Acute lymphoblastic leukaemia

01OverviewDefinition, clinical context and the essential points that orientate the chapter.

ALL is a clonal precursor B- or T-cell malignancy that replaces marrow and can infiltrate lymph nodes, spleen, CNS, testes and mediastinum. Presentation includes fatigue, fever, bruising, bone or joint pain, lymphadenopathy and hepatosplenomegaly. T-ALL commonly presents in adolescent or young adult men with a mediastinal mass. Assess ability to lie flat, stridor, superior vena cava obstruction and pericardial effusion before sedation, general anaesthesia or central access. In stable patients avoid corticosteroids until diagnostic samples are secured because they can rapidly lyse blasts and alter phenotype.

Diagnosis requires integrated morphology, flow and genetics. Bone marrow establishes burden and supplies flow cytometry, karyotype, FISH and molecular tests; trephine supports difficult aspirates. Flow defines B-lineage markers such as CD19, CD22, CD79a and cytoplasmic CD3 for T lineage, while also identifying targets for immunotherapy and a leukaemia-associated phenotype for MRD. Urgently determine BCR::ABL1, KMT2A rearrangement, hypodiploidy and other current risk lesions. Use a validated quantitative molecular or flow assay for later response, and consider germline referral when phenotype or family history supports it.

Stabilise sepsis, lysis and anatomy. Obtain cultures and give local neutropenic-sepsis antibiotics promptly. Classify tumour-lysis risk from count, LDH, disease burden and renal function; provide hydration, allopurinol or rasburicase and frequent potassium, phosphate, calcium, urate and creatinine tests. A large mediastinal mass demands senior anaesthetic and respiratory planning; supine sedation can convert partial compression into complete obstruction. Treat symptomatic hyperleukocytosis with protocol steroids or chemotherapy after essential samples, avoiding routine leukapheresis unless a specialist team identifies an exceptional indication.

Curative treatment is protocolised and multi-phase. Induction commonly combines a corticosteroid, vincristine, anthracycline and asparaginase with age- and fitness-adjusted additions. Consolidation and delayed intensification eradicate resistant compartments. Intrathecal methotrexate-based CNS treatment occurs throughout; cranial radiotherapy is reserved for selected indications. Maintenance commonly uses oral mercaptopurine and weekly methotrexate with protocol pulses for two to three years. Each medicine has dose-modification rules based on cytopenia, liver, pancreas, thrombosis, infection and pharmacogenetics; do not reconstruct the regimen from individual SmPCs.

Philadelphia-positive B-ALL integrates a BCR::ABL1 TKI from early treatment. Imatinib, dasatinib or ponatinib selection and dose depend on the current UK protocol, mutation, cardiovascular risk and CNS strategy. Molecular BCR::ABL1 response and flow MRD guide whether allogeneic transplantation is needed. A discordance between BCR::ABL1 and flow can reflect multilineage disease and needs expert interpretation. Do not manage Ph-positive ALL like chronic-phase CML: chemotherapy or immunotherapy, CNS treatment and transplant assessment remain central.

Blinatumomab links CD19-positive blasts to T cells. Current NICE recommendations include eligible MRD-negative adults at consolidation, MRD-positive first remission and previously treated Philadelphia-negative B-ALL. A remission MRD regimen is continuous IV 28 micrograms/day for 28 days followed by 14 treatment-free days. Admit or closely observe for cycle starts according to the SmPC; premedicate and monitor for cytokine-release syndrome, encephalopathy, seizures, infection, lysis and line or pump failure. Interrupt and restart only through grade-specific rules.

Inotuzumab ozogamicin targets CD22 and can bridge relapsed or refractory B-ALL to transplant. Its first cycle total is 1.8 mg/m² divided across days 1, 8 and 15; later dosing depends on whether remission occurs. The key harm is sinusoidal obstruction syndrome, especially around allogeneic transplant and with dual-alkylator conditioning. Limit cycles before transplant when possible and monitor weight, bilirubin, liver tests and painful hepatomegaly. Relapsed disease requires repeat marrow, flow antigen expression, BCR::ABL1 or other genetics and CNS assessment because the clone may evolve.

Supportive care follows phase-specific transfusion, infection, fertility and vaccination protocols. Asparaginase can cause both thrombosis and bleeding, so monitoring and re-exposure decisions must use the regimen rather than an isolated fibrinogen result.

Key points

Suspect ALL with unexplained cytopenias, circulating blasts, bone pain, lymphadenopathy, hepatosplenomegaly, testicular symptoms or a mediastinal mass; total WBC may be low, normal or high.
First-line confirmation is expert FBC and film followed urgently by marrow aspirate and trephine, multiparameter flow, cytogenetics or FISH and a comprehensive molecular panel.
Determine B- versus T-lineage and urgently test BCR::ABL1 because Philadelphia-positive ALL requires a tyrosine kinase inhibitor integrated into the systemic protocol.
Preserve diagnostic material before non-essential corticosteroids: even brief steroid exposure can reduce blasts, obscure immunophenotype and complicate risk stratification.
Adult treatment is multi-phase: prephase when used, induction, consolidation or intensification, CNS-directed intrathecal therapy and prolonged maintenance, with exact drugs and timing set by UKALL or centre protocol.
Measurable residual disease after induction and consolidation is the principal response measure and guides blinatumomab, allogeneic transplant and relapse-risk decisions.
NICE now supports blinatumomab with chemotherapy at the start of consolidation for eligible adults with Philadelphia-negative, CD19-positive B-cell precursor ALL that is MRD negative.
Blinatumomab is also commissioned for defined MRD-positive remission and relapsed or refractory B-ALL populations; monitor cytokine-release and neurological toxicity in a trained service.
Relapsed B-ALL is re-phenotyped before commissioned antibody, TKI, cellular or transplant treatment is selected.

02AetiologyUnderlying causes, associations and risk factors, with why each one matters.

Acquired lymphoid lesions

Chromosomal rearrangements, aneuploidy and mutations alter differentiation and survival in an early B- or T-lymphoid precursor, creating a clonal blast population.

Age-related genetic spectrum

Philadelphia chromosome and other adverse lesions become more frequent with age, while selected favourable subtypes are enriched in children and young adults.

Inherited susceptibility

Down syndrome and rare germline cancer-predisposition or marrow-failure syndromes increase risk and can alter chemotherapy toxicity, family counselling and donor selection.

Therapy-related occurrence

A minority follows previous cytotoxic treatment or malignancy, often with high-risk genetics that influence transplant and trial decisions.

03PathophysiologyThe causal sequence from the underlying abnormality to symptoms and harm.

1
Lymphoblast expansion
An arrested B- or T-lineage progenitor proliferates in marrow and blood, displacing normal haematopoiesis and causing cytopenic infection, bleeding and anaemia.
2
Sanctuary-site persistence
The blood–brain and blood–testis barriers limit exposure to some systemic drugs, requiring scheduled intrathecal therapy and site-specific treatment even without symptoms.
3
High lysis potential
Rapidly proliferating, treatment-sensitive lymphoblasts can release potassium, phosphate and nucleic acids abruptly, causing arrhythmia, seizures and urate-mediated kidney injury.
4
Measurable residual clones
Submicroscopic surviving cells after induction predict relapse more accurately than morphology and can be targeted with immunotherapy or transplantation.

04Clinical features and red flagsSymptoms, examination findings, patterns of presentation and time-critical warnings.

Marrow failure

Pallor, fatigue, fever, oral ulceration, petechiae, bruising or bleeding reflects anaemia, neutropenia and thrombocytopenia.

Bone and tissue disease

Bone pain, lymph nodes, hepatosplenomegaly and testicular enlargement accompany marrow blasts and extramedullary infiltration.

T-lineage mediastinal massRed flag

Cough, orthopnoea, facial swelling, stridor or inability to lie flat signals compressive anterior mediastinal disease and procedural risk.

CNS involvement

Headache, vomiting, cranial nerve palsy, seizures or focal deficit raises concern for meningeal disease but lumbar puncture needs procedural safety.

Red flags requiring action

Fever, hypotension, confusion or hypoxia with neutropenia needs immediate broad-spectrum antibiotics; do not wait for leukaemia confirmation or a positive culture.
Orthopnoea, stridor, facial swelling, venous distension or inability to lie flat with an anterior mediastinal mass suggests airway or superior vena cava compromise and makes sedation hazardous.
Hyperkalaemia, hyperphosphataemia, hypocalcaemia, rising urate or creatinine before treatment suggests spontaneous tumour lysis and requires cardiac monitoring and metabolic intervention.
Headache, cranial neuropathy, vomiting, focal deficit, testicular enlargement or pain can represent sanctuary-site involvement and changes staging and treatment.

05InvestigationsWhat to request, why it matters and how to interpret it.

Investigation order

Read from the initial assessment onwards. Tests may run in parallel in urgent care; first-line, preferred, confirmatory, definitive and gold-standard labels appear only when the chapter explicitly states them.

01
First-line: FBC and expert filmFirst stepFirst line
Why
Identify cytopenias, blast burden and an urgent acute-leukaemia pattern.
Interpretation and limitations
Lymphoblast morphology is not sufficiently specific for lineage; a low blast count in blood does not exclude extensive marrow disease.
02
Reference-standard integrated marrow diagnosis
Why
Confirm precursor lineage and establish genetic risk and measurable disease markers.
Interpretation and limitations
Combine aspirate morphology, multiparameter flow, trephine histology, karyotype, FISH and molecular testing; mixed-phenotype cases require strict lineage criteria.
03
Urgent BCR::ABL1 and risk genetics
Why
Start a TKI promptly and identify biology affecting protocol and transplant.
Interpretation and limitations
Use rapid FISH or RT-PCR plus full transcript characterisation; document KMT2A, ploidy and the current accredited ALL panel rather than relying on Philadelphia status alone.
04
CNS and sanctuary assessment
Why
Identify disease that alters intrathecal frequency and local treatment.
Interpretation and limitations
Perform atraumatic lumbar puncture with flow or cytology only when platelets, coagulation, intracranial pressure and mediastinal anatomy are safe; examine testes clinically.
05
Measurable residual disease
Why
Quantify depth and kinetics of response below morphological remission.
Interpretation and limitations
Use validated flow or molecular testing at protocol time points. Confirm unexpected positivity and integrate sensitivity, regenerating marrow and genotype before transplant or immunotherapy decisions.
06
Treatment safety baseline
Why
Prevent lysis and organ-specific chemotherapy harm.
Interpretation and limitations
Check lysis chemistry, coagulation and fibrinogen, renal and liver function, amylase or lipase, viral serology, ECG, echocardiogram, pregnancy, fertility and HLA status.

06Differential diagnosisRealistic alternatives and the features that help distinguish them.

Acute myeloid leukaemia

AML can present identically with marrow failure and blasts; multiparameter flow, cytochemistry and defining molecular lesions establish lineage.

Lymphoblastic lymphoma

The same precursor biology may present predominantly as tissue disease with limited marrow blasts, particularly T-lineage mediastinal disease, and uses related protocols.

Infectious mononucleosis

EBV causes fever, nodes, splenomegaly and reactive lymphocytes, but the cells are heterogeneous mature lymphocytes rather than a clonal precursor population.

Aplastic or infiltrative marrow disease

Aplastic anaemia, lymphoma, metastatic cancer and marrow fibrosis cause cytopenias without the characteristic precursor flow and ALL genetic profile.

07ManagementImmediate care, first-line treatment, alternatives and escalation.

01Suspected ALLSecure samples and stabilise emergenciesFirst stepBlasts, unexplained cytopenia, mediastinal mass or lymphoblastic tissue disease is found.

1Obtain blood and marrow flow, genetic and MRD-marker material before non-essential steroid exposure when physiology permits.
2Treat sepsis and lysis, assess airway and SVC compromise and use anaesthetic expertise before sedation or supine procedures.
3Classify B or T lineage, BCR::ABL1 and current risk genetics through the specialist MDT.

02New diagnosisDeliver the complete multi-phase protocolIntegrated testing confirms ALL and curative treatment is appropriate.

1Choose the age-, fitness-, lineage- and genotype-appropriate UK protocol and complete organ, fertility and infection preparation.
2Give induction, CNS-directed treatment, consolidation or intensification and maintenance with protocol toxicity modifications.
3Measure MRD at each specified landmark and use result and genetics to select blinatumomab and allogeneic transplant.

03Philadelphia-positive ALLIntegrate TKI and MRDBCR::ABL1 is demonstrated in B-lineage ALL.

1Start the protocol-selected TKI promptly after interaction, cardiovascular and reproductive assessment.
2Continue systemic and CNS-directed ALL therapy and follow both flow and quantitative BCR::ABL1 response.
3Use response, mutation analysis and transplant fitness to choose consolidation, immunotherapy and allogeneic transplantation.

04Relapsed B-ALLReconfirm targets before salvageMarrow, molecular, CNS or testicular relapse occurs.

1Repeat marrow flow for CD19 and CD22, genetics and BCR::ABL1 mutation where relevant and restage sanctuary sites.
2Select commissioned blinatumomab, inotuzumab, TKI, CAR-T or chemotherapy according to target and prior therapy.
3Control lysis and toxicity and decide whether response leads to allogeneic transplant or another cellular strategy.

Key medicines and prescribing safety5 treatments · regimens, roles and cautions

Curative multi-phase eradication of systemic, resistant and CNS or testicular sanctuary disease.

Protocol adult ALL chemotherapy

Use the exact current UKALL or centre protocol for corticosteroid, vincristine, anthracycline, asparaginase, consolidation, intrathecal therapy and oral maintenance; doses are body-surface-area, age, phase and toxicity dependent and cannot be safely combined from a generic list.

Independently verify every phase and intrathecal route. Monitor marrow, infection, neuropathy, thrombosis, fibrinogen, antithrombin, pancreas, liver, glucose and cardiac function; apply TPMT or NUDT15 and interaction rules where required. Provide fertility and pregnancy counselling.

CD19-directed T-cell engager that can eradicate measurable residual B-ALL before relapse or transplantation and is also used in defined consolidation and relapsed settings.

Blinatumomab in MRD-positive remission

For adults at least 45 kg give 28 micrograms/day by continuous IV infusion on days 1–28 followed by 14 treatment-free days per cycle, for up to four cycles within the commissioned MRD-positive remission pathway.

Premedicate and use the exact indication-specific SmPC schedule. Monitor cytokine-release syndrome, encephalopathy, seizure, infection, lysis, pancreatitis and pump interruption; hospital observation is required for specified early days. Avoid pregnancy and breastfeeding.

CD22-targeted antibody–drug conjugate for relapsed or refractory B-cell precursor ALL, often to obtain remission before allogeneic transplant.

Inotuzumab ozogamicin

In cycle 1 give total 1.8 mg/m² IV as 0.8 mg/m² day 1 and 0.5 mg/m² on days 8 and 15; subsequent cycles use the remission-dependent SmPC schedule, usually 0.5 mg/m² on days 1, 8 and 15 after complete remission.

Monitor sinusoidal obstruction syndrome, bilirubin, liver tests, weight gain, painful hepatomegaly, QT, lysis, cytopenia and infection. Minimise cycles before transplant and avoid dual-alkylator conditioning when possible; use effective contraception and stop breastfeeding.

BCR::ABL1 kinase inhibition started early in Philadelphia-positive ALL to deepen molecular response and support curative systemic therapy.

Imatinib for Philadelphia-positive ALL

Give 600 mg orally once daily with a meal and large glass of water when imatinib is the TKI selected, integrated with the exact Ph-positive ALL chemotherapy or immunotherapy protocol rather than as isolated monotherapy in newly diagnosed disease.

Review CYP3A interactions, oedema, cytopenia, liver, renal and cardiac function and molecular response. It is teratogenic; prevent pregnancy during treatment and stop breastfeeding. A different TKI may be preferred for mutation, CNS penetration or protocol reasons.

Rapid destruction of existing uric acid in high-burden, highly treatment-sensitive ALL.

Rasburicase

Give 0.2 mg/kg IV once daily for up to 7 days for high-risk or established tumour lysis, individualising actual doses to burden, urate and response under the current BSH protocol.

Contraindicated in G6PD deficiency because of haemolysis and methaemoglobinaemia. Test at-risk ancestry if urgency permits and transport post-dose urate samples on ice for immediate analysis.

08ComplicationsImportant consequences, why they occur and why they matter clinically.

Sepsis and bleeding

Disease and prolonged multi-agent therapy suppress neutrophils and platelets, producing bacterial or fungal infection and mucosal, gastrointestinal or intracranial haemorrhage.

Tumour lysis

Spontaneous or treatment-triggered cell breakdown can cause acute kidney injury, arrhythmia, seizures and death without risk-adapted prophylaxis and frequent chemistry.

Treatment-specific organ injury

Asparaginase causes thrombosis, bleeding, pancreatitis and liver injury; anthracyclines cause cardiotoxicity, steroids metabolic toxicity and immunotherapies neurological or hepatic syndromes.

Relapse in marrow or sanctuary sites

Residual disease can recur in marrow, CNS or testes; lineage, antigen expression and genetics may change and require complete reassessment.

09Monitoring and follow-upTreatment response, safety checks and longer-term review.

During induction monitor FBC, cultures and infection, lysis chemistry, coagulation and fibrinogen, liver, pancreas, glucose, cardiac and neurological toxicity according to the phase protocol.
Track asparaginase activity and antithrombin or fibrinogen only as specified by the regimen and manage thrombosis, pancreatitis or hepatic toxicity through re-exposure rules.
Measure MRD after induction and at each consolidation landmark using the same validated method; repeat an unexpected result before irreversible transplant decisions when safe.
During blinatumomab monitor neurological examination, temperature, blood pressure, oxygenation, lysis chemistry, FBC, infection and uninterrupted pump delivery, especially at start and dose escalation.
After treatment monitor marrow and molecular relapse, CNS or testicular symptoms, cardiometabolic and bone effects, fertility, vaccination recovery, second malignancy and psychosocial function.

10Special situationsVariants, exceptions and circumstances that change the usual approach.

Steroids can erase evidence

ALL blasts are exquisitely steroid sensitive. When stable, obtain flow and genetic material before empiric steroids so lineage, targets and baseline MRD markers are preserved.

Mediastinal procedures are dangerous

A patient who cannot lie flat can lose airway or venous return after sedation. Diagnostic ambition must yield to awake, position-preserving anaesthetic planning.

MRD outranks morphology

A marrow with fewer than 5% blasts can still contain a clinically important resistant population that changes immunotherapy and transplant strategy.

CNS prophylaxis is universal

Absence of neurological signs does not remove sanctuary risk. Intrathecal therapy is built into the protocol, but safe timing prevents traumatic seeding and bleeding.

Antigen targets can disappear

CD19 or CD22 expression may change after targeted therapy. Re-biopsy at relapse prevents repeating an elegant treatment against a missing target.

11Common pitfallsFrequent interpretation and management errors.

01
Do not give non-essential corticosteroids before diagnostic flow and molecular samples in a stable suspected ALL presentation.
02
Do not sedate or lay flat a patient with symptomatic mediastinal compression without a senior airway plan.
03
Do not manage Philadelphia-positive ALL with a TKI alone as though it were chronic-phase CML.
04
Do not omit CNS-directed therapy because initial CSF is negative, and do not perform lumbar puncture through unsafe coagulopathy or pressure anatomy.
05
Do not call morphological remission adequate without the protocol MRD result.
06
Do not send a patient to transplant after inotuzumab without minimising sinusoidal obstruction risks and planning liver monitoring.