Introduction. Lymphoma from cells of the marginal zone in some cases can manifest itself only at the stage of histological transformation into aggressive lymphomas, including diffuse large B-cell lymphoma (DLBCL). Aim: to present a clinical observation of lymphoma transformed at the time of diagnosis from marginal zone cells to DLBCL. Main findings. A case report of relapsed DLBCL in the submandibular area is presented, which was observed for 11 years without treatment. At the time of relapse, a 81x43x88 mm mass in the lower lobe of the right lung with SUV max up to 19.27 was identified. Atypical resection of the lower lobe of the right lung was performed. Based on histology and immunohistochemistry, a diagnosis of DLBCL transformed from marginal zone B-cell lymphoma was established, with PCR confirming the identity of the clone of indolent and aggressive B-cell lymphoma. The patient received R-CHOP plus lenalidomide therapy and achieved complete remission.

Introduction. Primary mediastinal large B-cell lymphoma (PMBCL) is a rare non-Hodgkin lymphoma. Considering the immunophenotype of PMBCL, which differs from diffuse large B-cell lymphoma (DLBCL), Microsatellite Repeat (MSR) aberrations in regions flanking PD-L1/PD-L2 and CIITA genes were investigated. Aim: to study the prevalence of MSR aberrations in 19 loci of the COrDIS Plus panel and in the regions of the PD-L1/PD-L2, CIITA genes in PMBCL and DLBCL, and to compare it with the expression level of PD-L1 and HLA-DR in PMBCL. Materials and methods. The study included 137 patients, 86 (62,8%) with PMBCL and 51 (37.2%) with DLBCL. The analysis was conducted using the standard COrDIS Plus panel, which includes a set of primers for 19 loci of tetranucleotide repeats. The allelic imbalance (AI) of MSR close to the PD-L1/PD-L2 genes (9p24.1) (n = 68/86 (79.1%) for PMBCL, n = 36/51 (70.6 %) for DLBCL) and CIITA (16p13.13) (n = 71/86 (82.6 %) for PMBCL, n = 29/51 (56.9 %) for DLBCL) was investigated using STR analysis. Patients with homozygous inheritance for each of the studied markers were excluded from further analysis due to the inability to assess loss of heterozygosity (LOH). The expression of PD-L1 and HLA-DR was assessed by immunohistochemistry in 27/86 (31.4 %) PMBCL patients. Results. Homozygosity for both markers near the PD-L1/PD-L2 genes was found in 5/68 (7.4 %) of PMBCL patients and 10/36 (27.8 %) of DLBCL patients (p = 0.008). Aberrations of MSR flanking the PD-L1/PD-L2 genes were detected in 33/63 (52.4%) of PMBCL patients and 5/26 (19.2 %) of DLBCL patients (p = 0.003; OR 5.8; 95% CI [2.8-18.7]). Homozygosity for both markers near the CIITA gene was identified in 8/71 (11.3%) of PMBCL patients and 7/29 (24.1%) of DLBCL patients (p = 0.13). AI near the CIITA gene was found in 24/63 (38.1 %) of PMBCL patients, while no changes in the CIITA region were observed in the DLBCL group (p = 0.0001; OR 14.3; 95% CI [2.8-262.5]). Using the COrDIS Plus panel, the frequencies of tetranucleotide repeat aberrations did not significantly differ between PMBCL and DLBCL (p = 0.78 for LOH, p = 0.17 for EMAST). No correlation was found between MSR aberrations near the PD-L1/PD-L2 and CIITA genes and the expression levels of PD-L1 and HLA-DR (p = 0.402 and 0.668, respectively). Conclusion. A statistically significant more frequent alteration in the MSR marker profile of the PD-L1/PD-L2 and CIITA gene regions was found in PMBCL patients compared to DLBCL. Chromosomal microarray analysis in 2 out of 3 PMBCL cases revealed genetic aberrations involving the PD-L1/PD-L2 and/or CIITA genes, and AI of these genes was observed simultaneously with the MSR profile evaluation. This confirms the different pathogenesis of these diseases and suggests that the presence of AI in these loci indicates the involvement of these genes in the pathogenesis. There is no correlation between AI in the PD-L1/PD-L2 and CIITA gene regions and the expression of PD-L1 and HLA-DR, respectively.

Introduction. The R-NHL-BFM-90 protocol has been successfully used for the treatment of Burkitt's lymphoma and diffuse large B-cell lymphoma (DLBCL) in children and adolescents, as well as adult T-cell lymphomas. The protocol was modified for the treatment of adult patients with de novo nodal DLBCL. Aim: to evaluate the efficacy and toxicity of the R-mNHL-BFM-90 and R-DA-EPOCH-21 protocols in adult patients with de novo nodal DLBCL with 2 or more signs of poor prognosis, as well as to determine the role of auto-HSCT in the consolidation of remission. Materials and methods. From 2015 to 2021, 164 patients were evaluated for randomization. The study included 140 patients from 13 Russian medical centers. 89 (76 %) patients with de novo nodal DLBCL: R-DAEPOCH-21 20 (22.5 %) patients; R-DAEPOCH-21 + auto-HSCT 21 (23.5 %) patients; R-mNHL-BFM-90 20 (22.5 %) patients; R-mNHL- BFM-90 performed + auto-HSCT 28 (31.5 %) patients. In the high-intermediate and high-risk group, there were 12 (29.3 %) and 29 (70.7 %) patients on the R-DA-EPOCH-21 + auto- HSCT protocol and 15 (31.2 %) and 32 (66.7 %) on the R-mNHL- BFM-90 protocol + auto-HSCT, respectively. Results. The R-mNHL-BFM-90 protocol proved to be more effective. Complete remission in the high-risk group was achieved in 30 (93.7 %) patients versus 18 (62.0 %), there was no progression versus 3 (10.3 %) patients treated according to R-DA-EPOCH-21 (p = 0.0167). The five-year overall and event-free survival in the high-risk group was 97 % vs. 75 % (p = 0.01) and 97 % vs. 72 % (p = 0.0026), respectively. In the intermediate risk group, the results of therapy did not differ. The toxicity of the R-mNHL-BFM-90 protocol exceeded the toxicity of R-DA-EPOCH-21 only in neutropenic fever (p = 0.04) and grade 3-4 thrombocytopenia (p = 0.0009). Conclusion. The R-mNHL-BFM-90 protocol is effective for the treatment of patients with nodal de novo DLBCL diffuse large B-cell lymphoma of high-risk adults; its toxicity is acceptable. However, on the R-DA-EPOCH-21 therapy, the results of therapy are unsatisfactory. The R-DA-EPOCH-21 protocol with auto-HSCT was more effective than without auto-HSCT, however, due to the small number of patients, the results were unpresentative. The results of therapy according R-mNHL-BFM-90 protocol with auto-HSCT and without auto-HSCT were not differ.

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. Mycosis fungoides (MF) is classified as an orphan disease. Due to the rarity of pathology, and until recently the absence of an expert group and a specialized reference center for cutaneous lymphomas in Russia, possible treatment options for MF are presented by listing them without recommendations on the preferred indications for one or another option. This creates difficulties in choosing treatment methods and assessing their effectiveness.Aim. To characterize current treatment methods and their results in MF patients who were observed or received consultative and diagnostic care at the National Medical Research Center for Hematology.Materials and methods. The study included 210 patients: 115 with early disease stages and 95 with advanced stages.Results and conclusion. The most common treatment options were for early stages – local therapy, interferon therapy and systemic chemotherapy (CT), for advanced stages – combination therapy with interferon (+ PUVA therapy, methotrexate), interferon monotherapy and systemic CT. The frequency of systemic chemotherapy use in all lines of MF treatment was 21 %. When integrating statistical analysis using the probability of achieving an antitumor response, switching to 2nd line therapy, and accumulated incidence, the negative results of using chemotherapy in the MF treatment were clearly demonstrated.For the first time in Russia, a real practical situation of the applied MF treatment options is presented on our own large sample of patients. As the first line of therapy, the most common options were immunotherapy and phototherapy, however, in 12.4 % of cases, the use of systemic CT was registered, which is unjustified and leads to a decrease in the time to the next line of treatment and an increase in the cumulative incidence of adverse events. As a result of the use of non-chemotherapeutic approaches (interferon, etc.), the 3-year relapse-free survival rate is about 40 %, after chemotherapy – 9.4 %. Secondand third-line therapy provided more varied options, including combination treatment with interferon and methotrexate, as well as gemcitabine monotherapy, targeted therapy with brentuximab vedotin, and epigenetic therapy in the 3rd line. Studies with targeted agents in this patient population have demonstrated improved clinical outcomes, highlighting the need for their early use to achieve the best results.

Introduction. Peripheral T-cell lymphomas (PTCL) — a rare group of lymphoproliferative diseases characterized by an aggressive course and an unfavorable prognosis. The group is represented by heterogeneous nosological forms, in which standard treatment options lead to unsatisfactory results. Aim: to present the protocols for the treatment of PTCLMain findings. In total, 12 years of experience in the treatment of 724 patients with T-cell lymphomas (430 patients with primary cutaneous forms, 110 patients with leukemic variants and 184 with peripheral T-cell lymphomas) has been accumulated. The treatment results and therapeutic algorithms were analyzed. In the general group of patients, the 3-year overall survival (OS) and relapse-free survival (EFS) were 76 % and 70 %, respectively. The best treatment results were achieved in the groups of intestinal T-cell lymphoma, specifically (EATL), and angioimmunoblastic T-cell lymphoma (AITL), anaplastic large cell ALK-positive lymphoma (ALCL ALK+), and the worst — in the group of ALCL ALK- (5-year EFS 31 %). High-dose chemotherapy under the NHL BFM-90 program in the treatment of ALK+ ALCL allows achieving 10-year OS and EFS 87 % and 84 %, respectively, but the less toxic CHOEP program was not inferior in effectiveness: 5-year OS and EFS amounted to 93 % and 88 %, respectively. High survival rates of patients with EATL were achieved with the use of high-dose chemotherapy according to the LB-M-04 program followed by auto-HSCT in the first line of therapy: 5-year OS and EFS amounted to 79 % and 74 %, respectively. The positive role of AITL maintenance therapy has been shown: 5-year OS and EFS during its implementation amounted to 75 % and 49 % versus 41 % and 20 % in the absence of it. In the protocols for the treatment of extranodal NK/T cell lymphoma, radiation therapy was used in the first line of therapy, 5-year OS and EFS were 60 % and 42 %, respectively. The role of autologous hematopoietic stem cell transplantation (auto-HSCT) in all PTCL was evaluated: 5-year OS and EFS were 82 % and 58 % compared with 67 % and 49 % without auto-HSCT. The transplantation of allogeneic hematopoietic stem cells (allo-HSCT), even in the treatment of relapses of the disease, has shown its effectiveness: 9 out of 11 patients are alive and remain in remission of the disease.

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.

Aim. To determine the prognostic value of t(14;18)(q32;q21) in follicular lymphoma (FL) of grades 1–3А, to assess the chemotherapy efficacy in “t(14;18)+ FL” and “t(14;18)– FL” patients, and to analyze the cases of ineffective therapy. Materials & Methods. The retrospective/prospective study carried out at the National Research Center for Hematology in the period of 2001–2022 enrolled 362 patients with newly diagnosed FL of grades 1–3А. Their risk stratification was based on predictive models FLIPI and PPI3 (Personalized Predictive Index[1]). The patients were 30–81 years of age (median 52 years). There were 225 women and 137 men. They received the following regimens: R-B (n = 80), R-CHOP (n = 189), R-CHOP (4 cycles) + R-DHAP (2 cycles) (n = 28), and R-CHOP (4 cycles) + R-DHAP (2 cycles) + auto-HSCT in the first-line therapy (n = 65). For 2 years, maintenance rituximab therapy was administered to all the enrolled patients, whichever drug chemotherapy they received. Standard cytogenetic analysis and FISH were carried out in 265/362 (73 %) patients. Results. Patients were divided into two comparable groups: “t(14;18)+ FL” (n = 196) and “t(14;18)– FL” (n = 69). Patients without cytogenetics/FISH (n = 97) were excluded from the analysis. In patients without t(14;18), poor prognostic factors, such as grade 3А (p = 0.003) and Ki-67 > 35 % (p = 0.001), were identified significantly more often, and also high PPI3 risk was reported (p = 0.008). No differences (p = 0.84) were detected during FLIPI risk stratification of patients. Bone marrow lesions were observed significantly more often in “t(14;18)+ FL” compared to “t(14;18)– FL” (p = 0.002). The chemotherapy outcomes, such as 2-year EFS and OS, appeared to be considerably worse in “t(14;18)– FL” compared to “t(14;18)+ FL” patients. Conclusion. The group of FL patients with t(14;18) appeared to be most numerous and more prognostically favorable. Immunochemotherapy regimens R-B and R-CHOP are more justified in the first-line therapy of FL with low PPI3 risk. Therapy outcomes were comparable in efficacy. In intermediate and high PPI3 risk FL patients with t(14;18), the most effective first-line therapy was the one with consistent administration of R-CHOP, R-DHAP, and auto-HSCT. Based on the results of this study, FL of grades 1–3А without t(14;18) can well be considered to be a prognostically unfavorable variant of this malignant lymphoid tumor. The rate of early relapses/progression after the standard immunochemotherapy (R-B and R-CHOP), according to our data, is 60 %. In patients with newly diagnosed FL who received consistent administration of R-CHOP, R-DHAP, and auto-HSCT in the first-line therapy, this rate drops to 30 %. Our results clearly indicate the need for new FL treatment approaches.

Aim. To assess efficacy and safety of the Nivo-BeGEV (nivolumab combined with bendamustine, gemcitabine, and vinorelbine) immunochemotherapy in patients with relapsed/refractory (r/r) classical Hodgkin lymphoma (cHL) selected as candidates for autologous hematopoietic stem cell transplantation (auto-HSCT). Materials & Methods. During 2018–2022, the study enrolled 51 r/r cHL patients treated with the Nivo-BeGEV immunochemotherapy. The median age was 38 years (range 19–57 years). There were 30 men and 21 women. PET-CT was performed to assess the response according to the LYRIC criteria. Safety and tolerability were analyzed by registering adverse events in line with the NCI CTCAE criteria, version 5. Results. The median follow-up was 12 months (range 3–54 months). Complete remissions were reported in 100 % of cases. An early relapse was observed in 1 (2 %) patient. The 2-year overall and progression-free survivals were 100 % and 93 %, respectively. During Nivo-BeGEV administration, severe adverse events of grade 3/4 developed in 6 (13 %) out of 51 patients. Conclusion. The results of this multi-center prospective clinical study of the Nivo-BeGEV immunochemotherapy used as preparation for auto-HSCT in r/r cHL patients showed high efficacy irrespective of prior drug chemotherapy and its duration with an acceptable toxicity profile.

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.

Aim. To determine the incidence and prognostic value of mutations in exon 16 of EZH2 as well as those of polymorphism с.1582-21А>G (rs2072407) in EZH2 in patients with follicular lymphoma (FL) grades 1–3А in relation to morphologic and cytogenetic tumor characteristics. Materials & Methods. The prospective cohort study conducted by the National Research Center for Hematology from January 2017 to April 2021 enrolled 80 patients with newly diagnosed FL grades 1/2 and 3А. The median follow-up was 53 months. Molecular and cytogenetic analyses were based on biopsy samples of lymph nodes obtained before chemotherapy. The mutation status of exon 16 in EZH2 and the presence of intronic polymorphism rs2072407 in EZH2 were examined by Sanger sequencing method. Translocation t(14;18)(q32;q21) was detected by karyotyping or FISH. Results. Mutations in exon 16 of EZH2 (mutEZH2) were identified in 10/80 (13 %) patients. All patients showed missense mutation in codon 646 of EZH2. Translocation t(14;18) was detected in 45/80 (56 %) cases. Poor outcome in the cohort with no t(14;18) was observed 3 times more often than in the group of patients with t(14;18) (p = 0.0001). The presence of t(14;18) was associated with favorable prognosis irrespective of either the mutation status of exon 16 in EZH2 or the FL grade. The analysis of the polymorphism rs2072407 status yielded the following genotypes: AA in 24 % (n = 19), AG in 42 % (n = 34), and GG in 34 % (n = 27) of cases. The variants АА and AG were associated with higher risk of death (hazard ratio 2.9; 95% confidence interval 1.2–10.6; p = 0.01), whereas the genotype GG was associated with wtEZH2 (10 % vs. 37 %) and favorable prognosis (p = 0.065). Conclusion. Significant biological markers for favorable prognosis in FL appeared to be the presence of t(14;18)(q32;q21) and GG genotype of polymorphism rs2072407 in EZH2. The previously identified prognostic factors (grade 3А, bulky tumor lesions > 6 cm, Ki-67 > 35 %, and a short interval between symptom onset and chemotherapy start) were incorporated into a new unified personalized predictive (index PPI) FL model by supplementing it with two additional biological markers: the presence of t(14;18)(q32;q21) and GG genotype of polymorphism rs2072407. This approach may increase the prognostic value of the new personalized design which will provide the basis for risk-adapted algorithms for FL treatment.

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.

arms Conclusion: Long term data from the Phase 1 component of E4412 shows no late safety concerns, and significant durability of response in both N containing arms with median follow-up of nearly 3 years. Analysis of the impact of transplant and depth of response will be updated by the time of the meeting. Optimization of this strategy is ongoing in E4412, now a randomized phase 2 study comparing the doublet of BV-N to the triplet of BV-N-I. scheme (vinorelbine 20 mg/m2 on day 1, dexamethasone 20 mg/m2 on days 1–5, gemcitabine 800 mg/m2 on days 1 and 4, bendamustine 90 mg/m2 on days days 2 and 3, nivolumab 40 mg IV on day 0) with further assessment of response by PET/CT. When a complete metabolic response was achieved, an addi-tional one course of chemotherapy Nivo40-BeGEV was performed and then auto-HSCT (BeEAM) was held. If a partial remission after 2 cycles of chemotherapy and a complete remission after 4 cycles has not been achieved, the patient was excluded from the treatment protocol. Results: Treatment according to the Nivo40-BeGEV regimen was com- pleted in 35 patients. All patients achieved complete remission, most after 2 cycles - 34/35 (97.1%). Effective mobilization of HSC and auto- HSCT was performed in 30/34 (85.7%) patients. Complete remission of r/r cHL is maintained in 33/35 (94.2%) patients with a follow-up of 1–34 months, and 2/35 (5.7%) patients had an early relapse of the disease. EFS and OS were 95% and 100%, respectively, with a median follow-up of 13 months. Infectious, immune complications grade III-IV were not detected. Hematological toxicity grade III-IV has been observed in 3/35 (8.5%) patients. Conclusion: The combination of nivolumab at a fixed dose of 40 mg with chemotherapy BeGEV has demonstrated high efficacy and the absence of severe adverse eventes in patients with r/r cHL. Background: Novel agents such as brentuximab vedotin (BV) and check- point inhibitors (CPIs) have high response rates in patients with relapsed/ refractory (r/r) classical Hodgkin Lymphoma (cHL) and have recently been used as salvage regimens to induce remissions before autologous stem cell transplant (ASCT). Our aim was to compare the outcomes of pts receiving salvage chemotherapy (CT) as opposed to novel treatments (NT) for their first salvage regimen for r/r cHL since limiting data exists regarding their efficacy. Methods: Adult pts with r/r cHL who received their first salvage regimen (SR1) between January 2018 and June 2020 were retrospectively identified. Endpoints were to compare complete response (CR), overall response rate (ORR), and event free survival (EFS) between the CT and NT cohorts. Results: 120 pts were identified with a median age of 33 years (range 18– 85). 68% had advanced disease and 13% were early stage unfavorable at diagnosis. Many pts had poor prognostic characteristics including 43% with primary refractory disease, 52% with relapse <12 months from diagnosis, 38% with extranodal disease, and 26% with B-symptoms at time of relapse (Table 1). 65% of pts (n=78) and NT for SR1. 90% of CT pts received Ifosfamide, Carboplatin, and Etoposide (ICE) as SR1. Regimens used for NT treated pts included BV + Bendamustine (43%), BV alone (36%), BV + CPI Background: Advanced-stage classical Hodgkin’s lymphoma (cHL) is a curable malignancy, however up to 25% of patients may relapse follow-ing frontline multiagent-chemotherapy. Novel treatment options such as PD-1 inhibitors and antibody-drug conjugates (ADC) have demonstrated high efficacy with favorable safety profiles in frontline and relapsed cHL. Early reduction in volumetric and metabolic PET parameters have been reported as effective predictors of outcome in cHL. Here, we describe the changes in metabolic tumor volume (MTV), total lesion glycolysis (TLG), and maximum standardized uptake value (SUVmax) after two cycles of therapies containing nivolumab, brentuximab vedotin (Bv), or both in advanced cHL. Methods: We retrospectively enrolled subjects with newly diag-nosed, advanced stage cHL who received therapy in three protocols: Bv-nivolumab-AD,

Introduction. Over the past 5 years, signifi cant progress has been achieved in the treatment of patients with Ph-negative acute lymphoblastic leukemia (ALL). Treatment results were compared between two protocols of the Russian multicenter studies «ALL-2009» and «ALL-2016», in which multicomponent high-dose consolidation was not used. The principle of continuity of treatment was observed with modifi cation of doses of cytostatic drugs depending on the depth of cytopenia. Aim – to compare the 5-year results of two studies and to determine the factors of unfavorable prognosis in the treatment of patients with ALL. Materials and methods. The studies were performed from April 2009 to April 2016 (ALL-2009) and from April 2016 to September 2021 (ALL-2016), and 596 patients were included: 330 in ALL-2009 and 266 in ALL-2016. The analysis was performed in March 2022. The median age of patients in ALL-2009 was 28 years (15–55), in ALL-2016 – 32.5 years (18–55). Cytogenetic studies were performed in 242 patients in ALL-2009 (73.3 %) and 236 patients in ALL-2016 (88.7 %). Patients in the ALL-2016 protocol underwent a centralized assessment of minimal residual disease (MRD) by fl ow cytometry on protocol +70 day (after completion of two induction phases), +133 and +190 days. Transplantation of allogeneic stem hematopoietic cells was performed in 7 % of patients in ALL-2009 and in 9 % in ALL-2016. Results. Overall, relapse-free survival (OS, RFS) and the probability of relapse for a period of 3 years from the moment of inclusion of patients in a particular study were 59 %, 63 % and 23 % for ALL-2009, and for ALL-2016 – 64 %, 59 % and 22 %, respectively. For patients with B-cell precursor ALL, two cytogenetic risk groups were formed, in which long-term survival rates differed signifi cantly: the standard group (hyperploid set of chromosomes and normal karyotype) – OS 63 %, RFS 70 %, and high cytogenetic risk (any abnormal karyotype, except for hyperploidy) – OS 49 %, RFS 52 % (р = 0.001, р = 0.0014). In T-ALL, cytogenetic markers had no prognostic value, but the immunophenotype of early T-cell precursor turned out to be an important predictor of poor prognosis (the probability of relapse was 52 % compared with 15 % for all other immunophenotypic variants). According to the results of centralized monitoring of MRD, it was determined that for B-cell precursor ALL, the signifi cant negative factors are the high cytogenetic risk group and positive MRD status at +70 day, and for T-cells, the early immunophenotype and positive MRD status at +133 day.

Primary bone lymphoma (PBL) is a rare disease. In this article two cases of primary diffuse large B-cell lymphoma of bones are described, one case of solitary lesion and the other of multiple lesions. Both patients were treated with courses CHOEP in combination with radiotherapy and achieved a complete remission (CR). The patient with solitary lesion is still in CR with the follow-up of 33 months. The patient with multiple lesions where partial remission has been received died in 3 months after the end of therapy from disease progression. The authors discuss differential diagnosis and present a review of literature concerning PBL.

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.

Aim. To analyze the results of treatment in patients with acute myeloid leukemia (AML) within protocols AML-17 and modified AML-17 (mOML-17) as part of two consecutive pilot studies in order to develop the best treatment strategy for AML patients aged below 60 years. Materials and methods. The study included 89 AML patients who were aged below 60 years and received treatment within the AML-17 and mOML-17 protocols. Cytogenetic and molecular genetic studies were performed in all patients. The presence of mutations in the FLT3, NPM1, CEBPa genes was assessed by fragment analysis. 35 patients underwent a study for mutTP53, mutRUNX1 using next generation sequencing (NGS). The minimum residual population of tumor cells was evaluated by multicolor flow cytometry. Statistical analysis was performed using the procedures of the SAS 9.3 package. Results. Complete remission (CR) was achieved in 89.7% of patients treated with intensive chemotherapy (CT) courses and in 52.4% of patients treated with low-dose CT courses. 8.8% of intensively treated patients were refractory to therapy, and 38% did not respond to low-dose exposure. The early mortality rate was 3%. The overall survival and disease-free 3-year survival for patients included in 2 consecutive studies was were 60% and 67%, respectively. The level of minimal residual disease (MRD) after the first course of induction CT was an important prognostic indicator. The three-year relapse-free survival for patients in whom CR was achieved after the first course of induction CT and in whom MRD was not detected (MRD-negative status was obtained) was 90% compared to 43% for patients who were MRD positive after the first course of induction CT (p=0.00001). Conclusion. The key factor that significantly affects the long-term results of therapy is the rate of MRD after the first course of induction CT.

Aim. To analyze the efficacy and toxicity of different highdose chemotherapy protocols for the purpose of determining the optimal conditioning regimen with autologous hematopoietic stem cell transplantation (auto-HSCT). Materials & Methods. The present review provides the analysis of some comparative retrospective studies. The evidence-based analysis proceeded in two stages consisting of a search and then primary processing of available literature. The PubMed database was searched for publications for the period 2004-2020. Results. In relapsed and refractory non-Hodgkin’s lymphomas as well as in Hodgkin’s lymphoma, the literature analysis demonstrated satisfactory efficacy of carmustine as part of BEAM conditioning. With the use of the BEAM conditioning regimen with subsequent auto-HSCT, up to 50 % of complete remissions were achieved in patients with non-Hodgkin’s lymphomas and up to 70 % in patients with Hodgkin’s lymphoma. Comparative studies show that despite concerns about severe toxicity, the use of carmustine was not associated with an increase in the incidence of adverse events. Lung and liver toxicity proved to be comparable with that of being observed while using alternative programs of highdose chemotherapy and corresponded to 9 % and 6 % on LEAM and BEAM regimens, respectively. Besides, carmustine feasibility in primary diffuse large B-cell CNS lymphoma was considered and analyzed in the context of the lack of thiotepa. Conclusion. High efficacy of carmustine as part of BEAM conditioning with subsequent auto-HSCT was proved in extremely unfavorable patients with relapsed and refractory non-Hodgkin’s lymphomas and Hodgkin’s lymphoma with an acceptable toxicity profile. The study of carmustine in the therapy of primary CNS lymphoma seems to be аn important area of clinical studies aimed at developing rational treatment options.