Acute myeloid leukaemia in adults

doi:10.1016/S0140-6736(12)61727-9

The Lancet

Volume 381, Issue 9865, 9–15 February 2013, Pages 484-495

https://doi.org/10.1016/S0140-6736(12)61727-9 Get rights and content

Summary

The outlook for patients with acute myeloid leukaemia has improved in the past 30 years. Unlike other cancers, much of this progress is attributable to refinement of supportive treatment, rather than the introduction of new drugs. New antibacterial and antifungal agents, antiemetics, and improved transfusion support have decreased the rate of early death, and morbidity and mortality from allogeneic stem cell transplantation has been substantially reduced. However, more than half of young adult patients and about 90% of older patients still die from their disease. Refractoriness to initial induction treatment and, more frequently, relapse after complete remission, are still the main obstacles to cure. Accordingly, new treatment approaches with mechanisms of action different from those of conventional chemotherapy are needed. Our knowledge of the various chromosomal and molecular abnormalities implicated in the pathogenesis of the many subtypes of the disease has greatly expanded; as a result, clinical research is moving towards the investigation of new non-cytotoxic agents in combination with chemotherapy. The goal is to target the molecular abnormalities identified at diagnosis; however, several aberrations can coexist in subclones of acute myeloid leukaemia, making the disease less likely to be inhibited by a single agent.

Introduction

Acute myeloid leukaemia is a clonal disorder of haemopoietic stem cells characterised by the inhibition of differentiation and the subsequent accumulation of cells at various stages of incomplete maturation, and by reduced production of healthy haemopoietic elements. Cytopenias cause clinical manifestations, with symptoms of anaemia (eg, fatigue and dyspnoea), neutropenia (infections), and thrombocytopenia (haemorrhage), which are usually present at the time of diagnosis and are dominant throughout treatment. How growing leukaemic clones suppress normal polyclonal residual haemopoiesis is poorly understood, but this suppression is partly protective against the cytotoxic effects of chemotherapy because normal blood counts are regenerated when the leukaemia clone is reduced.

Section snippets

Clinical and genetic features

Acute myeloid leukaemia can occur in people of all ages, but is most common in older patients (older than 65 years). It can be caused by exposure to ionising radiation and drugs that damage DNA; a clear history of contact with known carcinogens in patients is unusual. Two types of chemotherapy-related acute myeloid leukaemia exist. Drugs that target topoisomerase II, such as anthracyclines and epipodophyllotoxins, can cause patients to develop rapidly proliferative disease with a monocytic

Cytogenetics and molecular genetics

The importance of cytogenetic findings related to initial response and long-term cure rate was identified in the 1980s and supported by large collaborative groups (table 1). Patients with core binding factor acute myeloid leukaemia, including t(8;21) and abn16q22, have cure rates of over 60% with high-dose cytarabine-based chemotherapy alone,12, 13 whereas those with other balanced translocations such as t(6;9)¹⁴ and abnormalities of chromosome 3q26, have very poor outcomes after chemotherapy.¹⁵

Treatment

Advanced age and the presence of comorbidities, which are often summarised as performance status, affect a patient's ability to survive the side-effects of intensive chemotherapy.⁵⁹ Several existing comorbidity indices are able to reliably quantify the presence and effect of other medical and psychosocial factors, helping to guide treatment decisions and comparisons across clinical trials that focus on high-risk older patients.60, 61 Major advances in supportive care have taken place, including

Acute promyelocytic leukaemia

Acute promyelocytic leukaemia is a distinct subtype of AML with a unique morphology characterised by hypergranulated promyelocytes and the presence of a t(15;17) translocation that results in an abnormal fusion protein termed PML/RARα. It is clinically characterised by a severe haemorrhagic diathesis. It is sensitive to anthracyclines, and studies show that a combination of anthracyclines and all-trans retinoic acid is the best induction approach, achieving CR rates of over 90% and, with

Acute myeloid leukaemia in older patients

More than half of patients with AML are older than 65 years and about a third are older than 75 years. Generally, older patients with AML have a very poor outcome—conventional induction treatment results in CR rates of 45–55%, and less than 10% of intensively treated patients survive for 5 years, with no improvement in these results in the decades.111, 112 Of note, these results are from multicentre trials based on aggressive treatment aimed at CR achievement, and do not take into account the

Future considerations

Treatment outcome of adult acute myeloid leukaemia, particularly in older patients, has not improved in the past 20 years despite a great improvement in our understanding of many of the biological aspects of this complex disease. To translate this knowledge into new treatments is difficult because the many mechanisms of resistance inherent in the stem cells responsible for AML cannot be targeted with available drugs. Indeed, we might have reached the limits of the benefits achievable with

Search strategy and selection criteria

We searched Medline for articles published in English from Jan 1, 2007 to Oct 30, 2012, using the search terms “acute myeloid leukaemia”, “prognostic factors”, “pathogenesis”, “epidemiology”, and “treatment”. Relevant references published before the search period were also included and references from relevant articles were also searched. Review articles and book chapters are cited to provide readers with more details and more references than this Seminar has room for.

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