Acute Lymphoblastic Leukaemia

Summary

What is Acute Lymphoblastic Leukaemia (ALL)?

Acute lymphoblastic leukaemia (ALL) is a type of blood cancer that affects immature white blood cells called lymphoblasts.

These abnormal cells multiply rapidly in the bone marrow, interfering with the production of healthy blood cells.

ALL can develop at any age. Although it is more common in children, it also affects adults, particularly older adults.

ALL is an aggressive disease that requires prompt treatment. However, many adults can achieve remission, and some can be cured with modern treatment.

ALL is closely related to lymphoblastic lymphoma (LBL). Both arise from immature lymphoid cells. ALL mainly involves the bone marrow and blood, whereas LBL usually presents as a tumour or enlarged lymph nodes. Their treatment approaches are similar.

Common Symptoms

Patients with ALL may experience:

• Fatigue and weakness: Due to anaemia (low haemoglobin).
• Fever and frequent infections: Due to reduced numbers of healthy white blood cells.
• Easy bruising or bleeding: Due to low platelet counts.
• Bone or joint pain: Due to abnormal cells accumulating in the bone marrow.
• Swollen lymph nodes: Particularly in the neck, armpits or groin.
• Loss of appetite and weight loss.
• Night sweats.

Symptoms may develop over several weeks.

Why Genetic and Chromosome Testing Is So Important

Not all cases of ALL are the same.

Two patients may have similar symptoms and blood counts but have different genetic abnormalities in their leukaemia cells.

These differences can significantly affect their treatment and chances of recovery.

Chromosome and genetic testing is therefore an essential part of diagnosing ALL in adults.

What Is Cytogenetic Testing?

Our cells normally contain 46 chromosomes, which carry our genetic information.

In ALL, some chromosomes may become rearranged, deleted or duplicated.

Cytogenetic and molecular tests look for these abnormalities.

The main tests include:

1. Karyotyping: Examines chromosomes under a microscope to identify major abnormalities.
2. FISH testing: Detects specific chromosome or gene abnormalities.
3. PCR testing: Detects particular genetic changes with high sensitivity.
4. Molecular sequencing: Identifies additional genetic abnormalities that may affect treatment.

These tests help doctors:

• Classify the type of ALL.
• Select the most effective treatment.
• Estimate the risk of relapse.
• Determine whether a stem cell transplant may be necessary.
• Monitor how well treatment is working.

Some important genetic abnormalities cannot be detected by routine chromosome examination alone. Additional molecular testing is therefore necessary.

Philadelphia Chromosome-Positive ALL (Ph+ ALL)

What Is the Philadelphia Chromosome?

One of the most important genetic abnormalities in adult ALL is the Philadelphia chromosome, also called Ph-positive ALL.

It occurs when genetic material from chromosomes 9 and 22 exchanges places.

This creates an abnormal gene called BCR::ABL1.

The abnormal gene produces a protein that continuously signals leukaemia cells to grow and multiply.

The Philadelphia chromosome is found in approximately 20% to 30% of adults with ALL, with its frequency increasing with age. It is particularly common in older adults.

Why Is Philadelphia-Positive ALL Different?

In the past, Philadelphia-positive ALL was considered a particularly high-risk form of leukaemia.

Conventional chemotherapy alone was often insufficient to prevent relapse.

However, the development of targeted medicines called tyrosine kinase inhibitors (TKIs) has dramatically improved treatment outcomes.

These medicines block the abnormal BCR::ABL1 protein responsible for driving leukaemia growth.

Examples include:

• Imatinib
• Dasatinib
• Ponatinib

The choice of medicine depends on the patient’s condition, genetic findings and treatment plan.

Why Early Detection of the Philadelphia Chromosome Matters

Identifying the Philadelphia chromosome at diagnosis allows doctors to introduce targeted treatment promptly.

A patient with Philadelphia-positive ALL requires a different treatment strategy from someone with Philadelphia-negative ALL.

This is why BCR::ABL1 testing should be performed early in the diagnostic assessment.

A normal chromosome examination does not completely exclude Philadelphia-positive ALL. FISH or molecular testing may still detect the BCR::ABL1 fusion gene.

How Is Adult ALL Treated?

Treatment of adult ALL has advanced considerably in recent years.

Traditionally, chemotherapy was the main treatment. Today, targeted therapies, immunotherapy and cellular therapies offer additional options, often improving outcomes while reducing the need for intensive chemotherapy in selected patients.

Treatment depends on the patient’s age, general health, type of ALL, genetic abnormalities and response to treatment.

1. Chemotherapy

Chemotherapy remains an important treatment for many adults with ALL.

It is usually given in several phases:

• Induction: To destroy leukaemia cells and achieve remission.
• Consolidation: To eliminate remaining leukaemia cells and reduce the risk of relapse.
• Maintenance: To prevent the leukaemia from returning.

Treatment usually extends over many months, with maintenance therapy sometimes continuing for approximately two years.

Younger, fitter adults may receive more intensive treatment, while older patients may benefit from less intensive approaches.

1. Targeted Therapy for Philadelphia-Positive ALL

Patients with Philadelphia-positive ALL can receive tyrosine kinase inhibitors (TKIs).

These medicines specifically block the abnormal BCR::ABL1 protein that drives leukaemia growth.

Examples include dasatinib and ponatinib.

TKIs are often combined with chemotherapy or immunotherapy.

Newer treatment approaches combining TKIs with blinatumomab have produced encouraging results, including deep molecular remissions in many patients.

Targeted therapy has transformed Philadelphia-positive ALL from a particularly difficult disease to treat into one with substantially improved outcomes.

1. Blinatumomab: Helping the Immune System Attack Leukaemia

Blinatumomab is a form of immunotherapy known as a bispecific T-cell engager (BiTE).

It works by connecting two types of cells:

• The patient’s own T cells, which are immune cells.
• Leukaemia cells carrying a protein called CD19.

By bringing these cells together, blinatumomab helps the immune system recognise and destroy the leukaemia cells.

Blinatumomab is used in selected patients with B-cell ALL, including:

• Newly diagnosed patients as part of certain treatment protocols.
• Patients with persistent measurable residual disease.
• Patients whose leukaemia has relapsed or failed to respond to treatment.

It may be combined with chemotherapy or targeted therapy.

Blinatumomab has become an important advance in the treatment of adult B-cell ALL.

1. CAR T-Cell Therapy

Chimeric Antigen Receptor (CAR) T-cell therapy is an advanced form of cellular immunotherapy.

Unlike conventional chemotherapy, CAR T-cell therapy uses the patient’s own immune cells to attack leukaemia.

The treatment involves several steps:

1. T cells are collected from the patient’s blood.
2. These cells are genetically modified in a specialised laboratory.
3. The modified T cells are programmed to recognise a protein, usually CD19, on leukaemia cells.
4. The CAR T cells are multiplied and infused back into the patient.
5. The modified cells recognise and attack the leukaemia.

CAR T-cell therapy can produce deep and sometimes long-lasting remissions in patients with relapsed or refractory B-cell ALL, including those who have failed several previous treatments.

However, it is not suitable for everyone.

Potential serious complications include cytokine release syndrome (a severe inflammatory reaction), neurological side effects and prolonged low blood counts.

CAR T-cell therapy is available only in specialised centres, and access depends on local availability and eligibility.

1. Allogeneic Bone Marrow Transplantation

An allogeneic haematopoietic stem cell transplant (HSCT), commonly called a bone marrow transplant, involves giving healthy blood-forming stem cells from a compatible donor.

The donor’s immune system can also recognise and attack any remaining leukaemia cells. This is known as the graft-versus-leukaemia effect.

Allogeneic transplantation may offer a chance of cure for selected patients, particularly those with:

• High-risk genetic abnormalities.
• Persistent measurable residual disease despite treatment.
• Poor response to initial therapy.
• Relapsed ALL.

However, transplantation carries significant risks, including infections, graft-versus-host disease and treatment-related mortality.

Not every patient with ALL requires a stem cell transplant.

With advances in targeted therapy, blinatumomab and CAR T-cell therapy, some patients may achieve long-term remission without transplantation.

The decision depends on genetic risk, MRD results, age, general health and the benefits and risks of the available treatments.

1. Preventing Leukaemia in the Brain and Spinal Cord

ALL can spread to the central nervous system, including the brain and spinal cord.

Even when there is no evidence of such involvement, patients generally require preventive treatment.

This usually involves chemotherapy injected into the fluid surrounding the brain and spinal cord, known as intrathecal chemotherapy.

Additional systemic treatment may also help protect the central nervous system.

What Is Measurable Residual Disease (MRD)?

Even when treatment successfully removes visible leukaemia cells from the blood and bone marrow, small numbers of abnormal cells may remain.

These cells may be too few to detect using conventional microscopy.

Specialised tests can detect these remaining cells. This is called measurable residual disease (MRD).

MRD testing is one of the most important advances in ALL management.

It helps doctors determine:

• Whether treatment is working effectively.
• Whether the leukaemia is responding deeply enough.
• Whether additional treatment may be needed.
• Whether a stem cell transplant should be considered.
• Whether the risk of relapse remains significant.

In Philadelphia-positive ALL, molecular tests can measure BCR::ABL1 levels. Other MRD methods may also be used.

Achieving MRD negativity is generally associated with better outcomes.

However, MRD results must be interpreted alongside the patient’s overall condition and genetic findings.

Can Adults With ALL Be Cured?

Yes. Some adults with ALL can be cured.

The likelihood of cure depends on several factors:

• Age and general health.
• Type of ALL.
• Chromosome and genetic abnormalities.
• Response to initial treatment.
• MRD results.
• Whether the disease has spread to the central nervous system.
• Availability of appropriate targeted treatments.

Younger adults generally tolerate intensive treatment better, but effective treatment options are increasingly available for older patients.

Philadelphia-positive ALL illustrates how genetic testing has transformed cancer treatment.

Previously considered a particularly difficult form of leukaemia to treat, it now has substantially better outcomes because of targeted therapy and immunotherapy.

CAR T-cell therapy and allogeneic transplantation also offer potentially curative options for selected patients.

Nevertheless, relapse remains possible, and prolonged follow-up is essential.

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Next Steps

If You Have Been Diagnosed With ALL

1. Consult a haematologist promptly

ALL progresses rapidly and requires specialist treatment.

1. Ensure appropriate diagnostic testing has been performed

This generally includes:

• Full blood count and blood film.
• Bone marrow aspiration and biopsy.
• Flow cytometry to identify the type of ALL.
• Cytogenetic and molecular testing, including Philadelphia chromosome/BCR::ABL1 testing.
• Assessment for involvement of the central nervous system.

1. Discuss your genetic test results

Ask your haematologist:

• Is my ALL Philadelphia-positive or Philadelphia-negative?
• Are there other important genetic abnormalities?
• Will targeted therapy be beneficial?
• How will my response to treatment be monitored?

1. Discuss your treatment plan

Treatment may involve chemotherapy, targeted therapy, immunotherapy, CAR T-cell therapy or stem cell transplantation.

The choice depends on your disease characteristics and overall health.

1. Attend regular follow-up appointments

Blood tests, bone marrow examinations and MRD monitoring may be necessary to assess treatment response and detect relapse.

1. Take prescribed medicines consistently

Do not stop or adjust chemotherapy, targeted therapy or other prescribed medicines without consulting your haematologist.

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Urgent Warning Signs

ALL and its treatment can cause serious complications, particularly infections and bleeding.

Seek immediate medical attention if you experience:

• Fever of 38°C or higher, especially during chemotherapy or when your white blood cell count is low.
• Shivering or chills, even without a documented fever.
• Uncontrolled bleeding, including persistent nosebleeds, bleeding gums or blood in the urine or stools.
• Severe headache, confusion, seizures or sudden visual changes.
• Difficulty breathing, chest pain or sudden shortness of breath.
• Severe weakness, fainting or inability to walk normally.
• Persistent vomiting or inability to drink fluids.
• Sudden severe abdominal pain.

If you are receiving chemotherapy and develop a fever, do not wait until your next appointment. Fever during neutropenia may indicate a life-threatening infection requiring urgent antibiotics.

For severe symptoms, attend the nearest emergency department immediately.

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Key Message

In adult ALL, genetic testing is not just about confirming the diagnosis. It can determine which treatment is most effective.

The Philadelphia chromosome is a particularly important example.

Detecting the BCR::ABL1 gene allows doctors to use targeted medicines that have substantially improved treatment outcomes.

Modern treatment now includes chemotherapy, targeted therapy, blinatumomab, CAR T-cell therapy and allogeneic stem cell transplantation for selected patients.

Combined with MRD monitoring, these advances allow treatment to be tailored more precisely to each patient.

Understanding the genetic characteristics of your leukaemia is an essential step towards receiving the most appropriate treatment.

This information is intended for patient education and does not replace individual medical advice from your treating haematologist.