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Frontiers in Cardiovascular Medicine 2023Pediatric acute myeloid leukemia (AML) therapy is associated with substantial short- and long-term treatment-related cardiotoxicity mainly due to high-dose anthracycline...
BACKGROUND
Pediatric acute myeloid leukemia (AML) therapy is associated with substantial short- and long-term treatment-related cardiotoxicity mainly due to high-dose anthracycline exposure. Early left ventricular systolic dysfunction (LVSD) compromises anthracycline delivery and is associated with inferior event-free and overall survival in pediatric AML. Thus, effective cardioprotective strategies and cardiotoxicity risk predictors are critical to optimize cancer therapy delivery and enable early interventions to prevent progressive LVSD. While dexrazoxane-based cardioprotection reduces short-term cardiotoxicity without compromising cancer survival, liposomal anthracycline formulations have the potential to mitigate cardiotoxicity while improving antitumor efficacy. This overview summarizes the rationale and methodology of cardiac substudies within AAML1831, a randomized Children's Oncology Group Phase 3 study of CPX-351, a liposomal formulation of daunorubicin and cytarabine, in comparison with standard daunorubicin/cytarabine with dexrazoxane in the treatment of pediatric AML.
METHODS/DESIGN
Children (age <22 years) with newly diagnosed AML were enrolled and randomized to CPX-351-containing induction 1 and 2 (Arm A) or standard daunorubicin and dexrazoxane-containing induction (Arm B). Embedded cardiac correlative studies aim to compare the efficacy of this liposomal anthracycline formulation to dexrazoxane for primary prevention of cardiotoxicity by detailed core lab analysis of standardized echocardiograms and serial cardiac biomarkers throughout AML therapy and in follow-up. In addition, AAML1831 will assess the ability of early changes in sensitive echo indices (e.g., global longitudinal strain) and cardiac biomarkers (e.g., troponin and natriuretic peptides) to predict subsequent LVSD. Finally, AAML1831 establishes expert consensus-based strategies in cardiac monitoring and anthracycline dose modification to balance the potentially competing priorities of cardiotoxicity reduction with optimal leukemia therapy.
DISCUSSION
This study will inform diagnostic, prognostic, preventative, and treatment strategies regarding cardiotoxicity during pediatric AML therapy. Together, these measures have the potential to improve leukemia-free and overall survival and long-term cardiovascular health in children with AML. https://clinicaltrials.gov/, identifier NCT04293562.
PubMed: 38107263
DOI: 10.3389/fcvm.2023.1286241 -
Journal of Oncology Pharmacy Practice :... Jul 2020Mitoxantrone is a chemotherapeutic agent approved for various diseases. The literature has been conflicting in classifying mitoxantrone as a vesicant or irritant.
INTRODUCTION
Mitoxantrone is a chemotherapeutic agent approved for various diseases. The literature has been conflicting in classifying mitoxantrone as a vesicant or irritant.
CASE REPORT
We report a patient who had an extravasation of mitoxantrone. Mitoxantrone was administered in 50 ml normal saline. After mitoxantrone was completely infused, the site appeared edematous and the blue color of mitoxantrone developed beneath the skin. The patient reported pain. The extravasation was treated with dexrazoxane and cold compresses. The pain improved each day. However, blistering developed five weeks later and the patient ultimately required surgical intervention for debridement and grafting.
DISCUSSION
Extravasation events are rare and there are few controlled studies. Because of the similarities in chemical structures and mechanism of actions between mitoxantrone and anthracyclines, mitoxantrone extravasation is often treated similar to anthracyclines. Mitoxantrone's classification is unclear, as some literature classifies it as a vesicant and others as an irritant. Our case supports the categorization of mitoxantrone as a vesicant.
Topics: Aged; Antineoplastic Agents; Cryotherapy; Extravasation of Diagnostic and Therapeutic Materials; Humans; Infusions, Intravenous; Male; Mitoxantrone
PubMed: 31902285
DOI: 10.1177/1078155219893736 -
Cureus Apr 2023Cancer is one of the leading causes of morbidity and mortality in the pediatric population with the most common cancer being acute lymphoblastic leukemia. One of the... (Review)
Review
Cancer is one of the leading causes of morbidity and mortality in the pediatric population with the most common cancer being acute lymphoblastic leukemia. One of the most common drugs used in the treatment is the anthracycline group of chemotherapeutic agents, and a major side effect is cardiotoxicity. Dexrazoxane, a member of the cardioprotective agents' group of medications, is the only current FDA-approved medication to tackle cardiotoxicity. The mechanism of action in which dexrazoxane is cardioprotective is by halting necroptosis in cardiomyocytes after anthracycline therapy and concurrently binds with iron and reduces the formation of anthracycline-iron complexes and reactive oxygen species. The efficacy of dexrazoxane has been demonstrated in clinical trials within the pediatric population with roughly 60%-80% reduction in risk of developing cardiotoxicity with a very tolerable and limited side effect profile. Further research is required to not only establish the efficacy of dexrazoxane within the pediatric population but also to explore other medications that may serve alongside the function of dexrazoxane.
PubMed: 37182052
DOI: 10.7759/cureus.37308 -
Aging Jan 2021Treatment of thoracic tumors with radiotherapy can lead to severe cardiac injury. We investigated the effects of dexrazoxane, a USFDA-approved cardioprotective drug...
Treatment of thoracic tumors with radiotherapy can lead to severe cardiac injury. We investigated the effects of dexrazoxane, a USFDA-approved cardioprotective drug administered with chemotherapy, on radiation-induced heart disease (RIHD) in a rat model. Male Sprague-Dawley rats were irradiated with a single dose of 20 Gy to the heart and treated with dexrazoxane at the time of irradiation and for 12 subsequent weeks. Dexrazoxane suppressed radiation-induced myocardial apoptosis and significantly reversed changes in serum cardiac troponin I levels and histopathological characteristics six months post-radiation. Treatment with dexrazoxane did not alter the radiosensitivity of thoracic tumors in a tumor formation experiment using male nude Balb/C mice with tumors generated by H292 cells. Dexrazoxane reduced the accumulation of reactive oxygen species in rat cardiac tissues, but not in tumors in nude mice. Transcriptome sequencing showed that and , which are involved in Toll-like receptor signaling, may be associated with the anti-RIHD effects of dexrazoxane. Immunohistochemistry revealed that dexrazoxane significantly decreased NF-κB p65 expression in cardiomyocytes. These findings suggest dexrazoxane may protect against RIHD by suppressing apoptosis and oxidative stress in cardiomyocytes.
Topics: Animals; Apoptosis; Dexrazoxane; Heart; Heart Diseases; Male; Mice; Mice, Nude; Protective Agents; Radiation Injuries, Experimental; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species
PubMed: 33406500
DOI: 10.18632/aging.202332 -
Cancer Feb 2022The objective of this study was to examine long-term outcomes among children newly diagnosed with cancer who were treated in dexrazoxane-containing clinical trials. (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
The objective of this study was to examine long-term outcomes among children newly diagnosed with cancer who were treated in dexrazoxane-containing clinical trials.
METHODS
P9404 (acute lymphoblastic leukemia/lymphoma [ALL]), P9425 and P9426 (Hodgkin lymphoma), P9754 (osteosarcoma), and Dana-Farber Cancer Institute 95-01 (ALL) enrolled 1308 patients between 1996 and 2001: 1066 were randomized (1:1) to doxorubicin with or without dexrazoxane, and 242 (from P9754) were nonrandomly assigned to receive dexrazoxane. Trial data were linked with the National Death Index, the Organ Procurement and Transplantation Network, the Pediatric Health Information System (PHIS), and Medicaid. Osteosarcoma survivors from the Childhood Cancer Survivor Study (CCSS; n = 495; no dexrazoxane) served as comparators in subanalyses. Follow-up events were assessed with cumulative incidence, Cox regression, and Fine-Gray methods.
RESULTS
In randomized trials (cumulative prescribed doxorubicin dose, 100-360 mg/m ; median follow-up, 18.6 years), dexrazoxane was not associated with relapse (hazard ratio [HR], 0.84; 95% confidence interval [CI], 0.63-1.13), second cancers (HR, 1.19; 95% CI, 0.62-2.30), all-cause mortality (HR, 1.07; 95% CI, 0.78-1.47), or cardiovascular mortality (HR, 1.45; 95% CI, 0.41-5.16). Among P9754 patients (all exposed to dexrazoxane; cumulative doxorubicin, 450-600 mg/m ; median follow-up, 16.6-18.4 years), no cardiovascular deaths or heart transplantation occurred. The 20-year heart transplantation rate among CCSS osteosarcoma survivors (mean doxorubicin, 377 ± 145 mg/m ) was 1.6% (vs 0% in P9754; P = .13). Among randomized patients, serious cardiovascular outcomes (cardiomyopathy, ischemic heart disease, and stroke) ascertained by PHIS/Medicaid occurred less commonly with dexrazoxane (5.6%) than without it (17.6%; P = .02), although cardiomyopathy rates alone did not differ (4.4% vs 8.1%; P = .35).
CONCLUSIONS
Dexrazoxane did not appear to adversely affect long-term mortality, event-free survival, or second cancer risk.
Topics: Child; Dexrazoxane; Doxorubicin; Follow-Up Studies; Hodgkin Disease; Humans; Outcome Assessment, Health Care; Precursor Cell Lymphoblastic Leukemia-Lymphoma
PubMed: 34644414
DOI: 10.1002/cncr.33974 -
Biochemical and Biophysical Research... Feb 2020Doxorubicin, as a first line chemotherapeutic agent, its usage is limited owing to cardiotoxicity. Necroptosis is a new form of programmed cell death, and recent...
Doxorubicin, as a first line chemotherapeutic agent, its usage is limited owing to cardiotoxicity. Necroptosis is a new form of programmed cell death, and recent investigations indicated that necroptosis is vitally involved in serious cardiac pathological conditions. Dexrazoxane is the only cardiac protective drug approved by FDA for anthracycline. We aimed to explore whether and how dexrazoxane regulates doxorubicin-induced cardiomyocyte necroptosis. First, doxorubicin could cause heart failure and reduce cardiomyocyte viability by promoting cell apoptosis and necroptosis in vivo and in vitro. Second, necroptosis plays an important role in doxorubicin induced cardiomyocyte injury, which could be inhibited by Nec-1. Third, dexrazoxane increased cell viability and protect heart function by decreasing both cardiomyocyte apoptosis and necroptosis after doxorubicin treatment. Forth, dexrazoxane attenuated doxorubicin-induced inflammation and necroptosis by the inhibition of p38MAPK/NF-κB pathways. These results indicated that dexrazoxane ameliorates cardiotoxicity and protects heart function by attenuating both apoptosis and necroptosis in doxorubicin induced cardiomyocyte injury.
Topics: Animals; Apoptosis; Cells, Cultured; Dexrazoxane; Dose-Response Relationship, Drug; Doxorubicin; Injections, Intraperitoneal; Male; Mice; Mice, Inbred C57BL; Myocytes, Cardiac; Necroptosis; Structure-Activity Relationship
PubMed: 31837803
DOI: 10.1016/j.bbrc.2019.12.027 -
Pharmacotherapy Dec 2021To describe the proposed mechanisms of chemotherapy-associated cardiomyopathy (CAC) and potential cardioprotective therapies for CAC including a comprehensive review of... (Review)
Review
OBJECTIVE
To describe the proposed mechanisms of chemotherapy-associated cardiomyopathy (CAC) and potential cardioprotective therapies for CAC including a comprehensive review of existing systematic analyses, guideline recommendations, and ongoing clinical trials.
DATA SOURCES
A literature search of MEDLINE was performed (from 1990 to June 2020) using the following search terms: anthracycline, trastuzumab, cardiomyopathy, cardiotoxicity, primary prevention, angiotensin-converting enzyme inhibitor (ACEI), angiotensin receptor blocker (ARB), beta blocker, dexrazoxane (DEX) as well as using individual names from select therapeutic categories.
STUDY SELECTION AND DATA EXTRACTION
Existing English language systematic analyses and guidelines were considered.
DATA SYNTHESIS
The mechanisms of CAC are multifaceted, but various cardioprotective therapies target many of these pathways. To date, anthracyclines and HER-2 targeted therapies have been the focus of cardioprotective trials to date as they are the most commonly implicated therapies in CAC. While traditional neurohormonal antagonists (ACEIs, ARBs, and beta blockers) and DEX performed favorably in many small clinical trials, the quality of available evidence remains limited. Hence, major guidelines lack consensus on an approach to primary prevention of CAC. Given the uncertain role of preventive therapy, monitoring for a symptomatic or asymptomatic decline in LV function is imperative with prompt evaluation should this occur. Numerous ongoing randomized controlled trials seek to either confirm the findings of these previous studies or identify new therapeutic agents to prevent CAC. Clinical implications are derived from the available literature as well as current guideline recommendations for CAC cardioprotection.
CONCLUSION
At this time, no single therapy has a clear cardioprotective benefit in preventing CAC nor is any therapy strongly recommended by current guidelines. Additional studies are needed to determine the optimal preventative regimens.
Topics: Cardiomyopathies; Cardiotoxicity; Clinical Trials as Topic; Humans
PubMed: 34806206
DOI: 10.1002/phar.2638 -
Advanced Drug Delivery Reviews Jun 2024Every year, more than a million people in the United States undergo chemotherapy or radiation therapy for cancer, as estimated by the CDC. While chemotherapy has been an... (Review)
Review
Every year, more than a million people in the United States undergo chemotherapy or radiation therapy for cancer, as estimated by the CDC. While chemotherapy has been an instrumental tool for treating cancer, it also causes severe adverse effects. The more commonly acknowledged adverse effects include hair loss, fatigue, and nausea, but a more severe and longer lasting side effect is cardiotoxicity. Cardiotoxicity, or heart damage, is a common complication of cancer treatments. It can range from mild to severe, and it can affect some patients temporarily or others permanently, even after they are cured of cancer. Dexrazoxane is the only FDA-approved drug for treating anthracycline induced cardiotoxicity, but it also has drawbacks and adverse effects. There is no other type of chemotherapy induced cardiotoxicity that has an approved treatment option. In this review, we discuss the pathophysiology of chemotherapeutic-induced cardiotoxicity, methods and guidelines of diagnosis, methods of treatment and mitigation, and current drug delivery approaches in therapeutic development.
PubMed: 38901637
DOI: 10.1016/j.addr.2024.115361 -
Journal of the American Heart... May 2024The only clinically approved drug that reduces doxorubicin cardiotoxicity is dexrazoxane, but its application is limited due to the risk of secondary malignancies. So,...
BACKGROUND
The only clinically approved drug that reduces doxorubicin cardiotoxicity is dexrazoxane, but its application is limited due to the risk of secondary malignancies. So, exploring alternative effective molecules to attenuate its cardiotoxicity is crucial. Colchicine is a safe and well-tolerated drug that helps reduce the production of reactive oxygen species. High doses of colchicine have been reported to block the fusion of autophagosomes and lysosomes in cancer cells. However, the impact of colchicine on the autophagy activity within cardiomyocytes remains inadequately elucidated. Recent studies have highlighted the beneficial effects of colchicine on patients with pericarditis, postprocedural atrial fibrillation, and coronary artery disease. It remains ambiguous how colchicine regulates autophagic flux in doxorubicin-induced heart failure.
METHODS AND RESULTS
Doxorubicin was administered to establish models of heart failure both in vivo and in vitro. Prior studies have reported that doxorubicin impeded the breakdown of autophagic vacuoles, resulting in damaged mitochondria and the accumulation of reactive oxygen species. Following the administration of a low dose of colchicine (0.1 mg/kg, daily), significant improvements were observed in heart function (left ventricular ejection fraction: doxorubicin group versus treatment group=43.75%±3.614% versus 57.07%±2.968%, =0.0373). In terms of mechanism, a low dose of colchicine facilitated the degradation of autolysosomes, thereby mitigating doxorubicin-induced cardiotoxicity.
CONCLUSIONS
Our research has shown that a low dose of colchicine is pivotal in restoring the autophagy activity, thereby attenuating the cardiotoxicity induced by doxorubicin. Consequently, colchicine emerges as a promising therapeutic candidate to improve doxorubicin cardiotoxicity.
Topics: Colchicine; Doxorubicin; Cardiotoxicity; Autophagy; Lysosomes; Animals; Myocytes, Cardiac; Disease Models, Animal; Male; Heart Failure; Antibiotics, Antineoplastic; Reactive Oxygen Species; Mice; Mice, Inbred C57BL; Ventricular Function, Left
PubMed: 38700005
DOI: 10.1161/JAHA.123.033700 -
Cardiovascular Drugs and Therapy Apr 2020Doxorubicin is a commonly used chemotherapeutic agent for the treatment of a range of cancers, but despite its success in improving cancer survival rates, doxorubicin is... (Review)
Review
Doxorubicin is a commonly used chemotherapeutic agent for the treatment of a range of cancers, but despite its success in improving cancer survival rates, doxorubicin is cardiotoxic and can lead to congestive heart failure. Therapeutic options for this patient group are limited to standard heart failure medications with the only drug specific for doxorubicin cardiotoxicity to reach FDA approval being dexrazoxane, an iron-chelating agent targeting oxidative stress. However, dexrazoxane has failed to live up to its expectations from preclinical studies while also bringing up concerns about its safety. Despite decades of research, the molecular mechanisms of doxorubicin cardiotoxicity are still poorly understood and oxidative stress is no longer considered to be the sole evil. Mitochondrial impairment, increased apoptosis, dysregulated autophagy and increased fibrosis have also been shown to be crucial players in doxorubicin cardiotoxicity. These cellular processes are all linked by one highly conserved intracellular kinase: adenosine monophosphate-activated protein kinase (AMPK). AMPK regulates mitochondrial biogenesis via PGC1α signalling, increases oxidative mitochondrial metabolism, decreases apoptosis through inhibition of mTOR signalling, increases autophagy through ULK1 and decreases fibrosis through inhibition of TGFβ signalling. AMPK therefore sits at the control point of many mechanisms shown to be involved in doxorubicin cardiotoxicity and cardiac AMPK signalling itself has been shown to be impaired by doxorubicin. In this review, we introduce different agents known to activate AMPK (metformin, statins, resveratrol, thiazolidinediones, AICAR, specific AMPK activators) as well as exercise and dietary restriction, and we discuss the existing evidence for their potential role in cardioprotection from doxorubicin cardiotoxicity.
Topics: AMP-Activated Protein Kinases; Aminoimidazole Carboxamide; Animals; Antibiotics, Antineoplastic; Caloric Restriction; Cardiotoxicity; Doxorubicin; Enzyme Activation; Enzyme Activators; Exercise; Heart Diseases; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Metformin; Mitochondria, Heart; Myocytes, Cardiac; Resveratrol; Ribonucleotides; Signal Transduction; Thiazolidinediones
PubMed: 32034646
DOI: 10.1007/s10557-020-06941-x