Acute Lymphocytic Leukemia

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Acute Lymphocytic Leukemia

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WHAT IS ACUTE LYMPHOCYTIC LEUKEMIA?

Leukemia

The word leukemia literally means "white blood" and is used to describe a variety of cancers that begin in the blood-forming cells of the bone marrow.

White blood cells ( leukocytes) evolve from immature cells referred to as blasts. Some of these blasts are called lymphoblasts (which become mature cells called lymphocytes ) or myeloblasts (which mature to myeloid cells). [ See Box Blood Cell Lines and Lymph System.]

Malignancy in these blasts is the source of leukemias:

Normally, blasts constitute 5% or less of healthy bone marrow.
In leukemia, however, these blasts remain abnormally immature and multiply continuously, eventually constituting between 30% and 100% of the bone marrow.
The malignant cells fill up the bone marrow and prevent production of healthy red cells, platelets, and mature white cells (leukocytes).
They spill out of the marrow into the blood stream and lymph system and can travel to the brain and spinal cord (the central nervous system).
As the number of normal cells decline, dangerous symptoms develop, which, if untreated, become lethal.

Leukemias are divided into two major types:

Acute (which progresses quickly with many immature white cells).
Chronic (which progresses more slowly and has more mature white cells).
Acute leukemias are in turn subdivided into two classifications:
Acute myeloid leukemia (AML).
Acute lymphocytic leukemia (ALL), which is the subject of this report.

Acute Lymphocytic Leukemia

Acute lymphocytic leukemia (ALL) is also known as acute lymphoid leukemia or acute lymphoblastic leukemia. Nearly 75% of childhood leukemias are of the ALL type. Malignancies in this disease can arise either in the T-cells or B-cells lymphocytes.

T-cell ALL is diagnosed in 15% of children and adults with ALL.
Between 80% and 85% of ALL cases, however, are of the B-cell lymphocyte lineage.

Blood Cell Lines and the Lymph System

Blood Cell Lines

In adults, blood cells are produced by the bone marrow, the spongy material filling the body's bones. The bone marrow produces two blood cell groups, myeloid and lymphoid.

Myeloid Cell Line. The myeloid cell line includes the following:

Immature cells called erythrocytes that later develop into red blood cells.
Blood clotting agents ( platelets).
Some white blood cells, including macrophages (which act as scavengers for foreign particles), eosinophils (which trigger allergies and also defend against parasites), and neutrophils (the main defenders against bacterial infections).

Lymphoid Cell Line. The lymphoid cell line includes the lymphocytes, which are the body's primary infection fighters. Among other vital functions, certain lymphocytes are responsible for producing antibodies, factors that can target and attack specific foreign agents (antigens).

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).

Lymphocytes and the Lymph System

The understanding of leukemia relies on understanding something of the lymphocytes and their passage through the body.

B-cells start and complete their structural growth and final form (known as differentiation) in the bone marrow.
T-cells also start out in the bone marrow but differentiate and mature in the thymus gland , located beneath the breastbone. This small gland is active mostly in the fetal stage through the first ten years of life, after which it atrophies (shrinks).
B-cell and T-cell lymphocytes leave these organs through the blood stream, which eventually branches out into the tiny blood vessels called capillaries.
Once they leave the capillaries, some lymphocytes migrate into the surrounding tissues. A proportion of these lymphocytes (along with fluid, proteins, and other substances) then enters the lymphatic vessels .
Lymphatic vessels begin as tiny, blind-ended tubes and lead to larger lymphatic ducts and branches until they drain into two ducts in the neck, where the fluid re-enters the blood stream.
Along the way, the fluid passes through lymph nodes , which are oval structures composed of lymph vessels, connective tissue, and white blood cells. Here, the lymphocytes either are filtered out or are added to the contents of the node.

WHAT ARE THE SYMPTOMS OF ACUTE LYMPHOCYTIC LEUKEMIA?

Acute lymphocytic leukemia may be difficult to recognize. Symptoms develop under the following conditions:

When there are insufficient healthy mature white blood cells (leukocytes) to mount a defense against infection.
When there are not enough healthy platelets to prevent bleeding.
When the depleted oxygen-bearing red blood cells are unable to provide enough oxygen to organs.

ALL often begins abruptly and intensely, but symptoms may also develop slowly over time. They may be present one day and absent the next, particularly in children. They include the following:

Patients with ALL may tire easily and have poor coloring from anemia caused by insufficient red blood cells.
Recurrent minor infections.
Bone pain.
Bruising, poor healing of minor cuts, or uncontrolled bleeding may result from only slight injury. Such bleeding events increase as the bone marrow fails to produce sufficient platelets to make a normal blood clot (a condition called thrombocytopenia).
Small, red spots on the skin known as petechiae may also form as a result of bleeding due to thrombocytopenia.

WHAT CAUSES ACUTE LYMPHOCYTIC LEUKEMIA?

Between 1973 and 1990, the number of acute lymphocytic leukemia cases in children under 15 rose by 27%. The causes of the disease are not known, but experts believe that ALL develops from a combination of genetic and environmental factors.

Genetic Factors

A number of genetic mutations associated with ALL have been identified. Missing or defective genes that suppress tumors are responsible for some of these cases.

Translocations. Up to 65% of leukemias contain genetic rearrangements, called translocations, in which some of the genetic material (genes) on a chromosome may be altered, or shuffled, between a pair of chromosomes.

For example the most common genetic injury in ALL is t(12;21), which means a translocation with a genetic shift between chromosome 12 and 21. It is also referred to as TEL-AML1 fusion and occurs in approximately 20% of ALL patients. Researchers believe that this translocation may occur during fetal development insome patients.
About 20% of adults and about 5% of children with ALL have a genetic abnormality called the Philadelphia (Ph) chromosome (t(9;22)).
Another important chromosome translocation is t(4;11) involving the MLL gene on chromosome II. Often occuring in children under one year old.
more information see Genetic Abnormalities under How Are Characteristics of Acute Lymphocytic Leukemia Cells Used for Determining a Prognosis?]

Ikaros. A defective gene known as Ikaros, which regulates lymphocyte development, may play a major role in childhood ALL.

WHO GETS ACUTE LYMPHOCYTIC LEUKEMIA?

Age and Gender

ALL in Children. About 3,800 cases of acute lymphocytic leukemia are expected to be diagnosed in 2002, with about 2,000 of them in children and young people under 20. Until recently, most studies listed it as the most common childhood cancer. (Some recent evidence suggests that cancers in the central nervous system may be surpassing ALL in children.) The disease typically develops in children between one and 10 years old, but the disease can strike from infancy to old age.

ALL in Adults. About 20% of ALL cases occur in adults. Adults who develop ALL are usually male and over 50 years old, with the highest risk being above age 70.

Ethnicity and ALL

Caucasian children are more likely to get ALL than African American children, although African American and Hispanic children who develop it do not appear to fare as well. Socioeconomic factors do not appear to completely explain this difference.

Hereditary Disorders

Certain inherited disorders can increase the risk for leukemia. For example, children with Down's syndrome have a 20-fold greater risk of developing acute leukemia than the general population. Other rare genetic disorders associated with increased risk include Bloom syndrome, Franconi's anemia, ataxia-telangiectasia, neurofibromatosis, Schwachman syndrome, IgA deficiency, and congenital X-linked agammaglobulinemia.

Exposure to Radiation

Radiation Treatments from Cancer Treatments. Exposure to repeated or high doses of ionizing radiation, which includes x-rays and gamma rays, has long been known to increase the chances of developing leukemia. Specifically, radiation for certain cancer treatments is a known cause of future leukemia. Children treated with radiation and chemotherapy for Hodgkin's disease are at higher risk for acute leukemia within two to 13 years after treatment (usually of the myeloid variety). Children under 10 are most susceptible to acute leukemia following exposure to radiation treatments. Susceptibility decreases between the ages of 10 and 19 then increases slowly again through age 50. After 50, a person is again at high risk of developing acute leukemia following ionizing radiation.

Exposed to Radiation from Noncancer Treatment Sources. Most people who are not treated for cancer have low exposure to radiation, so radiation from other sources is not a significant cause of leukemia. The following are some situations that may increase risk from radiation:

Fetal exposure to diagnostic x-rays (not ultrasound) before birth increases the danger of developing ALL by the age of 15 years.
One study of children who lived near a nuclear waste processing plant in France found an increased risk for leukemia, particularly if they ate local fish.
Reports of increased incidence in leukemia in peace keepers and military personnel who were stationed in Bosnia have sparked investigation of certain weapons that use depleted uranium an which were employed in the Balkan wars. Military officials say the risk is unlikely, but more research is needed.

Indoor radon also does not appear to increase the risk for leukemia. (Radon does increase the risk for lung cancer, however, particularly in smokers).

Exposure to Chemicals

To determine whether exposure to specific chemicals increase the rise for leukemia is a daunting challenge. About 75,000 synthetic chemicals were introduced in the first half of the century. In addition, investigators must study the emissions from cars, the pesticides in foods and in neighborhoods, and the runoffs in drinking water. Decades of research show that those who work in the petroleum industry (where benzene is derived) have a two to threefold increased risk of developing leukemia (most often acute myeloid). Others who may be at some risk for leukemia and lymphomas include painters, agricultural workers, distillers, dye users, furniture finishers, and rubber workers.

Infectious Agents

Researchers are studying a number of viruses or other infectious agents that may trigger the leukemia, particularly in genetically susceptible children. One researcher suggests, in fact, that a cluster of leukemia cases reported near a nuclear plant may not be due to radiation, as widely believed, but to increased exposure to viruses or infectious organisms brought in by a migrant work force. This is supported by clusters of ALL observed in different small geographical areas where inward migration rates were high.

Special viruses called retroviruses, or RNA tumor viruses, cause leukemia in animals, and the first of these viruses associated with human leukemia was human thymic leukemia virus -1 (HTLV-1), which may be responsible for some cases of adult acute T-cell leukemia. A strong viral or infectious suspect for ALL, however, has not yet emerged.

Electromagnetic Fields

Some studies have reported an association between cancer and high levels of electromagnetic radiation (EMR). Whether lower levels of radiation (eg, living near power lines, video screen emissions, small appliances, cell phones) play any major role is uncertain but probably unlikely. The following are some observations from studies on this subject:

Evidence is mixed on any risk for living near high-power electrical lines. One 2000 study suggested that people living in homes with wiring at very high current levels had a risk for ALL that was about 20% above average. A 2001 study reported a small increase in risk for people living near high-voltage cables. Others have found no evidence of risk. In any case, the risk is still very small.
Most studies have found that exposure to low-energy waves from household appliances does not increase the risk of childhood ALL.
A 2000 study of workers highly exposed to wireless communication devices found no risk for leukemia or other cancers.

HOW SERIOUS IS ACUTE LYMPHOCYTIC LEUKEMIA?

General Outlook

Acute lymphocytic leukemia is responsible for about 1,400 deaths a year, 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. Both the oldest and very young age groups tend to have lower survival rates, usually because the leukemia that develops in these patient groups tends to have genetic features that produce a more severe condition.

Outlook in Children with ALL. Survival rates in children with cancer, and leukemia in particular, have increased significantly in North America over the past three decades. More than 80% of children with ALL are now surviving at least ten years after the diagnosis is established.

Certain children are at higher risk for a poor outcome than others:

African-American and Hispanic children appear to have a poorer outcome than Non-Hispanic Caucasian children. Research is underway to determine whether social and economic differences or other factors are primarily responsible.
Survival rates in boys tend to be lower than in girls. The reason for this is not known, although it may be partially due to the boys' higher risks for less favorable genetic profiles and for T-cell ALL.
Survival rates in infants are improving but they are still poor. The best results are in children ages one to nine. Older children may require more aggressive treatment.
The prognosis may vary depending on other risk factors as well, including the subtype of the cancer, how high the white blood count is, degree of organ involvement, and genetic background.
Although children with precursor-B and early precursor-B tend to have a better prognosis than ALL patients with the B-cell stage and T-cell, advances in treatment are improving the outlook for patients with all these latter types.

Responding well to early treatment is a good sign regardless of the risk category.

Outlook in Adults with ALL. Adults tend to have a more severe condition than children, even if they are carrying the same ALL genes. Between 60% and 80% of adults with ALL can expect to achieve full remission with standard treatments and between 35% and 40% survive beyond two years with aggressive treatments. Younger adults with ALL have better long-term survival rates than older adults with the disease.

Long-Term Effects of ALL and its Treatments

Physical Effects. The intense treatments required by ALL can have some serious long-term effects, including future cancers, osteoporosis, heart disease, infections, and impaired physical growth and mental functioning. Treatment advances are helping to reduce these risks.

ALL survivors are at high risk for obesity, although one study indicated that lifestyle factors, such as adopting a pattern of reduced physical activity during treatment, plays the major role in this complication.

Psychologic and Mental Effects. Studies are finding that survivors of childhood leukemia tend to have more psychological problems, including stress, depression, anger, and confusion, than their physically healthy siblings. They are also more likely to be unemployed or working part time. Recognizing this and possibly getting outside psychologic support early on is important.

Effects on Caregivers

Parents also suffer, and one study found that they developed more symptoms of post-traumatic stress disorder than their children did. Mothers and fathers suffer equally.

HOW IS ACUTE LYMPHOCYTIC LEUKEMIA DIAGNOSED?

Complete Blood Cell Count

A complete blood cell count is the first step in diagnosing ALL. This test will often show various findings, including the following:

The presence of circulatory leukemic blast cells.
The presence and severity of anemia.
The count of a variety of blood cell types. (A high white blood cell count indicates a more severe disease.)
These tests will not always show the presence of leukemic cells.

Blood tests do not always detect leukemia, and about 10% of patients with ALL have a normal blood cell count.

Bone Marrow Biopsy

If the results of the blood tests are abnormal or the physician suspects leukemia despite normal cell counts, a bone marrow aspiration and biopsy are the next steps.

A local anesthetic is given. ( This is a very common and safe procedure. Hoever, because this test can produce considerable anxiety, particularly in children, parents may want to ask the physician if sedation is appropriate for their child.)
A needle is inserted into the bone, usually the rear hip bone. There may be brief pressure or pain. A small amount of marrow is withdrawn. (It looks like blood.)
A larger needle is then inserted into the same place and pushed down to the bone. The health professional will wiggle the needle from side to side to loosen a larger specimen for the biopsy. The patient will feel some pressure.
The sample is then taken to the lab to be analyzed. All the results are completed within a couple of days.

Normal bone marrow contains 5% or less blast cells (the immature cells that ordinarily develop into healthy blood cells). In leukemia, abnormal blasts constitute between 30% and 100% of the marrow.

Spinal Tap

If bone marrow examination confirms ALL, a spinal tap may be performed, which uses a needle inserted in to the spinal canal. The patient feels some pressure and usually must lie flat for about an hour afterward to prevent severe headache. This may be difficult for children, so parents should plan reading or other quit activities that will divert the child during that time.

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, leukemic cells are not found in the cerebrospinal fluid.

HOW ARE CHARACTERISTICS OF ACUTE LYMPHOCYTIC LEUKEMIA CELLS USED FOR DETERMINING A PROGNOSIS?

Once a diagnosis of leukemia has been made, further tests are performed to assess the following properties:

Whether the cells are myeloid or lymphocytic(i.e. the cell of origin).
Stage of maturity of the ALL B-cell.
Their immunologic features (the specific markers on the surface of the cancer cell that respond to antigens).
Their cytogenetics (the genetic makeup of the cells).
Their morphology (their physical characteristics).

Determining the Cell of Origin

First, the physician must determine the cell of origin (whether it is myeloid or lymphocytic). One method is to measure an enzyme called terminal deoxynucleotidyl transferase (TdT).

About 95% of all ALL types (except the subtype B-cell) have elevated TdT.
Only about 20% of cases of acute myeloid leukemia (AML) express TdT, however, so its use in determining the cell line is limited.

B-Cell Maturity

The stage of maturity of the leukemic B-cell helps determine prognosis. There are three stages:

Early precursor-B. Approximately 80% of ALL patients have the early precursor-B subtype, which is the least mature. It also offers the best prognosis.
Precursor-B. This is the intermediate stage.
B-cell. This is the mature cell and ALL in this stage is identical to Burkitt's non-Hodgkin's lymphoma. It is therefore treated differently from other ALL cases.

Immunological Markers

A series of tests are used to determine the immunologic pattern of the leukemia cell (how it can be expected to interact with the immune system).

On the surface of malignant ALL cells are markers for certain antigens (molecules that set off a targeted attack by the immune system using antibodies). Such antigens are proving to be very helpful in predicting outcome.

Important ones include the following:

CD10, more frequently referred to as CALLA (common ALL antigen). CALLA occurs in about half of all ALL cases and in about 80% of ALL B-precursor patients. It is associated with a good prognosis.
CD95. Likewise, the presence of CD95 has a positive influence.
CR19.
DR.

The surfaces of T-cell ALL cancer cells express several antigens as well. For example the presence one of these, CD2, suggests a favorable prognosis.

Genetic Abnormalities

Genetic tests are useful for a number of important criteria:

To diagnosis a specific ALL subtype.
Designing appropriate treatment.
Gauging prognosis.
Monitor patients throughout treatment and beyond.

Cytogenetics is a technique that researchers use to determine specific genetic abnormalities, which are found in nearly 65% of all leukemias. Detecting these genetic defects is helpful in making a full diagnosis of ALL and in planning the most appropriate therapy.

Translocations. Genetic translocations (defective alterations of genetic arrangements) may affect outlook. [For more details on translocations, see Genetic Factors, under What Causes Acute Lymphocytic Leukemia?] Examples include the following:

Patients with the t(12;21) genetic translocation (also referred to as TEL-AML1 fusion) have an excellent prognosis.
Patients who carry the defective gene called ETV6 often respond well to chemotherapy.
The t(4;11), sometimes referred to as MLL, is the most common translocation in children under one year. Unfortunately, it carries a poor outlook in anyone who carries it. A 2001 study suggested that this genetic variant may actually be a unique leukemia and require treatments that differ from standard ALL.
The Philadelphia translocation also t(9;22) indicates a poor outlook. It represents about 20% of adult and only about 5% of childhood cases.
The t(1;19) location occurs in about 5% of ALL childhood cases and requires aggressive treatment.

Ploidy. Ploidy refers to the number of chromosomes. Additional copies ( hyperdiploidy) or absence of copies ( hypodiploidy) of chromosomes affect prognosis. For example, in children hyperdiploidy is associated with a more favorable outcome and hypodiploidy with a poorer outcome. (Hypodiploidy occurs only in 1% of children with ALL.)

Morphology

The morphology of a cell includes its physical characteristics, such as shape and structure. To determine the morphology of the leukemia cells, samples of the bone marrow are taken and particular contents of the cells are stained with a dye. They are then examined under a microscope.

Acute lymphocytic leukemia cells are grouped according to the French-American-British (FAB) classification system into three ALL morphologic types. (It should be noted that this system is subjective and is now used to complement other diagnostic tests as mentioned above):

L1 cells. These are small blasts with scant amounts of cytoplasm (the substance in a cell between its membrane and nucleus). L1 cells usually contain a round nucleus and there is little variation among them. L1 represents the most common ALL morphology and offers the best prognosis. It occurs in about 85% of children and 30% of adults with ALL.
L2 cells. These cells are larger than L1 and have more abundant cytoplasm. They vary significantly among each other and have an irregularly shaped nucleus. L2 morphology conveys a poorer prognosis than L1, although the two cells' types are treated similarly. Subtype L2 is the most common morphologic type in ALL adults; 64% of adults with ALL have this subtype compared with only 15% of children.
L3 cells. These are uncommon. They resemble another malignancy called Burkitt's lymphoma and their treatments are now the same.

Drawing Conclusions from Cell Characteristics

Using the results of the tests described above, patients are classified into low-, average-, and high-risk groups, which have unique therapies. This information allows the doctor to diagnosis the type of leukemia and plan the best treatment.

Physicians attempt to make a prognosis and determine an optimal treatment plan by assessing all the cell characteristics plus the white blood cell count. As examples:

Patients who have an L1 or L2 morphology, a white blood cell count of less than 15,000 mm3, a t(12;21) genetic translocation, and a CALLA-positive antigen marker have an excellent outlook.
On the other hand, patients who have an L2 morphology, a white blood cell count greater than 30,000 mm3, and who lack the CALLA marker have a poorer prognosis and require more aggressive treatment.

WHAT ARE THE GENERAL GUIDELINES FOR TREATING ACUTE LYMPHOCYTIC LEUKEMIA?

The aim of the initial treatment phase is to achieve complete remission, in which there is no evidence of leukemia in the body, and in which the bone marrow has 5% or lower levels of blasts.

Treatment Phases

There are typically four treatment stages for the average-risk ALL patient, both children and adults.

Induction therapy and usually central nervous system prophylaxis (preventive treatment) to achieve a first remission.
Consolidation and maintenance to prevent relapse after remission.

Specific Treatments Used in ALL

The following are specific treatments used for ALL:

Chemotherapy is the primary treatment for each stage.
Radiation to the brain and spinal cord is also administered in some cases.
A bone marrow transplant is often recommended for relapsed ALL or in cases that cannot be induced into remission (refractory disease). It is also sometimes considered after remission is achieved for certain high risk ALL types. The timing of bone marrow transplantation can be controversial, particularly after a first remission, although it has produced excellent long-term survival rates in appropriate patients.
New drugs known as biological therapies are currently being investigated.

Short- and Long-Term Effects of Treatments

The intense treatments required by ALL can have serious short- and long-term side effects. Some long-term complications of particular concern are discussed below.

Osteoporosis. Loss of bone density (osteoporosis) is a side effect of corticosteroids. Patients or their parents should discuss approaches to reduce this risk.

Heart disease. Some of the treatments, increase risk factors for future heart disease, including unhealthy cholesterol levels and high blood pressure. ALL survivors should be sure to maintain a healthy lifestyle and be regularly monitored for heart risks to help reduce these effects.

Obesity. Children treated for ALL are at higher risk for obesity, possibly because the treatments trigger an earlier than normal occurrence in childhood weight gain. Corticosteroids, drugs used in treatments, also increase appetite, which contributes to the problem.

Impaired Mental and Neurologic Functioning. Cranial radiation and drugs used in chemotherapy, especially specific corticosteroids and intrathecal treatments may impair mental functioning and cause neurologic problems, such as movement problems. Advances in cranial radiation may reduce the neurologic and mental risks from this treatment, but it can occur with many other treatments as well. Of particular interest was a 2001 report suggesting that methylphenidate (Ritalin) may improve mental performance in children.

Infections. Some children may be more vulnerable to infections for some time after completing chemotherapy, although the immune system tends to improve over time.

Impaired Physical Growth. Cranial radiation can result in impaired growth.

Infertility. Chemotherapy, cranial radiation, or both can impair fertility in male and female patients.

WHAT ARE THE TREATMENTS TO ACHIEVE A FIRST REMISSION?

Induction Procedures

The aim of induction therapy, the first phase, is to reduce the body's burden of leukemia cells to undetectable levels. The general guidelines for induction therapy are as follows:

Patients are given intensive chemotherapy that uses powerful multi-drug regimens. (Infants require special regimens not discussed here.) [ See Box Drugs Used for Induction Chemotherapy.]
For both children and adults, some of these therapies are administered orally, others intravenously.
Hospitalization is usually necessary at some point to help prevent infection and to administer blood products. However, much of this therapy can be given on an outpatient basis.
After the first cycle of induction, bone marrow tests are done to determine if the patient is in remission.
Another bone marrow test is sometimes done about a week later to confirm the first results.
A bone marrow transplant is considered for patients who do not respond at all to induction treatment.

Drugs Used for Induction Chemotherapy

Drugs Used for Standard or Low-Risk Patients. A three-drug regimen is typically used for standard or low-risk patients. (A fourth drug may be added for adult patients.) Examples of drugs include the following:

Vincristine.
A corticosteroid (prednisone or dexamethasone).
Asparaginase. (Several forms are available. Investigation on a potent form called E-coli asparaginase (Asparaginase medac) is promising for preventing relapse, particularly second relapses, but this agent is very toxic and increases the risk for blood clots.)
For adult patients, a fourth drug may sometimes be used, such as cyclophosphamide.

When this regimen is used in conjunction with CNS prophylaxis [ see below ], remission rates of greater than 95% have been achieved in children. In a 2001 study, researchers reported that the most effective regimen for many children may employ dexamethasone after the first month with a longer duration for asparaginase (30 rather than the standard 20 weeks).

Drugs Used for High-Risk Children. A four or five-drug regimen is used for many high-risk children. An example of a four-drug regimen follows:

Vincristine, prednisone/dexamethasone, plus asparaginase, and an anthracycline (eg, daunomycin). Anthracyclines have been associated with later heart disease in some patients with other cancers, but a 2000 study reported that in low doses used for ALL children it did not pose a risk to the heart.

Drugs Used for Specific High-Risk Adults. Cyclophosphamide-based regimens are used in certain adult patients with particular genetic translocations or who have T-cell ALL.

Central Nervous System (CNS Prophylaxis)

CNS prophylaxis is critical for preventing disease that has spread to the brain, spine, and testes (called sanctuary disease sites). Although only 3% of children with ALL have evidence of leukemia in the central nervous system (CNS) at the time of diagnosis, leukemia will spread to this region in between 50% and 70% of children without preventive (prophylactic) treatment. The brain is one of the first sites for relapsing leukemia.

CNS prophylaxis involves the following:

It is often administered in conjunction with induction therapy before moving to consolidation, the next standard treatment phase, particularly if there are any leukemic cells detected in the spinal fluid.
It often employs intrathecal chemotherapy, in which a drug is injected directly into the spinal fluid. The drugs used are either methotrexate alone or a combination of methotrexate, hydrocortisone, and cytarabine. (Induction chemotherapy does not penetrate the blood-brain barrier sufficiently to destroy leukemic cells in the brain.)
In some cases, methotrexate with or without other drugs, is given as systemic (widespread) therapy at the same time as intrathecal chemotherapy. The addition of this treatment is effective in preventing relapse in the central nervous systems and can substitute for radiation to the skull.

Cranial Radiation Therapy. Some high-risk children also receive radiation to the skull (cranial irradiation), radiation to the spine, or both at the same time. This combination can be very toxic and can cause later learning problems. It is generally used only in children who have evidence of the disease in the central nervous system at the time of diagnosis. Later complications can include learning and neurologic problems. Using lower-dose units of radiation, however, is proving to be effective and to significantly reduce the risk for mental impairment. Cranial radiation is also associated with later risk factors for heart disease.

Supportive Treatment

Half of all ALL patients develop fever in the early stages, which should be treated with antibiotics, especially if patients also have neutropenia (low levels of the white blood cells called neutrophils).

Patients may also need to receive intravenous fluids and be treated for fluid imbalances, which can cause abnormal levels of sodium, potassium, calcium, and uric acid. Such treatments might include sodium bicarbonate, allopurinol, and aluminum hydroxide or calcium carbonate.

Red blood cell or platelet transfusions may be needed. (Patients who may have allogenic transplantations should not receive transfusions from potential donors.)

Indications for Remission after Induction Treatment

Remission is indicated by the following:

All signs and symptoms of leukemia disappear.
There are no abnormal cells in the blood, bone marrow, and cerebrospinal fluid.
The percentage of blast cells in the bone marrow is less than 5%.

Induction can produce extremely rapid results and the faster the time to remission the better the outlook:

A complete remission usually occurs within the first four weeks. Patients who show low disease levels within seven to 14 days have an excellent outlook, particularly if they have favorable genetic factors, and may need less -intensive treatments afterward.
Patients with high disease levels at 14 days or who require more than four weeks to achieve remission are at higher risk for relapse and most likely need more aggressive treatment.

WHAT ARE THE TREATMENTS DURING A FIRST REMISSION?

Consolidation and maintenance therapies follow induction and first remission in order to prevent a relapse. The specific treatment choices and degree of aggressiveness after induction therapy depend on a number of factors, particularly the risk factors for relapse. [ See Box Risk Factors for Relapse after a First Remission.]

Consolidation (or Intensification) Therapy

Consolidation therapy is additional treatment that is administered after induction therapy and before maintenance therapy. This is an intense regimen that is designed to prevent the high relapse rates that occur with induction therapy alone. (The benefits of this therapy are clearer in children than in older adults, who may just be given maintenance.)

Consolidation therapy usually continues for approximately six months and uses one to six courses of chemotherapy, depending on risk factors for relapse.

Examples of consolidation regimens for children at standard risk:

A limited number of courses of intermediate- or high-dose methotrexate, one of the oldest drugs used for leukemia.
An anthracycline agent, such as daunorubicin (Cerubidine), used for reinduction followed by cyclophosphamide (Cytoxan, Neosar) three months after remission. These are very powerful drugs, but when used in this way toxicity is limited.

More intense regimens are used for children at high-risk for relapse.

Maintenance

The last phase of treatment is maintenance, or continuation, therapy, which involves the following:

Maintenance therapy typically uses weekly administration of methotrexate (orally or intravenously) and daily doses of mercaptopurine. (Mercaptopurine should be given in the evening.)
Treatment continues for between two and three years for most children with ALL (with the exception of those with mature B-cell leukemia). It is not yet clear if prolonged maintenance therapy benefits adults with ALL.
If children were not given CNS prophylaxis before, it may be given now.

A maintenance regimen is usually less toxic and easier to tolerate than induction and consolidation. Some studies, however, are showing that overall survival could further be improved with more-aggressive maintenance therapies, including the following:

Pulses of vincristine and a corticosteroid added to the standard maintenance regimen. (One 2000 study reported that the intensive use of the corticosteroid prednisone caused severe bone damage and significant disability in 84% of children on this regimen. Dexamethasone is preferred in children.)
Longer term low-dose maintenance.
Intense regimens similar to induction (called reinduction).

Maintenance typically continues until continuous complete remission has lasted two to three years.

Investigation is ongoing to determine the optimal agents and schedules to use. For example the agent thioguanine may be a more effective choice than mercaptopurine. Researchers are also trying to pinpoint patients who would best benefit from aggressive maintenance treatments.

Risk Factors for Relapse after a First Remission

The following are factors that increase the risk for relapse after initial treatments:

Microscopic evidence of leukemia after 20 weeks of therapy (called minimal disease). (Advanced diagnostic techniques called polymerase chain reaction (PCR) tests are used for detection.)
Age over 30.
A high white blood cell count at the time of diagnosis.
Disease that has spread beyond the bone marrow to other organs.
Certain genetic abnormalities such as the presence of the Philadelphia chromosome or MLL gene translocations.
Patients with high disease levels after seven to 14 days of induction therapy.
The need for four or more weeks of induction chemotherapy in order to achieve a first complete remission. (One study suggested that a poor response, specifically to corticosteroids used in initial treatment, was a strong predictor for relapse.)

Patients with one or more of these risk factors may be candidates for bone marrow transplantation once they are in first remission.

Investigative Indicators for Predicting Relapse

A 2001 study suggested that test results showing elevated levels of a peptide called glutathione in blast cells may indicate a higher risk for relapse after treatment.

WHAT ARE THE TREATMENTS FOR PATIENTS WHO RELAPSE AFTER A FIRST REMISSION?

Between 50% and 70% of children and 40% and 50% of adults who achieved complete remission after initial therapy and who relapse will achieve a second complete remission. [ See Box Risk Factors for Relapse after a First Remission.]

Treatment for relapse after a first remission may be standard chemotherapy, more aggressive treatments, such as bone marrow transplant, or investigative agents.

The decision depends on a number of factors:

Children who relapse three or more years after achieving a first complete remission have an excellent chance for a second remission without aggressive treatments.
Those who relapse less than six months following initial treatment, especially while on chemotherapy, have about a 20% chance of long-term freedom from disease. In such cases, remission is possible following another course of standard chemotherapy but the duration of remission is usually less than six months.

Treatment decisions also rely on prior treatments and where the relapse has occurred. Relapse can occur in the bone marrow, central nervous system, or sanctuary disease sites (brain, spine, or testicles). The incidence of relapse in sanctuary sites is about 10%.

Candidates for transplantation include the following:

Patients who relapse following initial remission with standard chemotherapy.
High-risk patients in first remission who are unlikely to be cured by standard chemotherapy alone. Many adult patients may fall into this category. Studies on high-risk children have been conflicting about the value of transplants during a first remission, with a 2000 study reporting no significant advantage. A 2001 study on children with the Philadelphia chromosome, however, suggested that this approach offered a better chance for a cure.
Patients who fail to achieve a complete remission during initial chemotherapy.

Transplantation procedures do not appear to be offer any additional advantages for patients at low or standard risk.

Transplantation Procedures

Transplantation procedures are based on stem cells , which are produced in the bone marrow. Stem cells are the early forms for all blood cells in the body (including red, white, and immune cells). Cancer treatments can harm these growing cells as well as cancer cells. In order to administer high-dose chemotherapy for advanced cancer cases, transplantation procedures typically first remove these stem cells either directly ( hematopoietic blood stem cell transplantation ) or from bone marrow ( bone marrow transplantation ). The patient is treated and the blood cells are restored. [ See Box Transplantation Procedures for Acute Lymphatic Leukemia]

Investigative Agents

Immunotoxins. A genetically engineered agent (BL22) called an immunotoxin fuses an antibody that targets specific factors in the tumor with a toxic molecule that destroys the cell. This agent induced complete remission in 11 out of 16 patients who had hairy cell leukemia. Experts are hoping immunotoxins can be used for patients with acute lymphocytic leukemia.

Nucleoside Analogs. These agents have wide-spread effects against leukemia and have been investigated for some time with mixed results. Some newer nucleoside analogs being studied for refractory or relapsed leukemia include troxacitabine (Troxatyl) and clofarabine (Clofarex). Fludarabine (Fludara), an older agent with severe toxicity at high doses, is typically investigated as part of regimens that also includes cytosine arabinoside (ara-C) (another nucleoside analog) and other chemotherapy agents.

Imatinib (Gleevac). Imatinib (Gleevac) is a new agent that blocks an enzyme called tyrosine kinase, which is an important component in the Philadelphia chromosome. It is proving to be very beneficial for patients with chronic myeloid leukemia (CML). Studies are also now reporting possible benefits for ALL patients who have the Philadelphia chromosome, although more follow up is needed.

TRANSPLANTATION PROCEDURES FOR ACUTE LYMPHATIC LEUKEMIA

In order to administer high-dose chemotherapy for advanced cancer cases, stem cell transplantation procedures may be used. Stem cell procedures have proven to produce long-term survival and even cures in patients with aggressive (intermediate and high-grade) non-Hodgkin's lymphomas. These procedures are based on removal and replacement of stem cells , which are produced in the bone marrow. Stem cells are the early forms for all blood cells in the body (including red, white, and immune cells). Cancer treatments harm growing cells as well as cancer cells, and so the healthy stem cells must be replaced by transplanting them from the donor into the patient.

Collecting the Stem Cells

Sources of Cells. Stem cells must first be collected in one of the following ways:

From bone marrow (bone marrow transplantation).
Directly from blood (peripheral blood stem cell transplantation). Current evidence now appears to suggest that peripheral blood stem cell transplantation may be the superior approach. Studies are reporting survival rates of 45% in bone marrow transplant patients compared to 65% to 70% in stem-cell transplant patients, with benefits being significant in those with more severe disease.
From fetal umbilical cord or placentas. This procedure uses donor cells but has a lower risk for immune system rejection of the cells than with a standard donor transplant. It takes longer to restore blood cells with this process, however, so at this time its use is limited to children and sometimes adults with low weight. (Studies are now reporting some success for adults with normal weights.)

Donor or Patient Cells. The sources of marrow or blood cells can be taken from the patient or a donor:

If the bone marrow or stem cells are taken from a donor, the transplant is referred to as allogeneic. Allogenic transplants from genetically-matched sibling donors offer the best results in ALL. With new techniques, donor bone marrow from unrelated but immunologically similar donors is proving to be as effective as those from matched siblings. This approach is still reserved for patients in second remission or beyond.
If the marrow or blood cells are taken from an identical twin, the transplant is called syngeneic.
If the marrow or blood cells used are the patient's own, the transplant is called autologous. Autologous transplants in ALL patients are generally not beneficial, since there is some danger that the cells used may contain tumor cells and the cancer can regrow. Treatment advances that reduce this risk, however, may make autologous transplantation feasible in patients without family donors.
Blood Stem Cell Collection Procedure
The donor is usually given a drug called granulocyte colony-stimulating factor, or G-CSF (filgrastim, lenograstim) to stimulate stem cell growth.
The donor (or patient in an autologous procedure) then undergoes apheresis. With this process the blood is withdrawn from one of the patient's veins, then passes through a machine that filters out the white cells and platelets, which contain the stem cells. The blood is returned through another vein. The entire procedure takes three to four hours but needs to be repeated several times.
The stem cells are then frozen.

The Transplant Procedure

Allogeneic transplants are preceded by chemotherapy treatment known as conditioning. The point of this treatment is to inactivate the immune system and to kill any residual malignant cells.
The thawed donated stem cells are administered through a vein. This may take several hours. Patients may experience fever, chills, hives, shortness of breath, or a fall in blood pressure during the procedure.
The patient may be treated with granulocyte colony-stimulating factor after chemotherapy. The goal is to stimulate the growth of infection-fighting white blood cells. Because this increases immune factors, there is some concern that it might also heighten the immune attack against the donor cells, but to date, studies have been encouraging and are reporting a low risk. (Adding another substance, thrombopoietin, may prove to enhance stem cell production.)
The patient is kept in a protected environment to minimize infection and he or she usually needs blood cell replacement and nutritional support.

Success Rates

Two- to five-year survival rates after transplantation plus chemotherapy range from 40% to 80%. Certain patients with the Philadelphia chromosome, which carries a poor prognosis, may achieve significant success with an allogenic bone marrow transplant from a closely matched related donor.

Side Effects and Complications

Common side effects include nausea, vomiting, fatigue, mouth sores, and loss of appetite. The procedures themselves are fairly dangerous and carry a small risk for death. Potentially serious complications are the following:

Infection resulting from a weakened immune system. This is the most common side effect and can persist for several months after the transplant. Because the stem cell procedure is done more swiftly, the risk period is shorter than with bone marrow transplantation. Many patients develop severe herpes zoster virus infections (shingles) or have a recurrence of herpes simplex virus infections (cold sores and genital herpes). Pneumonia, cytomegalovirus, aspergillus (a type of fungus), and Pneumocystis carinii (a protozoan) are among the most important life-threatening infections.
Graft-versus-host-disease (GVHD) is a serious attack by the patient's immune system triggered by the donated new marrow. It occurs in over half of allogeneic transplants. GVHD can results in weight loss, bacterial infections, and skin and organ problems that may persist for up to three years after the procedure. In some cases it is fatal. Careful matching of the donor and preventive immunosuppressive drugs, such as corticosteroids, methotrexate, and cyclosporine (Sandimmune), may reduce the risk for this potentially life-threatening side effect.
Bleeding because of reduced platelets. This risk is highest within the first four weeks after BMT.
Infertility.
Organ complications to the liver, heart, kidney, or lungs.
Failure. The marrow graft may fail or new marrow cells may now grow.
Secondary Cancers. Transplant procedures pose a long-term risk of 2% to 10% for developing secondary cancers in the brain, oral cavity, thyroid, melanoma, or bone. One study reported that aggressive high-dose chemotherapy after bone marrow transplantation was associated with a 10% rate of leukemia or myelodysplasia within five years. The risk varies considerably depending on the patient's age, general health, menopausal status (for women), and previous history of radiation. Highest risks have been identified in patients receiving BMT before 10 years of age, probably because these patients are more likely to have received cranial irradiation. Patients, particularly men, who developed GVHD were at high risk for oral and skin cancers.

HOW IS A CHILD WITH ACUTE LYMPHOCYTIC LEUKEMIA MANAGED AT HOME?

Calling the Doctor

A parent should call the doctor if the child has any symptoms that are out of the ordinary, including (but not limited) to the following:

Any fever of 101˚F or higher.
Any signs of a flu or cold.
Shortness of breath.
Severe diarrhea.
Blood in the urine or stools.
Trouble urinating.

Preventing Infection

Tracking Neutrophils. Parents should track their child's absolute neutrophil count. This the measurement for the amount of white blood cells, and is an important gauge of a child's ability to fight infection.

Counts over 1,000, for instance, usually provide sufficient protection so that children can engage in normal activities, including school and other functions where they are exposed to other children.
If the count is between 500 and 1000, the child should avoid large groups.
If it falls between 200 and 500 the child should stay at home and should see only healthy visitors who have washed their hands vigorously.
Neutrophil counts below 200 indicate that the child is at high risk for infection and should have no visitors.

Maintaining Strict Hygiene. Children with ALL and anyone exposed to them, not only friends and family members but also doctors and nurses, should maintain strict hygiene:

Frequent hand washing with antibacterial soap is particularly essential.
Everyone should wash their hands before and after meals, after being outside, before preparing food, and after going to the bathroom.
When visiting the doctor, a parent should ask about a side entrance or areas where the ALL patient will not be exposed to other sick children.

Vaccinations. Siblings of ALL patients who require polio vaccinations should be given the killed virus (IPV), not the live polio vaccination (OPV). One study suggests that young survivors of leukemia have an increased risk for measles, mumps, and rubella (MMR), even if they have been previously vaccinated, and may benefit from reimmunization.

Other Precautions

Use a soft toothbrush when counts are low to prevent gum bleeding.
Avoid the common pain relievers known as nonsteroidal anti-inflammatory agents (NSAIDs). They increase the risk for bleeding and include ibuprofen (Advil, NSAIDs include aspirin, ibuprofen (Motrin IB, Advil, Nuprin, Rufen), naproxen (Aleve), ketoprofen (Actron, Orudis KT).
Some of the drugs used for leukemia cause extreme sun sensitivity. Children should wear sunblock and be covered with sun-protective clothing when going outside in order to avoid sunburn, which can cause skin infection.

WHERE ELSE CAN HELP BE FOUND FOR ACUTE LYMPHOCYTIC LEUKEMIA?

The Leukemia and Lymphoma Society, 1311 Mamaroneck Avenue, White Plains, NY 10605. Call (800-955-4572) or (914-949-5213) or on the Internet (http://www.leukemia-lymphoma.org).

American Cancer Society, 1599 Clifton Rd., NE. Atlanta, GA 30329.
Call (800-ACS-2345) or on the Internet (http://www.cancer.org) and (http://www.ca-journal.org).

National Cancer Institute, Bldg 31, room 10A03, 31 Center Drive, MSC 2580, Bethesda, MD 20892.
Call (800-4-CANCER) or on the Internet at (http://cancernet.nci.nih.gov/) or for clinical trials (http://cancertrials.nci.nih.gov/).

American Society of Pediatric Hematology/Oncology, 4700 W. Lake, Glenview, Il 60025-1485. Call (847-375-4716) or (http://www.aspho.org/).

Blood and Marrow Transplant Newsletter, 2900 Skokie Valley Road, Suite B, Highland Park, Illinois 60035. Call (888-597-7674) or (847-433-3313) or on the Internet (http://www.bmtnews.org/).

Children's Oncology Group, Children's National Medical Center - D.C. , Dept of Pediatric Hem-Onc, 111 Michigan Avenue NW, Washington, DC 20010-2970. (http://www.childrensoncologygroup.org/).

American Society of Clinical Oncology (http://www.asco.org) and its journal (http://www.jco.org).

National Coalition for Cancer Survivorship, 1010 Wayne Avenue, Suite 770, Silver Spring, MD 20910-5600. Call (301-650-9127) or (877-622-7937) or (http://www.cansearch.org).

The Candlelighters Childhood Cancer Foundation P.O. Box 498, Kensington MD 20895-0498. Call (800-366-2223) or (http://www.candlelighters.org).
Provides educational materials to families, support groups for parents and patients, and funding for special needs.

Childhood Leukemia Foundation, 1608 Rte 88 West, Ste 203, Brick, NJ 08724.
Call (888-CLF-7109) or (http://www.clf4kids.com/).
The objective of this organization is to address the psychological and emotional effects of leukemia.

Outlook: Life Beyond Childhood Cancer (http://www.outlook-life.org/).

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