Treatment of advanced stage (IIB to IV) mycosis fungoides

INTRODUCTION — Mycosis fungoides (MF) is an extranodal, usually indolent, non-Hodgkin lymphoma of T cell origin that primarily develops in the skin, but can ultimately involve the lymph nodes, blood, and visceral organs. Sézary syndrome (SS) is a more aggressive leukemic variant of cutaneous T cell lymphoma in which circulating malignant (Sézary) cells are observed in the peripheral blood.

The management of advanced stage MF will be discussed here. The management of early stage MF, the management of SS, and the clinical presentation, diagnosis, staging, and prognosis of MF and SS are presented separately. (See "Treatment of early stage (IA to IIA) mycosis fungoides" and "Clinical manifestations, pathologic features, and diagnosis of mycosis fungoides" and "Treatment of Sézary syndrome".)

PRETREATMENT EVALUATION — The standard staging system for MF is based on an evaluation of the skin (T), lymph nodes (N), visceral involvement (M), and blood (B) (table 1 and table 2) [1]. Details are presented separately. (See "Staging and prognosis of mycosis fungoides and Sézary syndrome", section on 'TNMB staging'.)

GOALS OF THERAPY — Advanced stage MF is most often a chronic disease with a persistent or relapsing course. Management is often orchestrated by a multidisciplinary team comprised of dermatologists, medical oncologists, and radiation oncologists. The choice of therapy at different time points is largely dependent on the goals of therapy, which include:

●Long-term disease control – Long-term disease control is the main goal of therapy for most patients with MF. Since most agents have a short duration of response after the cessation of therapy, maintenance therapy that incorporates agents with low toxicity, an absence of cumulative toxicity, and preservation of the immune response is usually preferred, even if these agents have a slower time to response or lower overall response rate than more toxic drugs. (See 'Long-term disease control' below.)

●Prompt symptom relief – Patients who have extreme symptoms limiting quality of life should be considered for therapies with a faster onset of action (eg, radiation), even if the long-term control is not as good with these agents. However, some faster-acting agents, such as cytotoxic chemotherapy, can depress the host immune response and may decrease the efficacy of immunomodulatory treatments in the future. In addition, patients often benefit from ancillary therapies, including skin-directed therapies, therapies directed at symptoms such as pruritus, and superinfections. (See 'Symptom control' below.)

●Addressing life-threatening (aggressive) disease – Patients with clinically aggressive disease are less likely to have long-term control with standard regimens and require more aggressive and toxic therapies given with curative intent. (See 'Aggressive disease' below.)

Consensus recommendations regarding the treatment of MF and Sézary syndrome have been proposed by the US Cutaneous Lymphoma Consortium, National Comprehensive Cancer Network (NCCN), British Association of Dermatologists/United Kingdom Cutaneous Lymphoma Group, European Organization for Research and Treatment of Cancer (EORTC), European Society of Medical Oncology (ESMO), and Japanese Dermatologic Association (JDA)/Japanese Skin Cancer Society (JSCS) [2-7]. Our approach is generally consistent with these guidelines.

LONG-TERM DISEASE CONTROL

Overview of disease management — Most patients with MF have a chronic clinical course with the application of sequential therapies that keep the disease under control with choice of therapies directed at the type and site of disease (eg, patch/plaque, tumor, erythroderma, extracutaneous disease). Since most agents have a short duration of response after the cessation of therapy, maintenance therapy that incorporates agents with low toxicity and preserves the immune response is usually preferred, even if these agents have a slower time to response or lower overall response (OR) rate than more toxic drugs. In contrast, more potent therapy is required for cases with an aggressive clinical presentation. (See 'Aggressive disease' below.)

There is no standard initial therapy, and experts differ in their preferred approach. Patients should be encouraged to participate in clinical trials. (See 'Clinical trials' below.)

Data regarding the efficacy of treatment come largely from retrospective case or cohort studies, or open-label, single arm clinical trials. Very few randomized trials have been performed. As such, it is difficult to accurately compare response, disease-specific survival, and overall survival rates among treatments. In addition, response criteria have changed over time and have not been demonstrated to correlate with prognosis. (See "Staging and prognosis of mycosis fungoides and Sézary syndrome".)

Decisions to continue or switch therapy are made on a clinical basis, incorporating data from the following:

●Complete skin examination including a determination of the type of skin lesions and the estimated percentage of total body surface area involved by patches, plaques, and tumor lesions.

●Survey of the lymph nodes and assessment for organomegaly.

●Complete blood count with manual differential and assessment for Sézary cells.

●Repeat imaging studies that were previously abnormal.

●Patient and physician perception of disease severity and symptom control. This factor is particularly important as most systemic therapies provide partial, as opposed to complete, responses.

Patients who demonstrate adequate clinical benefit should be considered for maintenance or taper regimens to maximize response duration. Patients who relapse off therapy may respond to retreatment with the same agent. Patients who relapse on therapy should generally be treated with alternate low toxicity drugs before moving on to more aggressive treatments for refractory disease. Patients whose disease cannot be adequately controlled with lower toxicity agents or who develop aggressive disease refractory to milder agents should be considered potential candidates for allogeneic hematopoietic cell transplantation (HCT), as this is the only known curative therapy for advanced stage MF or Sézary syndrome (SS). (See 'Hematopoietic cell transplantation' below.)

Cutaneous tumors

Limited extent — For most patients with cutaneous tumors involving a limited percent body surface area (typically <10 percent), we suggest treatment with local radiation to the tumors plus skin-directed therapy as needed for concurrent patch/plaque disease. Alternatively, systemic therapy similar to that given for more extensive tumor involvement can be used. These two approaches have not been compared directly in a prospective trial. However, a randomized trial demonstrated that there is no advantage in terms of survival to early aggressive combination therapy with radiation and chemotherapy when compared with conservative sequential topical therapies in the management of advanced disease [8]. With either approach, patients with multiple cutaneous tumors have a median survival of 3.5 to 4.0 years, and the majority will die from complications of MF [9,10]. (See "Treatment of early stage (IA to IIA) mycosis fungoides".)

Localized radiation therapy, especially using electrons, is most commonly used for MF, since the lesions are generally superficial. Electrons have a limited depth of penetration, which varies with the electron energy; in contrast, photons (X-rays) penetrate more deeply and are associated with greater risk of injury to deeper tissues. However, in instances where there is deep infiltration of disease or involvement of an extremity, photons can achieve a better dose distribution. MF is extremely sensitive to radiation therapy, and radiation results in complete clearance of treated tumors in >90 percent of cases. For treating individual tumor lesions, doses as low as 8 Gy delivered in a single fraction can achieve a complete response (CR) in as many as 95 percent of patients [11]. Total skin electron beam therapy can be considered in patients with limited tumors and extensive patch/plaque disease, and is the most effective way to reduce disease burden in these patients, but may be associated with more side effects than the combination of localized EBT plus other skin-directed therapies. Techniques for administration of radiation and associated side effects are presented separately. (See 'Total skin electron beam therapy' below and "Treatment of early stage (IA to IIA) mycosis fungoides", section on 'Total skin electron beam therapy'.)

Generalized tumor — For patients with generalized tumors (eg, >10 percent body surface area), equally acceptable treatment options are the use of total skin electron beam therapy (TSEBT), systemic therapies (eg, biologics/immunotherapies, histone deacetylase inhibitors, brentuximab vedotin [BV], single-agent chemotherapy) or combination therapies (systemic plus skin-directed or systemic plus systemic). BV can be especially effective for tumor stage disease. TSEBT can be followed by other skin-directed therapies or systemic therapies to prolong response duration. TSEBT often provides a CR, albeit temporary in most cases, while systemic agents generally provide partial responses but can be given in a maintenance fashion. A choice among these treatments is made based on patient preference and clinician experience. As an example, patients who live at a significant distance from their medical center may find the frequent visits required for TSEBT difficult and may prefer treatment with an oral systemic agent. In contrast, a choice among systemic therapies must take into account certain comorbidities that may be exacerbated with treatment (eg, hyperlipidemia with retinoids; autoimmune conditions with interferon). Systemic therapies are described in more detail separately. (See 'Generalized erythroderma' below.)

Total skin electron beam therapy — Total skin electron beam therapy (TSEBT) results in a CR in 44 to 74 percent of patients with tumor (stage IIB) disease [12-15]. TSEBT is typically followed by the use of an adjuvant therapy, either skin-directed (eg, nitrogen mustard or PUVA [psoralen plus ultraviolet A photochemotherapy]) or systemic (eg, interferon alfa, retinoids, or photopheresis), in order to prolong the response duration [16-18]. It remains unclear if such adjuvant therapy improves overall survival [12,13].

TSEBT may be given on a variety of schedules, most commonly variations of the "Stanford technique." On this schedule, a "cycle" of TSEBT is administered over two days using a six-field technique that delivers a dose of 1.5 to 2.4 Gy to anterior, posterior, and four opposed oblique fields. On the first day, treatment is applied to the anterior and two posterior oblique fields, while the posterior and two anterior oblique fields are treated on the second day. A total dose of 30 to 36 Gy has classically been administered over a 9- to 10-week period. A one-week break may be given after a dose of 15 to 20 Gy has been delivered to provide relief from the generalized skin erythema associated with treatment. Alternatively, treatment can be given in 12 Gy increments, with one- to two-week breaks between each increment. Of importance, some areas, such as the top of the scalp, the perineum, the underside of the breasts, panniculus folds, and the soles of the feet, are "shadowed" and may require supplemental treatment.

The ideal total radiation dose used for TSEBT is unknown. Initial studies used doses as low as 8 Gy and demonstrated high response rates and minimal toxicity, but significant relapse rates. The doses used were gradually increased over time to 30 to 36 Gy, a dose that is associated with greater toxicity but higher initial response rates. Subsequent studies have attempted to define an equally effective dose with minimal toxicity. Trials investigating doses as low as 4 Gy have demonstrated unacceptably short response durations (<3 months) [19,20]. A single center retrospective analysis of TSEBT dose in 102 patients with advanced stage MF demonstrated that TSEBT doses of 10 to <20 Gy and 20 to <30 Gy resulted in similar rates of OR, overall survival (OS), progression-free survival (PFS), and relapse-free survival (RFS) when compared with doses of ≥30 Gy [21]. Prospective phase II clinical trials report an mSWAT reduction of 61 to 100 percent (median 94 percent) after just 12 Gy with an OR rate of 88 percent and CR rate 27 percent [22]. These trials also show a duration of clinical benefit defined as time to progressive disease or institution of another total skin or systemic therapy of 42 to 134 weeks (median 71). These lower doses of TSEBT are an attractive option for palliation since they require only two to three weeks of treatment.

After the completion of TSEBT, adjuvant therapy with a variety of agents (eg, topical nitrogen mustard, bexarotene, photopheresis) may be administered for 6 to 12 months in order to maintain the clinical response. In addition, the routine use of emollients is encouraged as the skin is often chronically dry after completion of TSEBT.

Side effects of TSEBT include desquamation, xerosis, and erythema of the skin. These are presented in more detail separately. (See "Treatment of early stage (IA to IIA) mycosis fungoides", section on 'Total skin electron beam therapy'.)

Generalized erythroderma — Patients with generalized erythroderma (covering at least 80 percent of the body surface area) without any lymph node, visceral, or blood involvement can be treated with skin-directed therapies, systemic therapies, or a combination of the two. Caution must be used in this group because they often have severe pruritus and skin inflammation that can be further irritated by many topical therapies. Standard TSEBT is generally not used for patients with erythroderma and very atrophic skin because these patients may suffer severe desquamation with total doses as low as 4 Gy; however, patients with erythroderma and very thickened skin may tolerate standard TSEBT. For most patients with generalized erythroderma without additional manifestations, we typically administer both a skin-directed therapy (eg, topical steroids) and a systemic therapy (eg, methotrexate, retinoids). Other experts use skin-directed therapy alone and then proceed to systemic therapies upon progression or failure of response.

Topical therapy with nitrogen mustard or corticosteroids is the same as that used for early stage (IA to IIA) MF. Caution must be used in patients with erythroderma because topical therapies can exacerbate pruritus and skin inflammation. The use of topical therapies is presented in more detail separately. (See "Treatment of early stage (IA to IIA) mycosis fungoides".)

Choice among systemic therapies — For patients with widespread disease that does not respond adequately to skin-directed therapies alone, we offer systemic therapy alone or in conjunction with skin-directed therapies. Selection of systemic therapy may be informed by prior treatments, comorbid illnesses, toxicity, route of administration, patient preference/convenience, and clinician experience. Treatment may utilize a single systemic therapy or a combination of systemic treatments.

In general, we prefer immune preserving agents (eg, retinoids, low-dose methotrexate) or immunostimulatory (eg, interferon [IFN]) therapies prior to the use of more toxic regimens [23,24]. Most patients will relapse after initial treatment, and relapsed disease may respond to repeated treatment with the same agent or to other skin-directed or systemic therapies.

Few clinical trials have directly compared systemic agents for treatment of advanced MF, and various studies often differ based on criteria for enrollment, response, and outcomes. A phase 3 study reported superior responses, but higher rates of peripheral neuropathy, among patients with MF who were randomly assigned to treatment with BV compared with the physician's choice of methotrexate or bexarotene. Another phase 3 study (MAVORIC) reported superior outcomes and acceptable levels of toxicity for mogamulizumab (moga) compared with vorinostat, but caution is advised for patients who may undergo allogeneic hematopoietic cell transplantation (HCT) soon after receiving moga. (See 'Brentuximab vedotin' below and 'Mogamulizumab' below.)

Most other data regarding responses to systemic therapies are derived from modest sized studies that did not directly compare agents. Compared with studies of newer agents (eg, histone deacetylase inhibitors, BV), many older studies of IFN and systemic retinoids used less rigorous or objective response criteria. Furthermore, some patients with MF will experience spontaneous regressions following treatment with placebo [25].

Patients whose disease cannot be adequately controlled with various systemic therapies are candidates for allogeneic HCT, as this is the only known curative therapy for advanced stage MF or Sézary syndrome (SS). (See 'Hematopoietic cell transplantation' below.)

Systemic therapies for patients with advanced disease and/or in need of systemic therapy include one or a combination of the following:

●Brentuximab vedotin – Brentuximab vedotin (BV) is an anti-CD30 antibody conjugated with the tubulin disrupting agent, monomethyl auristatin E (MMAE). BV can be very effective (especially for tumor stage disease), but patients whose tumors express very low levels of CD30 (<5 percent) have a lower likelihood of responding to BV. The most common toxicity is peripheral neuropathy associated with MMAE. (See 'Brentuximab vedotin' below.)

●Mogamulizumab – Mogamulizumab (moga) is an antibody directed against the chemokine receptor CCR4, which is overexpressed on malignant T cells. Treatment is associated with acceptable levels of toxicity, but caution is advised for patients who may undergo allogeneic HCT soon after receiving moga as it may confer an increased risk of acute graft-versus-host disease (GVHD). (See 'Mogamulizumab' below.)

●Low-dose methotrexate – Low-dose oral or intravenous methotrexate offers a reasonable response rate, convenience, and favorable toxicity profile. It may be associated with mucositis, gastrointestinal effects, and myelosuppression; it is a potential teratogen, and it is occasionally associated with hepatic, renal, and pulmonary toxicity. (See 'Low-dose methotrexate' below.)

●Systemic retinoids – Approximately half of patients respond to treatment with systemic retinoids. Retinoids can be used alone, or more often, in combination with topical steroids, PUVA, or interferon. Retinoids are teratogenic. Common side effects include hyperlipidemia and central hypothyroidism. (See 'Systemic retinoids' below.)

●PUVA (psoralen + ultraviolet A photochemotherapy) – PUVA results in CR rates of 30 to 70 percent in patients with generalized erythroderma [26-28]. Treatments are administered several times a week. Acute complications include erythema, pruritus, blistering, skin dryness, and nausea. (See 'PUVA therapy' below.)

●Interferon – Interferon (IFN) alfa results in OR rates from 50 to 75 percent. IFN can be combined with other systemic (eg, retinoids) or skin-directed (topical agents, PUVA, TSEBT) therapy. IFN is associated with significant toxicities including fever, chills, and flu-like symptoms. It should be used with caution in patients with concomitant autoimmune conditions (eg, rheumatoid arthritis) or following solid organ transplantation. (See 'Interferon' below.)

●Histone deacetylase (HDAC) inhibitors – Approximately one-third of patients will respond to treatment with histone deacetylase (HDAC) inhibitors. HDAC inhibitors can be combined with other systemic (eg, IFN) or skin-directed (eg, TSEBT) therapy. Side effects include fatigue, nausea, diarrhea, thrombocytopenia, and nonspecific electrocardiogram effects. (See 'Vorinostat' below and 'Romidepsin' below.)

●Alemtuzumab – Low-dose alemtuzumab has demonstrated OR rates of up to 55 percent. Alemtuzumab is only appropriate for patients with erythrodermic MF with or without blood involvement (stages III and IVA). Patients with bulky lymph nodes are unlikely to respond. (See 'Alemtuzumab' below.)

Brentuximab vedotin — Brentuximab vedotin (BV) is an anti-CD30 monoclonal antibody conjugated with monomethyl auristatin E by a protease-cleavable linker and has established activity in lymphomas that express CD30. It has been approved by the US Food and Drug Administration (FDA) for treatment of Hodgkin lymphoma and systemic anaplastic large cell lymphoma (ALCL). BV is an option for patients with MF that has relapsed or progressed after radiation therapy or systemic treatment, and for patients with generalized tumors.

Studies that have evaluated use of BV in MF/SS include the following:

●In a phase II study, 33 patients were treated with BV (1.8 mg/kg) every three weeks for eight cycles, and those who were benefiting and tolerating treatment could receive up to eight additional cycles (16 total cycles) [29]. The OR rate was 70 percent, including responses in skin, blood, and extracutaneous compartments. Responses were observed in patients with all levels of CD30 expression, but were significantly lower in those with CD30 expression <5 percent. A reduction in skin tumor burden measured by mSWAT score decreased by at least 90 percent in one-quarter of patients.

Peripheral neuropathy was the primary toxicity and was observed in 66 percent of patients. Other common toxicities were fatigue (47 percent) and nausea (28 percent).

●An international, open-label trial randomly assigned 128 patients with MF (97 patients) or primary cutaneous ALCL to BV versus the physician's choice (PC) of bexarotene or methotrexate; at least one skin biopsy demonstrated that ≥10 percent of neoplastic cells or lymphoid infiltrate expressed CD30, and patients with Sézary syndrome were excluded [30]. Compared with PC, BV achieved superior rates of:

•OR that lasted at least four months (ORR4) – 56 versus 13 percent

•CR – 16 versus 2 percent

•Median PFS – 17 versus 4 months

•Symptomatic relief (measured by Skindex-29 score) – 28 versus 9

Superior efficacy of BV was independent of the level of CD30 expression. There were comparable rates of grade 3/4 adverse events, but higher rates of peripheral neuropathy (any grade) with BV (67 versus 6 percent).

Mogamulizumab — Mogamulizumab (moga) is a defucosylated humanized antibody directed against the chemokine receptor CCR4, which is overexpressed on malignant T cells [31]. Compared to vorinostat in the phase III MAVORIC trial, moga achieved superior PFS, response rate, and quality of life with acceptable levels of toxicity [32]. For patients with MF, moga achieved superior PFS (hazard ratio 0.72; 95% CI: 0.51 to 1.01), but the advantage was even greater for patients with Sézary syndrome, as described separately. Of note is that patients with large cell transformed disease were excluded. (See "Treatment of Sézary syndrome", section on 'Mogamulizumab'.)

Moga was approved by the FDA for treatment of adult patients with relapsed or refractory MF or SS after at least one prior systemic therapy [33]. Moga can deplete regulatory T cells, and some reports suggest that it may increase the risk of acute GVHD in patients who undergo allogeneic HCT soon after moga treatment (within six months), but this remains to be confirmed [34-36].

Low-dose methotrexate — Low-dose oral methotrexate (approximately 5 to 50 mg per week) or intravenous methotrexate (25 to 50 mg/m² once per week) results in OR rates of 30 to 50 percent [37]. Methotrexate can be combined with other systemic (eg, IFN) and/or skin-directed therapy. Common side effects of low-dose methotrexate include mucositis, gastrointestinal effects, and myelosuppression. Methotrexate can also result in hepatic, renal, and pulmonary toxicity, and it is an abortifacient that can also induce congenital anomalies if taken during pregnancy. (See "Major side effects of low-dose methotrexate".)    

Systemic retinoids — Systemic (oral) retinoids result in response rates of 45 to 55 percent (10 to 20 percent CR) depending on the dosing and severity of MF [38-43]. Bexarotene is approved by the FDA and European Medicines Agency's (EMA) for use in patients with advanced MF (stages IIB to IVB) who are refractory to at least one prior systemic therapy. Isotretinoin and acitretin are commercially available, but not FDA-approved for this indication [12]. Etretinate is available only in Japan.

A phase II/III trial of bexarotene in 94 patients with advanced stage MF (stages IIB to IVB) who were refractory to conventional therapy reported OR rates of 45 and 55 percent of patients started on oral doses of 300 and greater than 300 mg/m² per day, respectively [40]. No serious adverse events occurred; the most common toxicities included hyperlipemia (primarily hypertriglyceridemia, 82 percent), hypercholesterolemia (30 percent), hypothyroidism (29 percent), and headache (20 percent) [40,44]. (See "Central hypothyroidism".)

The recommended initial starting dose of bexarotene is 200 to 300 mg/m² per day orally. Alternatively, some clinicians start at very low doses (eg, 150 mg flat dose daily) and titrate up based on tolerance and response. Liver function, serum lipid levels, thyroid function (serum free T4), and complete blood counts (CBC) should be monitored in each patient during treatment [45]. We measure these levels before starting the drug. Lipid levels are then monitored weekly or biweekly until a plateau in the lipid response and then at four- to eight-week intervals thereafter. A comprehensive metabolic profile, CBC, and serum free T4 (not TSH) are checked monthly. Bexarotene must be used with caution in patients with hypertriglyceridemia, liver dysfunction, or risk factors for pancreatitis. Lipid lowering agents and/or thyroid hormone replacement are commonly required to mediate these side effects of bexarotene; however, patients taking bexarotene should not be treated with gemfibrozil because coadministration results in increased serum levels of bexarotene. Omega-3-fatty acids may be initiated prior to treatment with bexarotene to lessen the hypertriglyceridemia. (See "Hypertriglyceridemia in adults: Management", section on 'Marine omega-3 fatty acids'.)

Most toxicities due to systemic retinoids are reversible after cessation of therapy. The most common adverse effects of retinoids include photosensitivity, xerosis, myalgia, arthralgia, headaches, and impaired night vision. Retinoids have potential hepatotoxic and hyperlipidemic effects, necessitating monitoring. Patients receiving treatment with oral bexarotene are also at increased risk for hypertriglyceridemia and central hypothyroidism, and may require anti-lipidemic and thyroid replacement therapy [44]. The well-known teratogenic effects of retinoids must be carefully addressed in female patients. (See "Oral isotretinoin therapy for acne vulgaris" and "Central hypothyroidism".)

Interferon — Interferon (IFN) alfa is used primarily for the palliative management of relapsed or refractory advanced disease with OR rates from 53 to 74 percent (21 to 35 percent CR) [46,47]. However, the majority of patients will relapse during maintenance therapy.

IFN may be administered alone or, more commonly, in combination with topical or other systemic treatments [48,49]. As an example, the combination of IFN alfa plus PUVA results in CR and partial response (PR) rates of 75 to 80 percent and 6 to 20 percent, respectively, in patients with generalized patch/plaque disease (stages IB and IIA) [48,49]. Although the clinical response and response duration appear to be better with the combined regimen of PUVA and IFN, as compared with either treatment alone, randomized prospective clinical trials are needed to confirm this impression [26,50].

An additional benefit of combined therapy may be the suppression of anti-IFN-alfa antibody formation. None of the 24 patients with MF assayed in a clinical study developed antibodies [51], compared with a reported incidence of 4 to 46 percent in a variety of other cancer settings [52].

Administration of IFN alfa for MF is usually initiated at a dose of 3 to 5 million units subcutaneously (SQ) given three times a week. This dose is gradually increased, depending on the clinical response and the severity of adverse effects. For a regimen combining IFN and PUVA, the two treatments are initiated concurrently, each given three times per week. When a patient's skin clears completely, IFN is stopped and maintenance therapy with PUVA treatment at a reduced frequency is begun.

Manufacture of IFN alfa-2b was discontinued by Merck in 2019 and the remainder of supply is expected to be exhausted by March, 2022; it is uncertain if production by small-scale manufacturers will continue. Peginterferon alfa-2b is also discontinued, and is no longer distributed globally.

Romidepsin — Romidepsin (also known as depsipeptide) is a histone deacetylase (HDAC) inhibitor with activity in cutaneous T cell lymphoma (CTCL) [53]. It has demonstrated an OR rate of 35 percent in two separate studies and is approved by the FDA for the treatment of CTCL in patients with progressive, persistent, or recurrent disease on or following at least one prior systemic therapy.

A multi-institutional phase II trial evaluated the use of single-agent intravenous romidepsin in 71 patients with CTCL [54]. The patients had received a median of four prior therapies and 87 percent had advanced stage disease. The following results were noted:

●The OR and CR rates were 34 and 6 percent, respectively. The median duration of response was 11.1 months. Among those with a major response, the median time to progression was 15.1 months.

●Severe (grade 3/4), yet transient, granulocytopenia and lymphopenia were seen in 14 and 21 percent of patients, respectively. Nonhematologic side effects were generally mild, but included nausea, vomiting, fatigue, electrolyte abnormalities, and electrocardiographic changes.

An international phase II trial evaluated the use of romidepsin in 96 patients with CTCL who had received a median of two prior therapies [55]. Seventy-one percent had advanced stage disease:

●OR and CR rates were 34 and 6 percent, respectively. The median time to response was two months, and the median duration of response was 15 months.

●Of the 65 patients with moderate to severe pruritus at baseline, 28 (43 percent) had clinically meaningful improvement in pruritus, including patients who did not achieve objective disease response.

●Approximately half of patients had mild (grade 1/2) gastrointestinal side effects (mostly nausea, less commonly vomiting or diarrhea). Severe (grade 3/4) side effects were uncommon. The most common dose-limiting adverse effects were fatigue/asthenia and thrombocytopenia. A prolonged corrected QT interval was seen in two patients.

Romidepsin is administered as a single agent at a dose of 14 mg/m² administered by intravenous infusion over four hours on days 1, 8, and 15 of a 28-day cycle. Full prescribing information is available separately [56].

Several treatment-emergent changes in electrocardiograms (ECGs) (including T-wave and ST-segment changes) have been reported in clinical studies with romidepsin, but have not been shown to be clinically significant [55,57,58]. In patients with congenital long QT syndrome, patients with a history of significant cardiovascular disease, and patients taking anti-arrhythmic medicines or medicinal products that lead to significant QT prolongation, appropriate cardiovascular monitoring precautions should be considered, such as the monitoring of electrolytes and ECGs at baseline and periodically during treatment. Romidepsin is metabolized by CYP3A4. Co-administration of strong CYP3A4 inhibitors or potent CYP3A4 inducers should be avoided if possible.

Potassium and magnesium levels should be in the normal range before drug administration. There is no required monitoring of ECGs in patients who do not have the above risk factors. (See "Cardiotoxicity of cancer chemotherapy agents other than anthracyclines, HER2-targeted agents, and fluoropyrimidines", section on 'Histone deacetylase inhibitors'.)

Vorinostat — Vorinostat is an orally active HDAC inhibitor, with PR rates in MF of 30 percent [59-63]. It is approved by the FDA for the treatment of CTCL in patients with progressive, persistent, or recurrent disease after two systemic therapies [64].

The activity of vorinostat (starting dose 400 mg/day) was evaluated in 74 patients with stage IB or higher CTCL who had failed a median of three systemic therapies, one of which included bexarotene [65]. Thirty percent of subjects experienced a PR as measured by a modified skin severity weighted assessment tool; 32 percent had pruritus relief; one patient attained delayed CR on day 281.

Toxicities of vorinostat included diarrhea (46 percent), fatigue (49 percent), nausea (43 percent), anorexia (26 percent), and dysgeusia (24 percent) [65]. Hematologic abnormalities included anemia, thrombocytopenia (22 percent), and neutropenia, most of which were grade 1 or 2 in severity. The most common severe adverse event was pulmonary embolus, seen in four patients (5 percent). Patients enrolled in clinical studies were also instructed to drink at least 2 liters of fluid daily to avoid dehydration.

Several treatment-emergent morphological changes in ECGs, including T-wave and ST-segment changes, have been reported in clinical studies with HDAC inhibitors but have not been shown to be clinically significant [57,66]. In patients with congenital long QT syndrome, with a history of significant cardiovascular disease, or taking anti-arrhythmic medicines or medicinal products that lead to significant QT prolongation, appropriate cardiovascular monitoring precautions should be considered (ie, monitoring of electrolytes and ECGs at baseline and periodically during treatment).

Potassium and magnesium levels should be in the normal range before drug administration. There is no required monitoring of ECGs in patients who do not have the above risk factors. (See "Cardiotoxicity of cancer chemotherapy agents other than anthracyclines, HER2-targeted agents, and fluoropyrimidines", section on 'Histone deacetylase inhibitors'.)

Alemtuzumab — The anti-CD52 monoclonal antibody alemtuzumab has demonstrated OR rates of up to 55 percent [23,67,68]. Alemtuzumab is only appropriate for patients with erythrodermic MF with or without blood involvement (stages III and IVA) [23,24]. Patients with bulky lymph nodes are unlikely to respond [69].

Serious infections (cytomegalovirus, generalized herpes simplex, fatal aspergillosis and mycobacterium pneumonia) can be seen, especially in heavily pretreated patients, but are less common than in patients with other hematologic malignancies (eg, CLL) [69]. A low-dose, intermittent administration schedule of alemtuzumab (10 mg subcutaneously, three times a week) may reduce infectious complications in patients with MF [69,70]. Alemtuzumab therapy requires antibiotic and antiviral prophylaxis as well as close observation for the development of infection and cardiac toxicity [67].

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

PUVA therapy — PUVA (psoralen + ultraviolet A photochemotherapy) results in CR rates of 30 to 70 percent in patients with generalized erythroderma [26-28,72,73]. In such cases, PUVA must be started at a low dose followed by a very slow and cautious increase of UVA dose to avoid phototoxic reactions. Despite a good clinical response with PUVA alone, the majority of the patients relapse during maintenance therapy. (See "Treatment of early stage (IA to IIA) mycosis fungoides", section on 'Phototherapy'.)

The combined regimen of PUVA plus IFN alfa can be used as primary therapy or when patients fail to respond to IFN or PUVA alone. In one study, the CR and PR rates in stage III disease for the combined regimen of IFN and PUVA were 62 percent and 25 percent, respectively [48]. This combined regimen may result in improved clinical response and response duration beyond that observed with IFN or PUVA alone, although prospective randomized studies will be needed to confirm this impression. At this time, there is no clear evidence that prolongation of response duration leads to improvement in overall survival.

Extracutaneous disease

Peripheral blood involvement — Limited involvement of the peripheral blood (ie, absolute Sézary cell count <1000 cells/microL, B1) may be seen in patients with or without generalized erythroderma and is discussed here. In contrast, major involvement of the peripheral blood (SS, stage IVA1 disease) is discussed in more detail separately. (See "Treatment of Sézary syndrome".)

Patients with involvement of the peripheral blood require systemic therapy to target the malignant cells circulating in the blood. Skin-directed therapies may be added as adjunctive treatment if needed to control cutaneous lesions. Systemic treatment options include extracorporeal photopheresis (ECP) and systemic therapies used for patients with generalized erythroderma (retinoids, interferon, histone deacetylase inhibitors, low dose methotrexate). (See 'Choice among systemic therapies' above.)

Where available, we prefer the use of ECP because it is not immunosuppressive and can be combined with other systemic therapies (eg, IFN, retinoid) and skin-directed therapies. However, ECP requires a significant patient time commitment with travel to an expert center. In comparison, systemic treatment with bexarotene, IFN, or low dose methotrexate can be easily administered at home, but may be complicated by hyperlipidemia, fatigue, or liver toxicity, respectively.

Extracorporeal photopheresis — Extracorporeal photopheresis (ECP) is a method of delivering PUVA systemically by using an extracorporeal technique. It is often used as the primary therapy for patients with peripheral blood involvement with OR rates of 41 percent (21 percent complete) [74-77]. ECP is time consuming and only available at specialized centers, but is generally well tolerated and does not cause generalized immunosuppression. (See "Treatment of Sézary syndrome", section on 'Extracorporeal photopheresis (ECP)'.)

In one series, 83 percent of patients with erythrodermic MF and SS experienced >25 percent response to photopheresis [76,78]. The CR rate was only 21 percent, but 41 percent experienced ≥50 percent improvement in their skin disease (PR).

In another series of 65 patients with erythrodermic MF or SS, ECP monotherapy was associated with an increased "time to next treatment" compared to IFN, HDAC inhibitors, or chemotherapy alone [79].

If the response to photopheresis alone is partial or slow, response may improve after the addition of IFN or systemic retinoids as a combined modality regimen [75,80,81]. The dose for IFN is usually low, 3 to 5 million units subcutaneously (SQ) three times weekly, gradually increasing the dose if patient tolerance permits, but not exceeding 10 million units per dose. Oral bexarotene is the most commonly used retinoid for the combination therapy. The bexarotene dose for combination therapy ranges from 150 to 300 mg per day. (See 'Systemic retinoids' above and 'Interferon' above.)

Skin-directed therapies such as topical corticosteroids, topical nitrogen mustard, phototherapy, or TSEBT can be combined with ECP if additional skin-directed therapy is needed [82]. (See "Treatment of early stage (IA to IIA) mycosis fungoides", section on 'Our approach'.)

Lymph node or visceral involvement — Patients with lymph node or visceral involvement are principally treated with systemic therapy, although most regimens result in only temporary palliative control. Chemotherapy can be used alone or in combination with other skin-directed therapy (eg, radiation) or biological response modifiers (eg, IFN alfa). With combination chemotherapy regimens, overall CR and PR rates can reach 80 to 100 percent. However, in most cases, the median duration of response is less than one year, and, in many patients, less than a few months [83-85]. As such, these patients are potential candidates for allogeneic HCT. (See 'Hematopoietic cell transplantation' below.)

Megavoltage (4 to 15 MeV) photon irradiation can be used for palliative control of lymph node disease. Total doses of 24 to 30 Gy are delivered over three to four weeks providing local control of lymph nodes or visceral disease. This is often combined with systemic chemotherapy or IFN, depending on the severity of the extracutaneous involvement.

SYMPTOM CONTROL — Patients who have extreme symptoms limiting quality of life should be treated with therapies with a faster onset of action (eg, radiation or therapies for aggressive disease), even if the long-term control is not as good with these agents. Some of these agents can depress the host immune response and they may decrease the efficacy of immunomodulatory treatments. In addition, patients often benefit from ancillary therapies directed at symptoms related to pruritus and superinfections. (See 'Aggressive disease' below.)

Pruritus — Patients with MF have exfoliative erythroderma and may have severe itch, skin scaling, fissuring, and thickening of the palms and soles. General measures for the management of pruritus include moisturizers, nonirritating creams, topical corticosteroids, and antihistamines. However, even high doses of antihistamines may be ineffective in controlling the pruritus. Doxepin has a longer half-life and is useful when applied at bedtime. Some patients respond to the use of gabapentin as is used for other forms of neuropathic pain. 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".)

Importantly, a superimposed skin infection may worsen pruritus. Patients are frequently colonized with Staphylococcus aureus or other skin flora bacteria, and treatment of this can result in clinical improvement and decreased pruritus in the presence of infection. In general, systemic antibiotic use is reserved for patients with active signs of infection. In MF, signs of skin superinfection (which can occur in the absence of fever or leukocytosis) include skin erosions or fissures with yellow drainage/crusting.

Prevention of infections — Patients with MF are at high risk of infection, and infection can mimic the disease. However, prophylactic systemic antibiotics are not employed by the majority of specialists and cannot be advised. Instead, management involves repeated cultures of the skin (of skin erosions or fissures with yellow drainage/crusting) and treatment of identified bacteria. Antibiotic choice should be based on specific culture data and active signs of infection whenever possible. Clinicians must be aware of the potential for methicillin-resistant Staphylococcus aureus (MRSA) infection in this population. Those with erythrodermic disease are at risk for dissemination of herpes simplex virus and/or varicella zoster virus.

Dilute bleach baths, combined with topical antibiotics such as mupirocin, clindamycin, silver sulfadiazine, or retapamulin can be used for mild cases of superinfection. Moderate/severe cases of superinfection or definitive infection require systemic antibiotics. 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.

Skin-directed therapy — While most patients with advanced stage disease will be treated with a systemic agent as primary therapy, all should be considered for supplemental skin-directed treatment to optimize 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'.)

AGGRESSIVE DISEASE — Patients with clinically aggressive disease are less likely to have long-term control with standard regimens and require more aggressive and riskier therapies given with curative intent. Clinically aggressive disease is more common in patients with folliculotropic MF and those with large cell transformation.

For such patients, we often use agents with a shorter time to response, higher response rates, or demonstrated activity in aggressive T cell lymphomas. Options include romidepsin, single agent chemotherapy, and combination chemotherapy. Patients with disease that is difficult to control should be considered for allogeneic hematopoietic cell transplantation (HCT). While there is no agreed-upon timing for HCT, most experts agree that patients with a markedly reduced life expectancy (eg, <5 years) should be seen by a transplant specialist and evaluated for eligibility. (See "Determining eligibility for allogeneic hematopoietic cell transplantation".)

While transplant is associated with significant rates of morbidity and early mortality, it is more likely to be effective in the setting of chemotherapy-responsive disease. As such, transplant should not wait until all treatment options have been exhausted. (See 'Hematopoietic cell transplantation' below.)

Single agent chemotherapy — Most chemotherapy agents that have been used for other types of non-Hodgkin lymphoma have been investigated in patients with MF. The most commonly used single-agent chemotherapy regimens in MF and Sézary syndrome (SS) include [47,83,84,86]:

●Low-dose methotrexate – Low-dose oral or intravenous methotrexate can be combined with other systemic (eg, interferon) or skin-directed therapy (except for TSEBT). Common side effects of low-dose methotrexate include mucositis, gastrointestinal effects, and myelosuppression. Methotrexate can also result in hepatic, renal, and pulmonary toxicity, and is potentially teratogenic and is an abortifacient. (See 'Low-dose methotrexate' above.)

●Pegylated liposomal doxorubicin – Pegylated liposomal doxorubicin has demonstrated overall response (OR) rates of 40 to 80 percent in patients with relapsed or refractory cutaneous T cell lymphoma (CTCL) [87-91]. Patients with refractory stage IV disease have demonstrated an OR rate of 33 percent [89]. Pegylated liposomal doxorubicin is commonly administered in CTCL at a dose of 20 to 30 mg/m² given every three to four weeks. Although it has not been directly compared with other agents in relapsed/refractory disease, it is an acceptable treatment option in this setting. The most common side effects include mild anemia, lymphopenia, and palmar-plantar erythrodysesthesia.

●Gemcitabine – Gemcitabine (eg, 1200 mg/m² IV on days 1, 8, and 15 of a 28-day schedule) has demonstrated OR rates of 47 to 70 percent in patients with relapsed or refractory MF [92-94]. Treatment is well tolerated and hematologic toxicity is mild.

●Pralatrexate (low dose) – Pralatrexate is an antifolate that has demonstrated clinical activity in T cell lymphomas. High rates of thrombocytopenia and mucosal inflammation seen in trials of pralatrexate in peripheral T cell lymphoma resulted in an interest in using lower doses for the treatment of MF. A prospective dose de-escalation trial design was used in a study of 54 patients with relapsed or refractory CTCL to identify a pralatrexate dose with significant activity in MF, but with an acceptable toxicity profile [95]. The preferred regimen was low-dose pralatrexate 15 mg/m² per week administered for three out of four weeks along with folic acid 1 mg by mouth daily and vitamin B12 injections every other month. Of the 29 patients treated with this regimen of low-dose pralatrexate, responses were seen in 13 (45 percent) after a median of four treatment cycles. Toxicity was generally mild. The most common adverse effects seen at this dose and schedule were stomatitis, fatigue, nausea/vomiting, skin toxicity, edema, anemia, and pyrexia.

●Purine analogs – Both fludarabine and pentostatin have demonstrated clinical activity against MF with response rates as high as 50 to 70 percent [96-99]. Common side effects with these agents include significant/prolonged immunosuppression. Fludarabine has also been used in combination with interferon with an OR rate of 46 percent with a median response duration of 6.5 months [99]. (See "Treatment of hairy cell leukemia", section on 'Purine analogs'.)

Other agents that have been used in this setting include cyclophosphamide, chlorambucil [100], and etoposide [101,102]. None of these agents have been compared directly in a clinical trial. Of these, methotrexate has been used the longest and is therefore associated with the greatest clinical experience for the treatment of MF. Other agents may be associated with higher response rates, but may also demonstrate increased toxicity. A choice among agents depends on the patient's comorbidities and the physician's comfort with these agents.

Combination chemotherapy — Patients with refractory or frequently relapsing disease may require a combination of systemic therapies, either with biologic therapies or a combination of biologic therapy and chemotherapy, with or without topical therapy. Combination chemotherapy may result in faster responses, but there is no clear advantage to early aggressive combination therapy when compared with conservative sequential therapies in the management of advanced stage disease [47].

The most effective and commonly used combinations include [8,103-105]:

●Cyclophosphamide, vincristine, prednisone, and doxorubicin (CHOP) [103]

●Cyclophosphamide, vincristine and prednisone (CVP) [103]

●Cyclophosphamide, doxorubicin, vincristine, and etoposide (CAVE) [8,104]

●CVP with methotrexate (COMP) [105]

Interferon (IFN) alfa, systemic retinoids, or photopheresis may be used as an adjuvant agent after completion of the chemotherapy regimen. As examples:

●IFN alfa has been used in combination with systemic retinoids with a response rate of approximately 55 percent [38,39].

●Various chemotherapy regimens have been used in combination with total skin electron beam therapy (TSEBT) [8,85,106].

Responses may also be seen with other regimens employed in systemic peripheral T cell lymphoma. (See "Initial treatment of peripheral T cell lymphoma" and "Treatment of relapsed or refractory peripheral T cell lymphoma".)

Hematopoietic cell transplantation — Experience with hematopoietic cell transplantation (HCT) in MF is limited to a small number of case reports and case series [1,107-117]. Responses to autologous HCT appear to be common yet short-lived with a median estimated time to disease progression of a little over two months [1]. As such, autologous HCT is rarely if ever used for MF or SS. By comparison, allogeneic HCT may offer durable remissions in a subset of patients, perhaps due to a graft-versus-tumor effect [1,111,114].

Complete remission following allogeneic HCT has been described in several single patient case reports [110-112], small case series, and retrospective studies [1,47,117,118]. Eligibility and preparative regimens used have varied across studies.

One of the largest studies was an international retrospective analysis of patients with MF (36 patients) or SS (24 patients) who underwent related (75 percent) or unrelated allogeneic HCT with myeloablative (27 percent) or reduced intensity (73 percent) conditioning regimens [107,119]. The following outcomes were noted after a median follow-up of 36 months, and updated after a median follow-up of seven years:

●The estimated overall survival rates at one, three, five, and seven years were 66, 53, 46, and 44 percent, respectively. Survival was worse in patients who had an unrelated donor, myeloablative conditioning regimen, and/or advanced phase disease at the time of transplantation.

●The estimated progression-free survival rates at one and three years were 42 and 34 percent, respectively. Relapse occurred in 26 patients at a median of 3.8 months after HCT. Only two relapses occurred beyond two years post-transplant. Of the 26 relapses, 17 underwent donor lymphocyte infusion (DLI) and 10 achieved a complete or partial response after DLI. Eight remain alive at a median of eight years after transplant.

●The 100-day cumulative incidence of acute graft-versus-host disease (GVHD) was 40 percent. The cumulative incidence of chronic GVHD was 32 and 48 percent at one and two years post-HCT, respectively.

●Non-relapse mortality was 20 percent at one year and 22 percent at seven years. Factors associated with non-relapse mortality were myeloablative conditioning regimens and poor performance status at the time of HCT.

Allogeneic HCT appears to be most successful after initial disease control with induction therapy and before disease progression [107,120]. While there is no agreed-upon timing for HCT, most experts agree that patients with a markedly reduced life expectancy (eg, <5 years) should be seen by a transplant specialist and evaluated for eligibility. (See "Determining eligibility for allogeneic hematopoietic cell transplantation".)

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

●Mycosis fungoides (MF) is an extranodal, usually indolent, non-Hodgkin lymphoma of T cell origin that primarily develops in the skin, but can ultimately involve the lymph nodes, blood, and visceral organs. Advanced stage (IIB to IV) MF is a heterogeneous group that encompasses those patients that present with extracutaneous disease or advanced skin lesions (eg, tumors) (table 1). (See 'Pretreatment evaluation' above.)

●Advanced stage MF is often a chronic or persistent disease with a relapsing course. The main goals of therapy are long-term disease control, prompt symptom relief, and management of life-threatening (aggressive) disease. (See 'Goals of therapy' above.)

●Long-term control involves the serial administration of therapies directed at the type and site of disease (eg, patch/plaque, tumor, erythroderma, extracutaneous disease). Decisions to continue or switch therapy are made on a clinical basis. Agents with low toxicity that preserve the immune response are usually preferred. (See 'Overview of disease management' above.)

●For most patients with cutaneous tumors involving a limited percent body surface area (typically <10 percent), we suggest treatment with localized radiation to the tumors plus skin-directed therapy as needed for concurrent patch/plaque disease (Grade 2C).

●For patients with generalized tumors, total skin electron beam therapy (TSEBT) or systemic therapies are acceptable treatment options. TSEBT can be followed by other skin-directed therapies or systemic therapies to prolong response duration. An acceptable alternative is the off-label use of brentuximab vedotin. (See 'Cutaneous tumors' above.)

●For most patients with generalized erythroderma without blood involvement, we typically administer both a skin-directed therapy (eg, topical steroids) and a systemic therapy (eg, methotrexate, bexarotene). Other clinicians use skin-directed therapy alone and then proceed to systemic therapies upon progression of failure of response. (See 'Generalized erythroderma' above.)

●There is no consensus regarding the optimal systemic therapy for patients with advanced MF. Diverse agents are available and selection of therapy may be informed by prior treatments, comorbid illnesses, toxicity, route of administration, patient preference/convenience, and clinician experience. Treatment may utilize a single systemic therapy or a combination of systemic treatments. In general, we often prefer immune preserving agents or immunostimulatory (eg, interferon) therapies prior to the use of more toxic regimens. (See 'Choice among systemic therapies' above.)  

●For most patients with blood involvement, we recommend the use of a systemic therapy with or without skin-directed therapies rather than skin-directed therapies alone (Grade 1B). (See 'Peripheral blood involvement' above.)

●For patients with lymph node or visceral disease, we suggest treatment with romidepsin or systemic chemotherapy (Grade 2B). Local radiation therapy may be used in conjunction with systemic therapy for local control of visceral disease or lymph node involvement. (See 'Lymph node or visceral involvement' above.)

●Patients who have extreme symptoms limiting quality of life should be treated with therapies with a faster onset of action (eg, radiation or therapies for aggressive disease), even if the long-term control is not as good with these agents. In addition, patients often benefit from ancillary therapies directed at symptoms related to pruritus and superinfections. (See 'Symptom control' above.)

●Patients with clinically aggressive disease are less likely to have long-term control with standard regimens and require more aggressive and riskier therapies. For such patients, we use agents with a shorter time to response and a higher response rate. Options include romidepsin, brentuximab vedotin, single agent chemotherapy, and combination chemotherapy. Patients with disease that is difficult to control should be considered for allogeneic hematopoietic cell transplantation with curative intent. (See 'Aggressive disease' above.)