 |  |  | | | Adult Acute Myeloid 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 Myeloid Leukaemia? |
Acute Myeloid Leukaemia (AML) is sometimes referred to as Acute Non-Lymphocytic Leukaemia (ANLL), especially in American publications. AML is a form of cancer that affects the cells producing myeloid blood cells in the bone marrow. Myeloid cells are red blood cells, platelets and all white cells except lymphocytes.
Non-lymphocytic white cells include:
 | neutrophils - which mainly combat bacterial infection |
| monocytes -which destroy more resistant bacteria, give rise to tissue immune cells called macrophages and are essential for effective function of antibody producing lymphocytes |
| eosinophils -which are important in defence against parasites and which are involved in allergic reactions |
| basophils -which are also involved in allergic reactions and form part of the non-specific defenses triggered by local tissue damage |
In acute myeloid leukaemia cells, usually of the neutrophil family, but occasionally of the red cell or platelet types, are being produced abnormally. This is a block in the manufacture of the cells with immature cells known as blast cells accumulating in the bone marrow. These cells are unable to complete the maturation procession known as differentiation which results in too few normal blood cells reaching the circulation. The accumulation of blast cells in the marrow prevents production of other cell types leading to anaemia and low platelet counts. Blast cells tend to spill-over into the bloodstream and it is the presence of blast cells in the blood which leads to a diagnosis in most cases.
The forms which dominantly affect red-cell or platelet producing marrow cells are known as erythroleukaemia and acute megakaryocytic leukaemia respectively. Adult, for the purpose of this booklet, refers to patients over the age of 15 years.
| Who gets Acute Myeloid Leukaemia? |
Acute myeloid leukaemia affects all ages although only about 25% of cases occur in people under the age of 25 years. There is an exponential rise in incidence after the age of 40 years. The median age of onset is about 65 years. The incidence is slightly higher in males than in females. American studies have shown a higher incidence of one subtype called APL in people of Hispanic descent.
| What are the types of Acute Myeloid Leukaemia? |
The major system of classifying AML is by the appearance of the leukaemic cells. This system is described as the FAB classification after the group of French, American and British haematologists who designed the system. The FAB classification system for AML recognizes eight subtypes called M0 to M7. It is important to stress that these categories do not reflect severity of disease, for example M0 is neither better nor worse in outlook than M7.
| Show progressively greater degree of maturation of leukaemic cells | Special tests may be needed to distinguish M0 from ALL | 50% | | Acute promyelocytic leukaemia | Treated with retinoic acid; haemorrhage risk | 10% | | Acute myelomonocytic leukaemia | May present with gum swelling | 35-40% | | Acute monoblastic leukaemia | As for M4 | inc. with M4 | | Acute erythro leukaemia | Red cells affected | 4% | | Acute megakaryoblastic leukaemia | Platelet precursors affected. Ch>Ad | 1-3% |
Specialist laboratory tests called histochemistry and immunophenotyping may be of value in some instances. There may be particular difficulty in differentiating some cases of M0, M1 and M7- type AML from Acute Lymphoblastic Leukaemia (ALL). It is potentially difficult, but very important, to differentiate AML M0 from ALL because the treatment for these two diseases is very different. Both M0 and M7 are differentiated from other forms chiefly on the basis of immunophenotyping results. About 50-60% of patients with AML have the M1, M2, M3, M6 or M7 subtypes; about 40% have M4 or M5 subtypes. The treatment for all subtypes is essentially the same except for M3. This is sometimes known as Acute Promyelocytic Leukaemia (APL) and effective treatment of this type requires the use of a drug called All Trans Retinoic Acid (ATRA) alongside standard chemotherapy.
Detailed examination of chromosomes from leukaemic cells shows distinctive abnormalities in almost all cases. The study of these changes is termed cytogenetics and is of value in classifying AML into relative risk groups. The commonest type of change is called a translocation and involves exchange of material between two chromosomes. The implications of such changes are discussed below in the section on treatment planning.
When AML arises on a background of a previously diagnosed bone marrow condition it is known as secondary AML. The distinction is important because secondary AML is more likely to be associated with resistance to standard chemotherapy and has a poorer overall prognosis. Secondary AML is most often seen in elderly patients. In this group it may account for as many as 25 - 40% of cases. AML can occur as a complication of treatment with anti-cancer drugs. This form is referred to as treatment related AML (tAML) and, like secondary AML, it tends to be relatively resistant to standard therapies.
| What causes Acute Myeloid Leukaemia? |
The cause(s) of AML are unknown in most instances. One clearly identified risk factor is exposure to very high radiation levels such as that seen after the atom bomb explosions in Japan in 1945. Very few people in the Western world are exposed to levels of radiation high enough to increase the risk of leukaemia. An exception to this may be patients who have received radiotherapy for treatment of cancer. This is discussed below together with chemotherapy induced AML.
Certain chemical exposures have been clearly shown to increase the risk of AML. In particular, patients who have received chemotherapy or radiotherapy for other forms of cancer show a raised incidence of AML. This is often referred to as therapy-related AML. Therapy related AML occurs between 1 and 10 years after exposure depending on the drug responsible. It shows certain distinctive features and may be less responsive to standard forms of treatment than de-novo AML which arises without any obvious cause.
Benzene levels in exhaust fumes are far below the level known to cause leukaemia, whereas the amount of this chemical in cigarette smoke is thought to be a significant cause of adult AML. As described above, certain conditions affecting the bone marrow are associated with a significant risk of developing AML. This is particularly true in older patients over about 60 years of age. The conditions which are associated with secondary AML are often referred to as Antecedent Haematological Disorders (AHD) and include:
| Myelodysplastic Syndromes (MDS) |
| Refractory anaemia |
| Refractory anaemia with ring sideroblasts |
| Refractory anaemia with excess blasts |
| Refractory anaemia with excess blasts in transformation |
| Chronic myelomonocytic leukaemia |
| Myeloproliferative Disorders (MPD) |
| Essential thrombocythaemia |
| Polycythaemia rubra vera |
| Myelofibrosis |
| What are the signs and symptoms of Acute Myeloid Leukaemia? |
The signs and symptoms seen most often in acute myeloid leukaemia are:
| Fatigue and limited capacity for exercise |
| Breathlessness on exertion |
Caused by:
| Anaemia (lack of red blood cells) |
| Bruising within the skin |
| Bleeding from mucous membranes (e.g. gums) and from wounds and 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 |
This group of features fatigue, bleeding/bruising and infection/fever may be referred to as the classic triad when they are seen together. When first seen by a doctor almost all patients with AML will have at least one of these characteristic features; 50% of all patients will show the classic triad.
Less frequently, symptoms of AML may relate to leukaemia cells infiltrating into tissues. Examples of this include bone pain, enlarged lymph nodes (glands), enlarged liver or spleen, involvement of the central nervous system and chloromas (masses of leukaemic cells, often within the skin). Chloromas are rare, affecting less than 5% of patients. Very rarely a chloroma may be present without evidence of leukaemia in the bone marrow or blood. Such patients have a very high probability of rapidly developing overt leukaemia.
Certain presenting features are associated with specific FAB subtypes. FAB M3 is often associated with bleeding, sometimes severe. Patients with FAB M4/M5 subtypes may have swelling of the gums and are particularly likely to have enlargement of the liver, spleen or lymph nodes or skin involvement. They are also more likely to have involvement of the central nervous system and a condition called leukostasis, in which blood flow is slowed and even locally blocked by large numbers of leukaemic white blood cells.
| How is Acute Myeloid Leukaemia diagnosed? |
When a doctor examines a patient with AML there are no specific signs like the rashes seen in some infections. Where gum hypertrophy or chloroma is present this may be strongly suggestive of AML. Leukaemia is not a clinical diagnosis it requires the results of laboratory tests to confirm the diagnosis.
The main laboratory tests used in diagnosis of leukaemia are the full blood count and a bone marrow biopsy. Most patients with AML will have a low white cell count, and only in a minority of patients is the white blood cell count high. When the white count is raised, this is usually due to blast cells which have escaped from the bone marrow. In almost all cases, there will be blast cells present in the blood at the time of diagnosis. It is a part of the definition of AML that the number of abnormal cells (blasts) in the bone marrow must exceed 20% of the total number of nucleated cells. Many patients also have low red cell counts (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. The red cell count and platelet counts vary from normal to very low levels.
Chromosome analysis (cytogenetics) is of considerable importance in diagnosis and planning treatment of adult AML. The analysis is usually done on a bone marrow sample. Lumbar puncture (sampling of the fluid around the spine and brain) is likely to be done if symptoms suggest that the nervous system may be affected. Certain types of AML are associated with significant abnormalities of the clotting system so blood 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 patients are not particularly prone to negative side-effects from planned treatment.
| How is Acute Myeloid Leukaemia treated? |
Without effective treatment, AML will rapidly cause death. The aims of treatment are to achieve a disease-free state called remission and, by further treatment, to eradicate the disease and achieve a cure. With modern treatment protocols, which include aggressive treatment, the cure rate has improved significantly in younger (less than 60 years) patients. Older patients, over about 60 years of age, tend to do much less well than younger patients with AML. This is in part because many older patients have poor risk factors at the time of diagnosis and partly because they are often unable to receive the very intensive therapy needed for effective management of AML.
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 patient. Moreover, this gives an opportunity to insert a catheter (tube) into a major vein in order to give the treatment. All patients diagnosed with AML in the UK will be treated under the direction of a specialist in haematological cancer supported by specialist nurses. This is available in most large hospitals, but it is essential to receive total care. Total care includes the integration of specialist skills in all groups concerned with treatment including medical and nursing staff, pharmacy staff, laboratory services and other supportive staff. Patients with AML may well be asked to consider taking part in a clinical trial .There is considerable evidence that the improvements which have taken place have been achieved as a result of large clinical trials which take place in the UK.
PRINCIPLES OF TREATMENT
The specialist team will give advice on the treatment approaches available. These will vary largely according to the patients age and general physical condition. Young patients can usually tolerate an intensive approach to treatment and this will be offered. This involves up to four or five courses (blocks) of treatment, each of which consists of five to ten days of drug treatment. Usually these are spaced out by three to four week rest periods. When intensive treatment is not considered appropriate, usually in older or less fit patients, a less intensive approach is often used. In both of these approaches the goal is to return the bone marrow to normal functioning this is known as a remission. There are many elderly patients who develop AML whose general fitness will only allow for a gentle treatment approach. Here the aim is not to achieve remission but rather to contain the disease and to maintain quality of life and minimise the need for hospitalisation.
There are two main phases in the treatment of AML; remission induction and post-remission treatment. Post-remission treatment may be referred to as consolidation. Although some centres outside the UK routinely administer long-term, low-dose maintenance chemotherapy in adult AML, the value of such treatment remains controversial. Maintenance therapy is not included as part of any current UK treatment protocol for adult AML The UK consensus is that any reduction in relapses is outweighed by an increased risk of treatment-related mortality when extended maintenance treatment is given for AML.
Remission induction is achieved in most patients using two or more drugs in combination. It is normally possible to commence this stage of treatment even before all necessary tests have been completed in order to plan the further stages of treatment. Sometimes treatment is delayed for a few days for absolute confirmation of the diagnosis and to allow specialists tests to be carried out.
CENTRAL NERVOUS SYSTEM DIRECTED THERAPY
A potential, but uncommon, problem in the treatment of AML is Central Nervous System (CNS) relapse. CNS relapse appears to be a particular risk for AML M4 and M5 subtypes. The Cerebro-Spinal Fluid (CSF) which surrounds the brain and spinal cord contains a small number of lymphocytes in healthy people. Unfortunately, although leukaemic cells can enter the CSF, administration of drugs by mouth or by injection into a vein does not lead to sufficient accumulation in the fluid. There is therefore a risk that leukaemia cells may survive in this site. This is rare in AML but if the doctor thinks that you have symptoms or signs suggesting CNS disease, than a sample of the fluid will be obtained by a procedure called a lumbar puncture. If leukaemia cells are present then drugs will subsequently be given by the same route. All hospitals will have procedures in place to ensure that only appropriate drugs are given into the spinal fluid.
CNS involvement leading to generalized relapse is a great deal less common in AML than in ALL. This may be because the standard intravenous therapy for AML is more intensive, leading to higher drug levels in the CSF.
CNS directed therapy is only used in adult AML when there is clear evidence of leukaemia within the CNS either at diagnosis (<1% of cases) or at relapse. When it is considered necessary to use prophylactic CNS directed therapy in adult AML it is normal to give only one or two intra-spinal drug treatments. The drugs normally injected are methotrexate, cytarabine and steroids. These are normally given at the same time. Radiotherapy directed at the central nervous system is rarely used in treatment of adult AML.
TREATMENT PLANNING
A high proportion of younger patients (75-85%) will achieve remission (clearance of leukaemia cells from blood and bone marrow). In older patients, in whom the disease tends to be more resistant, about 50-60% will achieve a remission. In order to achieve complete remission in AML and the best chance of long-term survival it has been found that remission induction must involve very aggressive drug treatment. Although results are continually being improved, especially with better control of infection, as many as 5-10% of patients may not survive remission induction, because of complications such as infection or bleeding.
With the exception of the M3 subtype all AML patients receive very similar remission induction treatment. Patients with M3-type acute leukaemia (APL) receive a drug called all-trans retinoic acid (ATRA) as a key part of their treatment. This is because, if given standard therapy, this group of patients has a high risk of life-threatening bleeding, and this vitamin can cause the cells in this type of leukaemia to mature and die off naturally.
After remission has been achieved the aim is to prevent the disease from recurring, which is known as a relapse. More courses of intensive chemotherapy are needed but it is not yet known precisely how many courses should be given to achieve optimal results. Some patients may be considered for a stem cell transplant. The decisions about which treatment approach to take can be guided by risk or prognostic factors.
RISK FACTORS
In younger patients recent evidence has shown that the risk of relapse can vary from 30-80% in different patients. It is now possible to give general guidance on what factors predict how likely a patient is to relapse. About 20% of patients have disease which has a low risk of relapse. This is made up patients with of the acute promyelocytic subgroup or patients who have either of two particular chromosome abnormalities called t(8;21) or inversion 16. About 70% of patients in this low-risk group can be cured with intensive chemotherapy alone. At present stem cell transplants are not thought to be required for these patients. If a relapse occurs, however, a stem cell transplant would be considered.
About 15% of patients fall into a high-risk (of relapse) group. These patients can be identified by chromosome changes. These are changes involving chromosomes 3, 5 or 7 or cases where there are changes to many chromosomes (complex cytogenetics). The risk of relapse in this group is high and patients are likely to be offered new treatment approaches and a stem cell transplant will be considered.
Patients who are not considered to belong to either the high-risk or low-risk group have an intermediate risk of relapse. This group is referred to as the standard-risk group. Patients with standard-risk disease may receive chemotherapy alone or chemotherapy followed by a stem cell transplant because it is not yet absolutely clear which offers superior results. There are several other factors which will influence the treatment choice, e.g. age, white cell count at diagnosis, speed of response to initial treatment, etc. These are all factors which the doctor will weigh up when offering advice on the treatment approach to take.
REMISSION INDUCTION PHASE
This involves the use of several drugs in combination to clear all detectable leukaemia cells from the blood and bone marrow. 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. Patients who take only one treatment course to achieve complete remission have a significantly smaller risk of relapse.
Remission induction is essentially standard for all patients except those with APL. This stage normally involves the drug cytarabine plus an anthracycline (daunorubicin, mitoxantrone, or idarubicin). These combinations can be expected to achieve remission in most patients. It is common practice to also give a third drug such as etoposide or thioguanine in the expectation that this will increase the number of patients who will achieve complete remission. The intensity of treatment needed to achieve complete remission normally causes severe marrow suppression. During this period there are significant risks of haemorrhage or infection and expert supportive care is essential. A drug called allopurinol is given to prevent patients developing complications, including gout or kidney failure, as a result of the amount of uric acid released when tumour cells are killed and protein from them is broken down. Allopurinol is normally started at diagnosis and continued until most leukaemia has been eliminated.
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 are 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. Most units give oral antibiotics and antifungal agents routinely to try to prevent infections. There is some evidence that the use of growth factors to stimulate neutrophil production may reduce the duration and severity of infection risk but they are not routinely used in all patients. Occasionally, the destruction of cells is so rapid that a condition called tumour-lysis occurs and affects the kidneys this may require temporary use of an artificial kidney. Hair loss is almost inevitable but is temporary. Because of the risks of infection and haemorrhage, patients are likely to spend all or most of their treatment as in-patients in reverse barrier isolation very stringent anti-infection precautions. Chemotherapy will severely affect fertility. In the majority of patients, it will recover many weeks later in some cases it may not recover.
CONSOLIDATION/INTENSIFICATION
This is the post-induction or post-remission phase of therapy. 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 outcome it has been found necessary to give further blocks of treatment soon after completion of remission induction. Consolidation refers to further blocks of treatment with the same, or similar, drugs as used in remission induction at the same, or possibly lower, dosages. Intensification therapy either uses additional drugs or higher doses of the same drugs used in remission induction. IN some protocols consolidation therapy is intensified by using cytarabine. A special case of intensification is the use of stem-cell transplantation. This is discussed in detail below. A high proportion of clinical trials in adult AML are directed at establishing the optimum consolidation/intensification regimen to apply, and to determine exactly which patients should be considered for a stem cell transplant.
STEM CELL TRANSPLANTATION
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 patients the source of stem cells is now cells collected from the circulating blood. An SCT may be either allogeneic (from a donor) or autologous (the patient's own stem cells). A stem cell transplant involves use of very high dose chemotherapy (and possibly whole-body radiotherapy) to destroy the patients bone marrow and immune system. This is termed myeloablation. The destroyed marrow must then be repopulated with stem cells from a donor. The major hazard of this procedure is infection during the period when blood cell production is essentially absent. Improved supportive care, especially nursing, during this period has reduced the infection risk and decreased transplant-related mortality from 20% to 10% over the last 15 years.
Stem cell transplants from a donor, other than an identical twin, contain functioning cells from the donors immune system. These may recognize the recipients cells as foreign despite tissue matching and attack them. Certain tissues within the body seem more likely to provoke such an attack than others. This condition, of an immune attack by donor cells on the hosts body, is called Graft versus Host Disease (GvHD). There is a beneficial aspect to the immune response by donors cells the same process tends to destroy residual leukaemic cells very effectively. This is known as the Graft versus Leukaemia effect (GvL). Many clinical trials are seeking to achieve the maximum GvL-effect with the minimum of GvHD. Graft versus host disease and recurrence of the original disease (relapse) are two of the main hazards of bone marrow transplantation. Unfortunately, measures to reduce the risk of GvHD appear to increase the risk of relapse. This is because GvHD is accompanied by a beneficial graft versus leukaemia effect driven by similar immune mechanisms.
Allogeneic transplants carry a higher chance than autologous transplants of eliminating the leukaemia but they also carry a higher risk of graft rejection and of graft versus host disease. The preferred donor, where available, is a sibling with a closely matched tissue type. Where such a related donor is not available an unrelated donor from a volunteer panel may be considered in occasional patients who are young and who are at a high risk of relapse. The risks of rejection and of graft versus host disease are both greater with an unrelated donor. In acute leukaemia time constraints mean that many patients will not be able to find a matched unrelated donor from the various panels of volunteer donors. This is a particular problem for patients from ethnic minorities as tissue types differ in their frequencies between ethnic populations and most volunteer donors are Caucasian.
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. This is because there are no donor immune cells to kill residual leukaemia cells. The stem cells for this approach may be collected between the previous chemotherapy blocks from blood, bone marrow or sometimes both.
The European Blood and Marrow Transplant Handbook recommendations for use of stem cell transplants in adult AML indicate that donor transplants may be regarded as a routine option for intensification for all but the best risk patients if they have a matched sibling donor available. A role for unrelated donor stem cell transplants in first remission is less clearly established. There is more limited evidence to support use of autologous transplant in first remission. Current reports suggest that the results are as good as, but no better, than those from conventional chemotherapy are.
TREATMENT OF ACUTE PROMYELOCYTIC LEUKAEMIA
When standard chemotherapy has been the only treatment available for APL there was a high risk of potentially fatal bleeding during remission induction. Part of the disease process in APL is due to a translocation involving chromosomes 15 and 17 t(15;17) that produces a defective form of the receptor for Vitamin A (retinoic acid).Trials have been carried out with high doses of a compound called all-trans retinoic acid (ATRA). It was found that this could cause APL cells to mature and die without causing bleeding problems. If ATRA is used alone it can achieve a high rate of complete remission but relapse is virtually inevitable. Optimum treatment for remission induction is the use of standard chemotherapy alongside ATRA. The inclusion of maintenance therapy with ATRA can lead to two-year relapse-free survival rates of about 75%. A small minority of patients with APL who do not have the characteristic t(15;17) chromosome abnormality may not respond to ATRA. In patients with APL who do not respond to ATRA (refractory disease) or who suffer relapse arsenic trioxide has given very promising results.
TREATMENT OF RELAPSE
Although a high proportion of patients with AML will achieve a remission a significant proportion (30-80%) will relapse. This is to say their disease will return. Relapse is most likely in patients in the poor-risk group with a lower incidence in the standard-risk group and the lowest incidence in the good-risk group. As around 65% of patients with AML have standard-risk disease most relapses will occur in this group. Relapsed AML 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. The time of relapse is significant. Patients who relapse a long time after therapy have a better chance of responding to re-treatment. Patients with late relapses tend to have a higher incidence and duration of second remissions. During this period they will be considered for a transplant if they have not already received one. In patients who have received a donor transplant it may be possible to use immune system cells from the original donor to treat a relapse. This is known as Donor Lymphocyte Infusion (DLI). Unfortunately, for patients with AML who experience relapse the chances of long-term survival are poor at present. The best chance of success probably lies with patients with good-risk disease who have not had a transplant but who have a matched sibling donor available. If it is not feasible to give further aggressive therapy it may be possible to achieve reasonable control of the disease for a short period with low dose chemotherapy given on an outpatient basis.
Age is another important factor in determining the success of re-treatment. The chances of successful reinduction and a reasonable prospect of time free of disease is better in young patients, and gets poorer with increasing age. It is important for patients and families to discuss with the specialist team the prospects for successful treatments when relapse occurs.
Most relapses occur within the first two years. Although the chance of relapse becomes progressively less with time, particularly once all treatment has been completed, late relapses do occur. Typically late relapses appear to result not from development of drug resistance but because not all leukaemia cells have been eradicated by initial therapy.
AML IN THE ELDERLY (PATIENTS OVER 60 YEARS)
In patients who are over the age of 60 years when they are diagnosed with AML it is more difficult to obtain a remission and relapse is more common. Several factors contribute to this situation. One of these is the difficulty of giving full dose therapy to older patients. In this age group patients may well have other medical problems and they may not be able to withstand full doses of treatment. It is well established that any significant reduction in dose will reduce the chance of curing the leukaemia. It is clear that, whenever possible, older patients should receive full intensity remission induction therapy. Ideally, they should also receive full consolidation therapy but this may not be feasible.
Another factor with AML in older patients is the frequency of secondary AML arising after an initial diagnosis of myelodysplastic syndrome or of a myeloproliferative disorder. Patients of any age who have secondary AML are more likely to have poor-risk features and to show multi-drug resistance. Older patients are, in any case, more likely to have myelodysplastic features, poor-risk AML, and multi-drug resistance regardless of whether their disease is de-novo or secondary.
Elderly patients with AML may elect, or be advised by their physicians, to receive palliative rather than intensive treatment. For some patients in this group quality-of-life issues are more important than duration of survival. This is obviously a very individual decision which must be arrived at by individual patients, and their families, after full discussion with their specialist.
LONG TERM EFFECTS OF TREATMENT
Long-term survival of patients with AML has improved dramatically in younger patients, although much improvement is needed, for older patients in particular. Unfortunately, there may be 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 adverse effects of treatments.
Use of cranial and spinal irradiation to reduce the risk of CNS relapse is very uncommon in AML. Where whole body irradiation has been given, as part of the preparation for a stem cell transplant, it is virtually inevitable that the patient will be made sterile. Spinal or total body irradiation may expose the thyroid gland to a high enough dose to impair its function. For this reason, patients who have received radiotherapy which may affect the thyroid must have regular tests and may require thyroid supplements. Several years later cataracts may develop which can usually be successfully removed.
Long-term effects of chemotherapy 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 when combinations of drugs are administered in high doses over several blocks of treatment. There are known long-term adverse effects of certain drugs. A detailed discussion of these is not possible as they depend on interactions between drugs and vary between individuals. Detailed advice will be available from the specialists before treatment begins.
One common concern of patients is the effect on fertility. The impact of radiotherapy on fertility has been discussed above. Alkylating agents, nitrosureas and cyclophosphamide may all adversely affect the reproductive system. Cyclophosphamide and cytarabine, in particular, may affect sperm production in males causing sterility. It is very important that patients be 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 is apparently sterile as a consequence of chemotherapy to assume that this will always continue to be the case. In females, chemotherapy without radiotherapy is less likely to lead to sterility. An important consideration for both males and females is whether there is a risk of adverse affects on offspring from the treatment received. 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.
There are certain long-term consequences seen only in patients who have received stem cell transplants; these are discussed in detail in the booklet on transplantation.
Secondary cancers are a well established, although thankfully uncommon, consequence of drug and radiation therapy for adult leukaemia. The cumulative incidence of this is probably less than 2-3% at 20 years after completion of treatment. Modern treatment regimens which scrupulously minimize the use of drugs and radiotherapy known to cause secondary tumours mean that the incidence will probably be significantly lower for patients being treated on current protocols.
FOLLOW-UP
The main purpose of follow-up of patients treated for AML is the detection of relapse and of treatment complications. During the first year following completion of chemotherapy patients are normally checked every one to two 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 patients who have received treatment that may affect thyroid function or which may have affected the heart.
| Prognosis |
As discussed in the treatment sections, most patients can expect to achieve a good first remission. The major prognostic factor for long-term survival is the risk-group. Patients in the good risk group have about 70% chance of long-term survival given chemotherapy alone. For patients in this group who relapse, a stem cell transplant in second remission may be feasible. For patients in the standard- and poor-risk groups the availability of a matched sibling donor is of key significance. Patients who have such a donor available and who receive a transplant have about a 50% chance of long-term survival; survival is better in standard-risk than poor-risk patients. Where patients have relapsed the prognosis is poor with the possible exception of patients not previously transplanted who have a matched sibling donor.
Clinical trials currently have three main aims; to reduce the number of patients who relapse, to improve the management of relapsed disease and to minimize the impact of side-effects on those who are successfully treated for adult AML. Patients are advised to ask about trials available at the treatment centre.
| Summary |
Adult acute myeloid leukaemia is a form of cancer that affects blood-producing cells in the bone marrow. Although adult AML is a very serious disease that is almost uniformly fatal if not treated, it is potentially curable with standard chemotherapy, with or without stem cell transplantation. Patients in the best risk group have about a 70% chance of being long term survivors with chemotherapy alone. For those who relapse a stem cell transplant may be an option.
Younger patients in the standard and poor-risk groups have a somewhat better chance of survival if they have a matched sibling who can act as donor for a stem cell transplant. The outlook for patients whose disease has relapsed tends to be poor.
Treatment is based on the use of drugs in various combinations. The treatment of adult AML is based around a series of short blocks of treatment given over about four to six months, most or all of which is spent as an in-patient. A special case is acute promyelocytic leukaemia in which a drug called all-trans retinoic acid (ATRA) is a mainstay of treatment.
Stem cell transplantation is not appropriate for all groups of patients with adult AML. It is usually recommended in first remission for selected patients in standard and high risk groups but not for patients in good risk groups. Good risk patients have a high chance of successful re-treatment after relapse so the risks of stem cell transplant in first remission are not justified.
The prognosis for adult AML varies depending in part on characteristics of the patient such as age and other medical problems and in part on the features of their disease. Each patient should seek individual advice on their prognosis from their specialist. |
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