Leukaemia is cancer occurs in blood-forming cells of bone marrow, which is distinguished by unusual blood cells proliferation. Its four main categories are acute lymphoblastic leukaemia (ALL), chronic lymphocytic leukaemia (CLL), acute myelogenous leukaemia (AML) and chronic myelogenous leukaemia (CML). , , According to National Cancer Registry Malaysia, 1229 leukaemia cases had been reported in 2002. Hence, what are the current treatments accessible for this fatal disease?
According to "eMedicine", hematopoietic stem cell transplantation (HSCT) is the intravenous infusion of HSC to re-establish hematopoietic function in patients. , It is the only possible cure for some leukaemia patients. , Due to its high treatment-related mortality, HSCT is reserved for life-threatening conditions and leukaemia patients, who are resistant to chemotherapy or would not benefit from extended treatment.6,
Autologous HSCT uses HSC harvested from the patient before undergoing high-dose medication or therapies, which will cause partial or complete bone marrow ablation. Stored HSC is then returned to the patient's body to restore blood cell counts and reinitiate the immune system by myeloablative transplants. Since the patient receives his/her own stem cells, rejection risk which causes graft-versus-host-disease (GVHD), and infection during immune-comprised period is reduced.6,10,
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However, allogenic HSCT uses stem cells obtained from donor, whose human leukocyte antigen (HLA) matches the recipient. A perfect match at the loci of HLA gene, which code for A, B and DR antigens, is preferred. The donor may be related to the patients as sibling or even his/her identical twin. In this case, it is known as syngeneic HSCT since identical twins have similar tissue types. However, the donor with close HLA-matching may be unrelated to recipient. Ethnicity is important in HLA-matching, because genes of those from the same race, including HLA genes, are more likely to be matched.11,
Characteristics Marrow PB CB
Stem-cell content Adequate Good Low
Tumour cell contamination risk Autologous: High
Allogenic: Negligible Negligible
HLA-matching Close matching required Less restrictive
Engraftment Medium Fastest Slowest
Risk of GVHD Acute Higher than CB Lowest
Chronic Medium Highest Lowest
Table 1: Characteristics of Stem-cells Sources7
For bone marrow transplant, HSC is extracted from the bone of donor under spinal or general anaesthesia.6, Usually, pelvic bones which contain more bone marrow and HSC are chosen. Large needles are pierced through skin and inserted into the back of pelvic bone (iliac crest) to withdrawn the thick liquid marrow. The donor will normally felt sore for several days after the operation.
Besides that, peripheral blood stem cells (PBSC) are commonly used in allogeneic HSCT. Granulocyte-colony stimulating factor are injected daily to increase quantity of harvested HSC by mobilizing HSC from donor's bone marrow into peripheral circulation.6Blood is drawn from his/her arm by sterile catheter attached to special machine; where HSC are extracted by apheresis and the remaining blood is returned to donor.15The process is repeated for several days until sufficient HSC are collected.
Cord blood (CB) in infants' umbilical cord and placenta is another source of HSC. CB has a higher concentration of HSC than adult blood, but it is more suitable for transplantation in children, limited by the small quantity of 50ml of CB that can be extracted from an umbilical cord. Normally, CB of "saviour children", who are born after preimplantation genetic diagnosis for HLA matching, is donated to their sick siblings requiring HSCT.6
Alternatively, stem cells can be obtained from "spare embryos" produced by in vitro fertilisation (IVF). Numerous embryos are produced for fertility treatments, but not all are chosen and used for implantation. Embryonic stem (ES) cells can be obtained from inner cell mass of the extra embryos. However, embryos involved are destroyed in the process.
HSCT is carried out by infusing harvested HSC through intravenous catheter of the recipient. He/she will fell no pain although general anaesthesia is not used. If HSC used are frozen, they are thawed and the recipient will receive medication before transplant to prevent his/her body from reacting to dimethyl sulfoxide (DMSO) preservative used in freezing process. The infused HSC will travel by blood to recipient's bone marrow. Engraftment will occur as HSC start to grow and multiply in the bone marrow. After 2-6 weeks, healthy HSC available will be sufficient to restore normal blood counts.
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Economic and ethical implication
"My hope is that we come to understand clearly that it is a matter of scientific fact, and not of opinion, that the embryonic organisms we are being urged to exploit and discard are, like us, human beings."-- William L. Saunders Jr.
HSCT is considered experimental and new for treating cancer, and its researches are still underway. Stem cells researches had raised ethical issues, especially when ES cells are involved. The use of ES cells is opposed due to the fact that embryos are killed in the process of extracting ES cells. Their fundamental assertion is that life begins when zygote is formed by fertilization. Physical growth continuum between embryo and humans does not have any non-arbitrary point that represents a morally significant border. Therefore, embryo should
have the same status as developed human, despite apparent physical differences. Furthermore, all life is sacred and should not be treated lightly. Deliberate murder of humans in the name of science, even if they are just embryos, is incompatible with religious doctrine and cannot be justified by whatever reasons.
Besides, HSCT is very expensive. The total cost for HSCT varies, but it can easily exceed RM300000. Although treatment cost is lowered by the shorten recovery period due to technology advancement which allowed usage of PBSC, HSCT is still costly since it involved complicated technical procedure. Patients are unable to receive HSCT because they cannot afford its cost and the probability of finding a perfectly matched HSC donor is as low as 0.005%.21Therefore, it will only benefits a limited numbers of developed nations' citizens who can pay for it. Furthermore, there are some who argued that the research fund should be spent in solving basic health and nutrition problems faced by undeveloped countries to help more people.
Benefits, side effects and risks
Stage Transplantation Survival Rate (%)
Related Donor Unrelated Donor
ALL Complete response (CR)1 N/A 65 45
CR2 N/A 55 35
AML CR1 60 65 30
CR2 40 45 50
No remission 20 N/A 25
CML Chronic phase <1year N/A 70 55
>1year N/A 60 50
*Based on data from Center for International Blood & Marrow Transplant Research and National Marrow Donor Program.7
Leukaemia treatment usually starts with high-dose medication, which kills malignant cells and normal rapid-dividing cells, including healthy HSC, intestinal cells and hair follicle. Myelosuppression will occur, causing anaemia, weakened immune system and slow blood clotting. Therefore, HSCT is needed to restore blood cells production. Erythrocytes and platelets are transfused to solve bleeding problems due to low platelet levels before engraftment occurs.
When compared to syngeneic HSCT, survival rate of allogeneic HSCT is increased by graft-versus-tumour (GVT) phenomenon.10HSCT recipients with GVHD have lower cancer
relapse rate due to therapeutic immune reaction of grafted donor T-lymphocytes against their mutated cells. However, GVT is less effective in acute leukaemia, which grows rapidly, than chronic leukaemia. More leukocytes from donor can be infused with patient if cancer relapses after HSCT.
However, after HSCT, the recipient may temporary experiences fever, chills, chest tightness and pain, breathlessness, low blood pressure, less urine and fatigue.18GVHD is inflammatory condition caused by donor's immune cells which identify the recipient's body as foreign and attack his/her tissues, including skin, intestine and liver, causing symptoms of blistering, rashes, diarrhoea, infections, weight loss, jaundice, enlarged liver, abdominal cramps and pain.10, The newly restored immune system will recognize the differences between donor's and recipient's tissues, even if they are HLA-identical.6 Acute GVHD, which affects to of allogeneic HSC recipients, usually develops in 90 days after HSCT and is fatal. Meanwhile, chronic GVHD is the main cause of late treatment-related complications, which causes functional disability and fibrosis. Immunosuppressants are given for 6 months after HSCT to suppress immune system, prevent rejection and avoid GVHD.6,10
Infection is a major HSCT complication. The recipient will have low blood-cell counts during the first two weeks due to myeloablation. Decreased leukocyte levels will increase opportunistic infection risk and septic shock. Although prophylactic antibiotics are given to fight infection until blood counts normalized, immunosuppressant taken by patient to combat GVHD will worsen the situation and may be fatal. Besides, acquired immunity will be lost and re-vaccination is needed.6,17
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HSCT may cause sinuosoidal obstruction syndrome (SOS) resulting in severely injured liver and blocked hepatic vein sinuses. Enlarged liver, raised bilirubin level and fluid retention are its clinical characteristics. Mortality will increase if SOS is severe. Anticoagulants, defibrotide and ursodiol are given for treating SOS.6
Interferon therapy involves the use of interferon proteins released by cells in presence of pathogens which activate the immune system to eradicate pathogens or tumours. They can hinder viral replication within host cells and reduce leukemic cell proliferation, Interferon-Î± is normally injected under skin and often used to treat newly diagnosed patients who will not receive HSCT. , Its side effects, including aching, fever, appetite loss and depression, are more severe in elders.
Chemotherapy treats disease by using chemicals and drugs individually or in combination, to kill micro-organisms or malignant cells. For example, imatinib mesylate is a specific tyrosine kinase inhibitor which targets the molecular abnormality in CML.18According to "Cancer Facts & Figures 2009", the related nilotinib and dasatinib drugs often success in treating CML when imatinib failed. Furthermore, gemtuzumab ozogamicin is employed for treating AML patients who are unable to accept other chemotherapies or suffer from cancer relapse. The drugs can be taken orally, intravenously or injected into muscle, cerebrospinal fluid or under skin.
Radiotherapy utilizes ionizing radiation to kill cancerous cells by damaging their DNA. External beam radiation therapy is used if chemotherapy is ineffective or when cancer had spread. After determining the best radiation dose, beam angle and position by simulation, linear accelerator (linac), which can emit focused radiation from various angles, is used to aim a high-energy radiation beam at targeted position for several minutes. Although shields protect certain body parts and linac reduces skin reactions, normal cells may be damaged, causing sun-burned skin, fatigue, nausea, vomiting and diarrhoea.
Leukaemia and HSCT information from American Cancer Society (ACS: http://www.cancer.org/) is reliable. ACS is a national voluntary health organization dedicated to prevent cancer, save lives and reduce suffering from cancer through studies, education and advocacy. Furthermore, it is the largest source of private, non-profit cancer research funds in US. Articles uploaded in ACS website are based on extensive researches and regularly reviewed and revised to educate and provide the public with the latest and accurate in-depth
cancer information. Besides, "Cancer Facts & Figures 2009" published by ACS to summarize current scientific facts about cancer is reliable since it is based on incidence data which covers 85% of US population. 33
Leukemia& Lymphoma Society (LLS: http://www.leukemia-lymphoma.org/) is another reliable information source. Dated back to 1949, it is the world's largest voluntary health organization committed to cure leukaemia and help patients and their families through research funding, education and patient service. Its award-winning website contains up-to-date information on clinical trials and leukaemia treatment. Besides, its information on leukaemia and its treatment agrees with other sources, including Wikipedia and ACS.