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Acute Lymphoblastic Leukemia (ALL)

What is Acute Lymphoblastic Leukemia?

Acute lymphoblastic leukemia (ALL) is a cancer of the blood and bone marrow. In leukemia, cancer cells crowd out healthy blood cells, which can cause fever, fatigue, easy bruising, bleeding problems, infections, and other problems. Acute leukemia means symptoms typically worsen over a short period of time. Children may become sick very quickly and need medical attention right away.

ALL affects white blood cells called lymphocytes. These cells fight infection and help protect the body against disease. Patients with ALL have too many immature white blood cells (blasts) in their bone marrow. These cells don’t work normally. They crowd out normal white blood cells, red blood cells, and platelets. As a result, the body has a harder time fighting infections, the skin becomes pale, and the patient develops bleeding problems.

There are two types of lymphocytes: B-lymphocytes and T-lymphocytes. ALL may arise from either type of lymphocyte, so cases of ALL are either known as B-cell or T-cell ALL. B-cell ALL is the most common.

ALL has several subtypes. In many cases, doctors can use the subtype of ALL to make treatment decisions based on the risk group of the leukemia. See treatment section for more information.

Subtypes of ALL (World Health Organization, 2016)

B lymphoblastic leukemia

B-lymphoblastic leukemia, not otherwise specified
B-lymphoblastic leukemia with recurrent genetic abnormalities
B-lymphoblastic leukemia with translocation of chromosomes 9 and 22 (Philadelphia chromosome-positive ALL)
B-lymphoblastic leukemia with KMT 2A translocation
B-lymphoblastic leukemia with translocation of chromosomes 12 and 21 (ETV6-RUNX1)
B-lymphoblastic leukemia in children with more than 50 chromosomes
B-lymphoblastic leukemia in children with less than normal 46 chromosomes (hypodiploidy)
B-lymphoblastic leukemia with translocations of chromosomes 5 and 14 (IL3-IGH)
B-lymphoblastic leukemia with translocation of chromosomes 1 and 19 (TCF3-PBX1).
B-lymphoblastic leukemia/lymphoma, (Philadelphia chromosome–like)
B-lymphoblastic leukemia/lymphoma with iAMP21

T-lymphoblastic leukemia

Early T-cell precursor lymphoblastic leukemia

Natural killer (NK) cell lymphoblastic leukemia/lymphoma

Graphic showing the blood forming process and how it results in blast cells. The graphic begins with a blood stem cell. To the left, it branches off into myeloid stem cell, which branches into platelets, red blood cells, myeloblast, and monoblast. The myeloblast changes into white blood cells (also called granulocytes) and the monoblast changes into a monocyte. The right branch of blood stem cell goes to lymphoid stem cell, which branches into lymphoblasts (which changes into white blood cells) and blast cells.

ALL affects white blood cells called lymphocytes. Patients with ALL have too many immature white blood cells (blasts) in their bone marrow. These cells don’t work normally. They crowd out normal white blood cells, red blood cells, and platelets.

ALL is the most common type of childhood cancer. About 3,000 people younger than age 20 are found to have ALL each year in the United States. It most often occurs in children ages 2 to 5, but it also occurs in older children and adolescents. It affects slightly more boys than girls.

Signs and Symptoms of Acute Lymphoblastic Leukemia

In ALL, signs and symptoms may include:

  • Frequent infections
  • Fever
  • Easy bruising
  • Bleeding that is hard to stop
  • Tiny, flat, dark-red skin spots (petechiae) due to bleeding under the skin
  • Pain in the bones or joints
  • Lumps in the neck, underarm, stomach or groin
  • Pain or fullness below the rib cage
  • Feeling very tired or weak
  • Paleness
  • Loss of appetite
  • Shortness of breath
Illustration of two histology slides side by side highlights the difference between normal bloody cells and blood cells in newly diagnosed ALL.

Children with leukemia usually have a high number of white blood cells in their blood.

Diagnosis of Acute Lymphoblastic Leukemia

Bone marrow tests are usually required to diagnose leukemia. Doctors may begin to suspect leukemia after conducting a physical exam, taking a medical history, and look at the results of blood tests. Children with leukemia usually have a high number of white blood cells in their blood.

  1. At first, a physician will perform a physical exam and look at the patient’s medical history. During the physical exam, the doctor will check general signs of health, including signs of disease, such as lumps or anything else that seems unusual. The eyes, mouth, skin, and ears will be looked at carefully. A nervous system exam may be done. The doctor will feel the patient’s abdomen for signs of an enlarged spleen or liver.  

    In the medical history, doctors look for possible inherited conditions that could contribute to the development of childhood cancer. However, studies have shown that only 8-10 percent of childhood cancers are inherited. And just because someone has a genetic condition does not mean he or she will develop cancer.

    Possible risk factors: 

    • Being exposed to X-rays before birth
    • Previous chemotherapy or radiation therapy

    Having certain inherited conditions:

    • Down syndrome
    • Bloom syndrome
    • Certain forms of Fanconi anemia
    • Ataxia-telangiectasia
    • Li-Fraumeni syndrome
    • Constitutional mismatch repair deficiency (mutations in certain genes that stop DNA from repairing itself)
    • Diamond-Blackfan anemia
    • Shwachman-Diamond syndrome
    • Familial PAX5 syndrome
    • Familial ETV6 syndrome
    • Familial SH2B3 syndrome
  2. Complete blood count

    Doctors will order a blood test called a complete blood count. A sample of blood is drawn and checked for the number of red blood cells and platelets, the number and type of white blood cells, the amount of hemoglobin in the red blood cells, and the portion of the blood sample made up of red blood cells. In leukemia, the blood may have too many white blood cells and many of these cells can be blasts, an early form of cell that is usually found only in the bone marrow of healthy children.

    Blood chemistry studies

    A blood sample is checked to measure the amounts of certain substances released into the blood by organs and tissues in the body. An unusual (higher or lower than normal) amount of a substance can be a sign of disease.

    A young patient sits on an exam table with her parents nearby while a nurse draws a blood sample.

    Doctors may begin to suspect leukemia after conducting a physical exam, taking a medical history, and looking at the results of blood tests.

  3. Bone marrow tests like bone marrow aspiration and biopsy will confirm a diagnosis of cancer and pinpoint the type of cancer. Many children are asleep (sedated) during the procedure. If awake during the procedure, patients are given appropriate pain medicine.

    Bone marrow aspiration: Doctors will obtain bone marrow sample by inserting a thin, hollow needle into the hipbone. A pathologist will view the bone marrow under a microscope to look for signs of cancer.

    Microscope image that shows normal bone marrow

    This microscope image shows normal, healthy bone marrow.

    Microscope image shows bone marrow of a patient with acute lymphoblastic leukemia

    This microscope image shows the bone marrow of a patient with acute lymphoblastic leukemia.

    Bone marrow biopsy: Doctors will remove a small piece of bone tissue to determine how much the cancer has spread in the bone marrow. The biopsy is typically performed right before or after the aspiration.

    How is a bone marrow aspiration/ biopsy performed?

    • Patients will lie on their side on the bed or, less commonly, sit up with legs bent and crossed at the ankles. 
    • The doctor or nurse practitioner will feel the patient’s lower back to find the right spot for the test. 
    • Next, the person performing the test will put on gloves and clean the patient’s back with a germ-killing soap. Then, the health care provider might place plastic towels over the back, leaving only a small area of skin showing. 
    • If the patient is going to be awake during the aspirate or biopsy, numbing cream will be placed on the spot where the bone marrow aspirate or biopsy will be taken about one hour before the procedure. Liquid numbing medicine might be injected at the procedure site. 
    • The health care provider will insert a needle through the skin into the bone marrow. If both an aspiration and biopsy are done, a separate needle will be used for each procedure.
    • The health care provider will take out the needle and will clean the spot with alcohol and put on a bandage.
    A pediatric cancer patient is positioned for a bone marrow biopsy with a clinician's hands performing the procedure.

    Bone marrow tests are usually required to diagnose leukemia.

If cancer is determined, more tests will be performed to pinpoint the subtype of the cancer. These tests include:

  1. Immunophenotyping is used to diagnose specific types of leukemia by comparing the cancer cells to normal cells of the immune system.

    Immunohistochemistry and flow cytometry are the laboratory tests.

    • Immunohistochemistry is a test that uses antibodies to show specific proteins in a sample of tissue. The complexes of proteins and antibodies are stained brown or red and can be seen under a microscope.
    • In flow cytometry, cells are stained with a light-sensitive dye, placed in a fluid, and passed in a stream before a laser or other type of light. The test measures the number of cells, the percentage of live cells, and certain characteristics of cells, such as size, shape, and the presence of leukemia markers on the cell surface.
  2. Cytogenetic analysis involves laboratory tests in which pathologists look for certain changes in the chromosomes.

    One such test is FISH (fluorescence in situ hybridization). This test looks at genes or chromosomes in cells and tissues. Pieces of DNA that contain a fluorescent dye are made in the laboratory and added to cells or tissues on a glass slide. When these pieces of DNA attach to certain genes or areas of chromosomes on the slide, they light up.

  3. The doctor will recommend running laboratory tests to identify specific genes, proteins, and other factors involved in the leukemia. This examination is important because cancer is caused by mistakes (mutations) in the cell’s genes. Identifying these mistakes helps diagnose the specific subtype of leukemia. Based on that information, doctors can choose treatment options tailored to the individual case. Children whose leukemia shows mutations associated with a good outcome may receive less toxic treatments. On the other hand, doctors may prescribe more intensive treatments for patients with a leukemia with mutations associated with poorer outcomes. Mutations may be identified for which a treatment targeted to that specific mutation are available. 

Tests to determine if the cancer has spread include:

  1. A lumbar puncture is performed to collect a sample of cerebrospinal fluid from the spinal column to determine if the cancer has spread to the central nervous system. This procedure is also called an LP or spinal tap. 

    A needle is placed between two bones in the spine and into the fluid around the spinal cord. A sample of fluid is removed. It is checked under a microscope for signs that leukemia cells have spread to the brain and spinal cord. The body makes spinal fluid constantly, so it quickly replaces the small amount an LP takes. 

  2. An X-ray is a type of energy beam that can go through the body and onto film, making a picture of areas inside the body on a computer screen or special film. The chest X-ray is done to see if leukemia cells have formed a mass in the middle of the chest. 

Treatment of Acute Lymphoblastic Leukemia

Chemotherapy is the main therapy for childhood ALL. Treatment may also include targeted therapy, hematopoietic cell therapy (also called bone marrow transplant or stem cell transplant), immunotherapy, and radiation therapy.

Because of recent advances in treating ALL, there are many different treatment options. Doctors are increasingly able to tailor treatments to individual patients based on risk group.

Risk group

Risk group refers to the likelihood that the patient’s cancer either won’t respond to treatment (refractory) or it will return after an initial response to treatment (relapse) Patients in lower-risk groups generally receive less intensive therapies that can successfully treat the cancer. Patients in higher-risk groups usually receive more aggressive therapies.

Risk groups are determined by:

  • The child’s age. Children between the ages of 1 and 9 with B-cell ALL are considered lower-risk. Children younger than 1 and 10 or older are considered higher-risk patients.
  • The number of white blood cells in the blood at diagnosis. Children with more than 50,000 per cubic millimeter are considered higher-risk.
  • Whether the cancer began in B-lymphocytes or T-lymphocytes. T-cell ALL is considered higher-risk.
  • Whether there are certain changes in the chromosomes or genes. ALL cases that are positive for the ETV6-RUNX1 fusion gene are considered lower-risk. ALL that is positive for the Philadelphia chromosome or has a translocation of chromosomes 1 and 19 or that involves chromosome 11 have been considered higher-risk, but outcomes are improving with recent therapy.
  • Number of chromosomes. Hyperdiploid cases (more than 50 chromosomes) are considered lower-risk while hypodiploid cases (children less than 44 chromosomes) are considered higher-risk.
  • How quickly and how low the number of leukemia cells drop after initial treatment. Cases where leukemia cells drop dramatically during the first few weeks of therapy are considered lower-risk. Many pediatric cancer centers use highly sensitive tests to measure for minimal residual disease (MRD.)

Minimal residual disease (MRD) is a term used when there are so few leukemia cells in the bone marrow that they cannot be found using a microscope. Highly sensitive tests such as flow cytometry, polymerase chain reaction (PCR), and next generation sequencing can detect 1 leukemia cell in 10,000-100,000 normal cells in the bone marrow. Children who have positive MRD (more than 1 cell in 10,000 after completing the first phase of ALL treatment (induction)) are at the greatest risk of relapsing.

  • Whether leukemia cells are found in the cerebrospinal fluid at the time of diagnosis. If cells have spread, the case is considered higher-risk.

Three phases of treatment

Treatment for ALL has 3 phases and takes about 2 to 3 years to complete. Chemotherapy is the main treatment for ALL. Chemotherapy uses powerful medicines to stop the growth of cancer cells, either by killing the cells or stopping them from dividing. Children will likely be given a combination of different medicines. These drugs may be injected into the bloodstream (intravenously), given by mouth (orally), or placed directly into the cerebrospinal fluid (intrathecally).

The method of chemotherapy and types of medicine depend on the child’s risk group. Children with higher-risk leukemia generally receive more anticancer drugs and/or higher doses than children with lower-risk ALL.

1. Induction

The goal of induction therapy is to kill leukemia cells in the blood and bone marrow and bring the disease into remission. This phase usually lasts 4-6 weeks. Central nervous system (CNS) sanctuary therapy (also called CNS prophylaxis) may also be given during this time to kill leukemia cells that remain in the spinal fluid. These drugs are injected into the fluid-filled space between the thin layers of tissue that cover the spinal cord (intrathecally).

Treatment will include a combination of chemotherapy drugs. These drugs may include vincristine, steroids, and pegaspargase or Erwinia asparaginase, sometimes with an anthracycline drug such as doxorubicin or daunorubicin. In some protocols, a treatment regimen that includes cyclophosphamide, cytarabine, and 6-mercaptopurine is given during induction therapy.

2. Consolidation/intensification

The goal of consolidation/ intensification therapy is to destroy any remaining cells that could begin to grow and cause the leukemia to relapse. This phase usually lasts 8-16 weeks.

The patient is given different drugs such as cyclophosphamide, cytarabine, and/or 6-mercaptopurine (6-MP). Methotrexate with or without leucovorin rescue may also be administered.

3. Maintenance/Continuation

The goal of maintenance therapy, the last and longest phase, is to destroy any cancer cells that might have survived the first 2 phases. Maintenance may last 2 or 3 years.

This phase may include the drugs methotrexate, vincristine, steroids, 6-mercaptopurine (6-MP). In higher-risk patients, anthracycline drugs, cyclophosphamide, and cytarabine may be given.

Other therapies

Hematopoietic cell transplant (also called bone marrow transplant or stem cell transplant)

A hematopoietic cell transplant (also called bone marrow transplant or stem cell transplant) may be recommended for children who are at high risk for relapse or whose ALL is resistant to treatment. Doctors sometimes look at how well induction chemotherapy worked to decide whether a transplant is needed.

ALL patients whose leukemia is refractory (not responsive to treatment) or relapsed (returned) may be candidates for transplant if they are medically able and have a suitable donor.

Targeted therapy

Targeted therapy uses medicines that seek out and attack cancer cells without harming surrounding normal cells. This type of therapy is only possible if the cancer has identifiable markers that respond to available targeted drugs.


Immunotherapy is a type of cancer treatment that uses the immune system to fight cancer. In general, immunotherapies work by helping the immune system find cancer cells, so it can attack them and/or increase the immune system’s ability to respond to cancer.

One group of targeted therapy drugs is called tyrosine kinase inhibitors (TKIs). TKIs block the enzyme, tyrosine kinase, which is sometimes too active or found at high levels in certain cancer cells. Drugs called Imatinib mesylate and dasatinib are TKIs used to treat children with Philadelphia chromosome-positive ALL. Other TKIs under study include ruxolitinib for newly diagnosed high-risk ALL.

Another type of targeted therapy is known as monoclonal antibody therapy. It uses antibodies made in the laboratory to identify substances on cancer cells or normal substances that may help cancer cells grow. The antibodies attach to the cancer-promoting substances and kill the cancer cells, block their growth, or keep them from spreading. They may be used alone or to carry drugs, toxins, or radioactive material directly to cancer cells. Blinatumomab and inotuzumab are two monoclonal antibodies being studied to treat childhood ALL that is resistant to therapy (refractory). Also, antibodies can be expressed on the immune cells such as T cells and make immune cells directly attack leukemia cells. Such T cells are called as chimeric antigen receptor (CAR) T cells.

Adding the targeted therapy drugs, bortezomib and vorinostat, to standard ALL treatments is under study in infants with ALL because infant ALL is generally more difficult to treat. These drugs may be used in cases where patients are not responding well to treatment.

Prognosis (Treatment Outlook) of Acute Lymphoblastic Leukemia

About 98% of children with ALL go into remission within weeks after starting treatment.

More than 90% of children with ALL can be cured. Patients are considered cured after about 5 years in remission.

Survival rates for ALL patients in lower-risk groups can be more than 95%.

If patients have a form of ALL that does not respond to treatment (refractory) or comes back after treatment (relapsed), the medical team will discuss treatment options.

Late Effects of Acute Lymphoblastic Leukemia Treatment

A late effect is a health problem that occurs months or years after a disease is diagnosed or after treatment has ended. Late effects may be caused by cancer or cancer treatment. They may include physical, mental, and social problems and second cancers.

Late effects may include:

  • Recurrence of the ALL
  • Second cancers such as skin, brain cancer, bone, breast, soft tissue, and thyroid. With the elimination of cranial radiation as standard treatment for ALL, it is believed that the number of second cancers will drop in future years.
  • Heart and lung problems
  • Bone problems
  • Endocrine conditions
  • Gastrointestinal issues
  • Difficulties with mental flexibility, reasoning, planning, and organization
  • Depression
  • Sleep problems

Current Focus of Acute Lymphoblastic Leukemia Research

Current research focuses on developing more effective treatments for children whose cancer doesn’t respond to the original therapy and to develop more therapies that target the cancer cells without harming surrounding healthy cells. Researchers are also focused on developing treatments that don’t cause as many late effects in cancer survivors. The studies on late effects in the increasing number of long-term survivors will help with this issue.

Reviewed: June 2018