Section 1: Epidemiology and aetiology
Although it can present at any age, AML is largely a disease of the elderly, with a median age at diagnosis of 65 years, and is rare in children.1 Approximately 2,300 new cases are diagnosed each year in the UK.
AML can occur on a background of a previous haematological malignancy (usually myelodysplastic or myeloproliferative syndromes), or as secondary AML after chemotherapy or high-dose ionising radiation. In both cases, AML is associated with classic cytogenetic abnormalities and carries a poor prognosis.
Certain congenital conditions are associated with a high risk of AML, the most common being Down's syndrome.
In approximately 80% of cases, which are termed de novo AML, no preceding condition or risk factor is identified.
Formerly, classification of AML was based on morphological subtypes, but advances in understanding of the prognostic associations of genetic and molecular abnormalities have led to replacement of this system by the WHO classification.
This is based on genetic, biological and clinical features, which have prognostic relevance and determine treatment strategies.2
Although the most important prognostic information is determined by cytogenetic analysis of leukaemia cells, other molecular abnormalities also predict outcome.
The most common are mutations of FLT3, which confer additional risk and are present in 25% of patients with AML,3,4 and NPM1 mutations, associated with lower-risk disease in patients with normal cytogenetics.5
Additional factors predictive of adverse prognosis include age >60 years at diagnosis, elevated WCC (>100 x 109/L), treatment-induced AML, transformation from a prior haematological disorder, CNS involvement with leukaemia, systemic infection at diagnosis and failure to achieve remission with induction chemotherapy.6
Section 2: Making the diagnosis
AML usually presents acutely, with features of bone marrow failure. These include symptoms of anaemia, bleeding (often mucosal; epistaxis, gum bleeding, petechiae, menorrhagia) or infections (particularly chest, mouth or skin).
About 25% of patients will have hepatomegaly or splenomegaly at diagnosis, but lymphadenopathy is rare in AML.
In certain subtypes, patients may present with gum hypertrophy or skin nodules (due to leukaemic infiltration). Patients may complain of flu-like symptoms and weight loss.
The clinical condition of patients with AML may deteriorate extremely rapidly; most will be neutropenic at diagnosis (even if this is not reflected in their FBC), and must seek medical attention as an emergency if they become febrile or unwell before admission for chemotherapy.
Patients with a high WCC (usually >100 x 109/L) can also develop leukostatic symptoms (hypoxia, confusion and retinal haemorrhages), requiring emergency treatment.
An AML subtype requiring special consideration is acute promyelocytic leukaemia (APL), also known as AML M3. This makes up approximately 5% of AML in adults and has particular cytogenetic, morphological and clinical features.
The characteristic cytogenetic abnormality is a translocation between chromosomes 15 and 17 (t(15;17)). Many of these patients are overtly coagulopathic, with disseminated intravascular coagulation at presentation, making urgent diagnosis and immediate intervention essential.
CNS involvement in AML is rare at diagnosis (0.5% of patients), but is seen in 5% of patients relapsing from complete remission. This can present as headaches, meningism or cranial nerve palsies.
The initial investigation of AML is FBC and peripheral blood film.
Many patients will have a raised WCC (blasts), but it is not uncommon for AML to present with a normal or low WCC.
Most patients will have anaemia and/or thrombocytopenia at presentation. Leukaemic blasts can generally be identified on the blood film, and the APL subtype distinguished, but definitive diagnosis and confirmation of leukaemic lineage require further investigations.
The WHO definition of AML requires identification of >20% leukaemic blasts in the bone marrow.2 In addition to morphology, bone marrow samples and peripheral blood will be sent for immunophenotyping, which uses a panel of monoclonal antibodies to identify cell surface antigens and confirm clonality and lineage.
Bone marrow samples also undergo cytogenetic and molecular analyses, to allow risk stratification.
A diagnostic lumbar puncture is performed if any CNS features are present, but this procedure is not routinely necessary. Baseline organ function is assessed at diagnosis.
Section 3: Managing the condition
The treatment aim in fit patients is to achieve long-term remission. As supportive care has improved, patients up to (and occasionally over) the age of 70 can be managed with intensive treatment, divided into induction of remission and post-remission treatment (to prevent relapse).
Response is assessed with bone marrow aspirate, usually after each course of treatment. All patients should be entered into multicentre clinical trials where available.
In patients not suitable for intensive chemotherapy, long-term remission is not expected, so treatment is targeted at prolonging life and alleviating symptoms.
Although outcomes have improved for younger patients, the outlook for patients not suitable for intensive chemotherapy remains poor. There is no standard protocol for treating these patients; options include supportive care, low-dose traditional chemotherapy or newer agents, if available.
The APL subtype is very sensitive to anthracycline chemotherapy and uniquely sensitive to all-trans retinoic acid (ATRA), an oral vitamin A derivative that induces differentiation of promyeloblasts.
If APL is suspected, patients start treatment with ATRA immediately, while the diagnosis is confirmed. First-line treatment of APL entails a combination of ATRA and anthracyclines, usually for four courses,7 with intensive blood product support.
Induction chemotherapy comprises one to two courses of chemotherapy, usually an anthracycline plus cytarabine given via central IV access for three days then seven to 10 days respectively, following which, the patient remains in hospital for two to three weeks per course.
In this recovery phase, supportive care includes regular blood and platelet transfusions, and IV antibiotics for suspected/proven infections.
Post-remission treatment is determined by risk stratification; patients with favourable or standard risk cytogenetics and no other adverse prognostic factors receive two further courses of chemotherapy (usually cytarabine);8 allogeneic haematopoietic stem cell transplant (HCT) is recommended for those with adverse cytogenetic risk disease.6,9
Most intensive treatment is delivered on an inpatient basis, giving patients one to two weeks at home between each threeto four-week admission. In total, treatment takes four to six months, with a recovery period of three months following chemotherapy and six to 12 months following allogeneic HCT.
Patients who relapse after chemotherapy will, if well enough, receive alternative induction chemotherapy followed by allogeneic HCT.
Those who relapse after allogeneic HCT may be offered salvage chemotherapy followed by a second allograft, depending on first remission. Those refractory to treatment may be entered into clinical trials.
AML in pregnancy
Unless it is diagnosed in very late pregnancy, the maternal risk of leaving AML untreated until delivery is too high.
AML chemotherapy in the first trimester carries a very high risk of fetal malformation, and in this case, termination of pregnancy is discussed.
Chemotherapy can be administered in the second or third trimesters, with increased risks of abortion, premature delivery and growth retardation, and delivery is scheduled between chemotherapy courses or after completion of therapy.
APL can be treated with single-agent ATRA if diagnosed in the second or third trimesters, to avoid exposure to chemotherapy.
Azacitidine has been shown to significantly prolong survival in patients with 20-30% blasts.10
Responses to sorafenib alone, and synergistically with chemotherapy, have been demonstrated in patients with FLT3 mutations, including those with relapsed/refractory disease (unlicensed indication).11-13
New purine analogues
Clofarabine has obtained good responses as a monotherapy in patients with poor performance status, with equivalent remission rates in those with unfavourable cytogenetics (unlicensed indication).14
Section 4: Prognosis
With current induction chemotherapy, >80% of newly diagnosed patients aged <60 years="" achieve="" complete="" remission="" but="" a="" substantial="" proportion="" subsequently="" relapse="" p="">
Long-term remission following intensive treatment can be expected in 30-70% of patients, depending on risk classification.
APL has a far better prognosis, with long-term remission and potential cure expected in >80% of newly diagnosed patients. Patients with APL are monitored post-treatment for minimal residual disease (MRD) using PCR techniques to identify the t(15;17) fusion product PML/RARA.
Achievement of PCR negativity is associated with prolonged survival; persistence or re-emergence of PCR positivity is almost always followed by full haematological relapse.
The prognostic benefit of MRD techniques in non-APL patients has been demonstrated,15,16 but no role has yet been established for routine MRD monitoring.
Patients with AML will be followed up for at least five years, or life-long following allogeneic HCT.
|Long-term remission rates|
|Non-APL in children||60-70%|
|Non-APL in young adults||50%|
|Non-APL in elderly patients||<20%|
Section 5: Case study
A 28-year-old woman with no previous medical history presented to her GP with a three-week history of fatigue and a five-day history of shortness of breath on exertion and easy bruising.
Other than the bruising, clinical examination was unremarkable. FBC showed Hb 85g/L, WCC 32 x 109/L, platelets 23 x 109/L; blood film demonstrated large mononuclear cells with scanty cytoplasm and occasional Auer rods, consistent with myeloid blasts. The haematology team arranged for her urgent admission.
Immunophenotyping of peripheral blood confirmed a diagnosis of AML. Bone marrow aspirate showed 60% blasts on morphology, with normal cytogenetics, and was FLT3 positive, NPM1 negative.
Owing to her age, fertility was discussed, but treatment could not be delayed to allow egg harvesting. She was entered into the AML 17 MRC trial and received standard first-line induction chemotherapy.
When blood counts failed to recover four weeks later, remission status was reassessed and she received salvage chemotherapy. An unrelated donor search was started.
Following salvage chemotherapy, blood counts recovered but repeat bone marrow tests showed 10% residual blasts (<5% is required for morphological remission).
Given her failure to respond, an exceptional circumstances application was made for sorafenib.
After four weeks of this treatment, she achieved remission. A suitable donor was identified, so allogeneic HCT was scheduled.
The patient underwent allogeneic HCT four weeks later and four months post-allograft, she remains in remission.
Section 6: Evidence base
- Sanz MA, Grimwade D, Tallman MS et al. Management of acute promyelocytic leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet. Blood 2009; 113: 1875-91.
- Dohner H, Estey EH, Amadori S et al. Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European LeukemiaNet. Blood 2010; 115: 453-74.
- Macmillan Cancer Support. Acute myeloid leukaemia. www.macmillan.org.uk
Contributed by Dr Chloe Anthias, specialist registrar in haemato-oncology, Dr Mark Ethell, consultant in haemato-oncology, and Dr Michael Potter, consultant haematologist, The Royal Marsden Hospital (NHS and Private), London.
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1. National Cancer Institute. Surveillance, Epidemiology, and End Results Program.
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