Cumulative Anthracycline Dose Research Articles

Abstract 6382: Risk prediction of dyslipidemia in long-term survivors of childhood cancer: A report from the St. Jude Lifetime Cohort

Abstract Background: Dyslipidemia is a significant contributor to the increased risk of cardiovascular morbidity and premature mortality in long-term survivors of childhood cancer. Identifying individuals at risk at an early stage provides an opportunity for tailored prevention approaches. Methods: Long-term childhood cancer survivors from the St. Jude Lifetime Cohort, (SJLIFE, n=2,559; median age 41 years, range 20-77 years) were directly assessed for dyslipidemia. Risk factors under consideration included demographic characteristics, cancer treatment exposures (cumulative doses of anthracyclines, platinum agents, glucocorticoids, and radiation therapy), comorbid conditions at the time of assessment (hypertension, diabetes mellitus, growth hormone deficiency, hypogonadism, hypothyroidism, cardiomyopathy, and chronic kidney disease), and externally validated multi-ancestry general-population polygenic risk scores (PRSs) for lipid values (total cholesterol, LDL-C, HDL-C, and triglycerides). Multivariable logistic regression predicted a 15-year risk of dyslipidemia (CTCAE grade ≥2 hypercholesterolemia and/or hypertriglyceridemia) including variables selected by the stepwise approach. Performance of the model was assessed by the area under the receiver operating characteristic curve (AUC). Results: Dyslipidemia was clinically identified in 543 (25.1%) SJLIFE survivors. AUC of a clinical model with sex, race, age at prediction, and comorbid conditions (diabetes, growth hormone deficiency, hypogonadism, hypothyroidism, and hypertension) was 0.80 (95% CI, 0.78-0.82). Inclusion of cancer treatment exposures (cumulative doses of anthracyclines, cisplatin, carboplatin, glucocorticoids, abdominal and cranial radiation therapy) significantly increased AUC to 0.82 (95% CI, 0.80-0.84; P=2.1×10-4). Addition of two PRSs for LDL-C (one included only genome-wide significant variants adjusted for statins and another consisted of all genome-wide variants) and the PRS for triglycerides provided further significant improvement in AUC to 0.86 (95% CI, 0.84-0.88; P=4.2×10-12). Conclusions: We developed a prediction model with good performance for identifying the risk of dyslipidemia in childhood cancer survivors. In addition to demographics and comorbidities, cancer treatments and inherited genetic factors contributed significantly to improving the risk prediction of dyslipidemia. Results may refine risk stratification for dyslipidemia in survivors and present opportunities for more precise and personalized preventive strategies to address cardiovascular health. Independent validation in survivors from the Childhood Cancer Survivor Study and the Dutch Childhood Cancer Survivor Study (DCCSS)-LATER is currently underway. Citation Format: Kateryna Petrykey, Kendrick Li, Lu Xie, Achal Neupane, Angela Delaney, Christine Yu, Stephanie B. Dixon, Bonnie Ky, Cindy Im, Isaac B. Rhea, Jeffrey A. Towbin, Jason N. Johnson, Melissa Bolier, Vincent G. Pluimakers, Linda Broer, Sebastian J. Neggers, Marry M. van den Heuvel-Eibrink, Rebecca M. Howell, Kirsten K. Ness, Melissa M. Hudson, Gregory T. Armstrong, Yutaka Yasui, Yadav Sapkota. Risk prediction of dyslipidemia in long-term survivors of childhood cancer: A report from the St. Jude Lifetime Cohort [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6382.

Left Ventricular Longitudinal Strain Abnormalities in Childhood Exposure to Anthracycline Chemotherapy.

Current mortality is low in cases of childhood acute leukemia. Dilated cardiomyopathy induced by anthracyclines remains the main cause of morbidity and mortality during mid-term and long-term follow-up. The aim of our study was to analyze the profile of left ventricular alterations in children treated with anthracyclines and to analyze risks and protective factors, including physical activity. Children and young adults with acute leukemia treated with anthracyclines between 2000 and 2018 during childhood were included. The physical activity performed by the patients before and after treatment was quantified in metabolic equivalent tasks, MET.h, per week. An echocardiographic assessment was performed, including strain analysis. Thirty-eight patients with a median age of 5 [3-8] years were included. Dilated cardiomyopathy was diagnosed in 3 patients and longitudinal strain abnormalities were observed in 11 patients (28.9%). Radiotherapy, cumulative anthracycline doses > 240 mg/m2, and the practice of physical activity > 14 MET.h per week (after leukemia treatment) were independently associated with strain abnormalities. In multivariate analysis, radiotherapy was significantly associated with an increased risk of LV GLS abnormalities (OR = 1.26 [1.01-1.57], p = 0.036), and physical activity > 14 MET.h/week after oncological treatment was significantly associated with a reduction in the risk of LV GLS abnormalities (OR of 0.03 [0.002-0.411], p = 0.009). The strain assessment of left ventricular function is an interesting tool for patient follow-up after leukemia treatment. Moderate and steady physical activity seems to be associated with fewer longitudinal strain abnormalities in patients treated with anthracyclines during childhood.

Assessment of Pazopanib-Related Heart Failure in Patients With Advanced Soft Tissue Sarcoma - A Single Institute Analysis.

Heart failure (HF) is one of the potential adverse events of pazopanib treatment for soft tissue sarcoma (STS), but detailed reports of such HF cases are scarce. This study determined the incidence and risk factors of HF following pazopanib treatment for STS at our Institute and the clinical outcomes.Methods and Results:This study retrospectively analyzed the cases of STS patients treated with pazopanib (n=151) between 2012 and 2020. HF occurred in 6 patients (3.9%) at the median onset of 137 (range 14-468) days after the treatment initiation. When their HF was diagnosed, pazopanib was interrupted in all 6 patients. No patients experienced HF-related death, and HF development was not a significant factor for poor overall survival. The cumulative doses of anthracyclines (>225 mg/m2) before pazopanib initiation (83% vs. 37%, P=0.031), pazopanib initiation at age ≥60 years (83% vs. 35%, P=0.026), and the baseline B-type natriuretic peptide (BNP) concentration (≥50 pg/mL) before pazopanib (67% vs. 11%, P=0.002) initiation were predictive factors for post-pazopanib treatment HF. The study findings highlight the effect of past anthracycline exposure and baseline BNP for pazopanib-associated HF. Although the study patients' clinical outcomes were generally favorable, periodic monitoring of cardiac function using ultrasonic echocardiography or serum markers is essential to detect events early and begin therapeutic intervention appropriately under a cardiologist's instructions.

Permanent longitudinal strain damage of cardiotoxic drugs in childhood cancer: What is the safe level?

ABSTRACT Objective: Anthracycline administration in children is associated with cardiac dysfunction. Speckle-tracking echocardiography (STE) can detect subclinical cardiac damage that may go undetected by conventional two-dimensional (2D) echocardiography. This study aims to investigate medium-term anthracycline cardiotoxicity using STE and determine a safer administrable level of anthracyclines (ACs). Methods: This observational case–control study enrolled 37 healthy controls and 78 pediatric cancer survivors who received chemotherapy. The patients were divided into two groups: cardiotoxic received (CR) and cardiotoxic free (CF). Data on segmental longitudinal strain (LS), global LS (GLS), and 2D echocardiographic parameters were collected after a drug-free period of at least one year. Results: A total of 115 children with a mean age of 108 ± 55 months, of whom 66% were males, were included in the study. Both the groups of cancer survivors exhibited significantly reduced GLS compared to healthy controls (CR vs. controls, P = 0.001; CF vs. controls, P = 0.013), but no significant difference in left ventricular ejection fraction (LVEF) was observed (P = 0.75). Overall, cancer survivors treated with ACs demonstrated a significant reduction in strain in 10 left ventricular segments, particularly in the basal segments (P < 0.05). Among CR patients, those with impaired GLS (n = 43, GLS worse than −21.9) had significantly higher mean age and cumulative anthracycline dose compared to CR patients with normal GLS (age, P = 0.024; anthracycline dosage, P = 0.036). Using an anthracycline cutoff of 223 mg/m2 resulted in a higher detection rate (49% vs. 25%) and fewer missed cases (51% vs. 74%) compared to the 360 mg/m2 anthracycline cutoff. Conclusion: Childhood cancer survivors demonstrate significantly reduced GLS while preserving a normal LVEF, which does not differ significantly from reference values of healthy children. The reduction in strain appears to be associated with higher anthracycline doses and older age. Lowering the anthracycline threshold to 223 mg/m2 may improve the predictability of a decline in cardiac function using strain imaging at medium-term follow-up.

Cardiovascular diseases after high-dose chemotherapy and autologous stem cell transplant for lymphoma: A Danish population-based study.

Cardiovascular diseases, especially congestive heart failure (CHF), are known complications of anthracyclines, but the risk for patients undergoing high-dose chemotherapy and autologous stem cell transplant (HDT-ASCT) is not well established. With T-cell therapies emerging as alternatives, studies of long-term complications after HDT-ASCT are warranted. Danish patients treated with HDT-ASCT for aggressive lymphoma between 2001 and 2017 were matched 1:5 on sex, birth year and Charlson comorbidity score to the general population. Events were captured using nationwide registers. A total of 787 patients treated with HDT-ASCT were identified. Median follow-up was 7.6 years. The risk of CHF was significantly increased in the HDT-ASCT population compared to matched comparators with an adjusted hazard ratio (HR) of 5.5 (3.8-8.1). The 10-year cumulative incidence of CHF was 8.0% versus 2.0% (p < 0.001). Male sex, ≥2 lines of therapy, hypertension and cumulative anthracycline dose (≥300 mg/m2 ) were risk factors for CHF. In a separate cohort of 4089 lymphoma patients, HDT-ASCT was also significantly associated with increased risk of CHF (adjusted HR of 2.6 [1.8-3.8]) when analysed as a time-dependent exposure. HDT-ASCT also increased the risk of other cardiac diseases. These findings are applicable for the benefit/risk assessment of HDT-ASCT versus novel therapies.

Cardiotoxicity Related Mortality Among Children with Acute Myeloid Leukemia in Low Middle Income Countries: Is It Treatment or Sepsis Related?

Background: Heart disease and cancer are two major causes of morbidity and mortality worldwide, accounting for at least 70% of the medical reasons for mortality across the globe. Modern treatment strategies led to improvements in cancer survival, however, these gains might be offset by the potential negative effect of cancer therapy on cardiovascular health. Over the last few decades, cooperative oncology group trials for pediatric acute myeloid leukemia (AML) have improved overall survival (OS) to nearly 65% by combining intensive chemotherapy with improved supportive care. Despite their efficacy, anthracyclines are linked to an increased risk of cardiotoxicity. Objectives:The study aimed to describe the incidence of cardiotoxicity among pediatric patients with acute myeloid leukemia, assess the effect of cardiotoxicity on treatment outcome in terms of overall survival (OS) and event free survival (EFS) and to determine the different risk factors (Age, gender, body mass index, cumulative doses of anthracyclines and sepsis) that may contribute to cardiotoxicity. Patient and Methods: A retrospective study, conducted at the National Cancer Institute (NCI), Cairo University, Egypt.,that included all pediatric patients ≤ 18 years old diagnosed and treated as Acute Myeloid Leukemia (AML) during the period from the first of January 2015 to the end of December 2019. Retrospective analysis of the different features of cardiotoxicity associated with the treatment of AML. Results : The study included 142 patients with a median age of 8.5 years old and M/F ratio 1.2:1.Out of the total study population, Eighty four patients (59.2%) developed cardiotoixicity in which 59.5% were acute onset cardiotoxicity and 40.5 % were chronic early cardiotoxicity and there was no detected cases of chronic late cardiotoxicity.Cardiac dysfunction was detected in 65/142 (45.8%) patients at time of death in association with sepsis. The cumulative incidence of cardiotoxicity was higher in the presence of blood stream infection with p value (p&amp;lt;0.001).55/84 (65.5%) patients with cardiotoxicity showed progressive cardiac dysfunction and they all died due to sepsis that was associated with cardiac dysfunction. At the end of the study the OS and EFS were 16.2 % and the median survival time was 1.9 month.The cumulative OS,EFS and the median survival time were reduced in the presence of acute cardiotoxicity with statistical significant p-value (p&amp;lt;0.001). Conclusion: The incidence of cardiotoxicity is high among pediatric AML patients and the most important risk factor for cardiotoxcity is blood stream infection. The Cumulative OS, EFS and median survival time are reduced in patients with acute cardiotoxicity which represents a major challenge that warrants more attention to the field of cardio-oncology.

Role of Clinical Risk Factors and B-Type Natriuretic Peptide in Assessing the Risk of Asymptomatic Cardiotoxicity in Breast Cancer Patients in Kazakhstan

The asymptomatic progression of chemotherapy-induced cardiotoxicity poses a significant risk to breast cancer patients. In the present single-center cohort study, a predictive model for evaluating the risk of cardiotoxicity during or by the end of chemotherapy was designed. The risk-prediction nomogram was delineated and assessed. In total, 34 patients out of 120 developed asymptomatic cardiotoxicity (28.3%). Of six explored biomarkers, only B-type natriuretic peptide showed a reliable pattern of incremental increase, revealing statistical significance between cardiotoxicity “+” and “−” groups by visit 4 or by the 9th month of monitoring (p 0.006). The following predictors were included in the model: age, hypertension, diabetes mellitus, baseline glomerular filtration rate, 6 min walk test measured at visit 4, BNP values at visit 4, left ventricular ejection fraction levels at visit 4, a total dose of radiotherapy received, and anthracycline cumulative doses. The model’s AUC was 0.72 (95% CI 0.59; 0.86), evidencing the satisfactory predictive ability of the model; sensitivity 100% (95% CI 90.36; 100.0) at a specificity of 66.67% (95% CI 50.33; 79.79); PPV 54.1% [95% CI 47.13; 60.91]; PVN 100% [95% CI 94.64; 100.00]. The calibration plot showed satisfactory agreement between predicted and actual chances (p = 0.98). The designed model can be applied in settings lacking speckle tracking echocardiography.

The use of high sensitivity troponin T as a biomarker of anthracycline cardiotoxicity

Abstract Introduction Anthracyclines are a highly effective class of chemotherapy used to treat a wide variety of malignancies. Their use is complicated by the development of cancer therapy-related cardiac dysfunction (CT-RCD), defined broadly as the development of left ventricular systolic dysfunction following cancer treatment. Troponin, a well-established marker of myocardial necrosis and early myocardial injury following anthracycline chemotherapy, may predict the subsequent development of CT-RCD. It is not known, however, at what timepoint troponin should be measured, or if there is a clinically relevant threshold that best predicts the development of CT-RCD. Purpose 1. To investigate if high sensitivity troponin T (hsTnT) accurately predicts the development of anthracycline CT-RCD 2. To establish the best timepoint at which hsTnT should be measured to predict CT-RCD 3. To establish the most clinically relevant hsTnT concentration to predict CT-RCD Methods In 2020 we introduced a clinical pathway for outpatients receiving anthracycline chemotherapy at our Institution. As part of this pathway, hsTnT concentrations are measured at baseline (pre-chemotherapy) and prior to each anthracycline cycle. In this study, we performed a prospective audit of outpatients receiving anthracycline chemotherapy for the treatment of breast or haematological malignancies. Troponin concentrations prior to each chemotherapy cycle were assessed and ROC curve analyses were performed to determine the most accurate timepoint and threshold to predict CT-RCD. CT-RCD was defined as a drop in the left ventricular ejection fraction (LVEF) of &amp;gt;10% from baseline to a value of &amp;lt;50%. Results 118 outpatients were treated with anthracycline chemotherapy between August 2020 and May 2022. 64 patients (54%) were treated for breast cancer and 54 (46%) for haematological malignancies. The mean age was 54±15yrs, with 71% females. At baseline, 27 (23%) of patients had a diagnosis of hypertension, 16 (14%) diabetes, 28 (24%) smoking history, 10 (8%) chronic kidney disease and 31 (26%) obesity. The median cumulative dose was 360mg/m² for Epirubicin and 300mg/m² for Doxorubicin. The baseline mean LVEF was 60.5±4%. 97/118 (82%) of patients had a follow up echocardiogram. 11/97 (11%) of patients developed CT-RCD. Mean hsTnT concentrations rose incrementally as the cumulative dose of anthracycline increased (Fig 1). Baseline hsTnT concentration was the most accurate predictor of subsequent CT-RCD (AUC 0.75), with a 75% sensitivity and 80% specificity for predicting CT-RCD if the baseline hsTnT concentration was ≥10.5ng/L. In addition, the baseline mean hsTnT concentration was significantly higher in patients with CT-RCD vs. those with no CT-RCD, P=0.0008 (Fig 2). Conclusions High sensitivity troponin T concentrations appear to be clinically useful in predicting subsequent CT-RCD, with the most accurate point of measurement being at baseline, prior to chemotherapy commencing.

Empagliflozin restores autophagy and ameliorates ponatinib-induced cardiomyocyte death

Abstract Background The tyrosine kinase inhibitor ponatinib has proven cardiovascular toxicity, for which no counteractive treatment is available at the moment. Sodium-glucose cotransporter type 2 (SGLT-2) inhibitors are approved drugs treat patients with chronic heart failure of different aetiologies. They play direct anticancer activity in SGLT2-expressing cancer cells, independent of glucose metabolism and through inhibition of oxidative phosphorylation. Ongoing studies are now testing empagliflozin (EMPA) in the prevention of left ventricular dysfunction in patients receiving high cumulative doses of anthracyclines. Aims To determine the effect of EMPA on cardiomyocytes in an in vitro model of PON-induced cardiac toxicity, and to assess underlying cardioprotective mechanisms. Methods and Results We exposed cardiomyocytes to PON (1.7 nM) or vehicle (DMSO) in the presence or absence of EMPA (100 and 500 nM) for 24 hours. Compared with vehicle, incubations with PON significantly reduced cell viability at 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT) assay, decreased autophagic cells at immunofluorescence assay (1±0.5 vs 6±1 fluorescence intensity/total area, p=0.0006, Figure 1), and increased cell senescence (15±5 vs 4±2 β-gal positivity/tissue area, p&amp;lt;0.02), effects all reverted by EMPA (p&amp;lt;0.01). We observed no significant effects of PON or EMPA on formation of reactive oxygen species. Compared with vehicle, PON significantly reduced serum response factor (SRF)/serum response elements (SRE) binding activity (25±9 vs 218±15 SRE complex abundance, arbitrary units, p&amp;lt;0.001), in parallel with a reduction in cardiac actin expression (0.32±0.06 vs 0.98±0,12 cardiac actin/GAPDH ratio, arbitrary units, p=0.001), which was reversed by EMPA (p=0.001). Conclusion EMPA attenuates PON cardiotoxicity by reducing senescence and enhancing autophagy, apparently independent of antioxidant mechanisms. This study suggests the design of clinical studies aimed at assessing the effects of EMPA on PON-induced cardiotoxicity.Legend to Figure 1.CON, control (vehicle, DMSO); PON, ponatinib; EMPA 100, empagliflozin 100 nM; EMPA 500, empagliflozin 500 nM

Abstract 17444: Racial and Ethnic Disparities in Anthracycline Cardiotoxicity

Introduction: There are limited data on anthracycline cardiotoxicity in racially and ethnically diverse populations. Aims: Our study sought to examine the incidence of cardiotoxicity and the changes in left ventricular ejection fraction (LVEF) in cancer survivors treated with anthracycline in a multiracial/ethnic community. Methods: We included consecutive adult patients who underwent anthracycline-based chemotherapy from 2016 to 2019 for any type of cancer. Patients with preexisting heart failure were excluded. The endpoint was the development of cardiotoxicity (defined as clinical HF or drop in LVEF≥10% to LVEF&lt;53%). Results: Our retrospective cohort included 925 patients (22% Non-Hispanic White (NHW), 25% Non-Hispanic Black (NHB), 31% Hispanic, and 2% Asian). Hypertension, diabetes, and hyperlipidemia were more prevalent in NHB, Hispanic, and Asian patients than in NHW patients. The mean cumulative anthracycline dose was 197±99 mg/m 2 and the mean LVEF was 64±5.7%, both similar across racial and ethnic groups. During a median follow-up of 21 months, 116 patients (13%) developed cardiotoxicity. The incidence of cardiotoxicity was significantly higher in NHB (16%), Hispanic (15%), and Asian (18%) patients compared to NHW patients (7%) (p=0.045). Of the 116 patients with cardiotoxicity, 21 patients had reduced ejection fraction (LVEF&lt;50%) and 81 had preserved ejection fraction (LVEF≥50%). Significantly more Hispanic patients developed cardiotoxicity with reduced ejection fraction (33.3%) compared to NHW (14.3%) and NHB (6.1%) patients (p=0.014). The mean decline in LVEF was higher in NHB patients (4% ± 9%) and Hispanic patients (6% ± 10%) than in NHW patients (3% ± 7%). Conclusions: In a large racially and ethnically diverse cohort of cancer survivors treated with anthracycline-based chemotherapy, NHB and Hispanic patients had an increased risk of cardiotoxicity and a greater decline in LVEF compared to their White counterparts.

616P Incidence of cardiotoxicity after high cumulative dose of anthracyclines in adult patients with advanced soft tissue sarcomas: A systematic review and meta-analysis

616P Incidence of cardiotoxicity after high cumulative dose of anthracyclines in adult patients with advanced soft tissue sarcomas: A systematic review and meta-analysis

Gene-Level Analysis of Anthracycline-Induced Cardiomyopathy in Cancer Survivors: A Report From COG-ALTE03N1, BMTSS, and CCSS

BackgroundAnthracyclines are highly effective in treating cancer, albeit with increased cardiomyopathy risk. Although risk is attributed to associations with single nucleotide polymorphisms (SNPs), multiple SNPs on a gene and their interactions remain unexamined. ObjectivesThis study examined gene-level associations with cardiomyopathy among cancer survivors using whole-exome sequencing data. MethodsFor discovery, 278 childhood cancer survivors (129 cases; 149 matched control subjects) from the COG (Children’s Oncology Group) study ALTE03N1 were included. Logic regression (machine learning) was used to identify gene-level SNP combinations for 7,212 genes and ordinal logistic regression to estimate gene-level associations with cardiomyopathy. Models were adjusted for primary cancer, age at cancer diagnosis, sex, race/ethnicity, cumulative anthracycline dose, chest radiation, cardiovascular risk factors, and 3 principal components. Statistical significance threshold of 6.93 × 10−6 accounted for multiple testing. Three independent cancer survivor populations (COG study, BMTSS [Blood or Marrow Transplant Survivor Study] and CCSS [Childhood Cancer Survivor Study]) were used to replicate gene-level associations and examine SNP-level associations from discovery genes using ordinal logistic, conditional logistic, and Cox regression models, respectively. ResultsMedian age at cancer diagnosis for discovery cases and control subjects was 6 years and 8 years, respectively. Gene-level association for P2RX7 (OR: 0.10; 95% CI: 0.04-0.27; P = 2.19 × 10−6) was successfully replicated (HR: 0.65; 95% CI: 0.47-0.90; P = 0.009) in the CCSS cohort. Additional signals were identified on TNIK, LRRK2, MEFV, NOBOX, and FBN3. Individual SNPs across all discovery genes, except FBN3, were replicated. ConclusionsIn our study, SNP sets having 1 or no copies of P2RX7 variant alleles were associated with reduced risk of cardiomyopathy, presenting a potential therapeutic target to mitigate cardiac outcomes in cancer survivors.

Acute and early-onset cardiotoxicity in children and adolescents with cancer: a systematic review

BackgroundCardiotoxicity is among the most important adverse effects of childhood cancer treatment. Anthracyclines, mitoxantrone and radiotherapy involving the heart are its main causes. Subclinical cardiac dysfunction may over time progress to clinical heart failure. The majority of previous studies have focused on late-onset cardiotoxicity. In this systematic review, we discuss the prevalence and risk factors for acute and early-onset cardiotoxicity in children and adolescents with cancer treated with anthracyclines, mitoxantrone or radiotherapy involving the heart.MethodsA literature search was performed within PubMed and reference lists of relevant studies. Studies were eligible if they reported on cardiotoxicity measured by clinical, echocardiographic and biochemical parameters routinely used in clinical practice during or within one year after the start of cancer treatment in ≥ 25 children and adolescents with cancer. Information about study population, treatment, outcomes of diagnostic tests used for cardiotoxicity assessment and risk factors was extracted and risk of bias was assessed.ResultsOur PubMed search yielded 3649 unique publications, 44 of which fulfilled the inclusion criteria. One additional study was identified by scanning the reference lists of relevant studies. In these 45 studies, acute and early-onset cardiotoxicity was studied in 7797 children and adolescents. Definitions of acute and early-onset cardiotoxicity prove to be highly heterogeneous. Prevalence rates varied for different cardiotoxicity definitions: systolic dysfunction (0.0–56.4%), diastolic dysfunction (30.0–100%), combinations of echocardiography and/or clinical parameters (0.0–38.1%), clinical symptoms (0.0–25.5%) and biomarker levels (0.0–37.5%). Shortening fraction and ejection fraction significantly decreased during treatment. Cumulative anthracycline dose proves to be an important risk factor.ConclusionsVarious definitions have been used to describe acute and early-onset cardiotoxicity due to childhood cancer treatment, complicating the establishment of its exact prevalence. Our findings underscore the importance of uniform international guidelines for the monitoring of cardiac function during and shortly after childhood cancer treatment.

Incidence and predictors of anthracycline-related left ventricular dysfunction in acute myeloid leukemia

IntroductionAnthracycline-related left ventricular dysfunction (ARLVD) is a concern in patients with acute myeloid leukemia (AML) undergoing anthracyclinecontaining induction chemotherapy. However, the incidence of ARLVD in the modern era of routine pretreatment left ventricular ejection fraction (LVEF) echocardiographic assessment, as well as the clinical and genetic predictors of ARLVD are not well understood. MethodsConsecutive adult patients with AML receiving anthracycline-containing induction chemotherapy at the Dana-Farber Cancer Institute from 2014 to 2022 were studied. Inclusion criteria included availability of a pre and post chemotherapy echocardiogram to assess the LVEF, pre-treatment LVEF > 50 %, as well as comprehensive diagnostic next generation sequencing assessing for the presence of myeloid mutations. The primary endpoint was the incidence of ARLVD defined as LVEF < 50 % post-induction. ResultsOut of 419 patients meeting inclusion criteria, 34 (8%) patients developed ARLVD. Among the 122/419 patients who did not undergo planned allogeneic stem cell transplantation (allo-SCT), ARLVD was the deciding factor for ineligibility in 4 patients (1%). Baseline cardiovascular comorbidities (hypertension, diabetes mellitus, hyperlipidemia, smoking and coronary artery disease) and cumulative anthracycline dose were not predictive of post-induction ARLVD. However, the presence of a JAK2 mutation (but not other myeloid mutations) was associated with an increased risk of ARLVD in multivariable analysis (OR 8.34, 95 % CI 1.55–39.3, p = 0.007). DiscussionIn a group of AML patients with normal LVEF prior to anthracycline-containing induction chemotherapy, ARLVD was infrequent and did not commonly preclude post-remission allo-SCT consolidation. Genetic predictors of ARLVD require further investigation in a larger patient cohort.

Recent advances in the Prevention and Treatment of Chemotherapy–induced Cardiotoxicity

The current study aimed to overview recent advances in preventing and treating chemotherapy-induced cardiotoxicity. Chemotherapy is widely used in cancer treatment, however, it can have adverse effects on the heart, leading to the development of risk factors, such as hypertension, obesity, dyslipidemia, and metabolic syndrome. Anthracycline compounds are the most commonly used chemotherapy agents and are associated with an increased risk of developing anthracycline-induced cardiotoxicity (AIC). The precise mechanisms underlying AIC remain a subject of debate, but evidence suggests that the primary causes are the generation of reactive oxygen species (ROS) and subsequent oxidative stress. Several risk factors have been linked to the development of AIC, including cumulative dose, pre-existing cardiac disease, age, gender, and cardiac risk factors. Genetic susceptibility may also play a role as a potential risk factor for AIC. In order to protect cardiac function, various strategies have been explored, such as developing less-toxic derivatives of anthracyclines, determining safer cumulative anthracycline doses, and identifying new cardioprotective agents. Prophylactic treatment with cardioprotective agents is the best approach for high-risk patients. This article reviewed the present strategies for protecting cancer patients from AIC based on effective cardioprotective drugs along with the balance between their benefits and potential adverse effects.

Evaluation of cardiac failure and recovery in acute myelogenous leukemia.

7038 Background: Cardiac failure causes significant comorbidity and death in acute myeloid leukemia (AML) patients, with incidence estimated at 10-15% (Neuendorff N Blood Adv. 2020). We sought to describe the post-treatment cardiac experience in AML survivors including factors associated with onset, persistence, and outcome of cardiac dysfunction during and following treatment. Methods: 86 patients with AML or other high-grade myeloid neoplasms treated with induction chemotherapy with or without allogeneic hematopoietic cell transplant were identified at the University of Washington/Fred Hutchinson Cancer Center from 1/2000-1/2022. All patients sustained cardiac dysfunction, defined as left ventricular ejection function (LVEF) decline of 10% with absolute LVEF below 50% during chemotherapy. A multivariable analysis was performed to compare those who recovered (LVEF recovery) and those who did not (LVEF non-recovery), examining baseline health factors, disease risk (ELN 2017), time to dysfunction and recovery, most probable cause of cardiac dysfunction based on cardiologist evaluation, and goal-directed medical therapy (GDMT) use and dosage. Results: 48% (41 out of 86) failed to recover following LVEF decline. This cohort tended to be older, male, and had more ASCVD risk factors ( p &lt; 0.05). Neither the choice of chemotherapy regimen ( p= 0.43) nor the cumulative anthracycline dose ( p= 0.44) was significantly different between the LVEF recovery and non-recovery groups. Onset of cardiac dysfunction tended to occur later in the LVEF recovery cohort (median 72 vs. 48.5 days, p= 0.660). In subjects who recovered, the median time to recovery was 87 days (range 2-268 days). When chemotherapy was identified as the probable cause, it was associated with greater likelihood of eventual recovery ( p= 0.014), whereas ischemic coronary etiology was associated with non-recovery ( p= 0.005). Failing to recover from cardiac dysfunction correlated with shorter survival (median 229 vs 650 days, p = 0.005). Multivariable analysis is shown in the Table below. Importantly, the use of GDMT with higher doses of renin-angiotensin inhibitor medications (RAASi) were associated with higher probability of recovery (not shown, p &lt; 0.05). Conclusions: The present study demonstrates recovery occurring in over half of AML patients who experienced cardiac dysfunction during their chemotherapy. Recovery was more common in patients whose cardiac dysfunction is precipitated by chemotherapy and in patients who received GDMT with aggressive use of RAASi. Since cardiac recovery was associated with improved survival, next steps include establishing a cardiac monitoring algorithm to initiate early and aggressive GDMT. [Table: see text]

Predicting therapy-induced cardiomyopathy in long-term survivors of childhood cancer: A report from the St. Jude Lifetime Cohort (SJLIFE) and the Childhood Cancer Survivor Study (CCSS).

12018 Background: Cancer-therapy-induced cardiomyopathy (CCM) is the leading noncancer cause of mortality among long-term survivors of childhood cancer, the prevalence of which increases with age. Early identification of survivors at risk provides opportunities for targeted prevention strategies. Here, we developed and validated a clinically applicable CCM prediction model based on survivor characteristics, treatment exposures and inherited genetic variation among long-term survivors of childhood cancer. Methods: Long-term survivors from SJLIFE (training cohort; n = 3,350; median age 34 years, range 8-72 years) and CCSS (validation cohort; n = 7,008; median age 36 years, range 11-64 years) were assessed by the five different general population polygenic risk scores (multiPRS) for dilated cardiomyopathy, hypertrophic cardiomyopathy, heart failure, ejection fraction and left ventricular end systolic volume. Multivariable logistic regression was used to predict 15-year risk of the CCM (defined as CTCAE grade ≥3 cardiomyopathy requiring heart failure medications or heart transplantation or leading to death). Model performance was assessed by the area under the receiver operating characteristic curve (AUC). Results: CCM was clinically identified in 150 (4.5%) SJLIFE and self-reported in 156 (2.1%) CCSS survivors, respectively. AUC of clinical models with attained age, sex, age at primary cancer diagnosis, cumulative anthracycline dose, mean heart radiation dose (heart RT), and genetic ancestry was 0.81 (95% CI, 0.78-0.85) in SJLIFE and 0.78 (95% CI, 0.74-0.81) in CCSS. Inclusion of cardiovascular risk factors (hypertension, dyslipidemia, and diabetes) significantly increased AUC to 0.83 (95% CI, 0.80-0.87; P= 0.011; SJLIFE) and 0.84 (95% CI, 0.80-0.87; P&lt; 0.001; CCSS). The addition of the multiPRS further provided significant but modest increases in AUC in SJLIFE (0.84; 95% CI, 0.81-0.87; P= 0.022) and CCSS (0.85; 95% CI, 0.81-0.88; P= 0.031). In low-risk survivors (exposed to &lt; 100 mg/m2 anthracyclines and &lt; 15 Gray heart RT), we observed a possibly larger magnitude AUC increase after adding multiPRS, 0.73 (95% CI, 0.65-0.82) to 0.76 (95% CI, 0.68-0.83; P= 0.11) in SJLIFE and 0.77 (95% CI, 0.65-0.90) to 0.82 (95% CI, 0.69-0.94; P= 0.073) in CCSS. Conclusions: Inherited polygenic factors contributed significantly to improve CCM prediction over available clinical risk factors and may be of benefit to low-risk survivors for whom routine cardiac surveillance is not currently recommended.

Left Ventricular-Arterial Coupling and Vascular Function in Childhood Cancer Survivors Exposed to Anthracycline Chemotherapy

Background: Cardiovascular (CV) diseases are a cause of increased long-term morbidity and mortality in childhood cancer survivors (CCSs) treated with anthracyclines. These drugs may affect not only the heart, but also the vascular system. Left ventricular-arterial coupling (LVAC) represents a reliable parameter of altered ventricular and vascular performance, with validated prognostic value and never investigated in this setting. Aim of this study was to assess, in CCSs and matched controls, LVAC changes, performed with different echocardiographic modalities, and their relationship with endothelial function. Methods: Twenty survivors treated with anthracyclines for childhood malignancies and a matched control group of 20 healthy subjects were enrolled. Arterial elastance (Ea), end-systolic elastance (Ees), Ea/Ees ratio, as well as three-dimensional (3D) LVAC (assessed by measurement of End Systolic Volume [ESV]/Stroke Volume [SV] ratio) were performed at rest. Endothelial function was evaluated by measurement of flow-mediated dilatation (FMD) of the brachial artery. Results: 3D SV and 3D ESV/SV ratio resulted respectively significantly lower and higher in CCSs than in controls, while Ea, Ees and Ea/Ees ratio were not different among groups. A positive correlation between 3D ESV/SV ratio and cumulative anthracycline doses, as well as with time after drug exposure were also found. Mean FMD was similar in CCSs and controls (8.45 ± 1.79 versus 9.41 ± 3.41, p = 0.34). Conclusions: In conclusion, conventional LVAC parameters were not shown to be significantly different between CCSs and controls; however, 3D SV and LVAC were significantly impaired in our population. In these patients, endothelial function was comparable to controls. Larger validation studies are therefore needed.

Chemotherapy-free treatment for acute promyelocytic leukemia: the pediatric view of a revolutionary tale.

The addition of all-trans retinoic acid (ATRA) to the standard anthracycline-base chemotherapy has revolutionized the treatment of acute promyelocytic leukemia (APL) over the last decades, becoming a model for precision medicine. The protocols based on the combination of ATRA and chemotherapy allowed obtaining excellent response rates both for children and adults. However, the persistence of anthracycline chemotherapy as a backbone was a matter of concern for both acute and long-term complications. Efforts in reducing anthracycline cumulative dose or even eliminating anthracycline have been pursued in more recent pediatric protocols thanks to the introduction of arsenic trioxide (ATO). The impressive results of the ATRA/ATO combinations led to the introduction of protocols completely chemotherapy-free for standard-risk adult patients as the standard of care, whereas pediatric chemo-free protocols are still currently under evaluation. In this Review, we will critically retrace the history of this unique revolution in precision medicine, discussing the peculiar advantages for pediatric patients with APL.

Abstract 4363: Monocyte-specific epigenetic age acceleration and cardiomyopathy risk among survivors of childhood cancer

Abstract Our assessment of epigenetic age acceleration (EAA), calculated with DNA methylation (DNAm) data generated from bulk DNA derived from peripheral blood mononuclear cells (PBMC), supports accelerated aging in childhood cancer survivors (CCS). It is challenging to disentangle variation of DNAm at cell-type specific levels from the effects of age-dependent cell type composition, and bulk measurements may obfuscate the links between EAA and age-related outcomes (e.g., cardiomyopathy). Methylation profiling was generated using Infinium EPIC BeadChips on PBMC-derived DNA from CCS in the St. Jude Lifetime Cohort. Tensor composition analysis was employed to deconvolute bulk DNAm and infer DNAm at each leukocyte subtype level, i.e., a single n (individuals) by m (DNAm sites) matrix of observed DNAm data was deconvoluted into multiple n by m matrices of DNAm data. Epigenetic age (EA, using Levine’s clock) and EAA (residuals from the fit of a simple linear regression of EA on chronological age at blood draw) were calculated for bulk PBMCs and each cell subtype (CD4T, CD8T, B, natural killer, and monocyte). Cardiomyopathy (CMP) was assessed by echocardiography, and severity graded (2 = moderate, 3 = severe/disabling, 4 = life-threatening and 5 = fatal) using a modified version of the National Cancer Institute Common Terminology Criteria for Adverse Events. Cumulative doses of anthracyclines and mean heart radiation doses (heart-RT) calculated through radiation dosimetry were abstracted from medical records. Associations between EAA and CMP were evaluated by multivariable Cox regression. Cell-type specific EA was highly correlated with bulk EA with Pearson r2 between 0.63 (CD8T) and 0.79 (CD4T), but the linear regression lines of cell-type specific EA against bulk EA differed in both intercept and slope, suggesting heterogeneity across leukocyte subtypes. Cell-type specific EAA was moderately correlated with bulk EAA with Pearson r2 between 0.23 (monocyte) and 0.29 (CD8T). Among 2,044 CCS (median age = 33.7 years), 104 (5.1%) developed CMP (≥grade 3). Among bulk EAA and five cell-type specific EAAs, monocyte EAA was the only one significantly associated with CMP (hazard ratio per standard deviation increase in EAA = 1.25, 95% CI = 1.04-1.50, P = 0.018). Cell sorting of PBMC followed by DNAm is currently underway for further validation. We showed an in-depth view of the variability of EAA across leukocyte subtypes, and more importantly, demonstrated that monocyte EAA was associated with CMP risk. Our novel finding is plausible and consistent with the literature implicating monocyte-derived cardiac macrophages in cardiac remodeling, which can be induced by cardiotoxic cancer treatment exposures in CCS. Therapeutic strategies that prevent deleterious effects of monocytes contributing to adverse cardiac remodeling, while sparing their essential immune functions, may prevent or ameliorate CMP among CCS. Citation Format: Cheng Chen, Qian Dong, Qin Na, Nan Song, John Easton, Heather L. Mulder, Emily Walker, Geoffrey Neale, Emily R. Finch, Qian Li, Yutaka Yasui, Daniel A. Mulrooney, Melissa M. Hudson, Kirsten K. Ness, Jinghui Zhang, Xiang Chen, Hui Wang, Leslie L. Robison, Zhaoming Wang. Monocyte-specific epigenetic age acceleration and cardiomyopathy risk among survivors of childhood cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4363.