Introduction & Demographics
• Acute myeloid leukaemia (AML) represents a heterogeneous group of disorders characterised by unregulated proliferation of immature myeloid precursors with arrested differentiation, which replace the normal bone marrow function.
Consequently most patients will present with the signs of bone marrow failure and a leucocytosis. Older patients often present with pancytopenia which may also suggest the presence of a preceding myelodysplastic syndrome. Bone pain is also common at presentation.
• AML is the commonest acute leukaemia in adults and becomes commoner with increasing age. Indeed, over half of patients with AML are already over 65 years.
Graph from Cancer Research UK web site (2013)
• The rising incidence of AML presents unique challenges in treating an ageing population and, whereas much progress has been made in treating younger adults with intensive chemotherapy over the last 30 years, the prognosis for AML in the older patients remains poor.
Fewer older patients achieve a complete remission with intensive chemotherapy compared to younger patients, and there is a higher relapse risk. This is partly explained by the more frequent occurrence of higher risk cytogenetic abnormalities and higher expression of multidrug resistance proteins and the FLT-3 internal tandem duplication in older patients. Around 10-20% of AML in older patients is secondary to some previous haematology disorder or to previous chemotherapy, particularly alkylating agents or anthracyclines for breast disease.
• The UK-MRC-AML11 study showed a complete remission (CR) rate of 55% overall, but only 25% in patients with adverse cytogenetics, when treated with standard induction schedules. This translates into an expected three survival of only 10% for patients aged 65-70 years and less than 5% for over 70 years.
• The patient presenting with AML will need a thorough assessment of the current clinical condition, with particular attention in the older patient to any comorbidity. The patient should be stabilised with red cell and platelet transfusion and other blood product support, if indicated, and prophylactic or therapeutic antibiotics. Consideration should be given to the baseline renal function and the threat of developing tumour lysis syndrome (TLS). This is not as common in AML as in lymphoid malignancies, but can still arise spontaneously or after chemotherapy has started and the patient should be adequately hydrated. Rasburicase may be needed for patients considered at high risk for TLS.
• Once the immediate risk to the patient is stabilised, a decision is needed as to the best course of treatment. As the patient ages, they become less tolerant of intensive chemotherapy and response rates fall. It remains unclear as to the relative balancing point between risk and benefit for many of those patients. The UK AML14 study aimed to study the differences between an intensive and non-intensive approach in a randomised fashion. However, it transpired that only *8* patients of **** in the study were actually randomised. It seems that the consulting physician, usually with some astute nursing observations, make decisions of the appropriateness of intensive chemo for an individual patient.
Various comorbidity scores have been developed to study this further and it is clear from this work that frailty, or perceived frailty, plays a large part in the doctor's decision. Equally important is a consideration of the patient's home and social circumstances and their own personal preferences. It is, therefore, crucial to give a full explanation of the burdens that intensive chemotherapy places on the patient. Some will choose a less aggressive approach.
• It is of critical importance to ensure all patients with compromised blood counts are adequately transfused with red cells and platelets. The threshold for red transfusion will vary among patients and it is the author's view that the haemoglobin should be supported to a level that allows the patient maximal function particularly if supportive care is the only treatment being offered. Similarly, platelet transfusions are often given at a threshold of below 10-20x109/L although this will vary if there is a planned invasive procedure, a febrile illness or evidence of bleeding or wet purpura. Prophylactic antibiotics and antifungals should be given as per local protocols and micro-organism sensitivity. Oral hygiene is of equal importance.
Treatment Options & Expected Outcomes
• As already discussed, the decision to treat with an intensive or a non-intensive strategy is not a simple one. There will be personal patient preference to consider which may override the scientific background. It is crucial that patients and their families have the opportunity to discuss the treatment options in an open and supportive manner, including a discussion of any available trial options.
• In patients without a significant comorbidity, intensive chemotherapy will result in CR in 50-60% of patients. There remains a high induction death rate of around 10%, which some patients will feel is significant. The presence of adverse cytogenetics significantly impacts on CR rates. The three year survival rates given in BOX X suggest that nearly all patients will inevitably relapse and so significant work remains to be done in the post-induction phase. The AML11 trial examined the role of additional courses of consolidation and showed no survival difference between a total of three cycles of chemotherapy and six cycles. Similarly, the Dutch HOVON group are examining the benefit of three cycles of chemotherapy compared to only two cycles, with no apparent difference on overall survival. Equally, there is no one single consolidation chemotherapy that is significantly superior to another. An attenuated high dose cytarabine arabinoside (araC), up to 1g/m2 for 6 doses (twice daily on days 1, 3 and 5) is an acceptable regimen, with due attention to renal and cerebellum toxicities.
• Nonetheless, most patients will relapse and bone marrow transplantation using a reduced intensity conditioning is important in reducing the relapse rate. This should be undertaken within a clinical trial where possible.
• The Dutch HOVON group has recently published results on increasing the dose of daunorubicin from 45mg/m2 to 90mg/m2. With 400 patents in each arm, the study showed an improved remission rate (64% v 54%) in favour of the higher dose with a trend to improved event-free survival and overall survival, without reaching statistical significance. The AML17 trial is examining this higher dose of anthracycline, admittedly in younger adults under 60 years.
Low Dose Cytarabine (LDAC)
• The results of the UK MRC-AML14 clearly showed a median survival advantage for older patients treated with LDAC (20mg bd subcutaneously for 10 days, repeated every 28 days) compared to patients receiving the standard at the time of hydroxycarbamide. Consequently, LDAC has become the standard non-intensive schedule against which others are to be judged. The AML16 and AML18 Pilot studies have already compared combinations of AraC with farnesyltransferase inhibitors or other drugs without improving on the 18% CR rate seen in AML14 or in overall survival. Similarly, other single agent options such as elacytarabine also failed to show an advantage over LDAC.
• It is worth observing that, although non-intensive, LDAC can induce quite marked cytopenias before counts improve and adequate antibiotic and blood product support is required.
• Azacitidine is a hypomethylating agent that has recently been approved by the National Institute for Health and Care Excellence (NICE: www.nice.org.uk) for treatment of AML and high risk MDS with ≤30% blasts. It is a therapeutic option in older people with AML although data in more proliferative AML with high blast counts is limited. The AML18 Pilot study examined the impact of azacitidine in AML compared to LDAC. If used, it must be remembered that this is a more intensive therapy than araC (which can be given in the patent's home) since it requires attendance at the Haematology Day Centre for 7 days each cycle. It is reasonable to perform a bone marrow after 2 cycles to ensure there is no disease progression, and it can take 6 cycles of therapy before attaining a response. It is also a financial challenge.
Treating AML in the older population remains a significant challenge and will become an increasingly common one over the next several years as the population ages. The fundamental question to answer is whether the patient is fit enough to tolerate the rigours of intensive chemotherapy, with a reduced-intensity transplant likely to present the best potential for cure, but at the cost of significant morbidity and mortality. Non-intensive schedules are preferred by most patients over 70 years and low-dose araC remains the standard of care if this approach is chosen.