Acute lymphoblastic leukaemia

Overview

Acute lymphoblastic leukaemia (ALL) is a fast-growing cancer of the blood and bone marrow. It develops when the bone marrow — the soft, spongy tissue inside the bones where blood cells are made — begins producing large numbers of abnormal, immature white blood cells called lymphoblasts (or simply “blasts”). These defective cells multiply rapidly, do not function properly, and gradually crowd out the healthy blood cells the body needs to survive.

The word “acute” means that the disease progresses quickly. Without treatment, ALL can become life-threatening within weeks to months, which is why prompt diagnosis and immediate therapy are essential. The words “lymphoblastic” (or “lymphocytic”) indicate that the cancer arises from the lymphoid line of blood cells — the same family of cells that would normally mature into lymphocytes, the white blood cells responsible for fighting infection.

ALL is the most common childhood cancer, accounting for roughly 25–30% of all cancers diagnosed in children under 15. The peak incidence occurs between the ages of 2 and 5 years. However, ALL is not exclusively a childhood disease — a significant number of cases occur in adults, and unfortunately the disease tends to be more aggressive and harder to cure in older patients.

The encouraging news is that ALL is one of the great success stories of modern oncology. Decades of clinical research have transformed it from an almost universally fatal illness into one of the most curable cancers, with long-term survival rates exceeding 90% in children treated at specialist centres in high-income countries.

What Happens Inside the Body?

To understand ALL, it helps to know a little about normal blood production. All blood cells originate in the bone marrow from a single type of “parent” cell called a haematopoietic stem cell. These stem cells divide and mature along two main pathways:

• Myeloid pathway – produces red blood cells, platelets, and certain white blood cells (neutrophils, monocytes, and others).
• Lymphoid pathway – produces lymphocytes: B cells, T cells, and natural killer (NK) cells.

In ALL, a genetic error occurs in a very early lymphoid cell. Instead of maturing into a functional lymphocyte, the cell becomes “stuck” at an immature stage and begins dividing uncontrollably. These lymphoblasts:

1. Accumulate in the bone marrow, physically crowding out normal blood-forming cells.
2. Spill into the bloodstream and circulate around the body.
3. Infiltrate organs such as the lymph nodes, spleen, liver, brain, spinal cord, and (in boys) the testicles.

Because the marrow is packed with leukaemic blasts, it cannot produce enough healthy cells. This leads to the three classic consequences of ALL:

Types of ALL

ALL is not a single uniform disease. Doctors classify it according to the type of lymphocyte involved and the specific genetic abnormalities found in the leukaemia cells. This classification is essential because it guides treatment and helps predict outcome.

Main types by cell lineage

Important genetic subtypes

• Philadelphia chromosome–positive (Ph+) ALL — carries the BCR-ABL1 gene fusion (also seen in chronic myeloid leukaemia). Common in adults. Once considered very high-risk, outcomes have improved dramatically with the addition of targeted drugs called tyrosine kinase inhibitors (e.g., imatinib, dasatinib).
• Hyperdiploid ALL — blast cells contain more than 50 chromosomes. Common in young children and associated with an excellent prognosis.
• ETV6-RUNX1 (t(12;21)) positive ALL — a favourable genetic subtype frequently found in children.
• KMT2A-rearranged ALL — often seen in infants under 1 year; associated with a more challenging prognosis.
• Hypodiploid and “Philadelphia-like” (Ph-like) ALL — subtypes associated with higher risk, increasingly identified through modern genetic testing.

Note: Historically, pathologists used the French-American-British (FAB) classification, describing blasts as L1, L2, or L3 based on appearance. Modern practice relies on immunophenotyping and genetic testing (the WHO classification), which provides far more useful treatment information. Blasts with “L3” features are now recognised as the leukaemic phase of Burkitt lymphoma** and are treated differently.

Causes and Risk Factors

In most people diagnosed with ALL, no clear cause is ever identified. What is known is that ALL begins with acquired genetic mutations in a single bone marrow cell — these changes are not usually inherited and are not the result of anything the patient or their parents did wrong.

Factors known to increase risk include:

• Genetic syndromes – children with Down syndrome have a substantially higher risk of ALL. Other associated conditions include Li-Fraumeni syndrome, Fanconi anaemia, Bloom syndrome, neurofibromatosis type 1, and ataxia-telangiectasia.
• Ionising radiation – high-dose exposure (e.g., radiation therapy for a previous cancer, or nuclear accidents) raises risk.
• Previous chemotherapy – certain drugs used to treat other cancers can, rarely, trigger leukaemia years later.
• Chemical exposure – prolonged contact with benzene and some industrial solvents has been linked to leukaemia.
• Having an identical twin with ALL – if one identical twin develops ALL in infancy or early childhood, the other twin has a modestly increased risk.
• Age and sex – risk peaks in children aged 2–5 and rises again in older adults; ALL is slightly more common in males.

It is important to know: ALL is not contagious, it cannot be “caught” from another person, and it is not caused by diet, lifestyle, injuries, or infections in any proven direct way.

How Does It Look?

This question can be answered from three perspectives: what the disease looks like inside the body, what it looks like under the microscope, and what it looks like in the patient themselves.

Inside the bone marrow

In a healthy person, bone marrow contains an organised mixture of cells at every stage of development, producing red cells, white cells, and platelets in balanced proportions. In ALL, a marrow sample looks strikingly different:

• The marrow is hypercellular — densely overpacked with cells.
• Up to 90% or more of these cells are identical, abnormal lymphoblasts, which have replaced the normal diverse population. A diagnosis of ALL requires that at least 20% of marrow cells are blasts (in practice, the figure is usually far higher).
• Normal “factories” for red cells, platelets, and healthy white cells are suppressed or pushed out, explaining why the patient becomes anaemic, infection-prone, and prone to bleeding.

Under the microscope

Lymphoblasts have a characteristic appearance when a blood or marrow sample is stained and examined:

• High nuclear-to-cytoplasmic ratio – the nucleus occupies almost the entire cell, with only a thin rim of blue (basophilic) cytoplasm around it.
• Round or slightly irregular nuclei with fine, immature-looking (“open”) chromatin.
• Nuclei may contain small, indistinct nucleoli.
• Cells are monotonous — thousands of near-identical copies of the same immature cell, which is itself a hallmark of cancer: the “clone” of one original abnormal cell.
• Unlike mature blood cells, blasts lack the specialised features (granules, lobed nuclei, haemoglobin) of fully developed cells.

On a routine blood film, a laboratory scientist may notice circulating blasts, a reduced platelet count, and a shortage of normal white cells — findings that trigger urgent referral.

The outward appearance of the patient

A person with ALL may visibly look unwell. Typical outward signs include:

• Pallor — unusually pale skin, lips, and inner eyelids due to anaemia.
• Bruises — multiple bruises in unusual places (back, chest, face) or after minimal knocks.
• Petechiae — clusters of tiny, flat, red-purple pinprick spots, often on the legs, caused by bleeding under the skin.
• Bleeding gums or frequent nosebleeds.
• Swollen lymph nodes — painless lumps in the neck, armpits, or groin.
• A swollen or distended abdomen — caused by enlargement of the liver and spleen.
• Infections that won’t clear — persistent fever, mouth ulcers, or sore throat.
• Sometimes painless swelling of a testicle, or signs of pressure in the chest (facial swelling, visible neck veins, breathlessness) when T-ALL forms a mass in the mediastinum.

In young children, parents may simply notice that their child has stopped running around, looks washed out, bruises very easily, or complains that their legs hurt.

Symptoms

The symptoms of ALL develop because of bone marrow failure and because leukaemia cells infiltrate other organs. They usually appear over days to a few weeks and worsen steadily. Any single symptom can have many harmless explanations, but a combination of the symptoms below — especially if persistent — warrants urgent medical assessment.

Symptoms caused by anaemia (too few red blood cells)

• Persistent, unexplained tiredness and weakness
• Pale skin and pale inner eyelids or gums
• Shortness of breath, especially on exertion
• Dizziness or feeling faint
• Rapid heartbeat
• Headaches and difficulty concentrating

Symptoms caused by neutropenia (too few functioning white cells)

• Fever that is persistent or keeps returning
• Frequent, severe, or unusual infections (throat infections, chest infections, skin infections)
• Mouth ulcers and sore gums
• Chills and night sweats

Symptoms caused by thrombocytopenia (too few platelets)

• Easy bruising with little or no injury
• Petechiae — pinpoint red or purple spots under the skin
• Bleeding gums or frequent nosebleeds
• Prolonged bleeding from minor cuts
• Blood in urine or stools
• In girls and women, unusually heavy menstrual periods

Symptoms caused by leukaemia cells infiltrating organs

• Bone and joint pain — the expanding marrow presses on bone from inside; in children this may cause a limp or refusal to walk, and it is sometimes mistaken for growing pains or arthritis
• Swollen lymph nodes in the neck, armpit, or groin
• Abdominal fullness, discomfort, and early satiety from an enlarged liver and spleen
• Painless testicular swelling (the testes are a “sanctuary site” where leukaemia cells can hide)
• Central nervous system symptoms — persistent headache, vomiting (especially in the morning), blurred or double vision, facial weakness, or seizures, caused by leukaemia cells affecting the brain and spinal cord
• Chest symptoms in T-ALL — cough, breathlessness, chest pain, or swelling of the face and arms due to a mediastinal mass pressing on the airway or major veins (a medical emergency)

General (constitutional) symptoms

• Unexplained weight loss
• Loss of appetite
• Drenching night sweats
• General malaise and irritability (particularly noticeable in young children)

### ⚠️ When to seek urgent medical help See a doctor promptly if you or your child has unexplained bruising, petechiae, persistent fever, ongoing fatigue with pallor, or bone pain lasting more than a couple of weeks. Seek emergency care for uncontrolled bleeding, severe breathlessness, confusion, or signs of severe infection (high fever with chills, rapid breathing, extreme lethargy).

Diagnosis

Diagnosing ALL involves several complementary tests. Many are performed on an urgent basis, and results are often available within days.

1. Full blood count (FBC/CBC) and blood film

Usually the first test. Typical findings include:

• Low haemoglobin (anaemia)
• Low platelet count
• White cell count that may be high, normal, or low — a high count does not exclude ALL, and neither does a normal one
• Circulating blast cells seen on the blood film

2. Bone marrow aspiration and biopsy

A small sample of marrow is taken, usually from the back of the hip bone, under local anaesthetic (children typically receive sedation or general anaesthesia). This confirms the diagnosis by demonstrating ≥20% lymphoblasts, and provides material for the specialised tests below.

3. Immunophenotyping (flow cytometry)

Antibodies tagged with fluorescent dyes identify the specific proteins (“markers”) on the surface of the blasts, confirming whether they are B-lineage or T-lineage and how mature they are. Markers assessed include CD19, CD22, CD79a, CD10 (B-lineage) and CD3, CD7 (T-lineage), among others.

4. Cytogenetic and molecular testing

• Karyotyping examines the chromosomes of the blast cells.
• FISH and PCR-based tests detect specific abnormalities such as BCR-ABL1, ETV6-RUNX1, KMT2A rearrangements, and chromosome number changes (hyperdiploidy/hypodiploidy).

These results determine risk group and whether targeted drugs (e.g., tyrosine kinase inhibitors) should be added.

5. Lumbar puncture (spinal tap)

A sample of cerebrospinal fluid is examined under the microscope to check whether leukaemia cells have reached the central nervous system. The first dose of chemotherapy into the spinal fluid (intrathecal chemotherapy) is often given at the same time.

6. Additional tests

• Blood chemistry — kidney and liver function, uric acid, and electrolytes (to anticipate tumour lysis syndrome, a metabolic complication caused by rapid breakdown of leukaemia cells when treatment starts).
• Chest X-ray or CT scan — to look for a mediastinal mass, particularly in T-ALL.
• HLA typing — if a stem cell transplant may be needed later.

7. Measurable (minimal) residual disease — MRD

During and after the early phases of treatment, highly sensitive techniques (flow cytometry or PCR) are used to detect one leukaemia cell among up to a million normal cells. The MRD response is one of the most powerful predictors of outcome and is now used to fine-tune treatment intensity.

Treatment

ALL treatment is intensive and prolonged, typically lasting 2 to 3 years in total, with the most intensive part delivered in the first 6–9 months. Treatment is given according to carefully designed protocols that differ for children and adults and are adjusted to each patient’s risk group.

Phases of treatment

Main treatments used

• Combination chemotherapy — the backbone of ALL therapy. Commonly used drugs include vincristine, corticosteroids (prednisolone/dexamethasone), asparaginase, anthracyclines (e.g., daunorubicin), methotrexate, mercaptopurine, and cyclophosphamide.
• Targeted therapy — tyrosine kinase inhibitors (imatinib, dasatinib, ponatinib) added to chemotherapy for Philadelphia-positive ALL have transformed outcomes in this subtype.
• Immunotherapy (increasingly used, particularly for relapsed/refractory or MRD-positive disease):
• Blinatumomab – a bispecific antibody that links a patient’s own T cells to CD19 on leukaemia cells, directing the immune system to kill them.
• Inotuzumab ozogamicin – an antibody–drug conjugate targeting CD22.
• CAR T-cell therapy (e.g., tisagenlecleucel) – the patient’s T cells are collected, genetically reprogrammed to attack CD19-positive leukaemia cells, and re-infused. A major advance for children and young adults with relapsed or refractory B-ALL.
• Haematopoietic stem cell (bone marrow) transplantation — reserved mainly for patients with high-risk disease, poor treatment response, or relapse. The patient’s diseased marrow is eradicated with high-dose therapy and replaced with healthy stem cells from a matched donor.
• Treatment of relapse — if ALL returns, options include re-induction chemotherapy, immunotherapy, CAR-T cells, and transplant; outcomes remain favourable for a substantial proportion of patients, especially children.

Supportive care — an essential part of therapy

• Blood and platelet transfusions
• Antibiotics, antifungals, and antivirals to prevent and treat infections; hospitalisation for fever during neutropenia
• Prevention of tumour lysis syndrome (fluids, allopurinol or rasburicase)
• Anti-sickness medication, pain relief, and nutritional support
• Psychological and social support for patients and families

Common side effects

Hair loss, nausea and vomiting, mouth sores, fatigue, increased infection risk, temporary infertility (sometimes permanent — fertility preservation should be discussed before treatment), steroid-related effects (weight gain, mood change, high blood sugar), and drug-specific toxicities. Most acute side effects resolve after treatment ends.

Prognosis and Outlook

Prognosis depends strongly on age, disease biology, and response to treatment:

• Children: approximately 85–90% or more achieve long-term cure in developed countries.
• Younger adults: roughly 60–70% long-term survival with modern regimens, improving further with immunotherapy.
• Older adults: outcomes are less favourable, but continue to improve with better-tolerated targeted and immune-based treatments.

Key prognostic factors

Living With and After ALL

• Follow-up care — regular clinic visits and blood tests continue for years after treatment to detect any relapse early and manage late effects.
• Late effects — some survivors experience long-term consequences such as heart problems (from anthracyclines), bone problems, secondary cancers, learning or attention difficulties (in children), hormonal issues, and infertility. Survivorship clinics increasingly monitor and address these.
• Infection precautions — during intensive treatment, live vaccines must be avoided; routine vaccinations are usually re-administered after immune recovery.
• Emotional wellbeing — anxiety, fear of relapse, and the strain of prolonged treatment affect patients and families alike. Psychological support, peer groups, and specialist charities can make a meaningful difference.
• Returning to normal life — most children return to school during maintenance therapy, and adults can often resume work, with adjustments during periods of low immunity.

Key Takeaways

• ALL is a fast-growing cancer of immature white blood cells and the most common childhood cancer, though it also affects adults.
• Symptoms arise from bone marrow failure: fatigue and pallor, infections and fever, easy bruising and bleeding, plus bone pain, swollen glands, and organ enlargement.
• Diagnosis relies on blood tests, bone marrow examination, immunophenotyping, and genetic testing.
• Treatment lasts 2–3 years and combines chemotherapy with, increasingly, targeted drugs, immunotherapy, or CAR-T cells; some patients need a stem cell transplant.
• Most children with ALL are cured. Early diagnosis and treatment at a specialist centre offer the best chance of a successful outcome.
• Anyone with persistent unexplained bruising, bleeding, fever, pallor, or bone pain should seek medical assessment without delay.

References

American Cancer Society (2024) Acute Lymphocytic Leukemia (ALL). Available at: https://www.cancer.org/cancer/types/acute-lymphocytic-leukemia.html (Accessed: 10 January 2025).

Blood Cancer UK (2024) Acute lymphoblastic leukaemia (ALL). Available at: https://bloodcancer.org.uk/understanding-blood-cancer/leukaemia/acute-lymphoblastic-leukaemia-all/ (Accessed: 10 January 2025).

Hunger, S.P. and Mullighan, C.G. (2015) ‘Acute lymphoblastic leukemia in children’, New England Journal of Medicine, 373(16), pp. 1541–1552.

Inaba, H., Greaves, M. and Mullighan, C.G. (2013) ‘Acute lymphoblastic leukaemia’, The Lancet, 381(9881), pp. 1943–1955.

Leukemia & Lymphoma Society (2024) Acute Lymphoblastic Leukemia. Available at: https://www.lls.org/leukemia/acute-lymphoblastic-leukemia (Accessed: 10 January 2025).

Malard, F. and Mohty, M. (2020) ‘Acute lymphoblastic leukaemia’, The Lancet, 395(10230), pp. 1146–1162.

National Cancer Institute (2024) Childhood Acute Lymphoblastic Leukemia Treatment (PDQ) – Health Professional Version. Available at: https://www.cancer.gov/types/leukemia/hp/child-all-treatment-pdq (Accessed: 10 January 2025).

NHS (2023) Acute lymphoblastic leukaemia. Available at: https://www.nhs.uk/conditions/acute-lymphoblastic-leukaemia/ (Accessed: 10 January 2025).

Swerdlow, S.H., Campo, E., Harris, N.L., Jaffe, E.S., Pileri, S.A., Stein, H., Thiele, J. and Vardiman, J.W. (eds) (2017) WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Revised 4th edn. Lyon: International Agency for Research on Cancer (IARC).

Terwilliger, T. and Abdul-Hay, M. (2017) ‘Acute lymphoblastic leukemia: a comprehensive review and 2017 update’, Blood Cancer Journal, 7(6), e577.