Cardiovascular toxicity of cancer therapies remains an urgent problem today. The creation of highly effect antitumor drugs also means the appearance of new adverse effects. Immune checkpoint inhibitors (ICI) is a new class of antitumor drugs that is different from traditional chemotherapeutic and targeted drugs. Immunotherapy with ICI (monoclonal antibodies targeting the cytotoxic T-lymphocyte associated antigen 4 (CTLA-4), programmed cell death protein 1 (PD-1) or its ligand (PD-L1)) significantly improved the results of treatment of cancer therapy. These drugs regulate antitumor immunity and promote cancer regression and improve survival, but can also cause a wide range of immunity-related adverse events (AEs). Although cardiotoxicity associated with ICI is rare, it is important because of its high mortality rates. In recent years, cases of myocarditis and fatal heart failure have been recorded more often in patients receiving ICI. This review focuses on the mechanisms of cardiotoxicity, methods for the prevention and treatment of these adverse events. Severe cardiovascular consequences associated with the use of ICI are important issues for oncologists, cardiologists and immunologists.

Cardiovascular toxicity of cancer therapies remains an urgent problem today. The creation of highly effect antitumor drugs also means the appearance of new adverse effects. Immune checkpoint inhibitors (ICI) is a new class of antitumor drugs that is different from traditional chemotherapeutic and targeted drugs. Immunotherapy with ICI (monoclonal antibodies targeting the cytotoxic T-lymphocyte associated antigen 4 (CTLA-4), programmed cell death protein 1 (PD-1) or its ligand (PD-L1)) significantly improved the results of treatment of cancer therapy. These drugs regulate antitumor immunity and promote cancer regression and improve survival, but can also cause a wide range of immunity-related adverse events (AEs). Although cardiotoxicity associated with ICI is rare, it is important because of its high mortality rates. In recent years, cases of myocarditis and fatal heart failure have been recorded more often in patients receiving ICI. This review focuses on the mechanisms of cardiotoxicity, methods for the prevention and treatment of these adverse events. Severe cardiovascular consequences associated with the use of ICI are important issues for oncologists, cardiologists and immunologists.

Radiation exposure of the chest is associated with a significant risk of subsequent development of cardiovascular diseases. Associated cardiovascular injuries include pericardial disease, coronary artery disease, valvular disease, conduction disease, cardiomyopathy, and vasculopathy. This article presents the development of different variants of pericardial radiation damage, methods of diagnosis and treatment of these complications. Radiation damage to the pericardium can manifest as acute pericarditis, effusion with tamponade or without cardiac tamponade, effusion-constrictive or classic constrictive pericarditis. Algorithms for the diagnosis and treatment of patients with radiation pericarditis in connection with a long asymptomatic course in a number of patients deserve special attention. Careful history taking and identifying prior radiotherapy is important in this category of patients. Untimely diagnosis and late treatment of these complications leads to a decrease in the quality of life of patients and increases the risk of cardiovascular mortality.

Aim. Early diagnosis and treatment of rhythm and conduction disorders in patients receiving ibrutinib. Materials & Methods. The trial included 206 patients with indications for ibrutinib, 193 of them are at different stages of treatment from 1.5 to 51 months. The trial enrolled the patients with chronic lymphocytic leukemia, mantle cell lymphoma, and Waldenstrom's macroglobulinemia, aged 59 to 72 years (with median age of 66 years): 70 women aged 54 to 71 years (with median age of 64 years), and 123 men aged 60 to 72 years (with median age of 66 years). For early detection of rhythm and conduction disorders all the patients received ECG monitoring and 24-hour Holter ECG monitoring. Results. Atrial fibrillation (AF) was identified in 21 (12 %) patients during ibrutinib therapy period of 1 to 24 months. Most often AF is registered within the first 6 months of ibrutinib therapy. Before its administration 18 (10.5 %) patients had history of prior AF. Thus, a total of 39 ibrutinib recipients with AF are followed-up. According to CHA2DS2-VASc 27 (69 %) of them have an indication for anticoagulant treatment. Severe atrioventricular block was diagnosed in 2 (1 %) patients that necessitated a pacemaker. In 2 (1 %) female patients severe supraventricular tachycardia with up to 295 BPM was registered which required ablation. In a patient with permanent atrial fibrillation rhythm pauses were identified and a pacemaker was installed. Conclusion. The presence of AF in ibrutinib recipients is not a withdrawal criterion and does not require ibrutinib therapy to be discontinued. Anticoagulants were administered to patients with AF according to existing guidelines in compliance with CHA2DS2-VASc which had to be approached with caution and required dynamic monitoring of patients. Severe rhythm and conduction disorders in ibrutinib recipients arise in rare cases (2 %). Such patients require cardiac surgery with subsequent ibrutinib treatment without dose reduction. Timely diagnosis and the correction of rhythm and conduction allow to avoid changing of antitumor therapy plan.

Background. Antithrombotic therapy in chronic lymphocytic leukemia (CLL) patients is challenging, as this category of patients is initially characterized by high risk of hemorrhagic complications. The use of ibrutinib influencing the platelet function constitutes an additional bleeding risk. A crucial task consists in risk minimization of both hemorrhagic complications and thrombosis while sticking to ibru-tinib treatment. Aim. To assess the feasibility of antithrombotic therapy in CLL patients receiving ibrutinib and having indications for this therapy, as well as the use of dual antiplatelet and dual antithrombotic therapies. Materials & Methods. The trial included patients with CLL (n = 190), mantle cell lymphoma (n = 5), and Waldenstrom macroglobulinemia (п = 2) aged 32 to 91 years (median 66 years). The number of female patients was 70, aged 39 to 83 years (median 64 years) and the number of male patients was 127, aged 32 to 91 years (median 66 years). The patients were at different stages of ibrutinib treatment within 5 to 56 months. In this work methods of nonparametric statistics were used. All data are shown in the form of median and interquartile range or absolute numbers and percentages. Results. Antithrombotic therapy during ibrutinib administration was used in 29 (14,7 %) patients. The new oral anticoagulants (NOAC) had to be prescribed to 26 patients with atrial fibrillation (AF). Dual antiplatelet therapy was used in 3 patients who underwent percutaneous coronary intervention with subsequent revascularization. In 2 patients with AF who underwent coronary stenting the dual antithrombotic therapy instead of the triple one was administered according to the management algorithm for patients with high risk of hemorrhagic complications. In 6 patients out of those who had AF and received NOAC the drug was withdrawn because of thrombocytopenia. Hemorrhagic manifestations which were the reason of NOAC withdrawal were observed in 1 female patient in the form of gross hematuria recurring when anticoagulant treatment was switched to the minimal effective doses and also when the administered anticoagulant was replaced with another one used in the minimal dose effective for stroke prevention in patients with AF. Hemorrhagic manifestations which were the reason of anticoagulant dose reduction emerged in 4 patients, and 3 patients required another anticoagulant for the same reason. In 5 patients there was no need to change the anticoagulant treatment. In 10 NOAC recipients no hemorrhagic syndrome was observed. None of 5 patients receiving dual antithrombotic therapy showed hemorrhagic complications within 3 to 14 months. The incidence of them in women is more than twice as high as in men. Conclusion. Hemorrhagic manifestations in patients receiving ibrutinib and antithrombotic therapy were not life threatening and, in most cases, did not require drug withdrawal. Thrombocytopenia was the main reason for NOAC withdrawal. A thorough follow-up of patients receiving ibrutinib and antithrombotic therapy allows for timely correction of it if necessary. It involves dose reduction, anticoagulant replacement, and in rare cases the withdrawal of antithrombotic therapy with subsequent consideration of the feasibility of its resumption. As a rule, the need for different variants of antithrombotic therapy is not an obstacle to either assignment or continuation of antineoplastic treatment with ibrutinib.

Introduction: The use of new oral anticoagulants (NOAC) in patients with chronic lymphocytic leukemia (CLL) is a difficult task due to the high risk of hemorrhagic complications in these patients associated with the course of CLL. The use of highly effective targeted therapy with ibrutinib (Ib), which affects platelet function, creates an additional risk of bleeding. It is important to assess the use of NOAC in CLL patients receiving Ib, taking into account the frequency and severity of hemorrhagic manifestations, the need to cancel, reduce the dose and replace with another NOAC. Methods: We have examined and observed in the dynamics of 197 patients with CLL who received Ib from 5 to 56 months at a dose of 420 mg per day as 1, 2, 3, and 4 lines of CLL therapy. We included patients with CLL aged 32 to 91 years (66.0 (59.0-72.0) years), of which 70 women aged 39 to 83 years (64.0 (54.0-71.0 ) years) and 127 men aged from 32 to 91 years (66.0 (60.0-72.0) years). All occurring hemorrhagic manifestations were evaluated in patients receiving Ib and NOAC, taking into account the glomerular filtration rate (GFR) and the level of platelets. Results: The need for NOAC occurred in patients with CLL and atrial fibrillation (AF) (n = 34). Rivaroxaban (n = 16), dabigatran (n = 6), apixaban (n = 12) were prescribed. Hemorrhagic manifestations were observed in 53.6% of patients receiving NOAC and Ib. They were hematomas (n = 12), petechiae (n = 3), nasal (n = 4) and gingival (n = 2) bleedings, hemorrhage into the anterior chamber of the eye (n = 1), gross hematuria (n = 3). A combination of several hemorrhagic manifestations was observed in 40% of CLL patients receiving NOAC. In 4 patients who received rivaroxaban in a dose of 20 mg it was changed to the minimum effective dose of apixaban 2, 5 mg twice a day, due to the development of recurrent nasal bleeding, gross hematuria, large recurrent hematomas. NOAC (rivaroxaban 20 mg per day) was canceled in 6 patients due to the development of thrombocytopenia (less than 100 * 109 / l). In 1 patient, the cancellation of NOAC was due to recurrent gross hematuria, developed on rivaroxaban 20 mg and 15 mg per day and apixaban 2, 5 mg twice a day. We did not reveal significant differences in platelet count indices in groups of patients with and without hemorrhages. In 12 patients receiving rivaroxaban 20 mg once a day (n = 6), dabigatran 150 mg twice a day (n = 2), apixaban 5 mg twice a day (n = 4) for periods ranging from 9 to 25 months with Ib therapy no hemorrhagic manifestations have been observed. Conclusions: Hemorrhagic manifestations occurring in CLL patients receiving NOAC and Ib treatment were not life-threatening, in most cases did not require the abolition of NOAC and a dose reduction of Ib. The development of thrombocytopenia was the main reason for the abolition of NOAC in patients with CLL. Keywords: chronic lymphocytic leukemia (CLL); ibrutinib.

Aim. To analyze adverse cardiovascular events in chronic myeloid leukemia (CML) patients who received various tyrosine kinase inhibitors (TKI). Materials & Methods. The trial included 97 CML patients with nilotinib, dasatinib or imatinib indications. By the time of examination the patients had undergone TKI therapy for 1-138 months. The three of them were sequentially treated with 2 drugs over the monitoring period. All CML patients were aged 22-79 years (median 53.5 years): 55 women were aged 22-71 years (median 53.5 years) and 42 men were aged 24-79 years (median 53 years). Results. The comparative analysis demonstrated significantly higher impact of nilotinib on daily maximum QTc duration compared with other TKIs. The patients who received nilotinib (n = 15) throughout 38 months had QTc of 0.47 s (interquartile range [IQR] 0.46-0.47 s), in imatinib group (n = 17) QTc was 0.43 s (IQR 0.43-0.44 s), and in dasatinib group (n = 4) QTc was 0.43 s (IQR 0.42-0.44 s) (p = 0.0008). Among all patients treated with nilotinib there were 62 % (31/50) with QTc > 0.46 s, in imatinib (6/41) and dasatinib (2/18) groups it was detected in 14.6 % and 11.1 % of patients, respectively (p = 0.0008). Five patients had QTc > 0.48 s, which is the criterion for discontinuation of treatment or dose reduction. In two patients the identified changes of QTc duration required TKI temporary suspension. After nilotinib dose reduction or discontinuation QTc duration normalized in all cases within 2 weeks. Decreased ankle-brachial index (ABI) < 0.9 without pronounced clinical symptoms was identified in two patients who received nilotinib. Afterwards they showed peripheral occlusive disease of lower extremities, and nilotinib treatment was discontinued. In patients treated with other TKIs no occlusive vascular lesions were observed. A case of chronic heart failure with reduced left ventricular ejection fraction developing on nilotinib therapy was revealed and described. Conclusion. Despite high specificity for BCR-ABL tyrosine kinase, new TKIs can, although rarely, induce cardiovascular adverse events. Prior to TKI treatment assignment CML patients should be examined with ECG and EchoCG with systolic function evaluation, and the measurement of pulmonary artery pressure as well as ABI. The examination should be repeated in the end of the 1st year TKI treatment if there is no reason for extra examinations. It is recommended to hold 24-hour ECG monitoring with QTc max measurement prior to nilotinib assignment, then once a year within 2 years of nilotinib treatment, and once in 6 months after 3 years of therapy.

Aim. To study volumetric and linear parameters of the left atrium (LA) in operated and non-operated patients with severe aortic stenosis (AS) in comparison with the control group of a similar age and gender.Material and methods. Eighty-one patients with AS were examined, 49 patients — in the long term after aortic valve replacement (AVR), and 30 patients of similar age and gender — without a heart defect. Echocardiography was performed using an Acuson Sequia 512 ultrasound scanner.Results. The volumetric parameters of LA (LA volume index (LAVI)) and the ratio of the minimum LA with LV volume at this time point (LAVmin/LV) were the most sensitive parameter when evaluating the LV diastolic function in patients with isolated AS when comparing non-operated and operated patients and the control group. The study of association of non-operated AS patients with LAVI (greater than or less than 32 ml/m2) showed only a slight divergence between the Kaplan-Meyer curves with a log-rank test of 0,15. Only the values of the LV ejection fraction (LVEF) differed from parameters of died (n=21) and alive patients at the time of the study (n=60): 61,0 (56,4-69,3)% in alive versus 46,4 (39,1-55,4)% in dead ones (p<0,0001). The time elapsed from the diagnosis to the date of the examination also differed: 0,5 (0,4-11,0) years in alive versus 7,0 (3,0-19,0) years in dead ones (p=0,004). With multiple regression, the highest and statistically significant beta coefficient was found only in LVEF (beta — -0,52, p=0,002).Conclusion. Linear and volumetric parameters of LA slightly associate with the age and gender of operated and non-operated AS patients. These parameters statistically significantly differ in the groups of non-operated AS patients and patients after AVR compared with the control group, including patients without heart disease. The values of linear and volumetric LA parameters in patients with AS after AVR are close to those in the control group.

This review presents modern strategies for the prevention and treatment of cardiotoxicity induced by the most commonly used anticancer drugs such as anthracycline antibiotics, monoclonal antibodies, tyrosine kinase inhibitors. There are a large number of conflicting data on ways to overcome the cardiotoxicity of anticancer drugs. The creation of a complex of diagnostic measures will allow to identify the earliest signs of heart damage during chemotherapy and to develop timely preventive measures to prevent cardiotoxicity, improve the quality of life and prognosis of patients. Currently, a large number of small publications on the prevalence, prediction and prevention of cardiotoxicity in cancer patients, including the primary and secondary prevention of cardiotoxicity, are available. Beta-blockers and inhibitors of angiotensin-converting enzyme most often use as cardioprotective agents. There is evidence of poor tolerability of treatment with these drugs for young patients. Most drugs reduce blood pressure, which can adversely affect the health of patients without associated hypertension. Coordinated work between cardiologists and oncologists is needed to create common terminology, to define cardiovascular events and create registers, meta-analyzes, generally accepted recommendations, guidelines for the management of patients at risk of developing cardiotoxicity. This review used published articles the Scopus, Pubmed database, articles from The New England Journal of Medicine, Annals of Oncology, and periodicals of the Russian Federation over the past 10 years, as well as publications from previous years.

Aim. To study the efficacy of ivabradine in the prevention of cardiotoxic effects due to chemotherapeutic drugs in patients with breast cancer. Material and methods. The open randomized uncontrolled study included 55 patients with breast cancer who had to undergo chemotherapy by anthracyclines. The inclusion criterion was a heart rate >70 beats/min. Collection of complaints and anamnesis, ECG, echocardiography, routine laboratory tests were performed in all patients initially and after 1, 3, 6 and 12 months. All patients were treated with polychemotherapy with anthracyclines in combination with cyclophosphamide and fluorouracil. The patients included into the study were randomized into two groups. Patients of the main group (n=23) were additionally prescribed ivabradine in a daily dose of 10 mg followed by a dose titration. Patients of the control group (n=32) received only polychemotherapy. Results. In the main group a decrease in heart rate was observed already by the first month (from 83.6±9.5 to 67.1±7.5 beats/min, p<0.001) and persisted until the 6th month (74.2±14.9 beats/min, p<0.001). In the main group, the frequency of complaints of palpitation significantly decreased by the 1st month of treatment (from 60.9% to 30%, p=0.05) with a slight increase in further observation. A significant increase in the left atrium diameter (from 35.0±4.0 to 35.9±3.9 cm; p=0.009), the left atrium volume (from 42.0±12.8 to 43.7±11.6 ml; p=0.02), the end diastolic left ventricle (LV) volume (from 81.5±16.5 to 88.8±16.5 ml, p=0.007) and the end systolic LV volume (from 30.7±8.1 to 32.3±6.2 ml; p=0.01) were found in the main group in a month after polychemotherapy. Dynamics of the main echocardiographic indices was similar in the control group. By 6 months of observation the indexed mass of LV myocardium significantly increased in the control group (from 66.9±14.6 to 74.3±19.0 g/m2; p=0.024) in the absence of that in the main group (from 65.4±15.2 to 70.7±11.3 g/m2; p>0.05). A significant change in the LV ejection fraction was not found in both groups. Significant differences in LV global longitudinal strain were found between groups in 1, 3 and 6 months of observation (p<0.05), but after 12 months the groups were comparable in longitudinal strain values. Conclusion. Ivabradine therapy in patients with breast cancer and heart rate >70 beats/min was safe and did not cause bradycardia. Ivabradine use was accompanied by a significant reduction in a number of patients with complaints of palpitation, contributed to the preservation of normalLV global longitudinal deformation in chemotherapy, while the control group had negative changes with a maximum by the 6th month of follow-up.

High efficacy of contemporary chemical and radiation treatments made it to success in treatment of oncohematological diseases. The fundamentals of many schemes of polychemotherapy of the first line are anthracyclines. Effective treatment of the main disease in many cases is followed by a variety of cardiovascular complications, including severe ones and fatal. It is necessary to consider the possibility not only for development of acute cardiotoxicity, but various complications from cardiovascular system after cessation of antitumor treatment. Algorithm of patients preparing for such treatment must include cardiovascular assessment before the start of drugs, and follow-up during the treatment course. Prevention and treatment of cardiotoxicity are complicated clinical issues due to irreversible and progressing character of most disorders of cardiovascular system. An important issue is a close collaboration of cardiologist and oncologist in patient’s management. It is necessary to have longterm dynamic follow-up of patients after chemotherapy for maximally early diagnostics of cardiovascular complications in long-term period after finishing of antitumor treatment.

Background & Aims. This paper presents the results of the observational study of ibrutinib in patients with chronic lymphocytic leukemia (CLL), conducted in SP Botkin Municipal Clinical Hospital. The main objective was the analysis of complications of ibrutinib and identification of factors, influencing the dosage regimen; the secondary objective was the estimation of the total response to treatment, event-free and overall survival. Materials & Methods. The study included 96 patients with CLL with indications for ibrutinib therapy. The median age was 64,9 years (range 32-91 years), the study population consisted of 69 (72 %) men and 27 (28 %) women. The condition of 25 (26 %) patients according to the ECOG scale was of > 3 points. The disease of stage C were diagnosed in 36 (37 %) patients. Deletion of 17p/TP53 mutations were detected in 29 (33 %) of 87 patients. Seventy patients had refractory CLL. The median of the number of the lines of the previous therapy was 3 (range 1-9). Adverse events were assessed in accordance with the CTCAE criteria, version 4.0; the bleeding severity was evaluated using ITP-specific bleeding score; hematological complications were classified according to the recommendations of IWCLL-2008. Results. Ibrutinib was administered at a dosage of 420 mg per day daily until progression or intolerable toxicity. The median duration of ibrutinib therapy was 10.3 months. brutinib was shown to have moderate toxicity, mostly of grade I or II. The bleeding was the most frequent complication. Of the hematological complications, thrombocytopenia was the most common (35 %); neutropenia < 1 x 109/L was observed in 4 patients. GIT complications were identified in 51 (53 %) patients. Atrial fibrillation was registered in 5 patients, who initially had sinus rhythm. The total of 144 infections were diagnosed in 64 (66 %) patients. Severe infections (> grade III) developed in 26 % of patients. The treatment response was assessed in 92 patients. The overall response to treatment was 89 %. Complete remission, partial remission and partial remission with lymphocytosis were achieved in 4 (4 %), 57 (62 %), and 21 (23 %) patients, respectively. The event-free survival and overall survival by the month 10 was 90 % and 91 %, respectively. For this observation period, ECOG status and the number of the lines of therapy prior to ibrutinib had the prognostic value. Conclusion. Ibrutinib was shown to have high efficiency in relapsed/refractory forms of CLL. The nature of the ibrutinib toxicity is fundamentally different from that of the conventional chemotherapy. The frequency of ibrutinib therapy complications and patients' non-compliance depends on the intensity of the previous treatment of CLL. Despite a short observation period, it can be concluded that ibrutinib had the greatest impact on the patient's quality of life when administered for the first relapse. The low toxicity of ibrutinib is likely to allow the combination with other antitumor agents.

Chronic heart failure following chemotherapy for cancer is a relevant issue of an adverse cardiovascular prognosis and premature death in cancer patients. This category of patients requires thorough and chronic monitoring of the cardiovascular system, prevention and treatment of cardiovascular complications of chemotherapy, such as IHD, systolic or diastolic myocardial dysfunction, arterial or pulmonary hypertension, pulmonary thromboembolism, pericarditis, stroke, and peripheral vascular disease. However, many aspects of this important interdisciplinary issue presently remain understudied. For instance, it is still impossible to predict long-term consequences of chemotherapy for cancer and development of the associated cardiovascular complications listed above. Baseline evaluation of the risk for cardiovascular complications is a major component in management of such patients. High-risk patients need an individual, detailed schedule of cardiovascular treatment throughout and after the course of chemotherapy. Furthermore, early detection of subclinical myocardial dysfunction is critical for prevention of the most threatening cardiovascular complications of chemotherapy, CHF. Detecting impaired LV EF following chemotherapy is, unfortunately, only a late predictor of irreversible changes, such as toxic cardiomyopathy and clinically pronounced, rapidly progressing CHF. Markers of myocardial injury, high-sensitivity troponins and natriuretic peptides, in combination with up-to-date EchoCG technologies have been recently used. Their use, for instance, for evaluation of LV myocardial global longitudinal strain to detect early, reversible changes in structure and mechanics of the myocardium is promising for ultimate improvement of prediction for such patients.