Childhood leukaemia and tumour lysis syndrome

• Acute lymphoblastic leukaemia (ALL) is the commonest cancer in children, accounting for roughly a quarter of cancers diagnosed before the age of 15 in the United States.
• A child with leukaemia usually presents with the consequences of bone marrow failure (pallor, bruising, fever) plus infiltration (bone pain, hepatosplenomegaly, and sometimes testicular or central nervous system disease).
• ALL is confirmed by a marrow with more than 25% lymphoblasts, then classified by immunophenotype (B- or T-cell) and by cytogenetics such as the ETV6::RUNX1 fusion (t(12;21)) or the Philadelphia chromosome.
• Treatment is risk-stratified and phased: remission induction, consolidation (intensification), and maintenance, with specific central nervous system-directed therapy throughout.
• Tumour lysis syndrome (TLS) is the life-threatening release of potassium, phosphate, nucleic acids and cytokines from rapidly dying tumour cells; prevention rests on vigorous hydration, allopurinol or rasburicase according to risk, and tight electrolyte monitoring.

By the end of this page you should be able to:

1. Explain why childhood ALL is the commonest childhood cancer and distinguish it from acute myeloid leukaemia (AML).
2. Reason from pathophysiology to the presenting symptoms and signs, including extramedullary disease.
3. Interpret a full blood count, immunophenotype and cytogenetic result when classifying a child with ALL.
4. Use the National Cancer Institute (NCI) risk groups and the treatment phases to explain management.
5. Explain the mechanisms and laboratory thresholds of TLS, and plan hydration and uric-acid lowering prophylaxis.
6. Outline the special features of leukaemia in children with Down syndrome and in low-resource settings.

A leukaemia is a clonal cancer of blood-forming cells that fills the bone marrow and spills into the blood. In children the two main forms are acute lymphoblastic leukaemia (ALL), a cancer of lymphoid progenitors, and acute myeloid leukaemia (AML), a cancer of myeloid progenitors. Both present acutely, with bone marrow failure and organ infiltration.

ALL is the commonest. AML accounts for about 20% of childhood leukaemias.^[2] Historically the French-American-British morphology groups (L1/L2/L3) were used; they are no longer recommended, because they add no prognostic information beyond immunophenotype and genetics.^[1]

ALL is classified first by lineage:

• B-lymphoblastic (B-ALL), about 80 to 85% of cases, expressing CD19 and usually CD10.
• T-lymphoblastic (T-ALL), most of the remainder, tending to present with a mediastinal mass.

B-ALL is subdivided immunophenotypically (common/pre-B/pro-B/mature) and genetically by the recurrent alterations below. T-ALL has its own genomics and is treated on T-cell-specific protocols.

AML in younger children is classified by WHO/genetic groups (for example, RUNX1::RUNX1T1 from t(8;21), CBFB::MYH11 from inv(16), KMT2A rearrangements, and FLT3 variants), most of which are not the same alterations seen in ALL.^[2] AML also has a distinctive, strongly curable form in children with Down syndrome, discussed later.

ALL represents about 25% of cancer diagnoses among children younger than 15 years and 75% or more of childhood leukaemias.^[1] In the United States it occurs at roughly 40 cases per million children aged 0 to 14 years, and about 20 per million adolescents aged 15 to 19 years, with a sharp peak in incidence between ages 1 and 4 years (about 76 per million).^[1] About 3,100 children and adolescents younger than 20 years are diagnosed with ALL each year in the United States.^[1]

Incidence is higher in children of Hispanic and American Indian/Alaska Native origin and about twice as high in White as in Black children at ages 1 to 4 years.^[1] Survival has improved dramatically: five-year survival rose from 60% to about 90% for children younger than 15 years between 1975 and 2020.^[1] AML accounts for about 20% of childhood leukaemias.^[2]

Most childhood leukaemia has no single preventable cause. Accepted risk factors include:^[1]

• Previous chemotherapy or high-dose ionising radiation (including therapeutic radiation for conditions such as tinea capitis or thymus enlargement).
• Genetic conditions: Down syndrome, neurofibromatosis type 1, Bloom syndrome, Fanconi anaemia, ataxia telangiectasia, Li-Fraumeni syndrome, constitutional mismatch repair deficiency.
• Common germline variants of small effect in genes such as ARID5B, IKZF1, CDKN2A/B and CEBPE, and rare high-penetrance variants.
• Carriers of a constitutional Robertsonian translocation involving chromosomes 15 and 21 are predisposed to ALL with intrachromosomal amplification of chromosome 21 (iAMP21).

Evidence that leukaemia can begin before birth comes from finding leukaemia-specific rearrangements (for example ETV6::RUNX1) in neonatal blood spots, at rates far higher than the later incidence of disease.^[1]

Down syndrome deserves special attention and is covered in its own section below.

Understanding the symptoms of leukaemia as consequences of two processes makes them easy to remember.

First, bone marrow failure. Blasts crowd out normal haematopoiesis:

• Loss of erythropoiesis causes anaemia and therefore pallor, fatigue and dyspnoea.
• Loss of megakaryopoiesis causes thrombocytopenia and therefore bruising and petechiae.
• Loss of mature granulocytes causes neutropenia and therefore fever and infection that can be serious.

A diagnostic marrow aspirate with more than 25% blasts is classified as M3 (M1 is under 5% blasts, M2 is 5 to 25%); almost all children with ALL present with an M3 marrow.^[1]

Second, infiltration. Lymphoblasts leave the marrow and infiltrate tissues:

• Bone and marrow infiltration gives bone pain, often felt as a limp or refusal to use a limb.
• Lymphoid and reticuloendothelial infiltration enlarges liver, spleen and lymph nodes.
• Testes and the central nervous system (CNS) are sanctuary sites that many drugs penetrate poorly.

The clinical syndrome is therefore predictable from where the blasts go and which normal blood lines they displace.

• Pallor, tiredness and breathlessness on effort, sometimes with palpitation.
• Bleeding: bruising, petechiae, prolonged nosebleeds, gum bleeding.
• Fever, often without an obvious source, sometimes representing the leukaemia itself rather than infection.
• Bone or joint pain, refusal to walk, or a limp.
• Abdominal fullness or discomfort from hepatosplenomegaly.
• Testicular swelling.
• Headache, vomiting or visual change from CNS disease, especially in T-ALL.

Leukaemia also produces a general unwell feeling; weight loss can occur.

• Pallor, tachycardia and possibly a flow murmur from anaemia.
• Petechiae, purpura or ecchymoses.
• Palpable liver, spleen and lymph nodes.
• Testicular enlargement or asymmetry.
• Neurological signs of CNS involvement: papilloedema, cranial nerve palsies, ataxia, features of raised intracranial pressure.
• Rarely, superior vena cava syndrome in T-ALL with a large mediastinal mass (facial swelling, breathlessness).

A blood count is almost always abnormal, so every febrile child with cytopenias deserves an explanation.

ALL can present as single-organ disease: a mediastinal mass in T-ALL, testicular swelling, or marrow fibrosis with pancytopenia but few blasts in the blood (the Aleutian phenotype is not specific). In a young infant, leukaemia cutis or extreme hyperleucocytosis may appear before the marrow is obviously leukaemic. These cases still require a marrow and a full panel of investigations.

The febrile, bruised, anaemic child with cytopenias has several mimics, which the history and tests usually separate.

First line

• Full blood count with film. Anaemia, thrombocytopenia and leucocytosis or leucopenia are common. Neutropenia is the dangerous element. Blasts appear in the blood in many but not all children.
• Reticulocyte count and, in selected children, haematinic studies to clarify anaemia.
• Chest radiograph if respiratory or mediastinal features; it can show a mediastinal mass.

Confirmatory

• Bone marrow aspiration (and trephine). This is the diagnostic test. Flow cytometry gives the immunophenotype. Cytogenetics (karyotype and fluorescence in situ hybridisation) and, increasingly, molecular panels define the genetic subtype.
• Lumbar puncture for cerebrospinal fluid cytology (CNS status, classified CNS1/2/3) and for the first intrathecal treatment.
• Renal function, electrolytes (including calcium, phosphate and uric acid), lactate dehydrogenase and liver function, before starting therapy. These also inform TLS risk.

Immunophenotype and cytogenetics (the classifications you actually need)

B-cell ALL is defined by lymphoid markers (CD19, HLA-DR, CD79a, CD10 in most). The cytogenetic subtypes that change management include:^[1]

• ETV6::RUNX1 fusion, t(12;21)(p13;q22) - formerly TEL::AML1. This is the commonest translocation in childhood ALL, usually in children aged 2 to 9 years, and is associated with a favourable outcome. It is cryptic on standard karyotyping and detected by fluorescence in situ hybridisation.
• BCR::ABL1 fusion, the Philadelphia chromosome, t(9;22)(q34;q11) - present in about 2% of standard-risk and 5% of high-risk childhood B-ALL, increasing in adolescence. It produces a tyrosine kinase and is treated with a tyrosine kinase inhibitor added to chemotherapy. ^[1]
• KMT2A (MLL) rearrangements - especially t(4;11)(q21;q23) in infants; very high white counts, early CNS disease, poor outcome.
• TCF3::PBX1, t(1;19)(q23;p13) - pre-B immunophenotype, higher CNS relapse risk.
• High hyperdiploidy (51 to 65 chromosomes) - roughly a third of standard-risk and 14% of high-risk B-ALL, associated with a favourable outcome, especially trisomies of chromosomes 4 and 10. ^[1]
• Hypodiploidy (under 44 chromosomes) and iAMP21 - unfavourable.
• BCR::ABL1-like and alterations of IKZF1 or CRLF2 are increasingly used for risk stratification.

T-ALL is distinguished by T-cell markers and frequent NOTCH1/FBXW7 pathway variants; it is treated on separate trials. ^[1]

AML work-up is analogous but looks for myeloid-specific genetics and for central nervous system or extramedullary disease.

ALL is diagnosed when the bone marrow contains more than 25% lymphoblasts (M3 marrow).^[1] In practice almost all cases present at this level. The stage is described by:

• CNS status: CNS1 (no blasts in cerebrospinal fluid), CNS2 (< 5 white cells per microlitre with blasts on cytospin), CNS3 (5 or more white cells per microlitre with blasts, or clinical CNS disease). About 3% present as CNS3.^[1]
• Testicular involvement on examination and imaging.
• Immunophenotype and cytogenetics.

For B-ALL the widely used National Cancer Institute (NCI) risk criteria divide patients by age and presenting white count:

• NCI standard risk: age 1 to under 10 years, and white cell count under 50,000 per microlitre at diagnosis.
• NCI high risk: age 10 years or older, or white count 50,000 per microlitre or more.^[1]

NCI risk is then modified by extramedullary disease, early response and genetics to place a child into more detailed risk groups, from favourable through very high risk. For example, children with both favourable cytogenetics (high hyperdiploidy with double trisomy 4/10, or ETV6::RUNX1) and low minimal residual disease have event-free survival above 95%.^[1] Children with hypodiploidy, KMT2A::AFF1, TCF3::HLF, or induction failure are high risk.^[1] Philadelphia-chromosome-positive ALL is managed with tyrosine kinase inhibitors and is no longer automatically referred for transplant in first remission in most protocols.^[1]

T-ALL and infants are risk-stratified on different, T- and infant-specific measures.

The principle of modern ALL therapy is intense multi-drug chemotherapy with CNS-directed treatment from the start, tailored to risk. A typical backbone has three phases:

1. Remission induction (about 4 to 6 weeks). The goal is a marrow with under 5% blasts. Standard combinations are a glucocorticoid (dexamethasone or prednisone), vincristine and an asparaginase, with an anthracycline added for high-risk disease, plus intrathecal therapy.^[1]

• Dexamethasone penetrates the CNS better than prednisone and lowers CNS relapse, at the cost of more osteonecrosis in adolescents and higher rates of infection in older children.^[1]
• Asparaginase can cause pancreatitis, thrombosis and allergic reactions; levels and amylase are monitored.
• Most children (about 98%) reach remission.^[1]

2. Consolidation and intensification (months). Higher-dose antimetabolites and additional drugs (for example high-dose methotrexate, 6-mercaptopurine, cyclophosphamide and cytarabine), with more intrathecal therapy. Delayed intensification phases (re-induction) improve outcome in standard-risk disease. High-risk disease may intensify further or proceed to transplantation.

3. Maintenance (18 to 30 months, longer for boys in some protocols). Daily 6-mercaptopurine, weekly methotrexate, and periodic vincristine and glucocorticoid pulses, with intrathecal therapy in some groups.^[1]

CNS-directed therapy. Active intrathecal methotrexate (with or without cytarabine and hydrocortisone) and, in high-risk disease, cranial radiation in restricted circumstances. Because drugs reach the cerebrospinal fluid poorly, this therapy is given even when no blasts are seen in the spinal fluid, since most children would otherwise relapse in the CNS.^[1]

Targeted and immune therapy. For Philadelphia-chromosome-positive ALL, a tyrosine kinase inhibitor (imatinib or dasatinib) is added to all phases.^[1] In relapsed or refractory B-ALL, blinatumomab (a CD19/CD3 bispecific antibody), inotuzumab (anti-CD22) and CD19 chimeric antigen receptor (CAR) T-cell therapy achieve remissions, sometimes as bridges to transplant.^[1] Nelarabine is used for T-ALL.

Supportive care. Prophylaxis against Pneumocystis jirovecii, fungal prophylaxis in many regimens, prompt treatment of neutropenic fever, and allopurinol or rasburicase around initiation, because TLS is most likely at the start.

AML is treated with intensive multi-agent chemotherapy with cytarabine as the backbone, an induction phase, consolidation, and in selected children an allogeneic stem cell transplant. Induction classically uses an anthracycline and cytarabine (for example the ADE regimen, or daunorubicin or mitoxantrone with cytarabine and etoposide), and post-remission chemotherapy uses high-dose cytarabine.^[2]

Key points:

• AML remission rates are lower than ALL remission rates; roughly 85 to 90% achieve remission on modern regimens.^[2]
• Children with acute promyelocytic leukaemia (APL, PML::RARA from t(15;17)) are treated with all-trans retinoic acid and arsenic trioxide (plus cytoreduction) rather than conventional chemotherapy, and have excellent outcomes.^[2]
• Children with core binding factor AML (t(8;21), inv(16)) generally do well with chemotherapy alone.
• FLT3-internal tandem duplication disease is treated with FLT3 inhibitors such as sorafenib or midostaurin added to chemotherapy in trial settings.^[2]
• Gemtuzumab ozogamicin (an anti-CD33 antibody-drug conjugate) improves event-free survival in some trials.^[2]
• Allogeneic haematopoietic stem cell transplantation in first remission is reserved for high-risk disease and for some children with a matched sibling donor in trials; the benefit of transplant is strongest with poor-risk cytogenetics.^[2]

CNS prophylaxis in AML uses intrathecal therapy; therapeutic cranial irradiation is used rarely. For detailed dosing and trial selection, follow the institutional protocol rather than a general page.

• Down syndrome carries a 20- to 30-fold increased risk of ALL and an over 100-fold increased risk of AML, with a cumulative leukaemia risk of about 2.1% by age 5 and 2.7% by age 30.^[1]
• Roughly half to two thirds of childhood leukaemias in Down syndrome are ALL and 2 to 3% of ALL cases occur in children with Down syndrome.^[1]
• ALL in Down syndrome shows a near-absence of T-cell disease and fewer favourable (ETV6::RUNX1, high hyperdiploidy) and unfavourable (BCR::ABL1, KMT2A) alterations. About 50 to 60% have CRLF2 rearrangements.^[1]
• AML in Down syndrome is usually megakaryoblastic and occurs before age 4 (median 1 year); it is exquisitely sensitive to cytarabine and has better outcomes on reduced-intensity regimens.^[1][2]
• Children with Down syndrome and ALL have higher treatment-related mortality, mainly from infection, and benefit from risk-group-appropriate treatment with dose modification in high-risk regimens.^[1]

Newborns with Down syndrome can have a self-limited myeloproliferative disorder in the first months of life that is clonal (usually involving GATA1). It resolves spontaneously in many but can progress to AML of Down syndrome within the first few years and requires haematology follow-up.^[2]

Infection (including neutropenic sepsis), haemorrhage, central line complications, mucositis, pancreatitis and thrombosis from asparaginase, vincristine neuropathy, steroid-related osteonecrosis and hyperglycaemia, anthracycline cardiotoxicity, and secondary malignancies (including therapy-related myeloid neoplasms after alkylating agents or topoisomerase II inhibitors). Many children also carry late effects including neurocognitive sequelae after cranial irradiation.

Outcomes depend strongly on subtype:

• With current regimens about 85% of children aged 1 to 18 years with newly diagnosed ALL are long-term event-free survivors, and more than 90% are alive at 5 years.^[1]
• B-ALL event-free survival is above 85% for children aged 1 to under 10 years with white counts under 50,000 per microlitre, and about 75% for high-risk disease.^[1]
• Infants with KMT2A rearrangements have 5-year event-free survival of only 35 to 40%.^[1]
• Hypodiploidy and induction failure carry high relapse rates.
• AML 5-year event-free and overall survival have improved and are roughly 55 to 70% in published series, with event-free survival around 45 to 55% and core binding factor AML and AML of Down syndrome doing better.^[2]

Relapses most often occur within the first 6 to 7 years after diagnosis; relapse-free children beyond this point have mortality approaching population levels.^[1]

TLS is an oncological emergency: the rapid bulk death of tumour cells, spontaneously or after therapy, releases intracellular potassium, phosphate and nucleic acids (metabolised to hypoxanthine, xanthine and uric acid) into the blood, together with cytokines. The result is the characteristic quadruple of hyperkalaemia, hyperphosphataemia, hypocalcaemia and hyperuricaemia, which can progress to arrhythmia, seizure, tetany, acute kidney injury and death from multi-organ failure.^[3]

Leukaemia (especially with high white counts) and lymphoma are the malignancies in which TLS is most common, and it tends to appear 48 to 72 hours after starting therapy or, less often, spontaneously.^[3][4]

When cells lyse, DNA is converted to adenosine and guanosine, then xanthine, which xanthine oxidase oxidises to uric acid. Because humans lack urate oxidase, uric acid is the end product. Hyperphosphataemia drives secondary hypocalcaemia, and both uric acid and calcium phosphate crystals obstruct renal tubules. High solute levels, low solubility, acidic urine and low flow favour crystallisation; high uric acid plus high phosphate is particularly dangerous because the crystals seed each other.^[3] Released cytokines can produce a systemic inflammatory picture and further kidney injury.

The Cairo-Bishop criteria define laboratory TLS when two or more of the following are present within 3 days before or 7 days after starting therapy: hyperuricemia (uric acid above 8.0 mg per decilitre in adults or above the age-appropriate upper limit in children), hyperphosphataemia (phosphorus above 4.5 mg per decilitre in adults or above 6.5 mg per decilitre in children), hyperkalaemia (potassium above 6.0 mmol per litre) and hypocalcaemia (corrected calcium under 7.0 mg per decilitre or ionised calcium under 1.12 mg per decilitre). Clinical TLS is laboratory TLS plus creatinine rise, arrhythmia, seizure, or death. (Any symptomatic hypocalcaemia should be regarded as clinical TLS.)^{[3] [4]}

Higher risk comes with a large tumour burden, leukaemias and lymphomas with high proliferative rates, high white count or lactate dehydrogenase, pre-existing renal impairment, dehydration, hypotension and acidic urine.^[3] Lactate dehydrogenase above twice the upper limit of normal and an elevated uric acid at presentation can help classify borderline cases as higher risk.^[3]

Hydration is the cornerstone. In adults at highest risk and in children with a bulky, lysing tumour, intravenous fluids at 2,500 to 3,000 mL per square metre per day increase urine flow and renal perfusion, dilute solutes, and reduce crystallisation.^[3] Expert consensus and Medscape summaries give practical equivalents:^[4]

• Low-risk patients: oral or intravenous fluids 2 to 3 litres per square metre daily, starting before therapy and continuing to the day after chemotherapy. ^[4]
• Intermediate- or high-risk patients: continuous intravenous infusion 2 to 3 litres per square metre daily, starting 24 to 48 hours before therapy and continuing 48 to 72 hours after, aiming for a urine output of 80 to 100 mL per square metre per hour (about 3 litres daily). Use isotonic fluids; avoid potassium, calcium and phosphate; monitor hydration status every 6 to 8 hours; use diuretics only in well-hydrated patients.^[4]

Uric acid reduction.

• Rasburicase (recombinant urate oxidase) converts uric acid to allantoin, which is very soluble. It is the preferred agent in high-risk children, acting within hours, and rasburicase-treated children are far less likely to need dialysis than those given allopurinol alone.^[3] Standard regimen is 0.2 mg per kilogram daily for 5 days, with many centres now using a single weight-based or fixed low dose; guidelines note that one dose suffices in most patients, with careful follow-up.^[4]
• Rasburicase is contraindicated in glucose-6-phosphate dehydrogenase (G6PD) deficiency (risk of haemolysis and methaemoglobinaemia) and in pregnancy. Screen patients of African or Mediterranean ancestry before use. Draw blood for uric acid into pre-chilled heparin tubes on ice and assay within 4 hours, because the enzyme continues to act in the tube.^[3][4]
• Allopurinol (a xanthine oxidase inhibitor) reduces uric acid production and is used where TLS risk is low or intermediate, or where rasburicase is unavailable. Oral prophylaxis in adults is typically 600 mg daily, with treatment doses of 600 to 900 mg daily (up to 500 mg per square metre daily), and intravenous preparations exist for patients unable to take tablets. It needs dose reduction in renal impairment, interacts with mercaptopurine, thioguanine and azathioprine, and can cause xanthine stones because xanthine is less soluble than uric acid. Some authors have questioned whether xanthine oxidase inhibitors are useful without rasburicase in high-risk disease.^[4][5]
• Febuxostat is a non-purine xanthine oxidase inhibitor that can be used in adults with allopurinol hypersensitivity or renal impairment, but paediatric safety and efficacy are not established and it carries a cardiovascular warning; it is generally second line.^[4][5]
• Urinary alkalinisation is controversial: it increases uric acid solubility but decreases calcium phosphate solubility and can worsen hypocalcaemia. If used, stop when hyperphosphataemia develops or uric acid normalises. The aim, if used, is urine pH 7.0 to 7.5; avoid overshooting.^[4][3]

Medical reduction of potassium, calcium and phosphate:

• Restrict potassium intake, withhold potassium-containing fluids, shift potassium intracellularly with insulin and glucose (with frequent glucose checks), and use calcium gluconate as membrane protection when the potassium is above 6.5 mmol per litre or the electrocardiogram shows changes.
• Treat hyperphosphataemia with oral phosphate binders (for example sevelamer), use the same insulin and glucose infusion as for potassium, and do not correct hypocalcaemia routinely: only treat symptomatic hypocalcaemia (tetany, arrhythmia), using the lowest dose needed, because excess calcium raises the calcium-phosphate product and drives tissue crystallisation. (Treatment is also withheld until phosphate is controlled to avoid calcification.)
• Monitoring in high-risk patients is at least three times daily for the first 48 to 72 hours, including urea and creatinine, uric acid, potassium, calcium, phosphate and lactate dehydrogenase, with a baseline electrocardiogram.^[4]

Dialysis. Indications include persistent hyperkalaemia or hyperphosphataemia despite treatment, volume overload, uraemia, symptomatic hypocalcaemia and hyperuricaemia; in TLS the thresholds for dialysis are lower and continuous renal replacement therapies are often favoured for phosphate removal.^[3][4]

Where rasburicase, rapid laboratory turnover and dialysis are unavailable, spontaneous TLS and acute kidney injury are far more common. A cohort of children in a resource-limited setting used universal febuxostat because of rasburicase unavailability and high G6PD prevalence, with acute kidney injury in 92% despite xanthine oxidase inhibition; the authors argue that universal rasburicase access is critical.^[5] Sensible measures still within reach are: ensure adequate hydration and urine output, monitor electrolytes as frequently as possible, avoid nephrotoxic drugs, start xanthine oxidase inhibition early rather than delaying, use phosphate binders and glucose-insulin infusions, and plan early referral for dialysis whenever feasible.^[5]

• ALL is the commonest childhood cancer, about 25% of cancers in children under 15; AML is about 20% of childhood leukaemias.
• Presentation reflects bone marrow failure (anaemia, thrombocytopenia, neutropenia) plus infiltration (hepatosplenomegaly, lymphadenopathy, bone pain, and testicular or CNS disease).
• Diagnosis requires a marrow with more than 25% blasts; immunophenotype distinguishes B- from T-ALL, and cytogenetics separates the major subtypes (ETV6::RUNX1 favourable, Philadelphia chromosome targeted with tyrosine kinase inhibitors, KMT2A rearrangement in infants high risk).
• NCI standard risk is age 1 to under 10 years with a white count under 50,000 per microlitre; high risk is age 10 or over or white count 50,000 or more. ^[1]
• Treatment is phased: induction (remission), consolidation (intensification), maintenance, with CNS-directed therapy throughout; blinatumomab, inotuzumab, CAR T-cell and targeted drugs matter in relapse and in specific subtypes.
• Children with Down syndrome have a markedly increased leukaemia risk and need treatment modifications, especially protection from treatment-related mortality.
• TLS is defined by hyperkalaemia, hyperphosphataemia, hypocalcaemia and hyperuricaemia 3 days before to 7 days after starting therapy; clinical TLS adds organ injury.
• Prevention is hydration 2,500 to 3,000 mL per square metre daily plus rasburicase for high-risk children (0.2 mg/kg/day) or allopurinol for lower risk, with G6PD screening and early dialysis when needed.

This topic should be read alongside the haematology chapter's acute leukaemias page, the acute lymphoblastic leukaemia staging and minimal residual disease notes, and the neutropenic fever, acute kidney injury, hyperkalaemia, hypocalcaemia and hyperuricaemia topics.