Cardioprotective Drugs for Acute Myeloid Leukemia

(AML 001 Trial)

Overseen By Avani Hopkins, RN

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: University of Virginia

Must not be taking: Beta blockers, ACE inhibitors

Disqualifiers: Pregnancy, Congestive heart failure, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

70 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial tests if taking beta blockers and ACE inhibitors can prevent heart damage in AML patients receiving daunorubicin chemotherapy. These medications help protect the heart by reducing stress and preventing damage. The study will compare heart health and quality of life between those who take these medications and those who do not.

Will I have to stop taking my current medications?

If you are currently using any beta blockers, ACE inhibitors, or angiotensin II receptor blockers, you will need to stop taking them before joining this trial. The trial does not specify about other medications, so it's best to discuss your current medications with the study team.

What data supports the effectiveness of cardioprotective drugs for preventing heart damage in patients with acute myeloid leukemia?

Research shows that cardioprotective drugs like beta-blockers and ACE inhibitors can help prevent heart damage caused by certain cancer treatments. These drugs have been found to reduce heart problems in patients receiving chemotherapy, which suggests they might also help protect the heart in acute myeloid leukemia patients. ^{1 2 3 4 5}

Is it safe to use cardioprotective drugs like ACE inhibitors and beta-blockers in humans?

Research shows that ACE inhibitors and beta-blockers are generally safe for humans and can help prevent heart problems caused by certain cancer treatments. They are used to protect heart function and have been studied for their safety in various conditions. ^{1 2 6 7 8}

How is the cardioprotective drug treatment for acute myeloid leukemia different from other treatments?

This treatment is unique because it uses beta blockers and ACE inhibitors, which are typically used to protect the heart from damage, to prevent heart problems caused by chemotherapy in acute myeloid leukemia patients. Unlike traditional cancer treatments that focus solely on attacking cancer cells, this approach aims to protect the heart from the harmful side effects of chemotherapy. ^{1 3 5 6 8}

Research Team

Michael Keng, MD

Principal Investigator

UVA

Eligibility Criteria

Adults over 18 with newly-diagnosed Acute Myeloid Leukemia (AML) who are about to start or have just started induction therapy without anthracycline can join. They must be able to take oral meds, have good organ function, and an ejection fraction ≥ 50%. Women of childbearing age and men must use contraception. Can't join if already using heart meds like beta blockers or ACEi, have severe illnesses/heart issues, pregnant/lactating women, or those with certain medical conditions.

Inclusion Criteria

I agree to use birth control or abstain from sex during my treatment.

I can take care of myself and am up and about more than half of my waking hours.

I am 18 or older and have been recently diagnosed with AML.

Exclusion Criteria

I have been diagnosed with congestive heart failure by my oncologist.

I do not have any severe or untreated infections.

I have moderate or severe heart valve disease.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Induction Treatment

Participants receive induction therapy for AML, including daunorubicin and potentially beta blocker and ACE inhibitor for cardioprotection

6 weeks

Multiple visits for chemotherapy administration and monitoring

Consolidation Treatment

Continuation of AML treatment and cardioprotective measures, with regular assessments via ECG/EKG and echocardiogram

Up to 6 months

Regular visits for treatment and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment, including assessments of heart function and quality of life

90 days after last anthracycline cycle

Regular follow-up visits

Treatment Details

Interventions

• Cardioprotection

Trial Overview The trial is testing whether taking a beta blocker and ACE inhibitor before starting chemotherapy can prevent heart damage caused by the drug daunorubicin in AML patients. Participants will either receive these drugs as prevention or not. The study measures how often heart damage occurs and monitors overall heart health and quality of life.

Participant Groups

Group I: Treatment arm (beta blocker and ACE inhibitor) Experimental Treatment 1 Intervention

Participants will receive a beta blocker (either metoprolol or carvedilol) and an ACE inhibitor (lisinopril) at standard doses based on tolerance starting from when they start induction therapy for AML through 90 days after the first day of the last cycle of therapy that includes an anthracycline (whether that is in the induction, re-induction, or consolidation phase of treatment). If participants are unable to tolerate either beta blocker (e.g., heart rate is low at baseline or is lowered to an unsafe level with the beta blocker), no beta blocker may be administered as part of this study treatment. They will also undergo regular assessments via ECG/EKG and echocardiogram, and to measure troponin levels.

Group II: Standard Clinical Care Active Control 1 Intervention

Participants will receive standard clinical care, but will also undergo regular assessments via ECG/EKG and echocardiogram, and to measure troponin levels

Cardioprotection is already approved in United States, European Union for the following indications:

Approved in United States as Beta blockers and ACE inhibitors for:

• Heart failure
• Hypertension
• Prevention of anthracycline-induced cardiotoxicity

Approved in European Union as Beta blockers and ACE inhibitors for:

• Heart failure
• Hypertension
• Prevention of anthracycline-induced cardiotoxicity

Who Is Running the Clinical Trial?

University of Virginia

Lead Sponsor

Trials

802

Recruited

1,342,000+

Findings from Research

The OVERCOME study is a randomized controlled trial involving 90 patients with acute leukemia or undergoing autologous stem cell transplantation, aimed at assessing the effectiveness of enalapril and carvedilol in preventing left ventricular dysfunction (LVD) caused by chemotherapy.

This study is significant as it is the first to evaluate the combined preventive effects of these medications on LVD in patients receiving intensive chemotherapy, with primary outcomes focused on changes in left ventricular ejection fraction and secondary outcomes including heart failure incidence.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prevention of chemotherapy-induced left ventricular dysfunction with enalapril and carvedilol: rationale and design of the OVERCOME trial. Bosch, X., Esteve, J., Sitges, M., et al.[2018]

A survey of Canadian hematologists revealed that interruptions in cardiovascular (CV) medications, such as statins and antiplatelets, are common among acute leukemia patients undergoing intensive chemotherapy, which can negatively affect their heart health.

The findings emphasize the importance of collaboration between hematology and cardiology teams, as well as the involvement of multidisciplinary healthcare professionals, to enhance cardiovascular care during leukemia treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Management of cardiovascular health in acute leukemia: a national survey. Durand, M., Lacaria, K., Sidsworth, M., et al.[2020]

A 52-year-old man with acute myeloid leukemia (AML) developed after coronary stenting was successfully treated with a combination of idarubicin and cytarabine, leading to over 6 years of disease-free survival.

The case highlights the importance of using antiplatelet drugs during chemotherapy for patients with coronary heart disease, emphasizing the need for personalized treatment strategies to manage potential adverse effects in complex cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New perspectives on treatment strategies for patient with acute myeloid leukemia and complex karyotype abnormalities after percutaneous coronary intervention: A case report. Wang, J., Chen, R., Lin, X., et al.[2022]

In a study of 1,014 pediatric patients with acute myeloid leukemia, dexrazoxane significantly reduced declines in heart function and the risk of left ventricular systolic dysfunction compared to those not receiving it.

Patients treated with dexrazoxane maintained similar rates of event-free survival and overall survival as those who did not receive it, suggesting that it effectively protects the heart without increasing the risk of cancer relapse or other toxicities.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of Dexrazoxane on Left Ventricular Systolic Function and Treatment Outcomes in Patients With Acute Myeloid Leukemia: A Report From the Children's Oncology Group. Getz, KD., Sung, L., Alonzo, TA., et al.[2021]

In a systematic review of 12 randomized controlled trials involving 1,035 cancer patients, cardioprotective drugs like RAAS blockers and β-blockers significantly reduced the risk of left ventricular ejection fraction (LVEF) decline caused by anthracycline treatment, indicating their potential to protect heart function.

While these cardioprotective drugs showed benefits in preventing cardiac damage, the overall clinical significance of these findings, including the non-significant reduction in heart failure and increase in hypotension, requires further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prevention of anthracycline-induced cardiotoxicity: a systematic review and meta-analysis. Caspani, F., Tralongo, AC., Campiotti, L., et al.[2021]

Prophylactic use of angiotensin-converting enzyme inhibitors (ACEI) and angiotensin-receptor blockers (ARB) can help preserve left ventricle ejection fraction (LVEF) in patients receiving anthracycline treatment, indicating a reduction in cardiotoxicity.

The study, which included 7 randomized controlled trials, found no significant increase in hypotensive events associated with ACEI/ARB use, suggesting these medications are safe for this purpose.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Protective Effects of ACEI/ARB on Left Ventricular Function in Anthracycline-Induced Chronic Cardiotoxicity: A Meta-Analysis of Randomized Controlled Trials. Lin, H., Liang, G., Wu, Y., et al.[2021]

AT1 blockers are as effective as ACE inhibitors in reducing overall mortality, cardiovascular mortality, and the risk of myocardial infarction in patients.

Patients using AT1 blockers experience fewer treatment withdrawals due to adverse reactions compared to those on ACE inhibitors, suggesting a better safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[AT1 blockers - comparability with ACE inhibitors]. Monhart, V.[2018]

Beta-blockers and ACE inhibitors/ARBs can significantly help prevent decreases in left ventricular function (LVEF) in cancer patients undergoing anthracycline-based chemotherapy, with beta-blockers showing a 2.57% improvement and ACE inhibitors/ARBs showing a 4.71% improvement in LVEF compared to controls.

The analysis included 769 patients for beta-blockers and 581 patients for ACE inhibitors/ARBs, but the results showed significant variability among studies, indicating a need for more systematic evidence to establish solid recommendations for cardioprotective strategies during chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Heart failure from cancer therapy: can we prevent it? Totzeck, M., Mincu, RI., Heusch, G., et al.[2021]

References

1. United States pubmed.ncbi.nlm.nih.gov

Prevention of chemotherapy-induced left ventricular dysfunction with enalapril and carvedilol: rationale and design of the OVERCOME trial. [2018]

2. United States pubmed.ncbi.nlm.nih.gov

Management of cardiovascular health in acute leukemia: a national survey. [2020]

3. United States pubmed.ncbi.nlm.nih.gov

New perspectives on treatment strategies for patient with acute myeloid leukemia and complex karyotype abnormalities after percutaneous coronary intervention: A case report. [2022]

4. United States pubmed.ncbi.nlm.nih.gov

Effect of Dexrazoxane on Left Ventricular Systolic Function and Treatment Outcomes in Patients With Acute Myeloid Leukemia: A Report From the Children's Oncology Group. [2021]

5. Italy pubmed.ncbi.nlm.nih.gov

Prevention of anthracycline-induced cardiotoxicity: a systematic review and meta-analysis. [2021]

6. Switzerland pubmed.ncbi.nlm.nih.gov

Protective Effects of ACEI/ARB on Left Ventricular Function in Anthracycline-Induced Chronic Cardiotoxicity: A Meta-Analysis of Randomized Controlled Trials. [2021]

7. Czech Republic pubmed.ncbi.nlm.nih.gov

[AT1 blockers - comparability with ACE inhibitors]. [2018]

8. England pubmed.ncbi.nlm.nih.gov

Heart failure from cancer therapy: can we prevent it? [2021]