British Association of Dermatologists and U.K. Cutaneous ...

GUIDELINESBJD

British Journal of Dermatology

British Association of Dermatologists and U.K. CutaneousLymphoma Group guidelines for the management of primarycutaneous lymphomas 2018D. Gilson,1 S.J. Whittaker iD ,2 F.J. Child,2 J.J. Scarisbrick iD ,3 T.M. Illidge iD ,4 E.J. Parry,5 M.F. Mohd Mustapa,6

L.S.Exton,6 E. Kanfer,7 K. Rezvani,8 C.E. Dearden iD 9 and S.L. Morris10

1Leeds Cancer Centre, St James’s University Hospital, Leeds LS9 7TF, U.K.2St John’s Institute of Dermatology, Guy’s and St Thomas NHS Foundation Trust, St Thomas’ Hospital, London SE1 7EH, U.K.3Queen Elizabeth Hospital, University Hospital Birmingham, Birmingham B15 2TH, U.K.4Institute of Cancer Sciences, University of Manchester, The Christie NHS Foundation Trust, Manchester M20 4BX, U.K.5Tameside Hospital Integrated Care NHS Foundation Trust, Ashton-under-Lyne OL6 9RW, U.K.6British Association of Dermatologists, Willan House, 4 Fitzroy Square, London, W1T 5HQ, U.K.7Haematology Department, Hammersmith Hospital, Du Cane Road, London W12 0HS, U.K.8The University of Texas MD Anderson Cancer Centre, Houston, TX, U.S.A.9Chronic Lymphocytic Leukaemia (CLL) Unit, The Royal Marsden NHS Foundation Trust, Sutton SW3 6JJ, U.K.10Guy’s and St Thomas’ NHS Foundation Trust, Guy’s Hospital, London SE1 9RT, U.K.

CorrespondenceSean Whittaker.

E-mails: [email protected]; [email protected]

Accepted for publication

14 September 2018

Funding sources

None.

Conflicts of interestS.J.W. has been on advisory boards for Actelion, Takeda and Innate Pharma (specific) and has

a collaborative research agreement with Galderma. J.J.S. has been a consultant for Innate

Pharma, Actelion Pharmaceuticals, Therakos (Mallinckrodt), Takeda and 4SC (specific) and

has received honoraria and meeting sponsorship from Teva, Therakos, Johnson & Johnson and

Takeda (specific). C.E.D. has been a consultant for Genzyme (specific). T.M.I. has been a con-

sultant and invited speaker for Takeda (specific). E.J.P. has been on the advisory board for and

an invited speaker for Actelion. The other authors declare no conflicts of interest.

D.G., S.J.W., F.J.C., J.J.S., T.M.I., E.J.P., E.K., K.R., C.E.D. and S.L.M. are members of the

guideline development group, with technical support provided by L.S.E. and M.F.M.M.

These guidelines were first produced jointly by the British Association of Dermatologists and the

U.K. Cutaneous Lymphoma Group (2003); reviewed and updated 2018.

This is an updated guideline prepared for the BAD Clinical Standards Unit, which includes the

Therapy & Guidelines Subcommittee. Members of the Clinical Standards Unit who have been

involved are P.M. McHenry (Chairman Therapy & Guidelines), T.A. Leslie, S. Wakelin, R.Y.P.

Hunasehally, M. Cork, G.A. Johnston, N. Chiang, F.S. Worsnop, A. Salim, D. Buckley, G. Petrof,

N. Callachand (British National Formulary), T. Flavell (British Dermatological Nursing Group),

A.A. Salad (BAD Scientific Administrator), L.S. Exton (BAD Guideline Research Fellow) and M.F.

Mohd Mustapa (BAD Clinical Standards Manager).

DOI 10.1111/bjd.17240

NICE has renewed accreditation of the process used by the BritishAssociation of Dermatologists to produce clinical guidelines. Therenewed accreditation is valid until 31 May 2021 and applies toguidance produced using the processes described in the updated guid-ance for writing a British Association of Dermatologists clinicalguideline – the adoption of the GRADE methodology 2016. Theoriginal accreditation term began on 12 May 2010. More infor-mation on accreditation can be viewed at www.nice.org.uk/accreditation.

Linked Editorial: Wang and Bagot. Br J Dermatol 2019; 180:443–444.

1.0 Purpose and scope

The overall objective of the guideline is to provide up-to-date,

evidence-based recommendations on the management of pri-

mary cutaneous lymphoma in the U.K. The document aims

to: (i) offer an appraisal of all relevant literature up to Febru-

ary 2018 focusing on any key developments; (ii) address

important, practical clinical questions relating to the primary

guideline objective; (iii) provide guideline recommendations

with, where appropriate, some health economic implications;

and (iv) discuss potential developments and future directions.

The guideline is presented as a detailed review with high-

lighted recommendations for practical use in the clinic (see

section 12). A patient information leaflet on mycosis fun-

goides is available on the British Association of Dermatologists

(BAD) website: www.bad.org.uk/for-the-public/patient-inf

ormation-leaflets. Further information can also be found at

www.lymphomas.org.uk/about-lymphoma.

1.1 Exclusions

These guidelines do not cover patients presenting with or found

to have skin involvement as part of a systemic lymphoma.

2.0 Methodology

This set of guidelines has been developed using the BAD’s recom-

mended methodology1 and with reference to the Appraisal of

Guidelines Research and Evaluation (AGREE II) instrument

(www.agreetrust.org).2 The recommendations were developed

for implementation in the National Health Service using a process

of considered judgement based on the evidence (Appendix S1;

see Supporting Information). Targeted literature searches were

carried out in the PubMed, MEDLINE and Embase databases and

the Cochrane Library, for meta-analyses, randomized and

© 2018 British Association of Dermatologists496 British Journal of Dermatology (2019) 180, pp496–526

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https://orcid.org/0000-0002-8011-4408

https://orcid.org/0000-0002-8011-4408

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https://orcid.org/0000-0003-3191-7324

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mailto:

mailto:

http://www.nice.org.uk/accreditation

http://www.nice.org.uk/accreditation

https://doi.org/10.1111/bjd.17523

https://doi.org/10.1111/bjd.17523

http://www.bad.org.uk/for-the-public/patient-information-leaflets

http://www.bad.org.uk/for-the-public/patient-information-leaflets

http://www.lymphomas.org.uk/about-lymphoma

nonrandomized controlled clinical trials, case series, case reports,

open studies and cohort studies on primary cutaneous lymphoma

and specified treatments to February 2018. The search terms and

strategies are detailed in Appendix S2 (see Supporting Informa-

tion). Additional relevant references were also retrieved from

citations in the reviewed literature.

All identified English-language titles were screened and those

relevant for first-round inclusion were selected for further scrutiny.

The abstracts for the shortlisted references were then reviewed and

the full papers of relevant material were obtained; disagreements in

the final selections were resolved by discussion with the entire

Guideline Development Group (GDG). The structure of the 2003

guidelines was then discussed and re-evaluated, with headings and

subheadings revised where appropriate; different coauthors were

allocated separate subsections. Each coauthor then performed a

detailed appraisal of the selected literature with discussions within

the GDG to resolve any issues, for example the quality of evidence

and making the appropriate recommendations. All subsections

were subsequently collated, circulated within the GDG and edited

to produce the final guideline.

3.0 Introduction

3.1. Incidence and epidemiology

Primary cutaneous lymphomas represent a heterogeneous

group of extranodal non-Hodgkin lymphomas, consisting of

cutaneous B-cell lymphoma (CBCL) and cutaneous T-cell lym-

phoma (CTCL). CTCL represents around 70% and CBCL about

30% of primary cutaneous lymphomas. Primary cutaneous

lymphomas have been defined by the European Organisation

for Research and Treatment of Cancer (EORTC)–World Health

Organization (WHO) classification3,4 and incorporated into

the most recent WHO classification (Table 1).5

These guidelines are broadly consistent with U.S. National

Comprehensive Cancer Network guidelines (www.nccn.org),

and the EORTC and European Society for Medical Oncology

clinical practice guidelines.4,6,7

Mycosis fungoides (MF) and S�ezary syndrome (SS) are the

most common clinicopathological subtypes of CTCL.3 A recent

U.K. National Cancer Information Network audit of newly

diagnosed cases of CTCL from 2009 to 2013 suggests an

annual incidence of 0�7 per 100 000 U.K. population, with a

significantly higher male incidence (1�6 : 1�0) and a peak age

between 50 and 74 years. Completion of staging data was

poor (7% in 2009, 20% in 2013).8 While the peak incidence

of MF/SS occurs in the 50–74-year age group, approximately

20% of patients are diagnosed with CTCL aged 25–49 years,

and MF may rarely present in childhood. Increasing age is a

poor prognostic factor and the vast majority of younger

patients present with early-stage disease where the outlook is

excellent. However, management of younger adults with

intermediate or advanced stages of CTCL may require a more

aggressive approach than usual.

MF and SS are closely related both clinically and pathogenetically

but are distinct from other relatively rare types of primary CTCL.

Of these rarer CTCLs, the primary cutaneous CD30+ lymphoprolif-

erative disorders have an excellent prognosis, while some of the

other CTCL variants have poor prognosis and are more closely

related to peripheral T-cell lymphomas (PTCLs).9

CBCL is classified into three main types: the more common,

low-grade primary cutaneous follicle centre lymphoma

(PCFCL) and primary cutaneous marginal zone lymphoma

(PCMZL), which can occur at any age, and the rare, primary

cutaneous, diffuse, large B-cell lymphoma (PCLBCL) leg type,

which occurs typically in elderly female patients.3

A list of the abbreviations used in this guideline is available

in Appendix S3 (see Supporting Information).

4.0 Diagnosis, staging, prognosis and endpoints

4.1 Diagnosis

The diagnosis of different cutaneous lymphoma variants is

based on an assessment of the clinical and pathological fea-

tures, which forms the basis for the National Cancer

Table 1 World Health Organization/European Organisation for

Research and Treatment of Cancer classification of primary cutaneous

lymphomas (italics indicate provisional entities)

Cutaneous B-cell lymphoma

• Indolent clinical behaviour

○ Primary cutaneous marginal zone B-cell lymphomaa

○ Primary cutaneous follicle centre lymphoma

• Intermediate behaviour

○ Primary cutaneous diffuse large B-cell

lymphoma, leg typeCutaneous T-cell lymphoma

• Indolent clinical behaviour

○ Mycosis fungoides (and variants)

○ Primary cutaneous CD30+ lymphoproliferative

disorder: anaplastic large cell lymphoma

○ Primary cutaneous CD30+ lymphoproliferative

disorder: lymphomatoid papulosis

○ Subcutaneous panniculitis-like T-cell lymphoma

○ Primary cutaneous CD4+ small/medium pleomorphic T-celllymphoproliferative disorderb

○ Primary cutaneous acral CD8+ T-cell lymphomab

○ Hydroa vacciniforme-like lymphoproliferative

disorderb

• Aggressive clinical behaviour

○ S�ezary syndrome

○ Extranodal natural killer/T-cell lymphoma, nasal type

○ Primary cutaneous aggressive epidermotropic cytotoxicCD8+ T-cell lymphoma

○ Primary cutaneous c/d T-cell lymphoma

○ Primary cutaneous peripheral T-cell lymphoma,

unspecified

aClassified as extranodal marginal zone lymphoma of mucosa-

associated lymphoid tissue (MALT lymphoma) in the 2016 ver-

sion. bChanges from the 2008 version.

© 2018 British Association of Dermatologists British Journal of Dermatology (2019) 180, pp496–526

BAD and U.K. CLG guidelines for primary cutaneous lymphomas 2018, D. Gilson et al. 497

http://www.nccn.org

Information Network minimum dataset for primary cutaneous

lymphomas. MF is characterized by a distinct clinical morphol-

ogy consisting of polymorphic patches or plaques, with the

more advanced cutaneous stage associated with tumours and

erythroderma; peripheral adenopathy may or may not be pre-

sent. SS is much less common (5% of CTCL) and is defined

according to the WHO criteria by the presence of erythro-

derma, peripheral lymphadenopathy and S�ezary cells compris-

ing > 1000 cells lL�1, or with a CD4 : CD8 ratio > 10 or

loss of one or more T-cell antigens on flow cytometry and a

T-cell clone (stage B2). Human T-lymphotropic virus-1 serol-

ogy should be checked in all patients to exclude adult T-cell

leukaemia/lymphoma, which can mimic CTCL. As for all new

patients with lymphoma, HIV status should also be checked,

in line with the Department of Health recommendations.10

Repeated biopsies may be required to establish the diagno-

sis, especially in MF. MF has a characteristic CD4+ epider-

motropic infiltrate of T cells, although rare CD8+ phenotypic

variants occur. T-cell receptor gene analysis is an important

diagnostic and staging technique especially in patients with

MF/SS, where analysis of peripheral blood provides critical

prognostic information. It is essential that results are always

interpreted in the context of the clinicopathological features.

Patients with other CTCL variants do not have the character-

istic polymorphic patches and plaques seen in MF and may

present with cutaneous tumours, nodules or subcutaneous

infiltration with distinctive pathology and immunophenotypic

findings.3 Lymphomatoid papulosis (LyP) represents part of a

spectrum of primary cutaneous CD30+ lymphoproliferative

disorders and is defined by a history of recurrent, self-healing

papules and nodules, and characteristic pathology.

CBCL presents with nodules, plaques and tumours with a

characteristic pathology and immunophenotype, and site local-

ization can be an important distinguishing feature. A definitive

diagnosis can only be made on a representative biopsy, prefer-

ably an excision or elliptical biopsy. Borrelia burgdorferi infection

has been reported in association with PCMZL, and serology is

indicated in all patients.11,12 Clonal IgH gene rearrangements

can aid diagnosis.13

4.2 Staging

Staging investigations should include a computed tomography

(CT) scan of the neck, chest, abdomen and pelvis in all patients

with CTCL and CBCL, with the exception of those with early

stages of MF (IA/IB) and LyP unless there is palpable lym-

phadenopathy.14,15 Positron emission tomography (PET) CT

should be considered for patients with PCLBCL leg type in keep-

ing with local policies for PET CT in aggressive B-cell lym-

phomas.16 The value of PET scans in MF/SS and other CTCL

variants remains unclear at present, although this may indicate

which nodal basin to sample.17,18 In MF and SS, morphological

assessment of peripheral blood for S�ezary cells is required (de-

fined as lymphocytes with hyperconvoluted nuclei). This should

be carried out by flow cytometry to quantify the total number

of S�ezary cells and T-cell-receptor gene analysis.

In SS, an identical clonal T-cell-receptor gene rearrangement

is detected in skin and peripheral blood in combination with

(i) a total S�ezary cell count > 1000 cells lL�1, (ii) an

expanded CD4+ T-cell population with a CD4 : CD8 ratio

≥ 10 or (iii) an expanded CD4+ T-cell population with abnor-

mal immunophenotype including CD4+ CD7� (> 30%) or

CD4+ CD26� (> 40%). Bone marrow aspirate and trephine

biopsies are rarely indicated in MF, SS and LyP, unless there is

an unexplained haematological abnormality, but they are more

commonly required for other CTCL variants and for high-

grade PCLBCL leg type. Bone marrow biopsy and aspirate is

considered optional for low-grade PCMZL but should be con-

sidered for PCFCL, as systemic follicle centre lymphoma with

secondary cutaneous involvement may occur.19,20 Serum lac-

tate dehydrogenase has prognostic significance and should be

checked at diagnosis.21

Existing staging systems for nodal lymphomas are not appli-

cable for primary cutaneous lymphomas. The original TNM

(primary tumour, regional nodes, metastasis) and clinical stag-

ing system for MF and SS22 has now been replaced by an

International Society for Cutaneous Lymphomas (ISCL)–EORTCrevised staging system,23 which distinguishes patches and pla-

ques, incorporates a molecular assessment of lymph node and

peripheral blood, and provides a quantitative method for

assessing peripheral blood disease in SS (Tables S1–S3; see

Supporting Information).24 These revised staging systems have

been adopted by the American Joint Committee on Cancer.25

4.3 Prognosis

Recent studies have defined prognostic risks with CTCL and

CBCL, providing rates for overall survival (OS), disease-specific

survival and progression-free survival (PFS) (Tables 2 and

3).21,26–30

Unlike CTCL, prognosis for CBCL is determined by the type

of primary CBCL, not its stage (Table 3).3,11,31–33 Most

patients with early stages of MF, primary cutaneous CD30+

lymphoproliferative disorders, and marginal zone and follicle

centre lymphomas have a good prognosis, but disease progres-

sion and disease-specific mortality may occur. The 5- and 10-

year OS rates for MF are 80% and 57%, respectively, with dis-

ease-specific survival rates of 89% and 75% at 5 and 10 years,

respectively.27 Approximately 25% of early-stage patients

develop disease progression.30 In contrast, patients with SS

have an 11% 5-year survival, with a median survival of

32 months from diagnosis. Patients with low-grade PCMZL

and PCFCL have 5-year OS rates approaching 100%, but for

PCLBCL leg type the prognosis is poor, with 5-year OS rates

of between 36% and 45%.

Several multivariate analyses of large cohorts of patients with

MF/SS have identified potential independent prognostic factors

at diagnosis. A study of 1502 U.K. patients identified separate

prognostic models for early and advanced MF.30,34 Specifically

for early-stage disease, male sex, age (≥ 60 years), presence of

plaques (T1b/T2b), histological evidence of folliculotropic dis-

ease and palpable or histologically confirmed dermatopathic

© 2018 British Association of DermatologistsBritish Journal of Dermatology (2019) 180, pp496–526

498 BAD and U.K. CLG guidelines for primary cutaneous lymphomas 2018, D. Gilson et al.

peripheral nodes (N1/Nx) were adverse factors for progression

and survival. For late-stage disease, nodal involvement (N2/3)

and blood and visceral disease are additional important prognos-

tic factors. Patients with stage IIB disease have a poor prognosis,

but published data show marked variation in survival, perhaps

reflecting the heterogeneous nature of tumour-stage disease in

terms of both tumour burden and biology.26,27 The probability

of survival for patients with stage III erythrodermic MF, without

evidence of lymph node or peripheral blood involvement, is

broadly similar to that for stage IIB MF.

A Cutaneous Lymphoma International Consortium study of

prognostic factors in 1275 patients with advanced MF/SS from

29 international sites confirmed similar survival probability for

patients with stage IIB and III disease, with significantly worse

survival in stage IV.21 Four independent prognostic factors

were identified, namely age > 60 years, large cell transforma-

tion in skin, raised lactate dehydrogenase and stage IV disease.

A prognostic index model combining these four factors identi-

fied three risk groups with significantly different 5-year sur-

vival rates: low risk (68%), intermediate risk (44%) and high

risk (28%).21 This prognostic index is in the process of being

prospectively validated.

4.4 Disease response and end points

Historically, most trials in cutaneous lymphomas have been ret-

rospective reports of case series or phase II studies, with no

standardized definitions of end points or response criteria. Con-

sequently, the detail and quality of response assessments have

been variable, and most studies have reported responses based

on assessment of skin disease alone. This has led to the publica-

tion of ISCL–EORTC consensus criteria for disease end points,

and assessment tools for MF/SS, which are based on utilization

of the modified Severity Weighted Assessment Tool technique

(Table S4; see Supporting Information)35 and include a global

scoring system based on responses of cutaneous and noncuta-

neous disease (Table S5; see Supporting Information).35

In addition, a similar consensus proposal is in preparation for

other primary non-MF/non-SS cutaneous lymphomas. These stan-

dards for disease assessment should now be routinely used for

monitoring clinical outcomes in all patients with primary cutaneous

lymphomas in conjunction with quality-of-life measurements.

5.0 National Institute for Health and CareExcellence Improving Outcomes Guidance forprimary cutaneous lymphomas

5.1 Specialist multidisciplinary teams

Primary cutaneous lymphomas are rare and heterogeneous

malignancies that can present considerable diagnostic difficul-

ties. In addition, effective standard treatments have yet to be

defined for many variants, particularly those with a poor prog-

nosis. As such, it is critical that patients have effective pathways

of care that allow rapid access to centres with broad experience

of primary cutaneous lymphomas. Such pathways have been

defined in the National Institute for Health and Care Excellence

(NICE) Improving Outcomes Guidance (IOG) for skin cancers

including melanoma (Table 4).36,37 Patients outside the groups

where review by the supranetwork skin lymphoma multidisci-

plinary team (MDT) is mandated may benefit from review by

this team, especially where there is difficulty in establishing a

diagnosis or the patient’s management is proving challenging,

depending on the expertise of the specialist skin MDT.

All patients with suspected or proven primary cutaneous lym-

phomas should be reviewed at regional specialist skin cancer

Table 2 Prognosis in mycosis fungoides/S�ezary syndrome21,26–30

Stage

Overall survival Disease-free survival Progression-free survival

5 year 10 year 5 year 10 year 5 year 10 year

IA T1a 97% 91% 100% 96% 95% 91%T1b 91% 80% 96% 92% 88% 82%

IB T2a 85% 75% 90% 82% 85% 72%T2b 81% 64% 86% 72% 75% 56%

IIA 78% 52% 89% 67% 83% 67%IIB 40–65% 34% 50–80% 42% 52% 42%

IIIA 47% 37% 54% 45% 47% 38%IIIB 40% 25% 48% 45% 18% 27%

IVA1 37% 18% 41% 20% 38% 17%IVA2 18% 15% 23% 20% 23% 20%

IVB 18% – 18–20% – 18% –

Table 3 Prognosis in primary non-mycosis fungoides/S�ezary

syndrome cutaneous lymphomas3,11,31–33

5-Year survival Overall Disease specific

pcCD30+ anaplastic large

cell lymphoma

90% NA

pcCD30+ lymphomatoid papulosis 100% NA

pc marginal zone lymphoma MZL > 95% 100%pc follicle centre lymphoma > 95% > 95%

pc diffuse large B-cell lymphoma 36–45% 61%

pc, primary cutaneous; NA, not available.



MDT meetings. There must be a close working relationship

between the regional specialist skin cancer and haemato-oncol-

ogy MDTs, especially for patients who develop systemic disease.

5.2 Supranetwork multidisciplinary teams

The NICE IOG also defines which patients with primary cuta-

neous lymphomas should be referred to supranetwork MDTs

across England (Table 5), at which dermatologists, clinical

oncologists, haemato-oncologists and both dermatopatholo-

gists and haematopathologists review the patient’s diagnosis

and management plan. The IOG recommends that all patients

with stage IIB or higher MF, and all with SS and rare CTCL

variants should be reviewed by the supranetwork MDT. These

supranetwork MDTs also provide the appropriate pathway to

review cases where diagnostic or classification difficulties arise.

Patients should be reviewed at supranetwork centres to pro-

vide access to clinical trials, which are often the standard of

care, and to agree on use of newly approved therapies.

The supranetwork MDT is also responsible for reviewing

patients who require specialist treatment options, such as total

skin electron beam therapy (TSEB) and extracorporeal photo-

pheresis (ECP). Although not stipulated in the IOG, patients

with stage IB disease that is refractory to skin-directed therapy

(SDT) should be referred to the supranetwork MDT to ensure

that they have appropriate access to clinical trials and TSEB. All

patients who are being considered for stem cell transplantation

should be reviewed by a supranetwork MDT.

6.0 Treatment of mycosis fungoides/S�ezarysyndrome

Therapeutic options range from SDT consisting of topical agents,

phototherapy and radiotherapy, to systemic treatment with

biologics, chemotherapy and stem cell transplantation. Selection

of appropriate treatment is based on the stage of disease. Follow-

ing treatment, patients with advanced disease often develop

recurrent, low-grade disease that can be responsive to SDT. There

have been very few randomized controlled studies. Recently

Quaglino et al. published a retrospective analysis of 853 patients

with advanced MF/SS from 21 centres.38 This large, multicentre

retrospective study showed a substantial heterogeneity of treat-

ment approaches in advanced MF/SS between U.S. and non-U.S.

centres, with up to 24 different drugs, modalities or combina-

tions used as first-line treatment, but these differences did not

influence survival outcome. However, it was observed that

chemotherapy, when used as first-line treatment, is associated

with a higher risk of death and/or change of therapy. For the pur-

poses of this guideline, separate recommendations for MF/SS

have been made according to stage.

6.1 Skin-directed treatment

6.1.1 Topical therapies

6.1.1.1 Stage IA–IIA mycosis fungoides

There have been few randomized controlled trials (RCTs) of

topical therapies for MF. The lack of well-controlled studies

Table 4 Clinical pathway for cutaneous lymphomas

Category Specialist MDT

Supranetwork

MDT

Stage IA–IIA MF Required a

Stage IA–IIA MF

refractory to skin-directedtherapy

Required Essential

Stage III–IVA1 erythrodermicMF/SS

Required Essential

Stage IIB–IV MF/SS Required EssentialpcCD30+ lymphoproliferative

disorders

Required a

CTCL variants Required Essential

CBCL Required a

MF, mycosis fungoides; SS, S�ezary syndrome; pc, primary cuta-

neous; CTCL, cutaneous T-cell lymphoma; CBCL, cutaneous B-

cell lymphoma; MDT, multidisciplinary team. aThese patients

may benefit from review by the supranetwork skin lymphoma

MDT. Table adapted from the National Institute for Health and

Care Excellence guidance.36

Table 5 Supranetwork multidisciplinary teams (MDTs) in England, as

per the National Institute for Health and Care Excellence Improving

Outcomes Guidance for skin cancer36 and other network skin

lymphoma services in the U.K.

TSEB ECP

Supranetwork MDTs

Birmingham (QueenElizabeth Hospital)

Yes (Coventry andWarwickshire

University Hospital)

Yes

Leeds (St James’s

University Hospital)

Yes No, referred to

RotherhamHospital

Liverpool (RoyalLiverpool Hospital)

Yes (ClatterbridgeHospital, Wirral)

Yes

London (Guy’s and StThomas’ Hospital)

Yes Yes

Manchester (TheChristie Hospital)

Yes Yes

Newcastle(Freeman Hospital)

Yes Yes

Nottingham(City Hospital)

Yes Yes

Other network skin lymphoma servicesBelfast Yes No, would be

referredCardiff No, referred to Guy’s

and St Thomas’

No, referred to

Bristol UniversityHospitals

Glasgow No, referred toNewcastle

Yes

TSEB, total skin electron beam; ECP, extracorporeal electrophore-

sis.



limits the quality of evidence, although all of the topical thera-

pies listed have some clinical efficacy for patches and thin pla-

ques (Table 6). However, accurate data on end points such as

duration of response and freedom from relapse are lacking.

Many of the topical therapies reviewed remain unlicensed for

use in MF.

6.1.1.1.1 Topical corticosteroids Topical corticosteroids, especially

class 1 (very potent) compounds, are effective for patches and

plaques in some patients with early-stage IA/IB MF, but

responses are rarely complete or durable.39

6.1.1.1.2 Topical mechlorethamine (nitrogen mustard) The single lar-

gest RCT randomized 260 patients to a standard nitrogen

mustard 0�02% ointment or a novel nitrogen mustard 0�02%gel preparation, used once daily for up to 12 months; no

adjunctive therapy was allowed. The gel preparation was sta-

tistically noninferior to the ointment, with response rates of

58�5% (gel) vs. 47�7% (ointment) as measured by the Com-

posite Assessment of Index Lesion Severity (CAILS).40 An

extension study of 98 patients who failed to achieve com-

plete response used a nitrogen mustard 0�04% gel, with a

CAILS response rate of 26% (6% complete response). Euro-

pean Medicines Agency (EMA) approval of this new gel

preparation (Ledaga�) provides a more practical formulation

than the historical, in-house compounded ointment and

aqueous solutions.

These trials confirm that mechlorethamine is an effective

topical therapy for early-stage MF. Previous studies have been

predominantly retrospective and confounded by the use of

other therapeutic modalities.41–46 A prospective, nonrandom-

ized study of 64 patients with early-stage MF treated with a

0�02% aqueous solution of mechlorethamine followed by

betamethasone cream twice weekly for 6 months reported

58% complete responses.47

The duration of response to mechlorethamine varies, and

the efficacy of maintenance therapy and whole-body applica-

tion remains unclear, but rare patients with stage IA disease

may be cured. Irritant contact dermatitis is the most com-

mon adverse effect, occurring in 10–40% of patients,

depending on the preparation used. A recent 30-year popula-

tion-based cohort study showed no increased risk of sec-

ondary cancers (including nonmelanoma skin cancer or

melanoma) in patients treated with mechlorethamine. Mortal-

ity and cause-specific mortality were not influenced by

mechlorethamine.46

6.1.1.1.3 Topical carmustine (BCNU) Limited data suggest that

topical carmustine has similar efficacy to mechloretha-

mine.48,49 However, it is more extensively absorbed, increas-

ing the risk of bone marrow suppression, although the

incidence of irritant contact dermatitis is lower (10%).

6.1.1.1.4 Other topical therapies Topical bexarotene (1% gel) has

been shown to be effective in prospective phase I/II open

studies50 and phase III trials for refractory or persistent, early-

stage MF.51 Although approved by the U.S. Food and Drug

Administration (FDA), topical bexarotene is not licensed in

Europe. Irritant contact dermatitis is common and was

reported in 12% of patients.

Limited data from case reports and series suggest that imi-

quimod 5% cream,52–59 5-fluorouracil cream,60 topical reti-

noid preparations (tazarotene 0�1%, tretinoin 0�1%)61 and

tacrolimus 0�1% ointment62 may have efficacy in early stages

of MF. The value of simple emollient therapy in MF was high-

lighted by a 24% placebo response rate to ointment base alone

in an RCT of topical peldesine (28% response rate, difference

not statistically significant).63

6.1.1.2 Stage IIB mycosis fungoides (MF); stage III–IVA1 MF/S�ezary syn-

drome (SS); stage IVA2–B MF/SS

There is no evidence to suggest that topical therapies have a

significant impact on the course of the disease for advanced

stages of MF/SS, although SDT can alleviate skin symptoms

such as pain and pruritus, and most patients will require inter-

mittent topical treatments, especially topical steroids.

Table 6 Topical therapy in mycosis fungoides

Therapy Design

Level of

evidencea Stage Response rate

Mechlorethamine RCT40 1+ IA–IIA 59% gel vs. 48% ointment(noninferiority design by CAILS)

Retrospective case series41–46 3 IA–IB 51–80% (IA) 26–68% (IB)Mechlorethamine +betamethasone

Prospective open-label phase II47 2+ IA–IB 58% complete response (duration 7�7 months)

Bexarotene gel Phase II50 2+ IA–IB 63%

Phase III51 IA–IIA 44%Carmustine (BCNU) Case series48,49 3 IA–IIA 76%

Corticosteroids Case series39 3 IA–IB 94% (IA), 82% (IB)

RCT, randomized controlled trial; CAILS, Composite Assessment of Index Lesion Severity. aSee Appendix S1 in the Supporting Information.



6.1.2 Phototherapy


Phototherapy (Table 7) is the standard of care for patients

with early stages of MF whose disease is not controlled by

topical therapy, producing high complete remission rates.64–91

However, the duration of response is often limited. Repeated

courses may be considered but the increased risk of skin can-

cer (including melanoma) limits the number of phototherapy

courses in a lifetime.

There are few comparative studies or RCTs involving pso-

ralen–ultraviolet A (PUVA), and most case series lack a vali-

dated scoring system to assess tumour burden. The critical

questions as to whether PUVA affects time to progression and

disease-specific survival remain unanswered.

6.1.2.1.1 Ultraviolet B phototherapy Both narrowband ultraviolet

(UV)B (TL-01: 311–313 nm) and broadband UVB (290–320 nm) phototherapy can produce high complete response

rates.64–69 Responses are more likely in patients who have

only patches. There have been no prospective RCTs of nar-

rowband UVB, but a retrospective case series showed it to be

as effective as PUVA for treatment of early-stage disease, with

no difference in time to relapse.70 In a paediatric case series,

high response rates were seen (> 80%), including a number

of complete responses in children with the hypopigmented

variant of MF.71

6.1.2.1.2 Ultraviolet A phototherapy High-dose UVA1 photother-

apy (340–400 nm), which penetrates more deeply than both

UVB and UVA, has shown clinical efficacy in a small case

series.72

6.1.2.1.3 Psoralen–ultraviolet A photochemotherapy Extensive, non-

randomized and retrospective case studies have reported

high complete response rates for PUVA in early stages.73–76

Data from an RCT showed that a minority (25–30% free-

dom from relapse at 5 years) of patients achieving a com-

plete response77 may have a prolonged duration of

response. Many patients receive maintenance therapy but

the benefits are uncertain.78,79 A retrospective study of

long-term outcomes following complete remission from

PUVA monotherapy at a single institution reported that 30–50% of patients had a durable remission (10-year disease-

free survival), but maintenance PUVA was given to almost

all responding patients.80 A total of 30% of patients showed

chronic photodamage and secondary skin cancers. This study

showed no significant difference in the OS rate for the non-

relapsing and relapsing patient cohorts. Recent data from a

prospective cohort study suggest that maintenance therapy

does not prevent future relapse.81,82

For PUVA, an increased risk has been identified for

patients receiving more than 250 treatments and/or

> 2000 J cm�2.83,84 Based on the data available, the cumula-

tive lifetime PUVA exposure should be limited (1200 J cm�2

and/or 250 sessions).85 For maintenance PUVA the risks

may outweigh the benefits, and generally this should be

avoided for those patients who achieve excellent clinical

responses, although there are some exceptional refractory

patients for whom maintenance treatment may provide

important symptomatic relief.

6.1.2.1.4 Photodynamic therapy Photodynamic therapy has been

reported as a treatment for solitary plaques that are resistant

to topical treatment. Small case series have shown durable

responses in 70–75% of patients.86,87 Photodynamic therapy

is safe and well tolerated and may be appropriate for certain

sites, but a specific therapeutic role in MF has yet to be

defined.

6.1.2.1.5 Excimer laser Several small case series have demon-

strated the efficacy of the 308-nm excimer laser in early-stage

skin disease. Treatment with an excimer laser appears to be

safe, effective and well tolerated for patches, but its precise

therapeutic role remains to be established.88–90

6.1.2.2 Stage IIB mycosis fungoides

Patients with tumours invariably have coexisting patches

and plaques and may benefit from phototherapy if individ-

ual tumours respond to other options such as localized

radiotherapy.

Table 7 Phototherapy in mycosis fungoides

Therapy Design (all nonrandomized) Level of evidencea Stage Response rate Response duration (months)

UVB Retrospective66 2� IA–IB 75% 51

UVB Retrospective65 2� IA–IB 71% 22NB UVB Retrospective68 2� IA–IB 84% 12�5 weeks

NB UVB Retrospective69 2� IA–IB 84% (IA), 78% (IB)NB UVB Retrospective91 2� IA–IB 100% > 60 (80% CR and 60% no recurrence)

PUVA Retrospective74 2� IA–IB 95% 43PUVA Prospective79 2+ IA–IB 100% 20 (IA), 17 (IB)

PUVA Retrospective80 2� IA–II 63% (CR) 39

Regimens: psoralen–ultraviolet A (PUVA), twice weekly for 12–14 weeks; Narrowband ultraviolet B (NB UVB), two to three times weekly

for 12–14 weeks. CR, complete response. aSee Appendix S1 in the Supporting Information.



6.1.2.3 Stage III/IVA1 erythrodermic mycosis fungoides/S�ezary syndrome

Patients with erythrodermic MF/SS are often intolerant of

phototherapy due to aggravation of pruritus, but they can

rarely respond.

6.1.2.4 Stage IVA2–B mycosis fungoides/S�ezary syndrome

PUVA can often be used as a salvage therapy, as patients with

advanced disease often relapse or have persistent low-grade

skin disease characterized by patches and plaques following

systemic treatments.

6.1.3 Combination psoralen–ultraviolet A regimens

PUVA combined with interferon-alpha or bexarotene does not

improve overall response but may improve duration of

response and can the reduce cumulative UVA dose (Table 8).

6.1.3.1 Stage IA–IIA mycosis fungoides6.1.3.1.1 Psoralen–ultraviolet A and interferon-alpha RCTs have estab-

lished that combined PUVA and interferon-alpha are associated

with a reduced cumulative UVA dose to best response and an

improved duration of response compared with both PUVA

alone and interferon-alpha combined with acitretin.92–94 How-

ever, overall complete response rates for PUVA and interferon-

alpha appear to be similar to those with PUVA alone.93,95–102

6.1.3.1.2 Psoralen–ultraviolet A and retinoids The combination of

PUVA and retinoids (acitretin) is associated with a reduction

in cumulative UVA dose to best response, but with no dif-

ference in response rates compared with PUVA alone.99

PUVA and bexarotene have also been combined safely, with

similar response rates to PUVA alone.100 Weaknesses of

these studies include the lack of a validated scoring system

to assess tumour burden, and data regarding the duration

of response and disease-free survival/OS. A recent RCT

(EORTC-21011) comparing PUVA with combined PUVA

and bexarotene showed no significant difference in response

rates or duration of response, but a trend for lower cumu-

lative UVA dose to achieve complete response in the combi-

nation arm was noted.77

6.1.3.2 Stage IIB mycosis fungoides (MF); stage III erythrodermic MF/

S�ezary syndrome (SS); stage IVA2–B MF/SS

Although there is a lack of data, combination regimens

involving PUVA have been utilized as first-line treatment for

patients with erythrodermic MF, but patients with SS toler-

ate PUVA poorly. In contrast, combination PUVA regimens

are rarely indicated as first-line therapy for tumour or nodal

disease, but are often used as an adjuvant or salvage ther-

apy for those patients with persistent cutaneous disease fol-

lowing debulking treatment for cutaneous tumours

or nodal/visceral disease, despite a lack of supportive

evidence.

6.1.4 Radiotherapy (localized radiotherapy)


MF is a highly radiosensitive malignancy, and localized radio-

therapy remains an effective treatment for patients with all

stages of disease.103–105 Palliative radiotherapy is very effec-

tive for plaques and small or large tumours, which respond

to relatively low doses of radiotherapy, such as 8 Gy in two

fractions.106 The dose-fractionation regimen should take into

account the size of the treatment area, the treatment site and

potential risk of acute and late damage to adjacent organs.

MF is a multifocal disease, and while local control with

radiotherapy is readily achievable, this is usually a palliative

approach. Therefore, it is appropriate to use the minimum

dose of radiotherapy to obtain local control. Using such a

low-dose approach also facilitates, if required, repeat treat-

ment or treatment to an adjacent area where fields may over-

lap with a previous treatment field. This is especially

important for sites with relatively poor skin tolerance to

radiotherapy, such as the lower legs. Single fractions of 7–8 Gy have been shown to be effective and convenient for

the patient, but allow less re-treatment and may not be suit-

able for areas of skin with poor tolerance.107 The use of

higher doses of radiotherapy is seldom justified. Localized

radiotherapy can be used at the same time as other SDT,

including phototherapy.

Table 8 Combination psoralen–ultraviolet A (PUVA) in mycosis fungoides/S�ezary syndrome

Therapy Design Level of evidencea Stage ORR (CR), % Number of patients

Duration

(months) 5-year RFS, %

PUVA + interferon Case studies94 2� IA–IV 89 9PUVA + interferon Case series97 2� IA–IV 68 (45) 22 20–75PUVA + interferon Prospective phase II96 2+ IB–IIA 98 (84) 89 14PUVA + interferon Case studies101 2� 100 (100) 5 74

PUVA + interferon Case studies93 2� IB–IVB 90 (100) 39PUVA + interferon Prospective phase II95 2+ IA–IVA 81 (75) 63 32 75

PUVA + bexarotene RCT EORTC-2101177 1+ IB–IIA 77 (31) 87 5�8 25PUVA + bexarotene Case series100 2� I–III 67 (29) 14 2–10PUVA + bexarotene Case series102 2� IA–IIB 100 (63) 8

ORR, overall response rate; RFS, relapse-free survival; RCT, randomized controlled trial; EORTC, European Organisation for Research and

Treatment of Cancer. aSee Appendix S1 in the Supporting Information.



For treatment of large areas of skin such as the trunk, limbs

or whole scalp, smaller doses per fraction should be considered,

for example 20 Gy in 10 fractions. Regions such as the eyelids

may also benefit from smaller doses per fraction to limit acute

and long-term toxicity; 4 Gy in two fractions may produce

symptomatic benefit in this situation

To define the radiotherapy clinical target volume (CTV) a

margin of ≥ 1 cm should be allowed around the disease pla-

que or tumour (gross tumour volume), and larger margins

may be required for some techniques. Further margins need

to be added according to the local protocol and radiotherapy

mode to determine the planning target volume and field size

required to treat the area. To ensure that the full dermis (3–5 mm thick) and a 5-mm-deep margin are being treated, the

treatment dose should be delivered to a depth of 8–10 mm

below the normal skin surface.

Rarely, MF can present as a solitary patch or plaque, and in

this setting local radiotherapy may be used with curative

intent (doses of 20–30 Gy in 2-Gy fractions).108–111

Modern radiotherapy techniques such as complex matched

electrons, intensity-modulated radiotherapy, helical Hi-ART

therapy (TomoTherapy�) and high-dose-rate brachytherapy

mould techniques are increasingly being used to treat large

areas of disease on curved surfaces of the skin such as the

scalp, trunk and limbs, and can provide excellent durable dis-

ease control for many patients.

6.1.4.2 Stage IIB mycosis fungoides

Low-dose palliative radiotherapy (e.g. 12 Gy in three fractions)

is very effective for MF tumours. Tumours involving large areas

require smaller doses per fraction, with schedules of 20–30 Gy

in 10–15 fractions. Radiotherapy field margins on the skin

should be determined as outlined above. The treatment depth

required is determined by the thickness of the tumour and its

depth of invasion, which in turn determines the radiotherapy

mode required, for example orthovoltage X-rays, electrons or

photons. The depth of invasion may need to be assessed using

ultrasound, CT or magnetic resonance imaging.

6.1.4.3 Stage III–IVA1 erythrodermic mycosis fungoides/S�ezary syndrome

Local radiotherapy may be used for patients who develop iso-

lated, symptomatic fissured lesions or tumours on a back-

ground of erythrodermic disease. It can also be useful for

treating extensive involvement of the hands and feet.

6.1.4.4 Stage IVA2–B mycosis fungoides/S�ezary syndrome

Localized, peripheral nodal disease can be treated with local

external beam radiotherapy, as per standard protocols for non-

Hodgkin lymphoma. Visceral metastases can also be treated

with external beam radiotherapy using the same dosing sched-

ules. Relatively low doses or single fractions can provide effec-

tive palliation and should be considered.112 Central nervous

system disease in MF has a very poor prognosis. Palliative

low-dose, whole-brain radiotherapy can be used in patients

who are fit for treatment with a good performance sta-

tus.113,114

6.1.5 Radiotherapy: total skin electron beam therapy

TSEB is a highly effective treatment for MF with excellent

complete response rates for all stages.115–134 EORTC consensus

guidelines for the use of TSEB in CTCL have been pub-

lished.115 Critical issues to be addressed include maintenance

of response to TSEB.


A systematic review and meta-analysis of mostly nonrandom-

ized studies has established that the rate of complete response

in patients with early-stage disease treated with TSEB is depen-

dent on the stage of disease, skin-surface dose and energy deliv-

ered, with very high complete response rates observed.116

Greater skin-surface dose (32–36 Gy) and higher energy (4–6-MeV electrons) are associated with a higher rate of complete

response and reasonable 5-year relapse-free survival

(Table 9).116–118 The conventional Stanford schedule of TSEB is

36 Gy delivered with a six dual-field technique to the whole

skin, delivering 2-Gy fractions per 2-day cycle over 9 weeks,

with local boost treatments to tumours and thick plaques, and

supplemental radiotherapy to a median dose of 20 Gy to ‘shad-

owed’ or self-shielding areas, such as the perineum, soles of

feet, scalp and inframammary folds.119 The standard U.K. mod-

ified Stanford protocol involved 30 Gy to the whole skin deliv-

ering 1�5-Gy fractions per 1-day cycle over 5 weeks.117 TSEB

delivering 30–36 Gy is associated with significant toxicity in

some patients. Fatigue has been reported in 38% of patients,

erythema and desquamation in 47–76%, alopecia in 95%,

lower-leg oedema in 26%, blisters in 19–52% and skin infec-

tion in 31–32%.117,120

A recent review has shown similar response rates and dura-

tion of response with lower doses of TSEB (10–30 Gy),121 but

a lower median response duration was reported following a

total dose of 10 Gy.122 Very low doses of TSEB (4 Gy) have

been tested, with reported inadequate responses.123 The results

of low-dose TSEB using 12 Gy have been reported from a

pooled analysis from three phase II trials. They showed an over-

all response rate (ORR) of 88%, with a median duration of clin-

ical benefit of 70�7 weeks.124 A series of low-dose TSEB (12 Gy

in eight fractions over 2 weeks) in 103 patients has shown a

similar very high ORR, with a median duration of response of

18 months in patients with stage IB MF and 10 months in

patients with stage IIB MF, with significantly less toxicity than

standard-dose TSEB.125 Studies of low-dose TSEB in combina-

tion with newer agents are currently under way.

One RCT comparing TSEB with topical mechlorethamine

showed similar rates of complete response and duration of

responses in early stages (IA–IB) of disease.126

The use of adjuvant PUVA and topical mechlorethamine after

TSEB has been reported, but the data are based on limited retro-

spective studies of small cohorts.127,128 It is not possible to rec-

ommend this as standard treatment, although PUVA can be used

as an effective early salvage therapy following TSEB. Further-

more, a recent report has shown no clinical advantage to the use

of topical mechlorethamine as adjuvant treatment after TSEB.119



TSEB should be considered as second-line treatment for

stage IB MF that has relapsed or is refractory to other SDT. It

can also be considered as first-line treatment in patients with

extensive cutaneous disease (stage T2b).

6.1.5.2 Stage IIB-IVB mycosis fungoides

Patients with tumour stage IIB MF can achieve high rates of

durable complete responses to TSEB.121 One RCT included

103 patients with MF/SS (all stages) and compared TSEB and

multiagent chemotherapy (CAVE; cyclophosphamide, doxoru-

bicin, vincristine and etoposide) with sequential topical ther-

apy including superficial radiotherapy and phototherapy. It

revealed a higher complete response rate in the TSEB–chemotherapy group (38% vs. 18%), but without a significant

difference in disease-free survival and OS.129 Nevertheless, a

combination of chemotherapy and TSEB can be invaluable for

patients with severe skin disease and late stages of disease

(stage IVA2–B). In addition, TSEB can be utilized as debulking

treatment prior to allogeneic stem cell transplantation.130

6.1.5.3 Stage III-IVA1 erythrodermic mycosis fungoides/S�ezary syndrome

A retrospective study of TSEB as monotherapy for erythroder-

mic CTCL noted a higher complete response rate and lower

rate of disease progression in patients without peripheral

blood involvement (stage III disease) and in those receiving a

more intense regimen (32–40 Gy).131 These retrospective data

suggest that TSEB can be considered as second-line, and even

first-line therapy for patients with erythrodermic MF, although

patients with erythrodermic disease can be very sensitive to

radiotherapy and have severe acute radiation reactions. A

radiotherapy test dose to a limited area of skin should be used

before treatment, and careful patient selection is advised.

A retrospective study comparing TSEB alone with TSEB

followed by ECP in erythrodermic MF/SS suggests that the

combination of TSEB and ECP is associated significantly with

improved disease-free and cause-specific survival when cor-

rected for peripheral blood and nodal involvement, but

these retrospective data may be open to selection bias.132

There may be potential for TSEB to be used alone or in

combination for both skin and blood debulking in patients

with SS, but this needs further investigation in clinical

trials.133

6.2 Systemic biological therapies

6.2.1 Interferon-alpha

Interferon-alpha is licensed in the European Union for the

treatment of MF/SS (Table 10). There have been numerous,

relatively small open nonrandomized studies of interferon-

alpha in all stages of pretreated MF/SS, with variable dose

schedules (3–9 megaunits, three to seven times weekly). ORRs

> 50% and complete response rates > 20% have been

reported. Response rates are higher in early stages of disease

and with higher doses of interferon.135–137 A small, random-

ized study comparing PEGylated interferon-alpha-2b plus

PUVA with standard interferon-alpha-2b plus PUVA showed a

higher ORR with less constitutional side-effects for patients

treated with PEGylated interferon-alpha-2b plus PUVA.94

However, the patients in the PEGylated interferon arm had a

higher rate of myelosuppression and liver toxicity than those

treated with standard interferon.


Although higher response rates have been reported for inter-

feron in patients with early-stage MF,135–137 interferon-alpha

should not be used in patients with early-stage MF who are

responsive to SDT, as these patients have a good prognosis

and there is no evidence that interferon affects long-term

outcome.

Table 9 Total skin electron beam (TSEB) therapy in mycosis fungoides/S�ezary syndrome

Therapy No. of patients Dose (Gy) Level of evidencea Stage ORR, % CR, % Median RFS/PFS (months)

High dose127 114 30–36 2+ IA 100 97 50

High dose117,119 103, 17 30–36 2+ IB 100 59–75 18–29High dose117,119 77, 19 30–36 2+ IIB 95–100 47 9

High dose117,131 3, 45 30–36 2+ III 100 33–60 6–9Low dose122,134 21 10 2+ IB–IV 95 57 VGPR 5�8Low dose124 33 12 3 IB–III 88 27 MDOCB 16–17Low dose121 33 5 to < 10 2+ IB–III 85–100 0–25 12

Low dose121 51 10 to < 20 2+ IB–III 96–100 7–52 25�7Low dose121 32 20 to < 30 2+ IB–III 83–100 29–37 29�3Low dose125 103 12 2+ IB–IV 87 18 13�2

54 IB 94 20 26�533 IIB 97 21 8�712 III 50 8 10�64 IV 25 0 –

ORR, overall response rate; CR, complete response; RFS, relapse-free survival; PFS, progression-free survival; VGPR, very good partial remis-

sion with modified Severity Weighted Assessment Tool score < 1; MDOCB, mean duration of clinical benefit (date of TSEB to date of next

whole-skin-equivalent treatment). aSee Appendix S1 in the Supporting Information.



However, for patients with early-stage MF who are refractory

to SDT, interferon and PUVA can be used in combination, and

evidence suggests that this may reduce the cumulative UV dose

required to achieve a complete response.99 One RCT comparing

PUVA and interferon with interferon plus acitretin in stage I

and II patients demonstrated that PUVA and interferon were

superior, with a 70% complete response rate compared with

38% for the drug combination.92

6.2.1.2 Stage IIB mycosis fungoides (MF); stage III–IVA1 erythrodermic

MF/S�ezary syndrome (SS); stage IVA2–B MF/SS

Most studies of interferon have involved patients with refrac-

tory, advanced-stage disease but have not distinguished

between patients with erythroderma and either tumour-stage

disease or nodal involvement. Responses are dose dependent

but complete response is rare.135,136,138 Responses have been

reported with combined interferon-alpha and acitretin in

patients with MF and SS resistant to interferon alone.139 Aviles

et al.140 reported good response rates (80%) at 1 year with

combinations of interferon (5 megaunits three times a week)

and methotrexate or interferon and trans-retinoic acid. Data on

combined interferon-alpha and bexarotene are currently lim-

ited to case series.141 Patients with erythrodermic MF treated

with immunosuppressive therapy such as ciclosporin for sus-

pected inflammatory disorders may have a more aggressive

disease course and worse outcome.142

6.2.2 Retinoids and rexinoids


Retinoic acid receptor retinoids (acitretin) have modest effects

in early stages of MF as monotherapy, but in combination

with PUVA they may reduce the cumulative UVA dose and

time to response, and improve duration of response,143,144

although the only RCT92 suggested no benefit.

Prospective studies of bexarotene, a retinoid X receptor rex-

inoid, have shown significant efficacy and good duration of

response with low rates of disease progression in early-stage

disease.145 Bexarotene has been used in combination with

PUVA;102,146 however, the EORTC-21011 RCT in low-risk MF

comparing PUVA alone with PUVA plus bexarotene showed

no difference in response rates.77



Bexarotene is licensed in the European Union for the treat-

ment of late-stage MF/SS refractory to at least one systemic

agent, and U.K. consensus guidelines for bexarotene prescrib-

ing and management have been published.147 Maximum

responses may take 6 months, and bexarotene should be con-

tinued until loss of response.

Prospective studies of bexarotene in refractory, late-stage

disease have shown encouraging ORRs and response durations

at doses of 300 mg m�2 daily,148 which have been confirmed

in subsequent case series.146,149 These results suggest that bex-

arotene has a useful role, particularly for erythrodermic dis-

ease, but monotherapy is unlikely to be effective for tumours

or nodal disease. Whether adjuvant bexarotene has a role in

maintaining remission or partial responses in those patients

with pretreated advanced disease is currently unknown.

6.2.3 Antibody therapies


At present, there is no evidence that antibody therapies should

be used for patients with early-stage disease.

Table 10 Biological therapies in mycosis fungoides/S�ezary syndrome

Therapy Design Level of evidenceb Stage ORR, % CR, % Duration

Interferon-a Case series135 2� IA–IVB 45–74 10–27 NA

Interferon-a Case series136 2� IA–IIA 88 ? NAInterferon-a Case series138 2� IIB–IVB 29–63 ? NA

Bexarotene Phase II145 2+ IA–IIA 54 0 516 daysBexarotene Phase II148 2+ IIB–IVB 45–51 0 299 days

Brentuximab vedotin Phase II160 2+ IB–IVB 73 35 32 weeks (range 3–93)Brentuximab vedotin Phase II161 2+ IB–IVB 70 3 54% of responders

progression free at 12 monthsBrentuximab vedotin RCT Phase III162 1+ 1A–IVB 56 16 16�7 months

Denileukin diftitoxa Phase II163 2 + + IB–IVA 30 10 6�9 monthsDenileukin diftitoxa RCT phase III164 1+ IA–III 44 10 > 2 years (PFS)

Alemtuzumab high dose Case series151,152 2� IIB–IV 37–100 25–47 6–9 monthsAlemtuzumab low dose Case series154,155 2� IIB–IV 85 21 TTF 12 months

Vorinostata Phase II165 2+ IB–IVA 24–29�7 0 106–185 daysRomidepsina Phase II166 2+ IB–IVA 34 6 13�7–14�9 months

Bortezomib Case series167 2� III–IV 70 10 7–14 months

ORR, overall response rate; CR, complete response; RCT, randomized controlled trial; NA, not available; PFS, progression-free survival; TTF,

time to treatment failure. aApproved by the U.S. Food and Drug Administration but not the European Medicines Agency. bSee Appendix S1

in the Supporting Information.



6.2.4 Alemtuzumab (CAMPATH-IH)


MF/S�ezary syndrome (SS); stage IIVA2–B MF/SS

Phase II trials of alemtuzumab (a humanized anti-CD52 anti-

body) in small cohorts of patients with advanced MF/SS have

shown encouraging ORRs.150–156 Reported overall response

and complete remission rates are high, but typically responses

are short lived, with only a minority of patients achieving

responses for longer than 12 months. Clinical responses are

best in SS, where symptomatic benefit may be dramatic. In

contrast, recent evidence suggests that alemtuzumab is ineffec-

tive in patients with MF with tumours and large cell transfor-

mation.157

Reports of possible cardiac toxicity158 have not been con-

firmed and the safety profile has been acceptable even in

elderly patients, although infection and specifically cytomega-

lovirus reactivation remains an issue and patients need irradi-

ated blood products.155 In the majority of studies,

alemtuzumab has been administered intravenously at the stan-

dard dose of 30 mg three times per week. However, one

study examined the use of a lower-dosage subcutaneous

schedule at 10 mg three times per week, with similar efficacy

but reduction in toxicity.154 Alemtuzumab remains an impor-

tant second-line therapeutic option for patients with advanced

disease, particularly erythrodermic stage III–IVA1 MF/SS.

6.2.5 Brentuximab vedotin

Brentuximab vedotin is an antibody–drug conjugate comprised of

an anti-CD30 monoclonal antibody attached by an enzyme-cleava-

ble linker to the antimicrotubule agent, monomethyl auristatin E,

which is released upon internalization into CD30-expressing

tumour cells. It is administered intravenously at 1�8 mg kg�1 over

30 min every 21 days, for a maximum of 16 cycles.159

Phase II trials demonstrated encouragingly high response

rates,160,161 where the proportion of CD30 tumour cell

expression appeared to correlate with tumour responses. Those

with < 5% CD30 expression had a lower likelihood of global

response than did those with CD30 expression ≥ 5%.161

Further to these phase II trials, a randomized, open-label

phase III trial (ALCANZA) was designed to evaluate single-agent

brentuximab vedotin vs. a control arm of the investigator’s

choice of standard therapies, namely methotrexate or bexaro-

tene, in patients with CD30-expressing CTCL, including those

with primary cutaneous anaplastic large cell lymphoma

(pcALCL) or MF. The primary end point was objective response

lasting at least 4 months (ORR4) as assessed by Global Response

Score. Brentuximab vedotin resulted in a statistically significant

improvement in the rate of ORR4 (56�3% vs. 12�5% in the con-

trol arm). The median PFS was 16�7 months vs. 3�5 months, a

significant difference favouring brentuximab (P < 0�001).In November 2016, the FDA granted brentuximab vedotin

Breakthrough Therapy designation for the treatment of

patients with CD30-expressing MF and pcALCL who require

systemic therapy and have received one prior systemic ther-

apy. The phase III data from this trial have also led to EMA

approval in patients with CD30+ CTCL.162 Peripheral neuropa-

thy is a frequent side-effect, occurring in over 60% of

patients, but resolution or improvement of symptoms on ces-

sation of treatment is reported.

Other biological therapies are listed in Table 10.163–167

6.3 Chemotherapy

Systemic chemotherapy (Table 11) is usually reserved for

patients with advanced disease, or disease refractory to SDT or

immunobiological therapy, and is palliative rather than cura-

tive.168–189 Although good responses are reported with both

single-agent and combination regimens, overall the results are

disappointing when compared with other lymphomas. A par-

ticular difficulty in interpreting data in this area is the variable

and largely suboptimal reporting of response assessment and

the heterogeneity of risk factors within the spectrum of the

Table 11 Chemotherapy in mycosis fungoides/S�ezary syndrome

Therapy Design Level of evidencea ORR, % CR, % Median RFS or PFS (months)

Pentostatin Case series174–177,181 2� 35–71 6–32 9Cladribine Case series178 2� 28–41 14–19 4�5Fludarabine Case series179,188 2� 30–51 11�4 5�9Liposomal doxorubicin Case series183 2� 80–88 45–66 15

Liposomal doxorubicin EORTC-21012184 2+ 40�8 6�1 6Gemcitabine Case series180–182 2� 68–75 8–22 10–15Methotrexate Case series170 2� 58 41 31Trimetrexate Case series171 2� 45 Not recorded

Pralatrexate Phase II189 2+ 45 Not recordedCombination chemotherapy Systematic review168 2+ 81 38 5–41Chlorambucil Case series169 2� 89 36 Not recordedEPOCH Phase II187 2+ 80 27 8

ORR, overall response rate; CR, complete response; RFS, relapse-free survival; PFS, progression-free survival; EORTC, European Organisation

for Research and Treatment of Cancer; EPOCH, etoposide, prednisolone, vincristine, cyclophosphamide, doxorubicin. aSee Appendix S1 in

the Supporting Information.



patients with MF and SS who are treated. In the absence of

randomized, phase III trials, comparison of response rates

across phase II studies is fraught with difficulties of interpreta-

tion, and therefore recommendations are subject to inherent

investigator and reporting bias.

6.3.1 Stage IA–IIA mycosis fungoides

Chemotherapy is contraindicated for early stages of disease, as

low-grade disease is relatively resistant to chemotherapy and

response duration is short.

6.3.2 Stage IIB mycosis fungoides (MF); stage III–IVA1erythrodermic MF/S�ezary syndrome (SS); stage IVA2–BMF/SS

Quaglino et al. found treatment heterogeneity between U.S.

and non-U.S. centres but no difference in survival.38 However,

a constant geographical feature was the finding that first-line

chemotherapy was associated with a higher risk of death.

One RCT comparing combination chemotherapy and TSEB

against conservative SDT showed a better overall response in

the combination arm but greater morbidity and no improve-

ment in OS.129 A systematic review of uncontrolled open

studies of single-agent regimens in 526 patients with CTCL treated

between 1988 and 1994 revealed OR rates of 62%, with com-

plete response rates of 33% and median response durations of

3–22 months.168 Single-agent therapies showing clinical effi-

cacy in MF/SS include alkylating agents (chlorambucil and

cyclophosphamide),169 antimetabolites (methotrexate and

trimetrexate),170,171 purine analogues (pentostatin, 2-chloro-

deoxyadenosine and fludarabine),172–179 the pyrimidine

antimetabolite gemcitabine180–182 and liposomal doxoru-

bicin.183,184 A recent U.K. prospective phase II study assessing

a combination regimen incorporating gemcitabine and bexaro-

tene in advanced MF/SS (GEMBEX) showed a low response

rate following chemotherapy at 12 weeks (31%, all with par-

tial response), reducing to a 14% ORR at 24 weeks despite

bexarotene maintenance. In addition, control of hyperlipi-

daemia was challenging with this combination.185

A systematic review of different combination chemotherapy regi-

mens in patients with MF and SS stages IIB–IVB treated between

1988 and 1994 showed an OR rate of 81% in 331 patients

and a complete response rate of 38%, with response duration

ranging from 5 to 41 months.168 The most commonly

reported regimen used in MF/SS is CHOP (cyclophosphamide,

doxorubicin, vincristine, prednisone). Prospective,

nonrandomized studies of other multiagent chemotherapy reg-

imens – VICOP-B (etoposide, idarubicin, cyclophosphamide,

vincristine, prednisolone, bleomycin) and EPOCH (etoposide,

prednisolone, vincristine, cyclophosphamide, doxorubicin) –have revealed similar OR rates and durations of response to

those for CHOP.186,187 Overall survival rates remain

unchanged for these more intensive regimens and toxicity

may be considerable; therefore, these regimens have little clin-

ical benefit over less intensive regimens.

The patient’s quality of life should always be considered

before embarking on chemotherapy regimens with limited

efficacy. Patients with CTCL are at high risk of neutropenic

sepsis, and therapy-related mortality with combination

chemotherapy is a significant risk. Single-agent regimens

appear to have similar efficacy to combination regimens but

with lower toxicity, and therefore are preferable as palliative

therapy in late stages of MF and SS. Durable responses with

either single- or multiagent regimens are rare.

The limited data suggest that methotrexate and pentostatin

are most appropriate for erythrodermic SS, while gemcitabine

and liposomal doxorubicin are more appropriate for advanced

stages of MF. Maintenance or adjuvant treatment with bioim-

munotherapy, SDT or TSEB for patients achieving a response

with chemotherapy may be considered. Patients frequently

relapse, with early stages of disease manifested by patches and

plaques, although there is no trial evidence suggesting that

any such approach improves outcomes, and further well-

designed studies are required.

While outcomes are invariably poor for patients with

advanced disease, with median survival of < 12 months (stage

IV), for those stage IVA2 patients with a good performance sta-

tus, the aim is to achieve a durable complete or good partial

remission and to proceed to a reduced-intensity allogeneic

transplant.

6.4 Extracorporeal photopheresis

6.4.1 Stage IA–IIA mycosis fungoides

Although responses to ECP have been reported in early-stage

MF, this is based mostly on a small number of patients in

poorly controlled single-centre studies, including some in

which patients were treated with adjuvant therapies

(Table 12).190–192 The only randomized study looking at

patients with early-stage MF treated with either PUVA or ECP

showed that PUVA was more effective over a 6-month treat-

ment period.193 Therefore, there is no evidence at present to

Table 12 Electrophoresis (ECP) in mycosis fungoides/S�ezary syndrome (adapted from Scarisbrick et al.)196

Therapy Design Level of evidencea Stage ORR, % CR, % OS (months)

ECP Systematic review 2+ IB–IV 63 20ECP Systematic review 2+ III 35–71 14–26 39–100ECP Multiple case series 2� III 31–86 0–33

ORR, overall response rate; CR, complete response; OS, overall survival. aSee Appendix S1 in the Supporting Information.



suggest that ECP should be used for patients with early-stage

disease.

6.4.2 Stage IIB mycosis fungoides

ECP is not effective for stage IIB MF.194,195

6.4.3 Stage III–IVA1 erythrodermic mycosis fungoides/

S�ezary syndrome

A systematic review of nonrandomized and mostly retrospective

studies of ECP in 650 patients from 30 published studies

showed an ORR of 63% and a complete response rate of

20%.196 Response rates are highest in those with erythrodermic

stage III–IVA1 MF/SS.190,197–200 Treatment is given on two

consecutive days and repeated every 4 weeks, but it may be

given more frequently (e.g. every 2 weeks) in those with a

high blood-tumour burden.194,196,201 Responses may take up

to 6 months to develop and therapy should continue until loss

of response. The U.K. consensus guidelines for ECP in CTCL

recommend ECP as first-line systemic treatment in patients with

erythrodermic CTCL with evidence of blood involvement, treat-

ing with one to two cycles per month. The guidelines were

recently updated in 2017 with the recommendation that ECP

treatment should be continued until loss of response.196,202

A recent U.K. audit report of 97 patients with CTCL treated

since 2010 found that 45% had received ECP as the first-line

systemic agent.203 The response rate at 6 months was 61%

and the median length of treatment was 9 months. There have

been numerous small case series of erythrodermic patients

treated with combinations of ECP, interferon-alpha and/or

retinoids, as well as bexarotene, which suggest that combina-

tion therapy can be highly effective, as both clinical and

molecular remissions have been documented.196,204–213

Although these studies were uncontrolled, the evidence sug-

gests that ECP can be an effective and well-tolerated therapy

for patients with erythrodermic stage III–IVA1 MF/SS and that

such patients may benefit from combination regimens com-

bining ECP with other systemic therapies. ECP is an FDA-

approved treatment for MF/SS. In contrast, there is a lack of

evidence for use of ECP in stage IVA2–B MF/SS.

6.5 Systemic therapies (Food and Drug Administration

but not European Medicines Agency approved)

6.5.1 Toxin therapies (denileukin diftitox: diphtheria

interleukin-2 fusion toxin; Ontak)

Denileukin diftitox is a fusion protein targeting the interleukin-

2 receptor (CD25). Large RCTs have shown significant efficacy

and improved PFS in all stages of disease (Table 9). Denileukin

diftitox is FDA but not EMA approved for MF/SS, but it is cur-

rently not available in the U.S.A. because of a manufacturing

change, and results of an ongoing trial are awaited. Toxicity

includes hypersensitivity reactions and vascular leak.


Toxin therapies should not be used for early-stage disease in

view of potential adverse effects, but denileukin diftitox can

be effective for early-stage patients who are resistant to SDT.


MF/S�ezary syndrome (SS); stage IVA2–B) MF/SSDenileukin diftitox (18 lg kg�1 per day for 5 days, as a 21-

day cycle) is effective in heavily pretreated patients with late

stages of disease,163,164,214 and efficacy may be improved by

combining with bexarotene.215

6.5.2 Histone deacetylase inhibitors

Histone deacetylase (HDAC) inhibitors are an emerging class of

drugs that increase acetylation of histones and nonhistone pro-

teins affecting gene transcription, which results in cell-cycle

arrest and apoptosis. Several phase II studies have established

that HDAC inhibitors have clinical efficacy in all stages of MF/

SS, with an acceptable safety profile.165,166,216,217 These studies

led to FDA approval for vorinostat (suberoylanilide hydroxamic

acid) and romidepsin for the treatment of refractory MF/SS.

Neither HDAC inhibitor is licensed for use in Europe.


HDAC inhibitors should not be used for early-stage MF but

can be effective for patients resistant or refractory to SDT.



Phase II studies of vorinostat and romidepsin have shown sim-

ilar ORRs in advanced disease including stage III

patients.165,166,216,217 Evaluation of patients on vorinostat for

over 2 years provides evidence of long-term safety and tolera-

bility.218 One study also showed a significant improvement in

pruritus in 43% of patients, including those who had no

objective clinical response.166

6.5.3 Other systemic chemotherapies

Pralatrexate belongs to a class of folate analogues, known as

the 10-deazaaminopterins, and is emerging as a promising

new agent in the treatment of T-cell lymphomas, including

CTCL. Phase II trials have demonstrated good response rates,

although adverse effects, including mucositis, are a con-

cern.219 A further study, using a lower dose of pralatrexate,

reported better tolerance but similar response rates.189

6.6 Systemic therapies (not Food and Drug

Administration or European Medicines Agency approved)

Bortezomib, a proteasome inhibitor, has shown clinical efficacy

in a small series of patients with advanced stages of CTCL,167

but its clinical role remains to be established. Temozolomide

has also been reported to be effective in a minority of patients



in a small multicentre study of patients with advanced MF/

SS220 and those with central nervous system progression.114

6.7 Autologous or allogeneic peripheral blood or bone

marrow stem cell transplant

Autologous haemopoietic stem cell transplant (HSCT) appears

to be associated with only short-term remission and is there-

fore difficult to justify.221–223 In contrast, allogeneic HSCT is a

complex form of immunotherapy aimed at consolidating treat-

ment of advanced MF/SS to produce a durable complete

remission.224 A retrospective study from the European Group

for Blood and Marrow Transplant (EBMT) included a hetero-

geneous group of patients who received both myeloablative

and reduced-intensity conditioning (RIC) regimens. The study

showed an estimated 3-year survival rate of 54%.225 However,

the treatment-related mortality of 25% at 1 year for CTCL was

a concern. The EBMT data suggested that alemtuzumab should

not be used as part of the pretransplant conditioning regimen

because of a higher rate of early relapse and increased treat-

ment-related mortality.225

A number of other case reports and small retrospective

series have also described clinical responses and durable

remissions of more than 3 years following myeloablative

allo-HSCT226–229 and reduced-intensity conditioning allo-

HSCT.229–234 A single-centre report described outcomes in 19

recipients of allo-HSCT using an RIC regimen that included

TSEB irradiation prior to transplant. Eleven patients achieved

sustained complete remissions, some of which were following

donor lymphocyte infusion, immunosuppression withdrawal

and/or chemotherapy.130 An update of this study utilizing

pretransplant TSEB in the majority of patients showed that

60% achieved complete skin remission as a result.235

A more recent analysis of the EBMT cohort (60 patients

with MF/SS) in 2014 reported an OS of 46% and PFS of 32%

at 5 years.236 Relapse or progression occurred in 45% at a

median of 3�8 months following HSCT, but many patients

were rescued with donor lymphocyte infusions. Nonrelapse

mortality was 22%, with the last nonrelapse death occurring

14 months following HSCT. Multivariate analysis confirmed

worse outcomes for myeloablative conditioning regimens and

transplants from unrelated donors.236 A meta-analysis of allo-

geneic or autologous SCT in MF and SS supports the view that

allogeneic transplantation provides a better survival and dis-

ease-free outcome than autologous transplantation.237

There is increasing enthusiasm for RIC allograft approaches

for a number of reasons. CTCL affects older patients, many of

whom have chronically infected skin tumours, and the risk of

life-threatening sepsis is lower with reduced-intensity allo-

grafts. Allogeneic transplant is successful in part because of

the graft-versus-lymphoma effect of the donor graft, indepen-

dent of the conditioning regimen, but this has to be balanced

against the morbidity associated with chronic graft-versus-host

disease.225 In addition, and relevant to the above, a major risk

following allogeneic transplant is disease relapse. Clearly,

some patients can be salvaged with donor lymphocyte

infusion, but this in turn may lead to significant graft-versus-

host disease.

Maximal benefit from RIC-HSCT is observed when it is per-

formed before patients develop highly refractory disease and

when there is low disease bulk at the time of transplanta-

tion.225 Appropriate data registration is required to identify

the optimal conditioning regimen for allo-HSCT and to define

clinical outcomes. Considering the numerous biological agents

that are becoming available and the potential efficacy of allo-

HSCT, younger patients with stage IIB–IV disease and poor

prognostic factors or aggressive disease should be reviewed at

supranetwork MDTs and, if appropriate, referred early to a

specialist transplant centre.

6.8 Future perspectives

FDA-approved therapies include topical bexarotene gel,

mechlorethamine gel, oral bexarotene, denileukin diftitox,

photopheresis and the HDAC inhibitors vorinostat and romi-

depsin.

In contrast, only topical mechlorethamine ointment for all

stages of MF, and interferon-alpha, brentuximab and oral bex-

arotene for late-stage refractory MF/SS, are EMA approved.

Currently, there is an unmet need for improved treatments in

CTCL and an urgent need for well-designed RCTs with appro-

priate clinical end points.

Until recently, denileukin diftitox was not available world-

wide because of manufacturing problems, although new clini-

cal trials have commenced.

Recommendations

• The diagnosis of MF and SS is based on a combination

of clinical and pathological criteria and requires close

MDT collaboration between different specialities.

(Strength of recommendation D (GPP))

• All patients with early-stage MF refractory to SDT and

late-stage MF/SS should be reviewed by supranetwork

MDTs to agree a management plan and provide the

opportunity for consideration in appropriate clinical

trials. (Strength of recommendation D (GPP))

• The aim of treatment is to control the patient’s disease

and symptoms with the minimum of intervention.

Management may range from an expectant policy

through to nonmyeloablative allogeneic stem cell trans-

plantation. (Strength of recommendation D (GPP))

• SDTs, including phototherapy and local radiotherapy,

are the standard of care for patients with early-stage

IA–IIA MF. (Strength of recommendation C)

• Patients with stage IA–IIA MF who are refractory to

SDT often require TSEB and systemic biological thera-

pies. There is no evidence to support the use of main-

tenance phototherapy. (Strength of recommendation C)

• Patients with stage IIB MF can have an unpredictable

clinical course: some patients develop only small and

infrequent skin tumours and often obtain durable



responses to localized radiotherapy and other SDT

options for persistent patches and plaques; other

patients develop extensive bulky skin tumours and

rapidly progressive disease requiring TSEB and systemic

chemotherapy. (Strength of recommendation C)

• Following treatment, patients with advanced MF may

develop recurrent, low-grade disease where SDT is a

treatment option. (Strength of recommendation D (GPP))

• Patients with erythrodermic MF (stage III) and SS

(stage IVA1) often require single or combination sys-

temic therapies such as methotrexate, photopheresis,

bexarotene and interferon-alpha as first-line treatment.

(Strength of recommendation C)

• Options for SS (stage IVA1–2) also include clinical tri-

als and alemtuzumab. (Strength of recommendation C)

• For stage IVA2–B MF/SS, radiotherapy (including TSEB

for selected stage IV patients) and single-agent

chemotherapy regimens are the preferred option, but

response duration is often short. (Strength of recommenda-

tion C)

• Brentuximab offers an effective option for refractory

stage IB disease and advanced stages of MF/SS with

tumour CD30 expression. (Strength of recommendation B)

• All patients with early-stage MF refractory to SDT and

stage IIB–IV MF/SS should be offered the opportunity

to participate in well-designed clinical trials. (Strength of

recommendation D (GPP))

• Autologous HSCT should not be considered for

advanced stages of MF/SS. (Strength of recommendation A)

• Reduced-intensity allogeneic HSCT should be considered

for selected groups of patients with advanced MF/SS to

consolidate treatment responses. (Strength of recommendation B)

• The conditioning regimens and outcomes of RIC allo-

HSCT should be collected through data registries such

as the EBMT registry. (Strength of recommendation D (GPP))

7.0 Treatment of non-mycosis fungoides/S�ezary syndrome primary cutaneous T-celllymphomas

7.1 Primary cutaneous CD30+ lymphoproliferative

disorders

Primary cutaneous CD30+ lymphoproliferative disorders rep-

resent a spectrum of disorders, and the diagnosis is depen-

dent on careful assessment of both clinical and pathological

features. Specifically, MF must be excluded by a clinical

evaluation that fails to identify pre-existing or coexistent

polymorphic patches and plaques in a characteristic limb-

girdle distribution. There is only one RCT involving this

condition, and the evidence is based on the EORTC, ISCL

and United States Cutaneous Lymphoma Consortium consen-

sus statement,15 which is the appropriate source for refer-

ences supporting all the treatment recommendations below.

7.1.1 Primary cutaneous CD30+ anaplastic large cell

lymphoma

pcALCL is characterized by solitary tumours, grouped tumours

or thick plaques of disease. Rarely, patients present with gener-

alized multifocal lesions. Partial regression may occur but it is

rarely complete, and this clinical feature helps to distinguish

pcALCL from LyP. The tumour phenotype is CD30+ ALK�, andthis CTCL variant is biologically distinct from its nodal counter-

part. The prognosis is excellent, with 5-year survival rates of

96%.31 Staging is based on the non-MF/SS staging recommen-

dations,24 and CT scans and bone marrow trephine biopsies are

required to confirm that the skin disease is not a manifestation

of a systemic lymphoma. Primary cutaneous CD30+ ALK+ ALCL

has been rarely described but there is no evidence that such

patients have a worse prognosis.

7.1.1.1 Surgery

Surgical excision can be an effective treatment for solitary

tumours. If the lesion has been completely excised with clear

histological margins, it may be appropriate to manage the

patient with adjuvant radiotherapy or active surveillance.

7.1.1.2 Radiotherapy

Radiotherapy is an effective treatment modality for pcALCL,

with very high complete remission rates reported. Cutaneous

recurrences have been reported in 41–64% of patients.15

International consensus recommends a dose of 24–30 Gy.238

7.1.1.3 Chemotherapy

Doxorubicin-based, multiagent chemotherapy regimens are

effective with high complete response rates, but response

duration is limited with relapses in > 60% of patients.15 Vin-

blastine has been effective as a single agent in pcALCL.239

There are only limited reports of single-agent chemotherapy

agents such as methotrexate, etoposide and gemcitabine.

7.1.1.4 Antibodies

The fusion toxin brentuximab vedotin (SGN-35) in a large

phase III RCT in pcALCL has shown significant benefit in

terms of durable response and improved PFS compared with

methotrexate or bexarotene.162

7.1.2 Lymphomatoid papulosis

LyP is characterized by recurrent, papulonodular eruptions that

resolve spontaneously to leave varioliform scars. The pathology

shows variable proportions of CD30+ large cells (type A–D).

7.1.2.1 Expectant policy

For patients with limited disease and infrequent eruptions, an

active monitoring policy is acceptable.

7.1.2.2 Phototherapy

Phototherapy is effective in LyP but there is a lack of data on

dosage, and relapse is common when treatment is withdrawn.



7.1.2.3 Chemotherapy

Weekly low-dose oral methotrexate is highly effective in LyP,

but only a minority of patients experience a durable remission

following treatment withdrawal.15

7.1.2.4 Radiotherapy

Radiotherapy can be very effective especially for patients with

regional LyP, and responses can be durable.15

7.1.2.5 Immunobiological therapy

There are very limited data on retinoids, interferon-alpha and

bexarotene, but responses have been reported with all of these

agents in LyP. Brentuximab is effective.160

7.2 Rare cutaneous T-cell lymphoma variants

There are various rare and aggressive CTCL variants including

cd CTCL and PTCL (not otherwise specified, NOS), which can

primarily involve cutaneous tissues. The diagnosis in such

cases requires careful evaluation of the clinical features, stag-

ing investigations and pathology. Human T-lymphotropic

virus-1 virology should be considered to exclude a cutaneous

presentation of adult T-cell leukaemias/lymphoma; there are

no controlled trial data. Treatment options are the same as

those recommended in the British Committee for Standards in

Haematology 2013 guidelines.240

Rare CTCL variants such as subcutaneous panniculitis-like T-

cell lymphoma (SPTCL), CD4+ small/medium T-cell lympho-

proliferative disorder, acral CD8+ T-cell lymphoma and

aggressive epidermotropic cytotoxic CD8+ CTCL are character-

ized by distinct clinical and/or pathological features and, with

the exception of the latter, have an excellent prognosis.

7.2.1 Subcutaneous panniculitis-like T-cell lymphoma

SPTCL is a rare CTCL variant characterized by subcutaneous

plaques and tumours and cytologically atypical CD8+ T cells

rimming fat lobules.241 Localized disease may respond to

radiotherapy. Patients may be steroid responsive but are

likely to relapse, although immunosuppressive drug therapy

has been more effective than chemotherapy for some

patients.242 Patients with haemophagocytic syndrome and

steroid-resistant disease respond to doxorubicin-based

chemotherapy regimens (CHOP), with durable remissions

reported.241 Durable responses have also been reported fol-

lowing high-dose chemotherapy and stem cell transplanta-

tion.243 Ciclosporin may be effective in patients failing

cytotoxic chemotherapy.244

7.2.2 CD4+ small/medium pleomorphic T-cell

lymphoproliferative disorder and primary cutaneous CD8+

acral T-cell lymphoma

Primary cutaneous small/medium CD4+ lymphoproliferative

disorder has an excellent prognosis, although it can be

difficult to distinguish from reactive lymphoid proliferations.

Surgical excision and local radiotherapy are acceptable treat-

ment options.245 Rare CD8+ acral CTCL variants also have an

excellent prognosis and can also be treated with surgical exci-

sion or radiotherapy.246 However, the disease may follow a

more aggressive path in patients who present with large

rapidly progressive tumours or multifocal disease; this requires

treatment as for PTCLs.247

7.2.3 CD8+ aggressive epidermotropic cytotoxic cutaneous

T-cell lymphoma and primary cutaneous cd T-cell

lymphoma

These rare CTCL variants are diagnosed on the basis of typical

clinicopathological features with usually widespread ulcerated

plaques. Systemic dissemination (central nervous system) is

common. Multiagent chemotherapy options such as CHOP-like

regimens are appropriate, and TSEB can be an effective pallia-

tive approach. Transplant options should be considered for eli-

gible patients.

Recommendations

• Primary cutaneous CD30+ lymphoproliferative disor-

ders are diagnosed on the basis of careful clinicopatho-

logical correlation. Staging investigations are not

appropriate for LyP but are essential for ALCL or bor-

derline cases. (Strength of recommendation D (GPP))

• Treatment for LyP ranges from an expectant policy for

patients with limited disease to phototherapy, radio-

therapy, low-dose methotrexate or interferon-alpha for

patients with extensive disease. (Strength of recommendation

C)

• Treatment for CD30+ pcALCL consists of surgical exci-

sion and/or radiotherapy for localized disease. (Strength

of recommendation B)

• Combination chemotherapy or brentuximab may be

appropriate for patients with CD30+ pcALCL with

extensive cutaneous disease or those with systemic pro-

gression. (Strength of recommendation B)

• Treatment of rare CTCL variants depends on the sub-

type, as some (SPTCL, CD4+ small/medium pleomor-

phic, CD8+ acral T-cell lymphoma) are indolent with

an excellent prognosis, while others are aggressive and

may require chemotherapy and consideration for stem

cell transplant in line with recommendations for sys-

temic PTCL (NOS). (Strength of recommendation C)

• Primary cutaneous PTCLs (NOS) are rare and heteroge-

neous in behaviour. Some present with limited skin

disease that can be managed with skin-directed options

such as radiotherapy, while others present with exten-

sive or bulky skin disease and will require treatment

options as for systemic PTCL (NOS). (Strength of recom-

mendation C)



8.0 Treatment of primary cutaneous B-celllymphomas

For the purpose of this guideline, separate recommendations

have been made for low-grade lymphomas (PCMZL and

PCFCL), high-grade PCLBCL and the rare PCLBCL (NOS).

PCMZL and PCFCL have an excellent prognosis, and although

cutaneous relapses are frequent, systemic spread is rare.

PCLBCLs are aggressive lymphomas with considerable mortal-

ity and require systemic chemotherapy in most instances.

There are no RCTs but there are published EORTC consensus

guidelines.11

8.1 Primary cutaneous marginal zone and follicle centre

lymphoma

8.1.1 Excision

Complete surgical excision may be considered for small

lesions for both diagnosis and therapy, but there is no litera-

ture to guide margins of resection. In patients with PCMZL

and PCFCL treated with complete excision, over 40% are

reported to relapse.11 Where the lesion has been excised com-

pletely, a policy of monitoring or radiotherapy to the scar

with a 1�5-cm margin to CTV around the scar238 can be con-

sidered to reduce the risk of local recurrence. In larger lesions

where complete excision would result in a significant cosmetic

scar or functional defect, a diagnostic biopsy should be per-

formed and followed by radiotherapy.

8.1.2 Antibiotics

In patients with PCMZL and positive B. burgdorferi serology

there are reports of complete response following antibiotic

treatment.11 The U.K. Health Protection Agency guidance on

treatment for Borrelia with oral antibiotics should be followed

before considering other therapies.

8.1.3 Radiotherapy

Radiotherapy is the standard treatment for both PCMZL and

PCFCL. The EORTC consensus recommendations11 reported data

on 132 patients with PCMZL and 460 with PCFCL treated with

radiotherapy. Of the patients with PCMZL, 99% achieved com-

plete remission and only 46% of patients showed one or more

relapses. Extracutaneous progression was reported in only three

of 132 patients, one of whom died of lymphoma. The radio-

therapy doses reported varied from 10 Gy to 50 Gy, and most

studies used a treatment margin around the tumour of 1–5 cm.

Of the patients with PCFCL, almost all achieved complete

response with radiotherapy. Three major studies in PCFCL

combining 147 patients reported a relapse rate of 30% when

margins > 2 cm were used.248–250 This differs from the

relapse rate of 67% in a small study that used margins of 0�5–1 cm, where frequent in-field and marginal recurrences were

reported.251 On the basis of this evidence, it is recommended

that the radiotherapy CTV should be the tumour plus a 1�5-cm margin of normal skin around the tumour.238

In the U.K., the standard radiotherapy dose for indolent

non-Hodgkin lymphoma is 24 Gy in 12 fractions, based on

the results of a multicentre, prospective RCT comparing 40 Gy

vs. 24 Gy in 2-Gy fractions for indolent follicular and mar-

ginal zone lymphoma.252 Lower doses or shorter fractionation

schedules (e.g. 8 Gy in two fractions for multiple lesions;

15 Gy in five fractions for solitary lesions) have been used in

many centres with good results.253 The Leiden group have

reported complete response rates of 72% and re-treatment

rates of 29% with 4 Gy in two fractions, and complete

response achieved in all patients retreated with 20 Gy in eight

fractions.106 A U.K. RCT has shown that 4 Gy in two fractions

can be effective in the palliative setting, with an ORR of

74�1% (complete response rate 44�3%). However, this was

significantly inferior to 24 Gy in 12 fractions, with an ORR of

81% and complete response rate of 60�3%.254 The OS rate

was the same with both fractionations but there were fewer

patients with PCMZL or PCFCL in this study.

8.1.4 Intralesional interferon

There are limited data on the use of interferon-alpha. Vandersee et al.

reported a 67% response rate in 15 patients, with 90% of responders

relapsing. The median time to relapse was 15�5 months.255

8.1.5 Rituximab

The limited data on rituximab are based on case reports and

small case series. Treatment is either as systemic therapy

375 mg m�2 intravenously weekly for 4–8 weeks, or as

intralesional therapy 5–30 mg one to three times per week.

For intralesional therapy, the complete response rates for both

PCMZL and PCFCL are reported to be 70–90%, with relapse

rates of 40–60%.256 Systemic therapy is preferred for more

widespread disease. For systemic therapy, the complete

response rates for PCMZL and PCFCL are similar, ranging from

67% to 87�5%, but again the relapse rates are relatively high,

with a median time to relapse of 25 months.257,258

8.1.6 Chemotherapy

There are relatively little data published on the results of

chemotherapy for PCMZL and PCFCL. For PCMZL, chlorambu-

cil for multifocal skin lesions is associated with a complete

response rate of 64% and relapse rate of 33%, based on

reports of 14 patients. CHOP is associated with a complete

response rate of 85% and relapse rate of 57%.11

For PCFCL, cumulative data on 104 patients from eight

studies treated with CHOP or CHOP-like regimens for wide-

spread skin lesions or high skin tumour burden give a com-

plete response rate of 85% with a relapse rate of 48%.11 Only

five patients received chemotherapy without an anthracycline

(COP or CVP; see section 6�3�2). There is a lack of data on

the efficacy of rituximab–CVP and rituximab–bendamustine,



which are the most commonly used regimens in nodal or sys-

temic indolent lymphomas, in disease confined to the skin.

As for systemic indolent lymphomas, it is appropriate to

manage patients with disease confined to the skin with watch-

ful waiting. Current evidence supports a role for single-agent

chemotherapy or rituximab for those patients with extensive

cutaneous disease and no systemic involvement. Patients with

systemic disease or high disease burden failing to respond to

single-agent systemic therapy should be managed according to

local guidelines for the management of systemic disease.

Recommendations

• Solitary lesions should be treated with the intention of

cure. (Strength of recommendation B)

• Small individual skin lesions can be completely excised

and monitored, but treatment with radiotherapy (tu-

mour or scar with a 2-cm margin of skin to define

CTV) is preferred to reduce the risk of local relapse.

(Strength of recommendation B)

• Following a diagnostic biopsy, the first-line treatment

for individual skin lesions should be radiotherapy. The

radiotherapy CTV should be the tumour plus a 1�5-cmmargin of normal skin around the tumour. (Strength of

recommendation B)

• Active monitoring is an option for patients with

asymptomatic disease. (Strength of recommendation D (GPP))

• Systemic chemotherapy should be reserved for

patients with widespread extensive lesions or high

tumour burden (stage T2c–T3), or patients with

nodal or visceral progression. Treatment is palliative,

and for disease confined to the skin consideration

should be given to single-agent rituximab, or chlo-

rambucil, as this is well tolerated and effective. Fur-

ther choice of chemotherapy should be in line with

local guidelines for the management of indolent lym-

phomas. (Strength of recommendation C)

• Patients who relapse with nodal or visceral lymphoma

should be treated according to local and national man-

agement guidelines for systemic lymphoma. (Strength of

recommendation B)

8.2 Primary cutaneous diffuse large B-cell lymphoma

8.2.1 Primary cutaneous diffuse large B-cell lymphoma leg

type

The number of reported cases of PCLBCL is small. The

response rate to radiotherapy alone is high, but relapse rates

are ≥ 58% with a significant risk of extracutaneous

recurrences.11 Data on CHOP-like chemotherapy, R-CHOP

and R-CHOP plus local radiotherapy are limited to small

numbers of patients and short follow-up periods. In a

review of 32 patients from eight separate studies treated

with CHOP-like chemotherapy, 81% achieved complete

response but 56% relapsed.11 Rituximab as a single treat-

ment has an ORR of 75% in eight reported cases but all

patients relapsed, with a median disease-free survival of

5�25 months.259 Current international consensus and guideli-

nes recommend that PCLBCL leg type should be treated like

a systemic diffuse large B-cell lymphoma (DLBCL), with

three to six cycles of R-CHOP and local radiotherapy of

30–36 Gy.6

8.2.2 Primary cutaneous diffuse large B-cell lymphoma

(not otherwise specified)

PCLBCL (NOS) includes rare morphological variants of DLBCL

such as anaplastic lymphoma, plasmablastic lymphoma, T-

cell/histiocyte rich large B-cell lymphoma and intravascular

large B-cell lymphoma, which may rarely present primarily in

the skin.3 These variants should be treated with systemic lym-

phoma chemotherapy protocols.

Recommendations

• PCLBCL leg type should be treated with R-CHOP

chemotherapy followed by local radiotherapy as per

local guidelines for systemic DLBCL. Current protocols

recommend three to six cycles of R-CHOP chemother-

apy followed by 30–36 Gy in 2-Gy fractions of local

radiotherapy. (Strength of recommendation B)

• Palliative radiotherapy alone can be considered for

patients unfit for chemotherapy. (Strength of recommenda-

tion D)

• PCLBCL (NOS) should be treated as per local guidelines

for systemic DLBCL. (Strength of recommendation B)

Future research recommendation

• Future trials should concentrate on improving clinical

outcomes for patients with PCLBCL. (Strength of recommen-

dation D (GPP))

9.0 Economic and practical considerations

• Primary cutaneous lymphomas are rare and consequently

the economic costs of treatment are modest, especially for

early stages of CTCL and primary cutaneous B-cell lym-

phomas. In contrast, advanced cutaneous T-cell lym-

phomas require complex and expensive interventions,

often with only palliative intent.

• There has been a growing difference between the U.S.A.

and European Union for approval of novel drugs. How-

ever, the emergence of several pharmaceutically sponsored

phase III RCTs in the last few years suggests that this issue

is likely to be resolved, allowing U.K. patients to have

access to these new treatments.



Fig 1. Treatment guidelines for mycosis fungoides. EBRT, external beam radiotherapy with photons or electrons for lymph node, soft tissue or

visceral lymphoma; ECP, extracorporeal photopheresis; IFN, interferon; MTX, methotrexate; PD, progressive disease; RIC-allo-SCT, reduced-

intensity allogeneic stem cell transplantation; SDT, skin-directed therapy (topical steroids, ultraviolet B, psoralen–ultraviolet A, skin radiotherapy,

topical nitrogen mustard); TSEB, total skin electron beam radiotherapy. Skin radiotherapy indicates superficial radiotherapy or EBRT to skin

patches, plaques and tumours. #Supranetwork: refers to the supranetwork multidisciplinary team (MDT) meeting for treatment decision. *PD and

exhausted first- and second-line options. **Chemotherapy as recommended by the supranetwork MDT. ***Consider only if the patient has

durable complete response. ↔ indicates that after treatment, patients may respond to treatments included in earlier ‘line’ options. Patients can

move between first- and second-line options.



• Because of disease rarity, few large RCTs have been con-

cluded. This situation is now improving as both the FDA

and EMA have adopted the same approach for orphan drug

indications, but for some interventions such as stem cell

transplantation the evidence base will develop only

through consistent use of data registries.

10.0 Future directions

• Low-risk, early-stage IA–IIA MF: future trials should

address the need to improve duration of response without

increasing toxicity following PUVA and TSEB.

• Early-stage IA–IIA MF refractory to SDT: future trials

should address the need to improve specific clinical end

points such as time to relapse or progression, PFS and OS.

• High-risk advanced-stage IIB–IV MF/SS: future trials are

required to address an urgent need to improve PFS and OS.

• The conditioning regimens and outcomes of RIC allo-

HSCT for selected groups of patients with advanced disease

should be collected through data registries such as the

EBMT registry, and large cohort studies should be pub-

lished with adequate follow-up.

• There is an urgent need for the identification of novel tar-

gets in CTCL based on improved understanding of disease

pathogenesis.

11.0 Recommended audit points

In the last 20 consecutive patients seen with primary cuta-

neous T-cell lymphoma:

1 Was the WHO 2016 classification used in recording the

following?

a Cutaneous lymphoma subtype.

b Tumour phenotype.

c Folliculotropism in MF.

d Large cell transformation in MF.

2 Were patients staged appropriately?

3 Is there a record of performance status?

4 Is there a record of S�ezary cell count, CD4 : CD8 ratio or

abnormal T-cell phenotype on flow cytometry at diagno-

sis and clinical evolution?

5 Is there an annual log of a cumulative treatment

summary?

Fig 2. Treatment guidelines for S�ezary syndrome. Palliative skin-directed therapy can be used for symptom control if required. Chemotherapy is as directed

by the supranetwork multidisciplinary team (MDT). EBRT, external beam radiotherapy; ECP, extracorporeal photopheresis; IFN, interferon; MTX,

methotrexate; PD, progressive disease; RIC-allo-SCT, reduced-intensity allogeneic stem cell transplantation; WCC, white cell count, 9 109. #Supranetwork: refer

to the supranetwork MDT meeting for treatment decision. †PD and exhausted first- and second-line options. ††May be used in combination.



The audit recommendation of 20 cases per department is to

reduce variation in the results due to a single patient, and to

allow benchmarking between different units. However,

departments unable to achieve this recommendation may

choose to audit all cases seen in the preceding 12 months.

12.0 Summary

Figures 1–4 show treatment guidelines for MF, SS, other

CTCLs and CBCL, respectively. See the manuscript for details

of the evidence.

13.0 Stakeholder involvement and peer review

The GDG consisted of consultant clinical dermatologists, haema-

tologists and oncologists. The draft document was circulated to

the BAD membership and the British Society for Haematology,

Royal College of Pathologists, British Dermatological Nursing

Group, Primary Care Dermatological Society, Royal College of

Radiologists, British Lymphoma Pathology Group, British Soci-

ety for Dermatopathology, U.K. Lymphoma Association and

Guy’s & St Thomas’ NHS Foundation Trust Skin Lymphoma Dis-

cussion Group for comments, and was peer reviewed by the

Fig 3. Treatment guidelines for other cutaneous T-cell lymphoma (CTCL). LyP, lymphomatoid papulosis; NK, natural killer; NOS, not otherwise

specified; pc, primary cutaneous; SDT, skin-directed therapy (topical steroids, ultraviolet B, psoralen–ultraviolet A, skin radiotherapy).



Clinical Standards Unit of the BAD (made up of the Therapy &

Guidelines Subcommittee) prior to publication.

14.0 Limitations of the guidelines

This document has been prepared on behalf of the BAD and is

based on the best data available when the document was pre-

pared. Please check the BAD website for any updates (http://

www.bad.org.uk/healthcare-professionals/clinical-standards/

clinical-guidelines).260 It is recognized that under certain con-

ditions it may be necessary to deviate from the guidelines

and that the results of future studies may require some of

the recommendations herein to be changed. Failure to

adhere to these guidelines should not necessarily be consid-

ered negligent, nor should adherence to these recommenda-

tions constitute a defence against a claim of negligence.

Limiting the review to English-language references was a

pragmatic decision but the authors recognize this may

exclude some important information published in other

languages.

15.0 Plans for guideline revision

The proposed revision date for this set of recommendations is

scheduled for 2023; where necessary, important interim

changes will be updated on the BAD website: http://

www.bad.org.uk/healthcare-professionals/clinical-standards/

clinical-guidelines.

16.0 Mogamulizumab update

On 20 September 2018, the Committee for Medicinal Prod-

ucts for Human Use (CHMP) adopted a positive opinion, rec-

ommending the granting of a marketing authorisation for the

medicinal product Poteligeo, intended for the treatment of

mycosis fungoides (MF) or S�ezary syndrome (SS) having

received at least one prior systemic therapy. The active sub-

stance of Poteligeo is mogamulizumab, a monoclonal antibody

(ATC code: L01XC25) that selectively binds to CC chemokine

receptor-4 (CCR4) expressed on the surface of some cancer

cells including T-cells of T-cell malignancies, such as MF and

Fig 4. Treatment guidelines for cutaneous B-cell lymphoma. PCFCL, primary cutaneous follicle centre lymphoma; PCLBCL, primary cutaneous

diffuse large B-cell lymphoma; PCMZL, primary cutaneous marginal zone lymphoma; R-bendamustine, rituximab with bendamustine; RCVP,

rituximab, cyclophosphamide, vincristine and prednisolone; R-CHOP, rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone.§Treatment is palliative; further therapy should be in line with local guidelines for the management of indolent lymphomas. §§In line with local

guidelines for systemic diffuse large B-cell lymphoma.



http://www.bad.org.uk/healthcare-professionals/clinical-standards/clinical-guidelines






SS, resulting in depletion of the target cells. The benefits with

Poteligeo are its ability to improve progression-free survival in

patients. The approval by FDA and EMA is supported by the

MAVORIC (Mogamulizumab anti-CCR4 Antibody Versus Com-

paratOR In CTCL) study, a Phase 3 open-label, multi-center,

randomized study of mogamulizumab versus vorinostat in

patients with MF and SS who have failed at least one prior sys-

temic treatment.261 The results showed that mogamulizumab

demonstrated significantly superior PFS at a median of

7�6 months [95% CI: 5�6, 10�2] compared to 3�1 months

with vorinostat [95% CI: 2�8, 4�0], [hazard ratio 0�53: 95%CI: 0�41, 0�69; P < 0�001]. The confirmed overall response

rate for mogamulizumab and vorinostat was 28% and 5%,

respectively (P < 0�001). These findings suggest that Moga-

mulizumab will have a key role in the treatment algorithm for

intermediate/advanced stages of MF/SS who are refractory to

at least one systemic treatment.

Acknowledgments

We are very grateful to Dr Jennie Wimperis (British Society

for Haematology) for her input and our U.K. CLG colleagues

Eve Gallop Evans, Eleanor James and Richard Cowan, as well

as everyone including the patient organizations who com-

mented on the draft during the consultation period.

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Supporting Information

Additional Supporting Information may be found in the online

version of this article at the publisher’s website:

Appendix S1 Levels of evidence and strength of recom-

mendation.

Appendix S2 Search strategy.

Appendix S3 List of abbreviations.

Table S1 Staging system for mycosis fungoides/S�ezary syn-

drome.

Table S2 Staging for mycosis fungoides/S�ezary syndrome

adapted from Olsen et al.23

Table S3 The International Society for Cutaneous Lym-

phomas–European Organisation for Research and Treatment of

Cancer staging system for non-mycosis fungoides/non-S�ezary

syndrome primary cutaneous lymphomas.24

Table S4 Modified Severity Weighted Assessment Tool

(mSWAT) in mycosis fungoides/S�ezary syndrome.

Table S5 Skin and global response in mycosis fungoides/

S�ezary syndrome.



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