Heart Failure in Patients with Acute Myeloid Leukemia (AML) Treated with Anthracycline Agents During Remission Induction Therapy: A Systematic Review and Meta-Analysis

Heart Failure in Patients with Acute Myeloid Leukemia (AML) Treated with Anthracycline Agents During Remission Induction Therapy: A Systematic Review and Meta-Analysis | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Heart Failure in Patients with Acute Myeloid Leukemia (AML) Treated with Anthracycline Agents During Remission Induction Therapy: A Systematic Review and Meta-Analysis Marijke Linschoten, Jesse Geels, Anna van Rhenen, Patrycja Gradowska, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6327060/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 10 Oct, 2025 Read the published version in Leukemia → Version 1 posted 11 You are reading this latest preprint version Abstract Patients with acute myeloid leukemia (AML) are at high risk of cardiovascular disease, particularly heart failure. Anthracyclines are integral to remission induction in patients eligible for intensive treatment and well-known for their association with cardiotoxicity. However, the incidence of heart failure and other cardiovascular adverse events (CVAEs), as well as differences across various anthracycline agents, has not been comprehensively assessed. We systematically searched PubMed and EMBASE for studies conducted in AML patients treated with anthracyclines during remission induction. Forty-one studies (5 995 patients), primarily clinical trials, published between February 1991 and March 2024 were included. The pooled proportion of heart failure was 3.2% (95%CI 1.0–6.2) overall and 2.3% (95%CI 1.4–3.3), 5.0% (95%CI 0.3–14.1) and 10.2% (95%CI 2.4–21.7) for patients treated with daunorubicin, idarubicin or mitoxantrone respectively. Cardiac function was infrequently monitored, and CVAE reporting often lacked detail. Since current adverse event grading systems primarily rely on clinical symptoms to determine severity, significant asymptomatic declines in cardiac function frequently go undetected. Enhanced CVAE monitoring and reporting are needed to better identify subclinical cardiotoxicity in AML patients, enabling timely intervention to prevent progression to more advanced stages of heart failure. Furthermore, early management might prevent delay of consolidation treatment. Health sciences/Diseases/Haematological diseases/Haematological cancer/Leukaemia/Acute myeloid leukaemia Health sciences/Health care/Quality of life Health sciences/Signs and symptoms Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction Over the past decades, advances in modern antineoplastic therapies and supportive treatment have led to improved survival rates in patients with acute myeloid leukemia (AML). 1 With the expanding population of AML survivors, greater attention should be directed toward managing and preventing treatment-related side-effects, to further improve cancer treatment tolerability as well as quality of life and survival in this patient population. A major concern for AML survivors is the increased long-term risk of cardiovascular disease (CVD). Studies indicate that leukemia survivors are significantly more likely to develop heart failure than the general population (adjusted hazard ratio 1.77 to 2.49). 2 – 3 Also when compared to survivors of other types of cancer, the risk appears particularly high. 2 – 4 Among long-term hematopoietic stem cell transplantation (HSCT) survivors, the cumulative incidence of symptomatic heart failure has been reported to be 5–6% 5-year post transplant, increasing to almost one in ten patients at 10-years. 5 – 6 The incidence of left ventricular systolic dysfunction (regardless of symptoms) has been described as high as 44%. 7–8 Patients with asymptomatic left ventricular dysfunction are at high risk to progress to more advanced heart failure stages. 9 Several factors are believed to contribute to the heightened cardiovascular risk in AML patients and survivors. Advances within the field of cardio-oncology have led to the identification of shared risk factors between cancer and CVD (e.g. smoking) and unique, cancer-driven biological mechanisms (e.g. clonal hematopoiesis of indeterminate potential). 10 – 14 Moreover, exposure to chemotherapeutic agents associated with cardiovascular toxicity is a critical driver in the development of CVD. 15 Anthracycline agents are especially well-known for their strong association with cardiotoxicity, particularly in causing myocardial dysfunction that can progress to heart failure. 15 These class of drugs are integral to the 7 + 3 regimen, the standard remission induction therapy for AML that has been in use for over five decades. 16 – 17 Despite the use of anthracycline-based regimens as first-line therapy and evidence from previous studies highlighting the high cardiovascular risk among AML survivors, a systematic assessment of the incidence of heart failure and cardiovascular adverse events (CVAEs) in this patient population has not been conducted. Previous studies have largely focused on children or patients with Down syndrome-associated AML, have been limited in sample size, or have examined only the risk of symptomatic heart failure within broader leukemia populations—often combining acute and chronic forms despite substantial differences in patient characteristics and treatment protocols, particularly anthracycline usage. 2 – 3 , 18 – 23 Considering that anthracycline agents, incorporated in the 7 + 3 regimen, are expected to remain the cornerstone of intensive remission induction therapy and their combination with targeted therapies is likely to further improve survival rates in the future, it is crucial to gain deeper insight into the cardiotoxicity of this regimen. With this systematic review we aim to contribute to this insight by evaluating and comparing the incidence of CVAEs, with special interest in heart failure, among AML patients treated with anthracycline agents during remission induction chemotherapy. Materials and methods Search strategy and selection criteria This systematic review and meta-analysis followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines (Supplementary Appendix p.2). 24 The initial literature search was conducted in PubMed and EMBASE from database inception to July 19th, 2023. An updated search was performed on April 13th, 2024. The full search string is provided in the Supplementary Appendix 4(p.5). We selected studies conducted in adult patients with AML, treated with an intensive anthracycline- (daunorubicin, idarubicin, CPX-351 or aclarubicin) or anthraquinone-containing (mitoxantrone) chemotherapeutic remission induction regimen in a first-line setting. Studies including patients with myelodysplastic syndrome (MDS) or secondary AML were also eligible. To minimize heterogeneity, we primarily included studies in which patients received an induction regimen consistent with the 2022 European Leukemia Network (ELN) recommendations. 17 Specifically, this included daunorubicin at 60 mg/m², idarubicin at 12 mg/m², or mitoxantrone at 12 mg/m² for 3 days, combined with conventional-dose cytarabine (100 or 200 mg/m²) for 7 days, or CPX-351 at 100 U/m² on days 1, 3, and 5. To examine the relationship between cumulative daunorubicin dose and heart failure, studies incorporating lower than conventional daunorubicin doses (45 mg/m 2 ) or higher daunorubicin doses (90 mg/m 2 ) were also included. Due to the limited availability of studies using mitoxantrone in line with ELN 2022 recommendations, we also included studies administering mitoxantrone doses below or above 12 mg/m 2 or for less or more than 3 days in combination with varying doses of cytarabine and/or etoposide. Furthermore, we also included studies using aclarubicin, as this anthracycline agent is reported to have lower cardiotoxicity compared to other anthracyclines. 25 – 26 Studies solely including patients with Down’s syndrome associated AML or promyelocytic leukemia (FAB-M3) were excluded. In addition, studies in patients with relapsed- or refractory disease, patients pre-exposed to an anthracycline- or anthraquinone agent for the treatment of AML or studies with the concurrent administration of chemotherapeutic agents other than cytarabine were deemed ineligible. Lastly, all non-English publications, review articles, letters and preclinical studies were excluded. Studies deemed eligible based on their title or abstract were assessed full-text and included in the analyses if they contained at least one of the following outcomes: (1) number of patients with clinical heart failure or subclinical left ventricular systolic dysfunction i.e. asymptomatic decline in left ventricular ejection fraction (LVEF); (2) number of patients with CVAEs annotated in grades, preferably with the use of a well-established toxicity grading system; (3) number of patients in whom treatment was discontinued due to heart failure; and (4) number of patients who died due to heart failure. Only articles that reported the incidence of CVAEs occurring during or directly after induction chemotherapy, prior to the initiation of consolidation chemotherapy or another line of treatment, were included. Studies that did not report CVAEs were included only if the publication explicitly confirmed that no other adverse events occurred beyond those detailed. Similarly, only studies specifying the reasons for treatment discontinuation and the cause of death for all patients were considered eligible for inclusion regarding treatment discontinuation and heart failure-related mortality. Where available, study protocols for the included studies were also reviewed. The screening and selection process of all the identified studies was performed independently by two researchers (JG and ML). A full list of in- and exclusion criteria as well as excluded studies after full text assessment is provided in the Supplementary Appendix (p.6). Any conflicts were settled by discussion until consensus was reached. In case one or multiple outcomes were lacking in a study published more recently and it was conceivable that this data was available based on the information provided in the article, authors were approached requesting for additional information. Data analysis Data was extracted from eligible studies manually by two independent researchers (JG and ML) and tabulated in a database. For each study the following information was extracted: study design, total sample size, sample size for which toxicity outcomes were reported, summary statistics describing the study population (e.g. median age and number of males and females), duration of follow-up, treatment regimen including cumulative anthracycline- or mitoxantrone dose, grading system used for adverse events reporting, and whether or not cardiac function was assessed before and after induction therapy. Furthermore, the following counts were collected for the outcomes of interest: the number of patients with (1) heart failure (including symptomatic heart failure and an asymptomatic decline in LVEF); (2) symptomatic heart failure versus an asymptomatic decline in LVEF; (3) grade 1–2 CVAEs; (4) grade 3–4 CVAEs; (5) treatment discontinuation due to heart failure; and (6) heart failure mortality. If included studies contained more than one eligible treatment arm (i.e. different anthracycline agents or doses used across arms), data extraction was performed for each treatment arm separately, effectively leading to > 1 subgroup derived from one study. If multiple studies were based on data of the same clinical trial, data were extracted from the article that reported the most complete toxicity outcomes. To estimate the proportion of patients developing heart failure, grade 1–2 or grade 3–4 CVAEs, meta-analyses of one-sample proportions were conducted. The Freeman-Tuckey double arcsine transformation was applied to extracted proportions to establish a normal distribution appropriate for pooling. 27 Proportion estimates are presented with 95% confidence intervals (CIs). Study weights in each analysis were determined using the inverse of their variance. A random effects model was used for pooling the summary proportions. Heterogeneity among studies was assessed using Cochran’s Q-test and quantified with the I 2 statistic, with values exceeding 50% considered indicative of substantial heterogeneity. Statistical significance was defined as a p-value less than 0.05. Sensitivity analyses were conducted by excluding outlier studies. All analyses were performed in R (version 1.4.1106) using the ‘ metafor’ package. 28 Risk of bias assessment Bias of individual studies was assessed with an adaptation of the Cochrane Risk of Bias tool. 29 Quality of the reporting of adverse events in each individual study was assessed using a modified checklist from the Better Reporting of Harms in Randomized Trials: An Extension of the CONSORT Statement. 30 A detailed description of the risk of bias assessment and the evaluation of the quality of adverse event reporting is provided in the Supplementary Appendix (p.22). Two researchers (JG and ML) independently performed the risk of bias assessment, solving any disagreements by discussion. Results The literature search strategy identified 10 204 unique records. Following title and abstract screening, 813 articles were assessed full text of which 41 studies (comprising 5 955 patients across 48 subgroups) published between February 1991 and March 2024 were retained for the final analyses (Fig. 1 ). Data was mainly derived from clinical trials (36 studies) and to a lesser extent from retrospective cohort studies (5 studies). The proportion of patients with heart failure was reported in 27 studies (n = 4 461 patients), of which five studies (n = 521 patients) reported to have assessed LVEF pre- and post- remission induction therapy as well as reported the number of patients who experienced a decline in LVEF post-induction. Grade 3–4 CVAEs were documented in 29 studies (n = 4 545 patients) while 12 studies (n = 1 997 patients) reported on grade 1–2 CVAEs. Daunorubicin was the most frequently incorporated anthracycline for remission induction, used in 20 (42%) subgroups. Idarubicin was used in 9 (19%), mitoxantrone in 11 (23%), CPX-351 in six (13%) and aclarubicin in 2 (4%) subgroups. Detailed characteristics of included studies are provided in the Supplementary Appendix (p.16). Heart failure Nine treatment subgroups (n = 1 801 patients) were included in the meta-analysis to assess the reported proportion of patients with heart failure during induction treatment with a 7 + 3 regimen using either daunorubicin 60 mg/m 2 or idarubicin 12 mg/m 2 in line with ELN recommendations. The pooled proportion of heart failure was 3.2% (95%CI 1.0–6.2; test for heterogeneity Q = 59.00, τ 2 = 0.0102 and I 2 = 86.4%; p < 0.01)(Fig. 2 ). No significant subgroup difference was observed in the proportion of patients with heart failure between those treated with daunorubicin versus idarubicin (p = 0.38). The number of patients with heart failure was higher among patients receiving a 7 + 3 induction regimen with daunorubicin doses of 90 mg/m 2 (n = 729) compared to those treated with a conventional 60 mg/m 2 dose (n = 1 029) with a pooled proportion of 4.8% (95%CI 2.3–8.1) versus 2.3% (95%CI 1.4–3.3) respectively, although not statistically significant (Fig. 3 ; test for subgroup differences: p = 0.07). Results of comparing patients treated with a lower-than-conventional daunorubicin dose (45 mg/m 2 ) to those receiving a conventional (60 mg/m 2 ) or high-dose (90 mg/m 2 ) daunorubicin are displayed in the Supplementary Appendix (Figure S1 and Figure S2; p.18). In total, 435 patients across 8 treatment subgroups were treated with various mitoxantrone-containing regimens. Mitoxantrone dosing varied: four subgroups received 10–12 mg/m² over three days, one subgroup received 10 mg/m² for four days, and three subgroups were treated with a single high-dose infusion of 80 mg/m². The pooled proportion of heart failure was 10.2% (95%CI 2.4–21.7; test for heterogeneity Q = 85.24, τ 2 = 0.0411 and I 2 = 91.8%; p < 0.01)(Fig. 4 ). After excluding two outlier studies in which cardiac function was actively monitored, the pooled proportion of heart failure was 4.1% (95%CI 0.9–8.8; test for heterogeneity Q = 10.64, τ 2 = 0.0064 and I 2 = 53.0%; p = 0.06)(Figure S3; Supplementary Appendix p.19). Two studies (n = 174 patients) reported on heart failure outcomes after CPX-351 treatment, in this group the pooled proportion was 4.6% (95%CI 0.0–14.0; test for heterogeneity Q = 4.56, τ 2 = 0.0105 and I 2 = 78.1%; p = 0.03)(Figure S4; Supplementary Appendix p.19). Among the three studies using aclarubicin, no patients (n = 151) were reported to have developed heart failure or heart-failure related mortality. 50 – 52 The pooled proportion of mortality- and treatment discontinuation due to heart failure among patients treated with an induction regimen following ELN 2022 recommendations was 2.0‰ (95‰CI 0.7–5.8) and 3.2‰ (95‰CI 0.6–18.0) with three heart failure deaths among 1 520 patients and one out of 310 patients who discontinued treatment due to heart failure (Figure S5 and Figure S6, Supplementary Appendix p. 20). Cardiovascular adverse events Eighteen treatment subgroups derived from 17 studies (n = 2 454 patients) reported on the occurrence of grade 3–4 CVAEs in patients treated with daunorubicin, idarubicin, mitoxantrone or CPX-351 according to the ELN 2022 recommendations. The pooled proportion of high-grade CVAEs was 3.3% (95%CI 1.9–5.0; test for heterogeneity Q = 59.24, τ 2 = 0.0050 and I 2 = 71.3%; p < 0.01)(Figure S7; Supplementary Appendix p.21). The pooled proportion of grade 1–2 CVAEs (n = 924 patients) was 9.7% (95%CI 4.8–16.0) (test for heterogeneity Q = 54.03, τ 2 = 0.0150 and I 2 = 85.2%; p < 0.01)(Figure S8; Supplementary Appendix p.21). Risk of bias and quality assessment The risk of bias and quality of the reporting of harms was assessed for each individual study and is shown in the Supplementary Appendix (p.23–24). Briefly, 23 studies (56%) were deemed to be at high risk of bias, 12 (29%) a moderate risk and 6 (15%) a low risk of bias. High risk of bias through poor specification of CVAEs was present in 11 of the 34 studies (32%) that were included in either the heart failure or CVAEs analyses. Six of the 34 (18%) studies were deemed to have a high risk of introducing bias through incomplete reporting of CVAEs. Six (18%) studies did not report the grading system used to assess AEs and were therefore considered as likely to introduce bias. Discussion This systematic review and meta-analysis provides a comprehensive evaluation of the incidence of heart failure and CVAEs in AML patients undergoing intensive remission induction therapy with anthracycline agents or mitoxantrone. The key findings of this study include: (1) the overall incidence of symptomatic heart failure during induction therapy was lower than 5%; (2) the incidence of heart failure increases with anthracycline-dose intensification; (3) cardiac function was infrequently monitored during induction therapy, and if monitored, reporting on the number of patients with a decline in LVEF was limited; and (4) patients treated with mitoxantrone-containing regimens may be at higher risk of heart failure when compared to those treated with regimens containing daunorubicin or idarubicin. The overall low incidence of symptomatic heart failure observed during or shortly after induction therapy is consistent with findings from previous clinical trials in patients with solid tumors, which helped establish maximum cumulative dose limits for anthracyclines aiming to keep symptomatic heart failure rates below 5%. 53–54 According to these studies, this corresponds to a doxorubicin cumulative dose between 400 and 550 mg/m 2 , equivalent to 480–660 mg/m 2 daunorubicin, 80–100 mg/m 2 idarubicin or 100-137.5 mg/m 2 mitoxantrone based on the conversion factors currently applied in clinical practice. 55 Given that patients treated for AML typically do not reach these cumulative doses, a low incidence of symptomatic heart failure was anticipated. However, recent large cohort studies highlight a significantly increased long-term risk of heart failure in patients treated for AML. Leukemia survivors are reported to face a 1.77 to 2.49 times higher risk of developing heart failure as compared to the general population. 2 – 3 Additionally, heart failure rates were found to be higher in leukemia survivors than in most other types of cancer. 2 – 4 The discrepancy between the low short-term heart failure risk observed in this study and the significantly increased long-term risk may be explained by considering anthracycline-induced cardiac dysfunction (AICD) as a progressive spectrum. 15 In the initial stages, AICD may be evident through elevated cardiac biomarkers (i.e. troponin) indicating a loss of cardiomyocytes. When myocardial damage surpasses a certain threshold, it leads to a measurable decline in myocardial contractility reflected by a decline in LVEF. 56 In 98% of the patients this LVEF decline can already be detected through serial assessment of cardiac function within the first year after initial anthracycline administration, with a median time-to-event between 3.0–3.5 months. 57 , 58 The onset of symptomatic heart failure is delayed in a great majority of patients by the activation of compensatory mechanisms including the renin-angiotensin-aldosterone system. 59 Nonetheless, patients with asymptomatic left ventricular systolic dysfunction have a fivefold higher risk of progressing to clinical heart failure compared to control subjects, making awareness of its occurrence important. 9 Early detection of subclinical cardiac dysfunction does not only facilitate the initiation of cardioprotective drugs, which could prevent further deterioration to more advanced heart failure stages, but also help identify AML patients at risk for adverse outcomes in later stages of treatment, i.e. HSCT. 15 Of the 27 studies included in this review that reported on the number of patients with heart failure, only eight reported to have assessed cardiac function both pre- and post-induction therapy and of these five detailed the number of patients who developed asymptomatic left ventricular dysfunction. In all these studies, the reported incidence of heart failure events overall was considerably higher than studies that did not mention serial assessment of cardiac function, ranging from 7.0–43.8%. 37, 41 , 43 , 46 , 48 This suggests that subclinical AICD may often go unrecognized in a clinical trial setting due to the lack of cardiac monitoring. This hypothesis is further supported by a small number of retrospective cohort studies that performed cardiac monitoring during induction therapy in patients with AML, reporting 8–9% of patients developing (asymptomatic) cardiac dysfunction. 21 – 22 Among patients monitored for up to two years following HSCT, even higher incidences have been reported, ranging from 7–33%. 20, 58 , 60–61 An additional key finding of this study was the rising incidence of heart failure among patients treated with higher doses of daunorubicin, underscoring the dose-response relationship between anthracyclines and heart failure. While idarubicin and mitoxantrone are typically dosed at 12 mg/m 2 in the 7 + 3 regimen, the optimal daunorubicin dose for induction therapy in fit patients remains a subject of ongoing debate. Three older trials investigating high-dose daunorubicin (90 mg/m 2 ) versus the previous standard daunorubicin dose (45 mg/m 2 ) demonstrated that high doses resulted in better overall survival and higher response rates. 40 , 62–63 This benefit was not demonstrated by two trials comparing high-dose daunorubicin (90 mg/m 2 ) to the current standard dose (60 mg/m 2 ). 64–65 None of these trials reported excess cardiotoxicity in the high-dose treatment arm; however, only in one of these trials specific heart failure outcomes and occurrence of subclinical declines in LVEF were reported. 62 The impact of anthracycline dose intensification on heart failure incidence in AML patients thereby remains unclear, highlighting the need for improved toxicity reporting. This includes specifying adverse events, conducting regular cardiac monitoring, and providing detailed documentation of subclinical declines in LVEF. Such comprehensive reporting is essential for accurately assessing the effects of anthracycline dose intensification on heart failure risk. The NCI Common Terminology Criteria for Adverse Events (CTCAE) is currently widely accepted as the standard system for classification and grading of severity of adverse events in the setting of oncology trials but poses major challenges when it comes to a heart failure. 66 Grading inconsistencies arise when different entry terms are used, as the same significant decline in LVEF can be classified as either a grade 3 or grade 1 adverse event depending on whether the entry of choice is ‘ejection fraction decreased’ or ‘heart failure’. 67 Another objective of this systematic review was to compare the incidence of heart failure and CVAEs among patients treated with induction regimens containing different anthracycline agents. A significant difference in the incidence of heart failure among patients treated with daunorubicin, idarubicin, and CPX-351 according to ELN 2022 recommendations could not be established. 17 However, our study did find a high proportion of patients of heart failure among those treated with a mitoxantrone-containing induction regimen of 10.2% (95%CI 2.4–21.7), as compared to 2.3% (95%CI 1.4–3.3) with daunorubicin and 5.0% (95%CI 0.3–14.1) with idarubicin. The high incidence among patients treated with mitoxantrone was predominantly driven by two studies in which patients were monitored for subclinical declines in LVEF. 43 , 48 The current ELN 2022 guidelines allow the treating clinician to choose between daunorubicin, idarubicin, or mitoxantrone for patients deemed fit for intensive induction therapy. 17 Currently, the cardiotoxicity risk of each anthracycline is derived by its doxorubicin-equivalent cumulative dose. 68 These equivalence ratios are largely derived from the agent’s antileukemic efficacy, extrapolated to hematologic toxicity, and then broadly applied to other organ systems. 68 However, a recent large multicenter cohort study in childhood cancer survivors, aimed at determining optimal dose equivalence ratios for cardiomyopathy between doxorubicin and other anthracyclines and mitoxantrone, revealed a significant underestimation of mitoxantrone’s association with long-term cardiomyopathy risk. 69 The results of this study led to a significantly higher conversion factor for mitoxantrone (10.5x doxorubicin dose instead of 4x) that is now used in the latest cardio-oncology guidelines of the European Society of Cardiology. 70 Previous meta-analyses comparing the incidence of cardiotoxicity in adult AML patients treated with idarubicin versus daunorubicin have reported no significant difference. 71–72 However, both these studies failed to specify the nature of the reported CVAEs, particularly (subclinical) heart failure. Similarly, two large phase III trials comparing the efficacy of mitoxantrone to daunorubicin and idarubicin failed to report cardiovascular adverse outcomes. 73–74 To the best of our knowledge, this is the first systematic review focusing on the incidence of heart failure in patients with AML treated with anthracycline-containing remission induction regimens. Previously, only a small number of retrospective cohort studies have investigated the occurrence of left ventricular systolic dysfunction in this patient population. 20 – 22 , 58 , 60–61 A key strength of this study is the inclusion of data from a large number of trials, which is particularly valuable in the context of mitoxantrone since this agent is less commonly used for remission induction. However, this study also has some limitations. Firstly, only a limited number of randomized controlled trials that met our inclusion criteria have directly compared different anthracyclines, and these studies were highly heterogeneous regarding treatment regimens. This prevented the pooling of outcomes exclusively from such studies. 36 – 37 , 51 , 75–77 Pooling outcomes across trials for a comparison of the cardiotoxicity of different anthracyclines also introduces heterogeneity by variations in study protocols, inconsistent adverse event reporting, and diverse study populations. Secondly, the lack of access to individual patient data restricted our ability to identify specific cardiovascular risk factors contributing to adverse cardiovascular outcomes. The findings of this systematic review carry significant implications for future research. Clinical trials should prioritize enhanced monitoring protocols for early detection of cardiac dysfunction and more precise specification of CVAEs. Currently, ambiguous CTCAE entry terms will contribute to significant variability in adverse event reporting. The CTCAE should be refined to offer comprehensive tools that help researchers accurately interpret and grade complex clinical syndromes, such as heart failure. 30 , 67 Furthermore, the higher incidence of heart failure observed in patients treated with mitoxantrone suggests possible heterogeneity among subgroups regarding the risk of AICD development. Large, prospective studies are necessary to identify and characterize these high-risk subgroups. Additionally, our study emphasizes the necessity for further research to validate the existing anthracycline conversion factors for cardiotoxicity, as the current factors are based on data from childhood cancer survivors. In conclusion, this study indicates that during remission induction therapy for AML, the overall occurrence of symptomatic heart failure and other high grade CVAEs is low. However, the limited monitoring of cardiac function and inadequate reporting of CVAEs likely lead to under-detection of these events, especially in high-risk subgroups. This hinders the ability to identify patients at risk for CVD after remission induction receiving additional AML treatment as well as later in life. Early recognition of such individuals is crucial, as implementing cardioprotective measures can prevent or reduce these complications. Therefore, the adoption of early screening for CVAEs and improved reporting of such events, along with revisions to established grading systems, are essential. Declarations Competing interests The authors declare no competing interests. Author contributions ML and AvR conceptualized the study, designed the research methodology and supervised the project. JG conducted the literature search. JG and ML screened the studies, extracted the data and performed the risk of bias assessment. JG performed the statistical analysis and interpreted the results with input from ML. JG drafted with initial manuscript with input from ML. AvR, FWA, ML and PG critically revised the manuscript. All authors read and approved the final manuscript. Acknowledgements ML is supported by.. FWA is supported by.. Data availability statement Template data collection forms, data extracted from included studies, data used for all analyses and analytic code are available upon request. References Kantarjian H, Kadia T, DiNardo C, Daver N, Borthakur G, Jabbour E, et al. Acute myeloid leukemia: current progress and future directions. Blood Cancer Journal. 2021; 11(2). Strongman H, Gadd S, Matthews A, Mansfield KE, Stanway S, Lyon AR, et al. Medium and long-term risks of specific cardiovascular diseases in survivors of 20 adult cancers: a population-based cohort study using multiple linked UK electronic health records databases. The Lancet. 2019; 394(10203):1041–54. 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Diagnosis and Management of AML in Adults: 2022 ELN Recommendations from an International Expert Panel. Blood. 2022; 140(12). Getz KD, Sung L, Ky B, Gerbing RB, Leger KJ, Leahy AB, et al. Occurrence of Treatment-Related Cardiotoxicity and Its Impact on Outcomes Among Children Treated in the AAML0531 Clinical Trial: A Report From the Children’s Oncology Group. Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology. 2019; 37(1):12–21. Kang Y, Assuncao BL, Denduluri S, McCurdy S, Luger S, Lefebvre B, et al. Symptomatic Heart Failure in Acute Leukemia Patients Treated With Anthracyclines. JACC: CardioOncology. 2019; 1(2):208–17. Mort MK, Sen JM, Morris AL, DeGregory KA, McLoughlin EM, Mort JF, et al. Evaluation of cardiomyopathy in acute myeloid leukemia patients treated with anthracyclines. Journal of Oncology Pharmacy Practice. 2019; 26(3):680–7. Stahl M, Giblin G, Liu Y, Winer ES, Garcia JS, Chen E, et al. Incidence and predictors of anthracycline-related left ventricular dysfunction in acute myeloid leukemia. Leukemia Research [Internet]. 2023; 132:107351. Boluda B, Solana‐Altabella A, Cano I, Martínez‐Cuadrón D, Acuña‐Cruz E, Torres-Miñana L, et al. Incidence and Risk Factors for Development of Cardiac Toxicity in Adult Patients with Newly Diagnosed Acute Myeloid Leukemia. Cancers. 2023; 15(8):2267–7. O’Brien MM, Taub JW, Chang MN, Massey GV, Stine KC, Raimondi SC, et al. Cardiomyopathy in Children With Down Syndrome Treated for Acute Myeloid Leukemia: A Report From the Children’s Oncology Group Study POG 9421. Journal of Clinical Oncology. 2008; 26(3):414–20. Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an Updated Guideline for Reporting Systematic Reviews. British Medical Journal. 2021; 372(71). Oki T, Takeuchi T, Oka S, Umezawa H. New Anthracycline Antibiotic Aclacinomycin A: Experimental Studies and Correlations with Clinical Trials. Recent results in cancer research. 1981; 21–40. Hori S, Shirai M, Hirano S, Oki T, Inui T, Tsukagoshi S, et al. Antitumor activity of new anthracycline antibiotics, aclacinomycin-A and its analogs, and their toxicity. Gann Japnese Journal of Cancer Research. 1977; 68(5):685-90. Freeman MF, Tukey JW. Transformations Related to the Angular and the Square Root. Annals of Mathematical Statistics. 1950; 21(4):607–11. Viechtbauer W. Conducting Meta-Analyses in R with the metafor package. Journal of Statistical Software. 2010; 36(3). Sterne JAC, Savović J, Page MJ, Elbers RG, Blencowe NS, Boutron I, et al. RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ. 2019; 366(1):l4898. Junqueira DR, Zorzela L, Golder S, Loke Y, Gagnier JJ, Julious SA, et al. CONSORT Harms 2022 statement, explanation, and elaboration: updated guideline for the reporting of harms in randomised trials. BMJ. 2023; 381:e073725. Holowiecki J, Grosicki S, Robak T, Kyrcz-Krzemien S, Giebel S, Hellmann A, et al. Addition of cladribine to daunorubicin and cytarabine increases complete remission rate after a single course of induction treatment in acute myeloid leukemia. Multicenter, phase III study. Leukemia. 2004; 18(5):989–97. Brunnberg U, Mohr M, Noppeney R, Dürk HA, Sauerland MC, Müller-Tidow C, et al. Induction therapy of AML with ara-C plus daunorubicin versus ara-C plus gemtuzumab ozogamicin: a randomized phase II trial in elderly patients. Annals of Oncology. 2012; 23(4):990–6. Holowiecki J, Grosicki S, Giebel S, Robak T, Kyrcz-Krzemien S, Kuliczkowski K, et al. Cladribine, But Not Fludarabine, Added to Daunorubicin and Cytarabine During Induction Prolongs Survival of Patients With Acute Myeloid Leukemia: A Multicenter, Randomized Phase III Study. Journal of Clinical Oncology. 2012; 30(20):2441–8. Walker AR, Marcucci G, Yin J, Blum W, Stock W, Kohlschmidt J, et al. Phase 3 randomized trial of chemotherapy with or without oblimersen in older AML patients: CALGB 10201 (Alliance). Blood Advances. 2021; 5(13):2775–87. Lübbert M, Wijermans PW, Kicinski M, Chantepie S, Van der Velden WJFM, Noppeney R, et al. 10-day decitabine versus 3 + 7 chemotherapy followed by allografting in older patients with acute myeloid leukaemia: an open-label, randomised, controlled, phase 3 trial. The Lancet Haematology. 2023; 10(11):e879–89. Mandelli F, Petti MC, Ardia A, Di Pietro N, Di Raimondo F, Ganzina F, et al. A randomised clinical trial comparing idarubicin and cytarabine to daunorubicin and cytarabine in the treatment of acute non-lymphoid leukaemia. European Journal of Cancer and Clinical Oncology. 1991; 27(6):750–5. Vogler WR, Velez-Garcia E, Weiner RS, Flaum MA, Bartolucci AA, Omura GA, et al. A phase III trial comparing idarubicin and daunorubicin in combination with cytarabine in acute myelogenous leukemia: a Southeastern Cancer Study Group Study. Journal of Clinical Oncology. 1992; 10(7):1103–11. Löwenberg B, Pabst T, Vellenga E, van Putten W, Schouten HC, Graux C, et al. Cytarabine Dose for Acute Myeloid Leukemia. New England Journal of Medicine. 2011; 364(11):1027–36. El Zeiny A, Abdel-Fattah R, Abbassie M, Farid S. Idarubicin versus Doxorubicin in Acute Myeloid Leukemia: A Parallel Randomized Trial with Pharmacoeconomic Analysis. Pharmaceutical Sciences. 2023; 19;30(1):135–42. Löwenberg B, Ossenkoppele GJ, van Putten W, Schouten HC, Graux C, Ferrant A, et al. High-Dose Daunorubicin in Older Patients with Acute Myeloid Leukemia. New England Journal of Medicine. 2009; 361(13):1235–48. Frey N, Jang JH, Szer J, Illés Á, Kim HJ, Ram R, et al. Eltrombopag treatment during induction chemotherapy for acute myeloid leukaemia: a randomised, double-blind, phase 2 study. The Lancet Haematology. 2019; 6(3):e122–31. Garcia-Manero G, Podoltsev NA, Othus M, Pagel JM, Radich JP, Fang M, et al. A randomized phase III study of standard versus high-dose cytarabine with or without vorinostat for AML. Leukemia. 2023; 38(1):58–66. Yin JAL, Johnson PRE, Davies JM, Flanagan NG, Gorst DW, Lewis MJ. Mitozantrone and cytosine arabinoside as first‐line therapy in elderly patients with acute myeloid leukaemia. British Journal of Haematology. 1991; 79(3):415–20. Shepherd JD, Reece DE, Barnett MJ, Klingemann HG, Nantel SH, Sutherland HJ, et al. Induction Therapy for Acute Myelogenous Leukemia in Patients Over 60 Years with Intermediate-Dose Cytosine Arabinoside, Mitoxantrone and Etoposide. Leukemia & Lymphoma. 1993; 9(3):211–5. Feldman E, Seiter K, Damon L, Linker C, Rugo H, Ries C, et al. A randomized trial of high- vs standard-dose mitoxantrone with cytarabine in elderly patients with acute myeloid leukemia. Leukemia. 1997; 11(4):485–9. Feldman EJ, Seiter K, Traganos F, Darzynkiewicz Z, Goff H, Pozzuoli M, et al. Phase II Evaluation of a High-Dose Mitoxantrone Based Induction Regimen in Untreated Adults with Acute Myeloid Leukemia. Leukemia & Lymphoma. 2000; 38(3-4):309–15. Grigg A, Reynolds J, McQuillan A, Juneja S, Iulio JD, Hui C, et al. Prognostic features for response and survival in elderly patients with de novo acute myeloid leukemia treated with mitoxantrone and intermediate dose cytarabine. Leukemia & Lymphoma. 2005; 46(3):367–75. Shaikh AY, Suryadevara S, Tripathi A, Ahmed M, Kane JL, Escobar J, et al. Mitoxantrone-Induced Cardiotoxicity in Acute Myeloid Leukemia-A Velocity Vector Imaging Analysis. Echocardiography. 2016; 33(8):1166–77. Braess J, Amler S, Kreuzer KA, Karsten Spiekermann, Lindemann HW, Lengfelder E, et al. Sequential high-dose cytarabine and mitoxantrone (S-HAM) versus standard double induction in acute myeloid leukemia—a phase 3 study. Leukemia. 2018; 32(12):2558–71. Jin J, Chen J, Suo S, Qian W, Meng H, Mai W, et al. Low-dose cytarabine, aclarubicin and granulocyte colony-stimulating factor priming regimen versus idarubicin plus cytarabine regimen as induction therapy for older patients with acute myeloid leukemia. Leukemia & Lymphoma. 2014; 56(6):1691–7. Morita Y, Kanamaru A, Miyazaki Y, Imanishi D, Yagasaki F, Tanimoto M, et al. Comparative analysis of remission induction therapy for high-risk MDS and AML progressed from MDS in the MDS200 study of Japan Adult Leukemia Study Group. International Journal of Hematology. 2010; 91(1):97–103. Staib P, Lathan B, Knöppel-Schwark S, Tesch H, Voliotis D, Steinmetz HT, et al. Cytosine arabinoside, etoposide and aclarubicin (AVA) for the treatment of acute myeloid leukemia (AML) in elderly patients. Annals of Oncology. 1998; 1;9(2):221–3. Swain SM, Whaley FS, Ewer MS. Congestive heart failure in patients treated with doxorubicin. Cancer. 2003; 97(11):2869–79. Von Hoff DD, Layard MW, Basa P, Davis Jr HL, Von Hoff AL, Rozencweig M, et al. Risk Factors for Doxorubicin-lnduced Congestive Heart Failure. Annals of Internal Medicine. 1979; 91(5):710. Shankar SM, Marina N, Hudson MM, Hodgson DC, Adams MJ, Landier W, et al. Monitoring for Cardiovascular Disease in Survivors of Childhood Cancer: Report From the Cardiovascular Disease Task Force of the Children’s Oncology Group. Pediatrics. 2008; 121(2):e387–96. 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. European Heart Journal. 2016; 37(36):2768–801. Cardinale D, Colombo A, Bacchiani G, Tedeschi I, Meroni CA, Veglia F, et al. Early Detection of Anthracycline Cardiotoxicity and Improvement With Heart Failure Therapy. Circulation. 2015; 131(22):1981–8. Linschoten MPM, Geels J, Teske AJ, Kamphuis JAM, Van Leeuwen EM, Corsten M, et al. Anthracycline-induced cardiotoxicity in patients with acute myeloid leukemia and high-risk myelodysplastic syndrome eligible for a hematopoietic stem cell transplant. [Manuscript in preparation]. Grosman-Rimon L, Billia F, Wright E, Carasso S, Elbaz-Greener G, Kachel E, et al. Neurohormones, inflammatory mediators, and cardiovascular injury in the setting of heart failure. Heart Failure Reviews. 2019; 25(5):685–701. Pasvolsky O, Morelli O, Rozovski U, Vaturi M, Wolach O, Amitai I, et al. Anthracycline-Induced Cardiotoxicity in Acute Myeloid Leukemia Patients Who Undergo Allogeneic Hematopoietic Stem Cell Transplantation. Clinical Lymphoma Myeloma and Leukemia. 2019; 19(7):e343–8. Additional Declarations There is NO conflict of interest to disclose. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6327060","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":436289742,"identity":"894578c3-1c2e-4fdd-97eb-195b058c1e94","order_by":0,"name":"Marijke Linschoten","email":"data:image/png;base64,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","orcid":"","institution":"Amsterdam UMC","correspondingAuthor":true,"prefix":"","firstName":"Marijke","middleName":"","lastName":"Linschoten","suffix":""},{"id":436289743,"identity":"ccd649bd-0431-41db-b011-fa7f89d8d3a4","order_by":1,"name":"Jesse Geels","email":"","orcid":"https://orcid.org/0009-0004-3858-3157","institution":"Amsterdam University Medical Centers","correspondingAuthor":false,"prefix":"","firstName":"Jesse","middleName":"","lastName":"Geels","suffix":""},{"id":436289744,"identity":"d321dee9-e1c3-4cb6-9d80-cd9cfb4a8cb5","order_by":2,"name":"Anna van Rhenen","email":"","orcid":"","institution":"University Medical Centre Utrecht","correspondingAuthor":false,"prefix":"","firstName":"Anna","middleName":"van","lastName":"Rhenen","suffix":""},{"id":436289745,"identity":"b0cd05f0-7994-4aa1-8fba-04b7d178aa3d","order_by":3,"name":"Patrycja Gradowska","email":"","orcid":"","institution":"Dutch-Belgian Hemato-Oncology Cooperative Group Data Center–Erasmus MC Cancer Institute","correspondingAuthor":false,"prefix":"","firstName":"Patrycja","middleName":"","lastName":"Gradowska","suffix":""},{"id":436289746,"identity":"c2aaacea-94bf-4dc5-b4fc-4e1747412a4d","order_by":4,"name":"Folkert Asselbergs","email":"","orcid":"","institution":"Amsterdam UMC","correspondingAuthor":false,"prefix":"","firstName":"Folkert","middleName":"","lastName":"Asselbergs","suffix":""}],"badges":[],"createdAt":"2025-03-28 09:55:21","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6327060/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6327060/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s41375-025-02753-w","type":"published","date":"2025-10-10T04:00:00+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":81032343,"identity":"46946b7e-ed66-4f38-adf5-6636fe29064f","added_by":"auto","created_at":"2025-04-21 11:31:50","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":212676,"visible":true,"origin":"","legend":"\u003cp\u003eFlowchart\u003c/p\u003e","description":"","filename":"Binder91.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6327060/v1/9013ed8c8dc8424ad3f08b94.jpg"},{"id":81030498,"identity":"ed752bcd-2179-4d4f-8e29-db9594161c03","added_by":"auto","created_at":"2025-04-21 11:15:51","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":351187,"visible":true,"origin":"","legend":"\u003cp\u003ePooled proportion of heart failure in patients treated with an ELN 2022 recommended remission induction regimen grouped by anthracycline agent\u003c/p\u003e","description":"","filename":"Binder92.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6327060/v1/3021d8d0711408f332054b94.jpg"},{"id":81030488,"identity":"23c387f7-3af0-4e60-9785-493055a65507","added_by":"auto","created_at":"2025-04-21 11:15:50","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":336280,"visible":true,"origin":"","legend":"\u003cp\u003ePooled proportion of heart failure in patients treated with 60 mg/m2 daunorubicin vs 90 mg/m2 daunorubicin\u003c/p\u003e","description":"","filename":"Binder93.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6327060/v1/2b5bafb5e1923f2e51691598.jpg"},{"id":81031821,"identity":"0c2b633c-4d49-4ddb-830c-1934a6b7e16e","added_by":"auto","created_at":"2025-04-21 11:23:50","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":286451,"visible":true,"origin":"","legend":"\u003cp\u003ePooled proportion of heart failure in patients treated with any mitoxantrone-containing induction regimen\u003c/p\u003e","description":"","filename":"Binder94.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6327060/v1/c15894fcf166122ab2d356cf.jpg"},{"id":93285731,"identity":"d0b895c5-a8c1-47cd-acca-26cfbbb28b41","added_by":"auto","created_at":"2025-10-11 07:12:27","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1767361,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6327060/v1/328aca85-8ec7-491b-9604-555b7299ee0d.pdf"},{"id":81032345,"identity":"c1e851f3-6e90-44bc-aa2b-50b5c0fedced","added_by":"auto","created_at":"2025-04-21 11:31:50","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":873486,"visible":true,"origin":"","legend":"Supplementary Appendix","description":"","filename":"SupplementaryAppendixmar28.docx","url":"https://assets-eu.researchsquare.com/files/rs-6327060/v1/25cac448c1b6982ce1ccbf98.docx"}],"financialInterests":"There is \u003cb\u003eNO\u003c/b\u003e conflict of interest to disclose.","formattedTitle":"Heart Failure in Patients with Acute Myeloid Leukemia (AML) Treated with Anthracycline Agents During Remission Induction Therapy: A Systematic Review and Meta-Analysis","fulltext":[{"header":"Introduction","content":"\u003cp\u003eOver the past decades, advances in modern antineoplastic therapies and supportive treatment have led to improved survival rates in patients with acute myeloid leukemia (AML).\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e With the expanding population of AML survivors, greater attention should be directed toward managing and preventing treatment-related side-effects, to further improve cancer treatment tolerability as well as quality of life and survival in this patient population.\u003c/p\u003e \u003cp\u003eA major concern for AML survivors is the increased long-term risk of cardiovascular disease (CVD). Studies indicate that leukemia survivors are significantly more likely to develop heart failure than the general population (adjusted hazard ratio 1.77 to 2.49).\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e Also when compared to survivors of other types of cancer, the risk appears particularly high.\u003csup\u003e\u003cspan additionalcitationids=\"CR3\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e Among long-term hematopoietic stem cell transplantation (HSCT) survivors, the cumulative incidence of symptomatic heart failure has been reported to be 5\u0026ndash;6% 5-year post transplant, increasing to almost one in ten patients at 10-years.\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e The incidence of left ventricular systolic dysfunction (regardless of symptoms) has been described as high as 44%.\u003csup\u003e7\u0026ndash;8\u003c/sup\u003e Patients with asymptomatic left ventricular dysfunction are at high risk to progress to more advanced heart failure stages.\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eSeveral factors are believed to contribute to the heightened cardiovascular risk in AML patients and survivors. Advances within the field of cardio-oncology have led to the identification of shared risk factors between cancer and CVD (e.g. smoking) and unique, cancer-driven biological mechanisms (e.g. clonal hematopoiesis of indeterminate potential).\u003csup\u003e\u003cspan additionalcitationids=\"CR11 CR12 CR13\" citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e Moreover, exposure to chemotherapeutic agents associated with cardiovascular toxicity is a critical driver in the development of CVD.\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e Anthracycline agents are especially well-known for their strong association with cardiotoxicity, particularly in causing myocardial dysfunction that can progress to heart failure.\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e These class of drugs are integral to the 7\u0026thinsp;+\u0026thinsp;3 regimen, the standard remission induction therapy for AML that has been in use for over five decades.\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eDespite the use of anthracycline-based regimens as first-line therapy and evidence from previous studies highlighting the high cardiovascular risk among AML survivors, a systematic assessment of the incidence of heart failure and cardiovascular adverse events (CVAEs) in this patient population has not been conducted. Previous studies have largely focused on children or patients with Down syndrome-associated AML, have been limited in sample size, or have examined only the risk of symptomatic heart failure within broader leukemia populations\u0026mdash;often combining acute and chronic forms despite substantial differences in patient characteristics and treatment protocols, particularly anthracycline usage.\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan additionalcitationids=\"CR19 CR20 CR21 CR22\" citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eConsidering that anthracycline agents, incorporated in the 7\u0026thinsp;+\u0026thinsp;3 regimen, are expected to remain the cornerstone of intensive remission induction therapy and their combination with targeted therapies is likely to further improve survival rates in the future, it is crucial to gain deeper insight into the cardiotoxicity of this regimen. With this systematic review we aim to contribute to this insight by evaluating and comparing the incidence of CVAEs, with special interest in heart failure, among AML patients treated with anthracycline agents during remission induction chemotherapy.\u003c/p\u003e"},{"header":"Materials and methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eSearch strategy and selection criteria\u003c/h2\u003e \u003cp\u003eThis systematic review and meta-analysis followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines (Supplementary Appendix p.2).\u003csup\u003e\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e The initial literature search was conducted in PubMed and EMBASE from database inception to July 19th, 2023. An updated search was performed on April 13th, 2024. The full search string is provided in the Supplementary Appendix 4(p.5). We selected studies conducted in adult patients with AML, treated with an intensive anthracycline- (daunorubicin, idarubicin, CPX-351 or aclarubicin) or anthraquinone-containing (mitoxantrone) chemotherapeutic remission induction regimen in a first-line setting. Studies including patients with myelodysplastic syndrome (MDS) or secondary AML were also eligible. To minimize heterogeneity, we primarily included studies in which patients received an induction regimen consistent with the 2022 European Leukemia Network (ELN) recommendations.\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e Specifically, this included daunorubicin at 60 mg/m\u0026sup2;, idarubicin at 12 mg/m\u0026sup2;, or mitoxantrone at 12 mg/m\u0026sup2; for 3 days, combined with conventional-dose cytarabine (100 or 200 mg/m\u0026sup2;) for 7 days, or CPX-351 at 100 U/m\u0026sup2; on days 1, 3, and 5. To examine the relationship between cumulative daunorubicin dose and heart failure, studies incorporating lower than conventional daunorubicin doses (45 mg/m\u003csup\u003e2\u003c/sup\u003e) or higher daunorubicin doses (90 mg/m\u003csup\u003e2\u003c/sup\u003e) were also included. Due to the limited availability of studies using mitoxantrone in line with ELN 2022 recommendations, we also included studies administering mitoxantrone doses below or above 12 mg/m\u003csup\u003e2\u003c/sup\u003e or for less or more than 3 days in combination with varying doses of cytarabine and/or etoposide. Furthermore, we also included studies using aclarubicin, as this anthracycline agent is reported to have lower cardiotoxicity compared to other anthracyclines.\u003csup\u003e\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eStudies solely including patients with Down\u0026rsquo;s syndrome associated AML or promyelocytic leukemia (FAB-M3) were excluded. In addition, studies in patients with relapsed- or refractory disease, patients pre-exposed to an anthracycline- or anthraquinone agent for the treatment of AML or studies with the concurrent administration of chemotherapeutic agents other than cytarabine were deemed ineligible. Lastly, all non-English publications, review articles, letters and preclinical studies were excluded.\u003c/p\u003e \u003cp\u003eStudies deemed eligible based on their title or abstract were assessed full-text and included in the analyses if they contained at least one of the following outcomes: (1) number of patients with clinical heart failure or subclinical left ventricular systolic dysfunction i.e. asymptomatic decline in left ventricular ejection fraction (LVEF); (2) number of patients with CVAEs annotated in grades, preferably with the use of a well-established toxicity grading system; (3) number of patients in whom treatment was discontinued due to heart failure; and (4) number of patients who died due to heart failure. Only articles that reported the incidence of CVAEs occurring during or directly after induction chemotherapy, prior to the initiation of consolidation chemotherapy or another line of treatment, were included. Studies that did not report CVAEs were included only if the publication explicitly confirmed that no other adverse events occurred beyond those detailed. Similarly, only studies specifying the reasons for treatment discontinuation and the cause of death for all patients were considered eligible for inclusion regarding treatment discontinuation and heart failure-related mortality. Where available, study protocols for the included studies were also reviewed. The screening and selection process of all the identified studies was performed independently by two researchers (JG and ML). A full list of in- and exclusion criteria as well as excluded studies after full text assessment is provided in the Supplementary Appendix (p.6). Any conflicts were settled by discussion until consensus was reached. In case one or multiple outcomes were lacking in a study published more recently and it was conceivable that this data was available based on the information provided in the article, authors were approached requesting for additional information.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eData analysis\u003c/h2\u003e \u003cp\u003eData was extracted from eligible studies manually by two independent researchers (JG and ML) and tabulated in a database. For each study the following information was extracted: study design, total sample size, sample size for which toxicity outcomes were reported, summary statistics describing the study population (e.g. median age and number of males and females), duration of follow-up, treatment regimen including cumulative anthracycline- or mitoxantrone dose, grading system used for adverse events reporting, and whether or not cardiac function was assessed before and after induction therapy. Furthermore, the following counts were collected for the outcomes of interest: the number of patients with (1) heart failure (including symptomatic heart failure and an asymptomatic decline in LVEF); (2) symptomatic heart failure versus an asymptomatic decline in LVEF; (3) grade 1\u0026ndash;2 CVAEs; (4) grade 3\u0026ndash;4 CVAEs; (5) treatment discontinuation due to heart failure; and (6) heart failure mortality. If included studies contained more than one eligible treatment arm (i.e. different anthracycline agents or doses used across arms), data extraction was performed for each treatment arm separately, effectively leading to \u0026gt;\u0026thinsp;1 subgroup derived from one study. If multiple studies were based on data of the same clinical trial, data were extracted from the article that reported the most complete toxicity outcomes.\u003c/p\u003e \u003cp\u003eTo estimate the proportion of patients developing heart failure, grade 1\u0026ndash;2 or grade 3\u0026ndash;4 CVAEs, meta-analyses of one-sample proportions were conducted. The Freeman-Tuckey double arcsine transformation was applied to extracted proportions to establish a normal distribution appropriate for pooling.\u003csup\u003e\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e Proportion estimates are presented with 95% confidence intervals (CIs). Study weights in each analysis were determined using the inverse of their variance. A random effects model was used for pooling the summary proportions. Heterogeneity among studies was assessed using Cochran\u0026rsquo;s Q-test and quantified with the \u003cem\u003eI\u003c/em\u003e\u003csup\u003e\u003cem\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/em\u003e\u003c/sup\u003e statistic, with values exceeding 50% considered indicative of substantial heterogeneity. Statistical significance was defined as a p-value less than 0.05. Sensitivity analyses were conducted by excluding outlier studies. All analyses were performed in R (version 1.4.1106) using the \u0026lsquo;\u003cem\u003emetafor\u0026rsquo;\u003c/em\u003e package.\u003csup\u003e\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eRisk of bias assessment\u003c/h3\u003e\n\u003cp\u003eBias of individual studies was assessed with an adaptation of the Cochrane Risk of Bias tool.\u003csup\u003e\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u003c/sup\u003e Quality of the reporting of adverse events in each individual study was assessed using a modified checklist from the Better Reporting of Harms in Randomized Trials: An Extension of the CONSORT Statement.\u003csup\u003e\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u003c/sup\u003e A detailed description of the risk of bias assessment and the evaluation of the quality of adverse event reporting is provided in the Supplementary Appendix (p.22). Two researchers (JG and ML) independently performed the risk of bias assessment, solving any disagreements by discussion.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eThe literature search strategy identified 10 204 unique records. Following title and abstract screening, 813 articles were assessed full text of which 41 studies (comprising 5 955 patients across 48 subgroups) published between February 1991 and March 2024 were retained for the final analyses (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Data was mainly derived from clinical trials (36 studies) and to a lesser extent from retrospective cohort studies (5 studies). The proportion of patients with heart failure was reported in 27 studies (n\u0026thinsp;=\u0026thinsp;4 461 patients), of which five studies (n\u0026thinsp;=\u0026thinsp;521 patients) reported to have assessed LVEF pre- and post- remission induction therapy as well as reported the number of patients who experienced a decline in LVEF post-induction. Grade 3\u0026ndash;4 CVAEs were documented in 29 studies (n\u0026thinsp;=\u0026thinsp;4 545 patients) while 12 studies (n\u0026thinsp;=\u0026thinsp;1 997 patients) reported on grade 1\u0026ndash;2 CVAEs. Daunorubicin was the most frequently incorporated anthracycline for remission induction, used in 20 (42%) subgroups. Idarubicin was used in 9 (19%), mitoxantrone in 11 (23%), CPX-351 in six (13%) and aclarubicin in 2 (4%) subgroups. Detailed characteristics of included studies are provided in the Supplementary Appendix (p.16).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e\n\u003ch3\u003eHeart failure\u003c/h3\u003e\n\u003cp\u003eNine treatment subgroups (n\u0026thinsp;=\u0026thinsp;1 801 patients) were included in the meta-analysis to assess the reported proportion of patients with heart failure during induction treatment with a 7\u0026thinsp;+\u0026thinsp;3 regimen using either daunorubicin 60 mg/m\u003csup\u003e2\u003c/sup\u003e or idarubicin 12 mg/m\u003csup\u003e2\u003c/sup\u003e in line with ELN recommendations. The pooled proportion of heart failure was 3.2% (95%CI 1.0\u0026ndash;6.2; test for heterogeneity Q\u0026thinsp;=\u0026thinsp;59.00, τ\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0.0102 and \u003cem\u003eI\u003c/em\u003e\u003csup\u003e\u003cem\u003e2\u003c/em\u003e\u003c/sup\u003e\u0026thinsp;\u003cem\u003e=\u003c/em\u003e\u0026thinsp;86.4%; p\u0026thinsp;\u0026lt;\u0026thinsp;0.01)(Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). No significant subgroup difference was observed in the proportion of patients with heart failure between those treated with daunorubicin versus idarubicin (p\u0026thinsp;=\u0026thinsp;0.38).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe number of patients with heart failure was higher among patients receiving a 7\u0026thinsp;+\u0026thinsp;3 induction regimen with daunorubicin doses of 90 mg/m\u003csup\u003e2\u003c/sup\u003e (n\u0026thinsp;=\u0026thinsp;729) compared to those treated with a conventional 60 mg/m\u003csup\u003e2\u003c/sup\u003e dose (n\u0026thinsp;=\u0026thinsp;1 029) with a pooled proportion of 4.8% (95%CI 2.3\u0026ndash;8.1) versus 2.3% (95%CI 1.4\u0026ndash;3.3) respectively, although not statistically significant (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e; test for subgroup differences: p\u0026thinsp;=\u0026thinsp;0.07). Results of comparing patients treated with a lower-than-conventional daunorubicin dose (45 mg/m\u003csup\u003e2\u003c/sup\u003e) to those receiving a conventional (60 mg/m\u003csup\u003e2\u003c/sup\u003e) or high-dose (90 mg/m\u003csup\u003e2\u003c/sup\u003e) daunorubicin are displayed in the Supplementary Appendix (Figure \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e and Figure S2; p.18).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eIn total, 435 patients across 8 treatment subgroups were treated with various mitoxantrone-containing regimens. Mitoxantrone dosing varied: four subgroups received 10\u0026ndash;12 mg/m\u0026sup2; over three days, one subgroup received 10 mg/m\u0026sup2; for four days, and three subgroups were treated with a single high-dose infusion of 80 mg/m\u0026sup2;. The pooled proportion of heart failure was 10.2% (95%CI 2.4\u0026ndash;21.7; test for heterogeneity Q\u0026thinsp;=\u0026thinsp;85.24, τ\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0.0411 and \u003cem\u003eI\u003c/em\u003e\u003csup\u003e\u003cem\u003e2\u003c/em\u003e\u003c/sup\u003e\u0026thinsp;\u003cem\u003e=\u003c/em\u003e\u0026thinsp;91.8%; p\u0026thinsp;\u0026lt;\u0026thinsp;0.01)(Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). After excluding two outlier studies in which cardiac function was actively monitored, the pooled proportion of heart failure was 4.1% (95%CI 0.9\u0026ndash;8.8; test for heterogeneity Q\u0026thinsp;=\u0026thinsp;10.64, τ\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0.0064 and \u003cem\u003eI\u003c/em\u003e\u003csup\u003e\u003cem\u003e2\u003c/em\u003e\u003c/sup\u003e\u0026thinsp;\u003cem\u003e=\u003c/em\u003e\u0026thinsp;53.0%; p\u0026thinsp;=\u0026thinsp;0.06)(Figure S3; Supplementary Appendix p.19).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eTwo studies (n\u0026thinsp;=\u0026thinsp;174 patients) reported on heart failure outcomes after CPX-351 treatment, in this group the pooled proportion was 4.6% (95%CI 0.0\u0026ndash;14.0; test for heterogeneity Q\u0026thinsp;=\u0026thinsp;4.56, τ\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0.0105 and \u003cem\u003eI\u003c/em\u003e\u003csup\u003e\u003cem\u003e2\u003c/em\u003e\u003c/sup\u003e\u0026thinsp;\u003cem\u003e=\u003c/em\u003e\u0026thinsp;78.1%; p\u0026thinsp;=\u0026thinsp;0.03)(Figure S4; Supplementary Appendix p.19). Among the three studies using aclarubicin, no patients (n\u0026thinsp;=\u0026thinsp;151) were reported to have developed heart failure or heart-failure related mortality.\u003csup\u003e\u003cspan additionalcitationids=\"CR51\" citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e52\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eThe pooled proportion of mortality- and treatment discontinuation due to heart failure among patients treated with an induction regimen following ELN 2022 recommendations was 2.0\u0026permil; (95\u0026permil;CI 0.7\u0026ndash;5.8) and 3.2\u0026permil; (95\u0026permil;CI 0.6\u0026ndash;18.0) with three heart failure deaths among 1 520 patients and one out of 310 patients who discontinued treatment due to heart failure (Figure S5 and Figure S6, Supplementary Appendix p. 20).\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eCardiovascular adverse events\u003c/h2\u003e \u003cp\u003eEighteen treatment subgroups derived from 17 studies (n\u0026thinsp;=\u0026thinsp;2 454 patients) reported on the occurrence of grade 3\u0026ndash;4 CVAEs in patients treated with daunorubicin, idarubicin, mitoxantrone or CPX-351 according to the ELN 2022 recommendations. The pooled proportion of high-grade CVAEs was 3.3% (95%CI 1.9\u0026ndash;5.0; test for heterogeneity Q\u0026thinsp;=\u0026thinsp;59.24, τ\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0.0050 and \u003cem\u003eI\u003c/em\u003e\u003csup\u003e\u003cem\u003e2\u003c/em\u003e\u003c/sup\u003e\u0026thinsp;\u003cem\u003e=\u003c/em\u003e\u0026thinsp;71.3%; p\u0026thinsp;\u0026lt;\u0026thinsp;0.01)(Figure S7; Supplementary Appendix p.21). The pooled proportion of grade 1\u0026ndash;2 CVAEs (n\u0026thinsp;=\u0026thinsp;924 patients) was 9.7% (95%CI 4.8\u0026ndash;16.0) (test for heterogeneity Q\u0026thinsp;=\u0026thinsp;54.03, τ\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0.0150 and \u003cem\u003eI\u003c/em\u003e\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;85.2%; p\u0026thinsp;\u0026lt;\u0026thinsp;0.01)(Figure S8; Supplementary Appendix p.21).\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eRisk of bias and quality assessment\u003c/h3\u003e\n\u003cp\u003eThe risk of bias and quality of the reporting of harms was assessed for each individual study and is shown in the Supplementary Appendix (p.23\u0026ndash;24). Briefly, 23 studies (56%) were deemed to be at high risk of bias, 12 (29%) a moderate risk and 6 (15%) a low risk of bias. High risk of bias through poor specification of CVAEs was present in 11 of the 34 studies (32%) that were included in either the heart failure or CVAEs analyses. Six of the 34 (18%) studies were deemed to have a high risk of introducing bias through incomplete reporting of CVAEs. Six (18%) studies did not report the grading system used to assess AEs and were therefore considered as likely to introduce bias.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis systematic review and meta-analysis provides a comprehensive evaluation of the incidence of heart failure and CVAEs in AML patients undergoing intensive remission induction therapy with anthracycline agents or mitoxantrone. The key findings of this study include: (1) the overall incidence of symptomatic heart failure during induction therapy was lower than 5%; (2) the incidence of heart failure increases with anthracycline-dose intensification; (3) cardiac function was infrequently monitored during induction therapy, and if monitored, reporting on the number of patients with a decline in LVEF was limited; and (4) patients treated with mitoxantrone-containing regimens may be at higher risk of heart failure when compared to those treated with regimens containing daunorubicin or idarubicin.\u003c/p\u003e \u003cp\u003eThe overall low incidence of symptomatic heart failure observed during or shortly after induction therapy is consistent with findings from previous clinical trials in patients with solid tumors, which helped establish maximum cumulative dose limits for anthracyclines aiming to keep symptomatic heart failure rates below 5%.\u003csup\u003e53\u0026ndash;54\u003c/sup\u003e According to these studies, this corresponds to a doxorubicin cumulative dose between 400 and 550 mg/m\u003csup\u003e2\u003c/sup\u003e, equivalent to 480\u0026ndash;660 mg/m\u003csup\u003e2\u003c/sup\u003e daunorubicin, 80\u0026ndash;100 mg/m\u003csup\u003e2\u003c/sup\u003e idarubicin or 100-137.5 mg/m\u003csup\u003e2\u003c/sup\u003e mitoxantrone based on the conversion factors currently applied in clinical practice.\u003csup\u003e\u003cspan citationid=\"CR55\" class=\"CitationRef\"\u003e55\u003c/span\u003e\u003c/sup\u003e Given that patients treated for AML typically do not reach these cumulative doses, a low incidence of symptomatic heart failure was anticipated.\u003c/p\u003e \u003cp\u003eHowever, recent large cohort studies highlight a significantly increased long-term risk of heart failure in patients treated for AML. Leukemia survivors are reported to face a 1.77 to 2.49 times higher risk of developing heart failure as compared to the general population.\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e Additionally, heart failure rates were found to be higher in leukemia survivors than in most other types of cancer.\u003csup\u003e\u003cspan additionalcitationids=\"CR3\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e The discrepancy between the low short-term heart failure risk observed in this study and the significantly increased long-term risk may be explained by considering anthracycline-induced cardiac dysfunction (AICD) as a progressive spectrum.\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e In the initial stages, AICD may be evident through elevated cardiac biomarkers (i.e. troponin) indicating a loss of cardiomyocytes. When myocardial damage surpasses a certain threshold, it leads to a measurable decline in myocardial contractility reflected by a decline in LVEF.\u003csup\u003e\u003cspan citationid=\"CR56\" class=\"CitationRef\"\u003e56\u003c/span\u003e\u003c/sup\u003e In 98% of the patients this LVEF decline can already be detected through serial assessment of cardiac function within the first year after initial anthracycline administration, with a median time-to-event between 3.0\u0026ndash;3.5 months.\u003csup\u003e\u003cspan citationid=\"CR57\" class=\"CitationRef\"\u003e57\u003c/span\u003e, \u003cspan citationid=\"CR58\" class=\"CitationRef\"\u003e58\u003c/span\u003e\u003c/sup\u003e The onset of symptomatic heart failure is delayed in a great majority of patients by the activation of compensatory mechanisms including the renin-angiotensin-aldosterone system.\u003csup\u003e\u003cspan citationid=\"CR59\" class=\"CitationRef\"\u003e59\u003c/span\u003e\u003c/sup\u003e Nonetheless, patients with asymptomatic left ventricular systolic dysfunction have a fivefold higher risk of progressing to clinical heart failure compared to control subjects, making awareness of its occurrence important.\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e Early detection of subclinical cardiac dysfunction does not only facilitate the initiation of cardioprotective drugs, which could prevent further deterioration to more advanced heart failure stages, but also help identify AML patients at risk for adverse outcomes in later stages of treatment, i.e. HSCT.\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eOf the 27 studies included in this review that reported on the number of patients with heart failure, only eight reported to have assessed cardiac function both pre- and post-induction therapy and of these five detailed the number of patients who developed asymptomatic left ventricular dysfunction. In all these studies, the reported incidence of heart failure events overall was considerably higher than studies that did not mention serial assessment of cardiac function, ranging from 7.0\u0026ndash;43.8%.\u003csup\u003e37, \u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e, \u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e, \u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e, \u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e\u003c/sup\u003e This suggests that subclinical AICD may often go unrecognized in a clinical trial setting due to the lack of cardiac monitoring. This hypothesis is further supported by a small number of retrospective cohort studies that performed cardiac monitoring during induction therapy in patients with AML, reporting 8\u0026ndash;9% of patients developing (asymptomatic) cardiac dysfunction. \u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e Among patients monitored for up to two years following HSCT, even higher incidences have been reported, ranging from 7\u0026ndash;33%.\u003csup\u003e20, \u003cspan citationid=\"CR58\" class=\"CitationRef\"\u003e58\u003c/span\u003e, 60\u0026ndash;61\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eAn additional key finding of this study was the rising incidence of heart failure among patients treated with higher doses of daunorubicin, underscoring the dose-response relationship between anthracyclines and heart failure. While idarubicin and mitoxantrone are typically dosed at 12 mg/m\u003csup\u003e2\u003c/sup\u003e in the 7\u0026thinsp;+\u0026thinsp;3 regimen, the optimal daunorubicin dose for induction therapy in fit patients remains a subject of ongoing debate. Three older trials investigating high-dose daunorubicin (90 mg/m\u003csup\u003e2\u003c/sup\u003e) versus the previous standard daunorubicin dose (45 mg/m\u003csup\u003e2\u003c/sup\u003e) demonstrated that high doses resulted in better overall survival and higher response rates.\u003csup\u003e\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e, 62\u0026ndash;63\u003c/sup\u003e This benefit was not demonstrated by two trials comparing high-dose daunorubicin (90 mg/m\u003csup\u003e2\u003c/sup\u003e) to the current standard dose (60 mg/m\u003csup\u003e2\u003c/sup\u003e).\u003csup\u003e64\u0026ndash;65\u003c/sup\u003e None of these trials reported excess cardiotoxicity in the high-dose treatment arm; however, only in one of these trials specific heart failure outcomes and occurrence of subclinical declines in LVEF were reported.\u003csup\u003e62\u003c/sup\u003e The impact of anthracycline dose intensification on heart failure incidence in AML patients thereby remains unclear, highlighting the need for improved toxicity reporting. This includes specifying adverse events, conducting regular cardiac monitoring, and providing detailed documentation of subclinical declines in LVEF. Such comprehensive reporting is essential for accurately assessing the effects of anthracycline dose intensification on heart failure risk. The NCI Common Terminology Criteria for Adverse Events (CTCAE) is currently widely accepted as the standard system for classification and grading of severity of adverse events in the setting of oncology trials but poses major challenges when it comes to a heart failure.\u003csup\u003e66\u003c/sup\u003e Grading inconsistencies arise when different entry terms are used, as the same significant decline in LVEF can be classified as either a grade 3 or grade 1 adverse event depending on whether the entry of choice is \u0026lsquo;ejection fraction decreased\u0026rsquo; or \u0026lsquo;heart failure\u0026rsquo;.\u003csup\u003e67\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eAnother objective of this systematic review was to compare the incidence of heart failure and CVAEs among patients treated with induction regimens containing different anthracycline agents. A significant difference in the incidence of heart failure among patients treated with daunorubicin, idarubicin, and CPX-351 according to ELN 2022 recommendations could not be established.\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e However, our study did find a high proportion of patients of heart failure among those treated with a mitoxantrone-containing induction regimen of 10.2% (95%CI 2.4\u0026ndash;21.7), as compared to 2.3% (95%CI 1.4\u0026ndash;3.3) with daunorubicin and 5.0% (95%CI 0.3\u0026ndash;14.1) with idarubicin. The high incidence among patients treated with mitoxantrone was predominantly driven by two studies in which patients were monitored for subclinical declines in LVEF.\u003csup\u003e\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e, \u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e\u003c/sup\u003e The current ELN 2022 guidelines allow the treating clinician to choose between daunorubicin, idarubicin, or mitoxantrone for patients deemed fit for intensive induction therapy.\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e Currently, the cardiotoxicity risk of each anthracycline is derived by its doxorubicin-equivalent cumulative dose.\u003csup\u003e68\u003c/sup\u003e These equivalence ratios are largely derived from the agent\u0026rsquo;s antileukemic efficacy, extrapolated to hematologic toxicity, and then broadly applied to other organ systems.\u003csup\u003e68\u003c/sup\u003e However, a recent large multicenter cohort study in childhood cancer survivors, aimed at determining optimal dose equivalence ratios for cardiomyopathy between doxorubicin and other anthracyclines and mitoxantrone, revealed a significant underestimation of mitoxantrone\u0026rsquo;s association with long-term cardiomyopathy risk.\u003csup\u003e69\u003c/sup\u003e The results of this study led to a significantly higher conversion factor for mitoxantrone (10.5x doxorubicin dose instead of 4x) that is now used in the latest cardio-oncology guidelines of the European Society of Cardiology.\u003csup\u003e70\u003c/sup\u003e Previous meta-analyses comparing the incidence of cardiotoxicity in adult AML patients treated with idarubicin versus daunorubicin have reported no significant difference.\u003csup\u003e71\u0026ndash;72\u003c/sup\u003e However, both these studies failed to specify the nature of the reported CVAEs, particularly (subclinical) heart failure. Similarly, two large phase III trials comparing the efficacy of mitoxantrone to daunorubicin and idarubicin failed to report cardiovascular adverse outcomes.\u003csup\u003e73\u0026ndash;74\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eTo the best of our knowledge, this is the first systematic review focusing on the incidence of heart failure in patients with AML treated with anthracycline-containing remission induction regimens. Previously, only a small number of retrospective cohort studies have investigated the occurrence of left ventricular systolic dysfunction in this patient population.\u003csup\u003e\u003cspan additionalcitationids=\"CR21\" citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR58\" class=\"CitationRef\"\u003e58\u003c/span\u003e, 60\u0026ndash;61\u003c/sup\u003e A key strength of this study is the inclusion of data from a large number of trials, which is particularly valuable in the context of mitoxantrone since this agent is less commonly used for remission induction. However, this study also has some limitations. Firstly, only a limited number of randomized controlled trials that met our inclusion criteria have directly compared different anthracyclines, and these studies were highly heterogeneous regarding treatment regimens. This prevented the pooling of outcomes exclusively from such studies.\u003csup\u003e\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e, \u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e, 75\u0026ndash;77\u003c/sup\u003e Pooling outcomes across trials for a comparison of the cardiotoxicity of different anthracyclines also introduces heterogeneity by variations in study protocols, inconsistent adverse event reporting, and diverse study populations. Secondly, the lack of access to individual patient data restricted our ability to identify specific cardiovascular risk factors contributing to adverse cardiovascular outcomes.\u003c/p\u003e \u003cp\u003eThe findings of this systematic review carry significant implications for future research. Clinical trials should prioritize enhanced monitoring protocols for early detection of cardiac dysfunction and more precise specification of CVAEs. Currently, ambiguous CTCAE entry terms will contribute to significant variability in adverse event reporting. The CTCAE should be refined to offer comprehensive tools that help researchers accurately interpret and grade complex clinical syndromes, such as heart failure.\u003csup\u003e\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e, 67\u003c/sup\u003e Furthermore, the higher incidence of heart failure observed in patients treated with mitoxantrone suggests possible heterogeneity among subgroups regarding the risk of AICD development. Large, prospective studies are necessary to identify and characterize these high-risk subgroups. Additionally, our study emphasizes the necessity for further research to validate the existing anthracycline conversion factors for cardiotoxicity, as the current factors are based on data from childhood cancer survivors.\u003c/p\u003e \u003cp\u003eIn conclusion, this study indicates that during remission induction therapy for AML, the overall occurrence of symptomatic heart failure and other high grade CVAEs is low. However, the limited monitoring of cardiac function and inadequate reporting of CVAEs likely lead to under-detection of these events, especially in high-risk subgroups. This hinders the ability to identify patients at risk for CVD after remission induction receiving additional AML treatment as well as later in life. Early recognition of such individuals is crucial, as implementing cardioprotective measures can prevent or reduce these complications. Therefore, the adoption of early screening for CVAEs and improved reporting of such events, along with revisions to established grading systems, are essential.\u003c/p\u003e"},{"header":"Declarations","content":" \u003ch2\u003eCompeting interests\u003c/h2\u003e \u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eAuthor contributions\u003c/h2\u003e \u003cp\u003eML and AvR conceptualized the study, designed the research methodology and supervised the project. JG conducted the literature search. JG and ML screened the studies, extracted the data and performed the risk of bias assessment. JG performed the statistical analysis and interpreted the results with input from ML. JG drafted with initial manuscript with input from ML. AvR, FWA, ML and PG critically revised the manuscript. All authors read and approved the final manuscript.\u003c/p\u003e\u003ch2\u003eAcknowledgements\u003c/h2\u003e \u003cp\u003eML is supported by.. FWA is supported by..\u003c/p\u003e\u003ch2\u003eData availability statement\u003c/h2\u003e \u003cp\u003eTemplate data collection forms, data extracted from included studies, data used for all analyses and analytic code are available upon request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eKantarjian H, Kadia T, DiNardo C, Daver N, Borthakur G, Jabbour E, et al. Acute myeloid leukemia: current progress and future directions. Blood Cancer Journal. 2021; 11(2).\u003c/li\u003e\n\u003cli\u003eStrongman H, Gadd S, Matthews A, Mansfield KE, Stanway S, Lyon AR, et al. Medium and long-term risks of specific cardiovascular diseases in survivors of 20 adult cancers: a population-based cohort study using multiple linked UK electronic health records databases. The Lancet. 2019; 394(10203):1041\u0026ndash;54.\u003c/li\u003e\n\u003cli\u003ePaterson DI, Wiebe N, Cheung WY, Mackey JR, Pituskin E, Reiman A, et al. 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Monitoring for Cardiovascular Disease in Survivors of Childhood Cancer: Report From the Cardiovascular Disease Task Force of the Children\u0026rsquo;s Oncology Group. Pediatrics. 2008; 121(2):e387\u0026ndash;96.\u003c/li\u003e\n\u003cli\u003eZamorano JL, Lancellotti P, Rodriguez Mu\u0026ntilde;oz 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. European Heart Journal. 2016; 37(36):2768\u0026ndash;801.\u003c/li\u003e\n\u003cli\u003eCardinale D, Colombo A, Bacchiani G, Tedeschi I, Meroni CA, Veglia F, et al. Early Detection of Anthracycline Cardiotoxicity and Improvement With Heart Failure Therapy. Circulation. 2015; 131(22):1981\u0026ndash;8.\u003c/li\u003e\n\u003cli\u003eLinschoten MPM, Geels J, Teske AJ, Kamphuis JAM, Van Leeuwen EM, Corsten M, et al. Anthracycline-induced cardiotoxicity in patients with acute myeloid leukemia and high-risk myelodysplastic syndrome eligible for a hematopoietic stem cell transplant. [Manuscript in preparation].\u003c/li\u003e\n\u003cli\u003eGrosman-Rimon L, Billia F, Wright E, Carasso S, Elbaz-Greener G, Kachel E, et al. Neurohormones, inflammatory mediators, and cardiovascular injury in the setting of heart failure. Heart Failure Reviews. 2019; 25(5):685\u0026ndash;701.\u003c/li\u003e\n\u003cli\u003ePasvolsky O, Morelli O, Rozovski U, Vaturi M, Wolach O, Amitai I, et al. Anthracycline-Induced Cardiotoxicity in Acute Myeloid Leukemia Patients Who Undergo Allogeneic Hematopoietic Stem Cell Transplantation. Clinical Lymphoma Myeloma and Leukemia. 2019; 19(7):e343\u0026ndash;8.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"leukemia","isNatureJournal":false,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"leu","sideBox":"Learn more about [Leukemia](http://www.nature.com/leu/)","snPcode":"41375","submissionUrl":"https://mts-leu.nature.com/cgi-bin/main.plex","title":"Leukemia","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-6327060/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6327060/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003ePatients with acute myeloid leukemia (AML) are at high risk of cardiovascular disease, particularly heart failure. Anthracyclines are integral to remission induction in patients eligible for intensive treatment and well-known for their association with cardiotoxicity. However, the incidence of heart failure and other cardiovascular adverse events (CVAEs), as well as differences across various anthracycline agents, has not been comprehensively assessed. We systematically searched PubMed and EMBASE for studies conducted in AML patients treated with anthracyclines during remission induction. Forty-one studies (5 995 patients), primarily clinical trials, published between February 1991 and March 2024 were included. The pooled proportion of heart failure was 3.2% (95%CI 1.0\u0026ndash;6.2) overall and 2.3% (95%CI 1.4\u0026ndash;3.3), 5.0% (95%CI 0.3\u0026ndash;14.1) and 10.2% (95%CI 2.4\u0026ndash;21.7) for patients treated with daunorubicin, idarubicin or mitoxantrone respectively. Cardiac function was infrequently monitored, and CVAE reporting often lacked detail. Since current adverse event grading systems primarily rely on clinical symptoms to determine severity, significant asymptomatic declines in cardiac function frequently go undetected. Enhanced CVAE monitoring and reporting are needed to better identify subclinical cardiotoxicity in AML patients, enabling timely intervention to prevent progression to more advanced stages of heart failure. Furthermore, early management might prevent delay of consolidation treatment.\u003c/p\u003e","manuscriptTitle":"Heart Failure in Patients with Acute Myeloid Leukemia (AML) Treated with Anthracycline Agents During Remission Induction Therapy: A Systematic Review and Meta-Analysis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-04-21 11:15:45","doi":"10.21203/rs.3.rs-6327060/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"revise","date":"2025-05-06T09:44:50+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"This content is not available.","date":"2025-05-05T19:21:42+00:00","index":2,"fulltext":"This content is not available."},{"type":"editorInvitedReview","content":"This content is not available.","date":"2025-05-03T13:32:03+00:00","index":3,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2025-04-17T17:10:31+00:00","index":3,"fulltext":"This content is not available."},{"type":"editorInvitedReview","content":"This content is not available.","date":"2025-04-15T20:17:51+00:00","index":1,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2025-04-15T07:23:05+00:00","index":2,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2025-03-31T17:43:00+00:00","index":1,"fulltext":"This content is not available."},{"type":"reviewersInvited","content":"","date":"2025-03-31T10:53:28+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-03-31T10:29:04+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-03-31T10:28:55+00:00","index":"","fulltext":""},{"type":"submitted","content":"Leukemia","date":"2025-03-28T09:50:45+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"leukemia","isNatureJournal":false,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"leu","sideBox":"Learn more about [Leukemia](http://www.nature.com/leu/)","snPcode":"41375","submissionUrl":"https://mts-leu.nature.com/cgi-bin/main.plex","title":"Leukemia","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"0f4a06a0-56f0-467f-996d-66107aed7c9d","owner":[],"postedDate":"April 21st, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":46451187,"name":"Health sciences/Diseases/Haematological diseases/Haematological cancer/Leukaemia/Acute myeloid leukaemia"},{"id":46451188,"name":"Health sciences/Health care/Quality of life"},{"id":46451189,"name":"Health sciences/Signs and symptoms"}],"tags":[],"updatedAt":"2025-10-11T07:12:22+00:00","versionOfRecord":{"articleIdentity":"rs-6327060","link":"https://doi.org/10.1038/s41375-025-02753-w","journal":{"identity":"leukemia","isVorOnly":false,"title":"Leukemia"},"publishedOn":"2025-10-10 04:00:00","publishedOnDateReadable":"October 10th, 2025"},"versionCreatedAt":"2025-04-21 11:15:45","video":"","vorDoi":"10.1038/s41375-025-02753-w","vorDoiUrl":"https://doi.org/10.1038/s41375-025-02753-w","workflowStages":[]},"version":"v1","identity":"rs-6327060","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6327060","identity":"rs-6327060","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}