Aggressive non-follicular lymphomas: diffuse large B-cell lymphoma, high-grade B-cell lymphoma with c-MYC and BCL2/BCL6 rearrangements, primary mediastinal large B-cell lymphoma, gray zone lymphoma, Burkitt lymphoma, plasmablastic lymphoma: clinical guidelines

List of Abbreviations

EBV – Epstein-Barr virus

MALT – mucosa-associated lymphoid tissue lymphoma

Mtx/AraC/Pred – intrathecal administration of methotrexate**, cytarabine**, and prednisolone**

FISH – fluorescence in situ hybridization

aPTT – activated partial thromboplastin time

PFS – progression-free survival

HDCT with auto-HSCT – high-dose chemotherapy followed by autologous hematopoietic stem cell transplantation

BLCL – B-cell large cell lymphoma

GCs – glucocorticoids

BBB – blood-brain barrier

DLBCL – diffuse large B-cell lymphoma

IHC – immunohistochemistry

IPT — immunophenotyping by flow cytometry

BM – bone marrow

CT – computed tomography

BL – Burkitt lymphoma

LDH – lactate dehydrogenase

RT – radiotherapy

INR – international normalized ratio

IPI – International Prognostic Index

MRI – magnetic resonance imaging

NHL – non-Hodgkin lymphomas

OS – overall survival

PCNSL – primary central nervous system lymphoma

PMBCL – primary mediastinal large B-cell lymphoma

PET/CT – positron emission tomography combined with computed tomography

SD – single dose

TD – total dose

US – ultrasound examination

CNS – central nervous system

ECG – electrocardiography

Echo-CG – echocardiography

18F-FDG – Fludeoxyglucose [18F]

** – vital and essential drugs

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

Terms and Definitions

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

B-symptoms – nonspecific symptoms of tumor intoxication, including fever above 38°C for at least three consecutive days without signs of inflammation; drenching 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

Diffuse large B-cell lymphoma (DLBCL) encompasses a heterogeneous group of lymphoid neoplasms with diverse clinical, morphological, immunophenotypic, cytogenetic features, and varied treatment responses. The tumor substrate consists of large lymphoid B-cells characterized by marked atypia and polymorphism, with a large nucleus equal to or exceeding the size of a macrophage nucleus, or at least twice the size of a small lymphocyte nucleus. In most cases, tumor cells are arranged diffusely, but they may also be interspersed among non-tumor B-lymphocytes, sometimes against a T-cell background, or form focal clusters [1]. Depending on clinical manifestations, morphological, and molecular features, various types of large B-cell lymphomas are distinguished (see the classification section).

Double-Expressor lymphoma (DEL) – a variant of DLBCL with coexpression of c-MYC and BCL2 proteins in the absence of concurrent rearrangement of their encoding genes. In the 2017 WHO classification, DEL remained within the framework of DLBCL, not otherwise specified (NOS), due to the extreme heterogeneity of its immunomorphological and molecular-genetic characteristics.

Primary mediastinal large B-cell lymphoma (PMBCL) – a distinct variant of DLBCL involving the anterior-superior mediastinum at onset, with potential spread to surrounding organs and tissues [2, 3]. The definition of PMBCL as a separate variant of DLBCL was based primarily on clinical data; however, subsequent studies, including exome sequencing and gene expression profiling, fully confirmed the validity of this classification.

Mediastinal grey zone lymphoma (MGZL) (formerly B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and classical Hodgkin lymphoma) was first described in 1998 and subsequently designated as a separate nosological entity in the 2008 WHO classification of tumors of hematopoietic and lymphoid tissues.

Burkitt lymphoma (BL) – a highly aggressive lymphoma derived from immunologically mature germinal center B cells with a c-MYC gene rearrangement. Clinically characterized by an extremely aggressive course and predominantly extranodal localization.

High-grade B-cell lymphoma (HGBL) with c-MYC and/or BCL2/BCL6 gene rearrangements – a heterogeneous group of aggressive B-cell lymphomas that cannot be classified as DLBCL or BL based on their clinical and biological characteristics. It was first recognized as a separate category in the 2017 WHO classification. Previously, this nosology was designated as B-cell lymphoma, unclassifiable, intermediate between DLBCL and BL. According to the HGBL classification, two subtypes are distinguished. The first includes cases with concurrent c-MYC, BCL2, and/or BCL6 gene rearrangements: “double-hit” lymphoma (DHL). The second includes cases without rearrangements of the aforementioned genes, designated as high-grade B-cell lymphoma, not otherwise specified (HGBL NOS).

Plasmablastic lymphoma (PBL) – a rare and highly aggressive variant of large B-cell lymphoma. In the WHO classification, this lymphoma variant was recognized as a separate nosology in 2008. It is diagnosed in the overwhelming majority of cases in patients with HIV-associated or iatrogenic immunodeficiency. The development of PBL in immunocompetent patients is rare and has distinct clinical and molecular-genetic features [4].

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

The etiology of DLBCL remains unclear. The tumor most frequently arises de novo, but may also transform from a less aggressive lymphoma (CLL/small lymphocytic lymphoma, follicular lymphoma, marginal zone lymphoma, or the nodular lymphocyte-predominant variant of Hodgkin lymphoma). Concomitant immunodeficiency is also a significant risk factor; EBV-positive DLBCL occurs significantly more frequently in such patients.

The main pathogenic mechanisms of DLBCL involve disruption of cellular proliferation, maturation, and differentiation processes in B-lymphocytes. The first stage of B-lymphocyte differentiation (primary rearrangement of genes encoding immunoglobulin synthesis) takes place in the bone marrow. Cells with successful immunoglobulin gene rearrangements (naive B cells) leave the bone marrow and migrate to peripheral immune organs (lymph nodes, tonsils, spleen, Peyer's patches), where the second, antigen-dependent stage of B-lymphocyte differentiation occurs. In the germinal center of secondary lymphoid follicles, naive B cells that lack a complementary antigen and fail to produce a functional antibody undergo apoptosis. Those B lymphocytes that successfully synthesize antibodies after contact with corresponding antigens undergo critical modifications in the germinal center with the participation of follicular dendritic cells and T lymphocytes, such as immunoglobulin class switching (from IgM, IgD to IgG, IgA, or IgE) and somatic hypermutations (single nucleotide substitutions in hypervariable regions of immunoglobulins). Subsequently, B cells leave the secondary lymphoid follicle to become terminally differentiated plasma cells or long-lived memory B cells. Random errors in the regulation of these processes play a decisive role in the development of B-cell neoplasms, including DLBCL [5–11].

As demonstrated by molecular-genetic studies, many genes regulating germinal center events are implicated in the pathogenesis of DLBCL, with the most thoroughly studied mechanism being the rearrangement of the Bcl-6 gene located at locus 3q27 and expressed exclusively by germinal center B cells. Under physiological conditions, the Bcl-6 gene binds to specific regulatory DNA sequences and influences the transcription of other genes involved in the activation and terminal differentiation of B lymphocytes. Rearrangement of the 3q27 locus blocks the further differentiation of B cells into plasma cells, leading to the uncontrolled proliferation of germinal center B cells [12].

The pathogenesis of DEL is based on the overexpression of c-MYC and BCL2 proteins.

Overexpression of c-MYC leads to uncontrolled cell proliferation, blockade of differentiation, and DNA repair. Overexpression of the anti-apoptotic protein BCL2 ensures resistance to apoptosis. The most common mechanism leading to overexpression is an increase in the copy number of the c-MYC and BCL2 genes.

Enhanced transcription as a result of activating mutations or anomalies in their regulatory genes is also possible [13].

The obvious similarity in the pathogenetic mechanisms of DEL and DHL led to an attempt to combine these categories, designating DEL as an atypical variant of DHL. However, numerous studies have demonstrated that DEL is significantly more heterogeneous. In addition to anomalies of the two genes, the diversity of molecular mechanisms underlying DLBCL subtypes (GCB or ABC) is of great importance. It is important to note that DEL is also detected in 30% of high-grade B-cell lymphomas (HGBL, NOS) [14].

The etiology of PMBCL is currently unknown. PMBCL tumor cells are characterized by a unique gene expression profile and a mutational landscape of putative driver genes that differs from all variants of DLBCL and closely resembles that of classic Hodgkin lymphoma [2, 3]. The development of PMBCL is driven by several main pathogenetic mechanisms: activation of the JAK-STAT and NF-κB pathways and dysregulation of the immune response within the PMBCL microenvironment. PMBCL tumor cells possess the ability to "escape" immune surveillance by cells of the thymic microenvironment, accumulating genetic alterations that help protect the tumor from T-cell recognition. The mechanism of immune evasion consists in blocking T-cell activation and disrupting the expression of class II major histocompatibility complex (MHC-II) molecules [15]. Transcription of the MHC class II locus is strictly controlled by a multiprotein complex comprising RFX, X2BP, NF-Y, and CIITA, with the latter considered the main transcriptional regulator of MHC class II expression [16, 17]. The consequences of CIITA gene rearrangements are diverse, as evidenced by the presence of multiple translocation partners (including the PD-L1 and PD-L2 genes), as well as concomitant chromosomal aberrations [18–20]. Alterations in the CIITA gene can be represented not only by translocations, but also by deletions and mutations of the coding sequence [19, 21].

Also, one of the key mechanisms in the pathogenesis of PMBCL is amplification of genes localized at 9p23-24 (JAK2, PDL1, PDL2, JMJD2C), which are detected in 75% of cases. Following aggregation, JAK2 is activated and tumor cell proliferation increases due to activation of the JAK/STAT signaling pathway, which serves as an important component of receptor-mediated intracellular signal transduction for growth factors, hormones, and cytokines. JAK2 transcriptionally activates interleukin signaling pathways (IL-4 and IL-13) and enhances the expression of the PD-1 ligand, which leads to suppression of the T-cell response and growth of the tumor clone in the thymus. Proliferation and survival of tumor cells are potentiated by JMJD2C amplification in combination with JAK2 via histone H3 modification. The kinase activity of JAK2 is controlled via a negative feedback loop by the SOCS (suppressor of cytokine signaling) protein. Deletion of both SOCS1 alleles is observed in tumor cells, leading to altered phosphorylating activity of JAK2 and lifting the restriction on cell proliferation. One of the main mechanisms of PMBCL pathogenesis is dysregulation of the NF-kB signaling pathway and high expression of the MUM1 protein, which leads to active tumor cell proliferation and impaired apoptosis. Resistance of tumor cells to apoptosis is mediated through the REL proto-oncogene, which encodes a protein from the NF-kB family, along with increased expression of STAT1 (IL-13 signaling pathway) and TRAF1 [18, 19].

Considering the similar gene expression profile and mutational portrait of classic Hodgkin lymphoma (HL) and primary mediastinal large B-cell lymphoma (PMBCL), mediastinal gray-zone lymphoma (MGZL) is currently considered an intermediate or "overlap" form between these two lymphoma variants, with the thymic B cell serving as a common progenitor [22]. Gray-zone lymphoma (GZL) can be divided into two molecular subtypes: "PMBCL-like" and "DLBCL-like." This division correlates with tumor localization, specifically the presence or absence of mediastinal involvement. GZL with mediastinal involvement is characterized by mutations in the canonical and non-canonical NF-kB pathways and immune evasion, matching the portrait of HL and PMBCL (SOCS1, B2M, TNFAIP3, GNA13, LRRN3, and NFKBIA). Conversely, GZL without mediastinal involvement corresponds to the DLBCL portrait with a dominance of mutations related to apoptosis defects (TP53, BCL2), combined with BCL2/BCL6 gene rearrangements [23]. Thus, data obtained by Sarkozy C. et al. demonstrate the importance of correlating morphological and clinical findings.

Burkitt lymphoma (BL) is divided into 3 variants: endemic, sporadic, and immunodeficiency-associated [24]. The endemic variant of BL is most common in countries of equatorial Africa and Papua New Guinea, where this disease accounts for up to 75% of all childhood cancers. The disease is associated with infectious agents such as the Epstein-Barr virus (EBV) or malaria parasite (Plasmodium). The clinical presentation frequently involves the facial skeleton: the upper and lower jaws, the orbit, as well as the kidneys, testes, ovaries, salivary glands, breast, and the central nervous system.

The sporadic variant of BL is a typical BL based on morphological, immunophenotypic, and cytogenetic criteria, occurring outside the endemic zone.

The immunodeficiency-associated variant of BL is BL occurring against the background of immunodeficiency states (in HIV-infected patients, post-organ transplantation, and in patients with primary immunodeficiencies). It is most frequently encountered in HIV-infected patients, specifically during the early stages of development (prior to CD4+ cell depletion). It predominantly affects males. Frequent manifestations of the disease include lymphadenopathy, splenomegaly, and bone marrow involvement.

The leading role in the pathogenesis of DHL is played by the pathological activation of c-MYC gene expression. Stable overexpression of its protein leads to uncontrolled cell proliferation, blockade of differentiation, and DNA repair [25]. The presence of a BCL2 gene translocation as a second oncogenic event in DHL with c-MYC/BCL2 rearrangement leads to overexpression of the anti-apoptotic protein BCL2 and directly ensures resistance to apoptosis. In the case of DHL with c-MYC/BCL6 rearrangement, the oncogenic effect of the BCL6 transcription factor is exerted in a significantly more complex, indirect manner through the suppression of the expression of many target genes involved in the regulation of apoptosis, the cell cycle, proliferation, differentiation, and DNA repair (Torka et al., Outcomes of patients with limited-stage aggressive large B-cell lymphoma with high-risk cytogenetics 2020) [26]. Regardless of the mechanisms ensuring the high expression of c-MYC, BCL2, and BCL6 proteins, DHL tumor cells gain a dual advantage in proliferation rate and survival [27].

Plasmablastic lymphoma (PBL) originates from a plasmablast, a large activated B cell in the process of transforming into a plasma cell. Signaling that leads to plasma cell differentiation involves the inactivation of transcription factors PAX-5 and BCL-6 via the transcription factors BLIMP-1 and XBP1. A portion of activated B cells at the stage of plasma cell differentiation transforms into plasmablasts, phenotypically expresses CD38 and IRF-4/MUM-1, and loses CD20 expression. They may be present in reactive lymph nodes during viral infections such as Epstein-Barr virus (EBV) and HIV. It is believed that the key pathogenetic mechanism of PBL is T-cell control deficiency, which causes the immune system's inability to recognize and eliminate tumor clone cells against the background of impaired DNA repair and apoptosis blockade induced by persistent viral infection [28]. However, despite the obvious link between PBL development and HIV-associated immunodeficiency, the disease develops in immunocompetent patients in approximately 20–30% of cases. Further studies have demonstrated differences between "secondary" PBL associated with immunodeficiency and lymphoma developing in patients without overt immune impairment.

One of the most significant molecular prognostic factors in oncohematology is the TP53 gene. Mutations in the TP53 gene in aggressive B-cell lymphomas occur in approximately 25–30% of cases, although their detection rate varies significantly depending on the nosology [29]. The presence of pathogenic aberrations of this gene is, in most cases, unequivocally associated with an unfavorable disease course and chemotherapy resistance. However, the interpretation of TP53 mutation variants and their combination with other anomalies still presents a challenge and is the subject of ongoing scientific research. Another problem is the unavailability of TP53 mutation status analysis in routine practice. Immunohistochemical (IHC) assessment of p53 protein expression can be used as a surrogate marker for the presence of a pathogenic mutation. However, numerous studies have shown that the IHC pattern can vary depending on the nosological variant and the expression of p53-associated proteins, such as BCL6, MDM2, ARF, MYC, ARID1A, and others. Therefore, molecular testing for the TP53 mutation is preferred for accurate diagnosis and the development of risk-adapted treatment protocols [30].

1.3 Epidemiology of the Disease or Condition

Diffuse large B-cell lymphoma (DLBCL) is the most common variant of lymphoproliferative disorders in adults (30–40% of all non-Hodgkin lymphomas). The incidence averages 4–5 per 100,000 population; in individuals under 18 years of age, the frequency of this B-cell tumor variant does not exceed 8–10%. The risk of developing the disease is higher in individuals with hepatitis C virus seropositivity, human immunodeficiency virus (HIV) infection, and autoimmune diseases. The median age is approximately 60 years, and men and women are affected by DLBCL with almost equal frequency [1, 31]. DHL and PBL are rare (about 1–5%) and are diagnosed predominantly in patients aged 30–60 years. PMBCL accounts for 2–4% of non-Hodgkin lymphomas and occurs more frequently in young women [3]. BL predominantly affects males. In children, BL accounts for about 30–50% of all lymphomas. The male-to-female ratio is 3–4:1, and the median age is 8 years. In adults, BL is significantly less common, accounting for 2% of all lymphoma cases. It predominantly affects young men, with a male-to-female ratio of 3:1 and a median age of 25–30 years [32–34].

1.4 Features of Coding the Disease or Condition

• C83.3 – Diffuse large B-cell lymphoma

• C83.7 – Burkitt lymphoma

• C83.8 – Other types of diffuse non-Hodgkin lymphomas

• C83.9 – Diffuse non-Hodgkin lymphoma, unspecified

• C85.7 – Other and unspecified types of non-Hodgkin lymphoma

• C85.2 – Mediastinal (thymic) large B-cell lymphoma

• C91.8 – Mature B-cell Burkitt-type leukemia

1.5 Classification of the disease or condition

The diversity of clinical, morphological, and immunological characteristics, as well as recent molecular cytogenetic studies, have proven that DLBCL is not a single nosological entity, but rather a group of lymphoid tumors sharing a similar yet distinct pathogenesis. Currently, several variants of DLBCL are distinguished based on the level of tumor cell differentiation, types of cellular process dysregulation, and chromosomal abnormalities [1]. In accordance with the 2017 WHO classification, the following are recognized as distinct variants of DLBCL:

• DLBCL, not otherwise specified (NOS). This biologically heterogeneous group includes diseases that do not belong to any of the large cell lymphoma variants listed below:

• T-cell/histiocyte-rich large B-cell lymphoma

• Primary DLBCL of the central nervous system (PCNSL)

• Primary cutaneous DLBCL, leg type

• EBV-positive DLBCL, NOS

• DLBCL associated with chronic inflammation

• Lymphomatoid granulomatosis

• Large B-cell lymphoma with IRF4 rearrangement

• Primary mediastinal (thymic) large B-cell lymphoma (PMBCL)

• Intravascular large B-cell lymphoma

• ALK-positive large B-cell lymphoma

• Plasmablastic lymphoma

• HHV8-positive large B-cell lymphoma

• Primary effusion lymphoma

The following variants of aggressive B-cell lymphomas are considered separately [35]:

• High-grade B-cell lymphoma (HGBL) with MYC and BCL2 rearrangements

• High-grade B-cell lymphoma, NOS (HGBL, NOS)

• Mediastinal grey zone lymphoma (B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and Hodgkin lymphoma)

The 2022 WHO classification introduced a new category, "Transformations of indolent B-cell lymphomas," which includes follicular lymphoma, marginal zone lymphoma, small lymphocytic lymphoma/B-CLL, and lymphoplasmacytic lymphoma transformed into DLBCL. These cases are characterized by specific clinical and molecular-genetic features, and new approaches to their treatment may soon need to be developed.

1.6 Clinical presentation of the disease or condition

The clinical manifestations of DLBCL are diverse, not always specific, and are determined by the primary localization, growth rate, and dissemination of the tumor, as well as the presence or absence of intoxication symptoms (B-symptoms: body temperature >38°C for more than 3 days without signs of inflammation, drenching night sweats, 10% weight loss over the last 6 months). Lymphadenopathy may be observed; when mediastinal and/or thymic lymph nodes are involved, superior vena cava syndrome may develop (cyanosis; facial puffiness; swelling of the head, neck, upper extremities, and upper chest; collateral superficial venous distension; dyspnea, hoarseness, cough, etc.). Disease localized in the abdominal and/or retroperitoneal lymph nodes may manifest as pain and/or signs of impaired function of internal organs compressed by the tumor masses. In extranodal involvement, symptoms of impaired function of the respective organs and systems usually predominate. PCNSL manifests in most cases with focal and/or general cerebral neurological symptoms. Mental status changes, symptoms of increased intracranial pressure, and seizure episodes are common. Clinical manifestations of DHL and PBL are non-specific.

The clinical manifestations of PMBCL and PEL are due to the localization of the tumor in the mediastinum and, depending on its volume, range from asymptomatic to symptoms caused by the compression and/or invasion of mediastinal organs and structures (superior vena cava syndrome, pericardial involvement symptoms, less commonly pleural). Tumor intoxication symptoms may also be observed.

Clinical manifestations of BL are determined by the localization and volume of the tumor. B-symptoms are almost always present, most commonly rapidly progressive weight loss (up to 10 kg or more per month).

Extranodal tumor localization is characteristic of BL. The abdominal organs are most frequently affected: the small intestine (most often its terminal part), mesentery, as well as the stomach, large intestine, peritoneum, liver, and spleen. Specific bone marrow involvement is observed in 25–35% of cases, and central nervous system involvement in 20–25% of cases. Involvement of the kidneys, ovaries, testes, and abdominal and retroperitoneal lymph nodes (especially in the ileocecal region) is typical, while peripheral lymph node involvement is less common.

In 10–15% of cases of BL, involvement of Waldeyer's ring, salivary glands, upper and lower jaws, and orbit is noted. The mediastinum is rarely affected.

A characteristic symptom complex in BL is an "acute abdomen" clinical picture resulting from mechanical bowel obstruction, acute appendicitis, gastrointestinal bleeding, or perforation due to specific infiltration of the stomach and/or intestines. Physical examination may reveal abdominal distension due to the tumor and ascites. Tumor growth is rapid, and in most cases, by the time of hospital admission, abdominal organ involvement presents as a massive tumor conglomerate involving several internal organs. As a rule, patients with BL are admitted in serious or extremely serious condition caused by a high tumor burden, intoxication, exhaustion progressing to cachexia, and electrolyte disturbances. Frequently, the main therapeutic problem in BL patients at the early stage of the disease is progressive acute renal failure (ARF). The most common causes of its development are specific renal involvement, tumor lysis syndrome (TLS), and impaired urodynamics due to compression of the ureters by the tumor conglomerate, leading to postrenal anuria.

2. Diagnostics, medical indications and contraindications for diagnostic methods

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

Criteria for establishing the diagnosis/condition: The diagnoses of DLBCL, DEL, DHL, PMBCL, HGBCL, BL, and B-LBL are established on the basis of a lifetime pathomorphological examination of a tumor biopsy specimen using immunohistochemical methods. An excisional biopsy or an extended biopsy is strongly recommended, as the diagnostic yield of needle biopsies in lymphomas is relatively low and may lead to diagnostic errors (core needle biopsy should be performed only when a full biopsy is technically unfeasible) of a lymph node or lesion, followed by a pathomorphological examination (cytological and histological) using immunohistochemical methods. To clarify the diagnosis of BL and highly aggressive B-cell lymphomas (high-grade B-cell lymphoma with or without c-MYC and BCL2/BCL6 gene rearrangements), additional molecular-biological and cytogenetic studies of the biological material are required [37].

The striking clinical features of BL make it possible to suspect this diagnosis already on the basis of a careful evaluation of the anamnesis, clinical manifestations, primary standard laboratory parameters, and the results of the simplest initial diagnostic procedures (complex ultrasound of the abdominal organs). The further diagnostic process, acquisition, and examination of material must be carried out in an emergency setting aimed at verifying the diagnosis and promptly initiating an appropriate therapy program [24].

The diagnosis of PCNSL is established on the basis of a biopsy (open or stereotactic) of the brain or spinal cord tumor lesion. Extremely rarely, in the presence of pleocytosis in the cerebrospinal fluid, the diagnosis can be established by examining the cerebrospinal fluid (general [clinical] cerebrospinal fluid analysis, cytological examination of cerebrospinal fluid cells, examination of biological material [cerebrospinal fluid] by flow cytometry) [38].

2.1 Complaints and Anamnesis

• For patients with suspected DLBCL, DEL, DHL, PMBCL, HGBCL, BL, and B-LBL, as well as for all patients with verified DLBCL, DEL, DHL, PMBCL, HGBCL, BL, and B-LBL at each appointment (examination, consultation) with an oncologist or hematologist, it is recommended to collect complaints and anamnesis regarding blood and hematopoietic disorders to assess the patient's condition and determine factors that may influence the management strategy [24, 31, 39, 40].

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

Comments: Complaints are nonspecific and are determined by the primary site, growth rate, and dissemination of the tumor; any complaints related to organ and tissue involvement/dysfunction may be present. When taking the history, special attention should be paid to identifying nonspecific intoxication symptoms (body temperature >38°C for 3 days or more without signs of inflammation, profuse night sweats, weight loss of 10% of body weight over the last 6 months). In PCNSL, most cases present with complaints related to general cerebral (headache, nausea, vomiting) or focal neurological symptoms. Given the aggressive nature of the tumor, the disease history is typically short.

2.2 Physical Examination

• For patients with suspected DLBCL, DEL, DHL, PMBCL, HGBCL, BL, and B-LBL or with diagnosed DLBCL, DEL, DHL, PMBCL, HGBCL, BL, and B-LBL at the initial or follow-up visit, during follow-up examinations, and when relapse/disease progression is suspected, it is recommended to perform a general physical examination, palpation, and auscultation to clarify the extent of the disease and assess the patient's condition across organ systems [24, 31, 39, 40].

GCP CLEL 5Grade of Recommendation – 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

• For patients with suspected or confirmed DLBCL, DEL, DHL, PMBCL, HGBCL, BL, and B-LBL at the initial or follow-up visit, after the completion of each therapy cycle and before starting each new therapy cycle, when assessing remission after completion of therapy, during follow-up examinations, and when disease relapse is suspected, it is recommended to perform the following diagnostic tests to clarify the patient's condition, plan the therapeutic strategy, determine the need for its modification, and assess the need for supportive and concomitant therapy [39, 40]:

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

  • general (clinical) urinalysis;

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

  • in severely ill patients, as well as in the presence of signs of acute kidney injury (especially in BL) – assessment of acid-base balance and blood gases;

  • Coagulogram (screening hemostasis test) including the following parameters: prothrombin time in blood or plasma, INR, activated partial thromboplastin time, blood fibrinogen level, thrombin time, antithrombin III activity, plasminogen level, and D-dimer concentration in the blood [41, 42].

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

Comment: The complete blood count (CBC) includes a differential blood cell count using an automated analyzer; evaluation of erythrocyte, platelet, and leukocyte morphology from a blood smear; and, if necessary, an optical platelet count (Fonio method).

• For patients with suspected DEL, DHL, BL during the initial evaluation and at relapse, it is recommended to perform a standard cytogenetic study (karyotype) and detect t(14;18), t(8;22), t(8;14), and t(2;8) translocations in the biopsy (surgical) material using fluorescence in situ hybridization (FISH) to refine the diagnosis [39, 40].

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

• For patients with suspected DLBCL, DEL, DHL, PMBCL, HGBCL, BL, and B-LBL or with verified DLBCL, DEL, DHL, PMBCL, HGBCL, BL, and B-LBL who present with lymphocytosis in the complete blood count (regardless of the leukocyte count), as well as in the presence of predominant lymphoid cells, atypical lymphocytes, or blast morphology cells in the blood or another biological substrate at any stage of diagnosis and treatment, it is recommended to perform peripheral blood immunophenotyping to identify the lymphocyte subpopulation profile (basic) (IPT) [39, 40].

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

Comment: Performing IPT is advisable in the presence of lymphocytosis in the complete blood count (regardless of the leukocyte count), as well as when lymphoid cells, atypical lymphocytes, or blast morphology cells predominate in pleural, ascitic, or other biological fluids. IPT allows for the rapid differential diagnosis of neoplastic and reactive lymphocytosis, which is essential for determining the patient's further management. Materials for IPT can include cells from blood, bone marrow, effusion fluids, cerebrospinal fluid, homogenized tissue samples (spleen, lymph nodes, etc.), and cell suspension obtained from fine-needle aspiration biopsy of lymph nodes. The minimum IPT panel should include evaluation of CD19, CD20, CD10, CD5, CD23, CD3, CD45 expression, and immunoglobulin light chains (Ig-kappa, Ig-lambda). The scope of the study includes a differential count.

• For patients with DLBCL, DEL, DHL, PMBCL, HGBCL, BL, and B-LBL who present with clinical or laboratory signs of hemolysis prior to the first line of antineoplastic therapy, it is recommended to perform a direct antiglobulin test (direct Coombs test) to clarify the cause of hemolysis [39, 43–46].

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

• For previously untreated patients with DLBCL, DEL, DHL, PMBCL, HGBCL, BL, and B-LBL prior to the first line of antineoplastic therapy, it is recommended to determine AB0 blood groups, Rh factor (D antigen), and MNS erythrocyte antigen phenotype to enable blood transfusions if indicated before, during, or after therapy [39].

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

• For previously untreated patients with DLBCL, DEL, DHL, PMBCL, HGBCL, BL, and B-LBL prior to the first line of antineoplastic therapy, it is recommended to perform the following tests to rule out concomitant infectious diseases and plan necessary supportive therapy [39, 40]:

  • determination of hepatitis B virus surface antigen (HBsAg) in the blood;

  • determination of antibodies to hepatitis B virus surface antigen (HBsAg) in the blood

  • detection of antibodies to hepatitis B core antigen (HBcAg) in the blood;

  • detection of Hepatitis B virus DNA in the blood by polymerase chain reaction, qualitative assay (only in case of positive HBsAg and/or HBcAg tests)

  • detection of antibodies to hepatitis C virus in the blood and detection of Hepatitis C virus Core antigen

  • determination of the level of classes M and G antibodies (IgM, IgG) to human immunodeficiency virus HIV-1/2 and antigen p24 (Human immunodeficiency virus HIV 1/2 + Agp24) in the blood

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

• In patients with DLBCL, DEL, DHL, PMBCL, HGBL, BL, and LBL for whom cardiotoxic cytostatic agents and/or mediastinal radiation therapy are planned, it is recommended to measure blood levels of troponins I, T and N-terminal pro-B-type natriuretic peptide (NT-proBNP) to assess the risk of cardiovascular complications [47].

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

• In patients with DLBCL, DEL, DHL, PMBCL, HGBL, BL, and LBL under 18 years of age prior to anti-tumor therapy, as well as in all patients with DLBCL, DEL, DHL, PMBCL, HGBL, BL, and LBL regardless of age who are receiving or have received anti-tumor therapy, after the first episode of severe infection, it is recommended to evaluate immune status (determination of blood immunoglobulin G, A, and M levels) to clarify the risk of infectious complications and the need for appropriate prophylaxis [39, 48].

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

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

2.4 Instrumental Diagnostics

• In patients with newly diagnosed DLBCL, DEL, DHL, PMBCL, HGBL, BL, and LBL, when assessing treatment response, and when disease relapse is suspected, it is recommended—if available and in the absence of contraindications—to perform positron emission tomography combined with contrast-enhanced computed tomography using tumor-tropic radiopharmaceuticals (PET/CT) (fludeoxyglucose [18F]) for staging and evaluation of therapeutic response [39, 40, 49–51].

GCP BLoE 2Grade of Recommendation – B (Level of Evidence – 2).

Comments: PET/CT performed before treatment helps clarify the extent of the tumor process and detect extranodal involvement that may be poorly visualized on CT, which is essential for subsequent evaluation of therapeutic efficacy, treatment planning, and minimization of radiation exposure to healthy tissues. Treatment efficacy based on PET/CT results is assessed using the Deauville scale (see Appendix G2). PET/CT for disease diagnosis is undesirable in pregnant women [52].

• In patients with DLBCL, DEL, DHL, PMBCL, HGBL, BL, and LBL in whom PET/CT cannot be performed, when assessing treatment response, and when disease relapse is suspected, it is recommended to perform computed tomography (CT) of the head, neck, chest, abdomen, and pelvis (with contrast enhancement) for disease staging and to determine the presence, size, and extent of tumor lesions [39, 40].

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

Comments: pregnant patients should not undergo CT of the abdomen and pelvis due to the high radiation dose to the fetus [53, 54]. In pregnant patients, CT of the head, neck, and chest should be performed using a special lead apron to protect the fetus; however, magnetic resonance imaging (MRI) is the preferred imaging modality.

• In patients with contraindications to PET/CT and CT, or when PET/CT and CT are unavailable, at the time of diagnosis or when assessing treatment response, as well as when disease relapse is suspected, it is recommended to perform the following diagnostic examinations for disease staging and to determine the presence, size, and extent of tumor lesions [39]:

  • Targeted chest X-ray in two projections;

  • ultrasound examination of lymph nodes and internal organs, and in men, also ultrasound of the scrotum.

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

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

In pregnant patients, targeted chest X-ray must be performed using a special lead apron to protect the fetus.

• In patients with suspected PCNSL or a confirmed diagnosis of PCNSL, as well as in all patients with DLBCL, DEL, DHL, PMBCL, HGBL, BL, and LBL with neuroleukemia and/or neurological symptoms present at disease onset or during its course, before, after, or during treatment to rule out progression, it is recommended to perform brain MRI with intravenous contrast enhancement to clarify the extent of the tumor process or assess the anti-tumor effect [38, 55].

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

Comments: in pregnant patients, MRI should be performed without contrast enhancement [54]

• In patients with PCNSL detected by MRI, it is recommended—if available and in the absence of contraindications—to perform PET/CT of the brain/spinal cord with a contrast agent (11C-methionine) before treatment initiation, after its completion to assess efficacy, and when disease progression or relapse is suspected [56, 57].

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

Comments: the use of 11C-methionine PET/CT in patients with CNS involvement, compared to isolated MRI or CT, improves the accuracy of subsequent treatment response assessment and the diagnosis of relapse within residual mass areas.

• In patients with a confirmed diagnosis of DLBCL, DEL, DHL, PMBCL, HGBL, BL, and LBL scheduled for treatment of newly diagnosed disease or relapse, it is recommended to perform the following studies for timely detection of concomitant cardiovascular, respiratory, and digestive system pathologies and to determine the need for their prevention or treatment [24, 39]:

  • electrocardiography recording;

  • echocardiography;

  • esophagogastroscopy;

  • colonoscopy with bowel biopsy when bowel involvement is suspected;

  • duplex ultrasound of lower extremity vessels (arteries and veins) [58]

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

Comments: esophagogastroduodenoscopy is performed both to determine the extent of the tumor process and to rule out non-tumor pathologies requiring additional treatment or prevention of complications during therapy.

• In pregnant patients with DLBCL, DEL, DHL, PMBCL, HGBL, BL, and LBL, it is recommended to perform fetal ultrasound, as well as (from 22 weeks) fetal Doppler ultrasonography assessing fetoplacental, uteroplacental blood flow, and blood flow in the fetal middle cerebral artery before starting chemotherapy and before each subsequent chemotherapy course to assess fetal growth and development, amniotic fluid volume, and placental condition [59].

Level of Evidence CGrade of Recommendation 4Level of Evidence – C (Grade of Recommendation – 4).

• In pregnant patients with DLBCL, DEL, DHL, PMBCL, HGBL, BL, and LBL, it is recommended to perform fetal ultrasound before starting chemotherapy and before each subsequent chemotherapy course to assess fetal growth and development, amniotic fluid volume, and placental condition [59].

Level of Evidence CGrade of Recommendation 4Level of Evidence – C (Grade of Recommendation – 4).

2.5 Other Procedures

• In patients with suspected DLBCL, DEL, DHL, PMBCL, HGBL, BL, and LBL, suspected relapse of DLBCL, DEL, DHL, PMBCL, HGBL, BL, and LBL, as well as in cases of ambiguous interpretation of treatment response after completion of therapy, it is recommended to perform a biopsy (obtaining biopsy material) of a lymph node or other lesion, along with pathomorphological examination of the biopsy (surgical) material using immunohistochemical methods to verify the diagnosis [31, 39, 40].

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

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

• For diagnostic purposes, it is strongly recommended to perform an incisional tumor biopsy or an excisional lymph node biopsy.

• Fine-needle aspiration biopsy of a lymph node/tumor mass is not recommended, as it rarely yields diagnostically sufficient material, and therefore should only be used when the tumor lesion is difficult to access for biopsy (e.g., CNS) or when there is a high risk of surgical complications.:

  • 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 specimens must be accompanied by a requisition form containing patient information, duration and nature of the disease, lesion localization, and a description of the biopsy [60].

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

Histological and immunohistochemical features of various DLBCL types, as well as mandatory requirements for pathology reports, are presented in Section 7.1 of these guidelines. Descriptions of the morphological and immunohistochemical patterns of various DLBCL types are provided in Section 7.2 of these guidelines

• For patients with suspected or confirmed diagnosis of DLBCL, DEL, DHL, PMBCL, HGBCL, BL, and PMLBCL primarily (for disease staging), upon completion of therapy (to assess anti-tumor response), and in case of suspected disease relapse, it is recommended [31, 39, 50, 51]:

  • obtaining a bone marrow cytology specimen via puncture, bone marrow smear cytological examination (myelogram), and in case of an increased lymphoid cell count, presence of atypical lymphocytes, or cells with blastic morphology in the bone marrow – testing of the biological material (bone marrow aspirate) using flow cytometry, molecular genetic, and cytogenetic methods.

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

GCP BLoE 2Grade of Recommendation – B (Level of Evidence – 2).

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

In children, iliac crest trephine biopsy is not recommended, except in cases where it is the only way to clarify the diagnosis. Bone marrow puncture from 4 sites is scheduled routinely; if tumor cells are present, control punctures are performed after each block only until remission is achieved or if progression is suspected. The procedure must be performed under general anesthesia.

• For adult patients with a confirmed diagnosis of DLBCL, DEL, DHL, PMBCL, HGBCL, BL, and PMLBCL, if PET/CT is feasible for initial staging, upon therapy completion, and upon suspicion of disease relapse, it is recommended to perform a trephine biopsy regardless of how the bone marrow state is interpreted by PET/CT [61].

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

Comments: results of large multicenter studies (PETAL and OPTIMAL >60) have demonstrated that for routine staging of aggressive B-cell lymphomas, bone marrow trephine biopsy offers no advantages over PET/CT and can be excluded from the diagnostic algorithm.

• For patients with DLBCL, DEL, DHL, PMBCL, HGBCL, BL, and PMLBCL presenting with neurological symptoms at disease onset or during its course, as well as for patients in the high-risk CNS involvement group prior to starting therapy, it is recommended [24, 31, 39, 55]:

  • performing a lumbar puncture;

  • cerebrospinal fluid examination, including visual assessment, determination of protein and glucose concentration, microscopic examination of the cerebrospinal fluid, cell counting in a counting chamber (determination of pleocytosis) with leukocyte morphology evaluation in a smear, and, upon detection of an increased number of lymphoid elements, performing flow cytometry, molecular genetic, and cytogenetic studies of the cerebrospinal fluid.

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

Comments: The high-risk group for CNS involvement includes patients with 4–6 prognostic factors according to the CNS-IPI scale (see section 7.4 of these guidelines), as well as patients with HIV-associated lymphoma, testicular lymphoma, high-grade lymphoma with MYC, BCL-2 and/or BCL-6 translocations, high-grade B-cell lymphoma, unclassifiable, or DLBCL involving the kidneys or adrenal glands, and patients withstage IE DLBCL involving the breast. In children under 18 years of age, lumbar puncture is performed routinely during disease diagnosis.

• For patients with suspected or verified DLBCL, DEL, DHL, PMBCL, HGBCL, BL, and PMLBCL presenting with ascites, in the presence of clinical indications, it is recommended to perform paracentesis with controlled removal of peritoneal transudate (A11.30.001.001), cytological examination of peritoneal fluid, and testing of biological material (peritoneal fluid) by flow cytometry to clarify the extent of the tumor process [24].

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

• For patients with suspected or verified DLBCL, DEL, DHL, PMBCL, HGBCL, BL, and PMLBCL presenting with pleurisy, in the presence of clinical indications, it is recommended to perform pleural cavity drainage, cytological examination of pleural fluid, and testing of biological material (pleural fluid) by flow cytometry to clarify the extent of the tumor process and verify the diagnosis [24].

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

• For patients under 18 years of age with verified BL, especially if there are signs of congenital immunodeficiency or chromosome instability syndrome, it is recommended to perform a molecular biological blood test for Epstein-Barr virus to clarify the etiology and pathogenesis of the disease [24].

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

• For patients with verified DLBCL, DEL, DHL, PMBCL, HGBCL, BL, and PMLBCL during initial evaluation and treatment planning, it is recommended, depending on concomitant pathology, to have an initial appointment (examination, consultation) with a cardiologist, endocrinologist, neurologist, infectious disease specialist; for young children with BL – an initial appointment (examination, consultation) with a geneticist and an initial appointment (examination, consultation) with an allergist-immunologist, as well as with other medical specialists to determine the need for treatment of concomitant diseases [24, 39].

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

• In patients with verified DLBCL, DEL, DHL, PMBCL, HGBL, BL and PBL, during initial evaluation and treatment planning it is recommended to assess the risk of venous thromboembolic complications (VTE risk assessment using the Khorana score – see Appendix G3 of these guidelines) in order to identify patients requiring prophylaxis and to determine the methods of prevention of thrombotic complications during cytostatic therapy [41, 42, 62–64].

Level of Evidence CGrade of Recommendation 4Level of Evidence – C (Grade of Recommendation – 4).

• For women of childbearing potential with newly diagnosed DLBCL, DEL, DHL, PMBCL, HGBCL, BL, and PMLBCL, as well as with relapsed DLBCL, DEL, DHL, PMBCL, HGBCL, BL, and PMLBCL, prior to initiating therapy, it is recommended to perform a set of pregnancy tests to adjust therapeutic tactics and obtain an obstetrician-gynecologist consultation in case of pregnancy [39, 65].

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

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

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

Each treatment cycle begins if blood counts meet the following criteria:

• granulocytes >1 × 10⁹/L,

• platelets >100 × 10⁹/L.

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

If surgical complications of lymphomas are present (intestinal obstruction, bleeding, perforation, etc.), their urgent management with appropriate surgical interventions is required. Also, if present, correction of electrolyte disturbances, management of infectious complications, pain syndrome, and renal failure is necessary.

All treatment regimens for patients with DLBCL, DEL, DHL, PMBCL, HGBCL, and BL, except for PMLBCL, starting from the first cycle, must be administered with rituximab** intravenously or subcutaneously. Several large randomized trials have proven that the subcutaneous form of rituximab** is as effective and safe as the intravenous form. The first administration of the drug to all patients is carried out at a dose of 375 mg/m² intravenously; in the second and/or subsequent treatment cycles, rituximab** can be administered subcutaneously at a fixed dose of 1400 mg regardless of body surface area.

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

3.1 First-line therapy for DLBCL in adults

• For patients over 18 years of age with verified DLBCL and high tumor burden, it is recommended to start treatment with a pre-phase regimen combined with infusion therapy (2–3 liters per day) and #allopurinol** 600 mg/day to prevent tumor lysis syndrome (see section 3.7.) [203]:

  • cyclophosphamide** 200 mg/m² IV, days 1–3, + #dexamethasone** 10 mg/m² IV, days 1–3

  • #prednisolone** 100 mg orally for 5–7 days

  • #dexamethasone** 10 mg/m² IV, days 1–3

GCR CLOE 5Grade of Recommendations – C (Level of Evidence – 5).

Comment: pregnant patients #are not prescribed allopurinol**.

• For patients over 18 years of age with newly diagnosed stage I–II DLBCL, it is recommended to use one of the following therapeutic approaches:

  • 4 courses of immunochemotherapy according to the R-CHOP-21 scheme (for treatment regimen schemes, see Appendix A3.1) with additional administrations of 2 doses of rituximab** (4 R-CHOP + 2 R) followed by a restaging procedure (see section 7.6) [66–73].

  • 6 courses of immunochemotherapy according to the R-CHOP-21 scheme (for treatment regimen schemes, see Appendix A3.1) followed by a restaging procedure (see section 7.6) [66–73].

GOR BLOE 2Grade of Recommendation – B (Level of Evidence – 2).

Comment: in the absence of an anti-tumor response or if signs of progression are present, the patient is switched to second-line therapy.

• For patients over 18 years of age with newly diagnosed stage I–II DLBCL after completion of standard drug treatment regimens (R-CHOP, R-CHOEP, R-miniCHOP, R-CVP, R-CEOP, R-GCVP, R-CCOP, R-CNOP, R-MACOP-B, R-DA-EPOCH) and response assessment by PET/CT (treatment response evaluation using the Deauville scale, see Appendix G2), radiation therapy is recommended [37, 74].

  • if a complete metabolic response is achieved (1–3 scores on the Deauville scale (see Appendix G2) – directed to the areas of initial bulky affected lymph nodes («bulky») and/or areas of extranodal involvement at a total dose (TD) of 30–36 Gy in 15–18 fractions;

  • if a partial response is achieved (4 scores on the Deauville scale (see Appendix G2)) – directed to the involved area at a TD of 36–48 Gy in 18–24 fractions;

Level of Evidence CGrade of Recommendation 4Level of Evidence – C (Grade of Recommendation – 4).

• For patients aged 18 to 65 years with newly diagnosed stage I–II DLBCL with bulky lymph node involvement / a tumor mass («bulky»), without severe comorbid conditions, the use of intensive chemotherapy regimens (R-mNHL-BFM-90) (for treatment regimens, see Appendix A3.1.1) is recommended [75].     

GCP BLoE 2Grade of Recommendation – B (Level of Evidence – 2).

Comment: Administration of intensive treatment regimens is recommended in specialized hematology departments within regional/district/municipal hospitals that are licensed to provide high-tech medical care in hematology/oncology and are equipped with adequate transfusion, intensive care, dialysis, and other services.

• For patients aged 18 to 65 years with newly diagnosed stage I–II DLBCL with «bulky» disease (massive lymph node involvement/tumor mass), after completion of an intensive drug therapy program (R-mNHL-BFM-90, Hyper-CVAD, etc.) and PET/CT response assessment (treatment response evaluation using the Deauville scale, see Appendix G2), radiation therapy is not recommended [75–77].

GCR CLOE 5Grade of Recommendations – C (Level of Evidence – 5).

Comment: According to domestic and foreign studies, due to the high efficacy of intensive treatment regimens (provided they are fully implemented with adherence to doses and course timing), there are no indications for consolidating radiation therapy. If complete remission is not achieved, the patient is switched to second-line therapy.   

• For patients aged 18 to 65 years with partial tumor regression or minimal tumor regression and a metabolic response (4–5 scores on the Deauville scale), high-dose chemotherapy (HDCT) with autologous hematopoietic stem cell transplantation is recommended [75–77].

GCP BLoE 2Grade of Recommendation – B (Level of Evidence – 2).

Comment: The treatment program for stage I-II DLBCL including remission induction with standard chemotherapy regimens and remission consolidation with radiation therapy is comparable in efficacy to programs including remission induction with intensive regimens (R-mNHL-BFM-90, Hyper-CVAD, etc.) and remission consolidation with auto-HSCT in a portion of patients [75–77], but is clearly preferable due to the feasibility of its implementation in a broader range of practical healthcare settings.

• For patients over 18 years of age with newly diagnosed stage III–IV DLBCL, immunochemotherapy according to the following regimens is recommended: 6 cycles of R-CHOP-21 followed by 2 single-agent doses of rituximab**, 6 cycles of R-CHOEP-14 (under 60 years of age), 6 cycles of R-DA-EPOCH (under 60 years of age) (for treatment regimens, see Appendix A3.1), followed by restaging procedures (see section 7.6) [37, 66–68, 78–82, 121, 155, 331].

Level of Evidence CGrade of Recommendation 4Level of Evidence – C (Grade of Recommendation – 4).

• For patients over 18 years of age after completion of standard drug therapy and PET/CT, radiation therapy is recommended:

  • upon achieving a complete metabolic response (DC 1–3), consolidating radiation therapy is indicated for the areas of initially bulky or residual tumor masses at a TD of 30–36 Gy in 15–18 fractions

  • upon achieving a partial response (DC 4), the patient is switched to second-line chemotherapy. In the presence of individual contraindications to second-line chemotherapy, it is advisable to consider radiation therapy to clinically significant tumor foci at a TD of 36–48 Gy in 18–24 fractions [37, 66–68, 78–82]. At the same time, the TD value must correlate with the tolerance limits of organs at risk included in the planned irradiation volume [37, 66–68, 78–82, 357].

GCP BLoE 2Grade of Recommendation – B (Level of Evidence – 2).

Comment: in the absence of an antitumor response and/or in the presence of signs of DLBCL progression, the patient is switched to second-line therapy.

• For patients over 18 years of age with newly diagnosed DLBCL classified as intermediate and high risk (IPI 2–5), 6 cycles of Pola+R-CHP immunochemotherapy (for treatment regimens, see Appendix A3.1) followed by 2 single-agent doses of rituximab** (cycles 7–8) are recommended as an alternative regimen [83].

GOR BLOE 2Grade of Recommendation – B (Level of Evidence – 2).

Comment: the efficacy of the combination of polatuzumab vedotin with rituximab**, doxorubicin**, cyclophosphamide**, and #prednisolone** (Pola + R-CHP) in patients with newly diagnosed DLBCL (IPI 2–5) was demonstrated in the phase III multicenter, randomized, double-blind, placebo-controlled POLARIX study. The risk of relapse/progression in the polatuzumab vedotin group was reduced by 27% (HR 0.73, p <0.02) compared to the R-CHOP group.

Restaging procedure after 3 and 6 cycles (see section 7.6).

• For patients over 18 years of age with newly diagnosed DLBCL in the presence of severe cardiovascular pathology (left ventricular ejection fraction drop below 50%), immunochemotherapy regimens not containing doxorubicin** or utilizing pegylated liposomal doxorubicin** are recommended: CHOP with pegylated liposomal doxorubicin**, CEOP, CCOP, GCVP, CNOP in combination with rituximab** (see Appendix A3.1) [84–90].

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

• For patients over 18 years of age with verified DLBCL at high risk for CNS involvement (4–6 prognostic factors on the CNS-IPI scale – see section 7.4 of these guidelines, as well as patients with HIV-associated lymphoma, testicular lymphoma, high-grade B-cell lymphoma with MYC, BCL-2 and/or BCL-6 translocations, high-grade B-cell lymphoma, unclassifiable, or DLBCL with kidney or adrenal gland involvement, patients with stage IE DLBCL with breast involvement), CNS relapse prophylaxis is recommended, which includes 4 intrathecal administrations of methotrexate** (12 mg), cytarabine** (30 mg), #dexamethasone** (4 mg) and 2 systemic administrations of high-dose methotrexate** (1.5–3 g/m²) [31, 91].

GOR CLOE 3Grade of Recommendation – C (Level of Evidence – 3).

Comment: for pregnant patients, CNS relapse prophylaxis is performed without the administration of #methotrexate** [92]

• For patients over 18 years of age with a newly diagnosed DLBCL at high risk of CNS involvement (4–6 prognostic factors on the CNS-IPI scale – see section 7.4 of these guidelines, testicular lymphoma, with kidney or adrenal gland involvement, with breast involvement) without severe comorbid conditions, ECOG <3, the use of the R-mNHL-BFM-90 program in combination with #lenalidomide** and #ibrutinib** (treatment regimen see in Appendix A3.1.1) followed by autologous hematopoietic stem cell transplantation with BEAM conditioning is recommended as an alternative regimen [97–100].

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

• For patients over 18 years of age with newly diagnosed testicular DLBCL, orchifuniculectomy is recommended. Chemotherapy is administered in accordance with the recommendations for DLBCL of the corresponding stage with a high risk of CNS involvement. Radiation therapy is recommended to the entire scrotum at a TD of 26–30 Gy in 13–15 fractions with a consolidative intent upon achieving a complete metabolic response (DC 1–3 according to PET/CT) [31, 364, 365]. Sole radiation therapy for testicular DLBCL is performed only when chemotherapy is impossible (presence of severe comorbid conditions, older age).

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

• For patients over 18 years of age with newly diagnosed testicular DLBCL with regional lymph node involvement (in the ipsilateral renal hilum) after completion of drug therapy and PET/CT, it is advisable to consider radiation therapy:

  - upon achieving a complete metabolic response (DC 1–3), consolidating radiation therapy is indicated for the areas of initially bulky or residual tumor masses at a TD of 30–36 Gy in 15–18 fractions [358]

  - if a partial response (DC 4) is achieved, the patient is switched to second-line chemotherapy. If there are individual contraindications to second-line chemotherapy, radiation therapy to the residual lymph node conglomerate is recommended at a TD of 36-48 Gy in 18-24 fractions [37, 66–68, 78–82]. In this case, the TD value should be correlated with the tolerance limit of renal tissue, the volume of kidney tissue included in the planned irradiation volume, and the function of both kidneys according to static scintigraphy and biochemical parameters.

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

• For patients over 18 years of age with newly diagnosed widespread (II-IV) testicular diffuse large B-cell lymphoma (DLBCL), performing orchidofuniculectomy is not advisable. It is rational to perform a biopsy of the testicular tumor or any most accessible tumor focus. As an alternative chemotherapy regimen, the R-mNHL-BFM-90 program (blocks A, B) in combination with #lenalidomide** and #ibrutinib** (for the treatment regimen see Appendix A3.1.1) is recommended, followed by autologous hematopoietic cell transfusion in the WBC regimen with lumbar punctures and intrathecal administration of 3 antineoplastic drugs (cytarabine** 30 mg, #methotrexate** 15 mg, #dexamethasone** 4 mg). Radiation therapy with a consolidative purpose is not indicated [347].

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

• For patients over 18 years of age with newly diagnosed breast DLBCL (II-IV), performing radical mastectomy is not advisable. It is rational to perform a breast tumor biopsy. As an alternative chemotherapy regimen, the R-mNHL-BFM-90 program (blocks A, B) in combination with #lenalidomide** and #ibrutinib** (for the treatment regimen see Appendix A3.1.1) is recommended, followed by autologous hematopoietic cell transfusion in the WBC regimen with lumbar punctures and intrathecal administration of 3 antineoplastic drugs (cytarabine** 30 mg, #methotrexate 15 mg, #dexamethasone 4 mg). Radiation therapy with a consolidative purpose is not indicated [348].

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

• For patients aged 18 to 65 years with newly diagnosed highly aggressive B-cell lymphoma or high-risk DLBCL (aaIPI=3 or with additional risk factors for early progression, e.g., involvement of the CNS, bone marrow, testes, etc.) without concomitant comorbidity, intensive immunochemotherapy protocols are recommended: BFM-NHL-90m, B-NHL-2004M [93]

GOM BLOE 3Grade of Recommendation – B (Level of Evidence – 3),

• R-Hyper-CVAD [94] Grade of Recommendation – C (Level of Evidence – 4),

• R-CODOXM/R-IVAC [95] Grade of Recommendation – C (Level of Evidence – 2),

• R-mNHL-BFM-90, [96]

GOM CLOE 2Grade of Recommendation – C (Level of Evidence – 2).

• For patients aged 18 to 65 years with newly diagnosed non-GCB variant DLBCL with high MUM1 expression (>40%), high tumor burden, from the intermediate-high/high-risk group (IPI=3-5, aaIPI=2-3), without severe comorbidities, ECOG <3, the R-mNHL-BFM-90 program in combination with #lenalidomide** (for the treatment regimen see Appendix A3.1.1) is recommended as an alternative regimen [97–100].

GCP CLoE 5Grading of Recommendations Assessment, Development and Evaluation (GRADE) – C (Level of Evidence – 5)

Comment: Administration of intensive therapy programs is recommended in specialized hematology departments within regional/district hospitals that are licensed to provide high-tech medical care in hematology/oncology and are equipped with adequate transfusion, intensive care, dialysis, and other services. One of the largest retrospective studies [97] demonstrated that in patients with non-GCB variant DLBCL from the intermediate-high/high-risk group (IPI=3-5, aaIPI=2-3), the efficacy of the R-CHOP program is extremely low, with progression-free survival not exceeding 30%. A prerequisite for treating patients in this group is a pre-phase. For patients meeting all parameters except ECOG (3-4), indications for intensive therapy may be reconsidered after the pre-phase if there is a positive trend according to the ECOG scale.

• For patients aged 18 to 65 years with newly diagnosed non-GCB variant DLBCL with c-MYC+BCL2 co-expression (DEL) in the absence of combined c-MYC and/or BCL2/BCL6 gene rearrangement, from the intermediate-high/high-risk group (IPI=3-5, aaIPI=2-3), without severe comorbidities, ECOG <3, the R2-mNHL-BFM-90/Pola-R-EPCH program is recommended as an alternative regimen (for the treatment regimen see Appendix A3.1.1) [83, 98].

GOM BLOE 5Grade of Recommendation – B (Level of Evidence – 5)

Comment: This program is recommended for patients in whom c-MYC and/or BCL2, BCL6 gene rearrangements have been excluded by FISH testing. According to the phase III international POLARIX study presented by F. Morschhauser et al. in 2022 and 2023, the use of polatuzumab vedotin within the Pola-R-CHP program overcomes the negative prognostic significance of c-MYC and BCL2 protein co-expression (DEL) and reduces the risk of relapse/progression or death by 40% in this patient group compared to R-CHOP therapy. Administration of intensive therapy programs is recommended in specialized hematology departments within regional/district hospitals that are licensed to provide high-tech medical care in hematology/oncology and are equipped with adequate transfusion, intensive care, dialysis, and other services. For patients meeting all parameters except ECOG (3 and 4), indications for intensive therapy may be reconsidered after the pre-phase if there is a positive trend according to the ECOG scale.

• For patients aged 18 to 65 years with newly diagnosed GCB variant DLBCL with c-MYC+BCL2 co-expression (DEL) in the absence of combined c-MYC and/or BCL2/BCL6 gene rearrangement, from the intermediate-high/high-risk group (IPI=3-5, aaIPI=2-3), without severe comorbidities, ECOG <3, the R-mNHL-BFM-90/Pola-R-EPCH program is recommended as an alternative regimen [98, 101].

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

Comment: This program is recommended only in the absence of combined c-MYC and/or BCL2, BCL6 gene rearrangements excluded by FISH testing. According to the phase III international POLARIX study presented by F. Morschhauser et al. in 2022, the use of polatuzumab vedotin in the Pola-R-CHP program overcomes the negative prognostic significance of c-MYC and BCL2 protein co-expression (DEL) and reduces the risk of progression or death by 40% in this subgroup of patients compared to R-CHOP therapy. Administration of intensive therapy programs is recommended in specialized hematology departments within regional/district hospitals that are licensed to provide high-tech medical care in hematology/oncology and are equipped with adequate transfusion, intensive care, dialysis, and other services. For patients meeting all parameters except ECOG (3 and 4), indications for intensive therapy may be reconsidered after the pre-phase if there is a positive trend according to the ECOG scale.

• For patients aged 18 to 65 years with newly diagnosed high-grade B-cell lymphoma with combined c-MYC and BCL2 gene rearrangement (DHL) from the intermediate-high/high-risk group (IPI=3-5, aaIPI=2-3), without severe comorbidities, ECOG <3, the R-mNHL-BFM-90 program with #venetoclax** and polatuzumab vedotin (regimen with drug dosages is presented in Appendix A3) is recommended as an alternative regimen [98, 102, 103].

GCP CLoE 5Grading of Recommendations Assessment, Development and Evaluation (GRADE) – C (Level of Evidence – 5)

Comment: This program is recommended only in the presence of combined c-MYC and BCL2 gene rearrangements detected by FISH testing. In 2023, Andrew D. Zelenetz et al. demonstrated high efficacy of chemotherapy combined with polatuzumab vedotin and #venetoclax** (Ven 800 mg/day - Pola-R-CHP) in the first-line therapy of patients with aggressive high-grade B-cell lymphoma with c-MYC and BCL2 gene rearrangements (DHL). To reduce the incidence of adverse events associated with the 800 mg/day dose of #venetoclax**, the venetoclax** dose is reduced to 200 mg/day in our program. Administration of intensive therapy programs is recommended in specialized hematology departments within regional/district hospitals that are licensed to provide high-tech medical care in hematology/oncology and are equipped with adequate transfusion, intensive care, dialysis, and other services. For patients meeting all parameters except ECOG (3 and 4), indications for intensive therapy may be reconsidered after the pre-phase if there is a positive trend according to the ECOG scale.

• For patients aged 18 to 65 years with newly diagnosed high-grade B-cell lymphoma with concurrent c-MYC and BCL6 gene rearrangements (DHL) from the intermediate-high/high-risk group (IPI=3-5, aaIPI=2-3), without severe comorbid pathology, ECOG <3, the R-mNHL-BFM-90 regimen with #ibrutinib** (420 mg on days 1–10) and #lenalidomide** 25 mg on days 1–10 is recommended as an alternative regimen (the protocol schedule with drug dosages is provided in Appendix A3) [98, 102, 104].

GCP CLoE 5Grading of Recommendations Assessment, Development and Evaluation (GRADE) – C (Level of Evidence – 5)

Comment: This regimen is recommended only in the presence of c-MYC and BCL6 gene rearrangements detected by FISH analysis. The administration of intensive treatment regimens is recommended in specialized hematology departments within regional/district hospitals that are licensed to provide high-tech medical care of a hematological/oncological profile and are equipped with adequate transfusion, intensive care, dialysis, and other services. For patients meeting all parameters except ECOG (3 and 4), reconsideration of indications for intensive therapy is possible after a pre-phase if there is a positive trend according to the ECOG scale. 

• For patients older than 65 years and/or with severe comorbidities with newly diagnosed DLBCL and concurrent parenchymal CNS involvement, the R-CHOP treatment program is recommended (see Appendix A3.1) with the addition of 2–4 systemic administrations of high-dose methotrexate** (3.5 g/m²) [105].

Level of Evidence CGrade of Recommendation 4Level of Evidence – C (Grade of Recommendation – 4).

• For patients older than 65 years and/or with severe comorbidities with newly diagnosed DLBCL and concurrent leptomeningeal involvement of the brain/spinal cord (neuroleukemia), treatment according to the R-CHOP scheme is recommended with intrathecal administrations of antineoplastic agents (#methotrexate** 15 mg, cytarabine** 30 mg, #dexamethasone** 4 mg) twice a week until complete CSF clearance, followed by intrathecal administrations of the drugs once a month until the completion of the immunotherapy program, followed by high-dose methotrexate** administration [91].

GCP CLEL 3Grade of Recommendation – C (Level of Evidence – 3).

Comment: the choice of #methotrexate** dose for intravenous infusion is determined by age, presence of concomitant diseases and conditions, and renal excretory function. To reduce toxicity, it is recommended to limit the #methotrexate** infusion duration to 4 hours. CNS prophylaxis is performed at the early stages of the treatment program, if necessary with colony-stimulating factor support (one intrathecal administration on day 1 of cycles 1–4; high-dose #methotrexate** is prescribed on day 15 of cycles 1 or 2 and after the completion of the last treatment cycle). In some cases, in patients with a severe somatic condition or significant pleural effusion/ascites, systemic #methotrexate** may be used at the end of medical treatment (2 administrations with a 15-day interval).

For pregnant patients, CNS relapse prophylaxis is performed without the administration of #methotrexate** [92]

• For patients older than 65 years and/or with comorbidities, with newly diagnosed DLBCL who are not candidates for intensive therapy, in the presence of poor prognostic factors (IPI=3-5, non-GCB variant, advanced stages, presence of c-MYC, BCL2, BCL6 gene rearrangements, TP53 gene mutations, and others), the SMART-START or R-EPOCH/R-HMA programs are recommended as alternative regimens [98, 106–109].

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

Comment: When implementing the SMART-START program, special attention is paid to the frailest patients with cardiac pathology. If cardiac pathology with rhythm disturbance is present at baseline, develops during therapy, or carries a high risk of occurrence, #ibrutinib** may be replaced with #acalabrutinib** or #zanubrutinib as agents with lower cardiotoxicity [98].

• For patients over 80 years of age, with severe comorbidities and/or with a deteriorated performance status and newly diagnosed DLBCL, the use of less toxic immunochemotherapy regimens (R-CVP, BR, R-miniCHOP – see Appendix A3.1.1) is recommended [110–115]

Level of Evidence CGrade of Recommendation 4Level of Evidence – C (Grade of Recommendation – 4).

3.2 First-Line Therapy for Primary Mediastinal (Thymic) Large B-Cell Lymphoma in Adults

• For patients over 18 years of age with a confirmed diagnosis of PMBCL, one of the following immunochemotherapy regimens at the discretion of the attending physician is recommended (see Appendix A3.1) [116–123]:

  • DA-EPOCH-R

  • R-MACOP-B

  • R-CHOP

  • R-mNHL-BFM-90/R-EPOCH (PML-16 program)

  • R2-mNHL-BFM-90/R2-EPOCH (PML-19 program)

GCR BLOE 3Grade of Recommendations — B (Level of Evidence — 3).

Comment: the efficacy and advantages in achieving anti-tumor response, PFS, and OS of the R-MACOP-B and R-DA-EPOCH regimens over the R-CHOP regimen have been demonstrated in several international and domestic prospective and retrospective studies. The R-MACOP-B program is designed for outpatient day-hospital settings. The PML-16 and PML-19 programs have demonstrated high efficacy in a domestic prospective study. Achieving 100% overall and disease-free survival regardless of stage and prognostic factors, without the use of consolidative radiotherapy and high-dose therapy, provides grounds for omitting consolidation in patients with residual mediastinal masses [98, 127].

• For patients over 18 years of age with a confirmed diagnosis of PMBCL who achieve a complete metabolic response (Deauville score 1–3) after induction chemotherapy according to the R-DA-EPOCH, R-mNHL-BFM-90/R-EPOCH, and R2-mNHL-BFM-90/R2-EPOCH programs, observation is indicated [98, 127, 128, 332, 333].

GUR CLOE 4Grading of Recommendations Assessment, Development, and Evaluation (GRADE) – C (Level of Evidence – 4).

• For patients over 18 years of age with a confirmed diagnosis of PMBCL and baseline bulky mediastinal disease who achieve a complete metabolic response on PET/CT only after standard induction chemotherapy according to the R-CHOP and MACOP-B programs, consolidative involved-field radiotherapy to the mediastinal lesion area at a total dose (TD) of 30–36 Gy in 15–18 fractions is recommended [37, 116–121, 359, 360].

GOM CLOE 4Level of Evidence – C (Level of Data Reliability – 4).

• For patients over 18 years of age with a confirmed diagnosis of PMBCL and a partial metabolic response on PET/CT (Deauville score 4–5) with confirmed active tumor process based on biopsy, high-dose chemotherapy (HDCT) is indicated [335].

GOM CLOE 4Level of Evidence – C (Level of Data Reliability – 4).

• To improve immunochemotherapy outcomes, patients over 18 years of age with a newly diagnosed PMBCL may be recommended to receive #pembrolizumab** at 10 mg/kg of body weight or 200 mg as a 30-minute intravenous infusion or #nivolumab** at a fixed dose of 240 mg or 40 mg as a 60-minute intravenous infusion on day 0 of the cycle [98, 125–126, 342].

GOM CLOE 4Level of Evidence – C (Level of Data Reliability – 4).

• For patients over 18 years of age in whom HDCT cannot be performed, external beam radiotherapy to the residual tumor mass at a TD of 40–48 Gy should be considered [335].

GCR CLOE 5Grade of Recommendations – C (Level of Evidence – 5).

• For patients under 18 years of age with a confirmed diagnosis of PMBCL, DA-EPOCH-R therapy is recommended [336]

• For patients over 18 years of age with newly diagnosed mediastinal gray zone lymphoma (MGZL), the R-DA-EPOCH immunochemotherapy regimen including #dacarbazine** 375 mg/m² i.v. once on day 5 of the cycle (MGZL-2017) is recommended (the protocol schedule with drug dosages is provided in Appendix A3) [98].

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

Comments: simultaneously with the initiation of chemotherapy according to the R-DA-EPOCH regimen including #dacarbazine**, the patient should be discussed with one of the transplantation centers regarding the feasibility and necessity of performing autologous hematopoietic stem cell transplantation (auto-HSCT) [98].

• For patients over 18 years of age with newly diagnosed mediastinal gray zone lymphoma (MGZL), the MGZL-16 program (induction with 2 blocks A of R-m-NHL-BFM-90, followed by 4 courses of R-BEACOPP-14) is recommended as an alternative program (the protocol schedule with drug dosages is provided in Appendix A3) [98].

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

Comments: Considering that MGZL combines the characteristics of two aggressive lymphomas, it is rational to combine two different approaches into a single hybrid therapy program that have proven to be the most effective in PMBCL and HL.

3.3 Treatment of primary central nervous system lymphoma (PCNSL) in adults

• For patients aged 18 to 65 years without severe comorbid conditions and with newly verified PCNSL, treatment including high doses of methotrexate** (≥3000 mg/m²) is recommended (see Appendix A3.1) [129–133].

GCP BLoE 2Grade of Recommendation – B (Level of Evidence – 2).

Comments: The use of chemotherapy has significantly improved treatment outcomes for PCNSL. The choice of drugs for PCNSL treatment is determined by their activity in NHL and their ability to cross the blood-brain barrier (BBB). Standard protocols (CHOP, MACOP-B) used in other forms of NHL are ineffective for PCNSL because their component drugs cannot cross the BBB. Drugs capable of crossing the BBB include methotrexate**, cytarabine**, procarbazine**, vincristine**, carmustine**, lomustine**, #thiotepa [134, 137] cyclophosphamide**, etoposide**, #cisplatin** and glucocorticoids (treatment regimens with dosages are provided in Appendix A3) [129–136]. High-dose MTX** is one of the most frequently used drugs for PCNSL treatment. An MTX** dose of ≥1 g/m² already provides the necessary therapeutic concentration in the brain, and a dose of ≥3.5 g/m²—in the cerebrospinal fluid. Based on the available data, high-dose MTX monotherapy (3 to 8 g/m²) and its combination with other antineoplastic agents are recognized as the most effective treatment regimens. The preferred induction chemotherapy regimens in adult patients with PCNSL are the R-MPV and RL-MPV protocols. Before each chemotherapy course, in the absence of contraindications, lumbar punctures with intrathecal administration of 3 antineoplastic drugs (cytarabine** 30 mg, #methotrexate** 15 mg, #dexamethasone** 4 mg) are recommended. If neuroleukemia is detected initially, lumbar punctures are performed until cerebrospinal fluid (CSF) is cleared three times, and subsequently before each chemotherapy course. The R-MPV induction regimen includes a combination of rituximab**, methotrexate**, vincristine**, procarbazine** (see protocol schedules). The induction regimen of the "CNS-2021" RL-MPV protocol includes a combination of rituximab**, methotrexate**, vincristine**, procarbazine** and #lenalidomide** (see protocol schedules) [137–139]. In the absence of procarbazine**, an R-MV course is recommended with the addition of #lenalidomide** 25 mg/day or #ibrutinib** or #acalabrutinib** or #zanubrutinib for 10 days of each cycle [334]

• Patients aged 18 to 65 years without severe comorbid conditions with newly diagnosed PCNSL are recommended consolidation with auto-HSCT using high-dose conditioning regimens (see Appendix A3.1) [137–139].

Level of Evidence CGrade of Recommendation 4Level of Evidence – C (Grade of Recommendation – 4).

Based on clinical evaluation 2017.47.1 "Method for improving the efficacy of programmed chemotherapy for primary diffuse large B-cell lymphoma of the CNS" conducted at the National Research Center for Hematology of the Russian Ministry of Health between 2017 and 2019 in 18 patients, the advantage of using the R-MPV induction program followed by auto-HSCT with the TBC conditioning regimen was demonstrated for young PCNSL patients. Achieving complete remissions (100%), a 2-year overall survival probability (90%, median not reached), and a 2-year progression-free survival probability (90%, median not reached) in this prognostically unfavorable group of patients indicates high efficacy of the protocol with a low rate of predicted complications (infectious and toxic) – 30% [140, 141]. The TBC conditioning regimen includes thiotepa, #busulfan** [134, 137], cyclophosphamide** (see protocol schedules). Achieving complete remission is not a mandatory criterion before performing auto-HSCT. The obtained results also surpass the outcomes of using the standard conditioning regimen (BEAM) prior to auto-HSCT for patients with primary CNS lymphoma: the relapse rate with the BEAM regimen is 50% compared to 10% when using the TBC scheme [142].

Due to irregular supplies of thiotepa in 2021, a new protocol "CNS-2021" was developed at the National Research Center for Hematology of the Russian Ministry of Health. The induction regimen of the "CNS-2021" RL-MPV protocol includes a combination of rituximab**, methotrexate**, vincristine**, procarbazine** and #lenalidomide** (see protocol schedules). The BBC conditioning regimen includes #carmustine** (Arshad et al., 2023), #busulfan** [134, 137], cyclophosphamide** [139].

• Patients aged 18 years and older with PCNSL who are ineligible for high-dose chemotherapy and auto-HSCT are recommended to undergo remission consolidation using one of the following therapeutic strategies:

  • chemotherapy including high-dose cytarabine** +/– high-dose methotrexate** (see Appendix A3.1) [130,143]

  • whole-brain radiotherapy at a dose of 23.4–24 Gy in 12 fractions [135].

Level of Evidence CGrade of Recommendation 4Level of Evidence – C (Grade of Recommendation – 4).

Comments: currently, there is no evidence regarding the superiority of one remission consolidation therapy option over another in PCNSL. However, indications for whole-brain radiotherapy should be restricted to selected cases due to the high probability of developing delayed neurotoxicity. The clinical target volume (CTV) should include the entire brain, optic nerves, and posterior parts of the eyeballs (1/3) even in the absence of evidence of ocular involvement. If intraocular involvement is detected, both eyeballs should be included in the target volume. The inferior border of the radiation fields should be located at the junction of the cranial bones and the C1 vertebra, with a CTV-PTV (planning target volume) margin of 3-5 mm. Pre-radiation preparation and whole-brain RT should be performed using an individual fixation mask to ensure setup accuracy [146].

• Patients aged 18 to 65 years without severe comorbid conditions with newly diagnosed PCNSL, following the RL-MPV program and auto-HSCT, are recommended maintenance therapy with #nivolumab**, #pembrolizumab** 3 months after auto-HSCT for 6 months [139].

Level of Evidence CGrade of Recommendation 4Level of Evidence – C (Grade of Recommendation – 4).

• For patients aged 18 to 65 years with newly diagnosed PCNSL in whom high-dose methotrexate therapy (²) cannot be administered for various reasons (it is recommended to prescribe) a combination therapy of #lenalidomide** 25 mg/day, rituximab 375 mg/m², #ibrutinib** 560 mg/day/#acalabrutinib**/#zanubrutinib and #nivolumab** 2 mg/kg [334, 144, 349-351, 353-354] (see Appendix A3).

  Administration of drugs at standard doses is recommended: #lenalidomide** 25 mg/day for 21 days [349], #ibrutinib** at a dose of 560 mg/day [350], #nivolumab** 3 mg/kg every 2 weeks [351], rituximab** 375 mg/m² IV on day 1 of each cycle for 6-12 months [349]. (not used in children). In the presence of concomitant cardiac pathology, it is rational to prescribe #acalabrutinib** at a dose of 200 mg/day [353] or #zanubrutinib at a dose of 320 mg/day [354].

GCR CLOE 5Grade of Recommendations – C (Level of Evidence – 5).

• Patients aged 18 years and older with newly diagnosed PCNSL who, for various reasons, cannot receive therapy including high-dose #methotrexate** (≥3000 mg/m²), are recommended therapy with a combination of #temozolomide** and rituximab** (see Appendix A3.1) [145]. (not used in children)

GOM CLOE 4Level of Evidence – C (Level of Data Reliability – 4).

Comment: it is advisable to consider palliative RT in patients with PCNSL (whole-brain radiotherapy at a dose of 24–36 Gy in 12–18 fractions +/- subsequent "boost" to individual tumor lesions up to a total dose of 44-46 Gy) [146].

3.4 First-line therapy for DLBCL in children and adolescents under 18 years of age

• Patients under 18 years of age with a confirmed diagnosis of aggressive non-follicular B-cell lymphoma (DLBCL, BL, or PMBCL) are recommended to undergo multi-agent polychemotherapy based on BFM group protocols (see Appendix A3.1) depending on risk groups (see section 7.5) with the inclusion of rituximab** [151].

Level of Evidence CGrade of Recommendation 4Level of Evidence – C (Grade of Recommendation – 4).

Comment: if a persistent residual mass remains after block 4, the patient is recommended to undergo a follow-up examination (PET/CT and/or biopsy of the residual mass), or both procedures in doubtful cases. If there is no evidence of an active tumor process, the AA–BB–CC courses are continued. If viable tumor is confirmed, HSC apheresis, the ICE block, and auto-HSCT are performed. In case of initial CNS involvement (especially in the presence of infiltrative lesions), patients after block AA receive endolumbar therapy (2 administrations per block at the full age-adjusted dose of three drugs, except for administrations during block CC) or intraventricular therapy via an Ommaya reservoir.

3.5 Treatment of Burkitt lymphoma in adults

Treatment of BL is carried out as soon as possible and in an emergency medical care mode [24,152].

• For patients over 18 years of age with BL, it is recommended to provide emergency management of existing surgical complications (intestinal obstruction, bleeding, perforation), correction of electrolyte disturbances, management of infectious complications, and pain control [24, 152].

GCR BLOE 5Grade of Recommendations — B (Level of Evidence — 5).

• For patients over 18 years of age with BL presenting with acute renal failure, it is recommended to administer chemotherapy alongside daily hemodialysis sessions [153].

GCR CLOE 5Grade of Recommendations – C (Level of Evidence – 5).

• For patients over 18 years of age with BL, it is recommended to use high-dose pulsed chemotherapy +/– rituximab** as the primary treatment method (see Appendix A3.1) [154].

Level of Evidence CGrade of Recommendation 4Level of Evidence – C (Grade of Recommendation – 4).

Comments: In rare localized stages of the disease, the number of chemotherapy courses is reduced in accordance with the protocols. Poor prognostic factors requiring treatment intensification include: bone marrow and CNS involvement, LDH elevation >2 times the upper limit of normal, renal involvement, bone involvement (multifocal lesions), and tumor size greater than 10 cm.

• For patients over 18 years of age with BL in the 1st line of therapy, it is recommended to use intensive therapy according to the BL-M-22 (R-mNHL-BFM-90/R-EPOCH) program [98].

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

Comments: The program includes two branches. One branch comprises 4 blocks A and C in accordance with the previously presented BLM-04 protocol. The other branch provides the option of administering only 2 courses of block therapy (A and C) followed by consolidation with 2 courses of R-EPOCH in cases of: a) poor tolerability, development of severe infectious complications; b) localized stage or completely resected tumor (I, IIR).

• For patients over 18 years of age with BL in the 1st line of therapy, it is recommended to use intensive chemotherapy protocols: R-Hyper-CVAD, BL-M-04+/-R, LMB 95, CODOXM/IVAC+/-R (for regimens see Appendix A3.1) [24].

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

Comments: The primary rule in the treatment of BL is adherence to the "dose-interval" principle, i.e., administering full-dose courses while strictly maintaining the inter-course interval. Except for situations involving life-threatening complications, interrupting an initiated course of chemotherapy is not recommended. In exceptional cases involving severe infectious complications that could not be resolved by the end of the inter-course interval, extending the interval between courses is permissible.

• For patients over 18 years of age with BL, it is not recommended to administer therapy according to the R-CHOP regimen due to its ineffectiveness [24].

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

• For patients over 55 years of age without CNS involvement (not candidates for intensive chemotherapy), it is recommended to administer treatment according to the R-DA-EPOCH protocol (see Appendix A3.1) [155].

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

• For all patients with BL, it is recommended to insert a central venous catheter for administering chemotherapy and supportive care [24].

GCR CLOE 5Grade of Recommendations – C (Level of Evidence – 5).

• For patients with BL over 18 years of age receiving high-dose methotrexate**, it is recommended to monitor its elimination (serum concentration assay!) and adjust the dose of calcium folinate** daily until laboratory parameters normalize [24].

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

• For patients with BL over 18 years of age with massive extramedullary tumor lesions (mediastinal, abdominal, etc.), it is recommended to perform thrombotic complications prophylaxis monitored by a coagulogram (exploratory hemostasis assay) in accordance with existing venous thromboembolic complications prophylaxis protocols [62].

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

• For patients with BL over 18 years of age, it is recommended to perform mandatory neuroleukemia prophylaxis via intrathecal administration of 3 antineoplastic agents (cytarabine** 30 mg, #methotrexate** 15 mg, #dexamethasone** 4 mg) once per course throughout the entire therapy period [24].

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

Comments: Treatment of neuroleukemia must be performed according to standard rules: lumbar punctures with the administration of antineoplastic agents are performed 3 times a week until 3 normal cerebrospinal fluid analyses are obtained, due to the increased rate of infectious complications and high mortality risk associated with them. During subsequent chemotherapy blocks (after CSF sanitization), lumbar punctures with intrathecal administration of antineoplastic agents are performed twice per course.

In pregnant patients, CNS relapse prophylaxis is carried out without the administration of #methotrexate** [92]

Comments: Radiation therapy is not performed in Burkitt lymphoma, except for palliative care and special situations where chemotherapy cannot be administered.

3.6 Treatment of plasmablastic lymphoma in adults

• For patients aged 18 to 65 years with newly diagnosed plasmablastic lymphoma (PBL) without TP53 gene mutations and without severe comorbidities, it is recommended to administer therapy according to the mNHL-BFM-90 program (4 blocks A) in combination with #lenalidomide** [98, 157, 158].

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

Comment: Diagnosis and treatment of PBL present a challenge due to the rarity of this nosology and the lack of randomized trials. The CHOP program is ineffective. A slight advantage has been shown with more intensive programs (hyper-CVAD, EPOCH, CODOX-M/IVAC). By analogy with multiple myeloma, #lenalidomide** demonstrates efficacy in treating PBL both in combination with chemotherapy and as monotherapy. Administration of intensive therapy programs is recommended in specialized hematology departments within regional/district hospitals that are licensed to provide high-tech medical care in hematology/oncology and are equipped with adequate transfusion, intensive care, dialysis, and other services.

• For patients aged 18 to 65 years with newly diagnosed plasmablastic lymphoma (PBL) who harbor a TP53 gene mutation, without severe comorbidities, and in the presence of a compatible donor after intensive therapy according to the mNHL-BFM-90 program (2 blocks A) combined with #lenalidomide**, it is recommended to perform allogeneic hematopoietic stem cell transplantation [98].

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

Comment: Allo-HSCT can only be performed after prior discussion and approval at one of the specialized transplant centers, provided a suitable donor is available and remission is achieved with induction therapy. The allo-HSCT procedure should be planned as early as possible from the time of disease diagnosis.

• For patients over 18 years of age with newly diagnosed PBL, the EPOCH regimen with the addition of #bortezomib** may be recommended (the program is presented in Appendix A3) [159–162].

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

Comment: Prior to initiating PBL treatment in HIV-infected patients, an initial appointment (examination, consultation) with a primary infectious disease specialist experienced in managing HIV-infected patients is required. Concurrently with the initiation of chemotherapy, the patient's case must be discussed with one of the transplant centers regarding the feasibility and necessity of autologous HSCT.

3.6 Treatment of relapses of aggressive non-follicular B-cell lymphomas in adults

• For patients aged 18 to 65 years with relapsed/refractory forms of aggressive non-follicular B-cell lymphomas without significant comorbidities, it is recommended to administer intensive salvage therapy programs according to one of the following regimens:

  • R-DHAP [163] Grade of Recommendations — C (Level of Evidence — 4).

  • R-ESHAP Grade of Recommendations — C (Level of Evidence — 4).

  • R-ICE [165] Grade of Recommendations — C (Level of Evidence — 4).

  • R-GDP [166] Grade of Recommendations — C (Level of Evidence — 4).

  • R-GemOx [167] Grade of Recommendations — B (Level of Evidence — 3).

  • R-DHAX [168] Grade of Recommendations — B (Level of Evidence — 3).

  • R-MINE [169] Grade of Recommendations — B (Level of Evidence — 3).

  • #Polatuzumab vedotin + R-ICE [170] (for DLBCL only)

    Grade of Recommendations — C (Level of Evidence — 4).

  • Glofitamab monotherapy [185] (for DLBCL only)

    Grade of Recommendations — C (Level of Evidence — 4).

  • Glofitamab-GemOx [187] (for DLBCL only)

GCP BLoE 2Grade of Recommendation – B (Level of Evidence – 2).

Comments: The drugs used in these treatment regimens do not exert a damaging effect on hematopoietic stem cells and do not impair the quality of stem cell harvest for autologous transplantation.

• For patients aged 18 to 65 years with relapsed/refractory forms of aggressive non-follicular B-cell lymphomas without significant comorbidities, if an antitumor response to salvage therapy is achieved and if feasible, it is recommended to perform high-dose chemotherapy with autologous hematopoietic stem cell transfusion [171, 172].

Level of Evidence CGrade of Recommendation 4Level of Evidence – C (Grade of Recommendation – 4).

Comments: treatment tactics for relapses in patients after HDCT with auto-HSCT are determined by the patient's physical condition, as well as the volume of previously administered treatment. In young patients with a good performance status, the possibility of allo-HSCT (allo-BMT) can be considered. It is suggested to consider the participation of patients in this group in clinical trials.

• For patients with relapsed/refractory DLBCL aged over 65 years and/or with significant comorbidity who are not candidates for HDCT with auto-HSCT, it is recommended to administer less intensive second- and subsequent-line chemotherapy/immunochemotherapy regimens, such as:

  • R+/-GemOx [167, 173] Level of evidence reliability – C (level of validity of evidence – 3).

  • BR [174, 175],

  • R+/-CEPP [176],

  • R+/-GDP [166, 177],

  • R+/-#Gemcitabine** + #vinorelbine** [178],

  • #Polatuzumab vedotin + BR [179],

  • Rituximab** + #ibrutinib** + #lenalidomide** (for non-GCB, if no other available options) [180]

  • #Glofitamab monotherapy [185, 186]

    Grade of Recommendations — C (Level of Evidence — 4).

  • #Glofitamab-GemOx [187]

    (Regimen details are presented in Appendix A3.1.3.)

GCP BLoE 2Grade of Recommendation – B (Level of Evidence – 2).

• For patients with relapsed/refractory DLBCL whose relapse was diagnosed more than 6 months after the previous drug administration, it is recommended to add rituximab** to salvage therapy [89].

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

• For patients over 18 years of age with relapsed/refractory PMBCL, it is recommended to use #pembrolizumab** at a dose of 200 mg every 3 weeks as monotherapy or in combination with second-line platinum-containing regimens, or #nivolumab** at a dose of 240 mg IV with #brentuximab vedotin** 1.8 mg/kg IV every 3 weeks, or second-line therapy regimens [98, 125, 181, 126, 337, 338]

GOR BLOE 3Grade of Recommendation – B (Level of Evidence – 3).

• For patients over 18 years of age with relapsed/refractory primary mediastinal large B-cell lymphoma (PMBCL) with CNS involvement, it is recommended to administer 2 courses of the DHAP regimen integrated with #nivolumab** 40 mg/day, #lenalidomide** 25 mg/day, #procarbazine** 100 mg followed by autologous hematopoietic cell transplantation under the TBB conditioning regimen (#thiotepa 400 mg/day, carmustine** 400 mg/day, #busulfan** 4 mg/kg) [352] (see Appendix A3.1)

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

• For patients over 18 years of age with relapsed/refractory primary CNS lymphoma (PCNSL) that developed after whole-brain radiotherapy, it is recommended, depending on physical and neurological status, age, and comorbidities, to administer systemic chemotherapy (repeated administration of high-dose methotrexate** 3500 mg/m² IV infusion, day 1; cytarabine** 2000 mg/m² IV infusion twice daily, days 2–3 with or without rituximab**[130], #temozolomide** with or without rituximab**, #topotecan, DHAP, high-dose cytarabine) with or without high-dose chemotherapy followed by autologous stem cell transplantation, re-irradiation, or palliative care (regimens and drug doses are specified in Appendix A3.1.5) [129, 130, 182–184].

Level of Evidence CGrade of Recommendation 4Level of Evidence – C (Grade of Recommendation – 4).

Comments: for patients who received first-line regimens containing high-dose methotrexate** without radiotherapy, the choice between systemic chemotherapy and radiotherapy depends on the duration of response to first-line chemotherapy: if the effect is relatively prolonged (1 year or more), resumption of chemotherapy (the same or a different regimen) is recommended. If the response was short-lived or not achieved at all, radiotherapy is recommended: whole-brain or involved-site radiotherapy with or without systemic therapy. In other cases, palliative therapy is considered as an option, and for specific patient groups—high-dose chemotherapy with autologous hematopoietic stem cell transplantation (auto-HSCT).

• For patients over 18 years of age with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) (including those transformed from follicular lymphoma and marginal zone lymphoma) who have previously received at least two lines of systemic therapy, recommend glofitamab monotherapy [185].

GIB BLOE 4Grade of Recommendation – B (Level of Evidence – 4).

Comment: The efficacy of fixed-duration glofitamab monotherapy was evaluated in NP30179, an open-label, single-arm, multicenter, multi-cohort clinical trial involving 155 patients with relapsed or refractory DLBCL who had previously received at least two lines of systemic therapy. All patients had previously received chemotherapy and CD20 (cluster of differentiation 20) inhibitors; 33.5% of patients had previously received chimeric antigen receptor (CAR) T-cell therapy, and 18.1% of patients had undergone autologous hematopoietic cell transplantation. The majority of patients (89.7%) had refractory disease; 58.7% of patients had primary refractory disease, 84.5% of patients were refractory to their last prior therapy, and 88.5% of patients who had previously received CAR T-cell therapy were refractory to it. The primary efficacy endpoint was the complete response rate assessed by an independent review committee using the Lugano 2014 criteria, which was 40% [185]. Additional follow-up demonstrated that the median duration of complete response was 26.9 months, and 80.7% of patients with a complete response were alive at a median follow-up of 1.5 years [186].

• For patients over 18 years of age with relapsed or refractory DLBCL who have previously received at least one line of systemic therapy, it is recommended to administer glofitamab in combination with #gemcitabine** and #oxaliplatin** (Glofit-GemOx) (the treatment protocol with drug dosages is specified in Appendix A3) [187].

GCP BLoE 2Grade of Recommendation – B (Level of Evidence – 2).

Comment: The efficacy and safety of glofitamab in combination with #gemcitabine** and #oxaliplatin** (Glofit-GemOx) were evaluated in comparison with the combination of rituximab**, #gemcitabine**, and #oxaliplatin** (R-GemOx) in the STARGLO study—an open-label, multicenter, randomized clinical trial involving 274 patients with relapsed or refractory DLBCL who had previously received at least one line of systemic therapy. All patients were considered ineligible for hematopoietic stem cell transplantation; 62.8% had received one line of therapy, and 37.2% had received two or more lines of therapy. The majority of patients (55.8%) had primary refractory disease, and 60.6% of patients were refractory to their last prior therapy. The primary endpoint of the study was overall survival; secondary endpoints included progression-free survival assessed by an independent review committee, as well as the complete response rate. The primary analysis of the results demonstrated a significant benefit of glofitamab in combination with #gemcitabine** and #oxaliplatin** regarding overall survival (HR: 0.59; 95% CI: 0.40–0.89; p = 0.011). A significant benefit of this combination was also observed regarding progression-free survival (HR: 0.37; 95% CI: 0.25–0.55; p < 0.0001) and complete response rate (50.3 vs. 22.0%; 95% CI: 16.3–40.3; p < 0.0001).

Upon completion of therapy, a follow-up analysis was performed for all patients, in which glofitamab in combination with #gemcitabine** and #oxaliplatin** demonstrated an advantage in median overall survival (25.5 vs. 12.9 months; HR: 0.62; 95% CI: 0.43–0.88), median progression-free survival (13.8 vs. 3.6 months; HR: 0.40; 95% CI: 0.28–0.57), and the rate of achieving a complete response (58.5 vs. 25.3%; 95% CI: 19.7–44.4; p < 0.0001) compared with the rituximab**, #gemcitabine**, and #oxaliplatin** combination, respectively [187].

• For patients over 18 years of age with relapsed/refractory forms of aggressive B-cell lymphomas (DLBCL, PMBCL, DHL, DEL, BL, PBL) after 2 lines of therapy, or in the presence of TP53 mutations and refractoriness to 1st-line therapy, CAR-T (Chimeric Antigen Receptor T-Cell) cell therapy may be recommended [188–191].

GCP BLoE 2Grade of Recommendation – B (Level of Evidence – 2).

Comment: The international randomized phase III ZUMA-7 trial demonstrated that in patients over 18 years of age with relapsed/refractory aggressive B-cell lymphomas, the use of anti-CD19 CAR-T cells significantly increases the overall response rate (83% vs. 50%) and complete remission rate (65% vs. 32%) compared with standard salvage therapy. At a median follow-up of 24.9 months, the 2-year overall survival and event-free survival rates were 61% vs. 52%, respectively [192]. Results from another international multicenter randomized trial (TRANSFORM) demonstrated high efficacy of anti-CD19 CAR-T cells in patients with r/r DLBCL compared with standard second-line therapy: the median event-free survival was 10 months vs. 2.3 months, respectively [192, 193].

• For patients over 18 years of age with relapsed aggressive lymphomas, it is recommended to consider local radiotherapy with a consolidating or therapeutic intent targeting the relapse site. The feasibility and total radiation doses depend on the nature of the relapse, the patient's condition, and prior radiotherapy [363].

Level of Evidence CGrade of Recommendation 4Level of Evidence – C (Grade of Recommendation – 4).

Comments. Indications for radiation therapy are determined by the primary treatment program, the nature of the relapse (local or generalized) confirmed by PET/CT, the duration of the prior remission, the patient's general condition, and comorbid conditions. In general, for local and generalized relapse, the indications for radiation therapy and its parameters are similar to those for the treatment of locally advanced stages of aggressive lymphomas. Certain difficulties may arise in cases of relapse within previously irradiated lymphoma foci; however, the moderate doses currently used in most patients with aggressive lymphomas and the high technical level of modern radiation therapy make re-irradiation possible in most cases.

3.7 Management features in pregnant patients over 18 years of age

The management strategy for pregnant women over 18 years of age with aggressive lymphoma depends on three components: the aggressiveness of the lymphoma, the trimester in which the disease occurs (I, II, III trimester), and the woman's desire to preserve the pregnancy. The following management options are possible:

1. termination of pregnancy

2. administration of treatment during the II–III trimesters of pregnancy

3. postponement of treatment until the postpartum period

• Pregnant women over 18 years of age with DLBCL, PMBCL, DHL, DEL, BL, or B-ALL are recommended to undergo chemotherapy using R-CHOP or R-DA-EPOCH regimens, depending on the lymphoma variant and unfavorable prognostic factors [59, 194, 195].

Level of Evidence CGrade of Recommendation 4Level of Evidence – C (Grade of Recommendation – 4).

• Pregnant women over 18 years of age are not recommended to receive antimetabolite drugs (ATC group L01B) [92].

Level of Evidence CGrade of Recommendation 4Level of Evidence – C (Grade of Recommendation – 4).

• Pregnant women over 18 years of age with DLBCL, PMBCL, DHL, DEL, BL, or B-ALL are recommended to calculate drug doses similarly to the method used for non-pregnant patients [196].

Level of Evidence CGrade of Recommendation 4Level of Evidence – C (Grade of Recommendation – 4).

Comments: according to the International Commission on Radiological Protection, exposure of a pregnant woman to radiation doses of 100–200 mGy carries a high risk of fetal central nervous system malformations. Lower radiation doses may lead to intrauterine growth restriction (IUGR), childhood cancer, and fertility impairment.

• Pregnant women over 18 years of age with DLBCL, PMBCL, DHL, DEL, BL, or B-ALL are recommended to undergo delivery after 37 weeks of gestation in cases where prolonging the pregnancy until this term does not pose a serious threat to the health of the mother and fetus [198].

Level of Evidence CGrade of Recommendation 4Level of Evidence – C (Grade of Recommendation – 4).

• Pregnant women over 18 years of age with DLBCL, PMBCL, DHL, DEL, BL, or B-ALL are recommended to complete chemotherapy 2 weeks before the expected delivery date (no later than 35–36 weeks of gestation) due to the potential for myelosuppression in both the mother and the fetus [198, 199].

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

• Women over 18 years of age with DLBCL, PMBCL, DHL, DEL, BL, or B-ALL with indications for continued therapy are recommended to resume specific treatment 1–2 weeks after uncomplicated Cesarean section or 5–7 days after vaginal delivery [59, 339–341].

Level of Evidence CGrade of Recommendation 4Level of Evidence – C (Grade of Recommendation – 4).

Comments: treatment of aggressive lymphoma, when indicated, can be resumed immediately after vaginal delivery and 1 week after an uncomplicated Cesarean section [200].

• Women over 18 years of age with DLBCL, PMBCL, DHL, DEL, BL, or B-ALL for whom continuation of antitumor treatment is indicated after delivery are recommended to undergo lactation suppression [196].

LMR CLEL 4Level of Recommendation — C (Level of Evidence — 4).

3.8 Management features in HIV-infected patients over 18 years of age

• Patients over 18 years of age with HIV-infected DLBCL, PMBCL, DHL, DEL, BL, or B-ALL are recommended to receive therapy according to the relevant protocols against the background of ongoing antiretroviral therapy [201].

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

• HIV-infected patients over 18 years of age with DLBCL, PMBCL, DHL, DEL, BL, or B-ALL are not recommended to receive rituximab** if the CD4+ cell count is less than 100/µl due to an increased rate of infectious complications and a high risk of mortality from them [201].

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

3.9 Treatment response assessment

• All patients over 18 years of age with DLBCL, PMBCL, DHL, DEL, BL, or B-ALL upon completion of the entire treatment program are recommended to undergo a treatment response assessment in accordance with standard lymphoma response criteria (see section 7.6 of these guidelines) [39, 202].

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

3.10 Concomitant and supportive therapy in adults

• Patients over 18 years of age with DLBCL, PMBCL, DHL, DEL, BL, or B-ALL presenting with bulky tumor disease are recommended to receive prophylaxis and treatment for tumor lysis syndrome: #allopurinol** 10 mg/kg/day and infusion therapy 3 L/m²/day with alkalinization using sodium bicarbonate** solution 40–80 mmol/L under diuresis monitoring [98, 203, 204].

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

• Patients over 18 years of age with DLBCL, DEL, DHL, PMBCL, PMZL, or BL receiving glucocorticoids are recommended to undergo prophylaxis for gastric and duodenal ulcers [205].

CGR BLEL 1Level of recommendation grade – B (level of evidence – 1).

Comments: gastric or duodenal ulcer is one of the serious adverse effects of GCS therapy. Due to their ulcerogenic potential, antisecretory therapy is necessary when using GCS to prevent steroid-induced ulcers.

Based on a meta-analysis of 300 studies [206], gastric and duodenal ulcers heal in virtually all cases if the intragastric pH is maintained above 3 for 18 hours per day. Currently, two classes of drugs are used for antisecretory purposes to prevent gastric and duodenal ulcers, including during glucocorticoid therapy: proton pump inhibitors and H2-histamine receptor blockers [207, 208].

• Patients over 18 years of age with DLBCL, DEL, DHL, PMBCL, PMZL, or BL receiving antitumor chemotherapy or radiation therapy are recommended to use antiemetic drugs (serotonin 5-HT3 receptor antagonists, ATC group A04AA) and glucocorticoids (#dexamethasone** ATC group H02AB) for the prophylaxis of nausea and vomiting [209–211].

GCR CLOE 5Grade of Recommendations – C (Level of Evidence – 5).

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

• Patients over 18 years of age with DLBCL, DEL, DHL, PMBCL, PMZL, or BL undergoing chemoimmunotherapy regimens with a high risk of febrile neutropenia exceeding 20%, or an intermediate risk of FN of 10–20% in the presence of risk factors (age >65 years; severe comorbidities; renal or hepatic impairment; hemoglobin <12 g/dL; malnutrition; prolonged neutropenia or history of FN; absence of antimicrobial prophylaxis; ECOG ≥2; open wounds or wound infection; recent major surgery; female sex; chemoradiotherapy; cytopenia due to bone marrow involvement; HIV infection) are recommended to receive primary prophylaxis for febrile neutropenia using colony-stimulating factors of ATC group L03AA [212].

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

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

• Patients over 18 years of age with DLBCL, DEL, DHL, PMBCL, PMZL, or BL following a previously documented episode of FN or dose-limiting afebrile neutropenia (after a single episode of interval extension between courses and/or dose reduction) are recommended to receive secondary prophylaxis for febrile neutropenia using colony-stimulating factors of ATC group L03AA [212].

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

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

• Patients over 18 years of age with DLBCL, DEL, DHL, PMBCL, PMZL, or BL are recommended to receive prophylaxis for Pneumocystis jirovecii pneumonia during chemotherapy and between treatment cycles [213].

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

Comments: #co-trimoxazole [sulfamethoxazole+trimethoprim]** is the drug of choice for the prevention of Pneumocystis pneumonia, prescribed at 480 mg daily [98]. [332] Daily use of co-trimoxazole [sulfamethoxazole+trimethoprim]** simultaneously prevents infections caused by Toxoplasma gondii, Listeria monocytogenes, Nocardia asteroides. Patients infected with Pneumocystis jirovecii should not share a room with other immunocompromised patients.

• For patients older than 18 years with DLBCL, DEL, DHL, PMBCL, MZL, BL for whom intensive chemotherapy regimens are planned, it is recommended to place a central venous catheter for chemotherapy and supportive care (see section 7.11) [214].

GOM CLOE 4Level of Evidence – C (Level of Data Reliability – 4).

• For patients older than 18 years with DLBCL, DEL, DHL, PMBCL, MZL, BL who have identified symptomatic hypogammaglobulinemia (prior severe infection, IgG <4 g/L), it is recommended to administer replacement therapy with normal #human immunoglobulin** 0.2–0.4 g/kg (J06BA according to the ATC classification) IV every 3–4 weeks for 12 months to treat secondary immunodeficiency [48, 215].

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

Comment: therapy is performed under the control of IgG levels every 6 months; the dose of normal #human immunoglobulin** is reviewed every 6 months. After completion of therapy, lifelong monitoring of IgG levels is carried out once a year; in case of a recurrent decrease in IgG <4 g/L, repeated courses of replacement therapy with a similar drug in a similar regimen are administered for 12 months.

• For patients older than 18 years with DLBCL, DEL, DHL, PMBCL, MZL, BL and risk factors for thrombotic complications, for the prevention of venous thromboembolic complications, it is recommended to use antithrombotic agents (B01 according to the ATC classification) and physical methods of influence (compression knitwear, limb pneumatic massage) [216, 217].

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

• For patients older than 18 years with DLBCL, DEL, DHL, PMBCL, MZL, BL undergoing antineoplastic therapy with a risk of mucositis or upon the development of mucositis, it is recommended for prophylactic and therapeutic purposes to use glucocorticoids, somatostatin and analogues, antidiarrheal, intestinal anti-inflammatory and antimicrobial drugs, antiprotozoal drugs with antibacterial activity, glycopeptide antibiotics, local anesthetics, antidepressants, and nasogastric tube placement [218, 219].

GCP CLoE 5Grading of Recommendations Assessment, Development and Evaluation (GRADE) – C (Level of Evidence – 5)

Comments: the choice of method for the prevention and treatment of mucositis is determined by the severity and localization of the lesion.

• For patients older than 18 years with DLBCL, DEL, DHL, PMBCL, MZL, BL undergoing antineoplastic therapy for the prevention of water-electrolyte disorders, it is recommended to provide nutritional support [220, 221].

GCP CLoE 5Grading of Recommendations Assessment, Development and Evaluation (GRADE) – C (Level of Evidence – 5)

• For patients older than 18 years with DLBCL, DEL, DHL, PMBCL, MZL, BL, it is recommended to discuss the possibility of sperm or oocyte/embryo cryopreservation before starting therapy [222].

GCP CLoE 5Grading of Recommendations Assessment, Development and Evaluation (GRADE) – C (Level of Evidence – 5)

• For female patients older than 18 years with DLBCL, DEL, DHL, PMBCL, MZL, BL for whom pelvic radiation therapy is planned, it is recommended to discuss the need for homolateral oophoropexy for ovarian protection [223].

GCP CLoE 5Grading of Recommendations Assessment, Development and Evaluation (GRADE) – C (Level of Evidence – 5)

Comment: oophoropexy is especially indicated if the expected radiation dose to the ovaries exceeds 5 Gy, as this may cause long-term ovarian dysfunction. This can be avoided if radiation therapy is delivered from opposing fields at a split dose of 20 Gy and the ovary is located at least 2 cm away from the edge of the radiation field.

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

4. Medical Rehabilitation and Sanatorium-Resort Treatment

• For all patients older than 18 years with DLBCL, DEL, DHL, PMBCL, MZL, BL at all stages of disease therapy, as well as after the completion of medical treatment, it is recommended to provide comprehensive rehabilitation and, if necessary, supportive care [224, 225].

GCR CLOE 5Grade of Recommendations – C (Level of Evidence – 5).

Comment: there are no special rehabilitation methods for DLBCL, PMBCL, BL. Rehabilitation of patients with DLBCL, PMBCL, BL should be comprehensive, covering not only medical but also social and psychological aspects of the patient's adaptation to normal life. Such rehabilitation requires, in addition to medical care, the mandatory participation of social workers and medical psychologists. Rehabilitation programs are developed individually, depending on the identified complications of medical treatment, 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

There are currently no methods for the prevention of DLBCL, DEL, DHL, PMBCL, MZL, BL, as the etiological factors leading to the development of the disease are unknown.

• For patients older than 18 years who have completed treatment for DLBCL, DEL, DHL, PMBCL, MZL, BL with the achievement of CR, it is recommended to undergo follow-up care (dispensary observation) by an oncologist or hematologist with the following examination frequency: during the first year after completion of therapy every 3 months, 2nd year every 6 months, thereafter annually, and after 5 years every 2 years [31, 39, 40].

GCR CLOE 5Grade of Recommendations – C (Level of Evidence – 5).

Comment: follow-up care should include a thorough collection of complaints, clinical examination of the patient, chest imaging control (CT or radiography), abdominal ultrasound (comprehensive), and ultrasound of peripheral lymph node areas (ultrasound examination of lymph nodes [one anatomical region]). For patients who received anthracyclines and related compounds and bleomycin** in combination with mediastinal irradiation, cardiac function testing (electrocardiography and echocardiography) and pulmonary function testing (spirometry/lung volumes and flows) should be performed.

• For children and adolescents who have completed treatment for DLBCL, DEL, DHL, PMBCL, MZL, BL with the achievement of CR, it is recommended to undergo follow-up care by an oncologist or hematologist according to the schedule presented in Table 5.1 [226].

GCR CLOE 5Grade of Recommendations – C (Level of Evidence – 5).

Comment:

Table 5.1. Schedule of follow-up care for children under 18 years of age after completion of therapy for DLBCL

Table 5.2. Screening for cardiotoxic effects

6. Organization of Medical Care

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

1. in accordance with the regulations on the organization of 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 rendering care in the profile "hematology", "oncology" mandatory for implementation on the territory of the Russian Federation by all medical organizations;

3. based on these clinical guidelines;

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

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

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

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

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

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

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

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

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

Indications for planned hospitalization:

1. 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. Examination of the patient, 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/oncology inpatient facility is optional, but desirable).

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

3. Development of complications of aggressive non-follicular lymphomas: symptomatic lymphadenopathy and/or 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 24-hour or day hospital setting, established by a concilium of a medical organization providing hematological/oncological care, provided there are no complications of the underlying disease and/or treatment requiring drug correction and/or medical interventions in inpatient settings.

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 Morphological and immunohistochemical diagnosis of aggressive non-follicular B-cell lymphomas

The nosological form of DLBCL, DEL, DHL, PMBCL, MCL, BL is established taking into account clinical and anamestic data, the localization of the tumor lesion, based on a detailed morphological, expanded IHC study, using molecular tests in a number of cases.

The required scope of tests for the diagnosis of various variants of aggressive B-cell lymphomas is detailed in the guidelines "Algorithms for Diagnosis and Treatment Protocols of Blood System Diseases" edited by E.N. Parovichnikova, 2024 [98]

7.2 Staging of aggressive non-follicular B-cell lymphomas

Staging of DLBCL and PMBCL is carried out based on the results of the examination in accordance with the Ann Arbor classification criteria (Table 7.3.1). This classification is not applicable to PCNSL. The diagnosis of PCNSL is formulated indicating the localization of the lesion without specifying the stage.

Table 7.2.1. Staging of lymphomas according to Ann Arbor (Lugano modification, 2014) [227]:

To determine the extent of the tumor process in BL, the S.B. Murphy staging system is used (similarly — St. Jude)

Stage I:

• one single extranodal or nodal site, excluding mediastinal, abdominal, or epidural localization

Stage II:

• one extranodal tumor with regional lymph node involvement

• two or more lymph node regions on the same side of the diaphragm

• two single extranodal tumors with/without regional lymph node involvement on the same side of the diaphragm

• primary gastrointestinal tumor localized in the ileocecal region with/without mesenteric lymph node involvement

• mediastinal, abdominal, and epidural tumors are excluded

IIR – resected tumor (macroscopically completely removed)

IINR – unresected tumor (macroscopically incompletely removed)

Stage III:

• two single extranodal tumors on opposite sides of the diaphragm

• two or more lymph node areas on opposite sides of the diaphragm

• all primary intrathoracic tumors (mediastinal, pleural)

• all extensive intra-abdominal tumors (unresectable)

• all paraspinal and epidural tumors regardless of other site involvement

Stage IV:

• any of the tumor localizations listed above with initial central nervous system involvement and/or bone marrow involvement (blasts <25%) and/or multifocal skeletal involvement

Burkitt lymphoma/leukemia (Stage IV-ALL, L3 type):

• bone marrow contains >25% tumor cells

7.3 Treatment response assessment in lymphomas

Response assessment to treatment is carried out in accordance with the updated criteria proposed by the International Working Group on Lymphoma in 2007 and the Lugano classification [202, 227].

Complete remission (CR):

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

2. Lymph node dimensions:

   1. ≤1.5 cm in greatest diameter, if pre-treatment lymph node dimensions were greater than 1.5 cm

   2. ≤1.0 cm in greatest diameter, if pre-treatment lymph node dimensions were 1.5–1.1 cm

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

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

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

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

1. Residual changes detected solely by imaging studies, provided the tumor has decreased by more than 75% from baseline by the sum of its two greatest diameters. These residual changes must not increase for more than 3 months.

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

Partial remission (PR):

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

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

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

Stable disease

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

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

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

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

PET/CT significantly improves the accuracy of treatment response evaluation—allowing differentiation between partial and complete response in patients with residual masses, as well as early diagnosis of progression. When performing 18F-FDG PET/CT, treatment response is evaluated according to the Deauville five-point scale (see Appendix 2) [227, 230].

Treatment response in PCNSL should be evaluated in accordance with the International Primary CNS Lymphoma Collaborative Group recommendations from 2005 [231]

Table 7.4.1 International response criteria for PCNSL therapy.

When performing 11C-methionine brain/spine PET/CT, MRI-based response assessment is supplemented by PET/CT findings. The use of 11C-methionine PET/CT in patients with CNS involvement, compared to MRI or CT alone, improves the accuracy of treatment response assessment and the diagnosis of relapse within the residual mass area [56, 57]. It should be noted that at the time of establishing complete response, the patient must not have received any systemic corticosteroids for two weeks. Patients without significant baseline cerebrospinal fluid abnormalities do not require repeat lumbar puncture provided there are no delayed symptoms of leptomeningeal dissemination.

7.5 Radiation therapy for DLBCL in adults. General principles

For adult patients over 18 years of age with aggressive B-cell lymphomas, regardless of stage, morphological variant, and localization, achieving complete remission after induction therapy with intensive protocols (R-mNHL-BFM-90, R-Hyper-CVAD, etc.), radiotherapy as a consolidation of remission is not performed. For adult patients over 18 years of age with aggressive B-cell lymphomas who experience relapse after induction therapy with intensive protocols (R-mNHL-BFM-90, R-Hyper-CVAD, etc.), radiotherapy may be considered only as palliative care when chemotherapy or cellular therapy is unfeasible for various reasons.

• Radiotherapy in treatment-naive adult patients over 18 years of age with aggressive lymphomas is recommended as a component of combined immunochemoradiotherapy only for a strictly defined group of patients after standard chemotherapy [321, 322].

Level of Evidence CGrade of Recommendation 4Level of Evidence – C (Grade of Recommendation – 4).

Comment: given that in adult patients over 18 with DLBCL of advanced stages achieving complete remission after chemoimmunotherapy (R-CHOP or similar regimens), the 5-year local relapse probability is at least 50%, adjuvant radiotherapy to individual tumor sites is indicated only in the presence of local relapse risk factors (sites with a baseline size ≥5 cm or smaller sites with a baseline SUVmax ≥15) [322]. Regardless of morphological variant and primary lymphoma localization, achieving partial remission after chemoimmunotherapy allows radiotherapy to achieve a complete metabolic response (see Section 7.6).

• In relapsed and refractory adult patients over 18 years of age with aggressive lymphomas, radiotherapy is effective and recommended:

1) as an adjuvant to high-dose chemotherapy, including hematopoietic cell transfusion [324]. Recommended doses are 20–36 Gy depending on the location and prior radiation therapy.

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

2) as a component of patient preparation for CAR T-cell therapy [325]

Level of Evidence CGrade of Recommendation 4Level of Evidence – C (Grade of Recommendation – 4).

• In patients with aggressive lymphomas over the age of 18 presenting with life-threatening clinical conditions (airway compression by a rapidly growing tumor, esophageal, intestinal, urinary tract, biliary tract, or spinal cord compression, etc.), radiation therapy may be used alongside chemoimmunotherapy and surgical treatment as decided by a multidisciplinary oncology team.

• In patients over 18 years of age when PET-CT is not feasible, it is recommended to use X-ray computed tomography (preferably with contrast enhancement). These studies should be performed before and after the completion of medical treatment to determine the volume and dose of the upcoming irradiation [323, 328].

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

• When planning irradiation, a medical physicist must calculate the dose-volume histogram to determine the dose loads on organs at risk. When choosing irradiation programs, one should adhere to the QUANTEC guidelines for normal tissue dose constraints [329].

Comment: It is advisable to regularly verify patient positioning and treatment programs on the RT machine and to use advanced RT technologies, such as intensity-modulated radiation therapy (IMRT), deep inspiration breath-hold radiation therapy, and image-guided radiation therapy (IGRT), which demonstrate significant and clinically relevant advantages in reducing the dose load on organs at risk (such as the heart (including coronary arteries and valves), lungs, kidneys, spinal cord, esophagus, bone marrow, mammary glands, stomach, muscles, soft tissues, salivary glands) and reducing the risk of late normal tissue injury while achieving the primary treatment goal of local tumor control.

Comments: it is inadvisable to start RT on the last working day of the week and finish on the first working day of the week, as this may reduce the effectiveness of the ongoing treatment.

7.6 Infusion therapy in adult patients with aggressive B-cell lymphomas

Indications and scope of infusion therapy for aggressive B-cell lymphomas in adults are described in detail in the manual "Algorithms for Diagnosis and Treatment Protocols for Blood System Diseases" edited by E.N. Parovichnikova, 2024 [98].

7.7 Protocols for bone marrow aspiration and biopsy procedures in adults

Bone marrow aspiration and biopsy procedures are routine and performed in both outpatient and inpatient settings. Indications/contraindications and technical performance in adult patients are described in detail in the manual "Algorithms for Diagnosis and Treatment Protocols for Blood System Diseases" edited by E.N. Parovichnikova, 2024 [98] and in reference [235].

7.8 Vascular access management in adults

Vascular access is an essential component of modern chemotherapy in oncohematological patients. Indications for catheterization and technical performance in adults are described in detail in the manual "Algorithms for Diagnosis and Treatment Protocols for Blood System Diseases" edited by E.N. Parovichnikova, 2024 [98].

7.9 Management of the hematological patient in the adult intensive care unit

Patients with hematological diseases may develop various critical conditions due to diverse causes at the stages of diagnosis, treatment, and monitoring. Indications for transfer and therapy principles in adults are described in the manual "Algorithms for Diagnosis and Treatment Protocols for Blood System Diseases" edited by E.N. Parovichnikova, 2024 [98].

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

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

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

3. Natalia A. Falaleeva – Doctor of Medical Sciences, Head of the Department of Antitumor Drug Therapy at the A.F. Tsyb Medical Radiological Research Center — a 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. Evgeny E. Zvonkov – MD, DSc, Head of the Department of Lymphoproliferative Diseases, Head of the Department of Hematology and Lymphoma Chemotherapy with a Bone Marrow and Hematopoietic Stem Cell Transplantation Unit, National Research Center for Hematology of the Russian Ministry of Health, Member of the National Hematology Society

5. Gayane S. Tumyan – Doctor of Medical Sciences, Professor, Professor at the Department of Oncology and Palliative Medicine of the Russian Medical Academy of Continuous Professional Education of the Russian Ministry of Health, Leading Researcher at the Chemotherapy Department of Hemoblastoses of the N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health, Board Member of the Russian Society of Oncohematology.

6. Natalia B. Mikhailova – Doctor of Medical Sciences, Head of the Department of Clinical Oncology (Chemotherapy) at the R.M. Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantology, member of the Russian Society of Oncohematology.

7. Nelly G. Gabeeva – Candidate of Medical Sciences, Researcher at the Department of Hematology and Lymphoma Chemotherapy with Bone Marrow and Hematopoietic Stem Cell Transplantation Unit, National Medical Research Center for Hematology of the Russian Ministry of Health

8. Aminat U. Magomedova – Doctor of Medical Sciences, Leading Researcher at the Department of Intensive High-Dose Chemotherapy with 24-Hour and Day Hospital Facilities, National Medical Research Center for Hematology of the Russian Ministry of Health, member of the Association for the Promotion of Hematology and Bone Marrow Transplantation Development "National Hematological Society".

9. Yana K. Mangasarova – Candidate of Medical Sciences, Head of the Department of Lymphoproliferative Disease Chemotherapy with Bone Marrow and Hematopoietic Stem Cell Transplantation Unit and Day Hospital, National Medical Research Center for Hematology of the Russian Ministry of Health, member of the Association for the Promotion of Hematology and Bone Marrow Transplantation Development "National Hematological Society".

10. Daria A. Koroleva – Candidate of Medical Sciences, Hematologist at the Department of Hematology and Lymphoma Chemotherapy with Bone Marrow and Hematopoietic Stem Cell Transplantation Unit, National Medical Research Center for Hematology of the Russian Ministry of Health

11. Olga A. Aleshina – Candidate of Medical Sciences, Head of the Department of Cellular and Immune Therapy, National Medical Research Center for Hematology of the Russian Ministry of Health

12. Elena A. Baryakh – Doctor of Medical Sciences, Head of the Department of Hematology and Chemotherapy at City Clinical Hospital No. 52 of Moscow, Associate Professor at the Department of General Therapy of the Faculty of Continuous Medical Education at the N.I. Pirogov Russian National Research Medical University, member of the Russian Society of Oncohematology and the European Hematology Association

13. Roman G. Shmakov – Doctor of Medical Sciences, Professor, Director of the Institute of Obstetrics at the V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology of the Russian Ministry of Health, Chief freelance specialist in obstetrics of the Russian Ministry of Health

14. Evgenia S. Polushkina – Candidate of Medical Sciences, Senior Researcher at the V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology of the Russian Ministry of Health

15. Alexander G. Rumyantsev – Academician of the Russian Academy of Sciences, Doctor of Medical Sciences, 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

16. 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

17. Natalia V. Myakova – Doctor of Medical Sciences, Professor, Deputy Chief Medical Officer for Clinical Work, Head of the Oncohematology Department at the 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

18. Vadim V. Ptushkin – Doctor of Medical Sciences, Professor, Deputy Chief Medical Officer for Hematology at the S.P. Botkin City Clinical Hospital, Chief freelance hematologist of the Moscow Healthcare Department, member of the Association for the Promotion of Hematology and Bone Marrow Transplantation Development "National Hematological Society" and the Russian Society of Oncohematology.

19. Evgeny A. Osmanov – Doctor of Medical Sciences, 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.

20. Sergey N. Bondarenko – Candidate of Medical Sciences, R.M. Gorbacheva Research Institute of Pediatric Hematology and Transplantology, Saint Petersburg State Medical University

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

22. Olga Yu. Baranova – Candidate of Medical Sciences, Senior Researcher at the Hematology Department of the N.N. Blokhin National Medical Research Center of Oncology, member of the Association for the Promotion of Hematology and Bone Marrow Transplantation Development "National Hematological Society".

23. Tatiana S. Konstantinova – Sverdlovsk Regional Clinical Hospital No. 1, Regional Hematology Center, member of the Association for the Promotion of Hematology and Bone Marrow Transplantation Development "National Hematological Society" and the Russian Society of Oncohematology

24. Olga S. Samoylova – Candidate of Medical Sciences, Head of the Hematology Department at the N.A. Semashko Nizhny Novgorod Regional Clinical Hospital, member of the Association for the Promotion of Hematology and Bone Marrow Transplantation Development "National Hematological Society" and the Russian Society of Oncohematology

25. Tatiana S. Kaporskaya – Candidate of Medical Sciences, Head of the Hematology Department at the Irkutsk Order of the "Badge of Honor" Regional Clinical Hospital, member of the Association for the Promotion of Hematology and Bone Marrow Transplantation Development "National Hematological Society".

26. Valery A. Lapin – Candidate of Medical Sciences, Head of the Hematology Department at the Yaroslavl Regional Clinical Hospital

27. Kamil D. Kaplanov – Doctor of Medical Sciences, Head of Hematology Department No. 11 at the S.P. Botkin City Clinical Hospital of the Moscow Healthcare Department, member of the Russian Society of Oncohematology and the Association for the Promotion of Hematology and Bone Marrow Transplantation Development "National Hematological Society".

28. 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.

29. Alla M. Kovrigina – Doctor of Biological Sciences, Professor at the Department of Pathological Anatomy, Cytology and Molecular Pathology of the Institute of Advanced Training of the Federal Medical-Biological Agency, Head of the Pathological Anatomy Department at the National Medical Research Center for Hematology of the Russian Ministry of Health, Presidium member of the Russian Society of Pathologists, Board Member of the Russian Society of Oncohematology.

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

31. Dmitry M. Konovalov – Candidate of Medical Sciences, Head of the Pathological Anatomy Department at the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology of the Russian Ministry of Health, Presidium member of the Russian Society of Pathologists

32. Oksana P. Trofimova – Doctor of Medical Sciences, Leading Researcher at the Radiology Department of the N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health, Professor at the Academician L.V. Savitsky Department of Oncology and Palliative Medicine of the Russian Medical Academy of Continuous Professional Education of the Russian Ministry of Health

33. Evgeny V. Khmelevsky – Doctor of Medical Sciences, Chief freelance specialist radiologist of the Russian Ministry of Health, Head of the Radiotherapy Department at the P.A. Herzen Moscow Oncology Research Institute – a branch of the National Medical Research Radiological Center of the Russian Ministry of Health.

34. Vladimir M. Sotnikov – Doctor of Medical Sciences, Professor, Head of the Methodological Accreditation and Simulation Center for Radiotherapy at the Russian Scientific Center of Roentgenology and Radiology of the Russian Ministry of Health.

35. Nikolay V. Ilyin – Doctor of Medical Sciences, Professor, Chief Researcher at the Department of Fundamental Research, Professor at the Department of Radiology, Surgery and Oncology at the Granov Russian Scientific Center of Radiology and Surgical Technologies of the Russian Ministry of Health.

36. Yulia N. Vinogradova – Doctor of Medical Sciences, Head of the Department of Radiation and Combined Treatment Methods, Professor at the Department of Radiology, Surgery and Oncology at the Granov Russian Scientific Center of Radiology and Surgical Technologies of the Russian Ministry of Health.

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

There is no conflict of interest.

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience for these clinical guidelines:

1. Hematologists.

2. Oncologists.

3. Pediatric oncologists.

4. Radiologists.

5. Radiation therapists.

5. Medical students.

Methodology for evidence collection

Methods used for the collection/selection of evidence:

• electronic database searching.

Databases used to collect/select evidence. The evidence base for the guidelines includes publications from the Cochrane Library, PubMed, and MEDLINE databases. The search depth was 40 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 were discussed and approved by leading specialists from relevant federal centers of the Russian Federation and practicing physicians.

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 DLBCL, DEL, DHL, PMBCL, MCL, BL

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

A3.1.1 DLBCL treatment regimens in adults

R-CHOP

• Rituximab**

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

    or

  • 375 mg/m² IV infusion for cycle 1, then rituximab** 1400 mg SC, day 0 or 1 [73, 266–269]

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

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

• Vincristine** 1.4 mg/m² (total max 2 mg) IV, day 1

• #Prednisolone** 100 mg orally, days 1–5

Treatment is resumed on day 22 in the R-CHOP-21 protocol and on day 15 in the R-CHOP-14 protocol

Filgrastim** 5 mcg/kg subcutaneously (SC) 24–72 hours after the end of antineoplastic drug administration and until neutrophil count recovery after the nadir, or pegfilgrastim 6 mg, or empegfilgrastim** 7.5 mg subcutaneously once, at least 24 hours after the end of antineoplastic drug administration [212].

In elderly patients with cardiovascular comorbidities, pegylated liposomal #doxorubicin** 30 mg/m² IV infusion, day 1 may be used [85]

R-CVP [112, 113]

• Rituximab**

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

    or

  • 375 mg/m² IV infusion 1st cycle, then rituximab 1400 mg SC, day 0 or 1 [266–269]

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

• Vincristine** 1.4 mg/m² (total max 2 mg) IV, day 1

• #Prednisolone** 40 mg/m² orally, days 1–5

Treatment is resumed on day 22

BR [114, 115]

• Rituximab**

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

  • or

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

Treatment is resumed on day 28

R-miniCHOP (for patients over 80 years old and with comorbidities) [110, 111]

• Rituximab**

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

• #Doxorubicin** 25 mg/m² IV infusion, day 1

• #Cyclophosphamide** 400 mg/m² IV infusion, day 1

• Vincristine** 1 mg IV, day 1

• #Prednisolone** 40 mg/m² orally, days 1–5

Treatment is resumed on day 22

R-CEOP [31, 86]

• Rituximab**

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

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

• #Etoposide** 50 mg/m² IV, day 1 and 100 mg/m2 orally days 2 and 3

• Vincristine** 1.4 mg/m² (total max 2 mg) IV, day 1

• #Prednisolone** 40 mg/m² orally, days 1–5

Treatment is resumed on day 22

R-GCVP [87]

• Rituximab**

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

• #Gemcitabine** 750 mg/m² (cycle 1), 875 mg/m² (cycle 2), 1000 mg/m² (cycle 3 and subsequent) IV infusion, days 1, 8

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

• Vincristine** 1.4 mg/m² (total max 2 mg) IV, day 1

• #Prednisolone** 100 mg orally, days 1–5

Gemcitabine** dose escalation is performed in the absence of hematological toxicity. Treatment is resumed on day 22

R-CCOP [84]

• Rituximab** [89]

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

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

• Pegylated liposomal doxorubicin** 30 mg/m² IV infusion, day 1

• Vincristine** 2 mg IV, day 1

• #Prednisolone** 60 mg/m² orally, days 1–5

R-CHOEP [270]

• Rituximab** [89]

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

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

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

• Vincristine** 1.4 mg/m² (total max 2 mg) IV, day 1

• #Etoposide** 100 mg/m² IV infusion, days 1–3

• #Prednisolone** 100 mg orally, days 1–5

Treatment is resumed on day 22

R-CNOP [271]

• Rituximab** [89]

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

• #Cyclophosphamide** 500 mg/m² IV infusion, day 1

• #Mitoxantrone** 10 mg/m² IV, day 1

• Vincristine** 1.0 mg/m² (total max 2 mg) IV, day 1

• #Prednisolone** 80 mg orally, days 1–5

Treatment is resumed on day 22

R-MACOP-B [122, 356]

• Rituximab**

  • 375 mg/m² IV infusion, day 1, wks. 1, 3, 5, 7, 9, 11

• Doxorubicin** 50 mg/m² IV infusion, day 1, wks. 1, 3, 5, 7, 9, 11

• #Cyclophosphamide** 350 mg/m² IV infusion, day 1, wks. 1, 3, 5, 7, 9, 11

• Vincristine** 1.4 mg/m² (total max 2 mg) IV, day 1, wks. 2, 4, 6, 8, 10, 12

• Methotrexate** 400 mg/m² IV infusion, day 1, wks. 2, 6, 10

• Calcium folinate** 15 mg orally every 6 hours × 6 doses, starting 24 hours after methotrexate **

• Bleomycin** 10 mg/m² IV, day 1, wks. 4, 8, 12

• #Prednisolone** 75 mg/day orally continuously for 10 weeks with a gradual dose reduction over 11–12 weeks or weeks 1, 3, 5, 7, 9, 11 only

R-mNHL-BFM-90 [75]

Treatment regimen: pre-phase, followed by 4 alternating blocks (A, B, A, B).

Pre-phase:

• #Cyclophosphamide** 200 mg/m² IV, days 1–3

• #Dexamethasone** 10 mg/m² IV, days 1–3

Block A:

• Rituximab** 375 mg/m ² IV, day 0

• #Ifosfamide** 800 mg/m² IV, days 1–5

• Methotrexate** 1.0 g/m² IV (over 12 h), day 1

• Vincristine** 2 mg IV bolus, day 1

• Doxorubicin** 50 mg/m ² IV, day 3

• Cytarabine** 150 mg/m² IV every 12 h, days 4–5 (4 administrations in total)

• #Etoposide** 120 mg/m² IV, days 4–5

• #Dexamethasone** 10 mg/m² IV, days 1–5

Block B

• Rituximab** 375 mg/m ² IV, day 0

• Methotrexate** 1.0 g/m² IV (over 12 h), day 1

• Vincristine** 2 mg IV bolus, day 1

• Doxorubicin** 25 mg/m ² IV, days 4–5

• #Cyclophosphamide** 200 mg/m² IV, days 1–5

• #Dexamethasone** 10 mg/m² IV, days 1–5

DA-R-EPOCH, DA-EPOCH-R [119, 336, 346]

• Rituximab**

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

• Etoposide** 50 mg/m²/day IV, days 1–4 (continuous 96-hour infusion)

• Doxorubicin** 10 mg/m²/day IV, days 1–4 (continuous 96-hour infusion)

• #Vincristine** 0.4 mg/m²/day IV, days 1–4 (continuous 96-hour infusion)

• Cyclophosphamide** 750 mg/m² IV, day 5

• #Prednisolone** 60 mg/m² twice a day orally, days 1–5

Treatment is resumed on day 22

1 course is administered at this dosage. Thereafter, the doses of etoposide**, doxorubicin**, and cyclophosphamide** are adjusted relative to the previous course based on the lowest blood count values determined during and after the course, according to the following scheme:

• neutrophils > 0.5 × 10⁹/L, platelets > 25 × 10⁹/L — 25% dose increase

• neutrophils < 0.5 × 10⁹/L on 1–2 measurements, platelets > 25 × 10⁹/L — maintain previous course doses

• neutrophils < 0.5 × 10⁹/L on 3 or more measurements, platelets < 25 × 10⁹/L — 25% dose reduction

Pola+R-CHP [83]

• Rituximab** 375 mg/m² IV infusion, day 0 or 1, cycles 1–8

• Polatuzumab vedotin 1.8 mg/kg IV infusion, day 1, cycles 1–6

• Cyclophosphamide** 750 mg/m² IV infusion, day 1, cycles 1–6

• Doxorubicin** 50 mg/m² IV infusion, day 1, cycles 1–6

• #Prednisolone** 100 mg orally, days 1–5, cycles 1–6

Treatment is resumed on day 22 (duration of each cycle is 21 days). Total of 8 cycles.

On day 1, after administration of #prednisolone**, the remaining drugs can be administered in any sequence.

R-EPOCH/R-HMA [98, 109, 331]

Cycles 1, 3 (R-EPOCH):

• Rituximab** 375 mg/m² IV infusion, day 0

• Etoposide** 50 mg/m²/day IV, days 1–4 (continuous 96-hour infusion)

• Doxorubicin** 10 mg/m²/day IV, days 1–4 (continuous 96-hour infusion)

• #Vincristine** 0.4 mg/day IV, days 1–4 (continuous 96-hour infusion)

• Cyclophosphamide** 750 mg/m² IV, day 5

• #Prednisolone** 60 mg/m² twice daily orally, days 1–5 or #Dexamethasone** 10 mg/m² IV, days 1–5

Cycles 2, 4 (R-HMA):

• Rituximab** 375 mg/m² IV infusion, day 0

• Methotrexate** 500 mg/m² IV as a continuous 24-hour infusion, day 1

• Cytarabine** 1000 mg/m² IV every 12 h, days 2–3 (total of 4 administrations)

• #Dexamethasone** 10 mg/m² IV, days 1–5

For DLBCL patients with MUM1 protein expression, #Lenalidomide** 25 mg orally once daily from days 1 to 10 of each cycle is added to the therapy

mSMART-START [98]

• Rituximab** 375 mg/m² IV, infusion on day 0

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

• Vincristine** 1.4 mg/m2 IV bolus, day 1

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

• #Prednisolone** 60 mg/m² daily orally, days 1–5

• #Lenalidomide** 25 mg daily orally from days 1 to 10 of each course

• #Ibrutinib** 280 mg daily orally from days 1 to 10 of each course

bioSMART-START [98]

• Rituximab** 375 mg/m² IV, infusion on day 0

• #Lenalidomide** 25 mg daily orally from days 1 to 10 of each course

• #Ibrutinib** 280 mg daily orally from days 1 to 10 of each course

Treatment regimen for non-GCB DLBCL in adults

R2-mNHL-BFM-90 [82]

Treatment regimen: pre-phase, followed by 4 alternating blocks (A, B, A, B) with #lenalidomide**

Pre-phase:

• Cyclophosphamide** 200 mg/m² IV, days 1–3

• #Dexamethasone** 10 mg/m² IV, days 1–3

Block A:

• Rituximab** 375 mg/m² IV, day 0

• #Ifosfamide** 800 mg/m² IV, days 1–5

• Methotrexate** 1.0 g/m² IV (over 12 h), day 1

• Vincristine** 2 mg IV bolus, day 1

• Doxorubicin** 50 mg/m² IV, day 3

• Cytarabine** 150 mg/m² IV every 12 h, days 4–5 (4 administrations in total)

• #Etoposide** 120 mg/m² IV, days 4–5

• #Dexamethasone** 10 mg/m² IV, days 1–5 per os from days 1 to 10 of each course

Block B

• Rituximab** 375 mg/m² IV, day 0

• Methotrexate** 1.0 g/m² IV (over 12 h), day 1

• Vincristine** 2 mg IV bolus, day 1

• Doxorubicin** 25 mg/m² IV, days 4–5

• Cyclophosphamide** 200 mg/m² IV, days 1–5

• #Dexamethasone** 10 mg/m² IV, days 1–5 per os from days 1 to 10 of each course

Treatment regimen for non-GCB DLBCL with c-MYC+BCL2 co-expression (DEL) in adults [98]

Treatment regimen: pre-phase, followed by 2 alternating blocks (A, A) with #lenalidomide** and 2 courses of R-EPOCH with #polatuzumab vedotin

Pre-phase:

• Cyclophosphamide** 200 mg/m² IV, days 1–3

• #Dexamethasone** 10 mg/m² IV, days 1–3

Block A:

• Rituximab 375 mg/m² IV, day 0

• #Ifosfamide** 800 mg/m² IV, days 1–5

• Methotrexate** 1.0 g/m² IV (over 12 h), day 1

• Vincristine** 2 mg IV bolus, day 1

• Doxorubicin** 50 mg/m² IV, day 3

• Cytarabine** 150 mg/m² IV every 12 h, days 4–5 (4 administrations in total)

• #Etoposide** 120 mg/m² IV, days 4–5

• #Dexamethasone** 10 mg/m² IV, days 1–5

• #Lenalidomide** 25 mg per os from days 1 to 10 of the course

Pola-R-EPCH

• Rituximab** 375 mg/m² IV infusion, day 0, all cycles of the course

• Etoposide** 50 mg/m²/day IV, days 1–4 (continuous 96-hour infusion)

• Doxorubicin** 10 mg/m²/day IV, days 1–4 (continuous 96-hour infusion)

• Cyclophosphamide** 750 mg/m² IV, day 5

• #Prednisolone** 60 mg/m² twice a day orally, days 1–5

• #Polatuzumab vedotin 1.8 mg/kg IV infusion, day 1, cycles 2, 4

*It is important to remember that vincristine** is excluded from courses containing #polatuzumab vedotin*.

Treatment regimen for GCB DLBCL with c-MYC+BCL2 co-expression (DEL) in adults[98, 83]

Treatment regimen: pre-phase, followed by 2 alternating blocks (A, A) and 2 courses of R-EPOCH with #polatuzumab vedotin

Pre-phase:

• Cyclophosphamide** 200 mg/m² IV, days 1–3

• #Dexamethasone** 10 mg/m² IV, days 1–3

Block A:

• Rituximab 375 mg/m² IV, day 0

• #Ifosfamide** 800 mg/m² IV, days 1–5

• Methotrexate** 1.0 g/m² IV (over 12 h), day 1

• Vincristine** 2 mg IV bolus, day 1

• Doxorubicin** 50 mg/m² IV, day 3

• Cytarabine** 150 mg/m² IV every 12 h, days 4–5 (4 administrations in total)

• #Etoposide** 120 mg/m² IV, days 4–5

• #Dexamethasone** 10 mg/m² IV, days 1–5

Pola-R-EPCH

• Rituximab** 375 mg/m² IV infusion, day 0, all cycles of the course

• Etoposide** 50 mg/m²/day IV, days 1–4 (continuous 96-hour infusion)

• Doxorubicin** 10 mg/m²/day IV, days 1–4 (continuous 96-hour infusion)

• Cyclophosphamide** 750 mg/m² IV, day 5

• #Prednisolone** 60 mg/m² twice a day orally, days 1–5

• #Polatuzumab vedotin 1.8 mg/kg IV infusion, day 1, cycles 2, 4

*It is important to remember that vincristine** is excluded from courses containing #polatuzumab vedotin*.

Treatment regimen for DHL with c-MYC+BCL2 rearrangement in adults [98]

Treatment regimen: pre-phase, followed by 4 alternating blocks (A, B, A, B) with venetoclax** and #polatuzumab vedotin.

Pre-phase:

• Cyclophosphamide** 200 mg/m² IV, days 1–3

• #Dexamethasone** 10 mg/m² IV, days 1–3

Block A:

• Rituximab** 375 mg/m² IV, day 0

• #Ifosfamide** 800 mg/m² IV, days 1–5

• Methotrexate** 1.0 g/m² IV (over 12 h), day 1

• Vincristine** 2 mg IV bolus, day 1

• Doxorubicin** 50 mg/m² IV, day 3

• Cytarabine** 150 mg/m² IV every 12 h, days 4–5 (4 administrations in total)

• #Etoposide** 120 mg/m² IV, days 4–5

• #Dexamethasone** 10 mg/m² IV, days 1–5

• #Venetoclax** 200 mg per os from days 1 to 10 of the course

Block B

• Rituximab** 375 mg/m² IV, day 0

• Methotrexate** 1.0 g/m² IV (over 12 h), day 1

• Doxorubicin** 25 mg/m² IV, days 4–5

• Cyclophosphamide** 200 mg/m² IV, days 1–5

• #Dexamethasone** 10 mg/m² IV, days 1–5

• #Polatuzumab vedotin 1.8 mg/kg IV infusion, day 1

*It is important to remember that vincristine** is excluded from courses containing polatuzumab vedotin*.

Treatment regimen for DHL with c-MYC+BCL6 rearrangement in adults [98, 102]

Treatment regimen: pre-phase, followed by 4 alternating blocks (A, B, A, B) with #lenalidomide** and ibrutinib**.

Pre-phase:

• Cyclophosphamide** 200 mg/m² IV, days 1–3

• #Dexamethasone** 10 mg/m² IV, days 1–3

Block A:

• Rituximab** 375 mg/m² IV, day 0

• #Ifosfamide** 800 mg/m² IV, days 1–5

• Methotrexate** 1.0 g/m² IV (over 12 h), day 1

• Vincristine** 2 mg IV bolus, day 1

• Doxorubicin** 50 mg/m² IV, day 3

• Cytarabine** 150 mg/m² IV every 12 h, days 4–5 (4 administrations in total)

• #Etoposide** 120 mg/m² IV, days 4–5

• #Dexamethasone** 10 mg/m² IV, days 1–5

• #Ibrutinib** 420 mg per os from days 1 to 10 of the course

• #Lenalidomide** 25 mg per os from days 1 to 10 of the course

Block B

• Rituximab** 375 mg/m² IV, day 0

• Methotrexate** 1.0 g/m² IV (over 12 h), day 1

• Vincristine** 2 mg IV bolus, day 1

• Doxorubicin** 25 mg/m² IV, days 4–5

• Cyclophosphamide** 200 mg/m² IV, days 1–5

• #Dexamethasone** 10 mg/m² IV, days 1–5

• #Ibrutinib** 420 mg per os from days 1 to 10 of the course

• #Lenalidomide** 25 mg per os from days 1 to 10 of the course

Treatment regimens for primary mediastinal large B-cell lymphoma (PMLBCL-16, PMLBCL-19) in adults [98, 127]

PMLBCL-16 treatment regimen: pre-phase, followed by 2 blocks (A, B) + 4 courses of R-EPOCH

Pre-phase:

• Cyclophosphamide** 200 mg/m² IV, days 1–3

• #Dexamethasone** 10 mg/m² IV, days 1–3

Block A:

• Rituximab** 375 mg/m² IV, day 0

• #Ifosfamide** 800 mg/m² IV, days 1–5

• Methotrexate** 1.0 g/m² IV (over 12 h), day 1

• Vincristine** 2 mg IV bolus, day 1

• #Doxorubicin** 50 mg/m² IV, day 3

• Cytarabine** 150 mg/m² IV every 12 h, days 4–5 (4 administrations in total)

• #Etoposide** 120 mg/m² IV, days 4–5

• #Dexamethasone** 10 mg/m² IV, days 1–5

Block B

• Rituximab** 375 mg/m² IV, day 0

• Methotrexate** 1.0 g/m² IV (over 12 h), day 1

• Vincristine** 2 mg IV bolus, day 1

• Doxorubicin** 25 mg/m² IV, days 4–5

• Cyclophosphamide** 200 mg/m² IV, days 1–5

• #Dexamethasone** 10 mg/m² IV, days 1–5

R-EPOCH course:

• Rituximab** 375 mg/m² IV infusion, day 0

• Etoposide** 50 mg/m²/day IV, days 1–4 (continuous 96-hour infusion)

• Doxorubicin** 10 mg/m²/day IV, days 1–4 (continuous 96-hour infusion)

• #Vincristine** 0.4 mg/day IV, days 1–4 (continuous 96-hour infusion)

• Cyclophosphamide** 750 mg/m² IV, day 5

• #Prednisolone** 60 mg/m² twice daily orally, days 1–5 or #Dexamethasone** 10 mg/m² IV infusion, days 1–5

PMLBCL-19 treatment regimen: pre-phase, followed by 2 blocks (A, B) + 2 courses of R-EPOCH with #Lenalidomide**

Pre-phase:

• Cyclophosphamide** 200 mg/m² IV, days 1–3

• #Dexamethasone** 10 mg/m² IV, days 1–3

Block A:

• Rituximab** 375 mg/m² IV, day 0

• #Ifosfamide** 800 mg/m² IV, days 1–5

• Methotrexate** 1.0 g/m² IV (over 12 h), day 1

• Vincristine** 2 mg IV bolus, day 1

• Doxorubicin** 50 mg/m² IV, day 3

• Cytarabine** 150 mg/m² IV every 12 h, days 4–5 (4 administrations in total)

• #Etoposide** 120 mg/m² IV, days 4–5

• #Dexamethasone** 10 mg/m² IV, days 1–5

• #Lenalidomide** 25 mg per os from days 1 to 10 of the course

Block B

• Rituximab** 375 mg/m² IV, day 0

• Methotrexate** 1.0 g/m² IV (over 12 h), day 1

• Vincristine** 2 mg IV bolus, day 1

• Doxorubicin** 25 mg/m² IV, days 4–5

• Cyclophosphamide** 200 mg/m² IV, days 1–5

• #Dexamethasone** 10 mg/m² IV, days 1–5

• #Lenalidomide** 25 mg per os from days 1 to 10 of the course

R-EPOCH course:

• Rituximab** 375 mg/m² IV infusion, day 0

• Etoposide** 50 mg/m²/day IV, days 1–4 (continuous 96-hour infusion)

• Doxorubicin** 10 mg/m²/day IV, days 1–4 (continuous 96-hour infusion)

• #Vincristine** 0.4 mg/day IV, days 1–4 (continuous 96-hour infusion)

• Cyclophosphamide** 750 mg/m² IV, day 5

• #Prednisolone** 60 mg/m² twice daily orally, days 1–5 or #Dexamethasone** 10 mg/m² IV infusion, days 1–5

• #Lenalidomide** 25 mg per os from days 1 to 10 of the course

Treatment regimen for gray zone mediastinal lymphoma (GZML-16) in adults [98]

Treatment regimen: pre-phase, followed by 2 blocks (A, A) + 4 courses of R-BEACOPP-14

Pre-phase:

• Cyclophosphamide** 200 mg/m² IV, days 1–3

• #Dexamethasone** 10 mg/m² IV, days 1–3

Block A:

• Rituximab** 375 mg/m² IV, day 0

• #Ifosfamide** 800 mg/m² IV, days 1–5

• Methotrexate** 1.0 g/m² IV (over 12 h), day 1

• Vincristine** 2 mg IV bolus, day 1

• Doxorubicin** 50 mg/m² IV, day 3

• Cytarabine** 150 mg/m² IV every 12 h, days 4–5 (4 administrations in total)

• #Etoposide** 120 mg/m² IV, days 4–5

• #Dexamethasone** 10 mg/m² IV, days 1–5

R-BEACOPP-14

• Rituximab** 375 mg/m² IV infusion on day 0 of the cycle

• Doxorubicin** 25 mg/m² IV infusion, cycle day 1

• Cyclophosphamide** 650 mg/m² IV infusion, cycle day 1

• Etoposide** 100 mg/m² IV infusion, cycle days 1–3

• #Dacarbazine** 375 mg/m² IV infusion, cycle day 1

• Bleomycin** 10 mg/m² IV infusion, cycle day 8

• Vincristine** 1.4 mg/m² IV infusion, cycle day 8

• #Prednisolone** 80 mg/m² orally, cycle days 1–7

*Start of the next course on day 15

MGZL-2017 treatment protocol for gray zone lymphoma in adults

R-DA-EPOCH-Dacar [98]

• Dacarbazine** 375 mg/m² IV infusion, Day 5

• Rituximab** 375 mg/m² IV infusion, Day 1

• Etoposide** 50 mg/m² continuous IV infusion over 24 hours, Days 1–4

• #Prednisolone** 60 mg/m² orally twice daily, Days 1–5

• #Vincristine** 0.4 mg/m² continuous IV infusion over 24 hours, Days 1–4

• Doxorubicin** 10 mg/m² continuous IV infusion over 24 hours, Days 1–4

• Cyclophosphamide** 750 mg/m² IV bolus over 15 minutes, Day 5

Treatment regimens for plasmablastic lymphoma with/without TP53 mutation in adults [98]

Treatment regimen: pre-phase, followed by 4 blocks (A, A, A, A) with #lenalidomide**

Block A:

• Rituximab** 375 mg/m² IV, day 0

• #Ifosfamide** 800 mg/m² IV, days 1–5

• Methotrexate** 1.0 g/m² IV (over 12 h), day 1

• Vincristine** 2 mg IV bolus, day 1

• Doxorubicin** 50 mg/m² IV, day 3

• Cytarabine** 150 mg/m² IV every 12 h, days 4–5 (4 administrations in total)

• #Etoposide** 120 mg/m² IV, days 4–5

• #Dexamethasone** 10 mg/m² IV, days 1–5

• #Lenalidomide** 25 mg per os from days 1 to 10 of the course

For patients with a TP53 gene mutation, allo-HSCT should be considered if feasible.

V-EPOCH [161]

• Etoposide** 50 mg/m² continuous IV infusion over 24 hours, Days 1–4

• #Prednisolone** 60 mg/m² orally twice daily, Days 1–5

• #Vincristine** 0.4 mg/m² continuous IV infusion over 24 hours, Days 1–4

• Doxorubicin** 10 mg/m² continuous IV infusion over 24 hours, Days 1–4

• Cyclophosphamide** 750 mg/m² IV bolus over 15 minutes, Day 5

#Bortezomib** 1.3 mg/m² day 1 IV infusion

LB-M-22 treatment protocol for Burkitt lymphoma in adults [98]

Treatment regimen for limited/fully resected stages and cases of poor tolerability

Pre-phase, followed by 2 blocks of A and C, then optionally 2 cycles of R-EPOCH

A3.1.2 Treatment protocols for Burkitt lymphoma in adults

LB-M-04 [204]

Treatment regimen: pre-phase – A – C – A – C.

Pre-phase:

• Cyclophosphamide** 200 mg/m² IV, days 1–5

• #Dexamethasone** 20 mg IV, days 1–5

Block A:

• #Ifosfamide** 800 mg/m² IV, days 1–5

• Methotrexate** 1.5 g/m² IV (over 12 h), day 1

• Vincristine** 2 mg IV bolus on day 1

• Doxorubicin** 50 mg/m² IV, day 3

• Cytarabine** 150 mg/m² IV every 12 h, days 4–5 (4 administrations in total)

• #Etoposide** 100 mg/m² IV, days 4–5

• #Dexamethasone** 10 mg/m² IV, days 1–5

Block C:

• Methotrexate** 1.5 g/m² IV (over 12 h), day 1

• Vinblastine** 10 mg IV, day 1

• Cytarabine** 2 g/m² IV every 12 h, days 2–3 (4 administrations total)

• #Etoposide** 150 mg/m² IV, days 3–5

• #Dexamethasone** 20 mg IV, days 1–5

CNS leukemia prophylaxis is performed on day 1 of the pre-phase and day 1 of each block via intrathecal chemotherapy administration: cytarabine** 30 mg, #methotrexate** 15 mg (except in pregnant women), #prednisolone** 30 mg.

Rituximab** 375 mg/m² is administered on day 0 of each block (4 administrations total)

R-Hyper-CVAD/R-HMA [272]

Cycles 1, 3, 5, 7 (Hyper-CVAD):

• Rituximab** 375 mg/m² IV, days 1 and 11 (cycles 1, 3)

• Cyclophosphamide** 300 mg/m² IV every 12 h, days 1–3 (6 administrations total)

• #Dexamethasone** 40 mg IV or orally, days 1–4, 11–14

• Doxorubicin** 50 mg/m² via continuous 24-hour IV infusion into a central catheter, day 4

• Vincristine** 2 mg IV, days 4 and 11

Cycles 2, 4, 6, 8 (HMA):

• Rituximab** 375 mg/m² IV, days 2 and 8 (cycles 2, 4)

• Methotrexate** 1000 mg via continuous 24-hour IV infusion, day 1

• Cytarabine** 3 g/m² (1 g/m² in patients over 60 years) IV every 12 h, days 2–3 (4 administrations total)

CNS prophylaxis is performed during each course, totaling 16 intrathecal administrations: methotrexate** 12 mg intrathecally (except in pregnant women), day 2; #cytarabine** 100 mg intrathecally, day 7

Filgrastim** 5 mcg/kg subcutaneously (SC) 24–72 hours after completion of antineoplastic drug administration and until neutrophil counts recover from the nadir, or pegfilgrastim 6 mg or empegfilgrastim** 7.5 mg subcutaneously, single dose, at least 24 hours after completion of antineoplastic drug administration.

CODOX-M/IVAC [345]:

CODOX-M (cycles 1, 3)

• Rituximab** 375 mg/m2 IV days 1 and 9

• Cyclophosphamide** 800 mg/m² IV, day 1

• #Vincristine** 1.5 mg/m² (max 2 mg) IV, days 1, 8

• #Doxorubicin** 40 mg/m² IV, day 1

• #Cyclophosphamide** 200 mg/m²/day IV, days 2–5

• Methotrexate** 3000 mg/m² IV over 24 hours, day 10

• Cytarabine** 70 mg intrathecally, cycles 1, 3

• #Methotrexate** 15 mg intrathecally, cycles 1, 3

• Calcium folinate** 15 mg IV 24 hours after intrathecal methotrexate administration**

IVAC (cycles 2, 4)

• Rituximab** 375 mg/m2 IV days 3 and 7

• Etoposide** 60 mg/m² IV inf., days 1–5

• #Ifosfamide** 1500 mg/m² (in patients over 65 years old — 1 g/m²) IV, days 1–5

• Cytarabine** 2000 mg/m² (in patients over 65 years old — 1 g/m²), days 1–2 (4 infusions in total)

• Cytarabine** 70 mg intrathecally, cycle 2, 4,

• #Methotrexate** 15 mg intrathecally, cycle 2, 4

• G-CSF subcutaneously until granulocyte count >1 × 10⁹/L

Start of the next block — after stabilization of granulocyte count >1 × 10⁹/L and platelet count >75 × 10⁹/L

LMB 95[98]

Treatment regimen:

• Low-risk group

COPAD – COPAD

• Intermediate-risk group

COP–COPADM#1–COPADM#2–CYM#1–CYM#2– m1

• High-risk group

COP – COPADM #1 – COPADM #2 – CYVE #1– CYVE

#2– m1 – (RT 24 Gy for CNS involvement) – m2 – m3 – m4

COP

• #Cyclophosphamide** 300 mg/m² IV, day 1

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

• #Prednisolone** 60 mg/m² orally or IV, days 1–7

• #Methotrexate** 15 mg + #hydrocortisone** 15 mg intrathecally, day 1 (in the high-risk group – combined with cytarabine** 30 mg on days 1, 3, 5)

COPADM

• #Vincristine** 1.4 mg/m² (not exceeding 2 mg) IV, day 1 (+ day 6 in COPADM #2)

• #Methotrexate** 3 g/m² IV over 3 hours, in the high-risk group 8 g/m² over 4 hours, day 1

• Calcium folinate** 15 mg/m² IV 4 times a day, days 2–4

• Doxorubicin** 60 mg/m² IV, day 2

• #Cyclophosphamide** 500 mg/m² (1000 mg/m² in COPADM #2) IV every 12 hours, days 2–4 (6 infusions in total)

• #Prednisolone** 60 mg/m² IV or orally, days 1–6

• #Methotrexate** 15 mg + #hydrocortisone** 15 mg intrathecally, days 2, 6 (in the high-risk group combined with cytarabine** 30 mg on days 2, 4, 6)

COPAD

• #Vincristine** 1.4 mg/m² (not exceeding 2 mg) IV, days 1, 6

• Doxorubicin** 60 mg/m² IV, day 2

• #Cyclophosphamide** 500 mg/m² IV every 12 hours, days 2–4 (6 infusions in total)

• #Prednisolone** 60 mg/m² IV or orally, days 1–6

CYM

• #Methotrexate** 3 g/m² IV over 3 hours, day 1

• Calcium folinate** 15 mg/m² IV 4 times a day, days 2–4

• #Cytarabine** 100 mg/m²/day continuous infusion, days 2–6

• #Methotrexate** 15 mg + #hydrocortisone** 15 mg intrathecally, day 2

• #Cytarabine** 30 mg + #hydrocortisone** 15 mg intrathecally, day 6

CYVE

• #Cytarabine** 50 mg/m² continuous 12-hour infusion (prior to high-dose cytarabine**, 2000–800), days 1–5

• #Cytarabine** 3 g/m² IV (over 3 hours, 800–1100), days 2–5

• #Etoposide** 200 mg/m² IV, days 2–5 (1400–1600)

m1

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

• #Methotrexate** 3 g/m² IV over 3 hours (in the high-risk group 8 g/m² over 4 hours), day 1

• Calcium folinate** 15 mg/m² IV 4 times a day, days 2–4

• #Cyclophosphamide** 500 mg/m² IV, days 1, 2

• Doxorubicin** 60 mg/m² IV, day 2

• #Prednisolone** 60 mg/m² orally, days 1–5

• #Methotrexate** 15 mg + #hydrocortisone** 15 mg intrathecally (in the high-risk group combined with cytarabine** 30 mg), day 2

m3 is similar to m1, but without high-dose methotrexate** and intrathecal administration of antineoplastic agents

m2, m4

• #Etoposide** 150 mg/m² IV, days 1–3

• #Cytarabine** 100 mg/m²/day continuous 24-hour infusion, days 1–5

Start of the next block – after stabilization of granulocyte count >1.5 × 10⁹/L and platelet count >100 × 10⁹/L without G-CSF support

Interval between maintenance therapy courses (m1-m4) — 28 days

A3.1.3 Treatment regimens for relapses in patients with aggressive non-follicular B-cell lymphomas in adults

R+/-DHAP [31, 163]

• Rituximab** 375 mg/m2 IV, day 0 or 1

• #Dexamethasone** 40 mg IV, days 1–4

• #Cisplatin** 100 mg/m² IV inf. 12-hour infusion, day 1

• Cytarabine** 2 g/m² IV inf. twice a day, day 3

R+/-ESHAP [164]

• Rituximab** 375 mg/m2 IV, day 0 or 1

• #Etoposide** 40 mg/m² IV inf., days 1–4

• Methylprednisolone** 500 mg IV inf., days 1–5

• #Cisplatin** 25 mg/m²/day IV continuous infusion, days 1–4

R+/-ICE [165]

• Rituximab** 375 mg/m2 IV, day 0 or 1

• #Etoposide** 100 mg/m² IV infusion, days 1–3

• Ifosfamide** 5000 mg/m² IV 24-hour infusion, day 2

• #Carboplatin** AUC 5 using the Calvert formula; maximum 800 mg IV inf., day 2

Treatment is resumed on day 22

#Polatuzumab vedotin + R-ICE [170]

• #Polatuzumab vedotin 1.8 mg/kg IV, day 1

• Rituximab** 375 mg/m² IV, day 1

• #Etoposide** 100 mg/m² IV infusion, days 1–3

• Ifosfamide** 5000 mg/m² IV 24-hour infusion, day 2

• #Carboplatin** AUC 5 using the Calvert formula; maximum 800 mg IV inf., day 2

Treatment is resumed on day 22. Upon completion of two cycles of therapy, response assessment using PET-CT must be performed. If a complete response is achieved after two cycles of therapy, a third cycle of therapy can be administered or preparation for auto-HSCT can be initiated. If a partial response is achieved, a third cycle of Pola-R-ICE must be continued followed by response assessment.

Following auto-HSCT upon recovery of hematological parameters, three cycles of monotherapy with #polatuzumab vedotin (1.8 mg/kg IV) are administered, cycle 21 days. [170]

R+/-GDP [166, 177]

• Rituximab** 375 mg/m2 IV, day 0 or 1

• #Cisplatin** 75 mg/m² IV inf., day 1

• #Gemcitabine** 1000 mg/m² IV inf., days 1, 8

• #Dexamethasone** 40 mg orally, days 1–4

R+/-GemOx [167, 173]

• #Gemcitabine** 1200 mg/m² IV inf., day 1, 8

• #Oxaliplatin** 120 mg/m² IV inf., day 2

• Rituximab** 375 mg/m2 IV, day 1

R+/-DHAX [168]

• Rituximab** 375 mg/m2 IV, day 0 or 1

• #Dexamethasone** 40 mg IV, days 1–4

• #Oxaliplatin** 130 mg/m² IV inf., day 1

• Cytarabine** 2 g/m² IV inf., days 2, 3

R+/-MINE [169]

• Rituximab** 375 mg/m2 IV, day 0 or 1

• #Ifosfamide** 1500 mg/m² IV inf., day 1

• #Mesna** 1000 mg/m² IV inf., days 1–3

• #Etoposide** 150 mg/m² IV inf., days 1–3

• #Mitoxantrone** 12 mg/m² IV inf., day 1

BR [174, 175]

• Rituximab**:

  • 375 mg/m² IV inf., day 1 all cycles of the course

    or

  • 375 mg/m2 IV inf. cycle 1, then rituximab** 1400 mg SC, day 1 [266–269]

• #Bendamustine** 120 mg/m² IV inf., days 2, 3

Treatment is resumed on day 22

Pola-BR [179]

• #Polatuzumab vedotin 1.8 mg/kg IV infusion, day 1

• Rituximab** 375 mg/m² IV inf., day 1 all cycles of the course

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

Treatment is resumed on day 22 (duration of each cycle is 21 days). Total of 6 cycles.

On day 1 of each cycle, drugs can be administered in any sequence.

R+/-CEPP [176]

• Rituximab** 375 mg/m2 IV, day 0 or 1

• Cyclophosphamide** 600 mg/m2 IV inf., days 1, 8

• #Etoposide** 70 mg/m2 IV inf., days 1–3

• Procarbazine** 60 mg/m2 PO, days 1–10

• #Prednisolone** 60 mg/m2 PO, days 1–10

Course starts on day 28

R+/-#Gemcitabine** + #Vinorelbine** [178]

• Rituximab** 375 mg/m2 IV, day 0 or 1

• #Gemcitabine** 1000 mg/m² IV inf., days 1 and 8

• #Vinorelbine** 30 mg/m² IV, days 1 and 8

Treatment is resumed on day 22. Total of no more than 6 cycles

Rituximab** + Ibrutinib** + Lenalidomide**[180]

• Rituximab** 375 mg/m² IV inf., day 1

• #Lenalidomide** 25 mg PO once daily, days 1–21

• #Ibrutinib** 560 mg PO once daily continuously, days 1–28

A total of 6 cycles are administered. The cycle is resumed on day 29.

#Pembrolizumab** [181]

• #Pembrolizumab** 2 mg/kg of body weight or 200 mg as a 30-minute intravenous infusion every 3 weeks

Treatment is administered for 2 years or until unacceptable toxicity develops.

#Nivolumab**

• #Nivolumab** at a dose of 240 mg or 40 mg as a 60-minute intravenous infusion every 2 weeks [98, 125–126].

Treatment is administered for 2 years or until unacceptable toxicity develops.

#Brentuximab vedotin** [126]

• #Brentuximab vedotin** 1.8 mg/kg of body weight as a 30-minute intravenous infusion every 3 weeks

Treatment is administered for 2 years or until unacceptable toxicity develops.

Glofitamab (fixed-duration monotherapy) [186]

• #Obinutuzumab** Cycle 1 Day 1: 1000 mg IV

• Glofitamab Cycle 1: day 8 - 2.5 mg IV; day 15 – 10 mg IV; Cycles 2–12: day 1 – 30 mg IV

Treatment is resumed on day 22 (duration of each cycle is 21 days).

Glofitamab + GemOx [187]

• #Obinutuzumab** Cycle 1 Day 1: 1000 mg IV

• #Gemcitabine** Cycle 1 Day 2, Cycles 2–8 Day 1 - 1000 mg/m² IV

• #Oxaliplatin** Cycle 1 Day 2, Cycles 2–8 Day 1 - 100 mg/m² IV

• Glofitamab Cycle 1: day 8 - 2.5 mg IV; day 15 – 10 mg IV; Cycles 2–12: day 1 – 30 mg IV

Treatment is resumed on day 22 (duration of each cycle is 21 days). [187]

All patients must receive a single dose of #obinutuzumab** – 1000 mg on day 1 of cycle 1 (7 days before starting glofitamab treatment) to reduce the risk of cytokine release syndrome (CRS). At least one dose of tocilizumab** 8 mg/kg must be available prior to the glofitamab infusion in cycles 1 and 2 for use in the event of CRS development. Provision must be made for the administration of an additional dose of tocilizumab** within 8 hours from the administration of the previous tocilizumab dose**.[185, 367]

A3.1.5 Treatment regimens for adult patients with PCNSL

High-dose methotrexate monotherapy** [273,274]:

• Methotrexate** 8000 mg/m² IV inf. over 4 hours.

Resumption of treatment on day 15, total of 8 cycles

or

• Methotrexate** 3500 mg/m² IV inf. Resumption of treatment on day 22, total of 4 cycles, followed by radiation therapy

MT-R [131]

• Methotrexate** 8000 mg/m² IV inf. over 4 hours, day 1

• Rituximab** 375 mg/m² IV inf., day 3

• #Temozolomide** 150 mg/m² PO, days 7–11

Resumption of treatment on day 15. Total of 6 cycles

Methotrexate** + Cytarabine** [130]

• Methotrexate** 3500 mg/m² IV inf., day 1

• Cytarabine** 2000 mg/m² IV inf. twice daily, days 2–3

Resumption on day 22. Total of 4 cycles

MATRix [143]

• Rituximab** 375 mg/m² IV inf., days –5 and 0

• Methotrexate** 3500 mg/m² IV inf., day 1

• Cytarabine** 2000 mg/m² IV inf. twice daily, days 2–3

• #Thiotepa 30 mg/m² IV, day 4

Resumption on day 22. Total of 4 cycles

#Temozolomide** + rituximab** [145]

• Rituximab** 375 mg/m² IV inf., day 1 (cycles 1–4)

• #Temozolomide** 150 mg/m² PO, days 1–5

Resume treatment on day 29. Total up to 12 cycles

R-MPV [140,141]

• Rituximab** 375 mg/m² IV drip, day 1

• Methotrexate** 3500 mg/m² IV inf. over 2 hours, day 2

• Vincristine** 2 mg IV, day 2

• Procarbazine** 100 mg/m² PO, days 2–8 of each odd-numbered cycle (1, 3)

Resume treatment on day 15, total 4 cycles

RL-MPV [98]

• Rituximab** 375 mg/m² IV drip, day 1

• Methotrexate** 3500 mg/m² IV inf. over 2 hours, day 2

• Vincristine** 2 mg IV, day 2

• Procarbazine** 100 mg/m² PO, days 2–8 of each odd-numbered cycle (1, 3)

• #Lenalidomide** 25 mg/day PO, days 2-8 of each odd-numbered cycle (1, 3)

• In the absence of procarbazine: #ibrutinib** 420 mg/day / #acalabrutinib** 200 mg/day / #zanubrutinib 320 mg/day PO, days 1-10 of each cycle, #lenalidomide** 25 mg/day PO, days 2-8 of each cycle

Resume treatment on day 15, total 4 cycles

TBC + auto-HSCT [98]

• Thiotepa 250 mg/m² IV inf., days –8, –7, –6 before auto-HSCT

• #Busulfan** 4 mg/kg PO, days –5, –4 before auto-HSCT

• Cyclophosphamide** 60 mg/kg IV inf., days –3, –2 before auto-HSCT

Autologous HSC transfusion on day 0

BEAC + auto-HSCT [98]

• Carmustine** 400 mg IV inf., day –6 before auto-HSCT

• #Busulfan** 4 mg/kg PO, days –5, –4 before auto-HSCT

• Cyclophosphamide** 60 mg/kg IV inf., days –3, –2 before auto-HSCT

Autologous HSC transfusion on day 0

Maintenance therapy with immune checkpoint inhibitors (L01XC Monoclonal antibodies) [351, 355]

• #Nivolumab** 3 mg/kg every 2 weeks for 6 months [351]

#Pembrolizumab** 200 mg every 3 weeks for 6 months [355]

A3.1.6 Treatment regimens for patients with PMBCL CNS relapse

DHAP + #nivolumab** + procarbazine** [352]

• #Nivolumab** 40 mg IV drip, day 1

• #Cisplatin** 100 mg/m2 IV inf. over 24 hours, day 2

• Cytarabine** 2000 mg/m² IV bid, day 3

• Procarbazine** 100 mg/m² PO, days 1–10

• #Lenalidomide** 25 mg/day PO, days 1-10

TBE + auto-HSCT [352]

• #Thiotepa 400 mg IV inf., day –5 before auto-HSCT

• Carmustine** 400 mg IV inf., day –4 before auto-HSCT

• #Busulfan 4 mg/kg PO, days –3, –2 before auto-HSCT

Autologous HSC transfusion on day 0

3.1.6 Therapy regimen for aggressive non-follicular B-cell lymphomas in patients under 18 years of age

B-NHL-2010M protocol [151, 275]

RG — risk group (see section 7.5), Cred — cytoreduction, r — rituximab**, RT — residual tumor mass (confirmed by PET/CT and/or biopsy), noRT — absence of residual tumor mass, SCT — with autologous hematopoietic cell transfusion

^† #Methotrexate**/cytarabine**/prednisolone**, usually once per block or twice in case of initial CNS involvement.

^‡ The dose of #calcium folinate** is determined based on the serum methotrexate** concentration.

Intervals between the start of courses (blocks) should not exceed 18–21 days. G-CSFs can be used to maintain these intervals.

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

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

If the required neutrophil count is not reached by the scheduled administration day, colony-stimulating factor administration is continued at previous doses until the neutrophil count reaches >1×10⁹/L with daily blood tests, after which blood tests are repeated every other day. Treatment is resumed once the aforementioned parameters are achieved.

If blood counts do not recover for an additional 14 days, or in case of repeated course postponement due to myelotoxicity for more than 10 days, drug doses are reduced to 75% of the initial dose (excluding vincristine**, bleomycin**, and #prednisolone**).

Appendix A3.3 Autologous hematopoietic stem cell transplantation in adults

Mobilization and collection of peripheral blood hematopoietic stem cells in patients over 18 years of age

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 cell transfusion (auto-HSCT) (A18.05.018 Hematopoietic cell transfusion), standard evaluation to exclude contraindications to high-dose therapy, comorbidity, patient consent, review of prior therapy - number of courses and completion dates, use of radiation therapy)

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

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

Conditioning regimens for auto-HSCT in patients over 18 years of age

For pre-transplant conditioning, the BEAM regimen 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), and #melphalan** (140 mg/m²/day × 1, day -1) [179–182]. Administration schedules and doses are presented in Table A3.2.5.

Table A3.3.5. BEAM pre-transplant conditioning regimen [292–296] in patients over 18 years of age

To reduce the toxicity of the BEAM pre-transplant conditioning regimen, lomustine is used instead of carmustine in some cases (CEAM / LEAM). Administration schedules and doses are presented in Table A3.3.6.

Table A3.3.6. CEAM/LEAM pre-transplant conditioning regimen in patients over 18 years of age [292, 296–299]

The efficacy of the Benda-EAM pre-transplant conditioning regimen has been confirmed in a number of clinical studies for lymphoproliferative diseases. Administration schedules and doses are presented in Table A3.3.7.

Table A3.3.7. Benda-EAM pre-transplant conditioning regimen in patients over 18 years of age [300, 301]

Conditioning regimen for primary central nervous system lymphoma in patients over 18 years of age

For pre-transplant conditioning in this category of patients, the TBC or BBC regimen is used [141, 302]. Administration schedules and doses are presented in Tables A3.3.8 and 3.3.9.

Table A3.3.8. TBC pre-transplant conditioning regimen in patients over 18 years of age

Table A3.3.8. BBC pre-transplant conditioning regimen

Antisecretory therapy

Currently, two classes of drugs are used for antisecretory purposes: proton pump inhibitors and H2-histamine receptor blockers [205, 303].

Appendix B. Physician Action Algorithms

Appendix B1.1 First-line treatment algorithm for a patient with DLBCL

Appendix B1.2 Second-line treatment algorithm for a patient with DLBCL

Appendix B2. First-line treatment algorithm for a patient with PCNSL

Appendix B3. First-line treatment algorithm for a patient with PMBCL

Appendix C. Patient Information

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

The main test to confirm the diagnosis of lymphoma is microscopic examination of a lymphoid tissue sample obtained by biopsy (surgical removal of a lymph node or a piece of tissue from the affected organ). This tissue is sent for morphological examination to a pathologist, whose main task is to determine whether tumor (lymphoma) cells are present in the studied tissue. If the physician finds tumor cells in the histological specimen, the next question to answer is what type of lymphoma we are dealing with. For this purpose, immunohistochemical and cytogenetic studies are performed.

Prognosis depends on many factors, including the extent of the lesion, which necessitates a complete and comprehensive evaluation. Timely and adequate treatment is the key to success. The patient must strictly follow all medical recommendations regarding the schedule and timing of diagnostic procedures, as well as all prescriptions concerning antitumor treatment and supportive care.

During treatment, if adverse events occur, the patient must report them to the physician in a timely manner to make prompt decisions regarding their management.

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

Appendix G1.

Eastern Cooperative Oncology Group (ECOG) performance status scale in adult patients

Eastern Cooperative Oncology Group performance status scale,

The ECOG Scale of Performance Status, 1982,

0, 1, 2, 3, 4, 5 scoring system to determine the somatic status of patients [207]

Notes: Assessment of the patient's general condition must be performed prior to initiating therapy. After a pre-phase or 1 course of therapy, the status may change, so the general condition can be reassessed.

Definition of risk groups for DLBCL, DEL, DHL, PMBCL, B-cell lymphoma unclassifiable, BL, and THRLBCL in adult patients

To analyze the individual risk of early progression, the International Prognostic Index (IPI) is used for the entire patient population (Table 7.4.1 [228]), along with the age-adjusted IPI (aaIPI) for patients under 60 years of age (Table 7.4.2 [229]), which have retained their significance in modern treatment regimens.

Table 1. International Prognostic Index (IPI)

Determination of prognostic groups.

International Prognostic Index (IPI) for DLBCL, DEL, DHL, PMBCL, B-cell lymphoma unclassifiable, BL, and THRLBCL.

International Prognostic Index, scoring system [343] for determining the prognosis of patients with DLBCL, DEL, DHL, PMBCL, B-cell lymphoma unclassifiable, BL, and THRLBCL.

scoring system 0, 1, 2, 3, 4, 5 for determining prognostic groups in patients over 18 years of age;

Notes: The International Prognostic Index is the clinical prognostic system for DLBCL, DEL, DHL, PMBCL, B-cell lymphoma unclassifiable, BL, and THRLBCL. Low risk by IPI — 3-year overall survival (OS) is 91%. Low-intermediate risk by IPI — median OS is 65–81 months. High-intermediate risk by IPI — median OS is 59 months. Each prognostic factor is scored as 1 point, and the points are then summed (maximum 5 points). Patients with 0 to 1 point are classified as low risk; 2 points as low-intermediate risk; 3 points as high-intermediate risk; 4–5 points as high risk.

¹According to various clinical trials.

Table 2 Age-adjusted International Prognostic Index for patients under 60 years of age (aaIPI)

Age-adjusted International Prognostic Index for DLBCL, DEL, DHL, PMBCL, B-cell lymphoma unclassifiable, BL, and THRLBCL, IPI, under 60 years (aaIPI)

Age-adjusted International Prognostic Index, scoring system [344] for determining the prognosis of patients under 60 years of age

scoring system 0, 1, 2, 3 for determining prognostic groups in patients aged 18 to 60 years;

Notes: for patients under 60 years of age, prognosis is determined by factors differing from the standard International Prognostic Index (IPI), without accounting for age and extranodal sites of involvement.

Prognostic models such as R-IPI (revised in the rituximab era**) or E-IPI (elderly scale) have been tested in smaller patient cohorts and may be considered as supplementary prognostic tools.

Table 3 CNS-IPI International Prognostic Index

Determination of prognostic groups

Central nervous system (CNS) relapse/progression risk International Prognostic Index for DLBCL (CNS-IPI), 2016 [368]

Central Nervous System International Prognostic Index (CNS-IPI) [368]

Scoring system 0, 1, 2, 3, 4, 5, 6 for assessing the risk of CNS relapse/progression in patients over 18 years of age.

According to the provided prognostic model, a high risk of CNS involvement in relapsed DLBCL, PMBCL, or BL is observed in patients with 4–6 prognostic factors, as well as in patients with HIV-associated lymphoma, testicular lymphoma, high-grade B-cell lymphoma with MYC, BCL-2, and/or BCL-6 translocations, high-grade B-cell lymphoma, unclassifiable, or DLBCL with kidney or adrenal gland involvement. Recent data indicate that stage IE breast DLBCL is a potential risk factor for CNS involvement.