Understanding acute lymphoblastic leukemia

Although acute lymphoblastic leukemia is a rare 

 of leukemia, it is the most common leukemia among children.

 It also affects adults, who comprise 4 out of every 10 cases of acute lymphoblastic leukemia.

 The risk of developing acute lymphoblastic leukemia is highest when under 5 years old or when over 50 years old.

Acute lymphoblastic leukemia usually develops quickly over the course of days or weeks and requires rapid 

. To understand which cells are affected in acute lymphoblastic leukemia, it helps to look at blood composition.

Blood is broadly made up of 4 components: 

Red blood cells that carry oxygen and give blood its distinctive color. 

Platelets, which are small cells involved in clotting and prevention of excessive bleeding. 

Plasma, the straw-colored fluid in which blood cells are suspended.

Under normal conditions, these components exist in relatively stable amounts in relation to each other. Acute lymphoblastic leukemia is a disease in which the number of white blood cells is no longer controlled correctly. White blood cells are produced more rapidly than normal within the bone marrow and are released before they are fully mature (these cells are known as lymphoblasts). This means that although there are more white blood cells in the blood, they do not function correctly. 

The overproduction of white blood cells reduces the amount of red blood cells and platelets that are produced, and this causes many of the 

1. Cancer Research UK. What is acute lymphoblastic leukaemia (ALL)? 

https://www.cancerresearchuk.org/about-cancer/acute-lymphoblastic-leukaemia-all/about

. Revised May 14, 2021. Accessed Feb 23, 2024.

2. American Cancer Society. Key statistics for acute lymphocytic leukemia (ALL). 

https://www.cancer.org/cancer/acute-lymphocytic-leukemia/about/key-statistics.html

. Revised Jan 17, 2024. Accessed Feb 23, 2024.

What is acute lymphoblastic leukemia?

What causes acute lymphoblastic leukemia?

Acute lymphoblastic leukemia occurs because of damage (mutations) in the genetic material (DNA) of a cell. Although some environmental factors are known to increase the likelihood of mutations, the cause of most cases of acute lymphoblastic leukemia remains unknown. Exposure to radiation and some chemicals (e.g. benzene) may increase the risk of developing acute lymphoblastic leukemia. Individuals with Down syndrome are at an increased risk of developing acute lymphoblastic leukemia, especially in childhood. Patients with a weak immune system and those who have received chemotherapy for a prior malignancy may also have an increased risk of developing leukemia. 

What symptoms might I experience with acute lymphoblastic leukemia?

The symptoms (your own experience) and signs (observed by a doctor) of acute lymphoblastic leukemia can be divided into 4 categories. As acute lymphoblastic leukemia affects the production of the three types of blood cells, each group produces different symptoms.

1. Low red blood cells (anemia) may cause:

2. Low white blood cells (leukopenia) may cause:

3. Symptoms of low platelets (thrombocytopenia) can be:

Small red dots on the skin called petechiae

In women, periods may be heavier or more frequent

4. General symptoms may occur, including:

A feeling of fullness or pain just below the ribs

Lumps in the neck, armpits, abdomen, or groin caused by swollen glands known as lymph nodes

Acute lymphoblastic leukemia is a rare disease and other conditions can cause similar symptoms; therefore, if you see any of the symptoms listed above in you or your child please speak to your doctor.

1. NHS inform. Causes of acute lymphoblastic leukaemia. 

https://www.nhsinform.scot/illnesses-and-conditions/cancer/cancer-types-in-adults/acute-lymphoblastic-leukaemia/#causes-of-acute-lymphoblastic-leukaemia

. Published November 13, 2023. Accessed Feb 22, 2024.

2. Leukemia & Lymphoma Society. Signs and Symptoms. 

https://www.lls.org/leukemia/acute-lymphoblastic-leukemia/signs-and-symptoms

3. Cancer Research UK. Symptoms of acute lymphoblastic leukaemia (ALL). 

https://www.cancerresearchuk.org/about-cancer/acute-lymphoblastic-leukaemia-all/symptoms

Causes & symptoms

What to expect on the journey to a diagnosis

Getting a diagnosis is important as it tells your doctor if you have acute lymphoblastic leukemia as opposed to another condition. If an acute lymphoblastic leukemia diagnosis is made, it can be used to predict how quickly the disease might progress and how it may respond to certain 

Diagnostic techniques can also show what 

 of acute lymphoblastic leukemia is present. Identifying the subtype increases the accuracy of your doctor's predictions about the course and severity of disease. 

, a visit to your doctors is advised. Identifying diseases early often makes them easier to manage and increases the chances of successful treatment.

During your appointment, you may be asked about your medical history and for a description of any changes that you may have noticed. Your doctor might perform a physical examination of any areas that are swollen, bleeding, or bruised, and check for possible signs of infection. 

Depending on the outcome of this assessment, your doctor may also want to take a blood sample to perform some initial blood tests.

Shows the amount of specific chemicals in the blood to assess the health of the liver and kidneys.

Shows the number of each group of blood cells present (red blood cells, white blood cells, and platelets).

Identifies changes in the appearance of cells under a microscope, which may indicate the presence of disease.

If your doctor feels that further tests are needed, a referral to a specialist may be made. This will most likely be a hematologist (a doctor who has undertaken specialist training in diseases of the blood). The hematologist will go over the results and may suggest that further tests are performed.

A sample is taken from the spongy marrow in the middle of the bone, normally from the hip. 

In the case of a bone marrow aspiration, the sample will be a liquid, whereas in a biopsy, a small section of bone filled with marrow will be collected. 

Bone marrow is where many blood cells are produced. Taking a sample from here can allow a hematopathologist (a specialist who studies blood cell diseases by looking at samples of cells and other tissues) to see what type of cells are being made and in what proportions. Cells that look unusual can be spotted using this test and classified according to any changes seen.

This test is used if there is a concern that the leukemia may have spread into the brain and spinal cord. It assesses the number of cells in the fluid that bathes these organs. It is performed by inserting a needle into the base of the spine and drawing out some fluid.

Further laboratory tests may be performed on the blood and bone marrow samples to diagnose and/or determine the specific type of acute lymphoblastic leukemia.

Reveals information about the type of cells present by exposing the cells to chemical dyes that only react with certain types of leukemia cells. This causes a color change that is visible under a microscope.

Allows the identification of leukemia cells by detecting specific proteins (known as antigens) on the surface of your cells. Different types of cells have different proteins, and the identification of these markers show scientists what type of acute lymphoblastic leukemia cells (B, T, or mixed) are present in the sample. This can tell doctors what specific type of acute lymphoblastic leukemia is present.

Acute lymphoblastic leukemia comprises several distinct genetic subtypes, identifying which subtype is present can help doctors make a diagnosis and inform treatment decisions. 

A range of different techniques will be used to examine the leukemic cells for abnormalities affecting the chromosomes and/or genetics. This will help determine the genetic subtype of acute lymphoblastic leukemia.

There are some serious conditions associated with cancer that can occur. More blood tests may be performed to monitor for the conditions listed below, so that the best treatment can be provided as soon as possible. 

While imaging is not essential for a diagnosis of acute lymphoblastic leukemia, it can be used to give a clearer picture of the health of your organs and show if the cancer has spread. They can also help to diagnose infections. You may have one or several forms of imaging performed.

This, in turn, can help predict the response to treatment. You may have one or several forms of imaging performed.

This is ideal for assessing soft tissue and fluid within the body. It uses high frequency soundwaves to create a dynamic image. This may be used to check your liver, spleen, and lymph nodes. The function of the heart may also be checked using a specialized form of ultrasound called echocardiography.

A method used to visualize what is going on within the body and spot any changes from normal that might indicate how far the cancer has spread. This scan also provides information on the health of multiple organs, particularly the head and chest.

Like a CT, an MRI scan takes pictures of the whole body from multiple angles, using magnetism and radio waves. 

For acute lymphoblastic leukemia, there is often no need for an MRI, but your doctor may suggest one if you have symptoms of:

Leukemia that has spread to the central nervous system

Once you or your child has a diagnosis, some of these tests may be repeated to show how you are responding to 

1. Leukemia & Lymphoma Society. Diagnosis. 

https://www.lls.org/leukemia/acute-lymphoblastic-leukemia/diagnosis

2. Cancer Research UK. Seeing your GP when you have symptoms of acute lymphoblastic leukaemia (ALL). 

https://www.cancerresearchuk.org/about-cancer/acute-lymphoblastic-leukaemia-all/getting-diagnosed/seeing-your-gp

3. American Cancer Society. Tests for acute lymphocytic leukemia (ALL). 

https://www.cancer.org/cancer/acute-lymphocytic-leukemia/detection-diagnosis-staging/how-diagnosed.html

. Published Oct 17, 2018. Accessed Feb 22, 2024.

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https://www.cancerresearchuk.org/about-cancer/acute-lymphoblastic-leukaemia-all/getting-diagnosed/referral-specialist

5. Cancer Research UK. CT scan for acute lymphoblastic leukaemia (ALL). 

https://www.cancerresearchuk.org/about-cancer/acute-lymphoblastic-leukaemia-all/getting-diagnosed/tests/ct-scan

6. Cancer Research UK. MRI scan for acute lymphoblastic leukaemia (ALL). 

https://www.cancerresearchuk.org/about-cancer/acute-lymphoblastic-leukaemia-all/getting-diagnosed/tests/mri-scan

Diagnosis

The World Health Organization (WHO) classification system is the most commonly used method to distinguish acute lymphoblastic leukemia subtypes.

Based on the type of white blood cell (lymphocyte) affected, two main subtypes can be found:

B-cell acute lymphoblastic leukemia, which is the most common type (75% of cases in adults; 80-85% of cases in children)

Most B-cell acute lymphoblastic leukemia stems from abnormal immature (pre) B cells.

Sometimes B-cell acute lymphoblastic leukemia develops from malignant mature B cells. You may also hear it called Burkitt-type acute lymphoblastic leukemia, as it is similar to another type of cancer called Burkitt lymphoma.

T-cell acute lymphoblastic leukemia (25% of cases in adults; 15% of cases in children)

More frequent in young adults and in men.

Leukemia subtypes can be further categorized into around 25 different subtypes according to the genetic abnormalities present. These genetic subtypes are very important for patient management, helping doctors to confirm a diagnosis and select the optimal treatment pathway; some genetic subtypes indicate that the disease will respond to a specific drug while others can indicate the aggressiveness of the leukemia. Doctors will use the genetic subtype in combination with other factors, like age and response to treatment, to determine the level of chemotherapy required by each patient.

The frequency of genetic subtypes varies by patient age and time of diagnosis.

Philadelphia-positive acute lymphoblastic leukemia

The most common genetic abnormality in adult acute lymphoblastic leukemia is the formation of the Philadelphia (Ph) chromosome; this is caused by the exchange of genetic material between Chromosomes 9 and 22 in leukemic cells, resulting in the creation of the 

 fusion gene. The presence of this fusion gene confers a sensitivity to a class of drug called tyrosine kinase inhibitors. Ph-positive acute lymphoblastic leukemia occurs in 25% of adults,

 You can read more about this and other therapies on the 

Philadelphia-like acute lymphoblastic leukemia

Characterized by a similar gene expression profile to Ph-positive acute lymphoblastic leukemia but lacking the 

 gene fusion. Although Ph-like acute lymphoblastic leukemia can occur at any age, it most frequently occurs in adolescents and adults. This subtype comprises two subgroups: 

 class fusions and JAK-STAT abnormality. The presence of an 

-class fusion, but not a JAK-STAT abnormality, confers a sensitivity to a type of drug called tyrosine kinase inhibitors, making these drugs more effective.

fusion or t(12;21)(p13;q21) acute lymphoblastic leukemia

This is a common genetic abnormality in children with acute lymphoblastic leukemia, occurring in ~25% of cases; however, it is very rare in adults. Children with 

-positive acute lymphoblastic leukemia generally have good outcomes.

High hyperpdiploid acute lymphoblastic leukemia

This is the most common genetic abnormality in children with acute lymphoblastic leukemia, occurring in 30% of cases and only occurring in around 10% of  adults. It is characterized by the multiple gain of whole chromosomes. Most children with high hyperdiploid acute lymphoblastic leukemia have a favourable prognosis.

 or MLL gene fusion acute lymphoblastic leukemia

 gene can occur at any age and are usually associated with aggressive disease. Around 80% of infant patients (aged <1 year) will have this genetic subtype. It is rare in children (5%) but starts to increase in frequency with age—accounting for around 10% of adults with  acute lymphoblastic leukemia.

Hypodiploidy acute lymphoblastic leukemia

This genetic subtype is characterized by multiple chromosome losses and associated with aggressive disease. There are two subgroups: near haploidy and low hypodiploidy. Both subgroups are rare in children, accounting for ~6% of cases. Near haploid acute lymphoblastic leukemia is extremely rare in adults, but low hypodiploidy occurs in ~6%, especially in older patients (aged >50 years).

This genetic subtype involves a very complex rearrangement of Chromosome 21 and gives rise to an aggressive form of the disease. It most frequently occurs in older children (aged 8–14 years) and is rare in other age groups.

-class gene fusion acute lymphoblastic leukemia

This genetic subtype comprises a series of gene fusions involving one of the following genes: 

. Similar to patients with the BCR::ABL1 fusion gene, these patients are usually sensitive to tyrosine kinase inhibitors, with many patients treated with imatinib or dasatinib, alongside standard chemotherapy. This genetic subtype is quite rare, accounting for 3–4% of cases in children.

Other B-cell acute lymphoblastic leukemia subtypes include  t(5;14)(q31.1;q32.3)/

T-cell acute lymphoblastic leukemia can be further classified according to both immunophenotype and genetics. Whilst many subtypes have been described in the research literature, the clinical relevance and prognostic value are not well understood. Further research is needed before these subtypes are widely and consistently used in the clinical setting.

This list of genetic subtypes is not exhaustive, we have focused on the most common subtypes used by doctors to make treatment decisions. The official classification of acute lymphoblastic leukemia can be found in the WHO classification.

1. Alaggio R, Amador C, Anagnostopoulos I, et al. The 5th edition of the World Health Organization classification of haematolymphoid tumours: lymphoid neoplasms. Leukemia. 2022;36(7):1720-1748. DOI: 

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https://www.lls.org/research/acute-lymphoblastic-leukemia-all

Types

There are a variety of different treatments that you or your child may receive for acute lymphoblastic leukemia. It is likely treatment will begin rapidly after receiving a 

Chemotherapy is the most common form of treatment for acute lymphoblastic leukemia. Chemotherapy works by killing rapidly dividing cells such as cancer cells. Treatment may involve the use of one or more chemotherapy drug at once, and often these agents are given straight into the bloodstream. The type of treatment you receive will depend on a number of factors such as your age and fitness levels.

1. Induction phase with high doses of therapy

May last 1 or 2 months. The aim of the induction phase is to reduce the number of leukemia cells to a point when they are no longer found on bone marrow samples (called complete remission). After this point, the normal blood cells in the marrow can regrow. While achieving a complete remission is a positive sign, it does not necessarily mean the disease is cured, as leukemia cells may be present in other parts of the body.

2. Consolidation with high doses of therapy

May last 1 or 2 months. The consolidation phase is designed to stop the acute lymphoblastic leukemia coming back and to destroy any leukemia cells that may be present in the blood but that are in such small numbers they do not show up on tests.

Maintenance is a less intense treatment phase that can last up to 2 years. It aims to maintain remission using lower doses of chemotherapy over a long period of time. Side effects should be less during this phase, allowing the return to normal activities.

Common chemotherapy agents used include: 

Steroids such as dexamethasone, prednisolone, and hydrocortisone taken before or alongside chemotherapy

These types of treatment target specific parts of cancer cells and may be more effective at treating certain subtypes. 

The Philadelphia chromosome is the name given to the product of swapping specific genetic material between chromosomes 9 and 22. This change is sensitive to treatment by tyrosine kinase inhibitors such as

Immunotherapy can be considered to be a specialized form of targeted therapy that uses specifically designed antibodies to treat acute lymphoblastic leukemia. Immunotherapy aims to encourage the patient’s immune system to target and kill leukemia cells.

The two main immunotherapeutic agents you may be treated with are

Blinatumomab is a special antibody used to treat some subtypes of B-cell acute lymphoblastic leukemia after unsuccessful prior chemotherapy. Treatment usually occurs in a hospital or clinic because it can cause some serious side effects.

Inotuzumabozogamicin is another unique antibody which is used to treat some subtypes of B-cell acute lymphoblastic leukemia after unsuccessful prior chemotherapy. It works by delivering the chemotherapy drug to the leukemia cells and killing them. 

CAR T-cells are a recent advancement in the treatment of acute lymphoblastic leukemia. White blood cells from the patient are taken and engineered  to specifically kill leukemic cells. These white blood cells are now called CAR T-cells and are multiplied before being given back to the patient. Tisagenlecleucel is a CAR T-cell product that can be used to treat acute lymphoblastic leukemia,

 it has been approved for use in children and young adults up to age 25 to treat B-cell acute lymphoblastic leukemia that has returned or is no longer responding to treatment.

Brexucabtageneautoleucel is approved to treat adults with B-cell acute lymphoblastic leukemia that has returned or is no longer responding to treatments.

High doses of targeted radiation, normally called X-rays, can be used to treat cancer, and this technique is called radiotherapy. This may be performed on the brain or spinal cord if the leukemia appears to have spread to these areas. Alternatively, radiotherapy may be used over the whole body (known as total body irradiation) prior to a stem cell transplant.

This procedure is used following chemotherapy or radiotherapy. High intensity treatment is used to kill the leukemic cells in the bone marrow (the spongy part of the bone); however, normal blood cells are killed too.

A transplant is used to replace the blood cells with healthy cells that function correctly. The healthy cells are normally provided by a donor. In a transplant, these healthy cells can be taken from the bone marrow or from the bloodstream.

Although many treatments for acute lymphoblastic leukemia are very good at killing cancer cells, some normal healthy cells may be damaged or killed during treatment as well. This may result in side effects.

For chemotherapy, traditional side effects associated with treatment are: 

Immunotherapy may increase the risk of infection along with: 

CAR T-cell therapy may result in serious side effects, for this reason it is only given in specialized medical centers by trained staff. The most common side effects include:

Cytokine release syndrome (CRS): symptoms including fever, chills, difficulty breathing, severe nausea, vomiting, diarrhea, severe muscle or joint pain, and feeling dizzy

Nervous system problems: can present as headaches, changes in consciousness, confusion or agitation, seizures, trouble speaking and understanding, or loss of balance

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https://www.cancer.org/cancer/types/acute-lymphocytic-leukemia/treating/typical-treatment.html

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https://www.cancer.org/cancer/acute-lymphocytic-leukemia/treating/targeted-therapy.html

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https://www.cancer.org/cancer/types/acute-lymphocytic-leukemia/treating/radiation-therapy.html

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https://www.cancer.org/cancer/types/acute-lymphocytic-leukemia/treating/bone-marrow-stem-cell.html

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. Published Sep 30, 2019. Accessed Feb 27, 2024.

Treatment

A prognosis is a description of the overall outlook or forecast of your disease. It may include positive or negative predictions about things like 

 needs. Your acute lymphoblastic leukemia prognosis is influenced by a number of factors, but even knowing these cannot tell you the exact course of the disease. Certain factors may indicate whether you require more aggressive treatment.

Age has an important influence on how the disease will progress and how you or your child will respond to treatment. In general, younger people have a better outlook.

Cure rates are better for children aged 1−9 years who have B-cell acute lymphoblastic leukemia. Children younger than 1 or older than 9 are considered to have a higher risk of seeing the disease return after treatment. This does not mean they cannot be cured, but that their prognosis is not as good as those patients who are 1–9 years old. Age does not appear to influence the outlook of patients with pre-T-cell acute lymphoblastic leukemia to the same extent – it is a less important factor in this disease subtype.

For teenagers and young adults between 15 and 24 years old with acute lymphoblastic leukemia, the prognosis remains fairly good, with 70% of patients being alive after 5 or more years from their diagnosis.

For adults aged 25–64, the chance of survival after 5 years is close to 40%. In people 65 and older, around 15% will survive 5 years or more following their diagnosis.

A high number of white blood cells at the time of diagnosis can indicate greater risk of a more difficult-to-treat disease. In these cases, patients often receive intensive treatment.

Precursor B-cell acute lymphoblastic leukemia tends to carry a more favorable prognosis than mature B-cell (sometimes called Burkitt) leukemia. Pre-T-cell acute lymphoblastic leukemia has a similar favorable outlook to pre-B-cell acute lymphoblastic leukemia.

Chromosomes are structures found in our cells that carry genetic information (our DNA). Under normal circumstances, a human cell has 46 chromosomes. In leukemic cells, sometimes chromosomes can be duplicated or deleted, so the total number may be different to the usual 46. When a cell has less than 44 chromosomes, it is called hypodiploid. Cells with greater than 50 chromosomes are known as hyperdiploid cells. 

Patients with hypodiploid acute lymphoblastic leukemia tend to have a less favorable prognosis than patients with hyperdiploid acute lymphoblastic leukemia.

In leukemic cells, your genetic material can undergo changes, including swapping of parts between chromosomes. This is known as translocation. Patients that have a translocation between chromosomes 12 and 21 have a more favorable outlook.

Other translocations indicate a poorer prognosis, including the Philadelphia chromosome translocation, which is caused by swapping of genetic material between chromosomes 9 and 22.

Prognosis is also affected by how your leukemia responds to initial treatment. Patients that achieve 

 (when there is no sign of leukemic cells on your bone marrow tests) after initial treatment have a better overall disease outlook.

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Prognosis

Remission is achieved when leukemic cells are no longer detectable in your bone marrow. This is the goal of 

. Usually, when a patient is in remission, the 

 of acute lymphoblastic leukemia are gone. The term ‘complete remission’ or ‘complete response’ is used when blood cell counts return to the normal level. Around 80% of adults and over 95% of children 

 with acute lymphoblastic leukemia will achieve a complete remission.

While a complete remission is the main goal of therapy, it does not necessarily mean the cancer is entirely gone. Very small numbers of leukemic cells can still be present, but at levels so low they do not appear when looking under the microscope at your bone marrow.

To find these very low numbers of leukemic cells, special techniques can be used, such as a polymerase chain reaction (PCR) test. This test can detect a low level of genetic material from leukemic cells in your bloodstream. It gives an indication of how many acute lymphoblastic leukemia cells are still left in your body.

Measurable residual disease (you may also hear it called minimal residual disease, or just MRD) is the name given to the small number of leukemic cells found by detection tests like PCR. If no leukemic cells are detected by a test, a patient is described as MRD negative – this is a very good sign in terms of disease outlook. If a patient is described as MRD positive, it means that the test picked up a very small number of leukemia cells remaining in the body, which can indicate a higher chance that the leukemia will return. This result can be used to guide treatment decisions going forward.