Acute leukaemia: AML, ALL and APL

At a glance

• Clonal expansion of blasts (20% or more in blood or marrow for most types) causing marrow failure. AML is the adult disease (median age about 68); ALL peaks in childhood with a second rise after 50.
• Acute promyelocytic leukaemia (APL, also called APML) is the emergency: DIC and early haemorrhagic death, but cure over 90% with ATRA and arsenic.
• AML treatment depends on fitness and genetics: intensive chemotherapy with transplant for the fit, venetoclax plus azacitidine for the unfit.
• ALL is treated with long multi-phase regimens; blinatumomab and TKIs (in Ph-positive disease) have improved survival.

Causes and risk factors

• Age (AML, rising after 60), prior chemotherapy (alkylators 5 to 10 years later with 5 or 7 abnormalities; topoisomerase II inhibitors 1 to 3 years later with KMT2A rearrangement), radiotherapy, benzene, smoking.
• Antecedent haematological disorder: MDS, myeloproliferative neoplasms, aplastic anaemia, PNH.
• Germline predisposition: Down syndrome, Fanconi anaemia, and adult-onset syndromes with DDX41, RUNX1, CEBPA or GATA2 mutations. Ask about family history before choosing a sibling donor.

Recognition

Feature	Clue
Marrow failure	Fatigue, infections, bruising, petechiae, mucosal bleeding
Leucostasis (usually AML with white cells over 100 x 10^9/L)	Hypoxia, pulmonary infiltrates, confusion, headache, retinal haemorrhage, priapism
Tissue infiltration	Gum hypertrophy and skin deposits (monocytic AML); lymphadenopathy, hepatosplenomegaly, bone pain, testes, CNS (ALL); mediastinal mass (T-ALL)
DIC	APL above all; also monocytic AML and hyperleucocytic disease
Tumour lysis	Spontaneous in ALL and high-count AML

Pitfall: a normal or low white cell count doesn't exclude acute leukaemia. Many patients, including most with APL, present with pancytopenia.

Investigations

• FBC and film: blasts, Auer rods (myeloid), abnormal promyelocytes and faggot cells (APL).
• Coagulation screen with fibrinogen and D-dimer in every new presentation, urgently. Low fibrinogen with a near-normal APTT suggests APL hyperfibrinolysis.
• TLS bloods: urate, potassium, phosphate, calcium, creatinine, LDH. See Tumour lysis syndrome.
• Bone marrow aspirate and trephine:
  • morphology and flow cytometry (myeloid CD13, CD33, CD117, MPO; B-ALL CD19, CD10, CD22, TdT; T-ALL CD3, CD7)
  • karyotype and FISH (PML::RARA, BCR::ABL1, KMT2A)
  • NGS panel: FLT3, NPM1, CEBPA, IDH1/2, TP53 and myelodysplasia-related genes. FLT3 results should come back within days, because midostaurin starts on day 8.
• HLA typing of the patient and siblings early if transplant is possible.
• Echocardiogram before anthracyclines; hepatitis B and C, HIV, CMV and VZV serology; fertility counselling; pregnancy test.
• Lumbar puncture in ALL, with intrathecal chemotherapy, once circulating blasts have cleared and coagulopathy is corrected. Not routine in AML.

Emergencies at presentation

• Leucostasis: urgent cytoreduction with hydroxyurea then induction. Avoid red cell transfusion while the count is very high, because it raises viscosity. Leukapheresis has no proven survival benefit and is contraindicated in APL.
• DIC: see Disseminated intravascular coagulation.
• Febrile neutropenia: empirical broad-spectrum antibiotics within an hour. See Febrile neutropenia.
• TLS prophylaxis: fluids plus allopurinol, or rasburicase if high risk.

AML

Classification and risk

• WHO 2022 (5th edition) and the International Consensus Classification (ICC 2022) define many AML types by genetics. With defining abnormalities such as NPM1 or core-binding factor fusions, AML can be diagnosed below 20% blasts (any count in WHO; 10% or more in ICC).

ELN 2022 genetic risk (intensive chemotherapy)

Risk	Genetics
Favourable	t(8;21) RUNX1::RUNX1T1; inv(16)/t(16;16) CBFB::MYH11; mutated NPM1 without FLT3-ITD; in-frame bZIP CEBPA mutation
Intermediate	NPM1 with FLT3-ITD; wild-type NPM1 with FLT3-ITD; t(9;11) MLLT3::KMT2A; abnormalities not otherwise classified
Adverse	t(6;9); other KMT2A rearrangements; t(9;22); inv(3)/t(3;3); -5 or del(5q), -7, -17/abn(17p); complex (3 or more abnormalities) or monosomal karyotype; myelodysplasia-related mutations (ASXL1, BCOR, EZH2, RUNX1, SF3B1, SRSF2, STAG2, U2AF1, ZRSR2); TP53 mutation (VAF 10% or more)

• ELN 2022 dropped the FLT3-ITD allelic ratio: any FLT3-ITD is now intermediate, because FLT3 inhibitors changed its prognosis.

ELN 2024 risk for less-intensive therapy (venetoclax with azacitidine)

Risk	Genetics
Favourable	NPM1 or IDH2 mutation, or other genetics, without FLT3-ITD, KRAS/NRAS or TP53 mutation; DDX41 mutation; IDH1 mutation with TP53 wild-type (for azacitidine plus ivosidenib)
Intermediate	FLT3-ITD and/or KRAS or NRAS mutation, TP53 wild-type
Adverse	TP53 mutation

Fit patients: intensive therapy

• Induction "7+3": cytarabine for 7 days plus daunorubicin (60 to 90 mg/m²) or idarubicin for 3 days. Complete remission in 60 to 80% of younger adults.
• Additions by genetics:
  • FLT3-mutated: midostaurin (RATIFY); quizartinib for FLT3-ITD (QuANTUM-First).
  • Core-binding factor or favourable AML (CD33-positive): gemtuzumab ozogamicin.
  • Therapy-related or myelodysplasia-related AML aged 60 to 75: CPX-351 (liposomal daunorubicin-cytarabine).
• Consolidation:
  • Favourable: intermediate- or high-dose cytarabine. Follow MRD (NPM1 or CBF transcripts by qPCR); molecular relapse prompts pre-emptive treatment.
  • Adverse, and most intermediate: allogeneic stem cell transplant in first remission.
• Maintenance: oral azacitidine (QUAZAR) for those in remission not proceeding to transplant; FLT3 inhibitor maintenance after transplant in selected patients.

Unfit patients: less-intensive therapy

• Usually 75 or older, or with major comorbidity. Fitness assessment matters more than age alone.
• Venetoclax plus azacitidine (VIALE-A): median overall survival 14.7 vs 9.6 months with azacitidine alone; remission about 66%. PBS-listed for untreated AML in patients ineligible for intensive induction.
• Practicalities: venetoclax ramp-up with TLS precautions; reduce the venetoclax dose with posaconazole or other strong CYP3A4 inhibitors; marrow at the end of cycle 1 and shorten venetoclax days if remission with marked cytopenias.
• Low-dose cytarabine plus venetoclax, or azacitidine plus ivosidenib for IDH1-mutated AML, are alternatives.
• Best supportive care (transfusion, hydroxyurea, palliative care) is right for some. See Recognising dying and illness trajectories.

Relapsed or refractory AML

• Re-test genetics. Gilteritinib for FLT3-mutated relapse (ADMIRAL, better than salvage chemotherapy). IDH inhibitors where available. Salvage chemotherapy (such as FLAG-Ida) as a bridge to transplant.

APL

• t(15;17) PML::RARA. Younger adults (median about 45). Usually low white cells with hypergranular promyelocytes; the microgranular variant has high counts.
• Coagulopathy: DIC plus hyperfibrinolysis. Most early deaths are from intracranial or pulmonary haemorrhage, often before treatment starts.

Immediate management

• Start ATRA on suspicion from the film. Don't wait for PML::RARA confirmation.
• Blood product support: platelets above 30 to 50 x 10^9/L, fibrinogen above 1.5 g/L with cryoprecipitate, plasma for prolonged PT.
• Avoid leukapheresis, central lines and lumbar puncture during coagulopathy.

Risk and treatment

Risk (Sanz)	Definition	Treatment
Low or intermediate	White cells 10 x 10^9/L or less	ATRA plus arsenic trioxide, chemotherapy-free (APL0406: better survival than ATRA plus idarubicin)
High	White cells over 10 x 10^9/L	ATRA plus arsenic with idarubicin (APOLLO 2025: 2-year event-free survival 88% vs 71% with ATRA-chemotherapy), or ATRA plus anthracycline-based chemotherapy

• Australia: the ALLG APML4 regimen combines ATRA, arsenic and idarubicin induction, with excellent long-term results.
• Follow PML::RARA by PCR after consolidation to confirm molecular remission.

Differentiation syndrome

• In up to a quarter, usually in the first 2 to 3 weeks of ATRA or arsenic.
• Features: fever, weight gain or oedema, dyspnoea, pulmonary infiltrates, pleural or pericardial effusions, hypotension, AKI.
• Treat on suspicion: dexamethasone 10 mg IV twice daily until resolved. Temporarily stop ATRA or arsenic only if severe.
• Prophylactic steroids are commonly used, especially with high white cells; hydroxyurea controls rising counts on ATRA-arsenic.

Arsenic trioxide toxicity

• QT prolongation and torsades: baseline ECG, then regular ECGs through induction. Keep potassium above 4.0 mmol/L and magnesium above 0.75 mmol/L (ELN 2019), withhold other QT-prolonging drugs, and hold arsenic if QTc is over 500 ms. See Long QT syndrome.
• Also hepatotoxicity, leucocytosis and neuropathy. ATRA causes headache and idiopathic intracranial hypertension.

ALL

• B-ALL about 75% of adult cases, T-ALL 25%.
• Philadelphia-positive (BCR::ABL1) ALL rises with age, to about half of cases over 60. Philadelphia-like ALL has a similar kinase-activated profile and poor outcomes.

Treatment

• Adolescents and young adults (to about 40): paediatric-inspired protocols (CALGB 10403 and similar) improve survival over adult regimens.
• Phases: induction (steroid, vincristine, asparaginase, anthracycline), consolidation, CNS prophylaxis (intrathecal and high-dose methotrexate), and maintenance for 2 to 3 years (daily mercaptopurine, weekly methotrexate, vincristine and steroid pulses).
• MRD after induction is the strongest prognostic factor and guides transplant.
• Blinatumomab (CD19 bispecific T-cell engager) in consolidation: E1910 in MRD-negative adults improved 3-year overall survival to 85% from 68%. PBS-listed for newly diagnosed pre-B-ALL in the consolidation phase, and for relapsed or refractory disease. Check the current restriction for MRD and cycle limits; E1910 gave 4 cycles.
• Ph-positive ALL: a TKI (dasatinib or ponatinib) with steroids, increasingly with blinatumomab instead of intensive chemotherapy; allogeneic transplant for persistent MRD.
• Relapse: blinatumomab, inotuzumab ozogamicin (CD22), CAR-T cell therapy, then allogeneic transplant.

ALL drug toxicity

Drug	Problem
Asparaginase	Hypersensitivity, pancreatitis, thrombosis (including cerebral venous sinus thrombosis), low fibrinogen, hepatotoxicity, hyperglycaemia
Vincristine	Neuropathy, constipation and ileus. Azoles (posaconazole, itraconazole) raise levels and cause severe neurotoxicity
Mercaptopurine	Myelotoxicity with low TPMT or NUDT15 activity; allopurinol interaction
High-dose methotrexate	AKI and mucositis: hydration, urine alkalinisation, folinic acid rescue, glucarpidase for toxic levels
Blinatumomab	Cytokine release syndrome and neurotoxicity (tremor, aphasia, seizures); admit for the first days of the first one or two cycles; later cycles are often given as outpatients
Steroids	Hyperglycaemia, avascular necrosis, infection

• PJP prophylaxis with co-trimoxazole throughout. See Complications of immunosuppression.

Supportive care

• Platelet transfusion below 10 x 10^9/L prophylactically (higher with fever, bleeding or procedures; 30 to 50 in APL).
• Antifungal prophylaxis with posaconazole in AML induction; aciclovir or valaciclovir; fluoroquinolone in expected prolonged neutropenia.
• Irradiated blood products after purine analogues (FLAG-Ida contains fludarabine) and around transplant.
• Early palliative care input for patients on non-curative pathways.

Pitfalls

• Waiting for genetic confirmation before ATRA in suspected APL.
• Leukapheresis or central line insertion in APL with DIC.
• Missing differentiation syndrome as "pneumonia" or "fluid overload".
• Transfusing red cells into hyperleucocytosis before cytoreduction.
• Forgetting the venetoclax dose reduction when posaconazole is started.
• Giving an azole with vincristine.
• Starting mercaptopurine without TPMT and NUDT15 results, or adding allopurinol without cutting the dose.
• Not sending FLT3 testing urgently: midostaurin must start by day 8.