Background. Follicular lymphoma (FL) is the most common type of indolent lymphomas and accounts for 20–30 % of all non-Hodgkin’s lymphomas detected. High risk of recurrence and elderly patients make it difficult to choose induction therapy for FL. The R–B course in comparison with the R–CHOP course increases the progressive free survival (PFS) of FL patients and is less toxic. International studies have not studied the efficacy and toxicity of the R–B course due to various cytological types of FL.

Aim of the study – assessment of the effectiveness and toxicity of the R–B course (with R support) in general and depending on the different cytological types of FL, the assessment of overall survival (OS) and PFS (adverse events: progression, relapse, death); identification of risk factors for an adverse event in general and death, in particular. The main endpoint of this study is selected BPV.

Materials and methods. We performed a prospective, multicenter, open-label trial in Russia since June 1, 2013 till June 1, 2018. The study included 74 patients with FL. Median age of patients was 59 years (from 30 to 78 years). Treatment was completed in 66 patients, so this group of patients was analyzed. Ratio between men and women was 1:2. 32/66 of patients (48 %) were older than 60 years old. Patients received rituximab 375 mg/m2 on day 1 and bendamustine 90 mg/m2 on days 1 and 2 of a 4-week cycle (6 cycles). 49/66 (74 %) of patients were diagnosed with FL grade 1, 10/66 (15 %) – grade 2, 7/66 (11 %) – grade 3A. 34/66 (52 %) patients had nodular tumor growth type, 28/66 (42 %) – nodular-diffuse, 4/66 (6 %) – diffuse. High risk according to FLIPI had 25/59 (42 %) of patients with cytologic grade of FL 1–2 and 7/7 (100 %) of patients with FL grade 3A. Extranodal lesions were revealed in 26/66 (39 %) of cases: in 4/66 of cases – orbit, in 2/66 – parotid gland, in 5/66 – lungs, in 4/66 – intestines, in 2/66 – stomach, 2/66 – pancreas, 2/66 – uterus, 2/66 – skin, 1/66 – subcutaneous tissue, 3/66 – vertebrae, in 1/66 – latticed maze and nasal passages, 1/66 – kidneys, 1/66 – root of the tongue. In 23/26 (88 %) of cases extranodal lesion was revealed in generalized stage of FL (including lymph nodes and bone marrow). Extranodal lesions were found in 37 % of patients with FL grade 1–2, and 57 % with FL grade 3A. Bulky also was observed more frequently in pts with FL grade 3 3/7 (43 %) than in patients with FL grade 1–2 20/59 (34 %). (The risk factors of an adverse event are also its predictors in this study.)

Results. Complete remission of disease was achieved in 40/66 (61 %) patients, partial remission – 13/66 (19 %) patients. Tumor progression observed in 11/66 (17 %) cases, patients were withdrawn from the protocol. А partial tumor response was achieved in 2/66 cases (3 %) and patients received high-dose therapy after 4 courses of R–B. Five-year (as well as the 3-year) overall survival (OS) of all patients (n = 66) in R–B was 90 % (95 % confidence interval (CI) 78–96), 5-year PFS – 70 % (95 % CI 55–85) and a 3-year PFS – 75 % (95 % CI 60–89). The cumulative incidence of relapse (considering competing risks of progression and death) at the 3th year after initiation of treatment was 11 % (95 % CI 3–19). The following independent statistically significant (p ≤0.05) predictors of PFS (measured in the onset of the disease) were determined (as a result of a stepwise multivariate cox regression analysis): 1) cytological type of tumor (only type 3A is significant); 2) involvement of nodal zones (more than 4); 3) presence of a conglomerate of tumor lymph nodes larger than 6 cm (bulky); 4) Ki-67 protein expression (more than 35 %). The first 3 characteristics (as well as the sign «presence of extranodal foci», close to the level of significance) are independent statistically significant predictors of OS. In the single factor analysis the following characteristics (besides the above) were significant: index FLIPI (significant only 5 points against all others), bone marrow damage, β2-microglobulin (more than 2.2 mg/L), age (over 68 years) and hemoglobin (less than 110 g/dL).

Conclusion 1. The independent negative predictors of OS and PFS in follicular lymphoma were determined. 2. Of the predictors of an adverse event identified, the greatest risk (as a result of a multivariate analysis) is associated with a 3A cytological type of tumor. 3. The FLIPI index has a predictive value not only for the determination of OS, but also for the PFS (moreover, in reduced dichotomous form: 5 points against all the others combined). 4. An increase in the time interval between the first manifestations of follicular lymphoma (lymph node enlargement / appearance of a tumor formation) and the start of therapy beyond a certain threshold value (estimated to be approximately 22 months) is associated (according to the results of univariate analysis) with an increased risk of an adverse event. One of the reasons for the increase in this time interval is associated with expectant medical tactics adopted during the slow development of the clinical picture of the disease. The obtained result shows that the low rate of development of the clinical picture of the disease does not correlate with the low risk of adverse events, and, therefore, cannot be a determining factor when deciding whether to start treatment. 5. The morphology of the tumor is the determining factor in the choice of induction therapy. 6. After achieving full/partial remission of FL, there is a constant risk of recurrence of the disease (by the age of 3 from the termination of treatment, the risk is 11 % (95 % CI 3–19)). 7. The R–B course effectively sanitizes the bone marrow. 8. The R–B allows performing stem cells mobilization and autoSCT that is actual in FL patients with bone marrow involvement. 9. The treatment regimen of R–B is effective and has a relatively low toxicity, so it is advisable in the treatment of elderly patients.

Cutaneous T-cell lymphomas (CTCL) are a heterogeneous group of extranodal non-Hodgkin’s lymphomas that are characterized by skin infiltration with malignant monoclonal T lymphocytes. More common in adults aged 55 to 60 years, the annual incidence is about 0.5 per 100 000 people. Mycosis fungoides, Sézary syndrome and CD30+ lymphoproliferative diseases are the main subtypes of CTCL. To date, CTCL have a complex concept of etiopathogenesis, diagnosis, therapy and prognosis. The article presented summary data on these issues.

Mycosis fungoides – the most common form of cutaneous T-cell lymphoma. The pathogenesis of this disease is complex and remains unclear. The article contains a review of the literature devoted to the main mechanisms of T-lymphocytes malignant proliferation, known to date. Data on dysregulation of immune, genetic and epigenetic mechanisms, as well as the role of microenvironment cells in the proliferation of T lymphocytes, are given. Immunophenotypic characteristics and cellular composition of the infiltrate in patients with mycosis fungoides, are described depending on the stage of the disease. Prospective directions in studying molecular-biological predictors of malignant lymphoproliferative diseases development are highlighted.

Ibrutinib, an irreversible Bruton tyrosine kinase inhibitor (Btk), is a highly effective drug for treatment a number of B-cell lymphoproliferative disorders and, more recently, graft-versus-host disease. However, a number of potentially adverse events are possible in this therapy, partly related to the non-selective mechanism of the drug’s action. Thus, ibrutinib therapy significantly increases the risks of hemorrhagiccomplications compared to standard chemotherapy, especially when combined with a disagregant or anticoagulant therapy, which necessitates the development of clinical recommendations taking into account individual risks for the prevention and treatment of bleeding complications in patients receiving ibrutinib. There is currently an amount of data on the combined use of ibrutinib with disaggregant or anticoagulant therapy is limited, and it is therefore recommended that alternative therapy be considered in patients with a high cardiovascular risk ora reduction in the doses of disaggregante or anticoagulant drugs if abrogation or alternative therapy with ibrutinib is not possible. Also takinginto account the antiplatelet effects of a non-selective Btk inhibitor, a modification of the disaggregant therapy in patients with low cardiovascular risk is possible. This review is summarized available data on mechanisms of bleeding development and proposed strategies for reducingrisks and treating hemorrhagic complications of therapy with ibrutinib.

Introduction. Patients with hematological malignancies undergoing chemotherapy (CT) have high incidence of infections which profile is affected by various factors including neutropenia.

Objective was to evaluate incidence and type of infections in patients with de novo acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) according to neutropenia duration.

Materials and methods. Prospective study (2013–2015) included 110 patients (66 AML, 44 ALL) that received 480 CT cycles throughout 6 month.

Results. Neutropenia with median duration of 15 (2–55) days was in 288 (60 %) of CT cycles. Infections occurred in 242 (50 %) of CT cycles and predominated in neutropenic compared to non-neutropenic patients (80 % vs 6 %, p <0.0001). Infections prevailed in patients with AML compared to ALL patients (93 % vs 18 %, p <0.0001) as in patients with neutropenia (96 % vs 45 %, p <0.0001) and without neutropenia (27 % vs 4 %, p = 0.02). Prolongation of neutropenia from 1–7 days to ≥22 days was associated with increase of infections rate from 52 to 96 % (p <0.0001). Incidence of infections in AML patients was high (92–100 %) regardless of neutropenia duration, whereas in ALL patients it increased from 25–33 to 91 % if neutropenia lengthened from 2 weeks to ≥22 days. During neutropenia the probability of fever of unknown origin was 33.9 %, clinically documented infection – 31.3 %, bacteremia – 17.2 %. They predominated in the first 2 weeks of neutropenia. Probability of invasive aspergillosis (IA) increased after 28 days of neutropenia and reached 66 % on the 55th day. First case of IA in patients with ALL was on 28th day of neutropenia whilst in AML patients – 4 (44 %) of 9 occurred more early (6–16 days of neutropenia). Nine (6 %) of 110 patients died, 4 (4 %) of them due to infection.

Conclusions. Neutropenia was a predictor of infectious complications in patients with AML and ALL. Correlation between duration of neutropenia and incidence of infections was in patients with ALL, whereas in AML patients the rate of infections was high regardless of neutropenia duration. In patients with neutropenia for 2 weeks the most common types of infection were fever of unknown origin, clinically documented infection and bacteremia whilst IA predominated if neutropenia duration was ≥28 days.

The aim of the study was to evaluate the profile and risk factors for acquisition of infections in patients with de novo multiple myeloma (MM) on the 1st chemotherapy cycle (CC).

Materials and methods. Study included patients with de novo MM undergoing chemotherapy from January 2013 till November 2017 in National Research Center for Hematology, Russia.

Results. A total of 156 patients with de novo MM (median age 61 years) were included in the study. Follow-up period was 21–82 days (median 26 days), first CC contained bоrtezomib. Infections occurred in 77 (49.4 %) of patients with MM, from them 29 (37.7 %) – on admission, 48 (62.3 %) – throughout treatment. Solitary infections were in 47 (61%) of patients, multiple infections – in 30 (39 %) of patients. The most prevalent type of infection was pneumonia (62.3 %), followed by urinary tract infections (27.3 %) and herpesvirus infections (24.7 %). 30% of patients with infections were afebrile. Significant risk factors associated with infections at admission and during CC were ECOG score 4, anemia, hypercalcemia, humoral immunodeficiency, admission from other hospital, use of antibiotics prior to first CC. Additional risk factors for infections at admission were Durie–Salmon stage III MM, paresis, lower extremity paraplegia and dysfunction of the pelvic organs, whereas during treatment – ISS stage III MM and renal failure. Infections were uncommon in patients with ISS stage I MM (7.8 %). Mortality after 1st CC was 1.9 % caused by pneumonia and acute respiratory failure.

Conclusions. Patients with de novo MM undergoing 1st CC had high incidence of infections with a prevalence of pneumonia. Factors associated with infections were stage III MM, serious illness, admission from other hospital, humoral immunodeficiency, and renal failure.

Introduction. The main features of bone marrow blasts cells in Burkitt lymphoma/leukemia (BL) are L3 morphology, mature immunophenotype of blasts with surface IgM expression, and presence of typical MYC gene rearrangements.

The aim of the study was to show discrepancy examples in laboratory signs of BL.

Patients and methods. 10 patients (8 boys and 2 girls) aged 1 to 18 years were included in the present study. The inclusion criterion was the identification of discrepancies between flow cytometric, morphological and cytogenetic data.

Results. In 2 cases there were no rearrangements of the MYC gene. In 2 patients, the L2 morphological variant went against the presence of typical MYC gene rearrangements. In one case, undifferentiated blasts cells were described by morphology together with presence of surface IgM, and atypical genetics. In 8 patients, there was no expression of surface IgM. Of these, patients with absence of cytomorphological data cytometric and genetic data were controversial.

Сonclusion. The cases presented in this study and the cases described in the literature demonstrate the importance of an attentive and comprehensive approach in evaluating the results of laboratory tests in the diagnosis of BL.

Platelet activating receptor CLEC-2 has been identified on platelet surface a decade ago. The only confirmed endogenous CLEC-2 agonist is podoplanin. Podoplanin is a transmembrane protein expressed by lymphatic endothelial cells, reticular fibroblastic cells in lymph nodes, kidney podocytes and by cells of certain tumors. Association of CLEC-2 with podoplanin is involved in processes of embryonic development (blood-lymph vessel separation and angiogenesis), maintaining of vascular integrity of small vessels during inflammation and prevention of blood-lymphatic mixing in high endothelial venules. However, CLEC-2 and podoplanin are contributing to tumor metastasis progression, Salmonella sepsis and deep-vein thrombosis. This makes CLEC-2 and podoplanin a perspective target for pharmacological treatment. Aspirin and Ibrutinib are considered to be perspective for abrogation of podoplanin-induced platelet activation via CLEC-2. The present review discusses already known pathological and physiological roles of CLEC-2 and possibilities of a targeted therapy for CLEC-2 associated diseases.

Background. L-asparaginase is an enzyme, widely used in the therapy of acute lymphoblastic leukemia in children and adults, but its use is limited due to a wide range of side effects and anaphylactic reactions. L-asparaginase loaded into erythrocytes can solve these problems. This enzyme is protected from the immune system and plasma proteases due to erythrocyte membrane, but continues to work inside the cell because its membrane is permeable to L-asparagine. Thus, the half-life of the drug increases and anaphylactic reactions reduce. The encapsulation of L-asparaginase into erythrocytes can be performed by various osmotic methods. Each of them is characterized by the amount of encapsulated enzyme, the cell yield, as well as by the quality indices of the survived erythrocytes. An important parameter of each method is the possibility to provide sterility of this dosage form for the clinical use.

The aim of the study was the comparing of three osmotic methods of L-asparaginase encapsulation into erythrocytes (hypo-osmotic lysis, dialysis and flow dialysis) to select the most promising method for clinical use.

Materials and methods. A suspension of erythrocytes of healthy donors (hematocrit 60–70%) was mixed with L-asparaginase from E. сoli. The procedures of hypotonic reversible lysis, dialysis in dialysis bags, or flow dialysis using pediatric dialyzers were performed. The physiological osmolality was restored in suspensions after the procedure by the addition of a hypertonic solution, and they were incubated for 30 min at 37 °C. Then the cells were washed in isotonic phosphate-buffered saline with pH 7.4. Activity of L-asparaginase, volume, hematocrit, hematological indices and osmotic cell fragility of erythrocytes were measured in the suspensions of erythrocytes before and after the enzyme encapsulation procedure.

Results. An optimal osmolality of the hypotonic buffer for each method was selected and was equal to 90–110 mOsm/kg. The yields of encapsulation were 4.2 ± 2.0, 6.0 ± 2.3 and 16.2 ± 2.2 % for hypotonic lysis, dialysis and flow dialysis, respectively. The hematological indices of the obtained erythrocyte-carriers differed from the corresponding parameters of the initial erythrocytes, but did not differ significantly for different methods.

Conclusion. Comparative investigation of mentioned above parameters allowed choosing the method of flow dialysis as the most promising for clinical use.