Early-onset Cardiotoxicity assessment related to anthracycline in children with leukemia. A Prospective Study

Adriana Linares Ballesteros; Roy Sanguino Lobo; Juan Camilo Villada Valencia; Oscar Arévalo Leal; Diana Constanza Plazas Hernández; Nelson Aponte Barrios; Iván Perdomo Ramírez

doi:10.25100/cm.v52i1.4542

. 2021 Feb 15;52(1):e2034542. doi: 10.25100/cm.v52i1.4542

Show available content in

View full-text in Spanish

Early-onset Cardiotoxicity assessment related to anthracycline in children with leukemia. A Prospective Study

Adriana Linares Ballesteros ^1,², Roy Sanguino Lobo ^3,^✉, Juan Camilo Villada Valencia ¹, Oscar Arévalo Leal ³, Diana Constanza Plazas Hernández ^1,², Nelson Aponte Barrios ², Iván Perdomo Ramírez ⁴

PMCID: PMC8054707 PMID: 33911320

Abstract

Background:

Acute leukemias are the most frequent malignancies in children. Advances in treatment have improved the overall survival to 80%. Almost 10% of children with cancer develop clinical cardiac toxicity. Total anthracycline cumulative dose is a risk factor for early-onset cardiotoxicity.

Objective:

To describe the incidence of early-onset cardiotoxicity in children with acute leukemia treated with chemotherapy.

Methods:

A prospective descriptive study of patients >1 y and <18 years diagnosed with acute leukemia. Assessed with electrocardiograma, echocardiography, and blood biomarkers at diagnosis and during the follow-up.

Results:

94 patients with acute lymphoblastic leukemia and 18 with acute myeloid leukemia were included. 20 patients (17.9%) developed early-onset cardiotoxicity. Statistically significant data was seen after anthracycline dose >150 mg/m², between the first echocardiographic evaluation and posterior analyses in the left ventricular fraction ejection with Teicholz p 0.05, Simpson p 0.018 and GLS p 0.004. In this study, there was no relation between blood biomarkers and cardiotoxicity.

Conclusions:

Cancer therapeutic-related cardiac dysfunction is related to anthracycline cumulative dose. In this study, echocardiographic follow-up was useful to predict risk factors for early cardiac dysfunction.

Keywords: child, leukemia, anthracyclines, antineoplastic agents, ventricular dysfunction, echocardiography, drug therapy

Remark

1) Why was this study conducted?

There are few prospective studies on the frequency of early cardiac toxicity in children receiving chemotherapy and possible predictors of this toxicity in children receiving acute leukemia treatment.

2) What were the most relevant results of the study?

Up to 75% of children have some abnormal cardiovascular finding during treatment. The usefulness of advanced echocardiography tools in predicting the risk of cardiac compromise with significant OR. We established GLS and GLS delta’s role as possible early markers of cardiac toxicity in children who received treatment for acute leukemias. Biomarkers were not predictors of cardiotoxicity in this study. The relationship between cardiac disease and cumulative anthracycline doses was demonstrated.

3) What do these results contribute?

Motivating the identification of cardiovascular compromise as an adverse effect of chemotherapy in children during cancer treatment and promoting measures to mitigate it, such as the use of cardiac protection strategies. It is necessary to conduct long-term follow-up of leukemia survivors to identify late chronic cardiovascular effects.

Open in a new tab

Introduction

Hematolymphoid neoplasms are the leading cause of childhood cancer in the world ¹. Advances in pediatric cancer therapeutics have led patients to higher overall survival and increased adverse effects from their therapy ². The percentage of children with cancer with symptomatic cardiovascular toxicity ranges from 7% to10% ³. The cellular damage produced by antineoplastics in the heart muscle is well known ⁴. Survivors of childhood cancer have an eight times higher risk of developing cardiovascular diseases throughout their lives ⁵. High cumulative doses of anthracyclines and chest radiotherapy exposure are the main risk factors for heart failure. However, other triggers have been described: high doses of alkylating agents, female gender, age less than four years, having Down syndrome, and the Afro-descendant race ⁶. We classified cardiac toxicity derived from cancer therapy according to the time of onset in the following categories: acute, when it occurs in the first week after exposure to the neoplastic agent; early-onset, which occurs between one week and up to a year after the end of antineoplastic treatment; and late-onset, that which occurs after one year of having finished treatment ⁷^,⁸. Despite the existence of guidelines for detecting and monitoring cardiovascular diseases in the adult population ⁹, few evidence-based consensus or reviews provide recommendations for the diagnosis and follow-up of cardiovascular complications ¹⁰ for patients with childhood cancer. Echocardiography is the primary diagnostic technique to evaluate the left ventricle’s systolic performance by estimating its ejection fraction. Other cardiovascular evaluation tools are serum biomarkers such as troponin T, troponin I, Brain Natriuretic Peptide, and the electrocardiogram. ⁷.

In a survival study of a cohort of children with acute lymphoblastic leukemia at a reference center for childhood cancer in Bogotá, a grade 3-4 cardiac toxicity frequency of 26.9% was found ¹¹. There are very few data on the frequency of cardiovascular complications derived from antineoplastic therapy in Colombian children.

The study’s main objective was to describe the frequency of early cardiac involvement in children with acute leukemias who received antineoplastic treatment at a referral center for childhood cancer. Secondary objectives were to describe the echocardiographic and electrocardiographic findings and describing the serum biomarkers’ behavior in the study group.

Materials and Methods

This is a prospective descriptive study, nested in a cohort of patients with a confirmed diagnosis of acute leukemias: acute lymphoid leukemia and acute myeloid leukemia, older than one year and younger than 18 years, in the period between October 1, 2017, and March 31, 2019. Participants were selected by non-probabilistic sequential convenience sampling of patients with a new diagnosis of acute lymphoblastic leukemia and acute myeloid leukemia.

Inclusion criteria

Patients older than 12 months and younger than 18 years with a new diagnosis of acute lymphoblastic leukemia and acute myeloid leukemia performed at HOMI Fundación Hospital de la Misericordia.

Exclusion criteria

Patients who did not start treatment at HOMI Fundación Hospital de la Misericordia.

Patients with a diagnosis of relapse of acute lymphoblastic leukemia or acute myeloid leukemia. Patient with a diagnosis of heart disease before the start of cancer treatment. Patients who did not complete at least two evaluations. Patients whose parents did not authorize their inclusion in the study.

Definitions

The patients with acute lymphoid leukemia were classified according to their risk as standard, intermediate, and high. The risk classification for acute lymphoid leukemia is based on the ALLCI protocol of the BFM group (Appendix 1) ¹².

Cardiac dysfunction related to cancer therapy: the decrease in the left ventricle’s systolic performance by estimating its ejection fraction below 53%, by estimating with the biplane Simpson’s method ¹³^,¹⁴.

Global longitudinal myocardial deformation: Considering the manufacturer of the echocardiography equipment used and the available literature, a deformation greater than -20.1% was considered a normal absolute value for all age groups ¹³^,¹⁴.

A decrease in the percentage of deformation greater than 15% compared to the baseline value at follow-up was considered significant (global longitudinal myocardial deformation Delta) ¹⁵.

Other associated cardiovascular disorders: coronary artery disease, arrhythmias, pericardial effusion, valve insufficiency (other than mild tricuspid or mitral regurgitation and considered physiological), thromboembolic disease, systemic arterial hypertension (defined as systolic or diastolic blood pressure higher than the 95th percentile for age, gender, and height), and pulmonary hypertension ⁸ (defined as an echocardiographic estimate of a pulmonary systolic pressure greater than or equal to 40 mmHg from the tricuspid regurgitation velocity and an estimate of pressure at the level of the right atrium in relation to the percentage of inferior vena cava collapse).

Acute toxicity: cardiovascular manifestations that appear in the first week of antineoplastic treatment ⁷^,⁸.

Early-onset toxicity: the appearance of cardiovascular manifestations after the first week and up to the first year after the end of treatment ⁷^,⁸.

Alterations in serum biomarkers: significant elevation of brain natriuretic peptide above 100 pg/mL of TnI with a value greater than 0.05 in ng/L and TnT value above 40 ng/L ¹⁶.

Alterations in the electrocardiogram (ECG): identifying alterations in impulse generation, AV conduction (atrioventricular), IV conduction (interventricular), and repolarization disorders ⁸.

Echocardiography evaluation: The taking and analysis of the echocardiographic studies were carried out by two pediatric cardiologists with more than five years of experience in evaluating patients with childhood cancer, performing ECG synchronized acquisitions (5 beats) for moving images. The three methods used to evaluate the systolic performance of the left ventricle were the ejection fraction (LVEF) estimated by the Simpson biplane method (LVEF (S)), the LVEF estimated by the Teicholz method (LVEF (T)), and the shortening fraction. An analysis of the global longitudinal strain was performed using the particle follow-up technique (Speckle tracking).

For quantifying the ejection fraction using the biplane Simpson method and the global longitudinal myocardial deformation analysis, the frames were obtained from the apical window in 4-chamber, 2-chamber, and three-chamber axes. The acquisition analysis was performed with the Phillips Affiniti 70C ultrasound machine software, version 1.7.1. For all cases, the operators located the basal points and the apical point to be analyzed in the three defined views, allowing automatic recognition of the endocardium in the first instance and manually correcting its location if necessary, using the editing function.

For the quantification of the ejection fractions by the Teicholz method and the shortening fraction, we used a static image acquired from the short axis of the ventricles.

All patients underwent 12-lead ECG evaluations and two-dimensional (2D) echocardiography with the Phillips Affiniti 70C, 5-1, and 8-3 MHz transducers.

Assessments were performed with serum biomarkers measured in peripheral or central venous blood processed by rapid test immunochromatography. The serum biomarkers evaluated were brain natriuretic peptide, troponin I (TnI), and troponin T (TnT). The reference values correspond to the technique used.

All the previously mentioned evaluations (echocardiogram, electrocardiogram, and biomarkers) were performed before starting treatment and at specific points of the acute lymphoid leukemia and acute myeloid leukemia treatment (Figure 1). For patients with high-risk of the acute lymphoid leukemia, the end of treatment was considered the last evaluation at the end of reinduction or the last evaluation before hematopoietic stem cell transplantation. For patients with acute myeloid leukemia, the end of treatment was considered the last evaluation before TPH or the evaluation after three cycles of consolidation.

The cumulative doses of anthracyclines by pathology were converted to equivalent doses of doxorubicin: 1 mg of daunorubicin is equivalent to 0.833 mg of doxorubicin ¹⁷.

Statistical analysis

According to the distribution after analysis with normality tests, the quantitative variables’ statistical analyses were carried out with central tendency and dispersion measures, means, standard deviation, or medians and ranges, after analysis with normality tests (Kolmogorov-Smirnov or Shapiro Wilk) to establish the behavior of the data as parametric or nonparametric. Qualitative variables were analyzed with Pearson’s Ji ² test and Fisher’s exact test. The echocardiography data were analyzed according to the accumulated dose of anthracyclines. In each treatment group, the Wilcoxon test for nonparametric paired samples was used. For the analysis of biochemical markers such as brain natriuretic peptide, patients were divided into two groups according to the presence or absence of cardiotoxicity and were analyzed with the Mann-Whitney U test for independent nonparametric samples. Statistical analysis was performed using the Statistical Package for Social Sciences (SPSS) for Windows, version 25.0. A value of p <0.05 was considered significant.

Ethical aspects

This study was classified as a “Minimal Risk” project. Informed consent was obtained from the parents of each patient. Assent was obtained from each of the patients or the patient’s legal representative if that were the case. This research protocol was approved by the institutional ethics committee, act 4848 CEI-11-17.

Results

One hundred thirteen patients were admitted: 94 with acute lymphoid leukemia and 19 with acute myeloid leukemia. One patient with acute myeloid leukemia was excluded from the study because he did not have data from the second evaluation; the results correspond to 112 patients. We analyzed 38 patients (33.9%) with high-risk acute lymphoblastic leukemia, 42 (37.5%) with intermediate-risk, 14 (12.5%) standard risk, and 18 patients with acute myeloid leukemia (16.0%). Thirteen patients died during follow-up; data was collected until pre-death assessment. Table 1 describes the demographic characteristics of the study population.

Table 1. Demographic characteristics of the study population.

Variables	LLA RE	LLA RI	LLA RA	LMA	Total
Number of patients (%)	14 (12.5%)	42 (27.5%)	38 (33.9%)	18 (16%)	112 (100%)
Median age in years (range)	3.4 (1-6)	6.6 (1.7-17.2)	9.4 (1.5-17.7)	9.0 (1.5-17.0)	6.35 (1.0- 17.7)
Female	8 (57.1%)	17 (40.5%)	13 (34.3%)	7 (38.9%)	45 (40.2%)
Median weight in kilograms (range)	12.8 (10.9-25.0)	20 (10.4-74.0)	19 (10-73)	31.5 (10-69)	20 (10-74)
Median height in cms (range)	97 (86-118)	118.5 (75-180)	122.5 (83-181)	129 (70-167)	114 (70-181)
Accumulated dose of anthracycline mg / m²	170	220	270	298	NA

Open in a new tab

ALL: acute lymphoblastic leukemia, ER: standard risk, IR: intermediate risk, AR: high risk.

Early-onset of cardiac dysfunction related to cancer therapy developed in 20 patients (17.9%); no patient had acute heart disease.

There was early-onset toxicity in patients with acute lymphoid leukemia high-risk with a median of 30 days in 4 patients and 120 mg/m² accumulated anthracyclines. By the third evaluation (end of intensification), eight patients presented early cardiotoxicity, with cumulative anthracyclines doses of 150 mg/m². At the last evaluation (end of reinduction), a cumulative 11 patients had cardiac involvement with cumulative anthracycline doses of 270 mg/m².

Cardiac dysfunction related to cancer therapy was found in two intermediate-risk patients with cumulative doses of 220 mg/m² of doxorubicin at the end of reinduction. In the standard-risk group, no patients had cardiac dysfunction related to cancer therapy.

In the children with acute myeloid leukemia group, seven patients had early cardiotoxicity, one of them after 180 mg/m² accumulated anthracyclines, and four patients after 298 mg/m² of anthracyclines. By the end of treatment, two additional patients had early heart disease. The decrease in LVEF (S) during follow-up, greater than ten percentage points compared to the previous LVEF (S), was a predictor for cardiotoxicity in patients with acute myeloid leukemia with an OR of 42.42 (95% CI: 4.6- 391.0).

Abnormal findings on the echocardiogram were presented in 65 patients (Tables 2 and 3).

Table 2. Early-onset cardiovascular findings according to the type of leukemia.

Description of the heart condition	Acute lymphoblastic leukemia			Acute myeloid leukemia	TOTAL
	Standard risk n: 14	Intermediate risk n: 42	High risk n: 38	n: 18	n: 112
CDRCT (FEVI <53%)	0 (0%)	2(1.8%)	11(9.8%)	7(6.3%)	20(17.9%)
ECG abnormalities	1(0.9%)	16(14.3%)	9(8.0%)	* 5(4.4%)	31(27.6%)
Pericardial effusion	2 (1.8%)	0	7(6.3%)	* 5(4.5%)	14(12.5%)
Valvular insufficiency	0	0	2(1.8%)	* 5(4.5%)	7 (6.2%)
Arterial hypertension	2 (1.8%)	5(4.5%)	7(6.3%)	0	14 (12.5%)
Pulmonary hypertension	1 (1.8%)	5(4.5%)	9 (8.0%)	2(1.8%)	17 (15.1%)
No abnormal cardiovascular findings	8 (57.1%)	9 (21.4%)	5 (13.1%)	5(27.7%)	27 (24.1%)

Open in a new tab

* Patients may have combined electrocardiographic and echocardiographic abnormalities or electrocardiographic abnormalities on more than one evaluation. CDRCT: Cardiac dysfunction related to cancer therapy

Table 3. Description of echocardiography values by type of leukemia and time of evaluation.

High-risk acute lymphoblastic leukemia
	At diagnosis (n= 38)	At the end of induction (n = 38)	At the end of consolidation (n = 30)	At the end of reinduction (n = 17)
LVEF (T) median (range)	66.0 (48- 77)	65.5 (37- 73)	70.5 (65- 76)	64.5 (50- 75)
LVEF (S) median (range)	63.5 (46- 70)	54.0 (42- 73)	62.5 (60- 65)	64.7 (53- 67)
FS median (range)	36.0 (23- 46)	35.0 (17- 41)	39.0 (34- 44)	34.5 (25- 43)
TAPSE median (range)	23 (14- 31)	19 (12- 25)	20 (18- 22)	21 (13- 25)
GLS median (range)	-22.0 (-30-18)	-16.6 (-22-15)	-22.5 (-23-22)	-24.2 (-26.3, -18.2)
Intermediate-risk acute lymphoblastic leukemia
	n= 42	n = 41	n = 40	n = 36
LVEF (T) median (range)	68.5 (54- 78)	68.5 (48- 79)	66.0 (56- 74)	64.5 (46- 74)
LVEF (S) median (range)	62.9 (53.8- 74.0)	62.1 (54- 71)	63.0 (54.8- 76.0)	62.1 (48- 75)
FS median (range)	37.0 (27- 46)	37.3 (24- 46)	36.0 (29- 43)	34.1 (22- 42)
TAPSE median (range)	22.0 (14- 33)	20.0 (13.5- 26.0)	22.0 (15- 32)	21.5 (14- 27)
GLS median (range)	-24.4 (-30-18)	-22.5 (-27.5, -17.2)	-23.3 (-31.0-19.6)	-22.7 (-28.0-17.4)
Standard-risk acute lymphoblastic leukemia
	n= 14	n= 14	n= 14	n= 14
LVEF (T) median (range)	65.5 (40- 74)	70.0 (57- 77)	65.0 (58- 72)	63.0 (60- 72)
LVEF (S) median (range)	60.2 (38- 65)	58.6 (55- 63.3)	60.0 (54.7- 67.7)	59.0 (55.7- 67.2)
FS median (range)	34.5 (19- 43)	38.5 (29- 44)	35.0 (30- 40)	33.0 (31- 40)
TAPSE median (range)	19.5 (16- 23)	19.0 (16- 25)	20.0 (16- 27)	18.0 (12- 23)
GLS median (range)	-23.4 (-26.6, -16.8)	-21.3 (-25.9, -16.3)	-24.1 (-26.7, -20.0)	-23.2 (-31, -19)
Acute Myeloid Leukemia
	n = 18	At the end of 7+3 (1st cycle), n = 18	At the end of 7+3 (2nd cycle), n = 18	At the end of treatment, n = 16
LVEF (T) median (range)	68.0 (64- 77)	68.0 (54- 76)	64.0 (38- 70)	63.0 (43- 73)
LVEF (S) median (range)	62.2 (55.5- 74.3)	63.0 (52.2- 69.8)	58.8 (32- 71)	59.9 (41.0- 64.4)
FS median (range)	37.0 (34- 48)	38.0 (27- 42)	33.0 (18- 38)	34.0 (21- 42)
TAPSE median (range)	22.0 (13- 32)	21.0 (13- 31)	22.0 (14- 31)	21.0 (12- 30)
GLS median (range)	-21 (-30-15)	-21.2 (-26.8, -17.4)	-21.5 (-27.0, -15.8)	-22.6 (-26.1, -16.1)

Open in a new tab

LVEF(T): left ventricular ejection fraction Teicholz method, LVEF (S): left ventricular ejection fraction Simpson method, FS: fraction shortening, TAPSE: tricuspid annular, plane systolic excursion, GLS: global longitudinal strain.

The most common ECG abnormalities were impulse generation disturbances and repolarization disorders (Appendix 2). There were no events of thromboembolism, peripheral vascular disease, coronary disease, or stroke.

It can be seen in Figure 2 how the LVEF evaluated with the Simpson method decreases from the start of treatment as the accumulated doses of anthracyclines are given. It is significant with values of accumulate anthracycline dose over 150 mg/m² (Figure 2).

In patients with high-risk leukemia, the factors related to cardiotoxicity were the presence of systemic arterial hypertension at any time of treatment with an OR: 8.57 (IC 95%: 1.35-54.35) p: 0.022, pulmonary hypertension with an OR: 4.11 (IC 95%: 1.12-15.05) p: 0.038, the global longitudinal myocardial deformation delta (global longitudinal myocardial deformation difference greater than 15%) with an OR: 19.5 (CI 95%: 4.57-83.09) p <0.000 and the decrease in LVEF (S) by more than ten percentage points with respect to the baseline evaluation by echocardiogram, with an OR: 56 (CI 95%: 6.31- 496) p< 0.000.

When performing the Wilcoxon test analysis for paired samples, a statistically significant difference was observed for LVEF (S) p: 0.018 and global longitudinal myocardial deformation p: 0.004 between the baseline echocardiogram evaluation and the evaluation after receiving 150 mg / m² of doxorubicin.

Serum biomarker analysis

No relationship was observed between the presence of cardiac involvement and alteration in TnI or TnT (Appendix 3).

Acute lymphoid leukemia standard risk: no patient presented elevation in serum biomarkers throughout all evaluations.

Acute lymphoid leukemia intermediate risk: 69% of patients with acute lymphoid leukemia intermediate-risk had no abnormality in serum biomarkers. There was an elevation of brain natriuretic peptide in 12 patients (29.3%), 11 after intensification, and one patient in the end-of-treatment evaluation.

In two patients with altered biomarkers, an associated repolarization disorder was found, without echocardiographic manifestations. Elevation of TnT was found in one patient; in the last evaluation, this patient presented LVEF <53% asymptomatic.

Acute lymphoid leukemia high risk: There was no alteration in TnT or TnI. In 8 patients (24.2%), brain natriuretic peptide elevation> 100 pg/mL was found during the study. One patient with elevated brain natriuretic peptide at the end of induction had a severe infection associated with it. At the time of the third evaluation (at the end of the second high-risk block 2), three patients presented elevation of brain natriuretic peptide secondary to cardiomyopathy in the clinical context of infection; in 2 patients, an elevation not related to infection was found. At the last evaluation, two patients had elevated brain natriuretic peptide, none related to infection or sepsis.

Acute myeloid leukemia: No patient presented alterations in troponin T or troponin I. Regarding brain natriuretic peptide, one patient presented elevation at diagnosis with recovery to normal values during follow-up, two presented elevation in the third evaluation (after the second 7+3 cycle), and three at the end of the treatment, one of them persisted with the abnormal value from the previous measurement.

Discussion

Cardiovascular compromise is the most frequent adverse effect, with a deterioration in the quality and life expectancy of children cured of acute leukemias ¹⁸^,¹⁹. The prospective methodology of this study allowed the real-time evaluation of the identification of early-onset cardiovascular compromise. Few prospective studies evaluate this complication; a critical aspect for identifying and reporting early toxicity is the difference in times used by the different authors ¹⁹^,²⁰.

Early-onset toxicity was found in 13.5% of patients with acute lymphoid leukemia high-risk ²¹, very similar to that found by Lipschultz et al. ¹⁹, who found 10% within the first year of exposure to anthracyclines. In this study, acute lymphoid leukemia high-risk patients presented cardiotoxicity with 150 mg/m² anthracycline cumulative doses at a median of 99 days. This lower frequency is similar to that reported by Militaru et al.’s prospective study, which found an LVEF drop below 50% in 28.5% of children with acute lymphoid leukemia at three months of treatment ²². It is not clear why the difference in the incidence of this condition with a similar evaluation period. There is an association between the accumulated dose of anthracycline and cardiomyopathy. A greater probability is reported with an accumulated dose> 250 mg/m², however, there is evidence of toxicity at doses starting at 45 mg/m^{2 (}²³^,²⁴. During this cohort’s follow-up, no patient presented toxicity with doses lower than 50 mg/m². Therefore, echocardiographic surveillance of patients with higher doses of anthracyclines must be carried out throughout treatment.

In the follow-up of childhood cancer survivors exposed to anthracyclines, estimating myocardial deformation and its changes over time exposed to chemotherapy can predict the appearance of cardiac dysfunction related to cancer therapy ¹⁴^,²⁵^,²⁶. Despite the heterogeneity in the data regarding the age of the patient, the type of cancer, and the evaluation techniques used, a meta-analysis found that changes in myocardial deformation precede changes in LVEF in exposed patients to anthracyclines, even at doses lower than those historically thought to be cardiotoxic ²⁷. Oikonomou et al. ²⁸ defined an abnormal absolute value of the global longitudinal myocardial deformation between -18 and -19% (with General Electric platforms), a cut-off point associated with cardiac dysfunction related to cancer therapy with an OR: 12.27 (CI 95%: 7.73-19.47); this is similar to what was found in the cohort of our study. The evidence of alterations in global longitudinal myocardial deformation is strong in favor of predicting the subsequent decrease in LVEF at diagnostic values of cardiac dysfunction related to cancer therapy (less than 53%), and that is why international guidelines have adopted the concept of subclinical left ventricular dysfunction in those patients with an LVEF greater than 53% but with a decrease in myocardial deformation (global longitudinal myocardial deformation delta) greater than 15% with respect to the baseline evaluation ^(8.14). Our study found that patients with acute lymphoid leukemia high-risk with global longitudinal myocardial deformation delta more than 15% had cardiac dysfunction related to cancer therapy.

The fall in LVEF (S) by more than ten percentage points, but less than 53%, constituted the leading risk factor for cardiac dysfunction related to cancer therapy in the population analyzed in this study. The vast majority of consensuses consider that a reduction in LVEF between 10% and 20% in asymptomatic patients is not a sufficiently sensitive parameter to define cardiac dysfunction ²⁷^-²⁹. Early identification of echocardiographic abnormalities described (defined as predictors of cardiac dysfunction related to cancer therapy) potentially makes it possible to identify patients with a higher risk of developing heart failure over time. The use of medications such as angiotensin-converting enzyme (ACE) inhibitors, beta-blockers ³⁰^,³¹, and the use of cardioprotection ³² could be considered.

In this study, the measurement of the left ventricular ejection fraction by the Teicholz method was compared with the biplane Simpson method, finding that the Teicholz method overestimated baseline LVEF compared to the biplane Simpson method, this is explained by its geometric assumptions and its regional rather than global character in the assessment of LVEF ¹⁷^,³⁰. Most consensuses recommend using the biplane Simpson method in 2D echocardiography since it has a better correlation with the current method of choice for estimating LVEF: 3D echocardiography. ¹⁷. Unfortunately, the use of the Simpson biplane method in pediatric oncology centers in the country is scarce.

No relationship was found between echocardiogram and ECG findings in patients with cardiac dysfunction, similar to that described by Pourier et al. ³³, who found no association between these two diagnostic tests in childhood cancer survivors in a 5-year follow-up. Few studies on children define electrocardiographic alterations related to early-onset cardiac dysfunction. Most publications describe the late effects associated with the use of anthracyclines ³⁴. Arrhythmias are more frequent in adults undergoing antineoplastic drugs with pre-existing cardiovascular diseases than in children who have transient rhythm disturbances ³⁵.

In this study, no relationship was found with female gender and age at diagnosis less than four years old, referenced in the literature as risk factors for cardiac toxicity associated with the use of antineoplastic drugs. ³⁶^-³⁸.

A higher incidence of cardiac toxicity was recorded in the group of patients with acute lymphoid leukemia for whom systemic arterial hypertension or pulmonary hypertension was documented in the follow-up and in the group of acute myeloid leukemia in whom pulmonary hypertension was found than in patients without these findings. This difference was statistically significant, unlike those reported in the literature on the low association of HTN and PHT with cardiac toxicity in the pediatric population ⁶.

In this study, no significant difference was documented between alterations in the cardiac biomarkers evaluated and the appearance of cardiac dysfunction related to cancer therapy or as predictors of it. This contrasts with the findings of the systematic review of the literature by Dolci et al. ³⁹, who found that troponin T’s elevation could predict the appearance of left ventricular dysfunction up to three months before the appearance of clinical manifestations of cardiomyopathy.

No association was found between the elevation of brain natriuretic peptide and the cumulative dose of anthracyclines or cardiotoxicity in acute lymphoid leukemia patients. Armenian et al. ⁴⁰ suggest using brain natriuretic peptide and troponins in symptomatic patients and not as predictors of toxicity.

One limitation of this study is that not all the patients completed the follow-up due to the disease’s circumstances; the variability between the echocardiography equipment and software means that the results found are applied to the patients evaluated with the technology methodology described.

Conclusions

Comprehensive cardiovascular evaluation and monitoring of patients with acute leukemias are essential, taking into account the high incidence of alterations in this system that in the short and long term can affect the quality of life and survival of these patients. In this study, the main risk predictors for cardiac dysfunction related to cancer therapy were a fall in LVEF of 10 percentage points (to values higher than 53%), alteration of global longitudinal myocardial deformation (absolute value and delta of global longitudinal myocardial deformation), and the presence of pulmonary and arterial hypertension. The timely identification of predictors of cardiac dysfunction in the pediatric population undergoing cancer therapy makes it possible to prevent complications and sequelae.

Appendix.

Appendix 1. Risk classification of patients with acute lymphoid leukemia.

Characteristics	Standard risk	Intermediate risk	High risk
Age at diagnosis	>1 year and <6 years	>1 year and <6 years	Any age
Leukocytes at diagnosis	<20,000/(L	>20,000/(L	Any leukocyte count
Response to steroids at day 15	Blasts <1,000/(L	Blasts <1,000/(L	Blasts >1,000 /(L
Minimal residual bone marrow disease at day 15	<0.1%	<10%	>10%
Bone marrow at day 15	M1 or M2	M1 or M2	M3
Bone marrow at day 33	M1	M1	M2 or M3
Molecular biology	Negative for t (9:22) (BCR/ABL) or t(4:11) (MLL/AF4)	Negative for t (9:22) (BCR/ABL) or t(4:11) (MLL/AF4)	Positive for t (9:22) (BCR/ABL) or t(4:11) (MLL/AF4) or hypodiploidy <45 chromosomes

Open in a new tab

Source: table of own elaboration. M1 = <5% blasts by morphology, M2 => 5% and <25% blasts by morphology, M3 => 25% blasts by morphology.

Appendix 2. Electrocardiographic alterations found in patients with early-onset condition, by type of leukemia and stage of evaluation.

	At diagnosis (n= 38)	At the end of induction (n = 37) DAA 100 mg / m^2.	End of intensification (n = 27) DAA 150 mg / m^2.	At the end of reinduction (n = 17) DAA270 mg / m^2.
High risk acute lymphoblastic leukemia
Electrocardiographic Alterations
Pulse generation	2	1	1	0
Intraventricular conduction	0	2	2	0
Repolarization disorders	2	0	0	3
Arrhythmias	0	S1, Q3, T3 AV block ^ grade 1	0	0
	At diagnosis (n= 42)	At the end of induction (n = 41) DAA 100 mg / m²	At end of early intensification (n = 40)	At the end of reinduction (n = 36) DAA: 120 mg/m²
Intermediate risk acute lymphoblastic leukemia
Electrocardiographic Alterations
Pulse generation	2	2	1		0
Intraventricular conduction	2	0	3		4
Repolarization disorders	1	0	3	3
Arrhythmias	0	2 arrhythmias: low atrial rhythm	1 block AV grade 1 1 without data	1 right branch block 1 TSV * 1 repolarization disorder
	At diagnosis (n= 14)	At the end of induction (n = 14) DAA 120 mg / m²	At the end of intensification (n = 13)	At the end of reinduction (n = 13) DAA120 mg / m²
Standard risk acute lymphoblastic leukemia
Electrocardiographic Alterations
Pulse generation	1	0	0	0
Intraventricular conduction	0	0	0	0
Repolarization disorders	0	1	0	0
Arrhythmias	0	1 without data	1 without data	0
	At diagnosis (n= 18)	At the end 7x3 (1) DAA 149 mg / m^2.	At the end of cycle 7x3 (2) DAA 149 mg / m^2.	At the end of treatment DAA 298 mg / m^2.
Acute myeloid leukemia
Electrocardiographic Alterations
Pulse generation	0	1	2	0
Repolarization disorders	1	2	0	3
Arrhythmias	0	1 patient with right bundle branch block	1 patient with low atrial rhythm	1 patient with low atrial rhythm

Open in a new tab

Source: table of own creation. ÂV: atrioventricular, SVT *: supraventricular tachycardia. DAA: cumulative dose of anthracyclines.

Appendix 3. Table of results of troponin by type of leukemia and stage of evaluation.

	At diagnosis	At the end of induction	End of intensification	At the end of reinduction
High risk acute lymphoblastic leukemia
	n= 38	n= 37	n= 27	n= 17
Troponin T
>40	38	37	26, 1 patient 47	17
Troponin I
>0.05	38	37	27	17
Intermediate risk acute lymphoblastic leukemia
	n= 42	n= 41	n= 40	n= 36
Troponin T
>40	42	41	40	35 1 value of 200
Troponin I
>0.05	42	41	40	36
Standard risk acute lymphoblastic leukemia
	n= 14	n= 14	n= 13	n= 13
Troponin T
>40	14	14	13	13
Troponin I
>0.05	14	14	13	13

Acute myeloid leukemia
	At diagnosis	At the end 7x3 (1)	At the end 7x3 (2)	At the end of treatment
Troponin T
>40	18	18	17	17
			1 patient 116
Troponin I
>0.05	18	18	17	17

Open in a new tab

Funding Statement

Universidad Nacional de Colombia-Bogotá Research Division, Hermes project # 37523, and the Research Office of HOMI Fundación Hospital de La Misericordia, Bogotá-Colombia

Notes:

Funding: This study was supported by Universidad Nacional de Colombia-Bogotá Research Division, Hermes project # 37523, and the Research Office of HOMI Fundación Hospital de La Misericordia, Bogotá-Colombia.

References

1.1. Steliarova-Foucher E, Colombet M, Ries LAG, Moreno F, Dolya A, Bray F, et al. International incidence of childhood cancer, 2001-10: a population-based registry study. Lancet Oncol. 2017;18(6):719-31.Doi: 10.1016/S1470-2045(17)30186-9. [DOI] [PMC free article] [PubMed]; Steliarova-Foucher E, Colombet M, Ries LAG, Moreno F, Dolya A, Bray F. International incidence of childhood cancer, 2001-10 a population-based registry study. Lancet Oncol. 2017;18(6):719–731. doi: 10.1016/S1470-2045(17)30186-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
2.2. Lancellotti P, Nkomo VT, Badano LP, Bergler-Klein J, Bergler J, Bogaert J, et al. Expert consensus for multi-modality imaging evaluation of cardiovascular complications of radiotherapy in adults: a report from the European Association of Cardiovascular Imaging and the American Society of Echocardiography. J Am Soc Echocardiogr. 2013;26(9):1013-32. Doi: 10.1016/j.echo.2013.07.005 [DOI] [PubMed]; Lancellotti P, Nkomo VT, Badano LP, Bergler-Klein J, Bergler J, Bogaert J. Expert consensus for multi-modality imaging evaluation of cardiovascular complications of radiotherapy in adults a report from the European Association of Cardiovascular Imaging and the American Society of Echocardiography. J Am Soc Echocardiogr. 2013;26(9):1013–1032. doi: 10.1016/j.echo.2013.07.005. [DOI] [PubMed] [Google Scholar]
3.3. Pignatelli RH, Ghazi P, Reddy SC-B, Thompson P, Cui Q, Castro J, et al. Abnormal myocardial strain indices in children receiving anthracycline chemotherapy. Pediatr Cardiol. 2015;36(8):1610-6. Doi: 10.1007/s00246-015-1203-8 [DOI] [PubMed]; Pignatelli RH, Ghazi P, Reddy SC-B, Thompson P, Cui Q, Castro J. Abnormal myocardial strain indices in children receiving anthracycline chemotherapy. Pediatr Cardiol. 2015;36(8):1610–1616. doi: 10.1007/s00246-015-1203-8. [DOI] [PubMed] [Google Scholar]
4.4. Kim H, Kang HJ, Park KD, Koh K-N, Im HJ, Seo JJ, et al. Risk factor analysis for secondary malignancy in dexrazoxane-treated pediatric cancer patients. Cancer Res Treat Off J Korean Cancer Assoc. 2019;51(1):357-67. Doi: 10.4143/crt.2017.457 [DOI] [PMC free article] [PubMed]; Kim H, Kang HJ, Park KD, Koh K-N, Im HJ, Seo JJ. Risk factor analysis for secondary malignancy in dexrazoxane-treated pediatric cancer patients. Cancer Res Treat Off J Korean Cancer Assoc. 2019;51(1):357–367. doi: 10.4143/crt.2017.457. [DOI] [PMC free article] [PubMed] [Google Scholar]
5.5. Tukenova M, Guibout C, Oberlin O, Doyon F, Mousannif A, Haddy N, et al. Role of cancer treatment in long-term overall and cardiovascular mortality after childhood cancer. J Clin Oncol. 2010;28(8):1308-15. Doi: 10.1200/JCO.2008.20.2267 [DOI] [PubMed]; Tukenova M, Guibout C, Oberlin O, Doyon F, Mousannif A, Haddy N. Role of cancer treatment in long-term overall and cardiovascular mortality after childhood cancer. J Clin Oncol. 2010;28(8):1308–1315. doi: 10.1200/JCO.2008.20.2267. [DOI] [PubMed] [Google Scholar]
6.6. Chow EJ, Chen Y, Kremer LC, Breslow NE, Hudson MM, Armstrong GT, et al. Individual prediction of heart failure among childhood cancer survivors. J Clin Oncol. 2015;33(5):394-402. Doi: 10.1200/JCO.2014.56.1373 [DOI] [PMC free article] [PubMed]; Chow EJ, Chen Y, Kremer LC, Breslow NE, Hudson MM, Armstrong GT. Individual prediction of heart failure among childhood cancer survivors. J Clin Oncol. 2015;33(5):394–402. doi: 10.1200/JCO.2014.56.1373. [DOI] [PMC free article] [PubMed] [Google Scholar]
7.7. Harake D, Franco VI, Henkel JM, Miller TL, Lipshultz SE. Cardiotoxicity in childhood cancer survivors: strategies for prevention and management. Future Cardiol. 2012;8(4):647-70. Doi: 10.2217/fca.12.44 [DOI] [PMC free article] [PubMed]; Harake D, Franco VI, Henkel JM, Miller TL, Lipshultz SE. Cardiotoxicity in childhood cancer survivors strategies for prevention and management. Future Cardiol. 2012;8(4):647–670. doi: 10.2217/fca.12.44. [DOI] [PMC free article] [PubMed] [Google Scholar]
8.8. Zamorano JL, Lancellotti P, Rodriguez Muñoz D, Aboyans V, Asteggiano R, Galderisi M, et al. 2016 ESC Position Paper on cancer treatments and cardiovascular toxicity developed under the auspices of the ESC Committee for Practice Guidelines: The Task Force for cancer treatments and cardiovascular toxicity of the European Society of Cardiology (ESC). Eur Heart J. 2016;37(36):2768-801. Doi: 10.1093/eurheartj/ehw211 [DOI] [PubMed]; Zamorano JL, Lancellotti P, Rodriguez Muñoz D, Aboyans V, Asteggiano R, Galderisi M. 2016 ESC Position Paper on cancer treatments and cardiovascular toxicity developed under the auspices of the ESC Committee for Practice Guidelines The Task Force for cancer treatments and cardiovascular toxicity of the European Society of Cardiology (ESC) Eur Heart J. 2016;37(36):2768–2801. doi: 10.1093/eurheartj/ehw211. [DOI] [PubMed] [Google Scholar]
9.9. Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE, Colvin MM, et al. 2017 ACC/AHA/HFSA focused update of the 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America. Circulation. 2017;136(6):e137-61. Doi: 10.1161/CIR.0000000000000509 [DOI] [PubMed]; Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE, Colvin MM. 2017 ACC/AHA/HFSA focused update of the 2013 ACCF/AHA guideline for the management of heart failure a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America. Circulation. 2017;136(6):e137–e161. doi: 10.1161/CIR.0000000000000509. [DOI] [PubMed] [Google Scholar]
10.10. Sieswerda E, Postma A, van Dalen EC, van der Pal HJH, Tissing WJE, Rammeloo LAJ, et al. Late effects of childhood cancer task force of the Dutch Childhood Oncology Group (DCOG LATER). The Dutch Childhood Oncology Group guideline for follow-up of asymptomatic cardiac dysfunction in childhood cancer survivors. Ann Oncol. 2012; 23(8): 2191-2198. Doi: 10.1093/annonc/mdr595 [DOI] [PubMed]; Sieswerda E, Postma A, van Dalen EC. van der Pal HJH.Tissing WJE.Rammeloo LAJ Late effects of childhood cancer task force of the Dutch Childhood Oncology Group (DCOG LATER) The Dutch Childhood Oncology Group guideline for follow-up of asymptomatic cardiac dysfunction in childhood cancer survivors. Ann Oncol. 2012;23(8):2191–2198. doi: 10.1093/annonc/mdr595. [DOI] [PubMed] [Google Scholar]
11.11. Trujillo ÁM, Linares A, Sarmiento IC, Trujillo ÁM, Linares A, Sarmiento IC. Intensive chemotherapy in children with acute lymphoblastic leukemia. Interim analysis in a referral center in Colombia. Rev Fac Med. 2016;64(3):417-25. Doi: 10.15446/revfacmed.v64n3.53961; Trujillo ÁM, Linares A, Sarmiento IC, Trujillo ÁM, Linares A, Sarmiento IC. Intensive chemotherapy in children with acute lymphoblastic leukemia Interim analysis in a referral center in Colombia. Rev Fac Med. 2016;64(3):417–425. doi: 10.15446/revfacmed.v64n3.53961. [DOI] [Google Scholar]
12.12. Stary J, Zimmermann M, Campbell M, Castillo L, Dibar E, Donska S, et al. Intensive chemotherapy for childhood acute lymphoblastic leukemia: results of the randomized intercontinental trial ALL IC-BFM 2002. J Clin Oncol. 2014;32(3):174-84. [DOI] [PubMed]; Stary J, Zimmermann M, Campbell M, Castillo L, Dibar E, Donska S. Intensive chemotherapy for childhood acute lymphoblastic leukemia results of the randomized intercontinental trial ALL IC-BFM 2002. J Clin Oncol. 2014;32(3):174–184. doi: 10.1200/JCO.2013.48.6522. [DOI] [PubMed] [Google Scholar]
13.13. Perez IE, Alam CT, Hernandez GA and Sanchassani R. Cancer therapy-related cardiac dysfunction: an overview for the clinician. Clin Med Insights Cardiol. 2019; 13: 1-11. Doi: 10.1177/1179546819866445 [DOI] [PMC free article] [PubMed]; Perez IE, Alam CT. Hernandez GA and Sanchassani R Cancer therapy-related cardiac dysfunction an overview for the clinician. Clin Med Insights Cardiol. 2019;13:1–11. doi: 10.1177/1179546819866445. [DOI] [PMC free article] [PubMed] [Google Scholar]
14.14. Plana JC, Galderisi M, Barac A, Ewer MS, Ky B, Scherrer-Crosbie M, et al. Expert consensus for multimodality imaging evaluation of adult patients during and after cancer therapy: a report from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. J Am Soc Echocardiogr. 2014;27(9):911-39 Doi: 10.1016/j.echo.2014.07.012 [DOI] [PubMed]; Plana JC, Galderisi M, Barac A, Ewer MS, Ky B, Scherrer-Crosbie M. Expert consensus for multimodality imaging evaluation of adult patients during and after cancer therapy a report from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. J Am Soc Echocardiogr. 2014;27(9):911–939. doi: 10.1016/j.echo.2014.07.012. [DOI] [PubMed] [Google Scholar]
15.15. Levy PT, Machefsky A, Sanchez AA, Patel MD, Rogal S, Fowler S, et al. Reference ranges of left ventricular strain measures by two-dimensional speckle-tracking echocardiography in children: a systematic review and meta-analysis. J Am Soc Echocardiogr. 2016;29(3):209-225.e6. Doi: 10.1016/j.echo.2015.11.016 [DOI] [PMC free article] [PubMed]; Levy PT, Machefsky A, Sanchez AA, Patel MD, Rogal S, Fowler S. Reference ranges of left ventricular strain measures by two-dimensional speckle-tracking echocardiography in children a systematic review and meta-analysis. J Am Soc Echocardiogr. 2016;29(3):209–225. doi: 10.1016/j.echo.2015.11.016. [DOI] [PMC free article] [PubMed] [Google Scholar]
16.16. Santaló Bel M, Guindo Soldevila J, Ordóñez Llanos J. Marcadores biológicos de necrosis miocárdica. Rev Esp Cardiol. 2003;56(7):703-20. Doi: 10.1016/S0300-8932(03)76942-5 [DOI] [PubMed]; Santaló Bel M, Guindo Soldevila J, Ordóñez Llanos J. Marcadores biológicos de necrosis miocárdica. Rev Esp Cardiol. 2003;56(7):703–720. doi: 10.1016/S0300-8932(03)76942-5. [DOI] [PubMed] [Google Scholar]
17.17. Feijen EAM, Leisenring WM, Stratton KL, Ness KK, van der Pal HJH, van Dalen EC, et al. Derivation of Anthracycline and Anthraquinone equivalence ratios to Doxorubicin for late-onset cardiotoxicity. JAMA Oncol. 2019;5(6):864-71. Doi: 10.1001/jamaoncol.2018.6634 [DOI] [PMC free article] [PubMed]; Feijen EAM, Leisenring WM, Stratton KL, Ness KK. van der Pal HJH.van Dalen EC Derivation of Anthracycline and Anthraquinone equivalence ratios to Doxorubicin for late-onset cardiotoxicity. JAMA Oncol. 2019;5(6):864–871. doi: 10.1001/jamaoncol.2018.6634. [DOI] [PMC free article] [PubMed] [Google Scholar]
18.18. Bansal N, Amdani SM, Hutchins KK, Lipshultz SE. Cardiovascular disease in survivors of childhood cancer. Curr Opin Pediatr. 2018;30(5):628-38. Doi: 10.1097/MOP.0000000000000675 [DOI] [PubMed]; Bansal N, Amdani SM, Hutchins KK, Lipshultz SE. Cardiovascular disease in survivors of childhood cancer. Curr Opin Pediatr. 2018;30(5):628–638. doi: 10.1097/MOP.0000000000000675. [DOI] [PubMed] [Google Scholar]
19.19. Lipshultz SE, Colan SD, Gelber RD, et al. Late cardiac effects of doxorubicin therapy for acute lymphoblastic leukemia i childhood. N Engl J Med. 1991; 324: 808-815. Doi: 10.1056/NEJM199103213241205 [DOI] [PubMed]; Lipshultz SE, Colan SD, Gelber RD. Late cardiac effects of doxorubicin therapy for acute lymphoblastic leukemia i childhood. N Engl J Med. 1991;324:808–815. doi: 10.1056/NEJM199103213241205. [DOI] [PubMed] [Google Scholar]
20.20. Mavinkurve-Groothuis AM, Marcus KA, Pourier M, Loonen J, Feuth T, Hoogerbrugge PM, et al. Myocardial 2D strain echocardiography and cardiac biomarkers in children during and shortly after anthracycline therapy for acute lymphoblastic leukaemia (ALL): a prospective study. Eur Heart J Cardiovasc Imaging. 2013;14(6):562-9. Doi: 10.1093/ehjci/jes217 [DOI] [PubMed]; Mavinkurve-Groothuis AM, Marcus KA, Pourier M, Loonen J, Feuth T, Hoogerbrugge PM. Myocardial 2D strain echocardiography and cardiac biomarkers in children during and shortly after anthracycline therapy for acute lymphoblastic leukaemia (ALL) a prospective study. Eur Heart J Cardiovasc Imaging. 2013;14(6):562–569. doi: 10.1093/ehjci/jes217. [DOI] [PubMed] [Google Scholar]
21.21. Giantris A, Lipshultz S, Abdurrahman L, Hinkle A, Asselin B. Anthracycline-induced cardiotoxicity in children and young adults. Crit Rev Oncol Hematol. 1998;27(1):53-68. Doi: 10.1016/S1040-8428(97)10007-5 [DOI] [PubMed]; Giantris A, Lipshultz S, Abdurrahman L, Hinkle A, Asselin B. Anthracycline-induced cardiotoxicity in children and young adults. Crit Rev Oncol Hematol. 1998;27(1):53–68. doi: 10.1016/S1040-8428(97)10007-5. [DOI] [PubMed] [Google Scholar]
22.22. Militaru A, Zus S, Cimpean AM, Iurciuc S, Matusz P, Iurciuc M, et al. Early diagnosis of cardiotoxicity in patients undergoing chemotherapy for acute lymphoblastic leukemia. Anticancer Res. 2019;39(6):3255-64. Doi: 10.21873/anticanres.13467 [DOI] [PubMed]; Militaru A, Zus S, Cimpean AM, Iurciuc S, Matusz P, Iurciuc M. Early diagnosis of cardiotoxicity in patients undergoing chemotherapy for acute lymphoblastic leukemia. Anticancer Res. 2019;39(6):3255–3264. doi: 10.21873/anticanres.13467. [DOI] [PubMed] [Google Scholar]
23.23. Lipshultz SE, Lipsitz SR, Sallan SE, Dalton VM, Mone SM, Gelber RD, et al. Chronic progressive cardiac dysfunction years after doxorubicin therapy for childhood acute lymphoblastic leukemia. J Clin Oncol Off J Am Soc Clin Oncol. 2005;23(12):2629-36. Doi: 10.1200/JCO.2005.12.121 [DOI] [PubMed]; Lipshultz SE, Lipsitz SR, Sallan SE, Dalton VM, Mone SM, Gelber RD. Chronic progressive cardiac dysfunction years after doxorubicin therapy for childhood acute lymphoblastic leukemia. J Clin Oncol Off J Am Soc Clin Oncol. 2005;23(12):2629–2636. doi: 10.1200/JCO.2005.12.121. [DOI] [PubMed] [Google Scholar]
24.24. Leger K, Slone T, Lemler M, Leonard D, Cochran C, Bowman WP, et al. Subclinical cardiotoxicity in childhood cancer survivors exposed to very low dose anthracycline therapy. Pediatr Blood Cancer. 2015;62(1):123-7. Doi: 10.1002/pbc.25206 [DOI] [PubMed]; Leger K, Slone T, Lemler M, Leonard D, Cochran C, Bowman WP. Subclinical cardiotoxicity in childhood cancer survivors exposed to very low dose anthracycline therapy. Pediatr Blood Cancer. 2015;62(1):123–127. doi: 10.1002/pbc.25206. [DOI] [PubMed] [Google Scholar]
25.25. Mavinkurve-Groothuis AMC, Groot-Loonen J, Marcus KA, Bellersen L, Feuth T, Bökkerink JPM, et al. Myocardial strain and strain rate in monitoring subclinical heart failure in asymptomatic long-term survivors of childhood cancer. Ultrasound Med Biol. 2010;36(11):1783-91. Doi: 10.1016/j.ultrasmedbio.2010.08.001 [DOI] [PubMed]; Mavinkurve-Groothuis AMC, Groot-Loonen J, Marcus KA, Bellersen L, Feuth T, Bökkerink JPM. Myocardial strain and strain rate in monitoring subclinical heart failure in asymptomatic long-term survivors of childhood cancer. Ultrasound Med Biol. 2010;36(11):1783–1791. doi: 10.1016/j.ultrasmedbio.2010.08.001. [DOI] [PubMed] [Google Scholar]
26.26. Motoki H, Koyama J, Nakazawa H, Aizawa K, Kasai H, Izawa A, et al. Torsion analysis in the early detection of anthracycline-mediated cardiomyopathy. Eur Heart J Cardiovasc Imaging. 2012;13(1):95-103. Doi: 10.1093/ejechocard/jer172 [DOI] [PubMed]; Motoki H, Koyama J, Nakazawa H, Aizawa K, Kasai H, Izawa A. Torsion analysis in the early detection of anthracycline-mediated cardiomyopathy. Eur Heart J Cardiovasc Imaging. 2012;13(1):95–103. doi: 10.1093/ejechocard/jer172. [DOI] [PubMed] [Google Scholar]
27.27. Thavendiranathan P, Poulin F, Lim K-D, Plana JC, Woo A, Marwick TH. Use of myocardial strain imaging by echocardiography for the early detection of cardiotoxicity in patients during and after cancer chemotherapy: a systematic review. J Am Coll Cardiol. 2014;63(25 Pt A):2751-68. Doi: 10.1016/j.jacc.2014.01.073 [DOI] [PubMed]; Thavendiranathan P, Poulin F, Lim K-D, Plana JC, Woo A, Marwick TH. Use of myocardial strain imaging by echocardiography for the early detection of cardiotoxicity in patients during and after cancer chemotherapy a systematic review. Pt AJ Am Coll Cardiol. 2014;63(25):2751–2768. doi: 10.1016/j.jacc.2014.01.073. [DOI] [PubMed] [Google Scholar]
28.28. Oikonomou EK, Kokkinidis DG, Kampaktsis PN, Amir EA, Marwick TH, Gupta D, et al. Assessment of prognostic value of left ventricular global longitudinal strain for early prediction of chemotherapy-induced cardiotoxicity: a systematic review and meta-analysis. JAMA Cardiol. 2019;4(10):1007-18. Doi: 10.1001/jamacardio.2019.2952 [DOI] [PMC free article] [PubMed]; Oikonomou EK, Kokkinidis DG, Kampaktsis PN, Amir EA, Marwick TH, Gupta D. Assessment of prognostic value of left ventricular global longitudinal strain for early prediction of chemotherapy-induced cardiotoxicity a systematic review and meta-analysis. JAMA Cardiol. 2019;4(10):1007–1018. doi: 10.1001/jamacardio.2019.2952. [DOI] [PMC free article] [PubMed] [Google Scholar]
29.29. Curigliano G, Lenihan D, Fradley M, Ganatra S, Barac A, Blaes A, et al. Management of cardiac disease in cancer patients throughout oncological treatment: ESMO consensus recommendations. Ann Oncol Off J Eur Soc Med Oncol. 2020;31(2):171-90 Doi: 10.1016/j.annonc.2019.10.023 [DOI] [PMC free article] [PubMed]; Curigliano G, Lenihan D, Fradley M, Ganatra S, Barac A, Blaes A. Management of cardiac disease in cancer patients throughout oncological treatment ESMO consensus recommendations. Ann Oncol Off J Eur Soc Med Oncol. 2020;31(2):171–190. doi: 10.1016/j.annonc.2019.10.023. [DOI] [PMC free article] [PubMed] [Google Scholar]
30.30. Avila MS, Ayub-Ferreira SM, de Barros Wanderley MR, das Dores Cruz F, Gonçalves Brandão SM, Rigaud VOC, et al. Carvedilol for prevention of chemotherapy-related cardiotoxicity: The CECCY Trial. J Am Coll Cardiol. 2018;71(20):2281-90. Doi: 10.1016/j.jacc.2018.02.049 [DOI] [PubMed]; Avila MS, Ayub-Ferreira SM. de Barros Wanderley MR.das Dores Cruz F.Gonçalves Brandão SM.Rigaud VOC Carvedilol for prevention of chemotherapy-related cardiotoxicity The CECCY Trial. J Am Coll Cardiol. 2018;71(20):2281–2290. doi: 10.1016/j.jacc.2018.02.049. [DOI] [PubMed] [Google Scholar]
31.31. Cardinale D, Colombo A, Sandri MT, Lamantia G, Colombo N, Civelli M, et al. Prevention of high-dose chemotherapy-induced cardiotoxicity in high-risk patients by angiotensin-converting enzyme inhibition. Circulation. 2006;114(23):2474-81. Doi: 10.1161/CIRCULATIONAHA.106.635144 [DOI] [PubMed]; Cardinale D, Colombo A, Sandri MT, Lamantia G, Colombo N, Civelli M. Prevention of high-dose chemotherapy-induced cardiotoxicity in high-risk patients by angiotensin-converting enzyme inhibition. Circulation. 2006;114(23):2474–2481. doi: 10.1161/CIRCULATIONAHA.106.635144. [DOI] [PubMed] [Google Scholar]
32.32. Reichardt P, Tabone M-D, Mora J, Morland B, Jones RL. Risk-benefit of dexrazoxane for preventing anthracycline-related cardiotoxicity: re-evaluating the European labeling. Future Oncol Lond Engl. 2018;14(25):2663-76. Doi: 10.2217/fon-2018-0210 [DOI] [PubMed]; Reichardt P, Tabone M-D, Mora J, Morland B, Jones RL. Risk-benefit of dexrazoxane for preventing anthracycline-related cardiotoxicity re-evaluating the European labeling. Future Oncol Lond Engl. 2018;14(25):2663–2676. doi: 10.2217/fon-2018-0210. [DOI] [PubMed] [Google Scholar]
33.33. Pourier MS, Mavinkurve-Groothuis AMC, Loonen J, Bökkerink JPM, Roeleveld N, Beer G, et al. Is screening for abnormal ECG patterns justified in long-term follow-up of childhood cancer survivors treated with anthracyclines?. Pediatr Blood Cancer. 2017;64(3). Doi: 10.1002/pbc.26243 [DOI] [PubMed]; Pourier MS, Mavinkurve-Groothuis AMC, Loonen J, Bökkerink JPM, Roeleveld N, Beer G, et al. Is screening for abnormal ECG patterns justified in long-term follow-up of childhood cancer survivors treated with anthracyclines? Pediatr Blood Cancer. 2017;64(3) doi: 10.1002/pbc.26243. [DOI] [PubMed] [Google Scholar]
34.34. Kocabas A, Kardelen F, Ertug H, Aldemir-Kocabas B, Tosun Ö, Yesilipek A, et al. Assessment of early-onset chronic progressive anthracycline cardiotoxicity in children: different response patterns of right and left ventricles. Pediatr Cardiol. 2014;35(1):82-8. Doi: 10.1007/s00246-013-0745-x [DOI] [PubMed]; Kocabas A, Kardelen F, Ertug H, Aldemir-Kocabas B, Tosun Ö, Yesilipek A. Assessment of early-onset chronic progressive anthracycline cardiotoxicity in children different response patterns of right and left ventricles. Pediatr Cardiol. 2014;35(1):82–88. doi: 10.1007/s00246-013-0745-x. [DOI] [PubMed] [Google Scholar]
35.35. Bansal N, Blanco JG, Sharma UC, Pokharel S, Shisler S, Lipshultz SE. Cardiovascular diseases in survivors of childhood cancer. Cancer Metastasis Rev. 2020;39(1):55-68. Doi: 10.1007/s10555-020-09859-w [DOI] [PMC free article] [PubMed]; Bansal N, Blanco JG, Sharma UC, Pokharel S, Shisler S, Lipshultz SE. Cardiovascular diseases in survivors of childhood cancer. Cancer Metastasis Rev. 2020;39(1):55–68. doi: 10.1007/s10555-020-09859-w. [DOI] [PMC free article] [PubMed] [Google Scholar]
36.36. Lipshultz SE, Lipsitz SR, Mone SM, Goorin AM, Sallan SE, Sanders SP, et al. Female sex and higher drug dose as risk factors for late cardiotoxic effects of doxorubicin therapy for childhood cancer. N Engl J Med. 1995; 332(26):1738-43. Doi: 10.1056/NEJM199506293322602 [DOI] [PubMed]; Lipshultz SE, Lipsitz SR, Mone SM, Goorin AM, Sallan SE, Sanders SP. Female sex and higher drug dose as risk factors for late cardiotoxic effects of doxorubicin therapy for childhood cancer. N Engl J Med. 1995;332(26):1738–1743. doi: 10.1056/NEJM199506293322602. [DOI] [PubMed] [Google Scholar]
37.37. Bansal N, Amdani S, Lipshultz ER, Lipshultz SE. Chemotherapy-induced cardiotoxicity in children. Expert Opin Drug Metab Toxicol. 2017;13(8):817-32. Doi: 10.1080/17425255.2017.1351547 [DOI] [PubMed]; Bansal N, Amdani S, Lipshultz ER, Lipshultz SE. Chemotherapy-induced cardiotoxicity in children. Expert Opin Drug Metab Toxicol. 2017;13(8):817–832. doi: 10.1080/17425255.2017.1351547. [DOI] [PubMed] [Google Scholar]
38.38. Hildebrandt MAT, Reyes M, Wu X, Pu X, Thompson KA, Ma J, et al. Hypertension Susceptibility Loci are Associated with Anthracycline-related Cardiotoxicity in Long-term Childhood Cancer Survivors. Sci Rep. 2017;7(1):9698. Doi: 10.1038/s41598-017-09517-2 [DOI] [PMC free article] [PubMed]; Hildebrandt MAT, Reyes M, Wu X, Pu X, Thompson KA, Ma J. Hypertension Susceptibility Loci are Associated with Anthracycline-related Cardiotoxicity in Long-term Childhood Cancer Survivors. Sci Rep. 2017;7(1):9698–9698. doi: 10.1038/s41598-017-09517-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
39.39. Dolci A, Dominici R, Cardinale D, Sandri MT, Panteghini M. Biochemical markers for predicting chemotherapy-induced cardiotoxicity: systematic review of the literature and recommendations for use. G Ital Cardiol. 2006. 2006;7(9):604-11. [PubMed]; Dolci A, Dominici R, Cardinale D, Sandri MT, Panteghini M. Biochemical markers for predicting chemotherapy-induced cardiotoxicity systematic review of the literature and recommendations for use. G Ital Cardiol. 2006. 2006;7(9):604–611. [PubMed] [Google Scholar]
40.40. Armenian SH, Hudson MM, Mulder RL, Chen MH, Constine LS, Dwyer M, et al. Recommendations for cardiomyopathy surveillance for survivors of childhood cancer: a report from the International Late Effects of Childhood Cancer Guideline Harmonization Group. Lancet Oncol. 2015; 16(3): e123-136. Doi: 10.1016/S1470-2045(14)70409-7 [DOI] [PMC free article] [PubMed]; Armenian SH, Hudson MM, Mulder RL, Chen MH, Constine LS, Dwyer M. Recommendations for cardiomyopathy surveillance for survivors of childhood cancer a report from the International Late Effects of Childhood Cancer Guideline Harmonization Group. Lancet Oncol. 2015;16(3):e123–e136. doi: 10.1016/S1470-2045(14)70409-7. [DOI] [PMC free article] [PubMed] [Google Scholar]

Colomb Med (Cali). 2021 Feb 15;52(1):e2034542. [Article in Spanish]

Evaluación de la cardiotoxicidad temprana asociada al tratamiento con antraciclinas en niños con Leucemia. Estudio prospectivo

Resumen

Antecedentes:

Las leucemias son la principal causa de cáncer infantil. Los avances en el tratamiento han llevado a los pacientes a una supervivencia global hasta del 80%. Cerca del 10% de los niños con cáncer tienen toxicidad cardiovascular sintomática, la dosis acumulada de antraciclinas es un factor de riesgo para afección cardíaca.

Objetivo:

Describir la frecuencia de afectación cardíaca temprana en niños con leucemias agudas que recibieron tratamiento antineoplásico.

Métodos:

Estudio prospectivo observacional, de pacientes <18 años con diagnóstico confirmado de leucemia aguda. Fueron evaluados con electrocardiograma, ecocardiograma bidimensional y biomarcadores séricos en diferentes momentos durante el tratamiento.

Resultados:

Se evaluaron 94 pacientes con leucemia linfoide aguda y 18 con leucemia mieloide aguda. 20 pacientes (17.9%) tuvieron disfunción cardiaca de inicio temprano. Se observaron diferencias estadísticamente significativas, después de recibir 150 mg/m² de antraciclinas, entre la evaluación del ecocardiograma basal y evaluaciones posteriores de la fracción de eyección ventricular izquierda por Teicholz p 0.05, fracción de eyección ventricular izquierda por Simpson p 0.018 y la deformación longitudinal global p 0.004. No se encontraron alteraciones en los niveles séricos de las troponinas y péptido natriurético cerebral.

Conclusiones:

La disfunción cardíaca relacionada con quimioterapia estuvo directamente relacionada con las dosis acumuladas de antraciclinas. En este estudio el uso del ecocardiograma como método de seguimiento permitió identificar factores predictores de riesgo para disfunción cardiaca temprana.

Palabras clave: niño, quimioterapia, toxicidad, biomarcadores, leucemia, ecocardiografía, antraciclinas, disfunción ventricular

Contribución del estudio

1) ¿Por qué se realizó este estudio?

Hay pocos estudios prospectivos sobre la frecuencia de toxicidad cardiaca temprana en niños que reciben quimioterapia y sobre los posibles predictores de esta toxicidad en niños que reciben tratamiento para leucemia aguda.

2) ¿Cuáles fueron los resultados más relevantes del estudio?

Motivar la identificación del compromiso cardiovascular como efecto adverso de la quimioterapia en los niños durante el tratamiento de cáncer y promover medidas para mitigarla como el uso de estrategias de protección cardiaca. Es necesario seguir a largo plazo a los supervivientes de leucemias para identificar los efectos cardiovasculares crónicos tardíos.

3¿Qué aportan estos resultados?

Open in a new tab

Introducción

Las neoplasias hematolinfoides son la principal causa de cáncer infantil en el mundo ¹. Los avances en la terapéutica del cáncer pediátrico han llevado a los pacientes a mayor sobrevida global, pero también a un aumento en los efectos adversos derivados de su terapia ². El porcentaje de niños con cáncer con toxicidad cardiovascular sintomática oscila entre 7-10% ³. El daño celular producido por los antineoplásicos en el músculo cardíaco es bien conocido ⁴, se estima que los supervivientes de cáncer infantil tienen ocho veces más de riesgo de presentar enfermedades cardiovasculares a lo largo de la vida ⁵. Altas dosis acumuladas de antraciclinas y la exposición a radioterapia torácica, son los principales factores de riesgo de falla cardíaca, aunque también se han descrito otros desencadenantes como dosis altas de alquilantes, el género femenino, edad inferior a 4 años, tener síndrome de Down y la raza afrodescendiente ⁶. La toxicidad cardíaca derivada de la terapia contra el cáncer se puede clasificar según el tiempo de aparición en aguda, sí ocurre en la primera semana después de la exposición al agente neoplásico; de inicio temprano, la que se presenta entre una semana y hasta un año después de finalizado el tratamiento antineoplásico y de inicio tardío, aquella que se presenta después de un año de haber terminado el tratamiento ⁷^,⁸. A pesar de la existencia de guías para la detección y monitorización de enfermedades cardiovasculares en la población adulta ⁹, para los pacientes con cáncer infantil existen pocos consensos basados en la evidencia o revisiones que den recomendaciones para el diagnóstico y seguimiento de las complicaciones cardiovasculares ¹⁰. La ecocardiografía es la principal técnica diagnóstica, para evaluar el desempeño sistólico del ventrículo izquierdo a través de la estimación de su fracción de eyección (FEVI). Otras herramientas utilizadas en la evaluación cardiovascular son los biomarcadores séricos como troponina T, troponina I, péptido natriurético cerebral y el electrocardiograma ⁷.

En un estudio de supervivencia de una cohorte de niños con leucemia linfoblástica aguda en un centro de referencia de cáncer infantil de Bogotá, se encontró una frecuencia de toxicidad cardíaca grado 3-4 del 26.9% ¹¹. En Colombia existen muy pocos datos acerca de la frecuencia de complicaciones cardiovasculares derivadas de la terapia antineoplásica en niños.

El objetivo principal de este estudio es describir la frecuencia de afectación cardíaca temprana en los niños con leucemias agudas que recibieron tratamiento antineoplásico en un centro de referencia de cáncer infantil. Como objetivos secundarios se busca describir los hallazgos ecocardiográficos y electrocardiográficos y describir el comportamiento de los biomarcadores séricos en el grupo de estudio.

Materiales y Métodos

Estudio prospectivo descriptivo, anidado en una cohorte de pacientes con diagnóstico confirmado de leucemias agudas: leucemia linfoide aguda y leucemia mieloide aguda, mayores de 1 año y menores de 18 años, en el período entre 1 de octubre del 2017 hasta el 31 de marzo del 2019. La selección de los participantes se realizó por muestreo no probabilístico secuencial por conveniencia de pacientes con diagnóstico nuevo de leucemia linfoblástica aguda y leucemia mieloide aguda.

Criterios de inclusión

pacientes mayores de 12 meses y menores de 18 años con diagnóstico nuevo de leucemia linfoblástica aguda y leucemia mieloide aguda realizado en HOMI Fundación Hospital de la Misericordia.

Criterios de exclusión

Pacientes que no iniciaron el tratamiento en HOMI Fundación Hospital Pediátrico de la Misericordia.

Pacientes con diagnóstico de recaída de leucemia linfoblástica aguda o de leucemia mieloide aguda. Paciente con diagnóstico de cardiopatía previo al inicio del tratamiento oncológico. Pacientes quienes no completaran al menos dos evaluaciones. Pacientes cuyos padres no autorizaron su inclusión en el estudio.

Definiciones

Los pacientes, con leucemia linfoblástica aguda fueron clasificados de acuerdo al riesgo en estándar, intermedio y alto. La clasificación de riesgo de leucemia linfoide aguda está basada en el protocolo ALLIC del grupo BFM (Anexo 1) ¹².

Disfunción cardiaca relacionada con la terapia para el cáncer: es el descenso de la FEVI por debajo del 53%, mediante la estimación del método de Simpson biplano ¹³^,¹⁴.

Deformación longitudinal global (strain): teniendo en cuenta el fabricante del equipo de ecocardiografía utilizado y la literatura disponible se consideró como un valor absoluto normal para todos los grupos de edad una deformación mayor a -20.1% ¹³^,¹⁴.

Una disminución del porcentaje de deformación mayor al 15% con respecto al valor basal en el seguimiento se consideró significativa (delta del deformación longitudinal global) ¹⁵.

Otras alteraciones cardiovasculares asociadas: enfermedad coronaria, arritmias, derrame pericárdico, insuficiencias valvulares (diferentes a insuficiencia tricuspídea o mitral leves y consideradas como fisiológicas), enfermedad trombo-embólica, hipertensión arterial sistémica (definida como una presión arterial sistólica o diastólica mayor al percentil 95 para la edad, el género y la talla) e hipertensión pulmonar ⁸ (definida como una estimación ecocardiográfica de una presión sistólica pulmonar mayor o igual a 40 mmHg a partir de la velocidad de regurgitación tricuspide y estimación de presión a nivel de la aurícula derecha en relación al porcentaje de colapso de la vena cava inferior) .

Toxicidad aguda: manifestaciones cardiovasculares que aparecen en la primera semana del tratamiento antineoplásico ⁷^,⁸.

Toxicidad de inicio temprano: aparición de las manifestaciones cardiovasculares después de la primera semana y hasta el primer año de terminado el tratamiento ⁷^,⁸.

Alteraciones de los biomarcadores séricos: elevación significativa del BNP por encima de 100 pg/mL, de la TnI con valor superior a 0.05 en ng/L y en la TnT valor por encima de 40 ng/L ¹⁶.

Alteraciones en el electrocardiograma: identificar alteraciones en la generación del impulso, en la conducción AV (aurículo-ventricular), en la conducción IV (interventricular) y los trastornos de repolarización ⁸.

Evaluación de ecocardiografía: la toma y el análisis de los estudios ecocardiográficos fue realizada por dos cardiólogos pediatras con más de 5 años de experiencia en evaluación de pacientes con cáncer infantil realizando adquisiciones sincronizadas con electrocardiograma (5 latidos) para las imágenes en movimiento. Los tres métodos utilizados para evaluar el desempeño sistólico del ventrículo izquierdo fueron la fracción de eyección (FEVI) estimada por el método de Simpson biplano (FEVI(S)), la FEVI estimada por el método de Teicholz (FEVI(T)) y la fracción de acortamiento. Se realizó un análisis de la deformación longitudinal global mediante la técnica de seguimiento de partículas (Speckle tracking).

Para la cuantificación de la fracción de eyección mediante el método de Simpson biplano y el análisis de la deformación longitudinal global se obtuvieron los fotogramas desde la ventana apical en ejes de 4 cámaras, 2 cámaras y tres cámaras. El análisis de las adquisiciones fue realizado con el software del equipo de ecocardiografía Phillips Affinity 70C software versión 1.7.1. Para todos los casos los operadores localizaron en las tres vistas definidas, los puntos basales y el punto apical a analizar permitiendo el reconocimiento automático del endocardio en primera instancia y corrigiendo manualmente la localización del mismo en caso de ser necesario mediante la función de edición.

Para la cuantificación de las fracciones de eyección por el método de Teicholz y fracción de acortamiento se utilizó una imagen estática adquirida desde el eje corto de los ventrículos.

A todos los pacientes se les realizaron evaluaciones de electrocardiograma de 12 derivaciones y ecocardiograma realizado con técnica bidimensional (2D) con equipo Phillips Affinity 70C, transductores 5-1 y 8-3 MHz.

Se realizaron evaluaciones con biomarcadores séricos medidos en sangre venosa periférica o central procesados por inmuno-cromatografía de prueba rápida. Los biomarcadores séricos evaluados fueron péptido natriurético cerebral (BNP), troponina I (TnI) y troponina T (TnT). Los valores de referencia corresponden a la técnica utilizada.

Todas las evaluaciones previamente mencionadas (ecocardiograma, electrocardiograma y biomarcadores) se realizaron previo al inicio de tratamiento y en determinados momentos del tratamiento de leucemia linfoblástica aguda y leucemia mieloide aguda (Figura 1). Para los pacientes con leucemia linfoblástica aguda de alto riesgo el fin de tratamiento se consideraba como la última evaluación al final de la reinducción o la última evaluación antes de ir a trasplante de progenitores hematopoyéticos (TPH); y para los pacientes con leucemia mieloide aguda el fin de tratamiento se consideraba como la última evaluación antes de TPH o la evaluación posterior a tres ciclos de consolidación.

Las dosis acumuladas de antraciclinas por patología fueron convertidas a dosis equivalentes de doxorrubicina, 1 mg de daunorrubicina equivale a 0.833 mg de doxorrubicina ¹⁷.

Análisis estadístico

los análisis estadísticos de las variables cuantitativas se realizaron con medidas de tendencia central y de dispersión, medias, desviación estándar o medianas y rangos, según la distribución previo análisis con pruebas de normalidad (Kolmogorov-Smirnov o Shapiro Wilk) para establecer el comportamiento de los datos como paramétricos o no paramétricos; las variables cualitativas se analizaron con la prueba de Chi cuadrado de Pearson y Prueba exacta de Fisher. Los datos de ecocardiografía se analizaron según la dosis acumulada de antraciclinas, en cada grupo de tratamiento se utilizó el test de Wilcoxon para muestras emparejadas no paramétricas. Para el análisis de los marcadores bioquímicos como el BNP, se dividieron los pacientes en dos grupos según la presencia o ausencia de cardiotoxicidad y se analizaron con la prueba de U de Mann-Whitney para muestras independientes no paramétricas. El análisis estadístico fue realizado utilizando el paquete estadístico para ciencias sociales (SPSS) para Windows, versión 25.0. Un valor de p <0.05 fue considerado como significativo.

Aspectos éticos

Este estudio fue catalogado como un proyecto de riesgo mínimo. Se obtuvo consentimiento informado de los padres y asentimiento de cada uno de los pacientes o del responsable legal del paciente si ese fuese el caso. Este protocolo de investigación fue aprobado por el comité de ética institucional, acta 4848 CEI-11-17.

Resultados

Ingresaron 113 pacientes: 94 con leucemia linfoide aguda y 19 con leucemia mieloide aguda. Un paciente con leucemia mieloide aguda fue excluido del estudio porque no tuvo datos de la segunda evaluacion, los resultados corresponden a 112 pacientes. Se analizaron 38 pacientes (33.9%) con leucemia linfoblástica aguda de riesgo alto, 42 (37.5%) de riesgo intermedio, 14 (12.5%) riesgo estándar y 18 pacientes con leucemia mieloide aguda (16.0%). 13 pacientes murieron durante el seguimiento, se tomaron los datos hasta la evaluación previa a la muerte. En la Tabla 1 se describen características demográficas de la población a estudio.

Tabla 1. Características demográficas de la población a estudio.

Variables	LLA RE	LLA RI	LLA RA	LMA	TOTAL
Número de pacientes (%)	14 (12.5%)	42 (27.5%)	38 (33.9%)	18 (16%)	112 (100%)
Edad en años Mediana (rango)	3.4 (1-6)	6.6 (1.7-17.2)	9.4 (1.5-17.7)	9.0 (1.5-17.0)	6.35 (1.0- 17.7)
Mujeres	8 (57.1%)	17 (40.5%)	13 (34.3%)	7 (38.9%)	45 (40.2%)
Peso en kilos Mediana (rango)	12.8 (10.9-25.0)	20 (10.4-74.0)	19 (10-73)	31.5 (10-69)	20 (10-74)
Talla en cm Mediana (rango)	97 (86-118)	118.5 (75-180)	122.5 (83-181)	129 (70-167)	114 (70-181)
Dosis acumulada de antraciclina mg/m²	170	220	270	298	NA

Open in a new tab

LLA: leucemia linfoblástica aguda, RE: riesgo estándar, RI: riesgo intermedio, RA: riesgo alto.

Se presentó una disfunción cardiaca relacionada con la terapia para el cáncer de inicio temprano en 20 pacientes (17.9%), ningún paciente tuvo afección cardiaca aguda.

En los pacientes con leucemia linfoblástica aguda de alto riesgo se presentó toxicidad de inicio temprano con una mediana de 30 días en 4 pacientes, y con 120 mg/m² acumulados de antraciclinas. Para la tercera evaluación, (final de la intensificación) 8 pacientes tenían cardiotoxicidad temprana, con dosis acumuladas de 150 mg/m² de antraciclinas. En la última evaluación (final de la reinducción), un acumulado de 11 pacientes tuvieron afección cardíaca con dosis acumuladas de antraciclinas de 270 mg/m².

Se encontró una disfunción cardiaca relacionada con la terapia para el cáncer en dos pacientes de riesgo intermedio con dosis acumuladas de 220 mg/m² de doxorrubicina, al final de la reinducción. En el grupo de riesgo estándar ningún paciente tuvo disfunción cardiaca relacionada con la terapia para el cáncer.

En los niños con leucemia mieloide aguda, 7 pacientes tuvieron cardiotoxicidad temprana, 1 de ellos después de 180 mg/m² acumulados de antraciclinas y 4 pacientes después de 298 mg/m² de antraciclinas. Para el final del tratamiento 2 pacientes adicionales tuvieron afección cardíaca temprana. El descenso de la FEVI(S) durante el seguimiento, mayor a 10 puntos porcentuales con respecto a la FEVI (S) anterior fue un predictor para cardiotoxicidad en los pacientes con leucemia mieloide aguda con un OR de 42.42 (IC 95%: 4.6-391.0).

Se presentaron hallazgos anormales en el ecocardiograma en 65 pacientes (Tablas 2 y 3).

Tabla 2. Alteraciones cardiovasculares de inicio temprano de acuerdo al tipo de leucemia.

Descripción de la afección cardíaca	leucemia linfoblástica aguda			leucemia mieloide aguda	Total
	Riesgo estándar n: 14	Riesgo intermedio n: 42	Riesgo Alto n: 38	n: 18	n: 112
DCRTC (FEVI <53%)	0 (0%)	2(1.8%)	11(9.8%)	7(6.3%)	20(17.9%)
Alteraciones en el ECG	1(0.9%)	16(14.3%)	9(8.0%)	*5(4.4%)	31(27.6%)
Derrame pericárdico	2 (1.8%)	0	7(6.3%)	*5(4.5%)	14(12.5%)
Insuficiencia valvular	0	0	2(1.8%)	*5(4.5%)	7 (6.2%)
Hipertensión arterial	2 (1.8%)	5(4.5%)	7(6.3%)	0	14 (12.5%)
Hipertensión pulmonar	1 (1.8%)	5(4.5%)	9 (8.0%)	2(1.8%)	17 (15.1%)
Sin hallazgos cardiovasculares anormales	8 (57.1%)	9 (21.4%)	5 (13.1%)	5(27.7%)	27 (24.1%)

Open in a new tab

* Pueden tener alteraciones electrocardiográficas y ecocardiográficas combinadas o pueden tener alteraciones electrocardiográficas en más de una evaluación. DCRTC: Disfunción cardiaca relacionada con la terapia para el cáncer. ECG: electrocardiograma

Tabla 3. Descripción de los valores de ecocardiografía por tipo de leucemia y momento de evaluación.

	Leucemia linfoblástica aguda de riesgo alto
	Al diagnóstico (n=38)	Al final de la inducción (n=38)	Al final consolidación (n=30)	Al final de reinducción (n=17)
FEVI (T) mediana (rango)	66.0 (48-77)	65.5 (37-73)	70.5 (65-76)	64.5 (50-75)
FEVI (S) mediana (rango)	63.5 (46-70)	54.0 (42-73)	62.5 (60-65)	64.7 (53-67)
FA mediana (rango)	36.0 (23-46)	35.0 (17-41)	39.0 (34-44)	34.5 (25-43)
TAPSE mediana (rango)	23 (14-31)	19 (12-25)	20 (18-22)	21 (13-25)
GLS mediana (rango)	-22.0 (-30 -18)	-16.6 (-22 -15)	-22.5 (-23 -22)	-24.2 (-26.3,-18.2)
Leucemia linfoblástica aguda de riesgo intermedio
	Al diagnóstico (n=42)	Al final de la inducción (n=41)	Al final consolidación (n=40)	Al final de reinducción (n=36)
FEVI (T) mediana (rango)	68.5 (54-78)	68.5 (48-79)	66.0 (56-74)	64.5 (46-74)
FEVI (S) mediana (rango)	62.9 (53.8-74.0)	62.1 (54-71)	63.0 (54.8-76.0)	62.1 (48-75)
FA mediana (rango)	37.0 (27-46)	37.3 (24-46)	36.0 (29-43)	34.1 (22-42)
TAPSE mediana (rango)	22.0 (14-33)	20.0 (13.5-26.0)	22.0 (15-32)	21.5 (14-27)
GLS mediana (rango)	-24.4 (-30 -18)	-22.5 (-27.5,-17.2)	-23.3 (-31.0 -19.6)	-22.7 (-28.0 ,-17.4)
Leucemia linfoblástica aguda de riesgo estándar
	Al diagnóstico (n=14)	Al final de la inducción (n=14)	Al final consolidación (n=14)	Al final de reinducción (n= 14)
FEVI (T) mediana (rango)	65.5 (40-74)	70.0 (57-77)	65.0 (58-72)	63.0 (60-72)
FEVI (S) mediana (rango)	60.2 (38-65)	58.6 (55-63,3)	60.0 (54.7-67.7)	59.0 (55.7-67.2)
FA mediana (rango)	34.5 (19-43)	38.5 (29-44)	35.0 (30-40)	33.0 (31-40)
TAPSE mediana (rango)	19.5 (16-23)	19.0 (16-25)	20.0 (16-27)	18.0 (12-23)
GLS mediana (rango)	-23.4 (-26.6,-16.8)	-21.3 (-25.9,-16.3)	-24.1 (-26.7,-20.0)	-23.2 (-31,-19)
Leucemia mieloide aguda
	Al diagnóstico n= 18	Al finalizar 7+3 (1^er ciclo) n=18	Al finalizar 7+3 (2º ciclo) n=18	Al fin de tratamiento n=16
FEVI (T) mediana (rango)	68.0 (64-77)	68.0 (54-76)	64.0 (38-70)	63.0 (43-73)
FEVI (S) mediana (rango)	62.2 (55,5-74,3)	63.0 (52.2-69.8)	58.8 (32-71)	59.9 (41.0-64.4)
FA mediana (rango)	37.0 (34-48)	38.0 (27-42)	33.0 (18-38)	34.0 (21-42)
TAPSE mediana (rango)	22.0 (13-32)	21.0 (13-31)	22.0 (14-31)	21.0 (12-30)
GLS mediana (rango)	-21 (-30 -15)	-21.2 (-26.8, -17.4 )	-21.5 (-27.0,-15.8)	-22.6 (-26.1,-16.1)

Open in a new tab

Fuente: tabla de creación propia. FEVI (T): fracción de eyección ventricular izquierda por método Teicholz, FEVI (S): fracción de eyección ventricular izquierda por método Simpson, FA: fracción de acortamiento, TAPSE: desplazamiento sistólico del plano del anillo tricuspídeo, GLS: deformidad longitudinal global.

Las alteraciones más frecuentes del electrocardiograma fueron alteración de la generación de impulso y los trastornos de repolarización (Anexo 2). No se presentaron eventos de tromboembolismo, enfermedad vascular periférica, enfermedad coronaria ni ataque cerebrovascular.

Puede observarse en la Figura 2 cómo la FEVI evaluada con método Simpson, disminuye desde el inicio de tratamiento a medida que se van dando las dosis de acumuladas de antraciclinas. Es significativo con valores >150 mg/m² acumulado de antraciclinas (Figura 2).

En los pacientes con leucemia de alto riesgo, los factores relacionados con cardiotoxicidad fueron la presencia de hipertensión arterial sistémica en cualquier momento del tratamiento con un OR: 8.57 (IC 95%: 1.35-54.35) p: 0,022, hipertensión pulmonar con un OR: 4.11 (IC 95%: 1.12-15.05) p: 0.038, el delta de la deformación longitudinal global (diferencia de la deformación longitudinal global mayor del 15%) con un OR: 19.5 (IC 95%: 4.57-83.09) p <0.000 y la disminución de la FEVI(S) en más de 10 puntos porcentuales respecto a la evaluación basal por ecocardiograma, con un OR: 56 (IC 95%: 6.31-496) p < 0.000.

Al realizar el análisis por test de Wilcoxon para muestras emparejadas, se observó una diferencia estadísticamente significativa para la FEVI (S) p: 0.018 y para la deformación longitudinal global p: 0.004 entre la evaluación del ecocardiograma basal y la evaluación después de recibir 150 mg/m² de doxorrubicina.

Análisis de biomarcadores séricos

No se observó relación entre la presencia de compromiso cardiaco y alteración en la TnI ni en la TnT (Anexo 3).

Para la leucemia linfoblástica aguda:

Riesgo estándar: ningún paciente presentó elevación en biomarcadores séricos a lo largo de todas las evaluaciones.

Riesgo intermedio: el 69% de los pacientes con leucemia linfoblástica aguda de riesgo intermedio no tuvieron anormalidad en los biomarcadores séricos. En 12 pacientes (29.3%) se presentó elevación del BNP, 11 posterior a la intensificación y 1 paciente en la evaluación de fin de tratamiento.

En dos pacientes con alteración de los biomarcadores se encontró trastorno de la repolarización asociada, sin manifestaciones ecocardiográficas. En un paciente se encontró elevación en la TnT, en la última evaluación, esta paciente presentó FEVI <53% asintomática.

Riesgo alto: No hubo alteración en TnT o TnI. En 8 pacientes (24.2%) se encontró elevación del BNP >100 pg/mL durante el estudio. Un paciente con elevación de BNP al final de la inducción tenía asociada una infección severa. En el momento de la tercera evaluación (al final del segundo bloque de alto riesgo 2), 3 pacientes presentaron elevación de BNP secundario a miocardiopatía en el contexto clínico de infección, en 2 pacientes se encontró elevación no relacionada a infección. En la última evaluación 2 pacientes tuvieron elevación del BNP, ninguno relacionado con infección o sepsis.

Leucemia mieloide aguda: ningún paciente presentó alteración en la troponina T ni en la Troponina I. En cuanto el BNP, 1 paciente presentó elevación al diagnóstico con recuperación a valores normales durante el seguimiento, 2 presentaron elevación en la tercera evaluación (después del segundo ciclo 7+3) y 3 al finalizar el tratamiento, 1 de ellos persistió con el valor anormal desde la medición anterior.

Discusión

El compromiso cardiovascular es el efecto adverso más frecuente, con deterioro de la calidad y expectativa de vida de los niños que se curan de leucemias agudas ¹⁸^,¹⁹. La metodología prospectiva de este estudio permitió la evaluación en tiempo real de la identificación del compromiso cardiovascular de aparición temprana, existen pocos estudios prospectivos que evalúen esta complicación, un aspecto importante para identificar e informar la toxicidad temprana es la diferencia de tiempos utilizados por los diferentes autores ¹⁹^,²⁰.

En 13.5% de los pacientes con leucemia linfoblástica aguda de alto riesgo se encontró toxicidad de inicio temprano²¹, muy similar a lo hallado por Lipschultz et al. ¹⁹, quienes encontraron 10% dentro del primer año de exposición a antraciclinas. En este estudio los pacientes con leucemia linfoblástica aguda de alto riesgo tuvieron cardiotoxicidad con dosis acumuladas de 150 mg/m² de antraciclinas, a una mediana de 99 días, una frecuencia menor a un plazo similar a la informada por Militaru et al. ²², en un estudio prospectivo encontraron caída de la FEVI por debajo de 50% en 28.5% de los niños con leucemia linfoblástica aguda a los tres meses de tratamiento. No es claro porque la diferencia en incidencia de esta afección con un período de evaluación similar. Hay asociación entre la dosis acumulada de antraciclina y cardiomiopatía, se informa mayor probabilidad con dosis acumulada >250 mg/m², sin embargo, hay evidencia de toxicidad con dosis desde 45 mg/m^{2 (}²³^,²⁴, durante el seguimiento de esta cohorte ningún paciente presentó toxicidad con dosis menores de 50 mg/m², por ello la vigilancia ecocardiográfica de los pacientes con mayores dosis de antraciclinas debe ser realizada de forma a lo largo del tratamiento.

En el seguimiento de los supervivientes de cáncer infantil expuestos a antraciclinas, la estimación de la deformación miocárdica y sus cambios a lo largo del tiempo expuestos a quimioterapia, pueden predecir la aparición de disfunción cardiaca relacionada con la terapia para el cáncer ¹⁴^,²⁵^,²⁶. A pesar de la heterogeneidad en los datos con respecto a la edad del paciente, el tipo de cáncer y las técnicas de evaluación utilizadas, un meta-análisis, encontró como los cambios en la deformación miocárdica preceden a los cambios en la FEVI en pacientes expuestos a antraciclinas, incluso con dosis inferiores a las que históricamente se pensaba que eran cardiotóxicas ²⁷. Oikonomou et al. ²⁸, definieron un valor absoluto anormal de la deformación longitudinal global entre -18 y -19% (con plataformas General Electric), punto de corte asociado a Disfunción cardiaca relacionada con la terapia para el cáncer con un OR: 12.27 (IC 95%: 7.73-19.47), esto es similar a lo encontrado en la cohorte de nuestro estudio. La evidencia de las alteraciones en la deformación longitudinal global es fuerte a favor de predecir la disminución posterior de la FEVI a valores diagnósticos de disfunción cardiaca relacionada con la terapia para el cáncer (menor de 53%) y es por esto que guías internacionales han adoptado el concepto de disfunción subclínica del ventrículo izquierdo en aquellos pacientes con una FEVI mayor al 53% pero con un descenso de la deformación longitudinal global (delta del deformación longitudinal global) mayor al 15% con respecto a la evaluación basal ⁸^,¹⁴, en nuestro trabajo se encontró que en pacientes con leucemia linfoblástica aguda de riesgo alto con delta de la deformación longitudinal global > 15% tuvieron disfunción cardiaca relacionada con la terapia para el cáncer.

La caída de la FEVI(S) en más de 10 puntos porcentuales, sin que fuera menor de 53%, constituyó el principal factor de riesgo para la disfunción cardiaca relacionada con la terapia para el cáncer en la población aquí analizada, la gran mayoría de los consensos consideran que una reducción de la FEVI entre el 10% al 20% en pacientes asintomáticos, no es un parámetro lo suficientemente sensible para definir disfunción cardiaca ²⁷^-²⁹. La identificación temprana de las anormalidades ecocardiográficas descritas (definidas en forma de predictores de disfunción cardiaca relacionada con la terapia para el cáncer), permiten en forma potencial identificar pacientes con mayor riesgo de desarrollar en el tiempo insuficiencia cardiaca. Se podría plantear el uso de medicamentos como los inhibidores de enzima convertidora de angiotensina (IECA), betabloqueadores ³⁰^,³¹ y el uso de cardioprotección ³² en aquellos pacientes con éstos hallazgos ecocardiográficos. En este estudio se comparó la medición la fracción de eyección del ventrículo izquierdo por el método de Teicholz contra el método de Simpson biplano, hallándose que el método de Teicholz sobrestimó la FEVI basal comparado con el método de Simpson biplano, esto se explica por sus asunciones geométricas y su carácter regional y no global en la evaluación de la FEVI ¹⁷^,³⁰. La mayoría de los consensos recomiendan en ecocardiografía 2D la utilización del método de Simpson biplano, ya que tiene una mejor correlación con el método de elección para la estimación de la FEVI en la actualidad, que es la ecocardiografía 3D ¹⁷. Desafortunadamente la utilización del método de Simpson biplano en los centros de oncología pediátrica del país es poca.

No se encontró relación entre los hallazgos de ecocardiograma y electrocardiograma en los pacientes con disfunción cardíaca, similar a lo descrito por Pourier et al. ³³, quienes no encontraron asociación entre estas dos pruebas diagnósticas en niños supervivientes de cáncer infantil en un seguimiento a 5 años. Son pocos los estudios en niños que definen las alteraciones electrocardiográficas relacionadas a disfunción cardiaca de inicio temprano; la mayoría de las publicaciones describen los efectos tardíos asociados al uso de antraciclinas ³⁴. Las arritmias son mas frecuentes en adultos sometidos a antineoplásicos con enfermedades cardiovasculares preexistentes, a diferencia de los niños que tienen alteraciones del ritmo transitorias ³⁵.

En este estudio, no se encontró relación con el género femenino y la edad al diagnóstico menor de 4 años, referenciados en la literatura como factores de riesgo para toxicidad cardíaca asociada al uso de antineoplásicos ³⁶^-³⁸.

En el grupo de los pacientes con leucemia linfoblástica aguda en quienes se documentó hipertensión arterial sistémica o hipertensión pulmonar en el seguimiento y en los del grupo de leucemia linfoblástica aguda en quienes se encontró hipertensión pulmonar, se registró una incidencia mas alta de toxicidad cardíaca comparado con los pacientes sin estos hallazgos, esta diferencia fue estadísticamente significativa, a diferencia de los informado la literatura sobre la baja asociación de HTA e HTP con toxicidad cardíaca en la población pediátrica ⁶.

En este estudio no se documentó una diferencia significativa entre alteraciones de los biomarcadores cardiacos evaluados y la aparición de disfunción cardiaca relacionada con la terapia para el cáncer o como predictores de esta, esto contrasta con los hallazgos de la revisión sistemática de la literatura de Dolci et al. ³⁹, quienes encontraron que la elevación de la troponina T podría predecir la aparición disfunción del ventrículo izquierdo hasta tres meses antes de la aparición de manifestaciones clínicas de cardiomiopatía.

No se encontró asociación entre la elevación del BNP y la dosis acumulada de antraciclinas ni con cardiotoxicidad en pacientes con la leucemia linfoblástica aguda; Armenian et al. ⁴⁰, sugieren el uso del BNP y troponinas en los pacientes sintomáticos y no como predictores de toxicidad.

Una limitante de este estudio es que no todos los pacientes completaron el seguimiento por circunstancias propias de la enfermedad, también la variabilidad entre los equipos y software de ecocardiografía hacen que los resultados encontrados se aplican a los pacientes evaluados con la tecnología y metodología descrita.

Conclusiones

La evaluación y seguimiento cardiovascular integral de los pacientes con leucemias agudas es fundamental, teniendo en cuenta la alta incidencia de alteraciones en este sistema que al corto y largo plazo pueden afectar la calidad de vida y la sobrevida de estos pacientes. En este estudio los principales predictores de riesgo para disfunción cardiaca relacionada con la terapia para el cáncer fueron la caída de la FEVI de 10 puntos porcentuales (a valores no menores de 53%), alteración de la deformación longitudinal global (valor absoluto y delta de la deformación longitudinal global), y la presencia de hipertensión pulmonar y arterial. La identificación oportuna de predictores de disfunción cardiaca en la población pediátrica sometida a terapia contra el cáncer, permite prevenir complicaciones y secuelas.

ANEXOS.

Anexo 1. Clasificación de riesgo de pacientes con leucemia linfoide aguda.

Características	Riesgo estándar	Riesgo intermedio	Riesgo alto
Edad al diagnóstico	>1 año y <6 años	>1 año y <6 años	Cualquier edad
Leucocitos al diagnóstico	<20,000/(L	>20,000/(L	Cualquier recuento de leucocitos
Respuesta a esteroides al día 15	Blastos <1,000 /(L	Blastos <1,000 /(L	Blastos >1,000 /(L
Enfermedad mínima residual en médula ósea al día 15	<0.1%	<10%	>10%
Médula ósea al día 15	M1 o M2	M1 o M2	M3
Médula ósea al día 33	M1	M1	M2 o M3
Biología molecular	Negativo para t(9:22) (BCR/ABL) ó t(4:11) (MLL/AF4)	Negativo para t(9:22) (BCR/ABL) ó t(4:11) (MLL/AF4)	Positivo para t(9:22) (BCR/ABL) ó t(4:11) (MLL/AF4) ó hipodiploidía < 45 cromosomas

Open in a new tab

Fuente: tabla de elaboración propia. M1=<5% blastos por morfología, M2 ≥5% y <25% blastos por morfología, M3 ≥25% blastos por morfología.

Anexo 2. Alteraciones electrocardiográficas encontradas en pacientes con afección de inicio temprano, por tipo de leucemia y etapa de evaluación.

	Al diagnóstico	Al final de la inducción DAA 100 mg/m²	Final intensificación DAA 150 mg/m²	Al final de reinducción DAA270 mg/m²
Leucemia linfoblástica aguda riesgo alto
	n= 38	n= 37	n= 27	n= 17
Alteraciones Electrocardiográficas
Generación de impulsos	2	1	1	0
Conducción Intraventricular	0	2	2	0
Trastornos de repolarización	2	0	0	3
Arritmias	0	S1, Q3, T3. bloqueo AV grado 1	0	0
Leucemia linfoblástica aguda riesgo intermedio
	n= 42	n= 41	n= 40	n= 36
Alteraciones Electrocardiográficas
Generación de impulso	2	2	1	0
Conducción Intraventricular	2	0	3	4
Trastornos de repolarización	1	0	3	3
Arritmias	0	2 arritmias: ritmo auricular bajo	1 bloqueo AV grado 1. 1 sin dato	1 bloqueo rama derecha. 1 TSV*. 1 trastorno de repolarización
Leucemia linfoblástica aguda riesgo estándar
	n= 14	n= 14	n= 13	n= 13
Alteraciones Electrocardiográficas
Generación de impulsos	1	0	0	0
Conducción Intraventricular	0	0	0	0
Trastornos de repolarización	0	1	0	0
Arritmias	0	1 sin dato	1 sin dato	0
Leucemia mieloide aguda
	n= 18	Al final 7+3 (1) DAA 149 mg/m²	Al final 7+3 (2) DAA 149 mg/m²	Al final de tratamiento DAA 298 mg/m²
Alteraciones Electrocardiográficas
Generación de impulsos	0	1	2	0
Trastornos de repolarización	1	2	0	3
Arritmias	0	1 paciente con bloqueo rama derecha	1 paciente con ritmo auricular bajo	1 paciente con ritmo auricular bajo

Open in a new tab

AV: auriculo ventricular, TSV*: taquicardia supraventricular. DAA: dosis acumuladas de antraciclinas.

Anexo 3. Tabla de resultados de troponinas por tipo de leucemia y etapa de evaluación.

	Al diagnóstico	Al final de la inducción	Al final consolidación	Al final de reinducción
Leucemia linfoblástica aguda riesgo alto
	n= 38	n= 37	n= 27	n= 17
Troponina T
>40	38	37	26, 1 paciente 47	17
Troponina I
>0.05	38	37	27	17
Leucemia linfoblástica aguda riesgo intermedio
	n= 42	n= 41	n= 40	n= 36
Troponina T
>40	42	41	40	35 1 valor de 200
Troponina I
>0.05	42	41	40	36
Leucemia linfoblástica aguda riesgo bajo
	n= 14	n= 14	n= 13	n= 13
Troponina T
>40	14	14	13	13
Troponina I
>0.05	14	14	13	13

Leucemia mieloide aguda
	Al diagnostico	Al final 7x3 (1)	Al final 7x3 (2)	Al final de tto
Troponina T
>40	18	18	17	17
			1 paciente 116
Troponina I
>0.05	18	18	17	17

Open in a new tab

Notas:

Financiación: Este estudio fue financiado con recursos de la Universidad Nacional de Colombia-División de Investigaciones de Bogotá, proyecto Hermes # 37523 y de la Oficina de Investigaciones de la Fundación Hospital de La Misericordia, Bogotá-Colombia.

[B1] 1.1. Steliarova-Foucher E, Colombet M, Ries LAG, Moreno F, Dolya A, Bray F, et al. International incidence of childhood cancer, 2001-10: a population-based registry study. Lancet Oncol. 2017;18(6):719-31.Doi: 10.1016/S1470-2045(17)30186-9. [DOI] [PMC free article] [PubMed]; Steliarova-Foucher E, Colombet M, Ries LAG, Moreno F, Dolya A, Bray F. International incidence of childhood cancer, 2001-10 a population-based registry study. Lancet Oncol. 2017;18(6):719–731. doi: 10.1016/S1470-2045(17)30186-9. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B2] 2.2. Lancellotti P, Nkomo VT, Badano LP, Bergler-Klein J, Bergler J, Bogaert J, et al. Expert consensus for multi-modality imaging evaluation of cardiovascular complications of radiotherapy in adults: a report from the European Association of Cardiovascular Imaging and the American Society of Echocardiography. J Am Soc Echocardiogr. 2013;26(9):1013-32. Doi: 10.1016/j.echo.2013.07.005 [DOI] [PubMed]; Lancellotti P, Nkomo VT, Badano LP, Bergler-Klein J, Bergler J, Bogaert J. Expert consensus for multi-modality imaging evaluation of cardiovascular complications of radiotherapy in adults a report from the European Association of Cardiovascular Imaging and the American Society of Echocardiography. J Am Soc Echocardiogr. 2013;26(9):1013–1032. doi: 10.1016/j.echo.2013.07.005. [DOI] [PubMed] [Google Scholar]

[B3] 3.3. Pignatelli RH, Ghazi P, Reddy SC-B, Thompson P, Cui Q, Castro J, et al. Abnormal myocardial strain indices in children receiving anthracycline chemotherapy. Pediatr Cardiol. 2015;36(8):1610-6. Doi: 10.1007/s00246-015-1203-8 [DOI] [PubMed]; Pignatelli RH, Ghazi P, Reddy SC-B, Thompson P, Cui Q, Castro J. Abnormal myocardial strain indices in children receiving anthracycline chemotherapy. Pediatr Cardiol. 2015;36(8):1610–1616. doi: 10.1007/s00246-015-1203-8. [DOI] [PubMed] [Google Scholar]

[B4] 4.4. Kim H, Kang HJ, Park KD, Koh K-N, Im HJ, Seo JJ, et al. Risk factor analysis for secondary malignancy in dexrazoxane-treated pediatric cancer patients. Cancer Res Treat Off J Korean Cancer Assoc. 2019;51(1):357-67. Doi: 10.4143/crt.2017.457 [DOI] [PMC free article] [PubMed]; Kim H, Kang HJ, Park KD, Koh K-N, Im HJ, Seo JJ. Risk factor analysis for secondary malignancy in dexrazoxane-treated pediatric cancer patients. Cancer Res Treat Off J Korean Cancer Assoc. 2019;51(1):357–367. doi: 10.4143/crt.2017.457. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B5] 5.5. Tukenova M, Guibout C, Oberlin O, Doyon F, Mousannif A, Haddy N, et al. Role of cancer treatment in long-term overall and cardiovascular mortality after childhood cancer. J Clin Oncol. 2010;28(8):1308-15. Doi: 10.1200/JCO.2008.20.2267 [DOI] [PubMed]; Tukenova M, Guibout C, Oberlin O, Doyon F, Mousannif A, Haddy N. Role of cancer treatment in long-term overall and cardiovascular mortality after childhood cancer. J Clin Oncol. 2010;28(8):1308–1315. doi: 10.1200/JCO.2008.20.2267. [DOI] [PubMed] [Google Scholar]

[B6] 6.6. Chow EJ, Chen Y, Kremer LC, Breslow NE, Hudson MM, Armstrong GT, et al. Individual prediction of heart failure among childhood cancer survivors. J Clin Oncol. 2015;33(5):394-402. Doi: 10.1200/JCO.2014.56.1373 [DOI] [PMC free article] [PubMed]; Chow EJ, Chen Y, Kremer LC, Breslow NE, Hudson MM, Armstrong GT. Individual prediction of heart failure among childhood cancer survivors. J Clin Oncol. 2015;33(5):394–402. doi: 10.1200/JCO.2014.56.1373. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B7] 7.7. Harake D, Franco VI, Henkel JM, Miller TL, Lipshultz SE. Cardiotoxicity in childhood cancer survivors: strategies for prevention and management. Future Cardiol. 2012;8(4):647-70. Doi: 10.2217/fca.12.44 [DOI] [PMC free article] [PubMed]; Harake D, Franco VI, Henkel JM, Miller TL, Lipshultz SE. Cardiotoxicity in childhood cancer survivors strategies for prevention and management. Future Cardiol. 2012;8(4):647–670. doi: 10.2217/fca.12.44. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B8] 8.8. Zamorano JL, Lancellotti P, Rodriguez Muñoz D, Aboyans V, Asteggiano R, Galderisi M, et al. 2016 ESC Position Paper on cancer treatments and cardiovascular toxicity developed under the auspices of the ESC Committee for Practice Guidelines: The Task Force for cancer treatments and cardiovascular toxicity of the European Society of Cardiology (ESC). Eur Heart J. 2016;37(36):2768-801. Doi: 10.1093/eurheartj/ehw211 [DOI] [PubMed]; Zamorano JL, Lancellotti P, Rodriguez Muñoz D, Aboyans V, Asteggiano R, Galderisi M. 2016 ESC Position Paper on cancer treatments and cardiovascular toxicity developed under the auspices of the ESC Committee for Practice Guidelines The Task Force for cancer treatments and cardiovascular toxicity of the European Society of Cardiology (ESC) Eur Heart J. 2016;37(36):2768–2801. doi: 10.1093/eurheartj/ehw211. [DOI] [PubMed] [Google Scholar]

[B9] 9.9. Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE, Colvin MM, et al. 2017 ACC/AHA/HFSA focused update of the 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America. Circulation. 2017;136(6):e137-61. Doi: 10.1161/CIR.0000000000000509 [DOI] [PubMed]; Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE, Colvin MM. 2017 ACC/AHA/HFSA focused update of the 2013 ACCF/AHA guideline for the management of heart failure a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America. Circulation. 2017;136(6):e137–e161. doi: 10.1161/CIR.0000000000000509. [DOI] [PubMed] [Google Scholar]

[B10] 10.10. Sieswerda E, Postma A, van Dalen EC, van der Pal HJH, Tissing WJE, Rammeloo LAJ, et al. Late effects of childhood cancer task force of the Dutch Childhood Oncology Group (DCOG LATER). The Dutch Childhood Oncology Group guideline for follow-up of asymptomatic cardiac dysfunction in childhood cancer survivors. Ann Oncol. 2012; 23(8): 2191-2198. Doi: 10.1093/annonc/mdr595 [DOI] [PubMed]; Sieswerda E, Postma A, van Dalen EC. van der Pal HJH.Tissing WJE.Rammeloo LAJ Late effects of childhood cancer task force of the Dutch Childhood Oncology Group (DCOG LATER) The Dutch Childhood Oncology Group guideline for follow-up of asymptomatic cardiac dysfunction in childhood cancer survivors. Ann Oncol. 2012;23(8):2191–2198. doi: 10.1093/annonc/mdr595. [DOI] [PubMed] [Google Scholar]

[B11] 11.11. Trujillo ÁM, Linares A, Sarmiento IC, Trujillo ÁM, Linares A, Sarmiento IC. Intensive chemotherapy in children with acute lymphoblastic leukemia. Interim analysis in a referral center in Colombia. Rev Fac Med. 2016;64(3):417-25. Doi: 10.15446/revfacmed.v64n3.53961; Trujillo ÁM, Linares A, Sarmiento IC, Trujillo ÁM, Linares A, Sarmiento IC. Intensive chemotherapy in children with acute lymphoblastic leukemia Interim analysis in a referral center in Colombia. Rev Fac Med. 2016;64(3):417–425. doi: 10.15446/revfacmed.v64n3.53961. [DOI] [Google Scholar]

[B12] 12.12. Stary J, Zimmermann M, Campbell M, Castillo L, Dibar E, Donska S, et al. Intensive chemotherapy for childhood acute lymphoblastic leukemia: results of the randomized intercontinental trial ALL IC-BFM 2002. J Clin Oncol. 2014;32(3):174-84. [DOI] [PubMed]; Stary J, Zimmermann M, Campbell M, Castillo L, Dibar E, Donska S. Intensive chemotherapy for childhood acute lymphoblastic leukemia results of the randomized intercontinental trial ALL IC-BFM 2002. J Clin Oncol. 2014;32(3):174–184. doi: 10.1200/JCO.2013.48.6522. [DOI] [PubMed] [Google Scholar]

[B13] 13.13. Perez IE, Alam CT, Hernandez GA and Sanchassani R. Cancer therapy-related cardiac dysfunction: an overview for the clinician. Clin Med Insights Cardiol. 2019; 13: 1-11. Doi: 10.1177/1179546819866445 [DOI] [PMC free article] [PubMed]; Perez IE, Alam CT. Hernandez GA and Sanchassani R Cancer therapy-related cardiac dysfunction an overview for the clinician. Clin Med Insights Cardiol. 2019;13:1–11. doi: 10.1177/1179546819866445. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B14] 14.14. Plana JC, Galderisi M, Barac A, Ewer MS, Ky B, Scherrer-Crosbie M, et al. Expert consensus for multimodality imaging evaluation of adult patients during and after cancer therapy: a report from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. J Am Soc Echocardiogr. 2014;27(9):911-39 Doi: 10.1016/j.echo.2014.07.012 [DOI] [PubMed]; Plana JC, Galderisi M, Barac A, Ewer MS, Ky B, Scherrer-Crosbie M. Expert consensus for multimodality imaging evaluation of adult patients during and after cancer therapy a report from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. J Am Soc Echocardiogr. 2014;27(9):911–939. doi: 10.1016/j.echo.2014.07.012. [DOI] [PubMed] [Google Scholar]

[B15] 15.15. Levy PT, Machefsky A, Sanchez AA, Patel MD, Rogal S, Fowler S, et al. Reference ranges of left ventricular strain measures by two-dimensional speckle-tracking echocardiography in children: a systematic review and meta-analysis. J Am Soc Echocardiogr. 2016;29(3):209-225.e6. Doi: 10.1016/j.echo.2015.11.016 [DOI] [PMC free article] [PubMed]; Levy PT, Machefsky A, Sanchez AA, Patel MD, Rogal S, Fowler S. Reference ranges of left ventricular strain measures by two-dimensional speckle-tracking echocardiography in children a systematic review and meta-analysis. J Am Soc Echocardiogr. 2016;29(3):209–225. doi: 10.1016/j.echo.2015.11.016. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B16] 16.16. Santaló Bel M, Guindo Soldevila J, Ordóñez Llanos J. Marcadores biológicos de necrosis miocárdica. Rev Esp Cardiol. 2003;56(7):703-20. Doi: 10.1016/S0300-8932(03)76942-5 [DOI] [PubMed]; Santaló Bel M, Guindo Soldevila J, Ordóñez Llanos J. Marcadores biológicos de necrosis miocárdica. Rev Esp Cardiol. 2003;56(7):703–720. doi: 10.1016/S0300-8932(03)76942-5. [DOI] [PubMed] [Google Scholar]

[B17] 17.17. Feijen EAM, Leisenring WM, Stratton KL, Ness KK, van der Pal HJH, van Dalen EC, et al. Derivation of Anthracycline and Anthraquinone equivalence ratios to Doxorubicin for late-onset cardiotoxicity. JAMA Oncol. 2019;5(6):864-71. Doi: 10.1001/jamaoncol.2018.6634 [DOI] [PMC free article] [PubMed]; Feijen EAM, Leisenring WM, Stratton KL, Ness KK. van der Pal HJH.van Dalen EC Derivation of Anthracycline and Anthraquinone equivalence ratios to Doxorubicin for late-onset cardiotoxicity. JAMA Oncol. 2019;5(6):864–871. doi: 10.1001/jamaoncol.2018.6634. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B18] 18.18. Bansal N, Amdani SM, Hutchins KK, Lipshultz SE. Cardiovascular disease in survivors of childhood cancer. Curr Opin Pediatr. 2018;30(5):628-38. Doi: 10.1097/MOP.0000000000000675 [DOI] [PubMed]; Bansal N, Amdani SM, Hutchins KK, Lipshultz SE. Cardiovascular disease in survivors of childhood cancer. Curr Opin Pediatr. 2018;30(5):628–638. doi: 10.1097/MOP.0000000000000675. [DOI] [PubMed] [Google Scholar]

[B19] 19.19. Lipshultz SE, Colan SD, Gelber RD, et al. Late cardiac effects of doxorubicin therapy for acute lymphoblastic leukemia i childhood. N Engl J Med. 1991; 324: 808-815. Doi: 10.1056/NEJM199103213241205 [DOI] [PubMed]; Lipshultz SE, Colan SD, Gelber RD. Late cardiac effects of doxorubicin therapy for acute lymphoblastic leukemia i childhood. N Engl J Med. 1991;324:808–815. doi: 10.1056/NEJM199103213241205. [DOI] [PubMed] [Google Scholar]

[B20] 20.20. Mavinkurve-Groothuis AM, Marcus KA, Pourier M, Loonen J, Feuth T, Hoogerbrugge PM, et al. Myocardial 2D strain echocardiography and cardiac biomarkers in children during and shortly after anthracycline therapy for acute lymphoblastic leukaemia (ALL): a prospective study. Eur Heart J Cardiovasc Imaging. 2013;14(6):562-9. Doi: 10.1093/ehjci/jes217 [DOI] [PubMed]; Mavinkurve-Groothuis AM, Marcus KA, Pourier M, Loonen J, Feuth T, Hoogerbrugge PM. Myocardial 2D strain echocardiography and cardiac biomarkers in children during and shortly after anthracycline therapy for acute lymphoblastic leukaemia (ALL) a prospective study. Eur Heart J Cardiovasc Imaging. 2013;14(6):562–569. doi: 10.1093/ehjci/jes217. [DOI] [PubMed] [Google Scholar]

[B21] 21.21. Giantris A, Lipshultz S, Abdurrahman L, Hinkle A, Asselin B. Anthracycline-induced cardiotoxicity in children and young adults. Crit Rev Oncol Hematol. 1998;27(1):53-68. Doi: 10.1016/S1040-8428(97)10007-5 [DOI] [PubMed]; Giantris A, Lipshultz S, Abdurrahman L, Hinkle A, Asselin B. Anthracycline-induced cardiotoxicity in children and young adults. Crit Rev Oncol Hematol. 1998;27(1):53–68. doi: 10.1016/S1040-8428(97)10007-5. [DOI] [PubMed] [Google Scholar]

[B22] 22.22. Militaru A, Zus S, Cimpean AM, Iurciuc S, Matusz P, Iurciuc M, et al. Early diagnosis of cardiotoxicity in patients undergoing chemotherapy for acute lymphoblastic leukemia. Anticancer Res. 2019;39(6):3255-64. Doi: 10.21873/anticanres.13467 [DOI] [PubMed]; Militaru A, Zus S, Cimpean AM, Iurciuc S, Matusz P, Iurciuc M. Early diagnosis of cardiotoxicity in patients undergoing chemotherapy for acute lymphoblastic leukemia. Anticancer Res. 2019;39(6):3255–3264. doi: 10.21873/anticanres.13467. [DOI] [PubMed] [Google Scholar]

[B23] 23.23. Lipshultz SE, Lipsitz SR, Sallan SE, Dalton VM, Mone SM, Gelber RD, et al. Chronic progressive cardiac dysfunction years after doxorubicin therapy for childhood acute lymphoblastic leukemia. J Clin Oncol Off J Am Soc Clin Oncol. 2005;23(12):2629-36. Doi: 10.1200/JCO.2005.12.121 [DOI] [PubMed]; Lipshultz SE, Lipsitz SR, Sallan SE, Dalton VM, Mone SM, Gelber RD. Chronic progressive cardiac dysfunction years after doxorubicin therapy for childhood acute lymphoblastic leukemia. J Clin Oncol Off J Am Soc Clin Oncol. 2005;23(12):2629–2636. doi: 10.1200/JCO.2005.12.121. [DOI] [PubMed] [Google Scholar]

[B24] 24.24. Leger K, Slone T, Lemler M, Leonard D, Cochran C, Bowman WP, et al. Subclinical cardiotoxicity in childhood cancer survivors exposed to very low dose anthracycline therapy. Pediatr Blood Cancer. 2015;62(1):123-7. Doi: 10.1002/pbc.25206 [DOI] [PubMed]; Leger K, Slone T, Lemler M, Leonard D, Cochran C, Bowman WP. Subclinical cardiotoxicity in childhood cancer survivors exposed to very low dose anthracycline therapy. Pediatr Blood Cancer. 2015;62(1):123–127. doi: 10.1002/pbc.25206. [DOI] [PubMed] [Google Scholar]

[B25] 25.25. Mavinkurve-Groothuis AMC, Groot-Loonen J, Marcus KA, Bellersen L, Feuth T, Bökkerink JPM, et al. Myocardial strain and strain rate in monitoring subclinical heart failure in asymptomatic long-term survivors of childhood cancer. Ultrasound Med Biol. 2010;36(11):1783-91. Doi: 10.1016/j.ultrasmedbio.2010.08.001 [DOI] [PubMed]; Mavinkurve-Groothuis AMC, Groot-Loonen J, Marcus KA, Bellersen L, Feuth T, Bökkerink JPM. Myocardial strain and strain rate in monitoring subclinical heart failure in asymptomatic long-term survivors of childhood cancer. Ultrasound Med Biol. 2010;36(11):1783–1791. doi: 10.1016/j.ultrasmedbio.2010.08.001. [DOI] [PubMed] [Google Scholar]

[B26] 26.26. Motoki H, Koyama J, Nakazawa H, Aizawa K, Kasai H, Izawa A, et al. Torsion analysis in the early detection of anthracycline-mediated cardiomyopathy. Eur Heart J Cardiovasc Imaging. 2012;13(1):95-103. Doi: 10.1093/ejechocard/jer172 [DOI] [PubMed]; Motoki H, Koyama J, Nakazawa H, Aizawa K, Kasai H, Izawa A. Torsion analysis in the early detection of anthracycline-mediated cardiomyopathy. Eur Heart J Cardiovasc Imaging. 2012;13(1):95–103. doi: 10.1093/ejechocard/jer172. [DOI] [PubMed] [Google Scholar]

[B27] 27.27. Thavendiranathan P, Poulin F, Lim K-D, Plana JC, Woo A, Marwick TH. Use of myocardial strain imaging by echocardiography for the early detection of cardiotoxicity in patients during and after cancer chemotherapy: a systematic review. J Am Coll Cardiol. 2014;63(25 Pt A):2751-68. Doi: 10.1016/j.jacc.2014.01.073 [DOI] [PubMed]; Thavendiranathan P, Poulin F, Lim K-D, Plana JC, Woo A, Marwick TH. Use of myocardial strain imaging by echocardiography for the early detection of cardiotoxicity in patients during and after cancer chemotherapy a systematic review. Pt AJ Am Coll Cardiol. 2014;63(25):2751–2768. doi: 10.1016/j.jacc.2014.01.073. [DOI] [PubMed] [Google Scholar]

[B28] 28.28. Oikonomou EK, Kokkinidis DG, Kampaktsis PN, Amir EA, Marwick TH, Gupta D, et al. Assessment of prognostic value of left ventricular global longitudinal strain for early prediction of chemotherapy-induced cardiotoxicity: a systematic review and meta-analysis. JAMA Cardiol. 2019;4(10):1007-18. Doi: 10.1001/jamacardio.2019.2952 [DOI] [PMC free article] [PubMed]; Oikonomou EK, Kokkinidis DG, Kampaktsis PN, Amir EA, Marwick TH, Gupta D. Assessment of prognostic value of left ventricular global longitudinal strain for early prediction of chemotherapy-induced cardiotoxicity a systematic review and meta-analysis. JAMA Cardiol. 2019;4(10):1007–1018. doi: 10.1001/jamacardio.2019.2952. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B29] 29.29. Curigliano G, Lenihan D, Fradley M, Ganatra S, Barac A, Blaes A, et al. Management of cardiac disease in cancer patients throughout oncological treatment: ESMO consensus recommendations. Ann Oncol Off J Eur Soc Med Oncol. 2020;31(2):171-90 Doi: 10.1016/j.annonc.2019.10.023 [DOI] [PMC free article] [PubMed]; Curigliano G, Lenihan D, Fradley M, Ganatra S, Barac A, Blaes A. Management of cardiac disease in cancer patients throughout oncological treatment ESMO consensus recommendations. Ann Oncol Off J Eur Soc Med Oncol. 2020;31(2):171–190. doi: 10.1016/j.annonc.2019.10.023. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B30] 30.30. Avila MS, Ayub-Ferreira SM, de Barros Wanderley MR, das Dores Cruz F, Gonçalves Brandão SM, Rigaud VOC, et al. Carvedilol for prevention of chemotherapy-related cardiotoxicity: The CECCY Trial. J Am Coll Cardiol. 2018;71(20):2281-90. Doi: 10.1016/j.jacc.2018.02.049 [DOI] [PubMed]; Avila MS, Ayub-Ferreira SM. de Barros Wanderley MR.das Dores Cruz F.Gonçalves Brandão SM.Rigaud VOC Carvedilol for prevention of chemotherapy-related cardiotoxicity The CECCY Trial. J Am Coll Cardiol. 2018;71(20):2281–2290. doi: 10.1016/j.jacc.2018.02.049. [DOI] [PubMed] [Google Scholar]

[B31] 31.31. Cardinale D, Colombo A, Sandri MT, Lamantia G, Colombo N, Civelli M, et al. Prevention of high-dose chemotherapy-induced cardiotoxicity in high-risk patients by angiotensin-converting enzyme inhibition. Circulation. 2006;114(23):2474-81. Doi: 10.1161/CIRCULATIONAHA.106.635144 [DOI] [PubMed]; Cardinale D, Colombo A, Sandri MT, Lamantia G, Colombo N, Civelli M. Prevention of high-dose chemotherapy-induced cardiotoxicity in high-risk patients by angiotensin-converting enzyme inhibition. Circulation. 2006;114(23):2474–2481. doi: 10.1161/CIRCULATIONAHA.106.635144. [DOI] [PubMed] [Google Scholar]

[B32] 32.32. Reichardt P, Tabone M-D, Mora J, Morland B, Jones RL. Risk-benefit of dexrazoxane for preventing anthracycline-related cardiotoxicity: re-evaluating the European labeling. Future Oncol Lond Engl. 2018;14(25):2663-76. Doi: 10.2217/fon-2018-0210 [DOI] [PubMed]; Reichardt P, Tabone M-D, Mora J, Morland B, Jones RL. Risk-benefit of dexrazoxane for preventing anthracycline-related cardiotoxicity re-evaluating the European labeling. Future Oncol Lond Engl. 2018;14(25):2663–2676. doi: 10.2217/fon-2018-0210. [DOI] [PubMed] [Google Scholar]

[B33] 33.33. Pourier MS, Mavinkurve-Groothuis AMC, Loonen J, Bökkerink JPM, Roeleveld N, Beer G, et al. Is screening for abnormal ECG patterns justified in long-term follow-up of childhood cancer survivors treated with anthracyclines?. Pediatr Blood Cancer. 2017;64(3). Doi: 10.1002/pbc.26243 [DOI] [PubMed]; Pourier MS, Mavinkurve-Groothuis AMC, Loonen J, Bökkerink JPM, Roeleveld N, Beer G, et al. Is screening for abnormal ECG patterns justified in long-term follow-up of childhood cancer survivors treated with anthracyclines? Pediatr Blood Cancer. 2017;64(3) doi: 10.1002/pbc.26243. [DOI] [PubMed] [Google Scholar]

[B34] 34.34. Kocabas A, Kardelen F, Ertug H, Aldemir-Kocabas B, Tosun Ö, Yesilipek A, et al. Assessment of early-onset chronic progressive anthracycline cardiotoxicity in children: different response patterns of right and left ventricles. Pediatr Cardiol. 2014;35(1):82-8. Doi: 10.1007/s00246-013-0745-x [DOI] [PubMed]; Kocabas A, Kardelen F, Ertug H, Aldemir-Kocabas B, Tosun Ö, Yesilipek A. Assessment of early-onset chronic progressive anthracycline cardiotoxicity in children different response patterns of right and left ventricles. Pediatr Cardiol. 2014;35(1):82–88. doi: 10.1007/s00246-013-0745-x. [DOI] [PubMed] [Google Scholar]

[B35] 35.35. Bansal N, Blanco JG, Sharma UC, Pokharel S, Shisler S, Lipshultz SE. Cardiovascular diseases in survivors of childhood cancer. Cancer Metastasis Rev. 2020;39(1):55-68. Doi: 10.1007/s10555-020-09859-w [DOI] [PMC free article] [PubMed]; Bansal N, Blanco JG, Sharma UC, Pokharel S, Shisler S, Lipshultz SE. Cardiovascular diseases in survivors of childhood cancer. Cancer Metastasis Rev. 2020;39(1):55–68. doi: 10.1007/s10555-020-09859-w. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B36] 36.36. Lipshultz SE, Lipsitz SR, Mone SM, Goorin AM, Sallan SE, Sanders SP, et al. Female sex and higher drug dose as risk factors for late cardiotoxic effects of doxorubicin therapy for childhood cancer. N Engl J Med. 1995; 332(26):1738-43. Doi: 10.1056/NEJM199506293322602 [DOI] [PubMed]; Lipshultz SE, Lipsitz SR, Mone SM, Goorin AM, Sallan SE, Sanders SP. Female sex and higher drug dose as risk factors for late cardiotoxic effects of doxorubicin therapy for childhood cancer. N Engl J Med. 1995;332(26):1738–1743. doi: 10.1056/NEJM199506293322602. [DOI] [PubMed] [Google Scholar]

[B37] 37.37. Bansal N, Amdani S, Lipshultz ER, Lipshultz SE. Chemotherapy-induced cardiotoxicity in children. Expert Opin Drug Metab Toxicol. 2017;13(8):817-32. Doi: 10.1080/17425255.2017.1351547 [DOI] [PubMed]; Bansal N, Amdani S, Lipshultz ER, Lipshultz SE. Chemotherapy-induced cardiotoxicity in children. Expert Opin Drug Metab Toxicol. 2017;13(8):817–832. doi: 10.1080/17425255.2017.1351547. [DOI] [PubMed] [Google Scholar]

[B38] 38.38. Hildebrandt MAT, Reyes M, Wu X, Pu X, Thompson KA, Ma J, et al. Hypertension Susceptibility Loci are Associated with Anthracycline-related Cardiotoxicity in Long-term Childhood Cancer Survivors. Sci Rep. 2017;7(1):9698. Doi: 10.1038/s41598-017-09517-2 [DOI] [PMC free article] [PubMed]; Hildebrandt MAT, Reyes M, Wu X, Pu X, Thompson KA, Ma J. Hypertension Susceptibility Loci are Associated with Anthracycline-related Cardiotoxicity in Long-term Childhood Cancer Survivors. Sci Rep. 2017;7(1):9698–9698. doi: 10.1038/s41598-017-09517-2. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B39] 39.39. Dolci A, Dominici R, Cardinale D, Sandri MT, Panteghini M. Biochemical markers for predicting chemotherapy-induced cardiotoxicity: systematic review of the literature and recommendations for use. G Ital Cardiol. 2006. 2006;7(9):604-11. [PubMed]; Dolci A, Dominici R, Cardinale D, Sandri MT, Panteghini M. Biochemical markers for predicting chemotherapy-induced cardiotoxicity systematic review of the literature and recommendations for use. G Ital Cardiol. 2006. 2006;7(9):604–611. [PubMed] [Google Scholar]

[B40] 40.40. Armenian SH, Hudson MM, Mulder RL, Chen MH, Constine LS, Dwyer M, et al. Recommendations for cardiomyopathy surveillance for survivors of childhood cancer: a report from the International Late Effects of Childhood Cancer Guideline Harmonization Group. Lancet Oncol. 2015; 16(3): e123-136. Doi: 10.1016/S1470-2045(14)70409-7 [DOI] [PMC free article] [PubMed]; Armenian SH, Hudson MM, Mulder RL, Chen MH, Constine LS, Dwyer M. Recommendations for cardiomyopathy surveillance for survivors of childhood cancer a report from the International Late Effects of Childhood Cancer Guideline Harmonization Group. Lancet Oncol. 2015;16(3):e123–e136. doi: 10.1016/S1470-2045(14)70409-7. [DOI] [PMC free article] [PubMed] [Google Scholar]

PERMALINK

Early-onset Cardiotoxicity assessment related to anthracycline in children with leukemia. A Prospective Study

Evaluación de la cardiotoxicidad temprana asociada al tratamiento con antraciclinas en niños con Leucemia. Estudio prospectivo

Adriana Linares Ballesteros

Roy Sanguino Lobo

Juan Camilo Villada Valencia

Oscar Arévalo Leal

Diana Constanza Plazas Hernández

Nelson Aponte Barrios

Iván Perdomo Ramírez

Abstract

Background:

Objective:

Methods:

Results:

Conclusions:

Remark

Introduction

Materials and Methods

Inclusion criteria

Exclusion criteria

Definitions

Figure 1. Study schema: time of evaluations with echocardiographic measurements, 12-lead electrocardiogram, and with biomarkers, according to type of leukemia.

Statistical analysis

Ethical aspects

Results

Table 1. Demographic characteristics of the study population.

Table 2. Early-onset cardiovascular findings according to the type of leukemia.

Table 3. Description of echocardiography values by type of leukemia and time of evaluation.

Figure 2. Changes in left ventricular ejection fraction by Simpson method by type of leukemia (evaluated with Wilcoxon test, statistically significant differences p <0.05).

Serum biomarker analysis

Discussion

Conclusions

Appendix.

Appendix 1. Risk classification of patients with acute lymphoid leukemia.

Appendix 2. Electrocardiographic alterations found in patients with early-onset condition, by type of leukemia and stage of evaluation.

Appendix 3. Table of results of troponin by type of leukemia and stage of evaluation.

Funding Statement

Notes:

References

Evaluación de la cardiotoxicidad temprana asociada al tratamiento con antraciclinas en niños con Leucemia. Estudio prospectivo

Resumen

Antecedentes:

Objetivo:

Métodos:

Resultados:

Conclusiones:

Contribución del estudio

Introducción

Materiales y Métodos

Criterios de inclusión

Criterios de exclusión

Definiciones

Figura 1. Momentos de evaluaciones con medidas ecocardiográficas, electrocardiograma de 12 derivaciones y con biomarcadores, según patología.

Análisis estadístico

Aspectos éticos

Resultados

Tabla 1. Características demográficas de la población a estudio.

Tabla 2. Alteraciones cardiovasculares de inicio temprano de acuerdo al tipo de leucemia.

Tabla 3. Descripción de los valores de ecocardiografía por tipo de leucemia y momento de evaluación.

Análisis de biomarcadores séricos

Discusión

Conclusiones

ANEXOS.

Anexo 1. Clasificación de riesgo de pacientes con leucemia linfoide aguda.

Anexo 2. Alteraciones electrocardiográficas encontradas en pacientes con afección de inicio temprano, por tipo de leucemia y etapa de evaluación.

Anexo 3. Tabla de resultados de troponinas por tipo de leucemia y etapa de evaluación.

Notas:

ACTIONS

PERMALINK

RESOURCES

Similar articles

Cited by other articles

Links to NCBI Databases