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Abstract and IntroductionAbstract

Sézary syndrome (SS) is a lymphoma of skin-homing T cells. SS is defined as desquamative erythroderma involving

at least 80% of the skin in addition to lymphadenopathy and leukemic involvement. Patients have a poor prognosis

with an estimated 5-year survival of 20–27% and estimated median survival of 14–36 months. The goals of therapy

are destruction of the malignant lymphocytes and correction of the immune imbalances caused by the malignant Th2

lymphocytes. Immunotherapeutics, such as interferons, retinoids, extracorporeal photopheresis and combination

therapy are first-line therapies because of their favorable side-effect profiles. This review will focus on this interesting

and expanding group of treatments. Chemotherapeutics, such as doxorubicin and gemcitabine, and monoclonal

antibodies such as alemtuzumab, are second-line therapies owing to the risk of iatrogenic immunosuppression andcumulative toxicity. SS requires combination therapy, utilizing multiple skin-directed and systemic agents. The goal of

this article is to discuss the treatment of SS, with a focus on immunotherapies

Introduction

Cutaneous T-cell lymphomas (CTCLs) are a diverse group of non-Hodgkin lymphomas caused by a malignant

population of skin-trafficking T cells. Mycosis fungoides (MF) and Sézary syndrome (SS) are the most common forms

of CTCL and represent approximately 65% of the cases.[1] MF and especially SS are rare diseases with annual

incidences in the USA of approximately 6.4 and 0.3 cases per million people, respectively.[2] The incidence has

increased with time and may in part be due to improved clinical awareness and advances in diagnostic testing, as well

as an increased number of new cases. The cause of most types of CTCL is unknown, with the exception of adult T-cellleukemia/lymphoma, which is caused by infection with human T-cell lymphotropic virus.

Sézary syndrome is defined by the WHO and European Organization of Research and Treatment of Cancer (EORTC)

as desquamative erythroderma (erythema involving at least 80% of the skin surface), lymphadenopathy and leukemic

involvement.[3] In addition to erythema, patients with SS will have a variable amount of scaling (Figure 1). Patients

often report having chills and intolerable pruritus that interferes with sleep and other activities. Lymphadenopathy can

be palpable or, in advanced cases, bulky and obvious on visual examination. Other manifestations of SS include

alopecia, abnormalities of the finger and toe nails, thickening (keratoderma) and fissures of the skin of the palms and

soles, and ectropion (eversion) of the lower lids.[4] The differential diagnosis includes pityriasis rubra pilaris, drug

eruption or drug-induced pseudolymphoma, psoriasis, atopic dermatitis, contact dermatitis or photodermatitis,

peripheral T-cell lymphoma and chronic lymphocytic leukemia. A single skin biopsy of erythroderma associated with

SS is only diagnostic in approximately 50% of cases. More commonly it is nonspecific, demonstrating spongiosis,

psoriasiform dermatitis, often with increased numbers of eosinophils, but small numbers of atypical lymphocytes.[5,6]

Specific findings, such as Pautrier microabscesses, epidermotropism of atypical lymphocytes or dense aggregates of

atypical lymphocytes in the dermis, are more common during patch/plaque stage MF.[5–8] Therefore, making the

diagnosis of SS requires a combination of suggestive clinical examination results, consistent histologic findings and

studies of the blood and/or lymph nodes.[7,9,10] Adjunctive studies include flow cytometry of the skin and blood,

peripheral blood for Sézary count (quantification of the large lymphocytes with cerebriform nuclei known as a Sézary

cell), PCR for clonal rearrangement of the T-cell receptor in the skin and/or blood and excisional lymph node

biopsy.[7,9–12] In particular, flow cytometry of the peripheral blood is a sensitive test that can identify the malignant T

cells by their loss of CD7 and CD26 antigens (which are present on normal T cells) even in the absence of clear lymphocytosis.[12] This method is used for both diagnosis and monitoring blood disease during and after therapy. The

Therapy of Sézary SyndromeJoslyn S Kirby, Ellen J Kim, Alain H Rook

Expert Rev Dermatol. 2009;4(6):567

http://www.expert-reviews.com/loi/edm


http://www.medscape.com/






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current staging system for MF and SS is the tumor–node–metastasis–blood (TNMB) classification and was updated in

2007 by the International Society for Cutaneous Lymphomas (ISCL) and EORTC.[3] The staging of cutaneous

lymphomas, including CTCL, has evolved over time to reflect advances in our understanding of the disease. The

current MF/SS staging system is detailed in & . Recently, the National Comprehensive Cancer Network (NCCN)

published clinical practice guidelines for the diagnosis, staging and treatment of MF/SS, which are available online,

under non-Hodgkin lymphomas and updated yearly.[201]

Table 1. TNMB stages of mycosis fungoides and Sézary syndrome.

TNMB

stageDefinition

Skin (T)

1 Limited patches, papules and/or plaques covering <10% of the skin suface

2 Patches, papules or plaques covering >10% of the skin surface

3 One or more tumors (>1 cm diameter)

4 Confluent erythema >80% body surface area

Node (N)

0 No clinically abnormal peripheral lymph nodes; biopsy not required

1 Clinically abnormal peripheral lymph nodes; histologically Dutch grade 1 or NCI LN0–2

2 Clinically abnormal peripheral lymph nodes; histologically Dutch grade 2 or NCI LN3

3 Clinically abnormal peripheral lymph nodes; histologically Dutch grade 3–4 or NCI LN4

X Clinically abnormal lymph nodes, no histological confirmation

Visceral/metastasis (M)

0 No visceral organ involvement

1 Visceral involvement (must have pathologic confirmation)

Blood (B)

0 Absence of significant blood involvement: >5% of peripheral blood lymphocytes are atypical (Sézary)

cells

1 Low blood tumor burden: >5% of peripheral blood lymphocytes are atypical (Sézary) cells

2 High blood tumor burden: !1000 Sézary cells per microliter with a positive clone

NCI: National Cancer Institute; TNMB: Tumor–node–metastasis–blood classification.

Table 2. International Society for Cutaneous Lymphomas/European Organization of Research and Treatment of Cancer

updated staging of mycosis fungoides and Sézary syndrome.

Stage Tumor Node Metastasis Blood

IA 1 0 0 0, 1

IB 2 0 0 0, 1

II 1–2 1, 2 0 0, 1



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IIB 3 0–2 0 0, 1

III 4 0–2 0 0, 1

IIIA 4 0–2 0 0

IIIB 4 0–2 0 1

IVA1 1–4 0–2 0 2

IVA2 1–4 3 0 0–2

IVB 1–4 0–3 0 0–2

Figure 1.



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A typical patient with Sézary syndrome and desquamative erythroderma.

The prognosis of MF/SS correlates with the stage of disease; worse prognosis is associated with advanced disease in

each organ (e.g., T1 vs T4 in the skin, B1 vs B2 for blood burden, N1 vs N3 in the lymph nodes) and with advanced

clinical stage (combining organ systems; e.g., IA versus IIA).[13,14] Patients with limited patches of MF (T1) have an

indolent disease that has no impact on their overall survival.[13] Patients with SS have advanced disease, evidenced

by widespread skin disease, nodal and blood involvement. The 5-year survival for SS is approximately 20–27% and

median survival is approximately 14.5–36 months.[13,15] Older age at the time of presentation, elevated lactate

dehydrogenase and eosinophilia are poor prognostic indicators.[16] SS patients not only have a higher risk of mortality,

but their disease symptoms and the treatment side effects also cause a considerable degree of morbidity.

The malignant cell in SS is typically a skin-homing Th2 (CD4+/CLA+/CCR4+/CD26") lymphocyte that produces a

variety of soluble factors, including IL-4, IL-5, IL-10 and in some cases, TGF-# ( ). These factors result in eosinophilia,

elevated IgE, impaired Th1 (cell-mediated) immunity, impaired dendritic cell (DC) and natural killer (NK) cell function

and number, and may play a role in the loss of the normal T-cell repertoire ( ).[17–19] In early patch stage MF,

progression is limited by interferon-secreting host CD8+ cytotoxic T cells.[20] Decreased IFN-$, IL-12 and iatrogenic

immunosuppression have been linked to disease progression.[21,22]

The normal T-cell repertoire is greatly diminishedin MF/SS patients, similar to advanced HIV infection.[19] Diminished T-cell repertoire probably results in impaired

antimicrobial and anti-tumor surveillance and increased risk of secondary malignancies and life-threatening

infections.[23–25] Immunotherapy with interferons, retinoids, phototherapy extracorporeal photopheresis (ECP) and

other agents can induce malignant T-cell apoptosis and thereby eliminate the malignant clone, and reestablish

balance between Th1 and Th2 immunity, normalizing cellular immunity and avoiding the use of chemotherapeutics. It

has been our experience that clearance of the circulating tumor cells has been uniformly associated with restoration of

normal cellular immunity. The qualities of immunotherapuetics, anti-tumor effects and favorable side-effect profiles,

make them first-line treatments and the focus of this review.

Box 1. Irregularities of the immune system in Sézary syndrome.

% Th2 lymphocyte population

& Th1 lymphocyte population

% IL-4, 5, 10

& Cytotoxic (CD8+) lymphocytes and natural killer cells

% Eosinophils

& IL-12, 15, IFN-$

% IgE

& Dendritic cell function and number

& T-cell repertoire

Box 1. Irregularities of the immune system in Sézary syndrome.

% Th2 lymphocyte population

& Th1 lymphocyte population

% IL-4, 5, 10

& Cytotoxic (CD8+) lymphocytes and natural killer cells

% Eosinophils



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& IL-12, 15, IFN-$

% IgE

& Dendritic cell function and number

& T-cell repertoire

In contrast to early MF, the treatment of SS must incorporate systemic treatments ( ) owing to the spread of malignantcells to the lymph nodes and blood. Skin-directed therapies ( ) are used to improve clinical response to systemic

therapies and as palliation for pruritus ( ). Stage-based therapeutic guidelines are available (e.g., the NCCN guidelines

for MF/SS have been available online since 2008); however, therapy is not formulaic and should take into account

previous responses to therapy, comorbidities, and efficacy.[26–28] Surprisingly, no treatment modality has been

definitively shown to be curative or to improve survival, although multiple reports suggest improved survival with ECP

alone or in combination.[29,30] Initial treatment of SS often consists of immunotherapies ( ), singly or in combination,

because of their favorable side-effect profile, decreased risk of iatrogenic immunosuppression and lack of cumulative

toxicity. Chemotherapeutics are considered for patients that have failed combination immunotherapy or have visceral

disease. Single chemotherapy agents are attempted prior to multidrug regimens or stem cell transplantation (SCT).

Patients that respond to either immunotherapy or chemotherapy are unlikely to maintain their response after

cessation. Tapering dosage or maintenance treatment with an immunotherapeutic modality is recommended to

prolong the duration of clinical response. Notably, unlike some malignancies that can become resistant to treatments,

MF/SS may respond to previously successful therapies and thus repeat courses of the same therapy are common.

Clinical trials and SCT are considerations for patients that are refractory or have contraindications to other therapies.

Table 3. Systemic therapies for Sézary syndrome.

Agent Effect

Immunotherapy

Retinoid/rexanoid

RAR agonist (isotretinoin)

RXR agonist (bexarotene)

Malignant cell apoptosis, % IFN-'

Malignant cell apoptosis, & tumor IL-4

% IL-2R expression on malignant lymphocytes

Interferon (IFN-$, IFN-')

Enhanced Th1 immunity

Inhibits malignant cell proliferation

& Th2 cytokines (IL-4, -5 and -10)

Vorinostat (histone deacetylase inhibitor) Malignant cell apoptosis

ECP

Malignant lymphocyte apoptosis

% DC recognition of lymphoma

GM-CSF % DC number and function

Other biologic therapy

Denileukin diftitox Kills CD-25+ (IL-2R+) lymphocytes

Chemotherapy

Methotrexate Antiproliferative/antimetabolite



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Single agent

Liposomal doxorubicin Cytotoxic

Gemcitibine Cytotoxic

Etoposide Cytotoxic

Chlorambucil Cytotoxic

Pentostatin T-cell inhibitory/depleting

Cyclophosamide Cytotoxic

Fludarabine Cytotoxic

Alemtuzumab Kills CD-52+ lymphocytes

Multiagent

EPOCH Cytotoxic

CHOP Cytotoxic

Other

Stem cell transplant

Induction: cytotoxic

Transplant: graft-versus-lymphoma effect

CHOP: Cyclophosphamide, doxorubicin, vincristine and prednisone; DC: Dendritic cell; ECP: Extracorporeal

photopheresis; EPOCH: Etoposide, prednisone, vincristine, cyclosporine and doxorubicin; GM-CSF: Granulocyte

macrophage colony-stimulating factor; IL-2R: IL-2 receptor; RAR: Retinoic acid receptor; RXR: Retinoid X receptor.

Table 4. Skin-directed therapies.

Agent Effect

Topical

Corticosteroids


& LC in skin

Nitrogen-mustard (mechlorethamine) or carmustine Cytotoxic

Retinoid/rexanoid Malignant lymphocyte apoptosis (see Table 3)

Light therapy

Narrow-band UVB


& LC in skin

Psoralens with UVA (PUVA)


& LC in skin

Radiation therapy

Total skin electron beam Malignant lymphocyte apoptosis

Localized electron beam Malignant lymphocyte apoptosis



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Table 5. Palliative therapies.

Agent Effect

Topical

Corticosteroids Antipruritic, anti-inflammatory

Pramoxine, menthol Anesthetic, antipruritic

Bleach bath Antibacterial

Antibiotics (e.g., mupirocin, bacitracin) Antibacterial

Systemic

Antihistamines (e.g., diphenhydramine, hydroxyzine, doxepin) Antipruritic, sedative

Gabapentin Antipruritic

Mirtazipine Antipruritic

Antibiotics (e.g., doxycycline, cephalexin) Antibacterial



Agent Effect

Immunotherapy

Retinoid/rexanoid











ECP




Other biologic therapy

Denileukin diftitox Kills CD-25+ (IL-2R+) lymphocytes

Chemotherapy


Single agent




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ECP




Other biologic therapy Denileukin diftitox Kills CD-25+ (IL-2R+) lymphocytes

Chemotherapy


Single agent



Etoposide Cytotoxic






Multiagent

EPOCH Cytotoxic

CHOP Cytotoxic

Other







Extracorporeal Photophoresis

Extracorporeal photopheresis was introduced as a therapy for CTCL in early 1980s by Edelson and approved by the

US FDA in 1988.[31] It is considered by many to be first-line therapy for SS. During ECP, whole blood is removed from

the patient (225 ml or 0.47 pints); the buffy coat containing the leukocytes is separated and extracorporeally combined

with 8-methoxypsoralen, a photosensitizer, then exposed to UVA light and infused back into the patient. The remaining

portion of the blood, including red blood cells, is reinfused.[32,33] ECP is typically performed on two consecutive days

every month. The frequency of treatment can be increased for resistant cases and alternative protocols have also

been used.[34] A patient should be treated for at least 6–9 months before ECP is considered a therapeutic failure. ECP

is a specialized treatment and not widely available; patients often travel some distance to large medical centers where

the equipment is available. Adverse effects are uncommon but include transient hypotension, low-grade fever,



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transiently increased cutaneous erythema and anemia due to incomplete red blood cell return after separation.

Contraindications include coagulation abnormalities, allergy to methoxypsoralen and advanced heart, hepatic or renal

disease because of intolerance to alterations in blood volume. Initially, ECP was thought to primarily debulk the

atypical lymphocytes in the blood; however, only 2–5% of lymphocytes are exposed to the 8-methoxypsoralen. An

additional effect, aside from reduction of circulating malignant T-cells, is an immunomodulatory effect on Th1/Th2

cytokine production and enhanced DC processing of malignant cells.[35,36] DCs are integral to immune recognition of

malignant lymphocytes via MHC presentation of stem cell antigens and destruction by CD8+ lymphocytes.[37] The

overall response rate (OR) of ECP is 53–83% and the complete response rate (CR) is 8–26% and varies based ontreatment protocol, prior therapies, additional adjuvant therapies and duration of disease.[38,39] Potential adjuvant

therapies include IFN-$, IFN-', bexarotene, and granulocyte–macrophage colony-stimulating factor (GM-CSF).[40]

Interferon

Interferons are a family of glycoproteins with a myriad of biological effects, including antiproliferative and

immunoregulatory effects.[41] In the therapy of SS these effects include inhibition of Th2 cytokine production, inhibition

of stem cell growth and improvement of cell-mediated cytotoxicity.[41] IFN-$2a and 2b are biologically similar, differ by

only one amino acid and have been used to treat MF and SS. Interferon is dosed per million units (MU) and is typically

administered by subcutaneous injection that yields at least 80% absorption. Previous reviews have demonstratedsimilar response rates for IFN-$2a and 2b.[42,43] IFN-$ is commonly administered as a 3–9-MU dose subcutaneously

three-times weekly to daily.[43] A review by Bunn et al. of IFN-$ for MF and SS found an OR of 55% and CR of 17%.

There was no analysis of patients with advanced disease (SS). Olsen et al. and Papa et al. reported an OR of 60 and

70%, respectively, for patients with stage III and IV disease treated with IFN-$.[44,45] Higher dose regimens (>10

MU/day)may result in better response rates than low-dose regimens (3–5 MU daily or three-times weekly); however,

this was not statistically significant in one study.[45,46] The use of high-dose regimens is often limited by intolerance of

adverse effects, but low-dose regimens are generally well tolerated. The most common side effects include fever,

chills, arthralgias, myalgias and malaise. These effects are dose-dependent and improve with acetaminophen and

continued therapy. Patients with worsening constitutional symptoms after prolonged interferon (IFN) therapy should be

evaluated for infection and not have their symptoms ascribed to treatment.[43] Additional dose-dependent side effects

include anorexia, weight loss, depression, decrease in cognitive function and memory, motor dysfunction, peripheral

neuropathy, psychosis, hair thinning, changes in sexual function and, rarely, autoimmune phenomena (thyroiditis,

nephritis, psoriasis). Myelosuppression and transaminitis can occur at doses used to treat SS, but rarely necessitates

cessation of therapy. IFN-$ is also available in a pegylated form that has a longer half-life, requiring only once weekly

administration, which is particularly useful for children who may have a fear of injections.

IFN-' has no homology to IFN-$ and is a useful alternative for cases refractory to IFN-$.[47] IFN-' can increase DC

function and IL-12 production, both of which are important to normalization of immunity and reduction in the malignant

cell population.[22] IFN-' therapy is started at 50 (g (half a vial) three-times per week and increased as tolerated to

100 (g three- to five-times per week. IFN-' is typically better tolerated than IFN-$, particularly among the elderly. IFN-'

appears to be associated with a lower incidence of depression or other cognitive disorders. IFN-$ or -' can becombined together or with one or more of the following treatments: ECP, bexarotene, methotrexate, denileukin diftitox,

or skin-directed therapies (e.g., phototherapy, electron beam radiation therapy).

Retinoids

Retinoids are a group of synthetic and natural chemicals that mimic the effects of vitamin A. Retinoids bind one of two

families of receptors known as the retinoic acid receptor and retinoid X receptor. The receptors are found in the

nucleus and function as transcription factors influencing transcription of genes involved in inflammation, cellular

differentiation and apoptosis.[48] Bexarotene, the first retinoid X receptor-specific oral retinoid to be studied in humans,

is approved for the treatment of CTCL and has been studied most extensively for MF.[49,50]

Guidelines have beenpublished on the use of bexarotene for CTCL.[51,52] Bexarotene is administered daily at a dose of 150 mg/m2 and

increased to 300 mg/m2 as tolerated. Dose escalation is encouraged since efficacy is dose-related. The most common



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was a trend towards greater responses among those who received the higher dose. Three patients with Stage IV

CTCL had a response (two partial responses and one clinical complete response). The total number of stage IV

patients treated was not reported. The soluble form of the IL-2R is found at particularly high levels in SS patients with

a high burden of circulating cells and has been shown to correlate with disease burden and prognosis.[72] High levels

of the soluble form of IL-2R may act as a sink, binding the fusion protein so it is unavailable to bind the IL-2R on the

malignant lymphocyte, resulting in diminished effect. The side effects of this treatment make it less commonly used.

The major side effects are a vascular leak syndrome (VLS) and infusion/hypersensitivity reactions which occurred in

25 and 60% of subjects in the Phase III study, respectively. VLS usually developed in the first 2 weeks after eachtreatment course. The exact etiology of VLS is unknown but may be due to dehydration, hypoalbuminemia and/or

increased capillary permeability. Caution should be used if considering treatment of patients with heart, kidney or liver

disease that cannot tolerate changes in volume status. Daily weights, extremity edema, blood pressure and serum

albumin levels should be monitored during therapy. The infusion/hypersensitivity reaction includes symptoms of

sudden back or chest pain, hypotension, dyspnea, angioedema, pruritus and/or a rash around the time of infusion.

Although not administered as part of the Phase III trial, it is a common practice to administer an intravenous dose of

corticosteroid, such as dexamethasone or methylprednisolone prior to or concomitant to the drug infusion to lessen

these symptoms. Decreasing the rate of infusion and preadministration of NSAIDs and/or antihistamines can also

ameliorate the symptoms. Additional less common side effects include thrombotic events, vision changes and

cytopenias, including thrombocytopenia, neutropenia and leukopenia. Lymphopenia (<1000 cells/(l) occurred in 70%of subjects, but 24% of subjects were lymphopenic at baseline and no adverse event or treatment interruption

occurred. In vitro studies demonstrated increased expression of the IL-2 receptor on leukemic lymphocytes treated

with bexarotene, prompting the use of this combination in a small number of patients.[73,74] Multimodality therapy of

denileukin diftitox (18 (g/kg) and bexarotene (!150 mg) has been studied in a Phase I trial. The OR and CR improved

to 67 and 28%, respectively.[74]

Chemokine

Sargramostim or GM-CSF is a potent stimulant of hematopoiesis but has also demonstrated effects against

malignancies such as CTCL, melanoma, leukemia and breast cancer.[75] Bouwhis et al. first reported the use of GM-

CSF as an adjuvant to multimodality therapy for SS. The patient had a complete response of his blood involvement

and partial improvement of his cutaneous disease. Sargramostim is also used by our group as an adjuvant to

multimodality therapy for recalcitrant SS.[30,40] The use of GM-CSF as an adjuvant to ECP is biologically plausible

because it increases DC number and function, which is a key component of the immunoregulatory effects of

ECP.[30,40,75]

Combination Biologics

Systemic therapies are combined for two main reasons; to enhance the quantity and quality of response rates and to

limit toxicity. Most studies of CTCL assess the outcomes of monotherapy; fewer studies with fewer patients have

assessed multimodality therapy. Several reviews discuss the utility of combination therapy.[26,40,76–78] Several

combination therapies are highlighted below. Multimodality therapy utilizing at least three therapies, ECP and a

combination of two or more other immunotherapies (IFN-$, IFN-', bexarotene, GM-CSF) was retrospectively studied in

28 patients with SS.[30] The results, an OR of 89 and CR of 29%, exemplify the potential benefits of multimodality

therapy. Similar successful reports (mostly retrospective studies) utilizing the combination of ECP, bexarotene and

IFN-$ or IFN-' have been published by this group and others.[40,47,53] A summary of the trails using combination

biologics is given in the following list:

Vorinostat and bexarotene: a Phase I trial of comparing multiple regimens of vorinostat with bexarotene, 18

evaluable patients including nine with stage IV disease has so far resulted in an OR of 22% and a CR of 5%,

and is still accruing patients;[68]

Vorinostat and IFN-': three patients with SS were treated with vorinostat and IFN-' and yielded an OR of



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100%, but none had a CR;[69]

Denileukin diftitox and bexarotene: the combination of denileukin diftitox (18 (g/kg) and bexarotene (!150 mg)

was studied in a Phase I trial. The OR and CR were 67 and 28%, respectively. Three patients had stage IV

disease; two patients were evaluable and neither had a response to treatment;[74]

ECP and bexarotene: two patients with SS treated with standard regimen ECP and bexarotene (300

mg/m2).

[79] One patient had a CR in the skin but no change in blood burden of disease. The second patient had

a partial response of both cutaneous and blood disease. The combination of bexarotene with ECP requires

careful monitoring of serum lipids the hypertriglyceridemia typically associated with bexarotene, can interfere

with the ability of the machine to discern the buffy coat from blood fats;

ECP and IFN: Dippel et al. treated 19 patients with advanced CTCL, 10 patients (two SS) received ECP alone

and nine patients (one SS) received ECP with IFN-$ (3–18 MU three-times weekly). None of the three SS

patients responded.[80] For all subjects, ECP alone yielded an OR of 20% and CR of 10%, while ECP and IFN

improved OR to 60% and CR to 40%. Gottlieb et al. studied ECP with IFN-$ (1.5–5 MU 3–5-times weekly) in 31

patients with CTCL.[29] The OR was 71% and CR was 25%. In total, 27 of the patients had leukemic

involvement. In this population, seven patients had a CR (26%) and 20 had some response (OR = 74%). An

earlier study combined IFN-$ (3–20 MU three-times weekly) and ECP to treat six patients with SS.[46] The OR

was 66%. No patient had a CR. A dose response with IFN-$ was suggested;

IFN and bexarotene: eight patients with SS were treated with bexarotene (300 mg/m2) and IFN-$ (3 MU three-

times weekly) for 8 weeks.[81] The OR was 37% and no patient obtained a CR.

Chemotherapy

Single-agent chemotherapies as well as combination chemotherapies () are generally reserved for patients refractory

to combination immunotherapy or those with bulky lymphadenopathy or visceral involvement. Recent reviews address

the use of conventional chemotherapeutics, such as liposomal doxorubicin, gemcitabine and others.[26,28] ORs rangefrom 16 to 70%.[28] Complete responses occur in 20–25% of these heavily pretreated patients. Time to response is

shorter than immunotherapies, but relapse is also rapid with responses maintained for 3–6 months. Toxicity from

chemotherapeutics is frequent and is episodic during therapy (cytopenias) or cumulative (neurotoxicity,

cardiomyopathy). Single-agent therapy is often attempted prior to combination therapies to limit toxicity and cumulative

dosages.


Agent Effect

Immunotherapy

Retinoid/rexanoid












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ECP




Other biologic therapy Denileukin diftitox Kills CD-25+ (IL-2R+) lymphocytes

Chemotherapy


Single agent



Etoposide Cytotoxic






Multiagent

EPOCH Cytotoxic

CHOP Cytotoxic

Other







Methotrexate (MTX), a folate antagonist, is sometimes not thought of as a conventional chemotherapeutic; however, it

has both antiproliferative and immunosuppressive effects.[82] It is discussed here briefly because it is both widely

available and commonly used to treat MF/SS. Zackheim et al. reviewed their experience with MTX treatment of SS

and MF.[83,84] For 29 patients with SS, MTX was usually administered weekly and the dose ranged from 5 to 125 mg.

Doses less than 25 mg (ten patients) were administered orally while doses exceeding 25 mg (19 patients) were given

by injection. The OR and CR for this study were 58 and 41%, respectively. Side effects included transaminitis (eight

patients), oral and/or cutaneous erosions (12 patients), nausea and/or diarrhea (11 patients), leukopenia or

thrombocytopenia (three patients) and pulmonary fibrosis (two patients). MTX has also been studied in combination

with IFN-$; MTX (10 mg/m2 twice weekly) and IFN-$ (9 MU three-times weekly) were used to treat 158 patients with

advanced-stage (IIB or higher) CTCL.[85] At 6 and 12 months, the CR was 31 and 49%, respectively. Patients were

given the combination treatment until CR then given maintenance therapy with IFN. If disease recurred combination



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therapy was reinstituted. The number of patients and outcomes for SS patients specifically was not discussed.

Chlorambucil, like cyclophosphamide, is an alkylating agent and is derived from nitrogen mustard. It is commonly

administered in conjunction with a corticosteroid; this combination is also known as the 'Winkelmann regimen' and has

been used to treat advanced CTCL including SS.[86–88] In 1989, Winkelmann et al. reviewed their experience with this

regimen. A total of 40 patients with SS were treated with a standard dose of chlorambucil 4 mg daily and prednisone

20 mg daily. Once erythrodermic patients treated with the Winkelmann regimen lived twice as long as those treated

otherwise. Of patients on long term therapy, seven (37%) out of 19 had a complete response for at least 1 year andten (59%) out of 17 had a significant decline in peripheral stem cells. Chlorambucil with corticosteroid for SS has also

been administered in twice-monthly pulses, similar to that used for chronic lymphocytic leukemia.[88] Higher doses are

given for fewer days with the hope that cumulative doses are lower. Coors et al. utilized this pulsed regimen for 13

patients with SS and an OR of 100% and a CR of 54%. Both reports noted improvement in pruritus at 1–3 months with

improvement in clinical examination taking longer (3–6 months). The most common main side effect was leukopenia.

Other side effects were carcinogenicity, seizures and infertility. The Winkelmann regimen has also been modified to

include ECP.[89]

Another agent that widely ablates immune cells similar to conventional chemotherapy is alemtuzumab, an anti-CD52,

humanized IgG monoclonal antibody. CD52 is a highly expressed glycoprotein found on normal and malignant B and

T lymphocytes, as well as NK cells. In vitro, alemtuzumab induces complement- and antibody-dependent cellular

cytotoxicity, as well as direct apoptosis of the malignant T cells.[90] The standard therapeutic schedule calls for

intravenous administration of escalating doses to 30 mg three-times a week for 12 weeks.[91] At these doses there is a

profound and long-lasting depletion of mature B and T lymphocytes, which contributes to the prevalence of grade 3/4

infectious events and hematologic toxicity. Alternative dosing schedules combining lower doses and subcutaneous

administration have been shown to preserve the efficacy of this agent, reduce the number of infectious complications

and eliminate infusion reactions.[92,93] Small studies of its use for SS have shown excellent results with CRs between

32 and 47%. In the largest series of patients with advanced MF/SS reported, alemtuzumab administered at the

standard (higher dose) schedule resulted in an OR of 65% and a CR of 32%; median pruritus scores decreased from

eight to two (out of ten).[94] An alternative low-dose regimen of subcutaneous alemtuzumab therapy resulted in an OR

of 86% (12 out of 14), CR in 21%, reduced median pruritus scored from nine to three (out of 10), and reduced the

frequency of infections.[92] With high-dose regimens infectious complications have been both highly prevalent and

dangerous. In studies of alemtuzumab for nodal lymphomas, 23–79% of patients developed an infection. The most

common infections are reactivation of herpes family viruses (Epstein–Barr virus and cytomegalovirus); however,

bacterial sepsis, atypical mycobacterial and fungal infections also occurred. Prophylaxis with

trimethoprim/sulfamethoxazole and valacyclovir, with or without voriconazole has been advocated. Hematologic

toxicity is also common; cytopenias (at least grade 2) occurred in up to 46%.[91] Monitoring of blood counts,

cytomegalovirus, Epstein–Barr virus and Sézary counts should be considered during treatment. The side effects and

profound suppression of malignant and normal lymphocytes make alemtuzumab very similar to conventional

chemotherapeutics; however, early studies demonstrate better response rates.

Stem Cell Transplantation

Stem cell transplantation has been used in a small proportion of patients with advanced and/or refractory CTCL. The

benefit of the allogeneic transplant includes not only the massive reduction in tumor burden by the chemotherapeutic

conditioning regimen, but also the sustained graft-versus-lymphoma (GVL) effect of the graft. The malignant

lymphocytes of the host are seen as 'nonself' by the graft and killed. Therefore, it is not surprising that autologous SCT

has not demonstrated durable remissions since there is no GVL effect.[95–97] Modifications in conditioning regimens,

such as nonmyeloablative or reduced-intensity regimens, can limit early toxicity and mortality; making SCT a safer

option for older patients and those with comorbidities.[97–99] A review by Introcaso et al. demonstrated that if the

patient can survive the early transplant period then there is a reasonable chance of a durable CR.[100] In this review,

14 of 17 patients survived and went into remission (CR 82%). Three patients (18%) died due to infections following

transplantation; this is within the range of published mortality rates for allogeneic SCT for other indications.[101] The



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goal of SCT for SS is to balance the benefit of the GVL effect against the detriment of graft-versus-host disease

(GVHD). Most SCT patients will develop GVHD and the extent can be limited or generalized; treatment is

immunosuppression. Various ECP regimens have also been found to be quite effective for GVHD and provide steroid-

sparing effects. Some patients feel they trade one chronic disease for another. Lymphoma relapse after allogeneic

SCT can be treated with a donor lymphocyte infusion to augment GVL effect.

Skin-directed Therapy

Skin-directed therapy ( & should always be a part of the treatment regimen and can be remissive or palliative. Both

psoralen with UVA (PUVA) phototherapy and total skin electron beam (TSEB) have the capacity to clear the skin with

the latter being substantially more potent. A recent case series established that TSEB administered to SS patients on

a stable regimen of ECP, interferon and bexarotene could clear not only the skin but the blood as well.[102] Skin-

directed therapy (including topical emollients, corticosteroids, retinoids, compounded nitrogen mustard or carmustine)

is also important for the considerable pruritus that can accompany SS and can lead to scratching and portals of entry

for bacteria. Erythrodermic patients have been shown to harbor Staphylococcus aureus and treatment of colonization

correlates with clinical improvement.[103] In addition to their abnormal skin barrier and colonization, the lymphoma-

induced immune imbalance and diminished cytotoxic response contribute to an increased risk of cutaneous and

systemic infections, which are a source of morbidity and mortality.[24]

Cutaneous infections with bacteria or herpessimplex virus are common and can become disseminated. In a series by Axelrod et al., the majority of SS patients

died of infections; pneumonia and bacteremia were the cause of death in 88% of these patients.[24] Notably, the

presence of extracutaneous disease (e.g., SS and visceral involvement) was the most important risk factor for

cutaneous and systemic infections. Pruritus also has an effect on quality of life. Multiple studies have demonstrated

negative effects on scores of emotional health (e.g., frustration, fear), physical functioning (e.g., ability to perform at

work or hobbies) and social wellbeing (e.g., visibility of rash, depression) due to skin symptoms (e.g., pruritus,

pain).[104–106]

Table 4. Skin-directed therapies.

Agent Effect

Topical

Corticosteroids


& LC in skin

Nitrogen-mustard (mechlorethamine) or carmustine Cytotoxic

Retinoid/rexanoid Malignant lymphocyte apoptosis (see Table 3)

Light therapy

Narrow-band UVB


& LC in skin

Psoralens with UVA (PUVA)


& LC in skin

Radiation therapy

Total skin electron beam Malignant lymphocyte apoptosis

Localized electron beam Malignant lymphocyte apoptosis



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Table 5. Palliative therapies.

Agent Effect

Topical


Pramoxine, menthol Anesthetic, antipruritic

Bleach bath Antibacterial

Antibiotics (e.g., mupirocin, bacitracin) Antibacterial

Systemic

Antihistamines (e.g., diphenhydramine, hydroxyzine, doxepin) Antipruritic, sedative

Gabapentin Antipruritic

Mirtazipine Antipruritic

Antibiotics (e.g., doxycycline, cephalexin) Antibacterial


In summary, the treatment of SS is not standardized, but multiple guidelines have been published.[26–28] The most

common course of disease for SS is one of multiple remissions and relapses. No treatment modality has been shown

to markedly alter the course of the disease, which has a median survival of approximately 14.5–36 months.[13] The

principles of treatment are to limit toxicity, maintain immune function, reduce tumor burden, correct immune imbalance

and improve quality of life. Treatment toxicity in the form of immunosuppression and cytopenias are especially

problematic for this population due to limited T-cell repertoire and reduced cytotoxic immune response.[17]

Multimodality therapy with both skin-directed and one or more systemic agents should be utilized to reduce the burden

of disease, control pruritus, limit infection and minimize treatment side effects.

Expert Commentary

Sézary syndrome is a rare and intriguing lymphoma of skin-homing T cells. Unlike other non-Hodgkin lymphomas,

first-line treatment for SS is not polychemotherapy or SCT. However, this should not be misconstrued to mean that SS

is any less serious a malignancy; the median survival ranges from only 14.5–36 months. ECP, a first-line therapy, was

developed as a means to treat the leukemic spread of the malignant cells with the same therapeutic principles of

PUVA phototherapy for the mycosis fungoides subtype of CTCL. This ingenious therapy has been used as a first-line

therapy since its development over 20 years ago yet the mechanisms of its effects are not completely understood. It

was initially thought to debulk the circulating malignant cells; however, it is now known that fewer than 5% of the

circulating malignant T cells are affected. The more likely explanation for SS improvement by ECP is via stimulation of

immune system destruction of the malignant lymphocytes. SS is a malignancy of immune cells that can be managed

by exploiting other aspects of the immune system. This article touches on several of the therapeutic options that

harness the antineoplastic immune response (immunotherapies) and avoid the toxicity of chemotherapy. The OR and

CR of individual immunotherapies are modest in some cases; however, to put this in perspective, the patients

receiving these drugs in clinical trials have often failed two or more other therapies. Also, the likelihood of achieving an

overall or complete response can be substantially improved by combining two or more immunotherapies. Treatment

decisions should include the likelihood to induce a response or remission, side effects, possibility for combination

therapy, patient comorbidities and cost/availability of the modality. Our favored first-line therapy for SS is ECP,

bexarotene and IFN-$; with the substitution of IFN-' if there is not sufficient improvement. This regimen is effective

and well-tolerated in many patients. Additional therapies that may be added to this combination regimen include skin-directed therapies such as PUVA, TSEB and other systemic immunomodulatory agents such as GM-CSF. This



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combination immunomodulatory approach is also often used as maintenance therapy to sustain responses. Clinical

trials can be considered for patients with refractory disease as there are many promising therapeutics that are being

developed (see 'Five-year view').

Five-year View

Research continues to illuminate the intricacies of the immune system and its associated disease states, particulary in

SS. The early success of immunotherapies, such ECP, retinoids and cytokines, has triggered further research of additional therapies and combination therapies. Romidepsin (depsipeptide) and panobinostat are HDAC inhibitors

currently in clinical trials, while vorinostat is currently FDA approved. Resiquimod and CpG oligodeoxynucleotides are

systemic Toll-like receptor agonists in development, while imiquimod, a topical Toll-like receptor agonist, is already

available for use. Additional immunotoxins are also being developed, similar to denileukin diftitox. LMB-2 is a fusion

protein combining Pseudomonas exotoxin and a monoclonal antibody against CD-25. Additional areas of research

include chemokine (e.g., CCR4) antagonists, transition-state inhibitors such as forodesine, serine-tyrosine kinase

inhibitors such as enzastaurin, monoclonal antibodies directed against CD4+ T-cells (zanolimumab) and new

conditioning regimens for SCT.

Sidebar Key Issues

Sézary syndrome (SS) is classically defined as the triad of desquamative erythroderma involving at least 80%

of the skin surface, lymphadenopathy and leukemic involvement.

Patients with SS have advanced disease with a 5-year survival of approximately 20–27% and estimated

median survival of 14–36 months.

The malignant cell in SS is typically a skin-homing Th2 (CD4+/CLA+/CCR4+/CD26") lymphocyte, which results

in immune imbalances, such as:

Elevated amounts of IL-4, -5 and -10;

Eosinophilia and elevated IgE;

Impaired Th1 (cell-mediated) immunity and dendritic cell function and number;

Loss of the normal T-cell repertoire.

Treatment principles include:

Combine immunotherapies to improve efficacy and limit toxicity from individual agents;

Avoid iatrogenic immunosuppression;

Combine skin-directed and systemic treatments to improve response rate and quality of life.

Durable remissions are uncommon, but can occur in up to 25–30% of patients with the multimodality approach

Consider maintenance therapy with an immunotherapy, such as interferon or bexarotene;

Previously successful therapies can be used repeatedly.

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Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest

in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment,consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

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