Approach

The aim of treatment is to improve symptoms and cosmetic appearance, and reduce the incidence of recurrence. Complete cure is rarely, if ever, achieved.[1][32] Treatment strategies include skin-directed therapy (mainstay of therapy for early disease stage IA, IB to IIA; some options may be used in advanced disease) and systemic treatment (usually reserved for more extensive >stage IIB or refractory disease).[32]

Treatment is individualised based on symptoms of disease, route of administration, toxicities, and overall goals of therapy.[5][31][32]

Skin directed-therapies and systemic regimens that have lower rates of cumulative toxicity, less immunosuppression, and/or higher efficacy that can be tolerated for longer durations are recommended for earlier lines of treatment. Patients who achieve a clinical benefit and/or those with disease responding to treatment should be considered for maintenance or tapering of regimens to optimise response using treatments with less risk of adverse effects and cumulative toxicity.[32]

Clinical trials may be considered in both early and advanced disease if the patient is a suitable candidate.[31][32]

Stage IA (limited skin involvement alone <10% body surface area [BSA])

Skin-directed therapy alone or in combination with other skin-directed therapies is often sufficient to treat stage IA disease.[5][31][32] In patients with histological evidence of folliculotropic mycosis fungoides (FMF), skin disease may be less responsive to topical therapies.

Systemic therapies (single-agent or combination treatments) should be reserved for patients with blood involvement, or when skin-directed therapies do not provide sufficient disease control, or who have disease that is not situated in regions of the body where skin-directed therapies can be applied.[32]

Skin-directed therapy - stage IA (limited skin involvement alone <10% BSA)

Topical corticosteroids

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

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]

Topical chlormethine

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

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 is the only FDA-approved topical retinoid for the treatment of MF or 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]

Topical carmustine

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]

Radiotherapy

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) or narrowband UVB (NB-UVB)

Phototherapy with 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]

Combination therapy

In order to improve response rates and minimise ultraviolet exposure, phototherapy can be combined with systemic treatments for stage IA, IB to IIA, and IIB.[31][32][55]​ 

Systemic therapy - stage IA (limited skin involvement alone <10% BSA)

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:[5][31][32]

  • Retinoids

    • 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

    • A well-established treatment for 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.[58][59]​ 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.

  • Methotrexate

    • 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.

Inadequate response or relapsed/refractory disease

Persistent or relapsed stage IA disease should be retreated with initial therapies. Patients who experience progression beyond stage IA with initial therapy should be treated according to the stage of the progression.[32]

Patients who are refractory to multiple previous therapies preferred for stage IA disease should be managed as patients with stage IB to IIA disease, or may be considered for radiotherapy, or a clinical trial (see section for stage IB to IIA).[5][32]

Stage IB to IIA (skin disease only with ≥10% BSA)

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] 

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 an inadequate response to skin-directed therapy.[32]

Skin-directed therapy - stage IB to IIA (skin disease only with ≥10% BSA)

For patients with a lower disease burden, with predominantly patch disease, initial treatment should be with the same skin-directed treatments as patients with stage 1A disease (see section on skin-directed therapy for stage IA).[5][31][32]

For patients with a higher disease burden, with predominantly plaque disease, skin-directed therapy may include (see stage IA for UVB or NB-UVB, topical corticosteroids, topical mechlorethamine):[32]

PUVA or UVA1

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 12-36 Gy)

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 inhibitors such as vorinostat or romidepsin, or mogamulizumab, or combining phototherapy with vorinostat or romidepsin.[32][67]

Systemic therapy - stage IB to IIA (skin disease only with ≥10% BSA)

In addition to those recommended for stage IA, preferred systemic therapy regimens for stage IB to IIA include:[5][32]

Brentuximab vedotin

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

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 the treatment of adults 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

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 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]

Inadequate response or relapsed/refractory disease

Patients with predominantly patch disease with low disease burden should be retreated with initial treatment options, or be treated as patients with high skin disease burden.[32] Those who relapse and experience progression from IB to IIA should be treated as appropriate for the relapsed disease stage.[32]​ 

Patients with predominantly plaque disease who have an inadequate response to initial treatment, or have persistent T1-T2 skin 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 (see section on stage IIB generalised tumour disease).[32]

Stage IIB (tumour stage disease without erythroderma)

First-line treatments for patients with stage IIB tumour disease include local radiotherapy, skin-directed therapy, TSEBT, or systemic therapy, or combinations of these treatments depending on whether the patient has limited or generalised tumour disease.[5][31][32]

Limited tumour disease

Radiotherapy or other skin-directed therapy alone or in combination are the preferred initial treatments for patients with stage IIB limited tumour disease (see sections on stage IA and IB to IIA skin-directed therapies).[5][32]​ For patients who do not respond to initial therapy, systemic therapy with or without radiotherapy should be considered.[32]

Preferred systemic therapy options include (see sections on stage IA and stage IB to IIA for further information on these treatments):[5][32]

  • Bexarotene

  • Brentuximab vedotin

  • Interferon alfa

  • Methotrexate

  • Mogamulizumab

  • Romidepsin

Inadequate response or relapsed/refractory disease

Those who experience persistent IA to IIA limited tumour lesions, should undergo another round of treatment with initial options.[32]​ Patients who relapse, or 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]

Generalised tumour disease

Treatment options for patients with stage IIB generalised tumour disease include TSEBT, or systemic therapy with skin-directed therapy, or combination therapy (see options for skin-directed therapy in stage IB to IIA).[5][32]

Preferred regimens for systemic therapy include (see sections on stage IA and stage IB to IIA for further information on these treatments):[5][32]

  • Bexarotene

  • Brentuximab vedotin

  • Interferon alfa

  • Methotrexate

  • Mogamulizumab

  • Romidepsin

Preferred regimens for systemic therapy stage IIB generalised tumour disease may also include:[5][31][32]

Liposomal doxorubicin

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

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

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

Combination therapy

The preferred combination treatments for stage IIB disease include phototherapy with interferon alfa or a retinoid, or a retinoid with interferon alfa.[31][32]

Inadequate response or relapsed/refractory disease

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]

Patients refractory to multiple therapies should be considered for a clinical trial, allogeneic haematopoietic cell transplant (HCT), or systemic therapy suggested for relapsed or refractory disease, which includes:[5][32]

  • Alemtuzumab

    • 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

    • Chlorambucil, an alkylating agent, has been demonstrated to be a safe and effective treatment for patients with 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

    • 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

    • 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

    • Intravenous purine analogues such as pentostatin, cladribine, and fludarabine have also been shown to be effective.[90][91][92] Common adverse effects include significant immunosuppression.

  • Bortezomib

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

Alternatively, patients refractory to multiple therapies may also consider suggested regimens for large cell transformation (LCT) MF (see section on LCT for further options).[32]

Stage III (erythrodermic disease)

Initial treatment options for stage III disease include systemic therapy with skin-directed therapy (see sections on stage IA or stage IB to IIA for details on skin-directed therapy).[5][31][32] Phototherapy and TSEBT may be associated with increased toxicity in patients with erythroderma and modification of dose/schedule may need to be considered.

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]

Preferred systemic options include (see sections on stage IA and stage IB to IIA for further information on these treatments):[5][32]

  • Bexarotene

  • Brentuximab vedotin

  • Interferon alfa

  • Methotrexate

  • Mogamulizumab

  • Romidepsin

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]

A number of characteristics have been identified in CTCL patients that suggest a high likelihood of responding to ECP. They include the following:[102]

  • Short duration of disease, preferably <2 years

  • Absence of bulky lymphadenopathy or major internal organ involvement

  • Leukocytosis/leukaemia less than 20,000/microlitre

  • Presence of a discrete number of Sézary cells (10% to 20% of mononuclear cells)

  • Normal or close to normal natural killer cell activity

  • Close to normal numbers of cytotoxic T lymphocytes, whereby suppressor CD8+ T cells should be above 15%

  • No prior intensive chemotherapy

  • Plaque-stage disease should not cover more than 10% to 15% of the skin surface area.

Combination therapy

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 SS.[103][104][105][106][107][108][109][110][111]

Recommended combination therapy for stage III disease may include:[5][32]

  • ECP + interferon alfa or a retinoid

  • ECP + interferon alfa + a retinoid

  • Phototherapy + interferon alfa or a retinoid

  • Phototherapy + ECP

  • A retinoid + interferon alfa

Inadequate response or relapsed/refractory disease

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

Patients with an inadequate response to multiple previous therapies should be considered for a clinical trial, allogeneic HCT, or systemic therapy for relapsed or refractory disease or suggested regimens for MF with LCT (see 'Inadequate response or relapsed/refractory disease' in the stage IIB generalised tumour disease section or treatment option in Stage IV LCT).[32]

Stage IV disease

Stage IV disease 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 (see sections on stage IA or stage IB to IIA for details on skin-directed therapy).[32]

SS stage IVA1 (T1-4, N0-2, M0, B2) or IVA2 (T1-4, N3, M0, B0 or B1 or B2)

Low to intermediate disease burden (e.g., blood atypical Sézary cells [ASC] <5 K/mm³)

Systemic therapy options include (see sections on stage IA, stage IB to IIA, and stage III for further information on these treatments):[5][32]

  • Bexarotene

  • Extracorporeal photopheresis (ECP)

  • Interferon alfa

  • Methotrexate

  • Mogamulizumab

  • Romidepsin

  • Vorinostat

Recommended combination therapy include:[5][32]

  • ECP + interferon alfa or a retinoid

  • ECP + interferon + a retinoid

  • Phototherapy + ECP

  • Phototherapy + interferon alfa or a retinoid

  • A retinoid + interferon alfa

High disease burden (e.g., blood ASC >5 K/mm³)

Systemic therapy options include (see sections on stage IA, stage IB to IIA, and stage III for further information on these treatments):[32]

  • Mogamulizumab

  • Romidepsin

Recommended combination therapies include:[5][32]

  • Phototherapy + ECP

  • Phototherapy + interferon alfa or a retinoid

  • ECP + interferon alfa or a retinoid

  • ECP + interferon alfa + a retinoid

  • A retinoid + interferon alfa

Inadequate response or relapsed/refractory disease

Patients who relapse or experience persistent disease should be retreated with initial treatment options. For inadequate response or disease refractory to multiple previous therapies, patients should consider a clinical trial, allogeneic HCT, or systemic therapy with regimens for relapsed or refractory disease (see 'Inadequate response or relapsed/refractory disease' in the stage IIB generalised tumour disease section for further treatment options).[32]

Non-SS 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)

Non-SS patients should be treated with systemic therapy with or without radiotherapy for local control. The recommended systemic options for this population include (see sections on stage IA, stage IB to IIA, and stage III for further information on these treatments):[5][32]

  • Brentuximab vedotin

  • Gemcitabine

  • Liposomal doxorubicin

  • Pralatrexate

  • Romidepsin

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).

Inadequate response or relapsed/refractory disease

Patients who relapse or experience persistent disease should be retreated with the initial treatments; alternatively, a clinical trial or allogeneic HCT may be considered.[32]

Patients with inadequate response or disease refractory to multiple previous therapies should consider entry into a clinical trial, allogenic HCT, or alternative systemic therapy (see 'Inadequate response or relapsed/refractory disease' in the stage IIB generalised tumour disease section for further treatment options).[5][32]

Large cell transformation (LCT)

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

Limited cutaneous lesions with LCT

For patients with limited cutaneous lesions with LCT, radiotherapy to lesions with LCT with concurrent management of coexisting disease based on clinical stage should be considered.[32]

Inadequate response or relapsed/refractory disease

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

For patients who experience inadequate response to treatment or have disease refractory to multiple previous therapies, a clinical trial or allogeneic HCT may be considered.[32] Systemic treatments for refractory disease, or for generalised cutaneous or extracutaneous lesions with LCT in addition to concurrent management of coexisting disease appropriate for clinical stage could be considered (see 'Inadequate response or relapsed/refractory disease' in the stage IIB generalised tumour disease section, or generalised cutaneous or extracutaneous lesions with LCT for further treatment options). 

Alternatively, patients may be treated with options for generalised cutaneous or extracutaneous lesions with LCT (see below).

Generalised cutaneous or extracutaneous lesions with LCT

Patients with generalised cutaneous or extracutaneous lesions with LCT should be treated with TSEBT or systemic therapy with skin-directed therapy.[32]​ (see sections stage IA or stage IB to IIA for details on skin-directed therapy).​

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.

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

Single-agent systemic therapies may include:[32]

  • Brentuximab vedotin

  • Gemcitabine

  • Liposomal doxorubicin

  • Pralatrexate

  • Romidepsin

Multi-agent combination regimens may include:[112]

  • 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)

Inadequate response or relapsed/refractory disease

Persistent disease should be retreated with the initial treatment options. Patients who experience relapse should be retreated with primary treatments, entered into a clinical trial, or consider allogeneic HCT.[32]

Patients who are refractory to multiple previous therapies should be entered into a clinical trial, or be treated with regimens suggested for relapsed or refractory disease (see 'Inadequate response or relapsed/refractory disease' in the stage IIB generalised tumour disease section for further treatment options).[32]

Allogeneic HCT may also be considered for these patients.[32]

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