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.

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.

Background. The study of genetic predictors of non-Hodgkin’s lymphomas prognosis is one of the most relevant areas of oncohematology. It is extremely interesting to search for integral markers that reflect the most important stages of tumor pathogenesis. DNA repair system plays one of the key roles in genomic instability. Aberrations of microsatellite repeats such as microsatellite instability (MSI), in particular elevated microsatellite alterations at selected tetranucleotide repeats (EMAST) is characteristic for mismatch repair system and loss of heterozygosity (LOH) is an integral feature of genomic instability.Objective. Analysis of MSI, EMAST, LOH significance in follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), and high-grade B-cell lymphoma (HGBL) patients.Materials and methods. The study was performed by multiplex PCR and fragment analysis with diagnostic panels COrDIS Plus and COrDIS MSI in 85 FL patients, 32 DLBCL patients, and 37 HGBL patients.Results. The frequency of LOH in the general FL group was 40/81 (49.4 %), MSI – 10/82 (12.2 %), EMAST – 15/81 (18.5 %). The frequency of LOH in the HGBL group was 21/31 (67.8 %), MSI – 11/37 (29.7 %), EMAST – 13/31 (41.9 %). The frequency of LOH in the DLBCL group was 18/29 (62.0 %), MSI – 5/32 (15.6 %), EMAST – 14/32 (43.8 %). When considering the morphological types of FL, it was noted that a higher frequency of genetic aberrations was characteristic of lymphomas with a more aggressive morphology (p <0.05). LOH identifies FL and HGBL patients with an unfavorable prognosis. The EMAST analysis allows identifying additional patients in the LOH+ cohort with early events and low EFS.Conclusion. LOH and EMAST have a prognostic value for FL and HGBL. No associations of LOH and EMAST with the survival were observed in DLBCL. Changes in mononucleotide repeats in FL, DLBCL and HGBL did not correspond to the MSI-H characteristic of solid tumors. For this reason, the clinical consequences of MSI-H in solid neoplasms, in particular the efficacy of immune checkpoint inhibitors, in lymphomas cannot be expected to be replicated solely on the basis of microsatellite aberrations detection.

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,

Aim. To analyze the first experience of administering polatu-zumab vedotin combined with bendamustine and rituximab (Pola-BR) in clinical practice at some specialized institutions in the Russian Federation. Materials & Methods. The prospective multi-center study enrolled 39 patients with relapsed/refractory aggressive В-cell non-Hodgkin’s lymphomas (B-NHLs): 31 (79 %) patients with diffuse large B-cell lymphoma, 7 (18 %) patients with primary mediastinal (thymic) large B-cell lymphoma, and 1 (3 %) patient with gray zone lymphoma. There were 20 men and 19 women aged 19-69 years (median 43 years). All the patients were treated with Pola-BR protocol: bendamustine 90 mg/m2 on Days 1 and 2, rituximab 375 mg/m2 on Day 1, and polatuzumab vedotin 1.8 mg/kg on Day 1 of each 21-day cycle. Full treatment with 6 cycles was completed by 19 patients. PET-CT was performed prior to therapy and after the 2nd, 4th, and 6th Pola-BR cycles. The tumor response was evaluated according to the Lugano 2014 criteria. The toxicity profile was assessed by means of reporting adverse events according to the NCI CTCAE, version 5.0. Results. Objective response to the therapy, according to the Lugano 2014 criteria, was identified in 24 (61.5 %) patients: 19 (48.7 %) of them showed the complete response, and 5 (12.8 %) of them showed the partial one. Stable disease as best response to the therapy was reported in 3 (7.7 %) patients, disease progression was observed in 12 (30.8 %) patients. By the time of data analysis, the median follow-up duration was 16.8 months (range 5.3-24.2 months). The 2-year overall survival (OS) was 44 % (95% confidence interval [95% CI] 24-62 %), the median OS was 20.8 months. The 2-year progression-free survival (PFS) was 27 % (95% CI 12-43 %), the median PFS was 7.3 months. Adverse events of grade 3/4 included anemia (n = 4; 10.3 %), neutropenia (n = 15; 38.5 %), thrombocytopenia (n = 3; 7.7 %), and febrile neutropenia (n = 2; 5.1 %). In 2 patients with history of hepatitis B, the virus reactivation was identified on Pola-BR therapy. No cases of peripheral neuropathy were observed. Conclusion. Results obtained in real-world clinical practice correspond to the previously published data and demonstrate that polatuzumab vedotin therapy (Pola-BR protocol) has a controllable toxicity profile and is, therefore, a promising chemotherapy method of relapsed/refractory aggressive B-NHL treatment.

Aim. To assess the detection rate of human herpes virus DNA (of cytomegalovirus, herpes simplex virus types 1 and 2 [HSV-1/2], human herpes virus type 6 [HHV-6], and Epstein-Barr virus) in different biological environments at different stages of autologous hematopoietic stem cell transplantation (auto-HSCT) as well as the effect of immune factors on reactivation of viruses under study. Materials & Methods. From 2019 to 2021 the study enrolled 87 lymphoma patients during and after auto-HSCT. Virological monitoring was performed on biological fluids (blood, saliva, urine, etc.) prior to conditioning regimen on Day 0 as well as on Day +5 and Day +10 after auto-HSCT. On these days (Day 0, Day +5, and Day +10) the immune factors (IgM, IgG, and IgA levels and pattern of lymphocyte subpopulation in peripheral blood) in 15 % (14/87) of patients were assessed in terms of their effect on herpes virus reactivation. Results. The overall rate of viral DNA detection increased from 26 % (26/87) to 42 % (37/87) of cases in the period of granulocytopoietic recovery. The most frequent were HHV-6 and HSV-1/2 reactivations reported in 23 % (20/87) and 16 % (14/87) of cases, respectively. The median B-lymphocyte proportion in peripheral blood of patients with herpes virus reactivation was 0.26 %, whereas in patients without reactivation it was 6.7 % (p = 0.019). The median absolute B-lymphocyte count in the cohort of patients with detected viral DNAs was 0.001 x 109/L, whereas in patients without them it was 0.098 x 109/L (p = 0.026). Conclusion. A high rate of herpes virus DNA detection in lymphoma patients after auto-HSCT affected neither transplant engraftment nor transplantation mortality. Immune predictors of virus infection reactivation were the decreasing proportion of B-cells in the total lymphocyte count and the absolute B-lymphocyte count in the peripheral blood prior to auto-HSCT.

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.

Aim. Pharmacoeconomic analysis of R-DA-EPOCH and R-mNHL-BFM-90 combination immunochemotherapy in patients with prognostically unfavorable diffuse large B-cell lymphoma within randomized multi-center clinical trial DLB-CL-2015. Materials & Methods. The pharmacoeconomic analysis conducted between September 2018 and February 2020 was based on the treatment data of 22 patients enrolled in the DLBCL-2015 randomized multi-center clinical trial. This paper deals with the estimation of treatment outcomes in only one center, i.e., the National Research Center for Hematology. The R-DA-EPOCH induction therapy was administered to 14 out of 22 patients, 8 patients received the R-mN-HL-BFM-90 block treatment. Within the R-DA-EPOCH group the second-line therapy was administered subsequently to 5 (36 %) out of 14 patients with partial remission or disease progression. The R-mNHL-BFM-90 treatment resulted in no need to assign second-line regimens. At the first stage, the efficacy of the compared induction therapy regimens was assessed. The next stage of the pharmacoeconomic study sought to analyze only the direct medical costs associated with the whole chemotherapy process. Further, the cost-effectiveness analysis was carried out, which allowed to estimate the financial resources necessary to achieve 1 case of complete remission (CR). A pharmacoeconomic decision-tree model was developed. Results. CR was achieved in all 8 patients (100 %) who received the R-mNHL-BFM-90 block treatment. In the R-DA-EPOCH group CR was achieved only in 9 (64 %) out of 14 patients. The total mean cost of achieving 1 CR case per patient at all stages of diagnosis and chemotherapy with account for bed turnover (induction, second-line therapy, total supportive care) using R-mNHL-BFM-90 was 1,640,757 rubles, whereas in the R-DA-EPOCH group it was 1,469,878 rubles per patient. However, cumulative treatment costs of R-DA-EPOCH including chemotherapy of the second and further lines and supportive care were 2,896,519 rubles which exceeded those in the R-mNHL-BFM-90 group. Due to its higher efficacy the R-mNHL-BFM-90 immunochemotherapy precludes additional costs associated with both chemotherapy of the second and further lines and supportive care. Conclusion. R-mNHL-BFM-90 as intensive induction block immunochemotherapy for DLBCL patients with poor prognosis is more effective than R-DA-EPOCH and allows to considerably reduce cumulative costs. It is possible due to complete preclusion of the costs of second-line chemotherapy and supportive care including blood component transfusions.

Analysis of microsatellite instability (MSI) is a routine study in the diagnostics of solid malignancies. The standard for determining MSI is a pentaplex PCR panel of mononucleotide repeats: NR-21, NR-24, NR-27, BAT-25, BAT-26. The presence of MSI is established based on differences in the length of markers in the tumor tissue and in the control, but due to the quasimonomorphic nature of standard mononucleotide loci the use of a control sample is not necessary in the diagnosis of MSI-positive solid tumors. The significance of the MSI phenomenon in oncohematology has not been established. This paper presents the results of a study of MSI in B-cell lymphomas: follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), high-grade B-cell lymphoma (HGBL). We have shown that aberrations of mononucleotide markers occur in these diseases, but the nature of the changes does not correspond to the classical MSI in solid neoplasms. This fact requires further study of the pathogenesis of such genetic disorders. Due to the possibility of ambiguous interpretation of the results of the MSI study for previously uncharacterized diseases, strict compliance with the methodology of parallel analysis of the tumor tissue and the control sample is mandatory.

Background. Primary mediastinal (thymic) large B-cell lymphoma (PMBCL) is an aggressive malignant lymphoproliférative disease which accounts for 2-3 % of all non-Hodgkin's lymphomas. In 40 % of PMBCL cases rearrangements of the MHC class II activator, i.e. CIITA gene, are observed. CIITA abnormalities lead to decreasing protein expression and surface expression of MHC class II, which results in lack of adaptive cell immunity targeted at tumor cells. Aim. To assess the rate and spectrum of cytogenetic and molecular genetic abnormalities of CIITA gene in PMBCL patients. Materials & Methods. The study enrolled 37 patients with diagnosed PMBCL: 10 men and 27 women aged 21-61 years (median of 31 years). Sanger sequencing was performed in 36 patients. In 20 patients CIITA/16p13.13 FISH and in 15 patients standard cytogenetic analysis were carried out. Results. In 3 (8.3 %) out of 36 patients the sequencing method detected mutations impairing CIITA gene function, as well as microdeletion in exon 1, deletion and nucleotide substitution in a splice donor site. Multiple somatic variations in intron 1 were identified in 21 (58.3 %) patients: in 11 (52.4 %) cases there were deletions and single nucleotide variants (SNV); the other 10 (47.6 %) patients showed only SNVs. In 13 (61.9 %) out of 21 cases the abnormalities of promoter IV and/or alternative exon 1 were observed. In 5 (25 %) out of 20 patients the FISH assay identified CIITA gene translocation. Standard cytogenetic analysis detected complex karyotype in 7 (46.6 %) out of 15 patients. The comparison of data showed hypermutagenesis in 8 out of 10 patients with FISH-detected chromosome aberrations, and in 3 (37.5 %) of them complex karyotype aberrations were found as well. Conclusion. Molecular genetic methods identified different somatic variations in CIITA gene affecting its functionally important regions, which can be of special interest for further studying the biology of tumors, including PMBCL.

Multipotent mesenchymal stromal cells (MSC) are the key regulators of hematopoiesis. We studied changes in MSC characteristics in patients with myeloid leukemia and patients with lymphoproliferative diseases. MSC were obtained from the bone marrow of patients at the time of diagnostic puncture using a standard technique. Their proliferative potential and expression of genes associated with differentiation and regulation of hematopoiesis were studied. The total cell production of MSC in patients with leukemia at the onset of the disease did not differ from that in the group of healthy donors. The relative expression of the IL6, TGFb1 and TGFb2, PPARG genes was similar in all patients. The relative expression of the JAG1, LIF, IGF1, CSF1, IL1b, and IL1bR1 genes in MSC of patients with leukemia was enhanced and the relative expression of SDF1 was unchanged in comparison with MSC from donors. MSC from patients with leukemia were characterized by enhanced relative expression of PDGFRA and PDGFRB, and reduced expression of SOX9. Changes functions of the stromal microenvironment in patients with hemoblastoses attested to the role of stromal cells in the maintenance and spread of tumor cells.

Background. Diffuse large B-cell lymphoma (DLBCL) is one of the most common and aggressive tumors of the lymphatic system. Despite the frequency of occurrence, there is no single algorithm for treating DLBCL patients with poor prognostic factors. R-CHOP therapy does not allow achieving long-term complete remissions. Therefore, there is a need for second and subsequent lines of therapy. At the same time, the effectiveness of each subsequent therapy is low, while the toxicity increases. There are many randomized trials of the DLBCL treatment; however, there are only a few studies on the comparative efficacy of high-dose chemotherapy at the induction stage.The objective of the study: the evaluation of the effectiveness and toxicity of R-DA-EPOCH and R-mNHL-BFM-90 induction courses in DLBCL patients with poor prognostic factors in a randomized multicenter clinical trial “DLBCL-2015”.Materials and methods. As of April 2021, 140 patients from 13 medical institutions in Russia were included in the randomized multicenter clinical trial DLBCL-2015. As part of this study, the analysis of pharmacoeconomic factors and effectiveness of combined immunochemotherapy R-DA-EPOCH and R-mNHL-BFM-90 in patients with prognostically unfavorable DLBCL had been performed. From January 2018 to April 2021, this study included 41 patients (21 men, 20 women) with a newly diagnosed DLBCL, with 2 or more factors of an unfavorable prognosis, who were treated at the National Research Center for Hematology of the Ministry of Health of the Russian Federation. Of these, 21 patients received R-DA-EPOCH, and 20, R-mNHL-BFM-90 therapy. Median age for R-DA-EPOCH patients was 52 years (range 30–64); for R-mNHL-BFM-90 patients, 40 years (range 18–60). All patients had high-intermediate and high risk according to the international (IPI) and age-adjusted (aaIPI) prognostic index. The primary protocol endpoints were rates of complete remission, partial remission, disease progression, and hematologic and non-hematologic toxicity. Side effects were assessed in accordance with the Common Terminology Criteria for Adverse Events (CTCAE) criteria.Results. By the end of 6 induction courses, the frequency of achieving complete remission on R-mNHL-BFM-90 therapy was 100 % (20/20) compared to R-DA-EPOCH, where the complete remission rate was 71.4 % (15/21) (p = 0.0097), partial remission and progression were 14.3 % (n = 3) and 14.3 % (n = 3), respectively. Hematological toxicity on therapy according to the R-mNHL-BFM-90 scheme exceeded that on R-DA-EPOCH in terms of myelotoxic agranulocytosis (p = 0.0536), anemia (p = 0.0464) and thrombocytopenia grade III–IV (p = 0.0206). When assessing non-hematological toxicity at the compared courses, no statistically significant differences were noted, all complications occurred with the same frequency.Conclusion. Treatment according to the R-mNHL-BFM-90 protocol is highly effective as first line therapy in high-intermediate and high-risk DLBCL patients. The hematologic toxicity is higher on the R-mNHL-BFM-90 than on the R-DA-EPOCH therapy, but it is acceptable. Non-hematological toxicity in both programs is comparable.

Aim. To compare NHL BFM-90 and CHOEP efficacy in adult patients with ALK-positive anaplastic large-cell lymphoma (ALK+ ALCL). Materials & Methods. Within the period from June 2014 to December 2019 the prospective randomized comparative study at the National Research Center for Hematology in Moscow included 23 ALK+ ALCL patients. In one study arm (n = 11) CHOEP was administered, whereas the other one (n = 12) received high-dose chemotherapy (CT) according to NHL BFM-90 protocol. The median age of patients in both arms was 33 and 40 years, respectively. Results. Overall survival (OS) and event-free survival (EFS) within 3 years were 91 % in the arm receiving CHOEP (this protocol was administered to all 11 patients), and 100 % in the arm receiving NHL BFM-90 (complete remission was achieved in all patients). Due to its toxicity NHL BFM-90 was fully implemented in 9 out of 12 patients. The 3-year OS and EFS in the CHOEP and NHL BFM-90 arms are comparable, and the difference between them is not significant. Conclusion. In ALK+ ALCL treatment high-dose CT according to NHL BFM-90 protocol has no advantage in terms of the 3-year OS and EFS compared to less toxic regimen CHOEP. A larger sample of patients is required to achieve significant results, which will further lead to a final judgement on feasibility of high-dose regimens in the treatment of adult patients with ALK+ ALCL.

Background. The management of aggressive lymphomas in pregnancy depends on the time of diagnosis and immu-nomorphological variant of tumor. The rarity of aggressive lymphomas in pregnant women, the absence of consistent approaches to the treatment of such patients, the lack of data on physical growth of children as well as the incidence of newborns’ congenital and acquired pathology make this subject of vital importance. Aim. To analyze the treatment results in patients with newly diagnosed aggressive lymphoma at different stages of pregnancy. Materials & Methods. From 1993 to 2020 at the National Research Center for Hematology 74 pregnant women with lymphomas were treated. Aggressive tumors were detected in 17 (23 %) of them: primary mediastinal (thymic) large B-cell lymphoma (п = 14), anaplastic large-cell lymphoma ALK+ (п = 1), high-grade B-cell lymphoma, unspecified (п = 1), and diffuse large B-cell lymphoma (п = 1). The median age of patients was 30 years (range 21-37 years). The median pregnancy stage on the diagnosis of aggressive lymphoma was 21 weeks (range 11-32 weeks). Results. In 1 case on the diagnosis of aggressive lymphoma at 11 weeks gestation dexamethasone 8 mg daily was administered up to the second trimester of pregnancy, afterwards the patient received polychemotherapy. On the diagnosis of aggressive lymphoma in the second (п = 13) and third (п = 2) trimesters of pregnancy the patients received polychemotherapy followed by delivery. In the third trimester of pregnancy delivery was performed with subsequent polychemotherapy in 1 patient. There were born 18 babies (1 pregnancy was multifetal): 8 girls and 10 boys. Conclusion. As a result of the chosen tactics and the work of interdisciplinary team of doctors all patients, who completed the treatment, are followed-up in complete remission. All born babies, despite chemotherapy and perinatal complications, are alive and develop without abnormalities.