Clinical Presentation

Mycosis fungoides and Sézary syndrome are neoplasias of malignant T lymphocytes that usually possess the helper/inducer cell surface phenotype. These kinds of neoplasms initially present as skin involvement and, as such, have been classified as cutaneous T-cell lymphomas.[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), adult T-cell leukemia/lymphoma (usually with systemic involvement), or subcutaneous panniculitic T-cell lymphoma.[2,3] These histologic types of T-cell lymphomas are discussed in Peripheral T-Cell Non-Hodgkin Lymphoma Treatment.

Typically, the natural history of mycosis fungoides is indolent.[4] Symptoms of the disease may present for long periods, in a range of 2 to 10 years, because cutaneous eruptions wax and wane before they receive a biopsy confirmation. Mycosis fungoides and Sézary syndrome are treatable with available topical therapy, systemic therapy, or both. To date, 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. Consultation with a pathologist who has expertise in distinguishing these conditions is important.[1]

Prognosis and Survival

The prognosis of patients with mycosis fungoides and Sézary syndrome 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.[5-8] The Cutaneous Lymphoma International Consortium retrospectively reviewed 1,275 patients and found 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 gender, 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 (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 have a 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 itself 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 progress from stage I or II disease to stage III or IV disease.[19-21] 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.[25-27] 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. [PubMed: 28872191]
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. [PubMed: 9207472]
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. [PubMed: 8068936]
4. Diamandidou E, Cohen PR, Kurzrock R: Mycosis fungoides and Sezary syndrome. Blood 88 (7): 2385-409, 1996. [PubMed: 8839829]
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. [PubMed: 20855822]
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. [PMC free article: PMC3857608] [PubMed: 22850569]
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. [PubMed: 12873880]
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. [PubMed: 25817937]
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. [PMC free article: PMC4979132] [PubMed: 26438120]
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. [PubMed: 8915308]
11. Vollmer RT: A review of survival in mycosis fungoides. Am J Clin Pathol 141 (5): 706-11, 2014. [PubMed: 24713743]
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. [PubMed: 10071312]
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. [PubMed: 11157031]
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. [PubMed: 23735705]
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. [PubMed: 17224541]
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. [PubMed: 28645647]
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. [PubMed: 10920140]
18. Lorincz AL: Cutaneous T-cell lymphoma (mycosis fungoides) Lancet 347 (9005): 871-6, 1996. [PubMed: 8622396]
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. [PubMed: 22674564]
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. [PubMed: 26053896]
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. [PubMed: 25458019]
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. [PubMed: 21145619]
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. [PubMed: 22640839]
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. [PubMed: 28012574]
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. [PubMed: 7661601]
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. [PubMed: 18647960]
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. [PubMed: 24438952]
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. [PubMed: 22160616]
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. [PubMed: 18489588]
30. Lebas E, Arrese JE, Nikkels AF: Risk Factors for Skin Infections in Mycosis Fungoides. Dermatology 232 (6): 731-737, 2016. [PubMed: 28249285]
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. [PubMed: 27276223]

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. [PubMed: 21145619]
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. [PubMed: 11745245]

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. [PubMed: 17540844]
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. [PubMed: 20855822]

Photodynamic Therapy

1. Psoralen and ultraviolet A radiation (PUVA).

   • Therapeutic trials with PUVA have shown an 80% to 90% complete remission rate with early cutaneous stages achieving the best responses. PUVA may be used in conjunction with systemic treatment.[3] Continued maintenance therapy with PUVA at more protracted intervals is generally required to prolong remission duration.[3-6] PUVA combined with interferon alpha-2a is associated with a high response rate.[3,7]
2. Narrowband ultraviolet B radiation.

   • Single-arm and retrospective comparisons confirm narrowband ultraviolet B with 80% to 90% complete remission rates, especially for patients with early cutaneous stages.[8,9]
   • 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% versus 62.2%; HR, 1.68; 95% CI, 1.02–2.76; P = .04), with no significant differences in adverse effects.[10][Level of evidence B3]
3. Extracorporeal photophoresis (ECP) alone [11-14] or in combination with total-skin electron-beam radiation (TSEB).[15] ECP is particularly applicable for Sézary syndrome and erythrodermic mycosis fungoides.[14]

   • 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-needing-treatment than other systemic options (P < .03).[14][Level of evidence C3]

Radiation Therapy

1. TSEB.

   • Electron-beam radiation 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 of as much 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.[16-20] Long-term disease-free survival (DFS) can be achieved in patients with unilesional mycosis fungoides treated with local radiation therapy.[21]
2. Local electron-beam radiation or orthovoltage radiation therapy may be used to palliate areas of bulky or symptomatic skin disease.[22,23]

Biologic Therapy

1. Interferon alpha or interferon gamma alone or in combination with topical therapy.[24,25]

   • A retrospective review of 198 patients with mycosis fungoides and Sézary syndrome compared time to next treatment (TTNT) between interferon alpha and conventional chemotherapy. Interferon alpha provided a longer TTNT of 8.7 months (95% confidence interval [CI], 6.0–18.0) than did chemotherapy, with a TTNT of 3.9 months (95% CI, 3.2–5.1) and P < .00001.[26][Level of evidence C3]

Chemotherapy

1. Topical chemotherapy with mechlorethamine (nitrogen mustard).

   • 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.[16,27,28]
2. Oral methotrexate (NCT00425555).[29]
3. Pegylated liposomal doxorubicin.[30-32]
4. Fludarabine, 2-chlorodeoxyadenosine, and pentostatin are active agents for mycosis fungoides and Sézary syndrome.[25,33-35]

   • Chemotherapeutic agents generally demonstrate short durations of response. In a retrospective review of 198 patients with advanced-stage disease, the median time before patients required new therapy was 4 months.[26] However, these comparisons may be confounded by the order in which the agents were introduced.
5. Single-agent chemotherapy or combination systemic chemotherapy (chlorambucil plus prednisone, mechlorethamine, cyclophosphamide, methotrexate, and combination chemotherapy) are often combined with treatment directed at the skin.[26,36-38]

   • Chemotherapeutic agents generally demonstrate short durations of response. In a retrospective review of 198 patients with advanced-stage disease, the median time before patients required new therapy was 4 months.[26] However, these comparisons may be confounded by the order in which the agents were introduced.
6. Pralatrexate (folate analog).[39,40]

   • Chemotherapeutic agents generally demonstrate short durations of response. In a retrospective review of 198 patients with advanced-stage disease, the median time before patients required new therapy was 4 months.[26]

Other Drug Therapy

1. Symptomatic management with topical corticosteroids. Low potency steroids can be used on the face with safety and efficacy.[41]
2. Bexarotene, an oral or topical retinoid (NCT00255801).[42,43]
3. Lenalidomide.[44]
4. Vorinostat or romidepsin or other histone deacetylase inhibitors (HDACi).[1,45-47]

   • 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).[26][Level of evidence C3]

Targeted Therapy

1. Brentuximab vedotin.[48,49]

   • 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.[48,49][Level of evidence C3]
2. Mogamulizumab.[50]

   1. In a prospective randomized trial, 372 previously treated patients received either mogamulizumab, a monoclonal antibody directed against C-C chemokine receptor 4, or vorinostat, the HDACi.

      • With a median follow-up of 17 months, the median PFS favored mogamulizumab at 7.7 months versus 3.1 months for vorinostat (HR, 0.53; 95% CI, 0.41−0.69; P < .0001).[50][Level of evidence B1]
      • In a preliminary study such as this, no overall survival (OS) was seen.

Transplantation

1. Allogeneic or autologous bone marrow transplantation.[51-54]

   • Among these highly selected patients, the 5-year OS rate ranges from 30% to 50%, with a relapse-free survival rate of 15% to 25%.[51-55]

Checkpoint Inhibitors

1. Pembrolizumab.

   • 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%.[56][Level of evidence C3]

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.[57][Level of evidence C3]

These types of treatments produce remissions, but long-term remissions are uncommon. Treatment, therefore, is considered palliative for most patients, although major symptomatic improvement is regularly achieved. Survival in excess of 8 years, however, is common for patients with early stages of disease. All patients with mycosis fungoides and Sézary syndrome are candidates for clinical trials evaluating new approaches to treatment.

References

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2. Trautinger F, Eder J, Assaf C, et al.: European Organisation for Research and Treatment of Cancer consensus recommendations for the treatment of mycosis fungoides/Sézary syndrome - Update 2017. Eur J Cancer 77: 57-74, 2017. [PubMed: 28365528]
3. 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. [PubMed: 26547257]
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34. 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. [PubMed: 7931473]
35. Kurzrock R, Pilat S, Duvic M: Pentostatin therapy of T-cell lymphomas with cutaneous manifestations. J Clin Oncol 17 (10): 3117-21, 1999. [PubMed: 10506607]
36. 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. [PubMed: 2594037]
37. Rosen ST, Foss FM: Chemotherapy for mycosis fungoides and the Sézary syndrome. Hematol Oncol Clin North Am 9 (5): 1109-16, 1995. [PubMed: 8522487]
38. Zackheim HS, Epstein EH: Low-dose methotrexate for the Sézary syndrome. J Am Acad Dermatol 21 (4 Pt 1): 757-62, 1989. [PubMed: 2808792]
39. 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. [PubMed: 22394596]
40. 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. [PubMed: 24589156]
41. 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. [PubMed: 30993584]
42. 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. [PubMed: 11331325]
43. 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. [PubMed: 14576658]
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. [PubMed: 24335103]
45. 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. [PubMed: 22981498]
46. 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. [PubMed: 17577020]
47. 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. [PMC free article: PMC2773225] [PubMed: 19826128]
48. 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. [PMC free article: PMC5089160] [PubMed: 26195720]
49. 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. [PMC free article: PMC4737859] [PubMed: 26261247]
50. 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. [PubMed: 30100375]
51. 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. [PubMed: 16135483]
52. 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. [PubMed: 20351328]
53. 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. [PubMed: 25154828]
54. 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. [PubMed: 22258991]
55. 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. [PMC free article: PMC4221526] [PubMed: 25068422]
56. 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. [PMC free article: PMC6943974] [PubMed: 31532724]
57. 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. [PMC free article: PMC6764271] [PubMed: 31331920]

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.

   • Psoralen and ultraviolet A (PUVA) radiation.[6-11]
   • Narrowband ultraviolet B radiation.[12,13]
2. Radiation therapy.

   • TSEB.[14-19]
   • Local electron-beam radiation or orthovoltage radiation therapy may be used to palliate areas of bulky or symptomatic skin disease.[20,21]
3. Biologic therapy.

   • Interferon alpha or interferon gamma alone or in combination with topical therapy.[22,23][Level of evidence C3]
4. Chemotherapy.

   • Topical chemotherapy with mechlorethamine (nitrogen mustard).[14,24,25]
   • Oral methotrexate (NCT00425555).[26]
   • Pegylated liposomal doxorubicin.[27-29]
   • Fludarabine, 2-chlorodeoxyadenosine, and pentostatin are active agents for MF.[30-33]
   • Single-agent chemotherapy or combination systemic chemotherapy (chlorambucil plus prednisone, mechlorethamine, cyclophosphamide, methotrexate, and combination chemotherapy) often combined with treatment directed at the skin.[4,23,34,35]
   • Pralatrexate (folate analog).[23,36,37]
5. Other drug therapy.

   • Symptomatic management with topical corticosteroids. Low potency steroids can be used on the face with safety and efficacy.[38]
   • Bexarotene, an oral or topical retinoid (NCT00255801).[39,40]
   • Lenalidomide.[41]
   • Vorinostat or romidepsin or other histone deacetylase inhibitors.[23,42-44][Level of evidence C3]
6. Targeted therapy.

   • Brentuximab vedotin.[45,46]

(Refer to the Treatment Option Overview for Mycosis Fungoides [Including Sézary Syndrome] section of this summary for more information on these treatment options.)

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. [PubMed: 8915308]
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. [PubMed: 10071312]
3. Vollmer RT: A review of survival in mycosis fungoides. Am J Clin Pathol 141 (5): 706-11, 2014. [PubMed: 24713743]
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. [PubMed: 2594037]
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. [PubMed: 16574401]
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. [PubMed: 7622650]
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. [PubMed: 1626959]
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. [PubMed: 15781671]
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. [PubMed: 7799028]
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. [PubMed: 26547257]
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. [PMC free article: PMC6439931] [PubMed: 30698622]
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. [PubMed: 28711574]
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. [PubMed: 23030414]
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. [PubMed: 10192339]
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. [PubMed: 9276369]
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. [PubMed: 15001254]
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. [PubMed: 10223240]
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. [PubMed: 21576575]
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. [PubMed: 9788416]
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. [PubMed: 22818412]
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. [PMC free article: PMC7122012] [PubMed: 31636100]
22. Olsen EA, Bunn PA: Interferon in the treatment of cutaneous T-cell lymphoma. Hematol Oncol Clin North Am 9 (5): 1089-107, 1995. [PubMed: 8522486]
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. [PubMed: 25336628]
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. [PMC free article: PMC3662469] [PubMed: 23069814]
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. [PubMed: 16172308]
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. [PubMed: 14576667]
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. [PubMed: 12942567]
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. [PubMed: 23045580]
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. [PubMed: 18559761]
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. [PubMed: 1353380]
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. [PubMed: 1453206]
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. [PubMed: 7931473]
33. Kurzrock R, Pilat S, Duvic M: Pentostatin therapy of T-cell lymphomas with cutaneous manifestations. J Clin Oncol 17 (10): 3117-21, 1999. [PubMed: 10506607]
34. Rosen ST, Foss FM: Chemotherapy for mycosis fungoides and the Sézary syndrome. Hematol Oncol Clin North Am 9 (5): 1109-16, 1995. [PubMed: 8522487]
35. Zackheim HS, Epstein EH: Low-dose methotrexate for the Sézary syndrome. J Am Acad Dermatol 21 (4 Pt 1): 757-62, 1989. [PubMed: 2808792]
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. [PubMed: 22394596]
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. [PubMed: 24589156]
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. [PubMed: 30993584]
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. [PubMed: 11331325]
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. [PubMed: 14576658]
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. [PubMed: 24335103]
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. [PubMed: 22981498]
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. [PubMed: 17577020]
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. [PMC free article: PMC2773225] [PubMed: 19826128]
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. [PMC free article: PMC5089160] [PubMed: 26195720]
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. [PMC free article: PMC4737859] [PubMed: 26261247]

Treatment Options for Stage III and Stage IV Mycosis Fungoides (Including 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.

   • Psoralen and ultraviolet A (PUVA) radiation.[6-10]
   • Narrowband ultraviolet B radiation.[11,12]
   • Extracorporeal photophoresis (ECP) alone [13-16] or in combination with TSEB.[17] ECP is particularly applicable for Sézary syndrome and erythrodermic mycosis fungoides.[16]
2. Radiation therapy.

   • TSEB.[18-23]
   • Local electron-beam radiation or orthovoltage radiation therapy may be used to palliate areas of bulky or symptomatic disease.[24,25]
3. Biologic therapy.

   • Interferon alpha alone or in combination with other agents, such as topical therapy.[26,27]
4. Chemotherapy.

   • Oral methotrexate (NCT00425555).[28]
   • Fludarabine, 2-chlorodeoxyadenosine, and pentostatin are active agents for mycosis fungoides and Sézary syndrome.[26,29-32]
   • Single-agent chemotherapy or combination systemic chemotherapy (chlorambucil plus prednisone, mechlorethamine, cyclophosphamide, methotrexate, and combination chemotherapy) often combined with treatment directed at the skin.[1,32-34]
   • Topical chemotherapy with mechlorethamine.[35,36]
   • Pegylated liposomal doxorubicin.[37-39]
   • Pralatrexate (folate analog).[32,40,41]
5. Other drug therapy.

   • Symptomatic management with topical corticosteroids. Low potency steroids can be used on the face with safety and efficacy.[42]
   • Lenalidomide.[43]
   • Bexarotene, an oral or topical retinoid.[44,45]
   • Vorinostat or romidepsin or other histone deacetylase inhibitors.[2,46-48]
6. Targeted therapy.

   • Brentuximab vedotin.[49,50]
7. Checkpoint inhibitors.

   • Pembrolizumab.[51]

(Refer to the Treatment Option Overview for Mycosis Fungoides [Including Sézary Syndrome] section of this summary for more information on these treatment options.)

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. [PubMed: 2594037]
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. [PubMed: 21145619]
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. [PubMed: 22640839]
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. [PubMed: 25458083]
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. [PubMed: 16574401]
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. [PubMed: 7622650]
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. [PubMed: 1626959]
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. [PubMed: 15781671]
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. [PubMed: 7799028]
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. [PubMed: 26547257]
11. 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. [PubMed: 28711574]
12. 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. [PubMed: 23030414]
13. 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. [PubMed: 3543674]
14. Heald PW, Perez MI, McKiernan G, et al.: Extracorporeal photochemotherapy for CTCL. Prog Clin Biol Res 337: 443-7, 1990. [PubMed: 2191335]
15. 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. [PubMed: 18241274]
16. 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. [PubMed: 31467061]
17. 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. [PubMed: 2032326]
18. 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. [PubMed: 10192339]
19. 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. [PubMed: 9276369]
20. 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. [PubMed: 15001254]
21. 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. [PubMed: 10223240]
22. 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. [PubMed: 21576575]
23. Micaily B, Miyamoto C, Kantor G, et al.: Radiotherapy for unilesional mycosis fungoides. Int J Radiat Oncol Biol Phys 42 (2): 361-4, 1998. [PubMed: 9788416]
24. 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. [PubMed: 22818412]
25. 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. [PMC free article: PMC7122012] [PubMed: 31636100]
26. 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. [PubMed: 1453206]
27. Olsen EA, Bunn PA: Interferon in the treatment of cutaneous T-cell lymphoma. Hematol Oncol Clin North Am 9 (5): 1089-107, 1995. [PubMed: 8522486]
28. 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. [PubMed: 14576667]
29. 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. [PubMed: 1353380]
30. 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. [PubMed: 7931473]
31. Kurzrock R, Pilat S, Duvic M: Pentostatin therapy of T-cell lymphomas with cutaneous manifestations. J Clin Oncol 17 (10): 3117-21, 1999. [PubMed: 10506607]
32. 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: 25336628]
33. Rosen ST, Foss FM: Chemotherapy for mycosis fungoides and the Sézary syndrome. Hematol Oncol Clin North Am 9 (5): 1109-16, 1995. [PubMed: 8522487]
34. Zackheim HS, Epstein EH: Low-dose methotrexate for the Sézary syndrome. J Am Acad Dermatol 21 (4 Pt 1): 757-62, 1989. [PubMed: 2808792]
35. 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. [PMC free article: PMC3662469] [PubMed: 23069814]
36. 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. [PubMed: 16172308]
37. 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. [PubMed: 23045580]
38. 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. [PubMed: 12942567]
39. 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. [PubMed: 18559761]
40. 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. [PubMed: 22394596]
41. 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. [PubMed: 24589156]
42. 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. [PubMed: 30993584]
43. 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. [PubMed: 24335103]
44. 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. [PubMed: 11331325]
45. 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. [PubMed: 14576658]
46. 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. [PubMed: 22981498]
47. 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. [PubMed: 17577020]
48. 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. [PMC free article: PMC2773225] [PubMed: 19826128]
49. 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. [PMC free article: PMC5089160] [PubMed: 26195720]
50. 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. [PMC free article: PMC4737859] [PubMed: 26261247]
51. 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. [PMC free article: PMC6943974] [PubMed: 31532724]

Treatment Options for Recurrent Mycosis Fungoides (Including Sézary Syndrome)

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

1. Radiation therapy.

   • Additional electron-beam radiation or a repeat of TSEB.
   • Photon radiation to bulky skin or nodal masses.[4]
2. Photodynamic therapy.

   • Topical treatment with mechlorethamine (nitrogen mustard) or PUVA.
   • PUVA combined with interferon alpha-2a is associated with a high response rate.[5]
   • Narrowband ultraviolet B radiation.[6,7]
   • Extracorporeal photophoresis has produced tumor regression in patients resistant to other therapies.[8,9]
3. Chemotherapy.

   • Pralatrexate (folate analog).[10,11]
   • Pegylated liposomal doxorubicin.[12-14]
   • Systemic chemotherapy: chlorambucil plus prednisone, mechlorethamine, cyclophosphamide, methotrexate, and combination chemotherapy.[15-18]
4. Other drug therapy.

   • Symptomatic management with topical corticosteroids.
   • Bexarotene, an oral or topical retinoid.[19,20]
   • Lenalidomide.[21]
   • Vorinostat or romidepsin or other histone deacetylase inhibitors.[22-24]
5. Biologic therapy.

   • Interferon alpha alone or in combination with other agents, such as topical therapy.[25,26]
6. Transplantation.

   • Allogeneic bone marrow or stem cell transplantation.[27-29,29-31]
7. Targeted therapy.

   • Brentuximab vedotin.[32,33]
   • Mogamulizumab.[34]

(Refer to the Treatment Option Overview for Mycosis Fungoides [Including Sézary Syndrome] section of this summary for more information on these treatment options.)

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. [PubMed: 7635786]
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. [PubMed: 16574401]
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. [PubMed: 20212249]
4. 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. [PubMed: 22818412]
5. 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. [PubMed: 7799028]
6. 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. [PubMed: 28711574]
7. 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. [PubMed: 23030414]
8. 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. [PubMed: 3543674]
9. Heald PW, Perez MI, McKiernan G, et al.: Extracorporeal photochemotherapy for CTCL. Prog Clin Biol Res 337: 443-7, 1990. [PubMed: 2191335]
10. 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. [PubMed: 22394596]
11. 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. [PubMed: 24589156]
12. 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. [PubMed: 23045580]
13. 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. [PubMed: 12942567]
14. 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. [PubMed: 18559761]
15. 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. [PubMed: 2594037]
16. Rosen ST, Foss FM: Chemotherapy for mycosis fungoides and the Sézary syndrome. Hematol Oncol Clin North Am 9 (5): 1109-16, 1995. [PubMed: 8522487]
17. Zackheim HS, Epstein EH: Low-dose methotrexate for the Sézary syndrome. J Am Acad Dermatol 21 (4 Pt 1): 757-62, 1989. [PubMed: 2808792]
18. 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: 25336628]
19. 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. [PubMed: 9053506]
20. 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. [PubMed: 11331325]
21. 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. [PubMed: 24335103]
22. 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. [PubMed: 22981498]
23. 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. [PubMed: 17577020]
24. 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. [PMC free article: PMC2773225] [PubMed: 19826128]
25. 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. [PubMed: 1453206]
26. Olsen EA, Bunn PA: Interferon in the treatment of cutaneous T-cell lymphoma. Hematol Oncol Clin North Am 9 (5): 1089-107, 1995. [PubMed: 8522486]
27. 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. [PubMed: 16135483]
28. 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. [PubMed: 20351328]
29. 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. [PubMed: 25154828]
30. 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. [PubMed: 22258991]
31. 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. [PMC free article: PMC4221526] [PubMed: 25068422]
32. 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. [PMC free article: PMC5089160] [PubMed: 26195720]
33. 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. [PMC free article: PMC4737859] [PubMed: 26261247]
34. 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. [PubMed: 30100375]

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 (including Sézary Syndrome). 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 (Including Sézary Syndrome) 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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PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as “NCI’s PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary].”

The preferred citation for this PDQ summary is:

PDQ® Adult Treatment Editorial Board. PDQ Mycosis Fungoides (Including Sézary Syndrome) 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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