Treatment of Sézary syndrome

INTRODUCTION — Sézary syndrome (SS) is an aggressive subtype of cutaneous T cell lymphoma (CTCL) that presents with erythroderma plus circulating malignant T lymphocytes (Sézary cells), with or without lymph node and/or visceral organ involvement. SS is closely related to mycosis fungoides (MF), and the two disorders are diagnosed and staged by the same criteria (table 1). (See "Clinical presentation, pathologic features, and diagnosis of Sézary syndrome" and "Clinical manifestations, pathologic features, and diagnosis of mycosis fungoides".)

Treatment of SS is discussed in this topic.

The clinical presentation, diagnosis, and staging of SS and the diagnosis and treatment of MF are presented separately.

●(See "Clinical presentation, pathologic features, and diagnosis of Sézary syndrome".)

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

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

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

●(See "Treatment of advanced stage (IIB to IV) mycosis fungoides".)

STAGING — Staging for cutaneous T cell lymphomas is based on evaluation of the skin (T), lymph nodes (N), viscera (M), and blood (B) (table 1) [1].

SS is defined by the presence of T₄ erythroderma (ie, involvement of ≥80 percent body surface area) plus B₂ involvement of peripheral blood (ie, ≥1000 Sézary cells/microL), and is staged based on the presence of nodal and/or visceral involvement, as follows [1]:

●Stage IVA1 – No significant lymph node or visceral involvement

●Stage IVA2 – Lymph node involvement, but no visceral involvement

●Stage IVB – Visceral involvement, with or without nodal involvement

Details of the staging of SS are provided separately. (See "Staging and prognosis of mycosis fungoides and Sézary syndrome", section on 'TNMB staging'.)

Patients with cutaneous disease plus lymph node and/or visceral involvement, but no B₂ blood involvement are considered to have MF, as discussed separately. (See "Clinical manifestations, pathologic features, and diagnosis of mycosis fungoides", section on 'Diagnosis'.)

CLINICAL APPROACH — Treatment for SS is similar to that for advanced MF, with some distinctive exceptions, including the use of extracorporeal photopheresis (ECP) and low dose alemtuzumab, and the need for adjuvant treatment to control pruritus. (See "Treatment of advanced stage (IIB to IV) mycosis fungoides".)

Given the leukemic blood involvement in SS, systemic treatments are generally required. Systemic therapy can be given alone (ie, as monotherapy), with skin-directed therapy (SDT), or with other systemic therapies (combination therapy with or without SDT). There is a paucity of controlled clinical trial data to direct the selection of treatment modality in patients with SS. In general, the following principles apply [2]:

●Treatments are primarily stage-based, but symptoms/tumor burden and the "tempo" of disease activity can vary widely and should inform treatment choice. Measures of increased tumor burden include the degree of skin infiltration, the presence of skin tumors, transformation to large cell histology, the extent of lymphadenopathy, the burden of circulating tumor cells, and the rate of increase in serum lactate dehydrogenase and peripheral white blood cell count. As an example, immunomodulatory therapies are preferred for patients with newly diagnosed, slowly progressive disease. In contrast, chemotherapeutic agents or targeted therapies may be preferred for more immediate disease control in patients with rapidly progressive disease.

●Medical comorbidities and treatment-related issues (cost, accessibility) affect treatment choice given the chronicity and recurrent nature of SS. As an example, interferon therapy should be used with caution in patients with concomitant autoimmune conditions or in solid organ transplant patients.

●Immune-enhancing/preserving agents should be used prior to chemotherapy, if possible.

●Response rates appear to be higher with combination approaches (eg, systemic agent[s] plus SDT).

●Clinicians should monitor for Staphylococcus aureus colonization/skin infection/bacteremia and other infections (fungal, viral) that can contribute to disease flare and will respond to antibiotics.

●The majority of patients with SS have severe pruritus; topical and systemic anti-pruritics are important adjuncts.

Data regarding treatment efficacy come from limited randomized clinical trials, open-label single arm studies, and retrospective case or cohort studies, but these studies are difficult to compare because of heterogeneous patient populations, varying study criteria, and different response measures [3]. We suggest consideration of a clinical trial before instituting systemic chemotherapy, because current therapy only rarely achieves durable responses [4-6].

Our approach is generally consistent with guidelines for treatment of mycosis fungoides (MF) and SS 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) [2,7-11].

INITIAL TREATMENT — There is no standard initial therapy for all patients with SS, and experts differ in their preferred approach.

Stratification by stage — Treatment is selected primarily on the basis of whether there is visceral involvement (stage IVB) or not (stage IVA), and is informed by the availability of treatment, tumor burden, disease tempo, comorbidities, and nature and extent of symptoms, as described in the sections that follow.

Stage IVA (no visceral involvement) — Initial treatment is similar for patients with stages IVA1 and IVA2 (ie, no visceral involvement), and treatment of these stages is discussed together. (See 'Staging' above.)

Group A agents (table 2) are preferred for initial systemic therapy of stage IVA SS based on their favorable efficacy, tolerability, and immune preservation. Skin-directed therapy (SDT) may be added to Group A treatments, if needed for symptom relief. Furthermore, multiple Group A therapies may be used concomitantly to attempt to achieve a faster and/or higher rate of response. (See 'Skin-directed therapy' below.)

For most patients with stage IV SS, we suggest extracorporeal photopheresis (ECP) plus a biological response modifier (BRM; eg, interferon [IFN] or a retinoid). ECP-based regimens are generally well tolerated and may be safely used for years, but ECP is only available at certain centers; selection of a BRM is informed by toxicity, patient comorbidities, cost, and drug availability, as described below. (See 'Extracorporeal photopheresis (ECP)' below and 'Biological response modifiers (BRM)' below.)

Other acceptable alternatives include:

●Single agent BRM (eg, IFN or a retinoid), with or without SDT

●Low dose oral methotrexate (MTX) with or without ECP and/or SDT

●Histone deacetylase inhibitors (HDACi; eg, vorinostat, romidepsin, belinostat) with or without ECP and/or SDT

Group A therapies can be combined (eg, IFN plus a retinoid, IFN plus MTX, IFN plus an HDACi), with or without ECP, but no particular combination has proven to be superior for all patients.

MTX and HDACi are more immunosuppressive than ECP, IFN, and retinoids, but generally less toxic and/or immunosuppressive than Group B treatments (table 2).

Stage IVB (visceral involvement) — For patients with stage IVB disease, we suggest initial therapy with an HDACi or a targeted therapy (eg, brentuximab vedotin) because they offer a favorable balance of efficacy, time to response, and toxicity. (See 'Histone deacetylase inhibitors' below and 'Targeted agents' below.)

Group B agents (table 2) are also acceptable options for initial treatment of stage IVB SS. (See 'Single-agent chemotherapy' below and 'Other agents' below.)

SDT (eg, localized radiation therapy [RT]) may be added to systemic therapy for local control of skin tumors or lymph node involvement. Phototherapy, particularly PUVA, may provide added benefit if used cautiously in the setting of erythroderma. (See 'Skin-directed therapy' below.)

After completion of the initial systemic regimen, Group A therapies (eg, ECP, IFN, retinoids) (table 2) and/or SDT may be used as adjuvant therapy to sustain a remission or to enhance symptom relief.

Combining two or more agents (eg, HDACi, targeted therapy, and/or two Group B agents) may lead to more rapid responses, but there is no evidence for a long-term advantage to combination therapy when compared with sequential single agent therapies in this setting.

Preferred initial therapies — Group A (table 2) therapies are preferred for initial treatment of advanced SS on the basis of their efficacy and toxicity [12]. Selection of initial therapy is influenced by disease stage and other considerations, as described above. (See 'Initial treatment' above.)

Extracorporeal photopheresis (ECP) — ECP is a preferred initial therapy for patients with stage IVA SS. ECP is a method of delivering PUVA (psoralen/8-methoxsalen + ultraviolet A photochemotherapy) systemically to the peripheral blood compartment using an extracorporeal leukapheresis procedure. ECP is approved by the US Food and Drug Administration (FDA) for the treatment of SS.

ECP is time consuming and only available at specialized centers, but it is generally well tolerated and does not cause generalized immunosuppression. Single arm trials of ECP monotherapy report ≥50 percent skin improvement in about one-quarter of patients, with five to six month median time to response. Combining ECP with a BRM (ie, IFN or a retinoid) generally results in quicker and more effective responses, with acceptable toxicity. (See 'Stage IVA (no visceral involvement)' above.)

While the preferred protocol and instrument varies by center, ECP is generally administered as two consecutive daily treatments every two to four weeks [13,14]. The total time of treatment (collection, photoactivation, and reinfusion) is 1.5 to 4 hours. Treatment should last for at least six months and until maximal response is achieved. It may then be gradually tapered to a maintenance regimen of one cycle (two consecutive treatments) once every 6 to 12 months, assuming that the patient continues to benefit. If the patient has improved, but continues to manifest a significant disease burden, addition of interferon, a retinoid, or SDT to ongoing ECP may result in further improvement.

Adverse effects, which are infrequent, include mild hypotension during treatment, occasional fatigue, headache, transient increased itching and need for adequate venous access. Most permanent indwelling tunneled pheresis catheters (eg, Hickman catheters) should be avoided in heavily colonized patients with SS, as they are at very high risk for line infections, particularly by Staphylococcus aureus; peripheral IV access should be used if at all possible. ECP is contraindicated in patients with sensitivity to psoralens. Very rarely, retinal toxicity has been reported likely due to abnormally elevated serum levels due to delayed metabolism of methoxsalen [15]. Heparin-induced thrombocytopenia, from the small amount of heparin used during ECP, has also been rarely observed; anticoagulation with calcium citrate can be substituted in these cases. Should patients experience chills and/or fever following ECP, infection should be suspected. The US FDA issued a MedWatch safety report of seven patients (four with chronic graft-versus-host disease [cGVHD] as the indication for ECP) from 2012 to 2018 who experienced venous thromboembolic events (VTE) during or soon after initiation of ECP [16] and two additional cGVHD patients with deep vein thrombosis (DVT) associated with ECP. No further follow-up alerts nor published studies have since emerged regarding the mechanism of action or relevant risk factors, but patients should be informed of this potential risk.

ECP monotherapy can take several months to see clinical responses with a median time to response of five to six months; one group reported a mean time to response of nine months [17]. Predictors of response to ECP monotherapy include erythrodermic skin disease (T₄), total white blood cell count <20,000/microL, Sézary count not more than 10 to 20 percent, <2 years from original diagnosis, no bulky lymphadenopathy, no visceral disease, no prior chemotherapy, and higher peripheral blood NK cell and CD8+ T cell count [14,17-19].

ECP can be combined with interferon and/or systemic retinoids, and administered at lower doses than when administered as monotherapy (eg, interferon alfa 1.5 to 5 million units subcutaneously three times weekly, interferon gamma 1 to 2 million units subcutaneously three times weekly, bexarotene 150 to 300 mg per day in a single dose). Such combination therapy can improve response rates. If additional SDTs are needed, topical corticosteroids, topical nitrogen mustard, carmustine (BCNU) ointment, phototherapy, or total skin electron beam therapy can be combined with ECP (as "multimodality therapy").

Initial reports of ECP-based combination therapy as the initial treatment of SS have demonstrated tolerability, excellent response rates, and possibly improved survival compared with historical data [20,21]. In one large single center retrospective study of 98 erythrodermic mycosis fungoides (MF) and SS patients treated with ECP-based combination therapy for at least three months over a 25-year period had an overall response rate (ORR) of 75 percent (30 percent complete, 45 percent partial) [22]. In another study, 12 patients with SS treated with topical steroids, PUVA, interferon alfa, and ECP showed a response rate of 42 percent (4 of 12 partial response, 1 of 12 stable disease) [23]. Randomized trials are needed to better compare the tolerability and efficacy of ECP monotherapy with those of combination therapy.

Biological response modifiers (BRM)

Interferons (IFN) — IFNs include IFN-alpha (IFN-alpha; IFN-alpha-2a, IFN-alpha-2b) and IFN-gamma. Support for off-label use of IFNs comes from single arm prospective studies of patients with SS and/or MF [2]. IFN-gamma may be used in cases where IFN-alpha resistance is suspected, as no cross resistance has been observed. Furthermore, IFN gamma may be added to a regimen that already includes IFN alpha. (See "Treatment of advanced stage (IIB to IV) mycosis fungoides".)

●Interferon alpha – IFN-alpha is a type 1 interferon that has been used to treat SS in doses ranging from 1.5 million units three times weekly to 6 to 9 million units daily with ORR ranging from 25 to 50 percent [24-26]. Pegylated IFN-alpha has a longer half-life but has not been directly compared to traditional IFN formulations. However, similar benefit may be achieved by using recombinant IFN alpha more frequently than three times weekly. Combination regimens utilize lower doses of IFN-alpha (1.5 to 3 million units three times weekly subcutaneously). Multimodality therapy (ECP plus IFNs plus bexarotene plus SDTs) has included pegylated IFN-alpha at doses of 1 mcg/kg subcutaneous injection once a week [27].

●Interferon gamma – IFN-gamma is a type 2 interferon. In the largest published series of IFN-gamma monotherapy, 16 patients with advanced cutaneous T cell lymphoma (CTCL) were treated with 250 mcg/m²/day intramuscularly for one week, followed by 500 mcg/m²/day [28]. The ORR was 31 percent. Of the two patients with SS, one had a partial response. IFN-gamma is usually dosed at 2 million units (100 mcg) subcutaneously three times weekly.

Side effects are dose dependent and include flu-like symptoms such as low grade fever, chills, myalgias (minimized with pretreatment with acetaminophen), fatigue, mild myelosuppression (anemia, neutropenia), mood effects/depression, elevated liver transaminases, hypothyroidism, and hair thinning. Low dose IFN-alpha (1.5 to 3 million units three times weekly subcutaneously) is better tolerated than the higher doses. Adverse effects with IFN-gamma are similar to, but milder than, those seen with IFN-alpha, particularly in the older adult population. There is a lower incidence of cognitive and mood disorders with IFN gamma and the frequency of autoimmune phenomenon is significantly less frequent.

Triggering or unmasking of autoimmune phenomena (eg, thyroiditis, psoriasis, vitiligo, colitis) may be observed. IFN therapy should be used with caution in patients with concomitant autoimmune conditions and, particularly, with solid organ transplants. It should also be used with caution in patients with a history of unstable coronary artery disease or left ventricular failure, especially those with any recent acute events.

Retinoids — Oral bexarotene is a systemic retinoid-X-receptor (RXR) specific retinoid that can be used as monotherapy or in combination with other systemic therapies (eg, ECP or IFN-alpha) or phototherapy for treatment of MF and SS. Bexarotene is approved by the FDA for the treatment of refractory MF/SS. Prior to the availability of bexarotene, other systemic retinoids that had been used off-label for the treatment of MF and SS included retinoic acid receptor (RAR) retinoids: isotretinoin, etretinate, acitretin, and all-trans retinoic acid (ATRA) [29]. Retinoids have not been compared directly with other treatment options in this population. Bexarotene monotherapy dosing is 300 mg/m², though lower doses are used when bexarotene is combined with SDTs or other systemic therapies (150 mg/m² or 150 to 300 mg daily). (See "Treatment of advanced stage (IIB to IV) mycosis fungoides".)

●A pivotal phase II/III trial of bexarotene in 94 patients with advanced stage MF (stages IIB to IVB) who were refractory to conventional therapy reported ORRs of 45 and 55 percent of patients started on oral doses of 300 and greater than 300 mg/m² per day, respectively [30]. Among the 17 patients with SS, four responded (24 percent).

●In a retrospective cohort study from the United Kingdom, seven of nine patients (78 percent) with SS demonstrated a response to bexarotene, with two (22 percent) achieving complete response with a median duration of response of nine months [31].

●A retrospective series reported an ORR of 24 percent among 17 patients with SS treated with ATRA [32].

●In another retrospective series of 32 patients with CTCL treated with acitretin either as monotherapy (six patients) or combination therapy (26 patients), the ORR was 29 percent [33]. One of the two patients with SS in this cohort had a partial response after treatment with acitretin plus ECP.

All systemic retinoids are teratogenic and absolutely contraindicated during pregnancy, and women of childbearing potential should take contraceptive precautions. Men taking retinoids should also take contraceptive precautions during and after systemic retinoid use (one month after bexarotene; up to three years after acitretin).

Additional side effects of oral bexarotene include dose-dependent leukopenia/neutropenia, anemia, hyperlipidemia, hypothalamic hypothyroidism (suppressed thyroid stimulating hormone [TSH]), and rarely abdominal discomfort, nausea, and anorexia. Hyperlipidemia is primarily manifested as hypertriglyceridemia, but elevated low density lipoproteins (LDL) and depressed high density lipoprotein (HDL) are also typically observed. These effects require treatment with lipid lowering agents and adherence to a low saturated fat, low cholesterol, and low refined carbohydrate diet. Lipid lowering agents that can be used include omega 3 fish oil, fenofibrate, and statins, but gemfibrozil should be avoided because it can cause elevation of bexarotene levels. For those with coronary disease and for whom LDLs remain high despite the administration of the above treatments, consideration can be given to using a PCSK9 inhibitor. Central hypothyroidism results in persistently low TSH levels and requires repletion with levothyroxine by monitoring free thyroxine (free T4) levels, not TSH [34,35]. (See "Hypertriglyceridemia in adults: Management", section on 'Treatment goals'.)

RAR retinoids cause mucous membrane dryness, cheilitis, photosensitivity, mood effects/depression, fatigue, mild hyperlipidemia, and occasional liver abnormalities.

Low dose methotrexate — Methotrexate can be used as monotherapy or in combination with other systemic therapies (eg, ECP, interferon alpha) for the treatment of MF and SS. It is approved by the FDA for the treatment of SS. It may be given at "low doses" (5 to 50 mg weekly, orally, intramuscularly, or intravenously) or "intermediate doses" with leucovorin rescue. In contrast to interferons, methotrexate can be used in patients with concomitant autoimmune diseases (ie, rheumatoid arthritis). (See "Treatment of advanced stage (IIB to IV) mycosis fungoides".)

In one study of 29 patients with erythrodermic MF, methotrexate given at a median weekly dose of 25 mg (range 5 to 125 mg per week) resulted in a response rate of 58 percent [36]. Among the 10 patients who fulfilled the 2007 criteria for SS (T₄B₂), the ORR was 50 percent, although it is unclear if response assessment included blood and nodal compartments.

Low dose methotrexate can be combined with other systemic and skin-directed agents. As examples:

●Methotrexate plus interferon – In one study, 158 patients with advanced MF and SS were treated with low dose methotrexate (10 mg/m², biweekly) and interferon alfa (9 million units, three times a week) as induction therapy for 6 or 12 months, followed by, if patients achieved a complete remission, interferon alpha maintenance until toxicity or relapse [37]. A 74 percent complete response rate was observed, and 71 percent remained progression-free over a median follow-up of 155 months. The regimen was well tolerated.

●Methotrexate plus ECP – In one report, a partial response was achieved in one of two patients with SS treated with ECP administered for two days every four weeks in combination with methotrexate (dose not reported) [38].

●Methotrexate plus etoposide – One patient treated with methotrexate 10 mg weekly and etoposide 25 mg daily achieved a complete response [39].

Low or intermediate dose oral methotrexate is generally well tolerated but can cause fatigue, oral ulcerations/mucositis, gastrointestinal effects, leukopenia, anemia, liver damage, idiosyncratic pneumonitis, and mild generalized immunosuppression. Methotrexate is a known abortifacient and teratogen and absolutely contraindicated during pregnancy, and women of childbearing potential should take contraceptive precautions. (See "Major side effects of low-dose methotrexate".)

Oral folic acid supplementation will decrease gastrointestinal symptoms, but it is not known whether it impairs efficacy. Leucovorin is used to rescue normal tissue if high dose methotrexate is used or to counteract acute toxicity, regardless of dose.

Histone deacetylase inhibitors — Histone deacetylase (HDAC) inhibitors have been studied in clinical trials of patients with refractory MF or SS. They are one of our preferred initial therapies for SS with extensive or transformed nodal or visceral involvement (stage IVA2/IVB). In general, HDAC inhibitors are more toxic than the BRMs (interferons, retinoids), but less toxic than traditional chemotherapy. In vitro studies also suggest that HDAC inhibitors are immunosuppressive, but less so than multidrug chemotherapy [40,41].

HDAC inhibitors can be safely combined with BRMs (eg, vorinostat and interferon gamma; romidepsin and interferon gamma; bexarotene and vorinostat; bexarotene and romidepsin) [42,43]. They may also be useful in patients with concomitant autoimmune T cell mediated disorders that would preclude the use of interferons [44]. Case reports have also suggested that HDAC inhibitors can be safely combined with RT in patients with CTCL and other cancers [45,46]. However, given the lack of randomized trials, it is not known whether these combinations provide a benefit over that seen with single agents.

Side effect profiles for this class of agents include fatigue, malaise, nausea, taste disturbance, anorexia, diarrhea or constipation, cytopenias (thrombocytopenia in particular), and electrocardiogram effects. Reports also suggest an increase in herpes virus infections [47]. More specific information is provided below.

Vorinostat — Vorinostat is an oral HDAC inhibitor approved by the FDA for the treatment of CTCL in patients with progressive, persistent, or recurrent disease after two systemic therapies [48]. The initial dosing is 400 mg daily but can be decreased to 400 mg daily Monday through Friday, or to 300 mg daily, in the setting of toxicity. Vorinostat can be combined with other therapies (eg, interferon gamma, bexarotene) [42,43]. (See "Treatment of advanced stage (IIB to IV) mycosis fungoides".)

●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 [49]. Thirty percent of subjects experienced a partial response as measured by a modified skin severity weighted assessment tool; 32 percent had pruritus relief; one patient attained delayed complete remission on day 281. Among the 13 patients with SS, the ORR was 30 percent (all partial responses).

●A similar response rate (36 percent) was seen in an earlier single center phase II study of vorinostat in CTCL [50].

●In another report, vorinostat was given in combination with ECP and interferon alfa in three patients with stage IIB or higher MF or SS [51]. The one patient with SS had stable disease.

●In three patients (one advanced MF, two SS), vorinostat was combined with interferon gamma with partial response [42].

Most toxicities are mild (grade 1/2) and include gastrointestinal effects (diarrhea, nausea, anorexia, taste disturbance), fatigue, cytopenias (anemia, thrombocytopenia, neutropenia), and nonspecific ECG effects (ST and T-wave abnormalities). Prior to administration, potassium and magnesium levels should be in the normal range and a baseline ECG should be considered. A mild elevation of creatinine can also be observed, which is reversible with increased oral fluid intake. Although HDAC inhibitors suppress normal T cell function, no formal infection prophylaxis regimens have been established [40].

Romidepsin — Romidepsin (also known as depsipeptide) is an intravenously administered HDAC inhibitor approved by the FDA for the treatment of CTCL with progressive, persistent, or recurrent disease on or following at least one prior systemic therapy. 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. Romidepsin can be combined with other therapies (eg, interferon gamma, bexarotene). RT can be administered in combination with romidepsin treatment [46]. (See "Treatment of advanced stage (IIB to IV) mycosis fungoides".)

In the two multicenter open label phase II trials of romidepsin in CTCL, the ORRs were 34 percent for both studies, with 5 to 6 percent complete response rates [52,53]. The median time to response was two months, and the median durations of response in the two studies were 11 months and 15 months. In one study, a clinically meaningful improvement in pruritus was observed in 43 percent of patients with moderate/severe pruritus at baseline (with improvement in pruritus observed even in some patients without objective clinical response) [54].

ECG changes have been reported in studies of romidepsin, including the pivotal phase II trial in which patients with prolonged QT interval, significant cardiac history, or on concomitant QT prolonging medications were excluded. Cytochrome P3A4 inhibitors or inducers should be avoided while on romidepsin. Baseline electrolytes and complete blood count should be checked prior to each infusion with special attention to potassium and magnesium repletion.

Side effects are similar to those seen with vorinostat. Fatigue, nausea, appetite disturbance, and gastrointestinal effects are more marked but more episodic than vorinostat, and are ameliorated with antiemetic premedication. The gastrointestinal toxicities are typically observed immediately after the infusion and subside a few days before next dose.

Other HDAC inhibitors — Belinostat is an intravenously administered HDAC inhibitor approved by the FDA for the treatment of refractory peripheral T cell lymphoma (PTCL). An open label multicenter trial of belinostat in patients with relapsed or refractory PTCL reported an ORR of 14 percent in the 29 patients with CTCL (seven with SS, 55 percent with stage IV disease) [55]. The most common treatment-related adverse events were nausea (43 percent), vomiting (21 percent), infusion site pain (13 percent), and dizziness (11 percent). Other HDAC inhibitors in development include panobinostat and quisinostat.

Targeted agents — Monoclonal antibodies directed against cell surface proteins are effective in SS.

Brentuximab vedotin — Brentuximab vedotin (BV) is an anti-CD30 monoclonal antibody conjugated with the tubulin inhibitor monomethylauristatin E that is approved by the FDA for CD30+ MF patients who have received prior therapy.

The open-label ALCANZA trial randomly assigned 97 patients with MF or SS (who had received at least one prior systemic therapy or radiation) to single agent BV (1.8 mg/kg every three weeks for up to 16 cycles) versus physician's choice of oral methotrexate (550 mg per week) or oral bexarotene (300 mg/m² per day) [56]. The proportion of patients achieving an objective global response lasting at least four months (ORR4) was 50 percent for BV versus 10 percent for physician's choice. Grade 3/4 adverse events were reported in 41 percent in the BV group and 47 percent of the physician's choice group; peripheral neuropathy was seen in 67 percent of the BV patients (9 percent grade ≥3). BV is most effective for those with CD30+ disease although, occasionally, those without CD30 expression on malignant cells will manifest a significant response [57].

Mogamulizumab — Mogamulizumab (Moga) is a defucosylated humanized antibody directed against the chemokine receptor CCR4, which is overexpressed on malignant T cells [58]. Mogamulizumab was approved by the FDA for treatment of adult patients with relapsed or refractory MF or SS after at least one prior systemic therapy [59].

The multicenter MAVORIC trial (NCT01728805) randomly assigned 372 patients with MF or SS who failed prior systemic therapy to Moga (1 mg/kg weekly x four, then every two weeks) or vorinostat (400 mg/day) [60]. Compared with vorinostat, patients treated with Moga had superior progression-free survival (PFS; seven versus four months) by independent review, ORR (37 versus 2 percent, and 21 versus 7 percent for SS and MF, respectively), and quality of life (measured by Skindex-29 and FACT-G). Infusion-related eruptions and skin eruptions due to drug were reported in 33 and 24 percent of patients treated with mogamulizumab; other reported toxicities were diarrhea (62 percent), nausea (43 percent), thrombocytopenia (31 percent), dysgeusia (29 percent), and elevated serum creatinine (28 percent).

Mogamulizumab can deplete normal regulatory T cells (Treg), and may increase the risk of acute graft-versus-host disease in patients who undergo allogeneic hematopoietic cell transplantation soon after mogamulizumab treatment, if administered <50 days before transplant [61]. (See "Clinical manifestations, diagnosis, and grading of acute graft-versus-host disease".)

Treg depletion may also be responsible for mogamulizumab-induced skin eruptions which can manifest with a variety of clinical and histologic features (spongiotic, lichenoid, granulomatous dermatitis) or mimic CTCL and may be associated with clinical response [62,63].

ADJUVANT THERAPY

Skin-directed therapy — Adjuvant skin-directed therapy (SDT) is a key component of the management of patients with SS. Patients with SS have exfoliative erythroderma and may have severe itch, skin scaling, fissuring, and thickening of the palms and soles. Importantly, some patients with especially inflamed or edematous erythroderma may experience skin irritation or flaring with the initiation of certain SDTs, and caution should be used especially when initiating topical retinoids, phototherapy, and total skin electron beam therapy. Details regarding specific SDTs are discussed separately. (See "Treatment of early stage (IA to IIA) mycosis fungoides".)

In general, the following principles apply:

●Topical or systemic corticosteroids are commonly employed in the treatment of patients with SS. Discontinuation is frequently associated with a flare of disease. Chronic use of topical steroids can result in skin atrophy. Adrenal suppression and/or osteoporosis can also occur in patients following the widespread application of topical steroids or the use of systemic steroids. (See "Treatment of early stage (IA to IIA) mycosis fungoides", section on 'Topical corticosteroids'.)

●Topical nitrogen mustard is a frequently employed treatment for mycosis fungoides (MF) and SS. The main adverse effects are skin irritation and an allergic contact dermatitis. Topical carmustine (BCNU) may also be useful to improve skin disease. (See "Treatment of early stage (IA to IIA) mycosis fungoides", section on 'Topical mechlorethamine'.)

●Phototherapy (UVB and PUVA) is a very active therapy for cutaneous involvement. In patients with SS, PUVA monotherapy produces responses in the skin and may result in responses in the blood but not the lymph nodes [64]. Side effects include nausea, pain, sunburn, and increased risk of nonmelanoma skin cancer. Cautious initiation is recommended for patients with erythroderma due to heightened photosensitivity. (See "Treatment of early stage (IA to IIA) mycosis fungoides", section on 'Phototherapy'.)

●Total skin electron beam therapy (TSEBT) should be used in conjunction with multimodality therapy if nodal, blood, or visceral involvement is present, unless palliation alone is the objective. A single institution retrospective study reported a >50 percent decrease in blood involvement among 6 of 11 patients with SS treated with TSEBT [65]. (See "Treatment of early stage (IA to IIA) mycosis fungoides", section on 'Total skin electron beam therapy'.)

●Use of TSEBT in erythrodermic patients is center-dependent. Some centers report that erythrodermic patients may not tolerate TSEBT as well as patients with patch, plaque, or tumor disease alone. In our experience, however, TSEBT is well tolerated and effective in SS [65]. Regimens using low dose TSEBT (10 to 12 Gy) can be used for palliation as a less time intensive option with fewer adverse effects [66]. We have observed long-term clinical improvement when TSEBT is combined with ECP, interferon, and bexarotene.

Pruritus — Pruritus is one of the most common and debilitating symptoms of patients with SS. 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 administered 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 SS 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 SS, signs of skin superinfection (which can occur in the absence of fever or leukocytosis) include skin erosions or fissures with yellow (golden) drainage/crusting.

Prevention of infections — Patients with SS 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. Chlorhexidine washes or 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. Intermittent chlorhexidine washes or 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 Staph aureus skin infections.

RESPONSE CRITERIA — In general, SS patients are followed monthly with a clinical evaluation of the skin, lymph nodes, liver, and spleen, as well as a complete blood count, lactate dehydrogenase (LDH), and comprehensive metabolic panel.

Historically, response criteria and end point definitions varied between various retrospective reports and clinical trials in patients with mycosis fungoides (MF) and SS. Many previous studies primarily focused on skin response as the primary outcome measure without uniform assessment of blood, nodal, or visceral responses. For patients with SS, overall response should be based on a composite assessment of skin, blood, nodal, and visceral compartments.

In 2011, based on several consensus conferences from 2004 to 2008, the ISCL/EORTC/USCLC published recommendations for clinical end points for MF/SS as follows [67]:

●Total body skin scoring by modified skin weight assessment tool (mSWAT) is recommended (table 3), keeping in mind that, by 2007 ISCL criteria, SS is defined as patches involving at least 80 percent body surface area (BSA) leading to a minimum score of 80. Other erythroderma skin score scales do exist and are often utilized in clinical trials in addition to mSWAT, and they account for the degree of scaling and fissuring. Skin response criteria for MF/SS have been proposed by an ISCL/USCLC/EORTC consensus paper (table 4).

●Peripheral lymph nodes, liver, and spleen are palpated during physical exam and followed by imaging modalities (computed tomography [CT] scan of the neck, chest, abdomen, and pelvis with contrast, or whole body combined positron emission tomography [PET]/CT). Nodal responses generally follow RECIST criteria (table 5), keeping in mind that, in the setting of MF/SS, reactive lymphadenopathy (N1, up to 1.5 cm in diameter) can be observed due to inflamed skin. While all SS patients should have baseline staging scans, to minimize radiation exposure SS patients without significant nodal or visceral involvement at baseline do not need routine follow-up scans unless there are clinical symptoms/signs of disease progression (skin progression, palpable nodes or organomegaly, increased LDH or eosinophilia, new B symptoms). SS patients with baseline nodal (stage IVA2) or visceral involvement (stage IVB) should have follow-up scans with frequency determined by clinical assessment of response and discretion of the clinician (generally every six months, but may vary).

●Measurement of peripheral blood malignant T cell burden varies among centers. Peripheral blood flow cytometry (eg, discrete aberrant CD4+CD7- or CD4+CD26- T-lymphocyte populations) or flow cytometry analysis of specific Vbeta expression, in conjunction with T cell receptor gene rearrangement studies of the peripheral blood and skin is the primary method used. A 5 micron peripheral blood smear Sézary cell count (reported as percentage of lymphocytes) was used previously. The percentage and absolute numbers of the aberrant T cell population are reported. Blood response criteria for MF/SS have been proposed by the ISCL/USCLC/EORTC consensus paper (table 4) with more recent proposed changes by the EORTC to utilize absolute numbers primarily [68].

●Overall or global response criteria for MF/SS have been proposed by the ISCL/USCLC/EORTC consensus paper (table 4).

●Pruritus relief is measured using validated quality of life questionnaires (FACT-G or Skindex29 or visual analog scale).

The time to response is variable and, in general, a prolonged trial of therapy (eg, six months for extracorporeal photopheresis [ECP]) is administered before identifying refractory disease. As long as there is at least stable disease, treatment is continued until a maximal response is demonstrated and then gradually tapered to maintain response. Patients who achieve a complete response are seen periodically after treatment discontinuation to evaluate for relapse. The frequency of these visits depends on the comfort of both the patient and physician. For patients with an immunotherapy-induced complete response, long-term continuation of treatment has been used to prevent relapse, particularly if the treatment was well tolerated.

RELAPSED OR REFRACTORY DISEASE

Choice of therapy — Most patients with SS will relapse after initial treatment, and some patients have disease that is refractory to initial or subsequent therapy. There is no standard treatment for patients with relapsed or refractory SS, and patients should be encouraged to participate in clinical trials.

Outside of a clinical trial, relapsed disease may respond to repeated treatment with the same agents or may be treated with other skin-directed therapies (SDTs) and/or systemic therapies. In general, immune preserving therapies such as those described for initial systemic therapy are preferred prior to the use of traditional chemotherapy. Younger patients with high-risk disease may be considered for allogeneic hematopoietic cell transplantation (HCT). (See 'Preferred initial therapies' above.)

Treatment with "Group B" therapies is typically reserved for patients with disease that is refractory to "Group A" therapies (eg, extracorporeal photopheresis [ECP]; biologic response modifiers [BRM]) (table 2). Most chemotherapy regimens tend to have short durability of response (one year or less), and long-term use is limited by toxicity. In contrast to management of refractory mycosis fungoides (MF), low dose alemtuzumab is notable for its efficacy in refractory SS. Regimens may be used as monotherapy or in combination with other SDTs or systemic BRMs. Multiagent chemotherapy regimens are used less commonly due to short duration of response, but may be necessary for refractory disease or if quicker disease control is needed. As an example, multiagent chemotherapy would be preferred in a patient with erythroderma and concomitant large-cell-transformed generalized tumors or transformed bulky nodal disease when brentuximab vedotin (BV) is not indicated (eg, CD30 negative tumor, prior treatment, or BV-refractory disease).

Single-agent chemotherapy

Pegylated liposomal doxorubicin — Pegylated liposomal doxorubicin (20 to 40 mg/m² intravenously) has been used off-label for the treatment of patients with relapsed or refractory cutaneous T cell lymphoma (CTCL) with overall response rates (ORR) ranging from 40 to 90 percent. Earlier studies demonstrated higher response rates, possibly due to inclusion of more heterogeneous patients (ie, earlier stage patients) than subsequent studies [69]. (See "Treatment of advanced stage (IIB to IV) mycosis fungoides".)

Two prospective, multicenter, nonrandomized trials have examined the efficacy of pegylated liposomal doxorubicin in advanced refractory MF and SS:

●Pegylated liposomal doxorubicin (40 mg/m² once every four weeks) resulted in an ORR of 56 percent in 25 patients with stage IIB to IVB MF/SS [70]. The median progression-free survival (PFS) was five months. Median overall survival (OS) was approximately 46 months.

●In another study, pegylated liposomal doxorubicin (20 mg/m² given day 1 and day 15 of a 28-day cycle) resulted in an ORR of 41 percent (3 complete, 17 partial) in 49 patients with stage IIB, IVA, or IVB MF (excluding T₂ erythrodermic SS) [69]. Median time to progression was 7.4 months.

Adverse effects are generally mild (grade 1/2) and include myelosuppression, cardiac symptoms, fatigue, and hand/foot syndrome erythrodysesthesia.

Gemcitabine — Gemcitabine is a pyrimidine antimetabolite that has been used off-label for the treatment of patients with relapsed or refractory MF/SS with ORRs of 65 to 75 percent [71-73]. Typical dosing is 1000 to 1200 mg/m² intravenously on days 1, 8, and 15 of a 28-day cycle. (See "Treatment of advanced stage (IIB to IV) mycosis fungoides".)

Data for the efficacy in patients with SS specifically are sparse, and nearly all published studies predate the 2007 consensus definition of SS. One study published in 2006 reported a 65 percent ORR in 20 patients with refractory MF/SS (all 11 patients with SS enrolled achieved a partial response) [72].

Adverse effects include myelosuppression, fever, transaminitis, hypersensitivity reaction, renal effects (hemolytic uremic syndrome), skin hyperpigmentation, and radiation recall/sensitization.

Purine and pyrimidine analogs — Fludarabine, cladribine (2-chlorodeoxyadenosine, 2-CDA), and pentostatin have been used off-label as monotherapy or in combination with other agents for the treatment of MF/SS with variable results:

●Fludarabine has been used as monotherapy or in combination with other agents for the treatment of MF/SS with response rates ranging from 19 to 35 percent, but potential severe adverse effects limit its use [74-76].

•In one study, 35 patients with refractory MF/SS were treated with intravenous fludarabine (25 mg/m² x 5 days in a 28-day cycle) combined with interferon alfa (5 to 7.5 million units three times weekly subcutaneously) [77]. The 11 patients with SS achieved an ORR of 27 percent (all complete).

•In another prospective cohort study, nine patients with MF/SS were treated with fludarabine (18 mg/m² on day 1) and cyclophosphamide (250 mg/m² x 3 days) in a 28-day cycle [78]. Of the eight patients with SS, the ORR was 63 percent. One patient attained a complete response.

•Fludarabine can cause myelosuppression (especially neutropenia), T cell dysfunction, increased infections, gastrointestinal symptoms, fatigue, increased risk of secondary malignancies, and rare pulmonary symptoms.

●Cladribine (2-chlorodeoxyadenosine, 2-CDA) is an intravenously administered nucleoside analog. There have been a variety of dosing schedules used.

•In the largest reported series, 24 patients with MF/SS were treated with cladribine (0.1 mg/kg/day continuous infusion for 5 to 7 days in a 28-day cycle) with an ORR of 24 percent (12 percent complete) [79].

•Two smaller series reported ORRs of 0 and 50 percent in patients with SS [80,81].

•Side effects of cladribine are primarily myelosuppression (leukopenia with both neutropenia and prolonged lymphopenia, thrombocytopenia), increased risk of infections, and, less likely, fever and nausea.

●Pentostatin (deoxycoformycin) is another intravenously administered purine analog.

•A multicenter phase II trial demonstrated a 33 percent response rate in SS (7 of 21 SS patients, one complete) using 4 mg/m² weekly x 3 weeks, every other week x 6 weeks, then monthly x 6 months [82].

•A more intensive regimen (5 mg/m² daily x 3 days every three weeks, with dose escalation/decrease of 1.25/m²/day based on tolerability) was reported with a 71 percent ORR in 14 patients with SS (four complete).

•Pentostatin has prolonged effects on lymphocyte count (CD4), and is associated with myelosuppression, increased infections, gastrointestinal side effects, liver function test abnormalities, and, less commonly, neurologic side effects, pulmonary toxicity, nephrotoxicity, and rash.

Other agents

Pralatrexate — Pralatrexate is an intravenously administered antifolate agent approved by the US Food and Drug Administration (FDA) for the treatment of refractory peripheral T cell lymphoma (PTCL), including refractory CTCL. (See "Treatment of advanced stage (IIB to IV) mycosis fungoides".)

High rates of thrombocytopenia and mucosal inflammation observed in trials of pralatrexate in peripheral T cell lymphoma resulted in an interest in using lower doses for the treatment of MF/SS. 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 [83]. 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.

Lenalidomide — Lenalidomide is an immunomodulatory agent with similarities to thalidomide that has demonstrated efficacy in patients with relapsed or refractory SS. In an open label, multicenter phase II trial of lenalidomide in 32 patients with refractory MF or SS (11 patients) and a median of six prior treatment regimens, the ORR was 28 percent (all partial) with a median duration of response of 10 months [84]. Nonhematologic toxicities were largely mild (grade 1/2) and included fatigue (59 percent); pain/burning, infection, constipation/diarrhea (34 percent each); and edema (47 percent). In this setting, the preferred starting dose is 10 mg daily for 21 days of a 28-day cycle. The dose is escalated by 5 mg each cycle to a maximum of 25 mg daily. Starting with a low dose is necessary to avoid a transient flare reaction that is seen when higher initial doses are used.

In the United States, the use of lenalidomide is subject to the RevAssist program (www.revlimid.com) developed in an attempt to minimize the potential for pregnancy among patients taking this medication and associated congenital anomalies.

Alemtuzumab — Alemtuzumab is an anti-CD52 humanized monoclonal antibody that is available in the United States only through a restricted distribution program and the package carries a boxed warning regarding the risk of autoimmunity, infusion reactions, and malignancies [85]. (See "Treatment of advanced stage (IIB to IV) mycosis fungoides".)

Several studies have reported that alemtuzumab results in higher ORRs (86 to 100 percent) in patients with SS when compared with those with patch/plaque/tumor MF [86-89]. In particular, low dose regimens (10 to 15 mg subcutaneously three times weekly until Sézary count <1000/microL) appear to have equal efficacy with greatly decreased risk of opportunistic infections when compared with higher doses [90]. The low dose regimen is administered subcutaneously, which is ideal in SS patients in whom indwelling venous catheters are at high risk for infection by skin bacteria. SS patients with more aggressive transformed disease, particularly those with bulky lymphadenopathy and tumors, do not typically respond as well to alemtuzumab.

Primary side effects include infusion/injection reactions, myelosuppression, marked lymphopenia, opportunistic infections, and cardiac effects. Opportunistic infections reported include cytomegalovirus reactivation, herpes simplex or zoster reactivation/dissemination, bacterial and fungal infections. The risk of infection necessitates prophylaxis with antimicrobials. CD4 counts may be depressed for a year after therapy.

Bortezomib — Bortezomib is an intravenously administered proteasome inhibitor. In an open label phase II trial of bortezomib in 12 patients with MF or PTCL, the ORR was 67 percent [91]. The efficacy in patients with SS has not been specifically described.

Pembrolizumab — Pembrolizumab is a humanized monoclonal immunoglobulin (Ig) G4 antibody directed against human cell surface receptor PD-1 (programmed death-1 or programmed cell death-1), which is an inhibitor of the immune checkpoint and has antineoplastic activities. (See "Principles of cancer immunotherapy", section on 'PD-1 and PD ligand 1/2'.)

A phase II open label study of single agent pembrolizumab treatment of 24 patients reported an ORR of 38 percent; an acute skin flare reaction was described in eight (50 percent) patients with SS, five of whom ultimately manifested a clinical response [92,93].

Combination chemotherapy — Patients with refractory or frequently relapsing tumor 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. This is described in more detail separately. (See "Treatment of advanced stage (IIB to IV) mycosis fungoides", section on 'Combination chemotherapy'.)

Hematopoietic stem cell transplantation — Allogeneic hematopoietic cell transplantation (HCT) following myeloablative or reduced intensity conditioning may result in durable remissions or meaningful "downstaging" in a subset of patients, perhaps due to a graft-versus-lymphoma effect. As experience with this modality grows, it is an option increasingly offered to selected patients with high-risk disease. A choice regarding the use of HCT must take into consideration the risk of treatment-related mortality and morbidity, including graft-versus-host disease (GVHD). In contrast, high-dose chemotherapy followed by autologous HCT is not recommended due to a uniformly high risk of relapse [94,95].

Eligibility for allogeneic HCT varies across countries and institutions, and there are few strict rules about who is and who is not an appropriate candidate. Instead, clinical judgment should be used for the majority of patients as to whether the long- and short-term risks of transplant outweigh the benefits. General eligibility criteria are discussed separately. (See "Determining eligibility for allogeneic hematopoietic cell transplantation".)

Data regarding the efficacy of allogeneic HCT in MF and SS come largely from case reports and case series [96-101]. Older series are limited by changes in the definitions of SS and response criteria, while newer series are limited by the inclusion of small numbers of patients with MF/SS.

The largest series was published by the European Bone Marrow Transplantation Group and included data on 60 patients with MF/SS who underwent myeloablative (27 percent) or reduced intensity (73 percent) conditioning followed by the administration of a graft from a sibling donor (75 percent) or matched unrelated donor (25 percent) transplant between 1997 and 2007 [97,102]. Of the 60 patients, 24 were identified with SS (defined using pre-2007 criteria). On analysis of the entire MF/SS cohort, nonrelapse mortality at one year was 20 percent. Nonrelapse mortality was more common following myeloablative regimens and in patients with poor performance status prior to HCT. Relapse occurred in 26 of 60 patients (43 percent) at a median of 3.8 months after transplant. Of these, 17 underwent donor lymphocyte infusion, which resulted in a partial or complete response in 10 patients. Acute GVHD affected 40 percent of the entire MF/SS cohort by day 100; chronic GVHD affected 48 percent of the cohort at two years post-transplant. Of the 24 patients with SS, estimated survival rates at one and three years were 75 and 58 percent, respectively, with corresponding rates of PFS of 42 and 38 percent, respectively.

The largest single center series was initially reported by MD Anderson Cancer Center in 2010 and updated in 2015 to include a total of 47 patients with MF/SS (at least 18 with SS) undergoing allogeneic HCT between 2001 and 2013 using a nonmyeloablative regimen [103,104]. Most received total skin electron beam radiation therapy one to two months prior to transplant, and a fludarabine/busulfan-based conditioning regimen. Nonrelapse mortality at two years was 17 percent. Rates of acute and chronic GVHD were 40 and 28 percent, respectively. Estimated four-year OS and PFS rates were 51 and 26 percent, respectively. Notably, patients with nontransformed SS had superior PFS compared with those with MF or transformed SS (PFS at four years 57 versus 10 percent). Although post-HCT relapse rates were high, one-third of relapsed patients responded to immunomodulation or additional therapy.

PROGNOSIS — While many patients with SS will respond to the initial therapy, the majority will have a course of multiple transient responses and relapses. The clinical course of patients with SS is more aggressive than that of those with early stage patch/plaque MF. Median survival rates reported in the literature range from three to four years [105-109]. As an example, a multicenter retrospective study of 1275 patients with MF/SS diagnosed using modern criteria, estimated median survival times for those with IVA and IVB disease were 48 and 33 months, respectively [109]. Among the 463 patients with stage IVA MF/SS, estimated survival rates at one, two, and five years were 88, 73, and 43 percent. Corresponding rates for the 35 patients with stage IVB MF/SS were 79, 54, and 39 percent. Clinico-pathologic features associated with worse survival included older age (>60 years), increased lactate dehydrogenase at diagnosis, and large cell transformation.

Additional details regarding the prognosis of patients with MF/SS are presented separately. (See "Staging and prognosis of mycosis fungoides and Sézary syndrome".)

CLINICAL TRIALS — Often there is no better therapy to offer a patient than enrollment onto a well-designed, scientifically valid, peer-reviewed clinical trial. In addition, we believe that 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

●Sézary syndrome (SS) is an aggressive leukemic variant of cutaneous T cell lymphoma (CTCL) in which a significant number of circulating malignant (Sézary) cells are observed in the peripheral blood.

●The standard staging system for CTCL is based on an evaluation of the skin (T), lymph nodes (N), viscera (M), and blood (B) (table 1). SS is equivalent to T₄ plus B₂ disease. Patients with SS are considered to have stage IVA1, IVA2, or IVB disease, depending on the presence of nodal and/or visceral involvement. (See 'Staging' above.)

●There is no standard initial therapy for patients with SS, and experts differ in their preferred approach. Systemic therapy can be given alone (ie, as monotherapy), with skin-directed therapy (SDT), or with other systemic therapies (combination therapy with or without SDT) (table 2). In general, immune enhancing or preserving treatments are used prior to chemotherapy (see 'Clinical approach' above):

•For most patients with SS, we recommend the use of a systemic therapy with or without SDTs rather than SDTs alone (Grade 1B).

Where available, we prefer the use of extracorporeal photopheresis (ECP) because it is not immunosuppressive and can be combined with other systemic therapies (eg, interferon, retinoids) and SDTs. A choice of combination therapy is generally guided by the side effect profile, affordability, and patient comorbidities. SDTs are important adjunctive agents that can enhance clinical response when combined with systemic agents. (See 'Stage IVA (no visceral involvement)' above and 'Extracorporeal photopheresis (ECP)' above.)

•For patients with solid organ IVB disease, we suggest treatment with romidepsin or systemic chemotherapy (Grade 2B). Combination chemotherapy may lead to faster responses, but there is no advantage to early aggressive combination therapy when compared with conservative sequential therapies in the management of advanced stage disease. Local radiation therapy may be used in conjunction with some systemic therapies for local control of skin tumors. (See 'Stage IVB (visceral involvement)' above.)

●Relapsed disease may respond to repeated treatment with the same agents or may be treated with other skin-directed or systemic therapies. In contrast to the other systemic therapies, low dose alemtuzumab has greater efficacy in patients with SS than seen in patients with mycosis fungoides (MF) and has less infectious complications than the traditional full dose regimen. (See 'Choice of therapy' above.)

●Patients with SS who have failed multiple systemic therapies should be referred for clinical trials and/or possible allogeneic hematopoietic cell transplantation (HCT). (See 'Hematopoietic stem cell transplantation' above.)

●Adjuvant SDT is a key component of the management of patients with SS. Pruritus is a common and debilitating symptom. Importantly, a superimposed skin infection may worsen pruritus and treatment of the infection can result in clinical improvement. (See 'Adjuvant therapy' above.)