Risk factors and survival outcomes in children with early cardiotoxicity after allogeneic hematopoietic stem cell transplantation

doi:10.21203/rs.3.rs-3766023/v1

We conducted a retrospective single-center study of pediatric patients who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) between January 2016 and December 2022 at the Children's Hospital Affiliated with Chongqing Medical University to evaluate the clinical characteristics of early cardiac events (ECEs) after allo-HSCT and its impact on survival outcome. We enrolled 444 patients who underwent allo-HSCT—304 males (68%) and 140 females (32%)—with a median age of 3.3 years (1.8-6.5 years) at transplantation. We found that 73 patients (16.4%) had ECEs after allo-HSCT. The ECEs included valvular disease (n=46), pericardial effusion (n=38), arrhythmia (n=9), heart failure (n=16), and dilated cardiomyopathy (n=1). Female sex, age ≥ 6 years, body mass index (BMI) < 16 kg/m2 and HLA-type mismatches were risk factors for ECEs. We designed a stratified cardiac risk score that included these risk factors, and the higher the score was, the greater the cumulative incidence of ECEs. The occurrence of an ECE had a significant negative effect on overall survival (OS) rates after allo-HSCT. In addition, stratified analysis based on the number of combined ECEs showed that the greater the number of combined ECEs, the more significant was the negative impact on OS rates.

Health sciences/Risk factors

Health sciences/Diseases/Haematological diseases/Haematological cancer

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) refers to the infusion of hematopoietic stem cells from normal donors into patients after whole-body irradiation, chemotherapy or immunosuppression to restore normal hematopoietic and immune function[¹].With the rapid development of allo-HSCT, an increasing number of children with hematological malignancies, primary immunodeficiency diseases, congenital genetic metabolic diseases and malignant tumors can be cured by allo-HSCT[²]. Although allo-HSCT significantly improves the survival rate of children, transplant-related complications still have a significant impact on the survival outcome of children[³]. Studies have shown that complications after allo-HSCT, such as cardiotoxicity, central nervous system damage, renal insufficiency, thrombotic microangiopathy (TMA), hepatic venous-occlusive disease (HVOD) and sepsis, significantly reduce the survival rate of patients[⁴].

Cardiotoxicity is not uncommon among allo-HSCT-related complications. The occurrence of cardiotoxicity increases the mortality rate of patients and reduces their long-term quality of life[⁵]. A study conducted in 1976 was the first to report cardiotoxicity after HSCT: two patients treated with high doses of cyclophosphamide (CY) died of fatal congestive heart failure[⁶]. In a prospective study, 227 children treated with HSCT underwent regular echocardiographic monitoring; 6.2% had new left ventricular systolic dysfunction, and 27.3% had new pericardial effusion[⁷]. The complications related to cardiotoxicity mainly include heart failure, pericardial effusion, arrhythmia, and valvular dysfunction[⁸]. In adults, the incidence of cardiotoxicity is associated with older age, history of treatment with CY, arrhythmia, hypertension, and diabetes[⁹-¹⁰]. In children, few studies have been reported, and treatment with anthracyclines and intracranial or chest radiation therapy have been found to be risk factors for cardiotoxicity[¹¹]. However, to our knowledge, the clinical characteristics and risk factors for early cardiotoxicity after allo-HSCT in children are unclear.

The main objective of our study was to analyze the incidence and risk factors for early cardiotoxicity after allo-HSCT in children and to explore the effects of early cardiotoxicity on survival outcomes.

Patients

Pediatric patients who underwent allo-HSCT at the Department of Hematology and Oncology, Affiliated Children's Hospital of Chongqing Medical University, from January 2016 to December 2022 were analyzed retrospectively. Patients who underwent nonfirst allo-HSCT or autologous HSCT, whose clinical data were incomplete, or who were lost to follow-up were excluded. This study was approved by the Ethics Committee of the Children's Hospital Affiliated with Chongqing Medical University and was conducted in accordance with the Declaration of Helsinki.

Transplantation procedures

High-resolution human leukocyte antigen (HLA) typing tests for 10 alleles (HLA-A, HLA-B, HLA-C, HLA-DR and HLA-DQ) were performed to identify the donor for allo-HSCT[¹²]. HLA 10/10 was defined as HLA-typing matched, and the rest were defined as HLA-typing mismatched. The types of donors included matched relatives and unrelated donors and mismatched relatives and unrelated donors. Our conditioning regimens were based on busulfan (BU) + CY or BU + fludarabine (FLU) and adjusted according to the disease characteristics and matching conditions. Some patients were given thiotepa, anti-human thymocyte globulin (ATG), melphalan, etc. No patients in our cohort received total body irradiation (TBI).

Prophylaxis for acute graft-versus-host disease (aGVHD) was mainly based on cyclosporine (CsA), which was used in combination with mycophenolate mofetil (MMF) and/or short-term methotrexate (MTX). Some patients were treated with methylprednisolone or tacrolimus as appropriate.

Definition and monitoring of early cardiac events

Early cardiac events (ECEs) were defined as any cardiac event of grade 2 or higher occurring within 100 days after allo-HSCT and included valvular disease, pericardial effusion, arrhythmia, heart failure, and dilated cardiomyopathy. Valvular disease included moderate or greater regurgitation of the mitral, tricuspid, or aortic valves. Pericardial effusion included small, medium and large amounts of pericardial effusion and pericardial tamponade. Arrhythmias included atrial tachycardia, supraventricular tachycardia, ventricular tachycardia, complete atrioventricular block, and frequent premature ventricular beats. The definition and grading of specific cardiac events referred to the Common Terminology Criteria for Adverse Events (CTCAE), version 4.0[¹³].

All patients underwent the same systematic pretransplant heart evaluation and posttransplant heart monitoring, which included myocardial marker, type B natriuretic peptide, electrocardiogram and cardiac ultrasound data. During the hospitalization of all patients who underwent allo-HSCT, we routinely carried out daily physical examinations, including the monitoring of vital signs, weight and fluid balance. We monitored the heart more frequently in patients with pretransplant cardiac events or posttransplant shortness of breath, rapid heart rate, edema, hepatosplenomegaly or dyspnea and asked cardiologists for professional evaluations.

Statistical analysis

Categorical variables are expressed herein as case numbers and percentage ratios (%) and were compared using chi-square tests or Fisher exact tests. Continuous variables are expressed as medians (Q1, Q3) and were compared using the Mann‒Whitney U test. The primary endpoints of this study were the cumulative incidence of ECE and risk factors for ECE after allo-HSCT. Considering that death before ECE was a competitive risk factor, univariate and multivariate analyses were performed using Fine and Gray competition-risks regression to evaluate the predictors of ECE. Overall survival (OS) was defined as the length of time from HSCT to death from any cause. The secondary endpoint of this study was the effect of ECE on patient outcomes. Using cardiac events as a time-dependent variable, univariate and multivariate Cox proportional hazards models were used to analyze the effects of ECE on OS. Variables with a P value <0.05 in the univariate analysis were included in the multivariate analysis. The results are expressed in terms of hazard ratios (HRs) and corresponding 95% confidence intervals (95% CIs). The Kaplan‒Meier method was used to construct survival curves, and the log-rank method was used to compare OS. SPSS software version 25.0 and R software version 4.1.2 were used for statistical analysis.

Patient characteristics

A total of 444 children who underwent allogeneic HSCT were included, including 304 males (68%) and 140 females (32%). The median age at transplantation was 3.3 years (1.8-6.5 years). There were 182 (41%) patients with primary immunodeficiency disease (PID), 118 (27%) with thalassemia major, 65 (15%) with acute leukemia, 62 (14%) with bone marrow failure syndrome, and 17 (3%) with other diseases. A total of 307 patients (69%) received unrelated donor hematopoietic stem cells, and 137 patients (31%) received related donor hematopoietic stem cells. There were 208 (47%) patients who were HLA-typing matched and 236 (53%) patients with HLA-typing mismatched. In terms of stem cell sources, 419 patients (94%) received peripheral blood. Patients with ECE were typically female (P=0.028), ≥6 years of age (P=0.001), accompanied by bone marrow failure syndrome (P=0), and HLA-type mismatches (P=0.035) and had a greater incidence of aGVHD (P=0.001). The patients and disease characteristics are shown in Table 1.

Incidence of early cardiac events

From days 0 to 100 after allo-HSCT, 73 patients (16.4%) had at least one cardiac event, for an overall incidence of 16.4% (95% CI, 12.9-19.8%; Figure 1). The median time for ECE was 15 days (7-32 days) after allo-HSCT. ECEs included valvular disease (n=46), pericardial effusion (n=38), arrhythmia (n=9), heart failure (n=16), and dilated cardiomyopathy (n=1). The most common was valvular disease, with a cumulative incidence of 10.4% (95% CI, 7.5-13.2%), and the least common was dilated cardiomyopathy, with a cumulative incidence of 0.2% (95% CI, 0-0.7%). The cumulative incidence of ECEs is shown in Table 2. Of the patients who experienced ECEs, 28 (38%) had more than one cardiac event, including 19 (26%) with two cardiac events and 9 (12%) with three cardiac events.

Risk factors for early cardiac events

According to the univariate analysis, female sex (HR, 1.883; P=0.008), age ≥6 years (HR, 2.188; P=0.001), body mass index (BMI) < 16 kg/m² (HR, 1.605; P=0.044), and HLA-typing mismatch (HR, 1.734; P=0.025) had significant effects on the occurrence of ECEs. According to our multivariate analysis, female sex (HR, 1.836; P=0.011), age ≥6 years (HR, 2.266; P=0.001), BMI < 16 kg/m² (HR, 1.651; P=0.035), and HLA-type mismatch (HR, 1.711; P=0.029) were also risk factors for ECE. However, the Cy-based conditioning regimen, history of treatment with CY or anthracycline, congenital heart disease, cardiac events before allo-HSCT, blood lipids, and blood glucose had no significant effect on the occurrence of ECEs (Table 3).

We designed a stratified cardiac risk score ranging from 0 to 4 that included female sex, age ≥6 years, BMI < 16 kg/m², and mismatched HLA typing to predict the risk of ECEs. Within 100 days after allo-HSCT, the cumulative incidences of cardiac events with scores of 0 (n=2), 1 (n=18), 2 (n=32), and 3-4 (n=21) were 2.4% (95% CI, 0-5.7%), 9.4% (95% CI, 5.24-13.6%), 16.7% (95% CI, 11.3-22.2%), and 22.7% (95% CI, 12.8-28.6%), respectively. Our analysis revealed that the cumulative incidence of ECEs increased significantly with increasing scores (P=0.00011; Figure 2). The cumulative incidences of ECEs in patients with scores of 0-1, 2 and 3-4 were 9.1% (95% CI, 5.2-12.8%), 21.9% (95% CI, 14.9-28.4%) and 27.3% (95% CI, 16.6-36.6%), respectively.

Survival outcomes

The deadline for follow-up was November 2023. During a median follow-up of 36.8 months (18.4-61.7 months), 71 patients died, 32 of whom had cardiac events. The causes of death in patients with ECEs included respiratory failure (n=15), hemorrhage involving important organs (intracranial, lung, or gastrointestinal bleeding) (n=6), severe GVHD (n=4), disease recurrence (n=3), heart failure (n=2), pericardial tamponade (n=1), and severe infection (n=1). The causes of death in patients without ECEs included respiratory failure (n=18), severe infection (n=6), severe GVHD (n=5), hemorrhage of important organs (intracranial, lung, or gastrointestinal) (n=5), and disease recurrence (n=5).

According to the univariate analysis, ECEs (HR=0.181; P=0.000), an HLA-type mismatch (HR=2.263; P=0.002), aGVHD (HR=2.211; P=0.004), and aGVHD grade (HR=3.257; P=0.000) had significant effects on the OS rate. According to the multivariate analysis, ECEs (HR, 4.485; P=0.000) and aGVHD grade (HR, 2.534; P=0.009) were risk factors for a decreased OS rate (Table 4).

The 1-year, 3-year, and 5-year OS rates in the ECE group were 60.3% (95% CI: 50.0%-72.6%), 56.9% (95% CI: 46.4%-69.7%), and 54.5% (95% CI: 43.7%-67.9%), respectively. The 1-year, 3-year, and 5-year OS rates in the group without ECEs were 91.4% (95% CI: 88.6%-94.3%), 90.1% (95% CI: 87.1%-93.3%), and 89.2% (95% CI: 85.9%-92.6%), respectively. Survival analysis revealed that ECEs had a significant negative impact on the OS rate after allo-HSCT (Figure 3). After stratification according to the number of combined ECEs, we found that the greater the number of combined cardiac events, the more significant was the negative impact on OS rates (P < 0.0001; Figure 4).

This paper is the first comprehensive and systematic report on the clinical characteristics of early cardiotoxicity in children after allo-HSCT. We analyzed the clinical features and survival outcomes of 444 pediatric patients who received allo-HSCT. The main findings of this study were that the incidence of ECEs after allo-HSCT was greater in pediatric patients and that female sex, age ≥6 years, BMI < 16 kg/m², and HLA-type mismatches were risk factors for ECE. Although most of the patients treated with allo-HSCT had a good prognosis, the OS rate of patients with ECEs was significantly lower than that of patients without any ECEs.

ECEs are a common complication after allo-HSCT. The incidence of ECEs during HSCT in adult patients ranged from 4.5% to 13.6%, mainly including heart failure, pericardial effusion, arrhythmia and acute coronary syndrome[10,14-][a14aa1a[a15aa2a][a16a]. In children, studies have suggested a 4.2% incidence of late cardiac events, including coronary artery disease (0.2%), cerebrovascular accidents (0.6%), cardiomyopathy (3%), and cardiac death (0.5%)[11]. In this study, 73 patients (16.4%) had at least one cardiac event, with a total incidence of 16.4%. The cumulative incidences of valvular disease, pericardial effusion, heart failure, arrhythmia and dilated cardiomyopathy were 10.4%, 8.6%, 3.6%, 2.0% and 0.2%, respectively. The definition of cardiac events tended to vary widely across studies, causing a wide variation in the reported incidence of cardiac events.

This study revealed that the risk factors for ECEs in pediatric patients were female sex, age ≥6 years, BMI < 16 kg/m², and mismatched HLA typing. We also designed a stratified cardiac risk score that incorporated these risk factors on a scale of 0-4. The results suggested that the cumulative incidence of ECE increased significantly with increasing score. Our stratified cardiac risk score is a good guideline for clinicians. Clinicians should conduct a comprehensive assessment of these risk predictors before allo-HSCT, and patients should be closely monitored for cardiotoxicity during allo-HSCT when their scores are high. According to a series of studies in adults, the risk factors for cardiotoxicity after HSCT include hypertension, dyslipidemia, diabetes, obesity, smoking, and physical inactivity[¹⁷-[a18aa3a][a19a]. In addition, treatments that include cardiotoxic drugs, CY and radiotherapy increase the risk of early cardiotoxicity after allo-HSCT.¹⁵Studies in children have shown that chemotherapy with anthracyclines and TBI are significant risk factors for cardiotoxicity and that dyslipidemia and diabetes increase the risk of cardiotoxicity[11,²⁰]. In addition, in the present study, treatment with anthracyclines and CY, dyslipidemia, elevated blood glucose, and cardiac events prior to allo-HSCT had no significant effect on ECEs. The reason might be that the diseases in the study cohort were different from those in the study cohort. Most of the patients in our cohort had nonmalignant tumors, such as PID, thalassemia major, or bone marrow failure syndrome, and their previous treatment course was very different from that of patients with acute leukemia.

Our previous studies revealed that pericardial effusion mainly occurred within 100 days after HSCT, and the GVHD grade, abnormal electrocardiogram before HSCT, HVOD, pulmonary infection, and Epstein–Barr virus infection were closely related to the occurrence of pericardial effusion after HSCT[²¹]. In this study, multiple ECEs, including pericardial effusion, were comprehensively analyzed, and female sex, age ≥6 years, BMI < 16 kg/m², and HLA-type mismatches were identified as ECE risk factors. Previous studies have shown that increasing age is a risk factor in patients treated with HSCT[²²]. Similarly, several studies have suggested that increasing age and female sex are risk factors for pericardial effusion after HSCT in children[²³-²⁴]. These results are consistent with our findings; therefore, heart-related examinations should be closely performed for older and female children during HSCT to avoid fatal cardiac events. A higher BMI in children and adolescents not only increases the incidence of pediatric cardiovascular disease (CVD) but also increases the risk of CVD morbidity and mortality in adulthood[²⁵-²⁶]. Long-term follow-up of 661 children with hematological malignancies treated with HSCT suggested that obese children with an increased BMI would have an increased risk of CVD over time[11]. In contrast, we found that a lower BMI was a risk factor for ECEs at our center. Given that the participants in other studies were children with hematological malignancies who received regular chemotherapy before HSCT, long-term use of glucocorticoids might increase the number of obese children. In our study cohort, PID and bone marrow failure syndrome accounted for a large proportion of the infections in children, and these patients might have had repeated infections before allo-HSCT. Moreover, these patients were underdeveloped and malnourished due to congenital genetic defects, which increase the risk of potential heart-related diseases. In adults, studies have suggested that HLA typing mismatches are closely related to ECE occurrence[10]. In children, other studies have shown that mismatched HLA typing has a significant impact on pericardial effusion[²⁷-²⁸], and the results of this study are consistent with these findings.

This study showed that the occurrence of ECEs after HSCT had a significant negative impact on OS, and the greater the number of combined cardiac events, the lower the OS rate was. Notably, ECEs and grade II-IV aGVHD were risk factors for reduced OS. In adults, many studies have confirmed that cardiac events such as pericardial effusion, arrhythmia, cardiomyopathy, and cardiac dysfunction after HSCT significantly reduce the OS rate[²⁹-[a30aa4a][a31aa5a][a32a]. Regarding children, a study analyzed severe patients who received HSCT with left ventricular systolic dysfunction, elevated right ventricular pressure, and moderate-to-severe pericardial effusion and found that when these abnormalities were present on echocardiography, the OS rate was significantly reduced[³³]. Similarly, other studies have shown that pericardial effusion increases mortality after HSCT[³⁴-³⁵]. GVHD occurs when immune-active T cells from the donor (graft) recognize the recipient (host) as a foreign body. GVHD, especially when present to a greater degree, was the most common life-threatening complication after HSCT[³⁶], which was confirmed in this study.

In summary, there was a higher incidence of ECE in children treated with allo-HSCT. Female sex, age ≥6 years, BMI < 16 kg/m², and HLA-typing mismatched were risk factors for ECEs, and our Stratified Cardiac Risk Score could better predict ECE occurrence. The occurrence of an ECE was closely associated with a lower OS rate. Therefore, to improve the survival rate of patients with HSCT, clinicians should make a comprehensive assessment of patients' heart-related risk factors before HSCT and increase the frequency of cardiac examination (echocardiography, electrocardiogram, myocardial markers, etc.) for patients with high risk during HSCT, to achieve early detection, diagnosis, and treatment.

Data availability

For data sharing, please contact the corresponding author ([email protected]).

Acknowledgments

The authors thank the patients and the nursing and support staff in the HSCT program.

Funding

This work was supported by the Program for Youth Innovation in Future Medicine, Chongqing Medical University (grant number W0132) and the Natural Science Foundation of Chongqing, China (CSTB2023NSCQ-MSX0212).

Authorship

Contribution: YD designed the research and edited the manuscript. YM, LZ, XL, QL, XG and JY provided detailed materials for this manuscript. KT collected and analyzed the data and wrote the manuscript.

Conflict of interest disclosure: The authors declare no competing interests.

ORCID profiles: KT, 0000-0002-8765-6963; YD, 0000-0001-9037-6420.

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Hertenstein B, Stefanic M, Schmeiser T, Scholz M, Göller V, Clausen M, et al. Cardiac toxicity of bone marrow transplantation: predictive value of cardiologic evaluation before transplant. J Clin Oncol. 1994;12(5):998-1004.
Pérez-Valencia AI, Cascos E, Carbonell-Ordeig S, Charry P, Gómez-Hernando M, Rodríguez-Lobato LG, et al. Incidence, risk factors, and impact of early cardiac toxicity after allogeneic hematopoietic cell transplant. Blood Adv. 2023;7(10):2018-2031.
Leger KJ, Baker KS, Cushing-Haugen KL, Flowers MED, Leisenring WM, Martin PJ, et al. Lifestyle factors and subsequent ischemic heart disease risk after hematopoietic cell transplantation. Cancer. 2018;124(7):1507-1515.
Tonorezos ES, Stillwell EE, Calloway JJ, Glew T, Wessler JD, Rebolledo BJ, et al. Arrhythmias in the setting of hematopoietic cell transplants. Bone Marrow Transplant. 2015;50(9):1212-1216.
Lin CJ, Vader JM, Slade M, DiPersio JF, Westervelt P, Romee R. Cardiomyopathy in patients after posttransplant cyclophosphamide-based hematopoietic cell transplantation. Cancer. 2017;123(10):1800-1809.

Table 1. Study patient characteristics.

Variables	Overall, N (%) (N=444)	Patients with ECE, n (%) (n=73)	Patients without ECE, n (%) (n=371)	P value
Sex
Male	304(68)	42(56)	262(71)	0.028
Female	140(32)	31(42)	109(29)
Age		5.6(2.2-9.7)	3.2(1.7-6)	0.005
<6 years	318(72)	41(56)	277(75)	0.001
≥6 years	126(28)	32(44)	94(25)
BMI		15.9(14.5-18.7)	16.4(15.1-17.8)	0.42
＜16 kg/m²	190(43)	37(51)	153(41)	0.136
≥16 kg/m²	254(57)	36(49)	218(59)
Diseases
PID	182(41)	23(32)	159(43)	0.000
Thalassemia major	118(27)	10(14)	108(29)
Acute leukemia	65 (15)	14(19)	51(14)
Bone marrow failure syndrome	62(14)	21(29)	41(11)
Others	17(3)	5 (7)	12(3)
Donor
Unrelated	307(69)	50(68)	257(69)	0.895
Related	137(31)	23(32)	114(31)
HLA typing
Matched	208(47)	26(36)	182(49)	0.035
Mismatched	236(53)	47(64)	189(51)
Stem cell source
PB	419(94)	68(93)	351(95)	0.829
Others	25 (6)	5 (7)	20(5)
AGVHD
Yes	266(60)	51(70)	215 (58)	0.058
No	178(40)	22(30)	156(42)
AGVHD grade
No~I°	286(64)	35 (48)	251(68)	0.001
II°~IV°	158(36)	38(52)	120(32)
Conditioning regimens
CY-based
Yes	405 (91)	66(90)	339(91)	0.79
No	39(9)	7(10)	32(9)
ATG-based
Yes	378(85)	64(88)	314(85)	0.505
No	66(15)	9(12)	57(15)
History of treatment with CY before allo-HSCT
Yes	25 (6)	7(10)	18(5)	0.184
No	419(94)	66(90)	353(95)
History of treatment with anthracyclines before allo-HSCT
Yes	60(14)	12(16)	48(13)	0.424
No	384(86)	61(84)	323(87)
Cardiac events before allo-HSCT
No	415 (94)	69(94)	346(93)	0.89
Pericardial effusion	6(1)	2(3)	4(1)	0.35
Arrhythmias	6(1)	0(0)	6(2)
Valvular disease	17(4)	2(3)	15 (4)
Congenital heart disease
Yes	68(15)	7(10)	61(16)	0.137
No	376(85)	66(90)	310(84)
Pulmonary infection before allo-HSCT
Yes	203(46)	27(37)	176(47)	0.101
No	241(54)	46(63)	195 (53)
Blood lipid anomalies before allo-HSCT
Yes	392(88)	62(85)	330(89)	0.329
No	52(12)	11(15)	41(11)
Blood glucose anomalies before allo-HSCT
Yes	431(97)	71(97)	360(97)	1.000
No	13(3)	2(3)	11(3)

AGVHD, acute graft-versus-host disease; ATG, anti-human thymocyte globulin; BMI, body mass index; CY, cyclophosphamide; ECE, early cardiac events; HLA, human leukocyte antigen; PB, peripheral blood stem cells; PID, primary immunodeficiency disease.

Table 2. Cumulative incidence of cardiac events within 100 days after allo-HSCT

Cardiac events	Incidence	95% CI
Any cardiac event	16.4%	12.9-19.8%
Valvular disease	10.4%	7.5-13.2%
Pericardial effusion	8.6%	5.9-11.1%
Heart failure	3.6%	1.9-5.3%
Arrhythmias	2.0%	0.7-3.3%
Dilated cardiomyopathy	0.2%	0-0.7%

Table 3. Univariate and multivariate analysis of risk factors for cardiac events within 100 days

Variables	Overall, N (%) (N=444)	Univariate		Multivariate
Variables	Overall, N (%) (N=444)	HR (95% CI)	P value	HR (95% CI)	P value
Sex
Male	304(68)	1		1
Female	140(32)	1.883 (1.182~3.000)	0.008	1.836(1.148~2.937)	0.011
Age
<6 years	318(72)	1		1
≥6 years	126(28)	2.188(1.377~3.477)	0.001	2.266(1.420~3.614)	0.001
BMI
＜16 kg/m²	190(43)	1		1
≥16 kg/m²	254(57)	1.605 (1.013~2.544)	0.044	1.651(1.035~2.634)	0.035
Donor
Unrelated	307(69)	1
Related	137(31)	0.876(0.533~1.439)	0.600
HLA typing
Matched	208(47)	1		1
Mismatched	236(53)	1.734(1.073~2.801)	0.025	1.711(1.056~2.772)	0.029
Stem cell source
PB	419(94)	1
Others	25 (6)	0.994(0.399~2.474)	0.989
Conditioning regimens
CY-based
Yes	405 (91)	1
No	39(9)	0.787(0.361~1.717)	0.547
ATG-based
Yes	378(85)	1
No	66(15)	1.534(0.762~3.088)	0.231
History of treatment with CY before allo-HSCT
Yes	25 (6)	1
No	419(94)	0.471(0.216~1.029)	0.059
History of treatment with anthracyclines before allo-HSCT
Yes	60(14)	1
No	384(86)	0.635 (0.341~1.182)	0.152
Cardiac events before allo-HSCT
Yes	29(6)	1
No	415 (94)	1.011(0.368~2.775)	0.983
Congenital heart disease
Yes	68(15)	1
No	376(85)	2.022(0.925~4.419)	0.078
Pulmonary infection before allo-HSCT
Yes	203 (46)	1
No	241(54)	1.443 (0.896~2.323)	0.131
Blood lipid anomalies before allo-HSCT
Yes	392(88)	1
No	52(12)	1.446(0.761~2.750)	0.260
Blood glucose anomalies before allo-HSCT
Yes	431(97)	1
No	13 (3)	1.026(0.251~4.192)	0.972

ATG, anti-human thymocyte globulin; BMI, body mass index; CY, cyclophosphamide; HLA, human leukocyte antigen; PB, peripheral blood stem cell.

Table 4. Univariate and multivariate analyses of risk factors for survival outcomes after allo-HSCT

Variables	Overall, N (%) (N=444)	Univariate		Multivariate
Variables	Overall, N (%) (N=444)	HR (95% CI)	P value	HR (95% CI)	P value
Early cardiac events
No	371(84)	1		1
Yes	73 (16)	5.523 (3.454~8.832)	0.000	4.485 (2.776~7.247)	0.000
Sex
Male	304(68)	1
Female	140(32)	1.304(0.805~2.114)	0.281
Age
<6 years	318(72)	1
≥6 years	126(28)	1.258(0.765~2.068)	0.366
BMI
＜16 kg/m²	190(43)	1
≥16 kg/m²	254(57)	0.845 (0.530~1.347)	0.479
Donor
Unrelated	307(69)	1
Related	137(31)	0.848(0.505~1.422)	0.531
HLA typing
Matched	208(47)	1		1
Mismatched	236(53)	2.263 (1.359~3.768)	0.002	1.585 (0.916~2.743)	0.100
Stem cell source
PB	419(94)	1
Others	25 (6)	0.710(0.223~2.256)	0.561
AGVHD
No	266(60)	1		1
Yes	178(40)	2.211(1.282~3.815)	0.004	0.835 (0.376~1.851)	0.656
AGVHD grade
No~I°	286(64)	1		1
II°~IV°	158(36)	3.257(2.016~5.261)	0.000	2.534(1.264~5.081)	0.009
Conditioning regimens
CY-based
Yes	405 (91)	1
No	39(9)	1.229(0.495~3.051)	0.656
ATG-based
Yes	378(85)	1
No	66(15)	2.085 (0.903~4.813)	0.085
History of treatment with CY before allo-HSCT
Yes	25 (6)	1
No	419(94)	0.978(0.357~2.683)	0.996
History of treatment with anthracyclines before allo-HSCT
Yes	60(14)	1
No	384(86)	0.767(0.412~1.427)	0.402
Cardiac events before allo-HSCT
Yes	29(6)	1
No	415 (94)	5.181(0.720~37.303)	0.102
Congenital heart disease
Yes	68(15)	1
No	376(85)	1.471(0.705~3.069)	0.304
Pulmonary infection before allo-HSCT
Yes	203 (46)	1
No	241(54)	1.062(0.666~1.696)	0.799
Blood lipid anomalies before allo-HSCT
Yes	392(88)	1
No	52(12)	1.258(0.644~2.455)	0.501
Blood glucose anomalies before allo-HSCT
Yes	431(97)	1
No	13 (3)	1.569(0.494~4.986)	0.445

AGVHD, acute graft-versus-host disease; ATG, anti-human thymocyte globulin; BMI, body mass index; CY, cyclophosphamide; HLA, human leukocyte antigen; PB, peripheral blood stem cell.

The authors have declared there is NO conflict of interest to disclose.

Risk factors and survival outcomes in children with early cardiotoxicity after allogeneic hematopoietic stem cell transplantation

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Abstract

Figures

Introduction

Methods

Results

Discussion

Declarations

References

Footnotes

Tables

Additional Declarations

Status:

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