RU2831407C1 - Method of treating patients with primary diffuse large b-cell lymphoma of central nervous system - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention relates to oncology and chemotherapy. Three-stage approach is followed for treating the patients diagnosed with primary diffuse large B-cell lymphoma of the central nervous system. First stage includes 4 courses of induction chemotherapy with the combined use of the preparation Lenalidomide by the oral administration from 2nd to 8th day of the cycle in dosage of 25 mg/day, of the preparation Rituximab by intravenous drop-by-drop introduction on the first day of the cycle of the preparation Rituximab in dosage of 375 mg/m², intravenous drop-by-drop introduction on 2nd day of the cycle of the preparation Methotrexate in dosage of 3,500 mg/m², intravenous bolus introduction on 2nd day of the cycle of the preparation Vincristine in dosage of 2 mg, oral administration of the preparation Procarbazine in dosage of 100 mg/m² from 2nd to 8th days of the cycle. Application of accompanying therapy, which includes water load, hypouricemic therapy, antiulcer therapy, anticoagulant therapy, antiemetic therapy, anticonvulsant therapy. Treatment involves the second stage of the therapy with the auto-HSCT in the air conditioning mode with the use of the preparations Carmustine, Busulfan, Cyclophosphamide with application of accompanying therapy, which includes water load, hypouricemic therapy, antiulcer therapy, anticoagulant therapy, antiemetic therapy, anticonvulsant therapy, hepatoprotective therapy. At the third stage, the therapy is carried out 3 months after the auto-HSCT of the maintenance therapy with PD-1 control point inhibitors, followed by a control examination every 3 months for 1 year, then every 6 months from 2nd year.

EFFECT: method enables reducing the risk of recurrent disease and increasing the survival rate, and also enables replacing the preparation Thiotepa in the therapy of the patients diagnosed with primary diffuse large B-cell lymphoma of the central nervous system.

38 cl, 7 ex, 7 tbl, 9 dwg

Description

Central nervous system (CNS) lymphomas account for less than 3% of all brain tumors and less than 1% of non-Hodgkin lymphomas (NHL). Primary CNS lymphomas (PCNSL) account for 70 to 90% of cases, but secondary CNS involvement from systemic lymphomas may also be observed in 10 to 30% of patients. In 90% of cases, the morphological substrate in PCNSL is diffuse large B-cell lymphoma (DLBCL). Primary diffuse large B-cell lymphoma of the central nervous system (DLBCL CNS) occurs predominantly in males, with a median age of 65 years. The risk of developing the disease increases with age. The incidence rate is 4 cases per 1,000,000 population per year [1].

For PDLBCL of the CNS, isolated lesions of the parenchyma of the brain and/or spinal cord, the posterior chamber of the eye are characteristic. In 60-70% of cases of PDLBCL of the CNS, solitary lesions are observed with localization in the cerebral hemispheres with the involvement of the frontal-parietal lobes; multifocal spread of the tumor and involvement of the posterior chamber of the eye are less common [1].

The clinical picture is nonspecific and depends on the location of the tumor: various neurological symptoms develop, including focal neurological deficit (from 56% to 70%), changes in mental status and behavior (from 32% to 43%), symptoms of increased intracranial pressure (headaches, nausea, vomiting, optic disc edema - up to 30%) and seizures (from 11% to 14%) [1].

The task or problem that the researchers faced:

PDLBCL of the CNS is an extremely rare B-cell lymphoma, which is characterized by an aggressive course and a high percentage of early, usually incurable relapses. Since 1998, the Federal State Budgetary Institution "National Medical Research Center of Hematology" of the Ministry of Health of the Russian Federation has been working to find and develop effective polychemotherapy programs (PCT) for patients diagnosed with PDLBCL of the CNS. At the first stages, multicomponent PCT regimens were used, including cytostatic drugs capable of overcoming the blood-brain barrier (BBB). However, the 5-year relapse-free (RFS) and overall survival (OS) were no more than 20%. In addition, the use of such intensive PCT programs was also associated with long periods of cytopenia and the development of severe toxic and infectious complications [2]. Similar results were presented according to foreign researchers.

Currently, according to the current Russian clinical guidelines from 2020, for patients under 65 years of age with newly verified PDLBCL of the CNS, treatment with high doses of methotrexate (≥3000 mg/ ^m2 ) is recommended. Upon achieving complete remission after the first line of induction therapy, a remission consolidation stage is recommended using one of the following therapeutic strategies: high-dose chemotherapy (HDC) according to the HSC program (thiotepa, busulfan, cyclophosphamide) with autologous hematopoietic stem cell transplantation (auto-HSCT) or radiation therapy [3].

In the period from 2015 to 2022, a prospective study "CNS-2015" was initiated at the Federal State Budgetary Institution "National Medical Research Center of Hematology" of the Ministry of Health of the Russian Federation, which involves remission induction according to the R-MPV program with subsequent VCT according to the TVS program and auto-HSCT [4]. According to the results of the study, early relapses of the disease were noted in 20% of patients with CNS PDLBCL. In addition, since 2022, the use of chemotherapy drugs that are key in the treatment of CNS PDLBCL has become unavailable in the Russian Federation.

Thus, given such unsatisfactory results of therapy for patients diagnosed with PDLBCL of the CNS, there was a need to develop a new effective protocol that would significantly reduce the risks of relapse and increase the RFS and OS rates, as well as replace thiotepa, which is not available in the Russian Federation, in the therapy of patients diagnosed with PDLBCL with a drug approved for circulation in the Russian Federation. Thus, in 2021, a new 3-stage protocol for the treatment of patients with PDLBCL of the CNS was developed - "CNS-2021", the structure of this protocol is presented in Figure 1.

From the prior art, the following analogues of the method for treating patients with CNS PDVCCL are known, having the same purpose as the proposed invention.

The most effective approaches to the treatment of CNS PDBCCL include the use of intensive induction programs, followed by high-dose consolidation and auto-HSCT.

According to foreign data, the R-MPV/TBC program developed at MSKCC (Memorial Sloan Kettering Cancer Center) has similar efficacy in the treatment of patients with CNS PDBCCL. The proposed program included 2 stages: 1 induction stage - 5-7 courses according to the R-MPV program (rituximab, methotrexate, vincristine, procarbazine). The second stage was the implementation of auto-HSCT in a high-dose regimen according to the TBC program (thiotepa, busulfan, cyclophosphamide) [5]. In 2023, the long-term results of treatment of patients according to this protocol were published. Of the 32 patients included in the study, 26 completely completed therapy (R-MPV + auto-HSCT). Of the 26 patients, 2 (8%) developed early relapses of the disease at observation periods of +6 and +9 months. The criteria for early relapse are tumor recurrence within 6-12 months from the end of treatment. With a median follow-up of 12 years (5–15.5 years), the median PFS and OS were not achieved in 32 patients, with 5-year, 10-year, and 15-year PFS being 78%, 74.7%, and 74.7%, respectively [6].

The MSKKC program served as a prototype for the creation in 2015 of the Russian study “CNS-2015”, which is the second closest analogue of the claimed invention.

The CNS-2015 protocol had a number of differences from the original program: the number of R-MPV induction chemotherapy courses was reduced to 3-5 (instead of 5-7) and a 3rd stage of maintenance therapy with temozolomide was introduced for 2 years after auto-HSCT. According to the results of the prospective CNS-2015 study conducted from 2015 to 2022 at the National Medical Research Center of Hematology of the Ministry of Health of the Russian Federation, auto-HSCT was performed in 31 out of 36 patients. Of the 31 patients, 5 (16%) developed early relapses of the disease during the observation periods of +3, +4, +5, +5, +10 months after auto-HSCT [4].

The disadvantages of the above-mentioned analogues are the presence of early relapses of the disease (within 6-12 months after completion of therapy) and the use of the drug thiotepa, which is not available in the Russian Federation.

When developing the claimed invention (protocol "CNS-2021"), the basic principles of the previously used program "CNS-2015" were taken into account, which included the use of a 3-component scheme - induction of remission, consolidation of VCT/auto-HSCT and maintenance therapy.

The main differences of the new protocol were the integration of targeted drugs at the stages of induction and maintenance therapy, as well as the replacement of thiotepa with carmustine in the conditioning regimen before auto-HSCT.

The first stage is distinguished by the integration of the immunomodulator lenalidomide into the R-MPV (RL-MPV) cycles (Table 1). The reason for including lenalidomide in the therapy program was the lack of data on the similar thiotepa high efficiency of carmustine in the conditioning regimen before auto-HSCT, which is the basis for successful treatment of this group of patients. To maintain comparable efficacy, a decision was made to intensify the first stage of therapy by adding lenalidomide and conducting maintenance treatment.

Lenalidomide was chosen because of the high IRF/MUM1 expression characteristic of CNS PDLBCL [7]. Lenalidomide has multiple antitumor effects (immunological, antiangiogenic, and cytotoxic). Lenalidomide is a synthetic compound obtained using structural modifications of the chemical structure of thalidomide. Lenalidomide induces T-lymphocyte proliferation and increases the synthesis of interleukin-2 and interferon gamma, and increases the cytotoxic activity of native T-killers. In addition, lenalidomide inhibits angiogenesis by blocking the formation of microvessels and endothelial channels, as well as the migration of endothelial cells in an in vitro angiogenesis model. Lenalidomide inhibits the synthesis of proangiogenic vascular endothelial growth factor, the secretion of proinflammatory cytokines, including TNF-alpha, interleukin-1beta, 6 and 12 from lipopolysaccharide-stimulated peripheral blood mononuclear cells and increases the production of anti-inflammatory cytokine (interleukin-10) from these cells, resulting in inhibition of cyclooxygenase-2 expression, which affects increased cell proliferation [8].

The direct mechanism of antitumor action of lenalidomide in CNS lymphoma is based on its ability to bind to cereblon, the main protein of the E3 ubiquitin ligase complex. As a result, the mechanism of active ubiquitination and proteosomal degradation of the transcription factors IKZF1/3 (direct activators of MUM1 expression) is launched [7].

Currently, the registered indications for the use of lenalidomide include: multiple myeloma, myelodysplastic syndrome, and relapses of mantle cell lymphoma [9]. Lenalidomide has not been used as a first-line therapy for lymphomas, including CNS PDLBCL. However, according to foreign publications, its effectiveness in the treatment of CNS PDLBCL in the case of disease relapse has been confirmed - the median PFS was 6 months [7].

The main adverse events when using lenalidomide in monotherapy: neutropenia (39.4%), muscle weakness (27.2%), asthenia (17.6%), constipation (23.5%), muscle cramps (20.1%), thrombocytopenia (18.4%), anemia (17%), diarrhea (14.2%), rash (10.2%), the most common > 50% - venous thromboembolism (deep vein thrombosis, pulmonary embolism), pneumonia, tremor, hypoesthesia, dyspnea [9].

Given the lack of data on the combined use of lenalidomide with the R-MPV program (rituximab, methotrexate, vincristine, procarbazine), the duration of lenalidomide administration was reduced to 8 days of each cycle (the standard duration of therapy is 21-28 days) and accompanying therapy was developed, including infusion load, administration of calcium folinate to remove methotrexate metabolites - to prevent nephrotoxicity from methotrexate (given the predominant excretion of lenalidomide by the kidneys), anticoagulant therapy (sodium heparin) for the entire period of therapy to prevent thrombosis and venous thromboembolism. Severe toxicity of grade 3-4 was not registered during the RL-MPV program, no statistically significant difference in the frequency and severity of complications compared to the previously used CNS-2015 protocol was obtained (Table 2).

Table 1.

RL-MPV program

RL-MPV Preparations Dose Route of administration Days of introduction Rituximab 375 mg/ ^m2 intravenous drip Day 0 of the course Methotrexate 3500 mg/ ^m2 intravenous drip 1 day of the course Vincristine 2 mg intravenous jet 1 day of the course Procarbazine 100 mg/ ^m2 orally from 2 to 8 days of the course Dacarbazine* 375 mg/ ^m2 intravenous jet Day 2 of the course Lenalidomide 25 mg orally from 2 to 8 days of the course * - if procarbazine is not available, it is replaced with dacarbazine

Table 2.

RL-MPV Program Proprietary Toxicity Data

Complications RL-MPV (protocol "CNS-2021"
n = 17 R-MPV (protocol "CNS-2015"
n = 36 Increased transaminase activity 2 (12%) 8 (26%) Acute kidney injury not requiring RRT* 4 (23.5%) 3 (10%) Neutropenia 2 (12%) 1 (3%) Thrombocytopenia 2 (12%) 0 Increase in body temperature >38°C 4 (23.5%) 5 (14%) Pneumonia 2(12%) 2(6%) Bloodstream infection 2 (12%) 2 (6%) Pulmonary embolism 0 1 (3%) Subarachnoid hemorrhage 0 1(3%) Skin rash 0 0 Diarrhea 0 0 *RRT - renal replacement therapy

The second difference of the created protocol was the replacement of the drug thiotepa with the drug carmustine, due to the absence of thiotepa in the territory of the Russian Federation, and the creation of a new protocol of high-dose conditioning according to the BBC program, the description of which is given in Table 3.

According to its mechanism of action, thiotepa belongs to the alkylating compounds from the ethyleneimine group, leading to disruption of nucleic acid metabolism and blockade of mitosis.

The choice of carmustine as an alternative to thiotepa was based on:

A similar mechanism of action is also an alkylating compound. Carmustine is a bifunctional chloroethyl derivative of nitrosourea. Unlike classical chloroethylamines, carmustine enters the cell by passive diffusion, which is due to its high lipophilicity. It has been experimentally established that chloroethyl derivatives of nitrosourea are alkylating agents. At physiological pH and temperature values, spontaneous hydrolysis of the chloroethylnitrosourea molecule occurs with the formation of chloroethyldiazonium ion and isocyanate. The chloroethyldiazonium ion reacts with bases and phosphate groups of DNA and RNA (alkylates) with the formation of chloroethyl adducts, which are then realized in DNA-DNA and DNA-protein crosslinks. The antitumor activity of chloroethyl nitrosourea derivatives is currently associated with the formation of O6-chloroethylguanine, which is then converted into O6, N1-ethanoguanine. As a result of the reaction of the latter with cytosine of the opposite DNA strand, the crosslink N3-cytosinyl-N1-guanyl-ethane is formed. The appearance of these and other crosslinks leads to a violation of the matrix function of DNA and induces the process of apoptosis in the damaged cell. The antitumor activity of drugs is determined not only by the intensity of alkylation of DNA guanine in position O6, but also by the duration of this modification, determined by the activity of reparation enzymes, primarily O6-alkylguanine DNA transferase (O6-AGT). The function of this enzyme is that it transfers alkyl groups from O6-alkylguanine DNA to its own cysteine residue. As a result, unmodified guanine in DNA is restored. During this reparation, the integrity of the DNA structure is not violated and the risk of post-reparation errors is reduced. Determination of the activity of O6-AGT in tumor cells can be used to predict their sensitivity to alkyl nitrosoureas. The second group of compounds formed during spontaneous hydrolysis of chloroethyl nitrosoureas are isocyanates. These electrophilic compounds specifically interact (carbamoylate) with sulfhydryl and amino groups of proteins, including enzymes, which leads to inhibition of their activity. Carbamoylation of proteins is mainly responsible for the toxic effects of chloroethyl derivatives of nitrosoureas. The decrease in the concentration of nitrosoureas in plasma is biphasic. The half-life of the drug in the distribution phase (t1/2a) is 6 min, and in the second phase (t1/2(3) - 68 min [10,11].

High bioavailability for the central nervous system (90%) due to the ability to overcome the blood-brain barrier.

Currently, carmustine is registered as a therapy for malignant neoplasms of the brain (glioblastoma, medulloblastoma, etc.) and as part of combination therapy for Hodgkin's lymphoma and non-Hodgkin's lymphomas as second-line therapy for relapsed disease. In the first line of therapy, there are no registered indications for the use of carmustine in lymphoproliferative diseases [11]. In the developed protocol "CNS-2021", carmustine was included in the first line of therapy as one of the components of high-dose conditioning before auto-HSCT.

In addition, the combination of VSV (carmustine, busulfan, cyclophosphamide) has never been used in the world before (according to the available literature). A possible reason is the possibility of increased toxicity with the combination of busulfan and carmustine.

Among the clinically significant adverse effects of carmustine are liver dysfunction, hyperbilirubinemia, visual impairment, neuroretinitis, myelodepression, pneumonitis and pneumosclerosis, renal dysfunction, and hyperpigmentation upon contact with skin. The main adverse effects of busulfan include: myelodepression, interstitial pulmonary fibrosis, hepatotoxicity, development of esophageal varices, hepatic vein thrombosis, and nephropathy due to hyperuricemia [11].

Among the cross-adverse effects when using busulfan and carmustine, hepatotoxicity (development of veno-occlusive disease when taking busulfan; increased activity of transferases, hyperbilirubinemia, liver failure when using carmustine), nephrotoxicity (renal failure - when using carmustine; nephropathy - when using busulfan) are distinguished.

When developing the CNS-2021 protocol, it was assumed that the standard dose of carmustine used in conditioning regimens (400 mg/ ^m2 ) would be used [12], however, in order to prevent possible hepatotoxicity and nephrotoxicity, the dose of carmustine was reduced to 400 mg once and accompanying therapy was developed.

Concomitant therapy includes infusion loading and the use of drugs that disrupt uric acid synthesis (allopurinol) - to prevent nephrotoxicity and nephropathy, anticoagulant therapy (sodium heparin) from the start of chemotherapy and for 14 days after its completion (prevention of veno-occlusive disease) and hepatoprotective drugs (ursodeoxycholic acid) for the entire treatment period. No severe grade 4 toxicity was recorded during the VVS program, no statistically significant difference in the frequency and severity of complications compared to the previously used CNS-2015 protocol was obtained (Table 2).

Table 3. Protocol for high-dose conditioning of VSV before auto-HSC

BBC + auto-HSCT Preparations Dose Route of administration Days of introduction Carmustine* 400 mg intravenous drip - 6 days before auto-HSCT Busulfan 4 mg/kg orally -5, -4 days before auto-HSCT Cyclophosphamide 60 mg/kg intravenous drip - 3,-2 days before auto-HSCT Transfusion of auto-HSC intravenous drip Day 0

Table 4. BBC's own toxicity data

Complications Air Force (protocol "CNS-2021"
n = 17 FA (protocol "CNS-2015"
n = 31 Stomatitis 17 (100%) 31 (100%) Enteropathy 7 (41%) 25 (80%) Urinary bacterial infection 0 2 (6%) Viral infections 10 (59%) 10 (34%) Increase in body temperature >38°C 10 (59%) 18 (60% Pneumonia 0 0 Bloodstream infection 0 4 (13%) Soft tissue infections 1 (6%) 1 (3%) Esophagitis 0 4 (13%) Convulsive syndrome 0 1 (3%) Myelotoxic agranulocytosis
Mean time to recovery of neutrophil count 17 (10%)
8 (7-12) days 31 (100%)
9 (8-14) days Thrombocytopenia
Mean time to recovery of neutrophil count 17 (100%)
10 (10-16) days 31 (100%)
12 (9-23) days Acute liver failure 0 0 Acute kidney injury 0 0

Taking into account the development of early relapses of the disease during the first 6 months based on the results of previously used treatment regimens, a stage of maintenance therapy was included in the new protocol. Previously, the need for maintenance therapy was proven only in patients with indolent ("sluggish") lymphomas (follicular lymphoma 1-3A cytological types, marginal zone cell lymphoma and mantle cell lymphoma). For patients with indolent lymphomas, maintenance therapy is carried out with the anti-CD20 monoclonal antibody rituximab for 2-3 years or more every 2-3 months (the interval and duration of maintenance therapy are determined individually). [13-16].

For indolent lymphomas, maintenance therapy can prevent the development of a full-blown relapse of the disease in some cases when minimal residual disease appears in the bone marrow, and as a result, it leads to an increase in overall survival. For aggressive lymphomas, such as DLBCL, Burkitt's lymphoma, etc., maintenance therapy is not performed. The lack of an advantage in increasing overall survival when using maintenance therapy for aggressive lymphomas has been proven by the results of randomized trials. In addition, serious adverse events or grade III/IV adverse events, including neutropenia and infections, were significantly more common in the maintenance therapy group [17]. However, a single-center study showed data indicating an improvement in progression-free survival in patients with systemic DLBCL when using anti-PD-1 inhibitors [18].

There are currently no data on the use of maintenance therapy with anti-PD-1 inhibitors in the first line for CNS PDLBCL. However, given the presence of early relapses of the disease, its use in patients with CNS PDLBCL is justified. The use of immune checkpoint inhibitors was chosen as maintenance therapy: anti-PD-1 inhibitors - nivolumab or pembrolizumab.

The use of maintenance therapy with checkpoint inhibitors (nivolumab/pembrolizumab) is due to the fact that CNS PDLBCL is characterized by activation of immune checkpoints, which is manifested by high expression of PD-L1 and PD-L2 on the surface of tumor cells, which are negative regulators of T-cell function [7]. Programmed cell death protein 1 (PD-1), expressed predominantly on activated T cells, is an important checkpoint receptor of the immune response. PD-1 transmits inhibitory signals to T cells after binding to PD-1 ligands (PD-L), PD-L1, or PD-L2 on tumor cells and in the tumor microenvironment. In addition to binding to PD-1, PD-L1 can bind to CD80/B7-1, and PD-L2 can bind to RGMb, promoting tolerance. B-cell lymphoma cells express major histocompatibility complex (MHC) class II and costimulatory molecules CD80/CD86, which are functionally active, allowing these cells to act as antigen-presenting cells. Up to 50% of patients with CNS PDLBCL lose expression of both MHC class I and class II. CNS PDLBCL also has a high frequency of 9p24.1 rearrangement associated with PD-L1/PD-L2 overexpression, resulting in decreased expression of MHC class II, which is associated with progressively decreased patient survival [19]. In other forms of B-NHL, the level of PD-L1 expression on tumor B cells is low: ~5% in follicular lymphoma, 10% in marginal zone cell lymphoma, and 0% in mantle cell lymphoma. A single retrospective study showed that when nivolumab was used in relapsed 4 patients with CNS PDLBCL, CR was achieved and no progression was observed in 3 cases with an observation period of 13 to 17 months [7].

The use of immune checkpoint inhibitors is aimed at switching on T-cell immunity due to the inhibition of PD-1, which blocks the activity of T-cells. Currently, the use of nivolumab and pembrolizumab is registered only for the treatment of several types of cancer and in relapsed Hodgkin's lymphoma after 3 lines of previous therapy, including auto-HSCT [20,21], as maintenance therapy for patients with CNS PDLBCL has not been used. Thus, the fundamental difference of the developed approach is the inclusion of checkpoint inhibitors (nivolumab, pembrolizumab) in the first line in patients with primary CNS lymphoma within 6 months after auto-HSCT (Table 5).

Among the main adverse events when using anti-PD-1 inhibitors are autoimmune complications - thrombocytopenia, anemia, thyroiditis, myocarditis, pulmonitis, hepatitis, colitis, etc. [20, 21]. However, when used within the framework of the CNS-2021 protocol, no adverse events were registered in any patient at the stage of maintenance therapy.

Table 5. Maintenance therapy after auto-HSCT

Supportive therapy Preparations Dose Route of administration Days of introduction Nivolumab from 3 mg/kg to 40 mg/day intravenous drip every 2 weeks for 6 months 3 months after auto-HSCT Pembrolizumab from 2 mg/kg to 100 mg/day intravenous drip every 2 weeks for 6 months 3 months after auto-HSCT

The description further provides a disclosure of the essence of the invention and its implementation.

Before starting therapy, the patient is examined, which includes the following.

A morphological study, clinical blood test, general urine test, biochemical blood test (total protein and protein fractions, creatinine, urea, uric acid, bilirubin, ALT, AST, alkaline phosphatase, LDH, amylase, electrolytes, glucose), blood test for acid-base balance (as indicated) are performed.

A comprehensive hematological analysis is performed, which allows one to assess how effectively the patient’s hemostasis works (coagulogram (APTT, PTI, TV, fibrinogen, XIIa-dependent fibrinolysis, D-dimer)).

A comprehensive molecular genetic study is performed, which allows assessing the genetic risk of thrombophilia. Immunochemical study of serum and urine, CRP, β2-microglobulin. The patient's blood is tested for hepatitis, HIV, syphilis. The patient's blood type and Rh factor are determined. The Reberg test is taken (creatinine clearance is determined using the Cockcroft-Gault formula). The patient undergoes ECG, echocardiography, magnetic resonance imaging of the brain with intravenous contrast, lumbar puncture with intrathecal administration of three cytostatics (methotrexate 15 mg, cytarabine 30 mg, dexamethasone 4 mg) with cytological, virological, microbiological studies of cerebrospinal fluid, a study of B-cell clonality in CSF, an immunophenotypic study of cerebrospinal fluid (in the absence of contraindications to lumbar puncture), electroencephalogram, MRI of the cerebral vessels (MR angiography) (as indicated), computed tomography of the abdominal organs, chest, pelvis / PET / CT study.

Verification of the morphological variant of the focal CNS formation is carried out (stereotactic biopsy, craniotomy with biopsy/removal of the intracerebral formation): histological and immunohistochemical studies on histological preparations of tumor biopsies (CD20, CD45, CD79, MuM1, BCL6, BCL2, CD10, Ki-67).

A cytogenetic study is performed - FISH for BCL2, BCL6, c-MYC, deletion 17p13, a molecular genetic study for the presence of the p.L625P mutation in the MYD88 gene in a tumor biopsy and free tumor DNA in the blood serum and cerebrospinal fluid (if a molecular hematology laboratory is available).

The patient undergoes a consultation with an ophthalmologist, a neurologist, an examination by a gynecologist, and a pregnancy test (for women).

A trephine biopsy is performed with a cytological examination of the bone marrow (myelogram), a histological examination of the trephine biopsy, and a study of the B-cell clonality of the bone marrow.

Fibrogastroduodenoscopy and fibrocolonoscopy with biopsy are performed in the presence of visible changes in the mucous membrane (as indicated)

At the patient’s request, sperm cryopreservation can be performed.

As noted earlier, the claimed invention consists of 3 stages of therapy included in a single protocol for the treatment of patients with CNS PDBCCL - "CNS-2021" (Figure 1).

At the first stage of therapy, the tumor mass is reduced and the neurological defect is eliminated by using a short-pulse program (R-MPV + lenalidomide). The list of drugs, dosage, route of administration and days of administration within one course of induction chemotherapy (CT) are given in Table 6.

As part of the first stage of the treatment protocol for patients with CNS PDBCCL, 4 cycles of induction chemotherapy are performed. The intervals between courses of induction chemotherapy are 6 (after 1.3 courses) and 12 days (after 2.4 courses).

Table 6

RL-MPV Preparations Dose Route of administration Days of introduction Rituximab 375 mg/ ^m2 intravenous drip 1 day of the course Methotrexate 3500 mg/ ^m2 intravenous drip 1 day of the course Vincristine 2 mg intravenous jet 1 day of the course Procarbazine 100 mg/ ^m2 orally from 2 to 8 days of the course Lenalidomide 25 mg orally from 2 to 8 days of the course

The intervals between chemotherapy courses are increasing for the entire period necessary to relieve the following complications:

Development of severe infectious complications requiring massive antimicrobial therapy;

Development of severe toxic complications (renal, liver, cardiac toxicity);

Development of long periods of cytopenia (leukopenia, thrombocytopenia), requiring replacement therapy with blood components.

As part of the first stage of therapy (RL-MPV) According to the treatment protocol for patients with CNS PDVC, medications are prescribed in the following order.

Rituximab is prescribed at a dose of 375 mg/m² on day 1 of the course. The drug is dissolved in 500 ml of 0.9% sodium chloride saline and administered intravenously using an infusion pump at an initial rate of 50 mg/h, with a further increase in the rate by 50 mg/h every hour, to a maximum of 400 mg/h. Premedication is administered 30 minutes before the administration of rituximab (analgesic/antipyretic: ketoprofen 100 mg intravenously by jet stream; antihistamine: diphenhydramine 10 mg intravenously by jet stream, glucocorticosteroid: dexamethasone 4 mg intravenously by jet stream).

Methotrexate is prescribed at a dose of 3.5 g / m² on the 2nd day of the RL-MPV course. The drug is dissolved in 1000 ml of physiological solution of 0.9% sodium chloride and administered over 2 hours. The day before and during the first 3 days of the course, a water load of at least 2 liters per day is carried out, 4% sodium bicarbonate is administered at a dose of 200 ml over 24 hours. To reduce the toxic effect of the drug, 6 hours after the end of the infusion, calcium folinate 25 mg intravenously by jet stream and 25 mg orally is administered every 3 hours (8 times a day). Monitoring of the concentration of methotrexate in the blood serum, the level of creatinine, urea, bilirubin, AST, ALT is carried out 24 hours after the start of the drug infusion. If the serum methotrexate level is high, calcium folinate administration is continued until the drug is completely eliminated (with dose adjustment depending on the methotrexate concentration).

Vincristine is prescribed at a dose of 2 mg/day on the 2nd day of the course. The drug is dissolved in 20 ml of physiological solution and administered intravenously by jet stream.

Procarbazine is prescribed at a dose of 100 mg/m² orally from the 2nd to the 8th day of each odd course (1,3).

Lenalidomide is administered at a dose of 25 mg orally from day 2 to day 10 of each odd-numbered course (1,3).

As part of the first stage of therapy (RL-MPV), accompanying therapy (infusion load) is carried out, which includes:

Water load. Hyperhydration is carried out at a rate of 3000 ml/m²intravenously per day, starting 1-2 days before the start of chemotherapy and ending 3-5 days after its completion, and correction of metabolic disorders. To assess the state of water balance, prevent volume overload, weigh the patient daily, monitor central venous pressure 2 times a day, diuresis and fluid balance - every 6 hours. Monitoring of electrolytes (especially potassium and calcium), creatinine, urea, uric acid, total protein, albumin, phosphates, urine pH - before polychemotherapy and on the second day after it. Monitoring of diuresis, fluid balance. In case of insufficient urine output - stimulation with furosemide at a dose of 1-10 mg / kg, in case of hypoalbuminemia - normalization of the albumin level.

Hypouricemic therapy. Allopurinol is prescribed orally at a dose of 300 mg per day for 10 days of chemotherapy in each course. Allopurinol inhibits the breakdown of xanthine and hypoxanthine to uric acid, inhibiting xanthine oxidase and reducing the formation of urates in the serum.

Restores folic acid synthesis. In order to restore folic acid synthesis, 12 hours after the completion of methotrexate infusion, calcium folinate is prescribed at a dose of 25 mg intravenously by jet stream in 20 ml and in case of nausea and vomiting with jet stream intravenously by drip in 100 ml of 0.9% sodium chloride 8 times a day. The same dose of calcium folinate is prescribed orally 8 times a day at equal time intervals. The residual concentration of methotrexate in the serum is determined 24 hours after the start of the infusion and then, if necessary, every 6 hours until it is normalized. Usually, the concentration of methotrexate is normalized in 24-48 hours (0 mmol/l).

Antiulcer therapy is carried out. For the prevention of erosive gastritis, omeprazole is prescribed, 20 mg 2 times a day. If oral administration of drugs is impossible, omeprazole 20 mg 2 times a day intravenously by jet stream.

Anticoagulant therapy is being administered. To prevent thrombotic complications, heparin is prescribed at an initial dose of 500 units/hour under the control of APTT. If hypercoagulation persists, the dose is increased by 250 units/hour until APTT equals 1.5-2.0 norms. If it is impossible to conduct a round-the-clock heparin infusion, low-molecular heparins are prescribed subcutaneously. Criteria for stopping heparin therapy: a decrease in the platelet count below 50×10⁹/l in the presence of a large tumor mass; a decrease in the platelet count below 100×10⁹/l with complete tumor regression; hemorrhagic syndrome.

Antiemetic therapy is administered. Before the introduction of antitumor drugs, ondansetron is prescribed at a dose of 8 mg intravenously by jet stream. If nausea occurs, an additional dose of the drug may be administered.

It is being held anticonvulsant therapy. For the purpose of preventing convulsive syndrome, the anticonvulsant drug levetiracetam is prescribed in a dosage of 500 mg/day to a maximum dose of 3 g/day, with the dosage adjusted under the control of an encephalogram.

If necessary, anti-edema therapy is prescribed using osmotic diuretics (mannitol in the form of a 24-hour infusion) and glucocorticosteroids (dexamethasone).

In the second stage of therapy auto-HSCT is performed in a myeloablative conditioning regimen (VVS - carmustine, busulfan, cyclophosphamide), aimed at eradicating a tumor clone with the properties of slowly dividing stem cells. The list of drugs, dosage, route of administration and days of administration are given in Table 7.

Table 7 High-dose chemotherapy program for VSV and auto-HSCT

BBC + auto-HSCT Preparations Dose Route of administration Days of introduction Carmustine* 400 mg intravenous drip - 6 days before auto-HSCT Busulfan 4 mg/kg orally -5, -4 days before auto-HSCT Cyclophosphamide 60 mg/kg intravenous drip - 3,-2 days before auto-HSCT Transfusion of auto-HSC intravenous drip Day 0

As part of the second stage of therapy of the treatment protocol for patients with CNS PDBCCL, medications are prescribed in the following order.

Carmustine is prescribed in a dose of 400 mg. The drug is diluted in 500 ml of physiological solution of 0.9% sodium chloride and administered intravenously by drip over 2 hours on the 6th day before auto-HSCT.

Busulfan is prescribed in a dose of 4 mg/kg orally on days -5, -4 before auto-HSCT. In order to prevent convulsive syndrome, anticonvulsants are prescribed: levetiracetam in a dose of 500 mg/day to a maximum dose of 3 g/day (the dose is adjusted under the control of the encephalogram and the degree of convulsive activity) or finlepsin in a dose of 200 mg/day and relanium in a dose of 10 mg/day, on the days of taking busulfan.

Cyclophosphamide is administered at a dose of 60 mg/kg on days -3 and -2 before auto-HSCT. The drug is diluted in 500 ml of 0.9% sodium chloride physiological solution. The duration of cyclophosphamide infusion is 2 hours. Dose adjustment: if the bilirubin level is 3-5 times the norm or AST activity is over 180 U/L, the dose is reduced by 25%. To reduce the toxic effect of the drug, uromitexan is administered simultaneously with cyclophosphamide infusion, 4 and 8 hours after the start of the infusion.

At the 2nd stage of therapy (BBC), accompanying therapy is carried out, which includes:

Water load. Hyperhydration is performed at the rate of 1000 ml/ ^m2 per day intravenously, starting 1-2 days before the start of chemotherapy and then for the entire period of therapy. To assess the state of water balance, prevent volume overload, the patient is weighed daily, central venous pressure is monitored 2 times a day, diuresis and fluid balance - every 6 hours. Monitoring of diuresis, fluid balance. In case of insufficient urine output - stimulation with furosemide at a dose of 1-10 mg/kg, in case of hypoalbuminemia - normalization of the albumin level.

Hypouricemic therapy is performed. Allopurinol is prescribed orally at a dose of 300 mg per day for 10 days of chemotherapy in each course. Allopurinol inhibits the breakdown of xanthine and hypoxanthine to uric acid, inhibiting xanthine oxidase and reducing the formation of urates in the serum.

Antiulcer therapy is being carried out. For the prevention of erosive gastritis, omeprazole is prescribed, 20 mg 2 times a day, or ranitidine, 150 mg 2 times a day. If oral administration of drugs is impossible, famotidine at a dosage of 20 mg 2 times a day intravenously by jet stream, or omeprazole at a dosage of 20 mg 2 times a day intravenously by jet stream 30 minutes before meals.

Anticoagulant therapy is being administered. To prevent thrombotic complications, heparin is prescribed at a dose of 500 units/hour under the control of APTT. Heparin therapy begins 1-2 days before the start of chemotherapy and continues up to 14 days after auto-HSC transfusion, regardless of the platelet count. If the platelet count decreases to less than 50x10⁹/l or the development of hemorrhagic complications, replacement transfusions with platelet concentrate are performed.

Antiemetic therapy is administered. Before the introduction of antitumor drugs, ondansetron is prescribed at a dose of 8 mg intravenously by jet stream. If nausea occurs, an additional dose of the drug may be administered.

Anticonvulsant therapy is carried out. In order to prevent convulsive syndrome, anticonvulsant drugs are prescribed (levetiracetam, maximum dose 3 g/day, the dose is adjusted under the control of the encephalogram).

Hepatoprotective therapy is carried out. To prevent hepatotoxicity, ursodeoxycholic acid is prescribed at a dose of 250 mg x 3 times a day orally, with a small amount of water.

The third maintenance stage is aimed at turning on T-cell immunity through the use of PD immune checkpoint inhibitors: nivolumab, pembrolizumab for 6 months.

As part of the third maintenance stage of therapy of the treatment protocol for patients with CNS PDBCCL, medications are prescribed in the following order.

Nivolumab is administered at a dose of at least 40 mg per day and up to 3 mg/kg/day 3 months after auto-HSCT for 6 months every 2 weeks. The drug is diluted in 150 ml of 0.9% sodium chloride saline and administered intravenously by drip over 40-60 minutes. Before the administration of nivolumab, ketoprofen should be administered at a dose of 100 mg for premedication.

Pembrolizumab is administered at a dose of at least 100 mg per day and up to 2 mg/kg/day 3 months after auto-HSCT for 6 months every 3 weeks. The drug is diluted in 150 ml of 0.9% sodium chloride saline and administered intravenously by drip over 40-60 minutes. Before the administration of pembrolizumab, ketoprofen should be administered at a dose of 100 mg for premedication.

Intermediate staging of the patient is carried out at the stages of induction and consolidation of remission (after each course of induction, after auto-HSCT) by implementing:

MRI of the brain with bolus contrast enhancement after each course of chemotherapy;

Encephalogram (as indicated);

Lumbar puncture with cytological, immunophenotypic, molecular genetic (B-cell clonality, MYD88 mutations) studies.

Control staging of the patient is carried out at the maintenance stage of therapy and every 3 months for the following six months and then every 6 months for 5 years by implementing:

MRI of the brain with bolus contrast enhancement

Encephalogram (as indicated);

Lumbar puncture with cytological, immunophenotypic, molecular genetic (B-cell clonality, MYD88 mutations) studies (subject to the presence of neuroleukemia at onset).

The patient's follow-up examination is carried out at the following time intervals:

- during the 1st year - every 3 months;

- from the 2nd year - every 6 months.

The essence of the invention is explained by examples of implementation and use, which do not limit the scope of legal protection.

Clinical case No. 1.

Patient Zh., 46 years old. History of the disease since March 2021, when severe headaches, episodes of dizziness, disorientation, and memory loss first appeared. According to MRI of the brain, a space-occupying lesion in the posterior cranial fossa on the right with invasion into the right cerebellar hemisphere, with severe edema of the right cerebellar hemisphere, internal occlusive hydrocephalus, and axial herniation were detected. In March 2021, a suboccipital paramedian resection craniotomy on the right was performed, removing the tumor from the right cerebellar hemisphere. According to histological and IHC studies, diffuse large B-cell lymphoma is suspected. In order to exclude the generalization of the process, PET/CT was performed in May 2021: in the right occipital region, there is a focus of hypermetabolism 50x40x30 mm, SUVmax 25.59. No data were found for the presence of foci of pathological density in other localizations.

The patient sought consultation at the Federal State Budgetary Institution "National Medical Research Center of Hematology" of the Ministry of Health of the Russian Federation. Based on histological and immunohistochemical studies, a diagnosis of primary DLBCL of the CNS was established: diffuse lymphoid infiltrate of medium and large cells with round-oval nuclei, morphology of centro- and immunoblasts. Tumor cells of the lymphoid infiltrate expressed CD20+, MUM.1+, BCL-6+, BCL-2+, c-Myc-positive <10% of tumor cells. The proliferative activity index according to Ki-67 was 70-80%.

Given the severity of the condition, the space-occupying lesion of the brain, and the risk of herniation, from May 2021 to June 2021, 4 courses of chemotherapy were administered according to the developed RL-MPV program (rituximab 375 mg/ ^m2 intravenously by drip on day 1 of the cycle, methotrexate 3500 mg/ ^m2 intravenously by drip on day 2 of the cycle for 2 hours, vincristine 2 mg intravenously by jet stream on day 2 of the cycle, procarbazine 100 mg/ ^m2 orally from days 2 to 8 of the cycle, lenalidomide 25 mg/day per os from days 2 to 8 of the cycle). Tolerability is satisfactory. No severe infectious and toxic complications were registered in the inter-course intervals. After the 2nd course of chemotherapy, leukopoiesis was stimulated to collect and prepare auto-HSC, collection and preparation of auto-HSC was performed. According to the control MRI of the brain (from 09.2021), complete remission of the disease was achieved.

In order to consolidate remission, high-dose chemotherapy (HDC) was administered in the VSV conditioning mode: carmustine 400 mg/day intravenously by drip on day -6 before auto-HSCT, busulfan 4 mg/kg orally on days -5, -4 before auto-HSCT, cyclophosphamide 60 mg/kg intravenously by drip on days -3, -2 before auto-HSCT. On day 0, a transfusion of 4.2×10 ⁶ /kg CD34+ cells was performed. The transfusion was tolerated satisfactorily. The post-transplant period was complicated by the development of myelotoxic agranulocytosis, thrombocytopenia, and infectious complications. Infection foci included stomatitis and anal fissure. Stimulation of hematopoiesis, massive replacement blood transfusion therapy, and antimicrobial therapy were administered. Nine days after auto-HSCT, restoration of the number of neutrophils and platelets, regression of infectious complications were noted. Maintenance therapy with nivolumab at a dose of 3 mg/kg/day every 2 weeks was administered for 6 months after auto-HSCT. Currently, with an observation period of +29 months after auto-HSCT, complete remission of the disease is maintained.

Clinical case No. 2.

Patient, F., 44 years old. History of the disease since February 2021, when after a new coronavirus infection (from January 2021), the patient noted a decrease in short-term memory, in March, a complete loss of memory for all events, severe drowsiness, apathy. On March 19, 2021, an electroencephalogram was performed, according to which moderate disturbances without epileptic activity of the brain, dysrhythmia were revealed.

On March 21, 2021, an MRI of the brain was performed: a formation was detected in the left hemisphere of the brain measuring 1.3 × 1.3 × 1.2 cm, with a zone of perifocal edema, compression of the anterior horn of the right lateral ventricle, a similar formation was detected in the area of the posterior leg of the internal capsule, measuring 1.9 × 2.1 × 1.9 cm.

As part of the oncosearch, a PET/CT study was performed: no data were found to indicate the presence of pathological foci of metabolic activity in other localizations.

Due to the presence of severe perifocal edema of the brain substance, dislocation of midline structures, and the threat of wedging, anti-edema therapy with glucocorticosteroid hormones was started. Against the background of the therapy, regression of tumor formations in the brain was noted, and therefore it was not possible to perform a biopsy at that time. Dexamethasone therapy was discontinued, 3 weeks after cancellation, a control MRI was performed (from 04/25/2021) - an increase in the size of tumor foci, the appearance of a new lesion measuring 3.4 mm were noted. On May 22, 2021, another MRI of the brain was performed: further negative dynamics were revealed - a formation in the area of the internal capsule 31 × 28 × 28 mm, with perifocal edema; transverse dislocation of structures, axial dislocation of structures.

In May 2021, a stereotactic biopsy with a biopsy of the tumor formation was performed: a lymphoproliferative disease was suspected. She independently sought consultation at the Federal State Budgetary Institution National Medical Research Center of Hematology of the Ministry of Health of the Russian Federation.

Based on histological and immunohistochemical studies, a diagnosis of primary DLBCL of the CNS was established: a massive infiltrate of large cells with the morphology of centroblasts and immunoblasts, areas of perivascular growth. Tumor cells expressed CD20+, BCL-2+, BCL-6+, MUM.1+, c-Myc - 40% of tumor cells. The proliferative activity index according to Ki-67 was 80% of positive cells.

Upon admission, the patient's condition was severe due to the onset of the underlying disease with CNS damage and neurological deficit. In the period from June 2021 to August 2021, the patient underwent 4 courses of chemotherapy according to the developed RL-MPV program (rituximab 375 mg/ ^m2 intravenously by drip on day 1 of the cycle, methotrexate 3500 mg/ ^m2 intravenously by drip on day 2 of the cycle for 2 hours, vincristine 2 mg intravenously by jet stream on day 2 of the cycle, procarbazine 100 mg/ ^m2 orally from days 2 to 8 of the cycle, lenalidomide 25 mg/day orally from days 2 to 8 of the cycle). Tolerability is satisfactory. No severe infectious and toxic complications were registered in the inter-course intervals. After the 2nd course of chemotherapy, leukopoiesis was stimulated to collect and prepare auto-HSC, collection and preparation of auto-HSC was performed. According to the control MRI of the brain (from 08.2021), complete remission of the disease was achieved.

In order to consolidate remission, high-dose chemotherapy (HDC) was administered in the VSV conditioning mode: carmustine 400 mg/day intravenously by drip on day -6 before auto-HSCT, busulfan 4 mg/kg orally on days -5, -4 before auto-HSCT, cyclophosphamide 60 mg/kg intravenously by drip on days -3, -2 before auto-HSCT. On day 0, a transfusion of 4.5×10 ⁶ /kg CD34+ cells was performed. The transfusion was tolerated satisfactorily. The post-transplant period was complicated by the development of myelotoxic agranulocytosis, thrombocytopenia, and infectious complications. Infection foci included stomatitis and enteropathy. Stimulation of hematopoiesis, replacement blood transfusion therapy, and antimicrobial therapy were administered. 15 days after auto-HSCT, restoration of the number of neutrophils and platelets, regression of infectious complications were noted. For 6 months after auto-HSCT, maintenance therapy with nivolumab was administered at a dose of 3 mg/kg/day every 2 weeks. Currently, with an observation period of +28 months after auto-HSCT, complete remission of the disease is maintained.

Clinical case No. 3.

Patient M., 51 years old. History of the disease since November 2021, when headache radiating to the neck, dizziness, unsteadiness of gait, nausea, increased blood pressure to 160/100 mm Hg, and motor aphasia first appeared. According to MRI of the brain, a tumor of the left temporoparietal localization 62 * 48 * 47 mm was detected, single foci up to 3 mm in the frontal lobes. In November 2021, the patient underwent osteoplastic trepanation of the skull in the left parietal-occipital region, microsurgical removal of the tumor in the left occipital lobe of the brain. During the initial histological examination (without IHC), a lymphoproliferative disease was suspected. The patient sought consultation at the Federal State Budgetary Institution "NMITs of Hematology" of the Ministry of Health of the Russian Federation.

Based on histological and immunohistochemical studies, a diagnosis of primary DLBCL of the CNS was established: a massive infiltrate of large cells with the morphology of centroblasts and immunoblasts, areas of perivascular growth. Tumor cells expressed CD20+, BCL-2+, BCL-6+, MUM.1+. The proliferative activity index according to Ki-67 was 90% of positive cells.

Upon admission, the patient's condition is severe, the severity of the condition is due to the onset of the underlying disease with damage to the central nervous system, decreased cognitive functions (aphasia, apraxia, memory loss, problems with verbal communication). Given the severity of the condition, in the period from January to March 2021, the patient underwent 4 courses of chemotherapy according to the developed RL-MPV program (rituximab 375 mg / m ² intravenously by drip on day 1 of the cycle, methotrexate 3500 mg / m ² intravenously by drip on day 2 of the cycle for 2 hours, vincristine 2 mg intravenously by jet stream on day 2 of the cycle, procarbazine 100 mg / m ² orally from days 2 to 8 of the cycle, lenalidomide 25 mg / day orally from days 2 to 8 of the cycle). Tolerability is satisfactory. No severe infectious or toxic complications were registered in the intervals between courses. After the 2nd course of chemotherapy, leukopoiesis was stimulated to collect and prepare auto-HSC, collection and preparation of auto-HSC was performed. According to the control MRI of the brain (from 03.2022), complete remission of the disease was achieved.

In order to consolidate remission, high-dose chemotherapy (HDC) was administered in the VSV conditioning mode: carmustine 400 mg/day intravenously by drip on day -6 before auto-HSCT, busulfan 4 mg/kg orally on days -5, -4 before auto-HSCT, cyclophosphamide 60 mg/kg intravenously by drip on days -3, -2 before auto-HSCT. On day 0, a transfusion of 8.8×10 ⁶ /kg CD34+ cells was performed. The patient tolerated the transfusion satisfactorily. The post-transplant period was complicated by the development of myelotoxic agranulocytosis, thrombocytopenia, and infectious complications. Among the foci of infection was stomatitis. Stimulation of hematopoiesis, replacement blood transfusion therapy, and antimicrobial therapy were performed. Nine days after auto-HSCT, restoration of the number of neutrophils and platelets, regression of infectious complications were noted. Maintenance therapy with nivolumab at a dose of 3 mg/kg/day every 2 weeks was administered for 6 months after auto-HSCT. Currently, with an observation period of +21 months after auto-HSCT, complete remission of the disease is maintained.

Clinical case No. 4.

Patient M., 20 years old. History of the disease since February 2022, when neurological symptoms in the form of short-term memory impairment and dizziness first appeared. According to MRI of the brain from March 2022, diffuse brain damage was revealed with a predominant lesion of the deep sections, spreading along the ependyma of the lateral ventricles with a transition to the genu of the corpus callosum. According to PET CT from 04/07/2022: foci of pathological metabolic activity were not detected. In June 2022, a stereotactic biopsy of the basal ganglia tumor on the right was performed at the Burdenko National Medical Research Center of Neurosurgery of the Ministry of Health of the Russian Federation. Based on the histological examination, a diagnosis of diffuse large B-cell lymphoma of the central nervous system was established.

For further treatment, the patient was referred to the Federal State Budgetary Institution "National Medical Research Center of Hematology" of the Ministry of Health of the Russian Federation. Based on the review of the finished histological and immunohistochemical preparations of the brain tumor biopsy, the diagnosis of primary DLBCL of the CNS was confirmed: large cells with round nuclei, distinct nucleoli, pronounced morphological signs of apoptosis. Infiltrate cells expressed CD20+, CD79a+, MUM.1+, BCL-2+, BCL-6+. The proliferative activity index for Ki-67 averaged 40% positive cells.

Given the severity of the condition, massive tumor damage to the central nervous system, from June 2022 to July 2022, the patient underwent 4 courses of chemotherapy according to the developed RL-MPV program (rituximab 375 mg / m ² intravenously by drip on day 1 of the cycle, methotrexate 3500 mg / m ² intravenously by drip on day 2 of the cycle for 2 hours, vincristine 2 mg intravenously by jet stream on day 2 of the cycle, procarbazine 100 mg / m ² orally from days 2 to 8 of the cycle, lenalidomide 25 mg / day orally from days 2 to 8 of the cycle). Tolerability is satisfactory. No severe infectious and toxic complications were registered in the inter-course intervals. After the 2nd course of chemotherapy, leukopoiesis was stimulated to collect and prepare auto-HSC, collection and preparation of auto-HSC was performed. According to the control MRI of the brain (from 09.2021), complete remission of the disease was achieved.

In order to consolidate remission, high-dose chemotherapy (HDC) was administered in the VSV conditioning mode: carmustine 400 mg/day intravenously by drip on day -6 before auto-HSCT, busulfan 4 mg/kg orally on days -5, -4 before auto-HSCT, cyclophosphamide 60 mg/kg intravenously by drip on days -3, -2 before auto-HSCT. On day 0, a transfusion of 5.2×10 ⁶ /kg CD34+ cells was performed. The transfusion was tolerated satisfactorily. The post-transplant period was complicated by the development of myelotoxic agranulocytosis, thrombocytopenia, and infectious complications. Infectious foci included mucositis, enteropathy, and inflammatory infiltrate in the right axillary region. Stimulation of hematopoiesis, massive replacement blood transfusion therapy, and antimicrobial therapy were performed. 10 days after auto-HSCT, restoration of the number of neutrophils and platelets and regression of infectious complications were noted. Maintenance therapy with pembrolizumab at a dose of 2 mg/kg/day every 3 weeks was performed for 6 months after auto-HSCT. Currently, with an observation period of +16 months after auto-HSCT, complete remission of the disease is maintained.

Clinical case No. 5.

Patient, M., 63 years old. History of the disease since June 2022 with the development of short-term memory impairment. According to MRI of the brain dated 06.2022, a space-occupying lesion was detected in the frontal lobe on the right, measuring up to 35x30x32 mm, surrounded by an edema zone of up to 22 mm without displacement of the midline structures. In June 2022, at the regional clinical hospital at the place of residence, a bone-plastic craniotomy was performed with removal of a tumor in the frontal lobe on the right; lymphoproliferative disease was suspected. The patient independently sought consultation at the Federal State Budgetary Institution "National Medical Research Center of Hematology" of the Ministry of Health of the Russian Federation.

Based on histological and immunohistochemical studies, a diagnosis of primary DLBCL of the CNS was established: brain tissue particles with a massive large-focal infiltrate of large cells with the morphology of centroblasts and immunoblasts, areas of perivascular growth. Tumor substrate cells express CD20+, MUM.1+. The proliferative activity index for Ki-67 is 80-90% positive cells.

From the history of concomitant diseases: type 2 diabetes mellitus, paroxysmal atrial fibrillation, stage III hypertension, LV hypertrophy with risk of grade 4 cardiovascular events.

Considering the severity of the condition caused by the onset of the underlying disease with CNS damage, neurological deficit, and concomitant comorbidity, in the period from June 2022 to September 2022, the patient underwent 4 courses of chemotherapy according to the developed RL-MPV program (rituximab 375 mg/ ^m2 intravenously by drip on day 1 of the cycle, methotrexate 3500 mg/ ^m2 intravenously by drip on day 2 of the cycle for 2 hours, vincristine 2 mg intravenously by jet stream on day 2 of the cycle, procarbazine 100 mg/ ^m2 orally from days 2 to 8 of the cycle, lenalidomide 25 mg/day orally from days 2 to 8 of the cycle). Tolerability is satisfactory. No severe infectious and toxic complications were registered in the inter-course intervals. After the 2nd course of chemotherapy, leukopoiesis stimulation was performed to collect and prepare auto-HSC, collection and preparation of auto-HSC was performed. According to the control MRI of the brain (from 09.2022), complete remission of the disease was achieved.

In order to consolidate remission, high-dose chemotherapy (HDC) was administered in the VSV conditioning mode: carmustine 400 mg/day intravenously by drip on day -6 before auto-HSCT, busulfan 4 mg/kg orally on days -5, -4 before auto-HSCT, cyclophosphamide 60 mg/kg intravenously by drip on days -3, -2 before auto-HSCT. On day 0, a transfusion of 12x10 ⁶ /kg CD34+ cells was performed. The patient tolerated the transfusion satisfactorily. The post-transplant period was complicated by the development of myelotoxic agranulocytosis, thrombocytopenia, and infectious complications. Infectious foci included pneumonia, stomatitis, and enteropathy. Stimulation of hematopoiesis, replacement blood transfusion therapy, and antimicrobial therapy were administered. Ten days after auto-HSCT, restoration of the number of neutrophils and platelets, regression of infectious complications were noted. Maintenance therapy with nivolumab at a dose of 3 mg/kg/day every 2 weeks was administered for 6 months after auto-HSCT. Currently, with an observation period of +15 months after auto-HSCT, complete remission of the disease is maintained.

Clinical case No. 6.

Patient Zh., 39 years old. History of the disease since April 2022, when she first noted an episode of dizziness, speech impairment, numbness in the left lower limb against the background of an increase in blood pressure to 170/110 mm Hg. At the place of residence, with a suspicion of acute cerebrovascular accident, a CT scan of the brain was performed, according to which cystic-glial changes in the cerebellum were revealed. In May 2022, a deterioration in the condition in the form of increased dizziness, the appearance of severe headaches, an episode of loss of consciousness was noted, an MRI of the brain was performed, according to the results of which a formation in the left frontal lobe was revealed, measuring 35x37x29 mm. According to emergency indications, the patient underwent stereotactic biopsy of the formation in the left frontal lobe. Based on the histological examination, a lymphoproliferative disease was suspected.

The patient independently sought consultation at the Federal State Budgetary Institution "National Medical Research Center of Hematology" of the Ministry of Health of the Russian Federation. Based on the review of histological and immunohistochemical studies, a diagnosis of primary DLBCL of the CNS was established: brain tissue particles with small focal infiltrates of large lymphoid cells with the morphology of centroblasts and immunoblasts, frequent mitotic figures. Tumor substrate cells monomorphically express CD20+, MUM.1+. The proliferative activity index for Ki-67 is up to 80% of positive cells.

Upon admission, the patient's condition was severe. The severity of the condition was due to the underlying disease with damage to the central nervous system, neurological symptoms in the form of unsteadiness of gait, dizziness.

Given the severity of the condition, in the period from August 2022 to October 2022, the patient underwent 4 courses of chemotherapy according to the developed RL-MPV program (rituximab 375 mg / m ² intravenously by drip on day 1 of the cycle, methotrexate 3500 mg / m ² intravenously by drip on day 2 of the cycle for 2 hours, vincristine 2 mg intravenously by jet stream on day 2 of the cycle, procarbazine 100 mg / m ² orally from days 2 to 8 of the cycle, lenalidomide 25 mg / day orally from days 2 to 8 of the cycle). Tolerability is satisfactory. No severe infectious and toxic complications were registered in the inter-course intervals. After the 2nd course of chemotherapy, leukopoiesis stimulation was performed to collect and prepare auto-HSC, collection and preparation of auto-HSC was performed. According to the control MRI of the brain (from 10.2022), complete remission of the disease was achieved.

In order to consolidate remission, high-dose chemotherapy (HDC) was administered in the VSV conditioning mode: carmustine 400 mg/day intravenously by drip on day -6 before auto-HSCT, busulfan 4 mg/kg per os on days -5, -4 before auto-HSCT, cyclophosphamide 60 mg/kg intravenously by drip on days -3, -2 before auto-HSCT. On day 0, a transfusion of 10.6x10 ⁶ /kg CD34+ cells was performed. The transfusion was tolerated satisfactorily. The post-transplant period was complicated by the development of myelotoxic agranulocytosis, thrombocytopenia, and infectious complications. Infectious foci included febrile fever, stomatitis, and enteropathy. Stimulation of hematopoiesis, replacement blood transfusion therapy, and antimicrobial therapy were administered. 12 days after auto-HSCT, restoration of the number of neutrophils and platelets, regression of infectious complications were noted. For 6 months after auto-HSCT, maintenance therapy with nivolumab was administered at a dose of 3 mg/kg/day every 2 weeks. Currently, with an observation period of +14 months after auto-HSCT, complete remission of the disease is maintained.

Clinical case No. 7.

Patient Zh., 54 years old. History of the disease since October 2022, when confusion, unsteadiness of gait, increased blood pressure to 190/110 mm Hg, impaired short-term memory, writing, headaches, loss of visual fields on the right were first noted. With suspected acute cerebrovascular accident, she was hospitalized at her place of residence, where, according to MRI of the brain, an intracerebral space-occupying lesion of the posterior parts of the corpus callosum with invasion into the right and left parietal-occipital regions was detected. In October 2022, the patient underwent stereotactic biopsy of the lesion.

The patient independently sought consultation at the Federal State Budgetary Institution "National Medical Research Center of Hematology" of the Ministry of Health of the Russian Federation. Based on the review of histological and immunohistochemical studies, a diagnosis of primary DLBCL of the CNS was established: brain tissue particles with focal and perivascular lymphoid infiltrate of medium- and large-sized cells with round-oval nuclei, centroblast morphology, with morphological signs of apoptosis. In ready-made IHC preparations, tumor substrate cells express CD20+, CD45+, CD79+, MUM.1+, BCL6+. The proliferative activity index for Ki-67 is 95% of positive cells.

Upon admission, the patient's condition was severe. The severity of the condition was due to the underlying disease, CNS damage, and neurological symptoms.

Given the severity of the condition, in the period from November 2022 to December 2022, the patient underwent 4 courses of chemotherapy according to the developed RL-MPV program (rituximab 375 mg / m ² intravenously by drip on day 1 of the cycle, methotrexate 3500 mg / m ² intravenously by drip on day 2 of the cycle for 2 hours, vincristine 2 mg intravenously by jet stream on day 2 of the cycle, procarbazine 100 mg / m ² orally from days 2 to 8 of the cycle, lenalidomide 25 mg / day orally from days 2 to 8 of the cycle). Tolerability is satisfactory. No severe infectious and toxic complications were registered in the inter-course intervals. After the 2nd course of chemotherapy, leukopoiesis stimulation was performed to collect and prepare auto-HSC, collection and preparation of auto-HSC was performed. According to the control MRI of the brain (from 12.2022), complete remission of the disease was achieved.

In order to consolidate remission, high-dose chemotherapy (HDC) was administered in the VSV conditioning mode: carmustine 400 mg/day intravenously by drip on day -6 before auto-HSCT, busulfan 4 mg/kg orally on days -5, -4 before auto-HSCT, cyclophosphamide 60 mg/kg intravenously by drip on days -3, -2 before auto-HSCT. On day 0, a transfusion of 4x10 ⁶ /kg CD34+ cells was performed. The transfusion was tolerated satisfactorily. The post-transplant period was complicated by the development of myelotoxic agranulocytosis, thrombocytopenia, and infectious complications. Infection foci included stomatitis. Stimulation of hematopoiesis, replacement blood transfusion therapy, and antimicrobial therapy were administered. Ten days after auto-HSCT, restoration of the number of neutrophils and platelets, regression of infectious complications were noted. Maintenance therapy with nivolumab at a dose of 3 mg/kg/day every 2 weeks was administered for 6 months after auto-HSCT. Currently, with an observation period of +11 months after auto-HSCT, complete remission of the disease is maintained.

Thus, the examples from clinical practice presented by the applicant and the given description of the claimed invention illustrate the achievement of the claimed technical result in view of the following.

Despite the absence of thiotepa in the Russian Federation, the use of the newly developed protocol "CNS-2021" made it possible to achieve high efficiency in the therapy of this group of patients. Thanks to the use of three-stage therapy according to the "CNS-2021" protocol, the applicant managed to achieve relapse-free survival rates of 86% and reduce the frequency of early relapses of the disease. Thus, in the period from 2022 to 2023, 17 patients with CNS PDLBCL, whose average age was 50 (20-66) years, were included in the prospective study "CNS-2021". With an average observation period of 9 (3-29) months, 15 patients out of 17 are alive in complete remission. Of the 17 patients, only 2 (11%) developed early relapses of the disease, compared with the previous therapy program, with the use of which up to 20% of patients died from the progression of the primary lymphatic brain tumor. The use of induction programs within the framework of the CNS-2021 protocol did not lead to the development of severe hematological and non-hematological toxicity, which made it possible to conduct chemotherapy courses in full in a timely manner. There were no fatal outcomes after myeloablative conditioning regimens and auto-HSCT. Thus, it follows from the presented materials that the claimed invention is a new method of treating patients diagnosed with CNS PDBCCL, due to the fact that it has not previously been explicitly disclosed in the closest analogues, which ensures the achievement of a technical result that is not expected for the elements of therapy included in the claimed invention. This technical result is achieved due to the features that distinguish the claimed invention from its closest analogues, namely: the use of a three-stage therapy for the treatment of patients diagnosed with CNS PDLBCL, including the combined use of lenalidomide with the R-MPV program (rituximab, methotrexate, vincristine, procarbazine) at the first stage and accompanying therapy consisting of an infusion load, the introduction of calcium folinate to remove methotrexate metabolites - to prevent nephrotoxicity from methotrexate, anticoagulant therapy (sodium heparin) for the entire period of therapy to prevent thrombosis and venous thromboembolism, including auto-HSCT in the VVS conditioning mode (carmustine, busulfan, cyclophosphamide) and including the use of maintenance therapy with checkpoint inhibitors (nivolumab, pembrolizumab).

The essence of the proposed invention is explained in the following graphic materials:

Fig. 1 This figure shows the CNS-2021 protocol diagram.

Fig. 2 This figure shows the event-free and overall survival rates in patients with CNS PDLBCL in the CNS-2021 protocol. The EFS and OS rates in patients with CNS PDLBCL were 86% and 86%, respectively. Of the 17 patients, only 2 developed early relapses of the disease, as a result of which both patients died.

Fig. 3 illustrates MRI scans of a patient from clinical case 1 before and after therapy. Number 1 is the image of the onset of the disease, number 2 is the image after therapy.

Fig. 4 illustrates MRI scans of the patient from clinical case 2 before and after therapy. Number 3 is the picture of the onset of the disease, number 4 is the picture after therapy.

Fig. 5 illustrates MRI scans of a patient from clinical case 3 before and after therapy. Number 5 is the picture of the onset of the disease, number 6 is the picture after therapy.

Fig. 6illustrates MRI scans of patient 4 from clinical case before and after therapy. Number 7 is a picture of the onset of the disease, number 8 is a picture after therapy.

Fig. 7 illustrates MRI scans of the patient from clinical case 5 before and after therapy. Number 9 is the picture of the onset of the disease, number 10 is the picture after therapy.

Fig. 8 illustrates MRI scans of the patient from clinical case 6 before and after therapy. Number 11 is the picture of the onset of the disease, number 12 is the picture after therapy.

Fig. 9 illustrates MRI scans of the patient from clinical case 7 before and after therapy. Number 13 is the picture of the onset of the disease, number 14 is the picture after therapy.

Sources of information taken into account when drafting the description of the invention for the application for the issuance of a Russian patent for an invention:

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Claims (38)

1. A method for the treatment of patients with primary diffuse large B-cell lymphoma of the central nervous system (PLBCL CNS), characterized in that it includes a three-stage approach for the treatment of patients diagnosed with PLBCL CNS, the first stage includes 4 courses of induction chemotherapy with the combined use of Lenalidomide by oral administration from days 2 to 8 of the cycle at a dosage of 25 mg / day, Rituximab by intravenous drip on day 1 of the cycle of Rituximab at a dosage of 375 mg / m ² , intravenous drip on day 2 of the cycle of Methotrexate at a dosage of 3500 mg / m ² , intravenous jet administration on day 2 of the cycle of Vincristine at a dosage of 2 mg, oral administration from days 2 to 8 of the cycle of Procarbazine at a dosage of 100 mg / m ² , the use of accompanying therapy, which includes water loading, hypouricemic therapy, antiulcer therapy, anticoagulant therapy, antiemetic therapy, anticonvulsant therapy, including auto-HSCT in the VVS conditioning mode with the use of Carmustine, Busulfan, Cyclophosphamide at the second stage of therapy with accompanying therapy that includes water loading, hypouricemic therapy, antiulcer therapy, anticoagulant therapy, antiemetic therapy, anticonvulsant therapy, hepatoprotective therapy, including maintenance therapy with PD-1 checkpoint inhibitors at the third stage of therapy 3 months after auto-HSCT and including a control examination every 3 months for 1 year, then every 6 months from the 2nd year. 2. The method according to claim 1, characterized in that the course of induction therapy includes accompanying therapy - an infusion load, which includes hyperhydration at the rate of 3000 ml/ ^m2 per day intravenously, starting 1-2 days before the start of chemotherapy and ending 3-5 days after its completion, and correction of metabolic disorders, includes monitoring of electrolytes potassium, calcium, creatinine, urea, uric acid, total protein, albumin, phosphates, urine pH before polychemotherapy and on the second day after it, includes monitoring of diuresis, fluid balance, in case of insufficient urine output - stimulation with furosemide at a dose of 1-10 mg/kg, in case of hypoalbuminemia - normalization of the albumin level. 3. The method according to paragraph 1, characterized in that the accompanying therapy included in the course of induction therapy includes hypouricemic therapy with the administration of the drug Allopurinol orally at a dose of 300 mg per day for 10 days of chemotherapy in each course. 4. The method according to claim 1, characterized in that the accompanying therapy included in the course of induction therapy includes restoration of folic acid synthesis by administering, 12 hours after completion of the methotrexate infusion, intravenous jet and oral calcium folinate at a dose of 25 mg in 20 ml of 0.9% sodium chloride 8 times a day, at equal intervals, with monitoring of the residual concentration of methotrexate in the serum to 0.4 mmol/l 24 hours after the start of the infusion and every 6 hours. 5. The method according to item 4, characterized in that, when nausea and vomiting develop, calcium folinate is administered at a dose of 25 mg intravenously by drip in 100 ml of 0.9% sodium chloride 8 times a day, at equal time intervals, with monitoring of the residual concentration of methotrexate in the serum to 0.4 mmol/l after 24 hours from the start of the infusion and every 6 hours. 6. The method according to claim 1, characterized in that the accompanying therapy included in the course of induction therapy includes antiulcer therapy, including oral administration of Omeprazole, 20 mg, twice a day. 7. The method according to claim 1, characterized in that the accompanying therapy included in the course of induction therapy includes antiulcer therapy, which, if oral administration of drugs is not possible, includes intravenous jet administration of omeprazole at a dosage of 20 mg 2 times a day. 8. The method according to claim 1, characterized in that the accompanying therapy included in the course of induction therapy includes anticoagulant therapy by intravenous administration of heparin at an initial dose of 500 units/hour under the control of APTT. 9. The method according to item 8, characterized in that, if hypercoagulation persists, the heparin dose is increased by 250 units/hour until APTT equal to 1.5-2.0 normal values is achieved. 10. The method according to item 9, characterized in that in the presence of contraindications to round-the-clock heparin infusion: heparin-induced thrombocytopenia, lack of effect from the heparin therapy, low molecular weight heparins are administered subcutaneously. 11. The method according to item 9, characterized in that the criteria for terminating heparin therapy are a decrease in the platelet count below 50×10 ⁹ /l in the presence of a large tumor mass, a decrease in the platelet count below 100×10 ⁹ /l in the case of complete regression of the tumor, and the manifestation of hemorrhagic syndrome. 12. The method according to claim 1, characterized in that the accompanying therapy included in the course of induction therapy includes antiemetic therapy, including the administration of Ondansetron at a dose of 8 mg intravenously by jet stream before the administration of antitumor drugs. 13. The method according to claim 1, characterized in that the accompanying therapy included in the course of induction therapy includes anticonvulsant therapy, including oral administration of the anticonvulsant drug Levetiracetam in a dosage of 500 mg/day to a maximum dose of 3 g/day with dose adjustment under the control of an encephalogram. 14. The method according to claim 1, characterized in that at the second stage of auto-HSCT therapy in the VVS conditioning mode, Carmustine is prescribed at a dose of 400 mg with the drug diluted in 500 ml of 0.9% sodium chloride and administered intravenously by drip for 2 hours on the 6th day before auto-HSCT. 15. The method according to item 1, characterized in that at the second stage of auto-HSCT therapy in the VVS conditioning mode, the drug Busulfan is administered at a dose of 4 mg/kg orally on the -5th and -4th days before auto-HSCT. 16. The method according to item 15, characterized in that on the days of taking busulfan for the purpose of preventing convulsive syndrome, anticonvulsant drugs Levetiracetam are prescribed in a dosage of 500 mg/day to a maximum dose of 3 g/day, depending on the encephalogram data and the presence of convulsive activity, or Finlepsin in a dosage of 200 mg/day and Relanium in a dosage of 10 mg/day. 17. The method according to claim 1, characterized in that at the second stage of auto-HSCT therapy in the VVS conditioning mode, Cyclophosphamide is administered at a dose of 60 mg/kg on days -3 and -2 before auto-HSCT with the drug diluted in 500 ml of 0.9% sodium chloride with a cyclophosphamide infusion duration of 2 hours. 18. The method according to paragraph 17, characterized in that when the bilirubin level is equal to 3-5 norms, or the AST activity is more than 180 U/L, the dose of cyclophosphamide is reduced by 25%. 19. The method according to item 18, characterized in that, in order to reduce the toxic effect of the drug Cyclophosphamide, uromitexan is prescribed simultaneously with the infusion of cyclophosphamide, 4 and 8 hours after the start of the infusion, at a dose of 15 mg/kg. 20. The method according to claim 1, characterized in that the accompanying therapy included in the second stage of auto-HSCT therapy in the VVS conditioning mode includes hyperhydration at the rate of 3000 ml/ ^m2 per day intravenously, starting 1-2 days before the start of chemotherapy and ending 3-5 days after its completion, and correction of metabolic disorders, includes monitoring of electrolytes of potassium, calcium, creatinine, urea, uric acid, total protein, albumins, phosphates, urine pH before polychemotherapy and on the second day after it, includes monitoring of diuresis, fluid balance, in case of insufficient urine output - stimulation with furosemide at a dose of 1-10 mg/kg, in case of hypoalbuminemia - normalization of the albumin level. 21. The method according to claim 1, characterized in that the accompanying therapy included in the second stage of auto-HSCT therapy in the VVS conditioning mode includes hypouricemic therapy with the administration of Allopurinol orally at a dose of 300 mg per day for 10 days of chemotherapy in each course. 22. The method according to claim 1, characterized in that the accompanying therapy included in the second stage of auto-HSCT therapy in the VVS conditioning mode includes antiulcer therapy, including taking the drug Omeprazole at a dosage of 20 mg 2 times a day. 23. The method according to claim 1, characterized in that the accompanying therapy included in the second stage of auto-HSCT therapy in the VVS conditioning mode includes antiulcer therapy, including taking the drug Ranitidine at a dosage of 150 mg 2 times a day. 24. The method according to claim 1, characterized in that the accompanying therapy included in the second stage of auto-HSCT therapy in the VVS conditioning mode includes antiulcer therapy, including, if oral administration of drugs is not possible, the drug Famotidine at a dosage of 20 mg 2 times a day intravenously by jet stream. 25. The method according to claim 1, characterized in that the accompanying therapy included in the second stage of auto-HSCT therapy in the VVS conditioning mode includes antiulcer therapy, including, if oral administration of drugs is not possible, the drug Omeprazole at a dosage of 20 mg 2 times a day intravenously by jet stream 30 minutes before meals. 26. The method according to claim 1, characterized in that the accompanying therapy included in the second stage of auto-HSCT therapy in the VVS conditioning mode includes anticoagulant therapy, including intravenous administration of heparin at an initial dose of 500 units/hour under the control of APTT, which begins 1-2 days before the start of chemotherapy and continues up to 14 days after the transfusion of auto-HSCT, regardless of the number of platelets. 27. The method according to item 16, characterized in that when the number of platelets decreases to less than 50×10 ⁹ /l or hemorrhagic complications develop, replacement transfusions with platelet concentrate are performed. 28. The method according to item 16, characterized in that, if hypercoagulation persists, the heparin dose is increased by 250 units/hour until APTT equal to 1.5-2.0 normal values is achieved. 29. The method according to claim 1, characterized in that the accompanying therapy included in the second stage of auto-HSCT therapy in the VVS conditioning mode includes antiemetic therapy, including the administration of the drug Ondansetron at a dose of 8 mg intravenously by jet stream before the administration of antitumor drugs. 30. The method according to claim 1, characterized in that the accompanying therapy included in the second stage of auto-HSCT therapy in the VVS conditioning mode includes anticonvulsant therapy, including oral administration of the anticonvulsant drug Levetiracetam at a maximum dose of 3 g/day, the dose is adjusted under the control of an encephalogram. 31. The method according to claim 1, characterized in that the accompanying therapy included in the second stage of auto-HSCT therapy in the VVS conditioning mode includes hepatoprotective therapy in the form of oral administration of ursodeoxycholic acid at a dose of 250 mg 3 times a day, washed down with a small amount of water. 32. The method according to claim 1, characterized in that the treatment of patients diagnosed with CNS PDBCCL includes, 3 months after auto-HSCT, for 6 months every 2 or 3 weeks, a third stage of therapy with PD-1 checkpoint inhibitors. 33. The method according to claim 32, characterized in that the therapy with PD-1 checkpoint inhibitors comprises administering the drug Nivolumab at a dose of at least 40 mg per day and up to 3 mg/kg/day. 34. The method according to claim 32, characterized in that the therapy with PD-1 checkpoint inhibitors comprises the administration of the drug Pembrolizumab at a dose of at least 100 mg per day and up to 2 mg/kg/day. 35. The method according to item 34, characterized in that the drug Nivolumab is diluted in 150 ml of 0.9% sodium chloride physiological solution and administered intravenously by drip over 40-60 minutes. 36. The method according to item 35, characterized in that the drug Pembrolizumab is diluted in 150 ml of 0.9% sodium chloride physiological solution and administered intravenously by drip over 40-60 minutes. 37. The method according to paragraphs 33-36, characterized in that before the administration of nivolumab and pembrolizumab, ketoprofen is administered at a dose of 100 mg for the purpose of premedication. 38. The method according to item 1, characterized in that the control examination, conducted every 3 months for 1 year, then every 6 months from the 2nd year, includes MRI of the brain with intravenous contrast enhancement, monitoring of the encephalogram and performing a lumbar puncture in the presence of tumor cells in the cerebrospinal fluid at the onset of the disease.