Treatment algorithm

Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer

ONGOING

stage IA disease: limited skin involvement alone <10% body surface area (without large cell transformation)

1st line – skin-directed therapy

Back
ONGOING
|
stage IA disease: limited skin involvement alone <10% body surface area (without large cell transformation)
1st line – 

skin-directed therapy

Skin-directed therapy alone or in combination with other skin-directed therapies is often sufficient to treat stage IA disease.[5][31] [32]

Topical corticosteroids have been shown to achieve good responses and symptomatic relief in early-stage disease.[5] One study demonstrated a complete response in 63% of patients with T1 disease (limited patches, papules, and/or plaques covering <10% of skin surface), and 25% in patients with T2 disease (patches, papules, or plaques covering 10% or more of skin surface), after a median follow-up of 9 months.[41] High-potency topical corticosteroids may be less well tolerated for intertriginous body areas or other areas such as the face.[32] Duration of treatment and the potency of the corticosteroid treatment can result in systemic absorption and skin atrophy. Optimal use of topical corticosteroids should be determined with the help of a dermatologist, and is dependent on lesion type and location.[32] 

Topical imiquimod can be considered for areas with few patches/plaques/small tumours that are recalcitrant to treatment or on sun-damaged skin such as the forearms, scalp, and face.[32] Evidence from case series suggests that imiquimod is effective for the treatment of early stage mycosis fungoides (MF) refractory to other therapies.[42][43][44][45]

Chlormethine, a potent DNA alkylating agent, has been shown to treat superficial skin disease with success.[5][46][47][48] Topical chlormethine treatment is associated with dermatitis, and can cause irritation when used on the face and intertriginous areas of the skin.[32] Treatment should be initiated at a less than daily use to assess tolerability, then slowly increase the application to the usual dose.[32] 

Topical retinoids may be considered for the treatment of cutaneous lesions in patients with early-stage cutaneous T-cell lymphoma (CTCL) who are refractory to other topical therapies, or who are unable to tolerate other therapies.[5]​​[49] Bexarotene gel is the only FDA-approved topical retinoid for the treatment of MF and Sézary syndrome (SS). In one trial, bexarotene gel has shown promising results as a lesion-directed treatment in early-stage CTCL (overall response rate of 63% and a clinical complete response rate of 21%, with median response duration of 99 weeks).[50] Topical retinoids can cause skin irritation including redness, peeling, and dermatitis when used on face and intertriginous body areas.[32] 

Carmustine, a potent DNA alkylating agent, has been shown to be an effective treatment for early stage patch/plaque MF, and has similar efficacy to chlormethine.[51][52] As topical carmustine is extensively absorbed, it is associated with an increased risk of bone marrow suppression.[5]

CTCL are radiosensitive tumours, and external beam radiotherapy plays an important role in the management of isolated localised skin disease, as well as in the palliation of thick patches and bulky tumour nodules.[53] Relatively low doses of low-energy radiotherapy are all that is required, and superficial skin disease can be effectively treated with doses given between 4 Gy and 40 Gy. Radiotherapy (24-30 Gy) is recommended as monotherapy for unilesional lesions with curative intent.[32] Low-dose radiotherapy (8-12 Gy) is usually given in combination with other therapies for palliative treatment.[32] 

Phototherapy with ultraviolet B (UVB) can be used to treat patch disease. One study reported a complete response rate of 83%, with a median duration of remission of 22 months.[54] Phototherapy use should be balanced against the risks in patients with a history of extensive squamoproliferative skin neoplasms or basal cell carcinomas or who have had melanoma, as a cumulative dose of UV is associated with increased risk of UV-associated skin neoplasms.[32] 

In order to improve response rates and minimise ultraviolet exposure, phototherapy can be combined with systemic treatments.[31][32][55]

Patients who are refractory to skin-directed treatment with or without systemic therapy should be managed as patients with stage IB to IIA, or may be considered for radiotherapy.[5][32]

Patients who experience progression >stage IA disease with initial therapy should be treated according to the stage of the progression.[32] 

See local specialist protocol for dosing guidelines.

Primary options

imiquimod topical

OR

chlormethine topical

OR

bexarotene topical

OR

carmustine

2nd line – systemic therapy

Back
ONGOING
|
stage IA disease: limited skin involvement alone <10% body surface area (without large cell transformation)
2nd line – 

systemic therapy

Systemic therapy in early disease may be considered for patients who experience disease relapse, or who are refractory to skin-directed therapy. Treatments may include bexarotene, interferon alfa, or methotrexate.[5][31][32]

Bexarotene, an oral retinoid, is well established as one of the systemic therapies for persistent or refractory early and advanced disease.[56][57] Bexarotene acts by selectively binding to the retinoid x receptor (RXR) family of nuclear receptors. Hypertriglyceridaemia and hypothyroidism are common but reversible adverse effects, and can usually be managed with the initiation of lipid-lowering drugs and thyroxine immediately before starting bexarotene. Alternative retinoids (e.g., acitretin, isotretinoin) may be considered in place of bexarotene.[32]

Interferon alfa is a well-established treatment for cutaneous T-cell lymphoma of various stages (usually beyond limited plaque disease). It may be considered for use before or after, or in combination with, other systemic therapies. Good response rates have been reported, with some remissions lasting >2 years.[59][109]​ A number of studies investigating the utility of combining interferon alfa with other therapies such as extracorporeal photopheresis (ECP), pentostatin, and fludarabine have failed to demonstrate significant improvements in response rates.[60][61]​ Interferon alfa 2a and 2b and peginterferon alfa 2b have been discontinued in the US. Peginterferon alfa 2a may be substituted for other interferon preparations.

One study found low-dose oral methotrexate as a single agent to be effective, with a response rate of 76% and a 5-year survival rate of 71%.[62] It is generally well tolerated.

See local specialist protocol for dosing guidelines.

Primary options

bexarotene

OR

peginterferon alfa 2a

OR

methotrexate

stage IB to IIA disease: skin disease only with ≥10% body surface area (without large cell transformation)

1st line – skin-directed therapy

Back
ONGOING
|
stage IB to IIA disease: skin disease only with ≥10% body surface area (without large cell transformation)
1st line – 

skin-directed therapy

Initial treatment of stage IB to IIA is with skin-directed therapies alone or in combination with other skin-directed therapies.[5][31][32]

For patients with limited patch or plaque disease, monotherapy with skin-directed therapy can be considered.[32]

For patients with a lower disease burden, with predominantly patch disease, initial treatment could include topical corticosteroids, topical imiquimod, topical chlormethine, topical retinoids (e.g., bexarotene), topical carmustine, radiotherapy, or phototherapy with narrowband UVB.[5][31][32]

For patients with a higher disease burden, with predominantly plaque disease, skin-directed therapy should include PUVA, UVA1, or total skin electron beam therapy (TSEBT).[32]

PUVA therapy (consisting of orally administered methoxsalen [8-methoxypsoralen], activated when exposed to long-wavelength ultraviolet light) is considered the treatment of choice for patients with plaque disease, due to increased penetration into the dermis, and remains one of the most effective therapies for patients with early disease. However, PUVA is associated with an increased skin toxicity compared with UVB, and there are few data regarding the effects of PUVA therapy on overall survival. Maintenance treatment may prolong the period of remission. Use of PUVA as a single therapy is generally restricted to early-stage cutaneous T-cell lymphoma, as patients with advanced disease are unlikely to achieve a complete response with PUVA alone. As far as possible, the total dose of PUVA should be restricted to <200 treatment sessions, due to the risk of secondary skin cancers associated with a high cumulative total UVA dose.

TSEBT is recommended in patients with a higher skin disease burden diffuse plaque involvement.[32] Usually, 4-MeV to 9-MeV electrons are delivered to the skin using a 6 or 8 field technique. This allows sparing of the structures below the dermis, as 80% is delivered in the first 1 cm and <5% beyond a 2-cm depth. High doses have been shown to achieve more durable remissions than lower doses.[63][64]​ Complete response rates for early disease range from 56% to 96%.[63][64][65]​ Response rates in advanced disease are generally lower, but good palliation has been achieved.[66] TSEBT may be followed with systemic therapies to maintain response.[32] There is limited safety data for the use of TSEBT in combination with systemic retinoids, histone deacetylase (HDAC) inhibitors such as vorinostat or romidepsin, or mogamulizumab, or combining phototherapy with vorinostat or romidepsin.[32][67]

Patients with predominantly patch disease with low disease burden should retreated with initial treatment options. Those who relapse with high disease burden should be treated as patients with predominantly plaque disease, or treated as appropriate for the relapsed disease stage.

In order to improve response rates and minimise ultraviolet exposure, phototherapy can be combined with systemic treatments such as interferon alfa or a retinoid for stage IA, IB to IIA, and IIIB.[31][32][55] 

Patients with initial stage IB to IIA predominantly plaque disease who relapse with or have persistent stage IB to IIA disease should be retreated with initial treatment options. Those who experience disease progression >1B to IIA should be treated according to clinical stage or progression.[32]​

Patients who are refractory to multiple previous therapies should consider TSEBT (if not previously administered), a clinical trial, or be managed as patients with stage IIB generalised lesions.[32]

See local specialist protocol for dosing guidelines.

Primary options

imiquimod topical

OR

chlormethine topical

OR

bexarotene topical

OR

carmustine

2nd line – systemic therapy

Back
ONGOING
|
stage IB to IIA disease: skin disease only with ≥10% body surface area (without large cell transformation)
2nd line – 

systemic therapy

Systemic therapies, single agent or combination therapies, should be considered for patients with extensive skin involvement, higher skin disease burden, predominantly plaque disease, blood involvement, and/or inadequate response to skin-directed therapy.[32]

Bexarotene, an oral retinoid, is well established as one of the systemic therapies for persistent or refractory early and advanced disease.[56][57] Bexarotene acts by selectively binding to the retinoid x receptor (RXR) family of nuclear receptors. Hypertriglyceridaemia and hypothyroidism are common but reversible adverse effects, and can usually be managed with the initiation of lipid-lowering drugs and thyroxine immediately before starting bexarotene. Alternative retinoids (e.g., acitretin, isotretinoin) may be considered in place of bexarotene.[32]

Interferon alfa is a well-established treatment for cutaneous T-cell lymphoma (CTCL) of various stages (usually beyond limited plaque disease). It may be considered for use before or after, or in combination with, other systemic therapies. Good response rates have been reported, with some remissions lasting >2 years.[59][109]​ A number of studies investigating the utility of combining interferon alfa with other therapies such as extracorporeal photopheresis (ECP), pentostatin, and fludarabine have failed to demonstrate significant improvements in response rates.[60][61]​ Interferon alfa 2a and 2b and peginterferon alfa 2b have been discontinued in the US. Peginterferon alfa 2a may be substituted for other interferon preparations.

One study found low-dose oral methotrexate as a single agent to be effective, with a response rate of 76% and a 5-year survival rate of 71%.[62] It is generally well tolerated.

Brentuximab vedotin, an antibody-drug conjugate that enables the cytotoxic drug monomethyl auristatin E (MMAE) to be targeted to CD30+ cancer cells, is approved by the FDA for the treatment of MF and SS. Phase 2 trials have demonstrated that brentuximab vedotin is highly active in CD30+ CTCL.[68][69] The overall response rate is 54% in MF, irrespective of CD30 status. Flares can be seen in MF when starting therapy, and the median time to response in MF is around 12 weeks, with durable remissions seen in some patients and a median duration of response of around 32 weeks. The common adverse effects include neuropathy, fatigue, and drug rash.[69] One phase 3 trial included previously-treated adult patients with CD30+ MF or primary cutaneous anaplastic large-cell lymphoma. It found a significant improvement in objective global response lasting at least 4 months with brentuximab vedotin (56%) versus physician's choice of methotrexate or bexarotene (13%).[70]

Mogamulizumab, a monoclonal antibody that binds to a protein CC chemokine receptor type 4 (CCR4) found on some cancer cells, is approved by the FDA for intravenous use for the treatment of adult patients with relapsed or refractory MF, or SS after at least one prior systemic therapy. One open-label, phase 3 randomised controlled trial demonstrated that mogamulizumab significantly improved progression-free survival, compared with vorinostat, for patients with relapsed or refractory MF or SS.[71] Serious adverse effects included pyrexia, cellulitis, pulmonary embolism, and sepsis. Evidence from a case study of two patients with refractory SS who had been treated with four and five prior systemic therapies respectively, reported that mogamulizumab combined with TSEBT achieved a global complete response in both patients at 9 weeks for the first patient, and 4 weeks for the second patient, and was well tolerated.[67] 

Histone deacetylase (HDAC) inhibitors (e.g., vorinostat, romidepsin) work by inducing histone acetylation and protein acetylation, resulting in downstream events of cell-cycle arrest and apoptosis.[72][73] Both are approved by the US FDA for the treatment of MF and SS. Various phase 2 trials have demonstrated improvements in skin lesions and other symptoms (e.g., pruritus) with vorinostat.[74][75]

See local specialist protocol for dosing guidelines.

Primary options

bexarotene

OR

peginterferon alfa 2a

OR

methotrexate

OR

brentuximab vedotin

OR

mogamulizumab

OR

vorinostat

OR

romidepsin

stage IIB disease: tumour disease and no erythroderma (without large cell transformation)

1st line – skin-directed therapy

Back
ONGOING
|
stage IIB disease: tumour disease and no erythroderma (without large cell transformation)
|
limited tumour disease
1st line – 

skin-directed therapy

Radiotherapy or other skin-directed therapy alone or in combination are the preferred initial treatments for patients with stage IIB limited tumour disease.[5][32]

Topical corticosteroids have been shown to achieve good responses and symptomatic relief in early-stage disease.[5] One study demonstrated a complete response in 63% of patients with T1 disease (limited patches, papules, and/or plaques covering <10% of skin surface), and 25% in patients with T2 disease (patches, papules, or plaques covering 10% or more of skin surface), after a median follow-up of 9 months.[41] High-potency topical corticosteroids may be less well tolerated for intertriginous body areas or other areas such as the face.[32] Duration of treatment and the potency of the corticosteroid treatment can result in systemic absorption and skin atrophy. Optimal use of topical corticosteroids should be determined with the help of a dermatologist, and is dependent on lesion type and location.[32] 

Topical imiquimod can be considered for areas with few patches/plaques/small tumours that are recalcitrant to treatment or on sun-damaged skin such as the forearms, scalp, and face.[32] Evidence from case series suggests that imiquimod is effective for the treatment of early stage MF refractory to other therapies.[42][43][44][45]

Chlormethine, a potent DNA alkylating agent, has been shown to treat superficial skin disease with success.[5][46][47][48] Topical chlormethine treatment is associated with dermatitis, and can cause irritation when used on the face and intertriginous areas of the skin.[32] Treatment should be initiated at a less than daily use to assess tolerability, then slowly increase the application to the usual dose.[32] 

Topical retinoids may be considered for the treatment of cutaneous lesions in patients with early-stage cutaneous T-cell lymphoma (CTCL) who are refractory to other topical therapies, or who are unable to tolerate other therapies.[5][32][49]​ Bexarotene gel is the only FDA-approved topical retinoid for the treatment of MF and SS. In one trial, bexarotene gel has shown promising results as a lesion-directed treatment in early-stage CTCL (overall response rate of 63% and a clinical complete response rate of 21%, with median response duration of 99 weeks).[50] Topical retinoids can cause skin irritation including redness, peeling, and dermatitis when used on face and intertriginous body areas.[32] 

Carmustine, a potent DNA alkylating agent, has been shown to be an effective treatment for early stage patch/plaque MF, and has similar efficacy to chlormethine.[51][52] As topical carmustine is extensively absorbed, it is associated with an increased risk of bone marrow suppression.[5]

CTCL are radiosensitive tumours, and external beam radiotherapy plays an important role in the management of isolated localised skin disease, as well as in the palliation of thick patches and bulky tumour nodules.[53] Relatively low doses of low-energy radiotherapy are all that is required, and superficial skin disease can be effectively treated with doses given between 4 Gy and 40 Gy. Radiotherapy (24-30 Gy) is recommended as monotherapy for unilesional lesions with curative intent.[32] Low-dose radiotherapy (8-12 Gy) is usually given in combination with other therapies for palliative treatment.[32] 

Phototherapy with ultraviolet B (UVB) can be used to treat patch disease. One study reported a complete response rate of 83%, with a median duration of remission of 22 months.[54] Phototherapy use should be balanced against the risks in patients with a history of extensive squamoproliferative skin neoplasms or basal cell carcinomas or who have had melanoma, as a cumulative dose of UV is associated with increased risk of UV-associated skin neoplasms.[32] PUVA therapy (consisting of orally administered methoxsalen [8-methoxypsoralen], activated when exposed to long-wavelength ultraviolet light) is considered the treatment of choice for patients with plaque disease, due to increased penetration into the dermis, and remains one of the most effective therapies for patients with early disease. However, PUVA is associated with an increased skin toxicity compared with UVB, and there are few data regarding the effects of PUVA therapy on overall survival. Maintenance treatment may prolong the period of remission. Use of PUVA as a single therapy is generally restricted to early-stage CTCL, as patients with advanced disease are unlikely to achieve a complete response with PUVA alone. As far as possible, the total dose of PUVA should be restricted to <200 treatment sessions, due to the risk of secondary skin cancers associated with a high cumulative total UVA dose.

TSEBT is recommended in patients with a higher skin disease burden diffuse plaque involvement.[32] Usually, 4-MeV to 9-MeV electrons are delivered to the skin using a 6 or 8 field technique. This allows sparing of the structures below the dermis, as 80% is delivered in the first 1 cm and <5% beyond a 2-cm depth. High doses have been shown to achieve more durable remissions than lower doses.[63][64]​ Complete response rates for early disease range from 56% to 96%.[63][64][65]​ Response rates in advanced disease are generally lower, but good palliation has been achieved.[66] TSEBT may be followed with systemic therapies to maintain response.[32] There is limited safety data for the use of TSEBT in combination with systemic retinoids, histone deacetylase (HDAC) inhibitors such as vorinostat or romidepsin, or mogamulizumab, or combining phototherapy with vorinostat or romidepsin.[32][67]

See local specialist protocol for dosing guidelines.

Primary options

imiquimod topical

OR

chlormethine topical

OR

bexarotene topical

OR

carmustine

Plus – systemic therapy

Back
ONGOING
|
stage IIB disease: tumour disease and no erythroderma (without large cell transformation)
|
limited tumour disease
Plus – 

systemic therapy

Treatment recommended for ALL patients in selected patient group

For patients who do not respond to initial therapy, systemic therapy should be considered.[32]

Preferred systemic therapy options include bexarotene, brentuximab vedotin, interferon alfa, methotrexate, mogamulizumab, romidepsin.[32]

Bexarotene, an oral retinoid, is well established as one of the systemic therapies for persistent or refractory early and advanced disease.[56][57] Bexarotene acts by selectively binding to the retinoid x receptor (RXR) family of nuclear receptors. Hypertriglyceridaemia and hypothyroidism are common but reversible adverse effects, and can usually be managed with the initiation of lipid-lowering drugs and thyroxine immediately before starting bexarotene. Alternative retinoids (e.g., acitretin, isotretinoin) may be considered in place of bexarotene.[32]

Interferon alfa is a well-established treatment for cutaneous T-cell lymphoma (CTCL) of various stages (usually beyond limited plaque disease). It may be considered for use before or after, or in combination with, other systemic therapies. Good response rates have been reported, with some remissions lasting >2 years.[59][109]​ A number of studies investigating the utility of combining interferon alfa with other therapies such as extracorporeal photopheresis (ECP), pentostatin, and fludarabine have failed to demonstrate significant improvements in response rates.[60][61]​ Interferon alfa 2a and 2b and peginterferon alfa 2b have been discontinued in the US. Peginterferon alfa 2a may be substituted for other interferon preparations.

One study found low-dose oral methotrexate as a single agent to be effective, with a response rate of 76% and a 5-year survival rate of 71%.[62] It is generally well tolerated.

Brentuximab vedotin, an antibody-drug conjugate that enables the cytotoxic drug monomethyl auristatin E (MMAE) to be targeted to CD30+ cancer cells, is approved by the FDA for the treatment of MF and SS. Phase 2 trials have demonstrated that brentuximab vedotin is highly active in CD30+ CTCL.[68][69] The overall response rate is 54% in MF, irrespective of CD30 status. Flares can be seen in MF when starting therapy, and the median time to response in MF is around 12 weeks, with durable remissions seen in some patients and a median duration of response of around 32 weeks. The common adverse effects include neuropathy, fatigue, and drug rash.[69] One phase 3 trial included previously-treated adult patients with CD30+ MF or primary cutaneous anaplastic large-cell lymphoma. It found a significant improvement in objective global response lasting at least 4 months with brentuximab vedotin (56%) versus physician's choice of methotrexate or bexarotene (13%).[70]

Mogamulizumab, a monoclonal antibody that binds to a protein CC chemokine receptor type 4 (CCR4) found on some cancer cells, is approved by the FDA for intravenous use for the treatment of adult patients with relapsed or refractory MF, or SS after at least one prior systemic therapy. One open-label, phase 3 randomised controlled trial demonstrated that mogamulizumab significantly improved progression-free survival, compared with vorinostat, for patients with relapsed or refractory MF or SS.[71] Serious adverse effects included pyrexia, cellulitis, pulmonary embolism, and sepsis. Evidence from a case study of two patients with refractory SS who had been treated with four and five prior systemic therapies respectively, reported that mogamulizumab combined with TSEBT achieved a global complete response in both patients at 9 weeks for the first patient, and 4 weeks for the second patient, and was well tolerated.[67] 

The histone deacetylase (HDAC) inhibitor romidepsin works by inducing histone acetylation and protein acetylation, resulting in downstream events of cell-cycle arrest and apoptosis.[72][73] It is approved by the US FDA for the treatment of MF and SS. 

Patients who experience persistent 1A to IIA tumour lesions should be retreated with initial therapy.[32]​ Patients who relapse, or who experience disease progression with >stage IIB should be treated according to clinical stage.[32]

Patients refractory to multiple therapies should be managed as patients with IIB generalised tumour disease (see below).[32]

See local specialist protocol for dosing guidelines.

Primary options

bexarotene

OR

peginterferon alfa 2a

OR

methotrexate

OR

brentuximab vedotin

OR

mogamulizumab

OR

romidepsin

Consider – radiotherapy

Back
ONGOING
|
stage IIB disease: tumour disease and no erythroderma (without large cell transformation)
|
limited tumour disease
Consider – 

radiotherapy

Additional treatment recommended for SOME patients in selected patient group

For patients who do not respond to initial therapy, systemic therapy with radiotherapy should be considered.[32]

1st line – skin-directed therapy

Back
ONGOING
|
stage IIB disease: tumour disease and no erythroderma (without large cell transformation)
|
generalised tumour disease
1st line – 

skin-directed therapy

For patients with generalised stage IIB tumour disease, systemic therapy with skin-directed therapy should be considered.[32]

Skin-directed therapies can include topical corticosteroids, topical imiquimod, topical chlormethine, topical retinoids (e.g., bexarotene), carmustine, UVB, PUVA, UVA1, or radiotherapy.

Topical corticosteroids have been shown to achieve good responses and symptomatic relief in early-stage disease.[5] One study demonstrated a complete response in 63% of patients with T1 disease (limited patches, papules, and/or plaques covering <10% of skin surface), and 25% in patients with T2 disease (patches, papules, or plaques covering 10% or more of skin surface), after a median follow-up of 9 months.[41] High-potency topical corticosteroids may be less well tolerated for intertriginous body areas or other areas such as the face.[32] Duration of treatment and the potency of the corticosteroid treatment can result in systemic absorption and skin atrophy. Optimal use of topical corticosteroids should be determined with the help of a dermatologist, and is dependent on lesion type and location.[32] 

Topical imiquimod can be considered for areas with few patches/plaques/small tumours that are recalcitrant to treatment or on sun-damaged skin such as the forearms, scalp, and face.[32] Evidence from case series suggests that imiquimod is effective for the treatment of early stage MF refractory to other therapies.[42][43][44][45]

Chlormethine, a potent DNA alkylating agent, has been shown to treat superficial skin disease with success.[5][46][47][48] Topical chlormethine treatment is associated with dermatitis, and can cause irritation when used on the face and intertriginous areas of the skin.[32] Treatment should be initiated at a less than daily use to assess tolerability, then slowly increase the application to the usual dose.[32] 

Topical retinoids may be considered for the treatment of cutaneous lesions in patients with early-stage cutaneous T-cell lymphoma (CTCL) who are refractory to other topical therapies, or who are unable to tolerate other therapies.[5]​​[49] Bexarotene gel is the only FDA-approved topical retinoid for the treatment of MF and SS. In one trial, bexarotene gel has shown promising results as a lesion-directed treatment in early-stage CTCL (overall response rate of 63% and a clinical complete response rate of 21%, with median response duration of 99 weeks).[50] Topical retinoids can cause skin irritation including redness, peeling, and dermatitis when used on face and intertriginous body areas.[32] 

Carmustine, a potent DNA alkylating agent, has been shown to be an effective treatment for early stage patch/plaque MF, and has similar efficacy to chlormethine.[51][52] As topical carmustine is extensively absorbed, it is associated with an increased risk of bone marrow suppression.[5]

CTCL are radiosensitive tumours, and external beam radiotherapy plays an important role in the management of isolated localised skin disease, as well as in the palliation of thick patches and bulky tumour nodules.[53] Relatively low doses of low-energy radiotherapy are all that is required, and superficial skin disease can be effectively treated with doses given between 4 Gy and 40 Gy. Radiotherapy (24-30 Gy) is recommended as monotherapy for unilesional lesions with curative intent.[32] Low-dose radiotherapy (8-12 Gy) is usually given in combination with other therapies for palliative treatment.[32] 

Phototherapy with ultraviolet B (UVB) can be used to treat patch disease. One study reported a complete response rate of 83%, with a median duration of remission of 22 months.[54] PUVA therapy (consisting of orally administered methoxsalen [8-methoxypsoralen], activated when exposed to long-wavelength ultraviolet light) is considered the treatment of choice for patients with plaque disease, due to increased penetration into the dermis, and remains one of the most effective therapies for patients with early disease. However, PUVA is associated with an increased skin toxicity compared with UVB, and there are few data regarding the effects of PUVA therapy on overall survival. Maintenance treatment may prolong the period of remission. Use of PUVA as a single therapy is generally restricted to early-stage CTCL, as patients with advanced disease are unlikely to achieve a complete response with PUVA alone. As far as possible, the total dose of PUVA should be restricted to <200 treatment sessions, due to the risk of secondary skin cancers associated with a high cumulative total UVA dose.

TSEBT is recommended in patients with a higher skin disease burden diffuse plaque involvement.[32] Usually, 4-MeV to 9-MeV electrons are delivered to the skin using a 6 or 8 field technique. This allows sparing of the structures below the dermis, as 80% is delivered in the first 1 cm and <5% beyond a 2-cm depth. High doses have been shown to achieve more durable remissions than lower doses.[63][64]​ Complete response rates for early disease range from 56% to 96%.[63][64][65]​ Response rates in advanced disease are generally lower, but good palliation has been achieved.[66] TSEBT may be followed with systemic therapies to maintain response.[32] There is limited safety data for the use of TSEBT in combination with systemic retinoids, histone deacetylase (HDAC) inhibitors such as vorinostat or romidepsin, or mogamulizumab, or combining phototherapy with vorinostat or romidepsin.[32][67]

Recommended combination therapies for stage IIB generalised tumour disease include phototherapy with interferon alfa or a retinoid, or a retinoid with interferon alfa.[32]

Patients who experience persistent generalised stage IIB disease should be retreated with the initial treatment options for stage IIB generalised tumour disease.[32] Patients who relapse or experience disease progression >stage IIB should be treated according to clinical stage.[32]

See local specialist protocol for dosing guidelines.

Primary options

imiquimod topical

OR

chlormethine topical

OR

bexarotene topical

OR

carmustine

Plus – systemic therapy

Back
ONGOING
|
stage IIB disease: tumour disease and no erythroderma (without large cell transformation)
|
generalised tumour disease
Plus – 

systemic therapy

Treatment recommended for ALL patients in selected patient group

Preferred systemic therapy options include bexarotene, brentuximab vedotin, interferon alfa, methotrexate, mogamulizumab, romidepsin, liposomal doxorubicin, pralatrexate, and gemcitabine.[32] 

Bexarotene, an oral retinoid, is well established as one of the systemic therapies for persistent or refractory early and advanced disease.[56][57] Bexarotene acts by selectively binding to the retinoid x receptor (RXR) family of nuclear receptors. Hypertriglyceridaemia and hypothyroidism are common but reversible adverse effects, and can usually be managed with the initiation of lipid-lowering drugs and thyroxine immediately before starting bexarotene. Alternative retinoids (e.g., acitretin, isotretinoin) may be considered in place of bexarotene.[32]

Interferon alfa is a well-established treatment for cutaneous T-cell lymphoma (CTCL) of various stages (usually beyond limited plaque disease). It may be considered for use before or after, or in combination with, other systemic therapies. Good response rates have been reported, with some remissions lasting >2 years.[59][109]​ A number of studies investigating the utility of combining interferon alfa with other therapies such as extracorporeal photopheresis (ECP), pentostatin, and fludarabine have failed to demonstrate significant improvements in response rates.[60][61]​ Interferon alfa 2a and 2b and peginterferon alfa 2b have been discontinued in the US. Peginterferon alfa 2a may be substituted for other interferon preparations.

One study found low-dose oral methotrexate as a single agent to be effective, with a response rate of 76% and a 5-year survival rate of 71%.[62] It is generally well tolerated.

Brentuximab vedotin, an antibody-drug conjugate that enables the cytotoxic drug monomethyl auristatin E (MMAE) to be targeted to CD30+ cancer cells, is approved by the FDA for the treatment of MF and SS. Phase 2 trials have demonstrated that brentuximab vedotin is highly active in CD30+ CTCL.[68][69] The overall response rate is 54% in MF, irrespective of CD30 status. Flares can be seen in MF when starting therapy, and the median time to response in MF is around 12 weeks, with durable remissions seen in some patients and a median duration of response of around 32 weeks. The common adverse effects include neuropathy, fatigue, and drug rash.[69] One phase 3 trial included previously-treated adult patients with CD30+ MF or primary cutaneous anaplastic large-cell lymphoma. It found a significant improvement in objective global response lasting at least 4 months with brentuximab vedotin (56%) versus physician's choice of methotrexate or bexarotene (13%).[70]

Mogamulizumab, a monoclonal antibody that binds to a protein CC chemokine receptor type 4 (CCR4) found on some cancer cells, is approved by the FDA for intravenous use for the treatment of adult patients with relapsed or refractory MF, or SS after at least one prior systemic therapy. One open-label, phase 3 randomised controlled trial demonstrated that mogamulizumab significantly improved progression-free survival, compared with vorinostat, for patients with relapsed or refractory MF or SS.[71] Serious adverse effects included pyrexia, cellulitis, pulmonary embolism, and sepsis. Evidence from a case study of two patients with refractory SS who had been treated with four and five prior systemic therapies respectively, reported that mogamulizumab combined with TSEBT achieved a global complete response in both patients at 9 weeks for the first patient, and 4 weeks for the second patient, and was well tolerated.[67] 

The histone deacetylase (HDAC) inhibitor romidepsin works by inducing histone acetylation and protein acetylation, resulting in downstream events of cell-cycle arrest and apoptosis.[72][73] It is approved by the US FDA for the treatment of MF and SS. 

Evidence from two phase 2 prospective open-label trials suggests that liposomal doxorubicin monotherapy improved overall response rates, median time to progression and median duration of response in patients with advanced CTCL (stage II to IV CTCL [including SS and transformed CTCL] or stage IIB to IVB MF, respectively) refractory to at least two previous lines of treatment.[76][77]

Pralatrexate, a dihydrofolate reductase inhibitor, has shown efficacy for patients with relapsed or refractory MF or SS.[78][79][80] Evidence suggests that pralatrexate either alone or in combination with low-dose bexarotene is well tolerated, and improves median response, median duration of treatment, and median progression-free survival in patients with relapsed, refractory, or transformed large cell MF.[78][79][80]

Gemcitabine, a pyrimidine antimetabolite, has demonstrated good response rates and is well tolerated in patients with pretreated cutaneous T-cell lymphoma.[81][82][83]

Patients who experience persistent T1 to T3 with generalised tumour lesions should be retreated with the initial treatment options for stage IIB generalised tumour disease.[32] Patients who relapse or experience disease progression >stage IIB should be treated according to clinical stage.[32]

See local specialist protocol for dosing guidelines.

Primary options

bexarotene

OR

peginterferon alfa 2a

OR

methotrexate

OR

brentuximab vedotin

OR

mogamulizumab

OR

romidepsin

OR

doxorubicin liposomal

OR

pralatrexate

OR

gemcitabine

stage III disease: erythrodermic (without large cell transformation)

1st line – skin-directed therapy

Back
ONGOING
|
stage III disease: erythrodermic (without large cell transformation)
1st line – 

skin-directed therapy

Initial treatment options for stage III disease include systemic therapy with skin-directed therapy.[5][31][32]

Skin-directed therapies can include topical corticosteroids, topical imiquimod, topical chlormethine, topical retinoids (e.g., bexarotene), topical carmustine, UVB, PUVA, UVA1, total skin electron beam therapy (TSEBT), or radiotherapy.[32]​ Phototherapy and TSEBT may be associated with increased toxicity in patients with erythroderma and modification of dose/schedule may need to be considered.

Topical corticosteroids have been shown to achieve good responses and symptomatic relief in early-stage disease.[5] One study demonstrated a complete response in 63% of patients with T1 disease (limited patches, papules, and/or plaques covering <10% of skin surface), and 25% in patients with T2 disease (patches, papules, or plaques covering 10% or more of skin surface), after a median follow-up of 9 months.[41] High-potency topical corticosteroids may be less well tolerated for intertriginous body areas or other areas such as the face.[32] Duration of treatment and the potency of the corticosteroid treatment can result in systemic absorption and skin atrophy. Optimal use of topical corticosteroids should be determined with the help of a dermatologist, and is dependent on lesion type and location.[32] 

Topical imiquimod can be considered for areas with few patches/plaques/small tumours that are recalcitrant to treatment or on sun-damaged skin such as the forearms, scalp, and face.[32] Evidence from case series suggests that imiquimod is effective for the treatment of early stage MF refractory to other therapies.[42][43][44][45]

Chlormethine, a potent DNA alkylating agent, has been shown to treat superficial skin disease with success.[5][46][47][48] Topical chlormethine treatment is associated with dermatitis, and can cause irritation when used on the face and intertriginous areas of the skin.[32] Treatment should be initiated at a less than daily use to assess tolerability, then slowly increase the application to the usual dose.[32] 

Topical retinoids may be considered for the treatment of cutaneous lesions in patients with early-stage cutaneous T-cell lymphoma (CTCL) who are refractory to other topical therapies, or who are unable to tolerate other therapies.[5]​​[49] Bexarotene gel is the only FDA-approved topical retinoid for the treatment of MF and SS. In one trial, bexarotene gel has shown promising results as a lesion-directed treatment in early-stage CTCL (overall response rate of 63% and a clinical complete response rate of 21%, with median response duration of 99 weeks).[50] Topical retinoids can cause skin irritation including redness, peeling, and dermatitis when used on face and intertriginous body areas.[32] 

Carmustine, a potent DNA alkylating agent, has been shown to be an effective treatment for early stage patch/plaque MF, and has similar efficacy to chlormethine.[51][52] As topical carmustine is extensively absorbed, it is associated with an increased risk of bone marrow suppression.[5]

CTCL are radiosensitive tumours, and external beam radiotherapy plays an important role in the management of isolated localised skin disease, as well as in the palliation of thick patches and bulky tumour nodules.[53] Relatively low doses of low-energy radiotherapy are all that is required, and superficial skin disease can be effectively treated with doses given between 4 Gy and 40 Gy. Radiotherapy (24-30 Gy) is recommended as monotherapy for unilesional lesions with curative intent.[32] Low-dose radiotherapy (8-12 Gy) is usually given in combination with other therapies for palliative treatment.[32] 

Phototherapy with ultraviolet B (UVB) can be used to treat patch disease. One study reported a complete response rate of 83%, with a median duration of remission of 22 months.[54] PUVA therapy (consisting of orally administered methoxsalen [8-methoxypsoralen], activated when exposed to long-wavelength ultraviolet light) is considered the treatment of choice for patients with plaque disease, due to increased penetration into the dermis, and remains one of the most effective therapies for patients with early disease. However, PUVA is associated with an increased skin toxicity compared with UVB, and there are few data regarding the effects of PUVA therapy on overall survival. Maintenance treatment may prolong the period of remission. Use of PUVA as a single therapy is generally restricted to early-stage CTCL, as patients with advanced disease are unlikely to achieve a complete response with PUVA alone. As far as possible, the total dose of PUVA should be restricted to <200 treatment sessions, due to the risk of secondary skin cancers associated with a high cumulative total UVA dose.

Total skin electron beam therapy (TSEBT) is recommended in patients with a higher skin disease burden diffuse plaque involvement.[32] Usually, 4-MeV to 9-MeV electrons are delivered to the skin using a 6 or 8 field technique. This allows sparing of the structures below the dermis, as 80% is delivered in the first 1 cm and <5% beyond a 2-cm depth. High doses have been shown to achieve more durable remissions than lower doses.[63][64]​ Complete response rates for early disease range from 56% to 96%.[63][64][65]​ Response rates in advanced disease are generally lower, but good palliation has been achieved.[66] TSEBT may be followed with systemic therapies to maintain response.[32] There is limited safety data for the use of TSEBT in combination with systemic retinoids, histone deacetylase (HDAC) inhibitors such as vorinostat or romidepsin, or mogamulizumab, or combining phototherapy with vorinostat or romidepsin.[32][67]

Patients who relapse or experience persistent stage III disease should be retreated with the initial treatments. Those who experience disease progression >stage III should be treated according to the stage of relapsed disease.[32]

See local specialist protocol for dosing guidelines.

Primary options

imiquimod topical

OR

chlormethine topical

OR

bexarotene topical

OR

carmustine

Plus – systemic therapy

Back
ONGOING
|
stage III disease: erythrodermic (without large cell transformation)
Plus – 

systemic therapy

Treatment recommended for ALL patients in selected patient group

Preferred systemic therapy options include bexarotene, brentuximab vedotin, interferon alfa, methotrexate, mogamulizumab, romidepsin, and extracorporeal photopheresis (ECP).[32] 

Bexarotene, an oral retinoid, is well established as one of the systemic therapies for persistent or refractory early and advanced disease.[56][57] Bexarotene acts by selectively binding to the retinoid x receptor (RXR) family of nuclear receptors. Hypertriglyceridaemia and hypothyroidism are common but reversible adverse effects, and can usually be managed with the initiation of lipid-lowering drugs and thyroxine immediately before starting bexarotene. Alternative retinoids (e.g., acitretin, isotretinoin) may be considered in place of bexarotene.[32]

Interferon alfa is a well-established treatment for cutaneous T-cell lymphoma (CTCL) of various stages (usually beyond limited plaque disease). It may be considered for use before or after, or in combination with, other systemic therapies. Good response rates have been reported, with some remissions lasting >2 years.[59][109]​ A number of studies investigating the utility of combining interferon alfa with other therapies such as ECP, pentostatin, and fludarabine have failed to demonstrate significant improvements in response rates.[60][61]​ Interferon alfa 2a and 2b and peginterferon alfa 2b have been discontinued in the US. Peginterferon alfa 2a may be substituted for other interferon preparations.

One study found low-dose oral methotrexate as a single agent to be effective, with a response rate of 76% and a 5-year survival rate of 71%.[62] It is generally well tolerated.

Brentuximab vedotin, an antibody-drug conjugate that enables the cytotoxic drug monomethyl auristatin E (MMAE) to be targeted to CD30+ cancer cells, is approved by the FDA for the treatment of MF and SS. Phase 2 trials have demonstrated that brentuximab vedotin is highly active in CD30+ CTCL.[68][69] The overall response rate is 54% in MF, irrespective of CD30 status. Flares can be seen in MF when starting therapy, and the median time to response in MF is around 12 weeks, with durable remissions seen in some patients and a median duration of response of around 32 weeks. The common adverse effects include neuropathy, fatigue, and drug rash.[69] One phase 3 trial included previously-treated adult patients with CD30+ MF or primary cutaneous anaplastic large-cell lymphoma. It found a significant improvement in objective global response lasting at least 4 months with brentuximab vedotin (56%) versus physician's choice of methotrexate or bexarotene (13%).[70]

Mogamulizumab, a monoclonal antibody that binds to a protein CC chemokine receptor type 4 (CCR4) found on some cancer cells, is approved by the FDA for intravenous use for the treatment of adult patients with relapsed or refractory MF, or SS after at least one prior systemic therapy. One open-label, phase 3 randomised controlled trial demonstrated that mogamulizumab significantly improved progression-free survival, compared with vorinostat, for patients with relapsed or refractory MF or SS.[71] Serious adverse effects included pyrexia, cellulitis, pulmonary embolism, and sepsis. Evidence from a case study of two patients with refractory SS who had been treated with four and five prior systemic therapies respectively, reported that mogamulizumab combined with TSEBT achieved a global complete response in both patients at 9 weeks for the first patient, and 4 weeks for the second patient, and was well tolerated.[67] 

The histone deacetylase (HDAC) inhibitor romidepsin works by inducing histone acetylation and protein acetylation, resulting in downstream events of cell-cycle arrest and apoptosis.[72][73] It is approved by the US FDA for the treatment of MF and SS. 

Extracorporeal photopheresis (ECP), a systemic form of PUVA, is recommended as an option for patients with stage III disease. ECP may be more appropriate in patients with some blood involvement.[5][32] ECP is an effective treatment that has been used to treat CTCL for over 30 years, it is well tolerated with a low adverse effect and toxicity profile.[98][99][100][101]

Combination therapies have been proposed due to the lack of response to ECP in a significant number of patients with advanced disease, as well as in patients with refractory Sézary syndrome.[103][104][105][106][107][108][109][110][111] Recommended combination therapy for stage III disease may include ECP + interferon alfa or a retinoid; ECP + interferon alfa + a retinoid; phototherapy + interferon alfa or a retinoid; phototherapy + ECP; a retinoid + interferon alfa.[5][32] 

Patients who relapse or experience persistent stage III disease should be retreated with the initial treatments. Those who experience disease progression >stage III should be treated according to the stage of relapsed disease.[32] 

See local specialist protocol for dosing guidelines.

Primary options

bexarotene

OR

peginterferon alfa 2a

OR

methotrexate

OR

brentuximab vedotin

OR

mogamulizumab

OR

romidepsin

Plus – antibiotics

Back
ONGOING
|
stage III disease: erythrodermic (without large cell transformation)
Plus – 

antibiotics

Treatment recommended for ALL patients in selected patient group

Systemic antibiotic therapy should be considered for patients with erythrodermic disease, as they are at an increased risk for secondary infection with skin pathogens.[32]​ Refer to local guidance for antibiotic treatment options.

stage IV disease: Sézary syndrome stage IVA1 or IVA2 (without large cell transformation)

1st line – skin-directed therapy

Back
ONGOING
|
stage IV disease: Sézary syndrome stage IVA1 or IVA2 (without large cell transformation)
|
low to intermediate disease burden (e.g., atypical Sézary cells <5 K/mm³)
1st line – 

skin-directed therapy

Stage IV Sézary syndrome stage IVA1 (T1-4, N0-2, M0, B2) or IVA2 (T1-4, N3, M0, B0 or B1 or B2) should be treated with combinations of systemic therapy plus skin-directed therapy.[5][32] Recommended treatment options depend on whether the patient has been diagnosed with SS, non-SS, or visceral disease. For patients with SS, treatment options may differ for patients with low as opposed to high disease burden.[32] 

For patients with stage IV Sézary syndrome with low to intermediate disease burden (e.g., blood atypical Sézary cells [ASC] <5 K/mm³), possible skin-directed therapies include topical corticosteroids, topical imiquimod, topical chlormethine, topical retinoids (e.g., bexarotene), topical carmustine, UVB, PUVA, UVA1, total skin electron beam therapy (TSEBT), or radiotherapy.[32] 

Topical corticosteroids have been shown to achieve good responses and symptomatic relief in early-stage disease.[5] One study demonstrated a complete response in 63% of patients with T1 disease (limited patches, papules, and/or plaques covering <10% of skin surface), and 25% in patients with T2 disease (patches, papules, or plaques covering 10% or more of skin surface), after a median follow-up of 9 months.[41] High-potency topical corticosteroids may be less well tolerated for intertriginous body areas or other areas such as the face.[32] Duration of treatment and the potency of the corticosteroid treatment can result in systemic absorption and skin atrophy. Optimal use of topical corticosteroids should be determined with the help of a dermatologist, and is dependent on lesion type and location.[32] 

Topical imiquimod can be considered for areas with few patches/plaques/small tumours that are recalcitrant to treatment or on sun-damaged skin such as the forearms, scalp, and face.[32] Evidence from case series suggests that imiquimod is effective for the treatment of early stage MF refractory to other therapies.[42][43][44][45]

Chlormethine, a potent DNA alkylating agent, has been shown to treat superficial skin disease with success.[5][46][47][48] Topical chlormethine treatment is associated with dermatitis, and can cause irritation when used on the face and intertriginous areas of the skin.[32] Treatment should be initiated at a less than daily use to assess tolerability, then slowly increase the application to the usual dose.[32] 

Topical retinoids may be considered for the treatment of cutaneous lesions in patients with early-stage cutaneous T-cell lymphoma (CTCL) who are refractory to other topical therapies, or who are unable to tolerate other therapies.[5]​​[49] Bexarotene gel is the only FDA-approved topical retinoid for the treatment of MF and SS. In one trial, bexarotene gel has shown promising results as a lesion-directed treatment in early-stage CTCL (overall response rate of 63% and a clinical complete response rate of 21%, with median response duration of 99 weeks).[50] Topical retinoids can cause skin irritation including redness, peeling, and dermatitis when used on face and intertriginous body areas.[32] 

Carmustine, a potent DNA alkylating agent, has been shown to be an effective treatment for early stage patch/plaque MF, and has similar efficacy to chlormethine.[51][52] As topical carmustine is extensively absorbed, it is associated with an increased risk of bone marrow suppression.[5]

CTCL are radiosensitive tumours, and external beam radiotherapy plays an important role in the management of isolated localised skin disease, as well as in the palliation of thick patches and bulky tumour nodules.[53] Relatively low doses of low-energy radiotherapy are all that is required, and superficial skin disease can be effectively treated with doses given between 4 Gy and 40 Gy. Radiotherapy (24-30 Gy) is recommended as monotherapy for unilesional lesions with curative intent.[32] Low-dose radiotherapy (8-12 Gy) is usually given in combination with other therapies for palliative treatment.[32] 

Phototherapy with ultraviolet B (UVB) can be used to treat patch disease. One study reported a complete response rate of 83%, with a median duration of remission of 22 months.[54] PUVA therapy (consisting of orally administered methoxsalen [8-methoxypsoralen], activated when exposed to long-wavelength ultraviolet light) is considered the treatment of choice for patients with plaque disease, due to increased penetration into the dermis, and remains one of the most effective therapies for patients with early disease. However, PUVA is associated with an increased skin toxicity compared with UVB, and there are few data regarding the effects of PUVA therapy on overall survival. Maintenance treatment may prolong the period of remission. Use of PUVA as a single therapy is generally restricted to early-stage CTCL, as patients with advanced disease are unlikely to achieve a complete response with PUVA alone. As far as possible, the total dose of PUVA should be restricted to <200 treatment sessions, due to the risk of secondary skin cancers associated with a high cumulative total UVA dose.

Total skin electron beam therapy (TSEBT) is recommended in patients with a higher skin disease burden diffuse plaque involvement.[32] Usually, 4-MeV to 9-MeV electrons are delivered to the skin using a 6 or 8 field technique. This allows sparing of the structures below the dermis, as 80% is delivered in the first 1 cm and <5% beyond a 2-cm depth. High doses have been shown to achieve more durable remissions than lower doses.[63][64]​ Complete response rates for early disease range from 56% to 96%.[63][64][65]​ Response rates in advanced disease are generally lower, but good palliation has been achieved.[66] TSEBT may be followed with systemic therapies to maintain response.[32] There is limited safety data for the use of TSEBT in combination with systemic retinoids, histone deacetylase (HDAC) inhibitors such as vorinostat or romidepsin, or mogamulizumab, or combining phototherapy with vorinostat or romidepsin.[32][67]

Patients who relapse or experience persistent stage IV Sézary syndrome with low to intermediate disease burden should be retreated with initial treatment options.[5][32]

See local specialist protocol for dosing guidelines.

Primary options

imiquimod topical

OR

chlormethine topical

OR

bexarotene topical

OR

carmustine

Plus – systemic therapy

Back
ONGOING
|
stage IV disease: Sézary syndrome stage IVA1 or IVA2 (without large cell transformation)
|
low to intermediate disease burden (e.g., atypical Sézary cells <5 K/mm³)
Plus – 

systemic therapy

Treatment recommended for ALL patients in selected patient group

Preferred systemic therapies for stage IV Sézary syndrome stage IVA1 (T1-4, N0-2, M0, B2) or IVA2 (T1-4, N3, M0, B0 or B1 or B2) with low to intermediate disease burden include bexarotene, extracorporeal photopheresis (ECP), interferon alfa, methotrexate, mogamulizumab, romidepsin, or vorinostat.[32] 

Bexarotene, an oral retinoid, is well established as one of the systemic therapies for persistent or refractory early and advanced disease.[56][57] Bexarotene acts by selectively binding to the retinoid x receptor (RXR) family of nuclear receptors. Hypertriglyceridaemia and hypothyroidism are common but reversible adverse effects, and can usually be managed with the initiation of lipid-lowering drugs and thyroxine immediately before starting bexarotene. Alternative retinoids (e.g., acitretin, isotretinoin) may be considered in place of bexarotene.[32]

Interferon alfa is a well-established treatment for cutaneous T-cell lymphoma (CTCL) of various stages (usually beyond limited plaque disease). It may be considered for use before or after, or in combination with, other systemic therapies. Good response rates have been reported, with some remissions lasting >2 years.[59][109]​ A number of studies investigating the utility of combining interferon alfa with other therapies such as ECP, pentostatin, and fludarabine have failed to demonstrate significant improvements in response rates.[60][61]​ Interferon alfa 2a and 2b and peginterferon alfa 2b have been discontinued in the US. Peginterferon alfa 2a may be substituted for other interferon preparations.

One study found low-dose oral methotrexate as a single agent to be effective, with a response rate of 76% and a 5-year survival rate of 71%.[62] It is generally well tolerated.

Mogamulizumab, a monoclonal antibody that binds to a protein CC chemokine receptor type 4 (CCR4) found on some cancer cells, is approved by the FDA for intravenous use for the treatment of adult patients with relapsed or refractory MF, or SS after at least one prior systemic therapy. One open-label, phase 3 randomised controlled trial demonstrated that mogamulizumab significantly improved progression-free survival, compared with vorinostat, for patients with relapsed or refractory MF or SS.[71] Serious adverse effects included pyrexia, cellulitis, pulmonary embolism, and sepsis. Evidence from a case study of two patients with refractory SS who had been treated with four and five prior systemic therapies respectively, reported that mogamulizumab combined with TSEBT achieved a global complete response in both patients at 9 weeks for the first patient, and 4 weeks for the second patient, and was well tolerated.[67] 

Histone deacetylase (HDAC) inhibitors (e.g., vorinostat, romidepsin) work by inducing histone acetylation and protein acetylation, resulting in downstream events of cell-cycle arrest and apoptosis.[72][73] Both are approved by the US FDA for the treatment of MF and SS. Various phase 2 trials have demonstrated improvements in skin lesions and other symptoms (e.g., pruritus) with vorinostat.[74][75]

Recommended combination therapy for patients with low disease burden include ECP + interferon alfa or a retinoid; ECP + interferon alfa + a retinoid; phototherapy + ECP ; phototherapy + interferon alfa or a retinoid; a retinoid + interferon.[5][32] 

Patients who relapse or experience persistent stage IV Sézary syndrome with low to intermediate disease burden should be retreated with initial treatment options.[32] 

See local specialist protocol for dosing guidelines.

Primary options

bexarotene

OR

peginterferon alfa 2a

OR

methotrexate

OR

mogamulizumab

OR

vorinostat

OR

romidepsin

1st line – skin-directed therapy

Back
ONGOING
|
stage IV disease: Sézary syndrome stage IVA1 or IVA2 (without large cell transformation)
|
high disease burden (e.g., atypical Sézary cells >5 K/mm³)
1st line – 

skin-directed therapy

Stage IV Sézary syndrome stage IVA1 (T1-4, N0-2, M0, B2) or IVA2 (T1-4, N3, M0, B0 or B1 or B2) should be treated with combinations of systemic therapy plus skin-directed therapy.[5][32] Recommended treatment options depend on whether the patient has been diagnosed with SS, non-SS, or visceral disease. For patients with SS, treatment options may differ for patients with low as opposed to high disease burden.[32] 

For patients with stage IV Sézary syndrome with high disease burden (e.g., blood atypical Sézary cells [ASC] >5 K/mm³), possible skin-directed therapies include topical corticosteroids, topical imiquimod, chlormethine, topical retinoids (e.g., bexarotene), topical carmustine, UVB, PUVA, UVA1, total skin electron beam therapy (TSEBT), or radiotherapy.[32] 

Topical corticosteroids have been shown to achieve good responses and symptomatic relief in early-stage disease.[5] One study demonstrated a complete response in 63% of patients with T1 disease (limited patches, papules, and/or plaques covering <10% of skin surface), and 25% in patients with T2 disease (patches, papules, or plaques covering 10% or more of skin surface), after a median follow-up of 9 months.[41] High-potency topical corticosteroids may be less well tolerated for intertriginous body areas or other areas such as the face.[32] Duration of treatment and the potency of the corticosteroid treatment can result in systemic absorption and skin atrophy. Optimal use of topical corticosteroids should be determined with the help of a dermatologist, and is dependent on lesion type and location.[32] 

Topical imiquimod can be considered for areas with few patches/plaques/small tumours that are recalcitrant to treatment or on sun-damaged skin such as the forearms, scalp, and face.[32] Evidence from case series suggests that imiquimod is effective for the treatment of early stage MF refractory to other therapies.[42][43][44][45]

Chlormethine, a potent DNA alkylating agent, has been shown to treat superficial skin disease with success.[5][46][47][48] Topical chlormethine treatment is associated with dermatitis, and can cause irritation when used on the face and intertriginous areas of the skin.[32] Treatment should be initiated at a less than daily use to assess tolerability, then slowly increase the application to the usual dose.[32] 

Topical retinoids may be considered for the treatment of cutaneous lesions in patients with early-stage cutaneous T-cell lymphoma (CTCL) who are refractory to other topical therapies, or who are unable to tolerate other therapies.[5]​​[49] Bexarotene gel is the only FDA-approved topical retinoid for the treatment of MF and SS. In one trial, bexarotene gel has shown promising results as a lesion-directed treatment in early-stage CTCL (overall response rate of 63% and a clinical complete response rate of 21%, with median response duration of 99 weeks).[50] Topical retinoids can cause skin irritation including redness, peeling, and dermatitis when used on face and intertriginous body areas.[32] 

Carmustine, a potent DNA alkylating agent, has been shown to be an effective treatment for early stage patch/plaque MF, and has similar efficacy to chlormethine.[51][52] As topical carmustine is extensively absorbed, it is associated with an increased risk of bone marrow suppression.[5]

CTCL are radiosensitive tumours, and external beam radiotherapy plays an important role in the management of isolated localised skin disease, as well as in the palliation of thick patches and bulky tumour nodules.[53] Relatively low doses of low-energy radiotherapy are all that is required, and superficial skin disease can be effectively treated with doses given between 4 Gy and 40 Gy. Radiotherapy (24-30 Gy) is recommended as monotherapy for unilesional lesions with curative intent.[32] Low-dose radiotherapy (8-12 Gy) is usually given in combination with other therapies for palliative treatment.[32] 

Phototherapy with ultraviolet B (UVB) can be used to treat patch disease. One study reported a complete response rate of 83%, with a median duration of remission of 22 months.[54] Phototherapy use should be balanced against the risks in patients with a history of extensive squamoproliferative skin neoplasms or basal cell carcinomas or who have had melanoma, as a cumulative dose of UV is associated with increased risk of UV-associated skin neoplasms.[32] PUVA therapy (consisting of orally administered methoxsalen [8-methoxypsoralen], activated when exposed to long-wavelength ultraviolet light) is considered the treatment of choice for patients with plaque disease, due to increased penetration into the dermis, and remains one of the most effective therapies for patients with early disease. However, PUVA is associated with an increased skin toxicity compared with UVB, and there are few data regarding the effects of PUVA therapy on overall survival. Maintenance treatment may prolong the period of remission. Use of PUVA as a single therapy is generally restricted to early-stage CTCL, as patients with advanced disease are unlikely to achieve a complete response with PUVA alone. As far as possible, the total dose of PUVA should be restricted to <200 treatment sessions, due to the risk of secondary skin cancers associated with a high cumulative total UVA dose.

Total skin electron beam therapy (TSEBT) is recommended in patients with a higher skin disease burden diffuse plaque involvement.[32] Usually, 4-MeV to 9-MeV electrons are delivered to the skin using a 6 or 8 field technique. This allows sparing of the structures below the dermis, as 80% is delivered in the first 1 cm and <5% beyond a 2-cm depth. High doses have been shown to achieve more durable remissions than lower doses.[63][64]​ Complete response rates for early disease range from 56% to 96%.[63][64][65]​ Response rates in advanced disease are generally lower, but good palliation has been achieved.[66] TSEBT may be followed with systemic therapies to maintain response.[32] There is limited safety data for the use of TSEBT in combination with systemic retinoids, histone deacetylase (HDAC) inhibitors such as vorinostat or romidepsin, or mogamulizumab, or combining phototherapy with vorinostat or romidepsin.[32][67]

Patients who relapse or experience persistent stage IV Sézary syndrome with high disease burden should be retreated with initial treatment options.[5][32]

See local specialist protocol for dosing guidelines.

Primary options

imiquimod topical

OR

chlormethine topical

OR

bexarotene topical

OR

carmustine

Plus – systemic therapy

Back
ONGOING
|
stage IV disease: Sézary syndrome stage IVA1 or IVA2 (without large cell transformation)
|
high disease burden (e.g., atypical Sézary cells >5 K/mm³)
Plus – 

systemic therapy

Treatment recommended for ALL patients in selected patient group

Preferred systemic therapies for patients with stage IV Sézary syndrome stage IVA1 (T1-4, N0-2, M0, B2) or IVA2 (T1-4, N3, M0, B0 or B1 or B2) with high disease burden include mogamulizumab and romidepsin.[5][32] 

Mogamulizumab, a monoclonal antibody that binds to a protein CC chemokine receptor type 4 (CCR4) found on some cancer cells, is approved by the FDA for intravenous use for the treatment of adult patients with relapsed or refractory MF, or SS after at least one prior systemic therapy. One open-label, phase 3 randomised controlled trial demonstrated that mogamulizumab significantly improved progression-free survival, compared with vorinostat, for patients with relapsed or refractory MF or SS.[71] Serious adverse effects included pyrexia, cellulitis, pulmonary embolism, and sepsis. Evidence from a case study of two patients with refractory SS who had been treated with four and five prior systemic therapies respectively, reported that mogamulizumab combined with TSEBT achieved a global complete response in both patients at 9 weeks for the first patient, and 4 weeks for the second patient, and was well tolerated.[67] 

The histone deacetylase (HDAC) inhibitor romidepsin works by inducing histone acetylation and protein acetylation, resulting in downstream events of cell-cycle arrest and apoptosis.[72][73] It is approved by the US FDA for the treatment of MF and SS. 

Recommended combination therapies for stage IV Sézary syndrome with high disease burden include phototherapy + ECP; phototherapy + interferon alfa or a retinoid; ECP + interferon alfa or a retinoid ; ECP + interferon alfa + a retinoid; a retinoid + interferon alfa.

Patients who relapse or experience persistent stage IV Sézary syndrome with high disease burden should be retreated with initial treatment options.[5][32]

See local specialist protocol for dosing guidelines.

Primary options

mogamulizumab

OR

romidepsin

stage IV disease: non-Sézary syndrome stage IVA2 or visceral disease/solid organ IVB (without large cell transformation)

1st line – systemic therapy

Back
ONGOING
|
stage IV disease: non-Sézary syndrome stage IVA2 or visceral disease/solid organ IVB (without large cell transformation)
1st line – 

systemic therapy

Stage IV non-Sézary syndrome stage IVA2 (T1-4, N3, M0, B0 or B1 or B2) or visceral disease/solid organ IVB (T1-4, N0-3, M1, B0 or B1 or B2) patients should be treated with systemic therapy with or without radiotherapy for local control.[32]

The recommended systemic options for stage IV non-Sézary syndrome or visceral/solid organ disease include brentuximab vedotin, gemcitabine, liposomal doxorubicin, pralatrexate, and romidepsin.[5][32]

Brentuximab vedotin, an antibody-drug conjugate that enables the cytotoxic drug monomethyl auristatin E (MMAE) to be targeted to CD30+ cancer cells, is approved by the FDA for the treatment of MF and SS. Phase 2 trials have demonstrated that brentuximab vedotin is highly active in CD30+ CTCL.[68][69] The overall response rate is 54% in MF, irrespective of CD30 status. Flares can be seen in MF when starting therapy, and the median time to response in MF is around 12 weeks, with durable remissions seen in some patients and a median duration of response of around 32 weeks. The common adverse effects include neuropathy, fatigue, and drug rash.[69] One phase 3 trial included previously-treated adult patients with CD30+ MF or primary cutaneous anaplastic large-cell lymphoma. It found a significant improvement in objective global response lasting at least 4 months with brentuximab vedotin (56%) versus physician's choice of methotrexate or bexarotene (13%).[70]

Gemcitabine, a pyrimidine antimetabolite, has demonstrated good response rates and is well tolerated in patients with pretreated cutaneous T-cell lymphoma.[81][82][83]

Evidence from two phase 2 prospective open-label trials suggests that liposomal doxorubicin monotherapy improved overall response rates, median time to progression, and median duration of response in patients with advanced cutaneous T-cell lymphoma (CTCL; stage II to IV CTCL [including SS and transformed CTCL] or stage IIB to IVB MF, respectively) refractory to at least two previous lines of treatment.[76][77]

Pralatrexate, a dihydrofolate reductase inhibitor, has shown efficacy for patients with relapsed or refractory MF or SS.[78][79][80] Evidence suggests that pralatrexate either alone or in combination with low-dose bexarotene is well tolerated, and improves median response, median duration of treatment, and median progression-free survival in patients with relapsed, refractory, or transformed large cell MF.[78][79][80]

The histone deacetylase (HDAC) inhibitor romidepsin works by inducing histone acetylation and protein acetylation, resulting in downstream events of cell-cycle arrest and apoptosis.[72][73] It is approved by the US FDA for the treatment of MF and SS. 

If disease is present in the lymph nodes and/or viscera, or there is suspicion of disease progression, patients should be reassessed after initial treatment, using imaging techniques based on the distribution of the disease (see Diagnosis section).[32]

Patients who relapse or experience persistent stage IV non-Sézary syndrome or visceral/solid organ disease should be retreated with the initial treatments; alternatively, a clinical trial or allogeneic haematopoietic cell transplant (HCT) may be considered.[32]

See local specialist protocol for dosing guidelines.

Primary options

brentuximab vedotin

OR

gemcitabine

OR

doxorubicin liposomal

OR

pralatrexate

OR

romidepsin

Consider – radiotherapy

Back
ONGOING
|
stage IV disease: non-Sézary syndrome stage IVA2 or visceral disease/solid organ IVB (without large cell transformation)
Consider – 

radiotherapy

Additional treatment recommended for SOME patients in selected patient group

Stage IV non-Sézary syndrome stage IVA2 (T1-4, N3, M0, B0 or B1 or B2) or visceral disease/solid organ IVB (T1-4, N0-3, M1, B0 or B1 or B2) patients should be treated with systemic therapy with or without radiotherapy for local control.[32]

2nd line – allogeneic haematopoietic cell transplant

Back
ONGOING
|
stage IV disease: non-Sézary syndrome stage IVA2 or visceral disease/solid organ IVB (without large cell transformation)
2nd line – 

allogeneic haematopoietic cell transplant

Patients who relapse or experience persistent stage IV non-Sézary syndrome stage IVA2 (T1-4, N3, M0, B0 or B1 or B2) or visceral disease/solid organ IVB (T1-4, N0-3, M1, B0 or B1 or B2) should be retreated with the initial treatments, alternatively allogeneic haematopoietic cell transplant (HCT) may be considered.[32]

Allogeneic HCT has demonstrated efficacy for the treatment of patients with advanced stage MF and SS who have received multiple previous therapies in a number of small prospective studies.[94][95][96][97] Allogeneic HCT is associated with better outcomes in patients with disease responding to primary treatment prior to transplant.[32]

large cell transformation

1st line – radiotherapy with stage-appropriate treatment

Back
ONGOING
|
large cell transformation
|
limited cutaneous lesions
1st line – 

radiotherapy with stage-appropriate treatment

Skin biopsy with greater than 25% of lymphoid/tumour cell infiltrates indicates large cell transformation (LCT).[32] LCT is significantly more likely in patients with advanced disease, but can occur in early disease, and is often aggressive.[32]

Radiotherapy to lesions with LCT, with concurrent management of coexisting disease based on clinical stage, is recommended for patients with limited cutaneous lesions with LCT.[32]

Relapse or persistent LCT should be managed with retreatment with radiotherapy and stage-appropriate treatment of coexisting disease.[32]

Patients with refractory disease to multiple previous therapies can be treated as patients with generalised cutaneous or extracutaneous lesions with LCT.

1st line – skin-directed therapy

Back
ONGOING
|
large cell transformation
|
generalised cutaneous or extracutaneous lesions
1st line – 

skin-directed therapy

Patients with generalised cutaneous or extracutaneous lesions with LCT should be treated with systemic treatment with skin-directed therapy.[32]

Potential skin-directed therapies for generalised cutaneous or extracutaneous lesions with LCT include topical corticosteroids, topical imiquimod, topical chlormethine, topical retinoids (e.g., bexarotene), topical carmustine, UVB, PUVA, UVA1, total skin electron beam therapy (TSEBT), or radiotherapy.[32]

Topical corticosteroids have been shown to achieve good responses and symptomatic relief in early-stage disease.[5] One study demonstrated a complete response in 63% of patients with T1 disease (limited patches, papules, and/or plaques covering <10% of skin surface), and 25% in patients with T2 disease (patches, papules, or plaques covering 10% or more of skin surface), after a median follow-up of 9 months.[41] High-potency topical corticosteroids may be less well tolerated for intertriginous body areas or other areas such as the face.[32] Duration of treatment and the potency of the corticosteroid treatment can result in systemic absorption and skin atrophy. Optimal use of topical corticosteroids should be determined with the help of a dermatologist, and is dependent on lesion type and location.[32] 

Topical imiquimod can be considered for areas with few patches/plaques/small tumours that are recalcitrant to treatment or on sun-damaged skin such as the forearms, scalp, and face.[32] Evidence from case series suggests that imiquimod is effective for the treatment of early stage MF refractory to other therapies.[42][43][44][45]

Chlormethine, a potent DNA alkylating agent, has been shown to treat superficial skin disease with success.[5][46][47][48] Topical chlormethine treatment is associated with dermatitis, and can cause irritation when used on the face and intertriginous areas of the skin.[32] Treatment should be initiated at a less than daily use to assess tolerability, then slowly increase the application to the usual dose.[32] 

Topical retinoids may be considered for the treatment of cutaneous lesions in patients with early-stage cutaneous T-cell lymphoma (CTCL) who are refractory to other topical therapies, or who are unable to tolerate other therapies.[5]​​[49] Bexarotene gel is the only FDA-approved topical retinoid for the treatment of MF and SS. In one trial, bexarotene gel has shown promising results as a lesion-directed treatment in early-stage CTCL (overall response rate of 63% and a clinical complete response rate of 21%, with median response duration of 99 weeks).[50] Topical retinoids can cause skin irritation including redness, peeling, and dermatitis when used on face and intertriginous body areas.[32] 

Carmustine, a potent DNA alkylating agent, has been shown to be an effective treatment for early stage patch/plaque MF, and has similar efficacy to chlormethine.[51][52] As topical carmustine is extensively absorbed, it is associated with an increased risk of bone marrow suppression.[5]

CTCL are radiosensitive tumours, and external beam radiotherapy plays an important role in the management of isolated localised skin disease, as well as in the palliation of thick patches and bulky tumour nodules.[53] Relatively low doses of low-energy radiotherapy are all that is required, and superficial skin disease can be effectively treated with doses given between 4 Gy and 40 Gy. Radiotherapy (24-30 Gy) is recommended as monotherapy for unilesional lesions with curative intent.[32] Low-dose radiotherapy (8-12 Gy) is usually given in combination with other therapies for palliative treatment.[32] 

Phototherapy with ultraviolet B (UVB) can be used to treat patch disease. One study reported a complete response rate of 83%, with a median duration of remission of 22 months.[54] PUVA therapy (consisting of orally administered methoxsalen [8-methoxypsoralen], activated when exposed to long-wavelength ultraviolet light) is considered the treatment of choice for patients with plaque disease, due to increased penetration into the dermis, and remains one of the most effective therapies for patients with early disease. However, PUVA is associated with an increased skin toxicity compared with UVB, and there are few data regarding the effects of PUVA therapy on overall survival. Maintenance treatment may prolong the period of remission. Use of PUVA as a single therapy is generally restricted to early-stage CTCL, as patients with advanced disease are unlikely to achieve a complete response with PUVA alone. As far as possible, the total dose of PUVA should be restricted to <200 treatment sessions, due to the risk of secondary skin cancers associated with a high cumulative total UVA dose.

Total skin electron beam therapy (TSEBT) is recommended in patients with a higher skin disease burden diffuse plaque involvement.[32] Usually, 4-MeV to 9-MeV electrons are delivered to the skin using a 6 or 8 field technique. This allows sparing of the structures below the dermis, as 80% is delivered in the first 1 cm and <5% beyond a 2-cm depth. High doses have been shown to achieve more durable remissions than lower doses.[63][64]​ Complete response rates for early disease range from 56% to 96%.[63][64][65]​ Response rates in advanced disease are generally lower, but good palliation has been achieved.[66] TSEBT may be followed with systemic therapies to maintain response.[32] There is limited safety data for the use of TSEBT in combination with systemic retinoids, histone deacetylase (HDAC) inhibitors such as vorinostat or romidepsin, or mogamulizumab, or combining phototherapy with vorinostat or romidepsin.[32][67]

Persistent generalised cutaneous or extracutaneous lesions with LCT should be retreated with the initial treatment options.[32] Retreatment should be considered for patients who experience relapse. Alternatively, patients should be entered into a clinical trial, or allogeneic HCT should be considered.[32]

See local specialist protocol for dosing guidelines.

Primary options

imiquimod topical

OR

chlormethine topical

OR

bexarotene topical

OR

carmustine

Plus – systemic therapy

Back
ONGOING
|
large cell transformation
|
generalised cutaneous or extracutaneous lesions
Plus – 

systemic therapy

Treatment recommended for ALL patients in selected patient group

In patients requiring systemic therapy, single agents are preferred over combination therapy due to the higher toxicity profiles associated with multi-agent regimens and the short-lived responses seen with time-limited combination chemotherapy.

Preferred single-agent systemic therapies for generalised cutaneous or extracutaneous lesions with LCT include brentuximab vedotin, gemcitabine, liposomal doxorubicin, pralatrexate, and romidepsin.[32]

Brentuximab vedotin, an antibody-drug conjugate that enables the cytotoxic drug monomethyl auristatin E (MMAE) to be targeted to CD30+ cancer cells, is approved by the FDA for the treatment of MF and SS. Phase 2 trials have demonstrated that brentuximab vedotin is highly active in CD30+ CTCL.[68][69] The overall response rate is 54% in MF, irrespective of CD30 status. Flares can be seen in MF when starting therapy, and the median time to response in MF is around 12 weeks, with durable remissions seen in some patients and a median duration of response of around 32 weeks. The common adverse effects include neuropathy, fatigue, and drug rash.[69] One phase 3 trial included previously-treated adult patients with CD30+ MF or primary cutaneous anaplastic large-cell lymphoma. It found a significant improvement in objective global response lasting at least 4 months with brentuximab vedotin (56%) versus physician's choice of methotrexate or bexarotene (13%).[70]

Gemcitabine, a pyrimidine antimetabolite, has demonstrated good response rates and is well tolerated in patients with pretreated cutaneous T-cell lymphoma.[81][82][83]

Evidence from two phase 2 prospective open-label trials suggests that liposomal doxorubicin monotherapy improved overall response rates, median time to progression and median duration of response in patients with advanced cutaneous T-cell lymphoma (CTCL; stage II to IV CTCL [including SS and transformed CTCL] or stage IIB to IVB MF, respectively) refractory to at least two previous lines of treatment.[76][77]

Pralatrexate, a dihydrofolate reductase inhibitor, has shown efficacy for patients with relapsed or refractory MF or SS.[78][79][80] Evidence suggests that pralatrexate either alone or in combination with low-dose bexarotene is well tolerated, and improves median response, median duration of treatment, and median progression-free survival in patients with relapsed, refractory, or transformed large cell MF.[78][79][80]

The histone deacetylase (HDAC) inhibitor romidepsin works by inducing histone acetylation and protein acetylation, resulting in downstream events of cell-cycle arrest and apoptosis.[72][73] It is approved by the US FDA for the treatment of MF and SS. 

Persistent generalised cutaneous or extracutaneous lesions with LCT should be retreated with the initial treatment options.[32] Retreatment should be considered for patients who experience relapse. Alternatively, patients should be entered into a clinical trial, or allogeneic HCT should be considered.[32]

See local specialist protocol for dosing guidelines.

Primary options

brentuximab vedotin

OR

gemcitabine

OR

doxorubicin liposomal

OR

pralatrexate

OR

romidepsin

2nd line – allogeneic haematopoietic cell transplant

Back
ONGOING
|
large cell transformation
|
generalised cutaneous or extracutaneous lesions
2nd line – 

allogeneic haematopoietic cell transplant

Patients with relapsed persistent generalised cutaneous or extracutaneous lesions with LCT should be retreated with the initial treatment options.[32] Alternatively, allogeneic haematopoietic cell transplant (HCT) should be considered or patients should be entered into a clinical trial.[32]

Plus – skin-directed therapy

Back
ONGOING
|
large cell transformation
|
generalised cutaneous or extracutaneous lesions
Plus – 

skin-directed therapy

Treatment recommended for ALL patients in selected patient group

Potential skin-directed therapies for generalised cutaneous or extracutaneous lesions with LCT include topical corticosteroids, topical imiquimod, topical chlormethine, topical retinoids (e.g., bexarotene), topical carmustine, UVB, PUVA, UVA1, TSEBT, or radiotherapy.[32]

Topical corticosteroids have been shown to achieve good responses and symptomatic relief in early-stage disease.[5] One study demonstrated a complete response in 63% of patients with T1 disease (limited patches, papules, and/or plaques covering <10% of skin surface), and 25% in patients with T2 disease (patches, papules, or plaques covering 10% or more of skin surface), after a median follow-up of 9 months.[41] High-potency topical corticosteroids may be less well tolerated for intertriginous body areas or other areas such as the face.[32] Duration of treatment and the potency of the corticosteroid treatment can result in systemic absorption and skin atrophy. Optimal use of topical corticosteroids should be determined with the help of a dermatologist, and is dependent on lesion type and location.[32] 

Topical imiquimod can be considered for areas with few patches/plaques/small tumours that are recalcitrant to treatment or on sun-damaged skin such as the forearms, scalp, and face.[32] Evidence from case series suggests that imiquimod is effective for the treatment of early stage MF refractory to other therapies.[42][43][44][45]

Chlormethine, a potent DNA alkylating agent, has been shown to treat superficial skin disease with success.[5][46][47][48] Topical chlormethine treatment is associated with dermatitis, and can cause irritation when used on the face and intertriginous areas of the skin.[32] Treatment should be initiated at a less than daily use to assess tolerability, then slowly increase the application to the usual dose.[32] 

Topical retinoids may be considered for the treatment of cutaneous lesions in patients with early-stage cutaneous T-cell lymphoma (CTCL) who are refractory to other topical therapies, or who are unable to tolerate other therapies.[5]​​[49] Bexarotene gel is the only FDA-approved topical retinoid for the treatment of MF and SS. In one trial, bexarotene gel has shown promising results as a lesion-directed treatment in early-stage CTCL (overall response rate of 63% and a clinical complete response rate of 21%, with median response duration of 99 weeks).[50] Topical retinoids can cause skin irritation including redness, peeling, and dermatitis when used on face and intertriginous body areas.[32] 

Carmustine, a potent DNA alkylating agent, has been shown to be an effective treatment for early stage patch/plaque MF, and has similar efficacy to chlormethine.[51][52] As topical carmustine is extensively absorbed, it is associated with an increased risk of bone marrow suppression.[5]

CTCL are radiosensitive tumours, and external beam radiotherapy plays an important role in the management of isolated localised skin disease, as well as in the palliation of thick patches and bulky tumour nodules.[53] Relatively low doses of low-energy radiotherapy are all that is required, and superficial skin disease can be effectively treated with doses given between 4 Gy and 40 Gy. Radiotherapy (24-30 Gy) is recommended as monotherapy for unilesional lesions with curative intent.[32] Low-dose radiotherapy (8-12 Gy) is usually given in combination with other therapies for palliative treatment.[32] 

Phototherapy with ultraviolet B (UVB) can be used to treat patch disease. One study reported a complete response rate of 83%, with a median duration of remission of 22 months.[54] PUVA therapy (consisting of orally administered methoxsalen [8-methoxypsoralen], activated when exposed to long-wavelength ultraviolet light) is considered the treatment of choice for patients with plaque disease, due to increased penetration into the dermis, and remains one of the most effective therapies for patients with early disease. However, PUVA is associated with an increased skin toxicity compared with UVB, and there are few data regarding the effects of PUVA therapy on overall survival. Maintenance treatment may prolong the period of remission. Use of PUVA as a single therapy is generally restricted to early-stage CTCL, as patients with advanced disease are unlikely to achieve a complete response with PUVA alone. As far as possible, the total dose of PUVA should be restricted to <200 treatment sessions, due to the risk of secondary skin cancers associated with a high cumulative total UVA dose.

Total skin electron beam therapy (TSEBT) is recommended in patients with a higher skin disease burden diffuse plaque involvement.[32] Usually, 4-MeV to 9-MeV electrons are delivered to the skin using a 6 or 8 field technique. This allows sparing of the structures below the dermis, as 80% is delivered in the first 1 cm and <5% beyond a 2-cm depth. High doses have been shown to achieve more durable remissions than lower doses.[63][64]​ Complete response rates for early disease range from 56% to 96%.[63][64][65]​ Response rates in advanced disease are generally lower, but good palliation has been achieved.[66] TSEBT may be followed with systemic therapies to maintain response.[32] There is limited safety data for the use of TSEBT in combination with systemic retinoids, histone deacetylase (HDAC) inhibitors such as vorinostat or romidepsin, or mogamulizumab, or combining phototherapy with vorinostat or romidepsin.[32][67]

Persistent generalised cutaneous or extracutaneous lesions with LCT should be retreated with the initial treatment options.[32] Retreatment should be considered for patients who experience relapse. Alternatively, patients should be entered into a clinical trial, or allogeneic HCT should be considered.[32]

See local specialist protocol for dosing guidelines.

Primary options

imiquimod topical

OR

chlormethine topical

OR

bexarotene topical

OR

carmustine

3rd line – multi-agent chemotherapy

Back
ONGOING
|
large cell transformation
|
generalised cutaneous or extracutaneous lesions
3rd line – 

multi-agent chemotherapy

Multi-agent chemotherapy regimens are reserved for patients with relapsed/refractory or extracutaneous disease. Most patients are treated with multiple single-agent systemic therapies before receiving multi-agent chemotherapy.[32]

Combination regimens may include: DHAP (dexamethasone, cytarabine, platinum compound [carboplatin, cisplatin, or oxaliplatin]); ESHAP (etoposide, methylprednisolone, cytarabine, platinum compound [cisplatin or oxaliplatin]); GDP (gemcitabine, dexamethasone, cisplatin); GemOx (gemcitabine, oxaliplatin); ICE (ifosfamide, carboplatin, etoposide).

Persistent generalised cutaneous or extracutaneous lesions with LCT should be retreated with the initial treatment options.[32] Retreatment should be considered for patients who experience relapse. Alternatively, patients should be entered into a clinical trial, or allogeneic HCT should be considered.[32]

See local specialist protocol for choice of regimen and dosing guidelines.

Plus – skin-directed therapy

Back
ONGOING
|
large cell transformation
|
generalised cutaneous or extracutaneous lesions
Plus – 

skin-directed therapy

Treatment recommended for ALL patients in selected patient group

Potential skin-directed therapies for generalised cutaneous or extracutaneous lesions with LCT include topical corticosteroids, topical imiquimod, topical chlormethine, topical retinoids (e.g., bexarotene), topical carmustine, UVB, PUVA, UVA1, TSEBT, or radiotherapy.[32]

Topical corticosteroids have been shown to achieve good responses and symptomatic relief in early-stage disease.[5] One study demonstrated a complete response in 63% of patients with T1 disease (limited patches, papules, and/or plaques covering <10% of skin surface), and 25% in patients with T2 disease (patches, papules, or plaques covering 10% or more of skin surface), after a median follow-up of 9 months.[41] High-potency topical corticosteroids may be less well tolerated for intertriginous body areas or other areas such as the face.[32] Duration of treatment and the potency of the corticosteroid treatment can result in systemic absorption and skin atrophy. Optimal use of topical corticosteroids should be determined with the help of a dermatologist, and is dependent on lesion type and location.[32] 

Topical imiquimod can be considered for areas with few patches/plaques/small tumours that are recalcitrant to treatment or on sun-damaged skin such as the forearms, scalp, and face.[32] Evidence from case series suggests that imiquimod is effective for the treatment of early stage MF refractory to other therapies.[42][43][44][45]

Chlormethine, a potent DNA alkylating agent, has been shown to treat superficial skin disease with success.[5][46][47][48] Topical chlormethine treatment is associated with dermatitis, and can cause irritation when used on the face and intertriginous areas of the skin.[32] Treatment should be initiated at a less than daily use to assess tolerability, then slowly increase the application to the usual dose.[32] 

Topical retinoids may be considered for the treatment of cutaneous lesions in patients with early-stage cutaneous T-cell lymphoma (CTCL) who are refractory to other topical therapies, or who are unable to tolerate other therapies.[5]​​[49] Bexarotene gel is the only FDA-approved topical retinoid for the treatment of MF and SS. In one trial, bexarotene gel has shown promising results as a lesion-directed treatment in early-stage CTCL (overall response rate of 63% and a clinical complete response rate of 21%, with median response duration of 99 weeks).[50] Topical retinoids can cause skin irritation including redness, peeling, and dermatitis when used on face and intertriginous body areas.[32] 

Carmustine, a potent DNA alkylating agent, has been shown to be an effective treatment for early stage patch/plaque MF, and has similar efficacy to chlormethine.[51][52] As topical carmustine is extensively absorbed, it is associated with an increased risk of bone marrow suppression.[5]

CTCL are radiosensitive tumours, and external beam radiotherapy plays an important role in the management of isolated localised skin disease, as well as in the palliation of thick patches and bulky tumour nodules.[53] Relatively low doses of low-energy radiotherapy are all that is required, and superficial skin disease can be effectively treated with doses given between 4 Gy and 40 Gy. Radiotherapy (24-30 Gy) is recommended as monotherapy for unilesional lesions with curative intent.[32] Low-dose radiotherapy (8-12 Gy) is usually given in combination with other therapies for palliative treatment.[32] 

Phototherapy with ultraviolet B (UVB) can be used to treat patch disease. One study reported a complete response rate of 83%, with a median duration of remission of 22 months.[54] PUVA therapy (consisting of orally administered methoxsalen [8-methoxypsoralen], activated when exposed to long-wavelength ultraviolet light) is considered the treatment of choice for patients with plaque disease, due to increased penetration into the dermis, and remains one of the most effective therapies for patients with early disease. However, PUVA is associated with an increased skin toxicity compared with UVB, and there are few data regarding the effects of PUVA therapy on overall survival. Maintenance treatment may prolong the period of remission. Use of PUVA as a single therapy is generally restricted to early-stage CTCL, as patients with advanced disease are unlikely to achieve a complete response with PUVA alone. As far as possible, the total dose of PUVA should be restricted to <200 treatment sessions, due to the risk of secondary skin cancers associated with a high cumulative total UVA dose.

Total skin electron beam therapy (TSEBT) is recommended in patients with a higher skin disease burden diffuse plaque involvement.[32] Usually, 4-MeV to 9-MeV electrons are delivered to the skin using a 6 or 8 field technique. This allows sparing of the structures below the dermis, as 80% is delivered in the first 1 cm and <5% beyond a 2-cm depth. High doses have been shown to achieve more durable remissions than lower doses.[63][64]​ Complete response rates for early disease range from 56% to 96%.[63][64][65]​ Response rates in advanced disease are generally lower, but good palliation has been achieved.[66] TSEBT may be followed with systemic therapies to maintain response.[32] There is limited safety data for the use of TSEBT in combination with systemic retinoids, histone deacetylase (HDAC) inhibitors such as vorinostat or romidepsin, or mogamulizumab, or combining phototherapy with vorinostat or romidepsin.[32][67]

Persistent generalised cutaneous or extracutaneous lesions with LCT should be retreated with the initial treatment options.[32] Retreatment should be considered for patients who experience relapse. Alternatively, patients should be entered into a clinical trial, or allogeneic HCT should be considered.[32]

See local specialist protocol for dosing guidelines.

Primary options

imiquimod topical

OR

chlormethine topical

OR

bexarotene topical

OR

carmustine

stage IIB, III, IV disease: refractory to multiple previous therapies (without large cell transformation)

1st line – systemic therapy

Back
ONGOING
|
stage IIB, III, IV disease: refractory to multiple previous therapies (without large cell transformation)
1st line – 

systemic therapy

Patients refractory to multiple therapies should be considered for alternative systemic therapy.[5][32]

Alemtuzumab, an anti-CD52 monoclonal antibody, has shown encouraging results in patients with advanced disease. One study demonstrated an overall response rate of 55% in patients with advanced MF (32% achieved complete response, 23% achieved partial response).[84] Subsequent evidence demonstrates that low-dose alemtuzumab has a high response rate for patients with SS (based on reduction in Sézary cell count) with a good toxicity profile, and may induce long-term remission for SS but not for patients with MF or patients with large cell transformation.[85][86]

Chlorambucil, an alkylating agent, has been demonstrated to be a safe and effective treatment for patients with cutaneous T-cell lymphoma (CTCL) in combination with fluocortolone in one uncontrolled pilot study.[87]

Cyclophosphamide is recommended as a potential single-agent systemic therapy for patients with >stage IIB who are refractory to multiple therapies.[32]

Etoposide, a topoisomerase inhibitor, which inhibits DNA synthesis by forming a complex topoisomerase II and DNA, has been found to be effective for patients with MF, and selected patients with progressive MF unresponsive to other treatments.[88]

Pembrolizumab, a PD1-inhibitor, demonstrated significant anti-tumour activity with durable response and favourable safety profile in patients with advanced MF/SS who had been unresponsive to an average of 4 previous treatments, in one phase 2 multicentre single-arm trial.[89] Pembrolizumab treatment was associated with transient worsening for erythroderma and pruritus in patients with SS.

Pentostatin, an intravenous purine analog, has been shown to be effective.[90][91][92] Common adverse effects include significant immunosuppression.  

Bortezomib, a proteasome inhibitor, demonstrated a 67% response rate among 15 patients, 10 of whom had CTCL, in one study.[93] It may be considered for patients with SS or MF with relapsed or refractory disease.[32]

Allogeneic hematopoietic cell transplant (HCT) has demonstrated efficacy for the treatment of patients with advanced stage MF and SS who have received multiple previous therapies in a number of small prospective studies.[94][95][96][97] Allogeneic HCT is associated with better outcomes in patients with disease responding to primary treatment prior to transplant.[32] 

Patients with stage IIB generalised tumours without erythroderma, or stage III erythrodermic disease who have an inadequate response to multiple therapies may also consider the treatments suggested for the treatment of large cell transformation MF which include single or multi-agent systemic therapies (see large cell transformation patient group for treatment options).[32]

See local specialist protocol for dosing guidelines.

Primary options

alemtuzumab

OR

chlorambucil

OR

cyclophosphamide

OR

etoposide

OR

pembrolizumab

OR

pentostatin

OR

bortezomib

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