Synonyms: acute myelogenous leukaemia, AML

Background

Classification

The traditional French-American-British (FAB) classification has divided AML into eight subtypes designated M0 to M7. It is still widely used.

However, the more recent World Health Organization (WHO) classification sub-categorises AML with the aim of increasing prognostic utility.

Epidemiology

AML has an incidence of 3.7 per 100,000 persons and an age-dependent mortality of 2.7 to nearly 18 per 100,000 persons.³ AML can occur at any age but Its incidence increases with age and the median age of onset is 70.⁴. Its significance has grown with an aging population: of the 2,000 cases of AML diagnosed annually in the UK, 1,400 will be in the over-60s.⁵ It is the most common 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 MDSs.⁶ 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 AML.
• 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.⁷ 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.
• 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, inherited as an autosomal dominant condition.⁸ They tend to present in the sixth or seventh 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.⁹ 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 prior to developing AML but also have cytogenetic abnormalities. Alkylating agents tend to give two to five years between exposure and the development of leukaemia but, for topoisomerase II inhibitors, latency is only three to six months.

Presentation

History¹⁰

The presentation may be related to bone marrow failure (causing anaemia, neutropenia and thrombocytopenia) or due to organ infiltration.

• 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 coronary heart disease, it may present with angina or myocardial infarction.
• Although white blood cell (WBC) 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.
• Haemorrhage in the lungs, gastrointestinal tract, and the central nervous system can be life-threatening.
• Splenomegaly can cause fullness in the left upper quadrant and early satiety.
• If WBC count is extremely high (>100 x 10⁹/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 bone pain.

Examination¹⁰

• The most common sites for infiltration are the liver, spleen and gums.
• Pallor may be obvious.
• Signs of infection can be nonspecific. Fever or pneumonia may present.
• Thrombocytopenia often causes petechiae on the lower limbs. 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.¹¹
• Gingivitis is common, with swollen, bleeding gums. This may lead to initial presentation at the dentist.

Investigations¹⁰

Blood tests

• Full blood count will often show a variable degree of anaemia and thrombocytopenia. Total WBC count may be normal, high or low, and sometimes extremely high, but neutrophils are usually depleted and blast cells are seen in their place.
• Clotting screen - DIC is common, especially in M3, with prolonged prothrombin time, low levels of fibrinogen and fibrin degradation products (FDPs) present.
• Lactate dehydrogenase levels 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 to treat infection.

Specialist diagnostic tests

• Bone marrow aspiration is the diagnostic procedure. The FAB classification requires more than 30% blast cells, whilst the WHO classification requires more than 20%, to make a diagnosis of AML.
• Cytochemical stains allow classification into seven 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, which shows the t(15;17) and is treated differently. 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.¹²

Imaging

• 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.

Management

• Treatment is coordinated in specialised centres and is frequently trial-based. Different regimes tend to be used for younger and older patients. It is delivered in two phases:
  • Induction (to attain remission)
  • Post-remission consolidation (intensification)
• A number of chemotherapeutic agents are used, including daunorubicin, mitoxantrone and arabinosylcytosine.
• The use and timing of stem cell transplantation (SCT) is controversial. Both allogenic (ideally with a fully HLA-matched sibling bone marrow donor; otherwise, using a matched unrelated donor or cord blood) and autologous transplantation have been used. A recent meta-analysis suggests that allogeneic SCT has significant relapse-free and overall survival benefit for intermediate- and high-risk AML but not for low-risk AML in first complete remission.¹³ Transplantation is usually reserved for relapse in those with low-risk AML.
• APL subtype is treated rather differently to the rest of AML. The use of all-trans retinoic acid (ATRA) and, more recently, arsenic trioxide (ATO), usually in combination with other chemotherapy agents, has transformed the treatment of the disease. Supportive treatment, in particular the management of DIC commonly associated with APL and the avoidance of invasive procedures wherever possible, are important.¹⁴

See references^15,16,17 for detailed discussion of current AML treatments.

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.

Prognosis

Prognosis is dependent upon age, cell type and the burden of the disease.^15,16,18 About 13% go on to develop secondary malignancies.

Children

• 75-90% achieve remission following induction and two-year survival rates of between 50-70%.
• 50% have an event-free five-year survival rate.
• BMT may be offered where there is a suitable donor and 60-70% will have long-term remission or cure.
• AML associated with Down's syndrome has a good prognosis.

Adults

• Overall, 60% to 70% achieve remission (worse as age increases >60). Remission periods tend to be shorter than in children.
• Cytogenetic analysis informs prognosis: patients with t(8;21), t(15;17), or inversion 16 have the best prognosis, with long-term survival rates of approximately 65% whilst those with normal cytogenetic findings have an intermediate prognosis and have a long-term survival rate of approximately 25%.
• Remission is less likely in AML following myelodysplasia or previous cytotoxic chemotherapy.
• Older patients tend to have a worse prognosis - in the over-60s, remission rates are about 60%, but remissions are usually transient, with median survival being 5-10 months, and probability of remaining in remission five years after diagnosis being less than 10% (compared with 30-35% of adults <60 years old). This is in part due to a higher incidence of less favourable cytogenic markers in AML in this age group, increased resistance to chemotherapy, poorer initial performance status and other medical comorbidities limiting the use of intensive chemotherapy.⁵
• In the APL subgroup, remission is achieved in 70-90%, although the risk of haemorrhagic complications is higher during induction.

Understanding of the biology and genetics can lead to improved treatment and survival.¹⁹

Document references

1. Vardiman JW, Harris NL, Brunning RD; The World Health Organization (WHO) classification of the myeloid neoplasms. Blood. 2002 Oct 1;100(7):2292-302. [abstract]
2. Vardiman JW, Thiele J, Arber DA, et al; The 2008 revision of the World Health Organization (WHO) classification of Blood. 2009 Jul 30;114(5):937-51. Epub 2009 Apr 8. [abstract]
3. Deschler B, Lubbert M; Acute myeloid leukemia: epidemiology and etiology. Cancer. 2006 Nov 1;107(9):2099-107. [abstract]
4. Estey E, Dohner H; Acute myeloid leukaemia. Lancet. 2006 Nov 25;368(9550):1894-907. [abstract]
5. Milligan DW, Grimwade D, Cullis JO, et al; Guidelines on the management of acute myeloid leukaemia in adults. Br J Haematol. 2006 Nov;135(4):450-74. Epub 2006 Oct 10.
6. Catenacci DV, Schiller GJ; Myelodysplasic syndromes: a comprehensive review. Blood Rev. 2005 Nov;19(6):301-19. [abstract]
7. Advisory Group on Ionising Radiation (AGIR), Health Protection Agency; Access to reports
8. OMIM 601626; Leukaemia, acute myeloid
9. Hijiya N, Ness KK, Ribeiro RC, et al; Acute leukemia as a secondary malignancy in children and adolescents: current Cancer. 2009 Jan 1;115(1):23-35. [abstract]
10. Seiter K Acute Myelogenous Leukemia, eMedicine, Nov 2009
11. Leukaemia, Specific Skin Lesions, DermIS (Dermatology Information System)
12. Haferlach T, Kohlmann A, Schnittger S, et al; Global approach to the diagnosis of leukemia using gene expression profiling. Blood. 2005 Aug 15;106(4):1189-98. Epub 2005 May 5. [abstract]
13. Koreth J, Schlenk R, Kopecky KJ, et al; Allogeneic stem cell transplantation for acute myeloid leukemia in first complete JAMA. 2009 Jun 10;301(22):2349-61. [abstract]
14. Sanz MA, Grimwade D, Tallman MS, et al; Guidelines on the management of acute promyelocytic leukemia: Recommendations from an expert panel on behalf of the European LeukemiaNet. Blood. 2008 Sep 23. [abstract]
15. Adult AML @ cancer.gov
16. Child AML @ cancer.gov
17. Dohner H, Estey EH, Amadori S, et al; Diagnosis and management of acute myeloid leukemia in adults: recommendations Blood. 2009 Oct 30. [abstract]
18. Kebriaei P, Kline J, Stock W, et al; Impact of disease burden at time of allogeneic stem cell transplantation in adults with acute myeloid leukemia and myelodysplastic syndromes. Bone Marrow Transplant. 2005 May;35(10):965-70. [abstract]
19. McKenzie SB; Advances in understanding the biology and genetics of acute myelocytic leukemia. Clin Lab Sci. 2005 Winter;18(1):28-37. [abstract]

Internet and further reading

• Macmillan Cancer Support (Cancerbackup); Acute myeloid leukaemia. Information for patients.

Acknowledgements