|  |  |  | | | | Chronic 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 chronic myeloid leukaemia? |
Chronic myeloid leukaemia (CML) is a form of cancer that starts in cells within the bone marrow called stem cells. Stem cells are immature blood cells which can divide many times and eventually produce all the lymphocytes and myeloid cells present in the blood. Throughout most stages of CML the majority of the leukaemia cells in both blood and bone marrow appear to be myeloid cells. Myeloid cells are red blood cells, platelets and all other white cells except lymphocytes.
Non-lymphocytic white cells include:
 | neutrophils- which mainly combat bacterial infection |
| monocytes - which destroy more resistant bacteria and give rise to tissue immune cells called macrophages and are essential for effective function of the antibody producing lymphocytes |
| eosinophils - which are important to defend against parasites and are involved in allergic reactions |
| basophils - which are also involved in allergic reactions and form part of the general immune response initiated by local tissue damage |
Throughout most stages of the disease the leukaemic cells found in the bone marrow and the circulating blood appear to be myeloid cells. In about 90% of cases of CML the leukaemic cells have a characteristic abnormal chromosome called the Philadelphia chromosome. This is not an inherited abnormality but is acquired by an individual stem cell when a portion of the genetic material on chromosome number 9 is exchanged with a portion of material on chromosome number 22. This exchange can be detected using sensitive laboratory tests and the presence of a Philadelphia chromosome is important both in terms of diagnosis and for monitoring response to treatment. This is often referred to as typical (or sometimes classical) chronic myeloid leukaemia. This booklet will describe the diagnosis, treatment and prognosis of the typical form of chronic myeloid leukaemia.
Chronic myeloid leukaemia is a form of leukaemia that progresses slowly during the chronic phase of the disease. This phase lasts four to six years on average then undergoes a transformation to a more rapidly progressing state. In about two-thirds of patients this shows itself by changes consistent with a so-called accelerated phase, which lasts about three to nine months, and then proceeds to a final or blast phase. In some patients the disease proceeds directly from chronic phase to blast phase without an intervening accelerated phase. During the blast phase the disease resembles acute leukaemia. In most cases the actual blast cells (immature white cells) resemble those seen in acute myeloid leukaemia (AML) (there is a separate booklet on Acute Myeloid Leukaemia available from Leukaemia Research Fund). However, in about a quarter of patients the leukaemia cells look more like the blast cells seen in acute lymphoblastic leukaemia (ALL). This is known as lymphoid blast crisis that presents with an overall poor outlook.
It is accepted that the only treatment that can cure CML is a stem cell transplant using stem cells from a matched donor. This treatment is not possible for all patients because some are too old and in other cases there is no suitable donor available. Drug treatment may prolong survival but is not currently considered curative. It is possible that a new drug called imatinib (trade name Gleevec or Glivec) may offer the chance of cure to a small proportion of patients without a stem cell transplant but it will take several years to prove or refute this notion.
| Who gets chronic myeloid leukaemia? |
Chronic myeloid leukaemia occurs at all ages, though very rarely in children below the age of 15.
The incidence increases with age. The average age at diagnosis is about 50 years. Roughly a third of cases affect people over the age of 60 years, which has implications for the selection of treatment. The incidence is slightly higher in males than in females. There are about 750 new cases each year in the UK.
| What are the types of chronic myeloid leukaemia? |
The Philadelphia chromosome is an acquired abnormality in which part of chromosome 9 is exchanged with part of chromosome 22. As a result, chromosome 22 is shortened, but with a section of chromosome 9 attached. This type of change is called a translocation and is written as t(9;22). The result of this translocation is that part of a gene called BCR joins with part of a gene called ABL. This produces a fusion gene called BCR-ABL, which has been shown to be a key factor in the development of typical CML. In about 90% of cases it is straightforward to demonstrate the presence of the Philadelphia chromosome. All patients with this abnormality also have the BCR-ABL fusion gene in the leukaemic cells. In about 5% of cases very sensitive methods can demonstrate the presence of the BCR-ABL gene in the leukaemic cells even though there is no evidence of the abnormal Philadelphia chromosome by conventional cytogenetics (examination of the chromosomes).
A drug called imatinib ( also known as Gleevec or Glivec), has been designed specifically to block the function of the abnormal protein produced by the BCR-ABL gene and can reduce the number of leukaemia cells in a person’s body to a much greater extent than any other drug. .
The remaining patients whose leukaemia cells lack the Philadelphia chromosome and the BCR-ABL gene are said to have atypical CML. A rare condition, which resembles CML, but shows significant clinical and laboratory differences, is called chronic neutrophilic leukaemia (CNL). The leukaemic cells lack the Philadelphia chromosome and the BCR-ABL fusion gene. The blood count and blood film are characterised by very high numbers of neutrophils with a mature appearance.
Another very rare condition which is thought to be closely related to CML, if not actually a subtype of CML, is called eosinophilic leukaemia. In this condition there is an excess of eosinophils, a type of white blood cell. The clinical pattern of this condition is not always easily distinguished from a non-malignant disease called hypereosinophilic syndrome.
Some patients with eosinophilic leukaemia have a fusion gene that resembles in some ways the BCR-ABL fusion gene of CML but involves a different gene, one called PDGFRA. (Hypereosinophilic syndrome and eosinophil leukaemia are dealt with in a separate Leukaemia Research Fund publication).
| What causes chronic myeloid leukaemia? |
The only clearly defined risk factor for chronic myeloid leukaemia is exposure to high levels of ionizing radiation. The incidence was markedly increased among survivors of the Hiroshima and Nagasaki atomic bomb explosions. There have been reports of people who developed CML following high-dose radiotherapy as part of cancer treatment. However, it is extremely unlikely that previously normal; person in the UK would be exposed to levels of radiation high enough to increase the risk of developing CML.
There is no evidence that family members of a patient with CML are at a higher risk to develop the condition than anyone else.
| What are the signs and symptoms of chronic myeloid leukaemia? |
Most patients with chronic myeloid leukaemia are diagnosed during the chronic phase and many will have no symptoms at the time of diagnosis. The proportion of CML patients without symptoms at diagnosis has increased from 15% to about 40%, as a result of more widespread use of routine blood testing.
When symptoms are present they are usually non-specific and gradual in onset. They include fatigue, loss of appetite, weight loss, increased sweating and unusual or excessive bleeding from various sites. If the spleen is enlarged there may be abdominal discomfort and a feeling of fullness when eating.
An enlarged spleen is a common finding on physical examination of patients with CML. It has become less common with the condition being diagnosed earlier but is still seen in about 50-60% of cases. The liver is enlarged in 10-30% of patients at the time of diagnosis.
The accelerated phase, experienced by about two-thirds of patients, is not usually marked by any change in symptoms. It is detected on the basis of changes in the blood and bone marrow. In some cases there may be fever, night sweats and enlargement of the spleen.
The blast crisis is usually associated with significant symptoms. These include weight loss, fever and bone pain. Patients may become anaemic (low haemoglobin levels) and may suffer bruising/bleeding problems and repeated infections because the bone marrow is failing to produce normal blood cells. In blast crisis it is possible that leukaemia cells will invade other tissues. In the skin it may lead to the production of small nodules or painful haemorrhages. Lymph nodes may become enlarged and the central nervous system (i.e. the brain and spinal cord) may be affected.
| How is chronic myeloid leukaemia diagnosed? |
It is becoming increasingly common for chronic myeloid leukaemia to be diagnosed by chance, in patients who have no specific symptoms. Patients typically have a raised white cell count with higher than normal numbers of immature white blood cells. The count is characteristically well above normal limits and may be very high. The cells appear normal through the microscope, unlike those seen in acute leukaemia, but there are forms of blood cells that are not normally seen outside the bone marrow.
Blood count and film are usually quite distinctive and the diagnosis is normally definite at this stage. A feature that tends to confirm the diagnosis is the presence of increased numbers of basophils (white blood cells), and to a lesser extent, eosinophils. The number of lymphocytes may be slightly elevated.
In most patients there is some degree of anaemia at the time of diagnosis, which is usually mild, but may be severe in those patients who have been diagnosed relatively late. The platelet count is often significantly raised in chronic phase CML and may be very high in a few patients.
It is usual for patients with chronic myeloid leukaemia to have a bone marrow sample taken soon after diagnosis. This confirms the diagnosis and provides important additional information. Normal bone marrow contains large numbers of fat cells with areas of blood cell production spaced between them. In CML there is very little fat present in the bone marrow, which is entirely filled with large numbers of leukaemia cells.
Cytogenetic studies are of great importance both in confirming the diagnosis of CML and in monitoring the response to treatment. The diagnosis of typical CML is confirmed in the 95% of patients who can be shown to have the BCR-ABL gene present (with or without the Philadelphia chromosome). For patients treated by stem cell transplantation levels of the BCR-ABL protein (produced by the fusion gene) may be of great significance in determining whether the transplant has been successful.
| How is chronic myeloid leukaemia staged? |
In most forms of cancer, some form of staging is used to assist in treatment planning and in making a likely prognosis. Staging relates chiefly to the spread of the cancer from its original site. In chronic myeloid leukaemia the disease is typically widespread at the time of diagnosis, which is why this form of staging is not used.
About 85% of patients are in chronic phase at the time of diagnosis, with the remainder being in accelerated phase or blast crisis. There is no formal definition of accelerated phase CML. It is a matter of medical judgment taking account of the clinical features present, the laboratory findings on blood and bone marrow samples and the changes in the cytogenetic characteristics of the leukaemia cells. In about one third of cases the disease appears to progress directly from chronic phase to blast crisis without an intervening stage.
Blast crisis is characterised by the presence of at least 30% blast cells in the bone marrow or circulating blood. Some patients will develop deposits of leukaemia cells outside the bone marrow. Although uncommon, it is usually followed by typical blast crisis within a few months. About half of all blast crises are myeloid, a quarter are lymphoid and the remainder are a mixture of the two. These terms refer to the appearance and characteristics of the blast cells seen in this stage. The distinction is important because it affects the likely response to treatment and prognosis.
The disease will progress from chronic phase into accelerated phase or blast crisis in about 5-10% of patients during the first two years after diagnosis. In each subsequent year the rate of progression remains steady which means that the disease will progress in 20% of CML patients per year.
In addition to the phases of chronic myeloid leukaemia there is are two prognostic staging systems, one designed by Joseph Sokal and colleagues in the 1980s and the other designed by Jurg Hasford (the Euro score) in the late 1990s. These systems are not directly comparable to the staging used for conditions like lymphoma and chronic lymphocytic leukaemia. The CML systems do not directly relate to how advanced the condition is but rather measure the aggressiveness of the disease. The systems classify patients into good- and poor-risk groups using a complex formulas based on the following features:
| Patient's age |
| Size of spleen |
| Percentage of blast cells in the blood |
| Number of platelets |
| Numbers of basophils |
| Numbers of eosinophils |
Patients with a low score on this system (few adverse features) have an average survival of around eight years while patients with a high score have an average survival of three to four years. The Sokal score was developed before interferon alpha was introduced for treatment of CML (see below) prompting modification of the existing system, which is now considered more reliable for these patients.
| How is chronic myeloid leukaemia treated? |
PRINCIPLES OF TREATMENT
No form of chemotherapy (drug treatment) is currently thought to cure CML. It is possible that the introduction of imatinib may cure occasional patients but it will require several years of comparative studies before the answers are known.
For the majority of patients, a stem cell transplant is not an option – because of the patient’s age or fitness or because no suitable donor is available. There is now general agreement that imatinib is the treatment of choice in this group. The National Institute for Clinical Excellence (NICE) recommended in September 2003 that imatinib should be available for all newly diagnosed CML patients. NICE advised that, for patients already receiving other treatments, the choice whether or not to switch to imatinib should be made on an individual basis, after discussion between patients and their specialists. For patients who cannot receive a transplant, treatment is aimed at prolonging the chronic phase of the disease to the greatest possible extent. For most patients imatinib can eliminate easily detectable signs of leukaemia from the blood, although leukaemia cells can still be detected by highly sensitive techniques. . A further benefit of imatinib is that the side effects are mild in the great majority of patients. Any patient who is considering trying for a pregnancy while taking imatinib should first discuss this with their specialist. Many patients who had a very poor quality of life on previous treatments have been able to return to a virtually normal life-style on imatinib. Patients who have complete resolution of symptoms on imatinib have sometimes stopped taking the drug. There is no evidence, at present, that imatinib can cure CML and patients should never cease therapy without discussing this with their specialist.
With progression into accelerated phase, chemotherapy tends to be less effective in controlling the white cell count. The current recommendation by NICE is that use of imatinib during accelerated or blast phase will probably not be effective in patients who have received this throughout chronic phase and it is not recommended. Many patients who formerly were free of symptoms will develop clinical signs and symptoms at this time.
By testing for the presence of the BCR-ABL gene the effectiveness of treatment can be monitored. When there is no clear evidence of disease in the blood or bone marrow, but BCR-ABL protein is still present, this is termed a complete haematological remission. When it is not possible to detect the BCR-ABL gene this is called a cytogenetic remission and is evidence of a more complete clearance of the disease. Imatinib has been found to achieve a higher rate of cytogenetic remission than any previous treatment other than a stem cell transplant.
Stem cell transplantation offers the possibility of cure for a selected group of patients but carries a significant cost in terms of treatment related deaths and long-term side- effects. A stem cell transplant using a normal donor is only available for patients who have a matched donor and who are young and fit enough to withstand the procedure. Currently this only applies to about one-fifth of patients.
There is a divide in opinion on the best management of young patients newly diagnosed with CML and who have a donor available. Probably about half of all specialists would recommend an immediate transplant, on the basis that this is potentially curative, while others would recommend initial treatment with imatinib, with transplant being reserved for the time when imatinib fails and/or the disease progresses. It is likely to take some years before there are sufficient data to resolve this question. A decision on when to transplant in this group will be arrived at following discussion between patients and their specialists.
A stem cell transplant from a donor carried out in accelerated phase or blast crisis can cure a patient but the treatment-related risk is very much higher. If patients with advanced disease are young and fit enough to be given intensive therapy they may be able to receive an autologous stem cell transplant, using their own stem cells harvested during chronic phase. This may enable patients to experience a second chronic phase.
Once the disease progresses into blast crisis it has effectively transformed to an aggressive acute leukaemia. The blood and bone marrow contain large numbers of very immature white cells (blast cells) and the condition responds poorly to treatment. At this stage treatment is principally aimed at alleviating symptoms. This is known as supportive care or palliative treatment.
Once patients enter blast crisis average survival is in the order of three to six months. Lymphoid blast crisis may respond to combinations of drugs including vincristine and steroids (prednisolone). The chemotherapy regimens are similar to those normally used to treat acute lymphoblastic leukaemia. Such treatment may be capable of inducing a second chronic phase although of much shorter duration than the initial chronic phase.
Since no chemotherapy regimen has been shown to prolong survival for non-lymphoid blast crisis, this group of patients may be invited to take part in studies of new drugs which are thought to offer potential benefits.
TREATMENT PLANNING
Chemotherapy
Until recently the use of either busulphan or hydroxyurea as a single drug treatment was considered standard treatment for newly diagnosed patients with chronic myeloid leukaemia. Although it may still be the preferred option for a small number of patients, it is no longer routinely used. The choice is now much more complex and lies between the use of imatinib alone or with other drugs, a donor stem cell transplant (if a donor is available) or an autologous stem cell transplant. These treatments are not mutually exclusive, for example a patient who is scheduled for a donor transplant will initially receive chemotherapy.
The National Centre for Clinical Excellence has recommended that imatinib should be available for all newly diagnosed patients with CML. The drug has been in use for about 5 years, but given the indolent nature of CML, this is not long enough to prove that it can prolong survival, however the excellent cytogenetic responses achieved have made specialists confident that it will. It is on this basis that NICE has recommended making the drug available to all new patients. For patients who do not initially respond to imatinib, there are various options:
| Persist at the current dosage (patients may show a delayed response) |
| Increase the dosage of imatinib |
| Combine imatinib with another drug or drugs |
| Offer a donor transplant (preferred option if a good donor available for a fit patient) |
| Offer a non-myeloablative stem cell transplant or a transplant using a less than ideal donor |
Prior to the widespread introduction of imatinib, interferon alpha was the treatment of choice for most patients with CML. Up to 80% of patients treated with interferon alpha will achieve a haematological remission and up to a quarter of patients will show a complete or major cytogenetic response. It is clearly established that patients who achieve a complete or major cytogenetic response with this drug survive significantly longer than those who do not. There is strong evidence that even those who fail to achieve cytogenetic responses with interferon alpha have a prolonged survival compared to patients treated with hydroxyurea or busulphan. Unfortunately, interferon alpha, unlike imatinib, tends to have severe side effects, which have a major impact on quality of life, so it is used infrequently at present.
Stem cell transplantation
(There is a separate booklet on Stem Cell Transplantation available from the Leukaemia Research Fund).
The only treatment currently considered to be potentially curative in CML is a donor stem cell transplant. Stem cell transplants (SCT) are potentially hazardous and the highest risk occurs early after the transplant is performed. The degree of risk varies according to patient characteristics, disease stage and the donor.
A scoring system has been designed to determine the likelihood of a successful outcome for donor transplantation. Younger patients with well-matched sibling donors who are transplanted in the chronic phase of the disease within one year of diagnosis may expect a greater than 70% chance of 5-year survival. On the other hand, older patients with poorly matched donors who are transplanted late in the course of their illness may have only about a 20% chance of 5-year survival.
Stem cell ransplantation using a normal donor carries a much higher risk in the short-term than chemotherapy but is the only treatment capable of curing chronic myeloid leukaemia. This means that shared decision making between doctor and patient is the norm for newly diagnosed CML patients. Patient's priorities will differ according to personal circumstances. A patient who is awaiting an important family event such as the birth of a grandchild may be unwilling to run a short-term risk. A younger patient with a greater potential life span may consider even a high-risk transplant an acceptable option. The transplant outlook scoring system, which is used to help predict the likelihood of a successful outcome, is of particular value in guiding such decisions.
Treatment of chronic phase
Imatinib is the preferred initial chemotherapy for newly diagnosed CML patients. This is based on the excellent cytogenetic response rate, combined with the good quality of life for patients treated with imatinib. There is, as yet, no clear evidence showing a survival advantage for patients whose disease responds well to this drug, but most experts anticipate that there will be a clear improvement in survival compared with earlier drugs. A number of studies are being carried out to determine whether there is an advantage in using imatinib in combination with other drugs.
An area of some concern with imatinib is its effect, if any, on the success of a stem cell transplant. With interferon this was a problem, since early studies showed a poor success rate in patients treated with interferon alpha before transplant compared with other patients. Further investigations have shown that this can be overcome by ceasing interferon alpha at least 90 days before transplantation. As evidence accumulates of the use of imatinib before transplant it is likely that a clear policy will emerge; at present, this decision is a matter for discussion by individual patients and specialist.
Soon after treatment has begun patients are likely to have stem cells harvested for a possible autologous transplant, that is for the return of their own stem cells. Stem cells are usually obtained from the blood rather than bone marrow. This is a simpler procedure avoiding the need for a general anaesthetic. In addition, recovery after such a transplant is usually quicker. Chemotherapy will reduce the number of leukaemia cells in bone marrow and blood and this in turn will reduce the numbers of malignant cells that remain in the stem cell harvest. If patients fail to respond to imatinib, alone or in combination, and are not candidates for an allogeneic (donor) transplant, they may be offered the option of an autologous transplant in chronic phase. This has proved to offer prolonged survival in this group of patients. Comparisons of the benefits of imatinib and autologous stem cell transplantation have not yet been completed which is why imatinib is first choice for patients who are responding to this drug.
For young patients with a well-matched sibling donor a transplant offers the possibility of cure. In this group a transplant may be planned early in treatment. Stem cell transplantation is discussed in detail below.
Treatment of accelerated phase
During accelerated phase CML is less likely to respond well to chemotherapy, including imatinib. It is at this time that autologous stem cell transplantation is most valuable as it has the potential to achieve a second chronic phase, which may be long lasting.
If a patient in accelerated phase has not yet received imatinib, either alone or in combination, it may be reasonable to consider this option. The response rate to imatinib is lower than for patients treated in chronic phase but may still offer prolonged survival, especially in combination with other drugs.
Other options in this phase include high-dose cytarabine, hydroxyurea, busulphan or palliative care. Allogeneic transplantation may offer 10-30% of patients a cure but is a high-risk option in this group. However, the percentage of patients that can be cured may be as high as 60% if an allogeneic transplant is carried out at the very earliest stage of progression from chronic to accelerated phase.
TREATMENT OF BLAST CRISIS
The average survival of patients who enter blast crisis is three to six months. Blast crisis may be lymphoid, myeloid or some mixture of the two. This categorisation is based on the characteristics of the blast cells in this phase of the disease. Lymphoid blast crisis may respond to a treatment regimen similar to that used for ALL. Such treatment may achieve a second chronic phase in up to 50% of eligible patients.
Intensive treatment with high-dose cytarabine or with a combination of cytarabine plus an anthracycline (e.g. daunorubicin) or a nucleoside analogue (eg fludarabine) may induce a short second chronic phase in 20-30% of patients with myeloid blast crisis. Imatinib has achieved highly significant responses in patients with myeloid blast crisis. However, this is in a small group of patients and large-scale studies will be needed to determine the potential contribution of imatinib for the management of blast crisis.
Allogeneic transplantation retains the capacity to achieve cure for patients in blast crisis but in practice only about 10% of recipients would be expected to be long-term survivors.
STEM CELL TRANSPLANTATION
Transplants are far more likely to be successful if carried out within the first year after diagnosis. There is presently no evidence to establish whether this will apply to patients who have been treated with imatinib for a year or more; some experts believe that, because the drug appears to clear the disease from the blood and marrow, there may be no adverse effects of delaying a transplant in a patient treated with imatinib. If no sibling donor is available then a decision on transplantation will depend on the availability of a matched unrelated donor and also on personal considerations and on the scoring system that takes the likelihood of success into account.
There is no absolute age limit for transplantation but the risk of transplant related death is much greater in older patients. The continuation of chemotherapy is more likely to be the recommended option in this group.
The role of transplantation at various stages of CML has been discussed above but there are two particular aspects requiring further consideration. Both procedures are modifications of transplant methodology, which were first introduced in the context of CML therapy, and are now being evaluated for a wider patient population.
The first of these is called donor lymphocyte infusion (DLI) and exploits a phenomenon called the graft versus leukaemia effect (GvL) in which functioning immune cells from the donor kill the patient's leukaemia cells.
When a person receives bone marrow from anyone other than an identical twin there is some degree of mismatch between the tissues of the recipient and the immune system cells of the donor. This typically results in an attack on host tissues by immune cells in the graft and is known as graft versus host disease (GvHD). In addition, there is a marked reduction in leukaemia cells following a donor transplant that is greater than expected with pre-transplant chemotherapy or radiotherapy due to the GvL- effect.
GvHD can be a serious complication of stem cell transplantation (SCT). Attempts have been made to prevent GvHD but this was found to lead to an increased rate of relapse (return of the original disease) due to loss of GvL. This finding confirmed the importance of GvL in a successful stem cell transplant.
Donor lymphocyte infusion has become the treatment of choice when a patient has received an allogeneic transplant and subsequently suffered a relapse. Immune system cells (lymphocytes) are harvested from the original donor and administered to the patient. In as many as 70% of patients this can achieve clearance of disease by activating the GvL-effect. Present data indicates that two-thirds of patients who receive DLI are alive at three years.
The second innovation is non-myeloablative transplantation, also known as reduced intensity conditioning SCT. Normally patients receive high-dose chemotherapy and sometimes radiotherapy before transplantation in order to destroy existing bone marrow cells which is called myeloablation. For many older patients or those who have other illnesses this procedure may be too harmful so they are unable to receive a transplant. Non-myeloablative transplantation employs lower doses of chemotherapy and/or radiation.
A non-myeloablative transplant exploits the observed importance of the GvL- effect in a stem cell transplant. This approach is designed to achieve sufficient suppression of the immune response in order to prevent graft rejection. The object, as with DLI, is to recruit the donor's immune system to destroy any remaining leukaemia cells.
It is necessary to stress that, despite the reduced intensity of pre-transplant treatment, the toxicity of this procedure remains relatively high compared to chemotherapy. Non-myeloablative transplants extend the possibility of allogeneic transplantation to a wider patient population but there will still be many patients who cannot undergo transplantation or who do not have a suitable donor available.
| Long- term effects of treatment |
Even though only about a third of patients will be able to receive transplants the most important long-term effects of treatment for CML are still those related to transplantation. It is possible that imatinib and other new drugs may lead to long-term survival without eradication of the leukaemia cells and without the need for a stem cell transplant. In this case long-term effects of treatment may become significant but, because these agents are so new, no evidence is yet available. There is some evidence that combinations of imatinib with older agents may be more toxic; well-designed clinical trials will be needed to determine the risks and benefits of this approach.
| Follow-up |
Follow-up of CML patients for long-term effects of treatment is currently focused on transplant recipients. Non-transplanted patients are effectively on active treatment throughout their lives and will be seen regularly in that context.
| Prognosis |
The outlook for newly diagnosed patients with CML is very variable. A young patient diagnosed in early chronic phase who has a tissue-matched sibling donor may have a good chance of being cured by a stem cell transplant. It is therefore very important that these patients discuss their outlook, including the feasibility and likelihood of success of a stem cell transplant, with their specialist in great detail. The minority of patients who are diagnosed in blast crisis, on the other hand, currently have a poor outlook.
Patients with CML are presented with an average survival measured in years with conservative therapy. The only currently curative therapy carries a significant risk of early death. This means that the choice of treatment may depend heavily on non-medical considerations. For example, if a patient has a very important family event approaching they may not wish to receive high-risk therapy even though this may be potentially curative. A parent of young children however may feel that it is justifiable to accept even a severe short-term risk in exchange for even a modest hope of seeing their children grow up.
Any consideration of prognosis must take account of the introduction of the drug imatinib, which is expected to have a major impact on the treatment and prognosis for CML. It is too early to reliably assess the impact of imatinib on the prognosis of patients with CML but many experts have made it clear that they have very high expectations. In particular, it has been suggested the drug might reduce the usually inexorable rate of transformation of chronic phase CML to blast crisis. If this proves to be true it is expected to very substantially prolong survival.
| Summary |
Chronic myeloid leukaemia is a form of leukaemia affecting a primitive stem cell. The disease is characterised by the presence of an abnormal chromosome derived from the exchange of genetic material between chromosomes 9 and 22. The abnormal chromosome 22 is called the Philadelphia chromosome and contains a fusion gene called BCR-ABL which is important to the development of CML. BCR-ABL has been the focus of targeted drug development and is of great value in monitoring the response to treatment.
CML typically shows three, although occasionally only two, consecutive phases. The great majority of patients are diagnosed in early chronic phase of the disease. The natural history of the condition involvesa change or transformation into a more aggressive state after an average of four to six years. In about two-thirds of cases the initial transformation is into accelerated phase which lasts for about three to nine months before further progressing into blast crisis. The remaining third of patients enter blast crisis directly from chronic phase. Blast crisis resembles acute leukaemia and has an average survival of about three to six months. However, some patients will respond to intensive therapy by entering into a second chronic phase which may extend survival.
A stem cell transplant may cure young patients with a well-matched sibling donor if done in early chronic phase. For older patients, patients with less well matched donors or those with late-stage disease a stem cell transplant is still potentially curative but the risks associated with the procedure are much greater. An autologous stem cell transplant performed in accelerated phase, using the patient's own cells , may achieve a second chronic phase. The duration of this may be shorter than the initial chronic phase.
For patients who either cannot receive a transplant or elect not to, treatment relies on the use of chemotherapy. The preferred agent for first line treatment is now imatinib, alone or in combination with other drugs. Imatinib induces very good cytogenetic responses compared with the drugs previously used. Additionally, the side effects are rarely severe which means that very few patients elect to discontinue treatment.
The other major area of development in the treatment of CML is the introduction of modifications to the standard stem cell transplant technique. These modifications exploit the ability of cells from the donor's immune system to destroy leukaemia cells. This may extend the use of stem cell transplants to patients who are currently not eligible and improve the success rate in all groups.
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