Chronic Ibrutinib Therapy Effect on Left Atrial Function

Study Overview
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Brief Summary
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Ibrutinib is an irreversible Bruton tyrosine-kinase inhibitor. In prospective studies, the ibrutinib efficacy in the treatment of various B-cell malignancies was established. Different ibrutinib side-effects have been found: diarrhea, arthralgia, infections, neutropenia, hypertension and increased risk of bleeding. Most of the mentioned side-effects were <3rd degree of severity and mostly didn't require dose adjustment or therapy discontinuation. Also, there was an increase in the incidence of atrial fibrillation (AFib) (6-16%). The AFib pathogenesis in this patient population is not clarified, but there are indications that ibrutinib inhibits phosphoinositide-3-kinase (PI3K)-Akt signal-pathway expressed in the myocytes. Regardless of the molecular pathogenesis, the clinical effect of ibrutinib on the myocardium, especially the left atrium, has not been studied. Hence, the aim of this study is to determine the ibrutinib effect on echocardiographic parameters of left atrial function. This study will be performed as a clinical, prospective, observational cohort study with a structured follow-up period of 12 months. All consecutive patients with hemato-oncologic diseases (including chronic lymphocytic leukemia, Mantle-cell lymphoma, Waldenstrom macroglobulinemia, etc.) prescribed with chronic ibrutinib therapy, who are able to understand and sign informed consent, will be enrolled. Primary objective is change of the left atrial function measured by the decrease of the left atrial strain deformation > 10%. Recruiting should not exceed 12 months with the minimal follow-up period of 12 months (24 months in total). Standardized statistical methods and tests will be done using SPSS Version 22.0 or newer. This unique study offers the possibility to show the long-term effect of chronic ibrutinib therapy on left atrial function assessed by transthoracic echocardiography. This observational data is needed to further refine the treatment of these patients and to prevent possible side-effects of ibrutinib which could endanger this specific patient population.

Official Title
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Long-term Effect of Chronic Ibrutinib Therapy on Left Atrial Function

Conditions
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Atrium; Beat, Echocardiography, Physiology, Therapy Adverse Effect

Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: patients with haemato-oncologic diseases (including chronic lymphocytic leukemia, Mantle-cell lymphoma, Waldenstrom macroglobulinaemia, etc.) patients prescribed with chronic ibrutinib therapy patients who are able to understand and sign informed consent Exclusion Criteria: patients with haemato-oncologic diseases who were prescribed with concomitant chemotherapy which can impact left atrial function patients < 18 years old patients with known or at initial echocardiography established dilated cardiomyopathy with left ventricular ejection fraction < 35% patients with permanent atrial fibrillation and dilated left atrium or dilated both atriums patients implanted with cardiac implantable electronic devices patients who underwent cardiac surgery patients with congenital heart diseases (surgically corrected or not) patients with severe valvular pathology patients with terminal renal disease patients with chronic obstructive pulmonary disease - GOLD grade 4 patients with life expectancy < 12 months patients not willing to undergo clinical follow-up or sign informed consent patients recruited in another clinical study

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| left atrial function change | change of the left atrial function measured by the decrease of the left atrial strain deformation > 10% assessed by transthoracic echocardiography | initial measurement, 3 months, 6 months and 12 months after initiation of ibrutinib therapy | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| left ventricular ejection fraction change | measurement of left ventricular systolic function change assessed by transthoracic echocardiography - method according to Simpson and Teicholz | initial measurement, 3 months, 6 months and 12 months after initiation of ibrutinib therapy | 
| left ventricular diastolic function change | measurement of left ventricular diastolic function change assessed by transthoracic echocardiography (E/A and E/E') | initial measurement, 3 months, 6 months and 12 months after initiation of ibrutinib therapy | 
| left atrial volume change | 2D and 3D left atrial volume change assessed by transthoracic echocardiography + left atrial dimension in PLAX and 4 chamber projection | initial measurement, 3 months, 6 months and 12 months after initiation of ibrutinib therapy | 
| P wave duration change | P wave duration and PQ interval duration change assessed in 12-lead electrocardiogram (in milliseconds) | initial measurement, 3 months, 6 months and 12 months after initiation of ibrutinib therapy | 
| left atrial pump function change | left atrial ejection fractionchange assessed by transthoracic echocardiography (doppler strain measurement method) | initial measurement, 3 months, 6 months and 12 months after initiation of ibrutinib therapy | 
| atrial fibrillation incidence | incidence of paroxysmal atrial fibrillation assessed by symptoms + ECG or 24-hours Holter-ECG | initial measurement, 3 months, 6 months and 12 months after initiation of ibrutinib therapy | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ibrutinib, echocardiography, left atrium, function, long-term