Acute Lymphoblastic Leukemia (ALL)
What is Acute Lymphoblastic Leukemia?
Acute lymphoblastic leukemia (ALL) is a cancer of the blood and bone marrow. It is the most common form of childhood cancer.
About 3,000 children and teens younger than 20 are diagnosed with ALL each year in the United States.
ALL most often occurs in children ages 2 to 5. It can also occur in older children and adolescents. It affects slightly more boys than girls.
ALL in infants is rare. About 90 cases of ALL in children younger than 1 are diagnosed each year in the United States.
The most common treatment for ALL is chemotherapy. Many advances have been made in ALL treatment. The overall cure rate for ALL in children is about 90%.
What Causes Acute Lymphoblastic Leukemia?
In leukemia, cancer cells grow rapidly in the bone marrow. These cancer cells are immature white blood cells called blasts. When this happens, healthy blood cells — white blood cells, red blood cells, and platelets — can’t do their jobs correctly.
ALL affects white blood cells called lymphocytes. These cells fight infection and help protect the body against disease.
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.
Most cases of ALL have no known cause.
Certain inherited syndromes are linked to an increased risk of ALL.
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.
Inherited syndromes associated with increased risk of ALL include:
- Down syndrome
- Neurofibromatosis type 1
- Bloom syndrome
- Ataxia-telangiectasia
- Li-Fraumeni syndrome
- Certain forms of Fanconi anemia
- Constitutional mismatch repair deficiency
- Diamond-Blackfan anemia
- Familial PAX5 syndrome
- Familial ETV6 syndrome
- Familial SH2B3 syndrome
What Are Signs and Symptoms of Acute Lymphoblastic Leukemia?
Acute leukemia means symptoms worsen quickly.
Children may become very sick and need medical attention right away.
In ALL, signs and symptoms may include:
- Fatigue
- Pain in the bones or joints
- Fever
- Frequent infections
- Easy bruising and bleeding that is hard to stop
- Tiny, flat, dark-red skin spots (petechiae)
- Lumps in the neck, underarm, stomach or groin
- Pain or fullness below the rib cage
- Paleness
- Loss of appetite
- Shortness of breath
- Enlarged liver
- Enlarged spleen
Children with leukemia usually have a high number of white blood cells in their blood.
How is Acute Lymphoblastic Leukemia Diagnosed?
Doctors may suspect leukemia after doing a physical exam, taking a medical history, and looking at the results of blood tests.
Bone marrow tests are required to confirm a leukemia diagnosis.
If leukemia is found, additional tests will be run to find out if ALL is in other parts of the body and to gather information about the subtype of ALL.
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During the exam and history, the provider will:
- Check general signs of health, including signs of disease, such as lumps or anything else that is unusual.
- Examine the eyes, mouth, skin, and ears. The provider will feel the patient’s abdomen for signs of an enlarged spleen or liver. In boys, the provider may also examine the testes.
- Ask about other medical conditions the patient may have and illnesses that relatives such as parents, siblings, and grandparents may have had. The provider is looking for possible inherited conditions that have an increased risk of cancer.
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A provider will draw blood to run tests. These tests include:
- Complete blood count – This test checks the counts of different types of blood cells. In ALL, the blood may have too many white blood cells. Many of these cells will be cancer cells.
- Blood chemistry studies – This test checks the amounts of certain substances in the blood. An unusual level (either higher or lower than normal) can be a sign of disease.
- Liver function tests
- Coagulation test – This test measures the blood’s ability to clot.
Doctors may begin to suspect leukemia after conducting a physical exam, taking a medical history, and looking at the results of blood tests.
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A bone marrow aspiration and biopsy will confirm a diagnosis of cancer. Patients usually have these procedures at the same time. Patients will either be sedated or have appropriate pain medication.
If cancer is diagnosed, more tests will be run on the bone marrow to pinpoint the subtype of the cancer.
Immunophenotyping
Immunophenotyping is used to diagnose specific types of leukemia. It compares 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.
Cytogenetic Analysis and Molecular and Genetic Testing
The doctor will recommend running laboratory tests to identify specific genes, proteins, and other factors involved in the leukemia.
This is important because cancer is caused by mistakes (mutations) in the cell’s genes. Identifying these mistakes helps diagnose the specific subtype of leukemia.
Using this 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.
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.
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 KMT2A 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 44 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) (provisional entity)
- B-lymphoblastic leukemia/lymphoma with intrachromosomal amplification 21 (iAMP21) (provisional entity)
T-lymphoblastic leukemia
- Early T-cell precursor lymphoblastic leukemia (provisional entity)
Natural killer (NK) cell lymphoblastic leukemia/lymphoma (provisional entity)
Tests After Cancer is Diagnosed
The care team will run tests to find out if it is in other parts of the body.
Lumbar Puncture
A lumbar puncture will show if leukemia has spread to the central nervous system. The test is also called an LP or spinal tap.
Patients may receive chemotherapy at the same time this is done. This is called prophylactic intrathecal chemotherapy. It is given to prevent ALL from spreading to the cerebrospinal fluid.
Chest X-ray
A chest X-ray will be done to see if leukemia cells have formed a mass in the middle of the chest.
Other Imaging Tests and Laboratory Tests
Other imaging studies and laboratory tests may be performed if patients have certain signs and symptoms.
Female patients of childbearing age may have pregnancy testing.
Male patients may be examined by ultrasound to see if the provider suspects testicle involvement. This is rare in ALL. It happens in 1-2% of males.
Fertility Counseling
Fertility counseling and/or preservation options should be presented to males and females, especially in adolescents.
Treatment of Acute Lymphoblastic Leukemia
Chemotherapy is the main treatment for childhood ALL. Treatment involves a combination of medicines. It takes 2 to 3 years to complete.
Treatment is generally given on an outpatient basis. But there may be times when the patient will need to be in the hospital.
Many cancer centers and hospitals in the United States treat ALL. The specific drugs, dosage, and schedule of delivery may vary somewhat. But the treatment principles are the same.
The treatment plan will depend on the results of the patient’s diagnostic tests.
Patients will have a surgical procedure to get a central venous access device. This device reduces the need for needle sticks. Patients can have blood drawn for laboratory tests and receive intravenous (IV) medicines, fluids, blood products, and nutrition through the device. After treatment has completed, it will be removed.
Patients may have to miss some school during treatment. But the treatment center, school, parents, and student can work together so the student can keep up with school as much as possible.
Risk group
Doctors are increasingly able to tailor treatments to individual patients based on their risk group.
Risk group refers to the chance that the patient’s cancer either won’t respond to treatment (refractory), or it will return after an initial response to treatment (relapse). There are treatment options for relapsed or refractory ALL.
Risk groups have different names depending on the treatment center. In general, these risk groups are called low, standard, high, and very high.
The method of chemotherapy and types of medicine depend on the child’s risk group. For example, children and teens with high-risk leukemia generally receive more anticancer drugs and/or higher doses than children with low-risk ALL.
In some cases, treatment may also include targeted therapy, immunotherapy, and hematopoietic cell transplant (also called bone marrow transplant or stem cell transplant).
Risk groups are determined by:
- Whether the cancer began in B-lymphocytes or T-lymphocytes — B-cell ALL is considered lower-risk than T-cell ALL.
- Age — Children between the ages of 1 and 9 with B-cell ALL are generally considered low-or standard-risk. Children younger than 1 and 10 or older are considered high-risk patients. (This age cut-off may vary among treatment centers.)
- White blood cell count at diagnosis — Children with a count of fewer than 50,000 are considered low-risk.
- Certain changes in the chromosomes or genes
- Favorable risk features: ALL cases positive for the ETV6-RUNX1 fusion gene are considered low-risk.
- Unfavorable risk features:
- Positive for the Philadelphia chromosome
- Translocation that involves chromosome 11 (KMT2A gene)
- Translocation that involves chromosomes 1 and 19 (TCF3-PBX1 fusion gene)
- Translocation that involves chromosomes 17 and 19 (TCF3-HLF fusion gene)
- Positive for iAMP21
- Number of chromosomes — Hyperdiploid cases (more than 50 chromosomes) are considered lower-risk while hypodiploid cases (children with less than 44 chromosomes) are considered higher-risk.
- Response to treatment — Cases where leukemia cells drop dramatically during the first few weeks of therapy are considered low-risk.
- Minimal Residual Disease — 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 10,000-1,000,000 normal cells in the bone marrow.
Children who have positive MRD (more than 1 cell in 10,000) after induction therapy are at the greatest risk of relapsing. The timing of MRD measurement varies depending on the center.
- Whether leukemia cells are found in the cerebrospinal fluid (CSF) at the time of diagnosis — If cells have spread to the CSF, the case is treated with more intrathecal therapy.
Phases of treatment
Week 1
Diagnostic workup, treatment prep
Doctors gather information to inform treatment.
- Blood tests
- Physical exam and history
- Chest X-ray
- Bone marrow aspirate and/or biopsy
- Lumbar puncture
Before treatment begins
The patient will undergo surgery to get a subcutaneous port or other venous access device to deliver chemotherapy, fluids, and take blood samples.
Next 4-6 weeks
Induction Phase
The goal of this phase is to use a combination of chemotherapies to destroy leukemia cells in the blood and bone marrow and bring the disease into remission. This phase is intense and may require hospital stays.
Central nervous system (CNS) sanctuary therapy may be given to destroy leukemia cells in the spinal fluid.
Doctors will look at how leukemia responds to induction therapy to determine how to proceed with therapy.
- Cases where leukemia cells drop dramatically are considered lower-risk.
- Many pediatric centers use highly sensitive tests to measure for minimal residual disease (MRD). Positive MRD indicates a greater risk of relapse and need for more intensive therapy.
- Doctors will decide if a hematopoietic cell transplant is needed.
Next 8-16 weeks
Consolidation/Intensification Phase
The goal of this more intensive phase involves a different combination of drugs to destroy any remaining cells that could cause leukemia to relapse. It may require hospital stays.
Patients who have Philadelphia chromosome-positive ALL may receive imatinib during this phase.
Next 2-3 years
Maintenance/Continuation Phase
If the leukemia stays in remission after the first 2 phases, maintenance therapy can begin. Its goal is to use a combination of chemotherapy drugs to destroy any leukemia cell that might remain after the first induction and consolidation phases.
Patients will likely have weekly chemotherapy and blood tests with periods of high-dose chemotherapy known as reinduction.
The first 9 months of treatment of ALL is usually the most intensive. Often patients can return to school after the first 9 months.
Follow Up Schedule
Year 1
The patient will return for follow-up visits once every 4 months.
These visits may include:
- Physical examination and medical history
- Blood tests and other laboratory tests
Year 2
Follow-up visits may change to once every 6 months.
Year 3-5
Follow-up visits may change to once a year.
Three phases of treatment
Treatment for ALL has 3 phases and takes about 2 to 3 years to complete.
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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. It is the most intensive phase of treatment.
Central nervous system (CNS) sanctuary therapy (also called CNS prophylaxis) will 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 may include vincristine, prednisone or dexamethasone, and pegaspargase or Erwinia asparaginase, sometimes with an anthracycline drug such as daunorubicin.
In some treatment protocols, cyclophosphamide, cytarabine, methotrexate, or 6-mercaptopurine may be given during induction therapy.
Patients will have a bone marrow aspirate/ biopsy during this phase to find out how the leukemia is responding to therapy.
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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.
It may include cyclophosphamide, cytarabine, 6-mercaptopurine (6-MP), thioguanine, vincristine, corticosteroids, and pegaspargase. Methotrexate with or without leucovorin rescue may also be given.
It may involve 6-8 cycles of chemotherapy over a period of up to 8 months.
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The goal of maintenance therapy is to destroy any cancer cells that might have survived the first 2 phases. Maintenance may last 2 to 3 years.
Maintenance regimens may involve daily doses of 6-mercaptopurine (6-MP), weekly methotrexate, and periodic doses of vincristine and corticosteroids.
In higher-risk patients, anthracycline drugs such as doxorubicin as well as cyclophosphamide and cytarabine may be given.
Other therapies
In some cases, doctors may recommend additional treatment options.
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 detectable gene markers that respond to available targeted drugs.
Targeted therapies drugs imatinib or dasatinib have been shown to be effective in treating Philadelphia chromosome-positive ALL and Philadelphia-like ALL.
Ruxolitinib may be used to treat a type of ALL called Philadelphia-like ALL.
Immunotherapy
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. It can then attack cancer cells and/or increase the immune system’s ability to respond to cancer.
Immunotherapy may include monoclonal antibody drugs such as blinatumomab, inotuzumab ozogamicin, and rituximab. The chimeric antigen receptor (CAR) T cell, such as tisagenlecleucel, may also be a possible treatment.
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. Patients must be medically able and have a suitable donor.
Doctors sometimes look at how well induction chemotherapy worked to decide whether a transplant is needed.
Radiation
Radiation is rarely used in ALL treatment. It may be given in cases where ALL has spread to the brain, spinal cord, or testicles. A 2019 study showed that radiation to the central nervous system for ALL may be omitted.
Radiation may also be given to prepare patients to receive a hematopoietic cell transplant (commonly known as bone marrow transplant or stem cell transplant.)
What Are the Side Effects of Acute Lymphoblastic Leukemia Treatment?
Side effects are hard to predict. They depend on the medicine and how a person reacts to it. Different people can have different reactions to the same medicine.
Side effects can happen during any phase of ALL treatment. The first weeks of treatment (induction phase) are the most intense and the most likely to produce serious side effects. There are treatments for these side effects.
Side effects may include:
- Infection
- Tumor lysis syndrome
- Bleeding
- Thrombosis (blood clots)
- Mucositis (mouth and throat sores)
- Peripheral neuropathy — This is a common side effect of the drug vincristine.
- Allergic reactions — This can happen with any drug. But some patients have reactions to the drugs pegaspargase and Erwinia asparaginase.
- High blood sugar
- Nausea and vomiting
- Hair loss
What is the Prognosis 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 low-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
Some ALL patients may have late effects. A late effect is a health problem that occurs months or years after treatment has ended.
Cancer patients should continue to be followed by their treatment center care team and/or a primary care provider in the community after cancer treatment. Late effects can often be treated or, in some cases, prevented.
Different treatments may have different late effects. Not all patients will have late effects. Patients who had the exact same treatment may experience different late effects.
ALL patients may be at risk for:
- Peripheral neuropathy
- Avascular necrosis (AVN), also called osteonecrosis
- Reduced bone density
- Infertility
- Problems with thinking and learning
- Obesity
- Endocrine conditions
- Cardiac problems
- Secondary cancer
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.
Researchers are also focused on developing treatments that don’t cause as many side effects during therapy and late effects in cancer survivors.
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Reviewed: February 2020