Treatment of advanced-stage (IIB to IV) mycosis fungoides

INTRODUCTION — Mycosis fungoides (MF) is the most common type of cutaneous T cell lymphoma. MF develops in the skin, but it can also involve lymph nodes, visceral organs, and blood. It shares clinical manifestations and pathologic features with Sézary syndrome, which is an aggressive leukemic variant with substantial circulating malignant cells.

Most patients with advanced-stage MF have a chronically relapsing disease course with intermittent or slow progression of cutaneous tumors, patch/plaque disease, and/or erythroderma; troublesome pruritus or other symptoms; and/or disease that involves lymph nodes, visceral organs, and/or blood. MF generally exhibits an indolent course, but patients are subject to multiple cutaneous relapses. Advanced-stage MF refers to stage IIB, stage III, and some cases of stage IV disease. Some patients experience an accelerated disease course in association with histologic transformation.

MF-related symptoms are often best controlled using a combination of systemic agents plus skin-directed therapy or other localized treatments. Treatment selection is influenced by efficacy, adverse effects, and complementarity of approaches. Because many patients receive multiple agents over the course of their illness, it is also important to consider cumulative toxicity, convenience, and cost of treatment.

Management of advanced-stage MF is discussed in this topic.

Related topics include:

●(See "Clinical manifestations, pathologic features, and diagnosis of mycosis fungoides".)

●(See "Staging and prognosis of mycosis fungoides and Sézary syndrome".)

●(See "Treatment of early stage (IA to IIA) mycosis fungoides".)

●(See "Treatment of Sézary syndrome".)

PRETREATMENT EVALUATION — Pretreatment evaluation of MF includes the assessment of symptoms and comorbid conditions that may affect treatment choice and disease staging.

Clinical and laboratory

●Clinical

•History of pruritus and other disease-related symptoms; the type, location, and duration of skin lesions; prior treatments.

•Complete skin examination, including the type of skin lesions and estimation of the extent of body surface area (BSA) involvement, and evaluation of lymph nodes and organomegaly.

●Laboratory

•Hematology – Complete blood count with manual differential.

•Chemistries – Complete metabolic panel with kidney function and liver functions tests, including lactate dehydrogenase.

•Pregnancy testing, if appropriate.

●Pathology – An adequate biopsy of skin and enlarged lymph nodes or suspected extracutaneous sites of involvement is needed for the diagnosis and staging of MF. Excisional or core needle biopsy should be performed, as fine-needle aspiration alone is not sufficient for the initial diagnosis of lymphoma. Bone marrow aspirate/biopsy is generally performed only to evaluate unexplained hematologic abnormalities.

Expert dermatopathology and/or hematopathology review is important to confirm the diagnosis of MF. Evaluation should include flow cytometry to quantitate circulating T cells with aberrant phenotype ("Sézary cells") and testing for clonal T cell receptor (TCR) gene rearrangement. These and other pathologic features of MF are discussed separately. (See "Clinical manifestations, pathologic features, and diagnosis of mycosis fungoides", section on 'Diagnosis'.)

For clinically aggressive disease, a repeat skin biopsy should be performed if there is suspicion of large cell transformation or folliculotropic MF.

●Imaging – Integrated whole-body positron emission tomography (PET)/computed tomography (CT) or contrast-enhanced CT of chest/abdomen/pelvis.

Staging — Staging of MF is based on the evaluation of skin (T), lymph nodes (N), visceral involvement (M), and blood (B) [1], as discussed separately. (See "Staging and prognosis of mycosis fungoides and Sézary syndrome", section on 'TNMB staging'.)

Some aspects of staging and treatment selection require estimation of the extent of BSA skin involvement. Smaller areas of involvement are readily estimated using the "palm method"; the palm of the patient's hand is approximately 0.5 percent of total BSA, while the palm plus palmar surface of all five fingers is slightly less than 1 percent [2]. Larger areas of involvement can be estimated based on one of the following methods:

●Rule of nines – This quick method of estimating total BSA for adults assigns 18 percent total BSA to each leg, 9 percent to each arm, 18 percent each to the anterior and posterior trunk, and 9 percent to the head [3].

●Lund-Browder chart – The Lund-Browder chart is the most accurate method for estimating the percentage BSA involvement for adults and children.

OVERVIEW OF TREATMENT — There is no single treatment approach that is optimal for all patients with advanced-stage MF. There are numerous effective treatments, but control of advanced-stage MF and its troublesome symptoms often requires a combination of systemic treatment plus skin-directed therapy and/or other localized approaches.

Treatment is individualized, with consideration of activity against specific disease manifestations and compartments, adverse effects, comorbidities, and patient preference. Because many patients receive various treatments over the course of their disease, consideration of convenience, cost, and cumulative toxicity of treatments is important for effective long-term disease management.

Referral to a specialized center with a multidisciplinary team (eg, dermatologists, medical oncologists, radiation oncologists, experienced nurses) or consultation with experts in MF may be helpful for management.

Our approach to treatment selection for advanced-stage MF [4] includes the following considerations:

●Compartmental disease burden – Systemic treatments exhibit differential efficacy across the sites, types, and burden of disease (eg, cutaneous patch/plaque disease, skin tumors, erythroderma, involvement of lymph nodes, blood, and viscera). Disease stage and compartment-specific activity must be considered when selecting therapy, as discussed below. (See 'Management' below.)

●Treatment approaches – Effective management of pruritus, infections, organ dysfunction, and other troublesome manifestations of advanced-stage MF generally requires multiple treatment modalities, which may include:

•Targeted/biologic agents – Targeted single-agent infusional drugs play important roles in managing MF. Brentuximab vedotin, mogamulizumab, and histone deacetylase inhibitors (HDACi; eg, romidepsin, vorinostat) are targeted/biologic agents with acceptable toxicity and substantial efficacy for particular disease manifestations/compartments [4]. For patients who achieve a response to a targeted agent, maintenance therapy (ie, continuous dosing, attenuated dosing, or increased intervals between treatments) can prolong the benefit. (See 'Systemic treatments' below.)

•Cytotoxic chemotherapy – Single-agent cytotoxic chemotherapy (eg, gemcitabine, liposomal doxorubicin, pralatrexate) can be effective against MF but may cause greater toxicity than targeted agents [5,6]. Although combination chemotherapy regimens can yield high response rates, the duration of response is generally short, and treatment is associated with significant toxicity. Cytotoxic chemotherapy is generally reserved for specific clinical situations or later lines of treatment. (See 'Clinically aggressive disease' below and 'Multiply relapsed or refractory MF' below.)

•Radiation therapy – Radiation therapy (RT) plays important roles in managing MF. Localized RT can control local sites of disease and is often used in combination with systemic agents and/or other treatments. Total skin electron beam therapy (TSEBT) is effective for some patients with extensive cutaneous disease. (See 'Radiation therapy' below.)

•Extracorporeal photopheresis – Extracorporeal photopheresis (ECP) treats blood extracorporeally with 8-methoxypsoralen and psoralen plus ultraviolet A photochemotherapy (PUVA therapy). It is especially effective for erythrodermic and/or blood involvement, and it is often combined with another systemic treatment (eg, bexarotene, interferon [IFN]).

●Treatment combinations – Many patients benefit from receiving more than one treatment approach at a time. Examples include complementary systemic treatments (eg, ECP plus a systemic agent, bexarotene plus IFN) or a systemic treatment plus RT.

Many patients use topical agents while receiving other therapy to enhance the response of MF and its symptoms. Effective management also requires attention to control cutaneous and other infections. (See 'General skin management' below.)

●Adverse effects and comorbidities – To maintain long-term disease control, quality of life, and patient well-being, agents that can be tolerated for longer durations of treatment with lower cumulative toxicity and less immunosuppression are preferred, especially for earlier lines of therapy. Certain adverse effects may constrain – but not exclude – treatment choice in the face of patient comorbidities. Examples include the tendency of brentuximab vedotin to worsen peripheral neuropathy or bexarotene to exacerbate hypertriglyceridemia or cause thyroid dysfunction.

●Patient preference – The chronic nature of MF places substantial demands on the patient. The burden varies according to whether treatments require parenteral versus oral administration, treatment frequency, access to specialized treatment facilities, cost, and other factors.

●Clinically aggressive disease – For some patients, MF can evolve from a relatively indolent disorder to a clinically aggressive disease [7]. A repeat skin biopsy should be performed if the pace or severity of disease accelerates because this may reflect the development of large cell transformation or folliculotropic MF. Patients with clinically aggressive disease often require distinctive treatment. (See 'Clinically aggressive disease' below.)

Our approach to the management of advanced-stage MF is consistent with recommendations from the United States Cutaneous Lymphoma Consortium, National Comprehensive Cancer Network (NCCN), European Organization for Research and Treatment of Cancer (EORTC), and other panels of experts [8-14].

MANAGEMENT — Management of advanced-stage MF is guided by the disease stage, including the types and extent of skin disease and involvement of lymph nodes, viscera, and blood. Treatment must be individualized, with consideration of disease compartment-specific efficacy, short-term and cumulative toxicity, availability, convenience, cost, and other factors. Most patients require multiple concurrent and sequential treatment modalities to manage the range of troublesome symptoms and disease manifestations of advanced-stage MF.

Clinical staging of MF is discussed separately. (See "Staging and prognosis of mycosis fungoides and Sézary syndrome".)

Details of administration, toxicity, and outcomes with individual treatment modalities are described below. (See 'Systemic treatments' below and 'Radiation therapy' below and 'Extracorporeal photopheresis' below and 'General skin management' below.)

Clinically aggressive disease, which can arise from any disease stage, requires distinctive management. (See 'Clinically aggressive disease' below.)

Stage IIB (tumor-stage disease) — Stage IIB MF refers to T3 skin disease (ie, one or more tumors ≥1 cm diameter), but these patients often have other cutaneous manifestations (eg, patch/plaque disease); there is no visceral involvement, N3, or B2 disease.

The treatment of stage IIB MF is guided by the extent of body surface area (BSA) involved by tumors, but management must also consider:

●Other cutaneous manifestations – Patch/plaque disease, pruritus, and related symptoms often benefit from adding systemic treatments, such as methotrexate, bexarotene, or interferons (IFNs), and/or topical therapy. (See 'Systemic treatments' below and 'General skin management' below.)

●Blood involvement – For patients who have blood involvement, aspects of the management of Sézary syndrome (SS) may apply. (See "Treatment of Sézary syndrome".)

●Symptomatic nodal involvement – For symptomatic nodal involvement, localized radiation may be helpful. (See 'Radiation therapy' below.)

Limited extent — For patients with a limited number of cutaneous tumors accompanied by patches and thin plaques involving <10 percent BSA, we suggest localized radiation therapy (RT) plus topical therapy rather than topical therapy alone or systemic therapy alone.

No randomized trials have compared treatments for limited tumor-stage disease, but topical therapies alone are often inadequate, and systemic therapy may not be required in this setting.

RT is often given along with a topical agent, but a complementary systemic agent (eg, methotrexate, bexarotene, IFN) can also be used.

●Topical treatments for MF are discussed separately. (See "Treatment of early stage (IA to IIA) mycosis fungoides", section on 'Topical agents'.)

●Systemic treatments (eg, methotrexate, bexarotene, IFN) can enhance symptom control provided by RT. (See 'Systemic treatments' below.)

For patients with limited tumors but patch or plaque disease that involves >10 percent BSA, total skin electron beam therapy (TSEBT) may be effective, but it may cause more adverse effects (AEs) than localized RT. (See 'Radiation therapy' below.)

Because MF lesions are generally superficial, localized RT usually uses electrons or low energy x-rays, which have only a limited depth of penetration. For treating individual tumors, doses as low as 8 gray (Gy) delivered in a single fraction can achieve a complete response (CR) in 95 percent of patients [15]. High energy x-rays may be used for deeply infiltrating disease or for involvement of an extremity, but high energy x-rays penetrate more deeply and are associated with a greater risk of injury to deeper tissues.

Generalized tumors — For patients with cutaneous tumors that involve ≥10 percent BSA, we suggest brentuximab vedotin based on its efficacy against cutaneous tumors and acceptable toxicity.

Patients with generalized tumors and patch/plaque disease often benefit from the addition of topical and/or systemic treatments, as described above. (See 'Limited extent' above.)

●Administration – Treatment and toxicity with brentuximab vedotin are described below. (See 'Brentuximab vedotin' below.)

●Outcomes – Studies that used brentuximab vedotin to treat MF include:

•In the ALCANZA trial, 131 patients with advanced-stage MF or primary cutaneous anaplastic large cell lymphoma were randomly assigned to brentuximab vedotin versus the physician's choice (PC) of methotrexate or oral bexarotene [16]. For the 97 patients with MF, brentuximab vedotin achieved a superior rate of median progression-free survival (PFS; 16 versus 4 months; hazard ratio [HR] 0.73 [95% CI 0.16-0.46]), overall response lasting ≥4 months (50 versus 10 percent), CR (10 versus 0 percent), patient-reported symptom burden, and treatment duration. Superiority of brentuximab was especially notable with tumor-stage MF, with 63 percent overall response lasting ≥4 months, compared with 5 percent using PC. Patients received up to 16 cycles of brentuximab vedotin (median 12 cycles). Grade ≥3 AEs were reported in 41 percent of patients in the brentuximab vedotin group (including 9 percent grade ≥3 peripheral neuropathy); one-half of patients with peripheral neuropathy required at least one dose modification (delay, reduction, or dose held), and 14 percent permanently discontinued it. One death was attributed to brentuximab vedotin. Grade ≥3 AEs were reported in 47 percent of the PC group.

With longer follow-up (median 46 months) of the ALCANZA trial, the robust and durable responses to brentuximab vedotin were confirmed [17]. There was no difference in overall survival (OS) between trial arms, but in patients with MF, the median PFS was 16.1 months with the brentuximab vedotin arm versus 3.5 months in the PC arm (HR 0.38 [95% CI 0.24-0.61]). While 41 percent of patients treated with brentuximab vedotin had ongoing peripheral neuropathy, all were grade ≤2.

•Brentuximab vedotin was associated with a 70 percent overall response rate (ORR) in 33 patients with MF or SS, including responses in skin, blood, and extracutaneous compartments [18]. One-quarter of patients experienced a ≥90 percent reduction in skin tumor burden based on mSWAT (modified Severity Weighted Assessment Tool) score [19].

Other options for treating generalized tumor disease when brentuximab vedotin is not available or when pre-existent peripheral neuropathy precludes it use include:

●Romidepsin – The treatment of 20 patients with relapsed or refractory (r/r) tumor-stage MF using romidepsin was associated with a 45 percent ORR (including 10 percent CR) and substantial reduction in pruritus [20]. No grade ≥3 gastrointestinal AEs were reported in patients with cutaneous tumors. Romidepsin administration and AEs are discussed below. (See 'Romidepsin' below.)

●Pralatrexate – Treatment with pralatrexate in six patients with generalized tumor-stage MF was associated with a 67 percent ORR (including 33 percent CR); grade ≥3 stomatitis was reported in 17 percent of 59 patients treated with pralatrexate 15 mg/m² weekly for three to four weeks [21]. Pralatrexate administration and AEs are discussed below. (See 'Pralatrexate' below.)

●Total skin electron beam therapy – TSEBT is often associated with a robust, but temporary, response in tumor-stage disease. TSEBT may be used after an initial response to brentuximab vedotin, especially for patients who become intolerant of brentuximab vedotin treatment. Concurrent or subsequent skin-directed therapy or a systemic agent can enhance and prolong the response to TSEBT, as discussed in greater detail below. (See 'Radiation therapy' below.)

Some experts favor treatment with single-agent gemcitabine or liposomal doxorubicin in this setting. (See 'Gemcitabine' below and 'Liposomal doxorubicin' below.)

By contrast to the agents above, methotrexate and systemic bexarotene were less efficacious than brentuximab in the ALCANZA trial [16], while mogamulizumab achieved only a 16 percent ORR for patients with tumor-stage disease in the MAVORIC trial [22].

Stage III (erythrodermic disease) MF — Stage III MF refers to confluent erythema involving ≥80 percent BSA (T4 skin involvement). Erythrodermic disease is often associated with circulating tumor cells.

Patients with T4 skin disease and B0 or B1 blood are classified as stage III MF, but their disease manifestations and treatment responses resemble those of SS (erythroderma with B2 blood involvement).

We generally manage patients with stage III MF like SS, as described separately. (See "Treatment of Sézary syndrome".)

Stage IVA1 Sézary syndrome — Patients with B2 blood involvement, T1 to T4 skin involvement, N0 to N2 lymph nodes, and no visceral disease are classified as stage IVA1 SS. Management of SS is discussed separately. (See "Treatment of Sézary syndrome".)

Stage IVA2 — Stage IVA2 disease is defined by N3 lymph node involvement; those patients with B2 blood involvement are considered to have stage IVA2 SS, while others (ie, B0 or B1) are classified as stage IVA2 MF.

Stage IVA2 Sézary syndrome — Patients with N3 lymph node disease, B2 blood involvement, T1 to T4 skin disease, and no visceral disease (M0) are classified as stage IVA2 SS, which is discussed separately. (See "Treatment of Sézary syndrome".)

Stage IVA2 mycosis fungoides — Patients with N3 lymph node disease, B0 to B1 blood, T1 to T4 skin involvement, and M0 are classified as stage IVA2 MF.

Treatment of stage IVA2 MF is individualized according to whether the skin disease is predominantly erythroderma versus patch/plaque/tumor-stage disease. However, disease manifestations vary, and management often requires a combination of systemic agents, topical therapy, extracorporeal photopheresis, and/or RT. Broadly, we consider the following aspects when designing therapy:

●For patients with T4 skin disease (erythema covering ≥80 percent BSA) we generally treat like SS, as discussed separately. (See "Treatment of Sézary syndrome".)

●For stage IVA2 MF with predominant patch, plaque, or tumor manifestations, treatment can use:

•The addition of localized RT (for symptomatic nodal disease) to the management of stage IIB MF. (See 'Generalized tumors' above.)

•Management like stage IVB MF. (See 'Stage IVB (visceral disease)' below.)

Stage IVB (visceral disease) — For patients with visceral disease (either bone marrow [BM] or non-BM visceral involvement), we suggest initial treatment with brentuximab vedotin, romidepsin, or pralatrexate.

Selection of an agent is influenced by compartment-specific efficacy, including the type of skin involvement, the burden of blood involvement, toxicity, comorbidities, clinician experience, and patient preference. We also consider the following in choosing a systemic agent for managing stage IVB MF [4]:

●Brentuximab vedotin, romidepsin, and pralatrexate are all effective for tumor-stage skin disease and for lymph node involvement.

●Patients with erythrodermic skin disease may benefit from romidepsin, but in our experience, it is difficult to tolerate in older/more frail patients.

●For patients with B2 disease, we generally do not use brentuximab vedotin because its activity in the blood compartment is not well defined. While it had activity against the blood compartment in phase 2 studies [18,23], patients with SS were excluded from the phase 3 ALCANZA trial [16].

●RT can be added, if needed, to control localized skin disease (8-12 Gy) or nodal disease (12-24 Gy, fractionated).

Outcomes with these agents include:

●Brentuximab vedotin – In the ALCANZA trial, brentuximab vedotin achieved superior ORR compared with methotrexate or bexarotene for the treatment of extranodal disease (46 versus 9 percent), but patients with B2 blood involvement were not eligible for enrollment [16]. Brentuximab vedotin was effective for nodal disease in patients with r/r cutaneous T cell lymphoma (CTCL) and peripheral T cell lymphoma (PTCL) [24-26].

●Romidepsin – Subgroup analysis of 96 patients with CTCL in a phase 2 study reported that romidepsin was associated with a 34 percent global ORR (including 6 percent CR), including a 33 percent ORR in the nodal compartment and 57 percent ORR in the blood compartment [27]. In another study, romidepsin was associated with a 45 percent ORR for skin tumors [20].

●Pralatrexate – Pralatrexate was associated with a 45 percent ORR against skin tumors in one study [28]. In another study, it was associated with a 45 percent ORR, but this study had no patients with stage IVB MF [21].

Other approaches can also be effective in this setting. Gemcitabine was associated with a 71 percent ORR (including a 12 percent CR) in 44 patients with MF or PTCL in one study [29] and a 54 percent ORR in 13 patients with MF in another report [30]. Liposomal doxorubicin was associated with a 41 percent ORR (including a 6 percent CR) and six-month median duration of response (DOR) in 49 patients with advanced-stage MF [31].

For selected patients (generally ≤65 years) who are eligible for allogeneic hematopoietic cell transplantation (HCT), we consider transplantation at the time of the best response to therapy. (See 'Hematopoietic cell transplantation' below.)

Clinically aggressive disease — Treatment is individualized for patients with clinically aggressive MF. For selected patients with clinically aggressive disease, allogeneic HCT at the time of best response is an option for transplant-eligible patients. (See 'Hematopoietic cell transplantation' below.)

Treatment of clinically aggressive MF is guided by pathologic features, efficacy, and toxicity:

●Large cell transformation– For patients with large cell transformation (LCT), we suggest brentuximab vedotin based on its efficacy in this setting.

Administration and toxicity of brentuximab vedotin are discussed below. (See 'Brentuximab vedotin' below.)

In the ALCANZA trial, brentuximab vedotin was more effective in patients with LCT than in those without LCT (ie, ORR 65 versus 39 percent); patients with LCT had a 15.5-month median PFS [32]. Brentuximab vedotin was associated with a 74 percent five-year OS among 23 patients with LCT in a retrospective single-center study [25]. In some settings, the approval of brentuximab vedotin requires demonstration of CD30 expression by >10 percent of tumor cells, even for LCT.

Pralatrexate, gemcitabine, pentostatin, and liposomal doxorubicin were associated with a 25 to 60 percent ORR in r/r MF, but the DOR is generally <6 months [28,30,31,33]. Combination chemotherapy generally yields only brief responses with increased toxicity, but it can provide disease control prior to planned allogeneic HCT [5,34]. Although MF cells express CCR4 [35], mogamulizumab achieved only an 11 percent ORR with r/r CCR4-expressing PTCL [36], and patients with LCT were not included in the MAVORIC trial that evaluated mogamulizumab [22].

●Folliculotropic MF – There is a wide spectrum of presentations of folliculotropic MF (FMF), and no treatment has proven superior.

As with LCT, brentuximab vedotin can be effective in patients who have FMF with extracutaneous disease. For patients with FMF that involves skin alone (ie, no extracutaneous involvement and no LCT), TSEBT, romidepsin, bexarotene, and other agents can be effective. As an example, in one study, romidepsin was associated with a 60 percent ORR in 10 patients with FMF [20].

SYSTEMIC TREATMENTS — Selection of systemic therapy is guided by symptoms, disease burden, sites/types of involvement (eg, skin tumors, erythroderma, nodal disease, blood disease, visceral involvement), toxicity, comorbid conditions, and prior treatments. No single approach offers a superior balance of efficacy and toxicity for all disease presentations and patients with advanced-stage MF.

We generally initiate treatment with less toxic regimens before moving on to those with more cumulative toxicity and/or long-term immunosuppression. Patients who experience a clinical benefit can receive maintenance therapy using attenuated dosing of the same agent to optimize duration of response (DOR). Patients with MF often experience multiple relapses and ultimately receive various treatments over the course of their disease. There is no preferred sequence of treatments, but patients who relapse with the same disease stage after the discontinuation of therapy often respond well to retreatment with the previous therapy. (See 'Overview of treatment' above.)

Preferred systemic agents for the treatment of patch/plaque disease, skin tumors, erythrodermic skin lesions, extracutaneous involvement, and large cell transformation are discussed in the various management sections. (See 'Management' above.)

Bexarotene, brentuximab vedotin, mogamulizumab, vorinostat, and romidepsin are approved by the US Food and Drug Administration (FDA) and/or the European Medicines Agency (EMA) for the treatment of MF and Sézary syndrome (SS). Other drugs that are described in the sections that follow are used as off-label treatments.

Brentuximab vedotin — Brentuximab vedotin is an anti-CD30 monoclonal antibody conjugated with monomethyl auristatin E that has demonstrated activity in CD30+ lymphomas. Brentuximab vedotin is among the most effective systemic treatments against tumor-stage disease, nodal or visceral involvement, and clinically aggressive MF.

●Administration – The typical starting dose is 1.8 mg/kg (to a maximum dose of 180 mg) given intravenously every three weeks. Treatment can be given indefinitely until intolerance or disease progression.

Brentuximab vedotin is approved by the FDA and EMA for the treatment of adults with MF who have received prior systemic therapy.

●Toxicity – Peripheral neuropathy is the most common dose-limiting adverse effect (AE) [37], which can generally be managed with dose reduction (eg, to 1.2 mg/kg) or by increasing the dosing interval.

Infusion reactions are uncommon, but anaphylaxis has been reported. (See "Infusion-related reactions to therapeutic monoclonal antibodies used for cancer therapy", section on 'Brentuximab'.)

Progressive multifocal leukoencephalopathy is a rare complication of brentuximab vedotin treatment and typically presents with subacute neurologic deficits, which may include altered mental status, visual symptoms, weakness, ataxia, and seizures. (See "Neurologic complications of cancer treatment with molecularly targeted and biologic agents", section on 'Brentuximab'.)

Outcomes with brentuximab vedotin for advanced-stage MF are presented above. (See 'Generalized tumors' above.)

Methotrexate — Low-dose oral methotrexate has activity against MF, is easily administered, and has a favorable toxicity profile.

Methotrexate is not specifically approved for MF by the FDA or EMA, but it has long been used in this setting.

●Administration – A typical starting dose of oral or subcutaneous methotrexate is 10 mg once weekly, but this may vary with the urgency to achieve a response (or to recognize that disease is not responsive to methotrexate). The dose can be adjusted based upon efficacy or tolerance. We increase the dose if there is no clinical improvement within eight weeks of therapy, but we do not typically use doses higher than 25 mg weekly.

Methotrexate is contraindicated in patients with liver disease or kidney disease. Methotrexate is contraindicated in pregnant patients, and it should not be used by females or males who plan a pregnancy in the short term.

Patients should be screened for viral hepatitis before initiating long-term methotrexate therapy. Those with hepatitis B or hepatitis C infection should receive an alternative systemic therapy, receive treatment to eradicate the infection before beginning methotrexate, or receive treatment to suppress viral replication during treatment. Complete blood count, aminotransaminases, and albumin should be monitored periodically.

Patients should take folic acid 1 mg daily on the five days of the week when they are not taking methotrexate. Proton-pump inhibitors can increase methotrexate levels and should be used with caution in this population.

We continue treatment with methotrexate until best response. Maintenance therapy using a decrease frequency of treatment can be continued for a maximum of three years to reduce the risk of liver fibrosis. In our experience, even once monthly dosing can be effective to maintain remissions.

Methotrexate can be reinstituted if there is a disease recurrence.

●Toxicity – AEs with low-dose methotrexate are generally mild, but many patients experience nausea, dyspepsia, headache, and fatigue.

Hepatotoxicity, pulmonary fibrosis, and myelosuppression are serious AEs, but they are uncommon with low-dose therapy. Methotrexate is an abortifacient that can induce congenital anomalies if taken during pregnancy. (See "Major adverse effects of low-dose methotrexate".)

●Outcomes – Outcomes with oral methotrexate in the ALCANZA trial are presented above. (See 'Brentuximab vedotin' above.)

Other studies of oral methotrexate for MF include:

•The treatment of 60 patients with low-dose methotrexate for patch/plaque disease was associated with a 33 percent ORR (overall response rate), including a 12 percent complete response (CR) [38]. The median time to treatment failure was 15 months, and treatment was discontinued in 9 percent of patients due to AEs.

•In a study of 29 patients with erythrodermic MF, low-dose methotrexate was associated with a 58 percent ORR, including a 41 percent CR [39]. The median survival was 8.4 years, median freedom from treatment failure was 31 months, and treatment was discontinued in 7 percent.

Bexarotene — Oral bexarotene is a systemic rexinoid (a synthetic agent that binds to the retinoid "X" receptor) that is widely used to treat MF, but it can be associated with hepatotoxicity and hyperlipidemia. Acitretin and isotretinoin are acceptable alternatives to bexarotene.

●Administration – We generally start bexarotene at 150 mg daily and adjust the dose based on tolerance and response. We generally do not exceed 300 mg/m² daily, but doses as high as 400 mg/m² may be used in some circumstances.

Bexarotene must be used with caution in patients with hypertriglyceridemia, liver dysfunction, or risk factors for pancreatitis. Given the high incidence of hyperlipidemia with bexarotene, we prescribe concomitant fenofibrate, but additional lipid lowering agents are sometimes necessary. Gemfibrozil should not be used because coadministration results in increased serum levels of bexarotene, while bexarotene lowers atorvastatin levels; rosuvastatin and other statins are better alternatives.

Bexarotene causes central hypothyroidism, and thyroid replacement must be adjusted based upon free T4 (thyroid stimulating hormone [TSH] level).

Complete blood count, liver function tests, serum lipid levels, and thyroid function (serum free T4) should be monitored during treatment [40].

Bexarotene is approved by the FDA and EMA for treatment of cutaneous manifestations of MF in patients who are refractory to at least one prior systemic therapy. Isotretinoin and acitretin are commercially available but not FDA-approved for this indication [41]. Etretinate is available only in Japan.

●Toxicity – The most common AEs are weakness, myalgia, arthralgia, xerosis, photosensitivity, headaches, and impaired night vision, most of which are reversible after cessation of therapy.

Retinoids have potential hepatotoxic and hyperlipidemic effects, necessitating monitoring. Women of childbearing potential should use two reliable forms of contraception, including at least one nonhormonal form, given the potential teratogenic effects of retinoids.

●Outcomes – Outcomes with bexarotene in the ALCANZA trial are reported above. (See 'Brentuximab vedotin' above.)

Other studies include:

•A multicenter study of 94 patients with advanced-stage MF reported a 45 percent ORR with bexarotene 300 mg/m²/day; the ORR was 55 percent with bexarotene >300 mg/m²/day [42]. Treatment was associated with the reduction of overall body surface area (BSA) involvement, index lesion surface area, adenopathy, cutaneous tumors, pruritus, and disease-related quality of life. The most frequent AEs included hypertriglyceridemia (which was associated rarely with pancreatitis), hypercholesterolemia, hypothyroidism, and headache. 

•The treatment of 22 patients with MF using bexarotene, with the addition of interferon alfa (IFNa) if there was no response within eight weeks, was associated with a 39 percent ORR [43].

•The treatment of 41 patients with advanced-stage MF was associated with a 46 percent ORR; the addition of psoralen ultraviolet A (PUVA), IFNa, topical nitrogen mustard, and/or extracorporeal photopheresis (ECP) in 16 patients was associated with a 69 percent ORR [44].

Mogamulizumab — Mogamulizumab is a defucosylated humanized antibody directed against the CCR4 chemokine receptor, which is overexpressed on malignant T cells [45]. Mogamulizumab is most often used to treat erythrodermic MF, with or without blood involvement.

●Administration – Mogamulizumab 1 mg/kg is given intravenously over ≥1 hour on days 1, 8, 15, and 22 of the first cycle and then on days 1 and 15 of subsequent cycles.

Mogamulizumab is approved by the FDA for the treatment of adults with relapsed or refractory (r/r) MF or SS after ≥1 prior systemic therapy.

●Toxicity – The most common AEs are mild infusion-related reactions and mogamulizumab-associated rash, which occurs in approximately one-third of patients; it is important to distinguish this rash from disease progression [46,47]. Mogamulizumab is generally well tolerated, including patients with advanced age or impaired performance status (PS).

Mogamulizumab can deplete regulatory T cells, and some reports suggest that it may increase the risk of acute graft-versus-host disease (GVHD) in patients who undergo allogeneic hematopoietic cell transplantation (HCT) within two to six months of treatment [48-50].

Outcomes with mogamulizumab in the phase 3 MAVORIC trial are presented separately. (See "Treatment of Sézary syndrome".)

Romidepsin — Romidepsin is a histone deacetylase inhibitor (HDACi) with activity against cutaneous T cell lymphoma (CTCL). It is active across disease compartments and is suitable for patients with skin involvement only, erythroderma, lymphadenopathy, and/or blood involvement [27]

●Administration – Romidepsin 14 mg/m² by intravenous infusion over four hours is given on days 1, 8, and 15 of a 28-day cycle.

Electrolytes should be evaluated before beginning therapy, and potassium and magnesium levels should be in the normal range before administration.

Romidepsin is metabolized by CYP3A4; coadministration of strong CYP3A4 inhibitors or inducers should be avoided if possible.

Electrocardiogram (ECG) should be performed prior to beginning treatment. The QT interval should be monitored periodically during treatment in patients with congenital long QT syndrome, significant cardiovascular disease, or taking antiarrhythmic medicines or other products that lead to significant QT prolongation.

Romidepsin is approved by the FDA for the treatment of CTCL in patients with progressive, persistent, or recurrent disease on or after ≥1 prior systemic therapy.

●Toxicity – Romidepsin is associated with cytopenias, mild nausea, vomiting, and fatigue in many patients and was associated with grade ≥3 AEs in one-third of patients in one study [20].

Romidepsin is associated with QT prolongation in a subset of patients, as described separately. (See "Cardiotoxicity of cancer chemotherapy agents other than anthracyclines, HER2-targeted agents, and fluoropyrimidines", section on 'Histone deacetylase inhibitors'.)

●Outcomes

•Romidepsin was associated with a 34 percent ORR (including a 6 percent CR) and 43 percent clinically meaningful improvement in pruritus among 96 patients with CTCL [51]. Grade ≥3 AEs were uncommon, but one-half of patients had mild (grade ≤2) nausea, vomiting, or diarrhea. Prolonged QT interval was reported in two patients. Subanalysis demonstrated clinical activity in the skin, lymph nodes, and blood; no patients with visceral involvement were enrolled [27].

•In patients with previously treated CTCL, romidepsin was associated with a 35 percent ORR (including a 5 percent CR) among 40 patients with erythroderma, while B2 blood involvement in 37 patients was associated with a 32 percent ORR (including a 5 percent CR) [27].

•A study in 71 patients with CTCL (a median of four prior therapies) reported a 34 percent ORR (including a 6 percent CR) and a 14-month median DOR [52].

Vorinostat — Vorinostat is an orally active HDACi.

●Administration – Vorinostat 400 mg/day is taken by mouth.

Vorinostat is approved by the FDA for treating CTCL in patients with progressive, persistent, or recurrent disease after two systemic therapies.

●Toxicity – Generally mild cytopenias, fatigue, diarrhea, nausea, and dysgeusia are common AEs.

As described above with romidepsin, some patients are at risk for QT prolongation.

●Outcomes – Studies of vorinostat include:

•The ORR was 30 percent in 74 patients with persistent, progressive, or treatment-refractory stage IB to IVA MF [19]. Treatment was continued for ≥2 years in six of the patients [53].

•The treatment of 33 heavily pretreated patients reported a 24 percent ORR, including relief of pruritus in nearly one-half [54]. The most common drug-related AEs were fatigue, thrombocytopenia, diarrhea, and nausea. The most common grade ≥3 AEs were thrombocytopenia and dehydration.

Interferons — Peginterferon alfa-2a is the only form of IFNa available in the United States.

●Administration – We begin treatment with peginterferon alfa-2a 45 to 90 mcg subcutaneously once weekly and adjust doses as tolerated. This is the only version of IFNa that is available in the United States [55].

Interferons (IFNs) have been used off-label for decades to treat MF/SS.

●Toxicity – The most common AEs are flu-like symptoms (eg, include fever, fatigue, chills, myalgias, arthralgias, headache). These symptoms usually diminish over time.

IFNa can cause depression and abnormalities of thyroid and liver function.

●Outcomes – Most studies used nonpegylated IFNa either alone or in combination with phototherapy or total skin electron beam therapy (TSEBT) [56]. Use of IFN to treat MF is based on single-arm prospective studies [11]. Prospective observational studies of single-agent IFNa reported a 20 to 70 percent ORR, with up to a 25 percent CR.

A trial that randomly assigned 43 patients with MF (stage IIA to IV) or SS to IFNa versus methotrexate reported no difference in efficacy, but IFNa was better tolerated and achieved more rapid responses [57]. Response rates were similar with IFNa and methotrexate (86 versus 82 percent ORR, respectively), as were improvements in mSWAT (modified Severity Weighted Assessment Tool) score, pruritus, and quality of life. More patients achieved a response with IFNa during the first month of treatment (71 versus 27 percent), and fewer patients did not tolerate IFNa (10 versus 55 percent).

Chemotherapy — Cytotoxic chemotherapy can be effective against MF, especially for multiply r/r disease or clinically aggressive disease (eg, large cell transformation). (See 'Clinically aggressive disease' above.)

Single agents are generally preferred over combination chemotherapy because multiagent regimens are associated with short-lived responses and increased toxicity. Nevertheless, combination chemotherapy can be useful to control disease prior to planned allogeneic HCT. Combination chemotherapy regimens used for r/r MF are like those used for r/r peripheral T cell lymphoma (PTCL), as discussed separately. (See "Treatment of relapsed or refractory peripheral T cell lymphoma".)

Gemcitabine, liposomal doxorubicin, and pralatrexate are the most commonly used cytotoxic chemotherapy agents, but other agents that have been used include cyclophosphamide, chlorambucil, etoposide, and purine analogs (eg, fludarabine, pentostatin) [58-60]. Single-agent or combination chemotherapy was independently associated with increased mortality in a large study of treatment patterns of patients with CTCLs [61].

Gemcitabine — Single-agent gemcitabine has activity against MF and modest toxicity.

●Administration – Gemcitabine 1200 mg/m² intravenously on days 1, 8, and 15 of a 28-day cycle.

●Toxicity – Treatment is well tolerated and hematologic toxicity is mild.

●Outcomes – Frontline treatment with gemcitabine in a study that included 26 patients with MF reported a 75 percent ORR, including a 22 percent CR; treatment was well tolerated [62]. The treatment of 19 patients with MF using gemcitabine reported a 48 percent ORR, including a 16 percent CR [63]. A study that included 30 patients with r/r MF reported a 71 percent ORR, including a 12 percent CR [29]. Among 13 patients with T3 MF, the ORR was 54 percent [30].

Liposomal doxorubicin — Liposomal doxorubicin is generally well tolerated and effective for MF.

●Administration – Liposomal doxorubicin 20 mg/m² intravenously on days 1 and 15, every 28 days.

●Toxicity – AEs are mild anemia, lymphopenia, and palmar-plantar erythrodysesthesia.

●Outcomes – Liposomal doxorubicin has activity against MF with moderate toxicity.

The treatment of 49 patients with advanced-stage MF was associated with a 41 percent ORR, including a ≥50 percent reduction of cutaneous manifestations in 61 percent; the median DOR was six months, and the median time to progression was seven months [31]. Treatment was well tolerated, with few grade ≥3 AEs.

Other studies include the treatment of 25 patients with advanced or refractory CTCL that was associated with a 56 percent ORR (including a 20 percent CR); the median overall survival (OS) was 44 months, and the median progression-free survival (PFS) in responding patients was five months [64]. The treatment of 34 patients with advanced CTCL reported an 88 percent ORR (including a 44 percent CR); the median OS was 18 months, event-free survival (EFS) was 12 months, and disease-free survival was 13 months. Grade ≥3 AEs were reported in 14 percent of patients [65]. In a study of 19 patients with r/r CTCL, the median OS, EFS, and PFS rates were 34, 18, and 19 months, respectively, and the ORR and CR rates were 84 and 42 percent, respectively; 11 percent of patients had grade ≥3 AEs [66].

Pralatrexate — Pralatrexate is a folate analog that inhibits dihydrofolate reductase to impair deoxyribonucleic acid (DNA) synthesis.

●Administration – We initiate treatment with pralatrexate 15 mg/m² intravenously weekly for three out of four weeks and escalate the dose to 30 mg/m², as tolerated only if clinically needed.

When treating with pralatrexate, it is important to include the following [67]:

•Vitamin B12 1000 mcg intramuscularly ≤10 weeks prior to starting pralatrexate and then every 8 to 10 weeks.

•Oral folic acid 1 to 1.25 mg daily ≤10 days before starting therapy and continuing for 30 days after last dose of pralatrexate.

•Some experts add oral leucovorin 25 mg three times daily for two consecutive days (a total of six doses), starting 24 hours after each dose of pralatrexate [67].

Pralatrexate is approved by the FDA for the treatment of patients with r/r PTCL.

●Toxicity – Primarily mucositis and cytopenias.

●Outcomes

•Treatment in 111 heavily pretreated patients with r/r PTCL (including 11 percent with transformed MF) in the PROPEL study reported a 15-month OS, four-month median PFS, and 29 percent ORR (including an 11 percent CR), with a 10-month median DOR [68]. The most common grade ≥3 AEs were thrombocytopenia (32 percent), mucositis (22 percent), neutropenia (22 percent), and anemia (18 percent).

•Treatment in 38 patients with r/r MF who progressed after >1 prior systemic therapy reported a 50 percent ORR [21], retrospective analysis of 12 patients with transformed MF reported a 58 percent ORR [28], and treatment of 29 patients with pralatrexate (median of four cycles) was associated with a 45 percent ORR [21].

Other systemic agents

●Alemtuzumab – The anti-CD52 monoclonal antibody alemtuzumab can be used to treat r/r MF. It is most effective for patients with erythroderma and SS.

•Administration – Alemtuzumab is generally given 10 mg three times a week subcutaneously; subcutaneous administration has largely replaced treatment using intravenous alemtuzumab.

Alemtuzumab therapy requires antibiotic and antiviral prophylaxis and close observation for infections and cardiac toxicity [69].

•Toxicity – Serious infections can occur, especially in heavily pretreated patients, but they may be less common with low-dose subcutaneous treatment.

Cytomegalovirus, generalized herpes simplex, fatal aspergillosis, and mycobacterial pneumonia can be seen, but they may be less common than in patients with other hematologic malignancies [70].

Heart failure or arrhythmias have occurred with alemtuzumab, but they are mostly improved after the discontinuation of treatment [69].

Autoimmune encephalitis (AIE) has been reported in association with alemtuzumab treatment [71]. Patients with subacute onset of memory impairment, altered mental status, psychiatric symptoms, neurologic findings, and/or seizures should be evaluated for AIE. (See "Autoimmune (including paraneoplastic) encephalitis: Clinical features and diagnosis".)

•Outcomes

-Intravenous alemtuzumab in 22 patients with stage III or IV MF was associated with a 55 percent ORR (including a 32 percent CR) [72]. It was more effective for erythrodermic skin disease rather than plaque/tumor-stage disease, and it reduced severe pruritus. One-half of patients had infectious complications, including fatal Mycobacterium infection, 10 months after treatment ended.

-Treatment of 19 heavily pretreated patients using intravenous and/or subcutaneous alemtuzumab for advanced erythrodermic MF or SS reported an 84 percent ORR (including a 47 percent CR) [73]. The median OS was 41 months, and the median PFS was six months. Toxicities included myelosuppression and infections, but most were transient and mild (grade 2).

-Retrospective analysis that included 16 patients with advanced MF (including 10 with large cell transformation) reported a 25 percent ORR; activity was greater in patients with SS [74]. Grade ≥3 infectious and hematologic AEs occurred in 62 and 26 percent, respectively, of the entire population of 39 patients.

-Treatment with low-dose alemtuzumab was associated with a CR in 76 percent of 17 patients who had erythroderma without superimposed plaques or tumors; skin-directed therapies controlled residual or emergent disease in the remaining patients [70].

●Pembrolizumab – Pembrolizumab is an inhibitory antibody against PD-1, which is expressed by exhausted T cells and malignant T cells of MF and SS. Pembrolizumab is not used as front-line therapy, but it has limited roles for managing refractory MF.

•Administration – Pembrolizumab 2 mg/kg intravenously every three weeks.

•Toxicity – Disease flare is seen in some patients, especially in those with erythroderma; this should be distinguished from disease progression. Rapid progression has been reported in patients, who are positive for human T-lymphotropic virus (HTLV), receiving pembrolizumab.

•Outcomes – A multicenter study of 24 patients with advanced-stage MF or SS treated with pembrolizumab reported a 38 percent ORR, including an 8 percent CR [75]. Responses were durable and among responding patients. Median duration of response was not reached with median follow-up of >1 year. Pembrolizumab was well tolerated, and AEs resolved after discontinuation.

Extracorporeal photopheresis — ECP is a systemic therapy, which is primarily used for skin or blood involvement, that treats blood extracorporeally with 8-methoxypsoralen and PUVA therapy.

ECP is generally well tolerated and does not cause generalized immunosuppression, but it is only available at specialized centers [76,77]. Skin-directed therapies (eg, topical corticosteroids, phototherapy, TSEBT), systemic bexarotene, or IFNa can be combined with ECP to improve or hasten the response [78-82].

A review of 28 studies (total 407 patients) that used ECP for erythroderma reported a median 63 percent clinical response, including a median 20 percent CR [83]. ECP is most efficacious when used as an early line of treatment and in patients with a lower blood tumor burden [84,85].

Other studies of ECP for MF include:

●ECP was associated with longer time to next treatment (TTNT) compared with other systemic treatments in a case series of 65 patients with erythrodermic MF or SS [84]. When ECP was used earlier in the disease course (ie, first to third line of therapy), the median time on treatment was 42 months, and the median TTNT was 12 months, which was significantly longer than TTNT with methotrexate, histone deacetylase inhibitors, and chemotherapy. No grade ≥3 AEs occurred with ECP.

●In one series, 83 percent of patients with erythrodermic MF and SS experienced >25 percent response to photopheresis [86,87]. The CR rate was only 21 percent, but 41 percent of patients experienced a partial response (≥50 percent improvement in skin disease).

●Robust and durable responses to ECP in another study, with a median OS of nine years from diagnosis and seven years from ECP initiation [88]. The ORR in skin was 74 percent, including 33 percent with a ≥ 50 percent partial skin response and 41 percent with a ≥ 90 percent improvement; median DORs were 14 and 9 months, respectively. Responses were comparable for patients with erythroderma and extensive patch-plaque disease.

●A single-institution study of erythrodermic CTCL reported a 63 percent ORR (including a 16 percent CR) with a 22-month DOR and 8-month median time to response [83]. Treatment was well tolerated, and there were no grade ≥3 AEs.

Guidelines for the use of ECP for CTCL and other disorders have been published [78]. Further details of ECP are presented separately. (See "Treatment of Sézary syndrome".)

RADIATION THERAPY — Radiation therapy (RT) is often combined with other modalities to treat MF.

●Localized radiation therapy – Localized RT can be used to treat skin or lymph node disease, as described above. (See 'Limited extent' above and 'Stage IVB (visceral disease)' above.)

•Skin disease – We treat with 8 to 12 gray (Gy).

•Lymph nodes – We generally use 12 to 24 Gy, fractionated.

●Total skin electron beam therapy – Total skin electron beam therapy (TSEBT) can control plaque or tumor grade skin disease without major cumulative toxicity. However, TSEBT should be used cautiously and with attenuated dosing in patients with erythrodermic disease, as it can cause severe desquamation and increase risk for secondary skin infections. (See 'Stage III (erythrodermic disease) MF' above.)

•Administration – The optimal dose and schedule of TSEBT is uncertain. Most patients initially receive 12 Gy, with the potential to give up to a total of 36 Gy depending upon the severity of initial skin involvement and rapidity of response. This approach reduces potential toxicity and permits flexibility for repeating treatment later in the course of disease.

-Low-dose TSEBT – Treatment with 10 to 12 Gy over two to three weeks is effective and may cause fewer short-term complications and greater potential for retreatment, if needed [89-94]. Doses as low as 8 Gy are associated with high response rates and minimal toxicity but significant relapse rates, while doses as low as 4 Gy demonstrated an unacceptably short duration of response (<3 months) [95,96].

-Conventional dose – A total dose of 30 to 36 Gy is given over 9 or 10 weeks; a one-week break may be given after 15 to 20 Gy to provide relief from generalized skin erythema associated with treatment. Most protocols are variations of the "Stanford technique" in which 1 to 2 Gy daily doses are given four or five days per week while standing on a rotating platform or in several (eg, six) different positions. Conventional-dose radiation has become less frequently used as low-dose regimens have gained wider acceptance.

The routine use of emollients is encouraged as the skin is often chronically dry after completing TSEBT.

A limited number of tumors can be focally irradiated at the outset of treatment to ensure adequate penetration of the beam. The top of the scalp, perineum, underside of breasts, panniculus folds, and soles of the feet may require supplemental treatment because they are "shadowed" during treatment.

•Combination therapy – TSEBT is generally combined with other systemic and/or skin-directed treatments for treating advanced-stage MF.

After completing TSEBT, skin-directed therapy (eg, topical bexarotene, PUVA [psoralen plus ultraviolet A photochemotherapy]) or systemic therapy (eg, interferon, retinoids, photopheresis) may be administered for 6 to 12 months. These combined approaches can maintain and prolong the clinical response, but it is uncertain if it improves overall survival (OS) [41,97-100].

•Toxicity – Adverse effects (AEs) include desquamation, xerosis, hair loss, and erythema, as discussed separately. (See "Treatment of early stage (IA to IIA) mycosis fungoides", section on 'Total skin electron beam therapy'.)

•Outcomes – Higher doses of TSEBT can achieve higher initial responses, but they are associated with greater toxicity. In addition, since many patients receive other therapies following TSEBT, valid comparisons of outcomes for low-dose versus high-dose regimens are difficult.

A trial that randomly assigned patients to TSEBT, with or without combination chemotherapy, reported no difference in OS or disease-free survival (DFS); combined modality treatment achieved a higher rate of complete response (CR), but it was considerably more toxic [101].

Comparisons of low-dose versus conventional dosing of TSEBT include:

-TSEBT ≥30 Gy was associated with a nonsignificant trend towards better rates of CR (44 to 74 percent) and clinical benefit for stage IIB MF [41,97,102,103].

-12 Gy TSEBT was associated with favorable outcomes and fewer grade 2 acute toxicities compared with conventional-dose TSEBT 30 Gy [92,104,105].

-A single-center retrospective analysis reported similar outcomes with doses of 10 to <20 Gy and 20 to <30 Gy compared with doses of ≥30 Gy [106]; treatment included 102 patients with skin-only MF (51 with generalized patch/plaque, 29 with tumor stage, and 22 with erythrodermic disease). The lower doses were associated with similar rates of OS, overall response rate (ORR), progression-free survival, and relapse-free survival. The ORRs (ie, >50 percent improvement) were ≥97 percent in patients who received ≥10 Gy but 90 percent in those receiving 5 to <10 Gy.

-There was a trend toward higher and longer clinical benefit among 45 patients with MF or Sézary syndrome receiving conventional-dose compared with low-dose TSEBT [107]. Among patients with MF, the OS was 77 months with conventional-dose regimens versus 14 months with low-dose regimens, and the median event-free survival was 15 versus 8 months, respectively, but there were fewer grade 2 AEs with low-dose therapy.

GENERAL SKIN MANAGEMENT — Patients with MF often have severe pruritus, scaling and fissuring of skin, and thickening of the palms and soles. Adjunctive measures should be used to control symptoms and prevent infectious complications.

●Topical agents – While advanced-stage disease is generally treated with a systemic agent, all patients should be considered for supplemental skin-directed treatment to optimize the benefit and quality of life. Skin-directed therapy for MF is discussed in detail separately. (See "Treatment of early stage (IA to IIA) mycosis fungoides", section on 'Skin-directed therapies'.)

●Pruritus – General measures for the management of pruritus include moisturizers, nonirritating creams, topical corticosteroids, and oral antihistamines. However, even high doses of antihistamines may not adequately control severe pruritus. A superimposed skin infection may worsen pruritus; signs of skin superinfection in patients with MF, which can occur in the absence of fever or leukocytosis, include skin erosions or fissures with yellow drainage/crusting. The prevention and management of skin infections are discussed below.

Doxepin has a long half-life and may be helpful when taken at bedtime. Gabapentin can also ameliorate severe pruritus associated with cutaneous T cell lymphoma. [108] For refractory cases, mirtazapine, aprepitant, or naltrexone may be added. For some MF patients, only prednisone provides relief of their pruritus; if used, it should be tapered to the lowest possible dose. (See "Pruritus: Therapies for localized pruritus" and "Pruritus: Therapies for generalized pruritus".)

●Prevention of infections – Patients with MF are at a high risk of infection, and infection can mimic the disease.

Prophylactic systemic antibiotics are not employed by most specialists for colonization without documented infection, even though patients are frequently colonized with Staphylococcus aureus or other skin flora bacteria. Repeated cultures of skin erosions or fissures with yellow drainage/crusting should be performed. Dilute bleach baths, combined with topical antibiotics, such as mupirocin, clindamycin, silver sulfadiazine, or retapamulin, can be used for symptomatic mild colonization or superinfection.

Moderate/severe cases of superinfection or definitive infection require systemic antibiotics. For documented active skin infections, antibiotic choice is guided by culture data. Clinicians must be aware of the potential for methicillin-resistant S. aureus (MRSA) infection in this population. (See "Methicillin-resistant Staphylococcus aureus (MRSA) in adults: Treatment of skin and soft tissue infections".)

Dilute bleach baths and a five-day course of intranasal mupirocin can be employed as a maintenance regimen for patients with a repeated history of S. aureus skin infections. Patients with erythrodermic disease are at risk for dissemination of herpes simplex virus and/or varicella zoster virus.

HEMATOPOIETIC CELL TRANSPLANTATION — Allogeneic hematopoietic cell transplantation (HCT) is the only curative treatment for advanced-stage MF, but it is generally reserved for medically fit patients with high-risk disease (eg, large cell transformation [LCT]) and/or multiply relapsed MF. Autologous HCT is not used to treat MF because responses are generally short lived [109,110].

●Indications – A decision to proceed with allogeneic HCT must be individualized and should consider the potential for a durable remission, risk of graft-versus-host disease (GVHD), possible post-transplant relapse, and alternative treatment options. There are no consensus criteria for transplantation, but most experts consider allogeneic HCT for transplant-eligible patients with a markedly reduced life expectancy (eg, <5 years) or who have progressive or refractory advanced MF.

We favor transplantation at the time of best response to systemic therapy rather than waiting for exhaustion of all treatment options because allogeneic HCT is more likely to be effective with treatment-responsive disease. A large international study of patients with advanced-stage MF and Sézary syndrome (SS; Retro-CLIPI) reported a 28 percent five-year overall survival (OS) in a high-risk group (age >60 years, stage IV disease, LCT, and elevated lactate dehydrogenase) [7].

●Eligibility – We refer patients who are <65 years with no major comorbidities to transplant specialists to assess eligibility for allogeneic HCT. Eligibility criteria for allogeneic HCT are discussed separately. (See "Determining eligibility for allogeneic hematopoietic cell transplantation".)

●Transplantation techniques – There is no preferred conditioning regimen, graft source, and post-transplant immunosuppression regimen in this setting, and choices are generally guided by institutional experience.

•Bridging therapy – Brentuximab vedotin can be used as bridging therapy without enhancing pretransplant toxicity [111].

Mogamulizumab should be used cautiously because it was associated with an increased risk of severe acute GVHD and nonrelapse mortality (NRM) in patients with adult T cell leukemia/lymphoma (perhaps because of depletion of CCR4-expressing regulatory T cells) [48]. This increased toxicity has not been proven with MF, and one study reported no increases in acute GVHD in transplanted patients with MF who received mogamulizumab ≥6 months prior to transplantation [49].

•Conditioning regimen – Incorporation of total skin electron beam therapy (TSEBT) into reduced-intensity conditioning (RIC) has been associated with improved outcomes, but myeloablative conditioning (MAC) and nonmyeloablative (NMA) conditioning regimens have also been used successfully.

•Graft source – Preferred graft sources (ie, peripheral blood stem/progenitor cells, bone marrow, umbilical cord blood) are discussed separately. (See "Hematopoietic cell transplantation (HCT): Sources of hematopoietic stem/progenitor cells", section on 'Preferred graft sources'.)

•Management of GVHD – Various post-transplant immunosuppression regimens have been used successfully, and the choice is guided by institutional experience.

●Outcomes – Improvements in peri-transplant management have led to improved outcomes, with better OS and progression-free survival (PFS) after allogeneic HCT compared with risk-matched patients who were not transplanted [112].

•The Center for International Blood and Marrow Transplant Registry (CIBMTR) reported outcomes for 129 patients who underwent allogeneic HCT for MF or SS [113]. Two-thirds of patients received RIC or NMA conditioning. The OS at one and five years was 54 and 32 percent, respectively; corresponding PFS rates were 31 and 17 percent. Disease relapse or progression at one and five years was 50 and 61 percent, respectively, and rates of NRM were 19 and 22 percent.

•A study from the European Group for Blood and Marrow Transplantation (EBMT) registry reported on 60 patients who underwent allogeneic HCT (36 patients with MF, 24 patients with SS) [114]. Patients underwent MAC (27 percent) or RIC (73 percent) and received matched-related (75 percent) or matched-unrelated donor grafts. Long-term follow-up reported a 44 percent seven-year OS and 30 percent seven-year PFS; importantly, 26 of the 27 surviving patients were in complete response (CR) after a median follow-up of seven years [115]. Relapse was the main cause of post-transplant failure, with 45 percent of patients experiencing relapse/progression (a median of four months after HCT); however, one-third of those patients remained alive at a median of eight years after transplantation. NRM was 22 percent at seven years, with the latest nonrelapse death 14 months after transplantation. Patients with advanced disease at transplant had an inferior OS (hazard ratio [HR] 3.72; 95% CI 1.49-9.30), lower PFS (HR 3.26; 95% CI 1.43-7.47), and more relapse/progression (HR 3.07; 95% CI 1.15-8.20). Grafts from unrelated donors were associated with an inferior OS (HR 4.81; 95% CI 2.20-10.51) and PFS (HR 2.17; 95% CI 1.09-4.31), and MAC was associated with higher NRM (HR 4.5; 95% CI 1.43-14.15) and a worse OS (HR 2.99; 95% CI 1.40-6.36).

•Allogeneic HCT in 35 patients (12 MF, 22 SS) using NMA conditioning that incorporated TSEBT, total lymphoid irradiation, and antithymocyte globulin (ATG) enabled outpatient graft infusion [112]. GVHD prophylaxis was cyclosporine or tacrolimus and mycophenolate prophylaxis. Patients with MF had a 31 percent CR. For the entire study population, rates of two-, three-, and five-year post-transplant OS were 68, 62, and 56 percent, respectively, and one- and two-year NRM were 3 and 14 percent, respectively. Patients with LCT had lower rates of CR compared with others (40 versus 80 percent). Day +180 cumulative grade 2 to 4 acute GVHD was 16 percent and moderate/severe chronic GVHD was 32 percent. Patients ≥65 years at HCT had similar outcomes to younger patients. Sustained molecular remission was seen in 43 percent of 30 patients, and this was associated with less disease progression/relapse compared with others (9 versus 87 percent).

MULTIPLY RELAPSED OR REFRACTORY MF — There is no consensus for the treatment of multiply relapsed or refractory MF.

Treatment selection should consider previous treatments, comorbidities, and disease manifestations (eg, skin tumors; erythroderma; nodal, visceral or blood involvement). However, treatment options are not limited to the preferred approaches for stage and disease manifestations described above. (See 'Management' above.)

Other approaches may be required in this setting. Some treatments are more intensive, have different toxicity profiles, or are less well characterized for MF than those used for earlier lines of therapy. Examples include different types of cytotoxic chemotherapy (eg, bortezomib, chlorambucil, cyclophosphamide, pentostatin, and temozolomide) or immunotherapy (eg, alemtuzumab, pembrolizumab). Options for combination chemotherapy are discussed separately. (See "Treatment of relapsed or refractory peripheral T cell lymphoma".)

For patients with multiply relapsed MF who are transplant eligible, allogeneic hematopoietic cell transplantation should be considered, as discussed above. (See 'Hematopoietic cell transplantation' above.)

For patients who are not transplant eligible, sequential treatment with various agents is used to relieve symptoms and prolong survival.

CLINICAL TRIALS — All patients with refractory skin involvement or extracutaneous disease should be considered candidates for enrollment in a clinical trial of novel agents. Additional information and instructions for referring a patient to an appropriate research center can be obtained from the United States National Institutes of Health (www.clinicaltrials.gov).

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Primary cutaneous lymphoma".)

SUMMARY AND RECOMMENDATIONS

●Description – Mycosis fungoides (MF) is the most common category of cutaneous T cell lymphoma. MF develops in skin, but it can involve lymph nodes, blood, and visceral organs. Many patients with advanced-stage MF experience chronic disease with multiple relapses and require various treatments over their disease course.

●Staging – Patients may have cutaneous tumors, erythroderma, and/or patch/plaque disease, with or without nodal, visceral, or blood involvement. Advanced-stage MF refers to stages IIB, III, some cases of IVA2, and stage IVB; other cases of stage IV disease are classified as Sézary syndrome (SS). (See 'Pretreatment evaluation' above.)

Details of MF/SS staging are discussed separately. (See "Staging and prognosis of mycosis fungoides and Sézary syndrome".)

●Overview – Symptom relief and long-term disease control are important goals of care, but no single treatment is optimal for all patients. Treatment should be individualized, with consideration of disease compartment-specific activity, toxicity, comorbidities, and patient preference. Many patients require multimodal treatment to effectively control pruritus and other troublesome symptoms. (See 'Overview of treatment' above.)

●Management

•Stage IIB (tumor-stage disease) – Management is guided by the extent of involved body surface area (BSA):

-Limited – For limited cutaneous tumors, we suggest radiation therapy (RT) plus topical therapy rather than systemic therapy or topical therapy alone (Grade 2C). (See 'Limited extent' above.)

When tumors are accompanied by patch/plaque disease involving <10 percent BSA, we generally use localized RT plus a topical agent. Total skin electron beam therapy (TSEBT) can be used with more extensive patch/plaque disease. (See 'Radiation therapy' above.)

-Generalized tumors – For cutaneous tumors that involve ≥10 percent BSA, we suggest brentuximab vedotin (Grade 2C). Other acceptable options include romidepsin, pralatrexate, or TSEBT, as described above. (See 'Generalized tumors' above.)

•Stage III (erythrodermic MF), stage IVA1 (SS), and stage IVA2 SS – Management is like that for SS, as discussed separately. (See "Treatment of Sézary syndrome".)

•Stage IVA2 MF – Management is informed by the presentation:

-Confluent erythroderma (≥80 percent BSA) – Generally managed like SS. (See "Treatment of Sézary syndrome".)

-Predominantly patch/plaque/tumor skin involvement – Described above. (See 'Stage IVA2 mycosis fungoides' above.)

•Stage IVB (visceral disease) – We suggest brentuximab vedotin, romidepsin, or pralatrexate, with treatment individualized for compartment-specific manifestations/symptoms, as discussed above (Grade 2C). (See 'Stage IVB (visceral disease)' above.)

•Clinically aggressive disease – Management varies with the histology (see 'Clinically aggressive disease' above):

-Large cell transformation – We suggest brentuximab vedotin (Grade 2C).

-Folliculotropic MF – Management varies with clinical presentation.

●Systemic agents – Administration, toxicity, and outcomes with individual systemic agents are presented above. (See 'Systemic treatments' above.)

●Radiation therapy – Localized RT and TSEBT can be used alone or with other treatments. (See 'Radiation therapy' above.)

●Skin management – Adjunctive approaches to control pruritus and skin infections are discussed. (See 'General skin management' above.)

●Allogeneic hematopoietic cell transplantation – Transplantation is generally reserved for patients with an adverse prognosis or multiply relapsed disease, as discussed above. (See 'Hematopoietic cell transplantation' above.)

●Relapsed/refractory disease – Management must be individualized, as discussed above. (See 'Multiply relapsed or refractory MF' above.)