Introduction. The use of invasive methods for diagnosing primary diffuse large B-cell lymphoma of the central nervous system (PDLBCL CNS) and primary vitreoretinal lymphoma (PVRL) is often associated with the development of severe neurological deficits and disability of patients. A promising direction in the diagnosis of PDLBCL CNS and PVRL is the use of non-invasive approaches based on molecular genetic methods for the determination of mutations in the MYD88 gene in the cerebrospinal fluid (CSF), vitreous fluid (VF) and free circulating tumor DNA (cfDNA) in blood serum. Aim: to present the potential of non-invasive diagnosis of PDLBCL CNS and PVRL. Main findings. The study included 6 patients (4 - PDLBCL CNS, 2 - PVRL). The average age was 64 (54-75) years. Despite increased cytosis in the CSF in all 4 patients with PDLBCL CNS, the tumor population was determined by flow cytometry in only half of the cases. According to a molecular genetic study, mutations in the MYD88 gene with an allelic load from 2.5% to 15% were detected in the genomic DNA of the CSF of all patients. In 2 patients with PVRL, mutations in the MYD88 gene were detected in VF with an allelic load of 4.2% and 6.6%, which was the only confirmation of the diagnosis. Currently, 5 patients have completed the treatment program and 1 is undergoing therapy. All 5 patients are in complete remission (CR) of the disease with follow-up periods from 1 to 8 months.

Background TP53 gene mutations (mutTP53) in ABL lead to chemoresistance and tumor progression. Retrospective studies demonstrate unsatisfactory results from standard R-CHOP program. The prognostic value of mutTP53 for ABL patients receiving intensive chemotherapy (CT) is still underinvestigated. Aims To evaluate the effectiveness of the R-mNHL-BFM-90 program in the treatment of mutTP53 ABL. Materials and Methods 119 patients with ABL were included: DLBCL n=55, HGL n=2, DHL/THL n=13, LB n=11, PML n=21, PBL n=3, FL3A/B n=14. Median age was 44 (18-88) years; M/W=62/57; IPI >2 in 66 (56%); bone marrow lesion in 10 (8%); multiple extranodal foci in 40 (33%). TP53 gene mutations were evaluated by next-generation sequencing or Sanger sequencing. Results MutTP53 were found in 29 of patients (24%): in DLBCL, 14 (25%) cases; HGL, 1 (50%); DHL/THL, 2 (15%); LB, 6 (55%); PML, 4 (19%); PBL, 1 (33%); FL3A/B, 1 (7%). Deletion of 17 chromosome (del17p) was detected in 9 (23%) of the 39 cases analyzed. In 8 (89%) cases, del17p was combined with mutTP53. In the mutTP53 group, 24 (83%) received R-mNHL-BFM-90 therapy, 11 (46%) in combination with targeted therapy. Relapse/progression (R/P) was noted for 11 (38%). Complete remission was achieved in 4 patients (CAR-T, 2; allo-HSCT, 1; BCMA, 1); partial remission in 1 (CAR-T); stabilization in 2 (palliative therapy); and death from other diseases in 4 patients. In 90 wtTP53 patients, 83 (92%) received R-mNHL-BFM-90 therapy, 42 of whom (51%) also received targeted therapy. R/P was noted for 11 (12%). Complete remission was achieved in 5 patients (CAR-T, 2; allo-HSCT, 1; CT, 2); partial remission in 3 (PCT); and death from other diseases in 3 patients. The mutTP53 group 3-year OS was 81% vs 95% in the wtTP53 group (P=0.0242); the 3-year EFS was 59% vs 86%, respectively (P=0.0004); median follow-up was 24 (2-68) months. Conclusion The R-mNHL-BFM-90 program improves the results of treatment for ABL patients with mutTP53. One can speculate that mitotic catastrophe, caused by intensive multicomponent CT, provokes irreversible changes, which might overcome TP53-mediated chemoresistance. Intensive CT in combination with modern cell therapy (CAR-T, BCMA, allo-HSCT) should determine the treatment success in these patients.

Aim. To study plasma cell-free DNA (pcfDNA) concentration and B-cell clonality in patients with diffuse large B-cell (DLBCL) and B-cell high-grade lymphomas prior to and at different stages of chemotherapy as well as the correlation between the data obtained and clinical and laboratory parameters. Materials & Methods. The study enrolled 23 DLBCL patients and 7 healthy donors (HD). Plasma was prepared from whole blood by centrifugation, pcfDNA was isolated with the commercial kit Qiagen (Germany). The concentration of pcfDNA was determined using fluorometer Qubit (USA). В-cell clonality was estimated by immunoglobulin gene analysis (BIOMED-2 protocol) in the tumor tissue and bone marrow core biopsy specimens obtained on diagnosis date as well as in the pcfDNA at 5 end points: prior to chemotherapy and after cycles 1, 2, 3, and 4. Results. Prior to therapy, all DLBCL patients showed significantly higher pcfDNA concentration than HD. Immunochemotherapy cycle 1 resulted in considerable increase in pcfDNA concentration. After cycle 2 and subsequent cycles, pcfDNA concentration gradually decreased. After cycle 4, the mean pcfDNA concentration was comparable with that of HD. In 95 % of patients В-cell clonality in pcfDNA corresponded to that identified in the tumor specimen. After immunochemotherapy cycle 1, В-cell clonality was detected in 50 % of patients, after cycle 2 it was shown by 15 %. Only 1 female patient retained В-cell clonality after therapy cycles 3 and 4. In HD, no В-cell clonality in pcfDNA was identified. Prior to therapy, the analysis revealed no correlation of either pcfDNA concentration or В-cell clonality in pcfDNA with age, sex, tumor spread, presence or absence of extranodal lesions, proliferation index Ki-67, and lactate dehydrogenase concentration. Conclusion. In patients with malignant hematological tumors, pcfDNA seems to be an interesting, easily accessible biological material deserving further investigation. Any studies of pcfDNA require long-term dynamical analysis and standardized methods of collection, storage and processing of the data obtained. In the long run, with more and more information, pcfDNA can become an important diagnostic marker of tumor heterogeneity and a reliable relapse predictor.

Topic: 22. Stem cell transplantation - Clinical Background: In most cases, follicular lymphoma (FL), the most common indolent lymphatic tumour, is highly sensitive to immunochemotherapy. The course of the disease is characterized by multiple relapses although overall survival (OS) is high. On the other hand, 20 % of patients have early tumour progression within the first 24 months of therapy (POD24) — they comprise a group with an extremely unfavourable prognosis and low OS. High-dose therapy (HDT) with autologous stem cell transplantation (ASCT) is usually used in relapses of FL and is a potentially curative method for 50 % of patients (C.Casulo Biol Blood Marrow Transplant 2018) 2021). The efficacy of ASCT as the first-line therapy of FL, including the effect on POD24, is poorly studied. Aims: To evaluate the efficacy and safety of HDT and ASCT as the first-line therapy of FL Methods: The study included patients aged 18–65 years with grade 1–3A FL t(14;18)+, stage III–IV or stage II + bulky, and at least one criterion for the initiation of treatment (Groupe d’Etude des Lymphomes Folliculaires Criteria). The patients received treatment according to the ‘FL-2015’ protocol: 4 R-CHOP, 2 R-DHAP and BeEAM (bendamustine, etoposide, cytarabine and melphalan) and ASCT. The primary endpoint was the overall response (OR)/ complete remission (CR) rate at the end of the chemotherapy course. Secondary endpoints were 3-year OS, progression-free (PFS) and event-free survival (EFS). Date of analysis: 12 February 2023. Peripheral blood and/or bone marrow of included patients was tested for minimal residual disease (MRD) by IGH-consensus PCR. Results: Since 2015, 35 patients have been included in the analysis: median age was 45 years (24 to 63 years). A total of 86 % of patients had stage IV tumours, 79 % had 3–5 FLIPI factors. After the end of treatment, OR/PR were 93 %/93 %. MRD-negativity was achieved in 96 % of patients. Kaplan-Meier (KM) estimation of 3-year OS, PFS and EFS were 95 %, 91 % and 85 %, respectively; median follow-up was 19 months (found by reverse KM method) (Fig 1 and 2, Tab.). POD24 rate was 3 %. There were no deaths due to early toxicity within 100 days after ASCT. Mortality not associated with relapses within the first 2 years after treatment was 7 %: 2 patients died of coronavirus infection after 16 and 22 months. No cases of secondary malignant tumours were registered. Summary/Conclusion: ASCT following HDT with BeEAM protocol as the first-line therapy in FL is highly effective and can significantly reduce the rate of POD24 and tumour-associated early mortality. Keywords: Chemotherapy toxicity, Autologous hematopoietic stem cell transplantation, Follicular lymphoma

Introduction. Relapses of primary mediastinal large B-cell lymphoma (PMBСL) with involvement of the central nervous system (CNS) are usually incurable. Therapy tactics in patients with PMBCL with relapse in the CNS have not been defined. Aim: to present clinical observations of the treatment of relapses of PMBCL with CNS involvement using the “R-PML-CNS-2022” protocol. Main findings. Two clinical observations of patients with relapses of PMBCL with involvement of the CNS are presented. In both cases, the “R-PML—CNS-2022” protocol was used as a second-line treatment, and a complete remission of the disease was achieved. In the first case, within 6 months after auto-HCT, maintenance therapy with pembrolizumab was performed. Complete remission of the disease continues for 15 months. In the second observation, maintenance therapy with pembrolizumab was also started, however, due to the development of autoimmune complications after 2 cycles, treatment was discontinued. Complete remission of the disease continues for 13 months. Conclusion. The development of a new strategy for the treatment of relapses of PMLCL with CNS lesion according to the “R-PML—CNS-2022” protocol is a potentially curative approach in this group of patients.

Introduction. The follicular lymphoma (FL) is the most common indolent lymphatic tumor with high sensitivity to immunochemotherapy un most cases. Although overall survival (OS) is generally long, the disease is characterized by multiple relapses. High-dose chemotherapy (HDCT) with transplantation of autologous hematopoietic stem cells (auto-HSCT) is used for recurrent FL. Aim: to evaluate the efficacy and safety of HDCT with aHSCT in the first line of FL therapy; identify risk factors for disease progression and refractoriness. Material and methods. A prospective single-center study (conducted from May 2015 to January 2023) included 35 patients aged 18–65 years (median 43) with PL 1–3A grade t(14;18)+ with stages III–IV or stage II with bulky, having at least one criterion for the need to start therapy (according to GELF). Patients were treated according to the FL-2015 protocol: 4 R-CHOP, 2 R-DHAP and BeEAM with auto-HSCT. The primary endpoint was the rate of overall response (OR) and/or complete remission (CR) at the end of chemotherapy. Secondary end points were 3-year survival rates: OS, relapse-free survival (RFS), progression-free survival (PFS), and event-free survival (EFS). Minimal residual disease (MRD) in blood and/or bone marrow was assessed by PCR based on immunoglobulin heavy chain (IGH) gene rearrangements and/or BCL2::IGH rearrangements. Statistical analysis (by intent to treat) was performed on January 12, 2023. Results. 86 % of patients had stage IV tumor and 79 % had 3–5 FLIPI factors. After the end of treatment, OR and PR were 90 % and 90 %, the incidence of POD24 was 3 %. After the end of induction (4 courses of R-CHOP), MRD-negativity was achieved in 77 % and 53 % of patients as determined by PCR-IGH and BCL2::IGH. After the full completion of the FL-2015 protocol, MRD was not detected in 96 % of patients (according to PCR-IGH). Three-year overall survival, disease-free survival, progression-free survival and event-free survival were respectively: 90 %, 90 %, 95 % and 85 % (with the same standarderror of 9 %) at a median follow-up (by inverse Kaplan-Meier estimate) of 19 months (range: from 1 to 91 months) There were no deaths due to early toxicity within 100 days of auto-HSCT. Prognostically unfavorable independent statistically significant (р < 0.01; Wald test; hazard ratio > 1) predictors of progression and refractoriness according to the results of multivariate analysis using the Fine-Grey competing risk model (р = 0.052 for the model) were: bone marrow disease, ECOG high risk, patient age > 50 years, stage 4 disease, elevated serum lactate dehydrogenase and B-symptoms. Conclusion. The use of HDCT with auto-HSCT in the first line in patients with FL is highly effective and can significantly reduce the incidence of POD24 and early mortality from the tumor. The study is ongoing.

Introduction. The tactics of therapy for elderly comorbid patients with mantle cell lymphoma with unfavorable prognosis factors (complex karyotype, 17p13 deletion, mutations in the TP53 gene) have not been developed. The use of intensive chemotherapy regimens and transplantation of allogeneic hematopoietic stem cells (allo-HSCT) is impossible due to severe comorbidity in elderly patients. A rational approach is the use of a combination of ibrutinib and venetoclax. As an alternative to allo-HSCT, a new option for elderly patients with poor prognostic factors is Chimeric Antigen Receptor T-cell therapy (CAR-T) cell therapy. Aim — to present the experience of using ibrutinib and venetoclax with CAR-T-cell therapy in the first line of treatment in an elderly patient with MCL with a mutation in the TP53 gene and hyperleukocytosis. Main fi ndings . Patient M., 68 years old. The examination revealed hyperleukocytosis 978 × 10 9 /L, anemia (55 g/L), thrombocytopenia (30 × 10 9 /L), and splenomegaly 250 × 180 mm. According to the results of laboratory studies, the diagnosis of lymphoma from mantle cells with a complex karyotype, deletion 17p13, 13q14 and mutation p.R248W in exon 7 of the TP53 gene (VAF = 26 %) was verified. For cytoreductive purposes, two sessions of leukocytapheresis and prephase with cyclophosphamide (200 mg/m 2 ) and dexamethasone (10 mg/m 2 ) were performed. From day 3, therapy with ibrutinib 420 mg/day and venetoclax 100 mg/day was started. After 2 days, the leukocytes were 0.7 × 10 9 /L, and the size of the spleen decreased, as a result of which the development of tumor lysis syndrome was noted. As a result of intensive therapy, the patient’s condition stabilized, which allowed him to resume treatment. After 7 days, the number of leukocytes was 2.5 × 10 9 /L, neutrophils — 70 %, platelets — 90 × 10 9 /L, hemoglobin — 95 g/L. According to immunophenotyping, the population of B-lymphocytes was 4 %. According to NGS data, the allelic load of the mutation in the TP53 gene is 0.8 %. The patient underwent anti-CD19 CAR-T-cell therapy and achieved complete remission. Three months after therapy, MRD remains-negative remission and the persistence of CAR-T cells is determined.

Context: PMBCL is an NHL variant that responds to immune checkpoint inhibitors (ICIs) therapy in approximately half of the cases.Molecular factors predicting possible responses to immunotherapy for PMBCL are not yet described.Evaluation of programmed cell death ligand-1/ligand-2 (PD-L1/L2) expression level in tumor samples has proven clinical utility for ICI response prediction in various solid tumors.HLA-DR overexpression may be another marker associated with response to anti-PD-1/PD-L1 therapy.MHCII gene expression is associated with the transcription of the gene encoding the CIITA trans-activator, a crucial MHCII gene regulatory factor.The PD-L1 and CIITA gene expression level could be affected by copy number variations associated with 9p24.1 and 16p13.13chromosomal lesions (losses or gains).Analysis of appropriate short tandem repeat (STR) markers is a straightforward way to detect these lesions.Objective: To analyze the possible association of STR allele imbalance (AI) in 9p24.1 with PD-L1 expression level and STR AI in 16p13.13 with HLA-DR expression level in tumor cells of PMBCL patients.Design: STR-loci at 9p24.1 and 16p13.13 of the paired tumor/control DNA samples were analyzed in a cohort of 27 PMBCL patients admitted to the National Medical Research Center for Hematology (2013)(2014)(2015)(2016)(2017)(2018)(2019)(2020).STR data was compared with the expression of PD-L1 and HLA-DR, respectively.An immunohistochemical study of PD-L1, HLA-DR, and tumor DNA extraction was performed on mediastinal biopsy samples from archival paraffin blocks.Patients: De novo-diagnosed PMBCL patients were included, while pretreated patients were excluded.Results: AI in the 9p24.1 was found in 14 of 27 patients (52%).PDL1 expression was found in 10 (6 with AI 9p24.1) of 27 patients (37%).AI in16p13.13 was found in 8 of 27 patients (30%).HLA-DR expression was observed in 20 (6 with AI 16p13.13) of 27(74%) patients with PMBCL.However, a significant correlation between STR aberrations and the expression of related genes has not been found (chi-square statistic, P>0.05).Conclusions: STR AI in 9p24.1 and 16p13.13 and PD-L1 and HLA-DR expression are highly frequent though probably independent events relevant to immunotherapy response in PMBCL.

Introduction . The introduction of chimeric antigen receptor (CAR) T-cell therapy is a promising treatment of patients with relapsed or refractory (R/R) B-cell lymphoproliferative diseases (LPDs). Aim — to present the results of CAR-T-cell therapy of 6 adult patients with B-cell LPDs. Materials and methods . This is a pilot study conducted in adult patients with R/R or persistent minimal residual disease B-cell LPDs treated with CAR-T-cells. The study was approved by a local ethical committee of National Research Center for Hematology. Patients did not have alternative options for effective and safe treatment. All patients signed an informed consent. All patients were lymphodeplated with fl udarabine and cyclophosphamide for 4 days before the introduction of CAR-T-lymphocytes. Cytokine release syndrome (CRS) was prevented by tocilizumab on the day of CAR-T-cell administration. The effi cacy and safety of CAR-T-cell therapy was evaluated. Results . From 01.01.2020 to 01.01.2022, 10 CAR-T-cell infusions were performed for 6 adult patients (age 19–68 years, median — 32 years) with B-cell LPDs: 4 — R/R B-acute lymphoblastic leukemia, 1 — R/R diffuse large B-cell lymphoma, 1 — persistence of MRD in mantle cell lymphoma. In all patients with a R/R, median — 4 (2–5) lines of chemotherapy and/ or immunotherapy were performed before CAR-T-cell therapy. CD19 CAR-T-cells received 3 patients, CD19/CD22 CAR-Tcells — 2 patients, CD19 and CD20 CAR-T-cells received 1 patient. Autologous CAR-T-cells received 4 (66 %) patients, allogeneic CAR-T-cells received 1 patient, and one patient had two CAR-T-cell administrations — 1 autologous and 1 allogeneic. The median number of CAR-T-cells was 0.5 × 10 6 /kg (from 0.1 × 10 6 /kg to 3 × 10 6 /kg). In 7 (87.5 %) of the 8 cases after CAR-T-cell administration, overall response to therapy (complete or partial remission) was achieved, and complete remission was achieved in 6 (75 %) cases. Side effects were noted after 8 of 10 CAR-T-cell transfusions: CRS in 40 % (CRS 1 — 10 %, CRS 2 — 20 %, CRS 3 — 10 %), ICANS in 10 %, tumor lysis syndrome in 20 %, multi-organ dysfunction syndrome in 10 %. There were no lethal complications due to CAR-T-cell administrations. The median follow-up period was 6 (1–16) months. Of the 6 patients, 2 (33 %) died from relapses and progression of LPD. One (17 %) patient died in complete remission from infectious complications. Three (50 %) patients are observed till now. The median time of CAR-T-cell circulation was 33 (6– 60) days. Conclusion . CAR-T-cell therapy is a promising treatment for R/R B-cell LPDs and LPDs with persistence of MRD after cytoreductive therapy. This type of therapy requires a multidisciplinary approach.

TP53 plays a key role in almost all cellular processes. Mutations in this gene are found in most types of neoplasms. Among hematological malignancies, TP53 lesions are the most actively studied in CLL, although available data for other lymphomas remains limited.To study the frequency and diversity of TP53 mutations in Russian patients with B-cell lymphomas.The study included 145 DNA samples from patients with B-cell lymphomas: 53 patients with DLBCL, 47 patients with MCL, and 45 patients with FL, 16 of whom experienced transformation to DLBCL. Mutations in TP53 (exons 4-10) in most samples were detected using NGS (138 patients) or Sanger sequencing (7 patients). The clinical significance of detected variants was assessed using the Seshat online tool based on the UMD TP53 database.TP53 mutations were detected in 24 DLBCL patients (45.4%), 21 of which were missense mutations, 2 were splicing site mutations, and 1 was an insertion. Sixteen variants were identified as (probably) pathogenic, and 8 mutations were of unclear significance. Del17p was simultaneously detected in 7 patients with TP53 mutations (of 11 examined). In MCL patients, mutations were found in 19 cases (40%). Eighteen were missense mutations, and 1 was a splicing mutation. Sixteen variants were identified as (probably) pathogenic, and 3 were variants of unclear significance. Chromosome 17 abnormalities were found in 7 MCL patients with TP53 mutations of 11 studied. In FL patients, TP53 mutations were detected in 12 cases (26.7%). Eight were missense mutations, 2 were nonsense mutations, 1 was a splicing mutation, and 1 was a deletion. Nine variants were recognized as (probably) pathogenic, and 2 were variants of unclear significance. Only 1 patient of 6 examined had del17p.The frequency of TP53 mutations in our cohort of patients with B-cell lymphomas was significantly higher than the frequency reported for other cohorts. This bias may be due to differences in patient selection. We are planning further studies examining the type of mutations, allelic loads, and combinations with other chromosome 17 lesions in association with the disease course.

Background: The TP53 gene plays a key role in cell cycle control, DNA repair, initiation of apoptosis, and other critical cellular processes. Mutations of this gene are found in almost all types of malignant neoplasms and the vast majority of cases are associated with poor prognosis. Among hematological malignancies, TP53 gene lesions are most actively studied in CLL, while for other lymphomas fewer data are available so far. Aims: To study the frequency, variation, and allelic load of TP53 mutations in Russian patients with B-cell lymphomas. Methods: The study included 145 DNA samples from patients with B-cell lymphomas admitted to the National Medical Research Center for Hematology (Moscow, Russia) in 2020-2021: 53 patients with DLBCL (29F, 24M, age 25-87 years, median 54 years), 47 patients with MCL (17F, 30M, age 42-73 years, median 59 years) and 45 patients with FL (28F, 17M, age 30-72 years, median 49 years), 16 of them with transformation to DLBCL. Mutations in the TP53 gene (exons 4-10) in most samples were detected using NGS according to Pavlova et al., or Sanger sequencing (7 patients). The clinical significance of the detected variants was assessed using the Seshat online tool based on the UMD TP53 database. Results: TP53 gene mutations were detected in 24 DLBCL patients (45.4%). Out of them were found 21 missense mutations (2 cases in the “hot spots” p.R249M and p.R282W and 2 cases in the same position p.G266), 2 splicing site mutations, and 1 insertion. Also, 16 variants were identified as (likely) pathogenic, 13 of which had a mutation load (VAF) greater than 15%. Of the 8 mutations of unclear significance, 4 had a VAF<10%. Del17p was simultaneously detected in 7 patients with TP53 mutations (out of 11 examined). In the MCL patients mutations were found in 19 cases (40%). 18 of them were missense mutations (4 in the “hot spot” p.R248 and 2 in the same position p.V173) and 1 splicing mutation. 16 variants were identified as (likely) pathogenic and had a VAF>14%. All 3 variants of unclear significance were minor. Chromosome 17 abnormalities were found in 7 MCL patients with TP53 mutations out of 11 studied. In the FL patients, TP53 mutations were detected in 12 cases (26.7%). Out of 8 missense mutations, 4 were in hotspots p.R175H, p.R248Q, p.R249M, p.R273H. Also in this group 2 nonsense mutations, 1 splicing mutation, and 1 deletion were observed. Of the 9 variants recognized as (likely) pathogenic, only 1 was minor, as were 2 variants of unclear significance. Only 1 patient with TP53 mutation out of 6 examined had del17p. All results are presented in Table 1. Image:Summary/Conclusion: The frequency of mutations in the TP53 gene in patients with B-cell lymphomas in our sample is significantly higher than according to the literature data. One can explain this bias by patient selection. A significant portion of DLBCL and FL patients admitted to our center in the state of progression or relapse. Most MCL cases were primary, however, MCL patients with advanced stages of the disease are more often admitted to the National Medical Research Center for Hematology. At the same time, the occurrence of “hot spots” mutations in MCL and FL is also higher than expected. Further studies concerning the type of mutations, their allelic load, and their combination with 17th chromosome lesions in association with disease course are on the way.

Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoid tumor among other non-Hodgkin lymphomas (30-40% of all cases). This type of lymphoma is characterized by significant differences in treatment response and the heterogeneity of clinical traits. Approximately 60% of patients are cured using standard chemotherapy (CT), while in 10-15% of cases, the tumor is characterized by an extremely aggressive course and resistance to even the most high-dose programs with autologous stem cell transplantation (auto-SCT). The activated B-cell (ABC) subtype of DLBCL is characterized by poor prognosis. Here, we describe a clinical case of diffuse ABC-DLBCL with an atypical disease course. Complete remission was achieved after four courses of CT, followed by autologous hematopoietic stem cell transplantation (auto-HSCT). However, early relapse occurred 2 months after the completion of treatment. According to the results of cytogenetic studies, significant chromosome breakdowns were observed. Exome sequencing allowed for the detection of several novel mutations that affect components of the NOTCH2 and NF-κB signaling pathways, a number of epigenetic regulators (KMT2D, CREBBP, EP300, ARID1A, MEF2B), as well as members of the immunoglobulin superfamily (CD58 and CD70). Whether these mutations were the result of therapy or were originally present in the lymphoid tumor remains unclear. Nevertheless, the introduction of genomic technologies into clinical practice is important for making a diagnosis and developing a DLBCL treatment regimen with the use of targeted drugs.

R-EPOCH\ R-BAC + ibrutinib + high-dose consolidation + auto-SCT led to deep responses in 71% of patients. Primary intensification makes it possible to implement the concept of "stop" therapy, which makes it cost-effective. The use of high-dose consolidation according to the Dara-BEAM program increases the effectiveness of treatment. We are continuing the study, which will increase the reliability of the results.

Introduction. Primary mediastinal lymphoma (PML) is an aggressive lymphoid tumor treatment success of which is determined by induction therapy. To date, none of the standard chemotherapy regimens (CT) have demonstrated an advantage in efficacy. Intensive therapy programs are associated with high toxicity.Aim — to evaluate the efficacy and toxicity of two pilot prospective treatment protocols PML-16 and PML-19 as well as the possibility of using the analysis of freely circulating tumor DNA (ctDNA) to assess MRD in patients with PML.Materials and methods. From January 2016 to January 2022, 34 previously untreated PML patients were included in the study; average age — 32; stage > I — in 60 %; extramediastinal lesions — in 14.7 %; bulky disease — in 73.5 % of patients. Positron emission tomography combined with computed tomography (PET-CT) was performed; ctDNA was determined to assess the completeness of remission.Results. Eighteen patients received treatment according to the PML-16 protocol (6 courses of chemotherapy; 2 blocks of RmNHL-BFM-90 + 4 courses of R-EPOCH). After the end of therapy, all 18 patients achieved PET-negative remission. The next 16 patients received treatment according to the PML-19 protocol (4 courses of chemotherapy; 2 blocks of R-mNHL-BFM-90 + 2 courses of R-EPOCH) in combination with lenalidomide. After the end of therapy, 9 (56 %) patients achieved PET-negative remission; 7 (44 %) retained pathological activity (D4–5 points). After 3 and 6 months 15 (94 %) patients achieved normalization of metabolic activity. Considering the high frequency of false-positive results in patients with PML, a ctDNA study was performed to determine the depth of remission in 15 patients. After the end of therapy, all 15 patients had complete elimination of ctDNA. Of these, 5 (33 %) remained PET-positive at the end of treatment. During further observation, after 3–6 months, in 4 patients the level of metabolic activity decreased to physiological without the use of consolidating therapy. After the end of therapy, one patient suffered the new coronavirus infection, COVID-19. A month later, residual formation of SUVmax 14.2 remained in the mediastinum. The patient is currently under observation. With a median follow-up of 36 months (9 to 76 months) all 34 patients are in remission.Conclusion. The effectiveness of PML-16 made it possible to abandon the consolidation therapy and refuted the idea of the need for 6 courses of CT. The combination of programs based on the application of the principle of high-dose shortpulse induction of remission (R-mNHL-BFM-90) in combination with the prolonged administration of medium doses (R-EPOCH) was crucial in achieving a successful result. The inclusion of lenalidomide in the “PML-19” program made it possible to achieve complete remission in 100 % of cases after 4 courses. The possibility of using DNA analysis to assess MRD in patients with PML was shown.