Acute myeloid leukaemia

Synonyms: acute myelogenous leukaemia, acute myeloblastic leukaemia

See also the separate Childhood Leukaemias article.

What is acute myeloid leukaemia?

Acute myeloid leukaemia (AML) is a malignant disease of the bone marrow in which precursors of blood cells are arrested in an early stage of development. Most acute myeloid leukaemia subtypes show more than 30% blasts of a myeloid lineage in the blood, bone marrow, or both. There is maturational arrest of bone marrow cells in the first stages of development. The mechanism involves the activation of abnormal genes through chromosomal translocations and other genetic abnormalities. This reduces the number of normal blood cells. In addition, failure of apoptosis leads to accumulation in various organs, especially the liver and the spleen.

Advances in genomics technologies have identified acute myeloid leukaemia as a genetically heterogeneous disease; many patients can now be categorised into clinicopathological subgroups based on their underlying molecular genetic defects.¹

Classification

Although historically classified by the largely descriptive French-American-British (FAB) criteria, myeloid neoplasms including AMLs are now classified according to the World Health Organization (WHO) classification from 2001, last revised in 2016.^{2 3}

WHO classification of myeloid neoplasms and acute leukaemia

The French-American-British (FAB) classification system divides acute myeloid leukaemia into eight subtypes:

• M0: acute myeloblastic leukaemia, minimally differentiated.

• M1: acute myeloblastic leukaemia, without maturation.

• M2: acute myeloblastic leukaemia, with granulocytic maturation.

• M3: promyelocytic, or acute promyelocytic leukaemia.

• M4: acute myelomonocytic leukaemia.

• M4eo: myelomonocytic together with bone marrow eosinophilia.

• M5a: acute monoblastic leukaemia.

• M5b: acute monocytic leukaemia.

• M6a: acute erythroid leukaemias, including erythroleukaemia.

• M6b: pure erythroid leukaemia.

• M7: acute megakaryoblastic leukaemia.

Acute myeloid leukaemia epidemiology

• AML is the most common acute leukaemia in adults. The incidence of the AMLs in the UK is 4.05/100,000. This is the highest in Europe.⁴

• Acute myeloid leukaemia can occur at any age but the incidence increases with age and the median age of onset is 67.⁵

• Its significance has grown with an ageing population.42% of all new acute myeloid leukaemia cases in the UK are diagnosed in people aged 75 and over.⁶

Risk factors for acute myeloid leukaemia

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

• Antecedent haematological disorders include MDSs.⁷ Other conditions that predispose patients to AML include:
  

  • Aplastic anaemia.

  • Myelofibrosis.

  • Paroxysmal nocturnal haemoglobinuria.

  • Polycythaemia 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 lymphocytic leukaemia but other studies linking leukaemia with radiation give conflicting results and sometimes methodology is poor. Survivors of the Japanese atomic bombs were more likely to develop leukaemia, as were scientists who were exposed to excessive radiation.⁸ Those with ankylosing spondylitis who have received radiotherapy are also more likely to develop leukaemia.

• 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 acute myeloid leukaemia seems to have a genetic component, inherited as an autosomal dominant condition.⁹ 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.¹⁰ 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.

Acute myeloid leukaemia symptoms

History

Symptoms of acute myeloid leukaemia may be related to bone marrow failure (causing anaemia, neutropenia and thrombocytopenia) or due to organ infiltration.¹¹

• 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, the 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 leukostasis with respiratory distress and altered mental status. Leukostasis is a medical emergency that requires immediate intervention.

• There can also be bone pain.

Examination

• 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.¹²

• Gingivitis is common, with swollen, bleeding gums. This may lead to initial presentation at the dentist.

Investigations

The diagnosis of acute myeloid leukaemia requires the examination of peripheral blood and bone marrow specimens, using morphology, cytochemistry, immunophenotyping, cytogenetics and molecular genetics.

Blood tests

• FBC 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 WHO classification requires more than 20% blasts in the peripheral blood, to make a diagnosis of AML.¹³

• Patients potentially suitable for allogeneic stem cell transplantation (alloSCT) should be HLA typed at diagnosis, as should their available first-degree family members. In high-risk disease (eg, poor karyotype), early matched unrelated donor allogeneic transplantation must be considered, and a donor search should be performed as early as possible.

• 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.

• Additional diagnostics include flow cytometry and fluorescence in situ hybridisation (FISH).³

• 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.

Acute myeloid leukaemia treatment and management^{3 13 14}

The usually accepted criteria of response in AMLs are blast clearance in the bone marrow to <5% of all nucleated cells, morphologically normal haematopoiesis and return of peripheral blood cell counts to normal levels. For detailed discussion of current acute myeloid leukemia treatments, see references .

• Treatment is co-ordinated 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). The standard combination for induction for is cytarabine, daunorubicin and gemtuzumab ozogamicin.

  • Patients with refractory disease have shown higher complete remission rates and similar overall survival (OS) by using higher doses of cytarabine or by using a combination of fludarabine, cytarabine, and amsacrine.

• Post-remission consolidation (intensification): patients in complete remission should undergo consolidation treatment with chemotherapy, stem cell replacement therapy (autologous, if available) or a combination of both.

• Stem cell transplantation (SCT):One study found that in subgroups of patients with negative measurable residual disease (MRD), after one or 2 course of chemotherapy, comparable OS was observed among the chemotherapy, autologous stem-cell transplant (auto-SCT), and allogeneic stem-cell transplant (allo-STC) groups. However, chemotherapy and auto-SCT had better graft-versus-host-disease-free, relapse-free survival than allo-SCT in both subgroups. For patients with negative MRD after three courses of chemotherapy, allo-SCT had better disease-free-survival than chemotherapy.

• 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.¹⁵

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. A meta-analysis found that, except for APL patients, early mortality was not reduced by leukophoresis which can thus not be generally recommended. If leukophoresis is applied, it should be accompanied by hydroxycarbamide, cytarabine or daunorubicin.¹⁷

Prognosis^{3 13}

• The prognosis and long-term survival rates of patients <65 years have improved over time, largely based upon improved supportive care and increased use of alloHCT). Despite this progress, age-standardised relative five-year survival for adult patients diagnosed between the years 2000 and 2007 was as low as 17%, mainly attributable to the minimal progress attained in AML patients >65 years.

• A study in 2020 reported that OS rates of children with AML had improved over the previous three decades, with the five-year survival rate being 65% to 75%.¹⁸

• By assessing prognostic factors, clinicians can decide whether a standard therapy or more intense therapy would be helpful in maintaining complete remission and OS rates. The prognostic factors are chromosomal abnormalities (favourable abnormalities include t(8;21), t(15;17), inversion of chromosome 16), genetic mutations (NPM1 gene has a favorable prognosis, and FLT3 gene has unfavourable prognosis). Worse outcomes have been noted with older age, white blood cell count greater than 100,000 at the time of diagnosis, s-AML, t-AML, and the presence of leukaemic cells in the central nervous system.

Post-remission consolidation (intensification).