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

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

Background . Splenic marginal zone lymphoma (SMZL) is an indolent non-Hodgkin’s B-cell lymphoma. It presents morphologically by mature lymphoid B-cells. They conform to these immunological characteristics of marginal zone lymphocytes from secondary follicles. The tumor B-cells of SMZL do not have specific markers of immunophenotype and requires the exclusion of other non-Hodgkin’s B-cell lymphomas. There is an annual increase in the incidence of SMZL. There are refractory forms and progressive course of the SMZL. There is a huge variety of the mechanisms of evading tumor cells from immunological control. Unlike solid tumors, B-lymphoproliferative diseases are characterized by the expression of HLA I/II and co-stimulatory molecules (CD80 and CD86). Therefore, tumor B-lymphocytes can act as antigen-presenting cells (APC) for T lymphocytes. The T-cell immune response is known to play an important role in antitumor control. It is known that effective activation of T-lymphocytes requires the formation of an immunological synapse and the presence of two activation signals (antigen recognition and co-stimulation of CD28-CD80/86). According to the modern concept of tumor development, there is a gradual selection of tumor clones. As a result, only tumor cells that are invisible to the immune system remain. Mechanisms of evasion of tumor B-cells of SMZL from immune surveillance are currently not fully understood and are being actively studied. Objective : to study the expression features of antigens involved in the formation of immunological synapse in patients with SMZL in peripheral blood. Materials and methods . The study includes 10 primary SMZL patients; all patients have stage IV according to the Ann Arbor classification. Splenectomy was performed for all patients as a first stage of treatment. Two patients had progression of SMZL after splenectomy, which required chemotherapy. The control group included 25 healthy donors. Peripheral blood was used as a material for analysis. The study was conducted on a 6-color BD FACS Canto II flow cytometer (BD Biosciences, USA) immediately after diagnosis. Results . Tumor B-cells of SMZL are different from B-cells of healthy donors with a greater proportion of CD80 + , FAS + , PD-1 + -cells, which may correspond to activated B-cells. The proportion of CD4+PD-1+ and CD8 + PD-1 + T-cells in patients with SMZL was higher in comparison with the control group. There was a large proportion of T-cells expressing PD-1 in the group of patients with SMZL progression after splenectomy in comparison with the group of patients with indolent course of SMZL. Conclusion. Thereby, tumor B-cells of the SMZL retains the features of non-tumor analogues. The most significant mechanism for evading immune surveillance in an SMZL is inhibition of the T-cell immunity via the PD-1–PD-L1 pathway. The most pronounced inhibition of T-cell immunity causes an uncontrolled tumor process.

Background. Splenic marginal zone lymphoma (SMZL) is an indolent non-Hodgkin’s B-cell lymphoma. It presents morphologically by mature lymphoid B-cells. They conform to these immunological characteristics of marginal zone lymphocytes from secondary follicles. The tumor B-cells of SMZL do not have specific markers of immunophenotype and requires the exclusion of other non-Hodgkin’s B-cell lymphomas. There is an annual increase in the incidence of SMZL. There are refractory forms and progressive course of the SMZL. There is a huge variety of the mechanisms of evading tumor cells from immunological control. Unlike solid tumors, B-lymphoproliferative diseases are characterized by the expression of HLA I/II and co-stimulatory molecules (CD80 and CD86). Therefore, tumor B-lymphocytes can act as antigen-presenting cells (APC) for T lymphocytes. The T-cell immune response is known to play an important role in antitumor control. It is known that effective activation of T-lymphocytes requires the formation of an immunological synapse and the presence of two activation signals (antigen recognition and co-stimulation of CD28-CD80/86). According to the modern concept of tumor development, there is a gradual selection of tumor clones. As a result, only tumor cells that are invisible to the immune system remain. Mechanisms of evasion of tumor B-cells of SMZL from immune surveillance are currently not fully understood and are being actively studied.Objective: to study the expression features of antigens involved in the formation of immunological synapse in patients with SMZL in peripheral blood.Materials and methods. The study includes 10 primary SMZL patients; all patients have stage IV according to the Ann Arbor classification. Splenectomy was performed for all patients as a first stage of treatment. Two patients had progression of SMZL after splenectomy, which required chemotherapy. The control group included 25 healthy donors. Peripheral blood was used as a material for analysis. The study was conducted on a 6-color BD FACS Canto II flow cytometer (BD Biosciences, USA) immediately after diagnosis.Results. Tumor B-cells of SMZL are different from B-cells of healthy donors with a greater proportion of CD80+, FAS+, PD-1+-cells, which may correspond to activated B-cells. The proportion of CD4+PD-1+ and CD8+PD-1+ T-cells in patients with SMZL was higher in comparison with the control group. There was a large proportion of T-cells expressing PD-1 in the group of patients with SMZL progression after splenectomy in comparison with the group of patients with indolent course of SMZL. Conclusion. Thereby, tumor B-cells of the SMZL retains the features of non-tumor analogues. The most significant mechanism for evading immune surveillance in an SMZL is inhibition of the T-cell immunity via the PD-1–PD-L1 pathway. The most pronounced inhibition of T-cell immunity causes an uncontrolled tumor process.

The aim of the study is to present a successful case in treating primary cutaneous anaplastic large cell lymphoma (PCALCL) occurring with common lesions of the skin and lung tissue. Materials and methods . For the verification of the diagnosis in a patient with three types of skin elements (spot, thin plaque with and without ulceration), differential diagnosis was performed between ulcerative pyoderma gangrenosum, PCALCL, large-cell transformation of mycosis fungoides, and secondary skin lesions under the nodal ALK-negtaive ALCL. A complex of studies, including histological, immunohisto - chemical, cytogenetic studies of skin tumor biopsy, allowed the verification of the PCALCL diagnosis. For the treatment of the patient, intensive induction chemotherapy was used followed by high-dose consolidation and autologous transplantation of hematopoietic stem cells. Results . The selected treatment tactics allowed a long-term complete remission of the disease to be achieved in a patient from the poor prognosis group. Conclusion . An algorithm for the differential diagnosis and tactics of treating is presented for a patient with primary anaplastic large cell lymphoma with a widespread skin lesion and extradermal foci.

The aim of the study is to present a successful case in treating primary cutaneous anaplastic large cell lymphoma (PCALCL) occurring with common lesions of the skin and lung tissue.Materials and methods. For the verification of the diagnosis in a patient with three types of skin elements (spot, thin plaque with and without ulceration), differential diagnosis was performed between ulcerative pyoderma gangrenosum, PCALCL, large-cell transformation of mycosis fungoides, and secondary skin lesions under the nodal ALK-negtaive ALCL. A complex of studies, including histological, immunohisto - chemical, cytogenetic studies of skin tumor biopsy, allowed the verification of the PCALCL diagnosis. For the treatment of the patient, intensive induction chemotherapy was used followed by high-dose consolidation and autologous transplantation of hematopoietic stem cells.Results. The selected treatment tactics allowed a long-term complete remission of the disease to be achieved in a patient from the poor prognosis group.Conclusion. An algorithm for the differential diagnosis and tactics of treating is presented for a patient with primary anaplastic large cell lymphoma with a widespread skin lesion and extradermal foci.

Chronic lymphocytic leukemia (CLL) is a lymphoproliferative disease manifested by accumulation of tumor B-cells with characteristic immunophenotype (CD19+CD5+CD23+) in bone marrow, peripheral blood and secondary lymphoid organs. The clinical course of CLL is heterogeneous. This is the most prevalent leukemia among older-aged patients. Despite the use of novel drugs refractory forms of disease remain. The latest discoveries in immunology enabled understanding of some mechanisms of tumor evasion from immune surveillance. The interaction of immune system cells occurs due to the development of immunological synapse that predominantly depends on the family of CD28/В7 molecules, the so-called immune checkpoints able to control the activating and inhibiting mechanisms of cells. The acquisition of tumor phenotype is a multistage process, in which cells obtain unique biological properties including the ability of being invisible to the immune system. As opposed to solid tumors in lymphoproliferative diseases tumor B-cells are able to express major histocompatibility complex class II and CD80 and CD86 co-stimulatory molecules. It proves their ability to present antigens to T-cells. Co-inhibitory molecules on the surface of tumor cells is a factor contributing to the inhibition of immune response. The present paper reviews current conceptions of biological properties and immunological interactions of CLL cells with the microenvironmental cells.

Contex. Angioimmunoblastic T-cell lymphoma (AITL) is a rare form of non-Hodgkins lymphoma, characterized by generalized lymphadenopathy, hepatosplenomegaly and dysproteinemia. Hypergammaglobulinaemia is revealed in 50-83% pts with AITL. However, the characteristics of immunoglobulinopathies observed in AITL are scarce. Objective: The aim of the study was to characterize quantitative and qualitative immunoglobulinopathies in patients with AITL at the onset of the disease. Patients and methods. 55 patients with newly diagnosed AITL were enrolled in the study, the male/female ratio was 30/25; median age was 61 (29-81) years. Diagnosis was based on standard WHO criteria. Immunochemical studies of blood serum included serum protein electrophoresis/immunofixation, nephelometric quantification of total immunoglobulins, serum free light chain assay. Results. Quantitative and qualitative immunoglobulinopathies were determined in 49 (89,1%) of 55 pts. Quantitative immunoglobulinopathies were revealed in 47 (85.5%) of 55 cases, qualitative - in 14 (25,5%). Combination quantitative and qualitative immunoglobulinopathies was observed in 12 (21,8%) of 55 pts. The detected immunoglobulinopathies were divided into 4 groups: polyclonal hypergammaglobulinaemia, hypogammaglobulinaemia, oligoclonal gammapathy, and monoclonal gammapathy. Polyclonal hypergammaglobulinaemia was marked in 41 (74.5%) of 55 pts, elevated level of IgG was determined in 27 (49,15%) of 55 cases, IgM - in 18 (32,7%) and IgA - in 21 (38.2%). Interestingly, polyclonal IgE hypergammaglobulinaemia was detected in 12 (48,0%) of 25 cases of performed studies. Hypogammaglobulinaemia was detected in 8 (14,5%) of 55 cases. Oligoclonal gammapathy was determined in 4 (7.3%) of 55 pts. Monoclonal gammapathy was revealed in 11 (20,0%) of 55 cases. The amount of monoclonal immunoglobulin varied from 2.6 to 14.1 g/l. Monoclonal immunoglobulin Gk was detected in 5 of 11 pts, Gλ - in 2, Mλ - in 2, Mk - in 2. Monoclonal gammapathy was accompanied by polyclonal hypergammaglobulinaemia in 9 of 11 cases, hypogammaglobulinaemia - in 2. Conclusions. Quantitative and qualitative immunoglobulinopathies are observed in most patients at the onset of AITL. Quantitative abnormalities were determined more often than qualitative. Monoclonal gammapathy can be a manifestation of lymphoproliferation and other concomitant disorders. The prognostic value of immunochemical parameters is still unclear and requires dynamic observation and study.

Background. Chronic lymphocytic leukemia (CLL) is a lymphoproliferative disease that manifests by the accumulation of tumor monoclonal B-lymphocytes in the bone marrow, peripheral blood and secondary lymphoid organs. Recently it was found that CLL cells are able to form immunological synapses with microenvironment cells, directly and indirectly affecting their function. Therefore, it became clear that the pathogenesis of CLL is not only escape of apoptosis but also the ability of CLL cells to cause T-lymphocyte anergy, thereby avoiding immune surveillance.Objective: to study the expression of FAS, co-stimulatory molecules CD80 and CD86, PD-1, PD-L1 on CLL cells, and also to study the basic subpopulations of T-cells (naїve, memory, effector cells).Materials and methods. The study included 46 CLL patients: 16 patients with disease progression after chemotherapy and 30 patients with newly diagnosed CLL. “Primary” patients are categorized according to J. Binet’s CLL stages. Stage A was established in 14 patients, B – 10, C – 6. The control group included 29 healthy donors. Peripheral blood was used as a material for analysis. The study was performed on a 6-color flow cytometer BD FACS Canto II (BD Biosciences, USA).Results. In CLL patients, the proportion of CD80+, CD86+, FAS+ B-cells was significantly lower than in donors. In “primary” patients the proportion of CD80 + CLL cells was higher than in patients with CLL progression. Among “primary” patients the proportion of CD80+ and CD86+ was lower in advanced stages of the disease. In patients with CLL progression the proportion of FAS+ B cells was higher than in “primary” patients. The proportion of PD-1+ B cells in CLL patients was higher than in donors and “primary” patients. The proportion of PD-1+ tumor cells was significantly lower in advanced stages of the disease. The proportion of PD-L1+ B cells in CLL patients was lower than in donors. Among the “primary” patients, the proportion of PD-L1+ B-lymphocytes was higher in stage A. The proportion of PD-1+ Thelpers was higher in CLL patients than in donors, and among “primary” patients it was higher in advanced stages of the disease. The proportion of PDL1+ T-helpers and cytotoxic T-cells in CLL patients was lower than in donors. The proportion of naїve cells (CD95-CD28+) in patients compared with donors was lower and the proportion of effector cells (CD95+ CD28–), memory cells (CD95 + CD28 +) was higher, a proportion of CD8+ memory T-cells was higher among patients in the advanced stage of CLL.Conclusion. Therefore, a decline the CD80/CD86+ B-cells in CLL can cause ineffectiveness of an immunological synapse between tumor cells and T-cells, which leads to anergy of T-lymphocytes. Decline expression of the FAS receptor allows tumor CLL cells to avoid FAS-mediated apoptosis. A change in the T-cell pool toward memory cells and effectors, the acquisition of a CD4+PD-1+ (“exhausted”) phenotype impaired antitumor immunity and possible leads to disease progression.

Nodal anaplastic ALK-negative large cell lymphoma (nALCL, ALK-) is a O-cell lymphoma that is characterized by aggressive clinical course and low sensitivity to NIID (cyclophosphamide, doxorubicin, vincristine, prednisolone) and other chemotherapy regimen. In the article we present a literature review and describe our clinical case of nALCL, ALK-. For the first time a combination of Brentuximab vedotin with modified program NHL-BFM-90 was used as a first-line therapy. As a result of immunochemotherapy a complete antineoplastic effect was obtained. For consolidation of this effect high-dose chemotherapy with following autologous blood stem cell transplantation was performed. The chosen treatment tactics allowed to achieve a complete remission in a medium risk group patient.

Breast implant-associated anaplastic large-cell lymphoma will be identified as a separate nosological entity in the 2017 adapted WHO classification due to differences in its clinical presentations, pathogenesis, and prognosis with those of nodal and cutaneous anaplastic large-cell lymphomas. The paper gives a review of the literature and describes the authors' own clinical case of common breast implant-associated anaplastic large-cell lymphoma involving breast tissue, axillary lymph nodes, anterior chest muscles, and bone marrow. The treatment policy chosen by the authors could achieve complete remission.

Breast implant-associated anaplastic large-cell lymphoma will be identified as a separate nosological entity in the 2017 adapted WHO classification due to differences in its clinical presentations, pathogenesis, and prognosis with those of nodal and cutaneous anaplastic large-cell lymphomas. The paper gives a review of the literature and describes the authors' own clinical case of common breast implant-associated anaplastic large-cell lymphoma involving breast tissue, axillary lymph nodes, anterior chest muscles, and bone marrow. The treatment policy chosen by the authors could achieve complete remission.Ассоциированная с имплантатом анапластическая крупноклеточная лимфома молочной железы будет выделена в отдельную нозологическую единицу в адаптированной классификации ВОЗ от 2017 г. в связи с различиями клинической картины, патогенеза и прогноза с нодальной и кожной анапластическими крупноклеточными лимфомами. В статье представлен обзор литературы и описано собственное клиническое наблюдение распространенной ассоциированной с имплантатом анапластической крупноклеточной лимфомы, протекающей с поражением ткани молочной железы, подмышечных лимфатических узлов, мышц передней грудной стенки и костного мозга. Выбранная нами тактика лечения позволила достигнуть полной ремиссии заболевания.

AIM To evaluate the efficiency of the treatment policy for patients with acute myeloid leukemia (AML) and hyperleukocytosis (HL), which is aimed at preventing rapid hypercytolysis and massive tumor lysis (cytolysis) syndrome and/or at reducing the degree of the latter at the start of induction polychemotherapy. SUBJECTS AND METHODS In 2010 to 2014, the Hematology Research Center, Ministry of Health of Russia, treated 92 patients with AML, out of them 18 patients were found to have white blood cell counts of 100 to 408-10(9)/1 (median, 130-10(9)/l) at the onset of the disease. All the examinees received cytoreductive therapy with hydroxyurea and, in presence of leukostasis and/or leukocytosis (≥150-10(9)/1), with leukocytapheresis. In case of reduced leukocytosis, plasmapheresis was carried out to prevent (treat) cytolysis. Daunorubicin was injected on days 3-5 of the 7+3 induction cycle. RESULTS The signs of leukostases were detected in more than half of the 18 patients with higher white blood cell counts: 13 (72%) with lung injury, including 5 of them with signs of respiratory distress syndrome, 6 (27.8%) with neurological symptomatology, 7 (38.9%) with disseminated intravascular coagulation syndrome, including 1 with intracranial hemorrhage. Cytoreduction therapy with hydroxyurea (10 mg/kg/day) was performed 1-5 (median 2) days before initiating induction chemotherapy in 17 patients; 9 patients underwent 1-2 (median 2) leukocytapheresis sessions. Sixteen patients received 1-4 (median 2) plasmapheresis sessions prior to and within the first days of the 7+3 treatment regimen. Daunorubicin (60 mg/m2) was administered to 16 patients on days 5-7 of the 7+3 cycle and to 2 patients on days 3-5 of the cycle. There were no signs of severe cytolysis with the development of multiple organ dysfunction in any patient. 50% (9/18) achieved remission after the first 7+3 cycle and 7 more examinees did after the second cycle. Thus, the remission rate was 89%; early mortality was 5.5% (1/18), three-year overall and relapse-free survival rates were 50%. CONCLUSION Adequate cytoreductive and accompanying therapies for AML with HL can virtually completely prevent massive tumor cytolysis syndrome and early mortality during the first days of induction chemotherapy.