Stage IV Mycosis Fungoides and the Sézary Syndrome

Current Clinical Trials

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 been shown to cure any patients, and insufficient data exist to determine if these agents prolong survival. Combination chemotherapy is not definitely superior to single agents. Even in stage IV disease, treatments directed at the skin may provide significant palliation.

A randomized study 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 symptomatic extracutaneous disease or for disease refractory to topical therapies. Patients of any stage were eligible. Although the complete response rate was higher with combined therapy, toxic effects were considerably greater, and no difference was seen in disease-free or overall survival between the two groups.[1][Level of evidence: 1iiA]

Treatment options:[2,3]

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

2. TSEB. Electron radiation of appropriate energies will penetrate only to the dermis, and the skin alone can be treated without systemic effects. This therapy requires an excellent radiation therapy facility with physics support, considerable technical expertise, and precise dosimetry. This therapy can produce excellent palliation and may be combined with systemic treatment.[6]

3. Ultraviolet B radiation is under clinical evaluation.

4. Symptomatic management with topical corticosteroids.

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

6. Fludarabine, 2-chlorodeoxyadenosine, and pentostatin are active agents for mycosis fungoides (MF) and Sézary syndrome.[7-9]

7. Interferon-alpha alone or in combination with topical therapy, as evidenced in the ECOG-1495 trial.[8,10]

8. Denileukin diftitox (interleukin-2 fused with diphtheria toxin).[3,11]

9. Systemic chemotherapy: chlorambucil plus prednisone, mechlorethamine, cyclophosphamide, methotrexate, and combination chemotherapy.[1,12,13]

10. Topical mechlorethamine (nitrogen mustard). This form of treatment may be used palliatively or to supplement therapeutic approaches directed against nodal or visceral disease. The overall complete remission rate in 243 patients was 64% and was related to stage; as many as 35% of stage IV patients had complete responses. Treatments are usually continued for 2 to 3 years.[14,15]

11. Extracorporeal photochemotherapy alone [16-19] or in combination with TSEB.[20]

12. Serotherapy with monoclonal antibodies.[21,22]

13. Bexarotene, an oral or topical retinoid.[23,24]

14. Pegylated liposomal doxorubicin.[25,26]

15. Vorinostat or romidepsin (oral histone deacetylase inhibitors).[27,28]

16. Alemtuzumab (a humanized monoclonal antibody targeting the CD52 antigen).[29]

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage IV mycosis fungoides/Sezary syndrome. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

1. Kaye FJ, Bunn PA Jr, 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 Abstract]
   
   
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 Abstract]
   
   
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 Abstract]
   
   
4. Herrmann JJ, Roenigk HH Jr, 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 Abstract]
   
   
5. Kuzel TM, Roenigk HH Jr, 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 Abstract]
   
   
6. 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 Abstract]
   
   
7. 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 Abstract]
   
   
8. 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 Abstract]
   
   
9. 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 Abstract]
   
   
10. Olsen EA, Bunn PA: Interferon in the treatment of cutaneous T-cell lymphoma. Hematol Oncol Clin North Am 9 (5): 1089-107, 1995.  [PUBMED Abstract]
    
    
11. Olsen E, Duvic M, Frankel A, et al.: Pivotal phase III trial of two dose levels of denileukin diftitox for the treatment of cutaneous T-cell lymphoma. J Clin Oncol 19 (2): 376-88, 2001.  [PUBMED Abstract]
    
    
12. Rosen ST, Foss FM: Chemotherapy for mycosis fungoides and the Sézary syndrome. Hematol Oncol Clin North Am 9 (5): 1109-16, 1995.  [PUBMED Abstract]
    
    
13. Zackheim HS, Epstein EH Jr: Low-dose methotrexate for the Sézary syndrome. J Am Acad Dermatol 21 (4 Pt 1): 757-62, 1989.  [PUBMED Abstract]
    
    
14. Vonderheid EC, Tan ET, Kantor AF, et al.: Long-term efficacy, curative potential, and carcinogenicity of topical mechlorethamine chemotherapy in cutaneous T cell lymphoma. J Am Acad Dermatol 20 (3): 416-28, 1989.  [PUBMED Abstract]
    
    
15. 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 Abstract]
    
    
16. 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 Abstract]
    
    
17. Heald PW, Perez MI, McKiernan G, et al.: Extracorporeal photochemotherapy for CTCL. Prog Clin Biol Res 337: 443-7, 1990.  [PUBMED Abstract]
    
    
18. Fraser-Andrews E, Seed P, Whittaker S, et al.: Extracorporeal photopheresis in Sézary syndrome. No significant effect in the survival of 44 patients with a peripheral blood T-cell clone. Arch Dermatol 134 (8): 1001-5, 1998.  [PUBMED Abstract]
    
    
19. 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 Abstract]
    
    
20. 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 Abstract]
    
    
21. Knox SJ, Levy R, Hodgkinson S, et al.: Observations on the effect of chimeric anti-CD4 monoclonal antibody in patients with mycosis fungoides. Blood 77 (1): 20-30, 1991.  [PUBMED Abstract]
    
    
22. Rosen ST, Zimmer AM, Goldman-Leikin R, et al.: Radioimmunodetection and radioimmunotherapy of cutaneous T cell lymphomas using an 131I-labeled monoclonal antibody: an Illinois Cancer Council Study. J Clin Oncol 5 (4): 562-73, 1987.  [PUBMED Abstract]
    
    
23. 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 Abstract]
    
    
24. 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 Abstract]
    
    
25. 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 Abstract]
    
    
26. 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 Abstract]
    
    
27. 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 Abstract]
    
    
28. 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.  [PUBMED Abstract]
    
    
29. 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 Abstract]