Acute Lymphocytic 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-thirds 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 patients 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. Patients must take strict precautions to avoid exposure to germs. Ways to prevent infection include:
New Drug Approvals
In 2012, the FDA approved two new drugs for treatment of adults with relapsed or refractory ALL:
The word leukemia literally means "white blood" and is used to describe a variety of cancers that begin in the blood-forming cells (lymphocytes) of the bone marrow.
Leukemias are divided into two major types:
Both leukemia and lymphomas (Hodgkin’s disease and non-Hodgkin’s lymphomas) are cancers of lymphocytes. 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.
White blood cells (leukocytes) evolve from immature cells referred to as blasts. Malignancy of these blast cells is the source of leukemias, which generally progress as follows:
Malignant blasts spill out of the marrow into the bloodstream and lymph system and can travel to the brain and spinal cord (the central nervous system). Some blasts are called lymphoblasts (which normally become mature cells called lymphocytes) and others are called myeloblasts (which mature to myeloid cells).
Acute leukemias subdivided into two classifications according to whether the malignant blasts are lymphocytes or myeloid:
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.
Doctors do not know exactly what causes acute lymphocytic leukemia (ALL). It is likely that ALL develops from a combination of genetic, biologic, and environmental factors.
Up to 65% of leukemias contain 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.
Acute lymphocytic leukemia is diagnosed in about 6,000 Americans each year. Children account for two-thirds 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. Each year, about 3,500 American children and adolescents are diagnosed with ALL. ALL can strike 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 - 50.
Caucasian 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.
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 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. Symptoms develop when:
ALL is diagnosed based on various tests.
The doctor will examine a patient 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. Patients 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.
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 30 - 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 patient 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.
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 is responsible for about 1,400 deaths a year in the U.S., and it can progress quickly if untreated. However, ALL is one of the most curable cancers and survival rates are now at an all-time high.
According to the American Cancer Society, certain factors can 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 patient 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 patients 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.
The following are specific treatments used for ALL:
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:
Both children and adults typically start with a 3-drug regimen. Imatinib (Gleevec) or dasatinib (Sprycel) may be added for patients with Philadelphia chromosome-positive ALL.
For children, the standard drugs are:
For adults, the standard drugs are:
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, spine, and testes (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 alone or a combination of 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:
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 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. Patients should make all efforts to prevent infection. The patient 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. Patients 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 include:
Consolidation and maintenance therapies follow induction and first remission. The goal of consolidation and maintenance therapies is to prevent a relapse.
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 - 8 months.
Examples of consolidation regimens for patients at standard risk:
More intense regimens are used for patients 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 - 3 years for most patients with ALL. It is not clear if maintenance therapy benefits patients who have certain specific types of ALL, such as T-cell ALL or mature B-cell ALL (Burkitt leukemia).
Relapse is when cancer returns after remission. Most patients with ALL achieve remission after induction therapy, but in some patients 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 patients with high-risk disease who are unlikely to achieve remission with chemotherapy alone. Transplantation does not offer any additional advantages for patients at low or standard risk.
Many different drugs are used to treat ALL relapses. These drugs include vincristine, asparaginase, anthracyclines (doxorubicin, daunorubicin), cyclophosphamide, cytarabine (ara-C), and epipodophyllotoxins (etoposide, teniposide). In 2012, the FDA approved Marqibo, a specially-formulated type of vincristine injection, for adults with Philadelphia chromosome-negative ALL. Other drugs for relapsed or refractory ALL include nelarabine (Arranon), for T-cell ALL, and clofarabine (Clolar). Corticosteroids, such as prednisone or dexamethasone, may also be used.
The most recently approved treatments for ALL are biologic drugs that are tyrosine kinase inhibitors (TKIs). Tyrosine kinase is a growth-stimulating protein. TKI drugs block the cell signals that trigger cancer growth. TKI drugs approved for adult patients with Philadelphia chromosome-positive (Ph+) ALL include:
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 patient 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 patient.
The stem cells to be given to the person with leukemia can come from either the patient (autologous) or a donor(allogeneic):
Sources of Cells. Stem cells can be obtained either from the donor’s:
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 four weeks and may require transfusions. Later side effects 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 - 12 months post-transplant for a patient’s immune system to fully recover. Many patients 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 jerovicii (a fungus) are among the most serious life-threatening infections.
It is very important that patients take precautions to avoid post-transplant infections. (See Home Management section of this report.)
Graft-versus-host disease (GVHD) is a serious attack by the patient's immune system triggered by the donated new marrow in allogeneic transplants.
Acute GVHD occurs in 30 - 50% of allogeneic transplants, usually within 25 days. Its severity ranges from very mild symptoms to a life-threatening condition (more often in older patients). 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 give patients immune-suppressing drugs such as steroids, methotrexate, cyclosporine, tacrolimus, and monoclonal antibodies.
Chronic GVHD can develop 70 - 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. Be sure to always wear sunscreen (SPF 15 or higher) on areas of the skin that are exposed to the sun. Stay in the shade when you go outside.
A parent should call the doctor if the child has any symptoms that are out of the ordinary, including (but not limited) to:
Tracking Neutrophils. 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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