Acute myeloid leukaemia (AML)

• Incidence
• Predisposing Factors
• Macroscopic Features
• Microscopic Features
• Natural History
• Clinical History
• Clinical Examination
• General Investigation
• Specific Investigations
• Prognosis
• Treatment Overview
• References
• Information on Other Types of Leukaemia
• Drugs/Products Associated with Acute Myeloid Leukaemia

Incidence

Acute myeloid leukaemia (AML) is uncommon with an average incidence of 2.3 per 100,000 people per year. It can occur at any age. It is usually (80%) in adults with the majority of cases occurring in people over the age of 60. However, it can occur in children, especially if there is a predisposition. There has been no observed difference in incidence between sexes.

Predisposing Factors

The cause of most cases of acute myeloid leukaemia is unknown. It often occurs on the background of another haematological (blood or bone marrow) condition, such as:

• Myelodysplastic syndromes;
• Chronic myeloid leukaemia;
• Myelofibrosis;
• Polycythaemia rubra vera;
• Essential thrombocythaemia;
• Severe aplastic anaemia.

It also occurs in individuals who have been exposed to:

• Previous radiotherapy or nuclear irradiation;
• Previous chemotherapy with alkylating agents or certain other chemotherapy agents and certain organic chemicals, such as Benzene and Toluene.

Certain individuals may inherit a predisposition to acute myeloid leukaemia, such as those with Fanconi’s anaemia or Down’s syndrome.

Macroscopic Features

In pathological specimens, tumours of the bone marrow spread to fill the marrow space within the bones.

Microscopic Features

Under the microscope, the marrow can be seen to be filled with large quantities of immature white cells (blasts). The blasts stain positive with Sudan black or myeloperoxidase.
The image below is that of a microscopic view of acute myeloid leukaemia. Three large monocytoid ‘eosinobasophils’’ with large purple/black granules and variable numbers of small eosinophil granules.

Natural History

Cancer cells spread from their origin – which is the blood-forming tissue of the bone marrow – to other parts of the body where blood travels.

Clinical History

Symptoms for this illness are those caused by lack of one or more of the 3 main components of the blood i.e. red blood cells, white blood cells or platelets. Nearly half of patients have had symptoms for 3 months or more prior to diagnosis.

• Lack of red cells causes anaemia, which in turn causes fatigue, weakness, shortness of breath, and swelling of the ankles.
• Lack of mature, functional white cells results in infection, e.g. of the mouth or skin. Nonspecific fever is present in about 10% of patients prior to diagnosis.
• Lack of platelets causes the tendency to bleed. Nose bleeds, bleeding from the gums or easy bruising may be seen.
• Some people present with bone pain, lymphadenopathy, cough, headache, sweating.
• Rarely, patients may even present with a mass lesion – e.g. soft tissues, breast, ovary, bone, etc – so-called granulocytic sarcoma.

Clinical Examination

Fever, splenomegaly (enlarged spleen), hepatomegaly (enlarged liver), lymphadenopathy (enlarged and tender lymph nodes), sternal tenderness and evidence of infection or haemorrhage may be found at diagnosis.

General Investigation

General investigations (FBP) may show anaemia (often severe). The mean white cell count (WCC) is 15,000/uL though 25-40% have low WCC (100,000). Leukaemic blasts are found in >95% patients in peripheral blood. Platelet counts are usually low.

Specific Investigations

More specific investigations may show leukaemic infiltrates on biopsy of skin lesions. Bone marrow aspirations are diagnostic. Apart from the microscopic changes described above, special immuno-chemistry testing may allow sub-classification of the type of leukaemia.

Prognosis

The most important prognostic factor is the attainment of complete remission (CR). This is defined as remission of the leukaemia (evidenced by disappearance of the blast cells) and attainment of near normal platelet and white cell levels. Older age at diagnosis (>60) and the presence of medical problems other than the AML also influence prognosis. Patients with certain molecular abnormalities – e.g. t(8;21), t(15;17), inv (16) have really good prognoses. The duration of the CR and the rapidity with which it is attained are other important factors.
Patients are likely to have better prognoses if the blast cells disappear early with treatment, and if there is a more prolonged remission. Around 65-75% of patients achieve CR with that chemotherapeutic regime – the others don’t because of a drug resistant leukaemia or fatal complications of bone marrow toxicity with the drugs. Infectious complications are the main cause of death.
Patients may subsequently relapse but approximately 25% of patients remain disease free at 5 years. Untreated, the average survival of someone with acute myeloid leukaemia was 6-8 weeks.

Treatment Overview

Treatment against the disease

The aim of treatment is to destroy the leukaemic cells as completely as possible and achieve complete remission. Before treatment, replacement of various blood components (e.g. platelets, red cells) may be required to prevent bleeding or severe anaemia.
Following induction of chemotherapy, it is usual for patients to receive consolidative treatment sometimes followed by maintenance therapy. The usual induction therapy involves cytarabine and an anthracyclene (e.g. daunorubicin). The addition of etoposide or other agents does not increase the CR rate but may increase CR duration.
Standard post-remission therapy includes either high dose chemotherapy or stem cell transplantation – patients receive their own stem cells collected while in remission (autologous) or another person’s stem cells (allogenic) – the latter has more complications but a greater success rate.
In the occurrence of a relapse – certain patients, notably younger patients, may benefit from stem cell transplantation (from a suitable donor if one is found). This rescues approximately 20% of relapsed patients with AML.

Monitoring

Improvement in symptoms is an important measurement. Specific monitoring includes monitoring the level of blast cells in the peripheral blood. An accurate picture of what is happening in the bone marrow can be achieved by a bone marrow aspiration.

Treatment of the symptoms

The symptoms that may require attention are infection, bleeding and anaemia. Anaemia may be treated with blood transfusions. Patients may also require platelet transfusions. Bacterial infections due to low neutrophil counts usually require urgent treatment with intravenous antibiotics. Care should also be taken to treat more unusual infections such as candida (thrush) in the mouth. Particularly during chemotherapy, the destruction of the leukaemic cells can produce large amounts of uric acid; therefore, prophylactic treatment with allopurinol is mandatory.

Regimens Used in the Treatment of This Disease

• Big ICE (Idarubicin + high dose Cytosine arabinoside + Etoposide);
• Little ICE.

Treatments Used in This Disease

• Bone Marrow Transplant.

References

1. Braunwald E, Fauci AS, Kasper DL, et al. Harrison’s Principles of Internal Medicine (15th edition). New York: McGraw-Hill Publishing; 2001. [Book]
2. Cotran RS, Kumar V, Collins T, Robbins SL. Robbins Pathologic Basis of Disease (6th edition). Philadelphia: WB Saunders Company; 1999. [Book]
3. Kumar P, Clark M (eds). Clinical Medicine (4th edition). Edinburgh: WB Saunders Company; 1998. [Book]
4. Canadian Cancer Society [online]. Disease progression of acute myelogenous leukaemia [cited 20 September 2018]. Available from: URL link

Information on Other Types of  Leukaemia

• Chronic Myeloid Leukaemia;
• Promyelocytic leukaemia;
• Multiple myeloma;
• Chronic lymphocytic leukaemia;
• Myelodysplastic syndrome;
• Acute lymphoblastic leukaemia.

Drugs/Products Used in the Treatment of This Disease

• Adriamycin Solution for Injection (Doxorubicin hydrochloride)
• Cytarabine (DBL) (Cytarabine)
• Daunorubicin Injection (Calcipotriol)
• Etoposide Ebewe (Etoposide injection)
• Glivec (Imatinib mesylate)
• Ledertrexate (Methotrexate)
• Zavedos (Idarubicin hydrochloride)