Trial Title:
Clinical and Diagnostic Significance of Endothelial Dysfunction and Myocardial Contractility in Patients With AML
NCT ID:
NCT05703126
Condition:
Acute Myeloid Leukemia, Adult
Cardiotoxicity
Endothelial Dysfunction
Conditions: Official terms:
Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Cardiotoxicity
N,N-dimethylarginine
Conditions: Keywords:
Acute Myeloid Leukemia
Cardiotoxicity
Endothelial Dysfunction
Polychemotherapy
Anthracyclines
Study type:
Interventional
Study phase:
N/A
Overall status:
Recruiting
Study design:
Allocation:
Non-Randomized
Intervention model:
Parallel Assignment
Primary purpose:
Diagnostic
Masking:
Single (Participant)
Intervention:
Intervention type:
Diagnostic Test
Intervention name:
History taking
Description:
Careful history taking, including using questionnaires, to identify risk factors for the
development of cardiovascular diseases using the SCORE scale.
Arm group label:
The control group
Arm group label:
The study group
Intervention type:
Diagnostic Test
Intervention name:
Anthropometry
Description:
Anthropometry: measurement of body weight and height. Calculation of body surface area
using the Du Bois formula.
Arm group label:
The control group
Arm group label:
The study group
Intervention type:
Diagnostic Test
Intervention name:
Complete blood count
Description:
Before and after each course of chemotherapy: Complete blood count with counting the
number of erythrocytes, leukocytes, leukocyte formula, platelets, erythrocyte
sedimentation rate.
Arm group label:
The control group
Arm group label:
The study group
Intervention type:
Diagnostic Test
Intervention name:
Biochemical blood test
Description:
Before and after each course of chemotherapy: Biochemical blood test with the
determination of the amount of total protein, total cholesterol, HDL cholesterol, LDL
cholesterol, triglycerides, creatinine, urea, AlAT, AsAT, LDH, glucose, C-reactive
protein, troponin T, proBNP.
Arm group label:
The control group
Arm group label:
The study group
Intervention type:
Diagnostic Test
Intervention name:
Coagulogram
Description:
Before and after each course of chemotherapy: Coagulogram parameters (fibrinogen, APTT,
INR).
Arm group label:
The control group
Arm group label:
The study group
Intervention type:
Diagnostic Test
Intervention name:
Immunoenzymatic analysis of the level of endothelin-1, asymmetric dimethylarginine
Description:
Before the start of the treatment and after each course of chemotherapy: Immunoenzymatic
analysis of the level of endothelin-1, asymmetric dimethylarginine.
Arm group label:
The control group
Arm group label:
The study group
Intervention type:
Diagnostic Test
Intervention name:
Stress echocardiography with the definition of global longitudinal deformation of the myocardium
Description:
Before the start of the treatment and after each course of chemotherapy: Stress
echocardiography with the definition of global longitudinal deformation of the
myocardium.
Arm group label:
The control group
Arm group label:
The study group
Intervention type:
Diagnostic Test
Intervention name:
Triplex scanning of neck vessels
Description:
Before the start of the treatment and after each course of chemotherapy: Triplex scanning
of neck vessels.
Arm group label:
The control group
Arm group label:
The study group
Intervention type:
Diagnostic Test
Intervention name:
Electrocardiography
Description:
Before and after each course of chemotherapy: Electrocardiography.
Arm group label:
The control group
Arm group label:
The study group
Intervention type:
Diagnostic Test
Intervention name:
Ultrasound of the abdominal cavity (with calculation of the area of the spleen) and lymph nodes
Description:
Before the start of the treatment and after each course of chemotherapy: Ultrasound of
the abdominal cavity (with calculation of the area of the spleen) and lymph nodes.
Arm group label:
The control group
Arm group label:
The study group
Intervention type:
Diagnostic Test
Intervention name:
Cytogenetic examination of the bone marrow to determine genetic abnormalities.
Description:
Before the start of the treatment: Cytogenetic examination of the bone marrow to
determine genetic abnormalities.
Arm group label:
The control group
Arm group label:
The study group
Intervention type:
Diagnostic Test
Intervention name:
Cytological examination of bone marrow cells with cytochemical examination
Description:
Before the start of the treatment and after each course of chemotherapy: Cytological
examination of bone marrow cells with cytochemical examination.
Arm group label:
The control group
Arm group label:
The study group
Intervention type:
Diagnostic Test
Intervention name:
Immunophenotypic examination of the bone marrow by flow cytometry
Description:
Before the start of the treatment: Immunophenotypic examination of the bone marrow by
flow cytometry.
Arm group label:
The control group
Arm group label:
The study group
Intervention type:
Diagnostic Test
Intervention name:
Determination of the presence of a FLT3 mutation using the PCR Method
Description:
Before the start of the treatment: Determination of the presence of a FLT3 mutation using
the PCR Method.
Arm group label:
The control group
Arm group label:
The study group
Intervention type:
Diagnostic Test
Intervention name:
laser Doppler flowmetry
Description:
Before the start of the treatment and after each course of chemotherapy: Examination of
microcirculation by laser Doppler flowmetry using the LAKK-OP apparatus (NPP Lazma,
Moscow, 2011) with respiratory and occlusion tests.
Arm group label:
The control group
Arm group label:
The study group
Summary:
Acute myeloid leukemia (AML) is a clonal neoplastic disease of the hematopoietic tissue
associated with a mutation in the precursor cell of hematopoiesis, which results in a
differentiation block and uncontrolled proliferation of immature myeloid cells.
Anthracycline antibiotics have been an integral part of the treatment of acute myeloid
leukemia since the 1970s. However, the clinical usefulness of anthracyclines is limited
primarily by the high incidence of cardiotoxicity. According to the European Society of
Cardiology guidelines for cardio-oncology, cardiovascular toxicity is defined as any
impairment of cardiac function associated with anticancer treatment, as the term
encompasses both a wide range of possible clinical manifestations and an etiological
relationship with various treatments, including chemotherapy, radiation therapy,
immunotherapy and treatment with targeted drugs. Cardiovascular toxicity can be acute,
subacute or delayed, manifesting many years after chemotherapy or radiation therapy,
involving a number of cardiac structures, which can lead to the development of heart
failure, coronary heart disease, valvular heart disease, arrhythmias, including cardiac
conduction disorders and diseases of the pericardium.
Anthracycline-induced cardiotoxicity is the negative effect of anthracyclines on normal
cardiac activity due to their toxic effects on the heart muscle and the cardiac
conduction system. Anthracycline-induced cardiotoxicity manifests as asymptomatic left
ventricular dysfunction in 57% of treated patients and restrictive or dilated
cardiomyopathy leading to congestive heart failure (CHF) in 16% to 20% of patients.
Anthracycline-induced congestive heart failure is often resistant to therapy and has a
mortality rate of up to 79%. Thus, there is a need for early detection of cardiovascular
dysfunction associated with chemotherapy treatment of acute myeloid leukemia in order to
timely prescribe drug therapy.
Purpose of the study To optimize the early detection of endothelial dysfunction and left
ventricular myocardial contractility in patients with acute myeloid leukemia during
chemotherapy treatment based on a comprehensive assessment of instrumental and laboratory
research parameters.
Expected results Based on a comprehensive analysis using laser Doppler flowmetry, stress
echocardiography with the determination of global longitudinal strain of the myocardium,
biochemical markers of endothelial damage and cardiac biomarkers, a correlation between
violations of the contractility of the left ventricular myocardium and violations of the
vasoregulatory function of the vascular endothelium will be revealed, which will allow
developing an algorithm for early detection of cardiomyopathy and vascular complications
in patients with acute myeloid leukemia during chemotherapy treatment.
Detailed description:
Acute myeloid leukemia (AML) is a clonal neoplastic disease of the hematopoietic tissue
associated with a mutation in the precursor cell of hematopoiesis, which results in a
differentiation block and uncontrolled proliferation of immature myeloid cells.
It is believed that AML affects an average of 3-5 people per 100,000 people per year. At
the same time, the incidence increases sharply at the age of over 60 years and amounts to
12-13 cases per 100 thousand of the population in people over the age of 80 years. The
median age of this disease is 65 years. With a population of 140 million inhabitants in
Russia, the estimated incidence rate (according to European and American researchers)
should be about 5 thousand cases.
Anthracycline antibiotics have been an integral part of the treatment of acute myeloid
leukemia since the 1970s. Anthracycline is usually given for 3 days (eg, daunorubicin
45-90 mg/m 2 daily, idarubicin 12 mg/m 2 daily) in combination with cytarabine (100-200
mg/m 2 daily) continuously for 7 days ) ("7+3" mode). Anthracyclines block the synthesis
of DNA and RNA by inhibiting the enzyme topoisomerase IIβ and mitochondrial topoisomerase
I. The subsequent disruption of DNA replication and transcription prevents the
proliferation of rapidly dividing cells. In addition, anthracyclines damage DNA,
proteins, and cell membranes by creating free oxygen radicals.
The clinical usefulness of anthracyclines is limited primarily by the high incidence of
cardiotoxicity. According to the European Society of Cardiology guidelines for cardio-
oncology, cardiovascular toxicity is defined as any impairment of cardiac function
associated with anticancer treatment, as the term encompasses both a wide range of
possible clinical manifestations and an etiological relationship with various treatments,
including chemotherapy, radiation therapy, immunotherapy and treatment with targeted
drugs. Cardiovascular toxicity can be acute, subacute or delayed, manifesting many years
after chemotherapy or radiation therapy, involving a number of cardiac structures, which
can lead to the development of heart failure, coronary heart disease, valvular heart
disease, arrhythmias, including cardiac conduction disorders, and diseases of the
pericardium.
Anthracycline-induced cardiotoxicity is the negative effect of anthracyclines on normal
cardiac activity due to their toxic effects on the heart muscle and the cardiac
conduction system. It is believed to be mediated in part by reactive oxygen species
generated by anthracycline treatment, which leads to lipid peroxidation and DNA damage in
cardiomyocytes. Other putative causes of anthracycline-induced cardiotoxicity include
accumulation of cardiotoxic anthracycline metabolites in the heart, disruption of calcium
homeostasis, mitochondrial damage, and induction of apoptosis.
Anthracycline-induced cardiotoxicity manifests as asymptomatic left ventricular
dysfunction in 57% of treated patients and restrictive or dilated cardiomyopathy leading
to congestive heart failure (CHF) in 16% to 20% of patients. Anthracycline-induced
congestive heart failure is often resistant to therapy and has a mortality rate of up to
79%. Thus, there is a need for early detection of cardiovascular dysfunction associated
with chemotherapy treatment of acute myeloid leukemia in order to timely prescribe drug
therapy.
Purpose of the study To optimize the early detection of endothelial dysfunction and left
ventricular myocardial contractility in patients with acute myeloid leukemia during
chemotherapy treatment based on a comprehensive assessment of instrumental and laboratory
research parameters.
Research objectives
1. To assess the state of endothelial function in patients with acute myeloid leukemia
receiving chemotherapy based on a comprehensive assessment, including laser Doppler
flowmetry and biochemical markers of endothelial damage (endothelin-1, asymmetric
dimethylarginine).
2. To characterize the contractility of the left ventricular myocardium in patients
with acute myeloid leukemia during chemotherapeutic treatment based on the
indicators of stress echocardiography with the determination of global longitudinal
deformation of the myocardium, as well as to assess the presence of myocardial
damage by determining the level of highly sensitive troponin and brain natriuretic
peptide.
3. To study the relationship between dynamic indicators of microcirculation, determined
by laser Doppler flowmetry, with indicators of contractility of the left ventricular
myocardium, detected using stress echocardiography with the determination of global
longitudinal deformation of the myocardium, and the results of laboratory methods
for assessing the function of the endothelium and myocardium.
4. To determine the frequency of development of various phenotypes of cardiovascular
toxicity.
5. To identify the most significant prognostic criteria for the development of
cardiotoxicity in patients with acute myeloid leukemia receiving chemotherapy.
Scientific novelty
1. For the first time, an algorithm for early detection of endothelial dysfunction and
left ventricular myocardial contractility in patients with acute myeloid leukemia
during chemotherapy treatment will be developed.
2. For the first time, the vasoregulatory function of the endothelium and the
contractility of the left ventricular myocardium in patients with acute myeloid
leukemia receiving chemotherapy will be studied based on a comprehensive assessment
using laser Doppler flowmetry, stress echocardiography with the determination of
global longitudinal deformation of the myocardium, biochemical markers of
endothelial damage and cardiac biomarkers.
Practical significance It is planned to develop an algorithm for early detection of
endothelial dysfunction and left ventricular myocardial contractility in patients with
acute myeloid leukemia during chemotherapy treatment based on a comprehensive assessment
using laser Doppler flowmetry, stress echocardiography with the determination of global
longitudinal myocardial strain, biochemical markers of endothelial damage and cardiac
biomarkers. .
Expected results Based on a comprehensive analysis using laser Doppler flowmetry, stress
echocardiography with the determination of global longitudinal strain of the myocardium,
biochemical markers of endothelial damage and cardiac biomarkers, a correlation between
violations of the contractility of the left ventricular myocardium and violations of the
vasoregulatory function of the vascular endothelium will be revealed, which will allow
developing an algorithm for early detection of cardiomyopathy and vascular complications
in patients with acute myeloid leukemia during chemotherapy treatment.
Research hypothesis:
The proposed algorithm for the early detection of cardiovascular complications in
patients with acute myeloid leukemia receiving chemotherapy treatment is an effective
method for diagnosing cardiovascular complications at subclinical stages for the timely
initiation of their therapy.
Study Design In total, it is planned to study 100 patients with acute myeloid leukemia
receiving chemotherapy, aged 18 to 65 years, without clinical signs of heart failure,
with an LV ejection fraction of more than 50% before the start of polychemotherapy.
The study group will include patients with acute myeloid leukemia receiving chemotherapy,
aged 18 to 65 years, without clinical signs of heart failure, with an LV ejection
fraction of more than 50% before the start of polychemotherapy, in whom in the course of
chemotherapy treatment after the next course of treatment a decrease in global
longitudinal strain of 15% or more relative to the initial values will be revealed.
The control group will consist of patients with acute myeloid leukemia receiving
chemotherapy, aged 18 to 65 years, without clinical signs of heart failure, with an LV
ejection fraction of more than 50% before the start of polychemotherapy, in whom no signs
of myocardial disease and endothelial dysfunction will be detected during chemotherapy.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
- patients with acute myeloid leukemia receiving anthracycline-containing
polychemotherapy regimens aged 18 to 65 years, without clinical signs of heart
failure, with an LV ejection fraction of more than 50% before starting chemotherapy;
- availability of informed consent of the patient to participate in the study.
Exclusion Criteria:
- acute violation of cerebral circulation in history;
- a history of myocardial infarction;
- the presence of diabetes mellitus type I and II;
- the presence of chronic kidney disease C1-C5 stages;
- the presence of stable angina III-IV functional classes;
- the presence of unstable angina pectoris;
- the presence of atrial fibrillation and flutter;
- the presence of arterial hypertension of 2-3 degrees;
- the presence of other oncological diseases;
- inflammatory diseases in the acute stage;
- diseases of the thyroid gland;
- therapy with any monoclonal antibodies in history;
- a positive test for the presence of HIV and hepatitis B and C;
- alcoholism, drug addiction;
- the presence of neuroleukemia, extramedullary foci of leukemia;
- refusal of the patient to be examined.
- the emergence of life-threatening situations during the study;
- development in patients of diseases related to the non-inclusion criteria;
- refusal of the patient to further examination.
Gender:
All
Gender based:
Yes
Minimum age:
18 Years
Maximum age:
65 Years
Healthy volunteers:
No
Locations:
Facility:
Name:
Clinics of the Samara Medical University
Address:
City:
Samara
Zip:
443079
Country:
Russian Federation
Status:
Recruiting
Contact:
Last name:
Angelika Antipova
Phone:
89228862745
Email:
a.v.antipova@samsmu.ru
Start date:
December 1, 2022
Completion date:
August 3, 2025
Lead sponsor:
Agency:
Samara State Medical University
Agency class:
Other
Source:
Samara State Medical University
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT05703126
