British Association of Dermatologists and U.K. Cutaneous Lymphoma Group Guidelines for the Management of Primary Cutaneous Lymphomas 2018

D. Gilson; S.J. Whittaker; F.J. Child; J.J. Scarisbrick; T.M. Illidge; E.J. Parry; M.F. Mohd Mustapa; L.S.Exton; E. Kanfer; K. Rezvani; C.E. Dearden; S.L. Morris

Disclosures

The British Journal of Dermatology. 2019;180(3):496-526.

Purpose and Scope

The overall objective of the guideline is to provide up-to-date, evidence-based recommendations on the management of primary cutaneous lymphoma in the U.K. The document aims to: (i) offer an appraisal of all relevant literature up to February 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 highlighted recommendations for practical use in the clinic (see section 12). A patient information leaflet on mycosis fungoides is available on the British Association of Dermatologists (BAD) website: www.bad.org.uk/for-the-public/patient-information-leaflets. Further information can also be found at www.lymphomas.org.uk/about-lymphoma.

Exclusions

These guidelines do not cover patients presenting with or found to have skin involvement as part of a systemic lymphoma.

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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 type
Cutaneous 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-cell lymphoproliferative disorderb ∘ Primary cutaneous acral CD8⁺ T-cell lymphomab ∘ Hydroa vacciniforme-like lymphoproliferative disorderb • Aggressive clinical behaviour ∘ Sézary syndrome ∘ Extranodal natural killer/T-cell lymphoma, nasal type ∘ Primary cutaneous aggressive epidermotropic cytotoxic CD8⁺ T-cell lymphoma ∘ Primary cutaneous γ/δ 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 version. ^bChanges from the 2008 version.

Table 2. Prognosis in mycosis fungoides/Sézary syndrome ^{21, 26–30}
Stage		Overall survival		Disease-free survival		Progression-free survival
Stage		5 year	10 year	5 year	10 year	5 year	10 year
IA	T1a	97%	91%	100%	96%	95%	91%
IA	T1b	91%	80%	96%	92%	88%	82%
IB	T2a	85%	75%	90%	82%	85%	72%
IB	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/Sézary syndrome cutaneous lymphomas ^{3, 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.

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-directed therapy	Required	Essential
Stage III–IVA1 erythrodermic MF/SS	Required	Essential
Stage IIB–IV MF/SS	Required	Essential
pcCD30⁺ lymphoproliferative disorders	Required	^a
CTCL variants	Required	Essential
CBCL	Required	^a

MF, mycosis fungoides; SS, Sézary syndrome; pc, primary cutaneous; 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 cancer ³⁶ and other network skin lymphoma services in the U.K
	TSEB	ECP
Supranetwork MDTs
Birmingham (Queen Elizabeth Hospital)	Yes (Coventry and Warwickshire University Hospital)	Yes
Leeds (St James's University Hospital)	Yes	No, referred to Rotherham Hospital
Liverpool (Royal Liverpool Hospital)	Yes (Clatterbridge Hospital, Wirral)	Yes
London (Guy's and St Thomas' Hospital)	Yes	Yes
Manchester (The Christie Hospital)	Yes	Yes
Newcastle (Freeman Hospital)	Yes	Yes
Nottingham (City Hospital)	Yes	Yes
Other network skin lymphoma services
Belfast	Yes	No, would be referred
Cardiff	No, referred to Guy's and St Thomas'	No, referred to Bristol University Hospitals
Glasgow	No, referred to Newcastle	Yes

TSEB, total skin electron beam; ECP, extracorporeal electrophoresis.

Table 6. Topical therapy in mycosis fungoides
Therapy	Design	Level of evidence^a	Stage	Response rate
Mechlorethamine	RCT⁴⁰	1+	IA–IIA	59% gel vs. 48% ointment (noninferiority design by CAILS)
Mechlorethamine	Retrospective case series^41–46	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%
Bexarotene gel	Phase III⁵¹	2+	IA–IIA	44%
Carmustine (BCNU)	Case series^{48, 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.

Table 7. Phototherapy in mycosis fungoides
Therapy	Design (all nonrandomized)	Level of evidence^a	Stage	Response rate	Response duration (months)
UVB	Retrospective⁶⁶	2−	IA–IB	75%	51
UVB	Retrospective⁶⁵	2−	IA–IB	71%	22
NB 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%	43
PUVA	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.

Table 8. Combination psoralen–ultraviolet A (PUVA) in mycosis fungoides/Sézary syndrome
Therapy	Design	Level of evidence^a	Stage	ORR (CR), %	Number of patients	Duration (months)	5-year RFS, %
PUVA + interferon	Case studies⁹⁴	2−	IA–IV	89	9
PUVA + interferon	Case series⁹⁷	2−	IA–IV	68 (45)	22		20–75
PUVA + interferon	Prospective phase II⁹⁶	2+	IB–IIA	98 (84)	89	14
PUVA + interferon	Case studies¹⁰¹	2−		100 (100)	5		74
PUVA + interferon	Case studies⁹³	2−	IB–IVB	90 (100)	39
PUVA + 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	25
PUVA + bexarotene	Case series¹⁰⁰	2−	I–III	67 (29)	14	2–10
PUVA + 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.

Table 9. Total skin electron beam (TSEB) therapy in mycosis fungoides/Sézary syndrome
Therapy	No. of patients	Dose (Gy)	Level of evidence^a	Stage	ORR, %	CR, %	Median RFS/PFS (months)
High dose¹²⁷	114	30–36	2+	IA	100	97	50
High dose^{117, 119}	103, 17	30–36	2+	IB	100	59–75	18–29
High dose^{117, 119}	77, 19	30–36	2+	IIB	95–100	47	9
High dose^{117, 131}	3, 45	30–36	2+	III	100	33–60	6–9
Low dose^{122, 134}	21	10	2+	IB–IV	95	57 VGPR	5·8
Low dose¹²⁴	33	12	3	IB–III	88	27	MDOCB 16–17
Low 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	25·7
Low dose¹²¹	32	20 to < 30	2+	IB–III	83–100	29–37	29·3
Low dose¹²⁵	103	12	2+	IB–IV	87	18	13·2
	54			IB	94	20	26·5
	33			IIB	97	21	8·7
	12			III	50	8	10·6
	4			IV	25	0	–

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

Table 10. Biological therapies in mycosis fungoides/Sézary syndrome
Therapy	Design	Level of evidence^b	Stage	ORR, %	CR, %	Duration
Interferon-α	Case series¹³⁵	2−	IA–IVB	45–74	10–27	NA
Interferon-α	Case series¹³⁶	2−	IA–IIA	88	?	NA
Interferon-α	Case series¹³⁸	2−	IIB–IVB	29–63	?	NA
Bexarotene	Phase II¹⁴⁵	2+	IA–IIA	54	0	516 days
Bexarotene	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 months
Brentuximab vedotin	RCT Phase III¹⁶²	1+	1A–IVB	56	16	16·7 months
Denileukin diftitox^a	Phase II¹⁶³	2 + +	IB–IVA	30	10	6·9 months
Denileukin diftitox^a	RCT phase III¹⁶⁴	1+	IA–III	44	10	> 2 years (PFS)
Alemtuzumab high dose	Case series^{151, 152}	2−	IIB–IV	37–100	25–47	6–9 months
Alemtuzumab low dose	Case series^{154, 155}	2−	IIB–IV	85	21	TTF 12 months
Vorinostat^a	Phase II¹⁶⁵	2+	IB–IVA	24–29·7	0	106–185 days
Romidepsin^a	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.

Table 11. Chemotherapy in mycosis fungoides/Sézary syndrome
Therapy	Design	Level of evidence^a	ORR, %	CR, %	Median RFS or PFS (months)
Pentostatin	Case series^{174–177, 181}	2−	35–71	6–32	9
Cladribine	Case series¹⁷⁸	2−	28–41	14–19	4·5
Fludarabine	Case series^{179, 188}	2−	30–51	11·4	5·9
Liposomal doxorubicin	Case series¹⁸³	2−	80–88	45–66	15
Liposomal doxorubicin	EORTC-21012¹⁸⁴	2+	40·8	6·1	6
Gemcitabine	Case series^180–182	2−	68–75	8–22	10–15
Methotrexate	Case series¹⁷⁰	2−	58	41	31
Trimetrexate	Case series¹⁷¹	2−	45		Not recorded
Pralatrexate	Phase II¹⁸⁹	2+	45		Not recorded
Combination chemotherapy	Systematic review¹⁶⁸	2+	81	38	5–41
Chlorambucil	Case series¹⁶⁹	2−	89	36	Not recorded
EPOCH	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.

Table 12. Electrophoresis (ECP) in mycosis fungoides/Sézary syndrome (adapted from Scarisbrick *et al*.) ¹⁹⁶
Therapy	Design	Level of evidence^a	Stage	ORR, %	CR, %	OS (months)
ECP	Systematic review	2+	IB–IV	63	20
ECP	Systematic review	2+	III	35–71	14–26	39–100
ECP	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.

Table S1. Staging system for mycosis fungoides/Sézary syndrome
Skin
T₁	Limited patches, papules and/or plaques covering < 10% of the skin surface
T_1a	Patch only
T_1b	Plaque ± patch
T₂	Patches, papules or plaques covering ≥ 10% of the skin surface
T_2a	Patch only
T_2b	Plaque ± patch
T₃	One or more tumours (≥ 1 cm diameter)
T₄	Confluence of erythema covering ≥ 80% body surface area
Node
N₀	No clinical abnormal peripheral lymph nodes; biopsy not required
N₁	Clinically abnormal peripheral lymph nodes; histopathology Dutch grade 1 or NCI LN_0–2
N_1a	Clone negative
N_1b	Clone positive
N₂	Clinical abnormal peripheral lymph nodes; histopathology Dutch grade 2 or NCI LN₃
N_2a	Clone negative
N_2b	Clone positive
N₃	Clinical abnormal peripheral lymph nodes; histopathology Dutch grade 3–4 or NCI LN₄; clone positive or negative
N₄	Clinical abnormal peripheral lymph nodes; no histological confirmation
Visceral
M₀	No visceral organ involvement
M₁	Visceral involvement; must have pathology confirmation and organ involved should be specified
Blood
B₀	Absence of significant blood involvement: ≤ 5% of peripheral blood lymphocytes are atypical (Sézary) cells
B_0a	Clone negative
B_0b	Clone positive
B₁	Low blood tumour burden: > 5% of peripheral blood lymphocytes are atypical (Sézary) cells but does not meet the criteria of B₂
B_1a	Clone negative
B_1b	Clone positive
B₂	High blood tumour burden: ≥ 1000 Sézary cells per μL with positive clone

NCI, National Cancer Institute.

Table S2. Staging for mycosis fungoides/Sézary syndrome adapted from Olsen *et al.* ²³
Stage	T	N	M	B
IA	1	0	0	0, 1
IB	2	0	0	0, 1
IIA	1, 2	1, 2	0	0, 1
IIB	3	0–2	0	0, 1
IIIA	4	0–2	0	0
IIIB	4	0–2	0	1
IVA1	1–4	0–2	0	2
IVA2	1–4	3	0	0–2
IVB	1–4	0–3	1	0–2

Table S3. The International Society for Cutaneous Lymphomas–European Organisation for Research and Treatment of Cancer staging system for non-mycosis fungoides/non-Sézary syndrome primary cutaneous lymphomas ²⁴
Skin
T₁	Solitary skin involvement
T_1a	A solitary lesion < 5 cm diameter
T_1b	A solitary lesion > 5 cm diameter
T₂	Regional skin involvement: multiple lesions limited to one body region or two contiguous body regions
T_2a	All disease encompassing in a < 15-cm-diameter circular area
T_2b	All disease encompassing in a > 15-cm- and < 30-cm-diameter circular area
T_2c	All disease encompassing in a > 30-cm-diameter circular area
T₃	Generalized skin involvement
T_3a	Multiple lesions involving two noncontiguous body regions
T_3b	Multiple lesions involving at least three body regions
Node
N₀	No clinical or pathological lymph node involvement
N₁	Involvement of one peripheral lymph node region that drains an area of current or prior skin involvement
N₂	Involvement of two or more peripheral lymph node regions or involvement of any lymph node region that does not drain an area of current or prior skin involvement
N₃	Involvement of central lymph nodes
Visceral
M₀	No evidence of extracutaneous non-lymph node disease
M₁	Extracutaneous non-lymph node disease present

Table S4. Modified Severity Weighted Assessment Tool (mSWAT) in mycosis fungoides/Sézary syndrome
Body region (% BSA in body region)	Assessment of involvement in patient's skin (% BSA)
Body region (% BSA in body region)	Patch (any size lesion without induration or significant elevation)	Plaque (any size lesion that is elevated or indurated)	Tumour (any solid or nodular lesion ≥ 1 cm in diameter)
Head (7%)
Neck (2%)
Anterior trunk (13%)
Arms (8%)
Forearms (6%)
Hands (5%)
Posterior trunk (13%)
Groin (1%)
Buttocks (5%)
Thighs (19%)
Legs (14%)
Feet (7%)
Sum (lesion % BSA)
Weighting factor	× 1	× 2	× 4
Subtotal
mSWAT score (sum of the subtotals)

BSA, body surface area.

Table S5. Skin and global response in mycosis fungoides/Sézary syndrome
Global score	Definition	Skin	Definition	Nodes
Complete response (CR)	Complete disappearance of all clinical evidence of disease	CR	100% clearance of skin lesions	All categories have CR or were never involved (NI)
Partial response (PR)	PR of measurable disease	CR	100% clearance of skin lesions	All categories do not have a CR/NI and no category has a PD
		PR	50–99% clearance of skin disease from baseline without new tumours	No category has a PD and if any category is involved at baseline, at least one has a CR or PR
		SD	< 25% increase or < 50% clearance in skin disease from baseline	In the case of cutaneous lymphomas with extracutaneous disease at baseline, at least one category has a CR or PR and no category has a PD
Stable disease (SD)	Failure to attain CR, PR or PD representative of all disease	PR	50–99% clearance of skin disease from baseline without new tumours	At least one category involved at baseline and no CR, PR or PD
Stable disease (SD)		SD	< 25% increase or < 50% clearance in skin disease from baseline	No category has a PD and for patients with extracutaneous disease at baseline, no CR or PR
Progressive disease (PD)	Progressive disease	PD	≥ 25% increase in skin disease from baseline or in those with CR or PR, increase of skin score of greater than the sum of nadir plus 50% baseline score (loss of response)	PD in any category
Relapse	Recurrence of disease in prior CR	Relapse	Any disease recurrence in those with CR	Relapse in any category

Sidebar 1

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 transplantation. (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 therapies. There is no evidence to support the use of maintenance 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 systemic 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 trials 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 recommendation 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))

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