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 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.

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 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.

Цель. Оценить частоту выявления ДНК вирусов герпеса человека (цитомегаловируса, вирусов простого герпеса 1-го и 2-го типов [HSV-1/2], герпеса человека 6-го типа [HHV-6], вируса Эпштейна—Барр) в различных биологических средах на разных этапах трансплантации аутологичных гемопоэтических стволовых клеток (аутоТСГК) и влияние иммунных факторов на реактивацию исследуемых вирусов. Материалы и методы. С 2019 по 2021 г. в исследование включено 87 пациентов с лимфомами во время и после выполнения аутоТГСК. При вирусологическом мониторинге исследовались различные биологические жидкости (кровь, слюна, моча и др.) по показаниям перед началом режима кондиционирования, в день 0, а также в дни +5 и +10 после аутоТСГК. У 15 % (14/87) больных в указанные дни (Д0, Д+5 и Д+10) оценивали влияние иммунных факторов (концентрацию IgM, IgG, IgA и субпопуляционный состав лимфоцитов периферической крови) на реактивацию герпесвирусов. Результаты. Общая частота обнаружения вирусных ДНК увеличилась с 26 (26/87) до 42 % (37/87) наблюдений в период восстановления гранулоцитопоэза. Наиболее часто отмечалась реактивация HHV-6 и HSV-1/2 — в 23 (20/87) и 16 % (14/87) случаев соответственно. В группе пациентов с реактивацией герпесвирусной инфекции медиана доли В-лимфоцитов в периферической крови составила 0,26 %, а в группе без реактивации — 6,7 % (p = 0,019). Медиана абсолютного содержания В-лимфоцитов в когорте пациентов с выявленными вирусными ДНК составила 0,001 × 109/л, а в группе без таковых — 0,098 × 109/л (p = 0,026). Заключение. Высокая частота выявления ДНК герпесвирусов у пациентов с лимфомами после аутоТГСК не оказывала влияния на приживление трансплантата и трансплантационную летальность. Иммунными предикторами реактивации вирусной инфекции служили два фактора: снижение доли В-клеток от общего числа всех лимфоцитов и абсолютное содержание В-лимфоцитов в периферической крови перед аутоТГСК.

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.

We studied changes in the bone tissue in patients with diffuse large B-cell lymphoma at the onset of the disease (N=41; before chemotherapy) and 5-16 years after the end of treatment (N=47). Osteodensitometry, biochemical markers of osteoporosis in the blood and urine, and gene expression in multipotent mesenchymal stromal cells were analyzed. In multipotent mesenchymal stromal cells of all patients, the expression of genes associated with bone and cartilage differentiation (FGF2, FGFR1, FGFR2, BGLAP, SPP1, TGFB1, and SOX9) was changed. In primary patients, the ratio of deoxypyridinoline/creatinine in the urine and blood level of β-cross-laps were increased, while plasma concentration of vitamin D was reduced, which indicates activation of bone resorption. No differences between the groups were revealed by osteodensitometry. No direct relationship between changes in gene expression in multipotent mesenchymal stromal cells and osteoporosis markers was found. The presence of a tumor in the body affects the bone marrow stroma, but achievement of remission and compensatory mechanisms provide age-appropriate condition of the bone tissue.

In diffuse large B-cell lymphoma, bone marrow involvement is rarely diagnosed. We compared the properties of bone marrow stromal progenitor cells and the concentration of fibroblast CFU in patients with diffuse large B-cell lymphoma without bone marrow involvement and in healthy donors. It was found that the properties of multipotent mesenchymal stromal cells in patients in the debut of the disease differed considerably from those in healthy donors. In particular, the total cell production in patients was significantly higher than in donors. In multipotent mesenchymal stromal cells of patients, some cell parameters were changes; the mean fluorescence intensity of the adhesion molecule ICAM1 on the cell surface was increased. The mean fluorescence intensity of mesenchymal stromal cell markers (HLA-ABC, CD73 and CD90) was significantly elevated. The relative expression of BMP4, MMP2, FGFR1, and ICAM1 genes in mesenchymal stromal cell was reduced, while the expression of FGFR2 gene was enhanced. Despite the absence of proven involvement of the bone marrow, the properties of mesenchymal stromal cells, the components in the stromal microenvironment niche regulating hemopoiesis are altered in patients with diffuse large B-cell lymphoma.

Mediastinal gray-zone lymphoma (MGZL, lymphoma with features intermediate between classical Hodgkin lymphoma and diffuse large B-cell lymphoma) was declared as a separate entity in WHO classification of Tumors of Haematopoetic and Lymphoid Tissues in 2008 and 2017 years. Despite of similar pathomorphological characteristics between primary mediastinal B-cell lymphoma and Hodgkin lymphoma, clinical features and optimal therapeutic approach to MGZL are not clearly defined. Usually MGZL manifests with mediastinal lymphadenopathy, although extranodal lesions often occur (grey-zone lymphoma, GZL). Patients with MGZL have unfavorable prognosis, taking into account high rate of relapse. This article describes two cases of MGZL. First case manifested by arrhythmias due to primary heart involvement. In spite of cardiac failure antracycline-containing chemotherapy (6 courses of R-DA-EPOCH) it allowed to achieve a complete remission and resolving of arrhythmias. Second case was represented by metachronous tumors: primary mediastinal B-cell lymphoma at the time of disease onset and classical Hodgkin lymphoma, NS II, diagnosed after disease progression. Thus, we demonstrated two examples of MGZL that differ by clinical manifestation, response to chemotherapy, which emphasizes an importance of pathogenesis studying, and using of new therapeutic approaches.

Aim of the issue was to determine indications for intratecal chemotherapy drugs administration to prevent relapse of diffuse large B-cell lymphoma (DLBCL) with central nervous system (CNS) involvement.MATERIALS AND METHODS:Since January 2009 to December 2018 102 patients with primary nodal DLBCL over 18 years old were treated in the National Research Center for Hematology, Moscow, Russian Federation. Diagnosis were established in all cases according to histological and immunohistochemical studies which made it possible to exclude the transformation of mature B-cell lymphoma into DLBCL.RESULTS:Isolated leptomeningeal involvement of CNS in the debut of the disease was detected in 1 (0.98%) out of 102 patients with DLBCL. Focal brain tissue involvement was not detected in any patient. More than half of the patients (54%) had a high risk of disease recurrence or progression with CNS involvement: in 8 (7.8%) patients had kidney/adrenal involvement, in the same proportion - bone marrow involvement, paranasal sinuses involvement - in 5 (4.9 %), epidural space - in 7 (6.9%) and breast - in 5 (4.9%) of patients. In 82 (80%) patients, a non-GCB (postgerminal differentiation of B-cell analog) molecular subtype of DLBCL was determined.CONCLUSION:The introduction of chemotherapy drugs into the spinal canal is recommended in isolated cases of leptomeningeal involvement of CNS at the time of DLBCL onset and is carried out according to standard recommendations. Prevention of relapse with involvement of central nervous system using intratecal chemotherapy in patients with nodal form of DLBCL is not indicated due to the absence of cases with disease progression or recurrence into CNS when patients were treated with R-m-NHL-BFM-90, R-DA-EPOCH and R-CHOP protocol.

Primary mediastinal large B-cell lymphoma (PMBCL) is a distinct type of large B-cell lymphoma. In this type of the disease, the neoplastic process is located in the anterior and superior mediastinum, frequently with compression of the superior vena cava and with tumor invasion into the adjacent organs and tissues: the pericardium, lung, pleura, etc. Despite the fact that in PMBCL progression, there may be involvement of extranodal organs, such as the kidney, adrenal glands, liver, and central nervous system, bone marrow (BM) injury is generally absent. Since BM injury in patients with diffuse large B-cell lymphoma is an independent poor prognostic indicator, there is reason to believe that BM involvement in PMBCL affects the prognosis. These cases may need intensified induction therapy followed by autologous hematopoietic stem cell transplantation; and BM injury should be monitored during the therapy. The paper gives reports of clinical cases of bone marrow involvement in 2 PMBCL patients treated at the National Research Center for Hematology, Ministry of Health of the Russian Federation.