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. | 2673 DMITRIEVA ET Al.

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effectiveness of rituximab-based chemotherapy in first-line (treatment cohort 1), but failed to demonstrate a benefit in the second-line setting (treatment cohort 2; Table 1). Furthermore, no evidence was found that prior rituximab exposure was associated with the effectiveness of rituximab-based chemotherapy in second-line (treatment cohort 3). Covariates associated with inferior TFS in that particular cohort were age per one-year increase and first-line therapy with a backbone of purine analogues, as compared with a backbone of alkylating agents. Conversely, patients with a longer time to next treatment had better TFS. Summary/Conclusion:In this comprehensive, population-based study, the effectiveness of first-line treatment with rituximab-based chemotherapy was not objectivated in second-line treatment. The lack of effectiveness of rituximab-based chemotherapy in second-line could not be explained by previous rituximab exposure.

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Цель. Ранняя диагностика и лечение нарушений ритма и проводимости у пациентов, принимающих ибрутиниб. Материалы и методы. Обследовано 206 пациентов, имевших показания к назначению ибрутиниба. Из них 193 больных находятся на разных этапах терапии-от 1,5 до 51 мес. Включены пациенты с хроническим лимфоцитарным лейкозом, мантийноклеточной лимфомой, макроглобулинемией Вальденстрема в возрасте 59-72 года (медиана 66 лет). Было 70 женщин в возрасте 54-71 год (медиана 64 года) и 123 мужчины в возрасте 60-72 года (медиана 66 лет). Для раннего выявления нарушений ритма и проводимости всем больным проводили ЭКГ в динамике, суточное мониторирование ЭКГ по Холтеру. Результаты. Фибрилляция предсердий (ФП) зарегистрирована у 21 (12 %) пациента в срок 1-24 мес. терапии ибрутинибом. Наиболее часто ФП регистрируется в первые 6 мес. терапии ибрутинибом. До назначения препарата ФП в анамнезе имели 18 (10,5 %) пациентов. Таким образом, под наблюдением находятся всего 39 больных с ФП, получающих ибрутиниб. Из них показания к назначению антикоагулянтов в соответствии со шкалой CHA 2 DS 2-VASc имеют 27 (69 %) пациентов. Тяжелая атриовентрикулярная блокада выявлена у 2 (1 %) больных, что потребовало установки электрокардиостимулятора (ЭКС). У 2 (1 %) пациенток зарегистрировано развитие тяжелой наджелудочковой тахикардии с частотой до 295 уд./мин, что потребовало проведения абляции. У одного из пациентов с постоянной формой ФП выявлены паузы ритма, установлен ЭКС. Заключение. Развитие ФП у больных, получающих лечение ибрутинибом, не является критерием отмены препарата и не требует прекращения его приема. Антикоагулянты пациентам с ФП назначали согласно существующим рекомендациям в соответствии со шкалой CHA 2 DS 2-VASc, что требовало осторожности и динамического наблюдения за больными. Тяжелые нарушения

INTRODUCTION patients undergoing planned cardioversion have high risk of left atrial appendage (LAA) trombosis. Transesophageal echocardiography (TEE) is usually performed to rule out LAA thrombosis. PURPOSE building a model for predicting the risk of thrombosis of LAA prior to TEE in patients with atrial fibrillation (AF) planned to cardioversion based anamnesis, clinic and transthoracic echocardiography (echo) using deep learning algorithms. METHODS From 12.2018, 100 patients with AF included in the hospital registry or planned cardioversion. All patients underwent echo and TEE . Other clinical data was collected from medical records, echo and TEE results. Deep learning neural network was constructed in R v. 3.5.3 for risk assessment of the LAA trombosis prior to TEE. The model was trained / verified for 70% / 30% included patients. RESULTS Among included, 47.0% were women, mean age was 67.8 ± 11.9 years. LAA thrombosis rate was 37.0%. The paroxysmal form of AF diagnosed in 22.0%, the rest had persistent form. Arterial hypertension was observed in 77.0%, diabetes mellitus - in 14.0%. Previous stroke was diagnosed in 5.0% of patients, previous myocardial infarction — in 3.0%, heart failure - in 51.0% of patients. Median of CHA2DS2VASc score was 3 (2; 4) points. The mean indexed volume of left atrium was 50.1 ± 13.7 ml/m2, for LAA - 4.0 ± 1.8 ml/m2. Mean ejection velocity in the LAA is 3.5 ± 1.3 cm/s. Before admission 24.0% of patients did not receive any anticoagulant therapy. The group was divided into «training» and «test» parts in the proportion of 70%/30%. Both groups were statistically comparable by cardiovascular deseases, risk factors, demography, age and treatment before admission. Neural network was trained on the following factors of the «training» group: gender, previous infarction, heart failure, score for CHA2DS2VASc, creatinine level, left atrial indexed volume and linear dimensions, transmitral E and mitral annulus e`, peak and mean pressures and square of mitral regurgitation, pulmonary veins systolic and diastolic flows, anamnestic anticoagulation and duration of its intake. 10-fold cross-validation was performed. Verification (comparison of the real results with the predicted by model) was made for the «test» group: the Cohen’s kappa was 0.68, 95%CI for positive predictive value was 65.3 - 98.6%, for negative predictive value - 35.9 - 99.6%, for model accuracy 67.6 - 97.3% , ROC analysis showed 91.7% for area under curve (95%CI 79.3 - 99.9%). CONCLUSION deep learning neural net for assessing the risk of thrombosis of LAA using only anamnestic and echo data can be used for experimentally prediction for pretest probability of thrombosis prior to TEE. Further verification of the model with more data is required.

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.

Background: Comorbidities influence survival in patients (pts) with CLL treated with chemo-immunotherapy (CIT) or ibrutinib. While IDELA has been studied in patients with comorbidities, the impact of comorbidities on survival and tolerance to therapy with IDELA is unknown. Aims: We report outcomes using the Cumulative Illness Rating Scale (CIRS) in pts with relapsed or refractory (R/R) CLL who were treated with IDELA on clinical trials in an effort to better define the population who may benefit the most from IDELA, or, by contrast, require closer monitoring while on the drug.