Search

Background. Chronic lymphocytic leukemia (CLL) is a slowly progressive malignant disease that results in uncontrolled proliferation and accumulation of B-lymphocytes in the blood and bone marrow, and is the most common form of leukemia in Western countries. Patients with CLL and chromosome 17 deletion or TP53 mutation who progress after treatment with immunological, chemotherapeutic, and targeted agents (e. g., ibrutinib) have a poor prognosis and represent a population with an unmet medical need. Clinical trial results have shown that venetoclax, a selective, bioavailable, orally administered inhibitor of the anti-apoptotic B-cell lymphoma protein, induces apoptosis in CLL cells and provides an alternative treatment option for CLL patients, either alone or in combination with rituximab.Aim. To evaluate the efficacy and safety of venetoclax in relapsed/refractory CLL in Russia routine clinical practice.Materials and methods. A multicenter observational prospective study P19-569 FORTE was conducted in Russia. The patients were monitored throughout the 24-month treatment period. During this period, the treating physician assessed the objective treatment response according to the International CLL Working Group criteria. The last minimal residual disease result obtained during treatment and the method of its assessment (if performed) were also to be recorded. The primary endpoint was the overall response rate at 12 months after initiation of treatment.Results. The study included 71 previously treated patients with relapsed/refractory CLL. The median age was 63 (35–83) years. All patients were white/Caucasian, and the majority were male. According to baseline characteristics, the study population included patients who had previously received intensive therapy: the median number of previous therapy lines was 3 (1–8). A number of factors associated with the risk of an unfavorable prognosis have been identified in patients, including chromosome 17 deletion or TP53 mutation.12 months after the start of treatment, the overall response rate was 68.6 %, complete remission was observed in 41.4 % of patients; in the venetoclax monotherapy subgroup these parameters were 63.3 and 42.9 %, in the venetoclax with ibrutinib subgroup – 81.0 and 38.1 %, respectively. 24 months after the start of treatment, the overall response rate was 71.4 %, complete remission was observed in 45.7 % of patients; in the venetoclax monotherapy subgroup these parameters were 67.3 and 46.9 %, in the venetoclax with ibrutinib subgroup – 81.0 and 42.9 %, respectively. During 24 months of treatment, minimal residual disease was assessed in 28 (40 %) patients, of whom 14 (50 %) had undetectable disease in the peripheral blood or bone marrow.There were 23 deaths during the study. The median overall survival was not achieved. No laboratory signs of tumor lysis syndrome were detected in patients. The majority of adverse events leading to death were CLL progression; the 2nd largest group were cases of SARS-CoV-2 infection.Conclusion. The obtained data confirm the possibility of venetoclax therapy in relapsed/refractory CLL patients.

Aim. To study the prognostic significance of gene mutations and intracellular signaling pathways involved in lymphomagenesis in patients with follicular lymphoma using next generation sequencing (NGS).Materials and methods. The prospective study included 26 patients with a median age of 51.5 years. Mutational screening was performed for cohort using custom NGS Panel of 118 genes. Gene set enrichment analysis (GSEA) was performed using Metascape. The data was analyzed in SPSS Statistics 26 and R 4.2.2.Results. The highest mutation frequency was noted in the genes: KMT2C – 50 %, KMT2D – 50 %, CREBBP – 31 %, NOTCH2 – 31 %, GNAS – 23 %. Missense mutations occurred with a frequency of 84.3 %. ARID1A gene mutation is an unfavorable prognostic factor according to progressive-free (p = 0.014) and event-free (p = 0.029) survival analysis. Tumor mutation burden (TMB) was defined as the number of mutations per megabase (Mb) of the coding sequence, the median TMB was 5.0 (3.3–8.3) mutations/Mb. The TMB threshold of 6 mutations/Mb divided patients into groups with high (44 %) and low (56 %) TMB. In the high TMB group, 2-year event-free survival was 27.3 % (95 % confidence interval 6.0–61.0), which was significantly lower than in low TMB group – 72.7 % (95 % confidence interval 41.9–91.6; p = 0.037). The most enriched cellular pathways according to GSEA results were regulation of cell activation (–log10(q-value) = 6.357), chromatin remodeling (–log10(q-value) = 5.707), histone modification (–log10(q-value) = 4.569). We have also demonstrated other possibilities of GSEA using follicular lymphoma as an example.Conclusion. TMB is a significant prognostic factor in patients with follicular lymphoma. We have shown that mutations in the MYC, CREBBP, EZH2, KMT2D genes lead to dysregulation in several intracellular processes, mediating complex molecular changes. The most enriched intracellular pathways in follicular lymphoma are those of chromatin remodeling, regulation of cell activation and histone modification.

Bruton's tyrosine kinase (BTK) inhibitors represent a class of drugs that have demonstrated their efficacy and safety in patients with chronic lymphocytic leukemia and non-Hodgkin's lymphomas who were considered refractory to any previously used type of therapy. BTK plays a key role in all stages of B lymphocyte development, but in recent years, there have been data indicating that BTK is also involved in the activation of myeloid cells.The aim of this study is to analyze and systematize all published materials on the immunomodulatory effects of BTK inhibitors (ibrutinib, acalabrutinib, etc.).A systematic review of the scientific literature was performed using a step-by-step search process in electronic databases (PubMed, Web of Science, ScienceDirect, and Scopus). The following keywords were used in the database search: “CLL”, “BTK”, “ibrutinib”, “COVID-19”, “allergy”, “inflammation.” The search for studies was conducted from the time of the first BTK inhibitor drug (ibrutinib) appearance in 2009 until December 2022.The results of the study on the influence of BTK inhibitors on the functional state of B and T lymphocytes, neutrophils, and monocytes/macrophages are presented. The immunomodulatory effects of ibrutinib on adaptive and innate immune system cells, including CD4+ and CD8+T lymphocytes and NK cells, are described. Since BTK inhibitors alter the functional activity of phagocytic cells and the ratio of T cell populations, there is a suggestion about the possibility of using these drugs for the treatment of other nosological forms, not only B cell malignancies, which is currently being studied in clinical trials. Data on the use of BTK inhibitors to combat hyperacute inflammation and to suppress allergic reactions, including anaphylaxis, are summarized. In addition, the expediency of short-term use of BTK inhibitors to reduce the risk of side effects during oral immunotherapy and for desensitization to drugs is discussed.The presented data indicate that BTK inhibitors are promising drugs with immunomodulatory effects. However, BTK inhibitors need to increase selectivity to reduce off-target effects on other kinases.

Active forms of oxygen are formed in the course of the organism's vital activity in biochemical reactions. These forms, when the pro/antioxidant balance is disturbed, trigger a cascade of lipid peroxidation, which can be the cause of the development of various pathological conditions. To prevent the negative influence of lipid peroxidation products in the body, a powerful antioxidant system is activated. This system consists of an enzymatic and a non-enzymatic link. An important aspect of the normal functioning of this system is the provision of the body with important trace elements. A number of minerals are included in the active center of antioxidant enzymes or have an effect on the reactions of non-enzymatic antioxidants. Research was conducted on fattening bulls of the Ukrainian meat breed. During the monitoring of microelements in feed, it was found that the vast majority of farm feed was deficient in copper, selenium and manganese and for this reason the animals consumed an insufficient amount of these minerals. These data were confirmed by the low content of these trace elements in blood serum. The addition of inorganic salts of microelements to the basic diet led to an increase in the concentration of copper, manganese and selenium in the blood serum by 20.5%, 37.3% and 23.9%. The study of the content of lipid peroxidation products showed that during the 30 days of the experiment, the level of lipid hydroperoxide increased by 25.5%, diene conjugates by 22.8%, and malonic dialdehyde by 22.0%. This indicates that against the background of increased age-related metabolism in the body of young animals, the oxidation-reduction reactions that are a predictor of the start of peroxidation processes increase. It was also noted that with a deficiency of certain trace elements, the activity of both the enzymatic and non-enzymatic links of the antioxidant system was reduced. Thus, in 30 days, the level of catalase, superoxide dismutase, and glutathione peroxidase decreased by 9.4%, 15.3%, and 13.0%, respectively. During this time, the content of tocopherol and ceruloplasmin decreased by 16.8% and 9.8%. Additives also had a positive effect on the activity of the antioxidant system by increasing its components. Additives of trace elements had different effects on the activity of antioxidant enzymes. The greatest effect on the level of catalase and superoxide dismutase was observed when copper salts were added, when the increase of these enzymes was noted by 1.11 and 1.23 times, respectively. Accordingly, the level of glutathione peroxidase was the highest in animals that received additional selenium – 1.21 times. The addition of copper also had the greatest biological effect on the important non-enzymatic component of antioxidant protection – ceruloplasmin. Its level increased by 1.24 times under the action of copper sulfate. The level of tocopherol was higher under the action of manganese, when its concentration was 1.11 times higher than the control. Against this background, there was a decrease in the products of lipid peroxidation: lipid hydroperoxides – 1.19 times under the action of selenium; diene conjugates – by 1.22 times and malonіс dialdehyde – by 1.11 times under the influence of copper and manganese compounds, respectively.

Background. An autologous stem cell transplant (ASCT) is the standard of treatment young and fit patients with multiple myeloma (MM). The using this method of treatment is limited due to the high consumption of economic and intellectual resources, the low availability of Cryobank departments in regions of Russia.Objective: to evaluate the efficacy and safety of using non-cryopreserved peripheral blood stem cells (non-CRYO PBSCs) in patients with multiple myeloma who underwent autologous transplantation.Materials and methods. We conducted a prospective study of the efficacy and safety of using non-CRYO PBSCs in patients with MM who underwent ASCT. The number of PBSCs apheresis procedures in 82.9 % (n = 29 pts) was 1 day, and in 17.1 % (n = 6 pts) was 2 days. After apheresis, PBSCs were stored at a temperature of +4…+6 °C in a blood bank refrigerator for up to 72 hours. During 4 years, ASCT using non-CRYO PBSCs was performed in 35 patients with MM. The average number CD34+ cell dose was 2.63 × 106 /kg. The median time to neutrophil engraftment was 11 days (range from 9 to 14). The median time to platelet engraftment was 12 days (range from 8 to 19). The control group included 43 patients with MM, who underwent PBSCs ASCT according to the traditional method, including preparation and cryopreservation of the apheresis product of PBSCs with cryoprotectant dimethyl sulfoxide, as well as subsequent defrosting on the day of transplantation (day 0).Results. There were no significant differences comparing the safety of ASCT in non-CRYO and CRYO PBSCs groups among such parameters as the viability of PBSCs, the frequency of complications, the time of hematopoietic engraftment, the need for platelet and red blood cells transfusion therapy, and time of hospitalization.Conclusion. Hence, the method of short-term storaging non-CRYO PBSCs is not inferior to the traditional method of controlled freezing, is more economical and can be used in medical organizations that do not have a Cryobank in their structure.