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Could Epigenetic Therapy Replace Current Treatment Methods for Acute Myeloid Leukaemia?

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According to the Centers for Disease Control and Prevention, in 2015, 1.2% of the United States population was reported as having active epilepsy (National Center for Chronic Disease Prevention and Health Promotion, 2018). This percentage corresponds to approximately 3.4 million people with epilepsy nationwide. The state of California has the highest number of reported cases of epilepsy in the nation with 427,700 cases in 2015 with approximately 59,000 cases involving children ages 0-17 (Zack & Kobau, 2017). Epilepsy is a common neurological disorder, also known as seizure disorder, and is characterized by recurrent seizures which are not always easily controlled by medication. There are various types of seizures that affect children with epilepsy with symptoms varying from convulsions and losing consciousness to rapid blinking and staring into space (National Center for Chronic Disease Prevention and Health Promotion, 2018). Children diagnosed with epilepsy may suffer from one or more types of seizures with variations in frequency, severity, and symptoms (Zack & Kobau, 2017).
The impact of childhood epilepsy is complex and extensive. It is typically unpredictable, dangerous, and often affects a client’s mental health due to social exclusion and stigmatization from society and peers. Previous research has shown that children with chronic health conditions including epilepsy are at increased risk for poor educational and vocational outcomes which can have an impact on future occupational performance (Maslow, Haydon, McRee, Ford, & Halpern, 2011). This, in combination with the stigma that many people with epilepsy endure, may ultimately impact the variety of occupations this population participates in.
Current research on epilepsy has identified the multi-faceted nature in which an epilepsy diagnosis impacts the person inclusively. Extensive research has reported that the crucial determinant in increasing overall well-being is becoming seizure-free (Birbeck, Hays, Cui, & Vickrey, 2002). However, that is not a goal that everyone can easily attain which generates the need to study alternative environments more critically in order to help promote health and wellness for this population. The purpose of this study is to explore the effects of a structured home-school environment on adolescents diagnosed with epilepsy on their academic achievement, social relationships and overall quality of life.
Several research questions were investigated throughout this study. First, what differences are there in academic achievement for adolescents with epilepsy in a structured homeschool learning environment in comparison to public schooling? Second, how are social relationships fostered in a structured homeschool environment for adolescents diagnosed with epilepsy?  Is there a difference in number of social relationship contacts and the strength of those relationships between these adolescents in comparison to a public school setting? Lastly, is the quality of life for adolescents with epilepsy better for those in a structured homeschool environment versus a public school learning environment?
This study is significantly important because of the bearing that academic and social domains have on present and future occupational engagement and the overall effect that an epilepsy diagnosis carries affecting one’s quality of life. In order to promote occupational engagement, an analysis of how the environment may be limiting the variety of occupations students with epilepsy participate in is necessary. In addition, taking into consideration the role the environment plays will help these students to build a successful foundation early in life in order to prevent possible occupational deprivation in the future. The profession of occupational therapy is uniquely positioned to address the prevention of occupational deprivation due to academic, psychosocial, and cognitive barriers through use of a variety of assessments. One of these assessments, the Canadian Occupational Performance Measure, seeks to address the occupational difficulties that children with epilepsy and their families face giving both the child and their families an opportunity to communicate which occupations are most important to them to help guide intervention (Fayed & Kerr, 2009). In this way, occupational therapists will be able to make a difference in how children interact and engage in occupations that may have been restricted previously and thus promote future success in occupational engagement.
Conceptual/Operational Definitions
This study defines the population with epilepsy as being diagnosed by a doctor, currently prescribed and taking anti-epileptic drugs, and reporting seizure frequency as at least four times in the last six months. Participants will be organized by seizure type but this study will not exclude any particular types of seizures. For the purpose of this research study, academic achievement can be defined similarly to the educational bodies of literature using the state standardized assessment by grade level for each participant and comparing those scores to the participant’s measured IQ level using the full Wechsler Intelligence Scale for Children and Adults (Wechsler, 1958; Wechsler, 2003). Social relationships will be measured by the frequency of social contacts daily, weekly and monthly reported by the participants and their family members. Additionally, data will be collected on the strength of these social relationships through use of a self-reported questionnaire given to the participant and their social contacts. Lastly, the quality of life of the participants will be measured through the Youth Quality of Life Instrument assessing four domains including sense of self, social relationships, environment, and general quality of life (Salum, Patrick, Isolan, Manfro, & Fleck, 2012; Edwards, Huebner, Connell, & Patrick, 2002).
 
 
 
 
Chapter 2: Literature Review
Although the customary goal prioritized in research for managing epilepsy focuses almost exclusively on seizure control and minimal side effects from medications, there are many other factors that impact the well-being of a child with epilepsy and their families. The topic of this literature review explores the effects that epilepsy has on children in the academic and social domains including overall quality of life. The literature will be broken down by subtopic and will discuss how epilepsy affects academic achievement, socialization, and quality of life, and how homeschooling may benefit the population of students with epilepsy. The discussion of these subtopics aid in supporting the need for the present research study which considers how a structured homeschool learning environment may be more favorable for students diagnosed with epilepsy.
Theoretical Framework for Study
The theoretical framework that informs this study is the PEOP model due to the interaction of the person, environment, occupation and performance (Cole & Tufano, 2008, p. 127). Similarly, this research study will explore how these four components interact resulting in lower levels of occupational performance for students diagnosed with epilepsy utilizing a cohort study design. Bodies of literature that will be addressed within this literature review include academic and psychosocial studies, and a variety of comparison studies related to children with epilepsy.
Academic Achievement
Many research studies over the years have come to the conclusion that children with epilepsy struggle academically (Braakman et al., 2012; Drewel, Bell, & Austin, 2009; Mitchell, Chavez, Lee, & Guzman, 1991). Although several studies have been criticized for recruiting participants with epilepsy that are also below average intelligence, potentially impacting the results for academic achievement, there are also many studies that eliminated the confounding variable excluding participants with global cognitive deficits and comorbidities (Fastenau, Shen, Dunn, & Austin, 2008; McNelis, Johnson, Huberty, & Austin, 2005; Reilly et al., 2014). These studies showed that while there were slight differences in the data for academic achievement, the results were very insignificant in comparison and still yielded significant evidence that children with an epilepsy diagnosis perform at lower levels of academic achievement than others their age and grade level.
Among the several studies that did exclude participants with global cognitive deficits (below average IQ) and comorbidities, research indicated that children with epilepsy achieve lower scores in mathematics, reading, and written language subtests including spelling (Braakman et al., 2012; Drewel et al., 2009; Jackson et al., 2013; Mitchell et al., 1991; Shoenfeld et al., 1999; Williams & Sharp, 1996). Another study indicated that children with epilepsy had significantly lower achievement scores in reading and mathematics subscales than children with chronic asthma (Austin, Huberty, Huster, & Dunn, 1999). This same study also found that children with epilepsy continue to perform significantly worse over time even when their condition improves. This distinguishes that the academic difficulties that participants with epilepsy undergo are specific to epilepsy and not simply the result of living with a chronic condition and that the risk to academic achievement is long-term. This information illustrates the critical importance in finding alternative ways to help these children succeed academically. The risk of low academic achievement is one that can impact social outcomes and employment as children with epilepsy enter into adulthood leading to potential occupational deprivation and a lack of engagement in meaningful occupations. Proactive methods for addressing academic difficulties with this population are not well-addressed throughout the literature, and are exactly what this population needs in order to prevent potential academic difficulties precluding this population from performing at their highest capacity.
Academic achievement and attention.
Among the difficulties that children with epilepsy face in the academic domain, children with epilepsy are also more likely to have significant deficits in attention (Semrud-Clikeman & Wical, 1999; Williams et al., 2001). In one study, attentional difficulties included problems staying focused and the child being unable to respond consistently (Semrud-Clikeman & Wical, 1999). In a traditional school setting, these difficulties can severely impact a student’s academic performance and in a classroom with 30 other students, a child may be more likely to fly under the radar for a prolonged period of time before a teacher notices these deficits. Although the study by Semrud-Clikeman and Wical (1999) included students concurrently diagnosed with attention deficit hyperactivity disorder (ADHD), their findings remained stable even when children diagnosed with ADHD were excluded from the study. This indicates that the strong association between an epilepsy diagnosis and deficits in attention is not due to any underlying attentional deficit disorder, but is specific to the epilepsy condition. This was found to be the case regardless of seizure type suggesting that the difficulties in attention may be due to a more general neurological element of the epilepsy disorder as a whole. This finding has strong clinical significance for occupational therapists evaluating and determining interventions for their clients with epilepsy who may similarly have obscured deficits with attention that go unnoticed.
An important relationship between auditory attention skills and academic achievement was also found through the use of the Number Letter Memory Subtest that is an assessment highly sensitive to inattentiveness (Williams et al., 2001). “A more generalized pattern of inattention, regardless of seizure type, may reduce the ability to attend to auditory information within the environment, resulting in decreased achievement” (Williams et al., 2001, p. 221-222). This relationship is critical to our understanding of the academic difficulties this population struggles with especially if their attentional difficulties are not severe enough to receive a diagnosis of ADHD. The need for more research and interventions to help promote academic success in this population is clear, but the direction of these interventions should also take into consideration the effect on attention, specifically auditory attention. Homeschooling is an intervention that can potentially impact a child’s academic performance but also may provide a learning environment that is more conducive to students with difficulties in maintaining attention. Having far fewer distractions in a homeschool environment and the flexibility for the student to work on their own schedule takes into consideration this element of attention and the difficulties affecting this population.
Furthermore, it was found that attention skills were more predictive of academic performance than other variables such as memory, epilepsy variables, socioeconomic status or self-esteem (Williams et al., 2001). However, there has been limited research that addresses interventions with the epilepsy population that focus on this aspect of attention and its connection to academic underachievement. This proposed study will do just that by investigating an alternative learning environment such as homeschooling that is unique and individualized to the student taking into consideration the complexity of effects of an epilepsy diagnosis including underlying difficulties in attention.
Effects on the Social Domain
In addition to the physical hazards that pose as a critical burden for those diagnosed with epilepsy, there is also the strain of social exclusion due to the negative attitudes held by teachers, peers and other members of society. Furthermore, one must take into consideration the social stigma that is often associated with epilepsy that can also have an impact on a student. This includes societal beliefs that people with epilepsy are unable to attain certain things due to their diagnosis such as attend school, marry, have kids, drive a car, or find employment (Austin, Shafer, & Deering, 2002).
Although the research for understanding the social stigma in relation to epilepsy is limited due to the complexity of the concept and possibly the lack of quantitative instruments that can directly measure social stigma, the studies that do exist demonstrate significant gaps in society’s knowledge of epilepsy and many misconceptions of what epilepsy is and how it affects those who are diagnosed (Ali, Tomek, & Lisk, 2014; Austin et al., 2002; Bishop & Boag, 2006; Savarese, Carpinelli, D’Elia, & Coppola, 2015). Among many of these studies, it was found that many people lacked the knowledge of what to do if someone had a seizure and also held inaccurate beliefs that epilepsy might be contagious or considered a mental illness (Ali et al., 2014; Austin et al., 2002; Savarese et al., 2015). Furthermore, teachers perceived students with epilepsy as unlike other students with only 25% of the sample of middle and high school teachers claiming that students with epilepsy would not be marginalized by other students (Savarese et al., 2015).
This illustrates that as children age, the stigma of an epilepsy diagnosis also becomes more burdensome. Teachers without proper expertise and knowledge to support a student with epilepsy will continue to contribute to the vicious cycle that promotes social stigma causing students with epilepsy to suffer without access to an academic learning environment that promotes their success. These misconstrued beliefs by the teachers may also subconsciously impact the quality of the support they provide to students with epilepsy in comparison to other students.
Although in one study related to social stigma, students with epilepsy reported that they didn’t feel that they were socially stigmatized, more than 50% of the sample reported that they keep their epilepsy a secret and 70% reported that they rarely or never talk to others about their epilepsy (Westbrook, Bauman, & Shinnar, 1992). Therefore, the lack of student scores indicating experiences of social stigma could potentially be due to a majority of the sample not disclosing their diagnosis in the first place. In another study, 70% of the sample of students responded that if they had a friend diagnosed with epilepsy they would want their friend to tell them; however the majority of this same sample reported that if they were diagnosed with epilepsy they would not tell their friends about their condition (Austin et al., 2002). These findings illustrate a strong indication of perceived negative consequences for being open about an epilepsy diagnosis. The study also indicated that respondents felt that an epilepsy diagnosis was more likely to make someone unpopular and more likely to be bullied (Austin, et al., 2002). This paints a clear picture of how typical students perceive those with an epilepsy diagnosis and indicates that the social environment for those with a chronic condition such as epilepsy has a variety of negative consequences. With a condition that is not always easily concealed, alternative environments such as homeschooling may provide a more positive social environment that will help foster this population’s self-esteem to negate the social stigma that continues to be prevalent in our society.
The above research relates to this proposed study because if students with epilepsy are encompassed in an environment that doesn’t fully understand their diagnosis and limitations and if a disclosure of their diagnosis elicits negative social consequences, students with epilepsy will continue to have difficulties with making social connections and fostering healthy relationships. Furthermore, the trend in research that teachers specifically continue to lack knowledge about the condition of epilepsy is worrisome (Bishop & Boag, 2006). Teacher attitudes and beliefs can directly impact the self-esteem and social connectedness of a student with epilepsy. Over time, these ensuing beliefs may impact the child’s engagement in occupations due to the development of poor self-esteem that may lead to occupational deprivation in the present and future and potentially a lower quality of life.
Quality of Life
The quality of life for people with epilepsy is dependent on a variety of variables. One of these variables includes the potential for becoming seizure-free which has had a majority of researchers’ support. Several studies throughout the literature indicated that the most significant levels of improvement in health-related quality of life measures wasn’t seizure frequency or severity but was seizure freedom (Birbeck et al., 2002; Leidy, Elixhauser, Vickrey, Means, & Willian, 1999; Stavem, Loge, & Kaasa, 2000). But then, what about those who are unable to attain seizure freedom despite their best efforts? This leads to the necessary critical analysis of quality of life and other potential factors that play a role in life satisfaction to provide these additional strategies to those with an epilepsy diagnosis to help improve their quality of life while living with this chronic condition.
Quality of life and comorbidities.
Another variable that has been commonly found in the research regarding quality of life is the potential for comorbidities. The populations of people with epilepsy are no different than other populations with chronic conditions and are more likely to suffer from more than one illness at the same time. The most prevalent of these comorbid conditions that people with epilepsy suffer from is anxiety and depression (Jacoby, Snape, Lane, & Baker, 2015; Leidy et al., 1999; Pulsipher, Seidenberg, Jones, & Hermann, 2006; Strine et al., 2005; Téllez-Zenteno, Matijevic, & Wiebe, 2005). One research study reported that an increase in the number of comorbid conditions was associated with lower levels of quality of life (Pulsipher et al., 2006). Although some of these conditions may be due to environmental or genetic predispositions, anxiety and depression can also be induced as a side effect from anti-epileptic medications making those with an epilepsy diagnosis even more likely to suffer from multiple diagnoses (Baker, Jacoby, Buck, Stalgis, & Monnet, 1997). Additionally, anxiety or depression may also stem from the social stigma and worry a student experiences about having a seizure in class. They may experience feelings of depression if their condition limits them from participating in activities that they enjoy or previously enjoyed. Homeschooling may be one way we can adapt the environment to limit the social anxiety of having a seizure in front of a large audience, limit the magnitude of anxiety someone with epilepsy may experience, and therefore increase the student’s overall quality of life.
In another study it was found that trait anxiety, defined as “stable individual differences in anxiety proneness,” was a significant contributor to quality of life (Jacoby et al., 2015, p. 151). This was also corroborated by Spielberger, Gorsuch, and Lushene (1970) who additionally reported that higher levels of trait anxiety is associated with self-reported difficulties in almost every facet of life including social and intimate relationships, health and well-being, future planning, and work adjustments. Although few studies have been done that specifically address the impact of anxiety on quality of life, the study conducted by Jacoby et al. (2015) included a very large sample size and utilized a large sample for the control group as well which adds to the reliability of the study. This has important clinical implications because it shows that professionals can help the client with epilepsy with their quality of life by beginning with addressing the trait anxiety they may be experiencing. Adaptations to the environment may be a helpful way to eliminate some of this anxiety which is why it is important to conduct the research to find out if a homeschooling environment may be a more holistic option to improve the lives of those with epilepsy.
The impact of sleep on quality of life.
A third variable that has been on the radar of several researchers although has not been researched extensively is that of sleeping difficulties and how lack of sleep may impact quality of life. It was found that the groups of people with epilepsy reported both an increase in nighttime sleep difficulties and also daytime sleepiness in comparison to controls attributed to anxiety (Jacoby et al., 2015). This is clinically important because of the extensive research that has associated sleep problems with academic difficulties and now we are being made aware of potential problems with quality of life. If students with epilepsy are having sleep difficulties it may be affecting multiple facets of their lives contributing to lower levels of quality of life. This information lends itself to discovering possible flexible schedules that can accommodate these sleeping difficulties, of which homeschooling may just be the answer.
Homeschooling
Over the last several decades, the population of students entering into a homeschooled environment has become more prevalent due to familial beliefs, religious convictions, and dissatisfaction with the public school system (Mayberry & Knowles, 1989). Although there has long been a debate comparing student achievement scores from those who are homeschooled and those attending public school, in general, several studies indicate that academic achievements of students who are homeschooled exceed those of their peers attending traditional schools (Martin-Chang, Gould, & Meuse, 2011; Ray, 2010; Rudner, 1999). However, many of these studies have flaws in their methodology including not randomizing their samples, not differentiating between two distinct divisions of homeschooling (structured and unstructured), and mistakenly comparing two different school structures without critically analyzing the difference in educational goals both structures may set out to achieve.
A structured homeschool environment is similar to the traditional schooling method in that teaching and learning takes place according to a defined curriculum (Martin-Chang et al., 2011; Neuman & Guterman, 2016). Unstructured homeschooling, on the other hand, also known as unschooling, is a more independent learning process aimed to be completely child-directed with little to no external obligations placed on the learning process (Martin-Chang et al., 2011; Neuman & Guterman, 2016).  The study conducted by Martin-Chang et al. (2011) was one of very few studies that differentiated between the structured and unstructured homeschooling options in order to address some of the methodological flaws in previous studies. This study found that children who were homeschooled in a structured environment outperformed both children in traditional schools and children in an unstructured homeschool environment. Interestingly, children who were homeschooled in an unstructured environment were not only outperformed by the structured division of homeschooling, but also the children in the traditional school environment (Martin-Chang et al., 2011). This illustrates that students without a diagnosis that are homeschooled within a structured environment can achieve academic success at the same level or higher than their peers attending traditional schooling, but the samples did not include students with chronic conditions. Research needs to be conducted to investigate whether this finding may also be generalizable to a population of students with a chronic condition such as epilepsy. Specifically, it will be important to distinguish if the population of students with epilepsy have better academic outcomes in a structured homeschool environment in comparison to their own performance in a traditional school environment, which is what this proposed study will help to determine.
Another reason parents often make the decision to homeschool their children is in order to provide a more flexible learning environment with individualized attention for their children with special needs (Duvall, Delquadri, & Ward, 2004; Duvall, Ward, Delquadri, & Greenwood, 1997). One research study reported that a group of homeschooled students with learning disabilities made more progress in reading, math and spelling than the control group comprised of students with learning disabilities attending public school (Duvall et al., 1997). These are the same subjects that children with epilepsy are struggling with in the traditional public school classroom mentioned in the previous section. While the limitations in this study involve a very small sample size which limits the generalizability of the findings, it makes a strong argument for producing research using the population of children with epilepsy. The age of the population in this study included elementary school and junior high school aged participants, which also begs the question if the findings may be similar for those at the high school level which is the specific population this proposed study intends to use.
Homeschooling and socialization.
Another factor that both proponents and opponents of homeschooling deem important in regards to homeschooling are the students’ opportunities for socialization and whether or not they still develop the social skills necessary to be a productive member of society. Those who oppose homeschooling argue that the homeschooling environment limits opportunities for children to socialize and may leave them feeling more isolated than they would if they were attending traditional school (cite). On the contrary, many homeschooled students when asked identified mostly positive experiences related to homeschooling (Montgomery, 1989; Mullins, 1992). For example, in the study conducted by Montgomery (1989) only two students out of 87 in the sample mentioned a disadvantage of homeschooling as having “fewer friends.” This was among a list of 242 experiences of homeschooling mentioned by the students of which only 3 experiences stated were deemed negative. Another study found that the slightly decreased frequency of social contacts made in a one month period by homeschoolers was not statistically significant when compared to students in traditional schools (Catham-Carpenter, 1994). Although home schooled students had fewer social contacts with peers than those attending traditional school, this is most likely due to the convenience of attending a traditional school with many opportunities for peer contact and may be different had the study been conducted during the summer months.
While there has been a moderate amount of research done on the effects of homeschooling, there has not been any research done on homeschooling with the population of children with epilepsy. Due to the multitude of advantages that have been addressed in many of these research studies, many of them align greatly with the needs of this population. Addressing these needs will give students a better chance to succeed potentially preventing future occupational deprivation that can occur without a strong educational foundation.
Conclusion
The research has been extensive in terms of how an epilepsy diagnosis may impact children, both academically and socially. It is apparent that these two domains are intricately linked to the overall quality of life of this population. Students with epilepsy struggle with low academic achievement that doesn’t improve even if their condition improves, social stigma that creates a learning environment that promotes anxiety and worry of being accepted, and the medication they take to control their seizures often have side effects that predispose them to comorbid conditions such as anxiety or depression that decrease their life satisfaction and overall quality of life. Without further research, this population will continue to struggle through adolescence. The profession of occupational therapy can address and analyze the context and the environment to make a difference in the success of this population in order to maximize their occupational engagement now and in the future. This proposed study will contribute to existing literature and help explore a potential solution to help this population succeed and provide encouragement for them to be productive members of society that engage in meaningful occupations every day.
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Could Epigenetic Therapy Replace Current Treatment Methods for Acute Myeloid Leukaemia?

Table of Contents
Abstract
Introduction
Literature Review
Glossary
Discussion
Conclusion
Evaluation
Bibliography

Abstract

Acute myeloid leukaemia is the most frequent type of acute leukaemia present in adults. The current treatments, which are quite effective, have rather severe side effects and the mortality rates are quite high. With the emergence of a new field, epigenetics offers hope of restoring the cell’s proper function instead of just killing cells which is what the current treatment for AMl. Epigenetics could prevent the suppression of tumour suppressor genes that cause AML to rise in the first place and reduce the need for a bone marrow transplant. Unfortunately, epigenetic drugs (azacitidine and decitabine) do not reduce mortality rates in comparison to cytarabine and daunorubicin, but Midostaurin, a targeted drug does reduce mortality rates for patients with the FLT3 mutation which suggests that targeted therapy may be more effective than general epigenetic drugs, thus suggesting that this may be a far superior treatment method than epigenetic drugs.

Introduction

With the completion of the human genome project in 2003 Bill Clinton triumphantly declared that ‘it is now conceivable that our children’s children will know the term cancer only as a constellation of stars’ (National Human Genome Research Institute, 2000).  Unfortunately, fourteen years later this does not seem likely to happen. We have made great strides in the field of disease and cancer but there is still a great deal left to learn. When this project was completed many thought that this was the answer to all maladies. But this is certainly not this case with the emergence of the field of epigenetics.
There is just more to disease than simply faulty genes. The addition of extra information to the DNA code, without actually changing the underlying DNA code, is called the epigenome. It is derived from the Greek word ‘epi’ which means ‘on’. Your epigenome controls which genes are switched on and which genes are switched off in all of your cells. For example, the gene to make insulin is turned on in your b cells in your pancreas but this same gene is also turned off in your muscle cells. This then leads one to think how this could perhaps be affected in cancerous cells, where tumour suppressor genes are turned off which eventually leads to rapid proliferation of these cells.
In this study, I will be looking at two primary chemotherapeutic agents (cytarabine the main drug and midostaurin, which is primarily used if a patient has an flt3 mutation) and the use of allogenic haemopoietic stem cell transplant and I will look at the efficacy of three epigenetic therapeutic agents, azacitidine and saha or suberoylanilide hydroxamic acid and decitabine. I will look at how survival rates are affected when these new agents are introduced and how this may also affect morbidity. Morbidity rates are slightly different to mortality rates in the fact that morbidity assess the quality of life of the patient, if the drugs are toxic then what problems this causes for the patient and how this affects their quality of life. I will be looking at how an emerging field, epigenetics, could change the way we treat disease, specifically cancers of the blood. Epigenetic therapy holds great hope for patients because unlike gene therapy the effect of the epigenetic drugs is reversible, histones can be deacetylated and DNA could be unmethylated again. Furthermore, the germ line will not be affected as when a sperm cell fertilises an egg cell, agents in the cytoplasm of the egg cell remove all the epigenetic markers that allowed those cells to become so specialised in the first place and what is left if a totipotent zygote[1]. Thus, if epigenetic drugs do have unintended consequences that have not yet been discovered then it is very unlikely that they will be transferred to the next generation.
Looking at AML is particularly important because it is a ‘disease of the elderly’ and with an ageing population, there will most likely be higher incidences of the disease and we must come up with less toxic treatment methods. Moreover, about 15-20% of patients who had a solid tumour and were treated with chemotherapy usually develop AML. This is a terrible consequence of treatment and highlights the desperate need for better treatments of cancer not just for AML but for a wide variety of cancers. (Kumar, 2011)
I will not however be looking at the economical aspect of these drugs. I think that efficacy must certainly be established before we look at the economic viability of the drugs. Whilst this would certainly be an interesting topic, as the potential lifelong requirement of some epigenetic drugs such as azacitidine may cause a great deal of stress and anxiety for patients who live in countries where lifesaving drugs are not necessarily guaranteed, America for example. This could be further investigated, but this essay will focus on efficacy. In order to determine whether epigenetic therapy can replace current chemotherapy agents, a higher efficacy for epigenetic agents needs to be determined when compared to standard chemotherapy. Efficacy can be defined by how well a drug achieves the desired goal, in this case removing as many cancerous cells as possible and preventing them from returning for as longs as possible. Efficacy can be measured in mortality rates but this must be then compared with morbidities and side effects of the drugs.

Literature Review

What is Acute Myeloid Leukaemia?
The bone marrow contains lots of stem cells, which eventually become either white blood cells (also known as leukocytes), red blood cells (also known as erythrocytes) or platelets. These cells are different to other cells in the body because the red blood cells do not just divide by mitosis in order to create more red blood cells because they do not contain any DNA. Therefore, new red blood cells need to be made in the bone marrow in order to replace any erythrocytes that have died. In healthy bone marrow stem cells differentiate into different types of cells depending on their environment. The differentiation pathway of various cells is illustrated in the diagram below. When these stem cells differentiate the cells become more specialised which allows them to perform a certain function better. An example is that erythrocytes do not contain any DNA to allow the cells to contain more haemoglobin (a protein that carries oxygen) which in turn allows the cell to transport more oxygen.
Figure 1. shows a schematic representation of the pathway that stem cells take in order to become different cells in the blood. (Martin, 2014)
However, in acute myeloid leukaemia, myeloid blasts, which are a type of immature white blood cell that have not fully differentiated, are abnormal. They do not follow the normal pathway to become healthy functioning monocytes and granulocytes. These abnormal cells are called ‘leukaemia cells’ and they build up in the bone marrow which means that there is less space for healthy white blood cells, red blood cells and platelets to develop. The cells also build up in the blood and causes severe problems. It means that there are not enough healthy blood cells and this is important as red blood cells carry oxygen to cells around the body and white blood cells are essential to the immune system as they help fight off invading pathogens. Platelets are also very important as they form blood clots at the site of a wound to prevent bacteria from getting in and infecting the wound and to also prevent more blood from escaping the body.
Because there are leukaemia cells present in the blood, this means that it is very easy for the cancer to metastasize (travel to different parts of the body and begin to rapidly divide at the new site, forming new tumours). The cancerous cells can spread to the brain, spinal cord, skin and even the gums. There are 12 different subtypes of AML and they are defined by how mature the cancer cells are when the patient is diagnosed and just how different the cells are to normal cells. (National Cancer Institute , 2017)
What Causes AML to Arise?
Cancerous cells usually arise from mutation in the DNA. A mutation is a change to the original DNA sequence. DNA consists of 4 bases (A, T, C, G). For example, is we had a fictional DNA sequence of ATTCGAGGCT, a mutation could mean substituting the first A for a C or removing the A altogether.
Mutations occur when DNA is not replicated faithfully. Many patients with AML have mutations in specific genes such as the FLT3, KIT or RAS gene. The FLT3 and KIT gene code for proteins that belong to the tyrosine kinase family. These proteins are situated on the cell membrane and they transmit signals into the cell. These genes control cell division and the KIT gene also codes for proteins that are important for the development of hematopoietic stem cells, which are cells in the bone marrow which eventually become blood cells, and immune cells called mast cells. (U.S. national Library of Medicine, 2017).
Mutations in the FLT3 occur in about 30% of patients with AML and is said to be ‘the most common molecular abnormality in acute myeloid leukaemia’. There are two prominent types of mutations that occur in this gene. One of them is an internal tandem duplication of DNA sequences found in exons 14 and 15. And the other type of mutation is a D835 mutation. Both of these mutations activate the FLT3 receptor tyrosine kinase protein in early haematopoietic cells (Mayo Clinic, n.d.). FLT3 mutations also become more common with age. (U.S. national Library of Medicine, 2017). A mutation in the FLT3 gene ‘leads to production of proteins that cause cell growth and inhibit cell death through apoptosis’. (Mayo Clinic, n.d.)
Larger changes that can occur to the DNA are changes to the chromosomes which occurs in most cases as 40-50% of patients with AML have the right number of chromosomes which are all the right shape and size. This is called a normal karyotype. (Kumar, 2011). There are four major changes that can occur to the chromosomes. One of them is translocation, which is the most common cause of leukaemia. It occurs when one part of a chromosome breaks off and attaches itself to a different chromosome. This can turn on oncogenes or turn off genes that would usually cause blood cells to mature such as RUNX1 and RARa. A deletion can also occur in a chromosome where a piece of a chromosome is lost. This results in a gene being lost and could potentially be a tumour suppressing gene.  An inversion can also occur when a part of a chromosome is reversed which can also result in losing a gene because the genes on the chromosome can now no longer be read.  Addition and duplication can also occur in chromosomes which leads to multiple copies of genes, which could potentially be devastating if a gene or several genes are oncogenes (American Cancer Society, 2016).
One of the characteristic traits of cancer cells is their uninhibited proliferation, where they divide many, many times (much more than the average cell) to produce a mass of cells, a tumour. This rapid division is associated with oncogenes and tumour suppressor genes. The former is associated with proteins that tell the cell to divide and the latter tells the cell when to stop dividing. It ensures that the cell does not begin to divide rapidly, which ensures that the cell does not become cancerous. But of course, this can go wrong. Patients with AML have a distinct lack of DNA methylation. This will be explored in the next section but DNA methylation is associated with genes being turned off so if a gene is hypomethylated (under methylated) then it does not have as many methyl groups as it should do, resulting in a gene being turned on. This of course is disastrous when this is a tumour suppressor gene. (Esteller, 2002)
What are the current treatments for leukaemia?
The treatment for AML is separated into different parts. When a patient is first diagnosed with AML they undergo induction therapy, which is the first part of their treatment and aims to eliminate as many leukaemia cells as possible. The intensity of the treatment is dependent on the person’s age and health. The most intensive chemotherapy is given to people under the age of 60. As the goal is to get rid of as many cancerous cells as possible usually very toxic drugs are prescribed. One chemotherapy drug is called cytarabine. This works by inhibiting DNA replication. It is converted to a certain form by the cell and is then incorporated into the DNA instead of cytidine (a DNA base). This then means that the DNA molecule cannot rotate so the DNA molecule cannot be replicated. Furthermore, it ‘also inhibits DNA polymerase, resulting in a decrease in DNA replication and repair’ (U.S. National Library of Medicine, 2005). Because it affects DNA replication this will most affect cells that rapidly divide, the leukaemia cells and stops them in their tracks. But this also means that the drug will attack hair growth as well and healthy tissue as well.
Another drug that is used is daunorubicin, which is an anthracycline. It is an antibiotic. The drug also affects the replication of DNA by interacting with it and it also affects the repair of DNA by repair mechanisms. And affects protein synthesis of the cell, causing it to die. (U.S. National Library of Medicine, 2005)
A variety of other drugs can also be given to patients, depending on the patients themselves and the stage of the cancer but this report will be looking at the two main drugs: Cytarabine and daunorubicin; It will also look at a drug given to patients who have the FLT3 mutation. This drug is called Midostaurin.
Cytarabine is known as a ‘cytotoxic antimetabolite’. Antimetabolites are very similar to normal substances within the cell, they attack cells at very specific phases in the cell cycle which in this case is the dividing phase as cancerous cells rapidly divide, therefore they are taken up by the cancerous cells. (Chemocare, n.d.) When they are inside the cells, they cause a deficiency of DNA and RNA in cancer cells (which are necessary to for cells to grow and multiply). This means that the cells grow in an unbalanced way and causes the cell to die. Unfortunately, as cytarabine affects rapidly dividing cells they can also affect normal healthy cells such as blood cells and hair cells, the reduction in the production of blood cells means that people are susceptible to infection. For this reason, doses of cytarabine are administered in various intervals to allow normal cells to recover from the detrimental effects of the drug. However, during this period, cancer cells will also recover and begin to replicate again. In most chemotherapy regimens, doses are administered in courses at various intervals to allow normal cells to recover from the adverse effects of the anticancer medicines between doses.
Radiation therapy may also be used as well if the leukaemia has spread to other parts of the body such as the brain or the spinal cord, or chemotherapy may also be given into the cerebrospinal fluid.
A stem cell or bone marrow transplant may be recommended a couple of weeks after the chemotherapy has been completed. A biopsy will be completed and it should show a few bone marrow cells and only a small portion of blasts. An autologous stem cell transplant means that stem cells from the patient are removed from their bone marrow or blood and is frozen before chemotherapy begins. After the treatment has finished, the stem cells are injected into the patient and after a couple of week the stem cells begin to differentiate into new white blood cells. For a bone marrow transplant a small portion of another person’s bone marrow, which is a match for the patients’, is taken and injected into the patient. This replaces the blood cells lost during chemotherapy. (American Cancer Society, 2017)
What is Epigenetics?
DNA codes for proteins, however, the specific proteins that each specialised cell produces is controlled by epigenetics. Epigenetics is additional to DNA, they are chemical ‘tags’, that changes the phenotype without changing the genotype. This means that the genotype, the complete set of alleles in a cell stays the same but the phenotype, the physical trait of the cell, what can be observed changes. This is way beta cells is the pancreas produce insulin but muscle cells do not. The complete set of chemical tags on a personas DNA makes up their epigenome. One chemical tag is a methyl group (one carbon atom and three hydrogen atoms, CH3). This can be attached to cytosine, base C, but only if the C is followed by a G (guanine). This C and G pair are known as CpG islands. If a methyl group is attached to a CpG island then other proteins are attracted to it and these proteins effectively turn the gene off, this is called DNA methylation. This means that the polypeptide that the gene codes for is no longer produced. However, if there are not many methyl groups attached to the CpG islands then the gene is turned on and the polypeptide will be produced (Carey, The Epigenetic Reolution, 2011). This is shown in the diagram below.
Figure 2: Shows A schematic representation of epigenetic markers on dna and how this affects gene expression
Epigenetic changes, the amount of methylation or other chemical tags, can be affected by the environment and any modifications to the epigenome can be passed on to daughter cells when the cell divides as the epigenetic tags are copied along with the DNA. There are many epigenetic processes such as methylation, acetylation, phosphorylation, ubiquitylation, and sumolyation, but in this report DNA methylation and histone acetylation will be the primary focus.
Epigenetic tags are added and removed by gene regulatory proteins, which use enzymes to add tags to the DNA or histones, which is the protein that DNA is wrapped around to prevent it from getting tangled up, or both the DNA and histones. (Carey, The Epigenetic Reolution, 2011)
The most widely studied process is DNA methylation. This is when a methyl group (CH3) is attached to a specific sequence of DNA. This makes the DNA wrap tighter around the histones. This makes the DNA harder to read by the enzyme RNA polymerase and therefore it is harder to be transcribed into RNA. Therefore, the protein that that specific sequence of DNA codes for is not produced by the ribosomes. (Weinhold, 2006)
What is Epigenetic Therapy?
Epigenetic therapy is when drugs are used to change the existing chemical tags on DNA. This could be adding or taking away a methyl group or histone modification. In the genome, there exist tumour suppressing genes which prevent a cell from dividing uncontrollably. So, if by demethylation that gene this could stop leukemic cells from endless proliferation. This would then be passed onto its daughter cells as epigenetic tags are copied, along with the DNA so this change would be apparent in all new cells, thus stopping more tumours from forming.
Furthermore, chromatin, a combination of DNA and histones, compresses the DNA so it can fit into cells. This also controls gene expression and any changes to the histones also change the structure of the chromatin. If the chromatin is very loose then that gene will be expressed but if it is tight then the gene will not be expressed. So, a drug could be used to change the structure of the chromatin which again will mean that an oncogene is not expressed.
For some tumour suppressor genes, the fact that it is compressed by the chromatin means that it behaves almost like an embryonic cell. However embryonic cells stop making copies of themselves when they receive a certain signal but cancerous cells never receive that signal because a growth limiting signal has been silenced by the addition of a methyl group.
In one study researchers removed a methyl group from a specific sequence of bases in the genome using a drug called 5-azacytidine and a HDAC inhibitor, which blocks histones. The chromatin coils loosed and some expression was restored. This could then be applied to restore the expression of growth limiting factor genes. (Johns Hopkins, n.d.)
Azacitidine and decitabine and SAHA are all drugs that have been approved for the use of treatment of AML and they are all epigenetic drugs. They change the chemical tags in a cell, causing that cell to behave differently. (Carey, The Epigenetic Revoltion, 2011)

Glossary

Discussion

Mortality Rates
There are two factors to consider when attempting to introduce a new treatment with a higher efficacy: mortality rates and morbidity rates. This section will talk about mortality rates.
Chemotherapy drugs are usually used in combination and the combinations vary depending on the patient. But one of the most common drugs is cytarabine. 66% of patients who receive standard induction therapy (cytarabine and daunorubicin) achieve remission. Remission is when the bone marrow ‘contains fewer than 5% blast cells, the blood cell counts are within normal limits, and there are no signs or symptoms of the disease’ (American Cancer Society, 2014). But this varies with each patient as age or genetic changes affect a patient’s prognosis. This is the short-term survival rate but over 5 years the survival rate lies around 30%, which means that the mortality rate lies at 70%. This can be seen in Figure 3 where patients who received high doses and intermediate doses had similar survival rates after five years. This shows that the efficacy of cytarabine remains the same regardless of dose. But in other study, higher doses of cytarabine were observed to be more effective in increasing remission rates.
 
Figure 3 Shows survival rates for high dose and intermediate doses of cytarabine. Graph A shows overall survival rates and graph B shows event free survival rates(Löwenberg, 2011)
A possible reason that cytarabine is not as effective as it could be, is the fact that it can be deactivated by the liver. The liver contains enzymes which remove an amino acid from cytarabine. This is normally a very important process as it converts dangerous products into urea by deamination, but in this instance, it renders cytarabine useless. It also means that cytarabine cannot affect any leukaemia cells that may be present in the liver, as there is a low concentration of it in the liver. If the leukaemia cells are not affected they can build up their and produce tumours. This will drastically affect survival rates because the liver performs so many functions and if it is dysfunctional then a liver transplant may be required and that in itself comes with a host of risks.
But on the other hand, this may not be as devastating as if these leukemic cells accumulated in other organs because the liver does have the ability to regenerate, to an extent, so if a patient were to undergo surgery to remove a, relatively small to medium sized, mass from the liver then they would not require an organ transplant, which would unfortunately not be the case with other organs.
On the other hand, one of the reasons that cytarabine is so effective as a drug is that it blocks the leukemic cells from replicating. By preventing the cells from replicating it is stopping the cancer at the very first stage. This is far more effective at getting rid of lots of leukemic cells, which is very important as induction therapy attempts to get rid of as many leukemic cells as possible in the first stage in order to minimise the devastating effects of the aggressive cancer. Cytarabine, when compared to decitabine (a hypomethylating agent) has been shown to kill more leukemic cells in vitro (in a colony assay) than decitabine[2]. This shows the higher toxicity of cytarabine for cancerous cells which indicates higher efficacy than epigenetic drugs. But these cells were observed under laboratory conditions instead of inside the body.
Although cytarabine has been shown to kill more leukemic cells in vitro this does not translate into better survival rates. When we look at the mortality rate when decitabine was used the mortality rate after 1 year was 28%. This is much lower than when cytarabine was used. In Figure 1 after 1 year the survival rate is 60%. From this the mortality rate can be deduced as 40%. Therefore, decitabine decreases mortality rate. This is probably due to the lower toxicity of decitabine. This is particularly important in elderly patients as highly toxic drugs will increase mortality rates as elderly patients are less able to tolerate the toxic chemicals.
This supports the idea that decitabine could replace cytotoxic agents for elderly patients who are less able to deal with aggressive treatments (Ramos, 2015)
In addition, there is a 12-hour gap between doses of cytarabine which could allow the cancerous cells time to regroup and allows them to build up again. If the time between doses were reduced this may prevent the cells from rapidly reproducing and prevent the number of these cancerous cells from increasing. However, this in itself comes with adverse side effects as it does not give the body time to recover and may in fact have more adverse side effects as the treatment progresses with more rounds of chemotherapy.
However, some patients are resistant to cytarabine, there is interference with the normal apoptic pathway in AML cells and decitabine reactivates the regulation of this pathway so can be used to treat patients who are resistant to cytarabine. (Momparler, 2013)
Epigenetic changes do not occur in a vacuum and actually the reduced efficacy of cytarabine is through epigenetic silencing. There is a protein that tells a cell to die. When the gene that codes for that protein is silenced through DNA methylation the protein is not produced and the cell does not die. Decitabine reactivates this gene, ‘Foxo3’, which then increases the TRAIL pathway. This pathway tells the cell to die, if it is abnormal. In doing this, cancerous cells are prevented from migrating to other parts of the body, preventing metastasis.
In one study 114 patients (17% of the total group) were given either azacitidine or decitabine or both of the drugs. They were also given a histone deacetlyase inhibitor. These patients received these drugs as part of their induction therapy, the first part of the treatment.

Figure 4 shows the probability of survival 10 years after initial diagnosis: A Kaplan-Meier Curve (Quintás-Cardama, 2012)
Patients who received epigenetic therapy had lower rates of achieving complete remission, in one study 28% of patients receiving epigenetic therapy achieved complete remission but 42% of patients who received chemotherapy achieved complete remission. Furthermore, the reduction of tumours was also less for the people receiving epigenetic therapy than for people receiving chemotherapy. In this study, the reduction of tumours was defined as:
‘ORR = CR + CR with incomplete platelet recovery’
It was 29% for patients receiving epigenetic therapy but 47% in patients who received standard chemotherapy treatments. The epigenetic therapy used in this study was a hypomethylating agent. However, the mortality rate was lower for epigenetic therapy:
‘The early mortality rates (mortality within the first 8 weeks of therapy) were 18% with intensive chemotherapy and 11% with hypomethylating agents’
and ‘The 2-year relapse-free survival rates with intensive chemotherapy and epigenetic therapy were 30% and 40%, respectively (P = .843). The median survival times were 6.7 and 6.5 months (P = .413), respectively’.
Therefore, although a higher percentage of patients achieved complete remission, this, unfortunately, did not mean that mortality rates decreased. (Quintás-Cardama, 2012)
Whilst decitabine and azacitidine improved complete remission rates but did not significantly decrease mortality rates, targeted therapy seems to have a different outcome.
Midostaurin is used to target patients with the FLT3 mutation. Patients who received this drug had a decrease of risk of death by 22% compared to a placebo. And 51.4% of patients were alive 4 years after initial diagnosis. (National Cancer Institute, 2017)
An example of a histone deacetlyase inhibitor is saha. It has the same effects as DNA methylation, in that it prevents acetyl group from attaching on to the lysine on the histone tails of certain gens. This means that the gene is not expressed as much. In one study SAHA increased the regulation of the TRAIL pathway which is what regulates the death of cancerous cells. The effect of SAHA was improved by using it with homoharringtonine. The combination prevented the growth of a culture of leukaemia cells in vivo and increased cells death. Therefore, SAHA in combination with homoharringtonine, at low concentrations can re-regulate the TRAIL pathway and can be used in treatments. (Cao, 2013)
This shows us that whilst SAHA may not be particularly effective on its own, it may be effective in combination with other drugs to regulate proper apoptic pathways. This is a very complex pathway and moves away from the tumour suppression gene into actually killing cells. This could be very useful as if it merely reactivated the tumour suppressor gene, this may be permanent and may result in patients taking lifelong medication with the fear of the cancer returning at any time. This is particularly similar to the effects of cytarabine which also induces apoptosis in leukemic cells. Therefore, this may work extremely well in induction therapy, in which the aim is to get rid of as many cancerous cells as possible but it may not stop the production of more cancerous cells once therapy stops. (Glozak & Seto, 2007)
Another study looked at the effects of histone deacetylases instead of hypomethylating agents, histone deacetylases are quite effective as they allow tumour suppressor genes to be expressed again. (Quintas-Cardama, 2010)
In one study involving decitabine which compared it against cytarabine, ‘patients demonstrated significantly improved complete remission rates, but the survival difference did not reach significance’ (Malik, 2014). This is the opposite of azacitidine which we saw earlier. However, the insignificant difference in survival rates could be attributed to the fact that the patients who took part in this study were elderly and elderly patients, unfortunately do have a lower overall survival rate when compared with younger adult patients. This is due to the fact that it is difficult for them to take on intense therapies and leads to comorbidities
Morbidity Rates
Another way to look at the efficacy of treatments is to look at morbidity rates. This looks at the problems that come with the use of therapeutic agents. If two agents have similar mortality rates then a drug with the higher efficacy will be the drug with the lower morbidity, i.e. fewer side effects or fewer severe side effects.
Cytarabine, for it to be most effective, requires the use of high doses but this comes with the side effect of cardiotoxicity. This means that the drug could cause heart disease, such as myocarditis (inflammation of the heart tissue) or arrhythmias (irregular beating of the hear) or cardiogenic shock (Albini, 2010). Furthermore, this is also a problem with daunorubicin, that it causes high levels of cardiotoxicity. It is also an antibiotic which comes with its own problems.
 
Figure 5shows possible damage to the heart and the mechanisms through which they are likely, where + = likely. (Albini, 2010)
Anthracyclines and cytarabine interfere with DNA replication as they get in between DNA base pairs. This action produces free hydroxyl radicals [OH] instead of the usual ion [OH]. These are extremely reactive molecules, as the oxygen has an unpaired electron. The cardiac muscle is particularly affected by these radicals and thus has the greatest damage done to it, even though this helps reduce tumours. (Hortobágyi, 2012)

Figure 6 shows the skeletal formula of Daunorubicin and Cytarabine  (National Center for Biotechnology Information., 2017)
On the other hand, epigenetic agents do not have this terrible side effect but SAHA does have other very similar side effects. These Include:

  • Fatigue
  • Diarrhea
  • Nausea
  • Taste changes
  • Increased blood glucose level (hyperglycemia)
  • Increased creatinine level (transient)
  • Increased level of protein in the urine
  • Low platelet count (thrombocytopenia) (ChemoCare, n.d.)

When compared to the side effects of cytarabine, these side effects appear quite similar and therefore it may not be a good replacement. On the other hand, if the side effects are very similar but does not have the side effect of cardiotoxicity and both drugs have similar mortality rates then SAHA could be a viable alternative because the morbidity of the drug will be lower than current chemotherapeutic agents. This could improve the quality of life of patients.
Again, the side effects of taking decitabine are very similar to the side effects associated with SAHA. They are:

  • Low blood counts. White and red blood cells and platelets may temporarily decrease. This can put you at increased risk for infection, anaemia and bleeding, and may increase need for blood or platelet transfusions.
  • Fatigue
  • Fever
  • Nausea
  • Cough
  • Petechiae (Tiny red dots on your skin,) and can occur with low platelet count
  • Constipation
  • Diarrhoea
  • Hyperglycaemia – high blood glucose levels (Chemocare, n.d.)

But again, SAHA has the benefit of not increasing the chances of heart failure.
If remission is achieved, patients may then get more chemo (consolidation). Up to half of patients that get this go into long-term remission (and may be cured). But this number is also affected by prognostic factors, such as a person’s age and whether the leukaemia cells have certain gene or chromosome changes. Using an allogeneic  stem cell transplant as consolidation has a higher success rate, but it also has a higher risk of death as a complication. (American Cancer Society, 2014)
Bone marrow transplants have been common treatment for AML for a while. In one cancer centre the survival rate one year after an allogenic bone marrow transplant was 75%, which surpassed their predictions of 62%.  They used another type of therapy when transplanting the bone marrow cells, called t cell therapy, in which they removed the t cells from the donor’s bone marrow cells. This meant that the patient’s immune system did not recognise the donor’s bone marrow cells as foreign cells and started to attack these cells. This is a very common problem with transplants and means that patients have to be on immunosuppressant’s for a while and this means that they are at a greater risk of infection. This is known as graft – v – host disease, where the transplant is recognised as a foreign cell by the body’s immune system and it then produces a response in order to try and kill these invading cells. This reduces the efficacy of the treatment. (Memorial Sloan Kettering, 2012) The side effects of bone marrow transplants can be quite severe and some of the symptoms include an itchy rash, dry eyes, dry flaky skin, shortness of breath, joint pain or jaundice, where the skin and the whites of the eyes gain a yellowish hue. Due to the risk of the patient rejecting the transplant and the severity of these side effects it is normally recommended that patients are relatively young in order to reap the most benefit from the treatment. (NHS, 2015). This is a problem as most cases of AML occur in elderly patients, therefore, for them this is not the ideal treatment despite it being relatively effective. Furthermore, bone marrow transplants are often allogenic (the transplant cells come from a donor rather than the patient) rather than autologous (where the cells come from the patient) because some of the cells taken from the patient may be leukaemia cells, therefore this may re-introduce the cancer into the body during the transplant. Furthermore, if bone marrow transplants are to be allogenic then a donor must be found who is a match for the patient. This means that the proteins on the donor cells and the patient cells are the same. This therefore reduce the risk of rejection by the patient’s immune system. (Cancer Research UK, 2015)in one study that analysed the outcome of allogenic and autologous stem cell transplants, the patients who received allogenic transplants had a 100% success rate, all of the patients had a successful outcome whereas only 94.7% of patients who received an autologous transplant had a successful outcome, but bearing in mind that all patients involved in the study were in complete remission.

Conclusion

In conclusion, epigenetic therapy cannot replace current treatment methods. The main reason is that every patient is different and using a very specific targeted course of treatment, for example using Midostaurin if they have the FLT3 mutation will be far more effective than using epigenetic agents. As the majority of patients who get diagnosed with AML are elderly epigenetic drugs could prove to be a less aggressive approach and decrease mortality rates in that age bracket although this is quite hard to determine due to the presence of comorbidities.
Furthermore, the use of targeted therapy which is specifically designed to deal with genetic mutations in patients reduces mortality rates much more than epigenetic therapy does. And since the goal of treatment is to reduce mortality rates targeted therapy appears to be the way forward in terms of treatments. In addition, epigenetic therapy will only affect the patient’s epigenetics and not all the causes of AML are epigenetic, some are genetic and the use of hypomethylating drugs will not be particularly useful.

Figure 7 shows a circos plot in which the cause of AML are linked to one another and demonstrates that there is no one single cause. For EXAMPLE, patients who have mutations with activation signalling could also have problems with Myeloid transcription factors.
Therefore, the use of decitabine or azacitidine would not be effective if a patient has a problem with myeloid transcription factors than if a targeted therapy was used for it.

Evaluation

I did achieve my aims, I found out what epigenetic agents are currently being trialled, how they work and how they compare to standard chemotherapeutic agents. I faced quite a few challenges in doing the project. The first of which was actually understanding the journals. They were quite complex, using complicated terms and the statistical analysis included in the journal were often quite a challenge to comprehend. I also struggled with time management, stumbling through the first few weeks as I was not sure about my topic and once I did choose a topic I still found it quite hard to start my research as I felt like there was so much information to sort through. To overcome this, I conducted some very preliminary research and identified some key questions to start with, such as: what exactly is epigenetics? What exactly is acute myeloid leukaemia? How does it arise? This allowed me to gain a foothold in the vast amount of research available online and narrow down my focus. I also scheduled in specific times in the week to do my research and write up my project so that I would be consistent over the weeks. I scheduled my research for Wednesday evenings, Thursday mornings and Sunday evenings as these were convenient times for me and still allowed me to do other things.
Another problem I faced was that over the summer holidays I was on holiday and I did not have access to the internet. Anticipating this I brought two books with me, which whilst I had read previously I could not remember precise details, and I reread them and made detailed notes on them, particularly the mechanisms by which epigenetic agents work.  Therefore, in the autumn term I had quite a bit of extra work but scheduled in some extra time in order to catch up.
During this project, I have learned that detailed planning is necessary to write a coherent argument that flows, I think this is particularly true for my project as there were so many technical terms that I had to keep track of. I have also learnt to narrow my research instead of just using google. At first, I used Google which provided me with not particularly relevant sources but then I came across the blood journal which was extremely useful as it focused on blood disorders and cancers of the blood. I learned that when putting together a project you should keep a detailed log of what you have done and make sure you write down everything you have learnt from your sources as at first, I did not do this and later on I forgot what I had learned from them.
The main limitation of my project is that I only used secondary data, which was the only available data for me. Furthermore, the studies I used in my discussion did not have the same number of patients and the doses of the drugs administered to each patient varied. This means that this is a naïve direct comparison, in which ‘comparison between two drugs refers to an assessment or analysis where clinical trial results for one drug are directly compared with clinical trial results for another drug. There is no attempt to adjust for any discordance in comparators between/among the trials’. (Kim, 2013)

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[1] In reality, not all epigenetic markers are removed.  A very select few genes are ‘imprinted’ with these markers to allow the cell to recognise which gene came from which parent. For more information look into ‘The Epigenetic Revolution’ Chapter 8 ‘The Battle of the Sexes’
[2] Reference needed


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