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Chronic myeloid leukaemia (CML) is a form of cancer which is caused by unregulated proliferation in myeloid cells in bone marrow.(1) The primary characteristic of CML is the presence of a reciprocal translocation of chromosome 9 and 22. Translocations in genetics occur when parts of different chromosomes rearrange and join together. This can lead to the formation of new fusion genes from two previously separated genes. These types of fusion genes are often implicated in cancer and are termed oncogenes and the proteins that they code for are oncoproteins.(2) It is the reciprocal t(9;22)(q34;q11) chromosomal translocation in CML that creates a derivative 9q+ and a small 22q-, known as the Philadelphia (Ph) chromosome. The small 22q- contains a BCR-ABL fusion gene which itself codes for an oncoprotein which has a deregulated tyrosine kinase activity. It is this deregulated activity which is responsible for the proliferative dysfunction in CML, Figure 1.(1)
Figure 1. The Philadelphia Chromosome (3)
Presence of this chromosomal abnormality while not definitive is usually indicative of CML and is seen in over 95% of patients. Consequently, presence of this translocation is used as part of a differential diagnosis in malignancies of the blood.(4) In order to fully understand the role of the BCR-ABL fusion gene in CML pathogenesis an understanding of the physiological role of the translocation partners (BCR and ABL) is required.(5) The ABL gene encodes a nonreceptor tyrosine kinase, the Abl protein, that is believed to play a regulatory role in a number of cellular processes including division, response to stress, adhesion and apoptosis.(6, 7) The role of the normal BCR gene product, the 160kD bcr protein is less clear though some association with serine-threonine kinase activity has been identified.(8) Since it is the Abl protein that has a multi-faceted role in normal cellular functioning it is unsurprising that the ABL coded portion of the Bcr-Abl oncoprotein is believed to be crucial to its transforming nature. Interestingly, the varying length in the Bcr sequence of the protein appears to mainly account for differences in phenotype (e.g. the P190, P210 and P230 form of the oncoprotein are associated with different specific forms of leukaemia).(9) Indeed, the Bcr section of the protein can in principle be replaced by another sequence and still permit the occurrence of leukaemia.(10)
The incidence rates of CML vary from 0.6 to 2 per 100,000 per year though these figures may be increasing due to the association of age with increasing prevalence. A rate of about 5 per 100,000 is typical in those aged over 65 years(11) and about 50% of all new cases of CML diagnosed will be in patients over 60 years of age.(12) There is also a higher incidence of the disease among men.(13) The origin of the condition is unclear though exposure to radiation is implicated and patients that have previously received radiation therapy for a malignancy are at a slightly higher risk of developing the condition.(14)
Figure 2. Haematopoiesis in humans (15)
There are three main stages which determine the natural history of CML, these are the chronic stage, the accelerated phase and the blast phase (sometimes termed "blast crisis"). Patients usually present in the chronic stage and may have remained asymptomatic for months or years before a diagnosis is made. The first indication a patient may have that something is wrong can be as part of a routine haematological test. However, symptoms of fatigue, malaise, abdominal discomfort from enlarged spleen (splenomegaly), weight loss, night sweats or a low grade fever, bone pain, priapism and an increased susceptibility to infection may all indicate CML.(16)
Following a tentative diagnosis on the basis of a complete blood count (which will usually show increase concentrations of all types of granulocytes) formal identification of the BCR-ABL (Philadelphia positive chromosome) is made via a cytogenetic technique. The most commonly employed techniques include fluorescence in situ hybridisation (FISH) and reverse-transcription polymerase chain reaction (RT-PCR) although other techniques such as Southern and Western blotting as well as CRKL phosphorylation assay are also used.(17)
Following clinical diagnosis using modern treatments the prognosis for patients is quite good, certainly in comparison to other cancers though the survival rates do show some inter-individual variability and will depend on the stage of disease that the patient presents with. Recent statistics suggest that for patients treated with Imatinib (discussed later) nearly 9 out of 10 will live for 7 years. Imatinib has not been in use for long enough to have statistics for how long it will keep CML under control over longer periods of time however, computer models have suggested it might be able to suppress CML for 19 years or longer.(18)
Monitoring of therapy effectiveness
The measuring of the effectiveness of treatment is carried out in a number of different ways including measuring the haematological response, cytogenetic response and molecular response. The haematological response is a measurement taken normally in the first three months of therapy. It is a measure of white and red cells as well as platelets and determines if they have returned to within the normal range. The cytogenetic response is when the number of cells with the Philadelphia chromosome has been reduced, if <35% of cells contain the Philadelphia chromosome this is referred to as a "major cytogenetic response." If no cells are detected which contain the Philadelphia Chromosome then this is usually expressed as a "complete cytogenetic response". A "complete molecular response" means that even using very sensitive techniques such as PCR no sign of the BCR-ABL transcript is found in the blood sample or bone marrow.(14, 19)
The treatment options for CML have improved dramatically over the years developing from potentially curative allogeneic stem cell transplant (SCT)(20) for those patients who were suitable (usually only 20-25%) or to treatment with interferon alpha (INF-Î±) with or without concomitant low-dose cytosine arabinoside (cytarabine)(21) for those not suitable.(22) More recently the use of tyrosine kinase inhibitors has revolutionised the treatment strategies for and helped to improve prognoses for many patients. The following section will review the development of treatments for CML and review the efficacy of modern practices.
Following its first recognition as a de novo malady in 1840's the original treatments for leukaemia did very little in terms of prolongation of patient life. In the 19th century the use of inorganic arsenic compounds helped to reduce leucocyte count and ameliorate splenomegaly. Following the introduction of radiation therapy in the earlier part of the 20th century for CML prolongation of life was achieved, though certainly not beyond 3-5 years.(23)
The introduction of the alkylsulfonate Busulfan in the 1950's had a dramatic effect on the treatment strategy landscape and the first clinical trial of its efficacy compared to radiation therapy in 1968 showed it to be superior to radiation therapy.(24) The fact that this alkylating agent was a simple drug compound that could be administered to patients on an outpatient basis also facilitated its acceptance though there were risks associated with its use including irreversible marrow aplasia following overdose. It should be noted however that its effect was entirely palliative since mean survival following treatment ranged from 35-47months.(25)
The introduction of hydroxycarbamide (hydroxyurea) in the 1960s also facilitated palliation in patients but similarly had limited effect on shortening progression of the condition. Its mechanism of action while unclear appears to be to block the ribonucleotide reductase system and thus inhibit DNA synthesis and it was shown to be more efficacious than Busulfan in a randomized comparison.(25)
One of the earlier examples of drugs used to target the condition either used alone or in combination with cytarabine was Interferon alpha. Interferon alpha was the first therapy that proved to have a positive effect on preventing the progression of the disease from the chronic stage and as such was very useful in the treatment for patients not suitable for stem cell transplantation.(26) Its use has largely been superseded following the discovery of the tyrosine kinase inhibitors (TKI) specifically Imatinib (see later).
Allogeneic Stem Cell transplant
The first stem cell transplant procedures in identical twin patients with a history of CML were carried out in the 1970s.(27) The stem cells used in the transplants were harvested from the bone marrow of the unaffected identical twin meaning that the cells were syngeneic. The success of the patients in this trial (they remained Philadelphia chromosome negative) encouraged researchers to consider the possibility of utilising this procedure in patients were a non-identical donor could be used (allogeneic transplant). In the 1980's transplants using human leukocyte antigen (HLA) identical siblings for affected patients became widespread and remained the treatment of choice for about 20 years for those patients deemed suitable for the procedure (usually younger patients). Those patients not deemed suitable were continued to be treated with other chemotherapeutic agents such as Interferon Alpha. In clinical practice today due to the efficacy of use and the impressive results with tyrosine kinase inhibitors allogeneic stem cell transplantation is usually reserved for younger patients-since it may provide a cure (28) or more often those patients that are deemed to have had a treatment failure with the standard therapeutics.
Recently the development of the tyrosine kinase inhibitor Imatinib has helped to revolutionise treatment of this disease and has dramatically improved the prognosis for patients. Developed in the late 1990's the findings of a study published by Druker et al showed that Imatinib was able to prevent proliferation of BCR_ABL transformed cells in a selective manner in vitro and in vivo and displayed a preferential activity in leukaemic cells in comparison to normal cells.(29) This began the process of its development as the treatment of choice for Philadelphia positive CML. Comparative randomized trials of patients in the chronic phase of Philadelphia positive CML were carried out between Imatinib and Interferon alpha with low-dose cytarabine (the IRIS [International Randomized Study of Interferon and STI571] trial). The results of these trials clearly showed that Imatinib displayed a higher overall rate of complete haematological response (95.3%) compared to the group receiving the combination Interferon alpha and cytarabine (55.5%).(30) Interestingly, following a five year follow up study the majority of patients that had been receiving treatment with the combination therapy had switched to Imatinib usually as a consequence of an inability to tolerate the treatment. However, analysis of the Imatinib group at this time indicated that an estimated 93% of patients displayed no progression to the accelerated phase or blast crisis.(31) The main side effects of Imatinib treatment were described as mild or moderate and included most commonly; superficial oedema, nausea, muscle cramps and rashes.(30)
Resistance to Imatinib
Almost immediately following its first use in the clinic the problem of resistance to Imatinib has been developing. A number of different mechanisms have been proposed to explain the pattern of resistance including; over expression of BCR-ABL, mutations in BCR-ABL and P-glycoprotein up-regulation amongst others.(32) A number of strategies have been proposed to counter the developing resistance to Imatinib and they include dosing modulation as well as combination therapy. More recently attempts to overcome the problem of Imatinib resistance have included the use of more powerful recently discovered tyrosine kinase inhibitors including Dasatinib and Nilotinib. The development of immunotherapy where immune targeting of the BCR-ABL fusion protein takes place is also a developing alternative strategy to moderate or potentially eliminate minimal residual disease.(33) Following the development of Imatinib new so called second generation tyrosine kinase inhibitors have been reported including Dasatinib and Nilotinib. The use of Dasatinib versus Imatinib in the treatment of CML is currently being investigated as part of a clinical trial(34)and their potential introduction as first line therapies has also been reviewed.(35)
Cost of treatment
The cost of treating a patient with a full course of Imatinib is expensive. Warren and co-workers investigated the cost to the NHS of treating a patient with Imatinib in 2004.(36) Based on their analysis the unit cost of treating a patient with Imatinib was £1581 per month versus £15 for hydroxyurea for the same period. These costs do not include outpatient visits and required testing and other services which may be required. Notwithstanding the significant cost of the medication/treatment to the NHS the authors pointed out in their analysis that Imatinib provided considerable health benefits to patients. The balance of providing excellent patient care and value for money within the NHS is a topic that is much in debate. Considerable analysis has been given to the decision process within NICE for the recommendation or rejection of certain treatments. A thorough discussion on this subject is beyond the scope of this text but has been dealt with elsewhere.(37)
The treatment options for this patient will depend on the stage of disease progression that he has presented with. Patients in the chronic stage which represent the majority of patients will be treated differently than those in the accelerated or blast stage. Consideration must also be given to any co-morbidity. Considering that the patient is quite elderly (78 years old) it is not unreasonable to assume that he may have other conditions which may influence the treatment he will receive. Also, as patients age their renal and hepatic function declines therefore a full battery of biochemical and haematological tests are required to determine organ function.
Similarly, the patient's medical history is required in order to check for previous surgeries and/or illnesses which may influence clinical treatment. Another important consideration is the patient's current medication. Some of the therapies used in the treatment of CML may interact with other medication. Imatinib for instance is mainly metabolized in the liver via the CYP3A4 enzyme therefore any medication that is known to either inhibit or induce this enzyme may have an effect on the levels of Imatinib or indeed Imatinib may affect the levels of those drugs in the plasma. Drugs implicated included; Phenobarbitol, Rifampicin, Simvastatin, Warfarin, Macrolides, St. John's Wort, Carbamazepine, Oxycarbamazepine, Phenytoin, Ketoconazole, Clozapine, Digoxin, Ciclosporin, Levothyroxine.(38) For patients suffering from liver disease the recommended maximum dose is 400mg daily. This dose should be reduced further if not tolerated. In patients with reduced renal function (creatinine clearance <60 mL.min-1) a max starting dose of 400 mg daily is recommended.(39)
Currently, the recommended first line treatment for adult patients with Philadelphia positive chronic myeloid leukaemia in the UK according to the NICE guidelines is Imatinib.(40) Treatment is given in the chronic phase but may also be offered in the accelerated phase or to patients in blast crisis on provision that it has not been used previously. Continued use following failure to stop disease progression is only recommended as part of a further clinical study. It must be pointed out however that the current NICE guidelines are a little dated (review date 2006) the most recent "Recommendations for the Management of BCR-ABL-positive Chronic Myeloid Leukaemia" by the British committee for standards in Haematology recognise the complication of the therapeutic field by the development of new drugs and thus set about to make a number of recommendations rather than dictate a specific guideline.(41)
Recently local guidelines in Scotland have suggested that patients upon first presenting should be offered leucapheresis if they are symptomatic or displaying extreme lecocytosis.(42) Hyperleukocytic leukaemia is when the white blood count is over 100 x 109/L.(43) Samples are then sent to the laboratory for analysis. Initial cytoreduction is then commenced with either Hydroxycarbamide or Imatinib which are used to reduce the symptoms of CML. It is worthwhile noting that if a patient is started on Imatinib before confirmation of diagnosis from the cytogenetics laboratory it may compromise their suitability for inclusion subsequently in a clinical trial.
Once the patient's diagnosis has been confirmed (either by FISH or by RT-PCR) the patient's prognostic score may be calculated. Prognostic scores are calculated using either the Hasford scoring system which uses information such as patient's age as well as spleen size, blast count, eosinophil count, basophil count and platelet count or the Sokal scoring system which uses age, spleen size, platelets and myeloblasts. If determined to be in the chronic stage of CML the patient is then started (or continued) on Imatinib 400mg daily and he should be considered for a clinical trial. Due to his age (78 years) this patient should still be considered for inclusion in a clinical trial. There is a predilection amongst physicians not to consider older patients in trials even though the correlation between older age and poor survival prognosis is no longer supported by the data since the introduction of Imatinib.(12) The dose of 400mg is based on the theory that a lower dose may promote drug resistance and that a higher dose may be less tolerated. Indeed, evidence exists which suggest that the use of high dose Imatinib is not recommended.(44) A number of side effects have been reported with Imatinib and may be treated according to their presentation. Short term use of corticosteroids has been suggested in the treatment of rashes that may present.(45)
Following treatment with Imatinib it is recommended that the patient's response is assessed using cytogenetic analysis of the bone marrow and/or RQ-PCR analysis (real time quantitative polymerase chain reaction) of a peripheral blood sample. Thereafter, peripheral blood samples may be analysed on a 3-monthly basis using RQ-PCR to determine disease status provided a complete cytogenetic response has been achieved. Analysis of the bone marrow may be carried out after 6 months and then every 12 months though this is at the discretion of the local cancer team.(42)
Advanced Stage and Blast crisis
If the results from the patients haematological test indicated that he is in the accelerated phase of CML then the treatment strategy may change slightly. The patient should still be considered for inclusion in a clinical trial though the dose of Imatinib should be increased to 600-800mg daily (provided that the accelerated phase is de novo i.e. the patient has not advanced from the chronic phase to the accelerated phase following treatment). Similarly, if the patient's tests suggest he is in blast crisis the dose may be increased further to 800mg though it is unlikely that he would present at this stage.
Though the clinical evidence for the use of Imatinib is significant as discussed earlier specifically in relation to the IRIS trial (Imatinib versus Interferon alpha) in the IRIS trial patients younger than 18 years and older than 70 years were excluded.(30, 31) Obviously, since the patient of interest here is 78 years it is worthwhile reviewing the literature to affirm the suitability of this treatment in this case. Recently, the tolerability and efficacy of Imatinib use in elderly patients with chronic phase CML has been investigated.(46) The median age in this "ELDERGLI" study was 76.6 years and it recognised some of the difficulties outlined earlier in this report, specifically in relation to co-morbidities in an elderly population. However, the authors report that the data relating to response rates and duration of response compares well with other data in the literature.(47) Also the authors note that both haematological toxicities and the rates and types of non-haematological toxicities are of a similar scale to those described in the IRIS report. The most common of these toxicities reported included oedema, GI symptoms and musculoskeletal secondary effects. Also, whilst the authors report a higher incidence of infections, cardiovascular events and secondary neoplasms compared to those seen in other trials the overall rate is not excessive and parallels that seen in this age-group in the general population. Also noteworthy is the fact that those patients that experienced a cardiovascular event were more often within that cohort that had a prior risk factor particularly hypertension.