Acute lymphocytic leukemia
Acute Lymphocytic Leukemia or Acute Lymphoblastic Leukemia (ALL)
There are four major types of leukemia. ALL is the most common in children, and the least common in adults. About 6,000 people are diagnosed with ALL each year. Children account for two third of these cases. In general, children with ALL have a better outlook than adults. Most children with ALL can be cured of this cancer.
Symptoms and Diagnosis
Symptoms of ALL include fatigue, pale skin, recurrent infections, bone pain, bruising, and small red spots under the skin. Doctors use various tests, including blood counts and bone marrow biopsies, to diagnose ALL.
ALL is treated with chemotherapy and, sometimes, radiation. Children receive different chemotherapy regimens than adults. Some people with advanced cancer that has not responded to these treatments may need a stem cell transplant.
Both chemotherapy and transplantation increase the risk for infection. People must take strict precautions to avoid exposure to germs. Ways to prevent infection include:
The word leukemia literally means "white blood" and is used to describe a variety of cancers that form in the white blood cells (lymphocytes) of the bone marrow. Bone marrow is the soft tissue in the center of the bones, where blood cells are produced. The bone marrow makes white blood cells, red blood cells, and platelets.
White blood cells are an essential part of the immune system. They are used by the body to fight infections and other foreign substances. The general name for white blood cells is leukocytes. Lymphocytes are a specific type of leukocyte. Leukocytes evolve from immature cells referred to as blasts. Immature lymphocytes are called lymphoblasts. Malignancy of these blast cells is the source of leukemias.
Both leukemia and lymphomas (Hodgkin disease and non-Hodgkin lymphomas) are cancers of leukocytes. The difference is that leukemia starts in the bone marrow while lymphomas originate in lymph nodes and then spread to the bone marrow or other organs.
Leukemias are classified based on how quickly they progress and the development of the cells.
There are four major types of leukemia:
Acute lymphocytic leukemia (ALL) is the focus of this report.
All leukemias involve an uncontrolled increase in the number of white blood cells. In acute leukemias, the bone marrow produces an overwhelming number of immature cells. These cancerous cells prevent healthy red cells, platelets, and mature white cells (leukocytes) from being made in the bone marrow. Life-threatening symptoms can then develop.
Cancer cells can spread to the bloodstream and lymph nodes. They can also travel to the brain and spinal cord (the central nervous system) and other parts of the body.
Acute Lymphocytic Leukemia
Acute lymphocytic leukemia (ALL) is also known as acute lymphoid leukemia or acute lymphoblastic leukemia. The majority of childhood leukemias are of the ALL type.
Lymphocytes are the body's primary immune cells. Among other vital functions, lymphocytes produce antibodies, factors that can target and attack specific foreign substances (antigens) and fight infections.
Lymphocytes develop in the thymus gland or bone marrow and are therefore categorized as either B cells (bone marrow-derived cells) or T cells (thymus gland-derived cells). ALL can arise from either T-cell or B-cell lymphocytes. Most cases of ALL involve B cells.
It is likely that ALL develops from a combination of genetic, biologic, and environmental factors.
Many leukemias involve genetic rearrangements, called translocations, in which some of the genetic material (genes) on a chromosome may be shuffled or swapped between a pair of chromosomes.
Translocations commonly associated with acute lymphocytic leukemia (ALL) include:
Acute lymphocytic leukemia (ALL) is diagnosed in about 6,000 Americans each year. Children account for two third of these new cases.
ALL in Children
ALL is the most common type of cancer diagnosed in children. ALL accounts for about 75% of cases of childhood leukemia. ALL can occur in children of all ages. But it is most likely to occur before age 5 years. It is slightly more common in boys than in girls.
ALL in Adults
ALL is the least common type of leukemia among adults. About 1 in 3 cases of ALL occur in adults. Adults over age 50 have a higher risk for ALL than those between the ages of 20 and 50.
Race and Ethnicity
White and Hispanic children have a higher risk for ALL than African American children.
ALL does not appear to run in families. Still, certain genetic disorders may increase risk. For example, children with Down syndrome have a 20-times greater risk of developing ALL than the general population. Other rare genetic disorders associated with increased risk include Klinefelter syndrome, Bloom syndrome, Fanconi anemia, ataxia-telangiectasia, neurofibromatosis, Shwachman syndrome, IgA deficiency, and congenital X-linked agammaglobulinemia.
Radiation and Chemical Exposure
Previous cancer treatment with high doses of radiation or chemotherapy can increase the risk for developing ALL. Prenatal exposure to x-rays may also increase risk in children. Lower levels of radiation (living near power lines, video screen emissions, small appliances, cell phones) are unlikely to pose any cancer risk.
The symptoms of acute lymphocytic leukemia (ALL) may be difficult to recognize. ALL usually begins abruptly and intensely, but in some cases symptoms may develop slowly. They may be present one day, and absent the next, particularly in children.
Leukemia symptoms are due to a lack of normal healthy cells in the blood. Some symptoms of ALL are very general and can mimic those of other disorders. Other symptoms are very specific to leukemia. For example, problems with bleeding and bruising are caused by a low count of blood-clotting (platelet) cells. Problems with frequent infections are due to the reduced numbers of healthy mature white blood cells (leukocytes).
General symptoms of ALL include:
Other symptoms of ALL include:
Acute lymphocytic leukemia (ALL) is diagnosed based on various tests.
The doctor will examine the person for signs of enlarged lymph nodes or enlarged liver or spleen. The doctor will also look for any signs of bruising or bleeding.
A complete blood cell count (CBC), which checks for numbers of white cells, red blood cells, and platelets, is the first step in diagnosing ALL. People with ALL generally have a higher than normal white blood count and lower than normal red blood cell and platelet counts.
Blood tests are also performed to evaluate liver, kidney, and blood clotting status and to check for levels of certain minerals and proteins.
Bone Marrow Biopsy
If blood test results are abnormal or the doctor suspects leukemia despite normal cell counts, a bone marrow aspiration and biopsy are the next steps. These are very common and safe procedures. However, because this test can produce considerable anxiety, particularly in children, parents may want to ask the doctor if sedation is appropriate for their child.
Normal bone marrow contains 5% or less of blast cells (the immature cells that ordinarily develop into healthy blood cells). In leukemia, abnormal blasts constitute between 20% to 100% of the marrow.
If bone marrow examination confirms ALL, a spinal tap (lumbar puncture) may be performed, which uses a needle inserted into the spinal canal. The person feels some pressure and usually must lie flat for about an hour afterward to prevent severe headache. This can be difficult, particularly for children, so parents should plan reading or other quiet activities that will divert the child during that time. Parents should also be certain that the doctor performing this test is experienced in this procedure.
A sample of cerebrospinal fluid with leukemia cells is a sign that the disease has spread to the central nervous system. In most cases of childhood ALL, leukemia cells are not found in the cerebrospinal fluid.
Tests Performed after Diagnosis
Once a diagnosis of leukemia has been made, further tests are performed on the bone marrow cells:
The results of cytogenetic, flow cytometry, immunophenotyping, and other tests can help provide information on types and subtypes of ALL cells. The particular subtype of cell can aid in determining prognosis and treatment.
An older classification system called the French-American-British (FAB) classification grouped ALL into L1, L2, and L3 subtypes. A newer classification system classifies ALL B cells or T cells based on their stage of maturity.
B-Cell ALL Subtype Classification:
T-Cell ALL Subtype Classification:
Acute lymphocytic leukemia can progress quickly if untreated. However, ALL is one of the most curable cancers and survival rates are now at an all-time high.
Certain factors help determine prognosis:
Other factors, such as central nervous system involvement or recurrence, may indicate a poorer prognosis.
There are typically three treatment stages for the average-risk person with ALL:
Because leukemia can also spread to the brain and spinal cord, where chemotherapy that is given intravenously or orally does not penetrate very well, most people also need radiation to the brain and spinal cord, or chemotherapy that is injected into the layers around them. This is called central nervous system prophylaxis (preventive treatment) and is given during all treatment phases to prevent the cancer from spreading to the brain and spinal cord.
Specific Treatments Used in ALL
The following are specific treatments used for ALL:
Enrolling in a clinical trial may be an option for some people. Scientists are working on finding new treatment options for ALL, including difficult to treat subtypes.
In 2013, researchers announced promising results from two clinical trials that involved a small number of adults and children with B-cell ALL. The trials tested an investigational treatment called targeted immunotherapy or more specifically, chimeric antigen receptor T-cell therapy (CAR-T). This cell therapy involves filtering T-cells from a person, and then genetically transforming the cells by introducing a special gene. The genetically engineered T-cells are then infused back into the person, where they target and attack the cancerous B cells.
As a result of the above research, in August 2017, the U.S. Food and Drug Administration approved Kymriah (tisagenlecleucel) for certain pediatric and young adults with B-cell precursor ALL that is refractory or in second or later relapse.
Treatment to Achieve Remission (Induction Therapy)
The aim of induction therapy, the first treatment phase, is to reduce the number of leukemia cells to undetectable levels. The general guidelines for induction therapy are as follows:
Drugs Used for Induction
Both children and adults typically start with a 3-drug regimen. Imatinib (Gleevec) or dasatinib (Sprycel) may be added for people with Philadelphia chromosome-positive ALL.
For children, the standard drugs are:
For adults, the standard drugs are:
Preventing Central Nervous System Disease (CNS Prophylaxis)
Chemotherapy given intravenously or orally does not penetrate the blood-brain barrier sufficiently to destroy leukemic cells in the brain. Since the brain is one of the first sites for relapsing leukemia, preventive treatment is administered to the brain and spine (called sanctuary disease sites). This is called CNS prophylaxis.
For children, CNS prophylaxis uses intrathecal chemotherapy, in which a drug is injected directly into the spinal fluid. Intrathecal chemotherapy is given with methotrexate (MTX), cytarabine, and hydrocortisone.
Some high-risk children may receive radiation to the skull (cranial radiation), radiation to the spine, or both along with intrathecal chemotherapy. This combination can be very toxic and is generally used only in children who have evidence of the disease in the central nervous system at the time of diagnosis. Long-term complications of high-dose cranial radiation can include learning and neurologic problems. Cranial radiation is also associated with increased risks for stroke and secondary cancers.
Adult CNS prophylaxis is performed in one of three ways:
Evidence of Remission after Induction Treatment
Survival in acute leukemia depends on complete remission (no signs of active cancer). Although not always clear-cut, remission is indicated by the following:
Induction can produce extremely rapid results. Nearly all children with ALL achieve remission after a month of induction treatment. The shorter the time to remission the better the outlook:
Side Effects and Complications
Side effects and complications of any chemotherapeutic regimen and radiation therapy are common, are more severe with higher doses, and increase over the course of treatment. Administering drugs for shorter duration can sometimes reduce toxicities without affecting the drugs' cancer-killing effects.
Common Side Effects
Typical side effects include:
Serious Side Effects
Serious side effects can also occur and may vary depending on the specific drugs used.
Infection from suppression of the immune system or from severe drops in white blood cells is a common and serious side effect. People should make all efforts to prevent infection. The person at high risk for infection may need potent antibiotics and antifungal medications as well as granulocyte colony-stimulating factors or G-CSF (lenograstim, filgrastim) to stimulate the growth of infection-fighting white blood cells. People should make all efforts to minimize exposure to bacteria and viruses. (See "Preventing Infection" in the Home Management section of this report.)
Other serious side effects may include:
Treatment During Remission (Consolidation and Maintenance)
Consolidation and maintenance therapies follow induction and first remission. The goal of consolidation and maintenance therapies is to prevent a relapse.
Consolidation (Intensification) Therapy
Because there is a high risk of the cancer returning (relapsing) after the first phase of treatment (induction therapy), an additional course of treatment is given next. This is called consolidation therapy (also called intensification therapy). Consolidation is an intense chemotherapy regimen that is designed to prevent a relapse and usually continues for about 4 to 8 months.
Examples of consolidation regimens for people at standard risk:
More intense regimens are used for people at high-risk for relapse.
The last phase of treatment is maintenance (also called continuation therapy):
A maintenance regimen is usually less toxic and easier to tolerate than induction and consolidation. Maintenance treatment lasts for about 2 to 3 years for most people with ALL. It is not clear if maintenance therapy benefits people who have certain specific types of ALL, such as T-cell ALL or mature B-cell ALL (Burkitt leukemia).
Treatment After Relapse
Relapse is when cancer returns after remission. Most people with ALL achieve remission after induction therapy, but in some people the disease returns.
The following are factors that increase the risk for relapse after initial treatments:
Treatment for relapse after a first remission may be standard chemotherapy or experimental drugs, or more aggressive treatments such as stem cell transplants.
The decision depends on a number of factors including how soon relapse occurs after treatment:
Transplantation procedures are reserved for people with high-risk disease who are unlikely to achieve remission with chemotherapy alone. Transplantation does not offer any additional advantages for people at low or standard risk.
Chemotherapy and Other Drugs Used After Relapse
Many different types of drugs are used to treat ALL relapses. These drugs include chemotherapeutic agents such as vincristine, asparaginase, anthracyclines (doxorubicin, daunorubicin), cyclophosphamide, cytarabine (ara-C), epipodophyllotoxins (etoposide, teniposide), and Marqibo, a specially-formulated type of vincristine injection, for adults with Philadelphia chromosome-negative ALL. Other chemotherapeutic drugs for relapsed or refractory ALL include nelarabine (Arranon), for T-cell ALL, and clofarabine (Clolar), for pediatric ALL patients.
Immunotherapeutic drugs include blinatumomab (Blincyto) and inotuzumab ozogamicin (Besponsa), both for B-cell precursor ALL.
The most recently approved approach to relapsed disease in the pediatric and young adult population is the use of chimeric antigen receptor (CAR) T-cell therapy, Kymriah (tisagenlecleucel).
The drugs known as tyrosine kinase inhibitors (TKIs) are also utilized in the relapsed setting. Tyrosine kinase is a growth-stimulating protein. TKI drugs block the cell signals that trigger cancer growth. TKI drugs approved for adults with Philadelphia chromosome-positive (Ph+) ALL include: Imatinib (Gleevec), Dasatinib (Sprycel), Ponatinib (Iclusig), and Bosutinib (Bosulif).
Stem cells that are made in the bone marrow are the early form of all blood cells in the body. They normally mature into red, white, or immune cells. To help the person survive high dose chemotherapy needed to cure leukemia that has returned treatment, or not responded to treatment, a stem cell transplantation procedure may be used. Stem cell transplantation replaces blood stem cells that were lost during the initial chemotherapy treatment. The lost stem cells are replaced by transplanting them from a donor into the person.
Types of Donors
The stem cells to be given to the person with leukemia can come from either the patient (autologous) or a donor (allogeneic):
The Blood Stem Cell Collection Procedure
Sources of Cells
Stem cells can be obtained either from the donor's:
The Transplant Procedure
Side Effects and Complications
Stem-cell transplantation is a serious and complex procedure that can cause many short- and long-term side effects and complications.
Early side effects of transplantation are similar to chemotherapy and include nausea, vomiting, fatigue, mouth sores, and loss of appetite. Bleeding because of reduced platelets is a high risk during the first month, people may require blood transfusions.
Later side effects can include fertility problems (if the ovaries are affected), thyroid gland problems (which can affect metabolism), lung damage (which can cause breathing problems) and bone damage.
Two of the most serious complications of transplantation are infection and graft-versus-host disease:
Infection resulting from a weakened immune system is the most common danger. The risk for infection is most critical during the first 6 weeks following the transplant, but it takes 6 to 12 months post-transplant for a person's immune system to fully recover. Many people develop severe herpes zoster virus infections (shingles) or have a recurrence of herpes simplex virus infections (cold sores and genital herpes). Pneumonia and infections with germs that normally do not cause serious infections such as cytomegalovirus, aspergillus (a type of fungus), and Pneumocystis jiroveci (a fungus) are among the most serious life-threatening infections.
It is very important that people take precautions to avoid post-transplant infections. (See Home Management section of this report.)
Graft-versus-host disease (GVHD)
GVHD is a serious attack by the person's immune system triggered by the donated new marrow in allogeneic transplants.
Acute GVHD occurs in 30% to 50% of allogeneic transplants, usually within 25 days. Its severity ranges from very mild symptoms to a life-threatening condition (more often in older people). The first sign of acute GVHD is a rash, which typically develops on the palms of hands and soles of feet and can then spread to the rest of the body. Other symptoms may include nausea, vomiting, stomach cramps, diarrhea, loss of appetite and jaundice (yellowing of skin and eyes). To prevent acute GVHD, doctors use immune-suppressing drugs such as steroids, methotrexate, cyclosporine, tacrolimus, and monoclonal antibodies.
Chronic GVHD can develop 70 to 400 days after the allogeneic transplant. Initial symptoms include those of acute GVHD. Skin, eyes, and mouth can become dry and irritated, and mouth sores may develop. Chronic GVHD can also sometimes affect the esophagus, gastrointestinal tract, and liver. Bacterial infections and chronic low-grade fever are common. Chronic GVHD is treated with similar medicines as acute GVHD.
Too much sun exposure can trigger GVHD. It is important for people to always wear sunscreen (SPF 15 or higher) on areas of the skin that are exposed to the sun. When outside, try to stay in the shade.
A parent should call the doctor if the child has any symptoms that are out of the ordinary, including (but not limited) to:
Parents should track their child's absolute neutrophil count. This measurement for the amount of white blood cells is an important gauge of a child's ability to fight infection.
It is very important to take precautions to prevent infection following chemotherapy or transplantation. Guidelines for infection prevention and control include:
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