Treating Leukaemia With Stem Cells

Leukaemia is a type of cancer with uncontrolled production of immature white blood cells (called "blasts") in the bо&ne marrо&w. (1)

During leukaemia, immature, non-functiо&ning, large blast cells, displace the normal bone marrow cells. Figure 1 illustrates the difference between blood in healthy bone marrow and affected by leukaemia. (2)

Figure 1

In order for blood cells to perform their job effectively, one must have enough of each type . Leukaemia patients have higher numbers of immature white blood cells (WBС&s). This results in a decreased count of platelets, WBС&s and red blood cells. All of these blood cells have an important role and if a fault in the production of correct amounts of each type develops, problems may arise. For example, WBС&s are essential in fighting pathogens, and because in leukaemia patients their production is being supressed or stopped, patients become very susceptible to even simple infections. (3)

One of the treatments used for leukaemia is a stem cell transplant. Not only can the transplant make one free from cancer, but also return the normal production of blood cells, which are sometimes destroyed along with the bone marrow, because of high radiation and intensive chemotherapy. (3)

In terms of causes, there is no definite known cause for any of the different types of leukaemia. There are however risk factors that increase the chances of leukaemia, for example overexposure to ionizing radiation. (4)

Leukaemia results from mutations in the DNA, which can activate oncogenes or deactivate tumour suppressor genes, which in turn would result in disrupted regulation of the cell cycle. For example, cells may become permanently switched on and begin uncontrolled division. (4) This may happen if an individual has a genetic predisposition towards developing leukaemia. This is mostly the case if there is a history of the disease in a family. (4) Though, some individuals with chromosomal abnormalities (Down syndrome) or some other genetic conditions have a greater risk of developing leukaemia, compared to those with history of disease in their family. (4)

It is clear from the risk factors listed above that neither can be proven to cause leukaemia directly, but may increase a person's chances of getting it.

Leukaemia affects people at any age. However children have the highest survival rates. For example, the 5 year relative survival rate for children with the most common type of leukaemia is 80% and it is almost twice as high as for adults, for whom the survival rate is 45%. Most (80%) of all new cases are diagnosed in people aged 50 or over. So, this is a disease that mainly affects older people, who also have the lowest survival rates. Statistics support this as more than half (55%) of deaths from leukaemia are for people aged 75 and over. (5)

With reference to Figure 3.1 we can see that, the Five-year relative survival rate in 2008 for the 80-99 age group was 19.2% for males and 22.1% for females, this is 50.3% (male) and 47.4% (female) lower than of 40-49 age group, with a survival rate of 69.5% for males and 61.5% for female. (6)

Figure 3.1: Leukaemia Five-Year Relative Survival Rates by Age, England 2005-2009

(6)

Despite the fact that the chance of survival for children and adults is quite promising, this is not the case if a relapse occurs.

For example, long-term survival after aggressive post remission chemotherapy for adults suffering from acute lymphoblastic leukemia is approximately 40% . (7)

However, the 5-year overall survival rate for those in relapse is 10%. Therefore it's important to seek treatment, which will maximize the DFS for those in relapse. Numerous studies suggest that a healthy stem cell transplant can achieve this. (8)

1.2 Descri ption of biology behind solution to the problem of treating leukaemia.

The aim of a bone marrow transplant (apart from maximizing the DFS for those in relapse) is to return a normal production of blood cells and to eliminate any cancer cells. A transplant also allows doctors to use higher doses of chemotherapy, therefore increasing the chances for a person to be free from cancer(chemotherapy kills cancer cells). Because even if a patient's bone marrow is destroyed by high doses of chemotherapy, there will be new healthy bone marrow available to replace that destroyed by cancer and treatment. (9)

When the stem cells come from the donor it is crucial that the donor and the patient are closely matched. A match is found by doing human leukocyte antigen (HLA) testing. (10) The most successful transplant outcomes occur when the patient and the donor HLA are well matched (6 out of 6 antigens would be the best match). (11)

Genes on chromosome 6 manage a person's HLA type. In order to test for a suitable donor, a swab scraping or blood sample should be taken. This allows doctors to see whether proteins on the surfaces of cells and the DNA of the patient and donor are close enough match. (11)

It is possible to match the donor and recipient in this way because, almost every cell in the body exhibits an HLA molecule on the cell surface. These molecules are used by the immune system to confirm that a particular cell is a part of the body. If there's a mismatch, the immune system may recognize a cell as a foreign invader and attack it. In terms of the success of the transplant it could mean rejection, because the patient's immune system will attack new bone marrow as a foreign body. (11)

Therefore, doctors will try and choose the closest match to ensure the lowest risk of GVHD, occurrence of which is highest if the recipient and donor are not related (60-80% chance of developing GVHD). (11)

First, siblings will be tested, because there's a one in four chance that siblings will have the same HLA type. Then, if siblings and family members are not a suitable match doctors will look for a transplant in a donor bank, which contains 9.5 million potential donors. (11)

When stem cells are collected from a donor's bone marrow, he/she has to undergo a minor surgical procedure under anesthetic. The surgeon inserts a hollow needle into the bones of the pelvis and removes several pints of liquid bone marrow. This bone marrow is then filtered to remove any fragments of tissue or bone. This is then placed into a normal IV bag and can be introduced into the recipient via their vein. This is usually carried out in a short time period (24 hours) but the bone marrow can be frozen and used at a later date. (12)

In a few weeks after the transplantation, the transplanted stem cells begin to produce new WBCs, platelet, and several weeks after that, new red blood cells .

Not only does the transplant replace the stem cells of a recipient, it can also treat certain types of leukaemia. Cells that come from a donor can find and kill cancer cells better than the immune cells of the donor. This is called the 'graft-versus-leukemia' effect.(13)

Figure 4 illustrates the 'route'stem cells have to undergo before being transplanted. (14)

The study conducted by pediatricians at the University of Milano-Bicocca, Italy, looks at the outcome of the treatment of acute lymphoblastic leukemia for 77 children, who were treated with aggressive chemotherapy and then subsequently injected with blood containing stem cells from donors` bone marrow, and 280 children, who were treated with normal, lower doses of chemotherapy. In a five-year time period 50% of the 'chemotherapy' group and 56% of the 'blood stem cell group' were alive. What is significant is that neither of the children from the 'blood containing stem cells' group relapsed after two years, while children from the 'chemotherapy group' continued to relapse at the five-year outlook of the study. This leads to an overall 16% difference in disease-free survival.(15)

'Knocking out the immune system and starting again with transplanted cells may mean remaining cancer cells are mopped up in an immunological reaction,' says Ken Campbell of the Leukemia Research Fund in London. (15)

Therefore according to this study we can see that not only is there a higher chance of survival but also a lower chance of having a relapse using a stem cells transplant for treating leukemia.

1.3 Explanation of methods and processes of using stem cells transplant, in producing effective solution for treating leukaemia.

The American society of Hematology states that 'Allogeneic hematopoietic stem cell transplantation (alloSCT) has been established as an effective consolidation therapy in acute myeloid leukemia (AML) in first or subsequent remission. No other established therapy applied during complete remission offers as strong an anti-leukemic effect' (16)

Statistics shows that a stem cell transplant can increase survival rate of patients who fail to achieve remission after one or more courses of chemotherapy. Without a stem cell transplant such patients have a very poor prognosis.(16)

A retrospective analysis of 130 patients with acute myeloid leukemia, who appeared to be resistant to a single induction course, shows that, under these circumstances, the relapse rate is 70% and the survival rate 14% at 5 years. (17)

However some studies suggest that the DFS rate for such patients can be as high as 40% when an allogeneic stem cell transplant is used.(16) The table 3 below illustrates findings from different studies, which represent the average of 49,2% of DFS rate for patients treated with allogeneic stem cells transplant.

(16)

Therefore, because we can see that this procedure offers greater hope of survival to patients who fail to achieve remission after traditional chemotherapy (without transplant 14 % survival) we can conclude that it is an effective solution for treating leukemia, because the chance of survival is greater.

Another study, with a greater and therefore more representative sample also shows that survival significantly improves for patients receiving a stem cell transplant. (18)

Outcomes for more than 38,000 transplant patients with life-threatening blood cancers were analyzed during a 12-year period. After 100 days of receiving a transplant, an improved survival rate for patients with myeloid leukemia could be seen (related transplant 85-94%& unrelated 63-86%). This indicates that a stem cell transplant has to be an effective treatment as survival rates after the transplant can go as high as 94%. (18)

Also, the number of transplants used for treating various blood cancers including ALL, AML has increased by 45% (from 2,520 to 3,668 patients annually), which may indicate that it is an effective treatment, because doctors are using it more. (18)

The effectiveness of the transplant can be seen if we compare survival rates of patients who were treated with transplant to the ones treated with chemotherapy.

Postremission therapy for Acute Mytloid Leukemia using cytarabine chemotherapy agent shows long term DFS rates ranging from 20% to 50%, while if allogeneic transplantation is done, DFS rates ranged from 45% to 60% , suggesting it is a more effective treatment. (19)

2.1 Implications of treating leukemia.

When deciding to treat leukaemia with stem cells one might consider the implications, which may follow the treatment. One of the most obvious one is the cost of the transplant itself and then the subsequent treatment, though there may be ethical issues associated with it, which I will talk about later.

'First global overview on HSCT activity demonstrates that HSCT is an accepted therapy worldwide today. Transplant activity is concentrated in countries with higher health care expenditures, higher GNI/capita and higher team density& hence, availability of resources, governmental support and access to a transplant center determine regional transplant activity.' (20) Therefore, we can conclude that if a patient lives in a country, whose economic activity doesn't fit the descri ption above, he/she will have lower chances of receiving a transplant than say a person who lives in a country with a thriving economy, high team density and health care expenditures.

Despite improved chances of successful cure with a stem cell transplant, it is not an easily accessible thing for everyone. In England, all of the treatment would be paid for by NHS, while in many countries a patient would have to pay for the treatment himself or rely on insurance. It should be taken into account that not all people have health insurance. For example in Ukraine, even though the health system is socialist (i.e medicine is free and the system should work in a similar way to the NHS) because of the shortage of finance in the country, for major treatments people would have to pay themselves. Therefore if a patient doesn't have money and the help of charitable organizations is not sufficient, treatment with stem cells could become impossible. For example in America allogeneic transplants can cost up to $200,000 or more. (20) This could mе&an that if a patient's insurа&nce won't cover such a prо&cedure and nе&ither will their personal incomе&, he or she will have a lot of difficultiе&s finding a way of receiving one.

There are, also, ethical issues associated with the procedure. For example if a transplant comes from a sibling, instead of unrelated donors, there is usually a very strong emotional relationship between the donor and the recipient. This means that the donor is likely to experience very deeply the suffering of his/her sibling, and, especially, the failure of the transplantation. Such a failure may engender in the donor the feeling of guilt, because it is his/her cells that caused (in someway) the patient's death or at least failed to save the patient. (22)

Another ethical issue referring to allogeneic transplant may concern the physician who is to make a HSCT. For example, in rare cases, when a perfect match is found between siblings, one sibling may demand financial benefits from the patient (usually a family legacy). The patient will most likely agree to such conditions, since he/she knows it's his/hers only way of saving his/her life. Such claims made by the donor, are not only immoral but also illegal. Therefore, if a physician who is to make a HSCT, finds out about such terms of donation, he faces the following dilemma: should he inform the court about the violation of law, which will ultimately decrease the chance of the transplantation (the sibling is likely to refuse to give his final consent) or ignore the violation of law and save the patient by doing the transplantation. Even though there seems to be no easy theoretical solution to this dilemma, the doctors usually do the transplantation, without hesitation. (22)

In Iran there's a market-approach to receiving stem cells, which means that donors can receive payments or other financial benefits for their donation. There's an ethical issue associated with such a market-approach, because according to Wojciech Zał&uski, who is a Chair for Legal Philosophy and Legal Ethics at Jagiellonian Universitythere's 'The problem is that they violate the requirements of distributive justice and accordingly exacerbate social inequalities, as they favor rich patients.' (22)

2.2 Benefits and risks that follow the treatment with stem cells.

(16) Even though stem cell transplant usually provides an increased chance of survival for patients suffering from leukaemia, one must consider the risks and side effects that go with it.

There's a suggestion that bone-marrow transplants containing hematopoietic
& stem cells may cause the development of a second cancer in the recipient. (23) 'Donna Forrest of the British Columbia Cancer Agency in Canada and her colleagues found that patients who had received bone-marrow transplants containing hematopoietic stem cells faced a 2.3 per cent risk of developing a secondary cancer, such as skin, lung, or breast cancer, over the course of 10 years - nearly twice the risk of the general population.' (23)

Medical records of more than 900 adult cases, most of whom suffered from leukemia, were reviewed by this team. This provides us with a representative sample, which allows us to draw the above conclusions, about a positive correlation between transplants and the development of a second cancer. (23)

One of the most common risks is the possibility for new cells (the graft), from the donor, reacting against the recipient's own tissue (the host). This is called Graft-versus-host disease. It happens when the immune cells from the donor see the recipient's body as foreign and attack it. (24)

There are two types of GVHD: acute and chronic. Symptoms in both acute and chronic GVHD range from mild to severe. (25)

Acute GVHD usually happens within the first 3 months after a transplant. Common acute symptoms include: abdominal pain, dry or irritated eyes, skin rash, jaundice, nausea, vomiting and diarrhea. (25)

Chronic GVHD usually starts more than 3 months after a transplant, and can last a lifetime. Chronic symptoms may include: fatigue, skin rashes, dry mouth and vagina dryness, shortness of breath, muscle weakness and chronic pain. (25)

Even though treatments for GVHD are available ( for example prednisone for chronic GVHD), they in themselves can cause severe health problems such as kidney and liver damage.

Chronic GVHD occurs in approximately 60&80% of long-term survivors of allogeneic hematopoietic cell transplant (HCT). This complication is a major cause of morbidity and mortality, accounting for about one-quarter of deaths in long-term survivors of transplants performed for leukemia. Yet, many cases, acute or chronic, can be treated successfully. In patients with extensive chronic GVHD treatment with prednisone resulted in 61% 5 year survival rate, despite the possible side effects listed above. (26)

Moreover, if we look at it from the different angle and 'forget' about the risks of having side effects GVHD may even be of benefit, as some of the cells involved in the reaction may also attack any cancer cells that may have survived from chemotherapy. According to Dr. Andy from Pittsburgh, Pennsylvania, United States 'Patients with GVHD had a higher chance of cure of their cancer.' (27)

There are however many more risks associated with GVHD, then there're benefits. For example, via the transplant recipients might get an infection from the donor's cells. This is particularly dangerous for leukaemia patients, because their immune system is suppressed by drugs (in order to prevent donor's immune system attacking new cells, which may be cited as a foreign body) and will not be able to fight the infection. As well as the risk of receiving an infection from donor, a patient becomes more susceptible to even minor infections from the surrounding, because of the immunosuppressive drugs.

One retrospective study shows evidence of this. Analysis of 1085 patients who received HCT identified 42 episodes of S. maltophilia infection in 31 HCT recipients. Findings were compared to treatment outcomes for recipients with 30 non-HCT patients with S. maltophilia infection. The authors of the study report 'The mortality rate in HCT recipients was significantly higher than that in non-HCT patients. Six of these latter seven patients died within 1 day from the onset of hemorrhage and the isolate was identified after death in most cases& one patient, who received empiric therapy for S. maltophilia and granulocyte transfusion, survived for more than 2 weeks.'

In terms of benefits, transplant allows doctors to use higher doses of radiation as well as chemotherapy, which provide a greater chance of killing all of the cancer.

Radiation therapy destroys cells by damaging their genetic material, making it impossible for these cells to continue to grow and divide. Radiation damages not only cancer cells but also normal cells. Most normal cells can recover from the effects of radiation and function properly. However, most doesn't mean all. Therefore doctors are very careful when choosing the strengths of radiation, in order to avoid permanent cell damage. However, with a stem cell transplant they don't have to fear permanently damaging normal blood cells, since BM transplant will provide the patient with all the required normal blood cells. Therefore, doctors can perform radiation on the whole body, which will increase the chances of all cancer cells being destroyed.

According to article 'Adult Acute Myeloid Leukemia in Remission' in national institute of cancer website patients who undergo nontransplant postremission therapy (for Acute Myeloid Leukemia) have long-term DFS rates that range from 20% to 50%.' The DFS rates using allogeneic transplantation in first complete remission (CR) have ranged from 45% to 60% (Acute Myeloid Leukemia).(30) This statistics shows that allogeneic transplantation can be a better treatment, compared to other treatments, because it generally gives the highest survival rate. Study below supports this.

Outcomes of treatment of childhood acute lymphoblastic leukemia, were analyzed via a retrospective study. Children were either treated with allogeneic BMT transplant or chemotherapy. And the findings are summarized as following: DFS rate at 5 years for children who received a BMT was 62% and relapse rate was 19, while for the ones treated with chemotherapy DFS rate at 5 years was 26% and relapse rate was 67%. Therefore, we can see from the data that another benefit of allogeneic stem cell transplant in treating leukemia is a higher chance of disease free survival after remission and lower relapse rate, when compared to other methods. (This is because of the graft-versus-leukemia effect , which arises because the donor stem cells make their own immune cells, which could help destroy any cancer cells that remain after high-dose treatment.) (31)

1.3 Alternative solutions for treatment of leukemia.

There are alternative treatments for treating leukaemia (apart from stem cells transplant and standard chemotherapy) and they may become more popular/widely used with time.

Biological therapy is one of the alternatives. It involves treating of a patient with substances that affect the immune system`s response to cancer. Interferon, a drug used against some types of leukaemia, is a form of biological therapy. Biological therapy or immunotherapy uses the body's immune system to fight cancer, using antibodies to target and destroy leukaemia cells. Therefore this may be applied before stem cell transplant, in the hope of curing the patient and avoiding the transplantation procedure. (32)

According to the National cancer institute website, scientists are currently working on the production of Monoclonal antibodies, or MAbs, which are ' laboratory-produced antibodies that bind to specific antigens expressed by cancer cells, such as a protein that is present on the surface of cancer cells but is absent from (or expressed at lower levels by) normal cells.' Certain MAbs can activate an immune repose, which will destroy cancer cells. MAbs work in a similar way to antibodies, naturally produced by B cells. When MAbs surround the surface of a cancer cell, they initiate its destruction by the immune system.