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

. Published May 14, 2018. Accessed Mar 22, 2021.

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

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

. Published Jan 12, 2021. Accessed Mar 22, 2021.

What is acute lymphoblastic leukemia?

What causes acute lymphoblastic leukemia?

Acute lymphoblastic leukemia occurs due to changes (mutations) in the genetic material (DNA) of a cell. The causes of these mutations are unknown. However, there are factors that might increase the risk of developing acute lymphoblastic leukemia, including: 

Certain genetic conditions, such as Down syndrome

A weakened immune system, such as that caused by infections with certain viruses

What symptoms might I experience with acute lymphoblastic leukemia?

The symptoms (your own experience) and signs (things seen 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, so if you see any of the symptoms listed above in yourself or your child please speak to your doctor.

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 the predictions that your doctor can make 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.

Reveals information about 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. Therefore, comprehensive genetic testing is now considered standard of care.

A range of different techniques, such as karyotyping and fluorescence in situ hybridization (FISH), 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.

In the UK, patients with acute lymphoblastic leukemia are eligible for whole genome sequencing. This is the most comprehensive and advanced genetic test available. For more information about whole genome sequencing, visit the Genomics England 

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. 

You may be tested to see if blood is clotting within your blood vessels. This is a syndrome called disseminated intravascular coagulation and can be associated with acute lymphoblastic leukemia.

Tumor lysis syndrome is an emergency condition that can occur spontaneously but normally happens following chemotherapy treatment. It can be tested for in the blood by measuring the levels of electrolytes and waste products such as urea.

Active infections, which may occur due to the low level of functioning white blood cells.

There are many different imaging methods used for diagnosis and staging of acute lymphoblastic leukemia. Some techniques are better at visualizing bone changes, whereas others focus on blood flow. Together these techniques can build up a comprehensive picture of what is happening in the body. 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 the organs and show if the cancer has spread. This, in turn, can help predict the response to treatment. You may have one or several forms of imaging performed.

This is good for looking at 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.

MRI allows monitoring of the blood movement and inflammation within the body, along with structural information, and it can identify areas of increased or decreased blood flow. Cancers are often able to increase their own blood supply. An MRI test can help locate a tumor within the body and see if it is all in one place or in multiple areas.

Like a CT scan, MRI can take pictures of the whole body from multiple angles. It uses magnetism and radio waves to capture an image.

Karyotyping, also known as cytogenetic analysis, looks at the chromosomes in a cell and checks them for abnormalities. Changes may be present that give physicians a clue about how the specific type of acute lymphoblastic leukemia will respond to treatment. A typical genetic technique is fluorescence 

 hybridization (FISH), which allows certain changes in DNA and chromosomes to be fluorescently labeled to show their presence within tissues or cell samples.

Chromosomal abnormalities, and mutations in certain genes, can be detected by polymerase chain reaction (PCR). You may have heard about this test in connection with COVID-19, but it can be useful in diagnosing many types of disease. It is a method to detect even very small amounts of DNA from a cancer cell. This is done to determine the type of acute lymphoblastic leukemia, but also to estimate how many cancer cells are left in the body, which is known as minimal residual disease (MRD).

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. 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 Mar 25, 2021

https://www.nhs.uk/conditions/acute-lymphoblastic-leukaemia/diagnosis/

 Published Sept 30, 2019. Accessed Mar 25, 2021.

Diagnosis

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

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

B-cell ALL (B-ALL), the most common type (80% of cases)

Most B-ALL stems from abnormal immature (pre) B cells.

Some B-ALL develops from malignant mature B cells. You may also hear it called Burkitt-type ALL, as it is similar to another type of cancer called Burkitt lymphoma.

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.

It is important to remember that the genetic abnormalities discussed in this section only affect leukemic cells and do not affect non-cancer cells. They are not inherited from your parents and are not passed on to your children.

The most common genetic abnormality in adult ALL 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 ALL occurs in 20–30% of adults, but only 2% of children. You can read more about this and other therapies on the 

Characterized by a similar gene expression profile to Ph-positive ALL but lacks the 

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

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

-class fusion, but not a JAK-STAT abnormality, confers sensitivity to a class of drug called tyrosine kinase inhibitors.

This is a common genetic abnormality in children with ALL, occurring in 25–30% of cases; however, it is very rare in adults. Children with 

-positive ALL generally have good outcomes and are usually treated with standard chemotherapy.

This is the most common genetic abnormality in children with ALL, occurring in 30–35% of cases andonly occurring in around 10% of  adults. It is characterized by the multiple gain of whole chromosomes. Most children with high hyperdiploid ALL have a very good response to chemotherapy.

 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 (2–3%) but starts to increase in frequency with age—accounting for around 10% of adults with ALL.

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 1–2% of cases. Near haploid ALL is extremely rare in adults but low hypodiploidy occurs in around 10%, 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.

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 2–3% of cases.

Other B-ALL subtypes include t(5;14)(q31.1;q32.3)/IGH::IL3, t(1;19)(q23.3;p13.3)/

T-cell ALL 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 ALL 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: 

 . Published May 14, 2021. Accessed Sep 5, 2023.

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.

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: 

CAR T-cells are a very new type of treatment for acute lymphoblastic leukemia. White blood cells from the patient are taken from the blood and engineered in the lab 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.

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

1. Cancer Research UK. About chemotherapy for ALL. 

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

. Published May 8, 2018. Accessed Mar 29, 2021.

2. American Cancer Society. Targeted therapy for acute lymphocytic leukemia (ALL). 

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

. Published Oct 17, 2018. Accessed Mar 29, 2021.

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

https://www.cancer.org/cancer/acute-lymphocytic-leukemia/treating/monoclonal-antibodies.html

https://www.nhs.uk/conditions/acute-lymphoblastic-leukaemia/treatment/

 Published Sep 30, 2019. Accessed Mar 29, 2021.

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.

1. American Cancer Society. Prognostic factors in childhood leukemia (ALL or AML). 

https://www.cancer.org/cancer/leukemia-in-children/detection-diagnosis-staging/prognostic-factors.html

. Published Feb 12, 2019. Accessed Mar 31, 2021.

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

. Published Apr 17, 2018. Accessed Mar 31, 2021.

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.

If remission is achieved following the first round of therapy (known as induction), the goal of the next treatment phases will be to maintain this state. If the number of leukemic cells increases during or after treatment, this is called a 

. Further treatment, potentially with different drugs, may then be required.

1. Cancer.Net. Leukemia - Acute lymphocytic - ALL: Treatment options. 

https://www.cancer.net/cancer-types/leukemia-acute-lymphocytic-all/treatment-options

. Published May 2017. Accessed Mar 31, 2021

Remission

When patients who have been treated for their acute lymphoblastic leukemia achieve a remission, but later show a new increase in the number of leukemic cells in their body, they are said to have relapsed. For children with acute lymphoblastic leukemia, only 10% will experience a relapse, whereas in adult patients, it can be as high as 50%.

A relapse can occur at any time, but it is more likely to happen within 2 years of the first treatment.

 Symptoms of a relapse are similar to those experienced with newly diagnosed acute lymphoblastic leukemia. A list of these symptoms can be found 

Diagnosis of a relapse is performed using the same tests that your doctor or healthcare provider used to initially diagnose your acute lymphoblastic leukemia. This list can be found 

Certain factors, such as age, presence of genetic changes, and specific type of acute lymphoblastic leukemia, can all increase your risk of relapse. More can be found about this subject on the 

A patient with acute lymphoblastic leukemia who has relapsed can still be cured, despite their increasing number of leukemic cells following initial treatment.

As with initial treatment, the main choice for treating relapse is also chemotherapy. The same chemotherapy agents given previously may be used again, or your doctor may try a different drug or a combination of agents. If your acute lymphoblastic leukemia is difficult to treat, you may be offered a stem cell transplant. More information on possible therapy options is available on our 

If a patient does not respond or achieve remission following treatment with a certain drug, they are said to be refractory to this drug. In this case, a different treatment should be given.

1. Leukaemia Care. Relapse in acute lymphoblastic leukaemia (ALL) 

https://media.leukaemiacare.org.uk/wp-content/uploads/Relapse-in-Acute-Lymphoblastic-Leukaemia-ALL-Web-Version.pdf

. Published Jan 2019. Accessed Mar 31, 2021.