 |  |  | | | Childhood Acute Lymphoblastic Leukaemia | | | | |
| | The booklets in this series are intended to provide general information about the diseases they describe.
In many cases the treatment of individual patients will differ from that described in the booklets.
At all times patients should rely on the advice of their specialist who is the only person with full information about their diagnosis and medical history.
 | What is acute lymphoblastic leukaemia? |
Acute Lymphoblastic Leukaemia (ALL) is a form of cancer that affects the lymphocytes and lymphocyte producing cells in the bone marrow. Lymphocytes are white blood cells that produce antibodies and are vital parts of the body's immune system. Lymphocytes can be classified into sub-groups according to their function the main groups are B-cells and T-cells. In ALL there is an accumulation of immature lymphocyte-precursor cells called blast cells in the bone marrow. Eventurally, the production of normal blood cells is affected by this and there is a reduction in the numbers of red cells, white cells and platelets in the blood.
| Who gets acute lymphoblastic leukaemia? |
Acute lymphoblastic leukaemia is the only form of leukaemia, and one of the few forms of cancer, that is more common in childhood. It is the single most common form of paediatric cancer accounting for about one-third of all cases in children. About 85% of cases of childhood leukaemia are of this type. The peak incidence of ALL occurs between the ages of about 2 and 4 years. Males are affected more often than females at all ages.
| What are the types of acute lymphoblastic leukaemia? |
There are two ways to describe the leukaemia cells in ALL which are used together rather than as alternatives. These look at different properties of the leukaemia cells. The only system which is of clinical importance is the immunological classification.
IMMUNOLOGY
The most important system is based on the type of lymphocyte affected, that is B-cell or T-cell. This is known as the immunological classification and is of great importance in planning treatment. The immunological classification together with characterisation of chromosome abnormalities is extremely useful in predicting the response to treatment. Approximately 80% of ALL in children have early (precursor) B-cell origin, about 15% are T-cell, and 5% are more mature B-cell derived. The mature B-cell type shows some resemblance to a condition called Burkitt’s lymphoma. Burkitt’s-type ALL has many features in common with Non-Hodgkin's lymphoma and is treated with similar drug combinations.
MORPHOLOGY
The other system of classification is mainly based on the appearance of the leukaemia cells under the microscope; this is called the morphology of the cells. This is described as the FAB classification after the group of French, American and British haematologists who designed the system. It classifies ALL as L1, L2 or L3; this system is not very important clinically because it does not help in planning treatment or predicting outcomes. L3 is the only clearly distinct type within the FAB system and this is also a separate category in the other, immunological, classification.
| What causes acute lymphoblastic leukaemia? |
There is no single proven cause of childhood ALL. There are a number of suggested causes, some of which are more controversial than others. A major study on the possible causes of childhood cancer, including leukaemia, has completed data collection. The majority of children born in Great Britain diagnosed with specific malignancies in England & Wales between 1992 and 1996, and in Scotland between 1991 and 1994, were enrolled into the study. The data from that study is currently being analysed and results have begun to be reported.
The hypotheses being considered are summarised in the following table.
IONISING RADIATION
This is the only clearly proven cause of childhood ALL. Children exposed to high levels of radiation before they are born or in early life have been shown to have a high risk of childhood leukaemia. The study is seeking to identify whether any children in the UK are exposed to levels of radiation high enough to cause ALL. The study is looking specifically at exposure to environmental radon gas. It is also considering the suggestion that radiation exposure of a parent before conception may increase the risk of childhood ALL. There have been a number of studies suggesting that this is not the case.
CHEMICALS AND DRUGS
The study is examining exposure ot parents and affected children to certain chemicals and drugs. These are either substances which are known to cause cancer in large amounts, such as benzene, or substances which have been suggested as possible risk factors such as vitamin K. There is, to date, no evidence that children in the UK are exposed to levels of benzene high enough to cause childhood leukaemia. Preliminary results on Vitamin K do not support the theory that it increases the risk of childhood leukaemia.
INFECTIONS
The currenlty most plausible proposed causes relate to the timing and pattern of exposure to infections. With improved hygiene in the general community, children are less exposed in early years to common infections. A rare consequence of a delayed first challenge to the immune system may be development of childhood leukaemia. A related suggestion places stress on exposure to novel infections through the mixing of different populations, for example in new towns. A number of lines of evidence exist to suggest that these may both be significant factors in causing childhood ALL. An important point is that the rarity of clusters of cases indicates that childhood ALL is likely to be a rare response to a common infection, rather than a common response to a rare infection. The practical importance of this is that even close contact with a child who subsequently develops ALL does not imply an increased risk of leukaemia.
ELECTROMAGNETIC RADIATION
A somewhat controversial proposal for the cause of childhood ALL is exposure to electromagnetic fields from power lines or electrical facilities. A recent UK study into the causes of childhood cancer looked specifically for evidence that proximity to powerlines or other electrical installations increased the risk of childhood leukaemia but found no such evidence. A number of international studies have reached the same conclusion. A recent report indicated that there may be an association between exposure to very high magnetic fields and a slight increase in risk of childhood leukaemia. The report stressed, however, that this association did not prove that exposure to powerlines caused leukaemia and that about 98.5% of children in the UK are never exposed to such high field strengths.
| What are the signs and symptoms of acute lymphoblastic leukaemia? |
The signs and symptoms seen most often in childhood acute lymphoblastic leukaemia are:
 | Fatigue and limited capacity for exercise |
| Breathlessnes |
Caused by:
| Anaemia (lack of red blood cells) |
| Bruising within the skin |
| Bleeding from mucous membranes (gums, etc.) and from the gut |
Caused by:
| Low platelet counts |
| Persistent infections |
| Fever – this is often present even in the absence of clear indications of infection |
Caused by:
| Low (normal) white cell counts, high numbers of abnormal cells and high metabolic rate |
On first being examined by a doctor about 60% of children with ALL have an enlarged liver and/or spleen. Over a half will have had a history of frequent and persistent fevers. About one-third of children with ALL will have enlarged lymph nodes (glands). In T-cell ALL enlargement of the lymph nodes within the chest (mediastinum) is common and this may affect the function of the heart and/or lungs.
| How is acute lymphoblastic leukaemia diagnosed?} |
When a doctor examines a child with ALL there are no specific signs like the rashes seen in some infections. Leukaemia is not a clinical diagnosis – it requires the results of laboratory tests to confirm the diagnosis.
FULL BLOOD COUNT
The main laboratory tests used in the diagnosis of leukaemia are the full blood count and bone marrow aspirate. Most children with acute lymphoblastic leukaemia will have a raised white cell count and almost all will have characteristic abnormal cells called blast cells in the bloodstream. Many children also have anaemia and/or low platelet counts – this happens because the leukaemia cells both crowd-out and actively inhibit production of normal blood cells in the marrow. Anaemia may be severe. Numbers of a type of white cell called a neutrophil may be very low. Neutrophils are the most important component of the body’s defence against infection and a reduction in their numbers leads to vulnerability to bacterial and fungal infections.
CHROMOSOME ANALYSIS
Chromosome analysis is of importance in planning treatment of childhood ALL. The analysis may be done on blood and/or bone marrow samples. The abnormalities being studied are found in the leukaemia cells but not in normal cells in the body. Detection of chromosome abnormalities found only in the leukaemia cells can be of value in guiding treatment decisions and in evaluating a child’s response to treatment.
Other investigations
Children with ALL may require X-rays and other imaging procedures (CAT scans, MRI scans) to determine which organs are affected and to what extent. Lumbar puncture (sampling of the fluid around the spine and brain) may be done especially if symptoms suggest that the nervous system may be affected. About 1 in 20 children has a significant abnormality of the clotting system so tests for this are routinely included. Various other tests are performed to assess general health, for example heart, liver and kidney function. These are important to ensure that children are not particularly prone to negative side-effects from planned treatment.
| How is acute lymphoblastic leukaemia treated? |
Acute lymphoblastic leukaemia is rapidly fatal without effective treatment. In children the aim of treatment is to achieve a disease-free state called remission and, by further treatment, to eradicate the disease and achieve a cure. A child is described as being in complete remission when it is not possible to detect leukaemia cells in either the blood or the bone marrow. This does not mean that all leukaemia cells have been killed as the laboratory tests available cannot detect leukaemia cells present below a certain threshold. Very sensitive laboratory methods can detect leukaemia cells in the bone marrow below the level at which standard tests are effective. The presence of such very small numbers of leukaemia cells following treatment is called minimal residual disease (MRD).
With modern treatment protocols, including aggressive treatment of children with relatively resistant disease, the cure rate is high. Treatment normally commences within a few days. Although there is a degree of urgency, it is considered better to wait until all the necessary information is available because this allows doctors to offer the appropriate treatment to each individual child. Virtually all children diagnosed with ALL in the UK are treated at specialist paediatric referral centers. Parents will almost certainly be asked to consider including their child in a clinical trial.
PRINCIPLES OF TREATMENT
There are three phases to treatment of ALL; remission induction, post-remission treatment or consolidation, and an extended period of maintenance treatment. Each of these elements is essential to a successful outcome. Remission induction is achieved in almost all children using essentially similar combinations of drugs. It is normally possible to commence this stage of treatment even before all necessary tests have been completed to plan the further stages of treatment. The initial stage treatment requires considerable supportive care because of the effects of the anti-cancer drugs. The necessary level of supportive care during remission induction can only be provided as an inpatient.
It is now common practice to use sophisticated tests to detect whether there are significant numbers of leukaemia cells still present at the end of the remission induction phase. The object of remission induction is to bring the disease under control. The presence of detectable numbers of leukaemia cells at the end of remission induction is called minimal residual disease (MRD). The MRD status of a child is valuable information in planning further therapy. The exact role of MRD testing in treatment planning is being evaluated in a number of comparative studies, it is not established as a standard part of ALL therapy.
Treatment of ALL involves an extended period of continuing treatment given as an outpatient. This lasts for two years for almost all girls and three years for boys. This is usually provided on a “shared care” basis with a partnership between the specialist centre and the child’s local hospital. Although the specialist centre retains overall responsibility, much of the care during continuing treatment is provided by the child’s local hospital. This provides major benefits for the child and the family; it frequently avoids the need for long journeys and reduces the disruption to family life these may cause. In cases where children have a long journey to their specialist centre this can greatly reduce the associated costs and the disruption to family life. For children who are of school age, this may also reduce the disruption to their education. The exact arrangements for each child, frequency of visits to the specialist centre etc., will vary and parents will be given a detailed care-plan showing what will happen when, and at which hospital. Although most treatment is now provided on a shared care basis, this should not inhibit parents from contacting the specialist centre if, at any time, they wish to discuss their child’s care with the specialists taking overall responsibility.
A significant problem in treatment of ALL is possible presence of leukaemia cells in the fluid which surrounds the brain and spinal cord (CSF). This is discussed in detail in the next section.
TREATMENT PLANNING
Initial treatment aimed at achieving a remission is essentially similar for all children. Almost all children will achieve remission (clearance of leukaemia cells from blood and bone marrow). For the very small number of children who fail to achieve a remission (refractory ALL) doctors may recommend purely supportive treatment or possibly a trial of innovative therapies. On achieving remission decisions must be made on the next stages of treatment. The child’s condition will be graded as low or high risk based on the results of laboratory investigations and, very importantly, on the speed of their initial response to treatment. It is now well established that sensitivity of the leukaemia to initial standard treatment is an important predictor of long-term outcome. Male sex, T-cell disease and very high white blood cell count at time of diagnosis are associated with poor outcome if the child is given standard treatment, as are certain patterns of chromosome abnormality. It has become increasingly clear that the careful choice of appropriate treatment protocols can greatly diminish the impact of these factors. A small percentage (1-2%) of children with ALL have an abnormality in their leukaemic cells known as the Philadelphia chromosome. This is an acquired abnormality, not inherited, and is associated with a higher risk of relapse on standard therapy.
Another well established risk association is the number of chromosomes present in the leukaemic cells. All cells normally have 46 chromosomes, in 23 pairs; in leukaemia it is common to find an abnormal number of chromosomes. In cases where the number is much higher than normal, children tend to respond very well to treatment and have a good chance of being cured. This is known as high hyperdiploidy. In cases where the number is lower than normal, which is called hypodiploidy, the likelihood of cure with standard treatment is much lower.
Provided that children with these poorer risk factors receive appropriate intensive therapy their outcomes are as good as other children. Children who do not respond promptly to initial treatment will be classed as poor risk, regardless of other features of their illness, and their treatment will be adjusted accordingly. It is important to stress that, because poor risk disease is uncommon, most relapses occur in children with standard or good risk disease features and so parents of such children should not be complacent. Equally, it is important to realize that, with tailored aggressive therapy, many children with high-risk disease can achieve lasting remission and cure.
In the past it was often recommended that children with poor risk disease undergo stem cell transplantation (see below) during their first remission. Stem cell transplantation requires use of high-dose chemotherapy and/or radiotherapy; these approaches carry an increased risk of severe, possibly fatal side-effects. With the greater success in this group of using conventional, although aggressive, chemotherapy this is now less often recommended. The evidence shows that it is reasonable in these children to offer treatment tailored to their risk category and then consider a transplant for those children who still relapse. This appears to offer an equally good long-term outcome with fewer side effects. Parents will be offered detailed discussion with their child’s specialist in order to consider treatment strategies. Parents of children with low-risk disease will not be advised to consider a transplant since for them the risk of the transplant procedure is greater than the risk of relapse. This group of children will normally receive extra treatment following remission induction followed by long-term oral chemotherapy. This takes their treatment duration to a total of two years for girls and three years for boys. There are currently attempts to identify an ultra-low risk group based on age, sex, and blood count at diagnosis and response to initial therapy. It may be safe to further reduce standard treatment in this group with no reduction in long-term survival. This would offer benefits in terms of reduced side-effects.
Supportive care will include barrier-nursing to protect against infection and intensive treatment with intravenous antibiotics or antifungal drugs if infection occurs. Children will usually require red blood cell transfusions and will often also require platelet transfusions. The child will usually have a tube, known as a central line, inserted into a large blood vessel to allow drugs, and possibly nutrition, to be given effectively and without repeated needle-pricks. There are various types of catheters used and medical or nursing staff will inform parents of the special requirements for care of the line. In some instances a child may find if difficult to eat or drink because of side-effects of chemotherapy. In this case it may be necessary for nutrition to be given by tube.
Remission induction phase
This involves the use of several drugs in combination to clear all detectable leukaemia cells from the blood and bone marrow. Treatment schedules (protocols) vary but this stage usually lasts between three weeks and two months. In children it has been found that the speed of response at this stage of treatment (time to achieve complete remission) is a strong predictor of final outcome. Children who take less than seven days to achieve complete remission have a very much smaller risk of relapse if given standard therapy. Children who take longer than one to two weeks to achieve complete remission are called slow responders. This group is now targeted with more aggressive consolidation therapy which has improved outcomes. This stage normally employs vincristine and prednisolone plus an anthracycline (daunorubicin, adriamycin, buridazone or idarubicin). These combinations can be expected to achieve remission in almost all children. A number of protocols also employ cyclophosphamide and asparaginase which are thought to improve the quality of remissions and affect outcomes in children with poor risk factors. CNS-directed therapy during this phase includes a drug called methotrexate being injected directly into the fluid around the spine. This is called an intrathecal injection. It was previously common practice to give radiotherapy directed at the head and possibly the spine during this stage. There are significant side-effects associated with this form of radiotherapy and this is normally now omitted except for high risk patients. High-dose intravenous methotrexate combined with intrathecal injections of the same drug is used for most patients. Even in the case of children with high-risk disease it may be possible to use less intensive CNS-directed radiotherapy.
A drug called allopurinol is given to prevent children developing kidney damage as a result of the amount of protein released when tumour cells are killed. Allopurinol is normally started as soon as a child is diagnosed, before any specific anti-leukaemia treatment. It is also important to maintain the child’s fluid intake to protect the kidneys from damage. The major short-term side effects during this period are related to bone marrow suppression. Low neutrophil and platelet counts increase the risk of infection and bleeding, respectively. Platelet transfusions can be given to reduce the risk of haemorrhage. Infection must be guarded against by good sterile precautions and prompt treatment must be given if infection occurs. There is some evidence that the use of growth factors to stimulate neutrophil production may reduce the duration and severity of infection risk. Occasionally, the destruction of cells is so rapid that a condition called tumour-lysis occurs which affects the kidneys – this may require temporary use of an artificial kidney. Hair loss is almost inevitable but is temporary.
Children will spend part of this stage of treatment as in-patients because of the risks of infection and haemorrhage. The exact length of hospital stay will vary from centre to centre and from child to child. This will be discussed with the parents at the time of treatment planning.
Consolidation
Consolidation therapy is also referred to as post-induction or post-remission therapy, or as intensification. Disappearance of leukaemia cells from the blood and bone marrow does not mean that all the leukaemia cells in the body have been killed. In order to optimize the outcome of treatment it has been found necessary to give further blocks of treatment soon after completion of remission induction. Consolidation protocols may vary greatly according to risk category and to the speed of remission induction. A high proportion of clinical trials in childhood ALL are directed at establishing the optimum number of blocks of treatment for children with different risk profiles. The number of blocks of treatment and the exact drug combinations used vary between clinical. The details of this phase of treatment will be outlined by the child’s specialist. Continuing treatment (see below ) will be given in between the blocks of consolidation therapy.
This stage of treatment typically lasts for several months on an outpatient basis. The drugs used are alternated to reduce the likelihood of the leukaemic cells becoming resistant to chemotherapy. Intervals of time are left between blocks of treatment. The reason for this is to allow the child’s normal cells a chance to recover and to minimize side-effects. It also allows drugs which only act at certain points during cell growth and division to have maximum impact. Current standard therapy includes four to five blocks of consolidation treatment. Extra blocks of treatment may be given after a gap of two or three months. This is called delayed intensification. For children with high-risk disease consolidation may be intensified by inclusion of additional blocks of treatment or by use of additional drugs. During this period CNS-directed therapy consists of intrathecal injections of methotrexate. Most of the time during consolidation treatment is spent as an outpatient although infections or low neutrophil counts may require admission to hospital.
Continuing Treatment (Maintenance Therapy)
Extended low-dose oral chemotherapy to prevent late relapse in children who appear to be in full remission is unique to the treatment of acute lymphoblastic leukaemia. The exact reasons for this requirement are not known but it is clear from a number of studies that omitting this phase of treatment leads to significantly worse results. This stage of treatment is as important as other aspects of treatment. In children continuing treatment typically extends to two years from the time of commencement of treatment for girls and three years for boys. The extended period for boys, regardless of risk status, is based on the results of several clinical trials. It is well established that boys, if treated with the same protocols, do less well than girls. It is believed that extended maintenance will reduce this difference. Continuing treatment can be carried out on an outpatient basis throughout and the child should be able to resume normal activities during this time.
Treatment during this stage involves taking daily tablets of mercaptopurine, or a similar drug, and weekly tablets of methotrexate. At monthly intervals vincristine injections are given along with 5-day courses of steroid tablets. Intrathecal methotrexate is given as CNS-directed treatment. The minority of children who have received cranial irradiation do not have intrathecal methotrexate during continuing therapy as there is no evidence that it is beneficial and it may add to overall toxicity. Depending on their progress and their risk status children may receive further intensive blocks of consolidation therapy.
During the extended maintenance phase of treatment it is usual to monitor children every two to three weeks. It may be necessary for drug doses to be adjusted based on results of these visits and so it is important that children attend regularly. Where a child has been referred to a specialist centre for treatment it is usually possible to arrange for blood tests to be done at a local hospital if this is more convenient. Shared care between specialist centres and local hospitals is now the normal practice and has offered substantial benefits to childhood leukaemia patients and their families.
CENTRAL NERVOUS SYSTEM DIRECTED THERAPY
For all risk groups a potential site of relapse is the Cerebro-Spinal Fluid (CSF) which surrounds the brain and spinal cord. Leukaemic cells can enter the CSF but, unfortunately, administration of drugs by mouth or by injection into a vein does not lead to sufficient accumulation of drug in the fluid to kill these leukaemic cells. There is therefore a risk that leukaemia cells may survive in this site. Only about three percent of children have detectable leukaemic cells in the CSF at the time of diagnosis but, without effective CNS-directed therapy 50% to 70% of children will develop leukaemia within the CNS. If it is not treated this may lead to symptoms affecting the nervous system including headaches and early morning vomiting (often without nausea). If CNS relapse occurs and is not treated than eventually the patient may experience relapse elsewhere. In order to prevent these problems it is normal to give Central Nervous System (CNS) directed therapy; this commences during remission induction and continues until completion of continuing treatment. It involves administering drugs directly into the fluid around the spine. This is done by a process called a lumbar puncture and is called intrathecal therapy. In some protocols children may also be recommended to receive radiotherapy to the head (cranial irradiation). Intrathecal therapy is likely to be continued certainly until completion of consolidation and possibly (if radiotherapy is omitted) until the end of continuing treatment.
STEM CELL TRANSPLANTATION
The overwhelming majority of children with ALL will respond very well to chemotherapy and will not require a stem cell transplant. A small proportion of children with high risk disease may be considered for a possible donor stem cell transplant while in first remission. Other than this, the place of stem cell transplant is restricted to treatment of children who have experienced a relapse early in their treatment or who have suffered more than one relapse.
Stem Cell Transplantation (SCT) is the term now used in place of Bone Marrow Transplantation (BMT). A bone marrow transplant is one form of SCT but for many children the source of stem cells is the circulating blood. An SCT may be either allogeneic (from a donor) or autologous (the child's own stem cells). A special type of transplant is a cord blood stem cell transplant. This uses stem cells harvested from the umbilical cord at the time of birth. It is of particular significance for children because the number of stem cells which can be obtained is not sufficient for an adult to be transplanted. Although this is still a donor transplant with a need for tissue matching, it is thought likely that a less exact match will be acceptable. Allogeneic transplants carry a higher chance of eliminating the leukaemia but they also carry a higher risk of graft rejection and of a condition called graft versus host disease.
The preferred donor, where available, is a sibling with a closely matched tissue type. The chance on any one sibling being a suitable donor is about 1 in 4. Given the small size of most families this means that few children will have a sibling donor available. Where such a related donor is not available an unrelated donor from a volunteer panel may be considered. The risks of rejection and of graft versus host disease (GvHD) are both greater with an unrelated donor. If a child is a candidate for a transplant it is commonplace to test siblings for compatibility before a firm decision is made. Parents should not assume that, because brothers or sisters are being tested, the decision has already been made. Autologous transplants are less inherently risky in terms of graft failure or graft versus host disease but there is a greater risk of return of the original leukaemia. It is a little surprising that graft versus host disease, or a very similar clinical picture, can occur in the context of an autologous transplant but this does occur although at a lower rate than for donor transplants.
Although it is not currently a routine procedure, certain centres are studying the use of parents as stem cell donors for selected high-risk children where a sibling donor is not available.
TREATMENT OF RELAPSE
Although a very high proportion (over 95%) of children with ALL will achieve a remission a significant proportion (20-25%) will relapse. This is to say their disease will return. Children with high-risk disease have a higher rate of relapse than children with good-risk disease. However, as the majority of children have good-risk disease most relapses will occur in this group. Relapsed ALL tends to be more resistant to treatment than the original disease. One reason for this is that relapse often occurs because the leukaemia cells have become resistant to drug treatment. This drug resistance is often not specific to a particular drug – it may affect all, or virtually all, anti-leukaemia drugs. This is known as Multi-Drug Resistance (MDR). A number of drugs are being studied which may be capable of preventing or reversing MDR. Two key factors in the outlook for children with relapse of ALL are the timing of relapse and whether the relapse has affected the bone marrow at the time it is discovered. When the relapse is only apparent in the CNS, or in the testis in boys, it is termed an extra-medullary relapse or a non-BM relapse. Early relapse and bone marrow relapse are independent predictors of a poor overall prognosis. So, the worst outlook is for bone marrow relapse within two years of initial diagnosis, while the best outlook is for isolated non-marrow relapse occurring late after diagnosis.
The most common site for late extra-medullary relapse is the testis. Like the CSF this is a sanctuary site where drugs do not easily penetrate and leukaemia cells may survive although destroyed elsewhere in the body. This form of relapse tends to respond well to intensive chemotherapy and radiation treatment (which must be to both testes even if leukaemia has only been detected in one). This treatment does, unfortunately, result in infertility. It will also impair production of testosterone (the male hormone) and hormone supplements may be required to stimulate puberty and subsequently. Research is being carried out into the possibility of preserving testis cells, taken at the time of diagnosis, even in pre-pubertal boys with the aim of restoring fertility.
Although the chance of relapse becomes progressively less likely with time, particularly once maintenance treatment has been completed, late relapses do occur. Children who experience late relapses can usually achieve a second remission quite easily which may be maintained for a long period of time. Repetition of original therapy in this group does not appear to achieve long-term cures and clinical trials are considering the ideal therapy to convert second remissions into cures. Treatment options and the likelihood of cure will be influenced by a number of factors including site of relapse. These will be discussed in detail by the child’s specialist.
Occurrence of relapse accounts for the difference between the very high remission rate in children and the lower overall cure rate of 75-80%. The first step in treating relapsed ALL is a repeat of the remission induction programme. This may involve an increased intensity of treatment compared with the original course. There are specific clinical trials designed to determine the ideal management of relapsed childhood ALL and parents are likely to be asked to consider entering their child in such a trial. The starting point for all clinical trials is the best, currently available therapy. Parents can refuse trial entry without prejudice to their child’s treatment and may withdraw at any time. The long-term success of re-treatment varies between almost 80% for the best risk group to less than 10% for the worst risk group. Clearly it is reasonable to offer children in the good-risk group standard chemotherapy while treatment of poorer risk groups is somewhat less standard. The role of transplants in the treatment of relapse is discussed above in the section on stem cell transplants.
LONG-TERM EFFECTS OF TREATMENT
Long-term survival of children with ALL has improved dramatically from around 4% in the early 1960s to around 75-80% in recent reports. Unfortunately, there are long-term adverse effects from certain aspects of treatment. Although efforts continue to improve survival still further, a major secondary aim of current clinical trials is to reduce the incidence and severity of the adverse effects of treatments. Use of cranial and spinal irradiation to reduce the risk of CNS relapse is associated with impairment of growth and educational achievement and with premature onset of puberty. Awareness of such long-term effects has led to a series of studies designed to ensure that children receive the absolute minimum of radiotherapy needed to minimize the risk of CNS relapse. Only a minority of children now receive routine cranial irradiation.
Where whole body irradiation has been given, as part of the preparation for a stem cell transplant, it is virtually inevitable that the child will be made sterile. There may also be impairment of hormone production by the testis or ovary and children may require replacement therapy to attain puberty. This is particularly likely when children have been irradiated at a young age. Boys may require localized radiotherapy to the testis in the case of testicular relapse. The younger the age at which this is done the more severe the impact on testis function. Spinal or total body irradiation may expose the thyroid gland to a high enough dose to impair its function. For this reason, children who have received radiotherapy which may affect the thyroid must have regular tests and may require thyroid supplements. The long-term effects of chemotherapy clearly depend on the drugs used, the intensity of treatment and in the case of some drugs, on the total amount of the drug received. It is more difficult to establish which drugs are responsible for which long-term effects in situations like childhood ALL where combinations of drugs are administered over long periods of time. There are known long-term adverse effects of certain drugs. A detailed analysis of these effects is not possible as they depend on interactions between drugs and may even vary between individuals. Detailed advice will be available from the specialists before a child begins treatment.
One common concern of parents and of older children is the effect on fertility. The majority of women who were treated as children for ALL using standard protocols will not have impaired fertility. Males are more likely to have impaired sperm production, and thus infertility, although this varies between patients and is hard to predict in any given case. Fortunately, the endocrine (hormone-producing) functions of the testis do not appear to be affected and most boys will undergo puberty normally and will have normal potency and sexual development. It is very important that men who were treated with chemotherapy as children are aware that fertility may return after very long periods of no sperm production. For this reason it would be unwise for a sexually active male who has been sterile as a consequence of chemotherapy to assume that this will always continue to be the case.
An important consideration for both males and females is whether there is a risk of adverse affects on offspring from treatment received during childhood. A number of large studies in Britain and abroad have confirmed that there is no increased risk of cancer or of an abnormality in children whose parents received treatment for cancer during childhood.
| The impact of radiotherapy on fertility has been discussed above. |
There are certain long-term consequences seen only in children who have received stem cell transplants; these are discussed in detail in the Leukaemia Research Fund booklet on stem cell transplants. Second cancers are a well established, although thankfully rare, consequence of drug and radiation therapy for childhood ALL. The types of cancer most often seen are brain tumours, especially in children treated with alkylating agents or with a class of drugs called epipodophyllotoxins. Current treatment protocols which avoid routine cranial irradiation may well reduce the incidence of this rare complication even further. Although there are significant long-term adverse effects of treatment for childhood ALL, a recent major study concluded that most former paediatric cancer children achieve their life goals.
FOLLOW-UP
The main purposes of follow-up of children treated for ALL are detection of relapse and detection of treatment complications. During the first year following completion of chemotherapy children are normally checked every two to three months. Checks will then gradually become less frequent until checks are given annually at 5 years and beyond. Long-term follow-up is particularly important for those children who have received treatment that may affect reproductive maturation. For this group of children hormone therapy may be necessary at an appropriate age to ensure that they achieve puberty. Neglect of such therapy may cause severe psychosocial distress to the child and peer group rejection. It can be expected that all paediatric specialist referral centres will have a programme in place to ensure such follow-up.
| Prognosis |
As discussed in the treatment sections, almost all children can expect to achieve a good first remission. The major prognostic factor at this point in treatment appears to be whether there is a prompt initial response to therapy. Factors such as age, sex, type of cell affected, cytogenetics and white blood cell count at time of diagnosis may be of importance in determining whether a child should receive standard therapy or more intensive treatment. The very small numbers of children who fail to achieve a first remission will receive highly individualized care and this will be discussed in detail by their specialist. Overall cure rates for childhood ALL have been reported to be as high as 80%, although at present many experts consider that 75% is a more realistic figure. Of the 20-25% of children who do relapse it is important to stress that most of them will come from the group designated as good-risk because most children fall into this group. Marked differences in prognosis in certain sub-groups (e.g. children with T-ALL) have been greatly reduced by selective use of aggressive therapy. Clinical trials currently have three main aims: to reduce the proportion of children who relapse, to improve management of relapsed disease and to minimize the impact of side-effects of treatment on those who are successfully treated for childhood ALL.
| Summary |
Childhood acute lymphoblastic leukaemia is a form of cancer which affects blood producing cells in the bone marrow. Although childhood ALL is a very serious disease which is almost uniformly fatal if not treated, it has a high chance of being curable with standard chemotherapy, with or without stem cell transplantation. Almost all children will achieve a remission but overall cure rates are between 70% and 80%. The difference between remission and cure rates is accounted for mainly by patients who experience relapse of their original disease.
Treatment is based on the use of drugs in various combinations. There are three phases to treatment of childhood ALL. The initial phase is called remission induction and uses relatively high drug doses to rapidly reduce the number of leukaemia cells in the body. This typically lasts about a month with part of that time spent as an in-patient. Consolidation therapy is intended to further reduce the number of leukaemic cells in the body and this treatment lasts for several months as an out-patient. Finally, and uniquely to this form of leukaemia, there is a maintenance phase extending to two years for girls, and three years for boys, from the time of diagnosis during which patients take low doses of drugs as out-patients.
Stem cell transplantation is not used routinely in the treatment of childhood ALL. It may be appropriate for patients who are thought to be at high risk of relapse or for patients who have experienced relapse but have achieved a second remission.
The prognosis for childhood ALL varies depending in part on characteristics of the child such as age and sex and in part on the features of their disease. The most important single prognostic factor seems to be the initial response to treatment. Designations such as good-risk or poor-risk are of considerable value in conducting comparative studies and offer guidance to doctors in planning treatment. Over recent years treatment planning has been improved and refined so that several groups of children who formerly had a poor prognosis can now be expected to do well. Because of the number of children in each group it must be remembered that most deaths which do occur are of children in the initially good risk group. Each family should seek individual advice on their child’s prognosis from that child’s specialist. |
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