Emerging treatment options for early mycosis fungoides

Figures & data

Table 1 Modified International Society for Cutaneous Lymphomas/European Organization for Research and Treatment of Cancer revisions to the tumor–node–metastasis–blood classification of mycosis fungoides/Sezary syndrome

TNMB	Description
Skin
T1	Limited patches, papules, and/or plaques covering <10% of the skin surface
T2	Patches, papules, or plaques covering ≥10% of the skin surface
T3	One or more tumors (≥1 cm diameter)
T4	Confluence of erythema covering ≥80% body surface area
Node
N0	No clinically abnormal lymph nodes
N1	Clinically abnormal lymph nodes; histopathology Dutch grade 1 or NCI LN0–LN2
N2	Clinically abnormal lymph nodes; histopathology Dutch grade 2 or NCI LN3
N3	Clinically abnormal lymph nodes; histopathology Dutch grade 3 or NCI LN4
NX	Clinically abnormal lymph nodes without histologic confirmation or inability to fully characterize the histologic subcategories
Visceral
M0	No visceral organ involvement
M1	Visceral involvement (must have pathology confirmation and organ involved should be specified)
Blood
B0	Absence of significant blood involvement: <5% of peripheral blood Sezary cells
B1	Low blood tumor burden: >5% of peripheral blood Sezary cells
B2	High blood tumor burden: ≥1000/μL Sezary cells with positive clone
	One of the following can be substituted for Sezary cells:
	− CD4/CD8 cells ≥ 10%
	− CD4+/CD7− cells ≥ 40%
	− CD4+/CD26− cells ≥ 30%
Stage	TNMB
IA	T1, N0, M0, B0–B1
IB	T2, N0, M0, B0–B1
IIA	T1–T2, N1–N2–NX, M0, B0–B1
IIB	T3, N0–N1–N2–NX, M0, B0
IIIA	T4, N0–N1–N2–NX, M0, B0
IIIB	T4, N0–N1–N2–NX, M0, B1
IVA1	T1–T4, N0–N1–N2–NX, M0, B2
IVA2	T1–T4, N3, M0, B0–B2
IVB	T1–T4, N1–N2–N3–NX, M1, B0–B2

Notes: © 2011. American Society of Clinical Oncology. All rights reserved. Reproduced with permission from Olsen EA, Whittaker S, Kim YH, et al. Clinical end points and response criteria in mycosis fungoides and Sezary syndrome: a consensus statement of the International Society for Cutaneous Lymphomas, the United Stated Cutaneous Lymphoma Consortium, and the cutaneous lymphoma task force of the European Organisation for Research and Treatment of Cancer. J Clin Oncol. 2011;29(18):2598–2607.⁶ Data obtained from 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 task force of the European Organization for Research and Treatment of Cancer (EORTC). Blood. 2007;110(6): 1713–1722.³

Abbreviations: NCI, National Cancer Institute; TNMB, tumor–node–metastasis–blood.

Table 2 Algorithm of diagnosis of early-stage mycosis fungoides⁸

	Criteria			Scoring system
	Basic	Additional	Other	Two points	One point
Clinical	Persistent and/or progressive patches/ thin plaques	Not in a sun-exposed location Size/shape variation Poikilodermia		Two points for basic criteria and two additional criteria	One point for basic criteria and one additional criteria
Histopathologic	Superficial lymphoid infiltrate	Epidermotropism without spongiosis Lymphoid atypia		Two points for basic criteria and two additional criteria	One point for basic criteria and one additional criteria
Molecular biologic			Clonal T-cell receptor gene rearrangement		One point for clonality
Immunopathologic			<CD2+, CD3+, and/or CD5+ cells <10% CD7 cells Epidermal/dermal discordance of CD2, CD3, CD5, or CD7 (deficiency)		One point for one or more criteria

Table 3 Recommended skin therapies for early-stage mycosis fungoides⁹

Localized involvement	Generalized involvement
Topical corticosteroids	Topical corticosteroids
Topical chemotherapeutics (nitrogen mustard, carmustine)	Topical chemotherapeutics (nitrogen mustard, carmustine)
Local radiation therapy	Phototherapy: UVB, PUVA
Topical retinoids	Total skin electron beam therapy
Phototherapy: UVB, PUVA

Abbreviations: PUVA, psoralen plus ultraviolet A; UVB, ultraviolet B.

Table 4 Summary of the efficacy, indications, advantages/disadvantages, and adverse effects of skin-directed therapies in plaques of mycosis fungoides

Treatment	Complete response	Advantages	Disadvantages	Adverse effects
Topical corticoids	60%–65% in T1 25% in T2	Simple therapy Easy to use	Short therapeutic effects	Cutaneous atrophy
Mechlorethamine (Nitrogen mustard)	26%–76%	Ointment causes fewer reactions	Important local reactions Availability could be a problem	Contact dermatitis Secondary cutaneous malignancy
Carmustine	86%	Rarely used	Important local reactions	Medullary suppression Telangiectasia
Topical bexarotene	21%	Simple therapy Easy to use	Expensive Availability could be a problem	Irritant dermatitis, pruritus, burning, skin inflammation
UVB	75%–83%	Good tolerability Feasible	Requires regular 2–3 times/week treatment	Erythema, pruritus
PUVA	79%–88%	Very good response	Requires regular 2–3 times/week treatment	Nausea, phototoxicity, cutaneous malignancy
Radiotherapy (electron beam)	96%	Very good response	Limited availability 6–10 weeks to complete Permanent cutaneous side effects	Pigmentation, pruritus, alopecia, telangiectasia, xerosis, anhidrosis, cutaneous malignancy

Abbreviations: PUVA, psoralen plus ultraviolet A radiation; UVB, ultraviolet B.

Table 5 Summary of the studies published of early-stage mycosis fungoides treated with photodynamic therapy

	Number of lesions/patches	Light	Photosensitizer	Type of lesion	Response/patches treated	Relapse
Svanberg et al^Citation20	4/2	Laser 630 nm	ALA	Patch	CR 2/4	NS
Wolf et al^Citation28	2/2	Visible light	ALA	Plaque	CR 2/2	None in 3–6 months
Ammann and Hunziker^Citation25	1/1	Visible light	ALA	Plaque	CR 1	NS
Edstrom et al^Citation24	5/1	630 nm	ALA	NS	CR 4/6	NS
Wang et al^Citation29	3/1	635 nm	ALA	Periocular	CR	None in 33 months
Orenstein et al^Citation30	6/2	580–720 nm	ALA	1 patch 2 tumors	CR	None in 24 months
Markham et al^Citation31	1/1	580–740 nm	ALA	Tumors	CR	None in 1 year
Edstrom et al^Citation23	12/10	600–730 nm	ALA	10 patches 2 tumors	1/10 plaques IR 2/2 tumors IR Rest PR or CR	In lesions with CR 4–19 months
Leman et al^Citation32	2/1	630 nm	ALA	Patch	CR	None in 1 year
Coors and Von den Driesch^Citation33	7/5	60–160 nm	ALA	5 patches 2 tumors	CR	None in 12–18 months
Zane et al^Citation34	5/5	635 nm	MAL	Patch	4 CR 1 PR	No recurrence in lesions with CR in 12–34 months
Recio et al^Citation26	2/2	PDL 585 nm	ALA	Plaques	CR	None in 24 months
Fernandez-Guarino et al^Citation35	24/12	630	MAL	Plaques	CR 6/12	None in 6–36 months

Abbreviations: ALA, aminolevulinic acid; CR, complete response; IR, incomplete response; MAL, methyl aminolevulinate; NS, not specified; PDL, pulsed dye laser; PR, partial response.

Table 6 Summary of case series published on the treatment of initial mycosis fungoides with excimer laser

Study	Number of patients	Maximum peak (mJ/cm^2)	Cumulative dose (J/cm^2)	Sessions/ frequency	Clinical response	Follow-up period	Comments
Passeron et al^Citation38	5	NS	2.4–16.1	12–21 sessions 2 sessions/week	CR 4 PR 1	3 months	Complete histological response in 3/5 patients
Kontos et al^Citation39	2	450	NS	14 and 22 3 sessions/week	1 CR 1 IR	NS	Clinical and histological response coincide
Upjohn et al^Citation40	8	600	6.56–8.35	20 sessions 2 sessions/week	6 CR 1 IR 1 LF	30 months	Clinical and histological response coincide 3/6 in CR recur at 12 months
Passeron et al^Citation41	10 29 lesions	NS	1.3–16.1	6–46 sessions 2 sessions/week	80% CR* 14% PR 6% IR	8–26 months	11% recur at 7 months* Clinical and histological response coincide

Note:

* Results analyzed by the number of lesions treated, not by the number of patients.

Abbreviations: CR, complete response; IR, incomplete response; LF, lost to follow-up; NS, not specified; PR, partial response.

Table 7 Published studies on mycosis fungoides treated with imiquimod

Author	Number of patients	Mode of application	Clinical response	Comments
Suchin et al^Citation50	1	Once daily, 4 months	CR	Local irritation
Dummer et al^Citation51	1	Once daily, 8 weeks	CR	Histological response not evaluated
Deeths et al^Citation52	6	3 times/week, 4 months	2 CR, 3 PR, 1 IR	Clinical and histological response coincide
Onsun et al^Citation53	1	3 times/week, 6 months	CR	Complete histological response
Soler-Machin et al^Citation54	1	3 times/week, 5 months	CR	Plaque on eyelid
Ardigo et al^Citation7	1	5 times/week, 24 months	CR	Complete histological response
Coors et al^Citation56	4	3–7 times/week, 8–16 weeks	2 CR, 2 IR	Histological response not evaluated
Chiam and Cham^Citation55	1	3 times/week, 5 months	CR	Plaque on penis
Martinez-Gonzalez et al^Citation57	4	3 times/week, 3 months	4 CR	Complete histological response in 3/4 cases

Abbreviations: CR, complete response; IR, incomplete response; PR, partial response.

OlsenEAWhittakerSKimYHClinical end points and response criteria in mycosis fungoides and Sezary syndrome: a consensus statement of the International Society for Cutaneous Lymphomas, the United Stated Cutaneous Lymphoma Consortium, and the cutaneous lymphoma task force of the European Organisation for Research and Treatment of CancerJ Clin Oncol201129182598260721576639

 PubMed Web of Science ®Google Scholar

OlsenEVonderheidEPimpinelliNRevisions to the staging and classification of mycosis fungoides and Sezary syndrome: a proposal of the International Society for Cutaneous Lymphomas (ISCL) and the cutaneous task force of the European Organization for Research and Treatment of Cancer (EORTC)Blood200711061713172217540844

 PubMed Web of Science ®Google Scholar

PimpinelliNOlsenEASantucciMDefining early mycosis fungoidesJ Am Acad Dermatol20055361053106316310068

 PubMed Web of Science ®Google Scholar

HortwitzSMOlsenEADuvicMPorcuPKimYHReview of the treatment of mycosis fungoides and Sezary syndrome: a stage-based approachJ Natl Compr Canc Netw20086443644218433609

 PubMedGoogle Scholar

SvanbergKAnderssonTKillanderDPhotodynamic therapy of non-melanoma malignant tumours of the skin using topical delta-amino levulinic acid sensitization and laser irradiationBr J Dermatol199413067437518011500

 PubMed Web of Science ®Google Scholar

WolfPFink-PuchesRCerroniLKerlHPhotodynamic therapy for mycosis fungoides after photosensitization with 5-aminolevulinic acidJ Am Acad Dermatol19943146786808089302

 PubMed Web of Science ®Google Scholar

AmmannRHunzikerTPhotodynamic therapy for mycosis fungoides after topical photosensitization with 5-aminolevulinic acid [letter]J Am Acad Dermatol19953335417657887

 PubMed Web of Science ®Google Scholar

EdstromDWRosAMParvitATopical 5-aminolevulinic acid-based photodynamic therapy for mycosis fungoides: a study of cell proliferation and apoptosis before and after therapyJ Invest Dermatol19981104701

 Web of Science ®Google Scholar

WangIBauerBAnderson-EngelsSSvanbergSSvanbergKPhotodynamic therapy utilizing delta aminolevulinic acid in non-melanoma skins malignancies of the eyelid and periocular skinActa Ophthalmol Scand199977218218810321535

 PubMedGoogle Scholar

OrensteinAHaikJTamirJPhotodynamic therapy of cutaneous lymphoma using 5-aminolevulinic acid topical applicationDermatol Surg200026876576910940064

 PubMed Web of Science ®Google Scholar

MarkhamTSheahanKCollinsPTopical 5-aminolaevulinic acid photodynamic therapy for tumour-stage mycosis fungoidesBr J Dermatol200114461262126311422054

 PubMed Web of Science ®Google Scholar

EdstromDWPortwitARosAMPhotodynamic therapy with topical 5-aminolevulinic acid for mycosis fungoides: clinical and histological responseActa Derm Venereol200181318418811558874

 PubMed Web of Science ®Google Scholar

LemanJADickDCMortonCATopical 5-ALA therapy for the treatment of cutaneous T-cell lymphomaClin Exp Dermatol200227251651812372098

 PubMed Web of Science ®Google Scholar

CoorsEAvon den DrieschPTopical photodynamic therapy for patients with therapy-resistant lesions of cutaneous T-cell lymphomaJ Am Acad Dermatol200450336336714988676

 PubMed Web of Science ®Google Scholar

ZaneCVenturiniMSalaRCalzavara-PintonPPhotodynamic therapy with mehtylaminolevulinate as a value treatment option for unilesional cutaneous T-cell lymphomaPhotodermatol Photoinmunol Photomed2006225254258

 Web of Science ®Google Scholar

RecioEDZambranoBAlonsoMLTopical 5-aminolevulinic acid photodynamic therapy for the treatment of unilesional mycosis fungoides: a report of two cases and review of the literatureInt J Dermatol200847441041318377612

 PubMed Web of Science ®Google Scholar

Fernandez-GuarinoMHartoAPerez-GarciaBMontullCde las HerasEJaenPPlaque-phase mycosis fungoides treated with photodynamic therapy: results in 12 patientsActas Dermosifiliogr20101019785791 Spanish21034709

 PubMedGoogle Scholar

PasseronTZakariaWOstovariNEfficacy of the 308-nm excimer laser in the treatment of mycosis fungoidesArch Dermatol2004140101291129315492207

 PubMedGoogle Scholar

KontosAPKerrHAMalickFFivensonDPLimHWWongHK308-nm excimer laser for the treatment of lymphomatoid papulosis and stage IA mycosis fungoidesPhotodermatol Photoinmmunol Photomed2006223168171

 PubMed Web of Science ®Google Scholar

UpjohnEFoleyPLanePLong-term clearance of patch-stage mycosis fungoides with the 308-nm excimer laserClin Exp Dermatol200732216817117137475

 PubMed Web of Science ®Google Scholar

PasseronTAngeliKCardot-LecciaNPerrinCLacourJPOrtonneJPTreatment of mycosis fungoides by 308-nm excimer laser: a clinical and histological study in 10 patientsAnn Dermatol Venereol20071343 Pt 1225231 French17389845

 PubMed Web of Science ®Google Scholar

SuchinKRJunkins-HopkinsJMRookAHTreatment of stage IA cutaneous T-cell lymphoma with topical application of the immune response modifier imiquimodArch Dermatol200213891137113912224972

 PubMed Web of Science ®Google Scholar

DummerRUrosevicMKempfWKazakovDBurgGImiquimod induces complete clearance of a PUVA-resistant plaque in mycosis fungoidesDermatology2003207111611812835571

 PubMed Web of Science ®Google Scholar

DeethsMJChapmanJTDellavalleRPZengCAelingJLTreatment of patch and plaque stage mycosis fungoides with imiquimod 5% creamJ Am Acad Dermatol200552227528015692473

 PubMed Web of Science ®Google Scholar

OnsunNUfacikHKuralYTopcuESomayAEfficacy of imiquimod in solitary plaques of mycosis fungoidesInt J Tissue React200527416717216440581

 PubMedGoogle Scholar

Soler-MachinJGilaberte-CalzadaYVera-AlvarezJCoscojuela-SantaliestraCMartinez-MoralesJOsan-TelloMImiquimod in treatment of palpebral micosis fungoidesArch Soc Esp Oftalmol2006814221223 Spanish16688647

 PubMedGoogle Scholar

ArdigòMCotaCBerardescaEUnilesional mycosis fungoides succesfully treated with topical imiquimodEur J Dermatol200616444616935811

 PubMed Web of Science ®Google Scholar

CoorsEASchulerGvon den DrieschPTopical imiquimod as treatment for different kinds of cutaneous lymphomaEur J Dermatol200616439139316935796

 PubMed Web of Science ®Google Scholar

ChiamLYChamYCSolitary plaque mycosis fungoides of the penis responding to topical imiquimod therapyBr J Dermatol2007156356056217300249

 PubMed Web of Science ®Google Scholar

Martinez-GonzalezMCVerea-HernandoMYebra-PimentelMTDel PozoJMazairaMFonsecaEImiquimod in micosis fungoidesEur J Dermatol200818214815218424373

 PubMed Web of Science ®Google Scholar