Sézary syndrome: clinical guidelines

List of Abbreviations

PUVA – psoralen + ultraviolet A radiation

RP – radiopharmaceutical

TBI – total skin electron beam irradiation

TCR – T-cell receptor

E-CTCL – erythrodermic cutaneous T-cell lymphoma

Terms and Definitions

Sézary syndrome is a cutaneous T-cell lymphoma characterized by erythroderma, generalized lymphadenopathy, and the presence of circulating malignant T-lymphocytes (Sézary cells) in the blood.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Sézary syndrome (SS) is a cutaneous T-cell lymphoma characterized by erythroderma, generalized lymphadenopathy, and the presence of circulating malignant T-lymphocytes (Sézary cells) in the blood.

1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)

The causes of Sézary syndrome are unknown. Immunophenotyping has shown that the proliferating malignant lymphocytes infiltrating the skin in Sézary syndrome are mature central memory T-lymphocytes expressing CD3, CD4, CD45RO, and CCR4 (markers of mature memory T-lymphocytes), as well as CCR7, L-selectin, and CD27 (markers of central memory T-lymphocytes) [1, 2]. The activation of T-lymphocyte proliferation leading to the development and progression of this disease is associated with mutations and/or chromosomal alterations in genes controlling tumor suppressor activity, epigenetic regulators, T-lymphocyte signaling pathways, as well as T-lymphocyte differentiation, survival, and skin homing [3–5].

The malignant T-lymphocyte population produces interleukin (IL)-4 and IL-10, corresponding to the T-helper type 2 (Th2) profile, and expresses the CD25 marker and Fox-P3 (forkhead box protein 3) protein, corresponding to the regulatory T-lymphocyte (suppressor T cell) profile [6–8]. As a result of the shift in immune responses toward the Th2 and regulatory T-cell profiles, the function of natural killer cells and CD8-expressing T-lymphocytes is suppressed, and dendritic cell function and differentiation are impaired, leading to suppression of the normal immune response, including responses to viral infections and neoplasms [8].

1.3 Epidemiology of the Disease or Condition

Sézary syndrome accounts for less than 5% of all primary cutaneous lymphomas. It predominantly affects elderly individuals, with a male predominance; the median age of onset is 60–65 years [7, 9]

1.4 Features of Coding the Disease or Condition

C84.1 – Sézary syndrome.

1.5 Classification of the disease or condition

Staging of Sézary syndrome is performed according to the revised TNM classification proposed by the International Society for Cutaneous Lymphomas and the European Organisation for Research and Treatment of Cancer (ISCL-EORTC staging system). Since patients with Sézary syndrome typically present with erythroderma (T₄) and B₂ blood involvement, they are classified as having stage IVA or IVB disease [9].

1.6 Clinical presentation of the disease or condition

Sézary syndrome begins with the development of erythroderma, which is accompanied by severe pruritus and/or scaling. The severity of erythroderma can vary from pinkish-red to bright red skin discoloration. Subsequently, palmoplantar keratoderma, alopecia, and onychodystrophy develop. Palpation reveals peripheral lymphadenopathy, which may result from dermatopathic lymphadenopathy or tumor involvement [7, 10]. Laboratory tests reveal a high count of Sézary cells in the peripheral blood.

2. Diagnostics, medical indications and contraindications for diagnostic methods

The International Society for Cutaneous Lymphomas (ISCL) and the European Organisation for Research and Treatment of Cancer (EORTC) have established the following diagnostic criteria for Sézary syndrome (Appendix G1) [9]:

- Absence of prior mycosis fungoides

- Generalized erythroderma (diffuse erythema affecting at least 80% of the body surface with or without scaling)

- Presence of a dominant T-cell clone in the blood (detected by PCR or Southern blot)

- Presence of one or more of the following features:

• absolute Sézary cell count in the blood ≥ 1000 cells/mm³

• elevated CD3+ or CD4+ cell count in the peripheral blood with a CD4/CD8 ratio ≥ 10 (determined by flow cytometry)

• elevated CD4+ cell count in the peripheral blood with an aberrant immunophenotype, including loss of CD7 expression (≥ 40% CD4+CD7- cells) or CD26 expression (≥ 30% CD4+CD26- cells).

2.1 Complaints and Anamnesis

Complaints and anamnesis are described in the "Clinical Presentation" section.

2.2 Physical Examination

Physical examination findings are described in the "Clinical Presentation" section.

2.3 Laboratory Diagnostics

Comments: Peripheral blood is used for immunophenotyping to determine the lymphocyte subpopulation profile (major and/or minor). The test is performed to detect circulating T-cell markers: CD3, CD4, CD7, and CD26. T-cells with aberrant expression of CD3, CD4, CD7, and CD26 markers are Sézary cells. Diagnostic significance is attributed to an absolute Sézary cell count in the blood ≥ 1000 cells/mm3 or an atypical lymphocyte count >5%. In this case, the total leukocyte count, total lymphocyte count, and the count of atypical lymphocytes per 100 lymphocytes are calculated. Diagnostic significance is also attributed to an elevated peripheral blood CD3+ or CD4+ cell count with a CD4/CD8 ratio ≥ 10, as well as an elevated peripheral blood CD4+ cell count with an aberrant immunophenotype, including loss of CD7 expression (≥ 40% CD4+CD7- cells) or CD26 expression (≥ 30% CD4+CD26- cells) [18].

Comments: Determination of CD2, CD3, CD4, CD5, CD7, CD8, CD20, and CD30 markers is required. Neoplastic T-cells in Sézary syndrome typically express CD3 and CD4, but do not express CD8. Loss of CD7 expression (a pan-T-cell marker) by more than 50% of infiltrating T-lymphocytes and expression of programmed cell death protein 1 (PD-1) by infiltrating T-lymphocytes confirm the diagnosis of Sézary syndrome in the differential diagnosis of erythroderma caused by inflammatory diseases [14]. A low count (less than 10%) of CD8-positive T-lymphocytes within the cutaneous infiltrate in a skin biopsy also points to a diagnosis of Sézary syndrome [14].

Comments: The patient's blood and skin biopsy material can be used to test for T-cell clonality. The proportion of skin biopsies from patients with cutaneous T-cell lymphomas that reveal monoclonal rearrangement of the T-cell receptor (TCR) gene by polymerase chain reaction may depend on the amplification method [7]. Detection of T-cell clones by polymerase chain reaction has been reported in skin biopsy specimens from 27 of 30 patients with Sézary syndrome [21]. Sequencing of lesional skin biopsies from patients with cutaneous T-cell lymphomas is considered more specific and sensitive for detecting T-cell clones compared to polymerase chain reaction [22].

Since monoclonality can also be detected in certain inflammatory diseases, the results of T-cell receptor gene rearrangement testing must be interpreted in conjunction with other patient evaluation data. The detection of identical T-cell clones in both the skin and blood may indicate Sézary syndrome rather than inflammatory causes of erythroderma [23].

Comments: Sézary cells in blood smears are identified as cells with irregularly shaped nuclei and multiple nuclear indentations, giving them a cerebriform appearance. There are 3 morphological variants of Sézary cells: small cell (cell size 8 to 11 µm), large cell (cell size 12 to 25 µm), and binucleated (cells with two nuclei). Blood smears must be used to determine the absolute and relative (percentage) count of these cells within the total lymphocyte population [25]. Detecting a blood Sézary cell count ≥ 1000 cells/mm³ confirms the diagnosis of Sézary syndrome [18].

Comments: Drugs used for the systemic therapy of Sézary syndrome have adverse effects, the detection of which requires a complete blood count.

Methotrexate**, even at standard therapeutic doses, can cause bone marrow suppression (leukopenia, thrombocytopenia, anemia). Before initiating treatment with methotrexate**, during therapy, or when resuming therapy after a break, a complete blood count with differential and platelet count must be performed. During treatment with methotrexate**, blood tests should be performed monthly for the first 6 months and at least every 3 months thereafter; if doses are increased, the frequency of testing should be increased accordingly. In the event of a significant decrease in leukocyte or platelet counts, methotrexate** treatment must be discontinued immediately and supportive symptomatic therapy initiated.

When using interferons, laboratory changes may occur, manifesting as leukopenia, lymphopenia, thrombocytopenia, and anemia. To promptly detect deviations from normal laboratory values that may arise during therapy, a complete blood count (CBC) should be repeated every 2 weeks. If the platelet count drops below 50×10⁹/L or the absolute neutrophil count drops below 0.50×10⁹/L, interferon treatment is recommended to be discontinued.

Patients receiving vorinostat therapy should be closely monitored with complete blood counts (CBC) at least once every 2 weeks for the first 2 months of treatment, and monthly thereafter, due to the potential for leukopenia, neutropenia, thrombocytopenia, and anemia.

Chlorambucil** may cause bone marrow suppression; therefore, during treatment, a systematic complete blood count with a differential blood cell count must be performed regularly (at least 2–3 times a week). When used in therapeutic doses, the drug suppresses lymphocyte production and has a lesser effect on neutrophil and thrombocytopenic counts, as well as hemoglobin levels. There is no need to discontinue the drug at the first signs of a decrease in neutrophil count, but it should be kept in mind that the decrease in neutrophils may continue for 10 or more days after the last dose.

A complete blood count must be monitored before and during prednisolone** therapy.

During doxorubicin** treatment, hematological parameters must be evaluated before and during each treatment cycle, including white blood cell count, platelet count, hemoglobin, and blood cell differentiation.

Before each administration of gemcitabine**, a clinical blood count with a quantitative blood cell count (platelets, leukocytes, neutrophils) must be monitored. In case of bone marrow suppression, treatment should be suspended or the drug dosage adjusted.

Since anemia, thrombocytopenia, and severe neutropenia may develop during brentuximab vedotin** treatment, a clinical blood count must be performed prior to each administration of the drug. If neutropenia is detected during treatment, the dosing intervals should be increased to manage it. In the event of grade 3 or 4 neutropenia, the dose of the drug must be reduced or treatment discontinued.

Comments:Drugs used for the systemic therapy of Sézary syndrome have adverse effects, the detection of which requires a general clinical blood chemistry test. Before starting methotrexate** therapy or resuming therapy after a break, it is necessary to determine the activity of aspartate aminotransferase and alanine aminotransferase in the blood, and to test for conjugated (direct) bilirubin, unconjugated (indirect) bilirubin, and albumin in the blood. During methotrexate** treatment, the general blood chemistry test must be repeated (monthly for the first 6 months and at least every 3 months thereafter; when increasing doses, it is advisable to increase the frequency of examinations). Methotrexate** treatment should not be initiated or must be suspended in the case of any existing or developing deviations in liver function tests. Values usually normalize within 2 weeks, after which treatment can be resumed. When using interferon, laboratory abnormalities may occur, manifesting as increased activity of alanine aminotransferase, alkaline phosphatase, and creatinine concentration. To timely detect laboratory abnormalities that may occur during interferon therapy, blood chemistry tests must be repeated every 4 weeks. If signs of liver dysfunction appear, the patient must be closely monitored. If liver dysfunction progresses, administration of the drug should be discontinued. Patients receiving vorinostat therapy, due to the potential for increased plasma creatinine concentration,/ the development of hypokalemia, and elevated blood glucose levels, should undergo rigorous monitoring of blood chemistry parameters, including plasma electrolyte concentrations (specifically sodium, potassium, total calcium, and blood chlorides), blood glucose, and blood creatinine at least once every 2 weeks for the first 2 months of treatment, and monthly thereafter. Blood glucose testing is especially necessary for patients with pre-existing diabetes or a risk of developing diabetes. Before and during prednisolone** therapy, glycemia and plasma electrolytes (specifically sodium, potassium, total calcium, blood chlorides, and blood glucose) must be monitored. During doxorubicin** treatment, liver function tests must be evaluated, specifically the activity of aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase in the blood, as well as testing for conjugated (direct) bilirubin, unconjugated (indirect) bilirubin, creatinine, and albumin in the blood. When using doxorubicin**, hyperuricemia may occur due to rapid tumor cell lysis; therefore, patients are advised to undergo blood uric acid and creatinine testing, electrolyte testing (specifically potassium and calcium in the blood), and prophylactic use of allopurinol** during therapy. In patients receiving gemcitabine** therapy, liver function must be periodically evaluated, specifically the activity of aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase in the blood, along with testing for conjugated (direct) bilirubin, unconjugated (indirect) bilirubin, creatinine, and albumin in the blood. In patients undergoing treatment with brentuximab vedotin**, liver functions must be regularly monitored, specifically the activity of aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase in the blood, along with testing for conjugated (direct) bilirubin, unconjugated (indirect) bilirubin, creatinine, and albumin in the blood. Regardless of medical history, serum glucose levels must be monitored by prescribing a blood glucose test in all patients receiving brentuximab vedotin** who have documented hyperglycemia.

Comments: Drugs used for the systemic therapy of Sézary syndrome have adverse effects, the detection of which requires a general (clinical) urinalysis. Damage to the kidneys and urinary tract can be caused by both the direct toxic effect of the drugs and the activation of infection against the background of immunosuppression. During methotrexate** therapy, activation of chronic infection is possible, including involvement of the urinary system [28]. Since methotrexate** is excreted predominantly by the kidneys, patients with impaired renal function may experience an increase in blood methotrexate concentrations, which can result in severe adverse reactions. The condition of patients at risk for renal impairment (e.g., elderly patients) must be carefully monitored. Patients receiving vorinostat therapy may develop proteinuria and hyperuricemia. Glucosuria and the potential development of leukocyturia must be monitored before and during prednisolone** therapy. In patients receiving gemcitabine** therapy, renal function must be periodically evaluated due to the possibility of acute renal failure and hemolytic uremic syndrome.

Comments: Elevated blood lactate dehydrogenase activity indicates an aggressive course of Sézary syndrome.

2.4 Instrumental Diagnostics

Comments: With the progression of Sézary syndrome, involvement of the chest organs, pelvic organs in women, pelvic organs in men, abdominal cavity, and retroperitoneal space is possible

Comments: Detection of lymph node or internal organ changes caused by pathological proliferation of T-lymphocytes indicates the progression of Sézary syndrome.

2.5 Other Procedures

During the examination of patients with Sézary syndrome, staging of the disease is performed according to the ISLE-EORTC recommendations (Appendix G1) [9].

Comments: The most frequent morphological feature of Sézary syndrome is a superficial perivascular or band-like infiltrate of large lymphocytes that may show signs of atypia (large, hyperchromatic, or convoluted nuclei) [12, 13]. Epidermotropism may be present [13, 14]. However, histological signs allowing a definitive diagnosis are often absent in Sézary syndrome. Histological signs of Sézary syndrome were absent in 39% of samples obtained from 41 patients [13]. In another study, epidermotropism was absent or minimally expressed in 19 of 31 patients with Sézary syndrome [15]. 

Comments: For biopsy, lymph nodes measuring 1.5 cm or more with a dense, uneven consistency are selected (histological examination, flow cytometry, determination of TCR gene rearrangement); the biopsy is performed by specialist physicians with surgical specialization, including an oncologist/hematologist. Pathomorphological examination of lymph node biopsy (surgical) material makes it possible to determine the presence of specific lymph node involvement. If specific lymph node involvement is detected, the patient is referred for further management and treatment to a hematologist or oncologist.

Comments: Bone marrow trephine biopsy is performed by specialists proficient in the technique of bone marrow trephine biopsy collection (surgeons, hematologists, or oncologists). Pathomorphological examination of bone marrow biopsy (surgical) material makes it possible to determine the presence of specific bone marrow involvement. If specific bone marrow involvement is detected, the patient is referred for further management and treatment to a hematologist or oncologist.

3. Treatment, including drug and non-drug therapies, diet therapy, and pain management

The choice of therapy for Sézary syndrome should be based on determining the severity of the disease (taking into account the degree of skin infiltration, presence/absence of skin nodules, severity of lymphadenopathy, degree of blood involvement intensity, level of lactate dehydrogenase and leukocytes in peripheral blood), its rate of progression, and its impact on the patient's quality of life. Principles of prescribing therapy for patients with Sézary syndrome:

- Treatment approaches are determined by tumor burden and progression rate

- Suppression of the immune response should be avoided whenever possible

- If systemic treatment is necessary, immunomodulating therapy is preferred over chemotherapy

- Combined or multimodal therapy (e.g., a combination of systemic immunomodulating and topical therapy) is more effective than any monotherapy

- Timely diagnosis and treatment of infectious complications (sometimes even in the absence of clinical signs of an infectious process on the skin) leads to an improvement in the patient's condition

Treatment of pruritus, which significantly reduces quality of life, is of great importance.

3.1 Conservative Treatment

First-line and second-line therapies for patients with Sézary syndrome are distinguished. First-line therapeutic agents are used to initiate therapy in patients with Sézary syndrome. In cases where the first-line therapeutic agent is insufficiently effective, combination therapy with first-line agents is possible.

Second-line therapy is used in the absence of a response to treatment, a refractory course of the disease, or its progression despite prior first-line treatment. The choice of treatment depends on the patient's age, severity of blood involvement, general somatic status, and previous treatment methods.

Comments: In case of intolerance to high doses, interferons are prescribed at 3–6 million IU daily or 3 times a week. When using the drug, laboratory abnormalities may occur, manifesting as leukopenia, lymphopenia, thrombocytopenia, anemia, increased activity of alanine aminotransferase and alkaline phosphatase, and increased concentrations of creatinine and uric acid. If signs of impaired liver function appear, the patient must be closely monitored. If symptoms progress, administration of the drug should be discontinued. Changes in the thyroid gland are possible during long-term administration of the drug. In patients with thyroid disorders, testing the blood level of thyroid-stimulating hormone (TSH) is required before starting treatment, and monitoring its level at least once every 6 months is recommended. Diabetes mellitus is very rare. With prolonged use, usually after several months of treatment, visual disorders are possible. An ophthalmological examination is recommended before starting therapy. If there are complaints of any visual disturbances, an immediate consultation with an ophthalmologist is necessary. Patients with diseases that can cause changes in the retina, such as diabetes mellitus or arterial hypertension, must undergo an ophthalmological examination at least once every 6 months. Patients with cardiovascular diseases and/or progressive malignant diseases require careful monitoring and periodic electrocardiogram recording. If mental and/or CNS changes occur, including the development of depression, observation by a psychiatrist is recommended during treatment and for 6 months after its completion.

or

#methotrexate** orally at a dose of less than 25–75 mg per week [7, 8, 36, 38, 39]

LE 5Grade of Recommendation C (Level of Evidence – 5)

Comments: Before starting treatment with #methotrexate** or when resuming therapy after a break, it is necessary to perform a complete blood count (CBC), evaluate the activity of "liver" enzymes, concentrations of bilirubin and serum albumin, as well as targeted chest radiography and functional renal tests. In the presence of clinical indications, tests are prescribed to rule out hepatitis.

During treatment with #methotrexate** (monthly for the first 6 months and at least every 3 months thereafter; when increasing doses, it is advisable to increase the frequency of examinations), the following tests are performed:

1. Examination of the oral cavity and throat to detect mucosal changes.

2. Complete blood count (CBC) with differential. Even when used in standard therapeutic doses, #methotrexate** can abruptly cause bone marrow suppression. In the event of a significant decrease in leukocyte or platelet count, #methotrexate** therapy must be discontinued immediately and symptomatic supportive therapy initiated.

3. Liver function tests, specifically determining the activity of aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase in the blood, as well as measuring conjugated (direct) bilirubin, unconjugated (indirect) bilirubin, creatinine, and albumin levels in the blood. Particular attention should be paid to detecting signs of liver injury. #Methotrexate** therapy should not be initiated or should be suspended in the event of any abnormalities in liver function test results or liver biopsy. Values typically normalize within 2 weeks, after which treatment may be resumed at the physician's discretion.

4. Renal function tests, specifically measuring blood urea, uric acid, creatinine, sodium, potassium, total calcium, and chloride levels, along with a urinalysis. Since #methotrexate** is excreted primarily by the kidneys, patients with renal impairment may experience elevated blood concentrations of #methotrexate**, which can lead to severe adverse reactions. The condition of patients at risk for renal impairment (e.g., elderly patients) must be carefully monitored.

5. Since #methotrexate** affects the immune system, it may alter the response to vaccination and affect the results of immunological tests. Special caution is required when treating patients with inactive, chronic infections (such as herpes zoster, tuberculosis, or viral hepatitis B or C) due to the potential for their reactivation. Vaccination with live vaccines should not be performed during #methotrexate** treatment.

Due to the potential for reactivation of chronic infection, patients scheduled for or undergoing #methotrexate** therapy may require testing for hepatitis B virus surface antigen (HBsAg) and antibodies to hepatitis B virus, as well as antibodies to hepatitis C virus in the blood to identify contraindications to systemic #methotrexate** therapy.

#Interferons (at the doses specified for first-line therapy, administered subcutaneously for #peginterferon alfa-2a**, and intramuscularly or subcutaneously for #interferon alfa-2b**) in combination with photochemotherapy using oral photosensitizers [7, 8, 36, 40, 41]

LOC 4Level of Clinical Recommendation C (Level of Evidence – 4)

or

#Methotrexate** orally at a dose of not more than 100 mg per week in combination with dermatological corticosteroids [7, 8, 36, 39]

LE 5Grade of Recommendation C (Level of Evidence – 5)

or

#Interferons (at the doses specified for first-line therapy, subcutaneously for #peginterferon alfa-2a**, intramuscularly or subcutaneously for #interferon alfa-2b) in combination with oral #methotrexate** [7, 8, 36, 42]

LOC 4Level of Clinical Recommendation C (Level of Evidence – 4)

Antineoplastic agents in combination with systemic corticosteroids [7, 8, 36]:

#Chlorambucil** 2–6 mg daily orally + #prednisolone** 20 mg daily orally [7, 8, 36]

LE 5Grade of Recommendation C (Level of Evidence – 5)

Comments: During #chlorambucil** therapy, the potential development of adverse events involving the hematopoietic system, gastrointestinal tract, urinary system, and others should be taken into account. The most frequent adverse effects of #chlorambucil** therapy are leukopenia (reversible if the drug is discontinued in a timely manner), thrombocytopenia, lymphopenia, neutropenia, and decreased hemoglobin levels. Irreversible bone marrow suppression occurs extremely rarely. Toxic-allergic hepatotoxicity (hepatic necrosis or cirrhosis, cholestasis, jaundice), hyperuricemia, or uric acid nephropathy are occasionally observed.

During #prednisolone** therapy, adverse events requiring monitoring may develop, including decreased glucose tolerance, "steroid" diabetes mellitus or manifestation of latent diabetes mellitus, adrenal suppression, fluid and sodium retention (peripheral edema), hypernatremia, hypokalemic syndrome (hypokalemia, arrhythmia, myalgia or muscle spasm, unusual weakness and fatigue), and in rare cases, elevated "liver" transaminases and alkaline phosphatase. Leukocyturia is also possible.

or

antineoplastic agents:

vorinostat orally at 400 mg daily until complete control is achieved (no signs of further progression) or until the appearance of unacceptable toxicity [7, 8, 36, 43, 44]

LE 5Grade of Recommendation C (Level of Evidence – 5)

Comments: Contraindicated in children under 18 years of age. Vorinostat therapy may cause thrombocytopenia and anemia, which may require dose interruption or discontinuation of treatment. Leukopenia and neutropenia may occur, requiring dose reduction. Increased plasma creatinine concentration has been noted. Hypokalemia and increased plasma creatinine may also develop, which may necessitate a dose reduction. Hyperglycemia has been observed during vorinostat therapy, which may require dietary management and/or hypoglycemic therapy. Proteinuria may occur.

or

#doxorubicin** 20 mg/m² intravenously every 2 weeks [7, 8, 36; 44]

Level of Evidence 5Grade of Recommendation C (Level of Evidence — 5)

Comments: Adverse events that may occur during #doxorubicin** therapy should be considered and monitored—leukopenia, neutropenia, thrombocytopenia, and anemia, elevated "liver" transaminases, hyperbilirubinemia, and cardiotoxicity. To reduce the risk of severe cardiotoxicity, regular monitoring of cardiac function is recommended before and during #doxorubicin** therapy, including assessment of left ventricular ejection fraction using echocardiography or multigated radionuclide angiography, as well as ECG monitoring. A rare adverse event of #doxorubicin** therapy is acute renal failure.

or

#gemcitabine** 1200 mg/m² on days 1, 8, and 15 of a 28-day cycle (3–6 courses) [7, 8, 36; 44].

LE 5Grade of Recommendation C (Level of Evidence – 5)

or

#gemcitabine** in low doses with prolonged infusion at 250 mg/m2 over 6 hours once a week [56]

GPP CLEL 4Level of Evidence Recommendation C (Level of Evidence – 4)

Comments: Adverse events that may occur during #gemcitabine** therapy should be considered and monitored—leukopenia (myelosuppression is usually mild to moderate and manifests primarily as changes in granulocyte counts), thrombocytopenia, anemia, frequently febrile neutropenia, and very rarely thrombocytosis. Hepatotoxicity may occur, manifesting as elevated "liver" transaminases and alkaline phosphatase, increased bilirubin levels, and infrequently—the development of hepatic failure and death. Genitourinary adverse events very frequently include hematuria and mild proteinuria, and frequently acute renal failure and hemolytic uremic syndrome.

brentuximab vedotin** at a dose of 1.8 mg/kg intravenously every 21 days. Treatment is administered for 8 cycles; if a partial response is achieved, an additional 8 cycles are permitted [31]

LOC 4Level of Clinical Recommendation C (Level of Evidence – 4)

Comments: Upon achieving gradual clinical resolution, continuation of therapy at a reduced dose of 1.2 mg/kg of body weight is possible. If side effects occur (most commonly peripheral polyneuropathy), a dose reduction to 1.2 mg/kg and an increase in the interval between cycles is acceptable. Treatment with brentuximab vedotin** may cause anemia, thrombocytopenia, and severe prolonged (≥1 week) neutropenia, which may increase the risk of severe infections. Cases of increased alanine aminotransferase and aspartate aminotransferase levels have been reported. Hyperglycemia has been reported in clinical trials in patients with an increased body mass index, both with and without a history of diabetes mellitus.

3.2 Surgical Treatment

Comments: Allogeneic hematopoietic stem cell transplantation is not performed in elderly patients.

3.3 Other Treatment

Comments: In case of intense pruritus, parenteral administration of systemic antihistamines is preferred, in accordance with the instructions

paracetamol** orally for children aged 12 years and older and adults 500–1000 mg 2–4 times a day [52]

Leveled Clinical Recommendation 5Grade of Recommendation C (Level of Evidence – 5)

or

celecoxib orally at an initial dose of 400 mg, followed, if necessary, by an additional dose of 200 mg on the first day. On subsequent days, 200 mg twice a day [52].

Leveled Clinical Recommendation 5Grade of Recommendation C (Level of Evidence – 5)

Comments: In patients with Sézary syndrome who develop acute or chronic pain syndrome, it is necessary to diagnose the cause of the pain syndrome and perform subsequent pathogenetic or symptomatic therapy of the pain syndrome in accordance with existing specialized guidelines [53, 54].

4. Medical Rehabilitation and Sanatorium-Resort Treatment

• There are no rehabilitation methods for Sézary syndrome. Nevertheless, comprehensive rehabilitation as well as supportive therapy, if necessary, is recommended for all patients with Sézary syndrome at all stages of disease treatment, as well as after the completion of medical treatment [55].

LoE 5Grade of Recommendation C (Level of Evidence 5)

Comments: Rehabilitation of patients with Sézary syndrome should cover not only medical, but also social and psychological aspects of the patient's adaptation to normal life. Such rehabilitation requires, in addition to medical care, the mandatory participation of social workers and medical psychologists. Rehabilitation programs are developed individually, depending on the identified complications of medical treatment, comorbid conditions, and social and psychological problems.

Rehabilitation for complications arising during the course of the disease and treatment is carried out within the framework of the respective nosologies.

Patients are advised to lead a healthy lifestyle, avoid excessive sun exposure and thermal physiotherapy.

5. Prevention and Dispensary Observation

There are currently no methods for the prevention of Sézary syndrome, as the etiological factor(s) leading to the development of the disease are unknown. Dispensary monitoring by a hematologist or oncologist is carried out during treatment and after achieving lymphoma remission. Pain management is carried out in accordance with palliative care standards.

Comment: The management of relapses is based on determining the stage of the disease, taking into account the development of resistance to previous therapies.

6. Organization of Medical Care

As part of the provision of primary health care, general practitioners, family physicians, upon detecting skin rashes, pruritus, or symptoms or signs of Sézary syndrome in patients, refer the patient to a dermatovenereology medical organization or an oncologist/hematologist's office for primary specialized health care, and also provide medical care in accordance with the recommendations of the dermatovenereology medical organization and/or oncologist/hematologist.

If it is impossible to provide medical care within the framework of primary specialized health care and if there are medical indications, the patient is referred to a medical organization providing specialized medical care.

Specialized, including high-tech, medical care is provided by a dermatovenereologist and/or hematologist and/or oncologist in inpatient settings.

Indications for scheduled hospitalization in a medical organization:

1) Indications for providing medical care in a day hospital setting:

- insufficient efficacy of treatment administered on an outpatient basis

- patient examination, including biopsy and other invasive interventions, in cases where it cannot be performed on an outpatient basis.

2) Indications for inpatient medical care:

- lack of response to ongoing outpatient treatment;

- need for systemic therapy;

- patient examination, including biopsy and other invasive interventions, in cases where it cannot be performed on an outpatient basis.

3) Indications for emergency hospitalization in a hospital of a medical organization providing specialized, including high-tech, medical care in the fields of hematology and oncology:

- Development of a severe infection (hospitalization in a hematology unit is not mandatory).

- Development of life-threatening cytopenias (profound anemia, hemorrhagic syndrome, neutropenia).

- Development of life-threatening complications of Sézary syndrome.

- Development of therapy complications, including tumor lysis syndrome, severe infusion reactions, myelotoxic agranulocytosis with fever, and other life-threatening complications.

Indications for discharging a patient from a medical organization:

- partial or complete regression of rashes.

- completion of a course of treatment or one of the stages of specialized, including high-tech, medical care in a round-the-clock or day hospital, provided there are no treatment complications requiring drug correction and/or medical interventions in inpatient settings.

7. Additional Information

Factors influencing the prognosis of the disease include:

• patient age

• elevated blood LDH

• lymph node involvement

• degree of severity of blood involvement

Criteria for Evaluating the Quality of Medical Care

Quality of care criteria for Sézary syndrome (outpatient stage)

Quality of medical care evaluation criteria for Sézary syndrome (inpatient stage)

References

Appendix A1. Working Group Composition

1. Kubanov, Alexey Alekseevich – Academician of the Russian Academy of Sciences, Doctor of Medical Sciences, Professor, President of the Russian Society of Dermatovenereologists and Cosmetologists.

2. Poddubnaya Irina Vladimirovna – Academician of the Russian Academy of Sciences, Honored Worker of Education of the RF, Doctor of Medical Sciences, Professor, Chairman of the Russian Society of Oncohematologists.

3. Belousova Irena Eduardovna – Doctor of Medical Sciences, Member of the Russian Society of Dermatovenereologists and Cosmetologists.

4. Samtsov Alexey Viktorovich – Doctor of Medical Sciences, Professor, Honored Scientist of the RF, Honored Doctor of the RF, Member of the Russian Society of Dermatovenereologists and Cosmetologists.

5. Znamenskaya Lyudmila Fedorovna – Doctor of Medical Sciences, Member of the Russian Society of Dermatovenereologists and Cosmetologists.

6. Chikin Vadim Viktorovich – Doctor of Medical Sciences, Member of the Russian Society of Dermatovenereologists and Cosmetologists.

7. Karamova Arfenya Eduardovna – Candidate of Medical Sciences, Member of the Russian Society of Dermatovenereologists and Cosmetologists.

8. Kuzmin Alexey Alexandrovich, Chief Physician of the Kirov Center for Oncology and Medical Radiology, Kirov.

9. Gorenkova Liliya Gamilevna – Candidate of Medical Sciences, Member of the Association for the Promotion of the Development of Hematology and Bone Marrow Transplantation "National Hematological Society".

10. Kravchenko Sergey Kirillovich – Candidate of Medical Sciences, Member of the Association for the Promotion of the Development of Hematology and Bone Marrow Transplantation "National Hematological Society".

11. Stefanov Dmitry Nikolaevich – Researcher, Head of the Scientific and Organizational Department, Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology of the Russian Ministry of Health, Member of the Russian Society of Oncohematologists.

12. Chernova Natalya Gennadievna – Doctor of Medical Sciences, Head of the Department of Hematology and Chemotherapy, Moscow Multidisciplinary Clinical Center "Kommunarka", Member of the National Hematological Society.

13. Vorontsova Anastasia Alexandrovna - Researcher, Member of the Russian Society of Dermatovenereologists and Cosmetologists.

Conflict of interest: The authors declare no conflict of interest.

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience for these clinical guidelines:

1. Medical specialists: dermatovenereologists, hematologists, oncologists.

2. Faculty members of medical educational institutions in the specialties "Dermatovenereology", "Hematology", "Oncology"

Table 1. Scale for assessing levels of reliable evidence (LRE) for diagnostic methods (diagnostic interventions)

Table 2. Scale for assessing the levels of evidence (LE) for prevention, treatment, and rehabilitation methods (preventive, therapeutic, and rehabilitative interventions)

Table 3. Scale for grading levels of recommendation certainty (LRC) for prevention, diagnostic, treatment, and rehabilitation methods (preventive, diagnostic, therapeutic, and rehabilitative interventions)

Procedure for updating clinical guidelines.

The mechanism for updating clinical guidelines provides for their systematic revision — at least once every three years, as well as upon the emergence of new evidence-based medicine data regarding the diagnosis, treatment, prevention, and rehabilitation of specific diseases, or in the presence of justified additions/comments to previously approved clinical guidelines, but no more frequently than once every 6 months.

Appendix A3. Reference Materials

These clinical guidelines were developed taking into account the following regulatory legal documents:

1. Procedure for the provision of medical care in the profile "dermatovenereology", approved by Order of the Ministry of Health of the Russian Federation No. 924n dated November 15, 2012.

2. Procedure for the provision of medical care in the profile "hematology", approved by Order of the Ministry of Health of the Russian Federation No. 930n dated November 15, 2012.

3. Order of the Ministry of Health of the Russian Federation and the Ministry of Labor and Social Protection of the Russian Federation dated May 31, 2019 No. 345n/372n "On approval of the Regulations on the organization of palliative medical care, including the procedure for interaction between medical organizations, social service organizations and public associations, other non-profit organizations operating in the field of health protection".

4. Staging of mycosis fungoides / Sézary syndrome according to ISLE-EORTC recommendations (Table 4).

Table 4. Staging of mycosis fungoides / Sézary syndrome according to ISLE-EORTC recommendations

Appendix B. Physician Action Algorithms

Appendix C. Patient Information

Strict adherence to the treatment regimen prescribed by the physician increases its efficacy.

Appendix G. Assessment Scales, Questionnaires, and Other Evaluation Tools

Scoring scales, questionnaires, and other patient-status assessment tools are not used in Sézary syndrome.