G, Duman N, Karahan S, et al.: Long-term follow-up of early mycosis fungoides patients treated with narrowband ultraviolet B phototherapy. J Dermatolog Treat 25 (3): 268-73, 2014.
19. Edelson R, Berger C, Gasparro F, et al.: Treatment of cutaneous T-cell lymphoma by extracorporeal photochemotherapy. Preliminary results. N Engl J Med 316 (6): 297-303, 1987.
20. Heald PW, Perez MI, McKiernan G, et al.: Extracorporeal photochemotherapy for CTCL. Prog Clin Biol Res 337: 443-7, 1990.
21. Gao C, McCormack C, van der Weyden C, et al.: Prolonged survival with the early use of a novel extracorporeal photopheresis regimen in patients with Sézary syndrome. Blood 134 (16): 1346-1350, 2019.
22. Lessin SR, Duvic M, Guitart J, et al.: Topical chemotherapy in cutaneous T-cell lymphoma: positive results of a randomized, controlled, multicenter trial testing the efficacy and safety of a novel mechlorethamine, 0.02%, gel in mycosis fungoides. JAMA Dermatol 149 (1): 25-32, 2013.
23. de Quatrebarbes J, Estève E, Bagot M, et al.: Treatment of early-stage mycosis fungoides with twice-weekly applications of mechlorethamine and topical corticosteroids: a prospective study. Arch Dermatol 141 (9): 1117-20, 2005.
24. Horwitz SM, Kim YH, Foss F, et al.: Identification of an active, well-tolerated dose of pralatrexate in patients with relapsed or refractory cutaneous T-cell lymphoma. Blood 119 (18): 4115-22, 2012.
25. Talpur R, Thompson A, Gangar P, et al.: Pralatrexate alone or in combination with bexarotene: long-term tolerability in relapsed/refractory mycosis fungoides. Clin Lymphoma Myeloma Leuk 14 (4): 297-304, 2014.
26. Hughes CF, Khot A, McCormack C, et al.: Lack of durable disease control with chemotherapy for mycosis fungoides and Sézary syndrome: a comparative study of systemic therapy. Blood 125 (1): 71-81, 2015.
27. Dummer R, Quaglino P, Becker JC, et al.: Prospective international multicenter phase II trial of intravenous pegylated liposomal doxorubicin monochemotherapy in patients with stage IIB, IVA, or IVB advanced mycosis fungoides: final results from EORTC 21012. J Clin Oncol 30 (33): 4091-7, 2012.
28. Wollina U, Dummer R, Brockmeyer NH, et al.: Multicenter study of pegylated liposomal doxorubicin in patients with cutaneous T-cell lymphoma. Cancer 98 (5): 993-1001, 2003.
29. Quereux G, Marques S, Nguyen JM, et al.: Prospective multicenter study of pegylated liposomal doxorubicin treatment in patients with advanced or refractory mycosis fungoides or Sézary syndrome. Arch Dermatol 144 (6): 727-33, 2008.
30. 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. N Engl J Med 321 (26): 1784-90, 1989.
31. Rosen ST, Foss FM: Chemotherapy for mycosis fungoides and the Sézary syndrome. Hematol Oncol Clin North Am 9 (5): 1109-16, 1995.
32. Zackheim HS, Epstein EH: Low-dose methotrexate for the Sézary syndrome. J Am Acad Dermatol 21 (4 Pt 1): 757-62, 1989.
33. Miller VA, Benedetti FM, Rigas JR, et al.: Initial clinical trial of a selective retinoid X receptor ligand, LGD1069. J Clin Oncol 15 (2): 790-5, 1997.
34. Duvic M, Hymes K, Heald P, et al.: Bexarotene is effective and safe for treatment of refractory advanced-stage cutaneous T-cell lymphoma: multinational phase II-III trial results. J Clin Oncol 19 (9): 2456-71, 2001.
35. Querfeld C, Rosen ST, Guitart J, et al.: Results of an open-label multicenter phase 2 trial of lenalidomide monotherapy in refractory mycosis fungoides and Sézary syndrome. Blood 123 (8): 1159-66, 2014.
36. Duvic M, Dummer R, Becker JC, et al.: Panobinostat activity in both bexarotene-exposed and -naïve patients with refractory cutaneous T-cell lymphoma: results of a phase II trial. Eur J Cancer 49 (2): 386-94, 2013.
37. Olsen EA, Kim YH, Kuzel TM, et al.: Phase IIb multicenter trial of vorinostat in patients with persistent, progressive, or treatment refractory cutaneous T-cell lymphoma. J Clin Oncol 25 (21): 3109-15, 2007.
38. Piekarz RL, Frye R, Turner M, et al.: Phase II multi-institutional trial of the histone deacetylase inhibitor romidepsin as monotherapy for patients with cutaneous T-cell lymphoma. J Clin Oncol 27 (32): 5410-7, 2009.
39. 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/Sézary syndrome. J Clin Oncol 10 (12): 1907-13, 1992.
40. Olsen EA, Bunn PA: Interferon in the treatment of cutaneous T-cell lymphoma. Hematol Oncol Clin North Am 9 (5): 1089-107, 1995.
41. Molina A, Zain J, Arber DA, et al.: Durable clinical, cytogenetic, and molecular remissions after allogeneic hematopoietic cell transplantation for refractory Sezary syndrome and mycosis fungoides. J Clin Oncol 23 (25): 6163-71, 2005.
42. Duvic M, Donato M, Dabaja B, et al.: Total skin electron beam and non-myeloablative allogeneic hematopoietic stem-cell transplantation in advanced mycosis fungoides and Sezary syndrome. J Clin Oncol 28 (14): 2365-72, 2010.
43. Duarte RF, Boumendil A, Onida F, et al.: Long-term outcome of allogeneic hematopoietic cell transplantation for patients with mycosis fungoides and Sézary syndrome: a European society for blood and marrow transplantation lymphoma working party extended analysis. J Clin Oncol 32 (29): 3347-8, 2014.
44. Schlaak M, Pickenhain J, Theurich S, et al.: Allogeneic stem cell transplantation versus conventional therapy for advanced primary cutaneous T-cell lymphoma. Cochrane Database Syst Rev 1: CD008908, 2012.
45. Lechowicz MJ, Lazarus HM, Carreras J, et al.: Allogeneic hematopoietic cell transplantation for mycosis fungoides and Sezary syndrome. Bone Marrow Transplant 49 (11): 1360-5, 2014.
46. Kim YH, Tavallaee M, Sundram U, et al.: Phase II Investigator-Initiated Study of Brentuximab Vedotin in Mycosis Fungoides and Sézary Syndrome With Variable CD30 Expression Level: A Multi-Institution Collaborative Project. J Clin Oncol 33 (32): 3750-8, 2015.
47. Duvic M, Tetzlaff MT, Gangar P, et al.: Results of a Phase II Trial of Brentuximab Vedotin for CD30+ Cutaneous T-Cell Lymphoma and Lymphomatoid Papulosis. J Clin Oncol 33 (32): 3759-65, 2015.
48. Kim YH, Bagot M, Pinter-Brown L, et al.: Mogamulizumab versus vorinostat in previously treated cutaneous T-cell lymphoma (MAVORIC): an international, open-label, randomised, controlled phase 3 trial. Lancet Oncol 19 (9): 1192-1204, 2018.
49. Sugio T, Kato K, Aoki T, et al.: Mogamulizumab Treatment Prior to Allogeneic Hematopoietic Stem Cell Transplantation Induces Severe Acute Graft-versus-Host Disease. Biol Blood Marrow Transplant 22 (9): 1608-1614, 2016.

Treatment of Primary Cutaneous Anaplastic Large Cell Lymphoma

Primary cutaneous anaplastic large cell lymphoma presents in the skin only with no preexisting lymphoproliferative disease and no extracutaneous sites of involvement.[1,2,3] Patients with this type of lymphoma have disease ranging from clinically benign lymphomatoid papulosis, marked by localized nodules that may regress spontaneously, to progressive and systemic illness requiring aggressive doxorubicin-based combination chemotherapy. This spectrum has been called the primary cutaneous CD30-positive T-cell lymphoproliferative disorder.

Patients with localized disease usually undergo radiation therapy. With more disseminated involvement, watchful waiting or doxorubicin-based combination chemotherapy is used.[1,2,3]

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References:

1. de Bruin PC, Beljaards RC, van Heerde P, et al.: Differences in clinical behaviour and immunophenotype between primary cutaneous and primary nodal anaplastic large cell lymphoma of T-cell or null cell phenotype. Histopathology 23 (2): 127-35, 1993.
2. Willemze R, Beljaards RC: Spectrum of primary cutaneous CD30 (Ki-1)-positive lymphoproliferative disorders. A proposal for classification and guidelines for management and treatment. J Am Acad Dermatol 28 (6): 973-80, 1993.
3. Kempf W, Pfaltz K, Vermeer MH, et al.: EORTC, ISCL, and USCLC consensus recommendations for the treatment of primary cutaneous CD30-positive lymphoproliferative disorders: lymphomatoid papulosis and primary cutaneous anaplastic large-cell lymphoma. Blood 118 (15): 4024-35, 2011.

Treatment of Subcutaneous Panniculitis-Like T-Cell Lymphoma

Subcutaneous panniculitis-like T-cell lymphoma (SPTCL) is localized to subcutaneous tissue and can be associated with hemophagocytic lymphohistiocytosis (HLH).[1,2,3,4] Anecdotal reports suggest that the presence or absence of HLH is an important prognostic indicator.[5] Patients with SPTCL have cells that express alpha-beta phenotype.

Patients with gamma-delta phenotype have a more aggressive clinical course that is instead classified as primary cutaneous gamma-delta T-cell lymphoma.[6,7,8] For more information, see Peripheral T-Cell Non-Hodgkin Lymphoma Treatment.

The management of SPTCL depends on the clinical presentation—including the severity of symptoms, cytopenias, and the presence or absence of HLH—and the apparent disease trajectory and aggressiveness. Indolent or smoldering forms of SPTCL are often treated with immunosuppression, including oral methotrexate [9] or cyclosporine.[10] In contrast, aggressive forms are frequently treated with combination chemotherapy such as CHO(E)P (cyclophosphamide, doxorubicin, vincristine, and prednisone with or without etoposide) with variable responses per anecdotal reports.[11] The JAK2 inhibitor ruxolitinib has also been used in SPTCL with associated HLH, including anecdotal reports of responses in patients with disease that did not respond to CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) therapy.[12] In cases of particularly aggressive or relapsed disease, consolidation with allogeneic stem cell transplant has also been used.[13,14]

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References:

1. Go RS, Wester SM: Immunophenotypic and molecular features, clinical outcomes, treatments, and prognostic factors associated with subcutaneous panniculitis-like T-cell lymphoma: a systematic analysis of 156 patients reported in the literature. Cancer 101 (6): 1404-13, 2004.
2. Marzano AV, Berti E, Paulli M, et al.: Cytophagic histiocytic panniculitis and subcutaneous panniculitis-like T-cell lymphoma: report of 7 cases. Arch Dermatol 136 (7): 889-96, 2000.
3. Hoque SR, Child FJ, Whittaker SJ, et al.: Subcutaneous panniculitis-like T-cell lymphoma: a clinicopathological, immunophenotypic and molecular analysis of six patients. Br J Dermatol 148 (3): 516-25, 2003.
4. Salhany KE, Macon WR, Choi JK, et al.: Subcutaneous panniculitis-like T-cell lymphoma: clinicopathologic, immunophenotypic, and genotypic analysis of alpha/beta and gamma/delta subtypes. Am J Surg Pathol 22 (7): 881-93, 1998.
5. Willemze R: Cutaneous lymphomas with a panniculitic presentation. Semin Diagn Pathol 34 (1): 36-43, 2017.
6. Massone C, Chott A, Metze D, et al.: Subcutaneous, blastic natural killer (NK), NK/T-cell, and other cytotoxic lymphomas of the skin: a morphologic, immunophenotypic, and molecular study of 50 patients. Am J Surg Pathol 28 (6): 719-35, 2004.
7. Arnulf B, Copie-Bergman C, Delfau-Larue MH, et al.: Nonhepatosplenic gammadelta T-cell lymphoma: a subset of cytotoxic lymphomas with mucosal or skin localization. Blood 91 (5): 1723-31, 1998.
8. Toro JR, Liewehr DJ, Pabby N, et al.: Gamma-delta T-cell phenotype is associated with significantly decreased survival in cutaneous T-cell lymphoma. Blood 101 (9): 3407-12, 2003.
9. Grinich E, Koon SM, Cascio MJ, et al.: Subcutaneous panniculitis-like T-cell lymphoma responsive to combination therapy with methotrexate and corticosteroids. Dermatol Online J 24 (9): , 2018.
10. Rojnuckarin P, Nakorn TN, Assanasen T, et al.: Cyclosporin in subcutaneous panniculitis-like T-cell lymphoma. Leuk Lymphoma 48 (3): 560-3, 2007.
11. Willemze R, Jansen PM, Cerroni L, et al.: Subcutaneous panniculitis-like T-cell lymphoma: definition, classification, and prognostic factors: an EORTC Cutaneous Lymphoma Group Study of 83 cases. Blood 111 (2): 838-45, 2008.
12. Lévy R, Fusaro M, Guerin F, et al.: Efficacy of ruxolitinib in subcutaneous panniculitis-like T-cell lymphoma and hemophagocytic lymphohistiocytosis. Blood Adv 4 (7): 1383-1387, 2020.
13. Weng W, Iragavarapu C, Weng GM, et al.: Long-term remission with allogeneic transplant in patients with refractory/relapsed cutaneous cytotoxic T-cell lymphoma. Blood Neoplasia 1 (2): 2024.
14. Ichii M, Hatanaka K, Imakita M, et al.: Successful treatment of refractory subcutaneous panniculitis-like T-cell lymphoma with allogeneic peripheral blood stem cell transplantation from HLA-mismatched sibling donor. Leuk Lymphoma 47 (10): 2250-2, 2006.

Treatment of Primary Cutaneous Gamma-Delta T-Cell Lymphoma

Primary cutaneous gamma-delta T-cell lymphoma (PCGDTCL) is a rare and extremely aggressive form of cutaneous T-cell lymphoma associated with a poor prognosis. These patients may manifest involvement of the epidermis, dermis, subcutaneous region, or mucosa with or without ulceration. PCGDTCL is treated similarly to the most aggressive peripheral T-cell lymphomas, with CHO(E)P (cyclophosphamide doxorubicin, vincristine, and prednisone with or without etoposide).[1,2,3,4,5] For patients achieving remission, there are reports of prolonged survival following consolidation with allogeneic stem cell transplant.[6]

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References:

1. Arnulf B, Copie-Bergman C, Delfau-Larue MH, et al.: Nonhepatosplenic gammadelta T-cell lymphoma: a subset of cytotoxic lymphomas with mucosal or skin localization. Blood 91 (5): 1723-31, 1998.
2. Toro JR, Liewehr DJ, Pabby N, et al.: Gamma-delta T-cell phenotype is associated with significantly decreased survival in cutaneous T-cell lymphoma. Blood 101 (9): 3407-12, 2003.
3. Le Gouill S, Milpied N, Buzyn A, et al.: Graft-versus-lymphoma effect for aggressive T-cell lymphomas in adults: a study by the Société Francaise de Greffe de Moëlle et de Thérapie Cellulaire. J Clin Oncol 26 (14): 2264-71, 2008.
4. Pro B, Allen P, Behdad A: Hepatosplenic T-cell lymphoma: a rare but challenging entity. Blood 136 (18): 2018-2026, 2020.
5. Alberti-Violetti S, Maronese CA, Venegoni L, et al.: Primary Cutaneous Gamma-Delta T Cell Lymphomas: A Case Series and Overview of the Literature. Dermatopathology (Basel) 8 (4): 515-524, 2021.
6. Isufi I, Seropian S, Gowda L, et al.: Outcomes for allogeneic stem cell transplantation in refractory mycosis fungoides and primary cutaneous gamma Delta T cell lymphomas. Leuk Lymphoma 61 (12): 2955-2961, 2020.

Treatment of Primary Cutaneous Aggressive Epidermotropic CD8-Positive T-Cell Lymphoma

Primary cutaneous aggressive epidermotropic CD8-positive T-cell lymphoma is another rare and especially aggressive form of cutaneous T-cell lymphoma. Patients typically present with ulcerative plaques or tumors, and mucosal involvement is common. Neoplastic cells are characterized by expression of CD8 and a cytotoxic phenotype.Primary cutaneous aggressive epidermotropic CD8+ T-cell lymphoma: proposed diagnostic criteria and therapeutic evaluation. Multimodal chemotherapy, such as CHO(E)P (cyclophosphamide, doxorubicin, vincristine, and prednisone with or without etoposide), is often used. Outcomes are generally poor, and prolonged remissions are extremely uncommon in the absence of allogeneic stem cell transplant.[1]

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References:

1. Guitart J, Martinez-Escala ME, Subtil A, et al.: Primary cutaneous aggressive epidermotropic cytotoxic T-cell lymphomas: reappraisal of a provisional entity in the 2016 WHO classification of cutaneous lymphomas. Mod Pathol 30 (5): 761-772, 2017.

Key References for Mycosis Fungoides and Other Cutaneous T-Cell Lymphomas

These references have been identified by members of the PDQ Adult Treatment Editorial Board as significant in the field of mycosis fungoides and other cutaneous T-cell lymphoma treatment. This list is provided to inform users of important studies that have helped shape the current understanding of and treatment options for MF/SS. Listed after each reference are the sections within this summary where the reference is cited.

• Agar NS, Wedgeworth E, Crichton S, et al.: Survival outcomes and prognostic factors in mycosis fungoides/Sézary syndrome: validation of the revised International Society for Cutaneous Lymphomas/European Organisation for Research and Treatment of Cancer staging proposal. J Clin Oncol 28 (31): 4730-9, 2010. [PUBMED Abstract]

  Cited in:

  • General Information About Mycosis Fungoides and Other Cutaneous T-Cell Lymphomas
  • Stage Information for Mycosis Fungoides and Other Cutaneous T-Cell Lymphomas
• Hughes CF, Khot A, McCormack C, et al.: Lack of durable disease control with chemotherapy for mycosis fungoides and Sézary syndrome: a comparative study of systemic therapy. Blood 125 (1): 71-81, 2015. [PUBMED Abstract]

  Cited in:

  • Treatment of Stage I and Stage II Mycosis Fungoides
  • Treatment of Stage III and Stage IV Mycosis Fungoides and Sézary Syndrome
  • Treatment of Recurrent Mycosis Fungoides and Sézary Syndrome
• Kadin ME, Hughey LC, Wood GS: Large-cell transformation of mycosis fungoides-differential diagnosis with implications for clinical management: a consensus statement of the US Cutaneous Lymphoma Consortium. J Am Acad Dermatol 70 (2): 374-6, 2014. [PUBMED Abstract]

  Cited in:

  • General Information About Mycosis Fungoides and Other Cutaneous T-Cell Lymphomas
• Quaglino P, Pimpinelli N, Berti E, et al.: Time course, clinical pathways, and long-term hazards risk trends of disease progression in patients with classic mycosis fungoides: a multicenter, retrospective follow-up study from the Italian Group of Cutaneous Lymphomas. Cancer 118 (23): 5830-9, 2012. [PUBMED Abstract]

  Cited in:

  • General Information About Mycosis Fungoides and Other Cutaneous T-Cell Lymphomas
• Talpur R, Singh L, Daulat S, et al.: Long-term outcomes of 1,263 patients with mycosis fungoides and Sézary syndrome from 1982 to 2009. Clin Cancer Res 18 (18): 5051-60, 2012. [PUBMED Abstract]

  Cited in:

  • General Information About Mycosis Fungoides and Other Cutaneous T-Cell Lymphomas

Latest Updates to This Summary (08 / 16 / 2024)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

Stage Information for Mycosis Fungoides and Other Cutaneous T-Cell Lymphomas

Revised Table 5, Definitions of TNM Stages IVA1, IVA2, and IVB to include peripheral blood involvement criteria for B2.

Treatment Option Overview for Mycosis Fungoides and Other Cutaneous T-Cell Lymphomas

Revised Table 6, Treatment Options for Mycosis Fungoides and Other Cutaneous T-Cell Lymphomas.

Treatment of Stage III and Stage IV Mycosis Fungoides and Sézary Syndrome

Added text to state that there are anecdotal reports of hyperprogression of T-cell malignancies following treatment with immune checkpoint inhibitors (cited Ratner et al. and Bennani et al. as references 53 and 54, respectively).

Treatment of Recurrent Mycosis Fungoides and Sézary Syndrome

Added text to state that mogamulizumab appeared to be especially effective in patients with blood involvement, such as those with Sézary syndrome.

Added text to state that mogamulizumab is often avoided in patients scheduled to undergo allogeneic stem cell transplant, based on data from a Japanese study (cited Sugio et al. as reference 49).

Treatment of Subcutaneous Panniculitis-Like T-Cell Lymphoma

This section was extensively revised.

Treatment of Primary Cutaneous Gamma-Delta T-Cell Lymphoma

Added this new section.

Treatment of Primary Cutaneous Aggressive Epidermotropic CD8-Positive T-Cell Lymphoma

Added this new section.

This summary is written and maintained by the PDQ Adult Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® Cancer Information for Health Professionals pages.

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of mycosis fungoides and other cutaneous T-cell lymphomas. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Board members review recently published articles each month to determine whether an article should:

• be discussed at a meeting,
• be cited with text, or
• replace or update an existing article that is already cited.

Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

The lead reviewers for Mycosis Fungoides and Other Cutaneous T-Cell Lymphomas Treatment are:

• Eric J. Seifter, MD (Johns Hopkins University)
• Cole H. Sterling, MD (Johns Hopkins University)

Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website's Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

Levels of Evidence

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Adult Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.

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The preferred citation for this PDQ summary is:

PDQ® Adult Treatment Editorial Board. PDQ Mycosis Fungoides and Other Cutaneous T-Cell Lymphomas Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/lymphoma/hp/mycosis-fungoides-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389288]

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Last Revised: 2024-08-16