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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests whether certain heart medications can protect the heart in people with acute myeloid leukemia (AML) who receive daunorubicin. While daunorubicin treats leukemia, it can also cause heart damage. Participants will be randomly assigned to take heart-protective drugs, such as beta blockers and ACE inhibitors, or to continue with standard care. The study will monitor the frequency of heart problems in each group. Those with AML who are starting daunorubicin treatment and are not already on heart medications might be suitable candidates. As a Phase 2 trial, this research measures the treatment's effectiveness in an initial, smaller group, offering participants a chance to contribute to important findings.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that certain heart medications, such as beta blockers and ACE inhibitors, can protect the heart from chemotherapy-induced damage. These drugs are often used to safeguard the heart and are generally safe for most individuals. Studies suggest they might reduce heart-related side effects when combined with treatments like daunorubicin, commonly administered to patients with acute myeloid leukemia (AML).

The FDA has approved beta blockers and ACE inhibitors for treating heart problems, confirming their safety. Most people tolerate them well, though some may experience mild side effects like dizziness or tiredness. If a patient cannot tolerate a beta blocker, the treatment can be adjusted to maintain safety.

In summary, these heart-protective drugs have a strong safety record and could help lower heart risks during AML treatment. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about cardioprotective treatments involving beta blockers and ACE inhibitors for Acute Myeloid Leukemia (AML) because they offer a novel approach to protecting the heart during cancer treatment. While standard care for AML often focuses on managing the leukemia itself, these drugs specifically aim to shield the heart from the damaging effects of anthracycline chemotherapy, a common component of AML therapy. By potentially reducing heart-related side effects, these treatments could improve the overall safety and quality of life for patients undergoing intensive cancer treatment.

What evidence suggests that this trial's treatments could be effective for preventing heart damage in AML patients?

In this trial, participants in the treatment arm will receive a combination of beta blockers and ACE inhibitors to protect the heart during chemotherapy with drugs such as daunorubicin. Research has shown that these heart medications can lower the risk of heart damage, a common side effect of anthracycline drugs used to treat acute myeloid leukemia (AML). Studies have found that these heart-protecting drugs can reduce chemotherapy's harmful effects on the heart by easing strain and preventing damage. Although these drugs are not officially approved for preventing heart damage in this specific situation, their use in similar cases suggests they can be helpful. Participants in the standard clinical care arm will not receive these medications but will undergo regular assessments to monitor heart health. ^{1 3 4 6 7}

Who Is on the Research Team?

Michael Keng, MD

Principal Investigator

UVA

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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]

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]

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]

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]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11817404/

Acute and Chronic Cardiovascular Adverse Events in ... The purpose of this systematic review is to explore the association of acute myeloid leukemia treatment with adverse cardiovascular events. Methods: We ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9938608/

Efficacy and safety of cardioprotective drugs in ... Prior studies have suggested that using common cardioprotective agents may attenuate chemotherapy-induced cardiotoxicity.

3. cancer.gov cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2021-13968

ACE Inhibitors and Beta Blockers for the Protection of ... This phase II trial tests whether taking medications from a group of drugs called ACE inhibitors and beta blockers help protect the heart while receiving ...

4. uvahealth.com uvahealth.com/clinicaltrials/study-patients-newly-diagnosed-acute-myeloid-leukemia-see-if-drugs-treating-heart

Study For Patients With Newly Diagnosed Acute Myeloid ... The beta blockers and ACE inhibitors used in this study are approved by the FDA for treating heart damage but not approved to prevent heart damage in this ...

5. ashpublications.org ashpublications.org/bloodadvances/article/4/4/762/452554/Anthracycline-related-cardiotoxicity-in-older

Anthracycline-related cardiotoxicity in older patients with acute ... Angiotensin-converting enzyme inhibitors (ACE-Is) and β-blockers are frequently used for management of LVEF decline and HF, and have been ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT04977180

Study Details | NCT04977180 | Cardioprotection in AML The hypothesis of the study is that taking a beta blocker and ACEi during initial therapy for AML and through about 90 days after they last take an ...

7. jacc.org jacc.org/doi/10.1016/j.jaccao.2024.06.005

Cardiovascular Considerations During Cancer Therapy The administration of certain cancer therapies can be associated with the development of cardiovascular toxicity or complications.