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Medication

Medication Summary

Cutaneous T-cell lymphomas are a heterogeneous group of entities. One should distinguish indolent, low-risk mycosis fungoides and Sézary syndrome from aggressive HTLV-1–associated adult T-cell leukemia/lymphoma.^[135]

Treatment for early-stage cutaneous T-cell lymphomas includes topical therapies with or without interferon alfa or oral agents, while advanced-stage patients are treated with chemotherapy and novel agents. Multiagent cytotoxic regimens may be palliative, but they seem to lack a demonstrated survival benefit.^[8]

Novel therapies for cutaneous T-cell lymphoma include bexarotene, which has demonstrated efficacy in advanced refractory cases of the disease. Other novel agents include the following:

Interleukin-12 ^[10]
Pentostatin (a potent adenosine deaminase inhibitor)
Gemcitabine ^[136]
Histone deacetylase inhibitors (eg, romidepsin ^[137])
NF-kappa-B inhibitors ^[138]
Immunomodulatory therapies
Allogeneic stem cell therapy
Mogamulizumab ^[109]
Brentuximab vedotin ^[108]

Mogamulizumab is approved by the FDA for treatment of mycosis fungoides and Sézary syndrome in adults. Brentuximab vedotin is approved by the FDA for previously untreated CD30-expressing peripheral T-cell lymphomas, in combination with cyclophosphamide, doxorubicin, and prednisone.

The value of new therapeutic approaches to cutaneous T-cell lymphoma needs to be critically assessed with regard to overall survival and disease-specific survival.

Class Summary

These agents inhibit cell growth and proliferation.

Chlorambucil (Leukeran)

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Chlorambucil alkylates and cross-links strands of DNA, inhibiting DNA replication and RNA transcription.

Vorinostat (Zolinza)

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Vorinostat is a histone deacetylase (HDAC) inhibitor. HDAC inhibition causes hypoacetylation of core nucleosomal histones, condenses chromatin structure, and represses gene transcription. This agent is indicated for treatment of progressive, persistent, or recurrent cutaneous T-cell lymphoma.

Methotrexate (Trexall, Otrexup, Rasuvo)

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Methotrexate is a folic acid antagonist that inhibits dihydrofolate reductase, an enzyme needed to make DNA.

Etoposide (Toposar)

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Etoposide inhibits topoisomerase II and causes DNA strand breakage, resulting in the arrest of cell proliferation in the late S or early G2 portion of the cell cycle.

Romidepsin (Istodax)

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Romidepsin is a histamine deacetylase (HDAC) inhibitor. It is indicated for cutaneous T-cell lymphoma in patients who have received at least one prior systemic therapy.

Denileukin diftitox (Ontak)

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This product was discontinued in January 2014. This is a fusion protein (amino acid sequence of diphtheria linked to IL-2 amino acid sequence) that selectively delivers cytotoxic activity of diphtheria toxin to targeted cells. Denileukin diftitox is used only in T-cell lymphoma in which malignant cells express the CD25 component of the IL-2 receptor. It interacts with the high-affinity IL-2 receptor on the surface of malignant cells to inhibit intracellular protein synthesis, which in turn causes cell death.

Carmustine (BiCNU)

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Carmustine alkylates and cross-links DNA strands, inhibiting cell proliferation.

Mechlorethamine (Mustargen)

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This is a topical nitrogen mustard that, as an alkylating agent, inhibits DNA replication.

Bexarotene (Targretin)

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Bexarotene (Targretin) is an X-receptor–specific retinoid. The receptor works as transcription factors that regulate genes that control cellular differentiation and proliferation. It may inhibit sebaceous gland differentiation and abnormal keratinization.

Class Summary

These agents may modulate the host immune system to inhibit the growth and proliferation of malignant cells.

Interferon alfa 2b (Intron-A)

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Interferon alfa 2b is a protein product manufactured by recombinant DNA technology. Its mechanism of antitumor activity is not clearly understood. However, direct antiproliferative effects against malignant cells and modulation of the host immune response may play important roles.

Class Summary

Monoclonal antibodies against a T-cell antigen may inhibit cell growth and proliferation of malignant cells.

Alemtuzumab (Campath, Lemtrada)

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Alemtuzumab is a monoclonal antibody against CD52, an antigen found on B cells, T cells, and almost all CLL cells. It binds to the CD52 receptor of lymphocytes, slowing the proliferation of leukocytes.

Mogamulizumab (mogamulizumab-kpkc, Poteligeo)

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CC chemokine receptor type 4 (CCR4)-directed monoclonal antibody indicated for adults with relapsed or refractory mycosis fungoides or Sézary syndrome after at least 1 prior systemic therapy.

Class Summary

Agents that induce secretion of interferon and other cytokines have shown efficacy. The topical alkylating agent, mechlorethamine, has also been shown to be effective.

Imiquimod 5% cream (Aldara, Zyclara)

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This agent binds to Toll-like receptors 7 and 8 and induces the secretion of interferon alfa and other cytokines. Its mechanism of action is unknown.

Mechlorethamine topical (Valchlor)

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Mechlorethamine topical is an alkylating agent that inhibits rapidly proliferating cells. It is indicated for mycosis fungoides-type cutaneous T-cell lymphoma.

Class Summary

Retinoids regulate genes that control cellular differentiation and proliferation.

Alitretinoin topical (Panretin)

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Off-label use. Alitretinoin is a retinoid, related to vitamin A. It has immunomodulating and anti-inflammatory effects. Binds to both retinoid acid receptor and retinoid X receptor.

Tazarotene gel (Avage, Fabior, Tazorac)

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This agent is a retinoid prodrug with an active metabolite that modulates the differentiation and proliferation of epithelial tissue. It may also have anti-inflammatory and immunomodulatory properties.

Class Summary

Corticosteroids have anti-inflammatory properties and cause profound and varied metabolic effects. Corticosteroids modify the body's immune response to diverse stimuli.

Prednisone (Rayos)

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Prednisone is an immunosuppressant; it should be used together with other agents such as low-dose chlorambucil and interferon alfa. Corticosteroids act as potent inhibitors of inflammation. They may cause profound and varied metabolic effects, particularly in relation to salt, water, and glucose tolerance, in addition to their modification of the immune response of the body.

Prednisolone (Orapred, Pediapred, Millipred)

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It is an immunosuppressant; it should be used together with other agents such as low-dose chlorambucil and interferon alfa. Corticosteroids act as potent inhibitors of inflammation. They may cause profound and varied metabolic effects, particularly in relation to salt, water, and glucose tolerance, in addition to their modification of the immune response of the body.

Brentuximab vedotin (Adcetris)

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CD30-directed antibody-drug conjugate (ADC) consisting of chimeric IgG1 antibody cAC10, specific for human CD30 and the microtubule disrupting agent, monomethyl auristatin E (MMAE, or vedotin). Indicated in previously untreated CD30-expressing peripheral T-cell lymphomas (PTCL), including angioimmunoblastic T-cell lymphoma and PTCL not otherwise specified, in combination with cyclophosphamide, doxorubicin, and prednisone (CHP).

Questions

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Media Gallery

Patch-stage mycosis fungoides.
Plaque-stage mycosis fungoides.
A 40-year-old woman complained of a recurrent skin rash, which she described as "bug bites." Skin biopsy results demonstrated an atypical lymphoid infiltrate that was CD30 positive. The clinical picture and pathologic findings were consistent with lymphomatoid papulosis. This condition has a benign natural history, despite clonal gene rearrangement in some cases. Skin eruptions occur in self-limited crops, which do not require treatment.
Erythroderma of Sézary syndrome.
Nail changes of Sézary syndrome.
Electron micrograph of a Sézary cell.
Tumor-stage mycosis fungoides.
Tumor-stage cutaneous T-cell lymphoma.
Patch-stage cutaneous T-cell lymphoma. Courtesy of Jeffrey Meffert, MD.
Plaque-stage parapsoriasis.
Patch-stage mycosis fungoides progressing to plaque stage, with cutaneous cigarette-paper appearance evident.
Partially confluent, erythematous plaques in advancing mycosis fungoides.
Close-up view of advancing plaque-stage mycosis fungoides with partially confluent, erythematous plaques.
Early patch-stage cutaneous T-cell lymphoma.
Hypopigmented cutaneous T-cell lymphoma. Courtesy of Jeffrey Meffert, MD.
Hypopigmented cutaneous T-cell lymphoma. Courtesy of Jeffrey Meffert, MD.
Nodular mycosis fungoides.
Middle-aged woman with mycosis fungoides showing ulceration and marked depigmentation of advanced disease.
Middle-aged woman with mycosis fungoides showing ulceration and marked depigmentation of advanced disease.
Middle-aged woman with mycosis fungoides showing ulceration and marked depigmentation of advanced disease.
Middle-aged woman with mycosis fungoides showing ulceration and marked depigmentation of advanced disease.
Mycosis fungoides with large, atypical T lymphocytes in the epidermis and dermis.
Mycosis fungoides with an epidermal nest of large, atypical T cells displaying bizarre, convoluted nuclei surrounded by a clear space (Pautrier microabscess).
A 42-year-old woman who had moved to the United States from Peru several year ago presented with an ulcerative lesion on her face near her nose, and destruction of her hard palate. Tissue biopsy revealed NK/T-cell lymphoma. Image courtesy of Jason Kolfenbach, MD, and Kevin Deane, MD, Division of Rheumatology, University of Colorado Denver School of Medicine.

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Table 1. WHO-EORTC Classification of Cutaneous T-Cell Lymphoma

WHO-EORTC Classification	Frequency (%)	5-Year Survival Rate (%)
Indolent Clinical Behavior
Mycosis fungoides	39	88
Mycosis fungoides variants and subtypes
Folliculotropic mycosis fungoides	5	75
Pagetoid reticulosis	< 1	100
Granulomatous slack skin	< 1	100
Primary cutaneous CD30⁺ lymphoproliferative disorder
Primary cutaneous anaplastic large cell lymphoma	8	95
Lymphomatoid papulosis	12	100
Subcutaneous panniculitis-like T-cell lymphoma (provisional)	1	82
Primary cutaneous CD4⁺ small/medium-sized pleomorphic T-cell lymphoma (provisional)	2	75
Aggressive Clinical Behavior
Sézary syndrome	2%	36%
Adult T-cell leukemia/lymphoma	< 1	NDA
Extranodal NK/T-cell lymphoma, nasal type	< 1	16
Primary cutaneous peripheral T-cell lymphoma, unspecified	2	15
Primary cutaneous peripheral T-cell lymphoma, rare subtypes
Primary cutaneous acral CD8⁺ T-cell lymphoma (provisional)	< 1	100
Primary cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma (provisional)	< 1	31
Primary cutaneous gamma/delta-positive T-cell lymphoma	< 1	11
Source: Adapted from Willemze et al. Blood. 2019;133(16):1703-14.^[3] EORTC = European Organization of Research and Treatment of Cancer; NDA = no data available; NK = natural killer; WHO = World Health Organization.

Table 2. Cluster Designations

CD Type	Representative Cells	Also Known As
CD2	T, NK	Sheep RBC
CD3	T
CD4	T subset	Helper
CD5	T
CD7	T, NK	Prothymocyte
CD8	T subset, NK	Suppressor
CD25	Active T, B, M	IL-2R (Tac)
CD30	Active T, B	Ki-1
CD45	T subset	CLA
CD56	NK	NCAM
B = B cell; CD = cluster designation; CLA = common leukocyte antigen; IL-2R = interleukin-2 receptor; M = M cell; NCAM = neural cell adhesion molecule; NK = natural killer; RBC = red blood cell; T = T cell; Tac = Tac antigen.

Table 3. Staging of Cutaneous T-Cell Lymphoma

Stage	Skin Lesions			Lymphadenopathy	Erythroderma	Histology
Stage	Patches/ plaques (less than10%)	Plaques/ plaques (10% or more)	Tumors	Lymphadenopathy	Erythroderma	Lymph Nodes	Viscera
IA	+	-	-	-	-	-	-
IB	+ or -	+	-	-	-	-	-
IIA	+ or -	+ or -	+ or -	+	-	-	-
IIB	+ or -	+ or -	+	+ or -	-	-	-
III	+ or -	+ or -	+ or -	+ or -	+	-	-
IVA	+ or -	+ or -	+ or -	+ or -	+ or -	+	-
IVB	+ or -	+ or -	+ or -	+ or -	+ or -	+ or -	+

Table 4. TNMB Staging of Cutaneous T-Cell Lymphoma

Stage Class	Stage	Definition
T (tumor)	T₁	Patches/plaques involving less than 10% of body surface
	T₂	Patches/plaques involving 10% or more of body surface
	T₃	Tumor(s) present on skin
	T₄	Erythroderma
N (nodes)	N₀	No enlarged lymph node present
	N₁	Enlarged lymph nodes, histologically uninvolved
	N₂	No enlarged lymph node; 1 or more nodes histologically involved*
	N₃	Enlarged lymph nodes, histologically involved
M (metastasis to viscera)	M₀	No visceral lesion present
M (metastasis to viscera)	M₁	Visceral involvement
B (blood involvement)	B₀	Circulating atypical lymphocytes (Sézary cells) less than 5% of lymphocytes
B (blood involvement)	B₁	Circulating atypical lymphocytes 5% or more of lymphocytes (Sézary syndrome)
*Uncommon finding, usually not considered/investigated.

Table 5. Comparison of Staging Systems for CTCL

Clinical Stage	TNM (B) Stage
IA	T₁ N₀ M₀
IIB	T₂ N₀ M₀
IIA	T₁ N₁ M₀	T₂ N₁ M₀
IIB	T₃ N₀ M₀	T₃ N₁ M₀
III	T₄ N₀ M₀	T₄ N₁ M₀
IVA	T₁ N₂ M₀	T₂ N₂ M₀	T₃ N₂ M₀	T₄ N₂ M₀
IVA	T₁ N₃ M₀	T₂ N₃ M₀	T₃ N₃ M₀	T₄ N₃ M₀
IVB	T₁ N₀ M₁	T₂ N₀ M₁	T₃ N₀ M₁	T₄ N₀ M₁
	T₁ N₁ M₁	T₂ N₁ M₁	T₃ N₁ M₁	T₄ N₁ M₁
	T₁ N₂ M₁	T₂ N₂ M₁	T₃ N₂ M₁	T₄ N₂ M₁
	T₁ N₃ M₁	T₂ N₃ M₁	T₃ N₃ M₁	T₄ N₃ M₁

Table 4. International Society for Cutaneous Lymphoma/European Organization for Research and Treatment of Cancer tumor-node-metastasis-blood revised classification for mycosis fungoides and Sezary syndrome

Skin	Involvement	Node	Involvement	Viscera	Involvement
T1	Patchy or plaquelike skin disease involving ≤10% of the skin surface area	N0	No abnormal lymph nodes	M0	No visceral organ involvement
T2	Patchy or plaquelike skin disease involving ≥10% of the skin surface area	N1	Histopathology Dutch Gr 1 or NCI LN 0-2	M1	Visceral organ involvement
T3	Tumors are present ≥1 cm in diameter	N2	Histopathology Dutch Gr 2 or NCI LN 3	MX	Abnormal visceral site; no histologic confirmation
T4	Erythroderma ≥80% of body area	N3	Histopathology Dutch Gr 3-4 or NCI LN 4	Blood	Involvement
		Nx	Abnormal lymph nodes; no histologic confirmation	B0	≤5% of peripheral blood lymphocytes are Sezary cells
				B1	>5% of peripheral blood lymphocytes are Sezary cells but do met B2 criteria
				B2	≥1000/mcL Sezary cells or CD4/CD8 ≥10 or ≥40% CD4+/CD7- or ≥30% CD4+/CD26- cells

Table 5. Staging classifications for mycosis fungoides and Sezary syndrome

Clinical Stage	5-Year Survival ^[131]	TNM (B) Stage
IA	98%	T₁N₀M₀B₀	T₁N₀M₀B₁
IB	89%	T₂N₀M₀B₀	T₂N₀M₀B₁
IIA	89%	T₁N₁M₀B₀	T₁N₁M₀B₁	T₁N₂M₀B₀	T₁N₂M₀B₁
IIA		T₂N₁M₀B₀	T₂N₁M₀B₁	T₂N₂M₀B₀	T₂N₂M₀B₁
IIB	56%	T₃N₀M₀B₀	T₃N₀M₀B₁	T₃N₁M₀B₀	T₃N₁M₀B₁
IIB		T₃N₂M₀B₀	T₃N₂M₀B₁
IIIA	54%	T₄N₀M₀B₀	T₄N₁M₀B₀	T₄N₂M₀B₀
IIIB	48%	T₄N₀M₀B₁	T₄N₁M₀B₁	T₄N₂M₀B₁
IVA1	41%	T₁N₀M₀B₂	T₂N₀M₀B₂	T₃N₀M₀B₂	T₄N₀M₀B₂
		T₁N₁M₀B₂	T₂N₁M₀B₂	T₃N₁M₀B₂	T₄N₁M₀B₂
		T₁N₂M₀B₂	T₂N₂M₀B₂	T₃N₂M₀B₂	T₄N₂M₀B₂
IVA2	23%	T₁N₃M₀B₀	T₂N₃M₀B₀	T₃N₃M₀B₀	T₄N₃M₀B₀
		T₁N₃M₀B₁	T₂N₃M₀B₁	T₃N₃M₀B₁	T₄N₃M₀B₁
		T₁N₃M₀B₂	T₂N₃M₀B₂	T₃N₃M₀B₂	T₄N₃M₀B₂
IVB	18%	T₁N₀M₁B₀	T₂N₀M₁B₀	T₃N₀M₁B₀	T₄N₀M₁B₀
		T₁N₁M₁B₁	T₂N₁M₁B₁	T₃N₁M₁B₁	T₄N₁M₁B₁
		T₁N₂M₁B₂	T₂N₂M₁B₂	T₃N₂M₁B₂	T₄N₂M₁B₂
		T₁N₃M₁B₃	T₂N₃M₁B₃	T₃N₃M₁B₃	T₄N₃M₁B₃

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Author

Lauren C Pinter-Brown, MD Director of Lymphoma Program, Clinical Professor of Medicine, Department of Internal Medicine, Division of Hematology and Oncology, University of California, Los Angeles, Medical Center

Lauren C Pinter-Brown, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, American Society of Hematology, SWOG

Disclosure: Nothing to disclose.

Coauthor(s)

Robert A Schwartz, MD, MPH Professor and Head of Dermatology, Professor of Pathology, Professor of Pediatrics, Professor of Medicine, Rutgers New Jersey Medical School

Robert A Schwartz, MD, MPH is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, New York Academy of Medicine, Royal College of Physicians of Edinburgh, Sigma Xi, The Scientific Research Honor Society

Disclosure: Nothing to disclose.

Chief Editor

Emmanuel C Besa, MD Professor Emeritus, Department of Medicine, Division of Hematologic Malignancies and Hematopoietic Stem Cell Transplantation, Kimmel Cancer Center, Jefferson Medical College of Thomas Jefferson University

Emmanuel C Besa, MD is a member of the following medical societies: American Association for Cancer Education, American Society of Clinical Oncology, American College of Clinical Pharmacology, American Federation for Medical Research, American Society of Hematology, New York Academy of Sciences

Disclosure: Nothing to disclose.

Additional Contributors

Francisco J Hernandez-Ilizaliturri, MD Professor of Medicine, Department of Medical Oncology, Associate Professor of Immunology, Department of Immunology, Chief, Lymphoma and Myeloma Section, Director, The Lymphoma Translational Research Program, Roswell Park Cancer Institute, University of Buffalo State University of New York School of Medicine and Biomedical Sciences

Francisco J Hernandez-Ilizaliturri, MD is a member of the following medical societies: American Association for Cancer Research, American Society of Hematology

Disclosure: Nothing to disclose.

Priyank P Patel, MD Hematology/Oncology Fellow, Roswell Park Cancer Institute, University

Priyank P Patel, MD is a member of the following medical societies: American Society of Hematology, American Society of Clinical Oncology, European Society for Medical Oncology, American College of Physicians

Disclosure: Nothing to disclose.

Acknowledgements

Günter Burg, MD Professor and Chairman Emeritus, Department of Dermatology, University of Zürich School of Medicine; Delegate of The Foundation for Modern Teaching and Learning in Medicine Faculty of Medicine, University of Zürich, Switzerland

Günter Burg, MD is a member of the following medical societies: American Academy of Dermatology, American Dermatological Association, International Society for Dermatologic Surgery, North American Clinical Dermatologic Society, and Pacific Dermatologic Association

Disclosure: Nothing to disclose

David F Butler, MD Professor of Dermatology, Texas A&M University College of Medicine; Chair, Department of Dermatology, Director, Dermatology Residency Training Program, Scott and White Clinic, Northside Clinic

David F Butler, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Medical Association, American Society for Dermatologic Surgery, American Society for MOHS Surgery, Association of Military Dermatologists, and Phi Beta Kappa