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.

Case Report In 2008, a 63-year-old patient was diagnosed with diffuse large B-cell lymphoma (DLBCL) with damage to the testicles and retroperitoneal lymph nodes. Six courses were conducted according to the DLBCL-CNS-2007 protocol. Complete remission was stated and maintenance therapy with Temodal® (temozolomide) was carried out until 2011. In May 2016, the patient began experiencing shortness of breath and sweating. A CT scan of the abdominal cavity revealed a soft tissue formation in the liver area up to 12 cm, and a late relapse of DLBCL was histologically determined. A prephase was carried out, 4 courses according to the R-DA-EPOCH program, with 2 injections of high doses of methotrexate. The patient underwent a PET study. Taking into account the late relapse and metabolic activity of the formation, the patient underwent autologous blood stem cell transplantation in November 2016. The patient went under observation in December 2016. In November 2017, negative dynamics were noted in the form of an increase in the size of the formation in the right kidney. Surgery was performed for the formation of the right kidney, and nephrectomy was performed because of squamous cell carcinoma of the kidney. In March 2018, the hemogram showed thrombocytopenia and hepatitis C was verified. Immunophenotypic study: 0.6%, corresponding to myeloid blast cells myelogram blasts 3.2%, hypogranulation cells predominate among myelocytes. Cytogenetic study: a clone with a derivative of chromosome 6, additional material on the long arm of chromosome 12, the short arm of chromosome 17. Histology of the bone marrow: a picture of a hypoplastic variant of the lesion in myelodysplastic syndrome (MDS). The patient was under dynamic observation and did not require chemotherapy. At the end of July 2018, the patient noted an increase in weakness and shortness of breath. The patient started taking antiviral therapy for hepatitis C. Negative dynamics were noted: the appearance of a nodular formation in the projection of the left adrenal gland, specific foci in the lungs, and an increase in intrathoracic lymph nodes. For morphological verification of the identified changes, the patient underwent a biopsy of intrathoracic nodes. In the lymph node, metastasis of clear cell squamous cell carcinoma of the kidney was found.

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.

ITI distinguishes cases of tLGLs among HGBLs. c-MYC/BCL2 HGBL DH and HGBL TH are frequently presented by GCB-lymphomas transformed from FL. c-MYC/BCL6 HGBL DH and HGBL NOS can develop from MZL with paraprotein secretion. Involvement of the CNS is characteristic of tLGLs.

Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous group of diseases of the lymphatic system, which is represented by de novo and secondary tumors resulting from the transformation of indolent lymphomas. In the absence of a long history of the disease at the stage of histological transformation (HT), it is difficult to distinguish between de novo and secondary diffuse large B-cell lymphoma. According to the data of a randomized study, we obtained clinical and laboratory data that are not typical for de novo diffuse large B-cell lymphoma. These include exclusive, predominant retroperitoneal localization, compression of the ureters/kidneys with or without the development of acute renal failure (ARF), unilateral lymphostasis of the leg due to compression of the inguinal, iliac lymph nodes by the conglomerate, intratumor in the central nervous system (CNS) at the onset/relapse/progression of the disease, discordant bone marrow involvement, blood involvement, paraprotein secretion.

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

Cancer is a leading causes of death. Despite significant success in the treatment of lymphatic system tumors, the problems of relapse, drug resistance and effectiveness of therapy remain relevant. Oncolytic viruses are able to replicate in tumor cells and destroy them without affecting normal, healthy tissues. By activating antitumor immunity, viruses are effective against malignant neoplasms of various nature. In lymphoproliferative diseases with a drug-resistant phenotype, many cases of remissions have been described after viral therapy. The current level of understanding of viral biology and the discovery of host cell interaction mechanisms made it possible to create unique strains with high oncoselectivity widely used in clinical practice in recent years.

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.

Our results showed that in cases of PR FL achievement, observation may be chosen, since the early R-DHAP appointment after FLT has no advantages over the later initiation in case of disease progression.

Background: NHL-BFM-90 chemotherapy is highly effective in pediatric aggressive B-cell lymphomas. Purpose: To evaluate the efficacy and toxicity of the R-mNHL-BFM-90 and R-DAEPOCH-21 programs in adult patients with de novo DLBCL. Patients and methods: Inclusion criteria: newly diagnosed DLBCL (NOS), no previous chemotherapy, 2 or more signs of poor prognosis, age 18-60. The protocol included 140 patients from 13 medical centers in Russia: R-DA-EPOCH-21 – 33; R-DAEPOCH-21+auto-HSCT - 29; R-mNHL-BFM-90 - 33; R-mNHL-BFM-90+ auto-HSCT -35 patients. R-DA-EPOCH-21 branch: 6 courses were performed. If CR was not achieved, 2 courses of R-DHAP were performed ± auto-HSCT. Branch R-mNHL-BFM-90 included 6 cycles: RA-RB-RA-RB-RA-RB. If CR was not achieved, 2 courses of R-DHAP ± auto-HSCTResults: Of 62 patients on R-DA-EPOCH-21±auto-HSCT, CR was achieved in 36 (58.1%) patients, PR was achieved in 14 (22.6%) patients, progression was reported in 6 (9.7%) patients, 3 (4.8%) patients had died, and treatment continued in 3 (4.8%) patients. Of 68 patients on R-mNHL-BFM-90±autoHSCT CR was achieved in 63 (92.7%) patients, PR was achieved in 2 (2.9%) patients, progression was not reported, 2 (2.9%) patients had died, and treatment continued in 1 (1.5%) patient. The 4-year OS of patients in the high-risk group 94% on R-mNHL-BFM-90 therapy, 81% on R-DA-EPOCH-21 therapy;. the 4-year EFS of patients in the high-risk group was 78% and 43%, respectively (p = 0.0004). Conclusion: R-mNHL-BFM-90 program is highly effective in de novo DLBCL NOS adult patients; toxicity is acceptable.

Context Anti-tumor effects in patients with non-Hodgkin lymphomas (NHL) receiving chemotherapy are achieved as a result of the synergy between cytotoxic effects of chemotherapy and anti-tumor autoimmunity. However, chemotherapeutic depletion of lymphoid cells may impair the effectiveness of the anti-tumor immune response. The dynamics of lymphocyte subpopulations during R(G)-DHAP therapy has not been previously analyzed and are of interest. Objective To analyze changes in lymphocyte fractions and determination of the time period for the restoration of T-cell and NK-cell immunity. Design The study included 5 patients with NHL. Lymphocyte subpopulations were examined at 6–7 time points: before treatment, on the 1st, 5th, 8th, 11th, 16th days of the inter-course break and before the start of the next cycle. Setting Analysis of the subpopulations of lymphocytes was performed using flow cytometry with a panel of antibodies for lymphocytes (CD45+), T-helper cells (CD3+CD4+), cytotoxic T-cells (CD3+CD8+), NK cells (CD3-CD56+) and B-lymphocytes (CD19+). Patients Inclusion criterion: NHL patients receiving R(G)-DHAP chemotherapy. Main Outcomes Measures Estimation of time parameters of dynamics of lymphocyte subpopulations. Results The number of lymphocytes critically decreases on the 1st day of the break after (R/G)-DHAP and gradually increased. CD8+ cells are most sensitive to chemotherapy. The number of CD4+ lymphocytes is characterized by the formation of a second minimum on the 10th–12th day of the inter-course break, while the dynamics of effector cytotoxic lymphocytes and NK cells is more linear and gradually increases. By day 16, the absolute number of lymphocytes is restored or approaching the level before the start of chemotherapy. Conclusions The parameters of the dynamics of lymphocytes under cytotoxic stress can be taken into account in the case of combined use of chemotherapy and immunotherapy. Anti-tumor effects in patients with non-Hodgkin lymphomas (NHL) receiving chemotherapy are achieved as a result of the synergy between cytotoxic effects of chemotherapy and anti-tumor autoimmunity. However, chemotherapeutic depletion of lymphoid cells may impair the effectiveness of the anti-tumor immune response. The dynamics of lymphocyte subpopulations during R(G)-DHAP therapy has not been previously analyzed and are of interest. To analyze changes in lymphocyte fractions and determination of the time period for the restoration of T-cell and NK-cell immunity. The study included 5 patients with NHL. Lymphocyte subpopulations were examined at 6–7 time points: before treatment, on the 1st, 5th, 8th, 11th, 16th days of the inter-course break and before the start of the next cycle. Analysis of the subpopulations of lymphocytes was performed using flow cytometry with a panel of antibodies for lymphocytes (CD45+), T-helper cells (CD3+CD4+), cytotoxic T-cells (CD3+CD8+), NK cells (CD3-CD56+) and B-lymphocytes (CD19+). Inclusion criterion: NHL patients receiving R(G)-DHAP chemotherapy. Estimation of time parameters of dynamics of lymphocyte subpopulations. The number of lymphocytes critically decreases on the 1st day of the break after (R/G)-DHAP and gradually increased. CD8+ cells are most sensitive to chemotherapy. The number of CD4+ lymphocytes is characterized by the formation of a second minimum on the 10th–12th day of the inter-course break, while the dynamics of effector cytotoxic lymphocytes and NK cells is more linear and gradually increases. By day 16, the absolute number of lymphocytes is restored or approaching the level before the start of chemotherapy. The parameters of the dynamics of lymphocytes under cytotoxic stress can be taken into account in the case of combined use of chemotherapy and immunotherapy.

Background. Genetic instability, an important phenomenon involved in oncogenic transformation and tumor progression, is associated with the insufficiency of the multicomponent DNA repair complex, in particular, the nucleotide mismatch repair (MMR) system. The MMR defect manifests itself as abnormalities in DNA microsatellite repeats, or microsatellite instability (MSI). In the studies of colorectal cancer, the role of MSI in prognostication of the disease, and defining the choice of specific therapy with immune checkpoint inhibitors has been proven.However, in lymphatic system tumors, the significance of this phenomenon is poorly understood. Determination of genetic instability in the onset of follicular lymphoma, a disease characterized by a heterogeneous course, may have prognostic value.Objective: to determine the genetic instability at the onset of follicular lymphoma.Materials and methods. Here we report an analysis of 24 microsatellite repeats and amelogenin loci in tumor cells of 46 follicular lymphoma patients.Results. In the studied cohort, lesions in microsatellite repeats were presented by MSI in 9 cases (19.6 %) and the loss of heterozygosity (LOH) in 19 cases (41.3 %). Most frequent lesions were found for the SE33 marker located at the q14 locus of chromosome 6. A significant association was shown between MSI and the double-hit follicular lymphoma group with rearrangements of the MYC and BCL2/BCL6 genes.Conclusion. Thus, our data indicate that the MSI phenomenon might be involved in the pathogenesis of the lymphatic tumors and particularly follicular lymphoma. However further studies on the expanded cohorts of patients are required to define the possible prognostic value of MSI in lymphatic tumors.

Памяти академика РАМН и РАН А.И. Воробьева. Актуальность. Хронология гранулоцитопоэза на модели периодического кроветворения изучена подробно. Однако закономерности влияния цитотоксического стресса, вызванного химиотерапией и иммунотерапией, на ритмы развития стволовой клетки исследованы недостаточно. Взаимодействие противоопухолевых препаратов и нормальных клеток гемопоэза имеет значение для оценки степени выраженности нежелательных явлений химиотерапии. Кроме того, актуальность исследования гемопоэза в условиях цитотоксического стресса определяется необходимостью прогнозировать иммунную реактивность организма как условие эффективности агентов иммунной терапии, реализующих свое действие через систему клеточного иммунитета. Цель. Исследование хронологических закономерностей динамики количества лейкоцитов после иммунохимиотерапии R(G)-DHAP при неходжкинских лимфомах. Материалы и методы. На примере 39 курсов терапии у 19 пациентов с неходжкинскими лимфомами мы проанализировали динамику изменения числа лейкоцитов после иммунохимиотерапии по схеме R(G)-DHAP. Профилактика гранулоцитопении гранулоцитарным колониестимулирующим фактором (Г-КСФ) проводилась после 18 из 39 циклов, в остальных случаях выполнялась запланированная ранее мобилизация гемопоэтических стволовых клеток по принятому протоколу. Результаты. Срок активации самостоятельного гранулоцитопоэза не зависит от проведения стимуляции Г-КСФ и общей дозы ростового фактора и соответствует в среднем 10-му или 11-му дню перерыва со дня окончания курса иммунохимиотерапии. Тенденция к уменьшению продолжительности агранулоцитоза при профилактическом применении Г-КСФ связана с транзиторным гиперлейкоцитозом в ранний срок после завершения иммунохимиотерапии. Программы на основе препаратов платины по типу R(G)-DHAP служат вероятной основой для комбинации с агентами иммунного противоопухолевого воздействия у пациентов с неудачами химиотерапии первой линии. Можно предположить, что интервал времени, предшествующий периоду активации миелопоэза в первые дни межкурсового перерыва, будет благоприятствовать инициации терапии препаратами иммунного воздействия после химиотерапии второй линии. Заключение. Определение динамики гранулоцитопоэза после цитотоксического стресса, вызванного иммунохимиотерапией R(G)-DHAP, позволяет планировать оптимальный режим введения Г-КСФ и прогнозировать оптимальные сроки иммунного противоопухолевого воздействия в сочетании с химиотерапией.

Background. Chronology of granulopoiesis based on periodic hematopoiesis model has been thoroughly studied. However, the pattern of influence of immunotherapy-induced cytotoxic stress on the biological rhythm of a stem cell development requires further investigation. The interaction of antitumor drugs with normal hematopoietic cells is relevant for assessing the intensity of chemotherapy adverse events. Besides, there is a demand for studying hematopoiesis under cytotoxic stress to predict immunological reactivity as a condition for efficacy of immunotherapeutic agents, the effect of which is based on cell immunity. Aim. To study the chronological pattern of leukocyte count dynamics after R(G)-DHAP immunochemotherapy in non-Hodgkin’s lymphomas. Materials & Methods. The dynamics of leukocyte count changes after R(G)-DHAP immunochemotherapy was analyzed using the data of 39 treatment courses in 19 non-Hodgkin’s lymphomas patients. After 18 out of 39 cycles of treatment granulocyte colony-stimulating factor (G-CSF) was administered to prevent granulocytopenia, in other cases the previously planned hematopoietic stem cell mobilization was performed according to the accepted protocol. Results. Time to activation of spontaneous granulopoiesis depends neither on G-CSF stimulation, nor on the total dose of growth-stimulating factor and corresponds on average to Day 10 or Day 11 of the break from the last day of immunochemotherapy. The tendency of shorter agranulocytosis duration on prophylactic use of G-CSF is associated with transient hyperleukocytosis at an early stage after completing immunochemotherapy. Regimens with platinum-based drugs, like R(G)-DHAP, are suggested to be combined with immunochemotherapeutic agents in patients with the failure of first-line chemotherapy. The time interval preceding myelopoiesis activation within the first days of the break between the courses is likely to contribute to the initiation of treatment with immunotherapeutic drugs after second-line chemotherapy. Conclusion. The determination of granulopoiesis dynamics under R(G)-DHAP immunochemotherapy-induced cytotoxic stress enables to plan the optimum G-CSF regimen and to predict the optimum timing of immune antitumor effect combined with chemotherapy.

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.

Background: High-grade B-cell lymphoma double-hit (HGBL DH) can arise from follicular lymphoma (FL). In the case of transformation of FL it accumulates a large number of additional mutations and secondary c-MYC gene rearrangement, which can make it resistant to standard immunochemotherapy. Aims: To evaluate an efficacy of induction regimen R-CHOP/R-DAEPOCH and modified BFM chemotherapy with rituximab in treatment of HGBL DH raised from FL. Methods: We studied13 FL pts with double- (9 - with c-MYC/8q24 and BCL2/18q21;4 - with c-MYC/8q24 and BCL6/3q27) and one pt with triple translocations involving c-MYC/8q24, BCL2/18q21 and BCL6/3q27 genes and deletion of17p13.10 pts had morphological signs of transformation into aggressive lymphoma;4 pts had FL 3A. There was 8 women and 6 men aged from 30 to 60 y. o. (median 47 y.o.). Lymph node with the highest FDG-accumulation according to PET-CT was chosen for biopsy and consequent immunohistochemistry and cytogenetics. The majority of pts had high12/14 and 2/14 - high-intermediate FLIPI score. All pts had advanced (III-IV) stage according to Ann-Arbor classification. 3 out of14 pt had a history of low-grade FL (16-96 months) without c-MYC rearrangement in primary biopsy samples, in other11 cases - anamnesis varied from 0,5 to 4,0 months. Lymphoma manifested by rapidly spread aggressive tumor with bulky disease: 2 pts had leukemic presentation of FL;1 pt had FL cells in cerebrospinal fluid;12/14 out of pts had several extranodal sites of involvement such as ovaries (2/8), kidneys or adrenals (6/14), paranasal sinuses (1/14);bones (3/14);soft tissues (4/14);lungs (3/14);stomach or intestine (4/14);spleen (4/14);liver (1/14). Ki-67 varied from 40 to 90%. An expression of c-MYC protein higher than 40% in11/13 of FL pts. We didn't revealed TP53 mutation within 7 out of 7 analyzed pts. Results: None of pts had previous therapy. 4 pts were treated with R-CHOP-21. 3/4 (75%) out of pts died due to progressive disease (PD),1/4 (25%) had partial remission (PR) after consequent therapy including obinutuzumab. 7 pts underwent modified BFM-protocol with Rituximab. 6/7 (86%) out of pts achieved complete remission (CR) after first-line treatment,1 pt died due COVID-19 in PD status (14%). Autologous stem cell transplantation (auto-SCT) was performed in 4 out of 7 pts. 3 pts underwent R-DA-EPOCH.1 pt achieved a CR after 6 courses,1 pt - after second-line 2 R-DHAP;auto-SCT was performed for consolidation.1 pt (33%) had PD after R-DA-EPOCH and another therapy. Rituximab supportive treatment was administrated only in 4 cases due to epidemiological situation. Median of observation was 9 months (1,0-59,5). We couldn't study TP53 mutation status in pts with PD, but we observed PD in one case with deletion of17p13. Summary/Conclusion: For better diagnostics of FL transformation into HGBL DH we should perform biopsy of lymph node with the most active FDG accumulation according to PET-CT. We observed a higher rate of CR in this pts cohort when treated with intensive induction immunochemotherapy (modified BFM chemotherapy with rituximab) in comparison with R-CHOP/R-DA-EPOCH (86% vs 25% and 33%, respectively), and lower rate of primary resistance/PD (14% vs 75% and 33%). Our data needs consequent confirmation or consideration within metanalysis due to rare diagnostics of FL with double translocations of c-MYC and BCL2/BCL6. We should initiate a randomized study to estimate if auto-SCT had any benefits in comparison with a new immunotherapy modalities in FL transformed into HGBL DH.

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.