Elsevier

The Lancet

Volume 368, Issue 9550, 25 November–1 December 2006, Pages 1894-1907
The Lancet

Seminar
Acute myeloid leukaemia

https://doi.org/10.1016/S0140-6736(06)69780-8Get rights and content

Summary

Acute myeloid leukaemia (AML) is a heterogeneous clonal disorder of haemopoietic progenitor cells and the most common malignant myeloid disorder in adults. The median age at presentation for patients with AML is 70 years. In the past few years, research in molecular biology has been instrumental in deciphering the pathogenesis of the disease. Genetic defects are thought to be the most important factors in determining the response to chemotherapy and outcome. Whereas significant progress has been made in the treatment of younger adults, the prospects for elderly patients have remained dismal, with median survival times of only a few months. This difference is related to comorbidities associated with ageing and to disease biology. Current efforts in clinical research focus on the assessment of targeted therapies. Such new approaches will probably lead to an increase in the cure rate.

Section snippets

Epidemiology

AML is the most common myeloid leukaemia, with a prevalence of 3·8 cases per 100 000 rising to 17·9 cases per 100 000 adults aged 65 years and older.1 The median at age at presentation is about 70 years, and three men are affected for every two women.

Risk factors for acquiring AML include exposure to ionising radiation, benzene, and cytotoxic chemotherapy. People who have survived atomic bombs are at high risk of AML, and Nakanishi and colleagues2 found that abnormalities of chromosomes 5 and 7

Pathogenesis

The number of people exposed to environmental causes of AML probably far exceeds the number who develop the disease. Development of AML after exposure may reflect genetic variation in enzymes that detoxify benzene and other carcinogens, such as NAD(P)H quinone oxidoreductase 1 (NQO1).14 A single 609C→T substitution in NQO1, lowers NQO1 actvity; if two alleles are mutant, enzyme activity is absent. About 20% of northern Europeans and white Americans are heterozygous for the 609T NQO1 variant,

Immunology

The hypothesis that AML blasts are antigenically distinct from normal blasts led to attempts in the 1970s to improve immune responsiveness to AML by use of BCG scarification36 or administration of killed AML blasts.37 Although initial reports of success were difficult to reproduce, subsequent data support the hypothesis. Perhaps the best evidence comes from demonstration of a graft-versus-leukaemia effect after allogeneic stem-cell transplantation.38 In particular, infusion of T-lymphocytes

Pathophysiology

The most common cause of death in AML is bone-marrow failure. The genetic reprogramming of AML blasts renders them ineffective at generating mature red cells, neutrophils, monocytes, and platelets. AML blasts also inhibit normal blasts from differentiating into mature progeny. Inhibition does not result from “crowding out” of normal blasts because there is no correlation between degree of cytopenia and marrow blast count; rather inhibition may be mediated by various chemokines produced by AML

Diagnosis

Demonstration of the accumulation of blasts resulting from the block in differentiation characteristic of AML18, 19 is the essential requirement for diagnosis. AML has typically been categorised with the FAB system, which is based on cytomorphology and cytochemistry.54 In this system, AML is confirmed when the marrow contains more than 30% blasts. The current WHO classification system (panel), which incorporates cytogenetic data and defines four major categories of AML, has lowered the blast

General considerations

For the past 30 years, treatment of AML has generally consisted of the combination of an anthracycline, such as daunorubicin or idarubicin, and cytarabine.29, 56, 57 Therapy consists of two phases. The first attempts to produce complete remission, defined as a marrow with less than 5% blasts, a neutrophil count greater than 1000, and a platelet count greater than 100 000.58 Complete remission is the only response that leads to cure and, at the least, to an extension in survival.59 The second

Search strategy and selection criteria

As academic specialists in AML who come from both sides of the Atlantic, who represent both a cooperative group and a large single centre, and who themselves are frequent reviewers, we felt comfortable with our knowledge of the relevant literature. Thus, we used no specific search strategy but used PubMed as necessary. References were selected on the basis of their ability to support the text, their appearance in high-impact journals, and recent date of their publication (49% published

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