Acute Myeloid Leukaemia (AML)

Acute Myelogenous Leukaemia, AML

In the UK the rate is 1.7, for males and 1.3 for females per 100,000 population per year. It can affect all age groups from the 1st birthday. The incidence increases with age up to the 6th decade and it is the commonest acute leukaemia in adults.

Risk factors

A number of predisposing factors have been postulated but most cases arise without apparent cause.

• Antecedent haematological disorders include myelodysplastic syndromes.¹ Other conditions that predispose patients to AML include:
  • Aplastic anaemia
  • Myelofibrosis
  • Paroxysmal nocturnal haemoglobinuria
  • Polycythaemia rubra vera
• Most patients with chronic myeloid leukaemia, a myeloproliferative disorder, eventually develop a blast phase indistinguishable from acute myeloid leukaemia.
• Radiation is certainly a risk factor for chronic lymphatic leukaemia but other studies linking leukaemia with radiation give conflicting results and sometimes methodology is poor.² Survivors of the Japanese atomic bombs were more likely to develop leukaemia as were scientists who were exposed to excessive radiation and those with ankylosing spondylitis who have received radiotherapy. A study of over 20,000 service personnel who were exposed to radiation in British nuclear testing in the Pacific between 1952 and 1967 were compared to a similar number of controls and by 1998 no excess mortality was seen, even for haematological malignancies.³
• Diagnostic criteria may also be involved as the decline in AML and CML have been mirrored by an increase in pre-leukaemic states such as myelodysplasia.
• Some congenital disorders predispose to the disease, usually in childhood but occasionally in early adulthood. These include:
  • Bloom's syndrome
  • Down's syndrome
  • Congenital neutropenia
  • Fanconi's anaemia
  • Neurofibromatosis
• Rare families have been described where AML seems to have a genetic component as an autosomal dominant.⁴ They tend to present in the 6th or 7th decade.
• Exposure to benzene can produce aplastic anaemia and pancytopenia. This can progress to AML, usually of the M6 variant.
• Patients who have survived cancer chemotherapy are at risk. Those who have had alkylating agents, with or without radiation, often have a myelodysplastic condition that can progress to AML with specific cytogenetic abnormalities. Patients who have received topoisomerase-II inhibitors do not have a myelodysplastic phase before AML but they also have cytogenetic abnormalities.
• Alkylating agents tend to give 2 to 5 years between exposure and the development of leukaemia but for topoisomerase-II inhibitors the latent period is only 3 to 6 months.

The presentation may be related to failure of development of cells in the marrow causing anaemia, neutropenia and thrombocytopenia or it can be due to infiltration of organs.

• Children or young adults may present with acute symptoms over a few days to a few weeks.
• Older people may present with fatigue over weeks or months.
• Dizziness and shortness of breath on exertion may present in older people and if there is CHD it may present with angina or myocardial infarction.
• Although white cell counts are very high, neutrophils are low and fever is a common presenting sign. There may be failure to respond to antibiotics.
• Bleeding may be caused by thrombocytopenia, coagulopathy resulting from disseminated intravascular coagulation (DIC), or both. Bleeding gums and multiple ecchymoses can occur.
• Haemorrhage from lungs, gastrointestinal tract, and the central nervous system can threaten life.
• Splenomegaly can cause fullness in the left upper quadrant and early satiety.
• If WBC is extremely high (>100,000 cells/ L) it can cause leucostasis with respiratory distress and altered mental status. Leucostasis is a medical emergency that requires immediate intervention.
• There can also be pain in the bone marrow.

• The commonest sites for infiltration are liver, spleen and gums
• Pallor may be obvious
• Signs of infection can be non-specific. Fever or pneumonia may present
• Thrombocytopenia often causes petechiae on the lower limbs. Disseminated intravascular coagulation (DIC) may aggravate the situation and cause larger lesions. Petechiae are small dots, purpura is larger and ecchymoses are larger bruises
• Hepatomegaly and splenomegaly may be found. Lymphadenopathy is less common.
• Leukaemia cutis is an uncommon condition due to infiltration of the skin
• Gingivitis is common with swollen, bleeding gums.

• FBC will often show a variable degree of anaemia and thrombocytopenia. Total WCC may be normal, high or low, sometimes extremely high, but neutrophils are usually depleted and blast cells are seen.
• Clotting Screen. DIC is common, especially in M3. Prothrombin time is prolonged, fibrinogen levels are low and fibrin degradation products (FDP) are present.
• Lactate dehydrogenase levels (LDL) are usually raised and rapid cell turnover may raise uric acid.
• Liver and renal function must be checked before initiating chemotherapy.
• The variants with acute monocytic leukaemia (M5) and acute myelomonocytic leukaemia (M4) can reduce potassium, calcium and magnesium
• If fever is present appropriate steps should be taken to identify and treat infection.
• Bone marrow aspiration is the diagnostic procedure. Over 30% blast cells is an important finding. Cytochemical stains allow classification into 7 of the subtypes M1 to M7. These stains may not be useful for M0 (acute undifferentiated leukaemia) or M7 (acute megakaryocytic leukaemia) and so flow cytometry is used. Cytogenetic studies are also performed to provide important information about prognosis. They are also useful to confirm APL (Acute promyelocytic leukaemia), which shows the t(15;17) and is treated differently.
• CXR may show pneumonia or signs of heart disease.
• Multiple gated acquisition (MUGA) scan is required because many chemotherapeutic agents used in treatment are cardiotoxic. ECG is also necessary.
• Chromosomal analyses are performed on children with AML to identify subgroups for prognostic assessment and to tailor therapy. Techniques such as gene expression profiling are increasingly used.⁵
• Patients who present with the CD34 antigen may need a different regimen to treat their disease.⁶

Treatment is coordinated in specialised centres and is in two parts:

• Induction (to attain remission)
• Post-remission consolidation (intensification)

The latter involves a number of courses of intensive chemotherapy and/or bone marrow transplantation (BMT). A number of chemotherapeutic agents are used including daunorubicin, mitoxantrone and arabinosylcytosine. Both allogenic and autologous bone marrow transplantation has been used. Different regimes tend to be used for younger and older patients. See references^7,8 for detailed discussion

Other aspects of care include blood product replacement, antibiotics for infection and allopurinol to reduce uric acid levels. Reverse barrier nursing may be necessary in the neutropenic phases of treatment. To reduce the risk of infection the diet does not allow uncooked vegetables and meat must be well cooked.

Prognosis is dependent upon age, cell type and the burden of the disease.^7,8,9 About 13% go on to develop secondary malignancies.

Children

• 75% - 90% achieve remission following induction although inducing profound bone marrow aplasia is usually necessary
• 50% have an event-free 5-year survival
• Once in remission, BMT may be offered where there is a suitable donor and 60-70% will have long term remission or cure
• WBC >100,000/ml at diagnosis has poorer prognosis
• AML and Down's syndrome - most can be cured
• APL subgroup - death from bleeding during induction more common
• Most achieve remission with a 2 years survival of between 50-70%

Adults

• 60% to 70% achieve remission (worse as age increases >60)
• Older patients may not be able to tolerate such toxic therapy
• Older patients do less well than younger ones but the median age of presentation is 70 years.¹⁰
• Cytogenetic analysis gives key to prognosis
• Remission less likely in AML following myelodysplasia or previous cytotoxic chemotherapy
• Consider allogenic BMT if available
• Remission periods shorter than in children
• 15%-25% will survive 3 years and may be cured
• APL (M3 subtype) - remission in 70-90%
• Maintenance therapy may be appropriate to prolong remission

Understanding of the biology and genetics can lead to improved treatment and survival.¹¹