Introduction. Currently, Ibrutinib is one of the most effective drugs for relapsed and refractory chronic lymphocytic leukemia treatment. In most patients with CLL, ibrutinib causes persistent remissions, but in some patients the disease progresses. Ibrutinib resistance in most cases is associated with the C481S mutation, which corresponds to the c.1441T>A and c.1442G>C substitutions in the BTK gene, however, other variants also exist.Aim — to evaluate variable allele fraction of the BTK gene mutations in patients with relapsed chronic lymphocytic leukemia using the in-house allele-specific real-time PCR test.Materials and methods. The study included material from 102 cases: 39 CLL patients with disease progression on ibrutinib therapy, 24 CLL patients with disease progression on the FCR/FCR-lite protocols, and 38 CLL treatment-naive patients. The control group included 118 patients with non-neoplastic hematological diseases.Results. Using in-house using AS-PCR, we detected the c.1442G>C mutation in 20 out of 39 CLL patients with progression on ibrutinib therapy. Mutation c.1442G>T was detected in 2 patients. In a single patient, two mutations were detected simultaneously: c.1441T>A and c.1442G>C. Another single patient had a combination of three mutations: c.1442G>C, c.1442G>T and c.1442G>A. In 15 patients with progression on ibrutinib therapy, mutations in the BTK gene were not detected. In treatment-naive CLL patients, in the group treated with FCR/FCR-lite regimens, and in the control group of patients with nonneoplastic diseases, mutations in the BTK gene were not detected.Conclusion. Variable allele fraction of exon 15 BTK gene mutations in the patients with CLL progression was successfully determined using in-house AS-PCR test: 50 % of patients had one mutation, 5 % had two mutations, and 2.5 % had three mutations in the BTK gene. Timely detection of these mutations before clinical recurrence may facilitate effective treatment strategy. Since clinical manifestations of ibrutinib resistance appear after an average of 1–2 years, we suggest monitoring BTK mutation load every 3 months in patients with CLL before relapse during treatment with ibrutinib.

Topic: 5. Chronic lymphocytic leukemia and related disorders - Biology & Translational Research Background: Inhibitors of Bruton tyrosine kinase (BTKi) have shown great efficacy in treating chronic lymphocytic leukemia (CLL). However, some patients develop resistance to the drug, leading to treatment failure. Resistance to covalent BTK inhibitors is associated with acquired C481S/F/Y mutations in exon 15 of the BTK gene, as well as mutations in PLCG2 gene. Other BTK mutations have been described that could potentially lead to refractoriness. Understanding the mutational landscape of CLL patients with refractory disease on BTKi therapy may help develop new therapeutic strategies. Aims: Characterization of BTK and PLCG2 gene mutations in CLL patients with resistance to covalent BTK inhibitors using next generations sequencing. Methods: The study included samples from 45 pts with clinical progression on BTK inhibitors therapy. There were 29 men, 16 women, median age 65.5 years (range 47-86), 43 patients received ibrutinib and 2 acalabrutinib. All patients received BTKi for CLL relapse, the median number of previous therapy line was 5 (range 1 – 6). The median duration of BTKi therapy before progression was 34.5 months (range 5,8 – 73 months). Mutations in the BTK (11, 15, 16 exons) and PLCG2 (19, 20, 24 exons) genes and their variant allele frequencies (VAF) were analyzed at time of clinical progression by next generation sequencing (NGS). Results: In total 29 (64%) patients had mutations in either BTK or PLCG2 gene. The most common BTK c.1442G>C mutation was found in 16 (35.6%) patients, the c.1442G>T mutation was found in 3 (6.7%) patients. In 6 cases (13.4%), two mutations were detected in the same C481 codon of the BTK gene. Finally 1 patient had simultaneously 4 mutations in the C481 codon, all with different VAF: c.1442G>C (VAF 32%), c.1442G>T (VAF 17%), c.1442G>A (VAF 7%), c.1441T>C (VAF 1.2%). Other parts of the BTK gene were affected by mutations much less frequently. Mutation BTK p.L528W:c.1583T>G gene (VAF 3.1%) was detected in 1 patient. One patient had 2 mutations in different domains of the BTK gene: p.C481S:c.1442G>C (VAF 33%) and p.T316A:c.946A>G (VAF 0.55 %). In 1 patient, two mutations were found simultaneously in the BTK and PLCG2 genes: p.C481S: c.1442G>C (VAF 25%) and p.L845F: c.2535A>C (VAF 3.4%). Time to progression in patients with mutations was significantly longer compared to patients without mutations (median 38,7 months (9 - 73) versus 25,5 months (5,8 - 57), p = 0,04). Only 1 patient had BTK c.1442G>C mutation detected at VAF >1% during the 1st year of treatment; in 21 (72%) patients mutations were detected after 24 months of therapy. Summary/Conclusion: Our study shows that BTK and/or PLCG2 mutations were found in 64.4% of patients with progression of CLL during BTKi therapy, and in 35.6% of patients the cause of resistance has not yet been identified. Most mutations in our sample were detected in the C481 codon of BTK gene after 2 years of treatment, suggesting that regular screening with simple PCR tests starting from the second year of treatment is a reasonable approach. NGS may expand data in cases with undetectable mutations. Further research concerning other potential markers of resistance to BTK inhibitors is also required. Keywords: Chronic lymphocytic leukemia, ibrutinib, Bruton’s tyrosine kinase inhibitor (BTKi), relapsed/refractory

Effective treatment and prevention of infections challenge management of patients with chronic lymphicytic leukemia (CLL). The COVID‐19 pandemic resulted in the reduction of outpatient hospital visits as a part of non‐pharmaceutical interventions that could affect the incidence of infectious complications. Study enrolled patients with CLL receiving ibrutinib or/and venetoclax who were observed at the Moscow City Centre of Hematology from 01 April 2017 to 31 March 2021. We found a reduction in the incidence of infectious episodes after the implementation of the lockdown in Moscow in 01 April 2020, when compared to data on the year prior to the lockdown ( p < 0.0001), as well as when compared to the predictive model ( p = 0.02), and based on individual infection profiles using cumulative sums ( p < 0.0001). Bacterial infections had 4.44‐fold decrease, bacterial in combination with undefined infections had 4.89‐fold decrease, viral infections had unsignificant changes. The decrease in the number of outpatient visits coincides with the time of the lockdown could be a likely factor, explaining a decline in the incidence of infection. Patients were clustered according incidence and severity of infectious episodes for subgroup mortality assessment. No differences in overall survival due to COVID‐19 were observed. Typical respiratory infections, bacterial and undefined, the transmission of which may be affected by patient‐to‐patient contact in the settings of out‐patient health care visits were decreased, possibly due to SARS‐CoV‐2 restrictive measures. A positive correlation between outpatient visits and the incidence of bronchial and upper respiratory tract infection points at the role of hospital‐acquired infection and attests to the necessity of reorganizing care for all patients with CLL.

Introduction Currently, venetoclax is the therapeutic choice for many patients with chronic lymphocytic leukemia progressed on ibrutinib. The optimal drug combinations with venetoclax, the goals and timing of therapy, as well as predictors of response are not yet clear. Only a few clinical trials have included patients with progression on ibrutinib (Kater AP, et.al., J Clin Oncol 2019). Approach to ibrutinib discontinuation and addition of antibodies to CD20 are still a matter of debates. Objectives The aim of this multicenter study was to retrospectively compare outcomes in patients who received venetoclax either alone or in combination with monoclonal antibodies to CD20, as well as outcome of patients who continued ibrutinib after switching to venetoclax. Methods The study included 122 patients with disease progression on ibrutinib according to iwCLL2018 criteria. The data were collected by 27 centers from 25 regions of Russia. Fifty four patients (44%) received venetoclax without monoclonal antibodies, 46 (38%) in combination with obinutuzumab, 22 (18%) with rituximab. Nineteen patients stopped ibrutinib before venetoclax with median interval between treatments of 10 days (range 0 - 91 days). All other patients received venetoclax concomitantly with ibrutinib for some time after progression. Patients who stopped ibrutinib less than 3 months from the date of onset of venetoclax were considered to have discontinued ibrutinib. Results The median age was 63 years (range 30-82), 76 patients were males (62%). Median progression free survival (PFS) for all patients was 26.5 months, overall survival (OS) was 35.2 months. Fifteen patients (12%) had Richter transformation before venetoclax. Overall survival of these patients was significantly worse when compared to other patients, with hazard ratio (HR) 3.46 95% CI 1,42 - 8,48 (p<0.0001). Twenty two patients stopped therapy before the event of death or progression. Reasons included toxicity (N=10), three consecutive confirmation of MRD-negative remission 3 months apart (N=11), and allogeneic stem cell transplantation (N=1). Patients who died or had progression within 3 months after the onset of venetoclax, as well as patients with Richter syndrome diagnosed before the onset of venetoclax were excluded from survival analysis. Table 1 presents patients' characteristics. On pre-treatment, poor outcome was significantly predicted by time to progression on ibrutinib <24 months (PFS: HR 0.53, 95% CI 0.27 - 1.06, p=0,04; OS: HR 0.45, 95% CI 0,22 - 0,93, p=0,01) and ECOG status > 2 (PFS: HR 0.37, 95% CI 0,1 - 1,35, p=0,007; OS: HR 0.32, 95% CI 0,08 - 1.27, p=0,002). There were no differences in baseline characteristics in patients who continued and discontinued ibrutinib, although in the former group more patients have developed Richter syndrome during treatment. Ibrutinib discontinuation was associated with better outcome (PFS: HR 3.72, 95% CI 1.95 - 7.09; OS: HR 3.93, 95% CI 1.96 - 7.88, Figure 1A, B). In total 15 deaths occurred before progression (COVID-19 - 11 patients, secondary cancers - 2, sudden death - 1, pneumonia - 1), and the majority (N = 13) in the group of patients who continued ibrutinib. The group of patients who received antibodies to CD20 was younger (63 versus 69 years, p=0.03), while other baseline parameters were similar. No significant differences were found in either PFS (HR 1.38, 95% CI 0.69 - 2.7) or OS (HR 1.36, 95% CI 0.67 - 2.8, Figure 1C, D). Subgroup analysis of patients who discontinued ibrutinib showed that patients who received venetoclax with monoclonal antibodies had better PFS compared to those on venetoclax alone (HR 6.32, 95% CI 1.43 - 27.8, p=0.045), while OS in the two subgroups did not differ. Conclusion Our data do not support the hypothesis that continuing ibrutinib therapy beyond 2 - 3 months in the context of progression on ibrutinib benefits patients. As evident from increase in PFS, it seems that patients who had discontinued ibrutinib may benefit from adding CD20 antibodies to venetoclax.

New Bruton’s tyrosine kinase (BTK) inhibitors caused drastic modifications in the therapy of chronic lymphocytic leukemia (CLL). Ibrutinib, the first in its class BTK inhibitor, showed high efficacy in many clinical studies. However, the treatment with BTK inhibitors as monotherapy must not be discontinued. Ibrutinib monotherapy inevitably leads to BTK inhibitor resistance and severe adverse events, which often results in treatment failure. Inhibitor BCL-2 venetoclax combined with BTK inhibitor can increase the therapy efficacy due to the synergetic effect of these agents on different CLL cell populations. Combined therapy potentially providing fixed-duration treatment can yield deeper responses. The present review focuses on ibrutinib and venetoclax combination, summarizes the latest data from clinical studies, and deals with feasibility of combined therapy in terms of its efficacy and safety profile.

Autoimmune hemolytic anemia (AIHA) and pure red cell aplasia (PRCA) are common complications of CLL. The optimal treatment of steroid refractory AIHA/PRCA is not well established. We conducted a multicenter study of ibrutinib and rituximab in patients with relapsed/refractory to steroids AIHA/PRCA and underlying CLL. Protocol included induction (ibrutinib 420 mg/day and rituximab, 8 weekly and 4 monthly infusions) and maintenance phase with ibrutinib alone until progression or unacceptable toxicity. Fifty patients were recruited (44—warm AIHA, 2—cold AIHA, 4—PRCA). After the induction 34 patients (74%) have achieved complete response, 10 (21.7%) partial response. Median time to hemoglobin normalization was 85 days. With regards to CLL response 9 (19%) patients have achieved CR, 2 (4%) patients—stabilization and 39 (78%)—PR. The median follow-up was 37.56 months. In AIHA group 2 patients had a relapse. Among 4 patients with PRCA 1 patient did not respond, and 1 patient had a relapse after CR, 2 remained in CR. The most common adverse events were neutropenia (62%), infections (72%), gastrointestinal complications (54%). In conclusion ibrutinib in combination with rituximab is an active second-line treatment option for patients with relapsed or refractory AIHA/PRCA and underlying CLL.

Introduction. Optimal therapy for elderly patients with chronic lymphocytic leukemia (CLL) is the subject of intensive research. Aim – to study the safety of obinutuzumab, as well as the selection of the optimal scheme of its use in patients with CLL, complicated by diabetes mellitus, renal insuffi ciency, cardiac comorbidity. Materials and methods. The study included primary patients with CLL having indications requiring therapy. The inclusion criteria were: Cumulative Illness Rating Scale, CIRS) (CIRS) > 6 and or glomerular fi ltration rate (GFR) < 70 mL/min, the lower limit of GFR was not restricted. The study focused on patients with diabetes mellitus, renal failure and signifi cant cardiac pathology. Patients with Richter’s syndrome, CNS involvement, HBs-antigen, and 17p deletion were not included. In the fi rst cycle obinutuzumab was administered at a dose of 100 or 25 mg on the fi rst day and 900 or 975 mg on the second day, then at a dose of 1000 mg on days 8 and 15. For all subsequent cycles, obinutuzumab was given at a dose of 1000 mg on day 1. The dosage of chlorambucil was 10 mg/m2 from days 1 to 7. Treatment cycles in totals of 6 were repeated every 28 days. Results. The study included 90 patients. Median age was 73.5 years, range – 60–89 years, there were 49 men (54 %) and 41 women (46 %). Twenty-four patients (27 %) had stage C, IGHV unmutated status was detected in 76 % of patients. The median creatinine clearance was 48.6 mL/min (25–110). The median CIRS score was 3 (range – 1–14). Thirty-one patients (34 %) had signifi cant cardiovascular comorbidity (previous myocardial infarction, coronary artery stenting or bypass, HF ≥ II NYHA, peripheral artery disease) as well as hemodynamically signifi cant valvular disease. Fifteen patients (17 %) had diabetes mellitus and 71 patients (79 %) had creatinine clearance < 70 ml/min. Infusion reactions to obinutuzumab grade ≥ II were reported in 29 patients (32 %). Hospitalization on the day of administration or the next day after the fi rst administration was required in 5 cases (5.5 %). Twenty-seven (30 %) patients could not complete 6 cycles. The largest number of patients (14 people, 15.5 %) stopped treatment after 1 course. The causes were the development of persistent cytopenia (n = 4), grade IV reaction to obinutuzumab (n = 3), patient’s refusal (n = 2), infectious complications (n = 2), severe tumor lysis syndrome (n = 1), acute pancreatitis (n = 1) and toxicodermia (n = 1). The leading cause of premature discontinuation on subsequent cycles was persistent neutropenia. Progression during treatment occurred in 3 patients only. Overall survival was signifi cantly predicted by CIRS (maximum discriminatory value of 3, p = 0.013) as well as GFR < 50 mL/min (p = 0.03). No other associations were identifi ed. At least 1 episode of grade III–IV neutropenia occurred in 41 % of patients. Grade IV neutropenia was associated with creatinine clearance < 60 mL/min (p = 0.05), baseline neutrophil level < 2 × 109/L (p = 0.0001), baseline monocyte level < 0.3 × 109/L (p = 0.007) and age > 70 years (p = 0.01). The effectiveness of treatment was evaluated in patients who completed at least 3 cycles of therapy. Complete remission was achieved in 26 patients (35 %), partial remission – in 41 (54 %), stabilization – in 4 (5 %), progression was noted in 3 (4 %). Sixteen patients (18 %) were not available to respond to the assessment. Minimal residual disease < 0.01 % in the bone marrow after completion of treatment was found in 17 patients (19 %), within 0.01–0.9 % – in 25 (28 %) patients. The median follow-up from the date of therapy initiation was 39.7 months (range – 0.6–72 months). The median relapse-free survival was not reached, and 2- and 3-year survival rates were 81 and 62 %, respectively. Poor relapse-free survival signifi cantly correlated with unmutated IGHV genes (HR = 2.4, 95 % CI: 1.12–5.0, p = 0.02) and partial response as opposed to complete response (HR = 3.35; 95 % CI: 1.45–7.7, p = 0.03). Conclusion. The results of our study have practical implications as obinutuzumab is actively integrated into modern treatment regimens. Infusion reactions pose a high risk of complications in elderly patients. The dose of obinutuzumab on day 1 of administration in elderly patients, should not exceed 25 mg. The G-Clb regimen may not be optimal in patients over 75 years of age due to the unpredictable risk of complications. In patients at high risk of neutropenia, it may be appropriate to consider primary prophylaxis. ClbG is an effective regimen that resulted in high rate of MRD-negative responses and prolonged relapse-free survival.

We describe a retrospective cohort, 156 patients with chronic lymphocytic leukemia (CLL) diagnosed with COVID-19, analyze factors associated with a severe disease course and the effects of various treatment regimens. Anti-SARS-CoV-2 IgG and IgM levels are significantly lower. Patients with CLL are more likely to have a severe course of COVID-19, with IL-6 levels acting as a consistent biomarker of disease severity. Ten patients had recurrent episodes, fatality rate of 20%. Overall survival did not differ between patients receiving ibrutinib monotherapy and anti-CD20 antibodies +/- chemotherapy. It seems that the immunodeficiency inherent to CLL influences outcomes to a larger degree than does the treatment. Glucocorticoids are not associated with significant OS improvement whereas anti-cytokine compounds usage seemed to be beneficial in patients with mild pulmonary involvement. Our data attest to the necessity of reorganizing health care for patients with CLL. Early administration of effective antiviral compounds and tailored vaccination protocols are warranted.

Abstract Autoimmune hemolytic anemia (AIHA) and pure red cell aplasia (PRCA) are common complications of CLL. The optimal treatment of steroid refractory AIHA/PRCA is not well established. We conducted a multicenter study of ibrutinib and rituximab in patients with relapsed/refractory to steroids AIHA/PRCA and underlying CLL. Protocol included induction (ibrutinib 420 mg/day and rituximab, 9 weekly and 3 monthly infusions) and maintenance phase with ibrutinib until progression or unacceptable toxicity. Fifty patients were recruited (44 – warm type AIHA, 2 – cold type AIHA, 4 – PRCA). After the induction phase 34 patients (74%) have achieved complete response, and 10 (21,7%) partial response. Median time to hemoglobin normalization was 85 days. With regards to CLL response 9 (19%) patients have achieved CR, 2 (4%) patients – stabilization and 39 (78%) – PR. The median follow-up was 37.56 months. In AIHA group 2 patients had a relapse. Among 4 patients with PRCA 1 patient did not respond, and 1 patient had a relapse after CR, 2 remained in CR. The most common adverse events were neutropenia (62%), infections (72%) and gastrointestinal complications (54%). In conclusion ibrutinib in combination with rituximab is an active second-line treatment option for patients with relapsed or refractory AIHA/PRCA and underlying CLL.

Background. In view of similar morphological and phenotypic characteristics of some B-cell lymphoproliferative diseases and despite the known phenotype of tumor cells, a search is currently underway for new diagnostic markers, the expression of which remains stable during chronic lymphocytic leukemia (CLL) treatment and can be used for both diagnosis and assessment of residual tumor population. One of such markers is ROR-1. Aim. To assess the expression and feasibility of the ROR-1 marker using В-lymphocytes in minimal residual disease (MRD) dynamics and monitoring in CLL. Materials & Methods. Hematological and immunophenotypic analyses were performed in 110 CLL patients (50 of them with newly diagnosed disease and 60 on therapy). In addition to that, 20 patients with reactive lymphocytosis and 32 donors were examined. The ROR-1 expression in В-lym-phocytes were measured with FACS Canto II flow cytometer using the following monoclonal antibody panel: CD45, CD19, CD20, and ROR-1. Results. The analysis showed that ROR-1 is essentially not expressed in normal and reactive В-lymphocytes and is detected in 100 % of CLL tumor cells both at disease onset and on therapy. The ROR-1 expression does not change during CLL treatment and can be used not only for CLL diagnosis but also for detection of MRD. Bone marrow aspirates (п = 64) and peripheral blood samples (п = 6) were analysed for MRD assessment by two methods: according to the standardized protocol, recommended by ERIC (European Research Initiative on CLL) in 2007, with FACS Canto II flow cytometer (BD Biosciences) and using DuraClone RE CLB Tube (Beckman Coulter) with Navious flow cytometer (Beckman Coulter).

The clinical course of the new coronavirus disease 2019 (COVID-19) has shown that patients with chronic lymphocytic leukemia (CLL) are characterized by a high mortality rate, poor response to standard treatment, and low virus-specific antibody response after recovery and/or vaccination. To date, there are no data on the safety and efficacy of the combined vector vaccine Sputnik V in patients with CLL. Here, we analyzed and compared the magnitudes of the antibody and T cell responses after vaccination with the Sputnik V vaccine among healthy donors and individuals with CLL with different statuses of preexposure to coronavirus. We found that vaccination of the COVID-19–recovered individuals resulted in the boosting of pre-existing immune responses in both healthy donors and CLL patients. However, the COVID-19–naïve CLL patients demonstrated a considerably lower antibody response than the healthy donors, although they developed a robust T cell response. Regardless of the previous infection, the individuals over 70 years old demonstrated a decreased response to vaccination, as did those receiving anti-CD20 therapy. In summary, we showed that Sputnik V, like other vaccines, did not induce a robust antibody response in individuals with CLL; however, it provided for the development of a significant anti-COVID-19 T cell response.

Profound immunological dysfunction is the key factor determining the development of infectious complications in chronic lymphocytic leukemia (CLL). The aim of this work is to assess the features of the subpopulation composition of T-lymphocytes (T-helpers (Th), cytotoxic T-lymphocytes (Tcyt), T regulatory cells (Treg), T-NK cells, naive Th, Th-memory, activated T-lymphocytes, TCRγδ cells) and NK cells in peripheral blood of patients with newly diagnosed chronic lymphocytic leukemia (CLL) and receiving ibrutinib therapy. Hematological and immunophenotypic studies have been performed in 30 patients with previously untreated CLL, 122 patients on ibrutinib therapy and 20 healthy donors. The subpopulation composition of T-lymphocytes (Th, Tcyt, Treg, T-NK, naive T-helpers, memory T-helpers, TCRγδ cells, activated T-lymphocytes) and NK cells has been assessed on flow cytometer (FACSCanto II (BD)) using the following panel of monoclonal antibodies: CD45, CD19, CD3, CD4, CD5, CD8, TCRγδ, CD127, CD16, CD56, CD57 CD45RA, CD45R0, HLA-DR, CD25. Compared to controls all CLL samples were found to have higher the absolute number of T-lymphocytes, NK cells and their subpopulations, T-helpers (especially of memory T-cells), cytotoxic T-cells, regulatory T-cells, TCRγδ T-cells, activated T-lymphocytes, increased cytotoxic potential of NK cells in previously untreated CLL patients. Patients who received ibrutinib therapy have registered a positive trend towards recovery of the subpopulation composition of T-lymphocytes and NK-cells. CLL patients have been found to have quantitative and functional changes in the subpopulations of T-lymphocytes and NK cells, indicating dysregulation of the immune response, and a high risk of developing infections. Monitoring of immunological parameters for ibrutinib therapy make possible to estimate impact of ibrutinib on the adaptive anti-CLL immune response.

Chronic lymphocytic leukemia (CLL) treatment landscape has changed dramatically with the recently developed drugs targeting the B-cell receptor (BCR) signalling pathway. Acalabrutinib, a second generation Bruton tyrosine kinase inhibitor, was approved in 2020 in Russia for the treatment of patients with CLL. Acalabrutinib was developed as a more selective Bruton tyrosine kinase inhibitor then ibrutinib. This drug is aimed at reducing the adverse events that limit the use of ibrutinib, such as atrial fibrillation and bleeding. Phase I/II multicenter studies have demonstrated the efficacy and safety of acalabrutinib monotherapy in untreated CLL patients and in patients with relapsed/refractory CLL and ibrutinib intolerance. Phase III trials, ASCEND and ELEVATE-TN, compared acalabrutinib monotherapy and a combination of acalabrutinib and obinutuzumab versus standard therapies and demonstrated improved efficacy and tolerability of acalabrutinib. A phase III trial comparing acalabrutinib and ibrutinib monotherapy (ELEVATE-RR) is ongoing. The results of this study along with real-life clinical data could determine the place of acalabrutinib in CLL treatment.

Professor, Head of the Department of Philosophy and History, DSMU) examines the impact of the coronavirus pandemic on Muslim religious life.The pandemic significantly changed the "technology" of most of the foundations of Islam -as a result, there was a temporary closure of mosques for the obligatory five-time prayer, including Friday;

В последнее время в связи с разработкой лекарств, мишенью которых являются звенья сигнального пути В-клеточного рецептора (B-cell receptor – BCR), существенно изменились подходы к терапии хронического лимфолейкоза (ХЛЛ). В 2020 г. в Российской Федерации для лечения пациентов с ХЛЛ одобрен акалабрутиниб, ингибитор тирозинкиназы Брутона II поколения. Акалабрутиниб разработан как более селективный ингибитор тирозинкиназы Брутона по сравнению с ибрутинибом. Данный препарат нацелен на уменьшение ограничивающих применение ибрутиниба нежелательных явлений, таких как фибрилляция предсердий и кровотечения. Многоцентровые исследования I/II фазы продемонстрировали эффективность и безопасность монотерапии акалабрутинибом у пациентов с ХЛЛ, ранее не получавших лечение, и у пациентов с рефрактерным/рецидивирующим ХЛЛ, а также непереносимостью ибрутиниба. Исследования III фазы, ASCEND и ELEVATE-TN, сравнивали монотерапию акалабрутинибом или комбинацию акалабрутиниба и обинутузумаба со стандартными методами лечения и продемонстрировали бoльшую эффективность и лучшую переносимость акалабрутиниба. Ко времени написания обзора продолжалось исследование III фазы – сравнение акалабрутиниба и монотерапии ибрутинибом (ELEVATE-RR). Результаты этого исследования и данные реальной клинической практики помогут прояснить оптимальное использование акалабрутиниба в лечении ХЛЛ.

Background Therapy with irreversible Bruton's tyrosine kinase inhibitor ibrutinib in chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL) is associated with bleeding. Objectives To propose the predictive markers of such bleeding, as well as mechanisms responsible for decreased bleeding at later therapy stages. Patients/Methods We investigate platelet functional activity in 50 CLL and 16 MCL patients on ibrutinib using flow cytometry and light transmission aggregometry. Results Prior to treatment, both patient groups had decreased platelet counts; impaired aggregation with adenosine diphosphate (ADP); and decreased binding of CD62P, PAC1, and annexin V upon stimulation. Bleeding in patients treated with ibrutinib was observed in 28 (56%) CLL patients, who had decreased aggregation with ADP and platelet count before therapy. Their platelet count on therapy did not change, platelet aggregation with ADP steadily improved, and aggregation with collagen first decreased and then increased in anticorrellation with bleeding. Bleeding in MCL was observed in 10 (62%) patients, who had decreased dense granule release before therapy. ADP and ristocetin induced platelet aggregation in ibrutinib-treated MCL patients increased on therapy, while collagen-induced aggregation evolved similarly to CLL patients. Conclusions Our results suggest that ibrutinib-dependent bleeding in CLL patients involves three mechanisms: decreased platelet count (the most important discriminator between bleeding and non-bleeding patients), impaired platelet response to ADP caused by CLL, and inhibition by ibrutinib. Initially, ibrutinib shifts the balance to bleeding, but then it is restored because of the improved response to ADP.