Follicular Lymphoma: Clinical Guidelines

List of Abbreviations

ALT – alanine aminotransferase

Anti-CD20 mAbs – anti-CD20 monoclonal antibodies (CD20 [cluster of differentiation 20] inhibitors)

AST – aspartate aminotransferase

auto-HSCT – autologous hematopoietic stem cell transplantation

aPTT – activated partial thromboplastin time

PFS – progression-free survival

HDCT — high-dose chemotherapy

WHO – World Health Organization

GC – glucocorticoids

DLBCL – diffuse large B-cell lymphoma

IPT – immunophenotyping of biological material for the detection of hemoblastosis markers

CT – computed tomography

LDH – lactate dehydrogenase

INR – international normalized ratio

MRI – magnetic resonance imaging

OS – overall survival

PFL – pediatric-type follicular lymphoma

PET – positron emission tomography

SFD – single focal dose

TFD – total focal dose

US – ultrasound examination

FL – follicular lymphoma

EGD – esophagogastroduodenoscopy

ECG – electrocardiography

Echo-CG – echocardiography

ECOG – performance status scale

FLIPI – Follicular Lymphoma International Prognostic Index

18F-FDG – Fludeoxyglucose [18F]

** – vital and essential drugs

# – drug used not in accordance with the indications, contraindications, routes of administration, and doses contained in the drug's instructions for use (off-label)Terms and definitions

ECOG – assessment of the patient's general condition using the scale developed by the Eastern Cooperative Oncology Group – 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

Follicular lymphoma (FL) is a neoplasm originating from germinal center B-cells (centrocytes and centroblasts [large transformed lymphoid cells]), which in the vast majority of cases exhibits at least partially a follicular growth pattern. Very rarely, FL presents on histological examination at disease onset with solely a diffuse growth pattern consisting of small and large lymphoid cells. Diffuse large B-cell lymphoma (DLBCL) consisting predominantly of centroblasts is considered a manifestation of FL progression resulting in DLBCL [1, 2].

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

The etiology of FL is unknown. A characteristic chromosomal aberration, t(14;18)(q32;q21), has been identified in FL; however, additional genetic and molecular events are required for FL development, alongside likely immunological influences on the transformed lymphoid cells from the cellular microenvironment.

1.3 Epidemiology of the Disease or Condition

FL ranks second globally in frequency among lymphomas, accounting for an average of 20% of all malignant lymphoproliferative disorders in adults. This figure varies significantly across geographic regions and also depends on the ethnic and racial background of patients: in Asian countries, the proportion of FL within the structure of lymphoproliferative diseases is substantially lower than in Europe at 9–10%. According to various sources, the incidence of FL in Western countries is 5–7 per 100,000 population. In the USA, this diagnosis is established in 14,000 individuals annually. The median patient age is 60 years, and the male-to-female ratio is approximately 1:1.7 [3].

In the age group under 18 years across various countries (Japan, USA, Europe), the frequency of pediatric FL is no more than 1%.

1.4 Features of Coding the Disease or Condition

C82 – Follicular (nodular) non-Hodgkin lymphoma:

C82.0 – Small cleaved cell follicular lymphoma

C82.1– Mixed small cleaved and large cell follicular lymphoma

C82.2 – Large cell follicular lymphoma

C82.7 – Other types of follicular non-Hodgkin lymphoma

C82.9 – Follicular non-Hodgkin lymphoma, unspecified

C85.9 – Non-Hodgkin lymphoma, unspecified type

1.5 Classification of the disease or condition

Based on morphological characteristics (depending on the ratio of follicular to diffuse tumor growth areas), FL is traditionally subdivided into three groups. Specifically, in the nodular type of FL, more than 75% of the tumor is represented by follicular involvement; in the nodular-diffuse type, this indicator ranges from 25% to 75%; and in the diffuse type, it is less than 25%. The cytological type of FL is determined by the cellular composition (the ratio of centrocytes to centroblasts calculated via microscopic evaluation of 10 involved follicles). In cytological type 1, the percentage of centroblasts ranges from 0 to 5; in cytological type 2, from 6 to 15; and when the centroblast count exceeds 15%, cytological type 3 FL is established. Type 3 FL is further subdivided into two subtypes based on the presence or absence of centrocytes in the histological specimen: type 3A is diagnosed if centrocytes are detected, and type 3B if they are absent. The majority of newly diagnosed FL cases (80–90%) are represented by cytological types 1–2 and can be grouped together due to the absence of significant differences in morphological and clinical manifestations [1].

When establishing a diagnosis, the presence of six variants of FL according to the 2017 WHO classification should be considered [1]:

1. Follicular lymphoma in situ (characterized by a low risk of disease progression).

2. Duodenal-type follicular lymphoma: the tumor is localized exclusively in the duodenum, the risk of dissemination is low, prognosis is favorable, the expression profile of the BCL2 family genes is similar to nodal FL; features shared with H. pylori-associated MALT lymphoma, in contrast to nodal FL, include high expression of CCL20 and MADCAM1.

3. Testicular-type follicular lymphoma: large cell (cytological type 3A), absence of t(14;18) translocation, absence of BCL2 protein expression, absence of BCL2 gene rearrangement and TP53 gene abnormalities, favorable prognosis; the presence of BCL6 protein expression indicates an alternative molecular pathway of pathogenesis (biologically distinct from nodal FL).

4. Large B-cell lymphoma with IRF4 rearrangement: typically involves cervical lymph nodes and Waldeyer's ring, minimal tendency for dissemination, microfollicles, CD10+, CD23+, BCL2 weak or absent expression, absence of t(14;18), absence of BCL2 gene rearrangement, but gene expression profile corresponds to nodal FL; del(1p36) is detected in the majority of cases but is not specific.

5. Pediatric-type follicular lymphoma – an indolent clonal follicular proliferation manifesting as localized lymphadenopathy primarily in the head and neck region and, extremely rarely, extranodal sites. Boys are affected more frequently. Cytologically, the tumor most commonly belongs to type 3 with a high proliferation index (median Ki-67 35%). In the vast majority of pediatric FL cases, aberrant BCL2 protein expression and rearrangement of the corresponding gene are not detected. Standardized staging systems and risk factors for pediatric FL have not been developed; the S. Murphy staging system adopted in pediatric hemato-oncology is most frequently used. Isolated cases of transformation into DLBCL have been described, predominantly in adolescents. As a rule, the clinical course is benign, and patients without transformation do not require urgent treatment initiation. The prognosis for pediatric FL is favorable; remissions have been achieved with moderate-intensity chemotherapy, and relapses are rare. Cases of achieving remission following the excision of solitary enlarged lymph nodes without recurrence in the absence of systemic therapy have been described. The localized anatomical distribution and benign clinical course raise the question of whether pediatric FL is a malignant neoplasm or represents a benign clonal proliferation with very low malignant potential.

6. Primary cutaneous follicle center lymphoma – characterized by localized skin involvement, absence of BCL-2 expression, and absence of t(14;18). The prognosis is favorable; for localized lesions, surgical treatment and involved-field radiotherapy are effective.

According to the new WHO classification [5th edition] [4], FL will encompass the following disease variants:

1. Follicular B-cell neoplasia in situ;

2. Follicular lymphoma

2.1. Classical FL;

2.2. FL with atypical cytological features;

2.3. FL with a predominantly diffuse growth pattern;

2.4. Follicular large B-cell lymphoma;

3. Pediatric-type follicular lymphoma;

4. Duodenal-type follicular lymphoma.

Primary cutaneous follicular lymphoma is addressed in a separate section.

For the first time in the 5th edition of the WHO classification, a new variant of FL will be distinguished – FL with atypical features, comprising two subvariants: the blastic variant and the large cell variant with centrocyte-like nuclei.

Blastic variant of FL (BVFL) is extremely rare – in 2.7% of cases, exhibits morphological features of a high-grade lymphoma, and does not meet any diagnostic criteria for FL (neither for FL type 3A nor type 3B). The tumor biopsy visualizes a follicular/nodular FL growth pattern, with the substrate represented by large cleaved cells or small- to medium-sized blastic cells. Tumor cells show high expression of MUM1 and Ki67; BCL2 gene rearrangements are absent, while BCL6 gene rearrangements are frequently diagnosed. In the treatment of BVFL, R-CHOP regimens are less effective than in FL cytological types 1–2 with a comparable FLIPI risk group.

The large-cell variant of FL with centrocyte-like nuclei is characterized by the predominance of large "cleaved" cells (centrocytes) in the tumor substrate and a small number of centroblasts. At low magnification, the histological specimen shows a follicular/nodular-diffuse growth pattern and frequently follicular and/or interfollicular fibrosis. On microscopy, the tumor cells appear as large cleaved cells with condensed chromatin and pale cytoplasm; nucleoli are typically absent. The mean nuclear diameter of the large cleaved cells was 10.1 µm, which is approximately twice that of normal lymphocytes and comparable to centroblasts. The BCL2 gene rearrangement occurs in 83% of cases; immunohistochemically, the tumor cells express BCL2 (84%), BCL6 (100%), and CD10 (88%), with a mean Ki67 of 81%. The most effective therapeutic regimen is the R-CHOP course.

1.6 Clinical presentation of the disease or condition

FL is primarily characterized by lymph node enlargement, involving both peripheral and visceral nodes. Lymph nodes in FL can present either as single, small, elastic nodes or as fairly large conglomerates. Other clinical symptoms may be absent for a long time. Over time, B symptoms develop—fatigue, sweating, and weight loss. Sometimes symptoms of FL may be related to specific infiltration of non-lymphoid organs. The disease is predominantly characterized by a prolonged indolent course, although an aggressive course of the lymphoma is possible in some cases.

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 grading scales for evidence and reliability of clinical recommendations) due to the lack of clinical studies dedicated to them. Despite this, they are necessary components of patient examination for establishing a diagnosis and selecting treatment tactics, as more effective and proven methods have not yet been developed.

Criteria for establishing the diagnosis/condition: the diagnosis of FL is established based on pathomorphological and immunohistochemical examination of biopsy material and is formulated in accordance with the revised WHO 2017 classification of tumors of hematopoietic and lymphoid tissues [1, 5]. Considering the proven differences in the clinical course of the two FL variants—with the presence/absence of t(14;18), the prognostic significance of t(14;18) in the course of FL, and fundamentally clear differences in antitumor response, it is advisable for patients to undergo a cytogenetic study (standard cytogenetic examination of the tumor biopsy or FISH on touch imprints/tissue sections from the paraffin block of the tumor biopsy) to detect t(14;18). To exclude additional genetic abnormalities, it is advisable to study BCL-6 and CMYC gene rearrangements (on touch imprints/tissue sections from the paraffin block of the tumor biopsy) [6-8].

2.1 Complaints and Anamnesis

• All patients with suspected FL, as well as all patients with verified FL at every medical consultation, are recommended to undergo a history taking for hematological and blood diseases to assess the patient's condition and determine factors that may influence the determination of the patient's treatment strategy [3, 5].

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

Comments: taking complaints and medical history will help determine the nature of the disease course (indolent or aggressive), as well as differentiate symptoms associated with FL from manifestations of other concomitant diseases and conditions.

2.2 Physical Examination

• All patients with suspected or confirmed FL, at the initial or follow-up consultation, during routine check-ups, and when relapse/disease progression is suspected, are recommended to undergo a physical examination (visual inspection, palpation, and auscultation) to clarify the extent of the disease and assess the patient's condition across organ systems [3, 5].

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 FL at the initial or follow-up consultation, after the completion of each treatment cycle and before the start of each new treatment cycle, during response assessment after completion of therapy, during follow-up examinations, and when disease relapse is suspected, are recommended to perform the following diagnostic tests to clarify the patient's condition, plan therapeutic tactics, determine the need for their modification, and assess the need for supportive and concomitant therapy [3, 5]:

• complete blood count (CBC) with differential including determination of total hemoglobin, erythrocytes, platelets, leukocytes, reticulocytes, leukocyte differential with absolute leukocyte and reticulocyte counts, and erythrocyte sedimentation rate (ESR);

• general (clinical) urinalysis;

• routine biochemical blood test including the following parameters: determination of lactate dehydrogenase (LDH), aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase, uric acid, urea, creatinine, glucose, total protein, albumin, total bilirubin, potassium, sodium, chlorides, total calcium, and beta-2-microglobulin levels in the blood (other biochemical parameters may be included at the physician's discretion);

• coagulation profile including the following parameters: prothrombin time, International Normalized Ratio (INR), activated partial thromboplastin time (APTT), fibrinogen, plasminogen, thrombin time, antithrombin III activity, and D-dimer concentration in the blood, as well as, if available, INR determination, antithrombin III activity, and plasminogen level.

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 previously untreated FL patients are recommended to undergo ABO blood grouping and Rh(D) factor testing prior to first-line anti-tumor therapy to enable blood transfusion, if indicated, before, during, or after therapy [3, 5].

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

• All previously untreated FL patients are recommended to undergo the following tests prior to first-line anti-tumor therapy to determine the presence of concomitant infectious diseases and plan necessary supportive care [3, 5]:

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

• molecular biological blood testing for human immunodeficiency virus HIV-1;

• molecular biological blood testing for Treponema pallidum.

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

Comment: values of viral hepatitis B markers are presented in Appendix A3.2

• All FL patients under 18 years of age before initiating anti-tumor therapy, as well as all FL patients regardless of age receiving or having received anti-tumor therapy, after the first episode of a severe infection are recommended to undergo immune status assessment (serum immunoglobulin G, A, and M levels) to clarify the risk of infectious complications and the need for appropriate prophylaxis [5].

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 "Supportive and Concomitant Therapy").

2.4 Instrumental Diagnostics

• All patients upon FL diagnosis, during treatment response evaluation, and when a relapse is suspected are recommended to undergo spiral computed tomography (CT) of the neck, chest, abdomen, and pelvis (with intravenous bolus contrast enhancement) for disease staging and to determine the presence, size, and extent of tumor lesions [5].

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

• Patients with contraindications to CT, or if CT is not feasible, upon FL diagnosis, during treatment response evaluation, and when a relapse is suspected are recommended to undergo the following diagnostic procedures for disease staging and to determine the presence, size, and extent of tumor lesions [5]:

• targeted chest radiography in two projections;

• ultrasound examination of lymph nodes and comprehensive ultrasound examination of internal organs.

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

• All patients upon FL diagnosis, during treatment response evaluation, and when a relapse is suspected are recommended, if available, to undergo whole-body positron emission tomography with tumorotropic radiopharmaceuticals (fludeoxyglucose, [18F]) for more accurate disease staging and better evaluation of the therapeutic effect [9].

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 makes it not only possible to refine the stage, but also to more accurately determine the localization of lesions, especially extranodal involvements that may be poorly diagnosed by CT, which is of substantial importance for the subsequent evaluation of induction therapy efficacy, high-quality planning of subsequent radiation therapy, and minimization of radiation exposure to healthy tissues. If PET/CT is available, it can be used in accordance with the revised response criteria, primarily in patients with low tumor burden, and also taking into account potential treatment adjustment.

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

• All patients with an established diagnosis of FL presenting with neurological symptoms prior to the initiation of treatment are recommended to undergo CT or MRI of the brain to rule out central nervous system (CNS) involvement and to plan antineoplastic therapy [5].

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

• All patients with an established diagnosis of FL scheduled for treatment of newly diagnosed disease or relapse are recommended to undergo the following examinations for the early detection of comorbid conditions involving the cardiovascular, respiratory, and digestive systems, and to determine the need for their prevention or treatment [5]:

• electrocardiogram recording;

• echocardiography;

• esophagogastroduodenoscopy;

• duplex ultrasound of lower extremity vessels (arteries and veins)

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

2.5 Other Procedures

• All patients with suspected FL, suspected FL relapse, or presenting with clinical features of FL transformation to DLBCL are recommended to undergo a biopsy (obtaining biopsy material) of a lymph node or other lesion, with pathological examination of the biopsy (surgical) material using immunohistochemical methods to verify the diagnosis [3, 5].

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.

• Fine-needle biopsies of lymphoid tissue have low diagnostic value

• Marginal biopsies of lymphoid tissue have low diagnostic value.

• Tissue fragmentation severely impedes its evaluation.

• Tissue samples for histological examination must be placed in fixative as quickly as possible. Drying of the tissue must be avoided.

• 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 patient information, duration and nature of the disease, localization of the lesion, and a description of the biopsy [10].

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.

The histological and immunohistochemical characteristics of FL, as well as mandatory requirements for the pathological report, are presented in section 7.1 of these guidelines. A description of the pathological and immunohistochemical picture of FL is provided in section 7.2 of these guidelines.

In case of FL progression and suspected FL transformation (in cases with uneven enlargement of various groups of affected lymph nodes, high LDH levels, or the presence of B symptoms), PET/CT is advisable to identify areas of probable transformation. If the tracer uptake intensity clearly differs across various zones, a biopsy of the most active lesion must be performed.

• All patients with suspected or confirmed FL initially (for disease staging), upon completion of therapy (for response assessment), and upon suspicion of disease relapse are recommended [5]:

  • obtaining a bone marrow cytological specimen by puncture, cytological examination of a bone marrow smear (myelogram), and in case of an increased number of lymphoid cells, presence of atypical lymphocytes, or cells with blast morphology in the bone marrow – analysis of biological material (bone marrow aspirate) by flow cytometry

  • 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 performed upon the appearance of unexplained cytopenia and fever (regardless of baseline involvement).

In children, iliac crest trephine biopsy must be performed under general anesthesia.

• Patients with verified FL presenting with absolute peripheral blood lymphocytosis at the initial workup are recommended immunophenotyping of biological material (peripheral blood) for differential diagnosis with reactive lymphocytosis [5].

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

Comments: immunophenotypic analysis (IPA) is mandatory in the presence of lymphocytosis in the complete blood count (regardless of leukocyte count) or myelogram, as well as in the predominance of lymphoid cells, atypical lymphocytes, or cells with blast morphology in pleural, ascitic, or other biological fluids. IPA allows for a rapid differential diagnosis of neoplastic and reactive lymphocytosis, which is important for determining the patient's further management strategy.

• For patients with verified follicular lymphoma (FL) during the initial evaluation and treatment planning, it is recommended to assess the risk of venous thromboembolic complications (using the Khorana VTE risk assessment scale – see Appendix G3 of these guidelines) in order to identify patients who require prescription and determination of methods for preventing thrombotic complications during cytostatic therapy [11, 12].

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

• All women of childbearing potential with newly diagnosed FL, as well as relapsed FL, prior to the initiation of therapy are recommended to undergo a set of pregnancy tests to adjust the therapeutic strategy, and to consult an obstetrician-gynecologist in case of pregnancy and the patient's desire to preserve it [5, 13].

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

• Women of childbearing potential with indolent FL who wish to preserve their reproductive function are recommended an initial consultation (examination, consultation) with an obstetrician-gynecologist to address the possibility of oocyte cryopreservation before starting chemotherapy and subsequent ovarian protection [5, 13].

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.

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

• granulocytes >1 × 10⁹/L,

• platelets >100 × 10⁹/L.

  For patients with cytopenia caused by bone marrow involvement, specific therapy is feasible even at lower leukocyte and platelet counts, provided that appropriate supportive care is administered 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 Indications for initiating FL therapy

• Patients with a verified diagnosis of FL are recommended to initiate therapy only in the presence of at least one of the following criteria [3, 10, 11]:

• involvement of ≥3 lymphatic regions with lymph node dimensions of ≥3 cm in diameter;

• any nodal or extranodal involvements greater than 7 cm in diameter (bulky);

• presence of B symptoms;

• splenomegaly;

• pleural effusion and/or ascites;

• cytopenia (leukocytes <1.0 × 10⁹/L and/or platelets <100 × 10⁹/L);

• leukemic blood profile (tumor cells >5.0 × 10⁹/L)

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

Comment: in the absence of the aforementioned indications for treatment initiation, a detailed clinical evaluation should be performed every 3 months, and instrumental imaging of lesions every 6 months. If no signs of disease activity are observed for 2 years, the interval can be extended to 6 and 12 months, respectively. According to the US National LymphoCare Study, 18% of FL patients are offered a watch-and-wait approach after diagnosis, with treatment deferred for 3 years or more in about 40% of patients, and spontaneous remission observed in 15–20% of cases. In most prospective studies, the median time to treatment was 2.5–3.5 years. However, the watch-and-wait approach is applicable only with an adequate assessment of the clinical situation and a realistic possibility of detailed dynamic monitoring, and it has alternative strategies.

3.2 First-line therapy for FL in patients over 18 years of age

• Previously untreated patients with grade 1–2 FL (cytological type), early stages (stage I–II), and low tumor burden are recommended to receive one of the following treatment regimens (at the discretion of the attending physician):

• involved-site radiation therapy, total dose 24–30 Gy [14–18]

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

• rituximab** (R) monotherapy (see Appendix A3.1) [19].

  Level of evidence A (grade of recommendation 2).

Comment: radiation therapy parameters are determined based on the initial extent of the disease, localization, and tumor volume. The definition of baseline lesions should be performed using computed tomography with intravenous bolus contrast enhancement and positron emission tomography.

To reduce the incidence of locoregional relapses, modern 3D-conformal external beam radiotherapy should be delivered using modern medical linear accelerators with multileaf collimators or a proton accelerator using a proton beam.

In the absence of linear accelerators, external beam radiotherapy may be delivered using teletherapy cobalt units.

When performing RT, special immobilization devices should be used to improve the accuracy and reproducibility of patient positioning. 3D conformal planning should be performed with contouring of the lung, cardiac tissues, and contralateral breast to minimize the dose load on them. The dose to a given target should be calculated according to the recommendations of the International Commission on Radiation Units and Measurements ICRU-50, 62, and 83 [20], and doses to normal tissues should be limited according to QUANTEC data, without compromising the coverage of the planned target volume [21].

C current time upon dosimetric planning of irradiation should    distinguish: general volume tumor – gross-tumor volume (GTV), clinical volume tumor – clinical target volume (CTV), planning volume target – planning target volume (PTV). PTV is determined in each specific case depending on the goal and objectives of radiation therapy.

In stages I and II FL, when the clinically detectable lesion is limited to lymph nodes, it must be taken into account that there is a probability of a larger tumor volume due to potential microscopic involvement of adjacent tissues. Therefore, when using radiotherapy as the sole treatment method, it is advisable to use the involved-site radiation therapy (ISRT) volume rather than involved-node radiotherapy (INRT). The planning target volume in early-stage FL will correspond to the clinical tumor volume (CTV) at the start of treatment.

Planning of external beam radiotherapy is carried out using visualization methods that allow obtaining three-dimensional images. Treatment should preferably be performed on a linear electron accelerator using standard dose fractionation (one fraction per day, 5 times a week), with a single focal dose of 1.8–2.0 Gy and a total focal dose (TFD) of 24–30 Gy to the affected areas. In the absence of complete tumor regression, additional local irradiation ("boost") with a TFD of 6–10 Gy can be used.

Rituximab** is used as an induction regimen of 4 weekly infusions, followed by 4 infusions every 2 months (short course) or maintenance therapy every 8 weeks for 2 years (extended course). Early initiation of rituximab treatment** has advantages in progression-free survival compared with the "watch and wait" approach, but there are currently no data on overall survival improvement. According to the RESORT study results, retreatment with a 4-week course of rituximab** upon disease progression is no less effective than its long-term administration. Obinutuzumab** is currently not used as monotherapy in patients with FL.

• Previously untreated patients with grade 1–2 FL, with advanced stages (III–IV) but low tumor burden, who have indications for treatment initiation, are recommended rituximab** monotherapy (see Appendix A3.1) to achieve remission [19]

  Level of evidence A (grade of recommendation 2).

• Previously untreated patients with grade 1–2 FL, with early stages (I–II) and generalized stages (III–IV) with high tumor burden, as well as patients with grade 3 FL, are recommended to undergo one of the following systemic drug therapy regimens (at the discretion of the attending physician – see Appendix A3.1) [20–24, 221]:

• 6 cycles of CHOP + obinutuzumab** or rituximab** + 2 additional infusions of obinutuzumab** or rituximab**, respectively (G/R-CHOP) (See Appendix A3).

• 6 cycles of bendamustine** + obinutuzumab** or rituximab** (G/R-B) (See Appendix A3).

• 8 cycles of CVP + obinutuzumab** or rituximab** (G/R-CVP) (See Appendix A3).

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

Comment: several large randomized controlled trials have shown that the addition of rituximab** to standard chemotherapy increases progression-free survival and overall survival of patients.

The phase III GALLIUM study compared the efficacy and safety of the third-generation CD20 (cluster of differentiation 20) inhibitor obinutuzumab** combined with various chemotherapy regimens (CHOP, CVP, or bendamustine**), followed by maintenance therapy with obinutuzumab** or rituximab** in patients with advanced follicular lymphoma.

Updated PFS data (at a median follow-up of 76.5 months) demonstrate consistent results: 5-year PFS was significantly higher in the obinutuzumab** + chemotherapy group than in the rituximab** + chemotherapy group (HR 0.76 [0.62–0.92], p=0.0043). The risk of progression, relapse, or death is 24% lower in the obinutuzumab**-containing immunochemotherapy group than in the rituximab-containing therapy group. Five-year PFS was 70.5% in the obinutuzumab** group and 63.2% in the rituximab** group (at a median follow-up of 76.5 months).

In recent years, immunochemotherapy has been the standard first-line treatment for the majority of patients with FL. When choosing anti-CD20 mAbs, preference is given to the most effective regimens—combinations with obinutuzumab**.

The combination of CHOP with obinutuzumab** or rituximab** is the preferred treatment regimen for patients with grade 3 FL or when tumor transformation is suspected (short anamnesis, elevated LDH, B symptoms, extranodal involvement, rapid enlargement of tumor foci). The efficacy of the anti-CD20 mAb and bendamustine** regimen is comparable to that of the anti-CD20 mAb and CHOP regimen, with a somewhat more favorable toxicity profile.

• Previously untreated elderly or frail patients with FL who cannot tolerate intensive polychemotherapy, in the presence of indications for treatment initiation, are recommended the use of chlorambucil** in combination with rituximab** [170]

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

• or cyclophosphamide** as monotherapy, or rituximab** as monotherapy (see Appendix A3.1) [19, 183–184].

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

• Patients with FL presenting with bulky or extranodal (bones, soft tissues, skin) disease who have achieved partial remission, if further systemic polychemotherapy is unfeasible (presence of severe comorbid conditions), are recommended to undergo radiotherapy to the residual tumor, TFD 26–30 Gy [15–17]

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

3.3 Consolidation of FL remission in patients over 18 years of age

• Patients with FL who have achieved complete or partial remission after first-line therapy with rituximab** monotherapy, rituximab**-containing chemotherapy, or obinutuzumab**-containing chemotherapy are recommended to receive maintenance therapy [19, 20, 22, 25, 26].

• maintenance therapy with rituximab** once every 2 months for 2 years, total of 12 infusions to maintain remission [19, 25, 26].

• maintenance therapy with obinutuzumab** once every 2 months (starting 2 months after the last dose of induction therapy) for 2 years, total of 12 infusions [20, 22].

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

Comment: maintenance therapy should be discontinued upon the appearance of signs of progression.

For patients who received bendamustine**-containing regimens, maintenance therapy increases the risk of infectious complications; therefore, upon achieving complete PET-negative remission in patients with severe infectious complications during induction therapy, maintenance therapy may be omitted [27].

• Patients with FL presenting with bulky or extranodal (bones, soft tissues, skin) disease who have achieved partial remission, if further systemic polychemotherapy is unfeasible (presence of severe comorbid conditions), are recommended to undergo radiotherapy to the residual tumor, TFD 26–30 Gy [14–18].

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

3.4 Treatment of relapsed and refractory forms of FL in patients over 18 years of age

The choice of optimal therapeutic tactics in patients with relapsed/refractory FL depends on: the time to relapse/progression relative to prior treatment, the type of prior treatment, the clinical presentation of relapse/progression, the patient's age and performance status, and the presence or absence of resistance to rituximab** .

• Patients with relapsed FL are recommended to initiate therapy only in the presence of at least one of the following criteria [3, 14, 15]:

• involvement of ≥3 lymphatic regions with lymph node dimensions of ≥3 cm in diameter;

• any nodal or extranodal involvements greater than 7 cm in diameter (bulky);

• presence of organ compression signs;

• intoxication symptoms, ECOG performance status >2 attributable to the tumor (if other causes have been excluded);

• splenomegaly;

• pleural effusion and/or ascites; symptoms of organ compression and impaired function, liver, kidney, or bone involvement;

• cytopenia (leukocytes <1.0 × 10⁹/L and/or platelets <100 × 10⁹/L);

• leukemic blood profile (tumor cells >5.0 × 10⁹/L)

• histologically/immunohistochemically confirmed transformation of FL into DLBCL

CGR CLEL 5Category of Recommendations C (Level of Evidence 5).

Comment: just as during the initial presentation, a watch-and-wait strategy may be offered to the patient during a relapse, and the initiation of treatment may be postponed if there are no indications of the kind listed above. The treatment strategy for relapses depends on many factors, but the decisive ones remain: the duration of the preceding remission and the method by which it was achieved. For example, the prognosis for repeated long-term survival in patients with FL progression during observation without antineoplastic therapy, or in patients with relapses less than 6 months after the completion of immunochemotherapy, differs fundamentally, as if two different diseases were concerned. OS (overall survival) directly depends on the time of disease progression. Interim analysis of OS in patients with or without disease progression within the first 24 months (POD24) shows that POD24 is associated with a high risk of transformation, refractory course, and early tumor-related mortality [29, 30].

• In patients with relapsed FL without signs of transformation to DLBCL developing less than 6 months after the last administration of rituximab**, if there are indications for initiating treatment, it is recommended to use alternative chemotherapy regimens (e.g., bendamustine** after CHOP) in combination with obinutuzumab** [24].

GGR ALEL 2Grade of Recommendation A (Level of Evidence 2).

Comment: Rituximab**-refractoriness** after first-line immunochemotherapy develops in 25% of patients [24]. Early disease progression (POD24) develops in 20% of patients who received first-line immunochemotherapy [25]. Patients with POD24 fall into the category of rituximab**-refractory, since rituximab**-refractoriness is defined as the lack of response or disease progression during rituximab**-containing therapy (monotherapy or as part of immunochemotherapy) or progression within 6 months after the last administration of rituximab**.

The randomized phase III GADOLIN study demonstrated high efficacy of obinutuzumab** in rituximab**-refractory FL. The use of obinutuzumab** in combination with bendamustine** followed by obinutuzumab** maintenance therapy more than doubled progression-free survival compared to bendamustine** monotherapy and also increased overall survival, which allows recommending obinutuzumab** in combination with bendamustine** followed by obinutuzumab** maintenance monotherapy for patients with follicular lymphoma who failed to respond to rituximab** or rituximab**-containing regimens, or who experienced disease progression during or after such treatment [26].

• In patients with relapsed FL without signs of transformation to DLBCL developing later than 6 months after the end of therapy (including maintenance therapy with rituximab**), if there are indications for initiating treatment, it is recommended to use one of the following drug therapy regimens (at the discretion of the attending physician):

• use of alternative chemotherapy regimens (e.g., bendamustine** after CHOP) in combination with obinutuzumab** or rituximab** [3, 10, 11, 24].

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

Comment: taking into account the fact that FL progression within the first 24 months is associated with low OS, preference is given to the most effective regimens—combinations with obinutuzumab**—when choosing anti-CD20 mAbs.

• use of a combination of rituximab** and #lenalidomide** (see Appendix A3) [25].

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

• For transplant-eligible patients with advanced stage and high tumor burden in case of confirmed refractoriness after the end of 1st-line therapy, it is recommended to use protocols for the treatment of relapsed aggressive NHL (GEMOX, ICE, DHAP, ESHAP, GDP, etc., in combination with mAbs [monoclonal antibodies and antibody-drug conjugates]) (see clinical guidelines for the treatment of aggressive non-Hodgkin lymphomas) and, if complete remission is achieved with therapy, to perform high-dose chemotherapy (HDCT) with autologous hematopoietic stem cell transplantation for remission consolidation (auto-HSCT) [33, 34, 35, 171, 185-188, 222].

GEMOX, GDP in combination with mAbs

GGR BLEL 2Grade of Recommendation B (Level of Evidence 2) [171, 187, 223].

ICE, DHAP, ESHAP in combination with MA

Level of Evidence CGrade of Recommendation 4Level of Evidence C (Reliability Grade of Evidence 4) [185-188, 222].

• For patients with relapse less than 24 months after the start of induction therapy who are candidates for transplantation, it is recommended to use relapse treatment protocols for aggressive NHL (GEMOX, ICE, DHAP, GDP, etc., in combination with MA) (see clinical guidelines for the treatment of aggressive non-Hodgkin lymphomas). If disease remission is achieved, high-dose chemotherapy (HDCT) followed by autologous hematopoietic stem cell transplantation is indicated to consolidate remission (auto-HSCT) [33, 34, 35, 171, 185-188, 222].

ICE, DHAP, ESHAP in combination with MA

Level of Evidence CGrade of Recommendation 4Level of Evidence C (Reliability Grade of Evidence 4) [185-188, 222].

Comment: In the group of follicular lymphoma (FL) patients with relapse within the first 24 months after completion of therapy (POD24), the risk of early tumor-related mortality increases. In this patient cohort, early high-dose chemotherapy with auto-HSCT significantly increases OS and PFS. The need for subsequent maintenance therapy with MA requires additional confirmation, as it is associated with severe hypogammaglobulinemia and leukopenia [36].

• For FL patients without signs of transformation to DLBCL who experience relapse more than 24 months after completion of induction therapy, when indications for treatment initiation are present, it is recommended to administer one of the following drug regimens (at the discretion of the attending physician):

• repetition of first-line chemotherapy or any other first-line regimen in combination with rituximab** or obinutuzumab** [3, 14, 15, 27]

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

• use of a combination of rituximab** and #lenalidomide** (see Appendix A3) [25].

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

Comment: according to the large international randomized phase III AUGMENT trial (N=358) comparing the efficacy of the combination of #lenalidomide**+rituximab** (R2) and rituximab** + placebo (control group) in patients with relapsed/refractory FL and marginal zone lymphoma (MZL), treatment with #lenalidomide** had a positive impact on such parameters as progression-free survival (PFS), overall response rate (ORR), and time to next anti-lymphoma therapy.

#Lenalidomide** was used at a dose of 20 mg/day from days 1 to 21 of a 28-day cycle (12 cycles); if the creatinine clearance was 30 to <60 ml/min, the dose of #lenalidomide** was 10 mg/day. Rituximab** was prescribed at a dose of 375 mg/m² on days 1, 8, 15, and 22 of the first cycle and on day 1 of cycles 2-5.

The study demonstrated a statistically significant improvement in progression-free survival (PFS) in the group of patients receiving the R2 regimen. The duration of PFS with the R2 combination compared to the control group was 39.4 months vs. 14.1 months, respectively (p <0.0001). The ORR in the R2 group was 78% vs. 53% in the control group (p = 0.001). The duration of response in the R2 group was 36.6 months, and in the control group 21.7 months (p <0.0015). The time to next anti-lymphoma therapy was not reached in the R2 group. In the control group, this parameter reached 32.3 months (p <0.0007).

• For FL patients who are candidates for transplantation and have an early FL relapse after auto-HSCT, allogeneic bone marrow transplantation is recommended where possible [37–42].

  Level of Evidence C (Reliability Grade of Evidence 4).

• For FL patients with relapse who responded to relapse therapy and are not candidates for auto-HSCT, anti-CD20 MA maintenance therapy is recommended [3, 14, 15, 20, 43].

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

Comment: in rituximab**-sensitive patients, maintenance therapy can be administered with rituximab** for intravenous or subcutaneous use every 8 weeks for 2 years. In cases of rituximab** refractoriness, when remission is achieved using a combination of obinutuzumab** and bendamustine**, obinutuzumab** is used at a dose of 1000 mg IV every 2 months for 2 years or until disease progression. For patients who received bendamustine-containing regimens** (BR or GB), maintenance therapy increases the risk of infectious complications; therefore, during treatment, it is necessary to monitor the frequency and severity of infectious complications, immunoglobulin concentrations, and promptly correct hypogammaglobulinemia [44-45].

• For patients with relapsed FL who have previously received at least two lines of systemic therapy, mosunetuzumab monotherapy is recommended according to the following regimen: 1 mg IV cycle 1 day 1; 2 mg IV cycle 1 day 8; 60 mg IV cycle 1 day 15 and cycle 2 day 1; 30 mg IV day 1 cycles 3–8 (or cycles 3–17 if complete response is absent after 8 cycles), cycle duration is 21 days [46, 182].

GCR BLOCE 3Grade of Recommendations B (Level of Evidence Confidence 3).

Comment: The non-comparative phase II multicenter study GO29781 (n = 90) demonstrated high efficacy of a fixed-duration course of mosunetuzumab monotherapy in patients with follicular lymphoma who experienced disease progression/relapse after at least two lines of prior therapy, including CD20 (cluster of differentiation 20) inhibitors and alkylating agents (L01A). The complete response rate evaluated by the Independent Review Committee (IRC)—the primary efficacy endpoint—was 60% (95% CI 49.1–70.1), and the objective response rate was 80% (95% CI 70.3–87.8). If a complete response was achieved after the end of 8 cycles of mosunetuzumab therapy, treatment was discontinued; in case of partial response or stable disease, the full course of treatment was 17 cycles [46]. With a median follow-up of 27 months, the median duration of response and median progression-free survival were not reached [47]. A comparative study evaluating the efficacy of mosunetuzumab monotherapy in third- or later-line follicular lymphoma therapy (clinical trial cohort GO29781) versus real-world clinical practice data for third- or later-line follicular lymphoma therapy (external control cohort) showed a significant advantage in complete response rate (60% vs 33%, hazard ratio 3.18; 95% CI, 1.41–7.17) and overall survival (hazard ratio 0.43, 95% CI 0.19–0.94) [182].

• For patients with relapsed FL who have previously received at least two lines of systemic therapy, anti-CD19 CAR-T (Chimeric Antigen Receptor T-Cell) therapy may be performed in specialized centers (preferably after mosunetuzumab) [48–50].

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

Comment: In the non-comparative phase II multicenter study ZUMA-5 (FL n = 127, DLBCL n = 31), the use of anti-CD19 chimeric antigen receptor T cells in patients with r/r indolent lymphomas resulted in an overall response rate of 92%, with a complete remission rate of 80%. In an updated analysis with a median follow-up of 41 months, 3-year OS and PFS were 75% and 65%, respectively. PFS was not reached in patients without POD24 and was 40 months in patients with POD24 [48, 49].

The non-comparative multinational phase II study ELARA demonstrated high efficacy of anti-CD19 chimeric antigen receptor T cells in patients with r/r FL after two or more lines of therapy, including after autologous HSCT. With a median follow-up of 29 months among 94 patients who responded to treatment, the overall response rate was 86%, and the complete remission rate was 68%. Median PFS was not reached. Two-year OS and PFS were 88% and 57%, respectively [50].

• For patients with FL transformation to DLBCL verified by repeat biopsy, the following tactics are recommended depending on prior treatment [14, 15]:

• if immunochemotherapy was not used initially (watch-and-wait approach, rituximab monotherapy**, radiation therapy), the R-CHOP regimen is recommended.

• if immunochemotherapy was used at initial disease presentation, therapy is recommended in accordance with the guidelines for the treatment of relapsed/refractory DLBCL, followed by high-dose chemotherapy with autologous HSCT upon achieving complete remission (therapy for patients who are candidates for autologous HSCT) and/or radiation therapy to initial involvement sites (upon achieving complete or partial remission) (therapy for patients who are not candidates for autologous HSCT).

CGR CLEL 5Category of Recommendations C (Level of Evidence 5).

• For patients with chemoresistant local relapse of FL, low-total-dose radiation therapy using large fractions—SD per fraction 4 Gy once or SD per fraction 2 Gy in 2 fractions—is recommended for palliative purposes [14, 15].

CGR CLEL 5Category of Recommendations C (Level of Evidence 5).

Comment: in certain clinical situations, the total focal dose to the pathological lesion can be increased up to 30 Gy.

3.5 Pediatric FL treatment

• For patients under 18 years of age with a verified diagnosis of stage I FL, surgical removal of the tumor followed by active surveillance is recommended [172, 189, 190].

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

• For patients under 18 years of age with a verified diagnosis of advanced-stage FL or those who cannot undergo surgical tumor removal without evidence of transformation to DLBCL, treatment in accordance with the guidelines for adult patients is recommended [51–53].

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

Comment: considering that this pathology is extremely rare, has a favorable course, and was only recently classified as a distinct nosology in the WHO classification, there is still insufficient robust evidence regarding the use of drugs in this patient group, and many drugs do not have registered indications for use in children. Therefore, therapy must be prescribed by a medical panel for life-saving indications.

3.6 Evaluation of treatment response

• For all patients with FL, after 3 cycles of chemotherapy and upon completion of the entire treatment program, assessment of treatment response is recommended in accordance with standard lymphoma response criteria (see Section 7.5 of these guidelines) to determine further management tactics [4, 54].

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

3.7 Supportive and concomitant therapy

• For patients with FL undergoing chemoimmunotherapy regimens with a high risk of febrile neutropenia (FN) exceeding 20%, or an intermediate risk of FN of 10–20% with risk factors, primary prophylaxis of febrile neutropenia with colony-stimulating factors (colony-stimulating factors (L03AA) per the ATC classification) is recommended [55–68, 173, 191, 198].

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

Comments: prophylactic administration of colony-stimulating factors (L03AA): filgrastim** 5 mcg/kg subcutaneously (SC) 24–72 hours after the completion of antineoplastic drug administration and until neutrophil counts recover from the nadir, or #pegfilgrastim at a dose of 6 mg or #empegfilgrastim** (in adults) at a dose of 7.5 mg subcutaneously, single dose, at least 24 hours after the completion of antineoplastic drug administration in accordance with the instructions for medical use for the prevention and treatment of neutropenia induced by cytotoxic tumor chemotherapy.

• For patients with FL following a previously documented episode of FN or dose-limiting afebrile neutropenia (following a single episode of cycle delay and/or dose reduction), secondary prophylaxis of febrile neutropenia with colony-stimulating factors (L03AA) is recommended [55–68].

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

• For patients with FL and secondary immunodeficiencies, replacement therapy with normal human immunoglobulin** 0.2–0.4 g/kg IV every 3–4 weeks for 12 months is recommended to treat the secondary immunodeficiency [69, 70, 193, 199–200]. Alternatively, at a fourfold lower dose of 0.05–0.1 g/kg weekly when using subcutaneous formulations of #normal human immunoglobulin** (average dose 0.2–0.4 g/kg over 4 weeks) [69, 70, 193]. Subcutaneous administration of normal human immunoglobulin** causes fewer systemic adverse events, provides stable IgG levels, and self-administration of normal human immunoglobulin** at home is an advantage for a number of patients [71, 72].

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

Comment: therapy is performed under the control of IgG levels every 6 months, with dose reassessment every 6 months. Upon completion of therapy, lifelong monitoring of IgG levels is carried out once a year; in case of recurrent IgG drop <4 g/L, repeated courses of replacement therapy with a similar drug in a similar regimen are performed for 12 months.

• For all FL patients with baseline bulky disease receiving antineoplastic therapy, prevention of tumor lysis syndrome is recommended in accordance with current dedicated guidelines [39].

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

• For patients with FL receiving glucocorticoids, prevention of gastric and duodenal ulcers is recommended [73, 177].

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

• For FL patients undergoing cytotoxic chemotherapy, developing hemorrhagic or infectious complications, anemia, or thrombocytopenia induced by intensive chemotherapy, or for therapeutic purposes in patients with pre-existing hemorrhagic complications, for volume replacement during plasmapheresis procedures in hyperleukocytosis, or when performing various procedures (trephine biopsy, lumbar puncture, central venous catheter insertion, etc.) under conditions of thrombocytopenia, replacement blood transfusion therapy with platelet concentrate, red blood cell suspension, fresh frozen plasma (FFP), blood coagulation factor VIII (ATC code B02BD), protease inhibitors, and antifibrinolytic agents (ATC code B02A) is recommended [205].

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)

Comment: in hematological diseases with known indications for repeated blood component transfusions (leukemias, lymphomas, myelodysplastic syndromes, aplastic anemia, etc.), to prevent transfusion-related adverse reactions and complications, the use of blood components with the following characteristics is recommended:

• leukoreduced — the leukocyte content in the transfused medium dose is reduced to 1 × 10^6 cells;

• irradiated red blood cells and platelets (gamma radiation or X-radiation at a dose of 25–50 Gy);

• limitation of donor plasma use through the application of additive solutions for red blood cells;

• following donor blood testing for viral infection markers using molecular biological methods.

• major reactions and complications associated with donor blood component transfusion are presented in section A3, Reference Information.

• All FL patients receiving antineoplastic chemo- or radiotherapy are recommended prophylaxis and treatment of nausea and vomiting depending on the emetogenic potential of the therapy administered, in accordance with current guidelines [75–81].

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

• For FL patients with risk factors for thrombotic complications, the use of anticoagulants (ATC code B01 Antithrombotic agents) and physical methods (elastic compression of the lower extremities, intermittent pneumatic compression of the lower extremities) is recommended to prevent venous thromboembolic complications [11–12, 82–88, 175, 201].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

• For FL patients presenting with acute or chronic pain, it is recommended to diagnose the cause of the pain syndrome and subsequently administer pathogenetic or symptomatic pain therapy in accordance with current guidelines [82–83].

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

• Patients over 18 years of age with FL receiving mosunetuzumab therapy are recommended prophylaxis and premedication in accordance with the Summary of Product Characteristics (SmPC) for at least the first two cycles to reduce the risk of cytokine release syndrome (CRS) [46–47].

GIB CLOE 4Grade of Recommendation – C (Level of Evidence – 4)

Comment: Patients receiving mosunetuzumab therapy should be monitored for signs or symptoms of cytokine release syndrome (CRS). The most common clinical manifestations of CRS are pyrexia, chills, hypotension, tachycardia, hypoxia, and headache. The probability of CRS is highest on days 1 and 15 of cycle 1 of mosunetuzumab therapy. Infusion-related reactions may be clinically indistinguishable from manifestations of CRS. If CRS or an infusion reaction is suspected, treatment with glucocorticoids (dexamethasone** IV (or an equivalent drug), 10 mg every 6 hours until clinical improvement) and/or tocilizumab** (IV, at a dose of 8 mg/kg, but not exceeding 800 mg per infusion) should be administered depending on indications. If there is no clinical improvement in CRS signs and symptoms after the first dose of tocilizumab**, a second dose may be administered 8 hours later (maximum 2 doses per CRS event and no more than 3 doses within 6 weeks) [46–47].

• For FL patients undergoing cytotoxic chemotherapy, nutritional support with parenteral micronutrient trace element complexes, crystalline amino acid solutions, carbohydrate solutions, lipid emulsions, and ready-to-use balanced oral formulas (polymeric, oligomeric) is recommended for the prevention of water and electrolyte imbalances, depending on the type of nutritional disorder [157–162].

GGR BLOE 1Grade of Recommendation B (Level of Evidence – 1)

• For FL patients of reproductive age, it is recommended to discuss the possibility of sperm or oocyte/embryo cryopreservation prior to initiating therapy [203].

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)

• For female patients with pelvic lymphadenopathy – girls and young women scheduled for pelvic radiation therapy – it is recommended to consider the need for homolateral ovariopexy for ovarian protection [204].

GCR CLEL 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 prolonged ovarian dysfunction may otherwise occur. This can be avoided if radiotherapy is delivered from opposing fields to a total dose (TD) of 20 Gy and the ovary is located at least 2 cm away from the treatment field border.

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.

FL patients undergoing cytotoxic chemotherapy, during inter-cycle intervals, following hematopoietic stem cell transplantation (HSCT), and during targeted and cellular therapy may develop various critical conditions due to multiple causes. Critical syndromes requiring transfer to the ICU include: sepsis, septic shock (SS), acute respiratory failure (ARF), acute renal failure (ARF), acute cerebrovascular accident (ACVA) of ischemic or hemorrhagic type, tumor lysis syndrome, life-threatening cardiac arrhythmias, and massive gastrointestinal bleeding. To treat life-threatening complications in hematological patients in the ICU, life-support methods are most frequently used: mechanical ventilation in 50–66% of patients; vasopressor therapy in 8–75.6% of patients; and renal replacement therapy in 3.2–61% of patients [206–207].

4. Medical Rehabilitation and Sanatorium-Resort Treatment

• All FL patients at all stages of disease therapy, as well as after the completion of medical treatment, are recommended comprehensive rehabilitation and, if necessary, supportive care [74].

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

Comment: There are no specific rehabilitation methods for FL. Rehabilitation for FL patients must be comprehensive, encompassing not only medical but also socio-psychological aspects of the patient's adaptation to normal life. Such rehabilitation requires, in addition to medical care, the mandatory involvement of social workers and clinical psychologists. Rehabilitation programs are developed individually, depending on identified complications of medical treatment, comorbidities, 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

Currently, there are no methods for preventing FL, as the etiological factors leading to the development of the disease remain unknown.

• Adult patients who have completed treatment for FL and achieved complete remission (CR) are recommended follow-up care with an oncologist or hematologist every 3 months during the first year after therapy completion, every 6 months during the 2nd year, annually thereafter, and every 2 years after 5 years [2–4].

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

Comment:follow-up observation should include a thorough history taking, clinical examination of the patient, chest X-ray control, and complex ultrasound of the abdominal cavity and peripheral lymph node groups.

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 of November 21, 2011 (as amended on May 25, 2019) "On the Fundamentals of Health Protection of Citizens in the Russian Federation," is organized and delivered:

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

2. in accordance with the procedure for providing care in the profiles of "hematology" and "oncology," 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 and other medical specialists at an ambulatory hematology/oncology care center, a primary hematology/oncology office, a primary hematology department, or an outpatient department of an oncological dispensary.

When FL is detected or suspected in a patient, general practitioners, district general practitioners, general 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, or to a primary hematology office or primary hematology department of a medical organization to receive primary specialized health care.

An 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 diseases to establish a diagnosis and provide specialized, including high-tech, medical care.

If FL is detected or suspected during the provision of emergency medical care, the patient is transferred or referred to medical organizations that provide medical care to patients with hematological 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 medical organizations that provide medical care to patients with FL, possess the necessary license, material and technical base, and certified specialists, in inpatient and day-care settings, and includes the prevention, 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 FL, the tactics of medical examination and treatment are determined by hematologists/oncologists, involving other medical specialists if necessary, and – if necessary – through a medical concilium. 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 hospitalization in a 24-hour or day hospital of a medical organization providing specialized, including high-tech, medical care in the profile "hematology" are determined by a hematologist/oncologist/medical concilium with the involvement of other medical specialists if necessary.

Indications for planned hospitalization:

1. Administration of therapy in cases requiring round-the-clock patient monitoring due to the severity of the condition caused by the tumor, or due to the risk of complications associated with the treatment program or comorbid conditions.

2. Patient examination, including biopsy and invasive interventions, in cases where it cannot be performed on an outpatient basis.

Indications for emergency hospitalization:

1. Development of a severe infection (hospitalization in a hematology department is optional).

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

3. Development of FL complications: symptomatic lymphadenopathy and organomegaly with the risk of severe complications, neuroleukemia, specific pleuritis, chylothorax, superior vena cava compression syndrome with signs of respiratory failure, and other life-threatening complications.

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

Indications for patient discharge from the hospital:

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

2. Refusal of the patient or their legal representative from specialized, including high-tech, medical care in a round-the-clock or day hospital setting established by the concilium of the medical organization providing oncological care, provided there are no complications of the underlying disease and/or treatment requiring drug correction and/or medical interventions in an inpatient setting.

3. The need to transfer the patient to another medical organization in the relevant medical specialty.

4. The medical commission's decision on the absence of indications for the patient to stay in the hospital due to the futility of treatment and the need to provide palliative care only.

7. Additional Information

7.1 Pathological and immunohistochemical diagnosis of FL

In FL, the histological report must take into account the cellular composition of tumor infiltrates and the pattern of tumor growth. According to the 2017 WHO classification, cytologic types 1 and 2 (up to 15 centroblasts per microscope high-power field at 400x magnification) must be combined. The majority of FLs belong to cytologic types 1–2. The third cytologic type is less common (20%) and is further subdivided into 3A (with the presence of centrocytes) and 3B (follicle-like/nodular structures formed by medium-sized and large lymphoid cells with round-oval and multilobulated nuclei displaying centroblast morphology). Histological examination may reveal tumor heterogeneity: the presence of areas of FL cytologic type 1–2 and FL type 3 in various ratios, and/or foci of diffuse large B-cell lymphoma (signs of transformation). In such cases, the proportion of the tumor area corresponding to FL of a particular cytologic type and diffuse large B-cell lymphoma should be indicated (as a percentage). FL 3B cannot contain fields of large cells with diffuse growth; in such cases, the diagnosis should be formulated as a combination of FL 3B and diffuse large B-cell lymphoma.

The histological report must also describe the pattern of tumor growth: follicular/nodular (tumor follicles occupy more than 75% of the lymph node area), nodular-diffuse (25%–75%), and predominantly diffuse growth type (less than 25%). The diffuse variant of FL is characteristic of inguinal lymph node FL presenting with del1p/mut TNFRSF14 in the absence of t(14;18). This tumor typically expresses CD23.

FL is a B-cell lymphoma with the immunophenotype CD20+, BCL-6+, CD10+/-, BCL-2+, CD5-, CD23-/+, Cyclin D1-. In a small proportion of cases, BCL-2 is not detected in FL cells. Sometimes this is due to the presence of a defective BCL-2 molecule, which can be detected using a spectrum of BCL-2 antibody clones (e.g., E17). In FL of cytologic type 1–2 with predominant diffuse growth, as well as in FL of cytologic type 3, CD10 expression may be absent, which is often combined with the absence of BCL-2 expression. In these cases, the diagnostic antibody panel is usually supplemented with other germinal (follicular) differentiation markers, such as HGAL (GCET2). In FL of cytologic type 3, MUM.1 expression may be present. The Ki-67 proliferative index in FL of cytologic type 1–2 usually does not exceed 20%; Ki-67 >30% is associated with an unfavorable prognosis. In FL of cytologic type 3, the proliferative index can reach 70–80%.

To confirm the diagnosis of FL and establish patient management tactics, a cytogenetic/FISH study is advisable to detect t(14;18) or BCL-2 rearrangement. However, t(14;18) is not detected in 10–20% of FL cases.

To rule out additional genetic abnormalities, it is advisable to test for BCL-6 and C-MYC gene rearrangements (on smears/tissue sections from the paraffin block of the tumor biopsy).

In case of bone marrow involvement, as an addition to traditional diagnostic methods (trephine biopsy, myelogram, immunophenotyping) for minimal residual disease monitoring, it is recommended, if possible, to test for BCL-cell clonality by PCR and BCL2::IGH translocation by PCR.

In approximately 1/3 of FL cases, transformation into diffuse large B-cell lymphoma is observed, and rarely into plasmablastic lymphoma, high-grade B-cell lymphoma associated with MYC, BCL-2 rearrangement, or B-lymphoblastic lymphoma.

7.2 Staging of FL

Staging of FL is carried out based on examination results in accordance with the Ann Arbor classification criteria (Table 7.3.1).

Table 7.2.1. Ann Arbor staging of lymphomas (Lugano modification, 2014) [54]:

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

7.3 Determination of FL risk groups

To analyze individual risk of early progression, two versions of the Follicular Lymphoma International Prognostic Index (FLIPI and FLIPI-2) are used (Table 7.4.1) [84–86].

Table 7.3.1 FLIPI and FLIPI-2

* lymphatic and extralymphatic involvement sites are included

** sites are defined according to the FLIPI template

The low-risk group includes patients with 0–1 factor, intermediate-risk with 2 factors, and high-risk with 3–5 factors.

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

1. Parovichnikova Elena Nikolaevna – MD, DSc, General Director of the National Medical Research Center for Hematology of the Russian Ministry of Health, Chairman of the Association for the Promotion of Hematology and Bone Marrow Transplantation Development "National Hematological Society".

2. Poddubnaya Irina Vladimirovna – Academician of the RAS, Honored Worker of Education of the RF, MD, DSc, Professor, Head of the Department of Oncology and Palliative Medicine named after Academician A.I. Savitsky, Vice-Rector for Clinical Work and International Cooperation at the Russian Medical Academy of Continuous Professional Education (RMAPO) of the Russian Ministry of Health, Chairman of the Russian Society of Oncohematology.

3. Natalia A. Falaleeva – MD, PhD, Head of the Department of Antitumor Drug Therapy, 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.

4. Tumyan Gayane Sergeevna – MD, DSc, Professor at the Department of Oncology and Palliative Medicine named after Academician A.I. Savitsky of the RMAPO of the Russian Ministry of Health, Head of the Chemotherapy Department for Hemoblastoses at the N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health, Board Member of the Russian Society of Oncohematology.

5. Zvonkov Evgeny Evgenievich – MD, DSc, Head of the Scientific Department, Head of the Department of Intensive High-Dose Chemotherapy of Lymphomas with 24-hour and Day Hospitals at the National Medical Research Center for Hematology of the Russian Ministry of Health.

6. Nesterova Ekaterina Sergeevna - PhD, Senior Researcher, Hematologist at the Department of Chemotherapy of Lymphatic Tumors with a BMT Unit and Hematopoietic Blood Stem Cells with a Day Hospital, National Medical Research Center for Hematology of the Russian Ministry of Health, Assistant at the I.A. Kassirsky and A.I. Vorobyov Department of Hematology and Transfusiology, Member of the Association for the Promotion of Hematology and Bone Marrow Transplantation Development "National Hematological Society".

7. Smolyaninova Anna Konstantinovna – Senior Researcher, PhD, Hematologist at the Department of Intensive High-Dose Chemotherapy of Lymphomas with 24-hour and Day Hospitals at the National Medical Research Center for Hematology of the Russian Ministry of Health.

8. Babicheva Lali Galimovna – PhD, Associate Professor at the Department of Oncology and Palliative Medicine named after Academician A.I. Savitsky of the RMAPO of the Russian Ministry of Health, Member of the Russian Society of Oncohematology.

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

10. Natalia V. Myakova – MD, PhD, Professor, Deputy Chief Medical Officer for Clinical Work, Head of the Department of Oncohematology, 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.

11. Rumyantsev Alexander Grigorievich– Academician of the RAS, 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.

12. Aleksey A. Maschan – Corresponding Member of the Russian Academy of Sciences, Doctor of Medical Sciences, 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

13. Ptushkin Vadim Vadimovich – MD, DSc, Professor, Deputy Chief Medical Officer for Hematology at the S.P. Botkin City Clinical Hospital, Chief freelance Specialist Hematologist of the Moscow Healthcare Department, Member of the National Hematological Society and the Russian Society of Oncohematology.

14. 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.

15. 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.

16. Krivolapov Yury Alexandrovich – MD, DSc, Professor, Head of the Department of Pathology of Clinical Molecular Morphology at the E.E. Eichwald Clinic of the 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 Division of the International Academy of Pathology.

17. Konovalov Dmitry Mikhailovich – PhD, Head of the Department of Pathology at the 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 Division of the International Academy of Pathology.

18. Sergey K. Kravchenko – Cand. of Sci. (Med.), Associate Professor, Head of the Department of Intensive High-Dose Chemotherapy with 24-hour and Day Hospital, National Research Center for Hematology of the Russian Ministry of Health, Member of the Association for the Promotion of Hematology and Bone Marrow Transplantation "National Hematology Society".

19. Gulnara N. Khusainova – Cand. of Sci. (Med.), Head of Chemotherapy Department No. 2, Republican Clinical Oncological Dispensary named after Professor M.Z. Sigal.

20. 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.

21. Sergey A. Ivanov – Professor of the Russian Academy of Sciences, MD, PhD, Director of the A.F. Tsyb Medical Radiological Research Center – branch of the National Medical Research Radiological Center of the Russian Ministry of Health.

22. Zhanna V. Khaylova – Cand. of Sci. (Med.), Deputy Director for Organizational and Methodological Work, A.F. Tsyb Medical Radiological Research Center – Branch of the National Medical Research Radiological Center of the Russian Ministry of Health.

23. Tigran G. Gevorkyan – Deputy Director of the Institute of Clinical and Economic Research, N.N. Blokhin National Medical Research Center of Oncology.

24. Oksana P. Trofimova – Dr. of Sci. (Med.), Professor at the A.I. Savitsky Department of Oncology and Palliative Medicine, Russian Medical Academy of Continuous Professional Education of the Russian Ministry of Health.

25. Vladimir M. Sotnikov – Dr. of Sci. (Med.), Head of the Methodological Accreditation and Simulation Center for Radiotherapy, Russian Scientific Center of Roentgenology and Radiology of the Russian Ministry of Health.

26. Yulia N. Vinogradova – Dr. of Sci. (Med.), Associate Professor, Head of the Department of Radiation and Combined Treatment Methods, A.M. Granov Russian National Research Center of Radiology and Surgical Technologies of the Russian Ministry of Health.

27. Nikolay V. Ilyin – Dr. of Sci. (Med.), Professor, Chief Researcher at the Department of Fundamental Research Methods, A.M. Granov Russian National Research Center of Radiology and Surgical Technologies.

28. Olga V. Mukhortova – Dr. of Sci. (Med.), Leading Researcher at the Department of Nuclear Diagnostics, Professor at the Department of Radiation 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 oncologists.

4. Radiologists and radiation therapists

5. Medical students.

Methodology for evidence collection

Methods used for the collection/selection of evidence:

• search for publications in specialized peer-reviewed periodicals 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).

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 guidelines have been discussed and approved by leading specialists of relevant federal centers of the Russian Federation and practicing physicians. The draft clinical guidelines was reviewed at working group meetings 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 treatment regimens for FL in patients over 18 years of age

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

Rituximab monotherapy** [19]

• Rituximab** 375 mg/m² IV infusion, once a week for 4 weeks

R-CHOP [20, 22]

• Rituximab**

• 375 mg/m² IV infusion, day 0 or 1 for all cycles

or

• 375 mg/m² IV infusion 1 cycle, then rituximab** 1400 mg SC, day 0 or 1 [20,100-103]

• Doxorubicin** 50 mg/m² IV infusion, day 1

• Cyclophosphamide** 750 mg/m² IV infusion, day 1

• #Vincristine** 1.4 mg/m² (total not exceeding 2 mg) IV, day 1

• Prednisolone** 100 mg orally, days 1-5

  Treatment is resumed on day 22

R-CVP [20, 22]

• Rituximab**

• 375 mg/m² IV infusion, day 0 or 1 for all cycles

  or

• 375 mg/m² IV infusion 1 cycle, then rituximab** 1400 mg SC, day 0 or 1 [20,100-103]

• Cyclophosphamide** 750 mg/m² IV infusion, day 1

• #Vincristine** 1.4 mg/m² (total not exceeding 2 mg) IV, day 1

• Prednisolone** 100 mg orally, days 1-5

Treatment is resumed on day 22

RB [20]

• Rituximab**

• 375 mg/m² IV infusion, day 0 or 1 all cycles of the course or

• 375 mg/m² IV infusion 1 cycle, then rituximab** 1400 mg SC, day 0 or 1 [20,100-103]

• #Bendamustine** 90 mg/m² IV infusion, days 1, 2

Treatment is resumed on day 29

GB (follicular lymphoma treatment regimen) [20]

• Obinutuzumab**

• Cycle 1: 1000 mg IV infusion, days 1, 8 and 15

• Cycles 2-6: 1000 mg IV infusion on day 1

• #Bendamustine** 90 mg/m² IV infusion on days 1 and 2

Treatment is resumed on day 29

G-CHOP (follicular lymphoma treatment regimen) [20]

• Obinutuzumab**

• Cycle 1: 1000 mg IV infusion, days 1, 8 and 15

• Cycles 2-8: 1000 mg IV infusion on day 1

• Doxorubicin** 50 mg/m² IV infusion, day 1

• Cyclophosphamide** 750 mg/m² IV infusion, day 1

• #Vincristine** 1.4 mg/m² (total not exceeding 2 mg) IV, day 1

• Prednisolone** 100 mg orally, days 1-5

Treatment is resumed on day 22

G-CVP (follicular lymphoma treatment regimen) [20]

• Obinutuzumab**

• Cycle 1: 1000 mg IV infusion, days 1, 8 and 15

• Cycles 2-8: 1000 mg IV infusion on day 1

• Cyclophosphamide** 750 mg/m² IV infusion, day 1

• #Vincristine** 1.4 mg/m² (total not exceeding 2 mg) IV, day 1

• Prednisolone** 100 mg orally, days 1-5

Treatment is resumed on day 22

R2 [25]

• Rituximab** 375 mg/m² IV infusion, days 1, 8, 15, 22 of the first cycle and on day 1 of cycles 2-5

• #Lenalidomide** 20 mg/day orally (with creatinine clearance of 30-60 ml/min – 10 mg/day), days 1-21

Treatment is resumed on day 29. A total of 12 cycles are administered.

Mosunetuzumab (fixed-duration monotherapy in adults) [46-47, 182]

• Mosunetuzumab

• Cycle 1: 1 mg IV day 1, 2 mg IV day 8, 60 mg IV day 15

• Cycle 2: 60 mg IV day 1

• Cycle 3-8: 30 mg IV day 1

In the absence of a complete response after 8 cycles of mosunetuzumab, continue therapy at the previous dose – 30 mg IV on day 1 of each 21-day cycle 9-17

Appendix A3.2. Significance of hepatitis B virus markers in FL

The significance of HBV infection markers and proposed actions are presented in Table 3.2.1

Table A3.2.1. Significance of hepatitis B virus markers

* If anti-CD20 administration is necessary, continuous intake of entecavir** 0.5 mg/day is indicated [104-108]. Entecavir** is prescribed for the entire period of treatment/maintenance therapy and for at least 1 year after completion of immunosuppressive therapy with repeated negative test results for hepatitis B virus DNA in the blood. The optimal duration of entecavir** therapy after completion of rituximab** therapy has not been established. If specific therapy is not indicated for a patient with FL, prophylactic administration of entecavir** is not necessary. If resistance to entecavir** develops, switching to tenofovir** is indicated.

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:

1. assessment of the patient's status (presence of indications for autologous hematopoietic stem cell transplantation (auto-HSCT), standard examination to exclude factors preventing high-dose treatment, comorbidities, patient consent, review of prior therapy - number of courses and dates of treatment completion, use of radiation therapy)

2. assessment of disease status - depth of antitumor response, presence of remission, time to achievement;

3. assessment of hematopoiesis status (histological examination of the bone marrow will reveal suppression of hematopoietic lineages, as well as bone marrow infiltration by tumor cells).

Risk factors for ineffective HSC mobilization:

Proven risk factors for failure include two parameters: if circulating blood CD34+ counts do not reach 20 cells per 1 µl on days 4-6 after the start of G-CSF (ATC L03AA Colony-stimulating factors) or if less than 2x10⁶ CD34+ cells/kg are harvested in 3 leukaphereses.

Criteria for a probable risk of HSC mobilization failure include a history of prior ineffective HSC mobilization; prolonged CT or radiation therapy, use of melphalan**, #lenalidomide** at previous stages of treatment; advanced phase of the disease requiring at least two lines of CT. Bone marrow cellularity of less than 30% at the time of mobilization and age over 65 years are also risk factors for ineffective mobilization [62]. In case of an insufficient number of harvested HSCs, the issue of growth factor dose escalation, repeat mobilization using a different regimen, or bone marrow exfusion is discussed. The goal of mobilization is to harvest an adequate number of CD34+ cells sufficient to perform one or two transplantations.

Below is a detailed description of drugs that stimulate the release of HSCs into the peripheral blood.

G-CSF (filgrastim**) is administered at a dose of 5 or 10 µg/kg/day subcutaneously depending on the HSC mobilization regimen. #Pegfilgrastim is administered once at a dose of 12 mg subcutaneously [64], empegfilgrastim** is administered once at a dose of 7.5 mg subcutaneously (adults) [55–68, 173, 191, 219, 220].

Plerixafor

Plerixafor is a selective reversible chemokine receptor CXCR4 antagonist. It blocks CXCR4 by binding to the SDF-1α factor, as a result of which HSCs "detach" from the bone marrow stroma and enter the peripheral blood. Plerixafor is used to enhance the mobilization of hematopoietic stem cells into the peripheral blood circulation for their collection and subsequent auto-HSCT in patients with lymphoma and multiple myeloma in combination with colony-stimulating factors. The recommended dose of plerixafor is 0.24 mg/kg/day. The drug is administered subcutaneously 6-11 hours before the start of apheresis after preliminary 4-day therapy with colony-stimulating factors. In clinical trials, the drug was usually used for 2-4 consecutive days (up to 7 days of continuous use).

HSC mobilization regimens

Currently, the following HSC mobilization regimens are widely used in oncohematology:

• Colony-stimulating factors (G-CSF) as monotherapy

• Colony-stimulating factors (G-CSF) after myelosuppressive chemotherapy (CT + G-CSF)

• Colony-stimulating factors (G-CSF) in combination with plerixafor

Colony-stimulating factors (G-CSF) as monotherapy

This regimen is also referred to as "mobilization under steady-state hematopoiesis," since the patient does not develop myelotoxic agranulocytosis (MTA).

Indications

• HSC mobilization in patients with oncohematological diseases;

• Remobilization following the failure of the initial HSC mobilization

HSC mobilization regimen

G-CSF (filgrastim**) is prescribed at a dose of 10 mcg/kg/day, administered subcutaneously in the morning (or 5 mcg twice daily). Leukapheresis begins on the fourth day of drug administration, provided there is an adequate number of CD34+ cells in the peripheral blood. Cell separation is initiated when their count exceeds 10–20 cells/µL. If the peripheral blood CD34+ count is less than 10 cells/µL, leukapheresis must be deferred and cell counts repeated the following day. The number of leukapheresis sessions depends on the HSC harvest results; securing an optimal yield of CD34+ cells requires 2 to 4 procedures (ranging from 1 to 5). On the final day of leukapheresis, the drug is not administered (Table A3.3.1).

Table A3.3.1. "G-CSF Monotherapy" HSC mobilization regimen

Colony-stimulating factors (G-CSF) following myelosuppressive chemotherapy

Indications

HSC mobilization in patients with oncohematological diseases

"CT + Colony-Stimulating Factors (G-CSF)" HSC mobilization regimen

Myelosuppressive CT stimulates the proliferation of stem and progenitor cells, leading to an increased release of HSCs from the bone marrow into the blood. The principle of this HSC mobilization regimen is as follows: the patient is administered an antineoplastic agent (or multiple agents) according to the appropriate treatment protocol, and then, following the development of MTA, stimulation of leukopoiesis is initiated using G-CSF (filgrastim**) at a dose of 5 mcg/kg/day. Provided that peripheral blood leukocytes recover and there is an adequate number of CD34+ cells among them, HSC collection procedures are commenced (typically on days 6–8 of colony-stimulating factor (G-CSF) administration).

Figure A3.3.1 presents the algorithm for determining indications for the first leukapheresis procedure. The number of leukapheresis procedures depends on the HSC harvest yield (from 1 to 5). Colony-stimulating factors (G-CSF) are not administered on the final day of leukapheresis.

Figure A3.3.1. Algorithm for determining indications for the first leukapheresis during "CT + G-CSF" HSC mobilization. CT – chemotherapy, MTA – myelotoxic agranulocytosis.

Standard HSC mobilization regimen currently in use: #cyclophosphamide** 4 g/m² + G-CSF (filgrastim**) at a dose of 5 mcg/kg/day (Table A3.2.2).

MTA typically develops approximately 7 days after drug administration, which serves as the indication for prescribing G-CSF (filgrastim**) at a dose of 5 mcg/kg/day. In cases where MTA does not develop, the dose of G-CSF (filgrastim**) is increased to 10 mcg/kg/day. Leukapheresis procedures begin on days 6–8 of G-CSF (filgrastim**) administration. The median date of the first HSC collection is day 15 following the administration of #cyclophosphamide**.

Colony-stimulating factors combined with plerixafor

Indications

Remobilization following the failure of the initial HSC mobilization using regimens that include antineoplastic agents combined with colony-stimulating factors, or the use of colony-stimulating factor monotherapy in patients with lymphomas;

Unsatisfactory results of current mobilization in patients with lymphomas.

Unsatisfactory results of current mobilization:

• peripheral blood CD34+ cell count on the day of the planned first leukapheresis is less than 10 cells/µL (for a planned single autologous transplantation) and 10–20 cells/µL (for a planned tandem autologous transplantation);

• less than 30–50% of the required number of CD34+ cells is harvested during the first leukapheresis.

HSC mobilization regimen

G-CSF (filgrastim**) is prescribed at a dose of 10 mcg/kg/day, administered subcutaneously in the morning. On the fourth day of G-CSF (filgrastim**) administration, plerixafor is administered 12 hours prior to leukapheresis at a dose of 240 mcg/kg subcutaneously. Based on the leukapheresis results, the need for repeated administration of plerixafor is determined (Table A3.3.2). Multiple administrations of plerixafor are possible.

Table A3.3.2. "Colony-stimulating factors + plerixafor" HSC mobilization regimen

Features of supportive care during HSC mobilization

Colony-stimulating factors (G-CSF) monotherapy and Colony-stimulating factors (G-CSF) combined with plerixafor

If peripheral venous access is difficult, a central venous perfusion catheter is placed prior to initiating HSC collection;

To prevent thrombotic complications, low-molecular-weight heparins (ATC Heparin group) (enoxaparin sodium** 40 mg or equivalent) are administered (from 18 years of age) at a prophylactic dose subcutaneously once daily during colony-stimulating factor (G-CSF) administration and for 2–3 days following its discontinuation;

Adequate analgesia for bone pain caused by the administration of colony-stimulating factors (G-CSF). Preference is given to opioid analgesics (trimeperidine** 10 mg IV, tramadol** 100 mg IV, fentanyl** 25 mcg/h transdermally); nonsteroidal anti-inflammatory and antirheumatic drugs may be used in the absence of myelotoxic agranulocytosis.

Leukapheresis

Leukapheresis is a semi-selective method of extracorporeal hemocorrection based on the separation of plasma and blood cells using centrifugal force and the isolation of the leukocyte fraction from the blood [208]. On the day of the anticipated first collection, a complete blood count (CBC) and flow cytometric analysis of CD34+CD31+ lymphocytes in the blood are performed.

The analysis of CD34+CD31+ lymphocytes + HSCs in the blood is calculated using the formula:

Absolute CD34+ cell count in blood (cells/µL) = fraction of CD34+ cells (%) × leukocyte count (10⁹/L) × 10

When the peripheral blood CD34+ cell count exceeds 10–20/µL, the first leukapheresis can be initiated. If the CD34+ cell count is less than 10/µL, it is advisable to defer cell collection on that day and repeat the analysis the following day. If the CD34+ cell count is less than 5/µL, discontinuation of mobilization or the potential use of plerixafor should be discussed.

Absolute contraindications to leukapheresis include severe decompensated somatic diseases and life-threatening conditions. Examples of relative contraindications include a significant decrease in hemoglobin or platelets, which can be managed with transfusion support prior to the procedure. Immediately before the procedure, blood pressure must be measured via equipment, the patient's general condition assessed, and the results of general clinical biochemical blood tests and a coagulogram (exploratory hemostasis evaluation) reviewed.

The HSC collection procedure takes approximately 3–4 hours. During leukapheresis, if hypocalcemia develops (manifested by paresthesia of the lips, tongue, or fingertips), the blood return rate must be slowed down.

An HSC sample is taken from the harvested product to determine the CD34+ cell content using a flow cytometer. There are numerous recommended protocols for counting CD34+ HSCs, with the ISHAGE (International Society of Hematotherapy and Graft Engineering) protocol being the most widely recognized [209].

Thus, a timely start to the first leukapheresis procedure and a well-established laboratory methodology, including flow cytometric analysis, are essential for successful HSC collection. Concurrently with the CD34+ cell count, fractionation of the harvested leukapheresis product is performed. Next, the CD34+ cell count in the resulting leukoconcentrate is determined. By obtaining the proportion of CD34+ cells out of all leukocytes in the leukoconcentrate, the number of CD34+ cells per 1 kg of the patient's body weight is calculated.

The obtained biomaterial with a cryoprotectant is transferred to a cryopreservation container, and air bubbles are carefully removed. Freezing and storage of the biomaterial are carried out in a container with liquid nitrogen vapor.

Patient evaluation prior to mobilization and HSC collection

Before initiating hematopoietic stem cell mobilization, it is necessary to determine the phase of the disease, assess the patient's somatic status, and evaluate hematopoiesis. To this end, all patients undergo a routine evaluation panel comprising both laboratory and instrumental methods.

Contraindications to auto-HSCT

Absolute contraindications to auto-HSCT

• disease progression/relapse;

• infectious diseases in the acute phase;

• diseases of the musculoskeletal system, circulatory system, digestive and respiratory organs, urogenital, endocrine, and nervous systems, as well as diseases of other organs and systems in the acute phase accompanied by persistent functional impairment;

• presence of "second" malignant neoplasms not in remission;

• therapy with immunosuppressants or other drugs that may affect the self-renewal capacity and pluripotency of hematopoietic stem cells;

• mental and behavioral disorders in the acute phase and/or posing a danger to the patient and others;

• mental and behavioral disorders due to psychoactive substance use;

• cachexia;

• pregnancy;

• early postoperative period with potential risks of postoperative wound infection during myelotoxic agranulocytosis.

• lack of signed informed consent for transplantation.

Relative contraindications for auto-HSCT

• infectious diseases in remission (foci of infection requiring sanitation);

• compensated diseases of the musculoskeletal system, circulatory system, digestive and respiratory organs, urogenital, endocrine and nervous systems, as well as diseases of other organs and systems;

• age over 65 years.

• presence of human immunodeficiency virus markers in the blood;

Evaluation of patients prior to auto-HSCT

Before performing autologous hematopoietic stem cell transplantation, it is necessary to determine the phase of the disease, assess the patient's performance status and hematopoiesis. To this end, all patients undergo a routine set of examinations, including both laboratory and instrumental methods.

Pre-transplantation conditioning regimens for auto-HSCT

The goal of high-dose chemotherapy is to eliminate tumor cells remaining after anti-tumor therapy with minimal toxic effects on organ systems [221, 222].

For pre-transplant conditioning, the BEAM regimen (adults) is used, which consists of #carmustine** (300 mg/m² × 1, day -6), #etoposide** (200 mg/m², days -5 to -2), cytarabine** (200 mg/m² twice daily, days -5 to -2), #melphalan** (140 mg/m²/day × 1, day -1) [134-138, 224]. Administration schedules and doses are presented in Table A3.3.3.

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 A3.3.3. BEAM pre-transplant conditioning regimen [134-138, 224] (adults)

To reduce the toxicity of the BEAM pre-transplant conditioning regimen, in some cases #lomustine** is used instead of #carmustine** (CEAM/LEAM) [138–141] (adults). Administration schedules and doses are presented in Table A3.3.4.

Table A3.3.4. CEAM/LEAM pre-transplant conditioning regimen [138–141] (adults)

A number of clinical studies have confirmed the efficacy of the Benda-EAM pre-transplant conditioning regimen in lymphoproliferative diseases [142-143, 211-212] (adults). Administration schedules and doses are presented in Table A3.3.5.

Table A3.3.5. Benda-EAM pre-transplant conditioning regimen [142-143, 211-212] (adults)

Appendix A3.4. CAR-T cell therapy in adults

CAR-T cell therapy includes the following stages:

1. Leukapheresis

2. Automated biomedical cell product manufacturing cycle

3. Lymphodepleting chemotherapy

4. Infusion of the autologous cellular product

Patient evaluation plan prior to CAR-T cell therapy

• Complete blood count with differential.

• General clinical blood chemistry test.

• Coagulation profile (screening hemostasis test).

• Fasting blood glucose test.

• Brain magnetic resonance imaging

• Electrocardiogram recording, interpretation, and analysis of electrocardiographic data.

• Echocardiography.

• Cardiopulmonary exercise testing.

• Electroencephalography.

• Specialist consultations: dentist (mandatory), obstetrician-gynecologist (mandatory for women), otorhinolaryngologist (as indicated), neurologist, ophthalmologist.

• Lymphocyte subset analysis.

• Blood immunoglobulin level test.

• Bone marrow aspiration cytological examination (myelogram).

• Lumbar puncture.

• Cytological examination of cerebrospinal fluid cells.

• Biobanking (preservation of tumor sample, DNA, RNA, serum).

Lymphodepleting chemotherapy in adults [225]

Lymphodepleting therapy is administered in accordance with published treatment protocols. During chemotherapy, the patient will receive infusion therapy at a volume of 2500 ml/m²/day, hyperuricemia prophylaxis, and antiemetic therapy in accordance with clinical guideline standards [214, 216, 217, 225, 226].

Prevention of cytokine release syndrome in adults

Tocilizumab**

Tocilizumab** is a recombinant humanized monoclonal antibody against the interleukin-6 receptor. The drug is administered on Day 0, 1 hour prior to the infusion of CD19 CAR-T cells, at a dose of 8 mg/kg (maximum dose 800 mg), as an intravenous infusion over 1 hour [214, 225].

Monitoring of cytokine release syndrome

• Measurement of axillary body temperature every 6 hours, assessment of vital signs every six hours.

• Laboratory monitoring: serum C-reactive protein and blood ferritin levels daily on days 1–14 following CD19 CAR-T cell infusion; general clinical blood chemistry test once every two days; coagulation profile (screening hemostasis test) three times a week.

Treatment of cytokine release syndrome in adults

In case of cytokine release syndrome > grade 1:

#Dexamethasone** 10 mg every 6-8 hours with an assessment of the severity of the condition and the dynamics of CRS criteria [216].

Tocilizumab** at a dose of 8 mg/kg (maximum dose 800 mg) as an intravenous infusion over 1 hour [216, 217, 226].

Toxic encephalopathy in adults

Expected manifestations of neurotoxicity

Neurological complications may include the following clinical manifestations: seizures, memory impairment, altered mental status, cranial nerve palsy, aphasia, ataxia. Monitoring of neurological complications includes a daily neurological examination. If toxic encephalopathy develops, a lumbar puncture and brain MRI are performed.

Treatment of encephalopathy includes #dexamethasone** at a dose of 10 mg every 6-8 hours with assessment of the severity of the condition and encephalopathy dynamics. If there is no response to dexamethasone, #anakira** is administered at a dose of 100 – 200 mg [217, 218, 226].

B-cell aplasia and hypogammaglobulinemia

B-cell aplasia is a direct consequence of the effective cytolytic activity of CAR-T cells against CD19-, CD20-, and CD22-positive targets. B-lymphopenia is a surrogate marker of CAR-T cell persistence and can last from 2 weeks to >1 year. The consequence of B-lymphopenia is hypogammaglobulinemia. Within the framework of this protocol, serum immunoglobulin concentrations are planned to be monitored at 3-week intervals. If the serum immunoglobulin concentration drops to <5 g/L, replacement therapy with normal human immunoglobulin** (IV or SC) will be provided at a dose of 0.4 g/kg of the patient's body weight [217].

Appendix B. Physician Action Algorithms

**Rituximab**

**Chlorambucil**

Appendix C. Patient Information

Lymphomas are tumors of lymphoid cells. Lymphoma is not a single disease; it is a large group comprising more than 30 different diseases that differ from one another in their manifestations, clinical course, and treatment response. The main thing to understand is that lymphomas behave and are treated completely differently. Therefore, simply saying "lymphoma" tells you nothing—to understand how to treat it, you need to know the specific subtype of lymphoma.

Follicular lymphoma is the most common subtype of indolent lymphomas. It accounts for one-third of all lymphoma cases. Indolent lymphomas grow very slowly, but are usually not completely curable: treatment can halt the growth of the lymphoma, but relapses eventually occur that require retreatment.

Very often, after diagnosis, there is no need for immediate treatment. In this case, a watch-and-wait approach is followed until the lymphoma begins to progress. Patients with indolent lymphomas live with the disease for many years. These years consist of alternating periods of remissions and relapses. Thanks to the efforts of scientists and physicians, great successes have been achieved in the treatment of lymphomas today.

In follicular lymphoma, abnormal lymphocytes do not die at their appointed time, but instead accumulate in the body. The rate of accumulation of these cells varies among patients. In some, follicular lymphoma persists for years and decades after diagnosis without causing any serious symptoms. In others, fairly rapid progression is observed, and symptoms quickly appear. In many cases, it is not necessary to start treatment immediately after diagnosis. Treatment is often delayed until the tumor cells begin to grow faster. Sometimes treatment is performed to relieve symptoms associated with local tumor growth. Today, follicular lymphoma is incurable, but most patients live for many years, and their life expectancy is the same as that of the general population.

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 [163]

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 [164]

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 different medical facilities, a 5-point visual analysis scale of PET data is used when assessing treatment response in lymphoma patients [164]. In this process, the intensity of 18F-FDG uptake in the lesion is compared with the intensity of uptake in unaffected areas of the mediastinum or the right lobe of the liver:

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.

The concept of X-scores has also been introduced to characterize the presence of 18F-FDG uptake foci of unclear, likely inflammatory origin, the connection 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 chemotherapyassociated thrombosis. Blood. 2008;111(10):4902-4907 [165]

Type: rating scale

Purpose: clinical assessment of the patient's general condition

Appendix G4. Calculation of transplantation risk using the EBMT score

Transplantation risk assessment is performed no more than 10 days before the start of pre-transplant conditioning [166].

The European Group for Blood and Marrow Transplantation risk score, 1988,

0, 1, 2 scoring system for determining transplantation risk [180].

Five-year transplantation-related mortality (%) according to the EBMT risk score

Appendix G5. HCT-CI Transplant Risk Assessment

Transplantation risk assessment is performed during the initial evaluation of the patient as a candidate for allo-HSCT and repeated no later than 10 days before the start of pre-transplant conditioning [167-168].

Hematopoietic Cell Transplantation-specific Comorbidity Index (HCT-CI), 

0, 1, 2, 3 scoring system for determining transplantation risk [181]

Low risk — 0 points.

Intermediate risk — 1–2 points.

High risk — 3–4 points.

Very high risk — 5 or more points.