Acute myeloid leukemia

At a glance

1. Acute myeloid leukaemia (AML) is a cancer of myeloid precursors whose blasts stop maturing and fill the marrow. It is the commonest acute leukaemia in adults (median age about 70), and untreated it kills in weeks to months.
2. It presents with marrow failure (tiredness, infections, bleeding), sometimes with swollen gums, skin deposits or a very high white count. It needs 20 per cent or more blasts in blood or marrow (fewer with a defining genetic lesion), typed by flow cytometry, cytogenetics and molecular tests.
3. Fever in acute leukaemia is neutropenic sepsis until proven otherwise, and antibiotics are given at once. The other emergencies are leucostasis, tumour lysis syndrome and DIC.
4. In suspected acute promyelocytic leukaemia (APL), ATRA is started at once, before the genetics are back. APL is now the most curable AML, yet early haemorrhage still kills.
5. Genetics set the ELN 2022 risk (favourable, intermediate, adverse), which decides consolidation: chemotherapy alone for favourable disease, an allogeneic stem cell transplant for most adverse and many intermediate cases in fit patients.
6. Fit patients have intensive induction (7+3, cytarabine with an anthracycline), with midostaurin for a FLT3 mutation (or quizartinib for FLT3-ITD) and CPX-351 for therapy-related or myelodysplasia-related AML. Unfit patients have venetoclax with azacitidine, or ivosidenib with azacitidine for an IDH1 mutation.
7. Measurable residual disease (MRD) predicts relapse. Five-year survival is about 55 per cent under 40 but only a few per cent over 70.

01Definition and overview

Acute myeloid leukaemia (AML) is a cancer of the myeloid precursors of the bone marrow. A haemopoietic stem or progenitor cell gathers mutations that block its maturation and drive its growth, so immature cells, blasts, fill the marrow and spill into the blood. Normal blood production fails within weeks, which is what makes it acute: untreated, AML kills in weeks to a few months through infection or bleeding.

In the chronic leukaemias, chronic myeloid leukaemia and chronic lymphocytic leukaemia, the cells still mature and the disease runs over years. The acute leukaemias are named by lineage: myeloid (AML, about four in five acute leukaemias in adults) or lymphoid (acute lymphoblastic leukaemia, ALL, the commonest cancer of childhood). Their presentation, first tests and emergencies are much the same, and this page holds them for both.

Two classifications have been in use since 2022, the WHO 5th edition and the International Consensus Classification (ICC). Both set the threshold at 20 per cent blasts in blood or marrow, put genetics first and count a myeloid sarcoma (a solid mass of blasts outside the marrow) as AML. They differ at the edges:

The French–American–British types (M0 to M7) live on in these names, and M3 is still heard for acute promyelocytic leukaemia.

in blood or marrow define AML, unless a defining genetic lesion is present

20per cent blastsin blood or marrow define AML, unless a defining genetic lesion is present

median age at diagnosis

70yearsmedian age at diagnosis

to the first antibiotic in neutropenic fever

1hourto the first antibiotic in neutropenic fever

02Etiology and pathophysiology

Who is at risk

Most AML has no cause beyond age, as mutations gather in ageing stem cells.

• Age. Clonal haematopoiesis, a clone of blood cells with one mutation (most often in DNMT3A, TET2 or ASXL1) but no disease, is common in older people and can precede AML, though few such clones progress.
• An earlier myeloid neoplasm. About a third of myelodysplastic syndromes (MDS) progress to AML, and so can myeloproliferative neoplasms such as polycythaemia vera. This secondary AML responds poorly to chemotherapy.
• Earlier cytotoxic treatment. Therapy-related AML follows alkylating agents (cyclophosphamide, melphalan) or radiotherapy after 5 to 10 years, often through a myelodysplastic phase, with loss of chromosomes 5 or 7 and TP53 mutations; it follows topoisomerase II inhibitors (etoposide, anthracyclines) after 1 to 3 years, often with a KMT2A rearrangement.
• Exposures. Ionising radiation, benzene (petrochemical, rubber and glue industries) and tobacco smoke, which contains benzene and raises the risk modestly.
• Inherited predisposition. Down syndrome raises the risk of both AML (in young children typically megakaryoblastic, with a GATA1 mutation) and ALL. Fanconi anaemia and other inherited marrow failure syndromes, and germline mutations in CEBPA, RUNX1, GATA2, DDX41 or TP53, raise the risk of AML and myelodysplasia. When the family history suggests a germline mutation, it must be excluded before a relative is chosen as stem cell donor.

How the leukaemia develops

AML usually grows in steps. A founding mutation in an epigenetic regulator (DNMT3A, TET2, IDH1 or IDH2) gives a stem cell's clone an edge, which is clonal haematopoiesis, not yet disease. A further hit, such as a fusion gene (RUNX1::RUNX1T1, PML::RARA) or an NPM1 mutation, blocks maturation, so the cells stay as blasts that can still divide; mutations in signalling genes (FLT3, KIT, NRAS) drive their growth, and high levels of the anti-apoptotic protein BCL2 keep them alive. The blasts fill the marrow and suppress normal haemopoiesis, causing anaemia, neutropenia and thrombocytopenia. The order simplifies: a typical AML carries several mutations from different gene families, its subclones evolve under treatment, and relapse often grows from a subclone that survived.

The genetic lesions that matter

03Clinical features

Symptoms build over a few weeks from marrow failure, infiltration and what blasts release; some patients are found on a routine count.

The nervous system is rarely involved in AML, so a lumbar puncture is done only for neurological symptoms; in ALL it is routine.

Severity is judged by the leukaemia (its ELN genetic risk, a secondary or therapy-related origin, the white count) and by the patient (age, performance status and other illness, which decide fitness for intensive treatment). In the first days, infection, bleeding, leucostasis and tumour lysis threaten life.

04Diagnosis and management

Making the diagnosis

ELN 2022 genetic risk

The European LeukemiaNet (ELN) risk groups, for patients treated intensively:

The table leaves out fine print (a myelodysplasia-related mutation does not override a favourable lesion, NPM1 with adverse cytogenetics is adverse, TP53 counts from a 10 per cent allele fraction), and the FLT3-ITD allelic ratio no longer counts. Response then refines the risk: measurable residual disease (MRD), leukaemia below what the microscope sees, is followed by flow cytometry (positive at 0.1 per cent of cells or more) or, more sensitively, by quantitative PCR for an NPM1 mutation or a fusion transcript. Persisting or rising MRD outweighs a favourable start.

Emergencies of acute leukaemia

These belong to every acute leukaemia, myeloid or lymphoid.

Hyperleucocytosis carries a high early death rate, mostly from bleeding into the brain and lungs and from respiratory failure. It also misleads the laboratory: blasts lyse in the tube (a falsely high potassium) and use up oxygen in a gas sample (a falsely low oxygen), so pulse oximetry is the better guide. Rasburicase is contraindicated in G6PD deficiency, where it causes haemolysis and methaemoglobinaemia; it also breaks down urate in the tube, so samples go to the laboratory on ice.

Supportive care

• Transfusion: platelets below 10 × 10⁹/L (higher with fever, bleeding or a procedure, 30 to 50 × 10⁹/L in APL), red cells at about 70 to 80 g/L, and irradiated blood components after purine analogues such as fludarabine and around a stem cell transplant.
• Access and infection: a central venous catheter (itself a common source of infection); antifungal prophylaxis with posaconazole during induction; in UK practice a fluoroquinolone through the weeks of profound neutropenia. G-CSF is not routine.

Treatment of fit patients

1. 1

   Induction

   "7+3": cytarabine 100 to 200 mg/m² a day by continuous infusion for 7 days, with daunorubicin 60 mg/m² (or idarubicin 12 mg/m²) on days 1 to 3. A FLT3 inhibitor is added from day 8 for a FLT3 mutation, and gemtuzumab ozogamicin for CD33-positive disease of favourable or intermediate risk. CPX-351, a liposome carrying both drugs, replaces 7+3 in therapy-related and myelodysplasia-related AML.

2. 2

   Response

   A marrow when the counts recover, after 3 to 4 weeks of aplasia. Complete remission means under 5 per cent marrow blasts, none in the blood or outside the marrow, neutrophils at least 1.0 × 10⁹/L and platelets at least 100 × 10⁹/L. About 60 to 80 per cent of younger adults reach it, 40 to 60 per cent of older ones. AML still present after two courses is refractory.

3. 3

   Consolidation

   By ELN risk and MRD. Favourable: intermediate-dose cytarabine, 2 to 4 cycles. Intermediate and adverse: an allogeneic stem cell transplant in first remission if the patient is fit and a donor is found.

4. 4

   Maintenance and follow-up

   Midostaurin (or quizartinib for FLT3-ITD) after consolidation for FLT3-mutated disease; oral azacitidine for patients in remission who will not have a transplant; MRD followed in blood and marrow.

The FLT3 inhibitors earned their place in randomised trials: midostaurin cut deaths by about a fifth in 717 adults under 60 with a FLT3 mutation, and quizartinib raised median survival from 15.1 to 31.9 months in 539 patients with FLT3-ITD.

An FDA approval does not mean an EU one. The newer drugs in the EU in late 2026:

Allogeneic stem cell transplantation

An allogeneic stem cell transplant replaces the patient's blood-forming system with a donor's after conditioning chemotherapy, with or without total body irradiation. Its power is largely the graft-versus-leukaemia effect of donor T cells; its price is graft-versus-host disease, infection and organ damage, with a non-relapse mortality commonly of 10 to 20 per cent, more in older and less fit patients. Donors are an HLA-identical sibling (each sibling has a one in four chance of matching), a matched unrelated volunteer or a haploidentical relative, and reduced-intensity conditioning allows it into the seventies. It is offered in first remission when the risk of relapse without it outweighs the risk of the transplant (adverse and most intermediate-risk AML; favourable risk only when MRD persists or returns), and in second remission after a relapse.

Patients unfit for intensive treatment

Many patients are too old or too ill for 7+3: in the trials, age 75 or more, or younger with poor performance status or serious heart, lung, kidney or liver disease. For them:

• Venetoclax with azacitidine (75 mg/m² on days 1 to 7 of each 28-day cycle) is the standard. In 431 patients with a median age of 76, remissions rose from 28 to 66 per cent and median survival from 9.6 to 14.7 months. Venetoclax is stepped up over three days (100, 200, then 400 mg) once the white count is below 25 × 10⁹/L, with tumour lysis prophylaxis, and its dose is cut to 100 mg or less with a strong CYP3A inhibitor such as posaconazole. Its main toxicity is long cytopenias, so the marrow is checked after the first cycle and, once in remission, the venetoclax days are shortened if the counts are slow to recover.
• An IDH1 mutation: ivosidenib with azacitidine, watching for a differentiation syndrome.
• Otherwise a hypomethylating agent alone, low-dose cytarabine with glasdegib, a trial, or supportive care with transfusions and hydroxycarbamide, which is palliation.

Relapsed and refractory AML

Most relapses come within 2 to 3 years, and mutations are tested again because relapse can bring new targets. A FLT3 mutation is treated with gilteritinib, which lengthens survival against salvage chemotherapy; otherwise salvage chemotherapy (such as FLAG-Ida) or venetoclax combinations aim at a second remission and a transplant. Menin inhibitors, oral drugs for relapse with a KMT2A rearrangement or an NPM1 mutation, cause a differentiation syndrome; approved in the USA, they are not yet authorised in the EU. Many patients are best served by palliative care.

Acute promyelocytic leukaemia

Acute promyelocytic leukaemia (APL) is AML with the t(15;17) translocation, which fuses PML to the retinoic acid receptor alpha gene (PML::RARA) and blocks maturation at the promyelocyte stage. The promyelocytes, packed with granules and often with bundles of Auer rods (faggot cells), expose tissue factor and switch on fibrinolysis: a DIC with low fibrinogen and platelets, bleeding from gums, skin and venepuncture sites, and fatal bleeding into the brain or lungs. The white count is usually low (high in the hypogranular variant). Haemorrhage drives early death: in a US registry of 1,400 patients, 17 per cent died early (24 per cent of those aged 55 or more).

1. 1

   Suspect it

   Promyelocytes with Auer rods on the film, or a leukaemia with a low fibrinogen, a high D-dimer and bleeding. Ask for urgent review of the film and for PML::RARA by FISH or PCR, which can be back within a day.

2. 2

   Start ATRA

   Start ATRA at once, before the genetics are back: all-trans retinoic acid 45 mg/m² a day by mouth in two doses. Stopping it if APL is excluded costs little; waiting costs lives.

3. 3

   Correct the coagulopathy

   Platelets above 30 to 50 × 10⁹/L, fibrinogen above 1.0 to 1.5 g/L with cryoprecipitate or fibrinogen concentrate, plasma for a long prothrombin time, checked at least daily. No routine heparin or tranexamic acid, and no central lines, lumbar punctures or other invasive procedures until the bleeding risk is controlled.

4. 4

   Treat by risk

   Standard risk (white count 10 × 10⁹/L or less): ATRA with arsenic trioxide, no chemotherapy, for induction and months of consolidation. High risk (above 10, with more bleeding, differentiation syndrome and relapse): ATRA with anthracycline-based chemotherapy, or ATRA and arsenic with a little chemotherapy or gemtuzumab ozogamicin to control the count (arsenic first-line in high-risk APL is outside its EU licence). PML::RARA is measured by PCR at the end of consolidation; high-risk patients are then tested every 3 months for up to 3 years, while standard-risk patients who are negative by then need little further testing.

In a trial of standard-risk APL, 97 per cent were alive and free of events at two years with ATRA and arsenic, against 86 per cent with ATRA and chemotherapy. Both drugs make the blasts mature, and the maturing cells can cause a differentiation syndrome (a quarter of 739 patients in one series, one in eight severely), peaking in the first and third weeks: fever, breathlessness, weight gain and oedema, lung infiltrates, effusions, low blood pressure and kidney injury. At the first sign, give dexamethasone 10 mg intravenously twice daily, and pause ATRA or arsenic only if it is severe. A white count above 5 × 10⁹/L and a raised creatinine predict the severe form, and many protocols give such patients steroid prophylaxis. The same syndrome follows gilteritinib and the IDH and menin inhibitors. Arsenic also prolongs the QT interval: an ECG before and during treatment, potassium and magnesium kept high-normal, and no other QT-prolonging drugs.

of patients with APL died early in a US registry, despite ATRA

17per centof patients with APL died early in a US registry, despite ATRA

event-free at two years with ATRA and arsenic in standard-risk APL

97per centevent-free at two years with ATRA and arsenic in standard-risk APL

had a differentiation syndrome in a large series

1 in 4patientshad a differentiation syndrome in a large series

05Epidemiology

AML is the commonest acute leukaemia in adults. A European registry study of 2000 to 2002 found about 3 new cases per 100,000 people a year, and the US rate is 4.4 per 100,000. It is rare in young adults and becomes steadily commoner with age; with a median age at diagnosis of about 70, many patients cannot have intensive treatment. It is slightly commoner in men. In children it accounts for about one in five leukaemias, most of the rest being ALL.

Cases are rising as the population ages and more people survive earlier cancer treatment, which makes therapy-related AML more frequent. APL is a minority of AML, though estimates of its share vary, from about 3 per cent of adult cases in a Swedish population registry to the 10 to 15 per cent quoted in textbooks. It affects younger people than other AML, so its share is higher among the young.

06Prognosis

Untreated, AML is fatal within months. With treatment, outcome depends above all on age and fitness, the genetics (ELN risk) and MRD. In England more than 40 per cent of patients are alive at one year and more than 20 per cent at five; in the USA five-year relative survival is about a third, against under 10 per cent in the 1970s. Five-year survival in a population-based registry covering one region of England (diagnoses 2010 to 2019):

• Among fit patients treated intensively, favourable-risk AML is cured in more than half, adverse-risk AML in a minority, mostly through a transplant; with a TP53 mutation, survival is often measured in months. Secondary and therapy-related AML do worse than de novo AML.
• APL, once the most rapidly fatal AML, is now the most curable: those who survive the first weeks are nearly all cured.
• MRD that persists after treatment, or returns in follow-up, foretells relapse, and relapse is rarely cured except by a transplant.

Follow-up is a blood count every 1 to 3 months for two years, then every 3 to 6 months to five years, with MRD where there is a marker (NPM1 or a fusion transcript) and a marrow if the count changes. New cytopenias or blasts in the blood mean relapse until shown otherwise. Survivors are watched for late effects: anthracycline heart damage, infertility, chronic graft-versus-host disease and second cancers after a transplant.

Check yourselfAnswer, then say how sure you were: a lucky guess still counts as a weak point.

1A 34-year-old woman has bleeding gums and bruising. Platelets are 18 × 10⁹/L, the film shows abnormal promyelocytes with bundles of Auer rods, and fibrinogen is 0.9 g/L. What is the most urgent step?

Start ATRA now and give platelets and cryoprecipitateWait for the PML::RARA result before treatingGive heparin and tranexamic acid for the DICTake a bone marrow trephine before any treatment

2A 79-year-old man with heart failure and diabetes has newly diagnosed AML with a normal karyotype and no FLT3 or IDH1 mutation. He lives independently and wants active treatment. What is the usual first-line choice?

Intensive 7+3 induction and then a transplantHydroxycarbamide alone to control the countVenetoclax with azacitidine in 28-day cyclesGemtuzumab ozogamicin added to 7+3

3A 45-year-old man with AML and a white count of 150 × 10⁹/L is about to start induction. His urate is 650 µmol/L, his creatinine is rising and he is known to have G6PD deficiency. Which plan for tumour lysis is right?

Rasburicase with intravenous fluids and monitoringIntravenous fluids, allopurinol and close monitoringSodium bicarbonate to alkalinise the urineFurosemide to force a diuresis before any fluids

4A 58-year-old woman with newly diagnosed monocytic AML has a white count of 190 × 10⁹/L, haemoglobin 68 g/L, platelets 9 × 10⁹/L, confusion and hypoxia with shadowing in both lungs. Which step should be avoided for now?

Starting hydroxycarbamide or chemotherapy at onceIntravenous fluids with tumour lysis prophylaxisA platelet transfusion for the low countA red cell transfusion to correct the anaemia

5A 46-year-old woman is in complete remission after 7+3 induction for AML with a mutated NPM1, no FLT3-ITD and a normal karyotype. What is the usual next step?

An allogeneic stem cell transplant in first remissionCytarabine consolidation with NPM1 monitoring by PCRGilteritinib maintenance for two yearsNo further treatment and a blood count every year