Nodal T-Cell Lymphomas: Clinical Guidelines

List of Abbreviations

ALK – anaplastic lymphoma kinase

PTCL-NOS – peripheral T-cell lymphoma, not otherwise specified

AITL – angioimmunoblastic T-cell lymphoma

ALCL – anaplastic large cell lymphoma

WHO – World Health Organization

IPT – immunophenotyping

PET/CT – positron emission tomography combined with computed tomography

PTCL – peripheral T-cell lymphomas

18F-FDG – Fludeoxyglucose [18F]

ESR – erythrocyte sedimentation rate

CT – chemotherapy

** – vital and essential drugs

# – drug used off-label (not in accordance with the indications, contraindications, routes of administration, or dosages specified in the drug's package insert)

Terms and Definitions

ECOG – Eastern Cooperative Oncology Group performance status scale – see Appendix G1.

B symptoms – nonspecific symptoms of tumor intoxication, including fever above 38°C for at least three consecutive days without signs of inflammation; profuse night sweats; weight loss of 10% of body weight over the last 6 months.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Nodal peripheral T-cell lymphomas (PTCL) represent a rather rare group of lymphoproliferative disorders whose substrate is a mature (post-thymic) activated T lymphocyte. Despite various pathomorphological and biological features, nodal T-cell lymphomas, with rare exceptions, are aggressive diseases with an extremely unfavorable prognosis [1].

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

The etiology of peripheral nodal T-cell lymphomas remains insufficiently studied [2], however, certain nosological forms are directly associated with the detection in blood and/or expression on tumor cells of the Epstein-Barr virus [3] or human T-cell lymphotropic virus type 1 [4]. It has also been shown that the risk of lymphoma increases in immunodeficiency states [5].

The pathogenesis of T-cell lymphomas is individual depending on the nosological entity, the presence or absence of certain chromosomal abnormalities, the tumor microenvironment reaction, and includes the suppression of immune response and inhibition of apoptosis via various signaling pathways [1].

1.3 Epidemiology of the Disease or Condition

Peripheral T-cell lymphomas are diagnosed in approximately 10% of all non-Hodgkin lymphomas cases [6, 7]. Within this group of lymphomas, the most common subtypes are peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS, 26%), angioimmunoblastic T-cell lymphoma (AITL, 19%), anaplastic large cell lymphoma (ALCL): anaplastic lymphoma kinase-positive (ALK-positive) (7%) and ALK-negative (6%). In childhood, ALK+ ALCL (approximately 13% of all non-Hodgkin lymphomas in patients under 18 years of age) and PTCL-NOS (1–2%) are predominantly observed.

1.4 Features of Coding the Disease or Condition

• C84.5 Other mature T/NK-cell lymphomas

  If T-cell origin or involvement is mentioned in connection with a specific lymphoma, the more specific description should be coded.

• C84.6 Anaplastic large cell lymphoma, ALK-positive

• C84.7 Anaplastic large cell lymphoma, ALK-negative

• C84.9 Mature T/NK-cell lymphoma, unspecified

• C86.0 Extranodal NK/T-cell lymphoma, nasal type

• C86.1 Hepatosplenic T-cell lymphoma

• C86.5 Angioimmunoblastic T-cell lymphoma

1.5 Classification of the disease or condition

In the revised 2022 WHO classification of tumors of hematopoietic and lymphoid tissues, nodal PTCLs are subdivided into the following nosological variants [8]:

• Nodal follicular helper T-cell lymphoma:

  - angioimmunoblastic type;

  - follicular type;

  - not otherwise specified

• Anaplastic large cell lymphoma, ALK-positive

• Anaplastic large cell lymphoma, ALK-negative

• Breast implant-associated anaplastic large cell lymphoma

The morphological and immunohistochemical description of various PTCL variants is provided in Section 7.2 of these guidelines.

In addition to identifying the PTCL variant, every patient with nodal PTCL must be staged according to the Ann Arbor classification [9] (see Section 7.3 of these guidelines), and assigned a risk group using one of the prognostic models for PTCL [10] (see Section 7.4 of these guidelines).

1.6 Clinical presentation of the disease or condition

PTCL is a heterogeneous group of lymphomas; therefore, in addition to the general clinical presentation (fatigue, night sweats, fever, weight loss), certain clinical features are specific to particular nosological entities [7].

In PTCL-NOS, the disease most commonly presents with lymphadenopathy of any localization, with secondary involvement of the bone marrow, spleen, and extranodal tissues (skin, gastrointestinal tract, less commonly lungs and central nervous system); the disease often runs its course with B-symptoms.

Angioimmunoblastic T-cell lymphoma is an aggressive disease with a rapid onset, prominent general symptoms, hepatosplenomegaly, generalized lymphadenopathy, bone marrow involvement, polyclonal hypergammaglobulinemia, and frequently involvement of serous membranes manifesting as pleural effusion, ascites, and arthritis. The clinical presentation and instrumental findings in other nodal T-cell lymphomas with Tfh phenotype are indistinguishable; however, the disease primarily arises in the lymph nodes, with less frequent involvement of the skin and bone marrow [11].

In ALK-positive ALCL, both lymph nodes and extranodal sites such as skin, bones, soft tissues, lungs, and liver are involved. Bowel and CNS involvement are rare. About 30% of patients have bone marrow involvement, sometimes detected only by IHC examination of trephine biopsy specimens or molecular genetic testing (presence of the NPM-ALK transcript). In the majority of patients (about 70%), the disease presents at stage III–IV with peripheral/abdominal lymphadenopathy, frequently with involvement of extranodal sites and bone marrow. Most patients have general symptoms, most commonly fever.

In ALK-negative ALCL, both lymph nodes and extranodal sites may be involved, although extralymphatic tissue involvement is less frequent than in ALK-positive ALCL. In the majority of patients, the disease presents at stage III–IV with peripheral/abdominal lymphadenopathy, and most patients have general symptoms [12].

In breast implant-associated ALCL, tumor cells may be localized in the postoperative seroma or infiltrate the fibrous pericapsular tissue, with potential involvement of locoregional lymph nodes, which determines the clinical presentation of the disease. About a third of patients have enlarged axillary lymph nodes; in rare cases, the disease is disseminated at the time of diagnosis [13].

2. Diagnostics, medical indications and contraindications for diagnostic methods

Many recommended diagnostic methods for the disease and related conditions have a limited evidence base (according to the trustworthiness of evidence and recommendation grading scales) due to the lack of dedicated clinical studies. Despite this, they are necessary components of patient evaluation to establish a diagnosis and select treatment tactics, as more effective and evidence-based methods have not yet been developed.

Criteria for establishing the diagnosis/condition: the diagnosis of PTCL is established based on pathomorphological examination of biopsy material using immunohistochemical methods and formulated in accordance with the 2017 WHO classification of tumors of hematopoietic and lymphoid tissues [1, 8].

2.1 Complaints and Anamnesis

• All patients with suspected T-cell lymphoma, as well as all patients with verified PTCL, at every medical visit are recommended to undergo a history-taking to assess the patient's condition and determine factors that may influence the choice of treatment strategy [1, 2]. All patients under 18 years of age with PTCL are recommended an initial appointment (examination, consultation) with an allergist-immunologist and, if necessary, an assessment of their immune status [55].

RG CLE 5Recommendation Grade C (Level of Evidence 5).

Comments: in nodal T-cell lymphomas, patients quite frequently present with complaints of general malaise, lymph node enlargement, night sweats, weight loss, and skin pruritus. The history of present illness is typically short-term (no more than 6 months).

Nodal T-cell lymphomas are extremely rare in younger patients; therefore, an initial appointment (examination, consultation) with an allergist-immunologist is necessary for diagnosing a potentially primary immunodeficiency state.

2.2 Physical Examination

• All patients with suspected PTCL, or with confirmed PTCL, during an initial or repeat visit, follow-up evaluations, and suspected disease relapse/progression are recommended to undergo a general physical examination, physical palpation, and physical auscultation to clarify the extent of the disease and assess the patient's organ-system status [1, 2, 14]

RG CLE 5Recommendation Grade C (Level of Evidence 5).

Comment: during the examination, it is necessary to evaluate the patient's general condition using the ECOG scale (see Appendix G1), as well as inspect the skin, tonsils, and oral cavity; palpation must include all accessible peripheral lymph node groups, the liver, and the spleen.

2.3 Laboratory Diagnostics

• All patients with suspected or confirmed PTCL at the initial or repeat visit, after the completion of each treatment cycle and before the start of each new cycle, when assessing remission after therapy completion, during follow-up evaluations, and when disease relapse is suspected are recommended to undergo the following diagnostic tests to clarify the patient's condition, plan therapeutic tactics, determine the need for their modification, and identify the need for supportive and concomitant therapy [1]:

  • complete blood count (CBC) with differential, including determination of total hemoglobin, erythrocytes, platelets, and leukocyte levels in the blood, differential leukocyte count (leukocyte formula), reticulocyte count, and erythrocyte sedimentation rate;

  • general (clinical) urinalysis;

  • general clinical blood chemistry panel including activities of lactate dehydrogenase (LDH), alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase in the blood, levels of urea, creatinine, albumin, total protein, total bilirubin, potassium, sodium, total calcium, chlorides in the blood, and beta-2-microglobulin in the blood (other biochemical parameters may be included at the physician's discretion);

  • Coagulogram (exploratory hemostasis screening) including the following parameters: prothrombin time, International Normalized Ratio (INR) determination, Activated Partial Thromboplastin Time (APTT), blood fibrinogen level testing, thrombin time determination, antithrombin III activity determination I, blood plasminogen level testing, and blood D-dimer concentration determination for selected patients – to assess the need for VTE prophylaxis [1, 15, 16].

RG CLE 5Recommendation Grade C (Level of Evidence 5).

Comment: the scope of the study includes differential blood cell counting using an automated analyzer; evaluation of erythrocyte, platelet, and leukocyte morphology via blood smear; and, if necessary, optical platelet counting (Fonio method).

• All patients with PTCL who present with clinical or laboratory signs of hemolysis before undergoing first-line anti-tumor therapy are recommended a direct antiglobulin test (direct Coombs test) to clarify the cause of hemolysis [1].

RG CLE 5Recommendation Grade C (Level of Evidence 5).

• All previously untreated patients with PTCL prior to first-line anti-tumor therapy, to enable blood transfusion if indicated before, during, or after therapy, are recommended [1]:

  • determination of major ABO blood groups, determination of the D antigen of the Rhesus system (Rh factor);

  • determination of subgroups and other minor blood groups A-1, A-2, D, Cc, E, Kell, Duffy.

RG CLE 5Recommendation Grade C (Level of Evidence 5).

• All previously untreated patients with PTCL prior to first-line anti-tumor therapy are recommended to undergo the following tests to rule out concomitant infectious diseases and plan necessary supportive therapy [1]:

  • molecular biological blood testing for Hepatitis B virus and Hepatitis C virus;

  • molecular biological blood testing for Human immunodeficiency virus HIV-1.

RG CLE 5Recommendation Grade C (Level of Evidence 5).

• All patients with PTCL under the age of 18 before starting antineoplastic therapy, as well as all patients with PTCL regardless of age who are receiving or have received antineoplastic therapy, after the first episode of a severe infection, are recommended to undergo immune status assessment – testing blood levels of immunoglobulins G, A, and M to clarify the risk of infectious complications and the need for appropriate prophylaxis [1, 17].

RG CLE 5Recommendation Grade C (Level of Evidence 5).

Comments: if IgG <4 g/L, the clinical situation is regarded as symptomatic hypogammaglobulinemia. In such cases, immunoglobulin replacement therapy is indicated (see section "Concomitant and Supportive Therapy")

• Patients over 18 years of age with verified extranodal NK/T-cell lymphoma before starting and after completing specific therapy are recommended to undergo molecular biological blood testing for Epstein-Barr virus to monitor the viral load in order to assess the efficacy of ongoing therapy [3].

GCR CLOE 4Grade of Recommendation C (Level of Evidence 4).

• Patients over 18 years of age with verified nodal T-cell lymphoma with Tfh phenotype, angioimmunoblastic type, before starting specific therapy, are recommended to undergo molecular biological testing to detect G17V mutations of the RHOA gene (quantitative) in the tumor biopsy specimen to verify the diagnosis [18].

GGR ALOC 2Grade of recommendation A (Level of evidence 2).

• Patients with suspected PTCL are recommended to undergo molecular genetic testing of the tumor biopsy specimen to detect clonal rearrangement of T-cell receptor gamma chain genes (in case of a negative result, additional testing of the TCR beta chain) [19].

RG CLE 5Recommendation Grade C (Level of Evidence 5).

Comments – performing differential diagnosis of nodal T-cell lymphomas from non-neoplastic diseases and other lymphoproliferative disorders can be challenging due to the absence of characteristic immunophenotypic and cytogenetic features in many forms of T-cell lymphomas. Detection of T-cell receptor gene rearrangements is an auxiliary, highly sensitive diagnostic method.

• Patients under 18 years of age with verified ALK+ ALCL before starting specific therapy are recommended to determine the expression of mNPM-ALK (quantitative) in peripheral blood or bone marrow to determine the prognosis of the disease [144].

GCR CLOE 4Grade of Recommendation C (Level of Evidence 4).

Comments – detection of the chimeric NPM-ALK gene transcript in the blood, which encodes a protein with tyrosine kinase activity that triggers malignant transformation, is one of the risk factors determining the treatment and prognosis of these patients [144]

2.4 Instrumental Diagnostics

• All patients upon establishment of a PTCL diagnosis, during evaluation of treatment response, as well as upon suspicion of disease relapse, are recommended to undergo contrast-enhanced CT of the neck, chest, abdominal cavity, and pelvic organs for disease staging and to clarify the presence, size, and extent of tumor lesions [1].

RG CLE 5Recommendation Grade C (Level of Evidence 5).

• Patients with contraindications to CT, or when CT is not feasible, upon establishing a PTCL diagnosis, when evaluating treatment response, or upon suspected disease relapse, are recommended to undergo the following diagnostic examinations for disease staging and to clarify the presence, size, and extent of tumor lesions [1]:

  • targeted chest radiography in two projections;

  • ultrasound examination of lymph nodes and internal organs.

RG CLE 5Recommendation Grade C (Level of Evidence 5).

Comments: ultrasound examination should assess peripheral lymph nodes, intra-abdominal and retroperitoneal nodes, abdominal and pelvic organs. Lymph nodes less than 1 cm in diameter are considered uninvolved, lymph nodes 1–2 cm in diameter require dynamic monitoring during therapy, and lymph nodes greater than 2 cm in diameter are considered involved.

• All patients upon establishing a PTCL diagnosis, during treatment response assessment, and upon suspected disease relapse, are recommended to undergo positron emission tomography combined with computed tomography (PET/CT) using tumor-tropic radiopharmaceuticals (RPh) or (as a secondary option when technical capabilities for PET/CT are lacking) whole-body positron emission tomography (PET) using tumor-tropic RPh, if available, for more accurate disease staging and better evaluation of the therapeutic effect [1, 20–22].

RG CLE 5Recommendation Grade C (Level of Evidence 5).

Comments: positron emission tomography combined with computed tomography (PET/CT) is a highly informative diagnostic method. PET/CT performed before treatment not only allows for staging refinement, but also more precisely determines the localization of lesions, especially extranodal involvements that may be poorly diagnosed on CT, which is essential for the subsequent evaluation of induction therapy efficacy, quality planning of subsequent radiation therapy, and minimization of exposure to healthy tissues. If PET/CT is available, it can be used in accordance with revised response criteria, primarily in patients with low tumor volume, as well as considering potential treatment adjustment.

If technical capabilities are available, PET/CT should be evaluated using the Deauville scale (see Appendix G2).

• All patients with a diagnosed PTCL for whom treatment is planned for newly diagnosed disease or relapse are recommended to undergo the following examinations for the timely detection of comorbidities of the cardiovascular, respiratory, and digestive systems and to determine the need for their prophylaxis or treatment [1]:

  • electrocardiogram recording;

  • echocardiography;

  • esophagogastroduodenoscopy;

  • ultrasound duplex scanning of lower extremity vessels (arteries and veins) [23, 26].

RG CLE 5Recommendation Grade C (Level of Evidence 5).

2.5 Other Procedures

• All patients with suspected PTCL, suspected PTCL relapse, or ambiguous interpretation of the antineoplastic response after treatment completion are recommended to undergo a biopsy (obtaining biopsy material) of a lymph node or other lesion, and pathological examination of the biopsy (surgical) material using immunohistochemical methods to verify the diagnosis [1, 2].

RG CLE 5Recommendation Grade C (Level of Evidence 5).

Comments: the choice of tissue and the volume of the biopsy must be adequate for the diagnostic task at hand.

• For diagnosis, it is strictly recommended to perform an extended tumor biopsy or an excisional lymph node biopsy.

  • Fine-needle aspiration biopsy and marginal biopsy of a lymph node/tumor mass are not recommended because they rarely yield diagnostically significant material and can therefore be used only when the tumor lesion is difficult to access for biopsy (e.g., CNS) or when there is a high risk of postoperative complications.

  • Tissue fragmentation severely impedes its evaluation.

  • Material for pathological examination must be placed in a fixative medium as quickly as possible. Drying of the material must not be allowed.

  • The ratio of the volume of the fixative medium to the volume of the fixed object must be at least 10:1.

  • Fixation time must not be less than 12 and more than 48 hours.

Inadequate (weak or excessive) fixation alters the morphological properties of the tissue and leads to artifactual IHC results.

Histological material must be accompanied by a referral form containing information about the patient, duration and nature of the disease, localization of the lesion, and description of the biopsy [24].

Diagnostic cavity surgeries—thoracoscopy/thoracotomy, laparoscopy/laparotomy with biopsy of intrathoracic, intra-abdominal lymph nodes, or liver—are performed only in the absence of enlarged peripheral lymph nodes and when verification of the diagnosis is otherwise impossible.

Histological and immunohistochemical characteristics of various PTCLs, as well as mandatory requirements for the pathological report, are presented in Section 7.1 of these guidelines. Descriptions of the morphological and immunohistochemical patterns of various PTCLs are presented in Section 7.2 of these guidelines.

• All patients with suspected or confirmed PTCL initially (for disease staging), after completion of therapy (to assess antineoplastic response), and upon suspected disease relapse are recommended [1, 2]:

  • obtaining a bone marrow cytologic specimen via puncture, cytologic examination of a bone marrow smear (myelogram), and in case of an increased number of lymphoid cells, presence of atypical lymphocytes or cells with blastic morphology in the bone marrow—immunophenotyping of the biological material (bone marrow aspirate) by flow cytometry. In patients under 18 years of age with initial bone marrow involvement, control puncture is performed after 1 course of therapy or later, but only until remission is achieved.

  • obtaining a bone marrow histological specimen (trephine biopsy), and pathological examination of bone marrow biopsy (surgical) material using immunohistochemical methods.

RG CLE 5Recommendation Grade C (Level of Evidence 5).

Comments: bone marrow examination (aspirate and trephine biopsy) is also recommended in cases of unexplained clinical cytopenia and fever (regardless of the presence of initial involvement).

In children, bone marrow puncture or iliac bone trephine biopsy must be performed under general anesthesia.

• In patients with verified PTCL presenting with absolute peripheral blood lymphocytosis during initial staging, immunophenotyping of biological material (peripheral blood) is recommended for differential diagnosis from reactive lymphocytosis [25, 147, 163].

GCR CLOE 4Grade of Recommendation C (Level of Evidence 4).

Comments: immunophenotypic analysis (flow cytometry) is mandatory in the presence of lymphocytosis in the complete blood count (regardless of the leukocyte count) or in the myelogram, as well as in the predominance of lymphoid cells, atypical lymphocytes, or cells with blastic morphology in pleural, ascitic, or other biological fluids. Flow cytometry enables rapid differential diagnosis between neoplastic and reactive lymphocytosis, which is essential for determining further diagnostic management for the patient.

• In patients with verified PTCL during initial staging and treatment planning, an initial evaluation (examination, consultation) by a cardiologist, endocrinologist, neurologist, infectious disease specialist, and other medical specialists is recommended depending on comorbidities to determine the need for treatment of concurrent conditions [1].

RG CLE 5Recommendation Grade C (Level of Evidence 5).

• In patients with verified PTCL during initial staging and treatment planning, it is recommended to assess the risk of venous thromboembolic events (using the Khorana VTE risk assessment score — see Appendix G3 of these guidelines) to identify patients requiring prescription and determination of methods for thrombotic complications prophylaxis during cytostatic therapy [15, 16, 26–28].

RG CLE 5Recommendation Grade C (Level of Evidence 5).

• In all women of childbearing potential with newly diagnosed PTCL, as well as relapsed PTCL, prior to initiating therapy, it is recommended to perform a set of pregnancy tests to adjust the therapeutic strategy, along with an initial obstetrician-gynecologist consultation in the case of pregnancy and the patient's desire to preserve it [1].

RG CLE 5Recommendation Grade C (Level of Evidence 5).

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

When choosing tactics and administering therapy, it should be taken into account that the patient may present with atypical disease manifestations or a combination of a specific disease with other pathologies, which may dictate changes by the attending physician in the algorithm for selecting optimal diagnostic and treatment tactics.

Given the presence of unmet medical needs (a high number of relapses, insufficient efficacy, and high toxicity of existing treatment regimens), as well as intensive research into novel diagnostic and treatment modalities, patient participation in research projects is recommended.

Each treatment cycle is initiated if the patient's condition meets the following criteria:

• granulocytes >1x10⁹/L,

• platelets >100x10⁹/L.

For patients with cytopenia caused by bone marrow involvement, specific therapy is feasible even at lower leukocyte and platelet counts; however, appropriate supportive care must be provided in such cases.

The patient discontinues treatment according to the protocol in cases of disease progression or toxic effects that preclude continuing chemotherapy at the required dose.

3.1 First-line therapy for adult patients with peripheral T-cell lymphomas

For patients with PTCL (including peripheral T-cell lymphoma, not otherwise specified [PTCL-NOS], nodal T-cell lymphomas with Tfh phenotype, systemic anaplastic large cell lymphoma ALK-positive and ALK-negative, and hepatosplenic T-cell lymphoma), one of the following regimens is recommended:

• For patients under 65 years of age and/or in the absence of severe comorbidities, it is recommended to use the BV-CHEP treatment regimen every 3 weeks for a duration of no more than 6 cycles (see Appendix A3.1) [29].

GCR CLOE 4Grade of Recommendation C (Level of Evidence 4).

• For patients over 65 years of age and/or in the presence of severe comorbidities, it is recommended to use the BV-CHP chemotherapy regimen (see Appendix A3.1) [30].

Level of Recommendations B (Level of Evidence 2)Level of Evidence 2Level of Recommendations B (Level of Evidence 2).

• For patients under 18 years of age with nodal PTCL, the therapy of choice is CHOP (4–6 courses) (see Appendix A3.1) followed by allogeneic hematopoietic stem cell transplantation (allo-HSCT), since these children typically have an underlying primary immunodeficiency. With an initial LDH level >2N, it is recommended to perform lumbar punctures during each block with administration of methotrexate** at an age-appropriate dose [146, 162, 163]. In the presence of CD30 expression on tumor cells, consideration may be given to prescribing #brentuximab vedotin** at a dose of 1.4–1.8 mg/kg IV every 21 days [160].

GPR BLEL 2Grade of Recommendation B (Level of Evidence 2).

Comment: according to the results of the ECHELON-2 prospective randomized trial, the inclusion of #brentuximab vedotin** in systemic chemotherapy achieved a clinically significant improvement in PFS and OS compared to the CHOP regimen: PFS: HR 0.70 (95% CI: 0.53, 0.91); 30% reduction in the risk of progression event, OS: HR 0.72 (95% CI: 0.53, 0.99); 28% reduction in the risk of death).

Several series of prospective randomized trials conducted by the German High-Grade Non-Hodgkin Lymphoma Study Group (DSHNHL) in patients over 18 years of age demonstrated improved treatment outcomes when etoposide** was added to CHOP courses in patients under 60 years of age, particularly with normal LDH levels. The use of this therapeutic regimen achieved a higher complete remission rate (88% vs 79% in the CHOP-treated group) and higher progression-free survival (69% and 58%, respectively).

Due to the higher incidence of febrile neutropenia with the A-CHP regimen compared to CHOP, primary G-CSF prophylaxis of febrile neutropenia is necessary when administering A-CHP therapy.

The increased probability of central nervous system relapse in patients with elevated LDH activity has led to the conclusion that regional intrathecal therapy is necessary [146].

• For patients with stage I–II PTCL over 65 years of age and/or with severe comorbidities, it is recommended to administer combination chemotherapy according to the CHOP schedule (see Appendix A3.1) [31, 161, 162].

GCR CLOE 4Grade of Recommendation C (Level of Evidence 4).

Comment: Retrospective clinical studies have shown that standard CHOP-21/14 chemotherapy regimens achieve 5-year overall survival and progression-free survival rates of 35% and 29%, respectively, while 5-year OS rates are higher in patients from the low IPI group compared to the high-risk group (66% and 22%, respectively).

Newly diagnosed PTCL patients older than 65 years are most often not included in high-dose chemotherapy protocols. Studies evaluating the role of anthracyclines and related compounds in treating this patient cohort remain contradictory, yet they do not currently permit excluding this class of drugs from first-line therapy; therefore, the CHOP regimen remains the therapy of choice. The addition of etoposide** does not improve treatment outcomes in elderly patients due to the high toxicity of the CHOEP regimen.

• For patients aged 18–60 years with PTCL who achieved CR after induction therapy, it is recommended to perform hematopoietic stimulation with mobilization and subsequent collection of hematopoietic stem cells (HSCs), followed by high-dose therapy using one of the conditioning regimens (for regimen descriptions, see Appendix A3.1.5) followed by HSC transplantation [33].

RG CLE 5Recommendation Grade C (Level of Evidence 5).

• For patients over 18 years of age with localized (I–II) stages of PTCL who achieved at least a partial remission and are not candidates for autologous HSCT, upon completion of induction therapy, it is recommended to administer involved-site radiotherapy at 30–36 Gy (in case of CR achievement after chemotherapy) or 40–50 Gy (in case of PR achievement after chemotherapy) to consolidate the achieved tumor response [34, 35].

RG CLE 5Recommendation Grade C (Level of Evidence 5).

• For patients over 18 years of age with nodal T-cell lymphomas with a TFH phenotype who achieved a tumor response following the induction chemotherapy program, regardless of whether autologous HSCT was performed, it is recommended to administer maintenance therapy for 1 year (metachronous administration of methotrexate** or using immunomodulators) [36].

RG CLE 5Recommendation Grade C (Level of Evidence 5).

Comment: In-depth study of pathogenesis led to the hypothesis that AITL and MDS may share a common precursor cell and, consequently, identical mutations, including TET2 mutations. Extrapolating these data to clinical practice, treatment protocols incorporating pyrimidine analogues (#azacitidine**) are being developed, and the rational use of maintenance therapy following completion of induction treatment is supported.

Since 2010, the team of authors at the National Research Center for Hematology first utilized and modified the ALL-2009 protocol—successfully applied in clinical practice for acute lymphoblastic leukemia—for the treatment of AITL. Unlike CHOP-like courses, this protocol is based on the principle of continuous and prolonged antitumor exposure [18]. The 5-year OS and PFS were 76% and 43%, respectively, with a maximum follow-up of 8 years. One of the new therapeutic options for AITL within this protocol was the use of maintenance therapy after completing the induction and consolidation programs. Maintenance therapy included low doses of methotrexate** or #lenalidomide**. Analysis of treatment outcomes showed a positive effect of maintenance therapy: the 5-year OS and LFS with maintenance were 75% and 49%, compared to 41% and 20% without it.

• In patients with newly diagnosed hepatosplenic T-cell lymphoma who achieve CR/PR, it is recommended to consult a specialized center performing autologous and allogeneic hematopoietic stem cell transplantation to evaluate the feasibility of allogeneic bone marrow transplantation (or auto-HSCT if allogeneic is not feasible). In children, ICE blocks and a BFM-oriented protocol for ALL treatment are used to achieve remission [37].

Comment: hepatosplenic T-cell lymphoma is the most aggressive form of T-cell lymphomas, with a median survival of less than 12 months if allo-HSCT consolidation is not performed.

3.2 First-line therapy for adult and pediatric patients with extranodal NK/T-cell lymphoma

• In previously untreated patients over 18 years of age with stage I–II extranodal NK/T-cell lymphoma, nasal type, it is recommended to administer one of the following treatment regimens [38]

• for "fit" patients, it is recommended to administer modified SMILE courses × 2 cycles or DDGP × 3 cycles followed by RT at a total dose of 45 Gy, or P-GEMOX × 2 cycles followed by RT and another 2–4 cycles of P-GEMOX [39, 40].

GPR BLEL 2Grade of Recommendation B (Level of Evidence 2)

• for "unfit" patients, the following regimens are recommended: concurrent chemoradiotherapy: RT at a total dose of 50 Gy and 3 courses of DeVIC (see Appendix A3.1) [41];

• or RT at a total dose of 40–44 Gy and weekly #cisplatin** administration (30 mg/m²), followed by consolidation with 3 courses of VIPD (see Appendix A3.1) [42];

• or sequential chemoradiotherapy: chemotherapy according to the VIPD regimen followed by RT at 36–44 Gy [43].

GCR CLOE 4Grade of Recommendation C (Level of Evidence 4).

• In previously untreated patients over 18 years of age with stage I–II extranodal NK/T-cell lymphoma, nasal type, who have contraindications to chemotherapy, it is recommended to administer RT at a total dose of 50–55 Gy [38].

RG CLE 5Recommendation Grade C (Level of Evidence 5).

• In previously untreated patients older and younger than 18 years with advanced stages of extranodal NK/T-cell lymphoma, nasal type, as well as with non-nasal forms of extranodal NK/T-cell lymphoma, it is recommended to administer chemotherapy including asparaginase** (4–6 courses of SMILE (older and younger than 18 years), DDGP (older and younger than 18 years), GELOX or P-GEMOX (older than 18 years), or AspMetDex (older than 18 years and predominantly for "unfit" patients – see Appendix A3.1), +/– RT at 45–50 Gy for remission induction [38, 44–46, 154–155].

GCR CLOE 4Grade of Recommendation C (Level of Evidence 4).

• In patients aged 18–60 years with non-nasal or advanced-stage nasal extranodal NK/T-cell lymphoma who achieve CR after induction therapy, it is recommended to perform hematopoietic stimulation with mobilization and subsequent collection of hematopoietic stem cells (HSCs), followed by high-dose therapy using one of the conditioning regimens (for regimen descriptions, see Appendix A3.1.5) followed by HSC transplantation [33].

RG CLE 5Recommendation Grade C (Level of Evidence 5).

3.3 First-line therapy for patients with implant-associated anaplastic large cell lymphoma

• In patients over 18 years of age with implant-associated anaplastic large cell lymphoma, it is recommended to surgically remove the implant along with the surrounding fibrous capsule and any mass adjacent to the capsule [47].

RG CLE 5Recommendation Grade C (Level of Evidence 5).

• In patients over 18 years of age with implant-associated anaplastic large cell lymphoma, in cases of focal breast parenchyma involvement and/or regional lymph node involvement, it is recommended to administer chemotherapy predominantly including brentuximab vedotin** (+CHP) (see Appendix A3.1) [47, 148].

RG CLE 5Recommendation Grade C (Level of Evidence 5).

Comment: implant-associated anaplastic large cell lymphoma has an indolent clinical course and generally a favorable prognosis; therefore, aggressive therapeutic approaches are not recommended for this disease. If the disease presents solely as a peri-implant breast effusion, postoperative medical treatment is not required [47].

3.4 First-line therapy in patients with intestinal T-cell lymphomas

• In patients with newly diagnosed intestinal T-cell lymphoma (enteropathy-associated T-cell lymphoma, monomorphic epitheliotropic intestinal T-cell lymphoma) aged 18–65 years without severe comorbid conditions, it is recommended to use intensive chemotherapy programs (LB-M-04, Hyper-CVAD), and upon achieving an antitumor response, to perform high-dose chemotherapy with autologous blood stem cell transplantation for remission consolidation [36, 48, 49].

GRG CLEL 5Guideline Recommendation Grade C (Level of Evidence LEL 5). – for Hyper-CVAD

GRG CLEL 4Guideline Recommendation Grade C (Level of Evidence LEL 4). – for LB-M-04

Comment: treatment escalation using high-dose methotrexate** and autologous hematopoietic stem cell transplantation (auto-HSCT) has demonstrated high efficacy—the overall 5-year survival reached 60% [4, 23]. Thus, the most important prognostic factors in this case are the patient's performance status and age—factors that allow for high-dose chemotherapy.

Surgical treatment is ineffective; surgical interventions are possible only in cases of high risk of obstruction, bleeding, or perforation, and at the same time they cause delays in initiating adequate multiagent chemotherapy, especially in cases of postoperative infectious complications.

Due to the rarity of the disease, there are no large clinical studies dedicated to the treatment of ITCL.

Intensive therapy programs should be administered in hematology departments of multidisciplinary regional/district hospitals that meet modern standards for high-tech medical care and are equipped with adequate transfusion, intensive care, dialysis, and other services.

• In patients with newly diagnosed intestinal T-cell lymphoma (enteropathy-associated T-cell lymphoma, monomorphic epitheliotropic intestinal T-cell lymphoma) over 60 years of age and/or with severe comorbid conditions, it is recommended to use the BV-CHEP treatment regimen every 3 weeks for no more than 6 cycles (see Appendix A3.1) [29].

• For patients over 65 years of age, the use of the BV-CHP chemotherapy regimen is recommended (see Appendix A3.1).

GCR CLOE 4Grade of Recommendation C (Level of Evidence 4).

Comment: according to the results of the prospective randomized ECHELON-2 study, the inclusion of brentuximab vedotin** in systemic chemotherapy provided a clinically significant improvement in PFS and OS compared to the CHOP regimen: PFS: HR 0.70 (95% CI: 0.53, 0.91); 30% reduction in the risk of a progression event; OS: HR 0.72 (95% CI: 0.53, 0.99); 28% reduction in the risk of death.

3.5 First-line therapy for ALK+ ALCL in children and adolescents under 18 years of age

• In patients under 18 years of age with ALK-positive ALCL without initial CNS involvement, it is recommended to administer multiagent chemotherapy according to the ALCL99 protocol—a pre-phase and 6 alternating A-B-A-B-A-B cycles (see Appendix A3.1). In the presence of high-risk factors—NPM-ALK transcript in the blood, non-common histological variant, poor response after 1 treatment block—an ALK inhibitor (#crizotinib** 165 mg/m²/day) is added to the therapy [51, 145, 152–153].

GPR CLoE 4Grade of Recommendation C (Level of Evidence 4).

Comment: the presence of residual tumor after therapy amounting to less than 30% of the initial volume in children under 18 years of age is not considered treatment failure and does not imply any modification of the treatment plan.

• In patients under 18 years of age with primary ALK-positive ALCL with CNS involvement, it is recommended to administer treatment in accordance with the guidelines for treating pediatric patients with aggressive non-follicular B-cell lymphomas with CNS involvement, without the use of #rituximab** [52], and cranial radiation therapy at a total dose of 18 Gy.

GCR CLOE 4Grade of Recommendation C (Level of Evidence 4).

3.6 Treatment of PTCL relapses

• For patients aged 18 years and older with relapsed or refractory forms of PTCL (including PTCL-NOS, nodal T-cell lymphomas with Tfh phenotype, systemic anaplastic large cell lymphoma ALK-positive and ALK-negative (ALCL), hepatosplenic T-cell lymphoma, intestinal T-cell lymphomas), it is recommended to administer brentuximab vedotin** as either initial or repeated use of the drug, even if the latter was used in the first-line treatment; monotherapy or combination with a chemotherapy regimen for the treatment of relapses is possible (see Appendix A3.1) [53, 54].

GCR CLOE 4Grade of Recommendation C (Level of Evidence 4).

Comment: In the randomized prospective ECHELON-2 study, efficacy analysis showed that after first-line therapy, the response to retreatment with BV** was 59% in the A+CHP group, and the response to initial treatment with BV** was 50% in the CHOP group.

• For patients with late relapse (remission duration > 1 year) of ALK-positive ALCL, therapy with #vinblastine** [55] and #crizotinib** [145, 152–153] is recommended (see Appendix A3.1).

• For patients under 18 years of age with early relapse (< 1 year) of ALK+ ALCL, second-line therapy is indicated: CC and CVA blocks with #crizotinib** for up to 1 year [152].

• For patients under 18 years of age with disease progression during therapy, CC, ICM, and ICI blocks with #crizotinib** and HSCT are indicated [152–153].

GPR CLoE 4Grade of Recommendation C (Level of Evidence 4).

• For patients older than 18 years with early relapse or progression of ALK-positive ALCL, second-line therapy courses (as for other PTCL types) with the addition of #crizotinib** are indicated [151].

RG CLE 5Recommendation Grade C (Level of Evidence 5).

• For patients under 65 years of age with relapsed or refractory forms of PTCL and without severe comorbidity, it is recommended to consult a specialized center performing autologous and allogeneic hematopoietic stem cell transplantation to address the feasibility and possibility of performing one of these two procedures and to determine further patient management strategy [56–63].

GCR CLOE 4Grade of Recommendation C (Level of Evidence 4).

Comment: Children under 18 years of age with early relapses of ALCL, after achieving remission, are indicated for allogeneic HSCT only.

• For patients older than 18 years with relapsed or refractory forms of PTCL, excluding those who are indicated for and can receive brentuximab vedotin** therapy, it is recommended to perform relapse chemotherapy using one of the second-line therapy regimens chosen by the attending physician or (if auto- or allo-HSCT is planned) according to the recommendation of the transplantation center (for regimen descriptions, see Appendix A3.1) [35]:

• ESHAP [64]

Level of Recommendations B (Level of Evidence 2)Level of Evidence 2Level of Recommendations B (Level of Evidence 2).

• DHAP [65]

• GDP [66]

• ICE [67]

GPR CLoE 4Grade of Recommendation C (Level of Evidence 4).

• For patients older than 18 years with relapsed or refractory forms of ALK-positive ALCL, as an alternative to cytostatic therapy, the use of a selective ALK inhibitor (#crizotinib** 250 mg/m² orally twice daily until progression) is recommended [68, 145].

GCR CLOE 4Grade of Recommendation C (Level of Evidence 4).

• In cases of relapse and/or refractory course of nodal T-cell lymphomas with Tfh phenotype in patients older than 18 years after systemic therapy (including CHOP/CHOEP and brentuximab vedotin**), the use of #lenalidomide** 25 mg daily for 21 days of a 28-day cycle as monotherapy is recommended [69–71].

GCR CLOE 4Grade of Recommendation C (Level of Evidence 4).

• For patients with relapsed or refractory forms of extranodal NK/T-cell lymphoma, it is recommended to perform relapse chemotherapy using one of the second-line therapy regimens based on #asparaginase** (4–6 courses of SMILE (for patients older and younger than 18 years), DDGP (for patients older and younger than 18 years), P-GEMOX (for patients older than 18 years), or AspMetDex (for patients older than 18 years and predominantly for "unfit" patients – see Appendix A3.1) [45, 46, 149, 150, 154–155].

LeR CLoE 4Level of Evidence C (Level of Certainty of Evidence 4) – for AspMetDex, SMILE, DDGP regimens

LeR CLoE 5Level of Evidence C (Level of Certainty of Evidence 5) – for P-GEMOX regimen

• For patients older than 18 years with advanced forms and non-nasal type of extranodal NK/T-cell lymphoma after failure of 2 lines of therapy, including regimens with #cisplatin** and #asparaginase**, as well as with relapse or progression of localized forms of extranodal NK/T-cell lymphoma, nasal type after radiation and chemotherapy, it is recommended to use #pembrolizumab** 2 mg/kg once every 3 weeks or #nivolumab** 40 mg once every 14 days [72, 73].

GCR CLOE 4Grade of Recommendation C (Level of Evidence 4).

3.7 Response assessment

• For all patients with PTCL, after 3 cycles of chemotherapy and upon completion of the entire treatment program, it is recommended to evaluate the response to therapy in accordance with standard lymphoma treatment response criteria (see section 7.5 of these guidelines) [1, 74].

RG CLE 5Recommendation Grade C (Level of Evidence 5).

3.8 Concomitant and supportive care

• For patients with PTCL with bulky tumor burden, hyperuricemia prophylaxis is recommended : #allopurinol** 10 mg/kg/day and infusion therapy 3 L/m²/day with alkalization of the solution using sodium bicarbonate** 40–80 mmol/L under diuresis control, planned administration of "loop diuretics", and laboratory monitoring of acid-base status [75, 76, 151].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5).

• For patients with PTCL receiving glucocorticoids, prophylaxis of gastric and duodenal ulcers is recommended [77].

GCR BLOC 1Grade of Recommendation B (Level of Evidence 1)

Comments: Gastric or duodenal ulcer is one of the serious adverse effects of GCS therapy (included in the prevention of ATG complications**). The mechanism of the ulcerogenic action of GCS consists of increasing hydrochloric acid secretion in the stomach, altering the qualitative composition of mucus, and inhibiting the regeneration of the surface epithelium. Due to their ulcerogenic potential, antisecretory therapy must be performed when using GCS to prevent steroid ulcers.

According to a meta-analysis of 300 studies [78], gastric and duodenal ulcers scar in almost all cases if the intragastric pH is maintained above 3 for 24 hours a day for 18 hours. Taking this rule into account, antacids, H2-histamine receptor blockers, and proton pump inhibitors (PPIs) can currently be considered as anti-ulcer therapy. According to one of the latest meta-analyses, the use of PPIs or H2-histamine receptor blockers significantly more effectively achieves ulcer healing and reduces the risk of rebleeding. Only drugs from these two groups make it possible to achieve and maintain the required gastric pH environment in which gastroduodenal ulcers heal.

Currently, two classes of drugs are used for antisecretory purposes to prevent gastric and duodenal ulcers, including during glucocorticoid therapy: proton pump inhibitors and H2-histamine receptor blockers [79, 80].

• For patients with PTCL receiving antitumor chemo- or radiotherapy, it is recommended to use antiemetic drugs (serotonin 5-HT3 receptor blockers, A04AA according to the ATC classification) and glucocorticoids (#dexamethasone^** H02AB according to the ATC classification) for the prevention of nausea and vomiting [81–83].

GCR CLOCE 5Grade of Recommendation C (Level of Evidence 5)

Comments: The choice of method for preventing nausea and vomiting is determined by the emetogenicity of the treatment regimen, individual threshold for nausea and vomiting, and comorbid conditions.

• For patients with PTCL older than 18 years undergoing chemoimmunotherapy courses with a high risk of febrile neutropenia exceeding 20%, or with an intermediate FN risk of 10–20% in the presence of risk factors (age > 65 years; severe concomitant diseases; renal or hepatic impairment; hemoglobin < 12 g/dL; malnutrition; prolonged neutropenia or history of FN; absence of antimicrobial prophylaxis; ECOG ≥ 2; open wounds or wound infection; recent major surgeries; female sex; chemoradiotherapy; cytopenia due to bone marrow tumor involvement; HIV infection), it is recommended to administer colony-stimulating factors to reduce the duration and frequency of neutropenia using G-CSF drugs of the L03AA group according to the ATC classification [84].

RG CLE 5Recommendation Grade C (Level of Evidence 5).

Comments: Prophylactic administration of granulocyte colony-stimulating factor (G-CSF): filgrastim** 5 mcg/kg subcutaneously (s.c.) 24–72 hours after the end of antineoplastic drug administration and until neutrophil counts recover from the nadir, or pegfilgrastim at a dose of 6 mg or lipegfilgrastim** at a dose of 7.5 mg subcutaneously, as a single dose, no earlier than 24 hours after the end of antineoplastic drug administration in accordance with the instructions for medical use to prevent the development of and to treat neutropenia caused by cytotoxic tumor chemotherapy.

• For patients with PTCL older than 18 years following a previously documented episode of FN or dose-limiting afebrile neutropenia (after a single episode of interval extension between courses and/or dose reduction), it is recommended to prescribe colony-stimulating factors to reduce the duration and frequency of neutropenia using G-CSF drugs of the L03AA group according to the ATC classification [84].

RG CLE 5Recommendation Grade C (Level of Evidence 5).

Comments: administration of colony-stimulating factors to reduce the duration and frequency of neutropenia: filgrastim** 5 mcg/kg subcutaneously (s.c.) 24–72 hours after the completion of antineoplastic drug administration and until neutrophil counts recover to normal limits, or pegfilgrastim at a dose of 6 mg or empegfilgrastim** at a dose of 7.5 mg subcutaneously, once, at least 24 hours after the completion of antineoplastic drug administration in accordance with the instructions for medical use for the treatment of neutropenia induced by cytotoxic tumor chemotherapy.

• In patients with PTCL during chemotherapy and in inter-cycle intervals, pneumocystis pneumonia prophylaxis is recommended [85].

LeR CLoE 5Level of Recommendation C (Level of Evidence — 5)

Comments: co-trimoxazole [sulfamethoxazole+trimethoprim]** is the drug of choice for pneumocystis pneumonia prophylaxis [85]. Daily use of co-trimoxazole [sulfamethoxazole+trimethoprim]** simultaneously prevents infections caused by Toxoplasma gondii, Listeria monocytogenes, and Nocardia asteroides. Patients infected with Pneumocystis jirovecii must not share a room with other immunocompromised patients.

• In patients with PTCL aged over 18 years for whom intensive chemotherapy regimens are planned, it is recommended to place a central venous catheter for chemotherapy and supportive care (see section 7.11) [86].

RG CLE 5Recommendation Grade C (Level of Evidence 5).

• In patients with PTCL and risk factors for thrombotic complications, for the purpose of venous thromboembolism prophylaxis, it is recommended to use anticoagulants (ATC code B01) and physical methods (compression stockings, pneumatic limb compression) [87, 88].

LeR CLoE 5Level of Recommendation C (Level of Evidence — 5)

• In patients with PTCL undergoing cytotoxic chemotherapy, nutritional support is recommended for the prevention of fluid and electrolyte imbalances [90, 91].

GCR BLOC 1Grade of Recommendation B (Level of Evidence 1)

• For patients of reproductive age with PTCL, it is recommended to discuss the possibility of sperm or oocyte/embryo cryopreservation prior to starting therapy [92].

GCR CLOCE 5Grade of Recommendation C (Level of Evidence 5)

• For female patients with PTCL (girls and young women) scheduled for pelvic radiotherapy, it is recommended to consider the need for homolateral oophoropexy for ovarian shielding [93].

GCR CLOCE 5Grade of Recommendation C (Level of Evidence 5)

Comment: oophoropexy is particularly indicated if the expected radiation dose to the ovaries exceeds 5 Gy, as this may lead to prolonged ovarian dysfunction. This can be avoided if radiotherapy is delivered via opposed fields to a total dose (TD) of 20 Gy and the ovary is located at least 2 cm away from the edge of the radiation field.

When performing an oophoropexy, the suture must be marked with a clip. The procedure is performed by a surgeon after consultation with a radiation oncologist prior to the start of subdiaphragmatic radiotherapy.

4. Medical Rehabilitation and Sanatorium-Resort Treatment

• In patients with PTCL at all stages of disease therapy, as well as after the completion of medical treatment, comprehensive rehabilitation and, if necessary, supportive care are recommended [94].

RG CLE 5Recommendation Grade C (Level of Evidence 5).

Comment: There are no specific rehabilitation methods for PTCL. Rehabilitation of patients with PTCL should be comprehensive, covering 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.

5. Prevention and Dispensary Observation

There are currently no methods for the prevention of PTCL, as the etiological factors leading to the development of the disease are unknown.

• Adult patients who have completed treatment for PTCL with the achievement of CR are recommended to undergo follow-up care by an oncologist or hematologist every 3 months during the first year after treatment completion, every 6 months during the 2nd year, annually thereafter, and every 2 years after 5 years [1,2].

RG CLE 5Recommendation Grade C (Level of Evidence 5).

Comment: Follow-up care should include a thorough review of complaints, physical examination, targeted chest X-ray in two projections or chest CT, abdominal ultrasound (comprehensive), and examination of peripheral lymph node groups. For patients who received anthracyclines and related compounds combined with mediastinal irradiation, cardiac function assessment (electrocardiography (ECG) and echocardiography (EchoCG)) and pulmonary function testing (unforced respiratory volumes and flows) should be performed.

• Children and adolescents who have completed treatment for PTCL with the achievement of CR are recommended to undergo follow-up care by an oncologist/pediatric oncologist or hematologist according to the schedule presented in Tables 5.1, 5.2, and 5.3 [1, 95, 96].

RG CLE 5Recommendation Grade C (Level of Evidence 5).

Comment: Table 5.1. Schedule of follow-up care for children after completion of treatment for PTCL (time from the end of RT)

Table 5.2. Screening for cardiotoxic effects

6. Organization of Medical Care

Medical care, with the exception of medical care provided as part of clinical trials, in accordance with Federal Law No. 323-FZ dated November 21, 2011 (as amended on May 25, 2019) "On the Fundamentals of Protecting Public Health in the Russian Federation", is organized and provided:

1) in accordance with the regulations on the organization of medical care by types of medical care, approved by the authorized federal executive body;

2) in accordance with the procedure for the provision of care in the "hematology" and "oncology" profiles, which is mandatory for implementation throughout the Russian Federation by all medical organizations;

3) based on these clinical guidelines;

4) taking into account the standards of medical care approved by the authorized federal executive body.

Primary specialized health care is provided by a hematologist/oncologist and other specialist physicians at an inpatient and outpatient hematology/oncology care center, or at a primary hematology/oncology office, primary hematology department, or outpatient department of an oncological dispensary.

When aggressive B-cell lymphomas are detected or suspected in a patient, general practitioners, district general practitioners, family physicians, specialist physicians, and mid-level medical personnel shall refer the patient in the established manner for a consultation at an outpatient hematology/oncology care center, primary hematology/oncology office, or hematology/oncology department of a medical organization to receive primary specialized health care.

The outpatient or inpatient hematologist/oncologist organizes the diagnostic tests necessary to establish a diagnosis, including the extent and stage of the disease.

If diagnostic tests cannot be performed, the attending physician refers the patient to a medical organization providing medical care to patients with hematological/oncological diseases to establish a diagnosis and provide specialized, including high-tech, medical care.

If an aggressive lymphoma is detected or suspected during the provision of emergency medical care, the patient is transferred or referred to medical organizations providing medical care to patients with hematological/oncological diseases to determine management tactics and the need for additional specialized antineoplastic treatment methods.

Specialized, including high-tech, medical care is provided by hematologists/oncologists in inpatient and day-hospital settings in medical organizations providing care to patients with aggressive lymphomas that have a license, the necessary material and technical base, and certified specialists, and includes the diagnosis and treatment of hematological diseases requiring special methods and complex unique medical technologies, as well as medical rehabilitation.

In a medical organization providing medical care to patients with aggressive lymphomas, the medical examination and treatment strategy is determined by hematologists/oncologists, with the involvement of other specialist physicians if necessary, and through a medical concilium when required. The decision of the medical concilium is formalized in a protocol, signed by the participating physicians, and entered into the patient's medical documentation.

Indications for admission to an inpatient or day care unit of a medical organization providing specialized, including high-tech, medical care in the profile of «hematology» or «oncology» are determined by a hematologist/oncologist/medical board, involving other medical specialists if necessary.

Indications for planned hospitalization:

1. Initiation of specific therapy.

2. Planned continuation of specific therapy.

3. Diagnostic procedures that require inpatient conditions.

Indications for emergency hospitalization:

1. Complications of the underlying disease requiring specific inpatient treatment.

2. Complications of specific therapy that are life-threatening and require appropriate inpatient treatment.

Indications for patient discharge from the hospital:

1. Completion of specific therapy (in the absence of life-threatening complications of specific therapy).

The conclusion regarding the feasibility of transferring the patient to a specialized medical organization is drawn after a preliminary consultation based on the provided medical documents and/or a preliminary examination of the patient by medical specialists of the medical organization to which the transfer is planned.

7. Additional Information

7.1 General requirements for morphological diagnosis of lymphomas

The diagnosis of peripheral T-cell lymphoma is established based on morphological and immunohistochemical examination of biopsy or surgical material. In some cases, molecular biological and genetic tests are necessary: study of T-cell clonality using gamma (beta or delta if necessary) T-cell receptor chain genes, testing for the RHOA gene G17V mutation (especially in differential diagnosis with nodal Tfh lymphomas, angioimmunoblastic type), and TP53 gene mutation (may affect prognosis and treatment selection).

The necessary scope of investigations for diagnosing various variants of nodal T-cell lymphomas is detailed in the manual «Diagnostic Algorithms and Treatment Protocols for Hematopoietic Diseases» edited by E.N. Parovichnikova, 2024. [151]

7.2 Morphological and immunohistochemical diagnosis of PTCL

Peripheral T-cell lymphoma [with immunophenotype], not otherwise specified

Peripheral T-cell lymphoma, not otherwise specified (PTCL, NOS) represents a group of non-Hodgkin lymphomas of diverse histological structure that lack specific features allowing these tumors to be classified into any other T-cell lymphoma category listed in the 2017 WHO classification. The term «not otherwise specified» emphasizes the absence of specific histological and immunophenotypic characteristics. The histological structure of PTCL, NOS and its cellular composition are quite variable. The tumor infiltrate is most frequently dominated by medium-sized to large cells with irregularly shaped nuclei; chromatin may be finely dispersed or hyperchromatic, and nucleoli are prominent in large cells. In some observations, small-sized lymphoid cells make up the bulk of the tumor. The heterogeneity of the infiltrate is usually driven by a marked reactive microenvironment (eosinophilic granulocytes, plasma cells, and epithelioid histiocytes present in varying numbers).

In the vast majority of cases, PTCL, NOS has a CD4+/CD8– immunophenotype; CD4–/CD8+, CD4+/CD8+, and CD4–/CD8– variants are less common. Aberrant loss of one or more pan-T-cell antigens (CD2, CD3, CD5, CD7) is frequently observed. A cytotoxic phenotype (TIA-1, perforin, granzyme B) may occur. The T-cell receptor β-protein (βF1) is typically expressed, in contrast to γδ T-cell lymphomas and NK-cell lymphomas. In some cases, a subset of tumor lymphocytes expresses CD30 (<80%), exceptionally rarely accompanied by CD15+, which can pose differential diagnostic challenges with classical Hodgkin lymphoma or anaplastic large cell lymphoma (ALK+ or ALK– with co-expression of CD15 and CD30).

Taking into account the features of histoarchitecture, cellular composition, and immunophenotype of the tumor cells, the following variants are distinguished:

1. lymphoepithelioid lymphoma (Lennert lymphoma) — the tumor infiltrate contains numerous epithelioid histiocytes forming clusters; the tumor T cells are usually CD8+.

2. Primary EBV+ nodal T- or NK-cell lymphoma

In most cases, T-cell receptor genes are clonally rearranged.

Angioimmunoblastic T-cell lymphoma and other lymphomas with a follicular T-helper phenotype

A non-tumor counterpart of angioimmunoblastic T-cell lymphoma (AITL) is considered to be a subpopulation of T-lymphocytes with the phenotype of follicular helper T cells (T_FH). Along with T-cell antigens, they express markers characteristic of B-lymphocytes from the germinal center of follicles — BCL6 and CD10. The biological role of T_FH consists in the production of chemokines/receptors (CXCL13 and CXCR5) that induce the proliferation of follicular dendritic cells and the migration of B-lymphocytes into the lymph node by enhancing their adhesion to the venular endothelium, which facilitates the passage of B-lymphocytes through the vascular wall.

AITL is characterized by the complete or partial effacement of the lymph node architecture. The histological structure of AITL is represented by three morphological variants. In the first variant (early-stage AITL), tumor cells surround hyperplastic follicles with well-formed germinal centers, but often without a discernible mantle zone. In the second variant (interfollicular growth), prominent remnants of follicles with signs of regression are preserved, and tumor cells occupy the paracortical zone, leading to its expansion. Complete or nearly complete effacement of the lymph node architecture resulting from the displacement of follicles by the tumor infiltrate is characteristic of the third (diffuse) histological variant of AITL.

The tumor infiltrate is polymorphic in character and consists of small and medium-sized T cells, usually having pale-staining or optically clear cytoplasm with distinct borders. Tumor lymphoid cells are sparse (<10%) compared to the reactive microenvironment: T cells, eosinophilic granulocytes, histiocytes, and plasma cells; proliferation of follicular dendritic cells is characteristic (well visualized using antibodies to CD21, sometimes antibodies to CD23 or CD35 should be used additionally), and occasional immunoblasts are encountered. A typical histological feature is the proliferation of postcapillary venules forming an arborizing network.

Tumor cells express CD3, CD4, as well as CD10, BCL-6, CD279 (PD-1), CXCL13, and CD278 (ICOS), i.e., they have an immunophenotype characteristic of T_FH (expression of at least two of the five listed T_FH markers is required). Large activated cells with centroblast/immunoblast morphology that form part of the tumor's reactive microenvironment have a B-cell phenotype and may harbor the Epstein-Barr virus. In rare cases, these cells become the source of transformation into EBV-positive diffuse large B-cell lymphoma.

Follicular T-cell lymphoma is characterized by a nodular/follicular growth pattern of a rather uniform infiltrate of medium-sized lymphoid cells, bearing a strong resemblance to follicular B-cell lymphomas. Another structural variant of follicular T-cell lymphoma bears resemblance to progressively transformed germinal centers in a lymph node. The phenotype of the neoplastic lymphocytes corresponds to T_FH: CD3, CD4, CD10, BCL-6, CD279 (PD-1), CXCL13, CD278 (ICOS). It differs from AITL by the absence of both high endothelial venules and an expanded network of follicular dendritic cells outside the follicles. There are case reports involving multiple biopsies performed at different times where the tumor architecture changed during follow-up from follicular T-cell lymphoma to typical AITL and vice versa.

Some lymphomas previously classified as peripheral T-cell lymphoma, not otherwise specified, exhibit a T_FH phenotype and certain structural features of AITL. Primarily, this refers to the growth of the neoplastic infiltrate in the T-cell zone (the morphological equivalent of T-cell zone lymphoma), but without a prominent non-neoplastic reactive component, arborizing high endothelial venules, and an expanded network of follicular dendritic cells. These tumors have been designated as TFH-phenotype lymphomas and are defined as a distinct clinicopathological (nosological) entity in the 2017 WHO classification.

Anaplastic large cell lymphoma, ALK-positive

Anaplastic large cell lymphoma (ALCL), ALK-positive is most frequently composed of large atypical lymphoid cells with abundant cytoplasm containing a perinuclear eosinophilic inclusion (in the Golgi zone) and polymorphic nuclei, among which kidney-shaped and horseshoe-shaped forms can be found. In addition to the "common" ALK+ large cell variant of ALCL, lymphohistiocytic, small cell, Hodgkin-like (resembling nodular sclerosis Hodgkin lymphoma), and hypocellular (non-common) variants occur. In the early stages of the disease, the tumor involves the lymph node partially, and tumor cell growth in the marginal and intermediate sinuses is frequently observed.

The critical diagnostic criterion for ALK+ ALCL is intense CD30 expression on the cell membrane and in the Golgi zone of large tumor cells. Small tumor cells may express CD30 more weakly or even be negative. Tumor cells express one or more T-cell antigens—CD2, CD3, CD4, CD5, CD7, CD8, although the expression of some or even all of these antigens may be lost. Up to 30–50% of tumors have a "null" phenotype according to immunohistochemical studies. Cells of the majority of ALK+ ALCL cases show expression of EMA, CD25, CD43, and the cytotoxic molecules TIA-1, granzyme B, and perforin.

ALK expression most commonly results from the synthesis of the NPM-ALK chimeric protein, the product of a fusion gene formed by the translocation of chromosomal segments 2 and 5. Locus 2p23 encodes anaplastic lymphoma kinase (ALK), while locus 5q35 contains the nucleophosmin (NPM1) gene, which encodes an acidic phosphoprotein localized in the nucleus and the nucleolar organizer regions. The t(2;5) translocation is most frequently accompanied by ALK protein expression in the nucleus and cytoplasm of large tumor cells and the nuclei of small cells. In other translocation variants, when other genes rather than NPM1 become the ALK fusion partner, immunohistochemical reactions most commonly stain only the cytoplasm or, less frequently, the cell membrane.

Anaplastic large cell lymphoma, ALK-negative

This clinicopathologic variant of T-cell CD30-positive lymphoma differs from ALK+ ALCL by genetic abnormalities that do not involve the ALK gene and, consequently, the absence of chimeric ALK protein expression. The morphological structure and immunophenotypic characteristics of ALK+ ALCL and ALK– ALCL are virtually identical. In the 2017 WHO classification, they are considered separate nosological entities based on significant clinical differences (the median age of patients with ALK– ALCL is higher, and the clinical course is more aggressive). Certain genetic abnormalities occurring in a significant proportion of ALK– ALCL cases (e.g., DUSP22 or TP63 rearrangements) have never been detected in ALK+ ALCL, although they are noted in some cases of peripheral T-cell lymphoma, not otherwise specified. ALK– ALCL with TP63 rearrangement has a poor prognosis, cases with DUSP22 rearrangement have a favorable prognosis, and cases lacking these rearrangements have an intermediate prognosis.

Extranodal NK/T-cell lymphoma, nasal type

NK/T-cell lymphoma, nasal type, is a tumor considered analogous to activated NK cells or cytotoxic T lymphocytes. The designation "nasal type" is due to the frequent primary localization of the tumor in the midline structures of the facial skeleton. The tumor also frequently involves the skin, lungs, small intestine, and kidneys. The lymphoma is characterized by diffuse growth, frequently combined with angiocentric (infiltration of the vessel wall) and angiodestructive (destruction of blood vessels) components. Involvement of blood vessels leads to massive ischemic necrosis of the tumor tissue. These morphological features can lead to misdiagnosis as granulomatosis with polyangiitis. The tumor is characterized by the expression of CD2, CD3 (ε clone, cytoplasmic), CD56+/–, TIA-1+, granzyme B+, perforin+; expression of CD4, CD5, CD8, CD16, and CD57 is absent. The tumor is characteristically associated with the Epstein-Barr virus. Detection of the virus by in situ hybridization (EBER CISH) in the majority of tumor cells is required for the diagnosis of this lymphoma. Immunohistochemical evaluation of Epstein-Barr virus latent membrane protein 1 (LMP-1) expression is insufficient, as this protein is usually absent in the cells of nasal-type NK/T-cell lymphomas.

T-cell lymphomas with primary intestinal involvement

The categorization of T-cell lymphomas with primary small intestinal involvement underwent changes in the 2017 WHO classification. Enteropathy-associated T-cell lymphoma (EATL) and monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL) are considered separate nosological entities. The latter was previously designated as type II EATL.

EATL is a tumor of intraepithelial T lymphocytes with primary involvement of the small intestine. It occurs in patients with celiac disease and is characterized by an aggressive clinical course and poor prognosis. Gross examination typically reveals numerous ulcerated nodules and plaques on the intestinal mucosa, strictures, and, less frequently, bulky exophytic masses. The mesentery and its lymph nodes are frequently involved.

Histologically, EATL is a polymorphic infiltrate with numerous large cells containing round or irregularly shaped nuclei, often of the vesicular type, and prominent nucleoli. The cytoplasm of the tumor cells is moderately abundant and pale-staining. Angiocentric and angioinvasive growth and, consequently, widespread zones of necrosis are characteristic, along with a significant admixture of reactive cells (T cells, histiocytes, eosinophils). The neoplastic lymphoid cells are typically CD3+, CD5–, CD7+, CD4–, CD8–/+, CD56–, and CD103+, and express cytotoxic molecules (TIA-1, granzyme B, perforin). Large-cell variants are almost always CD30+.

MEITL has no definite association with celiac disease. This lymphoma more frequently involves the jejunum than the ileum and may extend to the stomach (5% of cases). The tumor is a monomorphic infiltrate composed of small- to medium-sized cells with round nuclei containing condensed chromatin and inconspicuous nucleoli. The cytoplasm is moderately abundant and pale. The phenotype is characterized by the expression of CD3, CD8, and CD56, and the absence of CD5. Among cytotoxic molecules, TIA-1 is detected, whereas granzyme B and perforin are variably expressed. MATK is a sensitive and specific marker showing nuclear expression in MEITL cells.

Gastrointestinal T-cell lymphomas whose diagnostic features do not fit EATL or MEITL are designated as "intestinal T-cell lymphoma, not otherwise specified," with the caveat that this is a diagnostic definition rather than a distinct nosological entity. Its use may be warranted in certain situations, for example, when the biopsy material is inadequate or immunohistochemical data are incomplete.

Indolent T-cell lymphoproliferative disorder of the gastrointestinal tract is the result of clonal proliferation of lymphoid T cells within the gastrointestinal mucosa, predominantly in the small or (more often) large intestine. Lymphoid cells occupy the lamina propria and submucosa but do not infiltrate the epithelium. The lymphoid infiltrate typically has the immunophenotype: CD3+, CD8+, TIA+, granzyme B–, perforin–. The clinical course is indolent, but without response to cytotoxic therapy.

7.3 Staging of nodal PTCL

Staging of nodal PTCLs is performed based on evaluation according to the Ann Arbor classification criteria (Table 7.3.1).

Table 7.3.1. Ann Arbor Staging of Lymphomas (Lugano Modification, 2014) [9]:

Comments: tonsils, Waldeyer's ring, and spleen are considered nodal structures

Table 7.3.2 Staging of breast implant-associated anaplastic large cell lymphoma.

7.4 Determination of PTCL risk groups

To analyze the individual risk of early progression in patients over 18 years of age, the International Prognostic Index (IPI) and the age-adjusted index (aaIPI) (Table 7.4.1) [97] are used, which remain relevant in modern treatment regimens. Predictive models developed for peripheral T-cell lymphomas that demonstrate prognosis dependence on other factors may also be used: bone marrow involvement (PIT index) [98], and the tumor proliferative activity index Ki-67 (mPIT index) [99].

Table 7.4.1. Prognostic indices used in patients with PTCL

Prognostic factors for risk stratification of ALK+ ALCL in patients under 18 years include: stage (Ann Arbor), histological variant (common or non-common), and minimal disseminated disease (NPM-ALK transcript in blood or bone marrow prior to therapy)

7.5 Response assessment in lymphomas

Response assessment to treatment is performed in accordance with the updated criteria proposed by the International Working Group on Lymphoma in 2007 [74].

Complete remission (CR):

1. Complete disappearance of all evidence of disease, including findings detected by laboratory and imaging diagnostic methods, as well as clinical symptoms, if present before treatment initiation.

2. Lymph node dimensions:

   a. ≤1.5 cm in the greatest transverse diameter, if pre-treatment lymph node size was greater than 1.5 cm

   b. ≤1.0 cm in the greatest transverse diameter, if pre-treatment lymph node size was 1.5-1.1 cm

3. Liver and spleen, if enlarged before treatment, are no longer palpable, and imaging reveals no focal lesions within them.

4. Bone marrow with no evidence of tumor involvement. If the bone marrow morphological examination result is equivocal, the presence or absence of involvement must be determined immunohistochemically.

For HL, CR is considered confirmed if the achieved response persists for at least 3 months or further improvement is documented.

Unconfirmed complete remission (CRu) is stated only in patients who did not undergo PET-CT for response assessment:

1. Residual changes detected exclusively by imaging methods (especially residual masses at the site of bulky disease, most commonly in the mediastinum), provided the tumor has regressed by more than 75% from its baseline size based on the sum of the two largest perpendicular diameters. These residual changes must not increase in size for more than 3 months.

2. Other parameters: meeting the criteria for complete remission.

Partial remission (PR):

1. A decrease by at least 50% in the sum of the products of the diameters of all measured target lesions (lymph nodes and/or extranodal lesions). If the dimensions of the involved lesions are less than 3 cm in the greatest diameter, the 2 largest lesions must decrease by at least 50% in their greatest diameter. If there are more than 6 target lesions greater than 3 cm, evaluation of the 6 largest lesions clearly measurable in two perpendicular directions is sufficient. Mediastinal and/or retroperitoneal target lesions must be included in the measurements.

2. No appearance of new lesions, and no evidence of enlargement of any previously diagnosed lesions.

3. In cases of baseline bone marrow involvement, bone marrow status is not significant for defining PR. However, if bone marrow involvement persists during and/or after treatment completion, characterization of tumor cells is mandatory. Patients with baseline bone marrow involvement who clinically achieve CR after treatment completion, but exhibit persistent bone marrow involvement or have unassessable bone marrow, are classified as having PR.

Stable disease

Tumor parameters do not meet the criteria for CR, PR, or progression.

Relapse (after CR) or progression (after PR or stable disease)

1. Appearance of new lesions (enlarged lymph nodes or extranodal masses) greater than 1.5 cm in the greatest dimension during or after treatment completion, regardless of changes in the size of other lesions.

2. An increase of at least 25% in any previously documented lesion from its nadir size. For lesions less than 1 cm in the greatest dimension, an increase to 1.5 cm or more.

7.6 Specific considerations for RT dose planning on critical structures when irradiating patients with NK/T-cell lymphoma or peripheral T-cell lymphoma under 18 years of age [50, 157]

Skeletal system.

Radiosensitivity is highest in young children (under 6 years) and during the prepubertal period (11-13 years). Dose to the growth plates of long bones should be limited (not exceeding 20 Gy). Asymmetric irradiation of the axial skeleton can lead to kyphosis or scoliosis, whereas symmetric irradiation results in reduced linear growth. To prevent scoliosis, irradiation of the entire length of the spinal PTV must be symmetric. A dose gradient within vertebral bodies exceeding 20% is unacceptable.

Spinal cord.

In children under six years of age, the central nervous system undergoes maturation and is therefore particularly radiosensitive. The maximum dose to the cervical spinal cord must not exceed 20 Gy. Doses greater than 30 Gy to the spinal cord should be avoided, and individualized planning should aim to minimize the spinal cord dose without compromising the prescribed target dose.

Lungs.

Pulmonary tolerance in children is poorly understood and does not appear to differ significantly between adults and school-aged children. The dose specified in these recommendations (12-15 Gy) for total lung irradiation is unlikely to cause significant impairment of pulmonary function. However, whole-lung irradiation at a dose of 12 Gy in children under 6 years of age may lead to a permanent reduction in vital capacity.

Heart.

Myocardial and arterial dysfunction may occur after a long latency period (20 years or more) as a late consequence of radiation-induced endothelial proliferation. There is no clear data on the effect of age at the time of irradiation. Cardiac irradiation should be minimized, especially when combined with cardiotoxic anthracyclines and related compounds, which may decrease overall cardiac tolerance. Valve fibrosis and calcification may occur, potentially leading to valvular heart disease. Therefore, the irradiated cardiac volume and cardiac dose should be kept to a minimum. Doses to the heart exceeding 30 Gy are not recommended.

Breasts.

Late adverse deterministic effects on fully developed breasts are not expected. At the same time, undeveloped juvenile breasts are highly radiosensitive. Following irradiation of an undeveloped breast at a dose of 5 to 10 Gy, hypoplasia or aplasia of all or part of the breast may develop during adolescence.

Kidneys.

The kidneys are highly radiosensitive. There is no clear data on the effect of age at the time of irradiation. The recommended whole-kidney tolerance dose is 12 Gy. No significant long-term adverse effects are expected when the entire organ is irradiated to this dose. Partial kidney irradiation (e.g., the upper left renal pole during splenic and splenic pedicle irradiation) at a dose of 20 Gy or more may cause fibrosis of the renal upper pole and lead to localized functional impairment.

Liver.

Thyroid gland.

Patients may develop subclinical hypothyroidism after a latency period of 3-4 years or more following irradiation of the gland at a dose of 20 Gy or more. Subclinical hypothyroidism may resolve spontaneously, and the need for treatment in such cases is controversial. The risk of thyroid dysfunction increases with radiation doses up to 30 Gy and may lead to clinical hypothyroidism requiring hormone replacement therapy.

Testes.

The testes are the most radiosensitive organ. A dose of 1–2 Gy can lead to irreversible impairment of spermatogenesis. Therefore, the testes must be protected during irradiation of the iliac and/or inguinal regions using modern irradiation techniques or by direct shielding.

Ovaries.

Following a cumulative dose of 5–10 Gy, oocyte cell death is induced in the ovaries, leading to infertility. Endocrine insufficiency occurs after higher doses are reached (about 10–15 Gy). In such cases, hormone replacement therapy may be required depending on the hormonal status during the pubertal period. To avoid ovarian dysfunction, at least one ovary must be protected from the effects of radiation, including scattered radiation. It is recommended to consider surgical transposition of the ovaries out of the proposed radiation fields (oophoropexy).

Secondary neoplasms

Radiation therapy in childhood increases the risk of developing a wide range of secondary tumors. The most common is breast cancer in women who underwent mediastinal and axillary radiation therapy in childhood. Therefore, regular breast cancer screening is recommended for women over 25 years of age or 8 years after radiation therapy. Irradiation of the cervical lymph nodes increases the risk of developing thyroid tumors, including malignant ones.

7.7 Infusion and transfusion therapy in patients with nodal T-cell lymphomas

Indications and scope of both infusion and transfusion therapy for nodal T-cell lymphomas in adults are described in detail in the guidelines "Algorithms for Diagnostics and Treatment Protocols for Hematopoietic Diseases" edited by E.N. Parovichnikova, 2024 [89, 100, 151].

7.8 Protocols for bone marrow aspiration and biopsy procedures

Bone marrow aspiration and biopsy procedures are routine and performed in both outpatient and inpatient settings. Indications/contraindications and the technique for performing them in adult patients are described in detail in the guidelines "Algorithms for Diagnostics and Treatment Protocols for Hematopoietic Diseases" edited by E.N. Parovichnikova, 2024 [151] and reference [101-102].

7.9 Vascular access management

Vascular access provision is an essential component of modern chemotherapy in oncohematological patients. Indications for catheterization, performance technique, and its specific features in adults are described in detail in the guidelines "Algorithms for Diagnostics and Treatment Protocols for Hematopoietic Diseases" edited by E.N. Parovichnikova, 2024 [151] and references [103-121].

7.10 Management of hematological patients in the intensive care unit

Patients with hematological diseases may develop various critical conditions due to diverse causes at the stages of diagnosis, treatment, and follow-up. Indications for transfer and therapy principles in adults are described in the guidelines "Algorithms for Diagnostics and Treatment Protocols for Hematopoietic Diseases" edited by E.N. Parovichnikova, 2024 [151] and references [122-131].

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

1. Elena N. Parovichnikova – MD, DSc, General Director of the National Research Center for Hematology of the Russian Ministry of Health, Chairman of the National Hematology Society, Chief freelance hematologist of the Russian Ministry of Health

2. Irina V. Poddubnaya – Academician of the Russian Academy of Sciences, Honored Worker of Education of the RF, MD, PhD, Professor, Head of the Department of Oncology and Palliative Medicine, Vice-Rector for Clinical Work and International Cooperation at the Russian Medical Academy of Continuous Professional Education of the Russian Ministry of Health, Chairperson of the Russian Society of Oncohematology.

3. Gayane S. Tumyan – MD, DSc, Professor, Professor at the Department of Oncology and Palliative Medicine, Russian Medical Academy of Continuing Professional Education of the Russian Ministry of Health, Leading Researcher at the Chemotherapy Department for Hemoblastoses, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health, Board Member of the Russian Society of Oncohematology

4. Liliya G. Gorenkova – MD, PhD, Head of the Department of Hematology and Chemotherapy of Acute Leukemias and Lymphomas, National Research Center for Hematology of the Russian Ministry of Health, Member of the National Hematology Society

5. Natalia G. Chernova – MD, DSc, Head of the Medical Center, Kommunarka Moscow Multidisciplinary Clinical Center of the Moscow Healthcare Department

6. Natalia V. Myakova – MD, DSc, Deputy Chief Physician for Medical Work, Head of the Pediatric Oncohematology Department, Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology of the Russian Ministry of Health, Member of the National Society of Pediatric Hematologists and Oncologists

7. Alexander G. Rumyantsev – Academician of the Russian Academy of Sciences, MD, DSc, Professor, General Director of the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology of the Russian Ministry of Health, President of the National Society of Pediatric Hematologists and Oncologists

8. Alexey A. Maschan – Corresponding Member of the Russian Academy of Sciences, MD, DSc, Professor, Deputy General Director of the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology of the Russian Ministry of Health, Board Member of the National Society of Pediatric Hematologists and Oncologists

9. Evgeny E. Zvonkov – MD, DSc, Head of the Department of Lymphoproliferative Diseases, Head of the Department of Hematology and Lymphoma Chemotherapy with a Bone Marrow and Hematopoietic Stem Cell Transplantation Unit, National Research Center for Hematology of the Russian Ministry of Health, Member of the National Hematology Society

10. Evgeny A. Osmanov – MD, DSc, Professor, Head of the Department of Hematology and Bone Marrow Transplantation, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health, Professor at the Department of Oncology, I.M. Sechenov First Moscow State Medical University of the Russian Ministry of Health, Board Member of the Russian Society of Oncohematology

11. Sergey K. Kravchenko – MD, PhD, Associate Professor, Head of the Department of Intensive High-Dose Chemotherapy with 24-hour and Day Patient Facilities, National Research Center for Hematology of the Russian Ministry of Health, Member of the National Hematology Society

12. Natalia A. Falaleeva – MD, DSc, Head of the Antineoplastic Drug Treatment Department, A.F. Tsyb Medical Radiological Research Center – branch of the National Medical Research Radiological Center of the Russian Ministry of Health, Member of the Association of Oncologists of Russia and the Russian Association of Therapeutic Radiation Oncologists

13. Dmitry S. Blinov, MD, DSc, 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

14. Yury A. Shifrin – Junior Researcher at the Laboratory of Pharmacology and Health Technology Assessment, Clinical Pharmacologist, Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology of the Russian Ministry of Health

15. Natalia B. Mikhailova – MD, DSc, Head of the Department of Clinical Oncology (Chemotherapy), R.M. Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantology, Member of the Russian Society of Oncohematology

16. Vadim V. Ptushkin – MD, DSc, Professor, Deputy Chief Physician for Hematology, S.P. Botkin City Clinical Hospital, Chief freelance hematologist of the Moscow Healthcare Department, Member of the National Hematology Society and the Russian Society of Oncohematology

17. Vadim V. Baykov – MD, DSc, Professor at the Department of Pathological Anatomy, Head of the Pathomorphology Laboratory, R.M. Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantology, Academician I.P. Pavlov First Saint Petersburg State Medical University of the Russian Ministry of Health, Presidium Member of the Russian Society of Pathologists, Board Member of the Russian Society of Oncohematology

18. Alla M. Kovrigina – D.Sc. in Biological Sciences, Professor at the Department of Pathology, Cytology and Molecular Pathology, Institute of Advanced Training of the FMBA of Russia; Head of the Department of Pathology, National Medical Research Center for Hematology of the Russian Ministry of Health; Member of the Presidium of the Russian Society of Pathologists, Board Member of the Russian Society of Oncohematologists.

19. Yury A. Krivolapov – D.Sc. in Medical Sciences, Professor, Head of the Department of Pathology of Clinical Molecular Morphology, E.E. Eichwald Clinic, North-Western State Medical University named after I.I. Mechnikov of the Russian Ministry of Health; Member of the Pathology Panel of the European Lymphoma Research Network; Member of the European Bone Marrow Working Group; Member of the Presidium of the Russian Society of Pathologists.

20. Dmitry M. Konovalov – Ph.D. in Medical Sciences, Head of the Department of Pathology, Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology of the Russian Ministry of Health; Member of the Presidium of the Russian Society of Pathologists.

21. Lyubov S. Al-Radi – Ph.D. in Medical Sciences, Senior Researcher at the Consultative Hematology Department with a Day Hospital for Chemotherapy, National Medical Research Center for Hematology of the Russian Ministry of Health; Member of the Association for the Promotion of Hematology and Bone Marrow Transplantation Development "National Hematological Society".

22. Vadim V. Baykov – D.Sc. in Medical Sciences, Professor at the Department of Pathology, Head of the Pathomorphology Laboratory, R.M. Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantology, First Saint Petersburg State Medical University named after Academician I.P. Pavlov of the Russian Ministry of Health; Member of the Presidium of the Russian Society of Pathologists; Board Member of the Russian Society of Oncohematologists.

23. Oksana P. Trofimova – D.Sc. in Medical Sciences, Leading Researcher at the Radiology Department, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health; Associate Professor at the Department of Oncology, Russian Medical Academy of Continuous Professional Education of the Russian Ministry of Health; Member of the Russian Association of Therapeutic Radiation Oncologists.

24. Vladimir M. Sotnikov – D.Sc. in Medical Sciences, Head of the Radiation Therapy Laboratory, Russian Scientific Center of Roentgenology and Radiology of the Russian Ministry of Health.

25. Nikolay V. Ilyin – D.Sc. in Medical Sciences, Professor, Professor at the Department of Radiology, Surgery and Oncology, Chief Researcher at the Department of Radiation and Combined Treatment Methods, Academician A.M. Granov Russian Scientific Center of Radiology and Surgical Technologies of the Russian Ministry of Health.

26. Yulia N. Vinogradova – D.Sc. in Medical Sciences, Head of the Department of Radiation and Combined Treatment Methods, Chief Researcher at the Department of Radiation and Combined Treatment Methods, Academician A.M. Granov Russian Scientific Center of Radiology and Surgical Technologies of the Russian Ministry of Health.

27. Alexey A. Nevolskikh – MD, PhD, Deputy Director for Clinical Work, A.F. Tsyb Medical Radiological Research Center – branch of the National Medical Research Radiological Center of the Russian Ministry of Health.

28. Olga V. Mukhortova – D.Sc. in Medical Sciences, Professor at的天 Department of Diagnostic Radiology, Leading Researcher at the Department of Nuclear Diagnostics, A.N. Bakulev National Medical Research Center for Cardiovascular Surgery of the Russian Ministry of Health

There is no conflict of interest.

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience for these clinical guidelines:

1. Hematologists.

2. Oncologists.

3. Pediatric hematologist-oncologists.

4. Radiologists.

5. Medical students.

Methodology for evidence collection

Methods used for the collection/selection of evidence:

• search for publications in peer-reviewed journals with an impact factor >0.3;

• electronic database searching.

Databases used to collect/select evidence. The evidence base for the recommendations consists of publications included in the Cochrane Library, PUBMED, and MEDLINE databases. The search depth was 30 years.

Methods used for evidence analysis:

• reviews of published meta-analyses;

• systematic reviews with evidence tables.

Methods used for assessing the quality and strength of evidence:

• expert consensus;

• assessment of the significance of evidence in accordance with the evidence rating scheme (Tables 4, 5).

In these clinical guidelines, the levels of evidence for recommendations are given in parentheses in accordance with the scales developed by the American Society of Clinical Oncology (ASCO) and the European Society for Medical Oncology (ESMO).

Table A2.1. Scale for grading the levels of evidence (LE) for diagnostic methods (diagnostic interventions)

Table A2.2. Scale for assessing the levels of certainty of evidence for prevention, treatment, and rehabilitation methods (preventive, therapeutic, and rehabilitative interventions)

Table A2.3. Scale for assessing the grades of recommendation for prevention, diagnostic, treatment, and rehabilitation methods (preventive, diagnostic, therapeutic, and rehabilitative interventions)

Methodology for validation of guidelines

Methods of recommendation validation:

• external expert review;

• internal expert review.

Description of the guideline validation methodology. The preliminary version of these recommendations was reviewed by independent experts who were asked to comment on the quality of evidence interpretation and the development of the recommendations. An expert assessment of the presentation of the recommendations and their readability was also performed.

The recommendations were discussed and approved by leading specialists of specialized federal centers of the Russian Federation and practicing physicians. The draft clinical guidelines was reviewed at meetings of the working group in 2017–2018, at the Expert Forum on the Diagnosis and Treatment of Malignant Lymphoproliferative Diseases "Lymphoforum", the annual Russian Conference with International Participation "Malignant Lymphomas", and within the framework of the IV Congress of Hematologists of Russia.

Final edition. For the final edition and quality control, the recommendations were re-evaluated by the members of the authoring team, who concluded that all essential remarks and comments from experts were taken into account, and the risk of bias during development was minimized.

Appendix A3. Reference Materials

Appendix A3.1. Drug regimens

During chemotherapy, it is recommended to monitor the patient's weight and recalculate the doses of antineoplastic agents if the weight changes.

3.1.1 First-line treatment regimens in patients over 18 years of age with nodal T-cell lymphomas

CHOP [161-163]

Maintenance therapy in patients over 18 years of age with nodal T-cell lymphomas with Tfh phenotype [151]:

#dexamethasone** 10 mg/m² orally days 1-3

#methotrexate** 20 mg/m² IV or IM days 2, 9, 16, 23

Administered for 24 months from the end of induction therapy.

Or

#lenalidomide** 15-25 mg orally daily on days 1-21 of a 28-day cycle

Administered for 24 months from the end of induction therapy.

LB-M-04 [151]

Block A:

• #Dexamethasone**, 10 mg/m² IV infusion, days 1-5.

• Vincristine**, 1.4 mg/m² IV bolus (maximum 2 mg), day 1.

• #Methotrexate**, 1500 mg/m² IV infusion over 12 hours, day 1; 12 hours after the end of #methotrexate** infusion, calcium folinate** is administered.#

• Cytarabine**, 150 mg/m² IV infusion every 12 hours, days 4-5.

• #Etoposide**, 100 mg/m² IV infusion, days 4-5.

• #Ifosfamide**, 800 mg/m² IV infusion, days 1-5 (mandatory with mesna** administered during the infusion, 4 and 8 hours after the end of #ifosfamide** infusion, at a dose of 60% of the administered #ifosfamide** dose).

Block C:

• #Dexamethasone**, 10 mg/m² IV infusion, days 1-5.

• #Methotrexate**, 1500 mg/m² IV infusion over 12 hours, day 1; 12 hours after the end of #methotrexate** infusion, calcium folinate** is administered.#

• #Vinblastine**, 10 mg IV push, day 1.

• #Cytarabine**, 2 g/m² every 12 hours, 3-hour IV infusion, days 2-3.

• #Etoposide**, 150 mg/m² IV infusion, days 3-5.

3.1.2 Treatment regimens for relapsed nodal T-cell lymphomas

3.1.3 Treatment regimens for NK/T-cell lymphomas in patients over 18 years of age

SMILE [40]

GELOX or P-GEMOX [39]

DDGP [40]

Treatment regimens for NK/T-cell lymphomas in patients under 18 years of age

SMILE (mSMILE) [154]

DDGP [40, 151]

Intratechal administration of drugs (in patients under 18 years of age, CNS-directed therapy NOS) [132]

3.1.4 Treatment regimen for ALCL in patients under 18 years of age

ALCL 99 treatment protocol [51, 132, 153]:

Relapse treatment regimen for ALK+ ALCL in patients under 18 years of age [152]:

SR group (standard risk group)

#Vinblastine** (L01CA01) courses for 24 months and #crizotinib** (L01ED01) for 36 months (regimens and dosages are indicated below)

#VINBLASTINE** (L01CA01)

#Crizotinib** (L01ED01) 165 mg/m² daily orally long-term up to 36 months [152-153]

HR group (high-risk group)

All patients receive prophase.

CC course [146]

Days 1-3 – moisturizing eye drops

If nystagmus/ataxia develops – stop #cytarabine** infusion; if it recurs – discontinue permanently

Monitor blood pressure, allergic reactions, and arrhythmias during and for 5 hours after #etoposide** infusion

CVA course [146]

VHR group (very high-risk group)

All patients receive prophase [152, 153]

ICM [146]

ICI [146]

Treatment of relapsed ALK+ ALCL in patients over 18 years of age

Late relapses: monotherapy with #vinblastine** and #crizotinib** for 24 months [55, 151, 156]

VINBLASTINE** (L01CA01) [55]

#CRIZOTINIB** [151, 157]

The drug is administered orally at a dose of 250 mg twice daily continuously until disease progression or unacceptable toxicity (similar to pediatric practice, the duration of treatment is 24 months). Mandatory antiemetic therapy is recommended.

Appendix A3.2. Recommendations for dose reduction or schedule extension during myelosuppressive cytostatic therapy

Treatment should be administered at full doses according to the regimen if on the day of antineoplastic drug administration the neutrophil count is >1×10⁹/L and platelet count is >100×10⁹/L, but only if the nadir has already passed.

If the required neutrophil count is not reached by the scheduled date of antineoplastic administration, colony-stimulating factor administration is continued at previous doses until neutrophils reach >1×10⁹/L with daily blood count monitoring; thereafter, blood tests are repeated every other day. Treatment is resumed once the above parameters are achieved.

If blood counts recover within the subsequent 14 days, the next cycle is administered at full doses.

If blood counts do not recover within an additional 14 days, or in the event of a repeated cycle delay due to myelotoxicity of more than 10 days, drug doses are reduced to 75% of the starting dose (except for vincristine** and #prednisolone** doses).

If the required platelet count is not reached by the scheduled day of antineoplastic administration, subsequent blood tests are repeated on days 3, 7, 10, and 14; treatment is resumed once the above parameters are attained. If blood counts recover within an additional 14 days, the cycle is administered at full doses. If blood counts do not recover within an additional 14 days, dose reduction is performed in the next cycle according to the same scheme as for prolonged neutropenia.

Appendix A3.3. Autologous hematopoietic stem cell transplantation

Mobilization and collection of peripheral blood hematopoietic stem cells

Mobilization is a sharp increase in the number of hematopoietic stem cells (HSCs) in the peripheral blood under the influence of growth factors.

Several HSC mobilization regimens are used in oncohematology, each employing G-CSF (ATC L03AA Colony-stimulating factors).

Decision-making algorithm prior to HSC mobilization

• assessment of the patient's status (presence of indications for autologous hematopoietic stem cell transplantation (auto-HSCT), standard evaluation to rule out contraindications to high-dose therapy, comorbidity, patient consent, review of prior therapy – number of cycles and completion dates, use of radiation therapy)

• assessment of disease status – depth of antitumor response, presence of remission, time to its achievement;

• assessment of hematopoiesis (bone marrow biopsy to detect hematopoietic lineage suppression as well as bone marrow infiltration by tumor cells)

Pre-transplantation conditioning regimens for auto-HSCT

For pre-transplantation conditioning in NHL, the BEAM conditioning regimen is used, which consists of #carmustine** (300 mg/m², day –6), #etoposide** (200 mg/m², days –5 to –2), #cytarabine** (200 mg/m² twice daily, days –5 to –2), and #melphalan** (140 mg/m²/day, day –1) [134–135]. Administration schedules and doses are presented in Table 4.

Early toxicity of the BEAM regimen includes severe mucositis, nausea and vomiting, diarrhea, hepatotoxicity, nephrotoxicity, and non-infectious pulmonary complications.

Late toxicity includes pulmonary complications such as chronic interstitial fibrosis and decreased diffusing capacity of the lungs (21%), infection (30%), metabolic syndrome (17%), cardiovascular complications (12%), and secondary malignancies (20%).

Table 4. BEAM pre-transplantation conditioning regimen in patients over 18 years of age [134, 135–137]

To reduce the toxicity of the BEAM pre-transplantation conditioning regimen, #lomustine** is used instead of #carmustine** in certain cases (CEAM/LEAM). Administration schedules and doses are presented in Table 5.

Table 5. LEAM pre-transplantation conditioning regimen 137–140]

Antisecretory therapy

Currently, two classes of drugs are used for antisecretory purposes: proton pump inhibitors (PPIs) and H2-histamine receptor blockers [7].

Appendix B. Physician Action Algorithms

Appendix C. Patient Information

Lymphomas are tumors originating from lymphoid cells. Lymphoma is not a single disease; it is a large group comprising more than 30 different disorders that differ from one another in their manifestations, clinical course, and treatment response. Lymphomas behave and are treated quite differently. Therefore, simply using the word "lymphoma" means nothing—to understand how to treat it, one must know the specific variant of lymphoma.

Peripheral T-cell lymphoma belongs to a group of diseases that account for 10–15% of all human lymphomas. The name indicates that the tumor consists of T-cells. T-lymphocytes are the most formidable immune defenders, as they destroy foreign bacteria and the body's own diseased cells. Like an apple on a tree, the entire maturation process of a young cell into a mature T-lymphocyte goes through several stages. A disruption and the formation of a diseased tumor cell clone can occur at any stage. In peripheral T-cell lymphoma, the tumor arises at the final maturation stage, at the level of the mature T-cell. Tumor T-lymphocytes resemble normal cells found in the peripheral (circulating) blood, hence the name "peripheral."

Some peripheral T-cell lymphomas have specific features; for example, primary cutaneous peripheral T-cell lymphoma most commonly appears in the skin and subcutaneous tissue. However, the most frequent type, "peripheral T-cell lymphoma, not otherwise specified," has no characteristic features and can appear in all organs and tissues. The manifestations of this disease overlap with the signs of other lymphomas. Patients usually complain of pain due to tumor growth, which can occur anywhere in the body. In this disease, lymph nodes enlarge in groups in the neck, armpits, groin, and other areas. The patient may also be bothered by signs of the disease known as "B-symptoms": fever, rapid weight loss, and profuse sweating in the evening and at night. Peripheral T-cell lymphomas typically present with skin rashes and indurations.

To establish a correct diagnosis, a piece of the tumor or an enlarged lymph node is invariably biopsied for morphological and immunohistochemical examination. Only such a sophisticated, comprehensive analysis allows for an accurate diagnosis and effective treatment.

To determine precisely whether there are enlarged lymph nodes and what their number is in parts of the body that cannot be visualized on external examination, a computed tomography (CT) scan is required. The stage of the disease is determined using the Ann Arbor staging system, which reflects which organs and lymph nodes are involved.

Treating peripheral T-cell lymphoma, unspecified, is challenging. About 40% of cases are successfully treated. At the same time, physicians continuously strive to improve treatment outcomes by adopting new methods and utilizing novel drugs.

Angioimmunoblastic lymphoma belongs to the group of T-cell lymphomas. The disease manifestations generally overlap with those of other lymphomas: lymph nodes enlarge in groups in the neck, armpits, groin, and other areas; the liver and spleen often enlarge; and fluid accumulates in the pericardial and pleural cavities. Patients usually complain of pain due to tumor growth, which can occur anywhere in the body. As with other T-cell lymphomas, various skin rashes and indurations may occur. Autoimmune complications are also possible.

Treating angioimmunoblastic lymphoma is challenging. About 60% of cases are successfully treated. At the same time, physicians continuously strive to improve treatment outcomes by adopting new methods and utilizing novel drugs.

Anaplastic large cell lymphoma belongs to the aggressive class of T-cell lymphomas, characterized mainly by enlargement of the lymph nodes. In anaplastic lymphoma, tumor cells undergo such profound changes that they completely lose all features of maturation and appear as blastic cells. This is referred to as "anaplasia".

The treatment of anaplastic large cell lymphoma depends on the presence or absence of an enzyme called "ALK" in the tumor. It is detected during an immunohistochemical study of the lymph node. If the ALK enzyme is present, the lymphoma is called ALK-positive. Such lymphomas are successfully treated in 70% of cases. If milder, relatively small doses of medications fail to cure the patient, high-dose chemotherapy with autologous stem cell rescue is performed. If the ALK enzyme is absent, the lymphoma is called ALK-negative. The treatment outcomes for ALK-negative lymphomas are somewhat worse; however, new drugs are constantly emerging that help improve the treatment of such patients.

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

Appendix G1. Eastern Cooperative Oncology Group (ECOG) Performance Status Scale

Original title: The ECOG Scale of Performance Status

Source: Oken M.M. et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am. J. Clin. Oncol. 1982;5(6):649–65 [141]

Type: rating scale

Purpose: clinical assessment of the patient's general condition

Appendix G2. PET visual response evaluation scale

Original title: The Deauville five point scale

Source: Meignan M. et al. Report on the First International Workshop on Interim-PET-Scan in Lymphoma. Leuk Lymphoma. 2009;50(8):1257–1260 [142]

Type: rating scale

Purpose: evaluation of PET/CT scan results

Content and interpretation: to standardize, ensure reproducibility, and allow comparison of PET/CT results obtained in various medical institutions when assessing treatment efficacy in lymphoma patients, a 5-point visual scale for PET data analysis is used [142]. The intensity of Fludeoxyglucose [18F] uptake in the target lesion is compared with the uptake in the unaffected mediastinum or the right hepatic lobe:

Score 1 – no uptake in the previously identified pathological lesion;

Score 2 – uptake in the pathological lesion is no greater than uptake in the unaffected mediastinum;

Score 3 – uptake in the pathological lesion is higher than in the mediastinum, but no greater than uptake in the right lobe of the liver;

Score 4 – uptake in the pathological lesion is moderately higher than in the liver;

Score 5 – uptake in the pathological lesion is markedly higher than in the liver, or new disease-related lesions appear.

Additionally, the concept of X-scores has been introduced, characterizing the presence of Fludeoxyglucose [18F] uptake foci of uncertain, likely inflammatory genesis, the association of which with the underlying disease is unlikely.

Interpretation of PET results using the Deauville scale is performed comprehensively, taking into account clinical and baseline PET data, the stage of treatment, and other indicators of treatment response.

Appendix G3. Khorana Scale for VTE Risk Assessment in Patients Receiving Chemotherapy

Original title:

Source: Development and Validation of a predictive model for chemotherapy-associated thrombosis. Blood. 2008;111(10):4902–4907 [143]

Type: rating scale

Purpose: clinical assessment of the patient's general condition