Sézary syndrome: Treatment and prognosis

INTRODUCTION — 

Sézary syndrome (SS) is an aggressive cutaneous T cell lymphoma (CTCL) that presents with skin disease (usually erythroderma) plus a high burden of circulating malignant T lymphocytes ("Sézary cells"). Patients may also have lymph node and/or visceral organ involvement.

SS and mycosis fungoides (MF) share many clinical and pathologic features, diagnostic criteria, and staging schemes, but they have distinctive aspects of management.

Treatment of SS is discussed in this topic.

Related topics include:

●(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".)

OVERVIEW — 

Skin is the primary site of disease in SS, but by definition, there is a substantial burden of circulating tumor cells; SS may also involve lymph nodes and/or viscera. Patients typically experience a chronically relapsing disease course with troublesome pruritus, and they often require multiple lines of therapy.

Treatment of SS requires consideration of the affected disease compartments (ie, blood, skin, lymph nodes, viscera), symptom burden, and comorbid conditions. Systemic treatments are needed to manage the blood tumor burden, but no approach is optimal for all patients, and various modalities and agents can be used to manage symptoms (table 1). Systemic treatments may be given alone, or they may be combined with skin-directed therapies and/or other systemic agents.

Management of SS is stratified primarily according to disease stage (ie, based on visceral organ involvement), but it is also influenced by the burden and tempo of disease, the compartment-specific activity of various agents, toxicity, comorbidities, availability, and patient preferences. Given the chronic and recurrent nature of SS, many patients require long-term treatment using different approaches.

Most patients have severe pruritus and are at risk for skin infections/colonization that can exacerbate symptoms and complicate management. Topical and systemic antipruritics and infection control are important adjuncts to systemic therapy. (See 'Adjunctive treatments' below.)

Our approach is consistent with recommendations from the United States Cutaneous Lymphoma Consortium, National Comprehensive Cancer Network (NCCN), European Organization for Research and Treatment of Cancer (EORTC), and other panels of experts [1-7].

DIAGNOSIS AND STAGING — 

SS is a primary cutaneous T cell lymphoma with a substantial burden of blood involvement.

Diagnosis — The circulating tumor cells (formerly called "Sézary cells") are defined by flow cytometry as CD4+/CD26-, CD4+/CD7-, or lymphocyte populations with dim or absent CD2, CD3, or CD4. Cellular morphology is no longer considered adequate to quantitate circulating tumor cells [8].

Details of evaluation, pathologic features, and diagnostic criteria for SS are described separately (table 2). (See "Clinical presentation, pathologic features, and diagnosis of Sézary syndrome" and "Staging and prognosis of mycosis fungoides and Sézary syndrome".)

Staging — Assessment of skin (T), lymph nodes (N), viscera (M), and blood (B) involvement is used for TNMB classification and determining the corresponding clinical stage (table 2).

Patients with SS have B2 blood disease (ie, ≥1000 abnormal cells/microL) plus skin disease (T4), with or without involvement of lymph nodes (N1 to N3) or viscera (bone marrow or other organs; M1). Classification of lymph node involvement is based on pathologic findings rather than nodal size, rate of growth, or symptoms. Details of staging are described separately. (See "Staging and prognosis of mycosis fungoides and Sézary syndrome", section on 'Components of staging'.)

Clinical stages of SS are:

●Stage IVA – No visceral involvement; this can be further classified as:

•IVA1 – No lymph node involvement

•IVA2 – Lymph node involvement

●Stage IVB – Bone marrow or other visceral involvement, with or without nodal involvement

Further details of staging of SS and mycosis fungoides are presented separately. (See "Staging and prognosis of mycosis fungoides and Sézary syndrome".)

STAGE IVA SS (NO VISCERAL INVOLVEMENT)

Preferred treatments — For stage IVA SS with no visceral involvement, Sézary count <5000/microL, and/or lymph node involvement, we suggest initial treatment with extracorporeal photopheresis (ECP) with interferon or treatment with mogamulizumab. This suggestion is based on the balance of efficacy and toxicity with these treatments.

For stage IVA SS and lymph node involvement with at least partial effacement (ie, stage IVA2), initial treatment using bexarotene plus interferon is also acceptable. (See "Treatment of advanced-stage (IIB to IV) mycosis fungoides", section on 'Systemic treatments'.)

Management of patients with stage IVA SS with large cell transformation (LCT) or other aggressive features is like that for stage IVB SS, as described below. (See 'Other visceral involvement' below.)

Both ECP and mogamulizumab are well tolerated and effective in the blood compartment and for erythrodermic skin disease, which is the most common skin involvement with SS. Either approach can be used alone, they can be used together, or they can be used in combination with other agents (eg, interferons, bexarotene) to enhance and prolong the treatment response.

Management is individualized, with consideration of toxicity, convenience, the extent of lymph node enlargement/symptoms, and cost. ECP is not available in all clinical settings. Mogamulizumab is not approved for front-line therapy of SS by the US Food and Drug Administration (FDA), but it is effective for circulating abnormal T cells.

●ECP – ECP is effective in the blood compartment and for erythrodermic skin disease, especially when used early in the disease course and/or in combination with other systemic agents [9].

ECP is available at specialized centers, requires adequate venous access, generally involves two consecutive daily treatments (up to four hours each) every two to four weeks for ≥6 months, and responses are slow.

Administration, toxicity, and outcomes with ECP alone, or in combination with other agents (eg, interferon, retinoid), are discussed below. (See 'Extracorporeal photopheresis' below.)

●Mogamulizumab – Mogamulizumab is effective in the blood compartment and for erythrodermic skin disease.

Mogamulizumab is administered intravenously every one or two weeks. Mogamulizumab should not be used in patients with autoimmune diseases, and it appears to be less effective in patients with bulky lymph node involvement, tumor-stage skin disease (ie, T3), and/or LCT. There may be concerns about the use of mogamulizumab in patients who plan to proceed to allogeneic hematopoietic cell transplantation in the near term, as discussed below. (See 'Large cell transformation/aggressive disease' below.)

The phase 3 MAVORIC trial, which randomly assigned 167 patients with relapsed or refractory (r/r) SS and 204 patients with r/r mycosis fungoides (MF) to mogamulizumab versus vorinostat, reported superior outcomes with mogamulizumab [10]. Among the patients with SS, mogamulizumab achieved superior median progression-free survival (PFS; 41 versus 30 percent; hazard ratio [HR] 0.32 [95% CI 0.21-0.49]), overall response rate (ORR; 37 versus 2 percent), and median duration of response (DOR; 17 versus 7 percent). For the entire trial population, mogamulizumab also achieved superior median PFS (8 versus 3 months; HR 0.53 [95% CI 0.41-0.69]), median DOR (14 versus 9 months), and disease compartment-specific responses (blood [68 versus 19 percent], skin [42 versus 16 percent], and lymph nodes [17 versus 4 percent]); no visceral responses were reported with either agent. Serious adverse effects (AEs) were reported in 38 percent of patients treated with mogamulizumab and 25 percent of the vorinostat group.

Administration and toxicity of mogamulizumab are discussed below. (See 'Mogamulizumab' below.)

Alternative options — There is no consensus on a preferred alternative to ECP and mogamulizumab for stage IVA SS.

For patients with stage IVA SS with an inadequate response, disease progression, or intolerable adverse effects (AEs) with ECP- and/or mogamulizumab-based management, or where those approaches are not available, other acceptable options include (table 1):

●Topical therapies and/or single agents – Symptomatic relief can result from topical agents (eg, corticosteroids, bexarotene, mechlorethamine) and/or systemic agents (eg, bexarotene, methotrexate, interferon). (See "Treatment of early stage (IA to IIA) mycosis fungoides" and "Treatment of early stage (IA to IIA) mycosis fungoides", section on 'Systemic therapies'.)

●Romidepsin – Romidepsin requires frequent, prolonged infusions and can cause heart dysrhythmias and other AEs. Romidepsin is modestly immunosuppressive with occasional reactivation of Herpes zoster and Herpes simplex.

Administration, toxicity, and outcomes with romidepsin are discussed below. (See 'Romidepsin' below.)

●Total skin electron beam therapy (TSEBT) – Standard TSEBT or attenuated TSEBT (eg, 12 gray [Gy]) can be used to treat erythroderma and very thickened skin.

If TSEBT is used for a patient with atrophic skin, the dose/fractionation schedule should be modified to reduce skin toxicity.

Treatment with TSEBT is discussed in greater detail separately. (See "Treatment of advanced-stage (IIB to IV) mycosis fungoides", section on 'Radiation therapy'.)

For selected patients with an inadequate response to the above treatments, other options include pembrolizumab, brentuximab vedotin, and pralatrexate. (See 'Pembrolizumab' below and 'Other agents' below.)

STAGE IVB SS (VISCERAL INVOLVEMENT) — 

Stage IVB SS (ie, visceral involvement) is a heterogeneous category that requires individualized management.

Stage IVB SS, by definition, has visceral involvement plus B2 blood involvement. Patients with visceral disease, but lesser degrees of blood involvement (ie, B0 or B1), are considered to have stage IVB mycosis fungoides (MF), which is discussed separately. (See "Treatment of advanced-stage (IIB to IV) mycosis fungoides", section on 'Stage IVB (visceral disease)'.)

We stratify treatment of stage IVB SS based on whether the visceral disease involves bone marrow-only (M1a) versus other sites of visceral disease (M1b; with or without bone marrow involvement). Other considerations in selecting therapy include disease tempo and the nature and severity of skin and lymph node involvement.

Bone marrow only — Patients with stage IVA SS with bone marrow as the only site of visceral disease (M1a) are generally managed like stage IVA SS, as described above. (See 'Stage IVA SS (no visceral involvement)' above.)

Other visceral involvement — Treatment for patients with M1b visceral disease (ie, visceral involvement beyond bone marrow) is individualized according to the tempo of disease progression, symptoms, and involved disease compartments.

Large cell transformation/aggressive disease — For patients with large cell transformation (LCT), rapidly progressive disease, or bulky/symptomatic nodal disease, we suggest initial treatment with single-agent gemcitabine or liposomal doxorubicin rather than multiagent chemotherapy or other treatments. Rapid responses can be seen with either single-agent or multiagent chemotherapy, but neither approach alone achieves long-term disease control; single agents offer a more favorable balance of efficacy and toxicity.

LCT with multiple CD30-positive tumors is effective, while LCT that is restricted to small areas of the skin can be treated with localized radiation therapy (RT).

For selected younger, fit patients with aggressive disease, some experts favor initial treatment with multiagent chemotherapy in anticipation of allogeneic hematopoietic cell transplantation (HCT). (See 'Allogeneic transplantation' below.)

●Gemcitabine – Treatment with gemcitabine in 44 patients with relapsed/refractory peripheral T cell lymphoma (r/r PTCL; including MF) was associated with 71 percent overall response rate (ORR), including 12 percent complete response (CR) [11]. Median duration of CR and partial response (PR) were 15 and 10 months, respectively. Treatment was well tolerated, with mild hematologic toxicity.

In another study, 73 percent of 11 patients with SS responded to single-agent gemcitabine [12].

Administration, toxicity, and other studies of gemcitabine for SS are presented below. (See 'Gemcitabine' below.)

●Liposomal doxorubicin – Liposomal doxorubicin was associated with 32 percent ORR but no CRs among 25 patients with high tumor burden MF [13].

Administration, toxicity, and other studies of liposomal doxorubicin for SS or r/r PTCL are presented below. (See 'Liposomal doxorubicin' below.)

Either gemcitabine or liposomal doxorubicin can be given for up to six months, as tolerated. After six months, the other agent can be given. Additional systemic therapies (table 1) and/or skin-directed therapy can be used to supplement symptom relief and/or prolong the treatment response.

For patients with an inadequate or transient response to these single agents, treatment with brentuximab vedotin, pralatrexate, or romidepsin can be considered, although their benefits in this setting are not well defined. Treatment of stage IVB SS using sequential single agents is discussed below. (See 'Other M1b disease' below.)

For selected medically fit, younger patients with an inadequate or transient treatment response to single-agent therapy, allogeneic HCT may be an option. (See 'Allogeneic transplantation' below.)

Other M1b disease

Initial therapy — Treatment of stage IVB SS is individualized according to compartment-specific activity, comorbidities, toxicity, availability, cost, and patient preference.

We generally begin treatment with single-agent gemcitabine, liposomal doxorubicin, romidepsin, or brentuximab vedotin (if the lesions are CD30-positive), but there is no preferred agent or consensus order of single-agent therapy.

Most treatments provide only transient disease control in this setting, and activity in the visceral compartment is not well defined for many treatments. Pralatrexate can be effective for nodal/visceral disease, but responses in the blood compartment are not well defined.

The efficacy of brentuximab vedotin in this setting is uncertain because patients with SS were excluded from the phase 3 ALCANZA trial in MF that compared brentuximab vedotin versus methotrexate or bexarotene [14]. However, brentuximab vedotin is likely to be effective if the lesions are CD30-positive. Mogamulizumab is effective against the blood compartment, but it is not well studied against visceral disease and is unlikely to provide benefit.

Allogeneic HCT can be considered for medically fit patients who have only limited or transient responses to sequential single agents. Caution is advised when using mogamulizumab within six months of transplantation because of a possible increase in risk or severity of graft-versus-host disease. The use of allogeneic HCT in SS is discussed below. (See 'Allogeneic transplantation' below.)

Supplemental treatments — Symptom relief can be enhanced and prolonged by supplementing single agents with other systemic therapies (table 1) and adjunctive treatments. Topical agents or localized RT can also be added for local control of skin tumors, patch/plaque disease, or lymph node involvement. (See 'Skin-directed therapy' below.)

MONITORING AND RESPONSE — 

Patients should be monitored regularly for disease progression and adverse effects (AEs) of treatment.

Monitoring — We generally evaluate patients at least monthly during initial treatment to assess symptoms and AEs of treatment. We perform an interval history and targeted physical examination and obtain a complete blood count, comprehensive metabolic panel, and lactate dehydrogenase at these visits.

The schedule of follow-up visits can be reduced for patients who have no evidence of progressive disease and are tolerating treatment well. Further monitoring and follow-up are guided by the response to treatment.

●The time to disease response varies with the approach, but treatment should generally continue for several months before concluding that disease is refractory.

●We continue treatment for as long as there is stable or responsive disease and AEs are tolerable. Treatment should continue until a maximal response and then be tapered to maintain and prolong the response.

Patients who achieve a complete response (CR) should be seen periodically after treatment discontinuation to evaluate for relapse and AEs. The frequency of visits is guided by concerns of the patient and clinician.

Response assessment — For patients with SS, overall response is a composite of responses in skin, blood, nodal, and visceral compartments. Depending on the treatment and pace of disease, we initially evaluate response after three to six months of treatment.

Assessment should include clinical evaluation of the skin, flow cytometry to quantitate circulating tumor cells, and imaging of lymph node and organ involvement; for patients with bone marrow involvement, a repeat bone marrow examination may be performed. Formal response criteria have been published for use in clinical trials [8], but they are not routinely applied in clinical practice.

A summary of criteria that can be used in clinical practice follows:

●Blood – Quantitation of circulating tumor cells (ie, CD4+/CD26-, CD4+/CD7-, or other aberrant immunophenotype) by flow cytometry

•CR – <250 tumor cells/microL (considered stage B0)

•Partial response (PR) – >50 percent decrease of blood tumor cells compared with baseline

•Progressive disease (PD) – >50 percent increase from baseline and ≥5000 tumor cells/microL

•Stable disease (SD) – Not meeting criteria for CR, PR, or PD

●Skin – Based on clinical examination of skin

•CR – Complete clearance of skin lesions

•PR – 50 to <100 percent clearance of skin disease

•SD – >25 to <50 percent clearance

•PD – ≥25 percent increase in skin disease

●Lymph nodes – Based on repeat imaging using computed tomography (CT) or positron emission tomography (PET)/CT

•CR – Complete metabolic response by PET/CT (ie, 1-3 on five-point scale Deauville score (table 3)) or all nodes/nodal masses ≤1.5 cm

•PR – Partial metabolic response by PET/CT (ie, 4-5 on five-point scale) or ≥50 percent decrease in size

•SD – Metabolic activity (4-5 on five-point scale) and no new abnormalities

•PD – Metabolic activity (4-5 on five-point scale) with new or progressive nodal disease

●Viscera – Based on repeat imaging or repeat bone marrow examination

•CR – Complete metabolic response by PET/CT (ie, 1-3 on five-point Deauville score (table 3)) or enlarged organs returned to normal size; normal bone marrow morphology (if performed)

•PR – Partial metabolic response by PET/CT (ie, 4-5 on five-point scale) or >50 percent regression of spleen length or other extranodal sites

•SD – Metabolic activity (4-5 on five-point scale) and no new abnormalities

•PD – Metabolic activity (4-5 on five-point scale) with new or progressive visceral disease

TREATMENTS

Extracorporeal photopheresis — Extracorporeal photopheresis (ECP) is a method of delivering PUVA (psoralen/8-methoxsalen plus ultraviolet A photochemotherapy) systemically to the peripheral blood compartment via extracorporeal leukapheresis. ECP is an effective initial treatment for the blood compartment and erythrodermic skin disease, as described above. (See 'Stage IVA SS (no visceral involvement)' above.)

ECP is time consuming and is only available at specialized centers, but it is generally well tolerated and does not cause immunosuppression.

●Administration – ECP is generally administered as two consecutive daily treatments every two to four weeks. The total time of each treatment (collection, photoactivation, reinfusion) is 1.5 to 4 hours. The preferred protocol may vary among centers.

Treatment should continue for ≥6 months and until maximal response is achieved. It may then be gradually tapered to a maintenance regimen of one treatment cycle (ie, two consecutive treatments) once every 6 to 12 months, if the patient continues to benefit. If the patient has improved but continues to manifest a significant disease burden, a skin-directed or systemic immune-supporting treatment (SDT) can be added.

ECP can be combined with systemic agents (eg, interferon alfa [IFNa], bexarotene) or SDTs (eg, topical corticosteroid, topical nitrogen mustard, carmustine [BCNU] ointment, phototherapy, or total skin electron beam therapy [TSEBT]) to enhance and/or prolong both the cutaneous and blood responses. Doses of systemic agents are generally lower than when they are used as monotherapy, depending upon tolerance.

Adequate venous access is required for ECP, which should be via peripheral intravenous access whenever possible. Permanent indwelling tunneled pheresis catheters (eg, Hickman catheters) should be avoided in patients with SS, as they are at very high risk for skin colonization and line infections, particularly due to Staphylococcus aureus.

ECP is approved by the US Food and Drug Administration (FDA) for treatment of SS.

●Toxicity – Adverse effects (AEs) are infrequent but include mild hypotension during treatment, fatigue, headache, and a transient increase of pruritus.

Phototherapy should be used cautiously in patients with erythroderma. Patients should be informed of increased risk for infections. An infection should be suspected in patients who experience chills and/or fever following ECP.

Rarely, retinal toxicity has been reported (likely due to abnormally elevated serum levels of methoxsalen) [15]. Heparin-induced thrombocytopenia (from the small amount of heparin used during ECP) has also been observed; anticoagulation with calcium citrate can be substituted in these cases. The 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 deep vein thrombosis (DVT) in two additional patients receiving ECP for cGVHD.

●Outcomes – Single-arm trials of ECP monotherapy report ≥50 percent skin improvement in one-quarter of patients, with a median of five to six months until response. Combining ECP with IFNa or bexarotene generally results in quicker and more effective responses with acceptable toxicity [9].

•In a study of 65 patients with SS or erythrodermic mycosis fungoides (MF), ECP monotherapy was associated with longer median time to next treatment (TTNT; 14 months) compared with other approaches, including IFNa, histone deacetylase inhibitors, methotrexate, and other agents [17]. When ECP was used as the first to third line of therapy, median TTNT was 47 months. Median predicted overall survival (OS) was 120 months for the entire study population.

•ECP combined with IFNa or other systemic agents for the treatment of erythrodermic cutaneous T cell lymphoma (CTCL) was reported in various small studies.

-ECP plus ≥1 systemic agent (eg, IFNa, systemic retinoid) was associated with 75 percent overall response rate (ORR; including 30 percent complete response [CR]) in a single-center study of 98 patients with SS [18].

-Treatment with ECP plus IFNa in 22 patients with SS reported 45 percent ORR, while treatment with ECP plus IFNa and bexarotene was associated with 88 percent ORR (including 32 percent CR) [4]. In another study, 12 patients with SS treated with PUVA, topical steroids, and IFNa reported 42 percent ORR [19].

-Treatment with ECP plus bexarotene, IFN, and low-dose TSEBT in three patients with multiply refractory SS was associated with long-term (ie, >24 months) clinical and molecular remissions [20].

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 natural killer (NK) cell and CD8+ T cell count [21-24].

Systemic agents

Mogamulizumab — Mogamulizumab is a defucosylated humanized antibody directed against the chemokine receptor CCR4, which is overexpressed on malignant T cells [25].

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

A topical corticosteroid can enhance the response to mogamulizumab and treat mogamulizumab-associated rash (MAR).

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

●Toxicity – The most common AEs are mild infusion-related reactions and drug eruptions. Mogamulizumab is generally well tolerated, including in patients with advanced age or impaired performance status.

MAR can occur in up to one-half of patients treated with mogamulizumab; this can be especially distressing when it involves the face or scalp. Some patients experience myositis (eg, polymyositis, myocarditis). Mogamulizumab can deplete regulatory T cells, and some reports suggest that it may increase the risk of acute GVHD in patients who undergo allogeneic hematopoietic cell transplantation (HCT) within six months of treatment [26-28]

Caution is advised when treating with mogamulizumab within six months of transplantation because of a possible increase in risk or severity of GVHD, as discussed below. (See 'Large cell transformation/aggressive disease' above.)

Outcomes of treatment with mogamulizumab for SS in the MAVORIC trial are presented above [10]. (See 'Stage IVA SS (no visceral involvement)' above.)

Romidepsin — Romidepsin is a histone deacetylase inhibitor (HDACi) with activity against CTCLs. It is active across disease compartments in SS and suitable for patients with erythroderma, lymphadenopathy, and/or blood involvement.

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

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

Romidepsin is metabolized by CYP3A4; coadministration of strong CYP3A4 inhibitors or inducers should be avoided if possible (table 4).

Electrocardiogram (ECG) should be performed prior to beginning treatment. The QT interval should be monitored periodically during treatment in patients with congenital long QT syndrome, significant cardiovascular disease, and/or taking other products that lead to significant QT prolongation (table 5).

Romidepsin can be safely combined with IFN, bexarotene, or radiation therapy (RT) [29-33], but it is uncertain if these combinations provide a benefit over that seen with single agents.

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

●Toxicity – Romidepsin is associated with cytopenias and mild nausea, vomiting, and fatigue.

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

Due to the immune suppressive effects of romidepsin, there is a small risk for reactivation of herpesviruses, particularly Herpes zoster and Herpes simplex.

●Outcomes

•Romidepsin was associated with 34 percent ORR (including 6 percent CR) and significant improvement in pruritus in 43 percent of 96 patients with CTCL [34]. Subgroup analysis of compartment-specific activity reported 35 percent ORR (including 5 percent CR) in patients with erythroderma, 32 percent ORR (including 5 percent CR) in patients with B2 blood involvement, and 27 percent ORR (including 4 percent CR) in patients with lymphadenopathy; no patients with visceral involvement were enrolled [35]. Grade ≥3 AEs were uncommon, but one-half of patients had mild (grade ≤2) nausea, vomiting, or diarrhea; prolonged QT interval was reported in two patients [34].

•Treatment with romidepsin in 71 patients with previously treated CTCL (median of four prior therapies) was associated with 34 percent ORR (including 6 percent CR), median time to response was two months, and median duration of response (DOR) was 15 months [36].

•In another study, clinically meaningful improvement in pruritus was seen in 43 percent of patients with moderate/severe pruritus at baseline, and improvement was experienced even in some patients without an objective clinical response [37].

Alemtuzumab — Alemtuzumab is an anti-CD52 humanized monoclonal antibody that can be effective in r/r SS.

●Administration – Alemtuzumab can be given subcutaneously or intravenously, but subcutaneous administration obviates the need for an indwelling intravenous catheter, which can be associated with infections by skin bacteria. Examples of treatment schedules include:

•Subcutaneous alemtuzumab 10 mg three times a week.

•Intravenous alemtuzumab 30 mg over two hours three times per week for up to 12 weeks through an intravenous infusion line with a 0.22 micron in-line filter. The first dose is 3 mg, and this is increased to 10 mg and then to 30 mg as infusion-related reactions are tolerated.

Alemtuzumab therapy requires antibiotic, antifungal, and antiviral prophylaxis and close observation for infections and cardiac toxicity [38].

Alemtuzumab is available in the United States through a restricted distribution program, and the package carries a boxed warning regarding the risk of autoimmunity, infusion reactions, and malignancies [39]. (See "Treatment of advanced-stage (IIB to IV) mycosis fungoides".)

●Toxicity – Serious infections can occur, especially in heavily pretreated patients, but they may be less common when using low-dose subcutaneous administration. Cytomegalovirus reactivation, herpes simplex or zoster reactivation/dissemination, bacterial and fungal infections, fatal aspergillosis, and mycobacterium pneumonia can be seen, but they may be less common than in patients with other hematologic malignancies [40].

Infusion reactions can occur. Heart failure or arrhythmias have occurred with alemtuzumab, but they are mostly improved after discontinuation of treatment [38]. Autoimmune encephalitis (AIE) has been reported in association with alemtuzumab treatment.

●Outcomes – ORR of 86 to 100 percent reported in patients with SS is higher than in patients with patch/plaque/tumor MF [41-44]. Patients with transformed SS (ie, large cell transformation), especially when associated with bulky lymphadenopathy and tumor-stage disease, do not typically respond as well to alemtuzumab.

Pembrolizumab — Pembrolizumab is an inhibitory monoclonal antibody against PD-1, which is expressed by exhausted T cells and malignant T cells of MF and SS.

●Administration – Pembrolizumab 200 mg intravenously every three weeks or every six weeks.

The FDA label does not include SS as an indication.

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

●Outcomes – A multicenter study of 24 patients with advanced-stage MF or SS treated with pembrolizumab was associated with 38 percent ORR, including 8 percent CR [45]. Responses were durable among responding patients. Median DOR was not reached with follow-up of >1 year. Pembrolizumab was well tolerated, and AEs resolved after the discontinuation of treatment.

Other agents — Following are treatments that are used to treat MF or other PTCLs that have little evidence of efficacy with SS.

●Brentuximab vedotin – Brentuximab vedotin is an anti-CD30 monoclonal antibody conjugated with the tubulin inhibitor monomethylauristatin E.

•Administration – Administration and toxicity of brentuximab vedotin are discussed separately. (See "Treatment of advanced-stage (IIB to IV) mycosis fungoides", section on 'Brentuximab vedotin'.)

Brentuximab vedotin is approved by the FDA for CD30-positive SS/MF in patients who have received prior therapy.

•Outcomes – Brentuximab vedotin is efficacious in patients with MF, especially with large cell transformation of tumor-stage disease, but patients with SS were excluded from the phase 3 ALCANZA trial [14].

-Treatment of 13 patients with r/r SS was associated with 38 percent global response after a median of 6 cycles [46]. Disease compartment responses included skin (38 percent), blood (63 percent), and lymph nodes (50 percent), while 27 percent reported improved pruritus. CD30 positivity in skin was not associated with responses. The median time to response was six weeks, and the median duration of response was six months. Peripheral neuropathy occurred in 30 percent of patients but resolved in one-half of them.

-Treatment of 30 evaluable patients was associated with global response in 70 percent [47]. CD30 expression <5 percent was associated with a lower likelihood of global response.

●Pralatrexate – Pralatrexate is an intravenous antifolate agent with efficacy in r/r PTCL and CTCL.

Use of pralatrexate is associated with mucositis and cytopenias, and it should be accompanied by supplementation with folic acid and vitamin B12. Pralatrexate is approved by the FDA for treatment of r/r PTCL.

Administration, toxicity, and outcomes with pralatrexate for MF are discussed separately. (See "Treatment of advanced-stage (IIB to IV) mycosis fungoides".)

●Methotrexate – Oral methotrexate can be used alone or in combination with other systemic therapies (eg, ECP, IFNa) for the treatment of MF and SS. Oral methotrexate is approved by the FDA for treatment of adults with MF.

Oral methotrexate is generally well tolerated, but it can cause fatigue, oral ulcerations/mucositis, gastrointestinal effects, cytopenias, and other AEs. It is a known abortifacient/teratogen and is contraindicated during pregnancy; females of childbearing potential should take contraceptive precautions.

Administration, toxicity, and outcomes with oral methotrexate for MF are presented separately. (See "Treatment of advanced-stage (IIB to IV) mycosis fungoides".)

●Bexarotene – 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 IFNa) or phototherapy for treatment of MF and SS. Bexarotene is approved by the FDA for the treatment of r/r MF/SS.

Oral bexarotene is associated with cytopenias, hyperlipidemia, hypothalamic hypothyroidism, and other AEs. Treatment requires monitoring and management of thyroid and lipid AEs. Systemic retinoids are teratogenic and absolutely contraindicated during pregnancy; females of childbearing potential should take contraceptive precautions, and males should take contraceptive precautions during and for one month after the use of bexarotene is discontinued.

Administration, toxicity, and outcomes with oral bexarotene for MF are presented separately. (See "Treatment of advanced-stage (IIB to IV) mycosis fungoides".)

●Vorinostat – Vorinostat is an oral HDACi that is approved by the FDA for r/r CTCL after ≥2 systemic therapies.

Common AEs include mild cytopenias, hypokalemia, fatigue, diarrhea, and nausea.

Administration, toxicity, and outcomes of vorinostat for MF are presented separately. (See "Treatment of advanced-stage (IIB to IV) mycosis fungoides".)

●Interferon – Peginterferon alfa-2a is the only version of IFNa that is available in the United States.

The efficacy of IFNa is enhanced if it is used in combination with ECP, mogamulizumab, bexarotene, or PUVA.

The most common AEs are flu-like symptoms (eg, include fever, fatigue, chills, myalgias, arthralgias, and headache), which usually diminish over time. IFNa therapy should be used with caution in patients with heart disease, concomitant autoimmune conditions, or solid organ transplants; IFNa can trigger or unmask autoimmune phenomena (eg, thyroiditis, psoriasis, vitiligo, colitis).

Administration, toxicity, and outcomes with IFNa for MF are presented separately. (See "Treatment of advanced-stage (IIB to IV) mycosis fungoides", section on 'Interferons'.)

●Bortezomib – Bortezomib is an intravenously administered proteasome inhibitor. Bortezomib is not approved by the FDA for treatment of PTCL.

Treatment with bortezomib in 12 patients with MF or PTCL was associated with 67 percent ORR [48]. Its efficacy in patients with SS is not well defined.

●Lenalidomide – Lenalidomide is an immunomodulatory agent with efficacy in patients with r/r SS.

•Administration – The preferred starting dose is 10 mg daily for 21 days of a 28-day cycle, with dose escalation by 5 mg each cycle to a maximum of 25 mg daily. Starting with a low dose lessens the risk of a transient flare reaction.

•Toxicity – AEs are generally mild and include fatigue, pain/burning, infection, constipation/diarrhea, and edema. There is a risk of venous thromboembolism, and thromboprophylaxis should be considered.

Lenalidomide is contraindicated in pregnant patients because of the potential congenital anomalies. In the United States, lenalidomide is available only via the RevAssist program.

•Outcomes – In 32 heavily pretreated patients with r/r PTCL (including 11 with SS), lenalidomide was associated with 28 percent ORR (all partial) with median 10 months DOR [49]. Nonhematologic toxicities were largely mild (grade ≤2) and included fatigue, pain/burning, infection, constipation/diarrhea, and edema.

Cytotoxic chemotherapy — Single-agent or combination chemotherapy can be used for the treatment of SS. Chemotherapy treatment was independently associated with increased mortality in a large study of treatment patterns of patients with CTCL [50].

Liposomal doxorubicin

●Administration – Liposomal doxorubicin 20 to 40 mg/m² intravenously on days 1 and 15, every 28 days (one cycle) for up to six cycles.

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

●Outcomes – Liposomal doxorubicin has activity against CTCLs and is associated with moderate toxicity.

•Treatment of 49 patients with SS or advanced-stage MF was associated with 41 percent ORR, including ≥50 percent reduction of cutaneous manifestations in 61 percent; median DOR was six months, and median time to progression was seven months [13]. Treatment was well tolerated, with few grade ≥3 AEs.

•Treatment of 25 patients with advanced or refractory CTCL (including 10 with SS) was associated with 56 percent ORR (including 20 percent CR); median OS was 44 months, and median progression-free survival (PFS) in responding patients was 5 months [51].

•In a study of 19 patients with r/r CTCL, median OS, event-free survival, and PFS were 34, 18, and 19 months, respectively, and ORR and CR rates were 84 and 42 percent; 11 percent of patients had grade ≥3 AEs [52].

Gemcitabine — Single-agent gemcitabine has activity against SS/MF.

●Administration – Gemcitabine 1000 to 1200 mg/m² intravenously on days 1, 8, and 15 of a 28-day cycle.

Gemcitabine is not specifically labeled by the FDA for SS, but it has been used off-label in this setting.

●Toxicity – Treatment is generally well tolerated. AEs include mild hematologic toxicity, transaminitis, hypersensitivity reaction, skin hyperpigmentation, and radiation recall/sensitization.

●Outcomes

•Treatment of 24 patients with CTCL (including 6 with SS) reported 63 percent ORR in patients who received ≥3 cycles [53]. Most patients discontinued treatment before receiving the planned six cycles of therapy, including grade ≥3 neutropenia in 30 percent, 26 percent with serious infections, one case of hemolytic-uremic syndrome, one case of severe capillary leak syndrome, one with acute heart failure/arrhythmia, two with bullous and erosive dermatitis, and one with recurrent influenza-like syndrome.

•Other studies reported 50 to 75 percent ORR to gemcitabine for CTCL [11,12,54].

Combination chemotherapy — Combination chemotherapy can produce fast responses, but it is more toxic than sequential treatment with single agents, and responses are generally short-lived. We reserve combination chemotherapy for settings where a rapid response is needed and allogeneic HCT or a noncytotoxic systemic regimen is planned to consolidate the response. There is no clear advantage to early aggressive combination therapy compared with sequential therapies in this setting.

When using combination chemotherapy, we choose regimens that are used for r/r peripheral T cell lymphoma, as discussed separately. (See "Treatment of relapsed or refractory peripheral T cell lymphoma".)

ALLOGENEIC TRANSPLANTATION — 

Allogeneic hematopoietic cell transplantation (HCT) is the only curative treatment for SS, but it is generally reserved for patients with clinically aggressive SS or multiply relapsed disease.

The decision to proceed with allogeneic HCT is individualized, with consideration of age, fitness, alternative treatment approaches, comorbid conditions, availability of a suitable graft, and patient preference. Allogeneic HCT is an option for medically fit patients, and while there is no upper age limit for transplantation, many centers restrict allogeneic HCT to patients ≤70 years, as discussed separately. (See "Allogeneic hematopoietic cell transplantation: Indications, eligibility, and prognosis".)

●Timing – We favor transplantation at the time of best response to systemic therapy rather than waiting for an exhaustion of treatment options because allogeneic HCT is more likely to be effective with treatment-responsive disease.

Caution is advised in patients who were treated with mogamulizumab or alemtuzumab within six months of transplantation because of a possible increase in risk or severity of graft-versus-host disease or graft rejection caused by residual alemtuzumab.

●Bridging therapy – Bridging therapy is given while awaiting allogeneic HCT. The choice of bridging therapy should consider the pace of disease, clinical manifestations, comorbidities, institutional approach, and patient preference.

•Combination chemotherapy – Multiagent chemotherapy can be effective when a rapid and robust response is needed and when transplantation is expected soon thereafter. Combination chemotherapy can achieve fast and deep remissions, but responses are generally short-lived.

Potential regimens are like those used for r/r peripheral T cell lymphoma. Examples include gemcitabine plus liposomal doxorubicin, GVD (gemcitabine, vinorelbine, liposomal doxorubicin), or CHOP (cyclophosphamide, vincristine, doxorubicin, prednisone), as discussed separately. (See "Treatment of relapsed or refractory peripheral T cell lymphoma".)

•Single agents – Selection of a single agent as bridging therapy is like that described above. (See 'Large cell transformation/aggressive disease' above.)

Further discussion of indications, transplantation techniques, and outcomes with allogeneic HCT are discussed separately. (See "Treatment of advanced-stage (IIB to IV) mycosis fungoides", section on 'Hematopoietic cell transplantation'.)

ADJUNCTIVE TREATMENTS — 

Patients with SS often have exfoliative erythroderma and may experience severe itching, skin scaling, fissuring, and thickening of the palms and soles. Adjunctive treatments are often added to systemic therapy to control symptoms and reduce the risk for infections and other complications.

Skin-directed therapy — Skin-directed therapy (SDT) is a key component of the management of patients with SS and should be considered for all patients as an adjunct to systemic therapy.

Importantly, patients with especially inflamed or edematous erythroderma experience skin irritation or flaring with the initiation of certain SDTs; caution should be used, especially when initiating topical retinoids, phototherapy, and 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:

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

●Mustard agents – Topical nitrogen mustard is a frequently employed treatment for mycosis fungoides (MF) and SS. The main adverse effects (AEs) are skin irritation and allergic contact dermatitis. Topical carmustine (BCNU) 0.04% ointment may also be useful to improve skin disease. (See "Treatment of early stage (IA to IIA) mycosis fungoides", section on 'Topical mechlorethamine'.)

●Phototherapy – Phototherapy using ultraviolet B (UVB) or ultraviolet A (UVA) is active against cutaneous involvement. In patients with SS, UVA produces responses in the skin and may result in responses in the blood but not the lymph nodes [55]. AEs 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) – Use of TSEBT in erythrodermic patients varies among institutions. In our experience, TSEBT is well tolerated and effective in SS, but some centers report that erythrodermic patients may not tolerate TSEBT as well as patients with patch, plaque, or tumor-stage disease alone. TSEBT is generally used in multimodality therapy with extracorporeal photopheresis, interferon, and/or bexarotene. If palliation alone is the objective, low-dose TSEBT regimens (10 to 12 gray [Gy]) offer a less time-intensive option with few AEs [56]. Administration of TSEBT is discussed separately in greater detail. (See "Treatment of early stage (IA to IIA) mycosis fungoides", section on 'Total skin electron beam therapy'.)

Pruritus — Pruritus is one of the most common and debilitating symptoms in patients with SS. General measures for the management of pruritus include moisturizers, nonirritating creams, topical corticosteroids, and antihistamines.

Even high doses of antihistamines may not adequately control severe pruritus in patients with SS. Doxepin has a longer half-life and is useful when administered at bedtime. Some patients respond to gabapentin or pregabalin as used for other forms of neuropathic pain. For refractory cases, mirtazapine (and other SSRIs [selective serotonin reuptake inhibitors]), aprepitant, or naltrexone may be added. For some SS patients, only prednisone provides relief from their pruritus; if used, it should be tapered to the lowest possible dose. Nemolizumab is approved by the FDA for treatment of adults with prurigo nodularis and can be effective when used off-label for refractory pruritus in SS. (See "Pruritus: Therapies for localized pruritus".)

A superimposed skin infection may worsen pruritus. Signs of skin superinfection, which can occur in the absence of fever or leukocytosis, include skin erosions or fissures with yellow drainage/crusting.

Infections/bacterial colonization — Patients with MF are at high risk for infections that can mimic the disease itself.

Prophylactic systemic antibiotics are not routinely employed for skin colonization without documented infection, even though patients are frequently colonized with Staphylococcus aureus or other skin flora. Repeated cultures of skin erosions or fissures with yellow drainage/crusting should be performed. Chlorhexidine washes or diluted bleach baths combined with topical antibiotics (eg, mupirocin, clindamycin, silver sulfadiazine) can be used for colonization or mild superinfection.

Moderate/severe cases of superinfection or definitive infection require systemic antibiotics. For documented active skin infections, antibiotic choice is guided by culture data. Clinicians must be aware of the potential for methicillin-resistant S. aureus (MRSA) infection in this population. Diluted bleach baths and a five-day course of intranasal mupirocin can be employed as a maintenance regimen for patients with a repeated history of S. aureus skin infections. Patients with erythrodermic disease are also at risk for dissemination of herpes simplex virus and/or varicella zoster virus.

RECURRENT/RELAPSED DISEASE — 

There is no consensus for treatment of relapsed or refractory (r/r) SS. We encourage participation in clinical trials, when possible.

Sequential single agent therapy is used to relieve symptoms and prolong survival. Treatment selection should consider previous treatments, comorbidities, and disease manifestations (eg, skin tumors; erythroderma; nodal, visceral, or blood involvement). Relapsed disease may respond to repeated treatment with the same systemic therapies and skin-directed treatments that were previously effective.

●Treatment options for r/r SS are not limited to the preferred approaches for various disease manifestations that are described above. (See 'Stage IVA SS (no visceral involvement)' above and 'Stage IVB SS (visceral involvement)' above.)

●More intensive or riskier approaches may be required in this setting, including agents that are not often used as earlier lines of therapy. As an example, low-dose alemtuzumab has efficacy for r/r SS. (See 'Alemtuzumab' above.)

●Other options in this setting include bortezomib, chlorambucil, cyclophosphamide, pembrolizumab, and pentostatin. (See 'Systemic agents' above.)

●For patients with multiply relapsed SS who are transplant eligible, allogeneic hematopoietic cell transplantation should be considered. (See 'Large cell transformation/aggressive disease' above.)

PROGNOSIS — 

While many patients with SS respond to the initial therapy, most experience multiple transient responses and relapses.

The clinical course of patients with SS is more aggressive than that of those with early-stage patch/plaque mycosis fungoides (MF), with median survival of three to four years [57-61]. Additional details regarding the prognosis of patients with MF/SS and clinicopathologic features associated with outcomes 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

●Description – Sézary syndrome (SS) is an aggressive leukemic variant of cutaneous T cell lymphoma (CTCL) with a high burden of circulating malignant cells. SS shares aspects of clinical presentation, pathologic features, staging, and treatments with mycosis fungoides (MF), but it is distinguished by the high blood tumor burden.

●Overview – Patients with SS generally require systemic therapy, which can be given as monotherapy or together with skin-directed therapy or another systemic agent (table 1). Treatment is individualized with consideration of symptoms and sites/types of disease. No approach is optimal for all patients, and experts differ in their preferred agents and sequencing of therapy. (See 'Overview' above.)

●Staging – Assessment of skin (T), lymph nodes (N), viscera (M), and blood (B) involvement is used for TNMB classification and to determine the corresponding clinical stage (table 2). (See 'Staging' above.)

●Overview – Patients typically experience a chronically relapsing disease course with troublesome pruritus, and they often require multiple lines of therapy. Treatment is individualized and stratified according to whether there is visceral involvement (ie, liver, spleen, bone marrow). (See 'Overview' above.)

●Stage IVA SS (no visceral involvement) – For stage IVA SS, we suggest extracorporeal photopheresis (ECP) or mogamulizumab alone, together, and/or in combination with other agents (Grade 2C). (See 'Stage IVA SS (no visceral involvement)' above.)

●Stage IVB SS (visceral involvement) – Stratified according to bone marrow-only visceral disease versus other visceral involvement (with or without marrow disease). (See 'Stage IVB SS (visceral involvement)' above.)

•Bone marrow-only visceral disease (M1a) – We manage stage IVB SS with M1a visceral involvement like stage IVA SS. (See 'Bone marrow only' above.)

•Other visceral involvement (M1b) – Treatment is individualized according to disease tempo and adverse clinicopathologic features (see 'Stage IVB SS (visceral involvement)' above):

-Clinically aggressive – For large cell transformation, rapidly progressive disease, or bulky/symptomatic nodal disease, we suggest single-agent gemcitabine or liposomal doxorubicin rather than multiagent chemotherapy or other treatments (Grade 2C). (See 'Large cell transformation/aggressive disease' above.)

Supplementation with other systemic therapies (table 1) and/or skin-directed therapy can enhance symptom relief and/or prolong treatment response. After six months of single-agent treatment, the other single-agent chemotherapy can be given.

For inadequate/transient response, other single agents can be considered, while allogeneic hematopoietic cell transplantation (HCT) is an option for younger, fit patients.

-Others – For less aggressive M1b visceral disease, we suggest sequential single-agent therapy (Grade 2C). Treatment is individualized, with consideration of compartment-specific activity, comorbidities, toxicity, availability, cost, and patient preference. (See 'Other M1b disease' above.)

●Response monitoring – Clinical examination of skin, quantitation of circulating tumor cells by flow cytometry, imaging of node/organ involvement, and/or bone marrow examination. Response criteria are described above. (See 'Monitoring and response' above.)

●Treatments

•(See 'Extracorporeal photopheresis' above.)

•(See 'Mogamulizumab' above.)

•(See 'Romidepsin' above.)

•(See 'Alemtuzumab' above.)

•(See 'Pembrolizumab' above.)

•(See 'Other agents' above.)

•(See 'Liposomal doxorubicin' above.)

•(See 'Gemcitabine' above.)

•(See 'Combination chemotherapy' above.)

●Adjunctive management – Treatments to enhance responses to systemic therapies, relieve pruritus, and control infections are described above. (See 'Adjunctive treatments' above.)

●Relapsed/refractory disease – Treatment is individualized, with consideration of symptoms, disease manifestations, prior treatments, comorbidities, and patient preference. We encourage participation in clinical trials. (See 'Recurrent/relapsed disease' above.)