Acute leukaemia

Overview

Acute leukaemia is a cancer of immature blood cells (blasts). A mutated stem or progenitor cell keeps dividing but fails to mature. Blasts fill the marrow, crowd out normal blood production and spill into the blood and organs. Untreated, it kills in weeks to months.

• Acute myeloid leukaemia (AML): myeloid blasts; mainly older adults (median age around 65).
• Acute lymphoblastic leukaemia (ALL): lymphoblasts; the commonest cancer of childhood (peak in early childhood), also seen in adults.

The diagnosis rests on 20% or more blasts in the marrow or blood (WHO). Some AML types with specific genetic changes (e.g. t(15;17), t(8;21), inv(16)) count as AML whatever the blast count.

Risk factors

• Genetic: Down syndrome (risk of acute leukaemia about 30 times higher), Fanconi anaemia, ataxia telangiectasia, Bloom syndrome, Li–Fraumeni syndrome, Klinefelter syndrome; twin concordance.
• Radiation (atomic bomb survivors, radiotherapy).
• Chemicals: benzene, smoking.
• Previous chemotherapy: alkylating agents and topoisomerase II inhibitors (etoposide) → therapy-related AML.
• Pre-existing blood disease: myelodysplastic syndrome, myeloproliferative neoplasms (CML blast crisis), aplastic anaemia, PNH.
• Viruses: HTLV-1 (adult T-cell leukaemia/lymphoma).

Presentation

Symptoms come from marrow failure, tissue infiltration and substances released by leukaemic cells. The history is usually short (days to weeks).

Classification

AML (FAB types, still asked in MCQs)

The WHO system now groups AML mainly by genetics: defined genetic subtypes, AML arising from myelodysplasia, and therapy-related AML.

ALL

• B-ALL (most cases, especially children): CD10, CD19, CD20 (variable), TdT.
• T-ALL: CD3, CD7, TdT, no CD10; teenage boys with a mediastinal (thymic) mass and high white count.
• Old FAB L1–L3 (L3 = mature B-cell/Burkitt type) is now outdated.

Microscopic picture

• Blasts: large cells with a high nucleus-to-cytoplasm ratio, fine open chromatin and prominent nucleoli.
• Myeloblasts: more cytoplasm, often granular, several nucleoli, may contain Auer rods (pink-red needle-shaped crystals of myeloperoxidase).
• Lymphoblasts: smaller, scanty agranular cytoplasm, less obvious nucleoli; no Auer rods.
• APML: abnormal hypergranular promyelocytes with bundles of Auer rods (faggot cells).
• Leukaemic hiatus: blasts and a few mature neutrophils with almost no cells in between (unlike CML, which shows all stages).
• Marrow: hypercellular, replaced by blasts; reduced red cell precursors and megakaryocytes.

Lab investigations

Full blood count and film

• Anaemia (normocytic) and thrombocytopenia.
• White count usually raised (can be very high) but may be normal or low ("aleukaemic" leukaemia when blasts stay in the marrow).
• Blasts on the film in most cases.

Bone marrow aspirate and trephine (confirmatory)

• 20% or more blasts; hypercellular marrow.
• Trephine if the aspirate is a dry tap (fibrosis, packed marrow).

Cytochemistry

Immunophenotyping (flow cytometry): the key step to confirm lineage

Cytogenetics, FISH and molecular tests (for prognosis and targeted therapy)

Other tests

• Coagulation screen (PT, APTT, fibrinogen, D-dimers): looks for DIC, especially in APML.
• Biochemistry: urate, potassium, phosphate, calcium, creatinine, LDH, liver function (tumour lysis risk).
• Chest X-ray: mediastinal mass in T-ALL.
• Lumbar puncture in ALL (CNS involvement), done with platelet cover once blasts clear from the blood.
• ECG and echocardiogram before anthracyclines.
• HLA typing for possible transplant; viral serology (HIV, hepatitis B and C); blood group.

Role of the leucocyte alkaline phosphatase (LAP) score

• LAP is an enzyme in mature neutrophils. The score grades staining in 100 neutrophils.
• Low LAP: chronic myeloid leukaemia (also PNH).
• High LAP: leukaemoid reaction (reactive neutrophilia from infection or inflammation), polycythaemia vera, myelofibrosis, pregnancy, steroid treatment.
• Its classic use is to separate CML (low) from a leukaemoid reaction (high) when the white count is very high.
• It does not diagnose acute leukaemia; that needs the blast count, cytochemistry and flow cytometry. Today it has largely been replaced by BCR-ABL1 testing for CML.

Complications

• Infection (bacterial, fungal such as Aspergillus and Candida, viral, Pneumocystis): the leading cause of death during treatment. Neutropenic fever needs immediate IV broad-spectrum antibiotics.
• Bleeding: thrombocytopenia, DIC (APML), intracranial haemorrhage.
• Leukostasis: very high blast counts block small vessels in lungs and brain. Treat with hydration, urgent chemotherapy or hydroxycarbamide, sometimes leucapheresis; avoid red cell transfusion until the count falls (it raises viscosity).
• Tumour lysis syndrome: hyperkalaemia, hyperphosphataemia, hypocalcaemia, hyperuricaemia and acute kidney injury, especially in ALL and high counts. Prevent with IV fluids and allopurinol or rasburicase (rasburicase is contraindicated in G6PD deficiency).
• CNS and testicular relapse (ALL).
• APML differentiation syndrome on ATRA or arsenic: fever, breathlessness, pulmonary infiltrates, fluid retention; treat with dexamethasone.
• Late effects of treatment: infertility, cardiotoxicity (anthracyclines), second cancers, growth and learning problems in children, avascular necrosis (steroids).

Treatment

Supportive care (all patients)

• Treat in a specialist unit; central venous line (PICC or Hickman).
• Red cell transfusion for symptomatic anaemia (irradiated products when needed).
• Platelet transfusion: keep platelets above 10 × 10^9/L in stable patients, above 20 if septic and above 50 before procedures such as lumbar puncture.
• FFP and cryoprecipitate for DIC.
• Infection prevention: hand hygiene, isolation, prophylactic antifungals, antivirals and co-trimoxazole for Pneumocystis as indicated.
• Hydration and allopurinol (or rasburicase) for tumour lysis prevention.
• Sperm or egg storage where time allows; psychological support.

Specific treatment: the phases

1. Induction: intensive chemotherapy to achieve complete remission (normal blood counts and fewer than 5% blasts in the marrow).
2. Consolidation (intensification): further courses to kill remaining cells; without this, relapse is almost certain.
3. Maintenance: for ALL only (about 2 years of oral methotrexate and mercaptopurine).
4. Allogeneic stem cell transplant in first remission for high-risk disease if the patient is fit and a donor is available.
5. Minimal residual disease (MRD) testing guides how intensive treatment should be.

AML

• Induction: daunorubicin (an anthracycline) plus cytarabine.
• About 80% of fit adults under 60 reach remission.
• Consolidation: high-dose cytarabine; transplant for intermediate and adverse genetics; not for favourable genetics in first remission.
• Targeted add-ons: midostaurin (FLT3 mutation), gemtuzumab ozogamicin (anti-CD33).
• Older or unfit patients: low-intensity therapy (azacitidine, low-dose cytarabine, venetoclax combinations) or palliative care.

Acute promyelocytic leukaemia (APML)

• A medical emergency because of DIC and early bleeding deaths.
• Start ATRA (all-trans retinoic acid) as soon as APML is suspected on the film, before genetic confirmation.
• ATRA makes the abnormal promyelocytes differentiate; arsenic trioxide induces apoptosis. ATRA plus arsenic (or ATRA plus anthracycline chemotherapy in high-risk cases) gives remission in at least 90% of younger adults, and most are cured.
• Support coagulation with platelets, FFP and cryoprecipitate.
• Watch for differentiation syndrome.

ALL

• Induction: vincristine, a steroid (prednisolone or dexamethasone), an anthracycline and asparaginase.
• CNS-directed therapy for everyone: intrathecal methotrexate (± cytarabine, hydrocortisone) and high-dose systemic methotrexate; cranial irradiation only for very high risk. The CNS and testes are sanctuary sites where most drugs do not reach.
• Maintenance: about 2 years of daily mercaptopurine and weekly methotrexate with periodic vincristine and steroid pulses.
• Philadelphia-positive ALL: add a tyrosine kinase inhibitor (imatinib, dasatinib).
• Relapsed or refractory: blinatumomab (CD19/CD3), inotuzumab (anti-CD22), CAR-T cells, transplant.

Prognosis

• Childhood ALL: remission in almost all; up to about 80% alive without relapse at 5 years.
• Adult ALL: about 25–30% cured overall.
• AML in fit adults under 60: about 40% cured overall; much worse in the elderly.

Quick revision

• 20% or more blasts = acute leukaemia.
• ALL: children; TdT+, CD10/CD19 (B), CD3 (T); CNS and testes; mediastinal mass in T-ALL.
• AML: adults; Auer rods, MPO and Sudan black positive, CD13/CD33.
• M3 (APML): t(15;17), DIC, ATRA + arsenic trioxide; start ATRA on suspicion.
• M4/M5: gum hypertrophy. M7: Down syndrome under 5.
• LAP score: low in CML, high in leukaemoid reaction; not a test for acute leukaemia.
• Complications: infection, bleeding, DIC, leukostasis, tumour lysis.
• AML induction: daunorubicin + cytarabine. ALL: vincristine, steroid, anthracycline, asparaginase + intrathecal methotrexate + 2 years maintenance.
• Childhood ALL: excellent outcome; t(9;22) is poor risk (add imatinib).

Written by The House Job from standard references (Kumar and Clark's Clinical Medicine; Pathoma: Fundamentals of Pathology; BRS Pathology).

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