CARDIOVASCULAR DISEASE IN ALL PATIENTS 1

Cardiovascular Disease in Acute Lymphoblastic Leukemia Patients

McKenzie Morgan, Stacey Pezzenti, Emily Russell, Kailee Shumaker, John Slike

Centofanti School of Nursing, Youngstown State University

NURS 3749: Nursing Research

Dr. Danielle Class

April 9th, 2023

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Cardiovascular Disease in Acute Lymphoblastic Leukemia Patients

Introduction

Cancer has been a chronic disease that impacts our society tremendously and is seen

throughout various healthcare settings. One important type of cancer that affects individuals the

most especially in childhood cancer patients is acute lymphoblastic leukemia, which is also

known as ALL. ALL is a type of leukemia that affects the white blood cells and creates errors in

the DNA of the bone marrow. It is one thing to understand what the specific type of cancer is and

how it affects the body, but it is another to understand how it is treated and how that treatment

may affect the individuals during the treatment and possibly later on in life. Treatment and

adverse effects of different types of treatments often go hand in hand. We know that acute

lymphoblastic leukemia is treated with either chemotherapy agents or immunotherapy agents and

both play a significant role in helping cure this cancer. Unfortunately, with any cure there are

consequences; childhood ALL patients are at an increased risk of mortality and morbidity related

to different types of treatment exposure. Throughout this literature review, we need to

understand what chemotherapy and immunotherapy treatment is related to ALL, and the various

cardio-toxic effects chemotherapy and immunotherapy have on ALL patients, along with success

rates to the prevention of these cardio-toxic effects to help determine if chemotherapy causes an

increased risk of these patients developing severe cardiovascular disorders over immunotherapy.

PICOT

This literature review was conducted to identify if there was an increased risk of

developing cardiovascular conditions in pediatric cancer patients, especially after chemotherapy

or immunotherapy. The following PICOT question was developed: “Are acute lymphoblastic
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leukemia patients at an increased risk of developing cardiovascular diseases due to chemotherapy

treatment compared to patients who receive immunotherapy treatment?”

Search Strategy

We used PubMed as our search engine to find resources and literary works associated

with our research question. We used the following terms: cardiovascular disease, acute,

lymphoblastic, leukemia, chemotherapy, cardiotoxicity, survivors, and anthracycline. Our initial

search yielded fifty-six results until we extended our population size to obtain more results with

their abstracts being adequate to our question. Our initial population size was originally focused

only on pediatric leukemia survivors developing cardiac issues later on as a result of either

immunotherapy or chemotherapy treatment. We extended our population size to be more

inclusive to acquire more resources. We also narrowed down our terms, created a new search,

and selected peer-reviewed journal articles written in the English language. We limited the

literature from 2018 to 2023. The databases used in this search include PubMed and Medline.

Our final search yielded 589 results varying from journal articles, clinical trials, meta-analyses,

and systematic reviews. We strived to establish four to five themes out of the ten articles we

curated. We met our goal of generating five themes from our ten articles to support our research

question.

Chemotherapy in Acute Lymphoblastic Leukemia

The human body is composed of millions and millions of cells that work together to form

our organs and tissues. Each individual cell has its own DNA, and a nucleus in the center that

tells the cell what to do, how to work, and eventually die. A normal healthy cell follows these

instructions with no issues. However, when the DNA inside our cells is disrupted or changed in
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some way, it may lead to gene mutation. When gene mutation occurs, these healthy cells are no

longer able to follow instructions due to the change in DNA. When this happens, cells become

dysfunctional and can grow out of control, thus leading to cancer. The out-of-control cells begin

to grow rapidly, and when this occurs, they form a lump of cells, otherwise what we call a tumor.

In leukemia, this out-of-control cell growth comes from blood cells. The blood cells themselves

do not form a tumor, instead, they are built up in the blood or can build up in our bone marrow.

The cells also can ‘metastasis’ which is when they invade other tissues and lymphatic vessels

which carries them into the rest of the body (Mandal, 2019). So how exactly does chemotherapy

work against these cells?

Chemotherapy is one of the most common treatments for cancer. It is a variety of

different drugs used that strike against these rapidly growing cancer cells and try to prevent

further abnormal growth and cause cell death. Chemotherapy contains cytotoxic agents that have

the ability to disrupt rapid cell growth and prevent division (Mandal, 2019). Other cytotoxic

agents work not to prevent further division but instead kill the cells altogether. This is known as

apoptosis, or programmed cell death (Mandal, 2019). In leukemia, the cells are very fast

growing, meaning that they have the factor of growing and dividing more rapidly than other

forms of cancer. The rapid division factor makes it more susceptible to chemotherapy agents,

hence more likely to see a positive outcome versus other forms of slow-growing cancers that are

not as likely to respond to chemotherapy as fast.

There are a number of different chemotherapy drugs that work in different ways. A few

examples of these drugs are Alkylating agents, Antimetabolites, Topoisomerase inhibitors, and

Antitumor antibiotics. These drugs work to achieve the same thing, to prevent cancer cells from

growing and multiplying. However, they have different therapeutic actions. For example,
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Alkylating agents attack DNA within a cell that prevents the cell from dividing. Some examples

of these agents are Altretamine and Cyclophosphamide (Cleveland Clinic, 2022). Alkylating

agents are also the most common type of chemotherapy for cancer patients. Antimetabolites

change the genetic material of cancer cells that are used to grow and divide. Examples of this

group include Floxuridine and Methotrexate (Cleveland Clinic, 2022). Topoisomerase inhibitors

target an enzyme called “topoisomerase” which allows DNA to replicate. A few examples are

Teniposide and Topotecan. Similar to other agents, targeting this DNA can prevent growth and

division, as well as the destruction of the DNA (Cleveland Clinic, 2022). Lastly, antitumor

antibiotics also attack the DNA inside of the cell not allowing it to reproduce. Some examples of

these are Doxorubicin and Daunorubicin (Cleveland Clinic, 2022). These are just a few of the

many categories of chemotherapy agents. As stated before, all chemotherapies have one goal: to

prevent cancer cell growth and division.

While chemotherapy works to overall get rid of cancer, it has the ability to cause some

harsh side effects that the patient must endure. For reference, a handful of side effects include

fatigue, nausea, and vomiting, as well as hair loss, which is the most common. Other side effects

include bowel issues such as diarrhea or constipation, sores in the mouth, and a loss of appetite

(Cleveland Clinic, 2022). Another major adverse effect of chemotherapy is the effect it has on

certain blood cells, specifically neutrophils. It lowers the blood cell count of these cells causing

what we call neutropenia. Neutropenia is an abnormally low neutrophil count in the blood, which

causes a patient to become more prone to infection. Most patients you see in the hospital setting

who are doing rounds of chemotherapy will be placed on neutropenic precautions. This means

anyone who enters the patient’s room whether it is staff or visitors, must take extra precautions

to prevent the spread of any bacteria to the patient. Handwashing, and the absence of fresh
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flowers, fruits, or vegetables in the room are all examples of measures taken to ensure these

precautions (Cleveland Clinic, 2022).

To conclude the understanding of chemotherapy and how it works, it is important to

know that the overall goal is to eliminate the process of rapid growth and division of aggressive

cancerous cells. However, it is just as important to understand the adverse effects chemotherapy

has on the body, mainly the destruction of healthy cells in addition to the cancer ones.

Cardiovascular Issues Related to Chemotherapy

Chemotherapy use in pediatric cancer patients has become a concern related to cardiac

issues. Many individuals or survivors of childhood cancer have reported developing

cardiovascular issues later on in life after receiving treatment. A specific type of childhood

cancer such as acute lymphoblastic leukemia results in survivors developing cardiovascular

diseases. During this treatment, anthracycline is still the first–line chemotherapy drug used that

has significant efficacy in increasing the survival rate of these children. Cardiotoxicity is

recognized to be a side effect during any treatment with the use of anthracycline which causes

concern for its use. With consistent use of anthracycline drugs, there may be an effect on

individuals’ quality of life along with the survival rate of patients after beating cancer (Jin et al.,

2021). However, it is shown that anthracycline–induced cardiotoxicity can be categorized into

three types such as sub-acute, acute, and chronic based on the onset it occurs. The use of

anthracycline has increased the possibility of getting cardiotoxicity during treatment or years

later on.

A study done by Jin et.al (2021) was conducted by using a retrospective case study that

looked at children who had acute lymphoblastic leukemia and before each course of

chemotherapy they monitored their electrocardiogram (ECG) and echocardiography (Echo) to

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determine if there was any anthracycline–induced cardiotoxicity occurring. Jin’s study

uncovered with the induction of daunorubicin (DNR) on days 5 and 12 of treatment and the use

of vincristine (VCR) on days 5, 12, 16, and 26 that several of the participants or cases have

developed cardiac disorders after the administrations. According to their results, one of the cases

developed palpitations and chest distress and their ECGs showed sinus tachycardia and abnormal

T-waves. Although most patients developed cardiac arrhythmias from the DNR administration,

about 14 cases were shown to have a small amount of pericardial effusion, 11 cases with left

ventricular hypertrophy, and 5 with valve disorders (Jin et.al, 2021). Most of the anthracycline–

induced cardiotoxicity was originally found to cause a decline in the left ventricle ejection

fraction (LVEF) which is the volume of fluid ejected from the left ventricle with the contraction

of the heart. This decline can be presented by either arrhythmias, pericarditis, congestive heart

failure, or cardiomyopathy in pediatric patients who received anthracycline treatment.

With ALL, there have been other studies done to determine whether or not chemotherapy

has developed cardiovascular issues in these patients. One study done by the Swiss Medical

Weekly (2019) looks at how the treatment of chemotherapy affects acute lymphoblastic leukemia

survivors. According to the study, survivors have an increased risk of cardiovascular mortality

and morbidity which has been seen to be caused by chemotherapy treatment such as

anthracycline or even by chest radiotherapy (Hau et al., 2019). In their study, they used a

questionnaire that was sent to survivors that survived at least five years after their diagnosis

along with their siblings for comparison. Through the questionnaire, there was a section

specifically for cardiovascular problems that they were asked to explain if they had developed

any of the ones listed. There was a total of 511 ALL survivors that participated out of 707.

Survivors revealed that they had an increased risk or likelihood of developing cardiovascular
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problems. Also, about fourteen percent of the 511 have reported at least developing one

cardiovascular problem. This has been evident as well, with the majority reporting development

of heart failure. The risk is seen high with chemotherapy drugs such as anthracycline, but it is

even higher if the patient had experienced both the anthracycline and chest radiotherapy together

(Hau et al., 2019). Overall, between the two studies, there is shown to be an increased risk from

chemotherapy for these patients whether they develop cardiac diseases during treatment or later

on in life.

Immunotherapy in Acute Lymphoblastic Leukemia

The immune system is a vital part of our body- it protects us from various diseases and

illnesses. When the body notices harmful substances that don’t belong- also known as pathogens

such as bacteria, viruses, and even cancer they stimulate an immune response in which the

immune system starts producing antibodies to fight off the antigens. Antibodies are proteins

made by a form of white blood cell, the B-cell, also known as B-Lymphocytes. Lymphocytes are

part of the lymphatic system, and the two major lymphocytes are B-lymphocytes and T-

lymphocytes. Cytotoxic T-cells (killer T-cells) protect us by killing the infected cells and helper

T-cells help the B-cells gather surrounding cells to help kill the infected cells, through the release

of cytokines from the T-cells which aid in the body's immune response through a communication

system between cells (Markman, 2022 & Carter, 2021). The B-cells and T-cells work together in

the fight against the antigens.

Acute Lymphoblastic Leukemia (ALL) is a rapid growth of immature lymphocytes and

lymphoblasts (leukemic white blood cells) which are produced by the bone marrow. The

lymphoblasts divide rapidly, do not function correctly, and push out healthy cells.

Immunotherapy agents are used in the treatment of cancer by activating or suppressing the
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person's own immune system. Immunotherapy for the treatment of ALL can be used as a first

line of treatment or combined with other treatments. In most cases, immunotherapy is used when

other treatments in a treatment regimen have not been effective or when someone in remission

relapses (Seladi-Schulman Ph.D., 2021). In ALL, there are different forms of immunotherapy

that can be used- Monoclonal antibodies (mAbs), Conjugated Monoclonal Antibodies/Antibody

Drug Conjugates (ADC), and Chimeric Antigen Receptor (CAR) T-cell therapy. Monoclonal

Antibodies (mAbs) such as Blinatumomab (Blincyto), are laboratory-made antibodies that

produce the same action as natural antibodies we make in our body. In ALL, the mAbs work by

targeting specific proteins on the Lymphoblasts to help the immune system destroy them.

Monoclonal antibodies (mAbs) can also be placed in the category of targeted immunotherapy

due to their action to target (Seladi-Schulman Ph.D., 2021). Conjugated Monoclonal Antibodies

are Monoclonal Antibodies that are combined with a chemotherapy drug. When the mAb targets

the specific protein on the cancer cell, the chemotherapy drug will then destroy that cell. In this

case, the Conjugated mAb of choice is Inotuzumab Ozogamicin (Besponsa) which is used in the

treatment of someone with B-cell ALL that has relapsed or is resistant to other treatments. The

mAb is the pathway to the cancer cell for the chemotherapy drug to destroy that cell

(Chemocare, n.d.). Chimeric Antigen Receptor (CAR) T-cell immunotherapy uses the body's

naturally produced T-cells in part of the treatment of ALL. Before starting CAR T-cell therapy,

you will usually be given a different form of treatment such as chemotherapy for a couple of

days leading up to a procedure called Leukapheresis. During Leukapheresis, all of the T-cells (a

form of white blood cell) are taken out of the bloodstream. The T-cells are then altered in a

laboratory to have receptors on them so they can find and attach to certain cancer cells once

infused back into the body. For the treatment of ALL, the type of CAR T-cell immunotherapy
CARDIOVASCULAR DISEASE IN ALL PATIENTS 10

used is- Tisagenlecleucel (Kymriah). There are many different subgroups of ALL- the most

common being B-cell ALL and T-cell ALL, and many different factors that play into which kind

of immunotherapy a patient will receive. The overall effectiveness in the treatment of ALL with

immunotherapy also depends on many factors such as the type of ALL a person has, the stage

they are in with their ALL, the type of immunotherapy used, the types of other treatments they

have received, their age, and most of all: their overall health (Seladi-Schulman Ph.D., 2021).

With ALL, the five-year survival rate continues at a low rate due to relapses being at such

a high percentage. It is hoped that immunotherapy increases the rate of relapsed and resistant

blood cell cancers due to immunotherapy not having to depend on mechanisms that are so toxic

to healthy cells. An article by Shang et.al (2019) explained the different immunotherapies and

their mechanisms of action. Conventional cancer treatments such as Chemotherapy have been

around and used for many years now. Most patients will end up in remission but that does not

stop them from relapsing, gaining resistance to the treatments, and leading to the progression of

the disease and mortality. For ALL, immunotherapy targets for treatment are CD19, CD20,

CD22, and CD52 which are tumor markers. In the article Shang et.al (2019) explained that an

Antibody Drug Conjugate (ADC) Inotuzumab Ozogamicin combined with Calicheamicin is an

Anti-CD22 agent that produces higher remission rates in patients with either a high or low

number of cancer cells. Blinatumomab- a Monoclonal Antibody that targets CD19 has a higher

remission rate in patients with only a low number of cancer cells. Another immunotherapy used

is Chimeric Antigen Receptor (CAR) T-cell therapy. The (CAR) T-cell therapy focuses on tumor

marker CD19 and produces high remission rates greater than 70% without added treatments and

continuous remission. In order to improve the remission rates, it was noted in the article that

instead of using the patient's own T-cells, modifying them in the laboratory then inserting them
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back into the patient, they would focus on redesigning the Chimeric Antigen Receptor and use

healthy donor cells to implant into the patient (Shang et.al, 2019). Concluding the article, Shang

et.al expressed, “The use of immunotherapy in the treatment of Acute Leukemia has greatly

improved the choice of treatment” (2019, para. 48). With immunotherapy agents used in the

treatment of ALL, there is still further research needed due to toxic side effects on healthy cells.

Cardiovascular Issues Related to Immunotherapy

There have been many theories and studies implying that immunotherapies used to treat

cancer led to cardiovascular problems later on in life. Although some studies may lead you to

believe that immunotherapy agents may be safer than chemotherapy and radiation therapy, the

fact of the unknown is what may be the frightening factor. Immunotherapy agents are broken

down into two main groups, Active and Passive Immunotherapy. Immune Checkpoint Inhibitors

are immunotherapy agents that have recently been introduced in cancer therapy (Lobenwein et

al., 2020). Where the fear comes into play is the factor that the cardiotoxic risks of most

immunotherapies are unknown, since they are all so relatively new to the world. There have been

many studies that have been done on patients receiving immunotherapy. The main

cardiovascular side effect that has been brought to the table from these Immune Checkpoint

Inhibitors has been myocarditis. According to Lobenwein et al., “Patients diagnosed with

autoimmune myocarditis present with clinical signs of heart failure such as dyspnea, edema, and

fatigue. Angina pectoris, myocardial infarction, cardiac arrest, and cardiac shock due to

arrhythmias have also been described” (2020, p. 181). With the symptoms of adverse

cardiovascular effects coming about in these patients, the fear of the unknown becomes a big

scare in immunotherapy.
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In a different form of immunotherapy, bispecific T-cell engagers attempt to activate the

immune system in a different way. This is a newer class of monoclonal antibodies. With this type

of immunotherapy, T-cells are activated, cytokines are produced, and the cancer is looked to be

killed off. Although they try to use a different approach, many cardiovascular side effects are

still in the picture. Just a couple of acute symptoms are tachycardia and hypotension. Looking at

some long-term effects of this type of immunotherapy are fatal heart failure, myocarditis, and

myocardial infarction. This specific type of immunotherapy poses risks for severe side effects

because of the release of cytokines.

Another big treatment for cancers that pose risks is cytokine therapy. What this treatment

does is activates white blood cells to fight off infections, classified as a non-specific humoral

immunity (Lobenwein et al., 2020). Cytokine therapy is used for other cancer treatments as well

as Leukemia. One of the biggest side effects of this type of treatment is dilatative

cardiomyopathy. This is a condition that occurs when the left ventricle of the heart is enlarged.

This poses a big problem because it affects the heart’s ability to pump oxygenated blood to the

rest of the body. Autoimmune pericarditis, pericardial effusion with cardiac tamponade,

arrhythmias, and ischemic heart disease are all possible effects stemming from this specific type

of immunotherapy.

When these immunotherapies work to activate T-cells to treat these cancers, the

cardiovascular side effects mainly come from cytokine release syndrome. This is when large

amounts of cytokines get released causing severe or life-threatening effects. Trouble breathing,

tachycardia, and hypotension are a few key indicators of this happening. With all the different

immunotherapies out there, it is very interesting how well they can work. The fear comes into

play due to the factor of not knowing just how safe these therapies can be. Immunotherapy for
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the most part is still relatively new to the cancer treatment world. Many negative cardiovascular

side effects are already known, and there are still many more studies going on to show how much

these therapies will be used in the future.

Success Rates in the Prevention of Cardiovascular Issues

Two studies were conducted to implement monitoring signs for cardiotoxicity early on

for ALL survivors whether they received chemotherapy or immunotherapy from the data they

collected. These studies were assessed by using different methods. The first study had different

methods ranging from cardiopulmonary exercise testing, serum biomarkers, echocardiography,

tissue Doppler imaging, and speckle tracking. Cardiopulmonary exercise testing is a

comprehensive test that assesses a variety of cardiac and pulmonary conditions to determine

whether the heart, lungs, or skeletal muscles limit exercise capacity. Serum biomarkers are taken

via blood tests to indicate the presence, risk, or stage of the disease. Echocardiography is an

imaging test that is also known as a heart ultrasound. Tissue Doppler is a method used that

measures myocardial velocity. Speckle tracking is utilized to assess the function of left

ventricular function in the context of pathologies such as ischemic heart disease,

cardiomyopathies, and diastolic dysfunction.

The second study utilized methods varying from 2D echo, TDI, TTE, and 3D echo. 2D

echo is an ultrasound examination that uses very high-frequency sounds to make real-time

pictures and videos of your heart. TTE is a transthoracic echocardiogram test involving sound

waves to create images of the heart and is used to determine how well the heart is functioning

and identify causes of cardiac-related symptoms. The 3D echo technique is used to improve

image quality and reader confidence and assess structure and functionality. The goals of each
CARDIOVASCULAR DISEASE IN ALL PATIENTS 14

study are aligned with the intention to prevent future ALL patients from developing cardiac

diseases.

The first study had a sample size of seventy-nine pediatric cancer survivors ranging from

the ages of zero to eighteen years. The sample size was compared to a group of forty genders and

age matched with HCM or hypertrophic cardiomyopathy. The results from the first study are that

all patients were asymptomatic during the follow-up. Some abnormalities that were detected

during cardiovascular examinations in pediatric cancer survivors involve decreased exercise

capacity on CPED and evidence of diastolic dysfunction when using the tissue Doppler

echocardiography. The significance behind these results is that they have discovered a

correlation between the increased dosage of anthracycline during treatment and cardiac

dysfunction. “Patients with sarcomas received significantly higher doses of anthracycline

compared to the remaining patients. Twenty-six patients, most of them with Hodgkin lymphomas

and relapse ALL, also received mediastinal irradiation with heart exposure. All patients with

relapse ALL and one patient with ALL received mediastinal irradiation in the setting of total

body irradiation for preparation to bone marrow transplant” (Wolf et al., 2020, para. 16). These

results were obtained from cardiac serum biomarkers, decreased exercise capacity on CPET,

along with any abnormalities that were identified with speckle tracking and TDI.

The results from the second study conducted did not have any significant major

differences in 2D LVEF (left ventricle ejection fraction), diastolic parameters, & speckle

tracking derived myocardial strain were monitored between patients receiving treatment with

anthracyclines and controls. The findings from this study indicate that long-term CCS who have

undergone anthracycline therapy may have discovered features of myocardial dysfunction.

However, further research studies need to be conducted to perform the validity of new imaging
CARDIOVASCULAR DISEASE IN ALL PATIENTS 15

techniques. For example, the TTE and 3D Echo, to identify patients that may potentially be at

risk for cardiomyopathy in the long-term follow-up of CCS. “Novel imaging techniques,

including ST imaging and 3D echo, have been investigated, but further longitudinal studies are

necessary to clarify and optimize their role in routine clinical practice. The challenge with these

non-conventional methods is to understand whether an abnormal result may be considered

predictive of subsequent overt LV dysfunction, which might allow the identification of patients

at risk and undertaking early preventive strategies” (Sofia et al., 2021, para. 43). More research is

necessary to determine whether chemotherapy or immunotherapy treatment is more likely to

cause cardiac diseases in patients.

Conclusion

Overall, by looking at all of the studies it was shown that the use of chemotherapy agents

such as AC and DNR increased the risk of cardiotoxicity in acute lymphoblastic leukemia

patients during their treatment regimens. As for immunotherapy, more patients were shown to

have cardiovascular issues years after their initial treatment when they would be considered

"survivors" of ALL. Therefore, with the rise in the incidence of cardiovascular effects from

cancer treatments the need for early detection and prevention has been examined. Through

echocardiography and other invasive equipment, patients may have features of myocardial dial

dysfunction. Moving forward there needs to be more research into the cardiac effects of both

chemotherapy and immunotherapy as well as different imaging techniques used to identify

potential risks.
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