Immune thrombocytopenia (ITP) is an autoimmune disease characterized by increased platelet destruction and decreased platelet production. The formation of antibodies to platelet and megakaryocyte glycoproteins plays a major role in the pathophysiology of ITP. All treatment strategies for ITP attempt to increase platelet count and reduce the risk of bleeding complications. Corticosteroids remain the most commonly used first-line therapy for ITP, but their long-term use is limited due to the development of severe complications. Today the new treatment methods including the use of thrombopoietin receptor agonists (TPO-RA) romiplostim, eltrombopag and avatrombopag with a number of advantages over standard therapy are of great interest. These drugs are recommended for use in the second-line therapy and show high efficacy in patients with ITP, particularly in real clinical practice. In most cases TPO-RA provide stable and long-term remission of the disease, allowing you to reduce or discontinue the use of glucocorticosteroids and avoid splenectomy. Many studies of the mechanism of action, efficacy and toxicity of TPO-RA have been performed. the research results significantly expand our knowledge about these agents. This review provides comparative data of the TPO-RA safety and the main aspects of their clinical use. The features of the new drug avatrombopag, recently approved for use in the Russian federation, are described. the overview presents the advantages and limitations of each drug, possible adverse events and methods for their control.

Glucocorticosteroids (GCS) are the first-line treatment for idiopathic thrombocytopenic purpura (ITP). Despite their high efficacy in patients with newly diagnosed ITP, an adequate level of platelets remains after GCS withdrawal in only less than 20 % of patients. Additionally, GCS use is associated with an increased risk of different adverse reactions, including serious and life-threatening ones. Thrombopoietin receptor agonists represent a relatively new class of drugs for treating ITP as a second-line therapy. This paper reviews the risks of GCS pharmacotherapy, as well as the evidence supporting the use of thrombopoietin receptor agonists as both first-line and second-line treatment for patients with ITP.

Clinical efficiency of Dacogen (inhibitor of DNA hypermethylation) in 16 patients with MDS is presented. Bone marrow cytogenetic studies were performed in 6 patients; the detected chromosome aberrations included 5q deletion in 1 patient, X monosomy in 2 and multiple clonal rearrangements in 1. Results of this study indicated that after 4 courses of Dacogen (15mg/m2 i.v. 3 times daily for 3 days each course) significant clinical and hematological effects is received (according to standard criteria [1]): a complete response was in 3 patients; no partial response was registered; stabilization and bone marrow remission were achieved in 1 and 4 patients respectively. Response duration was 3.5 months. Drug myelotoxicity which would influence on intercourse interval and cause dose reduction during treatment was not revealed.

Background: At present, the diagnosis of lymphoproliferative disorders is based on the combination of blood or bone marrow smear morphology and immunophenotyping by flow cytometry. Immunophenotypic testing by flow cytometry technique is available only in big medical centers, which is not always convenient for a patient. Therefore, development of an available method for preliminary diagnosis of lymphoproliferative diseases not requiring special equipment seems relevant.Materials and methods: Peripheral blood mononuclear cells from 17 patients admitted to the hospital with suspicion of a lymphoproliferative disorder, and 17 healthy donors were studied on a cell biochip for determination of proportions of cells positive for various surface CD antigens. The diagnosis was verified by flow cytometry.Results: Compared to healthy controls and patients with T-cell lymphoproliferative disorders (TCLPD), the patients with B-cell lymphoproliferative disorders (BCLPD) had significantly lower proportion of CD7+ cells (medians, 7% and 73% respectively, p=2×10-6 for comparison with healthy controls; median 7% and 93% for comparison with TCLPD, p=0.032). In addition, the patients with BCLPD had higher proportion of peripheral СD19+ mononuclear cells, compared to that in the patients with TCLPD and healthy donors (medians 84% and 13% for comparison between BCLPD and healthy control, p=2×10-5; 84% and 3% for comparison of BCLPD and TCLPD, p=0.033). The patients with B-cell chronic lymphocytic leukemia had significantly higher CD5+ cells in the cell biochip compared to the patients with other BCLPD (medians 72% and 9%, p=0.024). The patients with TCLPD had significantly lower proportion of CD19+ cells than the healthy controls (medians, 3% and 13%, respectively, р=0.042).Conclusion: The study has demonstrated the potential to use the previously developed cell biochip for diagnosis of lymphoproliferative diseases. The biochip makes it possible to sort out white blood cells according to their surface differentiation antigen for their further morphological analysis. The cell biochip allows for the differential diagnosis between BCLPD and TCLPD and determination the lymphocyte clones based on the expression of immunoglobulin light chains.

Goals: an evaluation of effectiveness of Fludarabine, Cyclophosphomide and Rituximab (FCR therapy) for patients with newly diagnosed Chronic Lymphocytic Leukemia (CLL) for validation of results from multi-centered clinical trials in real clinical practice. Materials and methods: sixty six (66) patients with newly diagnosis of CLL were included to this prospective study with average age of 58 years old (39-73 years old). Stage I - II according to Rai staging system was found in 76% of patients; Stage III-IV – in 24 % of patients. All patients received 6-8 cycles of inductive FCR therapy: Rituximab 375 mg/m2, iv – first cycle, followed by 500 mg/m2, iv; Fludarabine – 25 mg/m2, iv – days 2,3 and 4 of a cycle; Cyclophosphamide – 250 mg/m2,iv– days 2,3 and 4 of a cycle). Patients were divided into two groups based on duration of induction cycles (IC). Group 1 had average IC of 36 days; Group 2 - 49 days. Evaluation of immunochemotherapy effectiveness was determined by presence of remissions (IWCLL-2008), progression-free survival (PFS) and overall survival (OS) (Kaplan – Meier method). Results: Complete Remission (CR) was observed more often in Group 1 (FCR-36) than in Group 2 (FCR-49) - 56.6% and 37.9% of patients, respectively (p > 0.05). Median PFS was 36 months in all patients; 45 months – in Group 1 (FCR-36) and was not achieved in Group 2 (FCR-49). Median OS was 45 months in Group 1 (FCR-36) and was not achieved in Group 2 (FCR-49). Conclusions: confirmation of FCR therapy effectiveness for newly diagnosed CLL patients was established in real clinical practice characterized by non-selective patient groups and prolonged induction therapy cycles. Results of this study provide validation for results from multi-centered clinical trials and could be reproduced on a greater scale in clinical practice. Keywords: Chronic Lymphocytic Leukemia (CLL), Chemotherapy, Immunotherapy No conflicts of interests pertinent to the abstract.

Aim. To assess the information content of conventional and additional immunophenotypic markers (CD200, CD305) in the differential diagnosis B-cell lymphoproliferative diseases by flow cytometry. Methods. An immunophenotypic study using 4-color flow cytometry was performed in 204 patients with different variants of B-cell non-Hodgkin's lymphomas. The study material included peripheral blood and bone marrow. The expression of CD45, CD19, CD20, CD22, CD79b, CD79a, CD5, CD10, CD23, FMC7, CD43, CD38, CD11c, CD103, CD25, CD 200, CD 305, light chains of immunoglobulins (kappa/lambda) using monoclonal antibodies (Becton Dickinson, USA) was evaluated. The intensity of antigen expression was assessed using mean fluorescence intensity (y. e.). Results. Conventional FMC7-positive expression revealed only half patients with different variants of leukemization of non-Hodgkin's lymphomas, whereas atypical positive expression of CD23 was observed in patients with marginal spleen lymphoma and follicular lymphoma in 27.3 and 28.6% of cases, respectively. In mantle cell lymphoma, expression of CD200 in B-cell was detected in a significantly smaller number of observations, accompanied by a significant decrease in the average intensity of CD200 fluorescence compared to B-cell chronic lymphocytic leukemia (B-CLL) cells. The mean fluorescence intensity (MFI) of CD305 in hairy cell leukemia is significantly higher than in splenic marginal zone lymphoma (SMZL) with villous lymphocytes. Conclusion. Different levels of the information content of some conventional markers were revealed in differential immunophenotypic diagnosis of B-cell lymphoproliferative diseases by flow cytometry; the use of additional markers CD200 and CD305 was highly informative in differential diagnostics between different variants of B-cell lymphoproliferative diseases with similar immunophenotypic and morphological characteristics of lymphoid elements.

Aim. To evaluate the concentration of immunoglobulin free light chains (FLC) in comparison with that of intact measurable paraproteins (PIg) in patients with relapsed/resistant multiple myeloma (RR MM) undergoing treatment with bortezomib.Materials and methods. A retrospective study included 15 patients with RR MM with intact measurable PIg. Following 6 cycles of bortezomib treatment, an evaluation of the treatment efficacy was performed using standard criteria and by analysing serum FLC of immunoglobulins (sFLC).Results. A partial response (PR) and small response was achieved in 4 and 5 patients, respectively. The stabilization of the disease was observed in 6 patients. No cases of complete response (CR) or stringent complete response (SCR) were recorded. On the basis of the data on the concentration of sFLC after treatment, all patients were divided into 2 groups: those with an abnormal (clonal) and normal κ/λ ratio. In 11 patients with a response lower than PR, sFLC κ/λ ratio was of a clonal nature, which corresponded to changes in the concentrations of intact PIg during treatment. In 4 cases with PR, the residual tumour was determined by the presence of intact PIg within the 32–45 % range under, however, a normal sFLC κ/λ ratio.Conclusion. Treatment with bortezomib affects all processes in MM with intact PIg, such as synthesis of FLC by tumour plasma cells, a decrease in the amount of circulating sFLC in blood and in the concentration of intact PIg. Normalization of sFLC κ/λ ratio under the achievement of PR could be considered as a prognostic factor in a favourable clinical outcome.

Objective: to study the efficacy and safety of the antitumor RVP program (lenalidomide, bortezomib, prednisone) as a first-line therapy in patients with multiple myeloma (MM). Materials and methods. A prospective study involved 39 patients with MM (15 women, 24 men), median age 61 years (30–76 years). All patients had Durie–Salmon stage III disease. According to the paraprotein isotype variant, 19 patients (48.7 %) had Gk myeloma, 8 (20.5 %) had Gλ, 4 (10.2 %) – Ak, 1 – Aλ, 1 – Dk, 1 – paraproteinemia Bens-Jones k and 1 – Bens-Jones λ, 2 – Dλ, and 2 patients – nonsecreting MM. The average level of plasma cells in the bone marrow was 31.7 % (0.8–80.0 %). In 14 (35.8 %) patients there were plasmacytomas of various localization (spine, cranial bones, clavicle, pleura). Nine (23.0 %) patients had renal failure, requiring the start of renal replacement therapy. The average Karnovsky index in the study group was 50 %. All patients received RVP therapy (lenalidomide 25 mg in 1–14 days, bortezomib 1.3 mg subcutaneously in 1, 4, 8, 11 days, prednisolone 60 mg/m2; the interval between courses was 42 days) as the first line therapy. Evaluation of therapy efficacy, characterized by overall survival, objective response rates (the number of complete, very good partial and partial remissions) was performed after 6 treatment courses. Results. The median follow-up was 15 months; the median of overall survival was not achieved. Objective antitumor response achieved in 29 (74.3 %) patients, including complete remissions in 3 (7.6 %), very good partial remissions – in 7 (17.9 %), partial remissions – in 19 (48.7 %) patients. In 2 out of 9 patients who received renal replacement therapy, independence from dialysis therapy was achieved. Cases of III–IV stage hematological and non-hematological toxicity in the study were not noted. Conclusion. The antitumor RVP program showed high efficacy and safety as a first-line therapy in a non-selective group of patients, including those with a complicated MM course.

Background: We have previously shown that the FAS, TNFR2, TRAIL, DR3, DR4/5 gene expression in patients with newly diagnosed chronic lymphoblastic leukemia (CLL) correlates with clinical manifestations of the disease: they are minimal in patients with high activity of the proapoptotic genes and low activity of the apoptosis-inhibiting genes, and advanced in patients with high expression of the anti-apoptotic and low expression of the pro-apoptotic genes.Aim: To compare the levels of expression of the external apoptosis pathway genes in patients with newly diagnosed CLL before and after chemotherapy with fludarabine, cyclophosphamide and rituximab (FCR), taking into account baseline clinical data and the response to treatment.Materials and methods: This prospective one-center cohort study included 23 patients with newly diagnosed CLL, who underwent clinical and diagnostic assessments and treatment from November 2014 to December 2017. Immunophenotyping of peripheral blood lymphocytes for CLL diagnosis was done by fourcolor flow cytometry. Expression of the external apoptosis pathway genes was assessed by realtime reverse transcriptase polymerase chain reaction. All patients were treated with a standard FCR regimen with subsequent maintenance treatment with rituximab.Results: There were more men (n = 16) than women among our 23 CLL patients. Median age was 64 years (range, from 47 to 77 years). Sixteen (16) patients had CLL Rai Grade I and II, and 7 patients had CLL Grades III and IV. For convenience of analysis, all patients were divided into two groups depending on the FAS gene expression. At baseline, the patients with high FAS expression had higher TNFR2 (p < 0.0015) and TRAIL (p < 0.0053) expression levels. Before FCR therapy, the patients with low FAS expression had higher lymphocyte counts (р = 0.0016) and lower erythrocyte counts (р = 0.0159). At baseline, there were more Grade I and II patients in the group with higher FAS expression (р = 0.0205). At day 3 after the end of a four day FCR cycle, there was an increase only of the FAS (p = 0.0025) and TRAIL (p = 0.0045) expression. After the completion of the first FCR cycle, lymphocyte counts in the patients with low FAS expression decreased earlier than those in the patients with high FAS expression (p = 0.0019). After six FCR cycles, complete or partial remission was obtained in 82% (19/23) of the patients. The patients with high FAS expression had higher complete remission rate (р = 0.026). No adverse events related to FCR were registered.Conclusion: The external apoptosis pathway genes are one of the key factors of the tumor progression in CLL. Our data on the effect of FCR therapy on the FAS and TRAIL gene expression make it possible to consider them as a target for this combination regimen and may become the rationale to develop new pharmaceutical molecules.

Introduction.The given data of fundamental studies of apoptosis processes in B-cell lymphocytic leukemia (B-CLL) testifies about the complexity and variety of mechanisms affecting the kinetics of normal cells and tumor lymphocytes in this disease. It is important to study the severity of clinical manifestations of the disease depending on the expression of the genes that modulate apoptosis.The purposeof the study is to compare the activity of genes encoding apoptosis modulators, the cell cycle and cancer-testicular PRAME protein with clinical manifestations of the disease in primary patients with B-CLL.Materials and methods.The level of expression of the proapoptotic genes FAS, TRAIL, TNFR2, DR4/5 and DR3, as well as the HSP27, XIAP genes, blocking apoptosis was determined in 23 patients with newly diagnosed chronic B-CLL. In addition, expression of genes TP53 and P21 and cancer-testis gene PRAME are tested.Results.According to the multivariate regression analysis, the FAS gene expression in the onset of the disease had the greatest impact on the clinical characteristics of the disease. In this connection, the patients were divided into groups with normal (group) and low gene level (group II). A low level of FAS expression (Me 387 %) was associated with stage II disease (p = 0.03), a large number of lympho cytes (p = 0.001), fewer erythrocytes (p = 0.08), and a lower level of TNFR2 gene expression (p = 0.08), high level of expression of XIAP, HSP27, P21. Overall, the anti-apoptotic potential in Group II patients was higher, which was accompanied by more pronounced clinical manifestations of the disease.Conclusions.The increased anti-apoptotic potential of tumor lymphocytes in newly diagnosed B-CLL is accompanied by a larger tumor mass and greater clinical and hematological manifestation of the disease.

Presence of Serum-Free Immunoglobulin Light Chains (sFLC) was analyzed for 15 patients with newly diagnosed Chronic Lymphocytic Leukemia (CLL). All patients were also characterized by peripheral blood lymphocytes' immunotype (including k/lambda), presence of absolute lymphocytosis and clinical data. Of the 15 patients 11 had elevated concentrations of monoclonal sFLC: 7 patients had elevated K sFLC (K/lambda ratio > 1,65); 4 patients had elevated) sFLC (K/lambda ratio < 0,26). The type of elevated clone for sFLC was the same as the isotype of clonal lymphocytosis. The remaining 4 of 15 patients did not have elevated concentrations of sFLC whereas clonal lymphocytosis (lambda type for all 4 patients) and absolute lymphocytosis were observed. 10 of 15 patients received 6 courses of RFC-therapy. For those patients sFLC concentration was measured before and after the therapy. In 6 of 10 patients tumor clone of sFLC was detected. After RFC-therapy, 4 of those patients demonstrated a reduction in concentrations of elevated sFLC on average for 63,1% and a normal K/lambda ratio that corresponded with the absence of clonal and absolute lymphosytosis. The remaining 2 patients did not have a decrease in sFLC concentrations and had abnormal k/lambda ratio, however, tumor clone lymphocytes and absolute lymphocytosis were not detected, that was presented with better overall clinical outcome. In 4 out of 10 patients that demonstrated no initial elevation in clonal sFLC, measured sFLC concentrations varied within the normal range. Conclusions: 73,7% of CLL patients in our study showed elevated concentrations of clonal sFLC. Serum-Free Light Chains concentration could serve as an integral criterion for evaluation of tumor mass and therapy effectiveness.

Clinical observations of plasma exchange therapy in patients with thrombotic thrombocytopenic purpura (UP) are presented. Difficulties in the early diagnosis and the role of the early use of the pathogenic treatment are considered. The impact of extracorporal therapy in patients with UP is discussed.

Efficiency of the multiple myeloma treatment with chemotherapy including bortezomib was assessed based on determination of the level of immunoglobulin free light chains in blood serum. The method enables estimation of changes in kinetic parameters of the residual tumor, detection of the disease course prognosis, and the choice of the optimal approach to the disease therapy.