Mantle Cell Lymphoma: Clinical Guidelines

List of Abbreviations

A. baumannii – Acinetobacter baumannii

ag-vWF – von Willebrand factor antigen

C. albicans – Candida albicans

C. neumonia – Chlamydophila neumonia

CIM – carbapenem inactivation method

C. difficile – Clostridioides difficile

E. faecalis – Enterococcus faecalis

E. faecium – Enterococcus faecium

E. coli – Escherichia coli

EBMT – European Society for Blood and Marrow Transplantation

K. neumonia – Klebsiella neumonia

KPC – Klebsiella neumonia carbapenemase

L. pneumophila – Legionella pneumophila

L. monocytogenes – Listeria monocytogenes

M. pneumonia – Mycoplasma pneumonia

MASCC – Multinational Association of Supportive Care in Cancer

mCIM – modified carbapenem inactivation method

MIPIb (Mantle cell lymphoma International Prognostic Index) – Mantle Cell Lymphoma International Prognostic Index biological

NDM – New Delhi metallo-β-lactamase

NK-1 – neurokinin-1

OXA-48 – oxacillinase-48

P. jirovecii – Pneumocystis jirovecii

R-maintenance – maintenance therapy with rituximab**

S. aureus – Staphylococcus aureus

S. maltophilia – Stenotrophomonas maltophilia

vWF – von Willebrand factor

VKA – vitamin K antagonists

AVT – abdominal venous thromboses

aHUS – atypical hemolytic-uremic syndrome

AICC – anti-inhibitor coagulant complex**

allo-HSCT – allogeneic hematopoietic stem cell transplantation

AST – aspartate aminotransferase

ALT – alanine aminotransferase

ATG** – antithymocyte globulin**

AT III – antithrombin III

auto-HSCT – autologous hematopoietic stem cell transplantation

allo-HSCT – allogeneic hematopoietic stem cell transplantation

APS – antiphospholipid syndrome

aPTT – activated partial thromboplastin time

BAL – bronchoalveolar lavage

ESBL – extended-spectrum β-lactamases

RFS – relapse-free survival

EFS – event-free survival

BTK – Bruton's tyrosine kinase

IVIG – intravenous immunoglobulin

VTE – venous thromboembolism

HIT – heparin-induced thrombocytopenia

GC – glucocorticoids

G-CSF – L03AA Colony-stimulating factors according to the ATC classification

DIC – disseminated intravascular coagulation

DNA – deoxyribonucleic acid

GIT – gastrointestinal bleeding

GI – gastrointestinal tract

iBTK – Bruton's tyrosine kinase (BTK) inhibitors

iBCL2 – (ATC group – other antineoplastic agents)

ITP – immune thrombocytopenia

IHC – immunohistochemical

BMI – body mass index

PPI – proton pump inhibitors

ITP – immune thrombocytopenia

IPT – immunophenotyping

CFU — colony-forming unit

CT – computed tomography

LDH – lactate dehydrogenase

MCL – mantle cell lymphoma

LU – lymph node

MDS — myelodysplastic syndrome

IU – international unit

INR – international normalized ratio

MPD – myeloproliferative disorders

MIC – minimum inhibitory concentration

MRI – magnetic resonance imaging

LMWH – low-molecular-weight heparins (ATC B01AB Heparin group)

5-HT – 5-hydroxytryptamine (serotonin)

UFH – unfractionated heparin (ATC B01AB Heparin group)

NHL – non-Hodgkin lymphoma

OS – overall survival

OR – overall response

ARF – acute renal failure

s.c. – subcutaneous

DOAC – direct oral anticoagulants (ATC B01AF Direct factor Xa inhibitors, B01AE Direct thrombin inhibitors)

CR – complete remission

PCT – polychemotherapy

PCR – polymerase chain reaction

PET – positron emission tomography

R/R – relapsed or refractory

FFP – fresh frozen plasma

TLS – tumor lysis syndrome

CSF – cerebrospinal fluid

TFD – total focal dose

TT – thrombin time

HSCT – hematopoietic stem cell transplantation

TMA – thrombotic microangiopathy

TBI ‒ total body irradiation

TTP — thrombotic thrombocytopenic purpura

PE – pulmonary embolism

CDU – color duplex ultrasonography

US – ultrasound examination

CKD – chronic kidney disease

CT – chemotherapy

CVC – central venous catheter

CNS – central nervous system

EGD – esophagogastroduodenoscopy

EchoCG – echocardiography

** – vital and essential drugs

# – off-label drug use (used outside of the indications, contraindications, routes of administration, or dosages contained in the medication's package insert)

Terms and Definitions

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

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

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Mantle cell lymphoma (MCL; syn.: mantle zone lymphoma, centrocytic lymphoma) is a mature B-cell lymphoma composed of small to medium-sized lymphoid cells with irregularly notched nuclei. In more than 95% of cases, a translocation involving the CCND1 gene is detected. Most cases of MCL are characterized by an aggressive clinical course, though indolent variants are also described [1].

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

The main (primary) oncogenic event in the pathogenesis of mantle cell lymphoma (MCL) is considered to be the translocation t(11;14)(q13;q32). The gene CCND1, located at the 13th locus of the long arm of chromosome 11, is transferred to the enhancer region of IgVH genes constitutionally hyperexpressed in B-lymphocytes [2, 3]. As a result, overexpression of the cell cycle regulatory protein cyclin D1 develops. Establishing the fact of cyclin D1 overexpression is one of the main immunological markers of MCL. Analysis of the breakpoint regions in 11q13 and 14q32 has shown that translocation occurs during the primary rearrangement of immunoglobulin genes in bone marrow progenitor cells of B-lymphopoiesis between one of the D and J segments of immunoglobulin genes. About 50% of rearrangements in 11q13 occur in the region designated as the major translocation cluster. The optimal method for determining t(11;14)(q13;q32) is fluorescence in situ hybridization in situ (FISH): the detection rate of translocation by this method in MCL reaches 99% [4]. The immunoglobulin light chain loci can also become partners for the cyclin D1-encoding gene: t(2;11)(p11;q13) and t(11;22)(q13;q11). Variant translocations occur in less than 1% of MCL cases. Cyclin D1 in complex with cyclin-dependent kinases 4 and 6 (CDK4/6) is a regulator of the transition of cells from the G1 to the S phase of the cell cycle. The active cyclin D1/CDK4(6) complex phosphorylates the retinoblastoma protein (RB), a blocking protein for the E2F transcription factor. The cyclin D1/CDK4 complex also has kinase-independent functions, binding in particular to the cell cycle blocking protein p27kip, which in turn titrates the cyclin E/CDK2 complex out of the nucleus. This further accelerates the cell cycle. In MCL, cyclin-dependent kinases CDK4 and CDK6, required for cyclin D1a function, are often overexpressed. In the case of CDK4, this is achieved through CDK4 gene amplification, while in the case of CDK6, a decrease in microRNA-29 expression is noted. This leads to stabilization of the CDK6 transcript and promotes protein hyperexpression, which is associated with shorter patient survival [5]. There is also a rarely occurring variant (<5% of cases) of cyclin D1-negative MCL [6, 7]. In this MCL variant, tumor cells have the same immunophenotype, but overexpression of cyclin D2 or D3 may be observed [8, 9]. However, the detection of cyclin D2 or D3 overexpression by immunohistochemical study cannot be used to verify the diagnosis of cyclin D1-negative MCL. This is due to the fact that an elevated level of cyclin D2 and D3 expression is characteristic of other B-cell lymphomas. A recent case series study of cyclin D1-negative MCL revealed the presence of rearrangements involving the gene CCND2 in 55% of cases, which was associated with a high level of cyclin D2 mRNA expression. The gene and microRNA expression profiles in patients with cyclin D1-negative MCL variants corresponded to cyclin D1-positive MCL variants [7, 8, 10]. The pathological features and clinical characteristics of cyclin D1-negative MCL are apparently similar to cyclin D1-positive MCL variants [8, 10]. Thus, in the absence of evidence to the contrary, the same treatment approaches should be selected for cyclin D1-negative MCL variants as for cyclin D1-positive MCL variants.

1.3 Epidemiology of the Disease or Condition

MCL accounts for approximately 3–5% of all newly diagnosed cases of non-Hodgkin lymphoma [11,12]. In Western Europe, Scandinavia, and the USA, its incidence ranges from 0.5 to 0.7 per 100,000 population, with the incidence rising to 3.9 per 100,000 in individuals over 65 years of age. It predominantly affects men over 60 years old (median age 65–75 years, M:F ratio >2:1). In the USA, 5,000 to 6,000 people are diagnosed annually, which indirectly indicates that at least 2,500 new cases should be detected annually in the Russian Federation.

1.4 Features of Coding the Disease or Condition

C83.1, C85.1 – mantle cell lymphoma.

1.5 Classification of the disease or condition

MCL is conventionally divided into three clinical and pathological variants: classical, aggressive (pleomorphic or blastic), and indolent. This division takes into account the 2017 WHO classification revision of lymphoid neoplasms and is supported by gene expression profiling analysis [1]. The classical variant of MCL (nodal or extranodal) is characterized by SOX11+ overexpression and the absence of immunoglobulin heavy chain variable gene (IGHV) somatic hypermutation. The Ki-67 proliferative index in this variant typically ranges from 10–30%. The indolent (leukemic non-nodal) subtype is characterized by mutated IGHV genes, lack of SOX11 expression, a leukemic peripheral blood picture, bone marrow and splenic involvement, low tumor burden, and a Ki-67 proliferative activity index <10% [13–15]. It is worth noting a number of cases with exclusive gastrointestinal (GI) tract or blood/bone marrow involvement that may express SOX11 and exhibit an indolent course.

The most aggressive variants of MCL (blastic or pleomorphic) are characterized by blastic or large-cell morphology, a high Ki-67 proliferative index >30%, the presence of B symptoms, and a low treatment response rate. The blastic variant can manifest either de novo (up to 20% of cases) or result from transformation driven by the accumulation of cytogenetic abnormalities. Aggressive variants are frequently associated with TP53 gene mutations. When assessing the prognostic impact of the most well-known cytogenetic abnormalities in 183 patients enrolled in clinical trials, a significant association was identified between TP53 gene mutations and a high Ki-67 proliferative index >30%, blastic morphology, and a low treatment response rate [16].

Risk groups for MCL have now been established based on a comprehensive morphological, cytogenetic, and molecular genetic evaluation. Specifically, ultra-high and high-risk groups are characterized by the presence of mutations in TP53, KMT2D, NSD2, CCND1, NOTCH1, CDKN2A, NOTCH2, SMARCA4 genes, typically combined with a de novo blastic/pleomorphic morphological variant, a high Ki-67 proliferative activity index, and a complex karyotype [17].

Staging

Staging of MCL is performed using the modified Ann Arbor classification (Table 1) [18, 19].

Table 1. Ann Arbor staging for MCL

1.6 Clinical presentation of the disease or condition

In 90% of cases, the diagnosis is established at stage III or IV, presenting with generalized lymphadenopathy, hepatosplenomegaly, and bone marrow involvement [20,21].

B symptoms—fever, night sweats, and weight loss of more than 10% over the preceding six months—are present in half of the cases. Splenomegaly is observed in more than 50% of patients. Leukocytosis with circulating MCL cells in the blood is frequently detected. The most common extranodal site in MCL is the gastrointestinal tract, presenting as lymphomatous polyposis of the colon or stomach. It should be borne in mind that even in the absence of overt polyps or visible mucosal changes, histological examination of biopsies may reveal areas of tumor infiltration. Involvement of the urogenital system, lungs, and soft tissues, including the head and neck soft tissues and periorbital tissues of the eye, may also occur. Central nervous system involvement is rarely diagnosed at initial presentation and may develop in patients with relapsed or refractory MCL. Additionally, in a small proportion of patients, particularly those with the blastic variant of MCL, isolated CNS relapses occur following initially successful treatment [22,23].

2. Diagnostics, medical indications and contraindications for diagnostic methods

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

Diagnostic criteria: the diagnosis of MCL is established based on a pathoanatomical examination of biopsy or surgical material using immunohistochemical methods.

2.1 Complaints and Anamnesis

• All patients with suspected MCL, as well as all patients with verified MCL at each visit, are recommended to undergo a history and symptom taking regarding blood and hematopoietic disorders to assess the patient's condition and to determine factors that may influence the choice of the patient's treatment strategy [18,24–26].

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

Comments. When taking the history of present illness and family history, the following should be ascertained: identification of factors preceding the development of the disease—bacterial or viral infection, stress, comorbid conditions, history of organ transplantation; family history—hematopoietic system diseases in blood relatives.

2.2 Physical Examination

• All patients with suspected or confirmed MCL at the initial or follow-up visit, during check-up examinations, and when disease relapse/progression is suspected, are recommended a thorough physical examination focusing on areas where lymph nodes are located, as well as an assessment of functional status and constitutional symptoms, visual examination, palpation, and auscultation, determination of general condition using the ECOG scale (see Appendix G), and examination of the tonsils and oral cavity to clarify disease dissemination and assess the patient's condition by organ systems [18,24–26].

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

Comments. Attention should be paid to the following factors: hyperthermia, weight loss and symptoms of intoxication, hepato- and splenomegaly, lymphadenopathy, pathology of the mammary glands, heart, lower limb veins, congenital anomalies.

2.3 Laboratory Diagnostics

• In all patients with suspected or confirmed MCL at the initial or follow-up visit, before 1st-line antitumor therapy, when assessing remission 1 month after therapy completion, during check-up examinations, upon suspicion of relapse/progression, and before subsequent lines of antitumor therapy (i.e., at all stages of diagnosis, treatment, and follow-up), it is recommended to perform a complete blood count (CBC) with differential to verify the diagnosis, clarify disease activity, assess the patient's condition, and develop an adequate therapeutic strategy [18,24–26].

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

Comments. The scope of the study includes differential blood cell counting using an automated analyzer; in case of deviation from the norm, an optical platelet count (Fonio method), lymphocyte morphology assessment via blood smear, and erythrocyte sedimentation rate are desirable.

• In all patients with suspected or confirmed MCL at the initial or follow-up visit, before 1st-line antitumor therapy, when assessing remission 1 month after therapy completion, during check-up examinations, upon suspicion of relapse/progression, and before subsequent lines of antitumor therapy (i.e., at all stages of diagnosis, treatment, and follow-up), it is recommended to perform a general routine biochemical blood test and blood glucose testing to assess the functional status of internal organs and detect concomitant pathology [18,24–26].

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

Comment. Includes mandatory determination of the following parameters: blood lactate dehydrogenase, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase activity, blood uric acid, urea, creatinine, total protein, albumin, total, direct, and conjugated bilirubin, sodium, potassium, chlorides, and total blood calcium.

• In all patients with suspected or confirmed MCL at the initial or follow-up visit, before 1st-line antitumor therapy, when assessing remission 1 month after therapy completion, during check-up examinations, upon suspicion of relapse/progression, and before subsequent lines of antitumor therapy (i.e., at all stages of diagnosis, treatment, and follow-up), it is recommended to perform a general (clinical) urinalysis to detect concomitant pathology and develop an adequate therapeutic strategy [18,24–26].

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

• In all patients with suspected or confirmed MCL at the initial or follow-up visit, before 1st-line antitumor therapy, when assessing remission 1 month after therapy completion, during check-up examinations, upon suspicion of relapse/progression, and before subsequent lines of antitumor therapy (i.e., at all stages of diagnosis, treatment, and follow-up), it is recommended to perform a coagulogram (screening hemostasis test) to assess the functional state of the liver, platelets, and the clotting system [18,24].

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

Comments. The coagulogram should include the determination of the following parameters: blood or plasma prothrombin (thromboplastin) time, international normalized ratio (INR), activated partial thromboplastin time, blood fibrinogen level, and blood thrombin time.

• All patients with MCL at the diagnostic stage and, if indicated, at any stage of treatment and/or follow-up, are recommended to undergo molecular biological blood testing for human immunodeficiency virus (testing for class M, G antibodies (IgM, IgG) to human immunodeficiency virus HIV-1/2 and p24 antigen (Human immunodeficiency virus HIV 1/2 + Agp24) in the blood) to clarify comorbidity and the need for antiretroviral therapy [18].

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

• All patients with MCL at the diagnostic stage and, if indicated, at any stage of treatment and/or follow-up, are recommended to undergo a comprehensive virological examination to detect hepatitis B virus markers in order to clarify the risk and, if necessary, prevent hepatitis B virus reactivation, which should include:

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

- determination of antibodies to hepatitis B surface antigen (HBsAg) in the blood;

- determination of antibodies to hepatitis B virus (Hepatitis B virus) core antigen (HBcAg) in the blood;

- determination of hepatitis B virus (Hepatitis B virus) DNA in the blood by polymerase chain reaction, qualitative assay (only with positive HBsAg and/or HBcAg tests) [18].

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

• All patients with MCL at the diagnostic stage and, if indicated, at any stage of treatment and/or follow-up, are recommended to determine antibodies to hepatitis C virus (Hepatitis C virus) in the blood and hepatitis C virus (Hepatitis C virus) Core antigen in the blood to clarify the risk and, if necessary, prevent hepatitis virus reactivation [18].

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

• All patients with MCL at the diagnostic stage and, if indicated, at any stage of treatment and/or follow-up, are recommended to determine AB0 blood groups, Rhesus system antigen D (Rh factor), and MNS system erythrocyte antigen phenotype to enable blood transfusion [18].

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

• Patients with MCL at the diagnostic stage and, in the presence of clinical or laboratory signs of hemolysis, at any stage of treatment and/or follow-up, are recommended to perform a direct antiglobulin test (direct Coombs test) to clarify the cause of hemolysis [18].

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

• Patients with MCL during initial examination, follow-up examination (remission assessment), prior to hematopoietic stem cell (HSC) mobilization and collection, and upon suspicion of disease relapse/progression, are recommended to obtain a bone marrow cytologic preparation via puncture and perform a cytologic examination of the bone marrow smear (myelogram) to assess bone marrow involvement and the state of other hematopoietic lineages [18,24–26].

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

• Patients with MCL during initial examination, follow-up examination (remission assessment), prior to HSC mobilization and collection, and upon suspicion of disease relapse/progression, are recommended to obtain a bone marrow histologic preparation and perform a pathoanatomical examination of bone marrow biopsy (surgical) material using immunohistochemical methods to assess the extent of bone marrow involvement and the state of other hematopoietic lineages [18,24–26].

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

Comments. Bone marrow aspirate examination (sternal or other) does not replace the pathomorphological examination of a trephine biopsy specimen. The absence of morphological signs of bone marrow involvement does not rule out minimal bone marrow involvement, which is detected by polymerase chain reaction or bone marrow aspirate flow cytometry.

• For patients with mantle cell lymphoma (MCL) during initial evaluation and suspected relapse, it is recommended to perform standard cytogenetic testing (karyotype) and determination of the t(11;14)(q13;q32) translocation in biopsy (surgical) material using fluorescence in situ hybridization (FISH) [4,27].

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

• For patients with MCL during initial evaluation, treatment/follow-up stages, and suspected relapse/disease progression, it is recommended, if indicated, to perform immunochemical blood serum testing: immunofixation electrophoresis for blood immunoglobulin monoclonal components, blood immunoglobulin light chain immunofixation, and measurement of blood immunoglobulin A, M, and G levels to rule out monoclonal gammopathy and determine normal immunoglobulin levels [18,24–26].

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

• For patients with MCL presenting with a blastoid variant ± hyperleukocytosis +/- generalized cerebral symptoms during initial evaluation, it is recommended to perform a lumbar puncture, cerebrospinal fluid cytological examination, and/or biological material (cerebrospinal fluid) testing by flow cytometry to rule out neurolymphomatosis [18,24–26].

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

Comments. Prophylactic intrathecal drug administration is at the discretion of the attending physician. There is no evidence regarding the efficacy of neurorelapse prophylaxis.

2.4 Instrumental Diagnostics

• For patients with MCL at any stage of diagnosis, treatment, follow-up, or rule-out of relapse, in the presence of clinical signs of brain tumor involvement (focal symptoms, generalized cerebral symptoms), it is recommended to perform contrast-enhanced brain magnetic resonance imaging (MRI) or intravenous contrast-enhanced brain computed tomography (CT) prior to lumbar puncture to identify or rule out brain tumor involvement [18,24–26].

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

• For patients with MCL at any stage of diagnosis, treatment, follow-up, or rule-out of relapse, in the presence of clinical signs of brain tumor involvement (focal symptoms, generalized cerebral symptoms), it is recommended to perform electroencephalography as indicated [18,24–26].

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

• For patients with MCL during initial evaluation, and in case of specific involvement detected—at treatment stages (response assessment), during follow-up, and when disease relapse is suspected—it is recommended to perform esophagogastroduodenoscopy with gastric mucosal biopsies, even in the absence of visual signs of organ involvement ("blind" biopsies), to rule out gastric tumor involvement [18,24–26].

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

• For patients with MCL during initial evaluation, and in case of specific involvement detected—at treatment stages (response assessment), during follow-up, and when disease relapse is suspected—it is recommended to perform colonoscopy with colonic mucosal biopsies, even in the absence of visual signs of organ involvement ("blind" biopsies), to rule out colonic tumor involvement [18,24–26].

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

• For all patients with MCL during initial staging, before initiating 1st-line and/or subsequent lines of therapy, during follow-up, and when relapse/disease progression is suspected, it is recommended to perform an electrocardiogram to assess the functional state of the cardiovascular system [18,24].

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

• For all patients with MCL at any stage—during initial staging, before and during anti-tumor therapy, during treatment efficacy evaluation and after its completion, as well as when relapse/disease progression is suspected, in the presence of cardiac pathology or clinical indications, it is recommended to perform echocardiography [18,24].

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

• For all patients with MCL during initial staging, before starting anti-tumor therapy, during treatment efficacy evaluation and after its completion, as well as when relapse/disease progression is suspected, it is recommended to perform computed tomography (CT) of the neck, chest, abdominal cavity, retroperitoneal space, and pelvis (preferably with intravenous contrast) to determine the presence and extent of lymphadenopathy or to assess the anti-tumor effect if serial imaging is performed [18,24–26].

GPP CLOE 5Grade of Recommendation – C (Level of Evidence 5).

• For patients with MCL at the diagnostic stage, before starting therapy, during treatment efficacy evaluation and after its completion, as well as when relapse/disease progression is suspected, and if there are contraindications to CT, it is recommended to perform a comprehensive ultrasound examination of lymph nodes, abdominal organs, and pelvic organs to determine the presence and extent of lymphadenopathy [18,24–26].

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

Comments. Ultrasound examination should evaluate peripheral lymph nodes, intra-abdominal and retroperitoneal nodes, abdominal and pelvic organs.

• For patients with MCL at any stage of diagnosis, treatment, follow-up, or rule-out of relapse, in the presence of clinical and instrumental signs of lung tissue and/or bronchial tree involvement, it is recommended to optionally perform bronchoscopy with bronchoalveolar lavage and analysis of the lavage fluid, including cytological examination, microbiological (culture) examination for aerobic and facultatively anaerobic microorganisms, and microbiological (culture) examination for fungi (yeast and mold) to rule out infectious involvement and identify the causative agent [28].

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

• For patients with MCL at the initial diagnosis stage, during anti-tumor therapy response assessment, during remission follow-up/assessment, and when relapse/disease progression is suspected, it is recommended to perform whole-body positron emission tomography (PET) with tumor-tropic radiopharmaceuticals (fluorodeoxyglucose [18F]) in case of residual lesions after completion of high-dose therapy and autologous hematopoietic stem cell transplantation (auto-HSCT) to address the need for radiation therapy [29–31].

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

For all patients with MCL, to confirm the diagnosis prior to 1st-line anti-tumor therapy and when relapse/disease progression is suspected, it is recommended to mandatory perform a biopsy of a lymph node or other lesion site (gastric biopsy for gastric involvement, bone biopsy for bone involvement, etc.) followed by pathomorphological examination of the biopsy (surgical) material using immunohistochemical methods [1,18,24–26].

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

Comments. Lymphoma is diagnosed solely based on the morphological examination of a biopsy specimen obtained via excision biopsy of the most accessible lymph node, or a gastric, colonic, etc. biopsy. Core-needle biopsy is uninformative for diagnosis. Cytological examination alone of punctates or touch imprints from lymph nodes or other tumor sites is insufficient for nosological verification of lymphomas. Morphological examination is performed using histological and immunohistochemical methods. In addition, cytological, molecular biological, and genetic testing is required. Immunohistochemistry must include determination of the expression of the following antigens: CD3, CD5, CD10, CD20, CD21, CD23, BCL2, BCL6, CyclinD1, SOX11, and Ki-67. When possible, TP53 and LEF1 should also be determined (to distinguish between indolent and aggressive forms and for differential diagnosis of CLL, respectively).

2.5 Other Procedures

• For all patients with MCL presenting with lymphocytosis in the complete blood count or myelogram (regardless of the leukocyte count), it is recommended to perform biological material (peripheral blood or bone marrow) testing by flow cytometry to determine the extent of disease and treatment strategy [24–26].

GPP CLoE 5Grade of Recommendation – C (Level of Evidence – 5).

Comments. Performing flow cytometry (FCM) is advisable in the presence of lymphocytosis in the complete blood count (regardless of the leukocyte count) or in the myelogram, as well as when lymphoid cells, atypical lymphocytes, or cells with blast morphology predominate in pleural, ascitic, or other biological fluids. FCM allows for the rapid differential diagnosis of neoplastic and reactive lymphocytosis, which is important for determining further patient management and diagnostic tactics.

Performing bone marrow FCM makes it possible to detect involvement even in the absence of convincing signs of morphological involvement according to the myelogram data. The minimal FCM panel should include CD3, CD19, CD20, CD10, CD5, CD23, Ig-κ, and Ig-λ. Whenever possible, it is useful to assess the expression of CD200 by tumor cells. The level of cyclin D1 expression can only be studied via immunohistochemical (IHC) analysis of a bone marrow trephine biopsy or other tissue.

Materials suitable for FCM include blood cells, bone marrow, effusion fluids, bronchoalveolar lavage, cerebrospinal fluid, homogenized tissue samples (spleen, lymph nodes, etc.), and cell suspensions obtained from fine-needle aspiration biopsy of lymph nodes.

• In patients with mantle cell lymphoma (MCL) during initial evaluation and when relapse/disease progression is suspected, it is recommended to perform testing for 17p locus deletion by FISH and TP53 gene mutation status to determine treatment strategy [16,26].

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

• In patients with MCL before mobilization and collection of autologous hematopoietic stem cells (auto-HSC), during remission assessment, and at follow-up evaluations, it is recommended to test for minimal residual disease (MRD) using flow cytometry to determine the completeness of remission and the feasibility of auto-HSC harvesting only if MRD-negative remission is achieved [32,33].

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

• In patients with MCL prescribed radiation therapy, topographic and tomimetric planning of radiation therapy is recommended to determine the target volume [18].

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

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

It should be borne in mind that a patient may present with atypical disease manifestations as well as a combination of a specific disease with other pathologies, which may dictate changes by the attending physician in the algorithm for selecting optimal diagnostic and treatment tactics. The backbone of modern MCL treatment is immunochemotherapy followed by consolidation and maintenance therapy (Table 2) [34–37]. The use of (R)CHOP-like regimens has suboptimal efficacy: complete remissions (CR) are achieved in one-third of cases, and the median event-free survival (EFS) is 16–20 months. [34–36].

The main trends in MCL therapy over the past decade are:

1. Intensification of induction therapy with high-dose #cytarabine** (3–4 cycles of 12 g/m²/cycle) for patients younger than 60–65 years [38,39];

2. Widespread use of auto-HSCT as consolidation of 1st remission in patients younger than 60–65 years [40–42];

3. Use of combinations of intermediate-dose cytarabine** with #bendamustine** and platinum-based drugs [43,44];

4. Gradual exclusion of high-dose methotrexate** from intensive therapy protocols, primarily due to the lack of convincing data on its efficacy and high toxicity in elderly patients [45];

5. Replacement of vincristine** with bortezomib** in the CHOP-like regimen for patients older than 60–65 years (VR-CAP regimen) [46];

6. Use of maintenance therapy with monoclonal antibodies (rituximab**) following auto-HSCT and intermediate-dose induction therapy (R-CHOP) [47,48];

7. Introduction of Bruton's tyrosine kinase (BTK) inhibitors (ibrutinib**/acalabrutinib**/zanubrutinib) (ATC group – Bruton's tyrosine kinase (BTK) inhibitors), BCL2 inhibitors (ATC group – other antineoplastic agents), and immunomodulators (ATC group – other immunosuppressants) into clinical practice [49–54].

Based on the results of various studies, the use of monoclonal antibodies, high-dose induction therapy, and autologous hematopoietic stem cell transplantation (auto-HSCT) remain the most effective means of achieving complete remissions, prolonged event-free and overall survival in patients younger than 60–65 years, predominantly in the group without TP53 gene mutations [39–42].

The inclusion of high-dose cytarabine** in induction therapy regimens allows achieving an overall response rate (ORR) of 90–95%, with CR in at least half of the cases. The goal of high-dose consolidation with auto-HSCT support is to achieve molecular remission, which correlates with longer progression-free survival (PFS). No plateau is observed on the EFS curve, but about half of the patients survive past the 10-year mark following high-dose therapy [55].

Reducing the dose of cytarabine** in induction chemotherapy from 12 to 4 g/m² leads to a decrease in the median EFS from 5 to 3 years, although CR is achieved in 89% and 84% of cases, respectively. This prompts the search for an induction chemotherapy regimen with optimal tolerability and efficacy in comorbid patients aged 55–65 years. Alternatives to high doses of cytarabine** and methotrexate** may include chemotherapy courses comprising intermediate doses of cytarabine** with #cisplatin** (R-DHAP), #bendamustine** (R-BAC), and/or #bortezomib** (R-HAD+B)*. Their high efficacy has been demonstrated not only in relapsed and refractory settings but also in treatment-naïve patients [43,45,56,57].

According to the randomized TRIANGLE trial conducted by the European MCL Network, comparable efficacy was demonstrated for the R-CHOP/R-DHAP program with the integration of ibrutinib** in first-line MCL treatment, both with and without auto-HSCT. Subgroup analysis revealed a benefit for groups with blastoid morphology and high p53 protein expression specifically when ibrutinib**-integrated regimens were used. Despite the short follow-up periods, this treatment regimen can be recommended for patients under 60–65 years of age, especially when auto-HSCT is not feasible [58].

If auto-HSCT is not feasible, particularly in regional medical facilities, an alternative consolidation approach—the Dexa-BEAM program (substituting #lomustine** for carmustine** if unavailable, yielding Dexa-CEAM)—may be used [33].

For patients younger than 60–65 years with TP53 gene mutations, standard MCL treatment approaches are ineffective [16]. For this patient subgroup, it is rational to consider targeted therapy with Bruton's tyrosine kinase (BTK) and BCL2 inhibitors (ATC group – other antineoplastic agents) and consolidation using cellular therapy options (allogeneic hematopoietic stem cell transplantation (allo-HSCT) or CAR-T cell therapy) in the first-line setting [33,39,59,60]. According to the BOVen study, high efficacy of multi-targeted therapy was demonstrated in the treatment of TP53-mutated MCL. The combination of zanubrutinib, #venetoclax**, and #obinutuzumab** as first-line therapy in MCL patients with TP53 mutations achieved 1-year progression-free survival (PFS) and overall survival (OS) rates of 84% and 96%, respectively [61].

According to a study conducted at the National Research Center for Hematology of the Russian Ministry of Health, the use of standard MCL treatment approaches in patients younger than 60–65 years with a complex karyotype yielded a PFS rate of 48% [62]. For this subgroup of patients, it is also rational to consider integrating targeted therapy with Bruton's tyrosine kinase (BTK) and BCL2 inhibitors (ATC group – other antineoplastic agents) into first-line induction regimens, along with consolidation via auto-HSCT or CAR-T cell therapy. In the event of relapse after auto-HSCT or CAR-T cell therapy, early integration of allo-HSCT into the treatment plan is rational [33].

The median age of patients with mantle cell lymphoma (MCL) is around 65 years, which limits intensive therapy in at least half of the cases. Continuous research into new immunopolychemotherapy regimens has not established a definitive "gold standard," but any intensification is associated with toxicity. For example, the addition of intermediate-dose cytarabine** to the rituximab**-bendamustine** (R-BAC) regimen significantly improves induction therapy outcomes, but only in fit patients under 70–75 years of age. When intermediate-dose regimens (R-CHOP or R-B) are not feasible in patients with poor performance status, lenalidomide** with rituximab** or metronomic therapy such as R-PEPC can be used. In some cases, radiation therapy is an option, especially for stages I–II of the disease. Unsatisfactory outcomes with intermediate-dose therapy drive the active clinical integration of novel targeted agents, such as Bruton's tyrosine kinase (BTK) inhibitors (acalabrutinib**, zanubrutinib, ibrutinib**), whose mechanism of action blocks signal transduction from the B-cell receptor to the cell nucleus [49,63,64].

For elderly, comorbid MCL patients older than 65 years with TP53 gene mutations, the integration of targeted agents (BTK inhibitors [ibrutinib**/acalabrutinib**/zanubrutinib] and BCL2 inhibitors [ATC group: other antineoplastic agents] – #venetoclax**) followed by consolidation with CAR-T cell therapy in the first-line setting is a rational approach [51].

An important feature of MCL therapy is the slow achievement of response and, consequently, the necessity of administering 6 to 8 cycles of induction therapy. However, several studies have shown that intensive induction therapy (R-BAC/R-Hd-Ara-C, R-DHAP) reduces the number of cycles to 4, which demonstrates comparable efficacy and mitigates the increased toxicity risks associated with 6–8 cycles [33,39,62,65]. Thus, treatment selection depends primarily on the patient's age and performance status, the presence of adverse molecular-genetic prognostic factors, and the availability of intensive therapy across healthcare facilities at various levels.

Table 2. Therapy for MCL patients according to age and performance status (see Appendix A3)

3.1. Localized (I-II) stages

• For patients with verified stage I–II MCL and an asymptomatic indolent course, it is recommended to apply a "watch and wait" strategy [24–26].

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

• For patients with verified stage I–II MCL without massive lymphadenopathy and risk factors, 4–6 cycles of R-CHOP chemotherapy and localized radiation therapy at a total focal dose (TFD) of 30 Gy upon achieving complete remission, or 36–40 Gy upon a partial response, may be used as first-line therapy [26].

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

Comments. With the advent of highly sensitive diagnostic methods, stage I–II in MCL is diagnosed extremely rarely (in 1–3% of cases). Standard therapy has not been established. Combined chemo-radiation therapy achieves remissions in 95% of patients.

• For patients under 60 years of age with verified stage I–II MCL with massive lymphadenopathy and/or adverse prognostic factors (see section 7.1), it is recommended to administer induction therapy according to the principles of treating advanced stages [25,26].

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

3.2. Patients under 65 years of age with good performance status who are candidates for high-dose therapy, first-line therapy.

• For patients under 65 years of age with verified MCL without significant comorbidities who are candidates for high-dose therapy, it is recommended to administer induction therapy using high doses of cytarabine** [39,66].

GRL ALEL 2Grade of Recommendation – A (Level of Evidence – 2).

Comments. The preferred induction therapy option is rotational regimens using #bendamustine** and high-dose cytarabine** (R-BAC/R-HD-Ara-C), whose high efficacy allows reducing the number of cycles to 4 with an acceptable toxicity profile [39]. A number of European researchers adhere to induction regimens that include intermediate doses of cytarabine** in combination with #cisplatin** (R-CHOP/R-DHAP) [67]. American studies predominantly propose using protocols R-Hyper-CVAD/R-HMA [38, 68, 69], R-MaxiCHOP/R-HD-Ara-C [69, 70] – see Appendix A3. If there is a high risk of tumor lysis syndrome, especially with hyperleukocytosis >50.0 x 10⁹/L, rituximab** may be omitted from the first cycle, or a pre-phase with cyclophosphamide** and dexamethasone** may be administered.

• For patients under 65 years of age with verified high-risk MCL with TP53 gene mutations, it is recommended to use multi-targeted therapy with the BTKi ibrutinib** in combination with #venetoclax** and CD20 (cluster of differentiation 20) inhibitors (rituximab** / #obinutuzumab**) [71].

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

Comment. Studies have shown that in patients with TP53 gene mutations, progression-free survival (PFS) and overall survival (OS) rates with standard treatment approaches are 0.8 and 1.2 years, respectively [16]. The most effective therapeutic strategy for this patient group is multi-targeted induction therapy.

• For patients under 65 years of age with verified high-risk MCL with TP53 gene mutations, it is recommended to use multi-targeted therapy with the BTKi acalabrutinib** in combination with #venetoclax** and CD20 (cluster of differentiation 20) inhibitors (rituximab** / #obinutuzumab**) [72–74].

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

• For patients under 65 years of age with verified high-risk MCL with TP53 gene mutations, it is recommended to use multi-targeted therapy with the BTKi zanubrutinib in combination with #venetoclax** and CD20 (cluster of differentiation 20) inhibitors (rituximab** / #obinutuzumab**) [61].

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

• For patients younger than 65 years with mantle cell lymphoma (MCL) from the high-risk group with a complex karyotype and 17p13 deletion, who are considered high-risk patients, it is recommended to administer therapy according to the R-BAC/R-HD-Ara-C regimen in combination with a BTKi and a BCL2i (ATC group – other antineoplastic agents) [33].

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

• For patients with verified MCL younger than 65 years without significant comorbidity, from the low- or intermediate-risk group who are not candidates for autologous hematopoietic stem cell transplantation (auto-HSCT), it is recommended to administer therapy according to the R-CHOP/R-DHAP regimen with the integration of ibrutinib** during the induction and maintenance phases of treatment without performing auto-HSCT [58].

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

Commentary. For patients with verified MCL younger than 65 years without significant comorbidity, as an alternative to auto-HSCT, intensive treatment regimens with the integration of targeted drugs followed by maintenance therapy can be used. Similar regimens with or without auto-HSCT can be applied when feasible in MCL patients younger than 65 years with a complex karyotype, blastoid morphology, 17p13 deletion, or a high proliferation index (greater than 30%). According to the randomized TRIANGLE trial, comparable efficacy was demonstrated for the R-CHOP/R-DHAP regimen with ibrutinib** and subsequent maintenance therapy with ibrutinib** and rituximab** with or without auto-HSCT [58]. As alternative regimens, the R-BAC/R-HD-Ara-C regimen with the integration of ibrutinib** +/- #venetoclax** can be used [33]. In the absence of ibrutinib** or in the presence of cardiac pathology (primarily a history of atrial fibrillation), the integration of next-generation BTKis (acalabrutinib**/zanubrutinib) is possible.

• For patients with verified MCL younger than 65 years without significant comorbidity who are candidates for high-dose therapy and auto-HSCT, it is recommended upon achieving a partial remission (PR) or complete remission (CR) to perform auto-HSCT within this algorithm [40–42,66]:

- collection of autologous hematopoietic stem cells (bone marrow harvest or hematopoietic cell cytapheresis) with in vivo graft purging to eliminate potential contamination with CD20+ cells using rituximab**;

- mobilization and collection of hematopoietic stem cells are performed upon achieving bone marrow clearance, confirmed by flow cytometry (minimal residual disease) and molecular genetic analysis of the bone marrow (B-cell clonality) after the cycle of therapy in which MRD negativity was achieved;

- conditioning regimen of the transplant center's choice (BEAM is the preferred regimen);

- transplantation of autologous hematopoietic stem cells (auto-HSCT).

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

Commentaries. Upon achieving complete remission, BEAM±R conditioning provides the best efficacy and safety. Due to irregular supplies of carmustine**, #lomustine** or bendamustine** 140 mg/m² once can be used in the conditioning regimen.

• For patients with verified MCL younger than 65 years without significant comorbidity, when auto-HSCT cannot be performed, it is recommended to administer the Dexa-BEAM regimen as consolidation [33].

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

Commentary. when auto-HSCT cannot be performed in medical facilities of various levels, the Dexa-BEAM program is recommended as an alternative consolidating approach (in the absence of carmustine**, substitution with #lomustine** is possible).

• For patients with verified MCL younger than 65 years without significant comorbidity after high-dose therapy and auto-HSCT, it is recommended to perform follow-up evaluations – CT, and if necessary – ultrasound (US), positron emission tomography combined with computed tomography using tumor-tropic radiopharmaceuticals ([18F]FDG-PET/CT), as well as monitoring of minimal residual disease in peripheral blood and bone marrow [25,26,32,75].

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

Commentaries. Endoscopic examination methods, especially colonoscopy, should be performed in patients with GI tract involvement once every 6 months. PET/CT scans should be performed once every 12 months. Most relapses occur within the first 3 years after auto-HSCT. Follow-up monitoring after auto-HSCT is carried out for at least 5 years with an interval of 3–6 months.

• For patients younger than 65 years with verified MCL with a blastoid variant of the disease, hyperleukocytosis, a mutation in the TP53 gene, and/or symptoms of CNS involvement, it is recommended to perform neuroleukemia prophylaxis – lumbar punctures with intrathecal administration of drugs in accordance with the recommendations for aggressive high-risk CNS non-follicular B-cell lymphomas [24,76].

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

• For patients younger than 65 years with MCL carrying a TP53 gene mutation, who are considered ultra-high-risk patients, following induction therapy, it is recommended to consult a transplant center to evaluate the possibility of allogeneic hematopoietic stem cell transplantation in the 1st remission of the disease [77, 78].

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

Commentaries. When performing allo-HSCT, auto-HSCT should be omitted.

• For patients with MCL carrying TP53 gene mutations who are considered ultra-high-risk patients, it is recommended to consider CAR-T cell therapy in the 1st remission of the disease [60].

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

Commentaries. CAR-T cell therapy may be considered only in individual cases at specialized licensed centers with the capability to perform it.

• For patients with verified MCL younger than 65 years without significant comorbidity after high-dose therapy and auto-HSCT, it is recommended to administer maintenance therapy with rituximab** 375 mg/m² IV once every 2 months for 3 years or longer [65].

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

Commentaries. In a randomized study by Le Gouill et al., the group of patients receiving rituximab** maintenance therapy starting 3 months after auto-HSCT showed a statistically significant improvement in EFS and OS compared to patients without maintenance therapy [65].

• For patients with verified MCL younger than 65 years without significant comorbidity after induction therapy and +/- auto-HSCT, it is recommended to administer maintenance therapy with rituximab** 375 mg/m² IV once every 2 months for up to 3 years or longer in combination with a BTKi (ibrutinib**/acalabrutinib**/zanubrutinib) until disease progression or unacceptable toxicity [58,79,80].

ibrutinib** – Level of evidence – B (Quality of evidence – 2).

acalabrutinib**/zanubrutinib – Level of evidence – C (Quality of evidence – 4).

3.3. Advanced stages in patients older than 65 years and patients who are not candidates for intensive therapy, first-line therapy.

The goal of therapy in this group is to achieve remission and maintain it with non-chemotherapeutic agents. The choice of tactics is primarily determined by the patient's performance status, presence of comorbidities, signs of renal failure, and unfavorable prognostic factors, primarily the TP53 gene mutation. Patients receive 4-8 cycles of induction chemotherapy followed by rituximab** maintenance for up to 5 years or longer. In some cases, somatically fit patients under 70 years of age may undergo auto-HSCT (BEAM-R conditioning regimen) [81].

• For patients with verified MCL older than 60–65 years in satisfactory physical condition who are nevertheless not candidates for intensive therapy, it is recommended to administer one of the following treatment regimens (at the discretion of the attending physician and the patient; for regimen descriptions, see Appendix A3):

- #Bendamustine**-containing regimens, R-BAC, RiBVD, RB (6 cycles) [43,44,82,83];

R-BAC, RiBVD – Level of recommendations – 4 (Quality of evidence – C).

RB – Level of recommendations – 2 (Quality of evidence – B).

- R-CHOP (8 cycles) – suboptimal response to therapy [46];

- VR-CAP (6 or 8 cycles) [84].

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

Comments. In a prospective randomized study, the efficacy of the R-B regimen was superior to R-CHOP with a more favorable toxicity profile: the median progression-free survival was 35.4 months vs. 22.1 months, respectively. However, with longer follow-up, the efficacy of both regimens was similar. The use of fludarabine** in 1st-line therapy is impractical due to high toxicity and prolonged bone marrow hypoplasia. More intensive induction options include the R-BAC scheme (rituximab** 375 mg/m² on days 0 or 1, #bendamustine** 70 mg/m² on days 1–2, and #cytarabine** 500 mg/m⁴ on days 2–4 once daily, six 28-day cycles) [85]. The use of more intensive therapy regimens is associated with high toxicity and the inability to complete the treatment plan, which negatively impacts the achievement of partial and complete remissions. Another therapy regimen used quite intensively in France is the RiBVD combination – rituximab** 375 mg/m² on day 1, #bendamustine** 90 mg/m² on days 1–2, #bortezomib** 1.3 mg/m² on days 1, 4, 8, and 11, and dexamethasone** 40 mg on day 1 once, six 28-day cycles [81]. The complete remission rate is 75%, and progression-free survival reaches 70% at 2 years. The VR-CAP regimen, involving the inclusion of bortezomib** at a dose of 1.3 mg/m² s.c. on days 1, 4, 8, and 11 in the R-CHOP regimen (excluding vincristine**), demonstrated an improvement in not only PFS but also OS with a moderate increase in toxicity and reversible episodes of polyneuropathy.

• Elderly comorbid patients with MCL and a TP53 gene mutation are recommended to undergo targeted therapy with BTKi and BCL2 inhibitors (ATC group: other antineoplastic agents) (ibrutinib**/acalabrutinib**/zanubrutinib + #venetoclax**). In addition, integrating targeted drugs into existing treatment regimens (R-BAC₅₀₀/R-B + BTKi +/- BCL2i) may be considered [51].

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

• In patients with MCL older than 65 years, with mutations in the TP53 gene, who are classified as ultra-high-risk patients, it is recommended to consider CAR-T cell therapy during the first remission of the disease [51].

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

Comments. CAR-T cell therapy may be considered only in individual cases at specialized licensed centers equipped to administer it.

• Patients with verified MCL older than 65 years with severe comorbidities are recommended to undergo one of the following treatment regimens (chosen by the attending physician; for regimen descriptions, see Appendix A3):

- R-CVP [46, 80];

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

- Lenalidomide** + rituximab** (lenalidomide** 25 mg (dose reduction for decreased creatinine clearance) on days 1–21 of a 28-day cycle) [50,86].

- Rituximab** + ibrutinib**/acalabrutinib**/zanubrutinib (ibrutinib** 560 mg until progression, acalabrutinib** 200 mg until progression, zanubrutinib 320 mg until progression) [53,54,75].

- Acalabrutinib** 200 mg – Level of evidence – C (Level of certainty of data – 4).

- Zanubrutinib 320 mg – Level of evidence – B (Level of certainty of data – 2).

Comments. Participation in 1st-line clinical trials is possible, as the use of novel low-toxicity targeted agents will likely increase overall survival in this patient group.

• Patients with verified MCL older than 65 years who are not candidates for intensive therapy, upon achieving remission after 1st-line treatment, are recommended maintenance therapy with rituximab** every 2 months at a dose of 375 mg/m² until disease progression [87].

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

• Patients with verified MCL older than 65 years are recommended maintenance therapy with rituximab** 375 mg/m² i.v. once every 2 months for up to 3 years or more in combination with BTKi and/or BCL2i (ATC group: other antineoplastic agents) (ibrutinib**/acalabrutinib**/zanubrutinib) until progression or intolerance [53,88,89].

For combination with acalabrutinib**/zanubrutinib – Level of evidence C (Level of certainty of data – 4).

For combination with ibrutinib** – Level of evidence B (Level of certainty of data – 2).

• Patients older than 65 years with verified MCL with a blastoid variant of the disease, hyperleukocytosis, and/or symptoms of CNS involvement are recommended neuroleukemia prophylaxis – lumbar punctures with intrathecal drug administration in accordance with recommendations for aggressive non-follicular B-cell lymphomas with a high risk of CNS involvement [24,76].

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

3.4. Therapy of relapsed and refractory forms

Relapse therapy is determined by the induction therapy regimen and the duration of remission.

• Patients with relapsed MCL are recommended one of the following therapeutic approaches (for regimen descriptions, see Appendix A3) [90]:

- combinations of #bendamustine** with rituximab** (BR) [91,92]

Level of Evidence BLevel of Confidence 2Level of recommendation B (level of evidence – 2).

- combinations of #bendamustine** with rituximab** and cytarabine** (R-BAC) [43]

GPP CLOE 4Grade of Recommendation C (Level of Evidence – 4).

- combinations of #bendamustine** with rituximab** and #bortezomib** in patients with relapses after high-dose cytarabine** and autologous HSCT [93];

GPP CLOE 4Grade of Recommendation C (Level of Evidence – 4).

- R-Hyper-CVAD/R-HMA [94] with possible integration of BTKi and/or BCL2i

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

- #R-DHAP+/- BTKi/BCL2i [95]

- Acalabrutinib** monotherapy [96,97];

Level of Evidence BGrade of Recommendation 3Level of Clinical Effectiveness – B (level of evidence – 3)

- Zanubrutinib monotherapy [98,99];

- Ibrutinib** monotherapy or in combination with rituximab** [100–103];

- High/intermediate doses of cytarabine** + #bortezomib** (R-HAD-B) in patients who received only CHOP-like or fludarabine**-containing regimens as 1st-line therapy [57];

- Gemcitabine**-containing regimens (R-GemOx, R-GIFOX) in patients with relapses after high-dose cytarabine** and auto-HSCT [104,105];

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

- Lenalidomide** monotherapy [106,107];

GCR BLEL 2Grade of Recommendation – B (Level of Evidence – 2)

- Lenalidomide** in combination with rituximab** [106,107];

- #Venetoclax** (upon progression after BTK inhibitors) [108,109];

- Ibrutinib**/acalabrutinib**/zanubrutinib + #venetoclax** (in case of aggressive relapse, blastoid variant, TP53 mutation) +/- anti-CD20 monoclonal antibodies (rituximab**/#obinutuzumab**). The BTK inhibitor is used until progression, #venetoclax** is used until progression at a dose of 400 mg daily [61,72,74,110,111];

- Ibrutinib**/lenalidomide** + rituximab** [112];

- #Venetoclax** + lenalidomide** + rituximab** [113].

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

• Patients with relapsed MCL after a prolonged (more than 3 years) remission who have not previously received high-dose chemotherapy with auto-HSCT, in case of a response to 2nd-line therapy, are recommended consolidation with high-dose chemotherapy and auto-HSCT [90].

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

• Patients under 60 years of age with relapsed MCL are recommended a consultation at a transplantation center regarding the possibility of allogeneic bone marrow transplantation and, if feasible (no contraindications, suitable donor available, chemosensitive relapse), undergoing allo-HSCT with a non-myeloablative conditioning regimen or, if possible, CAR-T cell therapy [114,115].

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

Comments. The use of ibrutinib** proved more effective compared to #bendamustine**-containing regimens when relapse occurred within the first 24 months. When relapse occurred after 24 months from the completion of CHT, the efficacy of ibrutinib** monotherapy was similar to #bendamustine**-containing regimens [116]. Several small studies demonstrate the efficacy of #venetoclax** monotherapy and the R-BAC scheme in case of relapse or refractory disease after BTK inhibitor therapy [117–123].

Acalabrutinib**. In a phase II study involving 124 patients with R/R MCL, at a median follow-up of 15 months, acalabrutinib** therapy achieved an ORR of 81% (CR rate was 40%) [96]. The 12-month PFS and OS were 67% and 87%, respectively. With longer follow-up (more than 24 months), the data were confirmed – the median PFS was 20 months, and the 24-month OS was 72% [124].

Ibrutinib** ± rituximab**. As monotherapy or in combination with rituximab**, ibrutinib** allows achieving sustained responses in patients with R/R MCL even after multiple lines of therapy [100–103]. At a median follow-up of 27 months, the ORR was 67% (CR 23%) with a median response duration of 18 months [101]. The 24-month PFS and OS were 31% and 47%, respectively.

Zanubrutinib. The efficacy of the drug was evaluated in two multicenter studies (a phase II study including 86 patients with R/R MCL and a phase I study including 48 patients, of whom 37 had R/R MCL) [98,99]. The ORR was 85% (CR 77%) and 87% (30% CR) in these two studies, respectively. At a median follow-up of 14 and 16 months, discontinuation of therapy due to progression was required in 22% and 33% of cases, respectively. The median PFS was 17 and 15 months, respectively [125].

Lenalidomide** + rituximab**. The combination of lenalidomide** and rituximab** achieved an overall response (OR) rate of 57% and complete response (CR) in 36% of patients [126]. The medians of response duration, progression-free survival (PFS), and overall survival (OS) were 19, 11, and 24 months, respectively. The efficacy of lenalidomide** monotherapy in relapsed/refractory mantle cell lymphoma (R/R MCL) was demonstrated in the multicenter phase II study MCL-001 (EMERGE) [104, 127, 128]. The medians of PFS and OS were 4 and 19 months, respectively [127]. In the multicenter MCL-002 (SPRINT) study, with a median follow-up of 16 months, lenalidomide** therapy statistically significantly improved PFS compared with investigator's choice (9 months vs. 5 months; p = 0.004) [106].

#Bendamustine** + rituximab**. In a multicenter phase II study involving 67 patients with indolent lymphomas and MCL (n=12), the use of the BR combination achieved an OR rate of 92% (CR 41%) [129]. The phase III StiL study, which included 219 patients with R/R follicular and indolent lymphomas and MCL (20%), demonstrated the superiority of the BR regimen over the combination of fludarabine** and rituximab** [130]. At a median follow-up of 96 months, the median PFS was 34 months versus 12 months (p < 0.0001).

#Bortezomib** ± rituximab**. In the phase II PINNACLE study, bortezomib** monotherapy achieved an OR in 33% of patients (CR in 8%) with a median response duration of 9 months [131]. The efficacy of the combination of #bortezomib** and rituximab** was demonstrated in a heavily pretreated group of patients with R/R MCL in a phase II study [132]. The OR rate was 40% for all 25 patients and 29% for patients with R/R MCL. The estimated 2-year PFS was 24% for all patients and 60% for patients who achieved a response.

Ibrutinib** + lenalidomide** + rituximab**. The OR rate with the combination of ibrutinib**, rituximab**, and lenalidomide** was 76% (CR 56%) at a median follow-up of 18 months [112].

#Venetoclax** + ibrutinib**. The inclusion of the combination of ibrutinib** and #venetoclax** is based on data from a phase II study in a group of patients with R/R MCL with an extremely poor prognosis (TP53 gene aberrations, high risk according to the MIPI scale) [110]. The CR rate was 42% by 16 weeks of therapy compared to 9% with ibrutinib** monotherapy in earlier studies in this prognostically unfavorable patient group (p < 0.001). In 78% of patients who achieved a response, its duration exceeded 15 months.

#Venetoclax**. The inclusion of this drug in clinical guidelines is based on the results of a phase I study evaluating the efficacy and safety of #venetoclax** in the treatment of patients with R/R non-Hodgkin lymphomas (n = 106, including 28 patients with MCL). The expected 12-month OS for the entire patient group was 70%, while for patients with R/R MCL it was 82%. High tumor burden, including in patients with MCL, is associated with the risk of tumor lysis syndrome. In this case, therapy may be started at 20 mg #venetoclax** daily with a gradual dose escalation to 400 mg daily over 5 weeks [117, 133].

Allogeneic hematopoietic stem cell transplantation (allo-HSCT). In a subgroup analysis of patients with MCL who underwent HSCT at the MD Anderson Cancer Center, the use of allo-HSCT (RIC, n = 35) in patients with R/R MCL showed satisfactory long-term results [134]. The majority of patients (62%) achieved CR prior to allo-HSCT (31% in second remission). The median PFS was 60 months, and the 6-year PFS and OS were 46% and 53%, respectively. The 3-month and 1-year transplant-related mortality (TRM) rates were 0% and 9%, respectively [134].

In another study evaluating the efficacy of allo-HSCT (RIC) in 33 patients with R/R MCL (42% of whom had a history of high-dose chemotherapy and auto-HSCT), the 2-year relapse-free survival and OS were 60% and 65%, respectively [135]. With a median follow-up of nearly 25 months, none of the 13 patients who received allo-HSCT after achieving a CR relapsed.

Thus, allo-HSCT is a potentially curative option for eligible patients with R/R MCL, provided that remission is achieved prior to the HSCT stage following second-line therapy [136].

CAR-T cell therapy

The key study evaluating the efficacy of anti-CD19 CAR-T cell therapy in patients with MCL is ZUMA-2. The study showed that at a median follow-up of 35.6 months, the overall response rate and CR were 91% and 68%, respectively. For the overall patient group, the median PFS and OS were 25.8 and 46.6 months, respectively. In patients who achieved CR, the median progression-free survival was 48 months. Furthermore, a subgroup analysis demonstrated that in patients with a TP53 gene mutation, the median PFS after CAR-T cell therapy was not reached [115].

3.5. Supportive Care

• For MCL patients with massive tumor burden, it is recommended to provide prophylaxis and treatment for tumor lysis syndrome: oral #allopurinol** – 100–900 mg/day (frequency: 2–4 times/day after meals) and infusion therapy 3 L/m²/day with alkalinization using a 4% sodium bicarbonate** solution 40–80 mmol/L under diuresis monitoring, planned administration of #furosemide**, and laboratory monitoring (acid-base status and blood gas analysis) [135,136,140].

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

• For MCL patients receiving glucocorticoids, it is recommended to provide prophylaxis for gastric and duodenal ulcers [140].

GCR BLEL 1Grade of Recommendation – B (Level of Evidence – 1)

Comments. Gastric or duodenal ulcer is one of the serious side effects of glucocorticoid therapy (included in the prevention of complications of antithymocyte globulin**). Due to their ulcerogenic potential, antisecretory therapy is necessary when using glucocorticoids to prevent steroid ulcers. According to a meta-analysis of 300 studies [141], gastric and duodenal ulcers scar in almost all cases if the intragastric pH is maintained above 3 throughout the day for 18 hours. According to one of the recent meta-analyses, the use of proton pump inhibitors (PPIs) or H2-receptor antagonists is significantly more effective in achieving ulcer scar healing and reducing the risk of rebleeding [139,140].

• For MCL patients receiving antitumor chemotherapy or radiation therapy, it is recommended to use antiemetic drugs (serotonin 5-HT3 receptor antagonists, NK-1 receptor antagonists (ATC A04AD Other antiemetics), glucocorticoids, gastrointestinal motility stimulators (metoclopramide**), anxiolytics, antipsychotics, proton pump inhibitors, H2-receptor antagonists) to prevent nausea and vomiting [144–146].

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

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

• For MCL patients undergoing chemoimmunotherapy regimens with a high risk of febrile neutropenia (FN) exceeding 20% (R-CHOP, DA-R-EPOCH, R-Hyper-CVAD, DHAP, ESHAP, ICE, GDP, MINE, R-BAC, R-BAC/R-Hd-Ara-C regimens) or with an intermediate risk of FN of 10–20% in the presence of risk factors (age >65 years; severe comorbidities; renal or hepatic failure; hemoglobin less than 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 tumor involvement; HIV infection), primary prophylaxis of febrile neutropenia with G-CSF preparations of the L03AA Colony-stimulating factors group according to the ATC classification is recommended [147].

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

Comments. Prophylactic administration of colony-stimulating factors (G-CSF): filgrastim** 5 mcg/kg subcutaneously (s/c) 24–72 hours after the end of antineoplastic drug administration and until neutrophil counts recover to normal after 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 end of antineoplastic drug administration in accordance with the instructions for medical use, for the purpose of preventing and treating neutropenia induced by cytotoxic tumor chemotherapy.

• For patients with malignant lymphomas following a previously documented episode of febrile neutropenia (FN) or dose-limiting afebrile neutropenia (after a single episode of cycle interval prolongation and/or dose reduction), secondary prophylaxis of febrile neutropenia with G-CSF agents belonging to the L03AA colony-stimulating factors group according to the ATC classification is recommended [147].

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

Comments. prophylactic administration of colony-stimulating factors (G-CSF): filgrastim** 5 mcg/kg subcutaneously (s/c) 24–72 hours after the completion of antineoplastic drug administration and until neutrophil counts recover from the nadir, or pegfilgrastim at a dose of 6 mg, or empegfilgrastim** at a dose of 7.5 mg subcutaneously, single dose, at least 24 hours after the completion of antineoplastic drug administration in accordance with the instructions for medical use for the purpose of preventing the development and treating neutropenia caused by cytotoxic chemotherapy of tumors.

• For patients with malignant lymphomas with planned intensive chemotherapy regimens, it is recommended to place a central venous catheter for chemotherapy and supportive care (see section 7.11) [148].

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

• For patients with malignant lymphomas and newly diagnosed symptomatic hypogammaglobulinemia (prior severe infection, IgG <4 g/L), replacement therapy with normal human immunoglobulin** 0.2–0.4 g/kg IV every 3–4 weeks for 12 months for the treatment of secondary immunodeficiency is recommended [150, 151].

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

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

• For patients with malignant lymphomas and risk factors for thrombotic complications, for the purpose of preventing venous thromboembolic complications, it is recommended to use anticoagulants (B01 Antithrombotic agents according to the ATC classification) and physical methods (elastic compression of the lower extremities, intermittent pneumatic compression of the lower extremities) [152, 153].

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

• For patients with malignant lymphomas undergoing cytotoxic chemotherapy, in the event of a risk of mucositis or the development of mucositis, the use of glucocorticoids, somatostatin and analogues, antidiarrheal, intestinal anti-inflammatory and antimicrobial drugs, antiprotozoal drugs, glycopeptide antibiotics, local anesthetics, antidepressants, and nasogastric tube placement is recommended for prophylactic and therapeutic purposes [154, 155].

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 with malignant lymphomas undergoing cytotoxic chemotherapy, for the prevention of water and electrolyte disturbances, nutritional support with parenteral micronutrient complexes, crystalline amino acid solutions, carbohydrate solutions, fat emulsions, and ready-to-use balanced oral mixtures (polymeric, oligomeric) is recommended depending on the type of nutritional disorder [156, 157].

GCR BLEL 1Grade of Recommendation – B (Level of Evidence – 1)

• For patients of reproductive age with malignant lymphomas, it is recommended to discuss the possibility of sperm or oocyte/embryo cryopreservation prior to starting therapy [157].

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

• For female patients with malignant lymphomas—girls and young women in whom pelvic radiation therapy is planned—it is recommended to consider the need for homilateral oophoropexy for ovarian protection [158].

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 to a total focal dose (TFD) 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 before initiating radiation therapy to the subdiaphragmatic region.

• For patients with malignant lymphomas undergoing cytotoxic chemotherapy, for the prevention of tumor lysis syndrome, in the event of dehydration, infectious, toxic, and hemorrhagic complications, or electrolyte disturbances, infusion therapy is recommended [159].

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

• For patients with malignant lymphomas undergoing cytotoxic chemotherapy, in the event of hemorrhagic, infectious complications, anemia, or thrombocytopenia induced by intensive chemotherapy, or for therapeutic purposes in patients with pre-existing hemorrhagic complications, for volume replacement during plasmapheresis procedures in hyperleukocytosis, and when performing various procedures (trephine biopsy, lumbar puncture, central venous catheter placement, etc.) under conditions of thrombocytopenia, replacement blood transfusion therapy with platelet concentrate, red blood cell suspension, fresh frozen plasma (FFP), coagulation factor VIII (B02BD according to the ATC classification), protease inhibitors, and antifibrinolytic agents (B02A according to the ATC classification) is recommended [160].

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

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

- leukoreduced — leukocyte content in the transfused medium dose is reduced to 1 × 10⁶ cells;

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

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

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

- The main reactions and complications associated with the transfusion of donor blood components are presented in Section A3 Reference Information.

• For patients with malignant lymphomas undergoing cytotoxic chemotherapy, in the event of toxic and infectious complications, electrolyte disturbances, the need for parenteral nutrition, blood sampling, etc., vascular access is recommended [161].

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

In patients with malignant lymphomas receiving cytotoxic chemotherapy, during inter-cycle intervals, after hematopoietic stem cell transplantation, and during targeted and cellular therapy, various critical conditions may develop due to a variety of causes. Critical syndromes requiring transfer to the intensive care unit (ICU) include: sepsis, septic shock (SS), acute respiratory failure, acute renal failure, ischemic or hemorrhagic acute cerebrovascular accident (stroke), tumor lysis syndrome, life-threatening cardiac arrhythmia, and massive gastrointestinal bleeding. To treat life-threatening complications in hematologic patients in the ICU, the following life support methods are most commonly used: mechanical ventilation in 50–66% of patients; vasopressor therapy in 8–75.6% of patients; renal replacement therapy in 3.2–61% of patients [163, 164].

3.6. Assessment of treatment response

• For all patients with malignant lymphomas after each cycle of chemotherapy and after the induction treatment course, as well as upon completion of the entire treatment program (chemotherapy or chemo-radiotherapy, maintenance therapy, etc.), response assessment is recommended in accordance with standard lymphoma treatment response criteria (see section 7.2 of these guidelines) [18, 165].

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

Comments. Additional evaluation during the induction course to assess therapeutic efficacy is performed when indicated due to suspected insufficient efficacy.

Treatment response assessment is performed in accordance with the updated criteria proposed by the International Working Group on Lymphoma in 2007 [164].

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 the greatest transverse diameter if baseline lymph node size was greater than 1.5 cm

   2. ≤1.0 cm in the greatest transverse diameter if baseline lymph node size was 1.5–1.1 cm

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

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

Complete response (CR) is considered confirmed if the achieved response persists for at least 2 weeks or further improvement is documented.

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

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

• 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. Absence of new lesions, absence of signs of enlargement of any previously diagnosed lesions.

3. In cases of initial bone marrow involvement, the bone marrow status is not significant for determining complete response (CR). However, if bone marrow involvement persists during and/or after completion of treatment, clarification of the characteristics of the tumor cells is mandatory. Patients with initial bone marrow involvement who achieve a clinical CR after completion of treatment, but in whom bone marrow involvement persists or cannot be assessed, are classified as having a partial response (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.

4. Medical Rehabilitation and Sanatorium-Resort Treatment

• Patients with mantle cell lymphoma (MCL) at all stages of disease therapy, as well as after completion of medical treatment, are recommended to undergo comprehensive rehabilitation [165].

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

Comments. There are no special rehabilitation methods for MCL. Rehabilitation of patients with MCL should be comprehensive, covering medical and socio-psychological aspects of the patient's adaptation to normal life. Rehabilitation programs are developed individually, depending on the identified complications of medical treatment, comorbid conditions, and social and psychological problems.

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

5. Prevention and Dispensary Observation

Currently, there are no methods for the prevention of MCL, as the etiological factors leading to the development of the disease are unknown.

• All patients with MCL throughout their lifetime—both during treatment and off-treatment—are recommended to follow the hematologist's prescriptions for treatment, avoid factors provoking the disease, modify the type and conditions of labor to non-hazardous and light work, limit insolation and physiotherapeutic treatment methods, and plan pregnancy [24, 90].

GCR CLEL 5Grade of Recommendations — C (Level of Evidence — 5).

Comments. Dispanserization (active clinical monitoring) by a hematologist or oncologist is carried out during treatment and after achieving lymphoma remission.

6. Organization of Medical Care

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

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

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

3. based on these clinical guidelines;

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

Primary specialized health care is provided by a hematologist/oncologist and other medical specialists at an outpatient hematological/oncological center or in a primary hematological/oncological office, primary hematological department, or the outpatient department of an oncological dispensary.

When MCL is detected or suspected in a patient, general practitioners, district general practitioners, general family physicians, medical specialists, and secondary medical personnel shall refer the patient in the established manner for a consultation at an outpatient hematological/oncological center or a primary hematological office or department of a medical organization to receive primary specialized health care.

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

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

When MCL 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 diseases to determine management tactics and the need for additional specialized anti-tumor treatment methods.

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

In a medical organization providing medical care to patients with MCL, the tactics of medical examination and treatment are established by hematologists/oncologists, involving other medical specialists if necessary, and through a medical panel (konsilium) when indicated. The decision of the medical panel is formalized in a protocol, signed by its participants, and entered into the patient's medical documentation.

Indications for hospitalization in a 24-hour or day hospital of a medical organization providing specialized, including high-tech, medical care in the fields of hematology and oncology are determined by a hematologist/oncologist or a medical panel, with the involvement of other medical specialists if necessary.

Indications for planned hospitalization:

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

2. Examination of the patient, including biopsies 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 inpatient unit is not strictly mandatory).

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

3. 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 the treatment course.

2. Completion of examination.

3. Achievement of the expected treatment effect.

4. In cases where, by decision of the medical commission, the patient's stay in the hospital is not indicated due to the futility of treatment and the necessity of providing palliative care only.

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

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

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

2. Poddubnaya Irina Vladimirovna – Academician of the RAS, Honored Worker of Education of the RF, MD, Professor, Head of the Department of Oncology and Palliative Medicine, Vice-Rector for Clinical Work and International Cooperation of the Russian Medical Academy of Continuous Professional Education of the Russian Ministry of Health, Chairman of the Russian Society of Oncohematologists.

3. Zvonkov Evgeny Evgenievich – MD, 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 Medical Research Center for Hematology of the Russian Ministry of Health, Member of the Association for the Promotion of Hematology and Bone Marrow Transplantation «National Hematological Society».

4. Tumyan Gayane Sergeevna – MD, Professor, Professor at the Department of Oncology and Palliative Medicine, Russian Medical Academy of Continuous Professional Education of the Russian Ministry of Health, Leading Researcher at the Chemotherapy Department of Hemoblastoses, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health, Board Member of the Russian Society of Oncohematologists.

5. Natalia A. Falaleeva – MD, PhD, Head of the Department of Antitumor Drug Therapy, A.F. Tsyb Medical Radiological Research Center – branch of the National Medical Research Radiological Center of the Russian Ministry of Health, Member of the Association of Oncologists of Russia and the Russian Association of Therapeutic Radiation Oncologists.

6. Koroleva Daria Aleksandrovna – PhD, Hematologist at the Department of Hematology and Lymphoma Chemotherapy with a Bone Marrow and Hematopoietic Stem Cell Transplantation Unit, 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 «National Hematological Society».

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

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

9. 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.

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

11. Mikhailova Natalia Borisovna – PhD, Head of the Department of Clinical Oncology, R.M. Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantology, Member of the Russian Society of Oncohematologists.

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

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

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

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

    Allogeneic Hematopoietic Stem Cell Transplantation Section

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

17. Kuzmina Larisa Anatolyevna – PhD, Head of the Department of Hemoblastosis Chemotherapy and Bone Marrow and Hematopoietic Stem Cell Transplantation, National Medical Research Center for Hematology of the Russian Ministry of Health.

18. Drokov Mikhail Yuryevich – PhD, Head of the Research Sector for Hemoblastosis Chemotherapy, Hematopoiesis Depressions and Bone Marrow Transplantation, National Medical Research Center for Hematology of the Russian Ministry of Health.

19. Vasilyeva Vera Alekseevna – PhD, Head of the Day Hospital for Immunochemotherapy after Bone Marrow and Hematopoietic Stem Cell Transplantation, National Medical Research Center for Hematology of the Russian Ministry of Health.

20. Vlasova Yulia Yuryevna – PhD, Head of the Adult Bone Marrow Transplantation Department, Research Institute of Pediatric Oncology, Hematology and Transplantology, Pavlov First Saint Petersburg State Medical University of the Ministry of Health of the Russian Federation.

21. Gaponova Tatyana Vladimirovna – MD, Chief Freelance Transfusiologist of the Ministry of Health of the Russian Federation, Deputy General Director of the National Medical Research Center for Hematology of the Russian Ministry of Health, Head of the Blood Cell Processing and Cryopreservation Department, National Medical Research Center for Hematology of the Russian Ministry of Health.

22. Gritsaev Sergey Vasilyevich – MD, Head of the Republican BMT Center, Russian Research Institute of Hematology and Transfusiology of the Federal Medical-Biological Agency.

23. Zaritsky Andrey Yuryevich – MD, Director of the Institute of Hematology, Almazov National Medical Research Centre.

24. Zyuzgin Ilya Sergeevich – Head of the Department of Hematology and Bone Marrow Transplantation, N.N. Petrov National Medical Research Center of Oncology of the Russian Ministry of Health.

25. Kaporskaya Tatyana Semenovna – PhD, Head of the Department of Hematology with a Bone Marrow Transplantation Unit, Irkutsk Order of the "Badge of Honour" Regional Clinical Hospital.

26. Klimko Nikolay Nikolaevich – MD, Professor, Head of the Department of Clinical Mycology, Allergology and Immunology, Mechnikov North-Western State Medical University.

27. Klyasova Galina Aleksandrovna – MD, Professor, Head of the Laboratory of Clinical Bacteriology, Mycology and Antibiotic Therapy, National Medical Research Center for Hematology of the Russian Ministry of Health.

28. Konstantinova Tatyana Semenovna – PhD, Head of the Hematology Department, Sverdlovsk Regional Hospital No. 1, Chief Freelance Hematologist of the Ural Federal District and Sverdlovsk Region, Associate Professor at the Ural State Medical University of the Ministry of Health of the Russian Federation.

29. Kulagin Alexander Dmitrievich – MD, Acting Director of the Research Institute of Pediatric Oncology, Hematology and Transplantology, Pavlov First Saint Petersburg State Medical University of the Ministry of Health of the Russian Federation.

30. Mikhailova Natalia Borisovna – PhD, Head of the Department of Clinical Oncology, R.M. Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantology, Member of the Russian Society of Oncohematologists.

31. Minaeva Natalia Viktorovna – Deputy Director for Clinical Work, Kirov Research Institute of Hematology and Blood Transfusion of the Federal Medical-Biological Agency.

32. Moiseev Ivan Sergeevich – MD, Deputy Director for Science, Research Institute of Pediatric Oncology, Hematology and Transplantology, Pavlov First Saint Petersburg State Medical University of the Ministry of Health of the Russian Federation.

33. Morozova Elena Vladislavovna – PhD, Head of the Department of Adult Hematology, Oncology and Transplantation, Research Institute of Pediatric Oncology, Hematology and Transplantology, Pavlov First Saint Petersburg State Medical University of the Ministry of Health of the Russian Federation.

34. Motorin Dmitry Vasilyevich – PhD, Hematologist at the Oncohematology Department No. 2, Senior Researcher, Almazov National Medical Research Centre of the Russian Ministry of Health.

35. Petrova Galina Dmitrievna – PhD, Head of the Department of Bone Marrow and Hematopoietic Stem Cell Transplantation, Department of Hematology and Bone Marrow Transplantation, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health.

36. Popova Marina Olegovna – PhD, Associate Professor at the Department of Hematology, Transfusiology and Transplantology, Faculty of Postgraduate Education, Pavlov First Saint Petersburg State Medical University.

37. Estrina Maria Arkadyevna – PhD, Head of the Clinical Transfusiology Department, Research Institute of Pediatric Oncology, Hematology and Transplantology, Pavlov First Saint Petersburg State Medical University of the Ministry of Health of the Russian Federation.

There is no conflict of interest.

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience for these clinical guidelines:

1. Hematologists.

2. Oncologists.

3. Medical students.

Evidence gathering methodology:

Methods used for the collection/selection of evidence:

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

• electronic database searching.

Databases used for evidence collection/selection:

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

Methods used for evidence analysis:

• reviews of published meta-analyses;

• systematic reviews with evidence tables.

Methods used for assessing the quality and strength of evidence:

• expert consensus;

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

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

Table 1. Levels of Evidence (LoE) grading scale for diagnostic methods (diagnostic interventions)

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

Table 3. Scale for assessing recommendation grades for preventive, diagnostic, treatment, and rehabilitation methods (preventive, diagnostic, therapeutic, and rehabilitation interventions)

Methodology for validation of recommendations:

Methods of recommendation validation:

• external expert review;

• internal expert review.

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

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

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

Appendix A3. Reference Materials

Appendix A3.1. Drug regimens

R-BAC/R-Hd-Ara-C

R-BAC – cycles 1, 3 [33, 39, 43]

• Rituximab**:

  • 375 mg/m² IV infusion, day 1 all treatment cycles [166–169].

• #Bendamustine** 70 mg/m² IV infusion, days 2, 3.

• #Cytarabine** 800 mg/m² IV infusion, days 2–4 [39].

Intervals between cycles: 28 days.

R-HD-ARA-C – cycles 2, 4 [33,39]

• Rituximab**:

  • 375 mg/m² IV infusion, day 1 all treatment cycles [166–169].

• Cytarabine** 3000 mg/m² x 2 times/day IV infusion, days 2–3.

Intervals between cycles: 28 days.

R-BAC/R-Hd-Ara-C + ibrutinib**+#venetoclax

#R-BAC + ibrutinib** + #venetoclax** [33]

• Ibrutinib** 560 mg orally starting from day 2 of cycle 1 continuously (until leukocyte count drops below 2 thousand/µL, platelet count below 100 thousand/µL)

• #Venetoclax** starting from day 15 of cycle 1 continuously with weekly dose escalation from 20 mg to 400 mg (until leukocyte count drops below 2 thousand/µL, platelet count below 100 thousand/µL)

• Rituximab**:

  • 375 mg/m² IV infusion, day 1 all treatment cycles [166–169].

• #Bendamustine** 70 mg/m² IV infusion, days 2, 3 starting from cycle 2 (total 2 cycles)

• #Cytarabine** 800 mg/m² IV infusion, days 2–4 starting from cycle 2 (total 2 cycles) [39]

Intervals between cycles: 28 days, ibrutinib** and #venetoclax** are resumed when leukocyte count recovers to >2 thousand/µL and platelet count to >100 thousand/µL. In case of cardiac toxicity, ibrutinib** may be replaced by acalabrutinib** at a dose of 200 mg/day or zanubrutinib at a dose of 320 mg/day

R-HD-ARA-C with ibrutinib** and #venetoclax** [33]

• Ibrutinib** 560 mg orally starting from day 2 of cycle 1 continuously (until leukocyte count drops below 2 thousand/µL, platelet count below 100 thousand/µL)

• #Venetoclax** starting from day 15 of cycle 1 continuously with weekly dose escalation from 20 mg to 400 mg (until leukocyte count drops below 2 thousand/µL, platelet count below 100 thousand/µL)

• Rituximab**:

  • 375 mg/m² IV infusion, day 1 all treatment cycles [166–169].

• Rituximab**:

  • 375 mg/m² IV infusion, day 1 all treatment cycles [166–169].

• Cytarabine** 3000 mg/m² x 2 times/day IV infusion, days 2–3.

Intervals between cycles: 28 days, ibrutinib** and #venetoclax** are resumed when leukocyte count recovers to >2 thousand/µL and platelet count to >100 thousand/µL. In case of cardiac toxicity, ibrutinib** may be replaced by acalabrutinib** at a dose of 200 mg/day or zanubrutinib at a dose of 320 mg/day

R-CHOP [84]

• Rituximab**:

  • 375 mg/m² IV infusion, day 0 or 1 all treatment cycles [166–169].

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

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

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

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

Treatment is resumed on day 22.

R-CVP [82]

• Rituximab**:

  • 375 mg/m² IV infusion, day 0 or 1 all treatment cycles [166–169].

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

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

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

Treatment is resumed on day 22.

RB [44]

• Rituximab**:

  • 375 mg/m² IV infusion, day 0 or 1 all treatment cycles [166–169].

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

Treatment is resumed on day 29.

#Bendamustine** + #bortezomib** + rituximab** [93]

• Rituximab**:

  • 375 mg/m² IV infusion, day 1 all treatment cycles [166–169].

• #Bendamustine** 90 mg/m² IV inf., days 1, 4.

• #Bortezomib** 1.3 mg/m² IV inf., days 1, 4, 8, 11.

Treatment is resumed on day 29.

VR-CAP [84]

• Rituximab**:

  • 375 mg/m² IV infusion, day 0 or 1 all treatment cycles [166–169].

• Bortezomib** 1.3 mg/m² SC, days 1, 4, 8, 11.

• Doxorubicin** 50 mg/m² IV inf. (short infusion over 20 min), day 1.

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

• Prednisolone** 100 mg orally or IV, days 1–5.

Treatment is resumed on day 22.

R-HyperCVAD/R-HMA [68]

Cycles 1, 3, 5, 7 (HyperCVAD):

• #Cyclophosphamide** 300 mg/m² IV every 12 h, days 1–3 (6 administrations in total).

• Dexamethasone** 40 mg IV or orally, days 1–4, 11–14.

• Doxorubicin** 50 mg/m² as a continuous 48-hour IV infusion via a central catheter, days 4–5 (25 mg/m²/day).

• #Vincristine** 2 mg IV, days 4, 11.

Cycles 2, 4, 6, 8 (HMA):

• #Methotrexate** 1000 mg/m² as a continuous 24-hour IV infusion (200 mg/m² bolus, then 800 mg/m² over 24 hours) day 1.

• Cytarabine** 3 g/m² (in patients older than 60 years — 1 g/m²) IV every 12 h, days 2–3 (4 administrations in total).

• Rituximab** 375 mg/m² IV [166–169]), day 0 or 1 of each cycle.

R-CHOP/R-DHAP [170]

Cycles 1, 3, 5 (R-CHOP)

• Rituximab**:

  • 375 mg/m² IV infusion, day 0 or 1 all treatment cycles [166–169].

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

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

• Etoposide** 75 mg/m² IV, day 1.

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

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

Cycles 2, 4, 6 (R-DHAP)

• Rituximab**:

  • 375 mg/m² IV inf., day 1 [166–169].

• #Cisplatin** 100 mg/m² IV continuous infusion over 24 hours (in renal impairment, #cisplatin** is replaced with #oxaliplatin** 120 mg/m² over 6 h).

• Cytarabine** 2000 mg/m² twice daily, day 2 (2 administrations in total).

• Dexamethasone** 40 mg IV, days 1–4.

Treatment is resumed on day 22 or after peripheral blood counts recover.

R-CHOP/R-DHAP + ibrutinib** (TRIANGLE)

Cycles 1, 2, 3 (R-CHOP+ibrutinib**)

• Rituximab**:

  • 375 mg/m² IV infusion, day 0 or 1 all treatment cycles [166–169].

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

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

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

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

• Ibrutinib** 560 mg daily orally, days 1–10.

Cycles 3, 4, 5 (R-DHAP)

• Rituximab**:

  • 375 mg/m² IV inf., day 1 [166–169].

• #Cisplatin** 100 mg/m² IV continuous infusion over 24 hours (in renal impairment, #cisplatin** is replaced with #oxaliplatin** 120 mg/m² over 6 h).

• Cytarabine** 2000 mg/m² twice daily, day 2 (2 administrations in total).

• Dexamethasone** 40 mg IV, days 1–4.

Treatment is resumed on day 22 or after peripheral blood counts recover. Following the induction phase, maintenance therapy with ibrutinib** is administered at 560 mg daily orally continuously for up to 2 years, potentially combined with rituximab** at 375 mg/m² every 2 months for 3 years.

R-MaxiCHOP/R-HAD [171]

Cycles 1, 3, 5 (R-MaxiCHOP)

• Rituximab**:

  • 375 mg/m² IV infusion, day 0 or 1 all treatment cycles [166–169].

• #Cyclophosphamide** 1200 mg/m² IV, day 1.

• #Doxorubicin** 75 mg/m² IV, day 1.

• #Vincristine** 2 mg IV, day 1.

• Prednisolone** 100 mg IV or orally, days 1–5.

Cycles 2, 4, 6 (R-HAD)

• Rituximab**:

  • 375 mg/m² IV inf., day 1 [166–169].

• Cytarabine** 3000 mg/m² (in patients older than 60 years — 2 g/m²) IV every 12 h, days 2–3 (4 administrations in total).

• Dexamethasone** 40 mg IV, days 1–4.

Treatment is resumed on day 22 or after peripheral blood counts recover; 6–8 courses of therapy are administered.

R-CHOP/R-HAD [171, 173, 174]

Cycles 1, 3, 5, 7 (R-CHOP)

• Rituximab**:

  • 375 mg/m² IV infusion, day 0 or 1 all treatment cycles [166–169].

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

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

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

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

Cycles 2, 4, 6, 8 (R-HAD)

• Rituximab**:

  • 375 mg/m² IV inf., day 1 [166–169].

• Cytarabine** 3000 mg/m² (at serum creatinine levels above 150 µmol/L and in patients older than 60 years — 2000 mg/m²) IV every 12 h, days 2–3 (4 administrations in total).

• Dexamethasone** 40 mg IV, days 1–4.

Treatment is resumed on day 22 or after peripheral blood counts recover; 6–8 courses of therapy are administered.

R-HAD + B [57]

• Rituximab**:

  • 375 mg/m² IV infusion, day 0 or 1 all treatment cycles [166–169].

• Cytarabine** 2000 mg/m² (in patients older than 60 years — 1000 mg/m²) IV, days 2–3.

• #Bortezomib** 1.5 mg/m² IV, days 1, 4.

• Dexamethasone** 40 mg IV, days 1–4.

Treatment is resumed on day 22

R-GemOx

• Rituximab**:

  • 375 mg/m² IV infusion, day 0 or 1 all treatment cycles [166–169].

• #Gemcitabine** 1000 mg/m² IV inf., day 1.

• #Oxaliplatin** 100 mg/m² IV inf., day 2.

Treatment is resumed on day 14.

R-GIFOX [105]

• Rituximab**:

  • 375 mg/m² IV inf., day 1 for all cycles of the course [166–169]

• #Gemcitabine** 1000 mg/m² IV inf., day 2.

• #Oxaliplatin** 130 mg/m² IV inf., day 3.

• Ifosfamide** 5000 mg/m² IV inf. (with mesna**), day 3 as a single 24-hour infusion in patients under 66 years of age, or fractionated over 3 days (days 3–5) in patients aged >65 years.

PEPC [64].

• Prednisolone** 20 mg orally.

• #Cyclophosphamide** 50 mg orally.

• Etoposide** 50 mg orally.

• #Procarbazine** 100 mg/m² orally.

With the PEPC regimen, drugs are taken daily until the leukocyte count drops below 3 × 10⁹/L. Administration is resumed after blood count recovery on a daily schedule, every other day, or on a fractionated schedule (5 days on, 2 days off) depending on individual tolerability. The daily dose of the drugs always remains constant; only the number of days per week the drugs are taken may be adjusted.

Ibrutinib monotherapy** [49]

Ibrutinib** 560 mg daily orally (4 capsules). Taken 2 hours after and 1 hour before meals. Wash down with a glass of water. All 4 capsules are taken together. If complications occur, it is preferable to temporarily reduce the dose rather than discontinue the drug entirely. If discontinuation is necessary, resume intake within 7 days. Administered daily until disease progression or unacceptable toxicity.

Acalabrutinib monotherapy** [96]

Acalabrutinib** 200 mg daily, 1 capsule (100 mg) twice daily regardless of food intake. Administered daily until disease progression or intolerable toxicity.

Zanubrutinib monotherapy [99]

Zanubrutinib 320 mg daily, 2 capsules (160 mg) once daily regardless of food intake. Administered daily until disease progression or unacceptable toxicity.

Ibrutinib** + rituximab** [103]

• Rituximab** – once weekly for 4 weeks, then once every 28 days for 2 years:

  • 375 mg/m² IV inf., day 1 for all cycles of the course [166–169]

• Ibrutinib** 560 mg daily orally (4 capsules). Taken 2 hours after and 1 hour before a meal. Wash down with a glass of water. All 4 capsules are taken together. In case of complications, it is preferable to temporarily reduce the dose of the drug rather than discontinue it entirely. If discontinuation is necessary, resume administration within 7 days. Administered daily until disease progression or unacceptable toxicity.

Ibrutinib** + rituximab** + #venetoclax** [33] for patients with TP53 gene mutations.

• Rituximab** – once monthly for 12 weeks:

  • 375 mg/m² IV inf., day 1 for all cycles of the course [166–169]

• Ibrutinib** 560 mg daily orally (4 capsules) starting from day 2. Taken 2 hours after and 1 hour before a meal. Wash down with a glass of water. All 4 capsules are taken together. In case of complications, it is preferable to temporarily reduce the dose of the drug rather than discontinue it entirely. If discontinuation is necessary, resume administration within 7 days. Administered daily until disease progression or unacceptable toxicity.

• #Venetoclax** starting from day 15 orally with a weekly dose escalation from 20 mg to 400 mg (20-50-100-200-400 mg) once daily at approximately the same time, with food. In case of complications, it is preferable to temporarily reduce the dose of the drug rather than discontinue it entirely. If discontinuation is necessary, resume administration within 7 days. Administered daily until disease progression or unacceptable toxicity.

Ibrutinib** + rituximab** + #venetoclax** [33] for the treatment of R/R MCL.

• Rituximab** – once weekly for 4 weeks, then once every 28 days for 2 years:

  • 375 mg/m² IV inf., day 1 for all cycles of the course [166–169]

• Ibrutinib** 560 mg daily orally (4 capsules). Taken 2 hours after and 1 hour before a meal. Wash down with a glass of water. All 4 capsules are taken together. In case of complications, it is preferable to temporarily reduce the dose of the drug rather than discontinue it entirely. If discontinuation is necessary, resume administration within 7 days. Administered daily for 12 weeks.

• #Venetoclax** starting from day 15 orally with a weekly dose escalation from 20 mg to 400 mg (20-50-100-200-400 mg) once daily at approximately the same time, with food. In case of complications, it is preferable to temporarily reduce the dose of the drug rather than discontinue it entirely. If discontinuation is necessary, resume administration within 7 days. Administered daily for 12 weeks.

Lenalidomide monotherapy** [106]

• Lenalidomide** 25 mg orally, days 1–21

Treatment is resumed on day 29 and continued until disease progression or unacceptable toxicity

#Lenalidomide** + rituximab** [107]

• #Lenalidomide** 25 mg daily, before, during, and after rituximab** administration, until disease progression or unacceptable toxicity

• Rituximab** 375 mg/m² IV infusion, 4 weekly infusions, after two 28-day cycles of #lenalidomide** (after 8 weeks of #lenalidomide** therapy)

Appendix A3.2. Main reactions and complications associated with donor blood component transfusion

Table 3.2.1. Main reactions and complications associated with donor blood component transfusion

* The blood component container associated with the transfusion reaction or complication is forwarded in the prescribed manner for an evaluation of quality and safety parameters.

Appendix A3.2. Autologous hematopoietic stem cell transplantation

Mobilization and collection of peripheral blood hematopoietic stem cells

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

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

Decision-making algorithm prior to HSC mobilization:

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

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

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

Risk factors for ineffective HSC mobilization:

Proven risk factors for mobilization failure include two parameters: circulating CD34+ cell counts below 20 cells/µL on days 4–6 after the start of G-CSF (ATC L03AA Colony-stimulating factors), or the collection of fewer than 2×10⁶ CD34+ cells/kg over 3 leukaphereses.

Criteria for probable HSC mobilization failure include a history of prior failed HSC mobilization; prolonged chemotherapy or radiation therapy; the use of fludarabine**, melphalan**, lenalidomide** in previous treatment lines; and advanced disease phase requiring at least two lines of chemotherapy. Bone marrow cellularity of less than 30% at the time of mobilization and age over 65 years are also risk factors for failed mobilization [174]. If the harvested HSC count is insufficient, options include escalating the growth factor dose, performing re-mobilization with a different regimen, or bone marrow harvest. The goal of mobilization is to harvest an adequate number of CD34+ cells sufficient to perform one or two transplants.

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

Agents used for HSC mobilization:

Colony-stimulating factors:

G-CSF is a glycoprotein that accelerates the proliferation of neutrophil progenitor cells in the bone marrow, differentiation toward mature neutrophils, and their release from the bone marrow into peripheral blood. The use of colony-stimulating factors, both following a course of chemotherapy (CT) and independently, leads to the mobilization of hematopoietic progenitor cells into the peripheral blood. Pharmacokinetic studies of colony-stimulating factors have demonstrated that the drug is rapidly eliminated from the body, requiring multiple injections. To prolong its duration of action, a polyethylene glycol (PEG)-conjugated (pegylated) formulation was developed. The circulation time of the pegylated form in the blood increases from 3.5 hours to 42 hours. A single injection maintains high neutrophil levels in the blood for 9 days [175].

G-CSF (filgrastim**) is administered at a dose of 5 or 10 µg/kg/day subcutaneously depending on the HSC mobilization regimen. #Pegfilgrastim is administered once at a dose of 12 mg subcutaneously [176].

Plerixafor

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

HSC mobilization regimens

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

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

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

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

Colony-stimulating factors (G-CSF) as monotherapy

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

Indications

• HSC mobilization in patients with oncohematological diseases;

• Re-mobilization following initial HSC mobilization failure using regimens that include myelosuppressive drugs.

HSC mobilization regimen

G-CSF (filgrastim**) is prescribed at a dose of 10 µg/kg/day, administered subcutaneously in the morning (or 5 µg twice daily). Leukapheresis begins on the fourth day of drug administration if an adequate number of CD34+ cells is present in the peripheral blood. When their count exceeds 10–20 cells/µL, cell separation is initiated. If CD34+ cells in the peripheral blood are below 10 cells/µL, leukapheresis should be deferred and cell counts repeated the following day. The number of leukapheresis sessions depends on the HSC harvest results; obtaining an optimal number of CD34+ cells requires 2–4 procedures (ranging from 1 to 5). On the final day of leukapheresis, the drug is not administered (Table A3.2.1).

Table A3.2.1. "G-CSF Monotherapy" HSC mobilization regimen

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

Indications

HSC mobilization in patients with oncohematological diseases

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

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

Figure A3.2.1 presents the algorithm for determining indications for the first leukapheresis. The number of leukaphereses depends on the hematopoietic stem cell (HSC) collection result (from 1 to 5). Colony-stimulating factors (G-CSF) are not administered on the final day of leukapheresis.

Figure A3.2.1. Algorithm for determining indications for the first leukapheresis during HSC mobilization with the "CT + G-CSF" regimen. CT – chemotherapy, MTA – myelotoxic agranulocytosis.

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

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

Colony-stimulating factors combined with plerixafor

Indications

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

Unsatisfactory results of current mobilization in patients with lymphomas.

Unsatisfactory results of current mobilization:

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

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

HSC mobilization regimen

G-CSF (filgrastim**) is prescribed at a dose of 10 µg/kg/day, administered subcutaneously in the morning. On the fourth day of G-CSF (filgrastim**) administration, plerixafor is given 12 hours prior to leukapheresis at a dose of 240 µg/kg subcutaneously. Based on the leukapheresis results, the need for repeated plerixafor administration is evaluated (Table A3.2.3). Multiple administrations of plerixafor are possible.

Table A3.2.3. "Colony-stimulating factors + plerixafor" HSC mobilization regimen

Features of supportive care during HSC mobilization

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

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

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

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

Leukapheresis and cryopreservation

Leukapheresis is a semi-selective method of extracorporeal hemocorrection based on the separation of plasma and blood cells using centrifugal force and the isolation of the leukocyte fraction from the blood [177]. On the day of the anticipated first harvest, a complete blood count and flow cytometry analysis of CD34+CD31+ lymphocytes in the blood are performed.

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

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

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

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

The HSC collection procedure lasts about 3–4 hours. If hypocalcemia develops during leukapheresis (manifested by paresthesia of the lips, tongue, and fingertips), the blood return rate must be slowed down.

A sample of HSCs is taken from the harvested product to determine the CD34+ cell content using a flow cytometer. There are numerous recommended protocols for counting CD34+ HSCs, with the ISHAGE protocol (International Society of Hematotherapy and Graft Engineering) being the most widely known [178].

Thus, timely initiation of the first leukapheresis procedure and a well-established laboratory technique, including flow cytometric analysis, are essential for successful HSC collection. Concurrently with counting CD34+ cells, the harvested leukapheresis product is fractionated. Next, CD34+ cells are counted in the resulting leukoconcentrate. Using the proportion of CD34+ cells among all leukocytes in the leukoconcentrate, the number of CD34+ cells per 1 kg of the patient's body weight is calculated.

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

Patient evaluation prior to mobilization and HSC collection

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

Contraindications to auto-HSCT

Absolute contraindications to auto-HSCT

• disease progression/relapse;

• infectious diseases in the acute phase;

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

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

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

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

• mental and behavioral disorders due to psychoactive substance use;

• cachexia;

• pregnancy;

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

• lack of signed informed consent for transplantation.

Relative contraindications for auto-HSCT

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

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

• age over 65 years.

• presence of human immunodeficiency virus markers in the blood;

Evaluation of patients prior to auto-HSCT

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

Pre-transplantation conditioning regimens for auto-HSCT

The goal of high-dose chemotherapy is to eradicate tumor cells remaining after anti-neoplastic therapy with minimal toxic impact on organ systems.

The BEAM conditioning regimen is used for pretransplantation preparation, consisting of #carmustine** (300 mg/m² × 1, day -6), #etoposide** (200 mg/m², days -5 to -2), cytarabine** (200 mg/m² b.i.d., 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.

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

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

Table A3.2.5. BEAM pretransplantation conditioning regimen [179–181,183,184]

To reduce the toxicity of the BEAM pretransplantation preparation regimen, #lomustine** is used instead of #carmustine** in certain cases (CEAM / LEAM). Administration schedules and doses are presented in Table A3.2.6.

Table A3.2.6. CEAM/LEAM pretransplantation conditioning regimen [179,184–187]

The efficacy of the Benda-EAM pretransplantation conditioning regimen in lymphoproliferative disorders has been confirmed in a number of clinical studies. Administration schedules and doses are presented in Table A3.2.7.

Table A3.2.7. Benda-EAM pretransplantation conditioning regimen [188–191]

Autologous hematopoietic stem cell infusion.

Hematopoietic stem cell infusion is performed into a central venous catheter observing aseptic and antiseptic principles.

The time interval from the end of chemotherapy to HSC infusion is at least 24 hours.

Before starting the transplantation procedure, the physician must inspect the cryopreserved bags containing HSCs, verify that the packaging is intact and undamaged, and match the identification data on the packaging with the patient's data.

The bag with the highest cellularity is selected for the first infusion. Metal objects (clamps, forceps, etc.) must not be used when handling the bag. If there are multiple packages of cryopreserved HSCs, it is advisable to take breaks between infusions. In some cases, HSC administration over 2 days is permissible (elderly or debilitated patients).

Cryopreserved HSCs are thawed in a water bath or a programmable thawer at a temperature of 37^oC. After thawing, the physician must ensure that no ice fragments or clots are present in the bag. Afterwards, the physician connects the bag to the infusion set.

In some cases, trimeperidine** at a standard dosage is used prior to administering the leukoconcentrate into the central venous catheter.

The initial rate of HSC infusion is 3–5 ml/min (4–5 minutes), after which the rate can be increased to the maximum possible. During and after HSC infusions, vital signs are monitored: blood pressure measurement on peripheral arteries, pulse examination, and respiratory rate measurement.

If hemolysis develops, the infusion of the next bag is suspended until complications are resolved.

After the infusion is completed, the central venous catheter lumen is flushed with normal saline (sodium chloride solution**).

Two hours after the completion of the infusion, a general general-clinical blood chemistry test and a general (clinical) urinalysis are performed to rule out hemolysis.

An operation protocol is completed in the medical chart, indicating the stages of HSC administration, time intervals, and the patient's condition.

A general (clinical) urinalysis is performed the next day.

Supportive care in auto-HSCT.

Infusion therapy

Infusion therapy is administered to all patients to reduce conditioning toxicity and prevent tumor lysis syndrome. At the pretransplantation conditioning stage, the volume of infusion therapy is 2–3 liters per day; post-transplantation, the infusion volume should be at least 1.5 liters per day, with the fluid load distributed evenly throughout the day. Solutions affecting the water-electrolyte balance are most commonly used: isotonic sodium chloride solution**, 5% dextrose solution**, compound sodium chloride solution [potassium chloride + calcium chloride + sodium chloride]**, and potassium and magnesium aspartate**. 4% sodium bicarbonate solution** is used to correct acidosis. In case of marked hypoalbuminemia or edema syndrome of non-protein origin, blood substitutes and blood plasma products (5–20% human albumin solutions**) are used. The saline solution typically includes 5% dextrose solution** and 4% potassium chloride + [Dextrose]** (KCl). At the pretransplantation conditioning stage, the daily amount of 4% KCl** is 120–150 ml; subsequently, the dose is titrated based on blood potassium levels. In significant hypokalemia, which may be caused by severe diarrhea or vomiting, continuous round-the-clock administration of 4% KCl solution** is used, with the infusion rate adjusted based on general-clinical blood chemistry data. In patients on hemodialysis, the volume of saline solutions should not exceed 1 liter per day, while potassium chloride** is prescribed only if hypokalemia develops. If febrile neutropenia/fever develops, the volume of infusion therapy should be increased to 3–4 liters per day under fluid balance monitoring.

Antisecretory therapy

Currently, two classes of drugs are used for antisecretory purposes: proton pump inhibitors and H2-histamine receptor blockers [141,194].

Appendix A3.2. Allogeneic hematopoietic stem cell transplantation

1. Patient selection for allogeneic hematopoietic stem cell transplantation

Indications for allo-HSCT [193]:

Medical indications for bone marrow and hematopoietic stem cell transplantation are defined by Order of the Russian Ministry of Health No. 875n dated December 12, 2018, "On Approval of the Procedure for Providing Medical Care for Diseases (Conditions) for Which Bone Marrow and Hematopoietic Stem Cell Transplantation (Grafting) Is Used, and Amendments to the Procedure for Providing Medical Care in the Profile of 'Surgery (Human Organ and/or Tissue Transplantation)', Approved by Order of the Ministry of Health of the Russian Federation No. 567n dated October 31, 2012" (Registered with the Russian Ministry of Health on January 9, 2019, No. 53256). Patients who may be considered candidates for allo-HSCT include those with:

• malignant and other neoplasms of lymphoid, hematopoietic, and related tissues;

• diseases of the blood and blood-forming organs and certain disorders involving the immune mechanism;

• congenital immunodeficiency syndromes;

• congenital anomalies (malformations), deformations and chromosomal abnormalities, endocrine system diseases, nutritional disorders and metabolic disorders that can be corrected by hematopoietic cell transplantation;

• malignant neoplasms of mesothelial and soft tissues (rhabdomyosarcoma);

• malignant neoplasms of bone and articular cartilage (Ewing sarcoma, chondrosarcoma, fibrosarcoma);

• neuroepithelial neoplasms (neuroblastoma, retinoblastoma);

• demyelinating diseases of the central nervous system (multiple sclerosis);

• germ cell neoplasms;

• complex and mixed stromal neoplasms (nephroblastoma);

• gliomas (primitive neuroectodermal tumor);

• malignant neoplasms of the liver and intrahepatic bile ducts (hepatoblastoma);

• diseases of the skin and subcutaneous tissue (scleroderma);

• systemic connective tissue disorders (systemic lupus erythematosus);

• other diseases (conditions) in which, in accordance with clinical guidelines (treatment protocols) for the provision of medical care, bone marrow or hematopoietic stem cell transplantation is used.

Main criteria for determining transplantation-related mortality risks in patients scheduled for allo-HSCT [193]:

• Presence of a verified diagnosis and status (remission, relapse, stabilization, progression) that serve as an indication for allo-HSCT.

• Assessment of allo-HSCT risks using EBMT and HCT-CI scores (Appendices G2 and G3).

• Assessment of recipient candidate status according to the ECOG performance status definition (Appendix G1).

• Assessment of psychological status, absence of acute psychiatric disorders.

• Assessment of renal functional state: serum creatinine concentration <177 µmol/l (<2 mg/dl) or creatinine clearance >50 ml/min/1.73 m².

• Assessment of the functional state of cardiac activity: left ventricular ejection fraction >35% by Simpson method, no history of unstable angina, no high-grade ventricular arrhythmias (Lown-Wolf grade IV–V rhythm disorders).

• Assessment of the functional state of the lungs: FEV1 ≥80%; whenever possible, determine the adjusted diffusing capacity for carbon monoxide (DLCO), which should be >35% of predicted.

• Assessment of the functional state of the liver:

- total bilirubin concentration ≤22 µmol/L (except for confirmed Gilbert's syndrome);

- total bilirubin concentration ≤30 µmol/L (except for confirmed Gilbert's syndrome).

Additional criteria for determining transplant-related mortality risks in patients scheduled for allo-HSCT [193]:

• Immunodeficient state: neutropenia, lymphopenia with a CD4+ concentration ≤200 cells/µL, hypogammaglobulinemia, asplenia, high-dose corticosteroid use during prior chemotherapy, and relation to the underlying disease.

• Infectious complications and their severity, significance, and duration during prior chemotherapy, indicating localization, pathogen sensitivity to systemic antibacterial drugs, and ongoing therapy: febrile neutropenia, pneumonia (with indication of identified pathogen or lack of pathogen verification), fungal infections, viral infections.

• Past medical history, including (COVID-19, tuberculosis, viral hepatitis)

• Presence of donor-specific anti-HLA antibodies in the recipient in case of unrelated partially matched or haploidentical HSCT

• Thrombotic and hemorrhagic events during prior therapy and causes upon verification

• Transfusion history, presence of data indicating refractoriness to donor blood component transfusions.

• Presence of hemochromatosis and/or laboratory signs of iron overload. History of transfusions from related donors.

• Presence of congenital or acquired defects

• Presence of prostheses, implants, and biomaterials.

• Presence of chronic diseases and their stage.

• Information on dental treatment within the last 6 months; if unavailable, a primary dental examination (consultation) is mandatory.

• Primary obstetrician-gynecologist examination (consultation) for women to identify the risk of dysfunctional uterine bleeding / perimenopausal status.

• Epileptiform activity confirmed by EEG results

• Nutritional status: overweight or underweight.

• Criteria that contraindicate allo-HSCT

• Pregnancy

• Liver cirrhosis, active viral hepatitis with signs of impaired liver function (hyperbilirubinemia, cytolysis syndrome, decreased protein-synthetic liver function)

• Presence of any uncontrolled infection.

• Other oncological diseases of various stages and localizations outside of remission.

List of laboratory and instrumental examinations for evaluating allo-HSCT candidates [193]:

• Complete blood count with differential.

• General clinical blood chemistry test.

• Coagulation profile (screening hemostasis test).

• Fasting blood glucose test.

• Serological tests for blood-borne infections (determination of antibodies of classes M and G (IgM, IgG) to human immunodeficiency virus HIV-1 in blood, determination of antibodies of classes M and G (IgM, IgG) to human immunodeficiency virus HIV-2 in blood, determination of hepatitis B virus surface antigen (HBsAg) in blood, determination of antibodies to hepatitis B virus surface antigen (HBsAg) in blood, determination of class M antibodies to hepatitis B virus core antigen (anti-HBc IgM) in blood, determination of class G antibodies to hepatitis B virus core antigen (anti-HBc IgG) in blood, determination of antibodies to hepatitis B virus e-antigen (anti-HBe) in blood, molecular biological blood test for Treponema pallidum.

• Determination of herpes simplex virus types 1 and 2 antigens in blood, molecular biological blood test for Epstein-Barr virus, determination of antibodies to human herpesvirus type 6 in blood, determination of antibodies to Toxoplasma gondii in blood (if available).

• Determination of hepatitis B virus DNA in blood by PCR, qualitative assay (if detected, also quantitative assay), determination of hepatitis C virus RNA in blood by PCR, qualitative assay (if detected, also quantitative assay).

• Computed tomography of the chest cavity. Computed tomography of other regions if necessary

• Positron emission tomography combined with computed tomography using tumorotropic radiopharmaceuticals (if necessary, in accordance with clinical guidelines [treatment protocols]).

• Magnetic resonance imaging of the brain if indicated (with digital recording on electronic media).

• X-ray or computed tomography of the paranasal sinuses, larynx.

• Ultrasound examination of the liver, spleen, kidneys.

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

• Echocardiography.

• Cardiopulmonary exercise testing (Ergospirometry)

• Esophagogastroduodenoscopy

• Electroencephalography if necessary

• Primary specialist consultations (examinations): dentist (mandatory), obstetrician-gynecologist (mandatory for women), otorhinolaryngologist (as indicated).

2. Selection of allogeneic HSC donors

Main criteria for the selection of allogeneic HSC donors [193]:

• Assessment of the donor candidate's status according to the ECOG scale (Appendix G1).

• Standard age of a donor candidate is 18–75 years. In specific cases, minor siblings may act as donors. The decision to clear a minor for donation is made by their parents in accordance with the current legislation of the Russian Federation.

• Adequate psychological state (legal capacity).

• Presence of HLA typing: for related donors — at least medium-to-low resolution; for unrelated donors — high resolution. Final requirements for typing resolution remain at the discretion of the transplant center performing the allo-HSCT.

• Serological tests for blood-borne infections (determination of antibodies of classes M and G (IgM, IgG) to human immunodeficiency virus HIV-1 in blood, determination of antibodies of classes M and G (IgM, IgG) to human immunodeficiency virus HIV-2 in blood, determination of hepatitis B virus surface antigen (HBsAg) in blood, determination of antibodies to hepatitis B virus surface antigen (HBsAg) in blood, determination of class M antibodies to hepatitis B virus core antigen (anti-HBc IgM) in blood, determination of class G antibodies to hepatitis B virus core antigen (anti-HBc IgG) in blood, determination of antibodies to hepatitis B virus e-antigen (anti-HBe) in blood, molecular biological blood test for Treponema pallidum

• Availability of examination results.

Additional criteria for the selection of allogeneic HSC donors [193]:

• Information on infectious status. Past diseases including (COVID-19, tuberculosis, viral hepatitis)

• Information on structural and congenital anomalies, presence of prosthetic biomaterial.

• Travel to Southeast Asia, Africa, Central and South America.

• Information on the presence of chronic diseases and their stage.

• Information on dental treatment, blood component transfusion, tattoos within at least 6 months prior to donation.

• History of pregnancies and childbirth.

• Weight of donor and recipient — if the donor's weight is less than 50% of the patient's weight, it is recommended to consider HSC as a graft source.

• Nutritional status: overweight or underweight (based on body mass index and/or blood albumin level).

• History of surgical interventions

• Anticipated difficult tracheal intubation (for bone marrow donors)

Contraindications for donation [193]

Medical contraindications for the harvest of allogeneic bone marrow and/or collection of allogeneic hematopoietic stem cells for transplantation include the following diseases (conditions) in the donor, which are defined by Order of the Russian Ministry of Health No. 875n dated December 12, 2018, "On approval of the Procedure for providing medical care for diseases (conditions) for the treatment of which bone marrow and hematopoietic stem cell transplantation is used, and introduction of amendments to the Procedure for providing medical care in the profile of 'surgery (human organ and/or tissue transplantation)' approved by Order of the Ministry of Health of the Russian Federation No. 567n dated October 31, 2012" (Registered with the Ministry of Justice of the Russian Federation on January 9, 2019, No. 53256).

Absolute medical contraindications [193]:

• infectious diseases in the acute phase;

• presence of human immunodeficiency virus markers in the blood;

• history of Creutzfeldt-Jakob disease;

• malignant neoplasms;

• cachexia;

• immunosuppressive therapy or other medicinal products that may affect the self-renewal capacity of the recipient's own population and the pluripotency of the bone marrow and hematopoietic stem cells (at the time of bone marrow harvest and hematopoietic stem cell collection and until discontinuation of the specified medicinal products and recovery of blood cell lineages);

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

• mental and behavioral disorders due to psychoactive substance use;

• pregnancy;

• breastfeeding;

• absence of signed donor informed consent for HSC or bone marrow collection;

Relative medical contraindications [193]:

• presence of infectious diseases in remission or a history of infectious diseases, including the detection of markers of viral hepatitis (except for a history of past hepatitis A) and syphilis;

• benign neoplasms;

• health disorders associated with impaired motor functions, diseases of the circulatory system, digestive system, respiratory system, genitourinary system, endocrine system, blood and hematopoietic organs and certain disorders involving the immune mechanism, and mental disorders accompanied by persistent impairment of bodily functions;

• If the donor has relative medical contraindications for bone marrow harvest and hematopoietic stem cell collection, the decision on bone marrow harvest or hematopoietic stem cell collection shall be made by a medical board (consilium of physicians) of the medical organization performing the transplantation.

Special cases:

Bone marrow harvest and hematopoietic stem cell collection from a related donor who has tested positive for markers of viral hepatitis (except for a history of past hepatitis A) or syphilis are permitted if it is impossible to identify another compatible donor, provided that the following conditions are met simultaneously:

• prior administration of etiotropic and symptomatic treatment for viral hepatitis (except for a history of past hepatitis A) and syphilis;

• presence of informed voluntary consent of the patient (recipient) for the medical intervention, indicating that the bone marrow and hematopoietic stem cells will be harvested from a donor who has tested positive for markers of viral hepatitis (except for a history of past hepatitis A) or syphilis.

List of laboratory and instrumental examinations for screening donor candidates [193]:

• Complete blood count (CBC) with differential

• General clinical blood chemistry test.

• Coagulation profile (screening hemostasis test).

• Fasting blood glucose test.

• Urinalysis (general clinical urine test).

• Serological tests for blood-borne infections (determination of antibodies of classes M and G (IgM, IgG) to human immunodeficiency virus HIV-1 in blood, determination of antibodies of classes M and G (IgM, IgG) to human immunodeficiency virus HIV-2 in blood, determination of hepatitis B virus surface antigen (HBsAg) in blood, determination of antibodies to hepatitis B virus surface antigen (HBsAg) in blood, determination of class M antibodies to hepatitis B virus core antigen (anti-HBc IgM) in blood, determination of class G antibodies to hepatitis B virus core antigen (anti-HBc IgG) in blood, determination of antibodies to hepatitis B virus e-antigen (anti-HBe) in blood, molecular biological blood test for Treponema pallidum.

• Determination of herpes simplex virus types 1 and 2 antigens in blood, molecular biological testing of blood for Epstein-Barr virus, and determination of antibodies to human herpesvirus type 6 in blood.

• Determination of Hepatitis B virus DNA in blood by PCR (qualitative assay), determination of Hepatitis C virus RNA in blood by PCR (qualitative assay).

• Electrocardiography: recording, decoding, description, and interpretation of electrocardiographic data; echocardiography as clinically indicated.

• Chest X-ray, or computed tomography of the chest cavity as clinically indicated.

• Ultrasound examination of the abdominal cavity (comprehensive) — as clinically indicated.

3. Protocol for Preparation and Infusion of Allogeneic Hematopoietic Stem Cells

CVC Insertion

Before initiating conditioning, a double- or triple-lumen central venous catheter (CVC) is inserted into the subclavian vein (or internal jugular vein, external jugular vein) of the patient.

Preparation for HSC Infusion

Ensure that the following conditions are met:

• The patient has signed a voluntary informed consent for transplantation.

• A CVC has been placed in the patient by the time of HSC administration. In the absence of an adequately functioning CVC at the time of infusion, infusion of the cell suspension through a peripheral vein is permitted, provided the dimethyl sulfoxide content does not exceed 10%.

• At least 36 hours have elapsed since the completion of administration of anti-tumor drugs included in the conditioning regimen.

• When using ciclosporin** starting on day -1 (for acute GVHD prophylaxis), the patient received at least 3 doses of the drug prior to HSC infusion.

• No other medications are administered during the HSC infusion.

• Plasmapheresis and/or hemodialysis are strictly prohibited during HSC administration.

If plasmapheresis and/or hemodialysis are necessary, the HSC infusion must be performed before and/or 24 hours after the completion of these procedures.

2–3 hours prior to allo-HSCT, infusion therapy with electrolyte solutions (500–1500 ml volume) is recommended if cryopreserved HSCs are used.

30 minutes prior to HSC administration, in patients with a history of transfusion reactions to blood components, premedication should be administered using systemic antihistamines and/or nonsteroidal anti-inflammatory and antirheumatic drugs and/or #methylprednisolone** (if #methylprednisolone** was used on the preceding day) [193].

In the event of any ABO incompatibility between donor and recipient, administration of #methylprednisolone** at a dose of 60 mg prior to HSC infusion is permitted [193].

Upon receipt of the HSC bag from the laboratory, it must be inspected: verification of the patient's or donor's full name (depending on the center's labeling requirements), date of birth, and blood type, as well as checking for external damage and/or foreign impurities in the bag (clots, bone fragments). If any "defects" are identified, the bag is returned to the laboratory for correction.

HSC Infusion

For the first infusion, select the bag with the highest cellularity. Metal instruments (clamps, forceps, etc.) must not be used when handling the bag. If cryopreserved HSCs are used, they are thawed beforehand in a water bath or automated thawing device at a temperature of 37°C. After thawing, the physician must verify that no residual ice fragments remain in the bag, and then puncture the bag using an infusion set. The infusion set must be equipped with a 150–260 micron filter (a standard blood infusion set features a 175-micron filter).

If hemolysis occurs, HSC infusion from the subsequent bag must not be performed. HSC infusions from subsequent bags may be resumed only after the erythrocyte lysis has been at least partially resolved. Upon completion of the infusion, the CVC lumen used for transplantation is flushed with normal sodium chloride** solution. Subsequently, the patient is kept under close medical observation. Round-the-clock monitoring by an anesthesiologist-resuscitologist and/or 24-hour bedside monitoring of vital functions and parameters may be performed as clinically indicated. Potassium blood levels must be checked 2 hours after the completion of the infusion.

4. Drugs Used in Conditioning Regimens and for GVHD Prophylaxis

4.1. Conditioning Regimen

The conditioning regimen includes chemotherapeutic agents and interventions characterized by pronounced immunosuppressive and/or myelosuppressive effects. The selection of drugs, doses, and sequence of chemotherapy administration within the conditioning regimen may vary. The choice of conditioning regimen is determined by the HSCT technological platform implemented at the transplant center, baseline characteristics of the donor-recipient pair, and other factors.

Table 5.1.1. Medications Used in Conditioning Regimens [193–197]

5.2. GVHD Prophylaxis

Drugs used for GVHD prophylaxis are combined into regimens, the choice of which is determined by the risk of GVHD development in each specific donor-recipient pair and the HSCT technological platform implemented at the transplant center.

Table 5.2.1. Medications Used for GVHD Prophylaxis [193–197]

Appendix A3.3. CAR-T cell therapy

CAR-T cell therapy includes the following stages:

1. Leukapheresis

2. Automated biomedical cell product manufacturing cycle

3. Lymphodepleting chemotherapy

4. Infusion of the autologous cellular product

Patient evaluation plan prior to CAR-T cell therapy

• Complete blood count with differential.

• General clinical blood chemistry test.

• Coagulation profile (screening hemostasis test).

• Fasting blood glucose test.

• Brain magnetic resonance imaging

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

• Echocardiography.

• Cardiopulmonary exercise testing.

• Electroencephalography.

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

• Lymphocyte subset analysis.

• Blood immunoglobulin level test.

• Bone marrow aspiration cytological examination (myelogram).

• Lumbar puncture.

• Cytological examination of cerebrospinal fluid cells.

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

Lymphodepleting chemotherapy [198]

Lymphodepleting therapy includes two drugs: #fludarabine** and #cyclophosphamide**. #Fludarabine** is administered at a total course dose of 120 mg/m² (30 mg/m² on days -5, -4, -3, and -2, each dose given as an intravenous infusion over 30 minutes). #Cyclophosphamide** is administered at a dose of 750 mg/m² (as an infusion over 1 hour on day -2) [198]. During chemotherapy, the patient will receive infusion therapy at a volume of 2500 mL/m²/day, hyperuricemia prophylaxis, and antiemetic therapy in accordance with standard clinical guidelines [199].

Prophylaxis of cytokine release syndrome

Tocilizumab**

#Tocilizumab** is a recombinant humanized monoclonal antibody against the interleukin-6 receptor. The drug is administered on day 0, 1 hour before the infusion of CD19 CAR-T cells, at a dose of 8 mg/kg (maximum dose 800 mg), as an intravenous infusion over 1 hour [198].

Monitoring of cytokine release syndrome

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

• Laboratory monitoring: serum C-reactive protein and blood ferritin levels daily on days 1–14 post-infusion of CD19 CAR-T cells; routine blood biochemistry every two days; coagulography (exploratory hemostasis assay) three times a week.

Treatment of cytokine release syndrome

If cytokine release syndrome > grade 1 develops:

#Dexamethasone** 10 mg every 6–8 hours with assessment of severity and CRS criteria dynamics [200].

#Tocilizumab** at a dose of 8 mg/kg (maximum dose 800 mg), as an intravenous infusion over 1 hour [201, 202].

Toxic encephalopathy

Expected manifestations of neurotoxicity

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

Encephalopathy therapy includes #dexamethasone** at a dose of 10 mg every 6–8 hours with assessment of condition severity and encephalopathy dynamics. If there is no response to dexamethasone, #anakinra** is administered at a dose of 100–200 mg [202].

B-cell aplasia and hypogammaglobulinemia

B-cell aplasia is a direct consequence of the effective cytolytic activity of CAR-T cells against CD19, CD20, and CD22-positive targets. B-lymphopenia is a surrogate marker of CAR-T cell persistence and can last from 2 weeks to >1 year. Hypogammaglobulinemia is a consequence of B-lymphopenia. Within this protocol, serum immunoglobulin concentrations will be monitored at 3-week intervals. If the serum immunoglobulin concentration drops to <5 g/L, replacement therapy with normal human immunoglobulin** (IV or SC) will be provided at a dose of 0.4 g/kg of the patient's body weight [201].

Appendix B. Physician Action Algorithms

Fig. 1. Management algorithms for a patient with mantle cell lymphoma.

Fig. 2. Treatment of patients with relapsed/refractory MCL according to age, performance status, and the presence/absence of TP53 gene mutations.

Appendix C. Patient Information

What is mantle cell lymphoma?

It is a tumor disease of the lymphatic tissue. Tumor cells originate from B cells located in the mantle zone of lymph nodes. As a rule, the first symptom of lymphoma is a significant enlargement of lymph nodes in the neck, armpits, or groin. In this case, unlike infectious diseases, the enlarged lymph nodes are painless, and their size does not decrease over time or with systemic antibacterial treatment. Sometimes, due to pressure from enlarged liver, spleen, and lymph nodes, there is a feeling of fullness in the abdomen, shortness of breath, dull aching pain in the lower back, or a sensation of pressure in the face or neck.

How to confirm that you have MCL?

The main test to confirm the diagnosis of lymphoma is microscopic examination of a sample of lymphoid tissue 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 pathomorphologist, 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.

Do you need treatment right now?

Very rarely, MCL does not require immediate initiation of therapy—when the tumor burden is very small, there are no signs of rapid tumor growth, and intoxication symptoms are absent.

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

Appendix G1. Determination of prognostic groups

Mantle Cell Lymphoma International Prognostic Index, MIPI, 2010,

Mantle Cell Lymphoma International Prognostic Index, scoring scale less than 5.7, from 5.7 to 6.2, greater than 6.2 [203] for determining the prognosis of MCL patients.

Notes:

The clinical prognostic system for MCL is the Mantle Cell Lymphoma International Prognostic Index (MIPI). Its modifications include the simplified index (sMIPI – Table 7.1.1) or combined indices that additionally account for the count of Ki-67-expressing cells – MIPI-c and MIPI_b [204].

Low risk by MIPI score – 5-year overall survival (OS) is 60%. Intermediate risk by MIPI score – median OS is 51 months. High risk by MIPI score – median OS is 29 months.

Table 7.1.1. Simplified Mantle Cell Lymphoma International Prognostic Index (sMIPI)

Each prognostic factor is scored from 0 to 3 points, which are then summed (maximum 11 points). Patients with 0 to 3 points are classified into the low-risk group; 4–5 points into the intermediate-risk group; 6–11 points into the high-risk group. The impact of LDH concentration was assessed by dividing the patient's serum LDH concentration by the upper limit of normal of the laboratory (for example, the patient has an LDH concentration of 390 U/L at diagnosis, and the laboratory normal range is 250–480 U/L; then the division is 390/480 = 0.81, which corresponds to 1 point).

Mantle Cell Lymphoma Biological International Prognostic Index, MIPIb, 2016,

Mantle Cell Lymphoma Biological International Prognostic Index, scoring scale less than 5.7, from 5.7 to 6.2, greater than 6.2 for determining the prognosis of MCL patients [205].

Notes:

Calculation of the combined biological variant of the MCL international prognostic index MIPI_b [206]:

MIPI_b = 0.03535 × age (years)

+ 0.6978 (if ECOG >1)

+ 1.367 × log10 (LDH/LDH upper limit of normal)

+ 0.9393 × log10 (white blood cell count)

+ 0,02142 × Ki-67 (%)

Risk groups when calculating MIPI_b:

1. Low: MIPI_b <5.7.

2. Intermediate: 5.7 < MIPI_b <6.5.

3. High: MIPI_b >6.5.

The use of the MIPI_b index avoids including young patients with the blastoid variant of the disease in the low-risk group.

Other independent adverse prognostic factors include the blastoid variant of the disease, a high proliferative index (Ki-67 >30%), complex karyotype, and TP53 deletions and mutations.

Eastern Cooperative Oncology Group (ECOG) performance status scale

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:

Appendix G2. Calculation of transplantation risk according to the EBMT scale

Transplantation risk assessment is performed no later than 10 days before the start of pre-transplantation conditioning [208].

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

Appendix G3. Calculation of transplantation risk according to the HCT-CI scale

Hematopoietic Cell Transplantation-specific Comorbidity Index (HCT-CI), 2005, (https://www.mdcalc.com/calc/3980/hematopoietic-cell-transplantation-specific-comorbidity-index-hct-ci)

Type — assessment scale

Contents: scoring scale – 0 points (low risk), 1–2 points (intermediate risk), 3–4 points (high risk), 5 or more points (very high risk) for assessing the patient's condition to be considered as a candidate for allogeneic hematopoietic stem cell transplantation (allo-HSCT).

Notes: Transplantation risk assessment is performed during the initial evaluation of the patient as a candidate for allo-HSCT and repeated no later than 10 days before the start of pre-transplantation conditioning [209, 210].